Publikacije

Popis znanstvenih publikacija na temu oralnog karcinoma pločastih stanica koji se obnavlja svakih 6 mjeseci u vrijeme trajanja projekta

ESTROGEN I ORALNI KARCINOM

Int J Mol Sci. 2018 Mar 2;19(3). pii: E713. doi: 10.3390/ijms19030713.Estrogen Receptor Signaling in Radiotherapy: From Molecular Mechanisms to Clinical Studies.Rong C1, Meinert ÉFRC2,3, Hess J4,5.

Numerous studies have established a proof of concept that abnormal expression and function of estrogen receptors (ER) are crucial processes in initiation and development of hormone-related cancers and also affect the efficacy of anti-cancer therapy. Radiotherapy has been applied as one of the most common and potent therapeutic strategies, which is synergistic with surgical excision, chemotherapy and targeted therapy for treating malignant tumors. However, the impact of ionizing radiation on ER expression and ER-related signaling in cancer tissue, as well as the interaction between endocrine and irradiation therapy remains largely elusive. This review will discuss recent findings on ER and ER-related signaling, which are relevant for cancer radiotherapy. In addition, we will summarize pre-clinical and clinical studies that evaluate the consequences of anti-estrogen and irradiation therapy in cancer, including emerging studies on head and neck cancer, which might improve the understanding and development of novel therapeutic strategies for estrogen-related cancers.

Oncol Rep. 2017 Oct;38(4):1915-1922. doi: 10.3892/or.2017.5867. Epub 2017 Aug 1.Age at menopause and hormone replacement therapy as risk factors for head and neck and oesophageal cancer (Review).McCarthy CE1, Field JK1, Marcus MW1.

There were ~986,000 cases of head and neck cancer (HNC) and oesophageal cancer diagnosed worldwide in 2012. The incidence of these types of cancer is much higher in males than females, although this disparity decreases in the elderly population, suggesting a role for hormones as a risk factor. This systematic review investigates the potential role of female hormones [age at menopause and use of hormone replacement therapy (HRT)] as risk factors for HNC/oesophageal squamous cell carcinoma (SCC). The electronic databases MEDLINE, Web of Science, EMBASE and Cochrane were searched. Only studies with at least 50 cases of HNC/oesophageal SCC, with data on age at menopause, smoking, alcohol, age and socioeconomic status or educational attainment, were included. The Newcastle Ottawa Scale was used for assessing risk of bias. Eight studies met the inclusion criteria (5 oesophageal SCC, 2 HNC and 1 combined oesophageal SCC and HNC). HRT was shown to reduce the risk of HNC (HR, 0.78; 95% CI, 0.61-0.99) in one study. Our results showed that earlier age at menopause is a risk factor for oesophageal SCC, with women entering menopause at <45 years having double the risk of those entering menopause at age >50 years. Similar, but less striking, results were observed for HNC. HRT was found to reduce the risk of HNC/oesophageal SCC, but the evidence is inconclusive. We, therefore, recommend that consideration should be given to collecting data on reproductive factors and exposure to HRT, as routine practice, in future epidemiological and clinical studies of these cancers. The concept of oestrogen deficiency as a risk for HNC/oesophageal SCC deserves further exploration in future laboratory and clinical studies.

Cancer Med. 2017 Aug;6(8):1998-2007. doi: 10.1002/cam4.1136. Epub 2017 Jul 14.Hormone factors play a favorable role in female head and neck cancer risk.Hashim D1, Sartori S2, La Vecchia C3, Serraino D4, Maso LD4, Negri E3, Smith E5, Levi F6, Boccia S1,7, Cadoni G8, Luu HN9,10, Lee YA11, Hashibe M11, Boffetta P1.

Due to lower female incidence, estimates of exogenous and endogenous hormonal factors in head and neck cancers (HNCs, comprising cancers of the oral cavity, oropharynx, hypopharynx, and larynx) among women have been inconsistent and unable to account for key HNC risk factors. We pooled data from 11 studies from Europe, North America, and Japan. Analysis included 1572 HNC female cases and 4343 controls. Pooled odds ratios (ORs) estimates and their 95% confidence intervals (CIs) were calculated using multivariate logistic regression models adjusting for tobacco smoking and alcohol drinking. Lower risk was observed in women who used hormone replacement therapy (HRT) (OR = 0.58; 95% CI: 0.34-0.77). Pregnancy (OR = 0.61; 95% CI: 0.42-0.90) and giving birth (OR = 0.59; 95% CI: 0.38-0.90) at <35 years of age were inversely associated with HNCs. An inverse association with HNC was observed with age at start of HRT use (OR = 0.59; 95% CI: 0.39-0.90) for each additional 10 years and with duration of use (OR = 0.87; 95% CI: 0.76-0.99 for every 3 years). Exogenous female hormone use is associated with a nearly twofold risk reduction in female HNCs. The lower female HNC incidence may, in part, be explained by endogenous and exogenous estrogen exposures.

J Exp Clin Cancer Res. 2017 Feb 6;36(1):25. doi: 10.1186/s13046-017-0496-2.Regulation of submaxillary gland androgen-regulated protein 3A via estrogen receptor 2 in radioresistant head and neck squamous cell carcinoma cells.Grünow J1,2, Rong C1, Hischmann J1, Zaoui K1, Flechtenmacher C3, Weber KJ4, Plinkert P1, Hess J5,6.

Molecular mechanisms of intrinsic or acquired radioresistance serve as critical barrier for curative therapy of head and neck squamous cell carcinoma (HNSCC) and remain a major obstacle for progression-free and disease-specific survival.HNSCC cell lines were treated with a protocol of fractionated irradiation (IR, 4× 2Gy) alone or in combination with antagonists of estrogen receptor signaling and viability was determined by a colony-forming assay (CFA). Expression of submaxillary gland androgen-regulated protein 3A (SMR3A) and estrogen receptor 2 (ESR2) were assessed in tumor cells in vitro by RQ-PCR, Western blot analysis and immunofluorescence staining, and by immunohistochemical staining of tissue microarrays containing tumor sections from patients with oropharyngeal squamous cell carcinoma (OPSCC), which were treated by definitive or adjuvant radiotherapy. Subgroups with distinct SMR3A and ESR2 expression patterns were correlated with clinical parameters and survival outcome including multivariable analysis.Fractionated irradiation (IR) revealed an accumulation of tumor cells with prominent SMR3A expression, which was accompanied by an up-regulation of the estrogen receptor 2 (ESR2). ESR2-dependent regulation of SMR3A was supported by induced expression after stimulation with estradiol (E2), which was impaired by co-treatment with 4-Hydroxytamoxifen (TAM) or Fulvestrant, respectively. Both drugs significantly sensitized FaDu cells to fractionated IR as determined by a CFA and accelerated apoptosis. These data suggest a critical role of ESR2 in radioresistance and that SMR3A might serve as a surrogate marker for active ESR2 signaling. In line with this assumption, ESR2-positive oropharyngeal squamous cell carcinoma (OPSCC) with high SMR3A expression had an unfavorable progression-free and disease-specific survival as compared to those tumors with low SMR3A expression.In summary, our findings provide compelling experimental evidence that HNSCC with SMR3A and ESR2 co-expression have a higher risk for treatment failure and these patients might benefit from clinically well-established drugs targeting estrogen receptor signaling.

 

 

 

Oncol Lett. 2016 Nov;12(5):3861-3865. Epub 2016 Sep 15.The prognostic significance of estrogen receptor β in head and neck squamous cell carcinoma.Grsic K1, Opacic IL1, Sitic S2, Milkovic Perisa M2, Suton P3, Sarcevic B2.

Head and neck squamous cell carcinoma (HNSCC) is the fifth most common cancer in the world. Although multimodal and targeted therapy is now used in therapeutic procedures, the survival of patients with HNSCC has remained unchanged over the last 30 years. A number of studies have demonstrated that the increased expression of intranuclear ERβ in breast, lung and colon cancer is a favorable prognostic marker associated with higher survival rates. However, the clinical significance of sex hormone receptors in HNSCC remains unclear. The current study aimed to assess the expression of ERβ in HNSCC immunohistochemically and investigate any possible association between ERβ expression, and clinical and histopathological factors, disease recurrence and patient survival. The present study included 174 patients (165 males and 9 females) with a median age of 60.8 years (range, 39-79) with HNSCC who were primary surgically treated between January 2000 and December 2006. Immunohistochemical reactions for ERβ demonstrated that 73 patients (42%) exhibited positive ERβ expression. Distribution of ERβ status among different head and neck subsites indicated that >40% of all negative cases were located in laryngeal primaries, while incidence of other sublocalization within positive cases was similar and comparable (P=0.04). Furthermore, a correlation was observed between ERβ immunopositivity and the survival of patients, with respect to the primary tumor site. Patients with ERβ positive oropharyngeal cancer had a survival rate of 35.3% at 5-years compared with 25% for patients with negative expression. However, ERβ status was not significantly correlated with any other clinical or histopathological parameter. After an average follow-up time of 38.5 months (range, 3-60 months), 54 patients (31.1%) had succumbed to disease recurrence while 50 (28.7%) succumbed to other causes. In conclusion, ERβ positivity indicates improved survival of patients with oropharyngeal cancer. Further research is required in order to implement novel therapeutic strategies.

Med Oral Patol Oral Cir Bucal. 2016 Sep 1;21(5):e554-8.Estrogen and Progesterone hormone receptor expression in oral cavity cancer.Grimm M1, Biegner T, Teriete P, Hoefert S, Krimmel M, Munz A, Reinert S.

Recent studies have shown an increase in the incidence of oral squamous cell carcinoma (OSCC) in younger patients. The hypothesis that tumors could be hormonally induced during pregnancy or in young female patients without the well-known risk factors alcohol or tobacco abuse seems to be plausible.Estrogen Receptor alpha (ERα) and Progesterone Receptor (PR) expression were analyzed in normal oral mucosa (n=5), oral precursor lesions (simple hyperplasia, n=11; squamous intraepithelial neoplasia, SIN I-III, n=35), and OSCC specimen. OSCCs were stratified in a young female (n=7) study cohort and older patients (n=46). In the young female study cohort three patients (n=3/7) developed OSCC during or shortly after pregnancy. Breast cancer tissues were used as positive control for ERα and PR expression.ERα expression was found in four oral precursor lesions (squamous intraepithelial neoplasia, SIN I-III, n=4/35, 11%) and in five OSCC specimen (n=5/46, 11%). The five ERα positive OSCC samples were older male patients. All patients within the young female study cohort were negatively stained for both ERα and PR.ER expression could be regarded as a seldom risk factor for OSCC. PR expression seems to be not relevant for the development of OSCC.

 

 

 

Anticancer Res. 2015 Nov;35(11):5867-72.Expression of Estrogen Receptors in OSCC in Relation to Histopathological Grade.Doll C1, Arsenic R2, Lage H2, Jöhrens K2, Hartwig S3, Nelson K4, Raguse JD3.

Estrogen receptor (ER)-mediated pathways are involved in the pathogenesis of several tumors. Preliminary studies have demonstrated a significant effect of ER agonists and antagonists on oral squamous cell carcinoma (OSCC) cell lines. Recent results suggest that ER subtype-specific expression patterns might depend on the grade of differentiation of OSCC. Therefore, the aim of the present study was to evaluate the expression of ERα and ERβ in OSCC and its correlation to histological tumor grade and gender.Tumor sections of 25 patients (13 males and 12 females) retrieved from OSCC databases with two different histological gradings (well-differentiated, poorly differentiated) were evaluated. The detection of ERα and ERβ expression in tumor cells and corresponding healthy mucosa adjacent to tumor was performed using immunohistochemistry.Well-differentiated OSCC showed no significant difference between the expression of ERβ in tumor cells and corresponding mucosa. In poorly-differentiated OSCC the expression of ERβ was significantly higher in tumor cells than in corresponding mucosa. In patients without regular alcohol and/or nicotine abuse, there was no significant difference of ERβ expression in OSCC compared to corresponding healthy mucosa in contrast to patients having these risk factors. Expression of ERα was found in one tumor.ERβ is the predominant ER sub-type expressed significantly higher in poorly-differentiated OSCC tumors compared to healthy mucosa adjacent to the tumor. Different expression patterns in relation to histological grade might suggest an influential role of ERβ in tumor (de-) differentiation of OSCC.

J Int Soc Prev Community Dent. 2014 Nov;4(Suppl 1):S1-4. doi: 10.4103/2231-0762.144557.Sex hormones in gender-specific risk for head and neck cancer: A review.

Nainani P1, Paliwal A1, Nagpal N1, Agrawal M2.

Despite the fact that numerous researches have been carried out to prevent head and neck cancer (HNC) and treat those patients, there is no reduction in morbidity rate because the underlying molecular pathogenesis is still poorly understood. Endocrine microenvironment is another vital factor besides other traditional risk factors like tobacco smoking, infections, and alcohol. It has been proven that sex hormone receptors are also expressed in larynx and lungs, in addition to sex organs. Sex hormones play a vital role in gene expression involved in the plethora of biological and neoplastic processes. The role of sex hormones in HNC is still divisive and very few researches have been conducted to describe their role. So, this article is an effort to attract the attention of researchers, endocrinologists, pathologists, and clinicians toward the impending role of sex hormones, with special emphasis on progesterone, estrogen, and prolactin in HNC onset and progression, along with their therapeutic role.

Steroids. 2017 Dec 20. pii: S0039-128X(17)30223-4. doi: 10.1016/j.steroids.2017.11.012. Estradiol receptor profile and estrogen responsiveness in laryngeal cancer and clinical outcomes.Schwartz N1, Verma A2, Muktipaty C2, Bivens C2, Schwartz Z3, Boyan BD4.

There is growing evidence that laryngeal cancers are responsive to sex hormones, specifically 17β-estradiol (E2), despite controversy regarding the presence and characterization of E2 receptors (ER). Determination of sex hormone responsiveness impacts the prognosis of laryngeal cancer patients and the treatment modalities implemented by their clinicians. Discovery of membrane-associated steroid hormone receptors and rapid membrane signaling opened the possibility that cancers previously labeled ‘non-hormone dependent’ and ‘ER negative’ might in fact be susceptible to the effects of E2 via these membrane receptors. ERα66 and ERβ, the classical nuclear receptors, are present in the membranes of different cancer cells via a mechanism referred to as trafficking. Novel splice variants of these traditional receptors, a key example being ERα36, have also been found in the caveolae of cancer cells. Previous work demonstrated that ERα36 has a role in the tumorigenesis of laryngeal cancer, enhancing both proliferation and the anti-apoptotic effect of E2 against chemotherapeutics. The present study showed that expression of different membrane ERs in laryngeal cancer is not uniform, which may result in differential and even antagonistic responses to E2. E2 had protective or deleterious effects in different cancer cell lines, stimulating proliferation and conferring anti-apoptotic potential to the cancer cells according to their receptor profile. These findings stress the importance of establishing the molecular and clinical characterization of the specific laryngeal tumor in order to tailor treatment accordingly, thus optimizing care while reducing adverse effects for individual patients.

 

ANDROGEN I ORLNI KARCINOM

Eur Arch Otorhinolaryngol. 2018 May;275(5):1289-1300. doi: 10.1007/s00405-018-4949-9. Epub 2018 Mar 26.Expression of hormone receptors in oropharyngeal squamous cell carcinoma.Mohamed H1,2, Aro K3, Jouhi L3, Mäkitie A3,4, Remes S5, Haglund C6,7, Atula T3, Hagström J5,7.

Hormone receptors play an important role in many types of cancers. Alongside factors associated with human papillomavirus (HPV) infection, hormonal receptors may impact the tumorigenesis of oropharyngeal cancer.This study consists of 199 consecutive oropharyngeal squamous cell carcinoma (OPSCC) patients diagnosed and treated with a curative intent. We examined androgen (AR), estrogen (ER; both alpha and beta), and progesterone receptor (PR) expressions using immunohistochemistry comparing tumor and patient characteristics.AR was expressed in 16%, PR in 27% and ER-beta in 63% of the tumors. HPV- and p16-positive tumors expressed more AR and less PR than their negative counterparts. High PR expression was associated with poor disease-specific and locoregional recurrence-free survival.AR, PR, and ER-beta are expressed in OPSCC, and AR and PR expressions are associated with HPV and p16 status. Furthermore, PR appears to have prognostic significance. This may allow us to investigate the role of anti-hormone receptors in the treatment of OPSCC.

J Pathol. 2017 Mar;241(4):448-462. doi: 10.1002/path.4839. Epub 2017 Jan 23.Reciprocal androgen receptor/interleukin-6 crosstalk drives oesophageal carcinoma progression and contributes to patient prognosis.Dong H1, Xu J2, Li W1, Gan J1, Lin W1, Ke J1, Jiang J1, Du L1, Chen Y3, Zhong X4, Zhang D5, Yeung SJ6, Li X2,7, Zhang H1,8,9.

Oesophageal squamous cell carcinoma (ESCC), a leading lethal malignancy of the digestive tract, is characterized by marked gender disparity. Clarifying the roles of the function and regulatory pathway of the androgen receptor (AR) will improve our understanding of oesophageal cancer progression, thereby facilitating the personalized management of ESCC. Here we report evidence to show that AR is a key mediator of inflammatory signals in ESCC cancer progression. High AR expression was associated with poor overall survival in tobacco-using ESCC patients but not in ESCC patients not using tobacco. A gain and loss of AR function enhanced and repressed ESCC cell growth, respectively, by altering cell cycle progression. In mice bearing human ESCC xenografts, silencing AR expression attenuated tumour growth, whereas AR overexpression promoted tumour growth in mice of different androgen statuses (male, female, and castrated male). Array assays revealed that the inflammatory cytokine interleukin-6 (IL6) is a prominent AR target gene in ESCC. By directly binding to the IL6 promoter, AR enhances IL6 transcription, and IL6 can in turn activate AR expression, thus forming a reciprocal regulatory circuit to sustain STAT3 oncogenic signalling in ESCC. Moreover, high expression levels of both AR and IL6 in human ESCC predict poor clinical outcome in tobacco users. Together, these data establish that AR promotes ESCC growth and is associated with poor patient prognosis. The discovery of a positive feedback loop between IL6 and AR bridges the knowledge gaps among lifestyle factor-associated inflammation, gender disparity, and oesophageal carcinoma. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

 

 

Int J Cancer. 2018 Mar 1. doi: 10.1002/ijc.31353. [Epub ahead of print]A clinicopathological study and prognostic factor analysis of 177 salivary duct carcinoma patients from The Netherlands.Boon E1, Bel M1, van Boxtel W1, van der Graaf WTA1,2, van Es RJJ3, Eerenstein SEJ4, Baatenburg de Jong RJ5, van den Brekel MWM6, van der Velden LA6,7, Witjes MJH8, Hoeben A9, Willems SM10, Bloemena E11, Smit LA12, Oosting SF13; PALGA Group, Jonker MA14, Flucke UE15, van Herpen CML1.

Salivary duct carcinoma (SDC) is a subtype of salivary gland cancer with a dismal prognosis and a need for better prognostication and novel treatments. The aim of this national cohort study was to investigate clinical outcome, prognostic factors, androgen receptor (AR) and human epidermal growth factor receptor 2 (HER2) expression. SDC patients diagnosed between 1990 and 2014 were identified by the Nationwide Network and Registry of Histo- and Cytopathology in the Netherlands (PALGA). Subsequently, medical records were evaluated and pathological diagnoses reviewed. Data were analyzed for overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS) and prognostic factors. AR was evaluated by immunohistochemistry (IHC), HER2 by IHC and fluorescent in-situ hybridization. A total of 177 patients were included. The median age was 65 years, 75% were male. At diagnosis, 68% presented with lymph node metastases and 6% with distant metastases. Median OS, DFS and DMFS were 51, 23 and 26 months, respectively. In patients presenting without distant metastases, the absolute number of positive lymph nodes was associated with poor OS and DMFS in a multivariable analysis. AR and HER2 were positive in 161/168 (96%) and 44/153 (29%) tumors, respectively, and were not prognostic factors. SDC has a dismal prognosis with primary lymph node involvement in the majority of patients. The absolute number of lymph node metastases was found to be the only prognostic factor for DMFS and OS. AR expression and-to a lesser extent-HER2 expression hold promise for systemic treatment in the metastatic and eventually adjuvant setting.

Oncotarget. 2017 Jul 13;8(33):55511-55524. doi: 10.18632/oncotarget.19224. eCollection 2017 Aug 15.Meta-analysis of microRNAs expression in head and neck cancer: uncovering association with outcome and mechanisms.Lubov J1, Maschietto M2, Ibrahim I1, Mlynarek A1, Hier M1, Kowalski LP3, Alaoui-Jamali MA1, da Silva SD1.

Head and neck squamous cell carcinoma (HNSCC) is often diagnosed at advanced stages, incurring significant high mortality and morbidity. This review explored the risk stratification of miRNAs, and investigated the impact of miRNA networking in HNSCC prognostication. We performed a meta-analysis and a systematic literature search on online databases for papers published prior to December 1, 2016. The list of miRNAs was uploaded to MetacoreTM to construct a protein-protein interaction network, which was used to identify targets of the miRNAs and potential drugs. In addition, a representative network was further validated by immunohistochemistry in a cohort of 100 patients. We found 116 studies that included 8,194 subjects, in which the relationship between miRNA expression and prognosis of HNSCC were analyzed. Significant elevated expressions of 27 miRNAs and decreased expression of 26 miRNAs were associated with poor outcome. After excluding the studies causing heterogeneity, a fixed model was applied, which showed a statistically significant association between increased expression of miR-21 and poor survival (Pooled HR = 1.81,95% CI = 0.66-2.95, P < 0.005). We identified four networks affected by the miRNAs expression and enriched in genes related to metabolic processes and regulation of cell mitogenesis in response to extracellular stimuli. One network point out to 16 miRNAs directly or indirectly involved in the regulation of androgen-receptor (AR). Evaluation of AR protein expression in our cohort revealed that patients with upregulation of AR had poor survival rates (log-rank test, P < 0.005). This study showed that miRNAs have potential prognostic value to serve as screening tool for HNSCC during the follow-up. In addition, the implementation of a network-based analysis may reveal proteins with potential to be used as a biomarker

J Exp Clin Cancer Res. 2017 Feb 6;36(1):25. doi: 10.1186/s13046-017-0496-2.Regulation of submaxillary gland androgen-regulated protein 3A via estrogen receptor 2 in radioresistant head and neck squamous cell carcinoma cells.Grünow J1,2, Rong C1, Hischmann J1, Zaoui K1, Flechtenmacher C3, Weber KJ4, Plinkert P1, Hess J5,6.

Molecular mechanisms of intrinsic or acquired radioresistance serve as critical barrier for curative therapy of head and neck squamous cell carcinoma (HNSCC) and remain a major obstacle for progression-free and disease-specific survival.HNSCC cell lines were treated with a protocol of fractionated irradiation (IR, 4× 2Gy) alone or in combination with antagonists of estrogen receptor signaling and viability was determined by a colony-forming assay (CFA). Expression of submaxillary gland androgen-regulated protein 3A (SMR3A) and estrogen receptor 2 (ESR2) were assessed in tumor cells in vitro by RQ-PCR, Western blot analysis and immunofluorescence staining, and by immunohistochemical staining of tissue microarrays containing tumor sections from patients with oropharyngeal squamous cell carcinoma (OPSCC), which were treated by definitive or adjuvant radiotherapy. Subgroups with distinct SMR3A and ESR2 expression patterns were correlated with clinical parameters and survival outcome including multivariable analysis.Fractionated irradiation (IR) revealed an accumulation of tumor cells with prominent SMR3A expression, which was accompanied by an up-regulation of the estrogen receptor 2 (ESR2). ESR2-dependent regulation of SMR3A was supported by induced expression after stimulation with estradiol (E2), which was impaired by co-treatment with 4-Hydroxytamoxifen (TAM) or Fulvestrant, respectively. Both drugs significantly sensitized FaDu cells to fractionated IR as determined by a CFA and accelerated apoptosis. These data suggest a critical role of ESR2 in radioresistance and that SMR3A might serve as a surrogate marker for active ESR2 signaling. In line with this assumption, ESR2-positive oropharyngeal squamous cell carcinoma (OPSCC) with high SMR3A expression had an unfavorable progression-free and disease-specific survival as compared to those tumors with low SMR3A expression.In summary, our findings provide compelling experimental evidence that HNSCC with SMR3A and ESR2 co-expression have a higher risk for treatment failure and these patients might benefit from clinically well-established drugs targeting estrogen receptor signaling.

J Pathol. 2017 Mar;241(4):448-462. doi: 10.1002/path.4839. Epub 2017 Jan 23.Reciprocal androgen receptor/interleukin-6 crosstalk drives oesophageal carcinoma progression and contributes to patient prognosis.Dong H1, Xu J2, Li W1, Gan J1, Lin W1, Ke J1, Jiang J1, Du L1, Chen Y3, Zhong X4, Zhang D5, Yeung SJ6, Li X2,7, Zhang H1,8,9.

Oesophageal squamous cell carcinoma (ESCC), a leading lethal malignancy of the digestive tract, is characterized by marked gender disparity. Clarifying the roles of the function and regulatory pathway of the androgen receptor (AR) will improve our understanding of oesophageal cancer progression, thereby facilitating the personalized management of ESCC. Here we report evidence to show that AR is a key mediator of inflammatory signals in ESCC cancer progression. High AR expression was associated with poor overall survival in tobacco-using ESCC patients but not in ESCC patients not using tobacco. A gain and loss of AR function enhanced and repressed ESCC cell growth, respectively, by altering cell cycle progression. In mice bearing human ESCC xenografts, silencing AR expression attenuated tumour growth, whereas AR overexpression promoted tumour growth in mice of different androgen statuses (male, female, and castrated male). Array assays revealed that the inflammatory cytokine interleukin-6 (IL6) is a prominent AR target gene in ESCC. By directly binding to the IL6 promoter, AR enhances IL6 transcription, and IL6 can in turn activate AR expression, thus forming a reciprocal regulatory circuit to sustain STAT3 oncogenic signalling in ESCC. Moreover, high expression levels of both AR and IL6 in human ESCC predict poor clinical outcome in tobacco users. Together, these data establish that AR promotes ESCC growth and is associated with poor patient prognosis. The discovery of a positive feedback loop between IL6 and AR bridges the knowledge gaps among lifestyle factor-associated inflammation, gender disparity, and oesophageal carcinoma

PLoS One. 2018 Jan 17;13(1):e0190325. doi: 10.1371/journal.pone.0190325. eCollection 2018.Association between circulating levels of sex steroid hormones and esophageal adenocarcinoma in the FINBAR Study.Petrick JL1, Falk RT1, Hyland PL1, Caron P2, Pfeiffer RM1, Wood SN1, Dawsey SM1, Abnet CC1, Taylor PR1, Guillemette C2, Murray LJ3, Anderson LA3, Cook MB1.

Esophageal adenocarcinoma (EA) is characterized by a strong male predominance. Sex steroid hormones have been hypothesized to underlie this sex disparity, but no population-based study to date has examined this potential association.Using mass spectrometry and ELISA, we quantitated sex steroid hormones and sex hormone binding globulin, respectively, in plasma from males- 172 EA cases and 185 controls-within the Factors Influencing the Barrett/Adenocarcinoma Relationship (FINBAR) Study, a case-control investigation conducted in Northern Ireland and Ireland. Multivariable adjusted logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between circulating hormones and EA.Higher androgen:estrogen ratio metrics were associated with increased odds of EA (e.g., testosterone:estradiol ratio ORQ4 v. Q1 = 2.58, 95%CI = 1.23-5.43; Ptrend = 0.009). All estrogens and androgens were associated with significant decreased odds of EA. When restricted to individuals with minimal to no decrease in body mass index, the size of association for the androgen:estrogen ratio was not greatly altered.This first study of sex steroid hormones and EA provides tentative evidence that androgen:estrogen balance may be a factor related to EA. Replication of these findings in prospective studies is needed to enhance confidence in the causality of this effect.

World J Gastroenterol. 2015 May 28;21(20):6146-56. doi: 10.3748/wjg.v21.i20.6146.Androgens and esophageal cancer: What do we know?Sukocheva OA1, Li B1, Due SL1, Hussey DJ1, Watson DI1.

Significant disparities exist between genders for the development and progression of several gastro-intestinal (GI) diseases including cancer. Differences in incidence between men vs women for colon, gastric and hepatocellular cancers suggest a role for steroid sex hormones in regulation of GI carcinogenesis. Involvement of intrinsic gender-linked mechanisms is also possible for esophageal adenocarcinoma as its incidence is disproportionally high among men. However, the cause of the observed gender differences and the potential role of androgens in esophageal carcinogenesis remains unclear, even though the cancer-promoting role of androgen receptors (AR) shown in other cancers such as prostate and bladder suggests this aspect warrants exploration. Several studies have demonstrated expression of ARs in esophageal cancer. However, only one study has suggested a potential link between AR signaling and outcome – poorer prognosis. Two groups have analyzed data from cohorts with prostate cancer and one of these found a decreased incidence of esophageal squamous and adenocarcinoma after androgen deprivation therapy. However, very limited information is available about the effects of androgen and AR-initiated signaling on esophageal cancer cell growth in vitro and in vivo. Possible mechanisms for androgens/AR involvement in the regulation of esophageal cancer growth are considered, and the potential use of AR as a prognostic factor and clinical target is highlighted, although insufficient evidence is available to support clinical trials of novel therapies. As esophageal adenocarcinoma is a gender linked cancer with a large male predominance further studies are warranted to clarify the role of androgens and ARs in shaping intracellular signaling and genomic responses in esophageal cancer.

Tumour Biol. 2015 Aug;36(8):5859-64. doi: 10.1007/s13277-015-3257-x. Epub 2015 Feb 28.Androgen receptor promotes esophageal cancer cell migration and proliferation via matrix metalloproteinase 2.Zhang Y1, Pan T, Zhong X, Cheng C.

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies worldwide. Androgen receptor (AR) plays an important role in many kinds of cancers. However, the molecular mechanisms of AR in ESCC are poorly characterized. In the present study, Western blot analysis and real-time quantitative PCR were performed to identify differentially expressed AR in 40 ESCC tissue samples, which revealed that the messenger RNA (mRNA) and protein expression of AR is upregulated in the ESCC tissue samples. AR overexpression induced increases in ESCC cell invasion and proliferation in vitro. Silencing of AR inhibited the proliferation of KYSE450 cells which have a relatively high level of AR, and the invasion of KYSE450 cells was distinctly suppressed. Furthermore, AR knockdown led to substantial reductions in matrix metalloproteinase 2 (MMP2) and p-AKT levels in ESCC cell lines, but no significant change in AKT and MMP9 expression. These results suggest that AR is involved in tumor progression, and thus, AR could represent selective targets for the molecularly targeted treatments of ESCC.

 

Ki-67, oral cancer

J Oral Pathol Med. 2018 Mar 23. doi: 10.1111/jop.12705. [Epub ahead of print]Visualizing the effects of metformin on tumor growth, vascularity, and metabolism in head and neck cancer.Verma A1,2, Rich LJ1, Vincent-Chong VK1, Seshadri M1,2,3.

The antidiabetic drug metformin (Met) is believed to inhibit tumor proliferation by altering the metabolism of cancer cells. In this study, we examined the effects of Met on tumor oxygenation, metabolism, and growth in head and neck squamous cell carcinoma (HNSCC) using non-invasive multimodal imaging.Severe combined immunodeficient (SCID) mice bearing orthotopic FaDu HNSCC xenografts were treated with Met (200 mg/kg, ip) once daily for 5 days. Tumor oxygen saturation (%sO2 ) and hemoglobin concentration (HbT) were measured using photoacoustic imaging (PAI). Fluorescence imaging was employed to measure intratumoral uptake of 2-deoxyglucosone (2-DG) following Met treatment while magnetic resonance imaging (MRI) was utilized to measure tumor volume. Correlative immunostaining of tumor sections for markers of proliferation (Ki67) and vascularity (CD31) was also performed.At 5 days post-Met treatment, PAI revealed a significant increase (P < .05) in %sO2 and HbT levels in treated tumors compared to untreated controls. Fluorescence imaging at this time point revealed a 46% decrease in mean 2-DG uptake compared to controls. No changes in hemodynamic parameters were observed in mouse salivary gland tissue. A significant decrease in Ki-67 staining (P < .001) and MR-based tumor volume was also observed in Met-treated tumors compared to controls with no change in CD31 + vessel count following Met therapy.Our results provide, for the first time, direct in vivo evidence of Met-induced changes in tumor microenvironmental parameters in HNSCC xenografts. Our findings highlight the utility of multimodal functional imaging for non-invasive mapping of the effects of Met in HNSCC.

J Contemp Dent Pract. 2018 Feb 1;19(2):170-176.Proliferative Index in Invasive Tumor Front of Oral Squamous Cell Carcinoma: A Potential Prognostic Indicator.Bhuyan L1, Sarangi S2, Das BK2, Das SN2, Nayak S3.

The aim of the study was to evaluate the proliferative index (PI) at their invasive front of oral cancer and their association with Bryne’s grades of oral squamous cell carcinoma (OSCC) and compare the PI with lymph node metastasis, site of involvement, and habits.The Ki-67 antigen expression was immunohistochemically evaluated in a total of 102 cases that included the histopathologically diagnosed archival specimens of OSCCs. They were subdivided by Bryne’s histopathological grading into grade I (40 cases), grade II (32 cases), and grade III (30 cases). The nucleus with brown stain was considered positive. Cells were counted under 400× magnification. The proliferative activity thus determined was then expressed as a percentage of Ki-67 labeling index (Ki-67 LI) positive cells.A stepwise increase in the mean Ki-67 LI was found from grade I to III squamous cell carcinoma, thus correlating with the histological grading. In addition, there was a higher PI seen in cases associated with metastatic lymph node, which concords with the higher biologic aggressiveness and poor prognosis of the lesion.The present study shows a definitive correlation of Ki-67 antigen with the Bryne’s histological grading, all the parameters of Bryne’s grading for OSCC and lymph node status of the patient proving its association as an effective tool to grade the tumors and finally read the prognosis of the tumor.Cell proliferation is regarded as one of the most important biologic mechanisms in oncogenesis. The role of cell proliferation in tumor progression has been inferred in studies concerned with human cancer by comparing the PI of normal tissue, preneoplastic and neoplastic lesions. The Ki-67 antigen-labeled cells can prove to be an effective aid to grade the tumors. It might be possible to standardize and objectify tumor grading among pathology laboratories.

J Oral Pathol Med. 2018 Feb;47(2):128-135. doi: 10.1111/jop.12653. Epub 2017 Nov 2.Cell proliferation is associated with intensity of tumor budding in oral squamous cell carcinoma.Marangon Junior H1,2, Leão PLR1, Melo VVM1, Caixeta ÂB1, Souza PEA1, de Aguiar MCF3, Horta MCR1.

Tumor budding is a morphological marker of cancer invasion, defined as the presence of isolated or small clusters of neoplastic cells at the tumor invasive front. This study aimed to evaluate the association between intensity of tumor budding and cell proliferation in oral squamous cell carcinoma (OSCC).Immunohistochemistry was employed in 163 OSCC samples to detect the cell proliferation marker Ki-67 and multicytokeratin (to identify OSCC cells in tumor budding evaluation). The Mann-Whitney test was used to evaluate differences in the cell proliferation index between samples with high-intensity tumor budding and samples with low-intensity or no tumor budding. In samples with high-intensity tumor budding, the Wilcoxon test was used to evaluate differences in the cell proliferation index between the budding area and the area outside the budding. The chi-square test assessed the association between cell proliferation index and intensity of tumor budding.The cell proliferation index was higher in samples with high-intensity tumor budding than in samples with low-intensity or no tumor budding (P < .05). Tumors with high-intensity tumor budding showed a higher cell proliferation index in the budding area than in the area outside the budding (P < .05). Finally, samples showing high-intensity tumor budding were associated with high cell proliferation index (P < .05).Cell proliferation is positively associated with intensity of tumor budding in OSCC. Moreover, in tumors showing high-intensity tumor budding, the budding area is the location of higher cell proliferation. These findings reinforce the hypothesis that tumor budding is associated with the biological behavior of OSCC.

J Dent (Shiraz). 2017 Sep;18(3):207-211.Evaluation of the Ki-67 and MCM3 Expression in Cytologic Smear of Oral Squamous Cell Carcinoma.Rezazadeh F1, Ebrahimi R2, Andisheh-Tadbir A3, Ashraf MJ4, Khademi B5.

Squamous cell carcinoma (SCC) is the most frequent oral cancer whose 5-year survival rate is 80% for early-detected lesions and nearly 30-50% for advanced lesions. Early detection of oral cancers and precancerous lesions can improve the patient’s survival and decrease the morbidity.This study aimed to evaluate and compare the Ki-67 and MCM3 expression in cytologic smear of oral SCC (OSCC).We examined 48 oral brush biopsies including 28 OSCC and 20 healthy non-smoking samples. Immunocytochemistry staining was performed for Ki-67 and MCM3 by using an EnVision-labeled peroxidase system, and labeling index (LI) was calculated.Out of 28 OSCC cases, 27(96.4%) cases contained MCM3 positive cells and 22(78%) cases contained Ki-67 positive cells. All normal mucosa were Ki-67 and MCM3 negative. MCM3 and Ki-67 LI were significantly higher in OSCC than normal mucosa (p< 0.001). MCM3 LI was significantly higher than Ki-67 LI in OSCC group (p< 0.001).Immunocytologic evaluation of Ki-67 and MCM3 can be used for early detection of OSCC. Furthermore, MCM3 may be a more sensitive cytologic biomarker than Ki-67 in SCC patients.

 

 

Hum Immunol. 2017 Nov;78(11-12):752-757. doi: 10.1016/j.humimm.2017.09.003. Epub 2017 Sep 21.Overexpression of immunomodulatory mediators in oral precancerous lesions.Gonçalves AS1, Mosconi C2, Jaeger F3, Wastowski IJ4, Aguiar MCF5, Silva TA6, Ribeiro-Rotta RF7, Costa NL8, Batista AC9.

Human leukocyte antigen (HLA) G and E, programmed cell death 1 ligand 1 (PD-L1), IL-10 and TGF-β are proteins involved in failure of the antitumor immune response. We investigated the expression of these immunomodulatory mediators in oral precancerous lesions (oral leukoplakia-OL; n=80) and whether these molecules were related to the risk of malignant transformation. Samples of normal mucosa (n=20) and oral squamous cells carcinoma (OSCC, n=20) were included as controls. Tissue and saliva samples were analyzed by immunohistochemistry and ELISA respectively. Fifteen OL samples showed severe dysplasia (18.7%) and 40 samples (50%) presented combined high Ki-67/p53. Irrespective of the degree of epithelial dysplasia and the proliferation/apoptosis index of OL, the expression of HLA-G, -E, PD-L1, IL-10, TGF-β2 and -β3 was higher to control (P<0.05) and similar to OSCC (P>0.05). The number of granzyme B+ cells in OL was similar to control (P=0.28) and lower compared to OSCC (P<0.01). Salivary concentrations of sHLA-G, IL-10 and TGF-β did not allow for a distinction between OL and healthy individuals. Overexpression of immunosuppressive mediators in the OL reflects the immune evasion potential of this lesion, which is apparently independent of at cytological and proliferation/apoptosis status.

Braz Oral Res. 2017 Aug 21;31:e66. doi: 10.1590/1807-3107BOR-2017.vol31.0066.

Ki-67 protein predicts survival in oral squamous carcinoma cells: an immunohistochemical study.Lopes VKM1, Jesus AS1, Souza LL1, Miyahara LAN1, Guimarães DM1, Pontes HAR1, Pontes FSC1, Carvalho PL2.

The aim of this study was to identify the expression of Ki-67 and MCM3 in oral squamous cell carcinoma (OSCC) as well as to address the correlation with patient survival and clinical features. Samples were collected from 51 patients with OSCC who presented for follow-up. Immunohistochemical expression of Ki-67 and MCM3 in all groups was performed. The scoring system was previous published by Tsurutani in 2005. We used Kappa index to evaluate observers agreement degree. The associations between protein expression and clinical variables were examined for statistical significance using the chi-squared test. The overall survival rates were estimated by the Kaplan-Meier method and the relationship between protein expression and survival was compared using the log-rank test (p < 0.05). The overall survival time for a patient with positive immunostaining for Ki-67 is shorter than for a patient with negative immunostaining, (log-rank test, p = 0.00882). Patients with tumor size T3 and T4 showed a statistically significant relationship with Ki-67 immunoexpression (log-rank test, p = 0.0174). The relationship between Ki-67 expression and the relation between age, gender, smoking, tumor site, lymph node metastasis and disease stage was not significant. The examiners agreement degree by Kappa presented p value < 0.05. There was not a significant correlation when we evaluated MCM3 expression regarding clinical characteristics and survival rate. From these results, the present study suggests that positive Ki-67 expression found in OSCC patients may contribute to predict the survival in OSCC samples, as well as the relation between the protein and the tumor size.

 

 

 

Br J Cancer. 2017 Sep 5;117(6):856-866. doi: 10.1038/bjc.2017.244. Epub 2017 Jul 27.Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis.Almangush A1,2,3, Heikkinen I1,2, Mäkitie AA4, Coletta RD5, Läärä E6, Leivo I7, Salo T2,8,9,10.

Identifying informative prognostic biomarkers for oral tongue squamous cell carcinoma (OTSCC) is of great importance in order to better predict tumour behaviour and to guide treatment planning. Here, we summarise existing evidence regarding immunohistochemical prognostic biomarkers for OTSCC.A systematic search of the literature was performed using the databases of Scopus, Ovid Medline, Web of Science and Cochrane Library. All studies which had investigated the prognostic significance of immunohistochemical biomarkers in OTSCC during the period from 1985 to 2015 were retrieved. For the five most often evaluated biomarkers a random-effects meta-analysis on overall survival was performed, including those studies that provided the necessary statistical results.A total of 174 studies conducted during the last three decades were found, and in these 184 biomarkers were evaluated for the prognostication of OTSCC. The five biomarkers most frequently assessed were p53, Ki-67, p16, VEGFs and cyclin D1. In the meta-analyses, the most promising results of the prognostic power for OTSCC were obtained for cyclin D1. For studies of VEGF A and C the results were equivocal, but the pooled analysis of VEGF A separately showed it to be a useful prognosticator for OTSCC. There was no sufficient evidence to support p53, Ki-67 and p16 as prognostic biomarkers for OTSCC. Limitations in the quality of the published studies (e.g., small cohorts, lack of compliance with REMARK guidelines) are widespread.Numerous biomarkers have been presented as useful prognosticators for OTSCC, but the quality of the conduct and reporting of original studies is overall unsatisfactory which does not allow reliable conclusions. The value of two biomarkers (VEGF-A and cyclin D1) should be validated in a multicentre study setting following REMARK guidelines.

J Appl Oral Sci. 2017 May-Jun;25(3):318-323. doi: 10.1590/1678-7757-2016-0238.Cell proliferation markers at the invasive tumor front of oral squamous cell carcinoma: comparative analysis in relation to clinicopathological parameters of patients.Cortegoso AVB1, Laureano NK2, Silva ADD2,3, Danilevicz CK2, Magnusson AS2, Visioli F2, Rados PV2.

To evaluate the number of AgNORs per nucleus and the expression of Ki-67 at the tumor invasion front (TIF) in relation to clinical parameters (TNM), TIF classification and the prognosis of oral squamous cell carcinomas in an Uruguayan population.This study was conducted through a retrospective survey from 2000 to 2010 at the National Institute of Cancer Montevideo, Uruguay and included 40 patients. The samples were obtained from the resection of the tumor and the TIF was defined according with Bryne, et al.5 (1992). Expression of Ki-67 was assessed by the percentage of positive tumor cells and the AgNOR was recorded as the mean AgNOR (mAgNOR) and the percentage of AgNOR per nucleus (pAgNOR). All analyzes were performed by a blinded and calibrated observer.No statistically significant association was observed between immunostaining of Ki-67 and AgNOR with the different types of TIF, regional metastasis and patients prognosis, however it was observed an increase in Ki-67 expression associated with worse patient’s clinical staging, although not statistically significant.Our results suggest that proliferation markers as AgNOR and Ki-67 are not prognostic markers at the tumor invasive front of carcinoma of oral squamous cell.

 

 

Otolaryngol Head Neck Surg. 2017 Nov;157(5):798-807. doi: 10.1177/0194599817709224. Epub 2017 Jun 13.Tumor Metabolism in the Microenvironment of Nodal Metastasis in Oral Squamous Cell Carcinoma.Curry J1, Tassone P1, Gill K1, Tuluc M2, BarAd V3, Mollaee M2, Whitaker-Menezes D4, Rodeck U5, Luginbuhl A1, Cognetti D1, Keane W1, Martinez-Outschoorn U4.

Objective In many cancers, including head and neck squamous cell carcinoma (HNSCC), different regions within a tumor have different metabolic phenotypes. Transfer of metabolites between compartments promotes tumor growth and aggressive behavior. Metabolic compartmentalization in HNSCC nodal metastases has not been studied, nor has its impact on extracapsular extension or clinical outcomes been determined. Study Design Retrospective analysis based on immunohistochemistry staining. Setting Tertiary care center. Subjects and Methods Primary tumors and nodal metastases from 34 surgically treated oral cavity HNSCC patients with extracapsular extension (ECE) were stained for monocarboyxlate transporter (MCT) 4, MCT1, translocase of outer mitochondrial membrane 20, and Ki-67. Strength of staining was assessed using a computer-assisted pathology algorithm. Immunohistochemistry (IHC) scores along with clinical factors were used to predict disease-free survival (DFS). Results Patterns of IHC staining showed metabolic compartmentalization both at the primary tumor sites and in nodal metastases. MCT4 staining in the perinodal stroma was significantly higher in specimens with ECE greater than 1 mm (macro-ECE, P = .01). Patients with high perinodal MCT4 staining were compared with those with low perinodal MCT4 staining. On multivariate analysis, only high perinodal MCT4 staining had a significant impact on DFS ( P = .02); patients with high perinodal MCT4 had worse survival. DFS was not significantly worsened by advancing T stage, N stage, ECE extent, or perineural invasion. Conclusion Oral HNSCC displays compartmentalized tumor metabolism at both primary and metastases. Greater cancer-associated stromal conversion around ECE, denoted by high stromal MCT4, may be a biomarker for aggressive disease and worsened DFS.

Stomatologiia (Mosk). 2017;96(2):33-35. doi: 10.17116/stomat201796233-35.[Immunohistochemical criteria for differential diagnostics of squamous epithelium changes in pyogenic granuloma and squamous cell carcinoma of the oral mucosa].

[Article in Russian; Abstract available in Russian from the publisher]Ivina AA1, Semkin VA2, Babichenko II3.

The paper presents an example of differential diagnostic studies for pyogenic granuloma and oral squamous cell carcinoma (SCC). In the described case immunohistochemistry with antibodies to Ki-67 and Gli1 was used as conventional histological procedure proved to be inconvenient for adequate diagnostics. The immunohistochemical study established increased proliferative activity of epithelial cells specific both pyogenic granuloma and oral SCC, but intensive Gli1 protein expression in membranes and cytoplasm of epithelial cells with malignant transformation allowed differentiation of these neoplasms.

Integr Cancer Ther. 2018 Mar;17(1):115-123. doi: 10.1177/1534735416684947. Epub 2017 Jan 19.A Randomized Double-Blind Placebo-Controlled Trial of Fruit and Vegetable Concentrates on Intermediate Biomarkers in Head and Neck Cancer.Datta M1, Shaw EG2, Lesser GJ3, Case LD3, Vitolins MZ3, Schneider C4, Frizzell B3, Sullivan C3, Lively M3, Franzmann E5, Hu JJ5.

Head and neck cancer (HNC) patients are at an increased risk for developing second primary tumors (SPTs). Diets rich in fruits and vegetables (FVs) may lower HNC risk. FV concentrates may offer a potential alternative to increasing FV intake.We conducted a randomized, double-blind, placebo-controlled trial to evaluate whether Juice PLUS+ (JP; a commercial product with multiple FV concentrates) has an effect on p27 and Ki-67, biomarkers associated with the risk of SPTs. During 2004-2008, we randomized 134 HNC patients to 12 weeks of JP (n = 72) or placebo (n = 62). Oral cavity mucosal biopsies and whole blood were obtained at baseline and after 12 weeks. All participants were given the opportunity to receive JP for 5 years following the end of the intervention period, and they were followed yearly for the development of SPTs.After 12 weeks, patients on JP had significantly higher serum α-carotene ( P = .009), β-carotene ( P < .0001), and lutein ( P = .003) but did not differ significantly in p27 ( P = .23) or Ki-67 ( P = .95). JP use following the initial 12-week trial was not significantly associated with SPT prevention.Despite increased serum micronutrient levels, our results do not suggest a clinical benefit of JP in HNC patients. Future studies should focus on longer intervention periods and/or modified supplement formulations with demonstrated chemopreventive properties.

Contemp Clin Dent. 2016 Oct-Dec;7(4):493-499.A study of Ki-67 expression and its clinicopathological determinants in nondysplastic oral leukoplakia.Mondal K1, Mandal R1, Sarkar BC2.

This study aimed at evaluation of the Ki-67 expression and thereby detection of the dysplastic potential in histopathologically nondysplastic oral leukoplakia (OL). Secondarily, another purpose was to correlate various clinicopathological factors with the labeling indices (LIs) of Ki-67 in those cases as well.In total, 97 OL cases were examined. Relevant clinical and demographic information was retrieved from the pro forma, prefilled by the patients themselves during their first visit.Ki-67 immunohistochemical staining was performed on paraffin-embedded tissue samples. Its LIs were calculated and correlated with different clinicopathological parameters using statistical software SPSS version 16.0.58.8% (57 cases) lesions exhibited a Ki-67 positivity of ≤5%, and 25.8% (25 cases) lesions exhibited it in the range of 6%-25%. Only 15 (15.4%) patches were stained positively between 26% and 60%. Patients’ age beyond 50 years, nonhomogeneous leukoplakia, and tobacco addiction were the significant risk factors for high Ki-67 scores (P < 0.05).Ki-67 is an essential immunohistochemical marker for epithelial dysplasia in OL, especially when the conventional histopathology fails to appreciate the same. In this purpose, Ki-67 labeling on a routine basis delivers the most convenient results for patients aged above 50 years, and/or addicted to tobacco products, and/or suffering from nonhomogeneous patches.

Arkh Patol. 2016;78(5):15-19. doi: 10.17116/patol201678515-19.[Value of the expression of Ki-67 and membrane protein glucose transporter GLUT1 in the diagnosis of neoplastic transformation of the oral mucosal epithelium].Ivina AA1, Semkin VA2, Babichenko II1.

to investigate the expression of GLUT1 protein in relation to the proliferative activity of cells and the degree of neoplastic transformation of the epithelium of the oral mucosa (OM).OM biopsies from 44 patients were investigated. 14 cases (31.9%) were diagnosed with focal epithelial hyperplasia of the OM; 13 (29.5%) cases had squamous intraepithelial neoplasia (SIN) and 17 (38.6%) had squamous cell carcinoma. Ten intact MO samples were used as a control group. Tissue antigens were determined using mouse monoclonal antibodies to Ki-67 and rabbit antibodies to GLUT1.

A direct correlation was found between the intensity of GLUT1 expression on the oral epithelial cell membranes and the proliferative activity of cells with an increase in the phenomena of cellular atypia.GLUT1 may be used as a marker for the early diagnosis of neoplastic transformation of stratified squamous epithelial cells.

J Oral Biol Craniofac Res. 2016 Sep-Dec;6(3):194-197. Epub 2016 Jun 29.Histologic and immunohistochemical evaluation of mirror image biopsies in oral squamous cell carcinoma.Gupta V1, Ramani P2.

The concept of field cancerization has frequently been quoted to explain the occurrence of multiple primary cancers in the head and neck region and recurrence following complete excision of the original tumor. The main objective is to study the occurrence of field changes in mirror image biopsy in relation to histopathological changes in the oral mucosa among oral cancer patients using hematoxylin and eosin and to study the expression pattern of cytokeratin, Ki-67 and p53 in oral squamous cell carcinoma and mirror image biopsy.A pilot study of 15 patients clinically diagnosed with carcinoma lesion and their corresponding mirror image sites were taken and stained using immunohistochemistry method for the expression of cytokeratin, Ki-67 and p53.Primary tumors showed strong positive staining for cytokeratin throughout both the epithelium and malignant epithelial islands but absence of staining for Ki-67 and p53.CK may be useful in predicting epithelial differentiation and Ki-67 and p53 act as weak indicators of malignant disease progression in oral tissues.

J Oral Pathol Med. 2017 May;46(5):346-352. doi: 10.1111/jop.12498. Epub 2016 Sep 8.p53 and ki67 as biomarkers in determining response to chemoprevention for oral leukoplakia.

Nagao T1,2,3,4, Warnakulasuriya S2, Sakuma H3, Miyabe S3, Hasegawa S5, Machida J3, Suzuki K6, Fukano H3, Shimozato K3, Hashimoto S4.

We performed a randomized controlled chemoprevention trial of oral leukoplakia by administrating a low dose of beta-carotene and vitamin C supplements. 17% of subjects in the experimental arm (4/23) demonstrated clinical remission (complete or partial response) at completion of the trial. The objective of this study was to determine whether baseline expression of p53 and ki67 demonstrated any differences between those responding or not responding to our intervention. A secondary objective was to elucidate any relationship between dietary factors and clinical responses.For this biomarker study, we included all subjects in the experimental group (n = 23) who were non-smokers. Among 16 who completed the trial for 1 year of supplementation, there were four responders and 12 non-responders at 1-year follow-up. Following immuno-staining for p53 and ki67, the percentage of positive cell nuclei were analyzed as labeling index (LI).Expression of p53 was greater in basal layers than in para-basal layers. Mean para-basal LI of p53 was higher in non-responding (26.0) than in responding subjects (11.2) (P = 0.028). ki67 LIs were not significantly different in the two groups.Expression of p53 was inversely related to clinical response to the supplements. Other biomarkers that may recognize subject’s responsiveness to chemoprevention require further study.

J Craniomaxillofac Surg. 2016 Sep;44(9):1430-5. doi: 10.1016/j.jcms.2016.06.011. Epub 2016 Jun 21.Ki67 Overexpression in mucosa distant from oral carcinoma: A poor prognostic factor in patients with long-term follow-up.Gissi DB1, Gabusi A2, Tarsitano A3, Badiali G3, Marchetti C3, Morandi L4, Foschini MP4, Montebugnoli L2.

The aggressive behavior of oral squamous cell carcinoma (OSCC) has recently been related to the mucosa surrounding the primary mass, consisting of genetically altered cells that might be responsible for cancer progression. The aim of the study was to determine whether an abnormal cell turnover in clinically and histologically “normal” mucosa distant from the primary tumor is associated with a poor prognosis in terms of locoregional control (LRC) of disease and disease-specific survival (DSS).This prospective study monitored 55 OSCC patients. Cell turnover in areas clinically and histologically distant from the tumor mass was evaluated by immunohistochemical expression of Ki67. A Ki67 value >20% was considered “high.”The mean follow-up period of the population studied was 53.7 ± 32.4 months (range 12-110 months). Multivariate analysis showed that the Ki67 value in distant mucosa was a powerful independent prognostic factor for LRC. In addition, high Ki67 expression in distant mucosa was the only variable statistically related to worse LRC (χ(2) = 9.5; p = 0.002) and DSS (χ(2) = 5.51; p = 0.02) in T1-2N0 OSCCs.The present study confirmed the role of Ki67 in tumor-distant areas as a prognostic marker for OSCC patients.

Rev Col Bras Cir. 2016 Mar-Apr;43(2):72-9. doi: 10.1590/0100-69912016002002.Expression of Ki-67 and P16 INK4a in chemically-induced perioral squamous cell carcinomas in mice.Alves ÂV1, Ribeiro DR1, Lima SO2, Reis FP2, Soares AF3, Gomes MZ4, Albuquerque RL Júnior4.

to evaluate the influence of Ki-67 and P16INK4a proteins immunohistochemical expressions on the clinical and morphological parameters of perioral squamous cell carcinoma induced with 9,10-dimethyl-1,2-benzanthracene (DMBA) in mice.we topically induced the lesions in the oral commissure of ten Swiss mice for 20 weeks, determining the time to tumors onset and the average tumor volume up to 26 weeks. In histopathological analysis, the variables studied were histological malignancy grade and the immunohistochemical expression of Ki-67 and P16INK4a proteins. The correlation between variables was determined by application of the Spearman correlation test.the mean time to onset of perioral lesions was 21.1 ± 2.13 weeks; mean tumor volume was 555.91 ± 205.52 mm3. Of the induced tumors, 80% were classified as low score and 20% high score. There was diffuse positivity for Ki-67 in 100% of lesions – Proliferation Index (PI) of 50.1 ± 18.0. There was a strong direct correlation between Ki-67 immunoreactivity and tumor volume (R = 0.702) and a low correlation with the malignancy score (R = 0.486). The P16INK4a protein expression was heterogeneous, showing a weak correlation with tumor volume (R = 0.334). There was no correlation between the immunohistochemical expression of the two proteins studied.in an experimental model of DMBA-induced perioral carcinogenesis, tumor progression was associated with the tumor proliferative fraction (Ki-67 positive cells) and with tumor histological grading, but not with P16INK4a expression.

J Cancer. 2016 Apr 10;7(7):758-67. doi: 10.7150/jca.14214. eCollection 2016.What is the Prognostic Significance of Ki-67 Positivity in Oral Squamous Cell Carcinoma?Xie S1, Liu Y1, Qiao X2, Hua RX3, Wang K1, Shan XF1, Cai ZG1.

Numerous studies have stated that Ki-67 is a good prognostic marker in oral squamous cell carcinoma (OSCC). However, some researchers believe the contrary. To address this controversy, we performed a systematic literature retrieval to estimate the prognostic significance of Ki-67 expression in patients with OSCC.Databases covering Pubmed, Ovid, Web of Science, Embase and the Cochrane library were searched regardless of publication year. Overall survival (OS), local recurrence (LR) and disease-free survival (DFS) were the main outcome measures. Relative risks (RRs) and its 95% confidential intervals (CIs) were used for statistical analysis.Twenty-seven articles with 2146 patients were included in this study. The results of the meta-analysis suggested that the pooled RRs and its CIs for OS, LR, and DFS were 1.45 (1.15 – 1.84), 1.76 (0.74 – 4.16) and 1.52 (1.07 – 2.14), respectively. However, the heterogeneities of OS and LR were obvious (I-squared (OS) = 59.4%, I-squared (LR) = 72.6%). After subgroup analysis based on systemic treatment, the cut-off value of Ki-67 expression, ethnicity and types of antibody, the heterogeneities became acceptable. It was observed that systemic treatment, cut-off values of Ki-67 expression, ethnicity and the types of antibody affected the results. The statistical analyses of subgroups suggested that non-systemic treatment, (OR=1.77, 95% CI = 1.39-2.25, p = 0.000) and Asian populations (OR=2.09, 95% CI = 1.32-3.32, p = 0.002) are high risks for Ki-67 high expression, and low cut-off value of Ki-67 expression (OR = 1.44, 95% CI = 1.001-2.072), MIB-1 antibody (OR = 1.48, OR 95% = 1.10-1.99) might affect the identification of results.According to this meta-analysis, high Ki-67 expression might be a negative prognostic marker of patients with OSCC, especially in Asian populations. In addition, Ki-67 expression affects the treatment response.

 

IL-6, oral cancer

Theranostics. 2018 Jan 1;8(4):921-940. doi: 10.7150/thno.22182. eCollection 2018.Cancer-associated Fibroblast-derived IL-6 Promotes Head and Neck Cancer Progression via the Osteopontin-NF-kappa B Signaling Pathway.Qin X1, Yan M1, Wang X1, Xu Q1,2, Wang X1, Zhu X1, Shi J1, Li Z1, Zhang J1, Chen W1,2.

Osteopontin (OPN), a chemokine-like protein, plays a crucial role in the proliferation and metastasis of various cancers. However, how tumor stroma modulates the expression of neoplastic OPN and the multifaceted roles of OPN in head and neck cancer (HNC) are unclear. In this study, we tried to investigate the bridging role of OPN between tumor stroma and cancer cells. Methods: Immunohistochemical staining and quantitative real-time PCR were used to detect OPN expression in HNC tissues, and the correlations between OPN expression and clinicopathologic features were then analyzed. We used a co-culture assay to study the modulatory role of IL-6 on OPN expression and immunoprecipitation analysis was used to determine the endogenous interaction between OPN and integrin αvβ3. Furthermore, a xenograft assay was carried out to confirm the tumor-promoting role and the potential therapeutic value of OPN in HNC. Results: We found that OPN was significantly up-regulated in HNCs, and the elevated OPN was correlated with poor prognosis. Moreover, we identified IL-6 secreted by cancer-associated fibroblasts (CAFs) as the major upstream molecule that triggers the induction of neoplastic OPN. As such, during the interaction of fibroblasts and cancer cells, the increased neoplastic OPN induced by stromal IL-6 accelerated the growth, migration and invasion of cancer cells. More importantly, we also showed that soluble OPN could promote HNC progression via the integrin αvβ3-NF-kappa B pathway, and the combination of OPN and IL-6 had a better prognostic and diagnostic performance in HNC than either molecule alone. Conclusion: Our study identified a novel modulatory role for OPN in HNC progression and further demonstrated that the combination of OPN and IL-6 might be a promising prognostic and diagnostic indicator as well as a potential cancer therapeutic target.

PLoS One. 2018 Jan 23;13(1):e0188847. doi: 10.1371/journal.pone.0188847. eCollection 2018.CXCL1 induces senescence of cancer-associated fibroblasts via autocrine loops in oral squamous cell carcinoma.Kim EK1, Moon S1,2, Kim DK1, Zhang X1,3, Kim J1.

Cancer-associated fibroblasts (CAFs) have emerged as one of the main factors related to cancer progression, however, the conversion mechanism of normal fibroblasts (NOFs) to CAFs has not been well elucidated. The aim of this study was to investigate the underlying mechanism of CAF transformation from NOFs in oral squamous cell carcinoma (OSCC). This study found that NOFs exposed to OSCC cells transformed to senescent cells. The cytokine antibody array showed the highest secretion levels of IL-6 and CXCL1 in NOFs co-cultured with OSCC cells. Despite that both IL-6 and CXCL1 induced the senescent phenotype of CAFs, CXCL1 secretion showed a cancer-specific response to transform NOFs into CAFs in OSCC, whereas IL-6 secretion was eventuated by common co-culture condition. Further, CXCL1 was released from NOFs co-cultured with OSCC cells, however, CXCL1 was undetectable in mono-cultured NOFs or co-cultured OSCC cells with NOFs. Taken together, this study demonstrates that CXCL1 can transform NOFs into senescent CAFs via an autocrine mechanism. These data might contribute to further understanding of CAFs and to development of a potential therapeutic approach targeting cancer cells-CAFs interactions.

J Oral Pathol Med. 2018 Mar;47(3):268-274. doi: 10.1111/jop.12670. Epub 2018 Jan 22.Proinflammatory cytokines as serum biomarker in oral carcinoma-A prospective multi-biomarker approach.Schiegnitz E1, Kämmerer PW1, Schön H1, Blatt S1, Berres M2,3, Sagheb K1, Al-Nawas B1.

Inflammation and cell-mediated immunity have a key role in different stages of carcinogenesis. The aim of this prospective study was to assess serum levels of proinflammatory cytokines interleukin-6 (IL-6), interleukin-8 (IL-8), soluble interleukin-2 receptor (sIL-2R), tumor necrosis factor alpha (TNF-α), and MHC class I polypeptide-related sequence B (MICB) in patients with oral premalignant lesion (OPL), oral squamous cell carcinoma (OSCC), and healthy controls in a multi-biomarker approach as a potential diagnostic and prognostic tool for OSCC.A total of 205 patients (81 with OSCC, 75 with OPL, and 49 healthy controls) were included in this prospective study. Cytokine concentrations were measured by commercial enzyme linked immunoassay and chemiluminescence immunoassay.IL-6, IL-8, and sIL-2R were significantly elevated in OSCC patients compared to healthy controls and to OPL patients. Higher T-Grade (>T2) and positive lymph node involvement resulted in significantly higher IL-6 values (P < .001 and P = .037). IL-6 serum values ≥5 pg/mL (n = 45) and sIL-2R serum values ≥623 U/mL (n = 19) indicated a significant lower survival rate compared to OSCC patients with low IL-6 (n = 36) and sIL-2R values (n = 62, P = .023 and P = .026). ROC and classification tree analyses identified the combination of IL-6 and IL-8 as diagnostic markers with good diagnostic accuracy.In conclusion, IL-6, IL-8, and sIL-2R are strongly associated with OSCC oncogenesis and IL-6 and sIL-2R seem to be promising and potent biomarkers for evaluating patients’ prognosis.

Oncotarget. 2017 Nov 1;8(59):100339-100352. doi: 10.18632/oncotarget.22225. eCollection 2017 Nov 21.Endothelial-derived interleukin-6 induces cancer stem cell motility by generating a chemotactic gradient towards blood vessels.Kim HS1, Chen YC2,3, Nör F1,4, Warner KA1, Andrews A1, Wagner VP4,5, Zhang Z1, Zhang Z2, Martins MD4,5, Pearson AT1,6,3, Yoon E2,7, Nör JE1,3,7,8.

Recent evidence suggests that the metastatic spread of head and neck squamous cell carcinomas (HNSCC) requires the function of cancer stem cells endowed with multipotency, self-renewal, and high tumorigenic potential. We demonstrated that cancer stem cells reside in perivascular niches and are characterized by high aldehyde dehydrogenase (ALDH) activity and high CD44 expression (ALDHhighCD44high) in HNSCC. Here, we hypothesize that endothelial cell-secreted interleukin-6 (IL-6) contributes to tumor progression by enhancing the migratory phenotype and survival of cancer stem cells. Analysis of tissue microarrays generated from the invasive fronts of 77 HNSCC patients followed-up for up to 11 years revealed that high expression of IL-6 receptor (IL-6R) (p=0.0217) or co-receptor gp130 (p=0.0422) correlates with low HNSCC patient survival. We observed that endothelial cell-secreted factors induce epithelial to mesenchymal transition (EMT) and enhance invasive capacity of HNSCC cancer stem cells. Conditioned medium from CRISPR/Cas9-mediated IL-6 knockout primary human endothelial cells is less chemotactic for cancer stem cells in a microfluidics-based system than medium from control endothelial cells (p<0.05). Blockade of the IL-6 pathway with a humanized anti-IL-6R antibody (tocilizumab) inhibited endothelial cell-induced motility in vitro and decreased the fraction of cancer stem cells in vivo. Notably, xenograft HNSCC tumors vascularized with IL-6-knockout endothelial cells exhibited slower tumor growth and smaller cancer stem cell fraction. These findings demonstrate that endothelial cell-secreted IL-6 enhances the motility and survival of highly tumorigenic cancer stem cells, suggesting that endothelial cells can create a chemotactic gradient that enables the movement of carcinoma cells towards blood vessels.

Int J Oral Maxillofac Surg. 2017 Nov 27. pii: S0901-5027(17)31675-2. doi: 10.1016/j.ijom.2017.09.016. [Epub ahead of print]Evaluation of saliva and plasma cytokine biomarkers in patients with oral squamous cell carcinoma.Lee LT1, Wong YK2, Hsiao HY1, Wang YW1, Chan MY3, Chang KW4.

The aim of this study was to investigate potential biomarkers in human saliva and plasma to aid in the early diagnosis of oral squamous cell carcinoma (OSCC). Saliva and plasma samples obtained from OSCC patients (n=41) and non-oral cancer patients (n=24) were analyzed by Luminex Bead-based Multiplex Assay. Data were analyzed using the non-parametric Mann-Whitney U-test, Kruskal-Wallis test, and receiver operating characteristics curve (ROC) to evaluate the predictive power of 14 biomarkers individually for OSCC diagnosis. The plasma level of IP-10 in early OSCC differed significantly from that in controls. Among the salivary biomarkers, IL-1β, IL-6, IL-8, MIP-1β, eotaxin and IFN-γ and TNF-α showed significant differences between OSCC patients and controls. With respect to carcinogenesis, significant differences in plasma levels of eotaxin, G-CSF, and IL-6 were found between OSCC stages III/IV and OSCC stages I/II. The area under the curve (AUC) for OSCC vs. control was greater than 0.7 for plasma IP-10 and saliva IL-1β, IL-6, IL-8, and TNF-α. The study findings indicate that salivary biomarkers may serve a useful role as a complementary adjunct for the early detection of oral OSCC. With regard to the evaluation of tumour progression, plasma eotaxin, G-CSF, and IL-6 may help in the detection of advanced OSCC. However, the correlation between saliva and plasma biomarkers in OSCC was weak.

Cell Mol Biol (Noisy-le-grand). 2017 Oct 31;63(10):131-136. doi: 10.14715/cmb/2017.63.10.21.Interleukin-6 secreted by oral cancer- associated fibroblast accelerated VEGF expression in tumor and stroma cells.Mirkeshavarz M1, Ganjibakhsh M2, Aminishakib P3, Farzaneh P2, Mahdavi N1, Vakhshiteh F2, Karimi A4, Gohari NS2, Kamali F5, Kharazifard MJ3, Shahzadeh Fazeli SA2, Nasimian A2.

Oral cancer represents the sixth most common cancer type worldwide. Patients with oral cancer express high levels of IL-6 which is associated with very poor prognosis. Previous studies illustrated that IL-6 cytokine induces angiogenesis. It has also been reported that the presence of Cancer- Associated Fibroblasts (CAFs) is essential for angiogenesis. In this study, we examined the correlation between IL-6 and CAF and the role of this correlation on VEGF production. In this study, quantitative expression level of IL-6 and VEGF in CAF and Oral Cancer Cells (OCCs) examined through Real Time PCR and ELISA and western blot analysis. In addition, maintenance and retention of IL-6 and VEGF checked out in co-culture experiment of CAF and OCC cells. These experiments demonstrated that in oral cancer, CAF cell line secretes significantly more IL-6 than OCC. Also IL-6 is a factor that causes VEGF secretion in CAF cell line. CAF is the basic and the most essential source for producing IL-6 in patients with oral cancer. Secreted IL-6 is able to induce VEGF production in both CAF and OCCs. Correlation between CAF, IL-6 and VEGF could be considered as an approach for cancer therapy.

Oncotarget. 2017 Jul 31;8(41):70422-70430. doi: 10.18632/oncotarget.19711. eCollection 2017 Sep 19.GMI ablates cancer stemness and cisplatin resistance in oral carcinomas stem cells through IL-6/Stat3 signaling inhibition.Wang TY1, Yu CC1,2,3, Hsieh PL3, Liao YW1, Yu CH1,2, Chou MY1,2.

Cancer stem cells (CSCs) have been identified to exert tumor-initiating ability, resulting in the recurrence, metastasis and chemoresistance of oral squamous cell carcinomas. In the present study, we showed that GMI, an immunomodulatory protein from Ganoderma microsporum, induc ed a cytotoxic effect in oral carcinomas stem cells (OCSCs). Treatment of GMI dose-dependently inhibited the expression of CSC markers, including ALDH1 activity and CD44 positivity. Moreover, GMI suppressed the self-renewal property, colony formation, migration, and invasion abilities as well as potentiated chemo-sensitivity in OCSCs. Our results suggested that the tumor suppressive effect of GMI was mediated through inhibition of IL-6/Stat3 signaling pathway. Furthermore, tumor growth was reduced in mice bearing xenograft tumors after oral administration of GMI. Taken together, we demonstrated the anti-CSC effect of GMI in oral cancer and GMI may serve as a natural cisplatin adjuvant to prevent cancer recurrence.

Stem Cells. 2017 Sep;35(9):2083-2094. doi: 10.1002/stem.2666. Epub 2017 Jul 31.Mesenchymal Stromal Cell-Derived Interleukin-6 Promotes Epithelial-Mesenchymal Transition and Acquisition of Epithelial Stem-Like Cell Properties in Ameloblastoma Epithelial Cells.Jiang C1,2,3, Zhang Q1, Shanti RM1,4,5, Shi S1, Chang TH1, Carrasco L1,4, Alawi F6, Le AD1,4.

Epithelial-mesenchymal transition (EMT), a biological process associated with cancer stem-like or cancer-initiating cell formation, contributes to the invasiveness, metastasis, drug resistance, and recurrence of the malignant tumors; it remains to be determined whether similar processes contribute to the pathogenesis and progression of ameloblastoma (AM), a benign but locally invasive odontogenic neoplasm. Here, we demonstrated that EMT- and stem cell-related genes were expressed in the epithelial islands of the most common histologic variant subtype, the follicular AM. Our results revealed elevated interleukin (IL)-6 signals that were differentially expressed in the stromal compartment of the follicular AM. To explore the stromal effect on tumor pathogenesis, we isolated and characterized both mesenchymal stromal cells (AM-MSCs) and epithelial cells (AM-EpiCs) from follicular AM and demonstrated that, in in vitro culture, AM-MSCs secreted a significantly higher level of IL-6 as compared to the counterpart AM-EpiCs. Furthermore, both in vitro and in vivo studies revealed that exogenous and AM-MSC-derived IL-6 induced the expression of EMT- and stem cell-related genes in AM-EpiCs, whereas such effects were significantly abrogated either by a specific inhibitor of STAT3 or ERK1/2, or by knockdown of Slug gene expression. These findings suggest that AM-MSC-derived IL-6 promotes tumor-stem like cell formation by inducing EMT process in AM-EpiCs through STAT3 and ERK1/2-mediated signaling pathways, implying a role in the etiology and progression of the benign but locally invasive neoplasm. Stem Cells 2017;35:2083-2094.

J Biol Regul Homeost Agents. 2017 Apr-Jun;31(2):263-267.Mast cell, pro-inflammatory and anti-inflammatory: Jekyll and Hyde, the story continues.Conti P1, Caraffa Al2, Kritas SK3, Ronconi G4, Lessiani G5, Toniato E6, Theoharides TC7.

IL-1 family members include inflammatory and anti-inflammatory cytokines. They can be beneficial or detrimental, not only in cancer, but also in inflammatory conditions. Mast cells (MCs) originate from CD34+/CD117+/CD13+ pluripotent hematopoietic stem cells, express c-Kit receptor (c-Kit-R), which regulates the proliferation and sustain the survival, differentiation and maturation of MCs. They are immune cells involved in innate and adaptive immunity, allergy, autoimmunity, cancer and inflammation. MCs along with T cells and macrophages release interleukin (IL)-10, which is a pleiotropic immunoregulatory cytokine with multiple biological effects. IL-10 inhibits Th1 inflammatory cells, in particular TNF mostly generated by macrophages and MCs, and down-regulates IFN-γ, IL-1 and IL-6. IL-37 is a family member cytokine which binds IL-18 receptor α chain and inhibits inflammatory mediators including TNF, IL-1, IL-6, IL-33 and nitric oxide (NO). IL-37 similar to IL-10 inhibits MC inflammatory cytokines in several disorders, including asthma, allergy, arthrtitis and cancer. Here we report a study comparing IL-10 with IL-37, two anti-inflammatory cytokines.

Pak J Pharm Sci. 2017 May;30(3):817-823.Detection of interleukins-6 and 8 in saliva as potential biomarkers of oral pre-malignant lesion and oral carcinoma: A breakthrough in salivary diagnostics in Pakistan.Khyani IAM1, Qureshi MA2, Mirza T2, Farooq MU1.

Oral cancer is at rise in our population due to increasing use of areca nut (Betel nut) with or without tobacco. It is the second frequent malignant tumour for both the gender in Pakistan. This non-interventional case control study was carried out with the aim to explore saliva as diagnostic medium for detecting interleukins (IL) 6 and 8 as biomarkers of pre-malignant lesions (PML) and oral carcinoma. Total 105 subjects were recruited and were divided into three groups “A”, “B” and “C” each comprising of 35 subjects. Group “A” comprised of cases with strong clinical evidence of oral PML. Group “B” constitute clinical and histologically proven OSCC and group “C” include disease free subjects as controls. Saliva from all the recruited subjects was procured by drooling method and stored at-200C before further process. All the collected samples were centrifuged at 4500 rpm for 15 minutes at 4oC. Supernatant fluid was used in ELISA for detection and quantification of IL-6 & IL-8. Data was analysed by using Chi-square test and multivariate analysis was done by non-parametric test. P-value of 0.05 was taken as standard reference. Significant co-relation was found for qualitative salivary detection of IL-6 and IL-8 among the groups (P<0.001 and <0.0001 respectively). Regarding quantitative salivary concentration of leukotrienes, no significant co-relation was found in levels of IL-6 among the groups while there was significant association of IL-8 levels between the groups (P<0.0001).On post Hoc multiple comparison, significant co-relation was found among oral PML group and controls (P=0.001) and OSCC group and control (P=<0.0001). In conclusion salivary detection of IL-6 & IL-8 could be used as probable biomarker for early detection of oral PML & OSCC in etiologically distinct population of Pakistan.

Oral Oncol. 2017 Jun;69:38-45. doi: 10.1016/j.oraloncology.2017.03.011. Epub 2017 Apr 9.IL6 is associated with response to dasatinib and cetuximab: Phase II clinical trial with mechanistic correlatives in cetuximab-resistant head and neck cancer.Stabile LP1, Egloff AM2, Gibson MK3, Gooding WE4, Ohr J5, Zhou P6, Rothenberger NJ1, Wang L6, Geiger JL5, Flaherty JT5, Grandis JR7, Bauman JE8.

Src family kinase (SFK) activation circumvents epidermal growth factor receptor (EGFR) targeting in head and neck squamous cell carcinoma (HNSCC); dual SFK-EGFR targeting could overcome cetuximab resistance.We conducted a Simon two-stage, phase II trial of the SFK inhibitor, dasatinib, and cetuximab in biomarker-unselected patients with cetuximab-resistant, recurrent/metastatic HNSCC. Pre- and post-treatment serum levels of interleukin-6 (IL6) were measured by ELISA. HNSCC cell lines were assessed for viability and effects of IL6 modulation following dasatinib-cetuximab treatment.In the first stage, 13 patients were evaluable for response: 7 had progressive and 6 had stable disease (SD). Enrollment was halted for futility, and biomarker analysis initiated. Low serum IL6 levels were associated with SD (raw p=0.028, adjusted p=0.14) and improved overall survival (p=0.010). The IL6 classifier was validated in a separate trial of the same combination, but was unable to segregate survival risk in a clinical trial of cetuximab and bevacizumab suggesting serum IL6 may be specific for the dasatinib-cetuximab combination. Enhanced in vitro HNSCC cell death was observed with dasatinib-cetuximab versus single agent treatment; addition of IL6-containing media abrogated this effect.Clinical benefit and overall survival from the dasatinib-cetuximab combination were improved among patients with low serum IL6. Preclinical studies support IL6 as a modifier of dasatinib-cetuximab response. In the setting of clinical cetuximab resistance, serum IL6 is a candidate predictive marker specific for combined dasatinib-cetuximab. The trial was modified and redesigned as a biomarker-enriched Phase II study enrolling patients with undetectable IL6.

PLoS One. 2017 May 18;12(5):e0177282. doi: 10.1371/journal.pone.0177282. eCollection 2017.Proteomics investigation of OSCC-specific salivary biomarkers in a Hungarian population highlights the importance of identification of population-tailored biomarkers.

Csősz É1, Lábiscsák P1, Kalló G1, Márkus B1, Emri M2, Szabó A3, Tar I4, Tőzsér J1, Kiss C5, Márton I4.

Oral squamous cell carcinoma (OSCC) accounting for about 90% of malignant oral lesions is the 6th most common malignancy worldwide. Diagnostic delay may contribute to dismal survival rate therefore, there is a need for developing specific and sensitive biomarkers to improve early detection. Hungarian population occupies the top places of statistics regarding OSCC incidence and mortality figures therefore, we aimed at finding potential salivary protein biomarkers suitable for the Hungarian population. In this study we investigated 14 proteins which were previously reported as significantly elevated in saliva of patients with OSCC. In case of IL-1α, IL-1β, IL-6, IL-8, TNF-α and VEGF a Luminex-based multiplex kit was utilized and the salivary concentrations were determined. In case of catalase, profilin-1, S100A9, CD59, galectin-3-bindig protein, CD44, thioredoxin and keratin-19, SRM-based targeted proteomic method was developed and the relative amount of the proteins was determined in the saliva of patients with OSCC and controls. After several rounds of optimization and using stable isotope-containing peptides, we developed an SRM-based method for rapid salivary protein detection. The validation of the selected potential biomarkers by ELISA revealed salivary protein S100A9 and IL-6 as useful protein biomarkers for OSCC detection improving the diagnostic accuracy for OSCC in the Hungarian population.A noninvasive diagnostic method to detect biomarkers useful for the early diagnosis of OSCC was developed. This can be an attractive strategy in screening saliva samples collected in a nation-wide multi-centric study in order to decrease morbidity, mortality, to enhance survival rate and to improve quality of life. The heterogeneity of protein biomarkers found in different ethnic groups presented in the literature highlights the importance of identification of population-tailored protein biomarkers.

Oncol Lett. 2017 Apr;13(4):2297-2303. doi: 10.3892/ol.2017.5703. Epub 2017 Feb 8.Variation and significance of secretory immunoglobulin A, interleukin 6 and dendritic cells in oral cancer.Zhang S1, Zhang X1, Yin K1, Li T1, Bao Y1, Chen Z1.

The present study aimed to determine changes in the concentration of secretory immunoglobulin A (SIgA) and interleukin 6 (IL-6) in the saliva of patients with oral cancer, to evaluate the abnormal expression of cluster of differentiation (CD) 1a, CD83, CD80 and CD86 on dendritic cells (DCs) of oral cancer tissues and to discuss the interaction between SIgA, IL-6 and DCs in oral cancer. A total of 40 patients between 27 and 70 years of age, median age 52 years, with primary oral cancer were enrolled in the present study, and a group of 20 healthy male and female volunteers was used as the control group. The concentration of SIgA and IL-6 in the saliva of the preoperative patients was determined by ELISA. The expression levels of CD1a, CD83, CD80 and CD86 were detected by immunohistochemistry and flow cytometry, which was performed on histopathological sections from paraffin-embedded tumor and corresponding adjacent control tissues. The specimens were assessed using the semi-quantitative immunoreactive score (IRS). The concentration of SIgA in the saliva from patients with oral cancer decreased, whereas the IL-6 level significantly increased compared with the control subjects (P<0.05). In addition, the decrease of SIgA level and increase of IL-6 level exhibited a negative correlation (r=-0.543, P<0.05). According to the IRS score, the expression levels of CD1a, CD83, CD80 and CD86 in the cancer tissue were lower than the expression levels of the control group (P<0.05). Furthermore, the expression of CD80 and CD86 exhibited no correlation with histological grade or pathological type (P>0.05), but exhibited a negative correlation with clinical stage and lymph node metastasis (P<0.05). The concentration of SIgA and IL-6 in saliva may be used as an auxiliary diagnostic indicator for oral cancer. The detection of CD80 and CD86 expressed on DCs in oral cancer tissue may be useful for the diagnosis and evaluation of the prognosis of tumors. The present study hypothesized that the use of SIgA vaccines or IL-6 inhibitors may be useful for reversing the immune deficiency associated with DCs in oral cancer.

Diagnostics (Basel). 2017 Apr 9;7(2). pii: E21. doi: 10.3390/diagnostics7020021.Salivary IL-8, IL-6 and TNF-α as Potential Diagnostic Biomarkers for Oral Cancer.Sahibzada HA1, Khurshid Z2, Khan RS3, Naseem M4, Siddique KM5, Mali M6, Zafar MS7,8.

Saliva has been useful as a liquid biopsy for the diagnosis of various oral or systemic diseases, and oral squamous cell carcinoma (OSCC) is no exception. While its early detection and prevention is important, salivary cytokines expression, specifically of Interleukin-8 (IL-8), Interleukin-6 (IL-6) and Tumor necrosis factor (TNF-α), does contribute to the pathogenesis of cancer and these cytokines serve as potential biomarkers. Their excessive production plays a role in cancer progression and establishment of angiogenesis. However, other inflammatory or immunological conditions may affect the levels of cytokines in saliva. This article reviews the expression of levels of specific cytokines i.e., IL-8, IL-6 and TNF-α, their signaling pathways in the development of oral cancer, and how they are essential for the diagnosis of OSCC and updates related to it. Apart from serum, the saliva-based test can be a cost-effective tool in the follow-up and diagnosis of OSCC. Moreover, large-scale investigations are still needed for the validation of salivary cytokines.

Diagn Pathol. 2017 Apr 5;12(1):32. doi: 10.1186/s13000-017-0623-6.Role of tumour-associated macrophages in oral squamous cells carcinoma progression: an update on current knowledge.Petruzzi MN1,2, Cherubini K3,4, Salum FG3,4, de Figueiredo MA3,4.

Oral squamous cell carcinoma (OSCC) accounts over 90% of malignant neoplasms of the oral cavity. This pathological entity is associated to a high mortality rate that has remained unchanged over the past decades. Tumour-associated macrophages (TAMs) are believed to have potential involvement in OSCC progression. However, the molecular networks involved in communication between stroma and cancer cells have not yet been fully elucidated.The role of M2 polarized cells in oral carcinogenesis is supported by a correlation between TAMs accumulation into OSCC stroma and poor clinical outcome. Signalling pathways such as the NF-κB and cytokines released in the tumour microenvironment promote a bidirectional cross-talk between M2 and OSCC cells. These interactions consequently result in an increased proliferation of malignant cells and enhances aggressiveness, thus reducing patients’ survival time.Here, we present a comprehensive review of the role of interleukin (IL)-1, IL-4, IL-6, IL-8, IL-10 and the receptor tyrosine kinase Axl in macrophage polarization to an M2 phenotype and OSCC progression. Understanding the molecular basis of oral carcinogenesis and metastatic spread of OSCC would promote the development of targeted treatment contributing to a more favourable prognosis.

Arch Oral Biol. 2017 Jun;78:129-134. doi: 10.1016/j.archoralbio.2017.02.012. Epub 2017 Feb 10.Increased tumor-infiltrating plasmacytoid dendritic cells predicts poor prognosis in oral squamous cell carcinoma.Han N1, Zhang Z2, Liu S1, Ow A3, Ruan M4, Yang W1, Zhang C1.

Accumulating evidence suggests that plasmacytoid dendritic cells (pDC) have a dual role not only in initiating anti-tumor immune responses but also in inducing immune tolerance to facilitate cancer development. The aim of this study was to investigate the distribution and function of tumor-infiltrating pDCs in primary oral squamous cell carcinoma (OSCC) and their relation to patient outcome.The distribution of pDCs in 10 normal oral mucosa and 60 OSCC tissues was detected by immunohistochemistry. The population of pDCs in six OSCC patients and six healthy donors was evaluated by flow cytometry. The relationship between tumor-infiltrating pDCs and clinicopathological data and patient outcome was analyzed accordingly. The capacity of pDCs to produce cytokines, such as IFN-α, IL-6, IL-8 and TNF-α in response to TLR-9 ligands (CpG-ODN) was measured by ELISA.PDCs were detected at high levels in 38.3% of the OSCC tissues, primarily in the stroma, but were absent in normal oral mucosa. The frequency of pDCs in OSCC tissue was significantly higher than that observed in normal oral mucosa. However, the distribution and population of circulating pDCs was similar between healthy donors and OSCC patients. Kaplan-Meier analysis revealed a significant association of increasing number of tumor-infiltrating pDCs with lymph node metastasis and overall survival. Multivariate analysis confirmed that high levels of tumor-infiltrating pDCs was an independent prognostic factor. Further cytokine analysis revealed a decreased secretion of IFN-α, IL-6 and TNF-α, which indicated an impaired function of tumor-infiltrating pDCs.The increased number of tumor-infiltrating pDCs correlates with an adverse outcome in primary OSCC patients. This finding is not only suggestive of the contribution of pDCs in the progression of oral cancer but also presents an opportunity and a new target for OSCC immune therapy in oral cancer management.

Cancer Res. 2017 May 1;77(9):2279-2291. doi: 10.1158/0008-5472.CAN-16-2446. Epub 2017 Feb 24.Soluble IL6R Expressed by Myeloid Cells Reduces Tumor-Specific Th1 Differentiation and Drives Tumor Progression.Tsukamoto H1, Fujieda K2,3, Hirayama M4, Ikeda T5, Yuno A4, Matsumura K2, Fukuma D4, Araki K6, Mizuta H3, Nakayama H4, Senju S2, Nishimura Y1.

IL6 produced by tumor cells promotes their survival, conferring a poor prognosis in patients with cancer. IL6 also contributes to immunosuppression of CD4+ T cell-mediated antitumor effects. In this study, we focused on the impact of IL6 trans-signaling mediated by soluble IL6 receptors (sIL6R) expressed in tumor-bearing hosts. Higher levels of sIL6R circulating in blood were observed in tumor-bearing mice, whereas the systemic increase of sIL6R was not prominent in tumor-bearing mice with myeloid cell-specific conditional deletion of IL6R even when tumor cells produced sIL6R. Abundant sIL6R was released by CD11b+ cells from tumor-bearing mice but not tumor-free mice. Notably, IL6-mediated defects in Th1 differentiation, T-cell helper activity for tumor-specific CD8+ T cells, and downstream antitumor effects were rescued by myeloid-specific deletion of sIL6R. Expression of the T-cell transcription factor c-Maf was upregulated in CD4+ T cells primed in tumor-bearing mice in an IL6-dependent manner. Investigations with c-Maf loss-of-function T cells revealed that c-Maf activity was responsible for IL6/sIL6R-induced Th1 suppression and defective T-cell-mediated antitumor responses. In patients with cancer, myeloid cell-derived sIL6R was also possibly associated with Th1 suppression and c-Maf expression. Our results argued that increased expression of sIL6R from myeloid cells and subsequent c-Maf induction were adverse events for counteracting tumor-specific Th1 generation. Overall, this work provides a mechanistic rationale for sIL6R targeting to improve the efficacy of T-cell-mediated cancer immunotherapy.

Asian Pac J Cancer Prev. 2016 Nov 1;17(11):4899-4906.Salivary and Serum Interleukin-6 Levels in Oral Premalignant Disorders and Squamous Cell Carcinoma: Diagnostic Value and Clinicopathologic CorrelationsDineshkumar T1, Ashwini BK, Rameshkumar A, Rajashree P, Ramya R, Rajkumar K.

To assess the diagnostic utility of serum and salivary interleukin 6 (IL-6) levels in the differential diagnosis of potentially malignant lesions and conditions (PMLs/PMCs) and oral squamous cell carcinoma (OSCC) in a high oral cancer prevalence region.After appropriate ethical clearance and informed consent, salivary and blood samples were collected from 100 participants in each group (OSCC, PMLs, and healthy controls). Serum and salivary IL-6 levels were measured by enzyme-linked immunosorbent assay and data were subjected to appropriate statistical analysis.Significant differences in IL-6 concentration were noted between OSCC and PML/C patients in both serum and saliva, with salivary levels being 2 to 3 fold higher than serum values in all the groups. Receiver operating characteristic curve analysis demonstrated 96% specificity and 99% sensitivity for salivary IL-6 in differentiating PML from OSCC.The results of the present study suggest that the pro-inflammatory cytokine, IL-6, is elevated in the saliva of patients with OSSC compared to PMD and controls, and thus may prove to have diagnostic and/or prognostic significance.

 

Neuropsychiatr Dis Treat. 2016 Oct 27;12:2789-2795. eCollection 2016.Production of inflammatory cytokines, cortisol, and Aβ1-40 in elderly oral cancer patients with postoperative delirium.Sun L1, Jia P2, Zhang J2, Zhang X2, Zhang Y2, Jiang H1, Jiang W2, Guo Y2.

Pathophysiological disorders after surgery might be related to postoperative delirium (POD). This study was designed to elucidate the pathogenesis of POD in elderly oral cancer patients by determining the perioperative kinetics of inflammatory cytokines, cortisol, and amyloid β1-40 (Aβ1-40).A total of 257 elderly oral cancer patients who underwent tumor resection surgery were selected. Venous blood was collected prior to surgery (T0), at the end of surgery (T1), and at 12 hours after surgery (T2). During the first three postoperative days, patients were examined using the confusion assessment method twice a day (8 am and 8 pm). Mini-Mental State Examination scores were recorded at T0 and on postoperative days 1, 3, and 7. Ultimately, 56 patients suffering from POD made up the POD group, and 56 patients randomly selected from a cohort of patients without POD were allocated to the no POD (NPOD) group. Subsequently, interleukin-6, C-reactive protein, procalcitonin, cortisol, and Aβ1-40 in plasma from the two groups were measured.The two groups displayed comparable basic characteristics. There were no differences in all tested biomarkers between the two groups at T0. However, after surgery, the biomarker levels displayed distinct patterns between the two groups. The peak levels of all biomarkers were higher in the POD group than in the NPOD group. Conversely, the Mini-Mental State Examination scores after surgery were lower in the POD group than in the no POD group.The boost of inflammatory cytokines, cortisol, and Aβ1-40 after surgery might be involved in POD onset among elderly oral cancer patients. POD was accompanied by progressive cognitive deficiency.

Oncotarget. 2016 Dec 6;7(49):81305-81321. doi: 10.18632/oncotarget.12874.Signal regulatory protein α associated with the progression of oral leukoplakia and oral squamous cell carcinoma regulates phenotype switch of macrophages.Ye X1, Zhang J1,2, Lu R1,2, Zhou G1,2.

Signal regulatory protein α (SIRPα) is a cell-surface protein expressed on macrophages that are regarded as an important component of the tumor microenvironment. The expression of SIRPα in oral leukoplakia (OLK) and oral squamous cell carcinoma (OSCC), and further explored the role of SIRPα on the phenotype, phagocytosis ability, migration, and invasion of macrophages in OSCC were investigated. The expression of SIRPα in OLK was higher than in OSCC, correlating with the expression of CD68 and CD163 on macrophages. After cultured with the conditioned media of oral cancer cells, the expression of SIRPα on THP-1 cells was decreased gradually. In co-culture system, macrophages were induced into M2 phenotype by oral cancer cells. Blockade of SIRPα inhibited phagocytosis ability and IL-6, TNF-α productions of macrophages. In addition, the proliferation, migration, and IL-10, TGF-β productions of macrophages were upregulated after blockade of SIRPα. Macrophages upregulated the expression of SIRPα and phagocytosis ability, and inhibited the migration and invasion when the activation of NF-κB was inhibited by pyrrolidine dithiocarbamate ammonium (PDTC). Hence, SIRPα might play an important role in the progression of OLK and oral cancer, and could be a pivotal therapeutic target in OSCC by regulating the phenotype of macrophages via targeting NF-κB.

 

 

Pathol Oncol Res. 2017 Apr;23(2):425-431. doi: 10.1007/s12253-016-0134-x. Epub 2016 Oct 15.Clinical Roles of Interleukin-6 and STAT3 in Oral Squamous Cell Carcinoma.Shinagawa K1, Yanamoto S2, Naruse T1, Kawakita A1, Morishita K1, Sakamoto Y1, Rokutanda S1, Umeda M1.

The effect inflammation has on cancer prognosis is marked by the presence of cytokines and chemokines. Interleukin-6 (IL-6) is one a multifunctional cytokine that regulates inflammatory responses. We investigated the roles of IL-6 and STAT3 and examined the relationship between IL-6 signaling and clinicopathological factors in patients with oral squamous cell carcinoma (OSCC). We retrospectively examined 116 patients who underwent radical surgery for OSCC. IL-6 and STAT3 expression were detected by immunohistochemistry. IL-6 and STAT3 positivity were detected by IHC, at 78.4 and 80.2 %, respectively. IL-6 expression was significantly associated with pattern of invasion (P = 0.004), vascular invasion (P = 0.003), and pathological nodal status (P = 0.019). Multivariate logistic regression analysis revealed that IL-6 expression was significantly associated with vascular invasion (P = 0.044). Meanwhile, there was no significant association between STAT3 expression and clinicopathological factors and no significant relationship between IL-6 and STAT3 expression. IL-6 expression was significantly associated with 5-year disease-free survival. These results suggest that IL-6 is involved in lymphangiogenesis and recurrence in OSCC.

J Formos Med Assoc. 2016 Dec;115(12):1032-1038. doi: 10.1016/j.jfma.2016.08.009. Epub 2016 Oct 11.Chemotherapeutic effects of luteolin on radio-sensitivity enhancement and interleukin-6/signal transducer and activator of transcription 3 signaling repression of oral cancer stem cells.Tu DG1, Lin WT2, Yu CC3, Lee SS4, Peng CY5, Lin T6, Yu CH7.

Previously, we successfully identified oral cancer stem cells (OCSC) displaying enhanced stemness and tumorigenic potentials. In the study, we investigated the chemotherapeutic effect of the flavonoid luteolin, commonly found in fruits and vegetables, on targeting OCSC.Oralspheres was applied to isolate OCSC. aldehyde dehydrogenase 1 activity and CD44 positivity of OCSC with luteolin treatment were assessed by flow cytometry analysis. Radio-sensitivity of OCSC treated with luteolin was examined. Invasion and colony-forming assays were performed to assess oncogenicity in OCSC. The expression of interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) was examined by enzyme-linked immunosorbent assay and western blot analysis.We showed that luteolin effectively inhibited the proliferation rate, self-renewal, aldehyde dehydrogenase 1 activity, and CD44 positivity of OCSC but did not cause significant cytotoxicity of normal epithelial cells. Moreover, luteolin restored radio-sensitivity in OCSC. Combined treatment with luteolin and radiation displayed synergistic effect on invasiveness and clonogenicity of OCSC. Mechanistically, treatment of luteolin resulted in inactivation of IL-6/STAT3 signaling.These results suggest that combined treatment of luteolin and radiation therapy can attenuate tumorigenicity of OCSC through IL-6/STAT3 signaling inactivation.

Br J Cancer. 2016 Nov 8;115(10):1234-1244. doi: 10.1038/bjc.2016.327. Epub 2016 Oct 13.IL-6 controls resistance to radiation by suppressing oxidative stress via the Nrf2-antioxidant pathway in oral squamous cell carcinoma.Matsuoka Y1, Nakayama H1, Yoshida R1, Hirosue A1, Nagata M1, Tanaka T1, Kawahara K1, Sakata J1, Arita H1, Nakashima H1, Shinriki S2,3, Fukuma D1, Ogi H1, Hiraki A4, Shinohara M1, Toya R5, Murakami R6.

In promoting tumour malignancy IL-6 signalling is considered to have an important role. However, the biological roles of IL-6 on radiosensitivity in oral squamous cell carcinoma (OSCC) remain largely unclear. The objective of this study is to determine the effects and molecular mechanisms of IL-6 on radiosensitivity in OSCC.Two OSCC cell lines, and OSCC tissue samples with radioresistant cells were used. We examined the effects of IL-6, or tocilizumab, a humanised anti-human IL-6 receptor antibody, or both on radiosensitivity and DNA damage after X-ray irradiation in vitro. In addition, we investigated the involvement of the Nrf2-antioxidant pathway in IL-6-mediated radioresistant mechanisms using OSCC cell lines and tissues.Increased levels of IL-6 suppressed radiation-induced cell death, and the blockade of IL-6 signalling by tocilizumab sensitised tumour cells to radiation. The radioresistant effect of IL-6 was associated with decreased DNA damage after radiation. We also found that IL-6 promotes the activation of not only the downstream molecule STAT3 but also the Nrf2-antioxidant pathway, leading to a significant decrease in oxidative stress by upregulating Mn-SOD.These results indicate that the blockade of IL-6 signalling combined with conventional radiotherapy could augment the treatment response and survival rate in patients with radioresistant OSCC.

Oral Surg Oral Med Oral Pathol Oral Radiol. 2016 Oct;122(4):483-490.e1. doi: 10.1016/j.oooo.2016.05.020. Epub 2016 Jun 9.Cytokines in saliva increase in head and neck cancer patients after treatment.Russo N1, Bellile E2, Murdoch-Kinch CA3, Liu M1, Eisbruch A4, Wolf GT5, D’Silva NJ6.

Approximately one-third of advanced head and neck squamous cell carcinomas (HNSCCs) recur within 2 years of treatment. Due to ease of collection, saliva is of interest to monitor changes that correlate with treatment. Previously this was a challenge due to xerostomia after conventional radiation. The emergence of gland-sparing radiation has made it possible to collect saliva post-treatment. This study investigated changes in cytokines in saliva pre- and post-treatment to provide foundational knowledge for future studies exploring the use of saliva to monitor treatment response.Pre- and post-treatment saliva was evaluated for 8 cytokines by multiplex assay and enzyme-linked immunosorbent assay.In oropharyngeal HNSCC, secretion of epidermal growth factor (EGF), GROα (Growth-regulated protein alpha), interleukin (IL)-1α, IL-β, IL-6, IL-8, tumor necrosis factor-α, and vascular endothelial growth factor increased significantly post-treatment. In additional patients, significant increases of GR-α and IL-6 were validated, but EGF showed no change.The uniqueness of this study is its comparison of salivary cytokines from HNSCC patients pre- and post-treatment.

Oncotarget. 2016 Jun 14;7(24):36539-36550. doi: 10.18632/oncotarget.9282.p70S6K promotes IL-6-induced epithelial-mesenchymal transition and metastasis of head and neck squamous cell carcinoma.Wu D1,2, Cheng J3, Sun G1, Wu S1, Li M1, Gao Z1, Zhai S1, Li P1, Su D4,5, Wang X1,4,6.

Head and neck squamous cell carcinoma (HNSCC) is the fifth most common cancer worldwide and a common cause of cancer-related death, with a 5-year survival rate of less than 60%. IL-6 has been suggested to play an important role in cancer metastasis, but its mechanism in HNSCC has not been fully clarified. p70S6K has been reported to induce epithelial-mesenchymal transition (EMT) of ovarian cancer, but its role in HNSCC remains unknown. In this study, we found that p70S6K and IL-6 were upregulated in high-metastatic HNSCC cell lines that underwent EMT when compared to paired low-metastatic cell lines. Overexpression of p70S6K promoted EMT and migration of HNSCC cells, while downregulation of p70S6K attenuated IL-6-induced EMT and cell migration. Furthermore, IL-6-induced p70S6K activation was attenuated by inhibitors of the PI3K/Akt/mTOR, MAPK/ERK, and JAK/STAT3 signaling pathways, suggesting that it located downstream of these pathways. These findings suggest that p70S6K promotes IL-6-induced EMT and metastasis of HNSCC. Targeting p70S6K for HNSCC therapy may benefit patients through the inhibition of tumor growth, as well as metastasis.

Oncol Rep. 2016 Jun;35(6):3265-74. doi: 10.3892/or.2016.4765. Epub 2016 Apr 20.Increased interleukin-6 expression is associated with poor prognosis and acquired cisplatin resistance in head and neck squamous cell carcinoma.Gao J1, Zhao S2, Halstensen TS1.

Increased expression of interleukin 6 (IL-6) is associated with poor prognosis and chemoresistance in many different carcinomas, but its role in head and neck squamous cell carcinoma (HNSCC) is still unsettled. Analyzing tumorous mRNA expression data from 399 HNSCC patients revealed that high IL-6 expression predicted poor prognosis. Similar tendency was observed in platinum treated patients, suggesting an IL-6 associated cisplatin resistance. IL-6 increase was also found in two in-house acquired cisplatin‑resistant HNSCC cell lines (both basaloid and conventional squamous cell carcinoma) by using microarray analysis. However, although the in-house acquired cisplatin-resistant cell lines had higher basal and markedly increased cisplatin-induced IL-6 expression, IL-6 did not mediate the cisplatin resistance as neither exogenous IL-6 nor IL-6R/gp130 inhibitors affected cisplatin sensitivity. Moreover, the IL-6/STAT3 pathway was impaired in the resistant cell lines, partly due to decreased IL-6R expression. Thus, high IL-6 expression correlated to poor prognosis and acquired cisplatin resistance, but it did not mediate cisplatin resistance in the HNSCC cell lines.

Med Oral Patol Oral Cir Bucal. 2016 Jan 1;21(1):e6-13.Expression of NF-κB and IL-6 in oral precancerous and cancerous lesions: An immunohistochemical study.Kamperos G1, Nikitakis N, Sfakianou A, Avgoustidis D, Sklavounou-Andrikopoulou A.

The purpose of this study was to evaluate the immunohistochemical expression of NF-κB and IL-6 in oral premalignant and malignant lesions and to investigate their possible correlation with the presence of subepithelial inflammation.Thirty two oral premalignant lesions, clinically compatible with leukoplakia or erythroplakia, were investigated. Microscopically, 11 of them showed hyperkeratosis and acanthosis (epithelial hyperplasia) and 21 showed dysplasia of varying degrees. Nine cases of OSCC and four control cases of normal oral mucosa were also included in the study. Immunohistochemical staining with NF-κB (p65) and IL-6 was performed. IL-6 and nuclear NF-κB staining were assessed as positive or negative. For cytoplasmic localization of NF-κB, a total score combining intensity and percentage of positive epithelial cells was additionally calculated. The presence of inflammation was also recorded.Intensity and total scores for NF-κΒ cytoplasmic immunostaining showed a statistically significant gradual increase from normal mucosa to OSCC (p=0.012 and p=0.026 respectively). Non-statistically significant increased NF-κΒ nuclear localization was detected in dysplasias and OSCCs. Positive statistical correlation was detected between the presence of inflammation and IL-6 expression (p=0.015). No correlation between NF-κΒ and IL-6 was detected.NF-κΒ is activated in the early stages of oral carcinogenesis. IL-6 may have an NF-κΒ-independent role, possibly through regulation of the inflammatory response.

Oral Surg Oral Med Oral Pathol Oral Radiol. 2015 Dec;120(6):751-60.e2. doi: 10.1016/j.oooo.2015.08.016. Epub 2015 Sep 5.Differences in sequential posttreatment salivary IL-6 levels between patients with and patients without locoregional recurrences of oral squamous cell carcinoma: Part III of a cohort study.Sato J1, Ohuchi M2, Wada M2, Ohga N3, Asaka T3, Yoshikawa K3, Miyakoshi M3, Hata H3, Satoh A4, Kitagawa Y5.

Sequential postoperative salivary interleukin-6 (IL-6) concentrations were examined in patients with oral squamous cell carcinoma (OSCC) who had early or late locoregional recurrences or those who did not.Twenty-seven consecutive patients with OSCC were originally included in the study. All patients underwent radical surgery. Four saliva samples were collected before (periods I and II) and after (periods III and IV) surgery, and IL-6 concentrations were measured.Although postoperative (period III: at the time of discharge) salivary IL-6 level was significantly higher in patients with early locoregional recurrence (P = .02) than in those without, no such relationships were observed for preoperative IL-6 concentrations (periods I and II). Postoperative (period IV: 24 months after surgery) IL-6 level was significantly higher in patients with late locoregional recurrence (P = .03) than in those without, but no such relationships were observed for IL-6 concentrations in periods I, II, and III.Sequential postoperative salivary IL-6 concentration may be a useful marker for diagnosis of early and late locoregional recurrence in OSCC.

 

VEGF, oral cancer

J Cancer Res Ther. 2018 Jan-Mar;14(2):421-427. doi: 10.4103/0973-1482.160908.Comparison of immunohistochemical expression of vascular endothelial growth factor and CD105 in oral squamous cell carcinoma: Its correlation with prognosis.Patil BR1, Bhat K2, Somannavar P3, Hosmani J3, Kotrashetti V3, Nayak R3.

Compare and correlate immunoexpression of vascular endothelial growth factor (VEGF) and CD105 in oral squamous cell carcinoma (OSCC), and correlate its expression with the prognosis of the patient.A retrospective study was carried out on total of 49 cases of OSCC. Detailed demographic and clinical data were obtained, and tissue sections were stained with hematoxylin and eosin to grade the tumor. Later each case was subjected for immunohistochemical analysis of CD105 and VEGF.All the cases showed positivity for both CD105 and VEGF but high expression was noted with CD105 compared to VEGF. Average microvascular density for CD105 was higher (69.5) in moderately differentiated squamous cell carcinoma (MDSCC) when compared to well differentiated squamous cell carcinoma (WDSCC) (52.16). When expression of CD105 and VEGF was compared in WDSCC and MDSCC, it was statistically insignificant. However when expression of CD105 and VEGF was compared with survival of the patient, survival rate was <2 years in CD105 and was statistically significant, but VEGF did not show any significant difference with survival rate.CD105 immunoexpression in OSCC predicts a poor outcome than VEGF. So it can be postulated that endoglin may have a particular role in the development of cancer and might be relatively more specific than commonly used endothelial markers for squamous cell carcinoma of the oral cavity.

Biochem Biophys Res Commun. 2018 Mar 4;497(2):583-590. doi: 10.1016/j.bbrc.2018.02.104. Epub 2018 Feb 17.TGF-β1/TβRII/Smad3 signaling pathway promotes VEGF expression in oral squamous cell carcinoma tumor-associated macrophages.Sun H1, Miao C1, Liu W1, Qiao X1, Yang W1, Li L2, Li C3.

Oral squamous cell carcinoma (OSCC) is the most common type of malignant cancer affecting the oral cavity. Tumor associated macrophages (TAMs) play a vital role in the initiation, progression and metastasis of OSCC. In this study, we investigated the correlation between macrophages and several clinical and pathological indicators, and we also explored how transforming growth factor-β1 (TGF-β1) effect on VEGF expression in TAMs. Seventy-two paraffin-embedded OSCC samples were collected. Association between macrophages density, micro vascular density (MVD) and clinical-pathological feature were explored by immunohistochemical staining. Western blot, ELISA and qRT-PCR were conducted to assess the VEGF expression in TAMs treated with or without neutralizing TGF-β1, TβRII and smad3 antibodies. Results showed that CD68+ macrophages were absent in normal tissues. Macrophages density was directly correlated to low pathological differentiation, late clinical staging and poor survival rate. MVD showed positive correlation with clinical staging and macrophages density. Furthermore, OSCC-associated macrophages expressed more VEGF than macrophages in healthy lymph nodes. However, when TGF-β1 or TβRII were neutralized or the Smad3 was inhibited, VEGF expression was down regulated as well. It is concluded that TGF-β1 could promote OSCC-associated macrophages to secrete more VEGF via TβRII/Smad3 signaling pathway. This result might explain the correlation between macrophages density and worse clinical-pathological condition.

 

PLoS One. 2017 Nov 17;12(11):e0187092. doi: 10.1371/journal.pone.0187092. eCollection 2017.Roles of VEGF-Flt-1 signaling in malignant behaviors of oral squamous cell carcinoma.Subarnbhesaj A1, Miyauchi M1, Chanbora C1, Mikuriya A1, Nguyen PT2, Furusho H1, Ayuningtyas NF1, Fujita M3, Toratani S4, Takechi M5, Niida S6, Takata T1.

Vascular endothelial growth factor (VEGF) is a highly specific signaling protein for vascular endothelial cells that plays a critical role in tumor growth and invasion through angiogenesis, and may contribute to cell migration and activation of pre-osteoclasts, osteoclasts and some tumor cells.We aimed to clarify the detailed roles of VEGF-Flt-1 signaling in bone invasion of oral squamous cell carcinoma (OSCC) cells.Forty-two (42) of 54 cases with gingival SCC (77.8%) strongly expressed VEGF, and had a significantly increased number of Flt-1+ osteoclasts (p<0.01) and more aggressive bone invasion (p<0.05). PlGF, a ligand of Flt-1, induced osteoclastogenesis in single culture of bone marrow cells (BMCs), and inhibition of Flt-1-signaling by VEGF tyrosine kinase inhibitor and It’s down stream (Akt and ERK1/2) inhibitos reduced osteoclastogenesis in PlGF-stimulated BMCs (p<0.01). In molecular level, PlGF stimulation significantly upregulated RANKL expression in Flt-1-expressing HSC2 cells via phosphorylation of Akt and ERK1/2. In the co-culture of VEGF-producing HSC2 cells and BMCs, number of TRAP-positive osteoclasts markedly increased (p<0.01). The osteoclastogenesis was significantly inhibited by RANKL-neutralizing antibody (p<0.01) as well as by VEGF tyrosine kinase inhibitor (p<0.01) and it’s downstream (Akt and ERK1/2) inhibitors (p<0.01, p<0.05, respectively).VEGF-Flt-1 signaling induces osteoclastogenesis in OSCC through two possible ways: 1) VEGF produced from OSCC cells can directly stimulate the Flt-1 pathway in preosteoclasts to induce migration to future bone resorbing area and differentiation into osteoclasts, and 2) VEGF-Flt-1 signaling upregulates RANKL expression in OSCC cells, which indirectly leads to osteoclast differentiation. Therefore, blocking of the VEGF-Flt-1 signaling may help inhibit bone invasion of OSCC.

Cell Mol Biol (Noisy-le-grand). 2017 Oct 31;63(10):131-136. doi: 10.14715/cmb/2017.63.10.21.Interleukin-6 secreted by oral cancer- associated fibroblast accelerated VEGF expression in tumor and stroma cells.

Mirkeshavarz M1, Ganjibakhsh M2, Aminishakib P3, Farzaneh P2, Mahdavi N1, Vakhshiteh F2, Karimi A4, Gohari NS2, Kamali F5, Kharazifard MJ3, Shahzadeh Fazeli SA2, Nasimian A2.

Oral cancer represents the sixth most common cancer type worldwide. Patients with oral cancer express high levels of IL-6 which is associated with very poor prognosis. Previous studies illustrated that IL-6 cytokine induces angiogenesis. It has also been reported that the presence of Cancer- Associated Fibroblasts (CAFs) is essential for angiogenesis. In this study, we examined the correlation between IL-6 and CAF and the role of this correlation on VEGF production. In this study, quantitative expression level of IL-6 and VEGF in CAF and Oral Cancer Cells (OCCs) examined through Real Time PCR and ELISA and western blot analysis. In addition, maintenance and retention of IL-6 and VEGF checked out in co-culture experiment of CAF and OCC cells. These experiments demonstrated that in oral cancer, CAF cell line secretes significantly more IL-6 than OCC. Also IL-6 is a factor that causes VEGF secretion in CAF cell line. CAF is the basic and the most essential source for producing IL-6 in patients with oral cancer. Secreted IL-6 is able to induce VEGF production in both CAF and OCCs. Correlation between CAF, IL-6 and VEGF could be considered as an approach for cancer therapy.

 

 

Br J Cancer. 2017 Sep 26;117(7):1007-1016. doi: 10.1038/bjc.2017.249. Epub 2017 Aug 3.The interplay of matrix metalloproteinase-8, transforming growth factor-β1 and vascular endothelial growth factor-C cooperatively contributes to the aggressiveness of oral tongue squamous cell carcinoma.Åström P1,2,3, Juurikka K1,2, Hadler-Olsen ES4, Svineng G4, Cervigne NK5,6, Coletta RD6, Risteli J1,2,3,7,8, Kauppila JH1,2,3,9, Skarp S10,11,12, Kuttner S13,14, Oteiza A13,14, Sutinen M1,2,3, Salo T1,2,3,15,16.

Matrix metalloproteinase-8 (MMP-8) has oncosuppressive properties in various cancers. We attempted to assess MMP-8 function in oral tongue squamous cell carcinoma (OTSCC).MMP-8 overexpressing OTSCC cells were used to study the effect of MMP-8 on proliferation, apoptosis, migration, invasion and gene and protein expression. Moreover, MMP-8 functions were assessed in the orthotopic mouse tongue cancer model and by immunohistochemistry in patient samples.MMP-8 reduced the invasion and migration of OTSCC cells and decreased the expression of MMP-1, cathepsin-K and vascular endothelial growth factor-C (VEGF-C). VEGF-C was induced by transforming growth factor-β1 (TGF-β1) in control cells, but not in MMP-8 overexpressing cells. In human OTSCC samples, low MMP-8 in combination with high VEGF-C was an independent predictor of poor cancer-specific survival. TGF-β1 treatment also restored the migration of MMP-8 overexpressing cells to the level of control cells. In mouse tongue cancer, MMP-8 did not inhibit metastasis, possibly because it was eliminated in the peripheral carcinoma cells.The suppressive effects of MMP-8 in OTSCC may be mediated through interference of TGF-β1 and VEGF-C function and altered proteinase expression. Together, low MMP-8 and high VEGF-C expression have strong independent prognostic value in OTSCC.

Br J Cancer. 2017 Sep 5;117(6):856-866. doi: 10.1038/bjc.2017.244. Epub 2017 Jul 27.Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis.Almangush A1,2,3, Heikkinen I1,2, Mäkitie AA4, Coletta RD5, Läärä E6, Leivo I7, Salo T2,8,9,10.

Identifying informative prognostic biomarkers for oral tongue squamous cell carcinoma (OTSCC) is of great importance in order to better predict tumour behaviour and to guide treatment planning. Here, we summarise existing evidence regarding immunohistochemical prognostic biomarkers for OTSCC.A systematic search of the literature was performed using the databases of Scopus, Ovid Medline, Web of Science and Cochrane Library. All studies which had investigated the prognostic significance of immunohistochemical biomarkers in OTSCC during the period from 1985 to 2015 were retrieved. For the five most often evaluated biomarkers a random-effects meta-analysis on overall survival was performed, including those studies that provided the necessary statistical results.A total of 174 studies conducted during the last three decades were found, and in these 184 biomarkers were evaluated for the prognostication of OTSCC. The five biomarkers most frequently assessed were p53, Ki-67, p16, VEGFs and cyclin D1. In the meta-analyses, the most promising results of the prognostic power for OTSCC were obtained for cyclin D1. For studies of VEGF A and C the results were equivocal, but the pooled analysis of VEGF A separately showed it to be a useful prognosticator for OTSCC. There was no sufficient evidence to support p53, Ki-67 and p16 as prognostic biomarkers for OTSCC. Limitations in the quality of the published studies (e.g., small cohorts, lack of compliance with REMARK guidelines) are widespread.Numerous biomarkers have been presented as useful prognosticators for OTSCC, but the quality of the conduct and reporting of original studies is overall unsatisfactory which does not allow reliable conclusions. The value of two biomarkers (VEGF-A and cyclin D1) should be validated in a multicentre study setting following REMARK guidelines.

JAMA Otolaryngol Head Neck Surg. 2017 Jul 1;143(7):670-678. doi: 10.1001/jamaoto.2016.3595.Association of Oral Cavity and Oropharyngeal Cancer Biomarkers in Surgical Drain Fluid With Patient Outcomes.Lassig AAD1, Joseph AM2, Lindgren BR3, Yueh B4.

Survival rates for head and neck cancer have been relatively stable for several decades. Individualized prognostic indicators are needed to identify patients at risk for poorer outcomes.To determine whether biomarker levels in surgical drain fluid of patients with head and neck cancer are associated with poor cancer outcomes.This prospective cohort study enrolled patients with squamous cell carcinoma (SCC) of the oral cavity and oropharynx who required surgical treatment from April 1, 2011, to February 1, 2016, at a tertiary or academic care center. Twenty patients, including 14 with stage IV disease, had complete specimen collection. Differences in cytokine and MMP levels by disease outcomes were evaluated.Patients underwent surgical treatment with drain placement as dictated by the standard of care. Drain fluid samples were collected every 8 hours postoperatively until drains were removed because of clinical criteria. Levels of cytokines and matrix metalloproteinases (MMPs) were measured using electrochemiluminescent, patterned array, multiplex technology.The primary clinical outcome measures were survival outcome and recurrence. The biomarkers measured included the cytokines basic fibroblastic growth factor, vascular endothelial growth factor isoform A, soluble fms-like tyrosine kinase-1 (sFlt-1), and placental growth factor (PIGF) and MMP-1, MMP-3, and MMP-9. Other clinical and pathologic cancer characteristics were recorded.In this cohort of 20 patients with SCC (15 men and 5 women; mean [SD] age, 63.5 [9.9] years), a significant association with recurrence was found for levels of MMP-1 (relative difference between groups, 2.78; 95% CI, 1.23-6.29), MMP-3 (relative difference between groups, 5.29; 95% CI, 2.14-13.05), and sFlt-1 (relative difference between groups, 3.75; 95% CI, 1.84-7.65). No biomarkers were associated with disease outcome. Vascular endothelial growth factor isoform A was associated with nodal metastasis (relative difference between groups, 1.98; 95% CI, 1.12-3.51), and basic fibroblastic growth factor was associated with lymphovascular invasion (relative difference between groups, 1.74; 95% CI, 1.02-2.97).In this pilot sample of patients with SCC of the oral cavity and oropharynx, MMP-1, MMP-3, and sFlt-1 levels in wound fluid were associated with poor clinical cancer outcomes in the form of recurrence. This finding is consistent with the literature of tumor microenvironment in saliva, serum, and tumor tissue biomarkers. To our knowledge, this report is the first of such findings in surgical drain fluid, an easily accessible means of cytokine measurement. Measurement of these biomarkers in surgical fluid potentially represents a novel means of assessing cancer prognosis in this population.

Cell Mol Biol (Noisy-le-grand). 2016 Dec 30;62(14):64-68. doi: 10.14715/cmb/ 2016.62.14.11.

VEGF mediated signaling in oral cancer.Lin X1, Khalid S2, Qureshi MZ3, Attar R4, Yaylim I5, Ucak I6, Yaqub A7, Fayyaz S8, Farooqi AA8, Ismail M9.

Increasingly it is being realized that oral cancer arises from genetic/epigenetic mutations, dysregulations of spatio-temporally controlled signal transduction cascades and loss of apoptosis. Epidemiological studies have provided a stronger association between tobacco use (chewed and smoked) and oral cancer. Nevertheless, alcohol has also gained attention as a significant risk factor, having a multiplicative synergistic cancer promoting effect with tobacco. Vascular Endothelial Growth Factor (VEGF) mediated signaling has gained limelight because of its instrumental role in endothelial cell proliferation, survival, invasion, migration, chemotaxis of bone marrow (BM)-derived progenitor cells, vasodilation and vascular permeability. In this review we provide most recent updates on involvement of VEGF/VEGFR signaling axis in oral cancer. We partition this multi-component review into different sections and summarize latest advancements related to therapies against VEGF/VEGFR signaling axis and how microRNAs tactfully modulate VEGF and VEGFR in oral cancers. Data obtained through preclinical and clinical studies has revealed that therapeutic benefits associated with VEGF-targeted therapy are complicated in different cancers and involve myriad of mechanisms. A better understanding of VEGF/VEGFR mediated signaling in oral cancers and testing of novel therapeutic agents in preclinical models will prove to be helpful in effective translation of safest drugs from benchtop to the bedside.

J Oral Pathol Med. 2017 Oct;46(9):710-716. doi: 10.1111/jop.12544. Epub 2017 Feb 7.Semiquantifiable angiogenesis parameters in association with the malignant transformation of oral leukoplakia.Thiem DGE1, Schneider S2, Venkatraman NT3, Kumar VV4, Brieger J5, Frerich B1, Kämmerer PW1.

Aim of the study was to assess the role of angiogenesis in the process of malignant transformation of clinical diagnosed oral leucoplakia (OL).A total of 131 histological preparations [oral leukoplakia/hyperkeratosis without dysplasia (OL; n = 49), oral leukoplakia/hyperkeratosis with mild dysplasia (OL-SIN1; n = 33), with moderate dysplasia (OL-SIN2; n = 13) and leukoplakia-derived oral squamous cell carcinoma (OL-OSCC; n = 36)] were evaluated for microvessel density (MVD), vessel diameter as well as for vascular endothelial growth factor (VEGF-A) expression. Data were compared within the groups.For MVD, there were significant differences between OL and OL-SIN 2/OL-OSCC (P < 0.05) and between OL-SIN 1 and OL-OSCC (P < 0.05). For OL-OSCC, vessel diameters were significantly increased compared with OL (P < 0.05). Expression of VEGF-A increased significantly gradually from OL-SIN 1 to OSCC (each P < 0.05). This was especially evident for lesions of the tongue when compared to the others.Angiogenesis increases during the transition from OL through dysplasia to OL-OSCC. In particular, OL-OSCCs of the tongue, VEGF-A expression may be used for estimation of malignant progression of OL.

Pathol Res Pract. 2016 Dec;212(12):1095-1101. doi: 10.1016/j.prp.2016.10.015. Epub 2016 Nov 2.Immunohistochemical comparative analysis of lymphatic vessel density and VEGF-C expression in squamous cell carcinomas of the tongue between young and old patients.

Marinho Bezerra de Oliveira Moura J1, de Souza Martins Câmara AC2, Weege Nonaka CF3, Pinto LP2, de Souza LB2.

Squamous cell carcinoma (SCC) of the oral cavity is a malignant epithelial tumor that most commonly involves the tongue, and mainly affects men between the fifth and seventh decades of life. This study compared the lymphatic vessel density and VEGF-C expression in SCCs of the tongue between young and old patients.Thirty-four SCCs of the tongue, 17 diagnosed in young patients (≤40y) and 17 diagnosed in old patients (>50y), were evaluated by immunohistochemistry. Lymphatic microdensity was determined based on the number of vessels immunoreactive to anti-D2-40 antibody. The percentage of neoplastic cells exhibiting cytoplasmic staining for VEGF-C was established for each case.Assessment of intratumoral lymphatic microdensity (ILMD) disclosed a median number of 6.20 lymphatic vessels in young patients and of 6.60 in old patients (p=0.809). Analysis of peritumoral lymphatic microdensity (PLMD) revealed a median number of 3.60 lymphatic vessels in young patients and of 3.40 in old patients (p=0.769). In the tumor core, analysis of the percentage of immunopositive cells for VEGF-C revealed a median number of 95.95% in young patients and of 55.48% in old patients (p<0.001). In the deep invasive front, the median number of immunopositive cells for VEGF-C was 97.93% in young patients and 66.09% in old patients (p<0.001).The results of this study suggest that the more aggressive biological behavior of SCC of the tongue in young patients may be related to a higher expression of VEGF-C.

Cancer Med. 2016 Oct;5(10):2977-2988. doi: 10.1002/cam4.866. Epub 2016 Sep 20.Recombinant canstatin inhibits VEGF-A-induced lymphangiogenesis and metastasis in an oral squamous cell carcinoma SCC-VII animal model.Hwang-Bo J1, Park JH1, Bae MG1, Chung IS2.

We describe the inhibitory effects of recombinant canstatin on tumor growth and lymphangiogenesis induced by an oral squamous cell carcinoma (SCC) using an orthotropic oral SCC animal model. Recombinant canstatin treatment decreased final tumor volumes and weights, as well as densities of blood and lymphatic vessels. Lung metastasis of oral SCC was significantly reduced in recombinant canstatin-treated animals. Recombinant canstatin reduced vascular endothelial growth factor (VEGF)-A expression in SCC-VII cells treated with the hypoxia mimetic agent, CoCl2 . VEGF-A induced in vivo lymphatic vessel formation in a Matrigel plug, but this was remarkably reduced in a recombinant canstatin-treated Matrigel. Recombinant canstatin suppressed the expression of vascular endothelial growth factor receptors (VEGFR)-1 and -2 stimulated by VEGF-A. Based on immunohistochemical analysis, recombinant canstatin significantly reduced the expression of VEGF-A, VEGFR-1, and -2 in SCC-VII-induced tumors. Recombinant canstatin did not affect the expression of VEGF-C or VEGFR-3. In addition, recombinant canstatin suppressed the VEGF-A-induced phosphorylation of VEGFR-1 and -2. Our results indicate that recombinant canstatin exhibits antitumoral and antilymphangiogenic activities against oral SCC cells. Antilymphangiogenic signaling by recombinant canstatin is probably mediated by the suppression of the integrin αvβ3/VEGFR-1 and/or -2 signaling induced by VEGF-A. Our results also suggest that recombinant canstatin has a high potential to inhibit oral SCC-induced tumors and lymphatic metastasis.

Oncol Rep. 2016 Nov;36(5):2444-2454. doi: 10.3892/or.2016.5116. Epub 2016 Sep 21.Use of NRP1, a novel biomarker, along with VEGF-C, VEGFR-3, CCR7 and SEMA3E, to predict lymph node metastasis in squamous cell carcinoma of the tongue.

Al-Shareef H1, Hiraoka SI1, Tanaka N2, Shogen Y1, Lee AD1, Bakhshishayan S1, Kogo M1.

Lymph node (LN) metastasis has been suggested as a major prognostic factor for oral cancer. Knockdown of the growth factors and receptors involved in these metastatic mechanisms could significantly reduce LN metastasis and improve the survival of oral cancer patients after treatment. The present study, therefore, aimed to evaluate the expression levels of the following growth factors and receptors in squamous cell carcinoma (SCC) of the tongue: the vascular endothelial growth factor (VEGF)‑C and VEGF‑D, which bind to the cell surface tyrosine kinase receptor VEGF receptor‑3 (VEGFR‑3); C‑C motif chemokine receptor 7 (CCR7); neuropilin (NRP)1 and NRP2; and semaphorin 3E (SEMA3E). Furthermore, we assessed microvessel density (MVD) and lymphatic vessel density (LVD) to demonstrate the correlation between these factors and regional LN metastasis, with respect to the clinicopathological features. Finally, we analyzed the correlation between these proteins and overall or disease‑free survival, in order to demonstrate their prognostic value. Univariate analysis revealed a significant association between LN metastasis and the expression levels of VEGF‑C, VEGFR‑3, CCR7, NRP1, and SEMA3E, as well as LVD, in SCC cells. In contrast, multivariate analysis identified associations between LN metastasis and NRP1 expression, as well as between LN metastasis and LVD; however, no correlation was found between LN metastasis and the expression levels of the other proteins. The expression levels of VEGF‑C, VEGFR‑3, NRP1, and SEMA3E, as well as LVD, were correlated with disease‑free survival time. These results indicate that LN metastasis is associated with poor survival in SCC. This study suggests that NRP1 expression and LVD are independent factors that are likely to predict the risk of LN metastasis in SCC of the tongue, whereas the expression of VEGF‑C, VEGFR‑3, CCR7, and SEMA3E are non‑independent predictive factors.

Int J Oral Maxillofac Surg. 2017 Jan;46(1):16-23. doi: 10.1016/j.ijom.2016.09.012. Epub 2016 Oct 11.Immunoexpression of VEGFR-3, but not the immunoexpression of VEGF-C or lymphatic density, is correlated with metastasis in lower lip squamous cell carcinoma.

de Aquino AR1, Nonaka CF2, de Carvalho CH3, Demeda CF4, de Souza LB4, Pinto LP4.

The purpose of this study was to evaluate the immunoexpression of vascular endothelial growth factor C (VEGF-C) and VEGF receptor 3 (VEGFR-3) and their correlation with intratumoural lymphatic density (ILD) and peritumoural lymphatic density (PLD) in metastatic and non-metastatic lower lip squamous cell carcinoma (LLSCC). Twenty-five LLSCC with regional nodal metastasis and 25 LLSCC without metastasis were selected. The percentages of VEGF-C and VEGFR-3 staining in each tumour core and at the deep invasive front were assessed. PLD and ILD were determined using anti-podoplanin antibody. Immunohistochemical findings were correlated with nodal metastasis, clinical staging, local recurrence, clinical outcome, and histological grade. Cytoplasmic immunoexpression of VEGFR-3 in the tumour core was associated with metastasis (P=0.009), patient death (P=0.008), and histological grade (P<0.005). PLD, ILD, and VEGF-C expression showed no significant associations with clinicopathological parameters (P>0.05). PLD and ILD were not significantly correlated with the immunoexpression of VEGF-C or VEGFR-3 (P>0.05). There was a significant positive correlation between PLD and ILD (P=0.004), and between cytoplasmic immunoreactivity of VEGF-C and VEGFR-3 (P=0.011). These results suggest an important role for VEGFR-3 in the progression of LLSCC, and highlight the possible influence of its expression on the prognosis of these tumours. ILD and PLD may not be associated with lymph node metastasis in LLSCC.

Pathobiology. 2017;84(2):80-86. doi: 10.1159/000447778. Epub 2016 Sep 1.Combined Analysis of Vascular Endothelial Growth Factor Expression with Cyclooxygenase-2 and Mast Cell Density in Oral Squamous Cell Carcinoma.

Akbarzadeh Baghban A1, Taghavi N, Shahla M.

Overexpression of vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) and increasing mast cell density (MCD) in premalignant and malignant oral lesions have been documented. However, their correlation with clinicopathologic parameters and survival rate in oral squamous cell carcinoma (OSCC) is not completely clear. This study aimed to assess these subjects.VEGF, COX-2, and mast cell tryptase expression were examined immunohistochemically in 57 cases of OSCC. The relationships between the markers’ expression and clinicopathologic data were assessed using bivariate and multivariate analysis.Spearman’s rank correlation coefficient showed a significant correlation between VEGF and COX-2 expression (r = 0.462, p < 0.001), as well as between VEGF expression and MCD (r = 0.306, p < 0.001). Multivariate analysis showed no significant correlation between the markers’ immunoexpression and overall survival (OS), but a significant correlation between mode of invasion and OS [hazard ratio 0.362 (95% CI: 0.138- 0.974); p = 0.038] was observed. An association between MCD and gender (p = 0.042) was also found, as MCD was higher in males.The significant correlation of VEGF expression with COX-2 expression and MCD may represent the roles of COX-2 and MCD in tumor angiogenesis by modulating VEGF production. However, VEGF, COX-2, and MCD are not useful indicators to predict prognosis in OSCC. Nevertheless, the mode of invasion can be considered as an independent prognostic factor in OSCC patients.

J Cancer Res Ther. 2016 Apr-Jun;12(2):447-57. doi: 10.4103/0973-1482.147765.Clinical significance of inflammatory mediators in the pathogenesis of oral cancer.Patel JB1, Shah FD1, Joshi GM2, Patel PS1.

Oral cancer has become a grave problem in many parts of the globe with two.thirds of the cases occurring in developing countries. Chronic inflammation plays a prominent role in the development of oral cancer. The rationale for molecular targeted prevention of oral cancer is promising. Therefore, there are continued improvements to our understanding of the molecular connections between inflammation and oral cancer. The inflammatory mediators including nuclear factor kappa B, vascular endothelial growth factor, inflammatory cytokines, prostaglandin pathways, p53, reactive oxygen and nitrogen species, and microRNAs are major key players in the pathogenesis of oral cancer. Currently, visual cytology.based techniques and biopsy are used to detect dysplasia and early stage of oral squamous cell carcinoma. These approaches are limited in their ability to judge the severities of oral lesions and are useful only after the appearance of visual changes. Thus, traditional cytological and biopsy assays combined with testing of inflammatory biomarkers would be beneficial for the efficient early detection of oral dysplastic lesions and early stages of oral squamous cell carcinoma.

Med J Islam Repub Iran. 2016 Apr 18;30:358. eCollection 2016.Vascular endothelial growth factor expression and vascular density in oral squamous cell carcinoma (OSCC): A study on clinical and histopathologic significance.Jalayer Naderi N1, Tirgari F2, Keshavarz Z3.

New blood vessels formation is a critical step in tumor progression. Vascular density affects the clinical outcome and prognosis of malignant tumors. The aim of this study was to investigate the relation between the Vascular Endothelial Growth Factor (VEGF) expression and vascular density with the clinical and histopathologic features in oral squamous cell carcinoma (OSCC).In this retrospective study, 22 paraffin embedded block of well-differentiated OSCC were examined immunohistochemically for VEGF expression. Vascular density was determined by counting the blood vessels in 6 fields with 100 (HPF) on hematoxylin-eosin stained slides. The relation between the VEGF expression and vascular density with clinical and histopathologic features were analyzed by t-test, ANOVA, and Chi-square tests.A significant relation between gender (P=0.06) and tumor size (p=0.05) with vascular density was obtained. The relation between VEGF expression and gender (p=0.41), age (p=0.35), lymph node involvement (p=0.38), tumor size (p=0.15) and tumor differentiation (p=0.34) was not significant. The relation between vascular density and age (p=0.55), lymph node involvement (p=0.20), and tumor differentiation (p=0.80) was not significant.Blood vessels formation relates to tumor size. Controlling the tumor size by manipulating the blood vessels formation may contribute to the inhibition of tumor progression in malignant tumors.

J Oral Pathol Med. 2017 Mar;46(3):194-200. doi: 10.1111/jop.12476. Epub 2016 Jul 15.Prognostic significance of VEGF-C in predicting micrometastasis and isolated tumour cells in N0 oral squamous cell carcinoma.Kazakydasan S1, Rahman ZA1,2, Ismail SM1,2, Abraham MT3, Kallarakkal TG1,2.

Lymph node metastasis in oral squamous cell carcinoma (OSCC) is a well-known independent prognostic factor. However, the identification of occult tumour cells within the lymph nodes has remained a challenge for the pathologist as well as the clinician.The aim of this study was to determine the prevalence of micrometastasis and isolated tumour cells (ITCs) in pathologically staged N0 OSCC of the tongue and buccal mucosa and to assess its correlation with vascular endothelial growth factor C, (VEGF-C) expression in the primary tumour.Thirty-four cases of N0 OSCC comprising of 17 cases each from the tongue and buccal mucosa were evaluated by immunohistochemistry for VEGF-C expression. The corresponding lymph nodes from levels I and II were pathologically examined and cross-detected for micrometastasis and ITCs with desmoglein 3 (DSG3).The prevalence of micrometastasis and ITCs in OSCC of the tongue and buccal mucosa was 23.5% and 17.6%, respectively. A total of 12 out of 151 lymph nodes contained micrometastatic tumour foci and ITCs. A higher expression of VEGF-C in the primary tumour was associated with a greater probability for the occurrence of micrometastasis and ITCs in the lymph nodes.High expression of VEGF-C in the primary tumour may be a good determinant for detection of occult tumour cells in the lymph nodes of OSCC cases.

Oral Dis. 2016 Oct;22(7):688-96. doi: 10.1111/odi.12522. Epub 2016 Jul 15.Granzyme B-truncated VEGF fusion protein represses angiogenesis and tumor growth of OSCC.

Lv XZ1, Zheng MY2, Lin ZQ2, Zhao M1, Wang H2, Zeng WS3.

To evaluate the antitumor effects of fusion protein hGrB-TV of human granzyme B (hGrB) and truncated vascular endothelial growth factor (tVEGF) on human oral squamous cell carcinoma (OSCC) in vitro and in vivo.The fusion protein hGrB-TV was expressed and purified from E. coli bacteria by affinity chromatography. The cytotoxcity of hGrB-TV on VEGFR-2 (Flk-1)(+) OSCC cells was analyzed in vitro. The antitumor therapeutic study was conducted on OSCC xenografts in vivo.The purified hGrB-TV fusion protein was selectively internalized into VEGFR-2 (Flk-1)(+) OSCC cells and endothelial cells. It can cleave inactive caspase 3 into its active p20 form. The hGrB-TV showed dose-dependent cytotoxicity on VEGFR-2(+) SCC-9 cells. The morphological changes and cytolysis were appeared within dozen minutes. However, no cytotoxicity was observed on VEGFR-2(-) cells. The hGrB alone or tVEGF alone did not have any toxicity on SCC-9 cells. In addition, hGrB-TV treatment completely destroyed the vasculature of the chick chorioallantoic membrane (CAM) in vivo and consequently led to chick embryo development arrest. Most importantly, the fusion protein hGrB-TV inhibited tumor angiogenesis and growth of human OSCC xenografts in nude mice without any apparent toxicity.The fusion protein hGrB-TV specifically inhibits angiogenesis and tumor growth of OSCC; hGrB-TV is a powerful and safe therapeutic molecule for tumor therapy.

Pathology. 2016 Apr;48(3):219-27. doi: 10.1016/j.pathol.2016.02.006. Epub 2016 Mar 10.Tumour-associated macrophages are recruited and differentiated in the neoplastic stroma of oral squamous cell carcinoma.Essa AA1, Yamazaki M2, Maruyama S3, Abé T4, Babkair H2, Raghib AM5, Megahed EM5, Cheng J2, Saku T6.

To confirm our hypothesis that macrophages recruited to fight against oral squamous cell carcinoma (SCC) invasion are functionally differentiated within neoplastic stromata, we analysed arrangements of macrophage subtypes and cancer-associated fibroblasts (CAFs) in their association with blood vasculatures in the neoplastic stroma. Surgical specimens of oral SCC were immunohistochemically examined for macrophage phenotypes (CD68, CD163, and CD204) and stromal environments (perlecan, connexin 43, and CD31). Human monocytes were co-cultured with ZK-1 cells of oral SCC origin in different culture conditions. SCC stromata were divided into two types: fascicular (fibroblast-rich) and reticular (perlecan-rich). Regardless of stromal types, CD68 positive (+)/CD163+/CD204+ macrophages were recruited when blood vessels were abundant. Connexin 43+ fibroblasts were enriched in the fascicular stroma, where blood vessels were depleted. In co-culture experiments, monocytes, in the presence of ZK-1 cells, showed TNF-α(low)/IL-12(low) and IL-10(high)/VEGF(high)/MMP-9(high) with increased expression levels for fibronectin and perlecan. With direct contact with monocytes, SCC cells also expressed CD68 and CD163. SCC stromata were characterised by CD163+/CD204+ tumour-associated macrophages (TAMs) and connexin 43+ CAFs. TAMs are differentiated from monocytes by the physical contact with oral SCC cells in the perlecan-rich neoplastic stroma, which is also induced by the cross-talk between SCC cells and stromal cells including TAMs.

J Dent Res. 2016 Jul;95(8):860-7. doi: 10.1177/0022034516641037. Epub 2016 Mar 24.Clinical Significance and Roles in Angiogenesis of Circulating Microparticles in Oral Cancer.Ren JG1, Zhang W1, Liu B2, Man QW3, Xiong XP1, Li C1, Zhu JY3, Wang WM3, Jia J2, Sun ZJ1, Zhang WF2, Chen G4, Zhao YF4.

Our recent study established the increased circulating microparticles (MPs) and their procoagulant activity in oral squamous cell carcinoma (OSCC). In the present study, we further evaluated different phenotypes of circulating MPs in OSCC patients and explored their clinical significance and effects on angiogenesis (a critical event in tumor progression). To conduct the study, circulating MPs in 45 OSCC patients and 18 healthy volunteers were characterized and quantified by transmission electron microscopy and flow cytometry. Correlations between circulating MPs and clinicopathologic data, microvessel density, and proangiogenic factor levels in patients with OSCC were analyzed by immunohistochemistry and Spearman rank correlation test. Additionally, the in vitro studies were performed with use of human umbilical vein endothelial cells. Our results showed that the levels of circulating MPs as well as the subsets of platelet-derived, endothelium-derived, and pan-leukocyte MPs in stages III to IV OSCC were significantly higher than stages I to II and healthy subjects. Moreover, these increased circulating MPs were significantly correlated with tumor size, TNM stages, microvessel density, and expression levels of vascular endothelial growth factor (VEGF) and matrix metallopeptidase 9 (MMP9) in OSCC patients. The in vitro studies revealed that circulating MPs isolated from OSCC patients could be effectively taken up by human umbilical vein endothelial cells and could promote the proliferation, migration, invasion, and tube formation of recipient endothelial cells, accompanied by increased expression of proangiogenic factors. In summary, circulating MPs play important roles in angiogenesis and local tumor progression of OSCC. Our results shed new light on the progression of OSCC and might be helpful to explore novel treatment strategies targeting tumor angiogenesis.

Pathol Res Pract. 2016 May;212(5):426-36. doi: 10.1016/j.prp.2016.02.016. Epub 2016 Feb 17.Differential immunohistochemical expression profiles of perlecan-binding growth factors in epithelial dysplasia, carcinoma in situ, and squamous cell carcinoma of the oral mucosa.Hasegawa M1, Cheng J2, Maruyama S3, Yamazaki M2, Abé T4, Babkair H2, Saito C5, Saku T6.

The intercellular deposit of perlecan, a basement-membrane type heparan sulfate proteoglycan, is considered to function as a growth factor reservoir and is enhanced in oral epithelial dysplasia and carcinoma in situ (CIS). However, it remains unknown which types of growth factors function in these perlecan-enriched epithelial conditions. The aim of this study was to determine immunohistochemically which growth factors were associated with perlecan in normal oral epithelia and in different epithelial lesions from dysplasia and CIS to squamous cell carcinoma (SCC). Eighty-one surgical tissue specimens of oral SCC containing different precancerous stages, along with ten of normal mucosa, were examined by immunohistochemistry for growth factors. In normal epithelia, perlecan and growth factors were not definitely expressed. In epithelial dysplasia, VEGF, SHH, KGF, Flt-1, and Flk-1were localized in the lower half of rete ridges (in concordance with perlecan, 33-100%), in which Ki-67 positive cells were densely packed. In CIS, perlecan and those growth factors/receptors were more strongly expressed in the cell proliferating zone (63-100%). In SCC, perlecan and KGF disappeared from carcinoma cells but emerged in the stromal space (65-100%), while VEGF, SHH, and VEGF receptors remained positive in SCC cells (0%). Immunofluorescence showed that the four growth factors were shown to be produced by three oral SCC cell lines and that their signals were partially overlapped with perlecan signals. The results indicate that perlecan and its binding growth factors are differentially expressed and function in specific manners before (dysplasia/CIS) and after (SCC) invasion of dysplasia/carcinoma cells.

J Oral Pathol Med. 2016 Aug;45(7):481-5. doi: 10.1111/jop.12398. Epub 2016 Feb 10.Elevated VEGFA mRNA levels in oral squamous cell carcinomas and tumor margins: a preliminary study.Sales CB1, Buim ME2, de Souza RO1, de Faro Valverde L3, Mathias Machado MC3, Reis MG1,3, Soares FA2, Ramos EA1,3, Gurgel Rocha CA1,3.

New blood vessel formation events are essential for tumor clonal expansion and progression. Despite the importance of vascular endothelial growth factor A (VEGFA) for tumor angiogenesis, few studies have evaluated the expression profile of this gene in oral squamous cell carcinoma (OSCC) and tumor margins (TM). This study aimed to evaluate the expression of the VEGFA gene and its protein in OSCC and TM.Gene expression was evaluated in cryopreserved samples of OSCCs (n = 44), TM (n = 7), and normal mucosa from healthy patients (n = 3; NM). Quantitative PCRs were performed using the TaqMan system for the VEGFA gene, and gene expression was determined using the 2(-∆∆CQ) method. For immunohistochemical evaluation, 27 OSCC samples were embedded in a tissue microarray (TMA) block and reactions were performed using the Advance system.VEGFA transcript levels were 1.7-fold higher in OSCC than in NM samples. VEGFA mRNA was overexpressed in TM samples compared to NM (3.4-fold) and OSCC (2.0-fold) samples. VEGFA transcript level was overexpressed in T3-T4 tumors, metastatic lymph nodes, and stage III-IV OSCCs. Immunoreactivity of the VEGFA protein was detected in the cytoplasm of parenchymal and stromal cells, mainly in endothelial cells and fibroblasts.Our results show that VEGFA was overexpressed in aggressive OSCCs and that VEGFA expression may be an important prognostic factor in this type of cancer. Finally, tumor margins may be involved in the production of angiogenic molecules.

PLoS One. 2015 Dec 2;10(12):e0144056. doi: 10.1371/journal.pone.0144056. eCollection 2015.Primary Tumor-Secreted Lymphangiogenic Factors Induce Pre-Metastatic Lymphvascular Niche Formation at Sentinel Lymph Nodes in Oral Squamous Cell Carcinoma.Wakisaka N1, Hasegawa Y2, Yoshimoto S3, Miura K4, Shiotani A5, Yokoyama J6, Sugasawa M7, Moriyama-Kita M1, Endo K1, Yoshizaki T1.

The objectives of this study were to evaluate the formation of lymphvascular niches in lymph nodes of patients with oral squamous cell carcinoma (OSCC), and investigate the roles of lymphangiogenic and angiogenic factors, such as vascular endothelial growth factor (VEGF)-A, VEGF-C, and VEGF-D, expressed in the primary tumors.Forty-four patients with previously untreated clinically late T2 or T3 OSCC of cN0 were evaluated for primary tumors and 166 sentinel lymph nodes (SLNs). Primary tumors were immunohistochemically analyzed for expressions of VEGFs. Densities of lymphatic vessels (LVDpodoplanin) and high endothelial venules (HEVD) in the SLNs were also calculated using antibodies for each marker, podoplanin and MECA-79, respectively.In 25 patients, all lymph nodes were metastasis-negative, whereas, in 19 patients, metastasis was positive for at least one lymph node (either at SLN, non-SLN, or nodal recurrence). From the analyses of 140 SLNs without metastasis, LVDpodoplanin in 50 SLNs of metastasis-positive cases was significantly higher than that in 90 SLNs of metastasis-negative cases (p = 0.0025). HEVD was not associated with lymph node metastasis. The patients with VEGF-A-High or VEGF-D-High tumors had significantly higher LVDpodoplanin than patients with their Low counterparts (p = 0.0233 and p = 0.0209, respectively). In cases with lymph node metastasis, the VEGF-D-expression score was significantly higher than in those without lymph node metastasis (p = 0.0006).These results suggest that lymph node lymphangiogenesis occurs before metastasis in OSCC. VEGF-A and VEGF-D play critical roles in this process. VEGF-D is a potential predictive marker of positive lymph node metastasis in cN0 patients.

Shanghai Kou Qiang Yi Xue. 2015 Aug;24(4):400-3.Suppression of VEGF protein expression by arctigenin in oral squamous cell carcinoma].Pu GR1, Liu FY, Wang B.

The expression of VEGF in 32 cases of oral squamous cell cancer and 20 adjacent tissue specimen were detected with immunohistochemistry. Human nude mouse transplantation tumor model of oral squamous cell cancer was prepared with HSC-3 cells line. Transplanted tumor growth and VEGF expression in transplanted tumor tissues were assayed after treatment with arctigenin. One-way ANOVA was used for comparison between groups with SPSS 16.0 software package.Compared with the adjacent tissue, immunohistochemical staining score of VEGF was significantly higher (P<0.01) in oral squamous cell carcinoma tissues. After treatment with arctigenin, the growth of oral squamous cell transplanted tumors in nude mouse was inhibited (P<0.05), and decreased weight in end point of observation was noted (P<0.05). There were significant differences between high dose group and low dose group (P<0.05). Compared with the nude mouse model group, the optical density of VEGF staining was significantly lower in arctigenin group (P<0.05). There were significant differences between high dose group and low dose group (P<0.05).Arctigenin can dose-dependently inhibit the growth of oral squamous cell carcinomas, and this effect may be related to down regulation of VEGF expression.

Mol Ther. 2016 Feb;24(1):106-16. doi: 10.1038/mt.2015.169. Epub 2015 Sep 16.Nanoparticle Delivered VEGF-A siRNA Enhances Photodynamic Therapy for Head and Neck Cancer Treatment.Lecaros RL1, Huang L1,2,3, Lee TC1, Hsu YC1,3,4.

Photodynamic therapy (PDT) is believed to promote hypoxic conditions to tumor cells leading to overexpression of angiogenic markers such as vascular endothelial growth factor (VEGF). In this study, PDT was combined with lipid-calcium-phosphate nanoparticles (LCP NPs) to deliver VEGF-A small interfering RNA (siVEGF-A) to human head and neck squamous cell carcinoma (HNSCC) xenograft models. VEGF-A were significantly decreased for groups treated with siVEGF-A in human oral squamous cancer cell (HOSCC), SCC4 and SAS models. Cleaved caspase-3 and in situ TdT-mediated dUTP nick-end labeling assay showed more apoptotic cells and reduced Ki-67 expression for treated groups compared to phosphate buffered saline (PBS) group. Indeed, the combined therapy showed significant tumor volume decrease to ~70 and ~120% in SCC4 and SAS models as compared with untreated PBS group, respectively. In vivo toxicity study suggests no toxicity of such LCP NP delivered siVEGF-A. In summary, results suggest that PDT combined with targeted VEGF-A gene therapy could be a potential therapeutic modality to achieve enhanced therapeutic outcome for HNSCC.

Clin Exp Metastasis. 2015 Oct;32(7):739-53. doi: 10.1007/s10585-015-9741-2. Epub 2015 Aug 29.Cellular fibronectin 1 promotes VEGF-C expression, lymphangiogenesis and lymph node metastasis associated with human oral squamous cell carcinoma.Morita Y1,2,3, Hata K1, Nakanishi M1, Omata T4, Morita N3,4,5, Yura Y2, Nishimura R1, Yoneda T6,7.

Lymph node metastasis (LNM) is associated with poor survival in patients with oral squamous cell carcinoma (OSCC). Vascular endothelial growth factor-C (VEGF-C) is thought to be responsible for increased lymphangiogenesis and LNM. Understanding of the mechanism by which VEGF-C expression is regulated in OSCC is thus important to design logic therapeutic interventions. We showed that inoculation of the SAS human OSCC cells expressing the venus GFP (V-SAS cells) into the tongue in nude mice developed LNM. V-SAS cells in LNM were isolated by FACS and re-inoculated into the tongue. This procedure was repeated eight times, establishing V-SAS-LM8 cells. Differential metastasis PCR array between the parental V-SAS and V-SAS-LM8 was performed to identify a molecule responsible for lymphangiogenesis and LNM. Fibronectin 1 (FN1) expression was elevated in V-SAS-LM8 cells compared to V-SAS-cells. V-SAS-LM8 tongue tumor showed increased expression of FN1 and VEGF-C, and promoted lymphangiogenesis and LNM compared with V-SAS tumor. Further, phosphorylation of focal adhesion kinase (FAK), a main downstream signaling molecule of FN1, was up-regulated, and epithelial-mesenchymal transition (EMT) was promoted in V-SAS-LM8 cells. Silencing of FN1 by shRNA in V-SAS-LM8 cells decreased FAK phosphorylation, VEGF-C expression and inhibited lymphangiogenesis and LNM. EMT was also reversed. The FAK phosphorylation inhibitor PF573228 also decreased VEGF-C expression and reversed EMT in V-SAS-LM8 cells. Finally, we detected intense FN1 expression in some clinical specimens obtained from OSCC patients with LNM. These results demonstrate that elevated expression of cellular FN1 and following activation of FAK lead to increased VEGF-C expression, lymphangiogenesis and LNM and promoted EMT in SAS human OSCC cells and suggest that FN1-phosphorylated FAK signaling cascade is a potential therapeutic target in the treatment of LNM in OSCC.

Oral Surg Oral Med Oral Pathol Oral Radiol. 2015 Oct;120(4):436-42. doi: 10.1016/j.oooo.2015.06.002. Epub 2015 Jun 15.Vascular endothelial growth factor C (VEGF-C) expression predicts metastasis in tongue cancer.Matsui T1, Shigeta T2, Umeda M3, Komori T2.

We present a retrospective analysis of 90 patients with T1-2 N0 SCC who underwent primary excision as initial treatment without preoperative radiotherapy or chemotherapy. We examined the clinicopathologic factors (gender, age, clinical stage, surgical margin, grade of differentiation, lymphatic invasion, tumor depth of invasion, pattern of invasion [POI]) and immunohistochemical factors (vascular endothelial growth factor [VEGF]-A and VEGF-C expression) to predict the probability of lymph node metastasis.The local progression-free 5-year survival rate was 100%. Tumor depth of invasion (≥4 mm, P = .022), POI (score >4, P = .000), and VEGF-C expression (P = .008) were associated with the lymph node metastasis of tongue SCC in a multiple logistic regression analysis (odds ratios [ORs]: 5.075, 17.383, and 9.533, respectively).The local control rate of tongue SCC in the early stages has significantly improved as a result of development of surgical techniques. On the other hand, we believe that tumor depth of invasion (≥4 mm), POI, and VEGF-C expression all need to be considered in the preoperative and postoperative planning stages for tongue cancer treatment.

Anticancer Res. 2018 Mar;38(3):1623-1628.

mTORC1 and mTORC2 Expression Levels in Oral Squamous Cell Carcinoma: An Immunohistochemical and Clinicopathological Study.

Kawasaki G1, Naruse T2, Furukawa K2, Umeda M2.

Mammalian target of rapamycin (mTOR) plays a critical role in the regulation of tumor cell motility, invasion and cancer cell metastasis. mTOR consists of two separate multi-protein complexes, mTOR complex (mTORC) 1 and mTORC2.We investigated the expression levels of mTORC1 and mTORC2 immunohistochemically in oral squamous cell carcinoma (OSCC).mTORC1 and mTORC2 were more highly expressed in tumors than in normal oral mucosa. mTORC1 expression was correlated with T classification, N classification, and survival rate (p<0.05), whereas mTORC2 expression was only correlated with T classification (p<0.05). Histologically, the expression levels of mTORC1 and mTORC2 correlated with cancer cell invasion and the expression of proliferating cell nuclear antigen (p<0.05), respectively. Expression levels of vascular endothelial growth factors and hypoxia-inducible factor 1 in the mTORC1 (-)/ mTORC2 (+) group were significantly lower than those in other groups.These findings suggested that mTORC1 and mTORC2 could be promising anti-tumor targets in OSCC, and mTORC1 (-)/mTORC2 (+) may have a correlation with the malignant potential of OSCC.

Anticancer Res. 2018 Mar;38(3):1361-1368.

Expression of Sphingosine Kinase-1 Is Associated with Invasiveness and Poor Prognosis of Oral Squamous Cell Carcinoma.

Kato K1, Shimasaki M2, Kato T3, Segami N3, Ueda Y2.

The expression of sphingosine kinase-1 (SphK1) has been reported in several cancers. However, the exact roles of SphK1 in cancer progression still remain unknown. The aim of the present study was to investigate SphK1 expression in oral squamous cell carcinoma (OSCC) and clarify the involvement of SphK1 in the proliferation and invasiveness of OSCC and its prognostic implications.Expression of SphK1, E-cadherin, vimentin, and Ki-67 were examined in 69 OSCC tissues immunohistochemically, as well as by western blot, and correlations between their expression and relationships with tumor invasiveness and prognosis were analyzed.SphK1 was expressed in the tumor cells of 38 of 69 OSCCs, particularly at the invasion front. Patients with OSCCs with high SphK1 expression showed higher invasive grades and unfavorable survival rates. SphK1 expression correlated with acquisition of vimentin expression and loss of E-cadherin expression; there was no significant difference in Ki-67 labeling indices between OSCCs with high and low SphK1 expression.These results demonstrate the involvement of SphK1 in the invasiveness of OSCC and in unfavorable prognosis, indicating its role in the epithelial-mesenchymal transition of OSCC cells.

Histopathology. 2018 Feb 22. doi: 10.1111/his.13496. [Epub ahead of print]

Immunohistochemical expression of CD44 in oral squamous cell carcinoma in relation to histomorphologic parameters and clinicopathological factors.

Boxberg M1, Götz C2, Haidari S2, Dorfner C2, Jesinghaus M1, Drecoll E1, Boskov M2, Wolff KD2, Weichert W1,3,4, Haller B5, Kolk A2.

Oral squamous cell carcinoma (OSCC) is characterized by its variable clinical course. In addition to the routinely used TNM/UICC systems, patient-specific prognostic/predictive biomarkers are needed. Promising biomarkers include the determination of the cancer stem cell (CSC) compartment, which can be identified by CD44 expression (amongst others).A well-characterized cohort of 108 therapy-naïve OSCC with complete long-term follow-up and matched lymph node metastases were evaluated for CD44 expression by immunohistochemistry. CD44 expression was correlated with histomorphological characteristics (including tumor differentiation, tumor budding), clinicopathological parameters and follow-up data.Overexpression of CD44 was detected in 37% of OSCC within tumor center, 39% at the invasive margin and 16% of lymph-node metastases. CD44 overexpression at the invasive margin was significantly correlated with poor histopathological differentiation and specifically with high tumor budding activity and single cell invasion as signs of epithelial to mesenchymal tumor transformation (EMT). CD44 overexpression within tumor core region and in lymph node metastasis was identified as an independent prognostic factor for poor overall, disease-specific and disease-free survival in subsets of patients with advanced OSCC.Our study demonstrates the association of CD44 with tumor aggressiveness and EMT as well as the independent prognostic impact of CD44 in a subset of OSCC, which underlines the role of tumor cell stemness as a key factor in malignant behaviour in this disease. This article is protected by copyright. All rights reserved.

Mol Clin Oncol. 2018 Mar;8(3):400-406. doi: 10.3892/mco.2018.1548. Epub 2018 Jan 10.

Low carbonyl reductase 1 expression is associated with poor prognosis in patients with oral squamous cell carcinoma.

Yamanouchi R1, Harada K1, Ferdous T1, Ueyama Y1.

Carbonyl reductase 1 (CBR1) is an enzyme that catalyzes the reduction of numerous compounds by using NADPH-dependent oxidoreductase activity. Decreased expression of CBR1 is associated with disease progression and an unfavorable outcome in several types of malignancies. The purpose of the current study was to determine whether CBR1 expression could be a useful prognostic factor in patients with oral squamous cell carcinoma (OSCC). Therefore, its mechanisms of action were investigated in order to understand how CBR1 affects cancer cell behavior in vitro. CBR1 expression was evaluated using immunohistochemistry and tissue samples obtained from 90 patients with OSCC. The associations between CBR1 expression, clinicopathological characteristics and patient survival were also analyzed. In addition, the role of CBR1 in cancer cell invasion and metastasis was examined, along with its underlying molecular mechanisms, via transfecting CBR1-siRNA into the HSC2 human OSCC cell line. Immunohistochemical analysis revealed that biopsy tissue samples of 71.1% of the patients with OSCC were positive for CBR1. In addition, CBR1 expression status was correlated with the N classification (P<0.0001), stage (P=0.0018) and outcome (P=0.0095). Furthermore, a statistical correlation was determined between the protein expression status and overall survival (P=0.0171). In vitro studies indicated that the suppression of CBR1 by CBR1-siRNA increased cancer cell proliferative, wound healing and migratory abilities. These findings suggest that low expression levels of CBR1 may affect cancer prognosis, and that CBR1 may have potential as a prognostic factor for patients with OSCC.

J Contemp Dent Pract. 2018 Feb 1;19(2):170-176.

Proliferative Index in Invasive Tumor Front of Oral Squamous Cell Carcinoma: A Potential Prognostic Indicator.

Bhuyan L1, Sarangi S2, Das BK2, Das SN2, Nayak S3.

The aim of the study was to evaluate the proliferative index (PI) at their invasive front of oral cancer and their association with Bryne’s grades of oral squamous cell carcinoma (OSCC) and compare the PI with lymph node metastasis, site of involvement, and habits.The Ki-67 antigen expression was immunohistochemically evaluated in a total of 102 cases that included the histopathologically diagnosed archival specimens of OSCCs. They were subdivided by Bryne’s histopathological grading into grade I (40 cases), grade II (32 cases), and grade III (30 cases). The nucleus with brown stain was considered positive. Cells were counted under 400× magnification. The proliferative activity thus determined was then expressed as a percentage of Ki-67 labeling index (Ki-67 LI) positive cells.A stepwise increase in the mean Ki-67 LI was found from grade I to III squamous cell carcinoma, thus correlating with the histological grading. In addition, there was a higher PI seen in cases associated with metastatic lymph node, which concords with the higher biologic aggressiveness and poor prognosis of the lesion.The present study shows a definitive correlation of Ki-67 antigen with the Bryne’s histological grading, all the parameters of Bryne’s grading for OSCC and lymph node status of the patient proving its association as an effective tool to grade the tumors and finally read the prognosis of the tumor.Cell proliferation is regarded as one of the most important biologic mechanisms in oncogenesis. The role of cell proliferation in tumor progression has been inferred in studies concerned with human cancer by comparing the PI of normal tissue, preneoplastic and neoplastic lesions. The Ki-67 antigen-labeled cells can prove to be an effective aid to grade the tumors. It might be possible to standardize and objectify tumor grading among pathology laboratories.

Anticancer Res. 2018 Feb;38(2):795-802.

PDGFRα/HER2 and PDGFRα/p53 Co-expression in Oral Squamous Cell Carcinoma.

Cierpikowski P1, Lis-Nawara A2, Gajdzis P3, Bar J2.

The purpose of this study was to explore the parallel expression of platelet-derived growth factor receptor α (PDGFRα) and human epidermal growth factor receptor 2 (HER2) or p53 in relation to clinicopathological parameters of oral squamous cell carcinoma (OSCC) to define their role in progressive growth of tumor.Expression of PDGFRα, HER2 and p53 was evaluated in 71 OSCC samples by immunohistochemistry. HER2 status was verified by fluorescence in situ hybridization.PDGFRα and p53 expression were associated with tumor grade (p=0.043 and p=0.040, respectively). HER2 expression was more frequent in advanced (III/IV) cancer (p=0.006). A positive correlation of PDGFRα with HER2 (r=0.267; p=0.024) and with p53 (r=0.266; p=0.025) was noted. PDGFRα/HER2 and PDGFRα/p53 co-expression was found more often in G3 than in G1 and G2 tumors (p=0.008 and p=0.015, respectively).Our study revealed that PDGFRα/HER2 and PDGFRα/p53 co-expression exists in poorly differentiated OSCCs, suggesting that cooperation between these proteins might enhance aggressive behavior of tumor.

Otolaryngol Head Neck Surg. 2018 Apr;158(4):667-676. doi: 10.1177/0194599817745284. Epub 2018 Jan 23.

Correlation of Inflammatory Markers, Survival, and COX2 Expression in Oral Cancer and Implications for Prognosis.

Sano Y1,2, Kogashiwa Y1, Araki R3, Enoki Y1, Ikeda T4, Yoda T2, Nakahira M1, Sugasawa M1.

Objective Peripheral blood-derived inflammation-based scores, such as the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and the combination of platelet count and NLR, have recently been proposed as prognostic markers in solid tumors. The purpose of this study was to investigate the validity of inflammatory markers as predictive prognostic factors for locally advanced oral squamous cell carcinoma (OSCC). In addition, we evaluated the potential correlation between systemic inflammation and local expression of COX2. Study Design Retrospective chart review and histologic analysis. Setting Tertiary referral academic center. Subjects and Methods We conducted a retrospective analysis of 94 patients with advanced OSCC treated with surgery at our hospital between 2007 and 2015. The relationship among patient survival, systemic inflammatory markers, and local COX2 expression was evaluated. Local COX2 expression in surgical specimens was measured by immunohistochemistry. Results High NLR and high PLR were associated with significantly shorter overall survival and cancer-specific survival. Multivariate analysis revealed that cN stage, NLR, and postoperative radiation/chemoradiation were significantly associated with overall survival and cancer-specific survival. PLR and combination of platelet count and NLR were significantly correlated with tumor expression of COX2. Finally, patients with cN2 stage disease and high local COX2 expression had a significantly worse prognosis than other patient groups. Conclusion Pretreatment inflammatory markers are useful as prognostic factors in advanced OSCC. Our study suggests that local COX2 may be affected by systemic inflammation and that the prognostic impact of COX2 expression depends on host factors and tumor characteristics.

J Oral Pathol Med. 2018 Jan 18. doi: 10.1111/jop.12682. [Epub ahead of print]

An immunohistochemical score to predict the outcome for oral squamous cell carcinoma.

Monteiro LS1, Diniz-Freitas M2, Warnakulasuriya S3,4, Garcia-Caballero T5, Forteza J6, Fraga M7.

Oral cancer is a major public health problem worldwide, with a poor survival. Our aim was to evaluate several protein markers in oral squamous cell carcinomas (OSCC) and analyse their prognostic value on patient’s survival.We analysed the expression of EGFR, p53, p27, p16, cyclin D1, cyclin A2, COX-2, Ki-67, Bcl-2, VEGFR-1 and VEGFR-2, by immunohistochemistry on 67 primary OSCC. Cancer-specific survival (CSS) analysis was evaluated by the Cox regression model.Markers showed variable expression between 27.9% and 95.2%. In univariate analysis for CSS, we found that four of the tested markers, namely high expression of p53 (P = .001), EGFR (P = .003), cyclin A2 (P = .005) and low expression of p16 (P = .019), along with clinical stage (P < .001), tumour size (P < .001), presence of nodal metastasis (P < .001) and perineural permeation (P = .039) were related to decreased survival. On the basis of these results, we constructed an immunohistochemical score hinging on the possibility that any tumour could express none of these four markers (score 0), one or two markers (score 1) and three or more markers (score 2). In multivariable analysis, this immunohistochemical score revealed an independent prognostic value on cancer-specific survival (P = .001; HR: 3.7: 95%CI 1.7-7.9). Moreover, we confirmed that in early-stage tumours (stage I or II) this score maintained its independent prognostic value (P = .025; HR: 7.9, 95%CI 1.3-49.1) on CSS.The expression of the markers p53, p16, EGFR and cyclin A in OSCC, combined to give an immunohistochemical score, may identify high-risk subgroups for decreased survival and to further guide therapeutic decisions.

Hum Pathol. 2018 Jan 4. pii: S0046-8177(17)30492-6. doi: 10.1016/j.humpath.2017.12.021. [Epub ahead of print]

Tumor budding as a novel predictor of occult metastasis in cT2N0 tongue squamous cell carcinoma.

Sakata J1, Yamana K1, Yoshida R2, Matsuoka Y1, Kawahara K1, Arita H1, Nakashima H1, Nagata M1, Hirosue A1, Kawaguchi S1, Gohara S1, Nagao Y1, Hiraki A3, Shinohara M4, Toya R5, Murakami R6, Nakayama H1.

Occult neck metastasis is an important prognostic factor in patients with tongue squamous cell carcinoma (TSCC) who are deemed clinically negative for neck metastasis. The purpose of this study was to identify predictive factors for occult neck metastasis arising from TSCC and to determine patient prognosis. Ninety-seven patients with cT2N0 TSCC who underwent surgical resection of their primary lesion as initial therapy were enrolled in this retrospective study. Cutoff values for depth of invasion (≥3.3 mm) and the tumor budding score (≥4) were determined using receiver operator characteristic analyses. Univariate and multivariate analyses revealed that a tumor budding score ≥4 is a significant independent predictive factor for the occurrence of occult neck metastasis, which in turn is a significant independent prognostic factor. When evaluating tumor budding, we demonstrated greater inter-observer and intra-observer agreement when using immunohistochemical staining for cytokeratin AE1/AE3 than with hematoxylin and eosin staining (HE). We conclude that the evaluation of tumor budding is effective for identifying populations at high risk of occult neck metastasis, which will enable the planning of appropriate therapeutic strategies for patients with cT2N0 TSCC. Furthermore, cytokeratin staining is recommended over HE staining for simpler and more accurate evaluation of tumor budding.

J Oral Pathol Med. 2018 Mar;47(3):246-252. doi: 10.1111/jop.12674. Epub 2018 Feb 1.

Focal adhesion kinases in head and neck squamous cell carcinoma.

Flores APC1, Dias KB1, Hildebrand LC1, Oliveira MG1, Lamers ML2, Sant’Ana Filho M1.

Focal adhesion kinase (FAK) phosphorylation contributes to the regulation of growth factors that promote cellular adhesion, mobility, and survival, being a key factor in tumor development. The objective of this study was to evaluate the immunohistochemical expression patterns of FAK and its phosphorylated forms, FAK Tyr-576 and FAK Tyr-925, in head and neck squamous cell carcinoma and non-neoplastic adjacent epithelial tissue (AE).The percentage of immunohistochemistry stained cells and its correlation with clinicopathological variables and prognosis were determined using samples from 54 patients.

FAK, FAK Tyr-576, and FAK Tyr-925 overexpression was observed in tumor zones and AE. FAK Tyr-576 immunostaining showed a relationship with tumor clinicopathological parameters. Moreover, positive immunostaining of FAK Tyr-576 in AEsue was associated with patients prognoses.Increased expression of FAK Tyr-576 could enable identification of tumors with a more aggressive behavior and epithelial alterations before the appearance of clinical or histological manifestations.

Oral Oncol. 2018 Jan;76:22-26. doi: 10.1016/j.oraloncology.2017.10.025. Epub 2017 Nov 29.

RACK1 is an organ-specific prognostic predictor in OSCC.

Liu S1, Liu J1, Wang J1, Cheng J1, Zeng X1, Ji N1, Li J2, Chen Q3.

This study aims to verify that RACK1 is an organ-specific prognostic predictor in patients with oral squamous cell carcinoma (OSCC).The RACK1 expression level was assessed by immunohistochemistry (IHC) in a total of 342 OSCC patients from 3 independent cohorts. The multivariate hazard ratios for Overall Survival (OS) was determined by Cox proportional hazards regression model. OS was analyzed in 460 Head Neck Squamous Cell Carcinoma (HNSCC) patients from TCGA data set. The expression level of RACK1 was analyzed in 60 cases multiple organ tissue microarrays representing both normal and cancer tissues by IHC, and in TCGA database of mRNA abundance in cancers and paired normal tissues.The median follow-up times of patients in the study was 74, 52, and 78 months. High expression of RACK1 was identified in tumors from 103 of 151 patients (68.2%), 51 of 83 patients (61.4%), and 59 of 108 patients (54.6%). Compared with low expression, high expression of RACK1 was strongly associated with worse OS, with HR of 0.5995 (95% CI, 0.3929 to 0.9147; P=0.0176), 0.4402 (95% CI, 0.2321 to 0.8348; P=0.0120), and 0.5010 (95% CI, 0.2886 to 0.8699; P=0.0141). This finding is consistent with TCGA HNSCC data (P=0.0276). Tissue microarrays analyses showed different protein expression level of RACK1 in multiple human carcinomas and this finding is consistent with the TCGA database analysis of RACK1 mRNA abundance.Our findings demonstrated that RACK1 is a good independent organ-specific predictor of the risk of death in OSCC.

J Oral Pathol Med. 2018 Mar;47(3):240-245. doi: 10.1111/jop.12673. Epub 2018 Jan 22.

EZH2 overexpression in head and neck cancer is related to lymph node metastasis.

Nienstedt JC1, Schroeder C2,3, Clauditz T2, Simon R2, Sauter G2, Muenscher A4, Blessmann M5, Hanken H6, Pflug C1.

Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the polycomb repressive complex 2, plays an important role in tumor development and progression by interacting with histone and non-histone proteins. EZH2 represents a putative therapeutic target and has been suggested as a prognostic marker in several cancer types.This study investigates the prognostic relevance of immunohistochemical EZH2 expression in head and neck squamous cell carcinoma. Tissue microarray sections with 667 cancers of oral cavity, oro- and hypopharynx and larynx were analyzed for EZH2 expression.Nuclear EZH2 staining was recorded in 322 (81.8%) of 394 cases. Staining was weak in 33 (10.2%), moderate in 128 (39.6%), and strong in 103 (32.0%) cancers. The prevalence of EZH2 expression in tumors of the oral cavity and the orohypopharynx was higher as compared to cancers of the larynx (P = .0023). EZH2 expression was correlated to presence of lymph node metastasis (P = .0089) but was unrelated to histological grade, tumor stage, surgical margin, or distant metastasis. EZH2 expression had no impact on patient survival.The high prevalence of EZH2 expression in head and neck squamous cell carcinoma stresses its capability as a therapeutic target.

J Clin Diagn Res. 2017 Sep;11(9):ZC51-ZC54. doi: 10.7860/JCDR/2017/29363.10601. Epub 2017 Sep 1.

Possible Role of Bcl-2 Expression in Metastatic and Non Metastatic Oral Squamous Cell Carcinoma.

Pavithra V1, Kumari K2, Haragannavar VC3, Rao RS4, Nambiar S5, Augustine D3, Sowmya SV6.

Oral carcinoma is a global health problem. India accounts for one-third of world burden with high prevalence rate of 2.5 million and mortality rate of 5.5 lacs per year. Oral carcinogenesis is a multistage process that frequently involves invasion and metastasis that needs early detection and treatment to improve the overall quality of life. The ability of Oral Squamous Cell Carcinoma (OSCC) to metastasize to lymph nodes does not always show a relationship with clinical staging. A spectrum of molecular mechanisms is involved in carcinogenesis, where defect in the regulation of apoptosis is assumed to contribute to the pathogenesis and progression of cancer. Apoptosis regulatory genes include the antiapoptotic protein such as B-cell lymphoma-2 (Bcl-2) gene that might be used as a molecular marker to evaluate the biological behaviour of oral cancer.To evaluate and correlate the Bcl-2 expression in OSCC patients with lymphnode metastasis and without metastasis.The study comprised of 30 samples, 15 cases of metastatic and 15 non-metastatic primary OSCC. All the cases were stained for routine Hematoxylin and Eosin (H&E), and Bcl-2 antibody by immunohistochemistry. The H&E stained sections were evaluated for Lymphocytic Infiltrate (LI) and Pattern Of Invasion (POI). Bcl-2 stained sections were evaluated for staining intensity and distribution. The differences between the groups were statistically analysed using chi-square test.The histopathological parameters, LI and POI did not show any statistical difference between the study groups. Expression of Bcl-2 in OSCC was 33.3% among the study groups, where metastatic group showed a positive expression of 13.3% and 20% in non-metastatic OSCC that did not show statistically significance among the study groups.There was no significant difference in the expression of Bcl-2 between the study groups. Apoptosis is regulated by interaction among the Bcl-2 gene family. Hence, evaluation of Bcl-2 along with other apoptotic regulating proteins could define the role in pathogenesis and prognosis of metastatic and non-metastatic OSCC.

Oncotarget. 2017 May 30;8(46):80348-80357. doi: 10.18632/oncotarget.18302. eCollection 2017 Oct 6.

KDM4A as a prognostic marker of oral squamous cell carcinoma: Evidence from tissue microarray studies in a multicenter cohort.

Jin X1,2, Xu H2, Wu X2, Li T2, Li J2, Zhou Y2, Dan H2, Jiang L2, Zeng X2, Ji P3,4,1, Chen Q2.

Previous studies have identified histone demethylase KDM4A to be a key epigenetic priming factor for the invasive squamous cell carcinoma growth and metastasis. The purpose of this study was to examine KDM4A as an independent prognostic marker in oral squamous cell carcinoma, using multicenter tissue microarrays.

The expression of KDM4A was significantly correlated with lymph node metastasis and TNM stage. KDM4A overexpression was associated with poor overall survival, and it was found to be a statistically significant independent predictor of all-cause mortality. These findings are validated by external TCGA HNSCC data. Addition of KDM4A expression improved the discriminatory accuracy of standard clinicopathologic features for prediction of cancer-specific survival (Model 4, area under the curve = 0.740, 95% confidence interval = 0.685 to 0.795, and Model 3, AUC = 0.695, 95% CI = 0.637 to 0.753, respectively).KDM4A expression was measured by immunohistochemistry, using tissue microarrays of OSCC samples collected from 313 patients. Kruskal-Wallis and chi-square tests were applied to investigate the correlation between KDM4A expression and clinicopathological factors. Overall survival analysis was performed using the Kaplan-Meier and multivariable logistic regression models, and the predictive ability of KDM4A in combination with known OSCC risk factors was evaluated. Receiver operating characteristic curves were used to assess discriminatory accuracy of these models. Additionally, disease-free survival was analyzed in patients with head and neck SCC reported on The Cancer Genome Atlas database.KDM4A expression is an independent predictor for the survival time of patients with OSCC and may be a valuable consideration to postoperative treatment options.

Oral Oncol. 2017 Nov;74:68-76. doi: 10.1016/j.oraloncology.2017.09.009. Epub 2017 Sep 27.

Prognostic value of c-MET in head and neck cancer: A systematic review and meta-analysis of aggregate data.

Szturz P1, Budíková M2, Vermorken JB3, Horová I2, Gál B4, Raymond E5, de Gramont A6, Faivre S7.

The hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (c-MET) ligand/receptor axis has been implicated in pathogenesis of malignant diseases including squamous cell carcinoma of the head and neck (SCCHN). Overexpression of c-MET has been reported as a common molecular abnormality in SCCHN, although its prognostic and predictive value remains to be validated.We systematically searched literature for studies evaluating c-MET expression on immunohistochemistry in newly diagnosed, non-metastatic SCCHN. The c-MET expressing cases were classified into three categories according to predefined cut-off values for positivity. Our aim was to assess the prevalence of c-MET expression and its relationship with selected clinicopathological variables.Twenty-eight studies with 2019 cases were included. Relative frequencies of c-MET expression above cut-off levels I, II, and III were 81.8%, 63.8%, and 46.2%, respectively. Differences between these three values were statistically significant (p<1.0×10-6). Above cut-off level II, c-MET positivity was associated with worse overall survival (p=4.0×10-6), positive nodal status (p=1.0×10-4), higher disease stage (p=7.0×10-4), older age (p=2.1×10-3), disease recurrence (p=2.0×10-2), and primary tumour localization in the oral cavity (p=2.3×10-2). Above cut-off level III, c-MET positivity was associated with worse disease-free or progression-free survival (p=9.0×10-6), p16 negativity (p=2.4×10-4), worse overall survival (p=4.0×10-4), positive epidermal growth factor receptor (EGFR) status (p=7.2×10-4), and larger primary tumours (p=4.6×10-3).In SCCHN, immunohistochemical overexpression of c-MET above cut-off levels III and particularly II was associated with inferior survival outcomes and advanced disease. Moreover, it represents a promising predictive biomarker for c-MET targeting, yet the optimal scoring method remains to be defined.

 

Oncol Lett. 2017 Nov;14(5):5434-5442. doi: 10.3892/ol.2017.6829. Epub 2017 Aug 25.

Impact of tumoral carbonic anhydrase IX and Ki-67 expression on survival in oral squamous cell carcinoma patients.

Brockton NT1, Lohavanichbutr P2, Enwere EK3, Upton MP4, Kornaga EN3, Nakoneshny SC5, Bose P5, Chen C2, Dort JC6.

Oral squamous cell carcinoma (OSCC) is the most commonly diagnosed type of head and neck cancer, accounting for ~300,000 new cases worldwide annually. Carbonic anhydrase IX (CAIX) and Ki-67 have been associated with reduced disease-specific survival (DSS) in patients with OSCC. We previously proposed a combined CAIX and Ki-67 signature of ‘functional hypoxia’ and sought to replicate this association in a larger independent cohort of patients with OSCC at the Fred Hutchinson Cancer Research Center (FHCRC) in Seattle. The study population included patients with incident primary OSCC treated at the University of Washington Medical Center and the Harborview Medical Center in Seattle between December 2003 and February 2012. Archived tumor blocks were obtained with tissue samples from 189 patients, and triplicate 0.6 mm cores were assembled into tissue microarrays (TMAs). Fluorescence immunohistochemistry and AQUAnalysis® were used to quantify the expression of tumoral CAIX (tCAIX) and stromal CAIX (sCAIX) and tumoral Ki-67 for each TMA core. Hazard ratios for DSS were calculated using Cox proportional hazards analysis. High tCAIX and sCAIX expression levels were associated with reduced DSS (aHR=1.003, 95% CI:1.00-1.01 and aHR=1.010, 95% CI:1.001-1.019, per AQUA score unit, respectively). Ki-67 expression was not associated with survival (aHR=1.01, 95% CI:0.99-1.02) in the FHCRC cohort. DSS for patients with high sCAIX and low Ki-67 did not differ from that of other patient groups. Elevated tCAIX was associated with reduced DSS as a continuous and as a dichotomized (75%) variable. sCAIX was associated with DSS as a continuous variable but not when dichotomized (75%). However, the previously proposed ‘functional hypoxia’ signature was not replicated in the current FHCRC study. The failure to replicate our prior observation of poorer survival in patients with combined high sCAIX and low tumoral Ki-67 was likely due to the absence of an association between tumoral Ki-67 and DSS in this cohort. However, the association between DSS and tCAIX and sCAIX supports a role for CAIX in OSCC clinical outcomes.

Oncotarget. 2017 Aug 19;8(43):74736-74754. doi: 10.18632/oncotarget.20360. eCollection 2017 Sep 26.

Fascin promotes migration and invasion and is a prognostic marker for oral squamous cell carcinoma.

Rodrigues PC1,2, Sawazaki-Calone I3, Ervolino de Oliveira C1, Soares Macedo CC1, Dourado MR1,2, Cervigne NK1,4, Miguel MC5, Ferreira do Carmo A1,5, Lambert DW6, Graner E1, Daniela da Silva S7,8, Alaoui-Jamali MA7,8, Paes Leme AF9, Salo TA1,2,10, Coletta RD1.

Oral squamous cell carcinoma (OSCC) prognosis is related to clinical stage and histological grade. However, this stratification needs to be refined. We conducted a comparative proteome study in microdissected samples from normal oral mucosa and OSCC to identify biomarkers for malignancy. Fascin and plectin were identified as differently expressed and both are implicated in several malignancies, but the clinical impacts of aberrant fascin and plectin expression in OSCCs remains largely unknown. Immunohistochemistry and real-time quantitative PCR were carried out in ex vivo OSCC samples and cell lines. A loss-of-function strategy using shRNA targeting fascin was employed to investigate in vitro and in vivo the fascin role on oral tumorigenesis. Transfections of microRNA mimics were performed to determine whether the fascin overexpression is regulated by miR-138 and miR-145. We found that fascin and plectin are frequently upregulated in OSCC samples and cell lines, but only fascin overexpression is an independent unfavorable prognostic indicator of disease-specific survival. In combination with advanced T stage, high fascin level is also an independent factor of disease-free survival. Knockdown of fascin in OSCC cells promoted cell adhesion and inhibited migration, invasion and EMT, and forced expression of miR-138 in OSCC cells significantly decreased the expression of fascin. In addition, fascin downregulation leads to reduced filopodia formation and decrease on paxillin expression. The subcutaneous xenograft model showed that tumors formed in the presence of low levels of fascin were significantly smaller compared to those formed with high fascin levels. Collectively, our findings suggest that fascin expression correlates with disease progression and may serve as a prognostic marker and therapeutic target for patients with OSCC.

J Oral Pathol Med. 2018 Feb;47(2):128-135. doi: 10.1111/jop.12653. Epub 2017 Nov 2.

Cell proliferation is associated with intensity of tumor budding in oral squamous cell carcinoma.

Marangon Junior H1,2, Leão PLR1, Melo VVM1, Caixeta ÂB1, Souza PEA1, de Aguiar MCF3, Horta MCR1.

Tumor budding is a morphological marker of cancer invasion, defined as the presence of isolated or small clusters of neoplastic cells at the tumor invasive front. This study aimed to evaluate the association between intensity of tumor budding and cell proliferation in oral squamous cell carcinoma (OSCC).Immunohistochemistry was employed in 163 OSCC samples to detect the cell proliferation marker Ki-67 and multicytokeratin (to identify OSCC cells in tumor budding evaluation). The Mann-Whitney test was used to evaluate differences in the cell proliferation index between samples with high-intensity tumor budding and samples with low-intensity or no tumor budding. In samples with high-intensity tumor budding, the Wilcoxon test was used to evaluate differences in the cell proliferation index between the budding area and the area outside the budding. The chi-square test assessed the association between cell proliferation index and intensity of tumor budding.The cell proliferation index was higher in samples with high-intensity tumor budding than in samples with low-intensity or no tumor budding (P < .05). Tumors with high-intensity tumor budding showed a higher cell proliferation index in the budding area than in the area outside the budding (P < .05). Finally, samples showing high-intensity tumor budding were associated with high cell proliferation index (P < .05).Cell proliferation is positively associated with intensity of tumor budding in OSCC. Moreover, in tumors showing high-intensity tumor budding, the budding area is the location of higher cell proliferation. These findings reinforce the hypothesis that tumor budding is associated with the biological behavior of OSCC.

J Cancer Res Clin Oncol. 2018 Jan;144(1):53-61. doi: 10.1007/s00432-017-2528-x. Epub 2017 Oct 11.

Prevalence of fibroblast growth factor receptor 1 (FGFR1) amplification in squamous cell carcinomas of the head and neck.

Clauditz TS1, Böttcher A2, Hanken H3, Borgmann K4, Sauter G5, Wilczak W5, Grob T6, Münscher A2.

FGFR1 is a receptor tyrosine kinases involved in tumor growth signaling, survival, and differentiation in many solid cancer types. There is growing evidence that FGFR1 amplification might predict therapy response to FGFR1 inhibitors in squamous cell lung cancers. To estimate the potential applicability of anti FGFR1 therapies in squamous cell carcinomas of the head and neck, we studied patterns of FGFR1 amplification using fluorescence in situ hybridization (FISH).A tissue microarray was constructed from 453 primary treatment-naive squamous cell carcinomas of the head and neck regions with histopathological and clinical follow-up data [including oral cavity (n = 222), oropharynx (n = 126), and larynx (n = 105)]. FGFR1 and centromere 8 copy numbers were assessed by dual-color FISH. FGFR1 amplification was defined as a copy number ratio FGFR1: centromere 8 ≥ 2.0. HPV sequencing and p16 immunohistochemistry (IHC) were applied to FGFR1-amplified cancers.FISH analysis was successful in 297 (66%) of the 453 cancers. FGFR1 amplification was found in 6% of analyzable tumors, and was more frequent in tumors of the oral cavity (13/133 amplified, 10%), than cancers of other localizations (1/79 oropharynx, 4/85 larynx; p = 0.007 and 0.159, respectively). One out of 18 FGFR1 amplified cancers was HPV positive. No associations were found between FGFR1 amplification and tumor phenotype or p16 IHC.Head and neck cancers are recurrently affected by FGFR1 amplification, with a predominance in cancers of the oral cavity. Finding only one HPV positive and FGFR1 amplified cancer argues against a causal relationship between HPV and FGFR1 amplifications.

Oncotarget. 2017 Jul 17;8(40):68252-68262. doi: 10.18632/oncotarget.19291. eCollection 2017 Sep 15.

Pyruvate kinase M2 deregulation enhances the metastatic potential of tongue squamous cell carcinoma.

Wang W#1, He Q#1, Sun J#1, Liu Z1, Zhao L1, Lu Z1, Zhou X2,3, Wang A1.

Pyruvate kinase M2 (PKM2) has been verified to correlate with the prognosis of many types of cancer. However, its role in the development and metastasis of tongue squamous cell carcinoma (TSCC) remains unclear. The immunohistochemistry (IHC) results confirmed that PKM2 is overexpressed in patients with TSCC. PKM2 up-regulation was related to lymph node metastasis and associated with reduced overall survival. According to the microarray analysis and Western blots, PKM2 expression was up-regulated in TSCC cells with enhanced metastatic potential. PKM2 knockdown inhibited cell migration and invasion, reduced SOD2 (manganese superoxide dismutase) activity and the intracellular H2O2 level, and inhibited tumour growth and lung metastasis in vivo. PKM2 overexpression promoted cell migration and invasion, and increased SOD2 activity and the intracellular H2O2 level. Moreover, miR-138 directly targeted PKM2 and inhibited PKM2 expression. Thus, PKM2 deregulation plays an important role in TSCC and may serve as a biomarker of metastatic potential or as a therapeutic target in patients with TSCC. PKM2, a miR-138 target gene, enhances the metastatic potential of TSCC through the SOD2-H2O2 pathway.

 

Olsen MH, Bøje CR, Kjær TK, Steding-Jessen M, Johansen C, Overgaard J, Dalton SO. Socioeconomic position and stage at diagnosis of head and neck cancer – a nationwide study from DAHANCA. Acta Oncol. 2015 May;54(5):759-66. doi: 10.3109/0284186X.2014.998279. Epub 2015 Mar 3.

Socioeconomic differences in survival after head and neck squamous cell carcinoma (HNSCC) are among the greatest for any malignancy. To improve our understanding of the mechanisms by which socioeconomic position influences HNSCC survival, we investigated the association between socioeconomic position and advanced stage HNSCC at diagnosis.Men and women with HNSCC diagnosed between 1992 and 2008 were identified in the Danish Head and Neck Cancer Group (DAHANCA) database, which contains detailed information on all cases of HNSCC treated in Denmark. Individual information on the following four socioeconomic indicators: highest attained educational level, cohabitation status, disposable income and degree of urbanisation were obtained from Statistics Denmark. For the 9683 cases on which there was full information, we estimated odds ratios (ORs) for a diagnosis of advanced stage (TNM III-IV) HNSCC in multivariate logistic regression models by site (glottic, non-glottic larynx, oropharynx, hypopharynx and oral cancer), with adjustment for age, gender, period of diagnosis, education, income, cohabitation status, degree of urbanisation and comorbidity in accordance with a causal diagram.For all HNSCC sites, the ORs for advanced stage at diagnosis were increased for patients with low income and for men living alone. For glottic and oral cancers, the ORs for advanced stage HNSCC increased systematically by decreasing length of education. Increased ORs were found for hypopharynx cancer patients living in rural areas or provincial cities. Having one or more comorbid conditions was associated with an increased OR for advanced stage oral cancer but with a decreased OR for oropharynx cancer.In this nationwide population-based study, socioeconomic differences in stage at diagnosis were found for all HNSCC subsites. Focus on the high risk for advanced stage HNSCC among vulnerable patients may be beneficial during referral and diagnosis in order to improve HNSCC outcomes.

Astrup GL, Hofsø K, Bjordal K, Guren MG, Vistad I, Cooper B, Miaskowski C, Rustøen T. Patient factors and quality of life outcomes differ among four subgroups of oncology patients based on symptom occurrence. Acta Oncol. 2017 Mar;56(3):462-470. doi: 10.1080/0284186X.2016.1273546. Epub 2017 Jan 12.

The purposes of this study were to determine if subgroups of oncology patients could be identified based on symptom occurrence rates and if these subgroups differed on a number of demographic and clinical characteristics, as well as on quality of life (QoL) outcomes.Latent class analysis (LCA) was used to identify subgroups (i.e. latent classes) of patients with distinct symptom experiences based on the occurrence rates for the 13 most common symptoms from the Memorial Symptom Assessment Scale. In total, 534 patients with breast, head and neck, colorectal, or ovarian cancer participated. Four latent classes of patients were identified based on probability of symptom occurrence: all low class [i.e. low probability for all symptoms (n = 152)], all high class (n = 149), high psychological class (n = 121), and low psychological class (n = 112). Patients in the all high class were significantly younger compared with patients in the all low class. Furthermore, compared to the other three classes, patients in the all high class had lower functional status and higher comorbidity scores, and reported poorer QoL scores. Patients in the high and low psychological classes had a moderate probability of reporting physical symptoms. Patients in the low psychological class reported a higher number of symptoms, a lower functional status, and poorer physical and total QoL scores.Distinct subgroups of oncology patients can be identified based on symptom occurrence rates. Patient characteristics that are associated with these subgroups can be used to identify patients who are at greater risk for multiple co-occurring symptoms and diminished QoL, so that these patients can be offered appropriate symptom management interventions.

Hagedoorn P, Vandenheede H, Vanthomme K, Willaert D, Gadeyne S. A cohort study into head and neck cancer mortality in Belgium (2001-11): Are individual socioeconomic differences conditional on area deprivation? Oral Oncol. 2016 Oct;61:76-82. doi: 10.1016/j.oraloncology.2016.08.014. Epub 2016 Aug 31.

The aim of this study is to assess to what extent individual and area-level socioeconomic position (SEP) are associated to head and neck cancer (HNC) mortality and to what extent they contribute to regional variation in HNC mortality in Belgium.Data on men aged 40-64 are collected from a population based dataset based on the 2001 Belgian census linked to register data on emigration and mortality for 2001-2011. Individual SEP is measured using education, employment status and housing conditions. Deprivation at municipal level is measured by a deprivation index. Absolute mortality differences are estimated by age standardised mortality rates. Multilevel Poisson models are used to estimate the association and interaction between HNC mortality and individual and area-level SEP, and to estimate the regional variation in HNC mortality.HNC mortality rates are significantly higher for men with a low SEP and men living in deprived areas. Cross-level interactions indicate that the association between individual SEP and HNC mortality is conditional on area deprivation. HNC mortality in deprived areas is especially high among high-SEP men. As a result, social disparities appear to be smaller in more deprived areas. Regional variation in HNC mortality was significant. Population composition partially explains this regional variation, while area deprivation and cross-level interactions explains little.Both individual and area-level deprivation are important determinants of HNC mortality. Underlying trends in incidence and survival, and risk factors, such as alcohol and tobacco use, should be explored further.

Van Hemelrijck WM, Willaert D, Gadeyne S. The geographic pattern of Belgian mortality: can socio-economic characteristics explain area differences? Arch Public Health. 2016 Jun 8;74:22. doi: 10.1186/s13690-016-0135-y. eCollection 2016.

Country averages for health outcomes hide important within-country variations. This paper probes into the geographic Belgian pattern of all-cause mortality and wishes to investigate the contribution of individual and area socio-economic characteristics to geographic mortality differences in men aged 45-64 during the period 2001-2011.Data originate from a linkage between the Belgian census of 2001 and register data on mortality and emigration during the period 2001-2011. Mortality rate ratios (MRRs) are estimated for districts and sub-districts compared to the Belgian average mortality level using Poisson regression modelling. Individual socio-economic position (SEP) indicators are added to examine the impact of these characteristics on the observed geographic pattern. In order to scrutinize the contribution of area-level socio-economic characteristics, random intercepts Poisson modelling is performed with predictors at the individual and the sub-district level. Random intercepts and slopes models are fitted to explore variability of individual-level SEP effects. All-cause MRRs for middle-aged Belgian men are higher in the geographic areas of the Walloon region and the Brussels-Capital Region (BCR) compared to those in the Flemish region. The highest MRRs are observed in the inner city of the BCR and in several Walloon cities. Their disadvantage can partially be explained by the lower individual SEP of men living in these areas. Similarly, the relatively low MRRs observed in the districts of Halle-Vilvoorde, Arlon and Virton can be related to the higher individual SEP. Among the area-level characteristics, both the percentage of men employed and the percentage of labourers in a sub-district have a protective effect on the individual MRR, regardless of individual SEP. Variability in individual-level SEP effects is limited.Individual SEP partly explains the observed mortality gap in Belgium for some areas. The percentage of men employed and the percentage of labourers in a sub-district have an additional effect on the individual MRR aside from that of individual SEP. However, these socio-economic factors cannot explain all of the observed differences. Other mechanisms such as public health policy, cultural habits and environmental influences contribute to the observed geographic pattern in all-cause mortality among middle-aged men.

Bryere J, Menvielle G, Dejardin O, Launay L, Molinie F, Stucker I, Luce D, Launoy G; ICARE group. Neighborhood deprivation and risk of head and neck cancer: A multilevel analysis from France. Oral Oncol. 2017 Aug;71:144-149. doi: 10.1016/j.oraloncology.2017.06.014. Epub 2017 Jun 26.

While it is known that cancer risk is related to area-level socioeconomic status, the extent to which these inequalities are explained by contextual effects is poorly documented especially for head and neck cancer.A case-control study, ICARE, included 2415 head and neck cancer cases and 3555 controls recruited between 2001 and 2007 from 10 French regions retrieved from a general cancer registry. Individual socioeconomic status was assessed using marital status, highest educational level and occupational social class. Area-level socioeconomic status was assessed using the French version of the European Deprivation Index (EDI). The relationship between both individual and area-based socioeconomic level and the risk of head and neck cancer was assessed by multilevel analyses.A higher risk for head and neck cancer was found in divorced compared with married individuals (OR=2.14, 95% CI=1.78-2.57), for individuals with a basic school-leaving qualification compared with those with higher education (OR=4.55 95% CI=3.72-5.57), for manual workers compared with managers (OR=4.91, 95% CI=3.92-6.15) and for individuals living in the most deprived areas compared with those living in the most affluent ones (OR=1.98, 95% CI=1.64-2.41). The influence of area-level socioeconomic status measured by EDI remained after controlling for individual socioeconomic characteristics (OR=1.51; 95% confidence interval: 1.23-1.85, p-value=0.0003).The role of individual socioeconomic status in the risk of head and neck cancer is undeniable, although contextual effects of deprived areas also increase the susceptibility of individuals developing the disease.

Shin JY, Yoon JK, Shin AK, Blumenfeld P, Mai M, Diaz AZ. Association of Insurance and Community-Level Socioeconomic Status With Treatment and Outcome of Squamous Cell Carcinoma of the Pharynx. JAMA Otolaryngol Head Neck Surg. 2017 Sep 1;143(9):899-907. doi: 10.1001/jamaoto.2017.0837.

This study extracted data from more than 1500 Commission on Cancer-accredited facilities collected in the National Cancer Database. A total of 35 559 patients diagnosed with SCC of the pharynx from 2004 through 2013 were identified. The χ2 test, Kaplan-Meier method, and Cox regression models were used to analyze data from April 1, 2016, through April 16, 2017.Among the 35 559 patients identified (75.6% men and 24.4% women; median age, 61 years [range, 18-90 years]), 15 146 (42.6%) had Medicare coverage; 13 061 (36.7%), private insurance; 4881 (13.7%), Medicaid coverage; and 2471 (6.9%), no insurance. Uninsured patients and Medicaid recipients were more likely to be younger, black, or Hispanic; to have lower median household income and lower educational attainment; to present with higher TNM stages of disease; and to start primary treatment at a later time from diagnosis. Those with private insurance (reference group) had significantly better overall survival than uninsured patients (hazard ratio [HR], 1.72; 95% CI, 1.59-1.87), Medicaid recipients (HR, 1.99; 95% CI, 1.88-2.12), or Medicare recipients (HR, 2.07; 95% CI, 1.99-2.16), as did those with median household income of at least $63 000 (reference) vs $48 000 to $62 999 (HR, 1.19; 95% CI, 1.13-1.26), $38 000 to $47 999 (HR, 1.31; 95% CI, 1.24-1.38), and less than $38 000 (HR, 1.51; 95% CI, 1.43-1.59). On multivariable analysis, insurance status and median household income remained independent prognostic factors for overall survival even after accounting for educational attainment, race, Charlson/Deyo comorbidity score, disease site, and TNM stage of disease.Insurance status and household income level are associated with outcome in patients with SCC of the pharynx. Those without insurance and with lower household income may significantly benefit from improving access to adequate, timely medical care. Additional investigations are necessary to develop targeted interventions to optimize access to standard medical treatments, adherence to physician management recommendations, and subsequently, prognosis in these patients at risk.

Andrade JO, Santos CA, Oliveira MC. Associated factors with oral cancer: a study of case control in a population of the Brazil’s Northeast. Rev Bras Epidemiol. 2015 Oct-Dec;18(4):894-905. doi: 10.1590/1980-5497201500040017.

This study aimed at assessing the association between factors such as age, sex, skin color, occupation, educational level, marital status, place of residence, and tobacco and alcohol consumptions and oral cancer in individuals in a city in the northeast of Brazil between 2002 and 2012.This is a case-control study. The case group consisted of 127 people attended at the Oral Injury Reference Center with histopathological diagnosis of oral squamous cell carcinoma. The control group consisted of 254 individuals treated at the same center. The study considered two controls for each case. The cases and controls were adjusted according to sex and age. Univariate and bivariate analyses were performed (Pearson χ2-test) to verify the correlation between the dependent variable (oral cancer) and the independent variables; odds ratio (OR) and the confidence interval of 95% (95%CI) were calculated. Finally, in the multivariate analysis, it was used as the hierarchical model with logistic regression to explain the interrelationships between the independent variables and oral cancer.Consumption of more than 20 cigarettes per day [OR = 6.64; 95%CI 2.07 – 21.32; p ≤ 0.001], an excessive alcohol consumption [OR = 3.25; 95%CI 1.03 – 10.22; p ≤ 0.044], and the synergistic consumption of tobacco and alcohol [OR = 9.65; 95%CI 1.57 – 59.08; p ≤ 0.014] are the most important risk factors for oral cancer.It was concluded that tobacco and alcohol consumptions are the most important factors for the development of oral cancer. Sociodemographic factors were not associated with this neoplasm after adjusting for smoking and drinking.

Lagergren J, Andersson G, Talbäck M, Drefahl S, Bihagen E, Härkönen J, Feychting M, Ljung R. Marital status, education, and income in relation to the risk of esophageal and gastric cancer by histological type and site. Cancer. 2016 Jan 15;122(2):207-12. doi: 10.1002/cncr.29731. Epub 2015 Oct 8.

A nationwide, Swedish population-based cohort study from 1991 to 2010 included individuals who were 50 years old or older. Data on exposures, covariates, and outcomes were obtained from well-maintained registers. Four esophagogastric tumor subtypes were analyzed in combination and separately: esophageal adenocarcinoma, esophageal squamous cell carcinoma, cardia adenocarcinoma, and noncardia gastric adenocarcinoma. Poisson regression was used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (CIs). Analyses were stratified by sex and adjusted for confounders.Among 4,734,227 participants (60,634,007 person-years), 24,095 developed esophageal or gastric cancer. In comparison with individuals in a long marriage, increased IRRs were found among participants who were in a shorter marriage or were never married, remarried, divorced, or widowed. These associations were indicated for each tumor subtype but were generally stronger for esophageal squamous cell carcinoma. Higher education and income were associated with decreased IRRs in a seemingly dose-response manner and similarly for each subtype. In comparison with the completion of only primary school, higher tertiary education rendered an IRR of 0.64 (95% CI, 0.60-0.69) for men and an IRR of 0.68 (95% CI, 0.61-0.75) for women. Comparing participants in the highest and lowest income brackets (highest 20% vs lowest 20%) revealed an IRR of 0.74 (95% CI, 0.70-0.79) for men and an IRR of 0.83 (95% CI, 0.76-0.91) for women.Divorce, widowhood, living alone, low educational attainment, and low income increase the risk of each subtype of esophageal and gastric cancer. These associations require attention when high-risk individuals are being identified

Baishya N, Das AK, Krishnatreya M, Das A, Das K, Kataki AC, Nandy P. A Pilot Study on Factors Associated with Presentation Delay in Patients Affected with Head and Neck Cancers. Asian Pac J Cancer Prev. 2015;16(11):4715-8.

Patient delay can contribute to a poor outcome in the management of head and neck cancers (HNC). The main objective of the present study was to investigate the factors associated with patient delay in our population.Patients with cancers of the head and neck attending a regional cancer center of North East India were consecutively interviewed during the period from June 2014 to November 2014. The participation of patients was voluntary. The questionnaire included information on age, gender, residential status, educational qualification, monthly family income, any family history of cancer, and history of prior awareness on cancer from television (TV) program and awareness program.Of 311 (n) patients, with an age range of 14-88 years (mean 55.4 years), 81.7% were males and 18.3% females (M:F=4.4). The overall median delay was 90 days (range=7 days-365 days), in illiterate patients the median delay was 90 days and 60 days in literate patients (P=0.002), the median delay in patients who had watched cancer awareness program on TV was 60 days and in patients who were unaware about cancer information from TV program had a median delay of 90 days (p=0.00021) and delay of <10 weeks was seen in 139 (44.6%) patients, a delay of 10-20 weeks in 98 (31.5%) patients, and a delay of 20-30 weeks in 63 (20.2%) patients.Education and awareness had a significant impact in reduction of median patient delay in our HNC cases.

Brusselaers N, Mattsson F, Lindblad M, Lagergren J. Association between education level and prognosis after esophageal cancer surgery: a Swedish population-based cohort study. PLoS One. 2015 Mar 26;10(3):e0121928. doi: 10.1371/journal.pone.0121928. eCollection 2015.

An association between education level and survival after esophageal cancer has recently been indicated, but remains uncertain. We conducted a large study with long follow-up to address this issue.This population-based cohort study included all patients operated for esophageal cancer in Sweden between 1987 and 2010 with follow-up until 2012. Level of education was categorized as compulsory (≤9 years), intermediate (10-12 years), or high (≥13 years). The main outcome measure was overall 5-year mortality after esophagectomy. Cox regression was used to estimate associations between education level and mortality, expressed as hazard ratios (HRs) with 95% confidence intervals (CIs), with adjustment for sex, age, co-morbidity, tumor stage, tumor histology, and assessing the impact of education level over time.Compared to patients with high education, the adjusted HR for mortality was 1.29 (95% CI 1.07-1.57) in the intermediate educated group and 1.42 (95% CI 1.17-1.71) in the compulsory educated group. The largest differences were found in early tumor stages (T-stage 0-1), with HRs of 1.73 (95% CI 1.00-2.99) and 2.58 (95% CI 1.51-4.42) for intermediate and compulsory educated patients respectively; and for squamous cell carcinoma, with corresponding HRs of 1.38 (95% CI 1.07-1.79) and 1.52 (95% CI 1.19-1.95) respectively.This Swedish population-based study showed an association between higher education level and improved survival after esophageal cancer surgery, independent of established prognostic factors. The associations were stronger in patients of an early tumor stage and squamous cell carcinoma.

Santi I, Kroll LE, Dietz A, Becher H, Ramroth H. To what degree is the association between educational inequality and laryngeal cancer explained by smoking, alcohol consumption, and occupational exposure? Scand J Work Environ Health. 2014 May 1;40(3):315-22. doi: 10.5271/sjweh.3403. Epub 2013 Nov 18.

The aim of this study was to measure the extent to which the association between socioeconomic status and laryngeal cancer among males is mediated by smoking, alcohol consumption, and occupational exposure.We used Karlson et al’s decomposition method for logit models, which returns the percentage of change in odds ratios (OR) due to confounding. This population-based, case-control study on laryngeal cancer was conducted in Germany in 1998-2000 and included 208 male cases and 702 controls. Information on occupational history, smoking, alcohol consumption, and education was collected through face-to-face interviews. Jobs coded according to ISCO-68 were linked to a recently developed job-classification index covering physical and psychosocial dimensions. A sub-index focused on jobs involving potentially carcinogenic agents (CAI) for the upper-aero digestive tract.When adjusted for smoking and alcohol consumption, higher OR were found for lower education. This OR decreased after further adjustment using the overall job index [2.9, 95% confidence interval (95% CI) 1.4-6.2], similar to the OR using the sub-index CAI (OR 2.7, 95% CI 1.3-5.8). Applying the Karlson et al method, 25.4% (95% CI 22.6-28.2%) of the reduction in these OR was due to occupational exposure (CAI), while smoking and alcohol consumption contributed to around 26.1% (95% CI 23.2-28.9%) and 2.7% (95% CI 1.7-3.8%), respectively.Occupational aspects, in particular the exposure to carcinogenic agents, explain a large portion of the association between low educational level and laryngeal cancer risk among males. Occupational effects are now easier to quantify using this recently developed and easily applicable index.

Santi I, Kroll LE, Dietz A, Becher H, Ramroth H. Occupation and educational inequalities in laryngeal cancer: the use of a job index. BMC Public Health. 2013 Nov 19;13:1080. doi: 10.1186/1471-2458-13-1080.

Previous studies tried to assess the association between socioeconomic status and laryngeal cancer. Alcohol and tobacco consumption explain already a large part of the social inequalities. Occupational exposures might explain a part of the remaining but the components and pathways of the socioeconomic contribution have yet to be fully disentangled. The aim of this study was to evaluate the role of occupation using different occupational indices, differentiating between physical, psycho-social and toxic exposures and trying to summarize the occupational burden into one variable.A population-based case-control study conducted in Germany in 1998-2000 included 208 male cases and 702 controls. Information on occupational history, smoking, alcohol consumption and education was collected with face-to-face interviews. A recently developed job-classification index was used to account for the occupational burden. A sub-index focussed on jobs involving potentially carcinogenic agents (CAI) for the upper aero digestive tract.When adjusted for smoking and alcohol consumption, higher odds ratios (ORs) were found for lower education. This OR decreased after further adjustment using the physical and psycho-social job indices (OR = 3.2, 95%-CI: 1.5-6.8), similar to the OR using the sub-index CAI (OR = 3.0, 95%-CI: 1.4-6.5).The use of an easily applicable control variable, simply constructed on standard occupational job classifications, provides the possibility to differentiate between educational and occupational contributions. Such an index might indirectly reflect the effect of carcinogenic agents, which are not collected in many studies.

Menvielle G, Rey G, Jougla E, Luce D. Diverging trends in educational inequalities in cancer mortality between men and women in the 2000s in France. BMC Public Health. 2013 Sep 10;13:823. doi: 10.1186/1471-2458-13-823.

Socioeconomic inequalities in cancer mortality have been observed in different European countries and the US until the end of the 1990s, with changes over time in the magnitude of these inequalities and contrasted situations between countries. The aim of this study is to estimate relative and absolute educational differences in cancer mortality in France between 1999 and 2007, and to compare these inequalities with those reported during the 1990s.Data from a representative sample including 1% of the French population were analysed. Educational differences among people aged 30-74 were quantified with hazard ratios and relative indices of inequality (RII) computed using Cox regression models as well as mortality rate difference and population attributable fraction.In the period 1999-2007, large relative inequalities were found among men for total cancer and smoking and/or alcohol related cancers mortality (lung, head and neck, oesophagus). Among women, educational differences were reported for total cancer, head and neck and uterus cancer mortality. No association was found between education and breast cancer mortality. Slight educational differences in colorectal cancer mortality were observed in men and women. For most frequent cancers, no change was observed in the magnitude of relative inequalities in mortality between the 1990s and the 2000s, although the RII for lung cancer increased both in men and women. Among women, a large increase in absolute inequalities in mortality was observed for all cancers combined, lung, head and neck and colorectal cancer. In contrast, among men, absolute inequalities in mortality decreased for all smoking and/or alcohol related cancers.Although social inequalities in cancer mortality are still high among men, an encouraging trend is observed. Among women though, the situation regarding social inequalities is less favourable, mainly due to a health improvement limited to higher educated women. These inequalities may be expected to further increase in future years.

Jemal A, Simard EP, Xu J, Ma J, Anderson RN. Selected cancers with increasing mortality rates by educational attainment in 26 states in the United States, 1993-2007. Cancer Causes Control. 2013 Mar;24(3):559-65. doi: 10.1007/s10552-012-9993-y. Epub 2012 May 22.

Mortality rates continue to increase for liver, esophagus, and pancreatic cancers in non-Hispanic whites and for liver cancer in non-Hispanic blacks. However, the extent to which trends vary by socioeconomic status (SES) is unknown.We calculated age-standardized death rates for liver, esophagus, and pancreas cancers for non-Hispanic whites and non-Hispanic blacks aged 25-64 years by sex and level of education (≤12, 13-15, and ≥16 years, as a SES proxy) during 1993-2007 using mortality data from 26 states with consistent education information on death certificates. Temporal trends were evaluated using log-linear regression, and rate ratios (RRs) with 95 % confidence intervals (CIs) compared death rates in persons with ≤12 versus ≥16 years of education.Generally, death rates increased for cancers of the liver, esophagus, and pancreas in non-Hispanic whites and non-Hispanic blacks (liver cancer only) with ≤12 and 13-15 years of education, with steeper increases in the least educated group. In contrast, rates remained stable in persons with ≥16 years of education. During 1993-2007, the RR (rates in ≤12 versus ≥16 years of education) increased for all three cancers, particularly for liver cancer among men which increased from 1.76 (95 % CI, 1.38-2.25) to 3.23 (95 % CI, 2.78-3.75) in non-Hispanic whites and from 1.28 (95 % CI, 0.71-2.30) to 3.64 (95 % CI, 2.44-5.44) in non-Hispanic blacks.The recent increase in mortality rates for liver, esophagus, and pancreatic cancers in non-Hispanic whites and for liver cancer in non-Hispanic blacks reflects increases among those with lower education levels.

Chen AY, DeSantis C, Jemal A. US mortality rates for oral cavity and pharyngeal cancer by educational attainment. Arch Otolaryngol Head Neck Surg. 2011 Nov;137(11):1094-9. doi: 10.1001/archoto.2011.180.

To describe trends in mortality rates for patients with oral cavity and pharynx cancer by educational attainment, race/ethnicity, sex, and association with human papillomavirus infection.Twenty-six states.White and black men and women aged 25 to 64 years.Age-standardized mortality rates for 2005 to 2007 and trends for 1993 to 2007.

From 1993 to 2007, overall mortality rates for patients with oral cavity and pharynx cancer decreased among black and white men and women; however, rates among white men have stabilized since 1999. The largest decreases in mortality rates were among black men and women with 12 years of education (-4.95% and -3.72%, respectively). Mortality rates for patients with oral cavity and pharynx cancers decreased significantly among men and women with more than 12 years of education, regardless of race/ethnicity (except for black women), whereas rates increased among white men with less than 12 years of education. Mortality trends vary substantially for human papillomavirus-related and human papillomavirus-unrelated sites.We observed decreasing mortality rates for patients with oral cavity and pharyngeal cancer among whites and blacks; however, decreases were greatest among those with at least 12 years of education. This difference in mortality trends may reflect the changing prevalence of smoking and sexual behaviors among populations of different educational attainment.

Johnson S, Corsten MJ, McDonald JT, Gupta M. Cancer prevalence and education by cancer site: logistic regression analysis. J Otolaryngol Head Neck Surg. 2010 Oct;39(5):555-60.

Previously, using the American National Health Interview Survey (NHIS) and a logistic regression analysis, we found that upper aerodigestive tract (UADT) cancer is correlated with low socioeconomic status (SES). The objective of this study was to determine if this correlation between low SES and cancer prevalence exists for other cancers.We again used the NHIS and employed education level as our main measure of SES. We controlled for potentially confounding factors, including smoking status and alcohol consumption.We found that only two cancer subsites shared the pattern of increased prevalence with low education level and decreased prevalence with high education level: UADT cancer and cervical cancer.UADT cancer and cervical cancer were the only two cancers identified that had a link between prevalence and lower education level. This raises the possibility that an associated risk factor for the two cancers is causing the relationship between lower education level and prevalence.

Mouw T, Koster A, Wright ME, Blank MM, Moore SC, Hollenbeck A, Schatzkin A. Education and risk of cancer in a large cohort of men and women in the United States. PLoS One. 2008;3(11):e3639. doi: 10.1371/journal.pone.0003639. Epub 2008 Nov 4.

Education inequalities in cancer incidence have long been noted. It is not clear, however, whether such inequalities persist in the United States, especially for less common malignancies and after adjustment for individual risk factors.Within the NIH-AARP Diet and Health Study, we examined the association between education and the risk of developing cancers in a prospective cohort of 498,455 participants who were 50-71 year old and without cancer at enrollment in 1995/96. During a maximum 8.2 years of follow-up we identified 40,443 cancers in men and 18,367 in women. In age-adjusted models, the least educated men (<high school), compared to those with the most education (post-graduate), had increased risks of developing cancers of the esophagus (RR: 2.64, 95%CI:1.86-3.75), head and neck (1.98, 1.54-2.54), stomach (2.32, 1.68-3.18), colon (1.31, 1.12-1. 53), rectum (1.68, 1.32-2.13), liver (1.90, 1.22-2.95), lung (3.67, 3.25-4.15), pleura (4.01, 1.91-8.42), bladder (1.56,1.33-1.83) and combined smoking-related cancers (2.41, 2.22-2.62). In contrast, lower education level was associated with a decreased risk of melanoma of the skin (0.43, 0.35-0.54) and local prostate cancers (0.79, 0.74-0.85). Women with the least education had increased risks of colon (1.60, 1.24-2.05), lung (2.14, 1.79-2.56), kidney (1.68, 1.12-2.54) and combined smoking-related cancers (1.66, 1.43-1.92) but a lower risk of melanoma of the skin (0.33, 0.22-0.51), endometrial (0.67, 0.51-0.89) and invasive breast cancers (0.72, 0.61-0.84). Adjustment for smoking and other risk factors did not eliminate these associations, except those for cancers of the head and neck, colon, and liver in men and kidney in women.We found a higher risk of malignant disease, particularly smoking- related cancers, among those in the lowest educational attainment category. Only some of the educational gradient is attributable to smoking. The persistence of substantial education inequalities in cancer incidence poses a challenge for etiologic research and public health policy.

Pinar T, Akdur R, Tuncbilek A, Altundag K, Cengiz M. The relationship between occupations and head and neck cancers. J Natl Med Assoc. 2007 Jan;99(1):64, 68-71.

The objective of this study was to investigate the relationship between occupation and head and neck cancers.In this case-control study, 206 Turkish patients with head and neck cancers comprised the case group. The control group consisted of 206 age- and sex-matched patients without malignant disease. All patients completed a questionnaire regarding occupation; tobacco and alcohol consumption; educational status; and history of any systemic disease, benign head and neck disease, and cancer among family members. High-risk jobs were considered those in the industries of construction, wood, mining, metal, chemistry and agriculture.Patients with head and neck cancers worked in high-risk occupations more frequently than did controls [odds ratio (OR): 3.42, p<0.05]. Cancer risk decreased with the increase in time interval between quitting the high-risk job and time of interview. Smokers were at higher risk than nonsmokers (OR: 3.33, p<0.05). The risk was also higher in patients who drank alcohol regularly (OR: 1.59, p<0.05). However, occupation was found to be an independent high-risk factor for head and neck cancers in regression analysis. Frequency of benign head and neck disease and family history of cancer were not significant risk factors (p>0.05).Our analysis showed that occupation and smoking were significant independent risk factors for the development of head and neck cancers among workers.

Menvielle G, Luce D, Goldberg P, Leclerc A. Smoking, alcohol drinking, occupational exposures and social inequalities in hypopharyngeal and laryngeal cancer. Int J Epidemiol. 2004 Aug;33(4):799-806. Epub 2004 May 20.

Social inequalities with regard to hypopharyngeal and laryngeal cancers are observed in many countries. Differences in alcohol and tobacco consumption are often proposed as an explanation for this finding. The aim of this work was to determine the extent to which alcohol and tobacco consumption, and occupational exposure, explain these inequalities.A hospital-based case-control study included 504 male cases (105 with glottic, 80 with supraglottic, 97 with epilaryngeal, and 201 with hypopharyngeal cancers) and 242 male controls with non-respiratory cancers. Information about sociodemographic characteristics, detailed alcohol and tobacco consumption, educational level, and occupational history were collected. Odds ratios (OR) and their 95% CI were computed using logistic regressions.When controlling for age only, laryngeal and hypopharyngeal cancers were strongly associated with educational level (OR for low versus high level = 3.22, 95% CI: 2.01, 5.18) and with all indicators based on occupation (OR for ever versus never manual worker = 2.54, 95% CI: 1.78, 3.62). When adjusted for alcohol and tobacco consumption, the OR decreased, but remained significant for occupation (OR for ever manual worker = 1.91, 95% CI: 1.23, 2.95). After further adjustment for occupational exposures, significant associations were no longer observed. Associations differed between subsites.Social inequalities observed for these cancers are not totally explained by alcohol and tobacco consumption; a substantial proportion could be attributable to occupational exposures.

Konski A, Berkey BA, Kian Ang K, Fu KK. Effect of education level on outcome of patients treated on Radiation Therapy Oncology Group Protocol 90-03. Cancer. 2003 Oct 1;98(7):1497-503.

It has been hypothesized that people in lower socioeconomic groups have worse outcomes because they present with advanced-stage cancers or receive inadequate treatment. The authors investigated this hypothesis by using education level as a proxy for socioeconomic status in patients treated on Radiation Therapy Oncology Group (RTOG) Protocol 90-03.RTOG 90-03 was a Phase III randomized trial investigating four different radiation fractionation schedules in the treatment of locally advanced head and neck carcinomas. Overall survival and locoregional control rates were analyzed by education level as measured by patient response on the demographic form at study entry.A significant difference was observed in the distribution of patients by education level between the standard fractionated radiation treatment arm and the hyperfractionated radiation treatment arm. More patients in the standard fractionated treatment arm had a higher education level (P = 0.018). Patients attending college had highly and significantly better overall survival and locoregional control than the other groups combined (P = 0.0056 and P = 0.025, respectively: from Cox proportional hazards models stratified by assigned treatment with educational level, T classification, N classification, Karnofsky performance status, primary site, and race). Multivariate analysis revealed that education level was significant for predicting both overall survival and locoregional control when comparing attended college/technical school compared with all other education levels.Patients attending college or technical school had improved overall survival and locoregional control. These differences cannot be explained by differences in tumor stage or treatment. Poorer overall health or lack of support systems contributing to these results needs to be investigated further.

 

Amizadeh M, Safari-Kamalabadi M, Askari-Saryazdi G, Amizadeh M, Reihani-Kermani H.Pesticide Exposure and Head and Neck Cancers: A Case-Control Study in an Agricultural Region. Iran J Otorhinolaryngol. 2017 Sep;29(94):275-285.

Causes of head and neck cancers (HNCs) are multifactorial, and few studies have investigated the association between chemical exposure and HNCs. The objective of this study was to investigate associations between HNCs, agricultural occupations, and pesticide exposure. The potential for the accumulation of pesticides in the adipose tissue of patients was also investigated.A structured questionnaire was used to collect information on demographics, occupation, and exposure to pesticides in a hospital-based case-control study. Pesticide residue in the adipose tissue of the neck in both cases and controls was also monitored via gas chromatography-mass spectroscopy.Thirty-one HNC cases were included in this study as well as 32 gender-, age-, and smoking-matched controls. An agricultural occupation was associated with HNC (odds ratio [OR], 3.26; 95% confidence interval [CI], 1.13-9.43) after controlling for age, sex, and smoking. Pesticide exposure was associated with total HNC cases (OR, 7.45; 95% CI, 1.78-3.07) and larynx cancer (OR, 9.33; 95% CI, 1.65-52.68). A dose-response pattern was observed for HNC cases (P=0.06) and larynx cancer (P=0.01). In tracing the pesticide residue, five chlorinated pesticides, namely dichlorodiphenyltrichloroethane (DDT), dichlorodipheny-ldichloroethane (DDD), dichlorodiphenyldichloroethylene (DDE), dieldrin, and lindane, were identified in the adipose tissue. Chlorinated pesticide detection was significantly associated with HNC (OR, 3.91; 95% CI 0.9-0.16.9).HNCs were found to be associated with pesticide exposure after controlling for confounders. A high education level was identified as a modifying factor decreasing the risk of HNCs. Further studies with larger number of subjects are recommended to assess these relationships in greater detail.

Fan CY, Chao HL, Lin CS, Huang WY, Chen CM, Lin KT, Lin CL, Kao CH.Risk of depressive disorder among patients with head and neck cancer: A nationwide population-based study. Head Neck. 2018 Feb;40(2):312-323. doi: 10.1002/hed.24961. Epub 2017 Sep 30.

We identified 48 548 patients from the National Health Insurance Research Database (NHIRD) in Taiwan who were newly diagnosed with head and neck cancer between 2000 and 2010. Each patient was randomly frequency-matched with an individual without head and neck cancer, based on index year, sex, age, occupation category, urbanization level, monthly income, and comorbidities. The Cox proportional Registry of Catastrophic Illnesses Patient Database regression analysis was performed to estimate the effect of head and neck cancer on the risk of depressive disorder.Patients with head and neck cancer had a significantly higher risk of depressive disorder than the matched cohort (adjusted hazard ratio [HR] 3.32; 95% confidence interval [CI] 3.05-3.61), with the highest risk seen in the hypopharynx and oropharynx.Patients with head and neck cancer had >3 times the incidence of depressive disorder, relative to the comparison group. Psychological evaluation and support are essential in head and neck cancer survivors.

.Pokharel M, Shrestha I, Dhakal A, Amatya RC. Socio Demographic Predictors in Delayed Presentation of Head and Neck Cancer. Kathmandu Univ Med J (KUMJ). 2016 Jul-Sept.;14(55):274-278.

Background Head and neck cancer is a major public health problem worldwide. In spite of the increase in incidence, there has been paucity of research on socio demographic factors influencing head and neck cancer. Objective To study the influence of various socio demographic factors on late presentation of head and neck cancer. Method Prospective, analytical study conducted in 69 patients with Head and neck malignancies in Department of Otorhinolaryngology and Head and Neck surgery, Kathmandu University School of Medical sciences between January 2015 to January 2016. Collected data were entered and analyzed using IBM SPSS statistical software 21.0. All the socio demographic variables were compared between the early and late presentation groups of patient using Chi-square test. A ‘p’ value of < 0.05 was considered statistically significant. Result Forty eight were male and 21 were female. The age of patients ranged from 34 to 70 years (mean age 52.03). Twenty patients were diagnosed in stage I, 13 in stage II, 20 in stage III and 16 in stage IV. Significant association was seen between stage of head and neck cancer and duration of illness (p=0.007), educational status of patient (p=0.003) and educational status of patient’s care taker (p=0.005). However, no statistical association was seen between stage at diagnosis of head and neck cancer and gender, type of family, previous consultation, systems of alternative medicine adopted before diagnosis, smoking habit, alcohol intake, tobacco chewing habit and occupation. Conclusion The results of this study suggest that educational status may influence the presentation of head and neck cancer.

Barul C, Fayossé A, Carton M, Pilorget C, Woronoff AS, Stücker I, Luce D; ICARE study group. Occupational exposure to chlorinated solvents and risk of head and neck cancer in men: a population-based case-control study in France. Environ Health. 2017 Jul 24;16(1):77. doi: 10.1186/s12940-017-0286-5.

Few epidemiological studies have investigated the link between occupational exposure to solvents and head and neck cancer risk, and available findings are sparse and inconsistent. The objective of this study was to examine the association between occupational exposure to chlorinated solvents and head and neck cancer risk.We analyzed data from 4637 men (1857 cases and 2780 controls) included in a population-based case-control study, ICARE (France). Occupational exposure to five chlorinated solvents (perchloroethylene [PCE], trichloroethylene [TCE], methylene chloride [MC], chloroform [CF], and carbon tetrachloride [CT]) was assessed through job-exposure matrices. Odds ratios (ORs) and confidence intervals (95% CI) were estimated by unconditional logistic regression, adjusted for age, tobacco smoking, alcohol consumption, asbestos exposure, and other potential confounders.We observed no association between chlorinated solvent exposure and head and neck cancer risk, despite a non-significant increase in risk among subjects who had the highest cumulative level of exposure to PCE, (OR = 1.81; 95% CI = 0.68 to 4.82). In subsite analysis, the risk of laryngeal cancer increased with cumulative exposure to PCE (p for trend = 0.04). The OR was 3.86 (95% CI = 1.30 to 11.48) for those exposed to the highest levels of PCE. A non-significant elevated risk of hypopharyngeal cancer was also observed in subjects exposed to the highest levels of MC (OR = 2.36; 95% CI = 0.98 to 5.85).Our findings provide evidence that high exposure to PCE increases the risk of laryngeal cancer, and suggest an association between exposure to MC and hypopharyngeal cancer. Exposure to other chlorinated solvents was not associated with the risk of head and neck cancer.

Steenland K, Barry V, Anttila A, Sallmén M, McElvenny D, Todd AC, Straif K. A cohort mortality study of lead-exposed workers in the USA, Finland and the UK. Occup Environ Med. 2017 Nov;74(11):785-791. doi: 10.1136/oemed-2017-104311. Epub 2017 May 25.

To investigate further whether inorganic lead is a carcinogen among adults, or associated with increased blood pressure and kidney damage, via a large mortality study.We conducted internal analyses via Cox regression of mortality in three cohorts of lead-exposed workers with blood lead (BL) data (USA, Finland, UK), including over 88 000 workers and over 14 000 deaths. Our exposure metric was maximum BL. We also conducted external analyses using country-specific background rates.The combined cohort had a median BL of 26 µg/dL, a mean first-year BL test of 1990 and was 96% male. Fifty per cent had more than one BL test (mean 7). Significant (p<0.05) positive trends, using the log of each worker’s maximum BL, were found for lung cancer, chronic obstructive pulmonary disease (COPD), stroke and heart disease, while borderline significant trends (0.05≤p≤0.10) were found for bladder cancer, brain cancer and larynx cancer. Most results were consistent across all three cohorts. In external comparisons, we found significantly elevated SMRs for those with BLs>40 µg/dL; for bladder, lung and larynx cancer; and for COPD. In a small subsample of the US cohort (n=115) who were interviewed, we found no association between smoking and BL.We found strong positive mortality trends, with increasing BL level, for several outcomes in internal analysis. Many of these outcomes are associated with smoking, for which we had no data. A borderline trend was found for brain cancer, not associated with smoking.

Xie SH, Yu IT, Tse LA, Au JSK, Lau JSM. Occupational risk factors for nasopharyngeal carcinoma in Hong Kong Chinese: a case-referent study. Int Arch Occup Environ Health. 2017 Jul;90(5):443-449. doi: 10.1007/s00420-017-1212-4. Epub 2017 Mar 2.

We conducted a case-referent study with 352 incident cases and 410 referents recruited between June 2010 and December 2012. Full occupational histories were obtained via face-to-face interviews. Unconditional logistic regressions were performed to estimate the odds ratios (ORs) for NPC associated with occupational risk factors.Workers of craft related trades and elementary occupations were at elevated NPC risk with the adjusted ORs of 2.09 [95% confidence interval (CI) 1.09, 4.01] and 2.14 (95% CI 1.04, 4.41), respectively, compared with those clerical support workers as the reference group. Occupational exposures to cotton dust, chemical fumes, and welding fumes were significantly associated with increased NPC risk after adjustment for confounders [adjusted ORs (95% CIs) 1.93 (1.13, 3.28), 13.11 (1.53, 112.17), and 9.18 (1.05, 80.35), respectively]. We also observed significant exposure-response relationship for the duration of exposure to cotton dust (P for trend = 0.0175). Those with occupational exposure to cotton dust for 15 years or more were at significantly increased risk of NPC (adjusted OR 2.08, 95% CI 1.01, 4.28).This study indicates that employment in craft related trades and elementary occupations, as well as occupational exposures to chemical fumes, welding fumes, and cotton dust may be associated with an increased risk of NPC. Further epidemiological studies remain warranted to clarify the roles of specific occupational risk factors on NPC development.

Zeng F, Lerro C Lavoué J, Huang H, Siemiatycki J, Zhao N, Ma S, Deziel NC, Friesen MC, Udelsman R, Zhang Y. Occupational exposure to pesticides and other biocides and risk of thyroid cancer. Occup Environ Med. 2017 Jul;74(7):502-510. doi: 10.1136/oemed-2016-103931. Epub 2017 Feb 15.

Using data from a population-based case-control study involving 462 incident thyroid cancer cases and 498 controls in Connecticut collected in 2010-2011, we examined the association with occupational exposure to biocides and pesticides through a job-exposure matrix. We used unconditional logistic regression models to estimate OR and 95% CI, adjusting for potential confounders. Individuals who were occupationally ever exposed to biocides had an increased risk of thyroid cancer (OR=1.65, 95% CI 1.16 to 2.35), and the highest risk was observed for the high cumulative probability of exposure (OR=2.18, 95% CI 1.28 to 3.73). The observed associations were similar when we restricted to papillary thyroid cancer and well-differentiated thyroid cancer. Stronger associations were observed for thyroid microcarcinomas (tumour size ≤1 cm). No significant association was observed for occupational exposure to pesticides.Our study provides the first evidence linking occupational exposure to biocides and risk of thyroid cancer. The results warrant further investigation.

Andrade JO, Santos CA, Oliveira MC. Associated factors with oral cancer: a study of case control in a population of the Brazil’s Northeast. Rev Bras Epidemiol. 2015 Oct-Dec;18(4):894-905. doi: 10.1590/1980-5497201500040017.

This study aimed at assessing the association between factors such as age, sex, skin color, occupation, educational level, marital status, place of residence, and tobacco and alcohol consumptions and oral cancer in individuals in a city in the northeast of Brazil between 2002 and 2012.This is a case-control study. The case group consisted of 127 people attended at the Oral Injury Reference Center with histopathological diagnosis of oral squamous cell carcinoma. The control group consisted of 254 individuals treated at the same center. The study considered two controls for each case. The cases and controls were adjusted according to sex and age. Univariate and bivariate analyses were performed (Pearson χ2-test) to verify the correlation between the dependent variable (oral cancer) and the independent variables; odds ratio (OR) and the confidence interval of 95% (95%CI) were calculated. Finally, in the multivariate analysis, it was used as the hierarchical model with logistic regression to explain the interrelationships between the independent variables and oral cancer.Consumption of more than 20 cigarettes per day [OR = 6.64; 95%CI 2.07 – 21.32; p ≤ 0.001], an excessive alcohol consumption [OR = 3.25; 95%CI 1.03 – 10.22; p ≤ 0.044], and the synergistic consumption of tobacco and alcohol [OR = 9.65; 95%CI 1.57 – 59.08; p ≤ 0.014] are the most important risk factors for oral cancer.It was concluded that tobacco and alcohol consumptions are the most important factors for the development of oral cancer. Sociodemographic factors were not associated with this neoplasm after adjusting for smoking and drinking.

Ba Y, Huang H, Lerro CC, Li S, Zhao N, Li A, Ma S, Udelsman R, Zhang Y. Occupation and Thyroid Cancer: A Population-Based, Case-Control Study in Connecticut. J Occup Environ Med. 2016 Mar;58(3):299-305. doi: 10.1097/JOM.0000000000000637.

A population-based, case-control study involving 462 histologically confirmed incident cases and 498 controls was conducted in Connecticut in 2010 to 2011.A significantly increased risk of thyroid cancer, particularly papillary microcarcinoma, was observed for those working as the health care practitioners and technical workers, health diagnosing and treating practitioners, and registered nurses. Those working in building and grounds cleaning, maintenance occupations, pest control, retail sales, and customer service also had increased risk for papillary thyroid cancer. Subjects who worked as cooks, janitors, cleaners, and customer service representatives were at an increased risk of papillary thyroid cancer with tumor size more than 1 cm.Certain occupations were associated with an increased risk of thyroid cancer, with some tumor size and subtype specificity.

Fogleman EV, Eliot M, Michaud DS, Nelson HH, McClean MD Langevin SM, Kelsey KT Occupational asphalt is not associated with head and neck cancer. Occup Med (Lond). 2015 Oct;65(7):570-3. doi: 10.1093/occmed/kqv102. Epub 2015 Aug 13.

Epidemiologic studies that evaluate the relationship between occupational asphalt exposure and head and neck cancer have had a limited ability to control for known risk factors such as smoking, alcohol and human papillomavirus (HPV).To better elucidate this relationship by including known risk factors in a large case-control study of head and neck squamous cell carcinoma (HNSCC) from the greater Boston area.We analysed the relationship between occupational asphalt exposure and HNSCC among men in the Greater Boston area of Massachusetts. Analyses were conducted using unconditional multivariable logistic regression, performed with adjustments for age, race, education, smoking, alcohol consumption and HPV serology.There were 753 cases and 913 controls. No associations between HNSCC and occupational asphalt exposure (neither among ever-exposed nor by occupational duration) were observed for exposures in any occupation or those restricted to the construction industry. We also observed no associations in subgroup analyses of never-smokers and ever-smokers. Adjusting for known risk factors further reduced the estimated effect of asphalt exposure on HNSCC risk.We found no evidence for an association between occupational asphalt exposure and HNSCC. The null findings from this well-controlled analysis could suggest that the risk estimates stemming from occupational cohort studies may be overestimated due to uncontrolled confounding and enhance the literature available for weighing cancer risk from occupational exposure to bitumen.

Langevin SM, McClean MD, Michaud DS, Eliot M, Nelson HH, Kelsey KT. Occupational dust exposure and head and neck squamous cell carcinoma risk in a population-based case-control study conducted in the greater Boston area. Cancer Med. 2013 Dec;2(6):978-86. doi: 10.1002/cam4.155. Epub 2013 Nov 4.

Head and neck cancers account for an estimated 549,000 global cancer diagnoses each year. While tobacco use, alcohol consumption, and HPV16 infection are considered to be the major risk factors for this disease, occupational risk factors, including exposure to asbestos, have also been described, although dust exposures other than asbestos have been historically understudied. We have investigated the relationship between occupational exposures to five types of dusts, including sawdust, concrete dust, leather dust, metal dust, and chimney soot, and head and neck squamous cell carcinomas (HNSCC) in the greater Boston area. We report findings from a population-based case-control study involving 951 incident HNSCC cases and 1193 controls, frequency matched on age (±3 years), sex, and town/neighborhood of residence. Multivariable logistic regression was used to assess the association between occupational exposure to each type of dust and HNSCC, overall and by primary tumor site. After adjusting for age, sex, race, smoking, alcohol consumption, education, and HPV16 serology, laryngeal carcinoma risk increased for each decade of occupational exposure to sawdust (OR = 1.2, 95% CI: 1.0, 1.3) and metal dust (OR = 1.2, 95% CI: 1.0, 1.4); and HNSCC risk increased for each decade of occupational leather dust exposure (OR = 1.5, 95% CI: 1.2, 1.9). We have provided evidence for an association between occupational sawdust and metal dust and laryngeal squamous cell carcinoma, and leather dust and HNSCC, with increasing risk with longer duration at the exposed occupation.

Purdue MP, Järvholm B, Bergdahl IA, Hayes RB, Baris D. Occupational exposures and head and neck cancers among Swedish construction workers. Scand J Work Environ Health. 2006 Aug;32(4):270-5.

Occupational exposures in the construction industry may increase the risk of head and neck cancers, although the epidemiologic evidence is limited by problems of low study power and inadequate adjustment for tobacco use. In an attempt to address this issue, the relationship between selected occupational exposures and head and neck cancer risk was investigated using data from a large cohort of Swedish construction workers.Altogether 510 squamous cell carcinomas of the head and neck (171 in the oral cavity, 112 in the pharynx, 227 in the larynx) were identified during 1971-2001 among 307 799 male workers in the Swedish construction industry. Exposure to diesel exhaust, asbestos, organic solvents, metal dust, asphalt, wood dust, stone dust, mineral wool, and cement dust was assessed using a semi-quantitative job-exposure matrix. Rate ratios (RR) and 95% confidence intervals (95% CI) were calculated for head and neck cancers in relation to occupational exposure, using Poisson regression with adjustment for age and smoking status.Asbestos exposure was related to an increased laryngeal cancer incidence (RR 1.9, 95% CI 1.2-3.1). Excesses of pharyngeal cancer were observed among workers exposed to cement dust (RR 1.9, 95% CI 1.2-3.1). No occupational exposures were associated with oral cavity cancer. These findings did not materially change upon additional adjustment for cigarette pack-years.These findings offer further evidence that asbestos increases the risk of laryngeal cancer. The observation of a positive association between cement dust exposure and pharyngeal cancer warrants further investigation.

Langevin SM, O’Sullivan MH, Valerio JL, Pawlita M, Applebaum KM, Eliot M, McClean MD, Kelsey KT. Occupational asbestos exposure is associated with pharyngeal squamous cell carcinoma in men from the greater Boston area. Occup Environ Med. 2013 Dec;70(12):858-63. doi: 10.1136/oemed-2013-101528. Epub 2013 Sep 27.

Asbestos is the name given to a group of naturally occurring silicate mineral fibres that were widely used in industry during the 20th century due to their desirable physical properties. Although use in the USA has fallen over the last three decades, significant exposure in the developing world continues and the burden of disease is considerable. Asbestos is a known risk factor for several malignant diseases, including lung cancer and mesothelioma, and has more recently been implicated in pharyngeal and laryngeal cancer. However, studies of asbestos and cancers of the larynx or pharynx with adequate sample size that control for major head and neck squamous cell carcinoma (HNSCC) risk factors remain relatively sparse.We report findings from a case-control study of 674 incident male HNSCC cases from the greater Boston region and 857 population-based male controls, matched on age (±3 years), sex, and town or neighbourhood of residence. Multivariable logistic regression was used to assess the association between occupational asbestos exposure and HNSCC by primary tumour site.190 cases (28.2%) and 203 controls (23.7%) reported occupational exposure to asbestos. Occupational asbestos exposure was associated with elevated risk of pharyngeal carcinoma in men (OR 1.41, 95% CI 1.01 to 1.97), adjusted for age, race, smoking, alcohol consumption, education, income and HPV16 serology, with borderline increasing risk for each decade in the exposed occupation (OR 1.10, 95% CI 0.99 to 1.23).These observations are consistent with mounting evidence that asbestos is a risk factor for pharyngeal cancer.

 

 

 

 

Riechelmann H.Occupational exposure and cancer of the oral cavity and pharynx]. Laryngorhinootologie. 2002 Aug;81(8):573-9.

 

Occupational risk factors for the development of laryngeal cancer are well accepted, whereas the etiologic relationship between occupational exposure to various noxious influences and the development of cancer of the oral cavity and pharynx remain a matter of debate. Based on published data, occupational risk factors for cancer of the oral cavity and pharynx should be evaluated.Publications since 1990 listed in the National Library of Medicine, textbooks and data obtained from the German Employer’s Liability Insurance Association were evaluated.In several tobacco- and alcohol-adjusted case-control and cohort studies, an association with occupation in construction and metalworking industries, as painters, carpenters and machine operators was consistently found. The relative risks or standardized mortality rates ranged between 1.5 and 3. Some recent investigations found an association for workers in the paper and rubber industry. The results in regard to the textile and woodworking industry were inconclusive.

Pukkala E, Martinsen JI, Lynge E, Gunnarsdottir HK, Sparén P, Tryggvadottir L, Weiderpass E, Kjaerheim K. Occupation and cancer – follow-up of 15 million people in five Nordic countries. Acta Oncol. 2009;48(5):646-790. doi: 10.1080/02841860902913546.

We present up to 45 years of cancer incidence data by occupational category for the Nordic populations. The study covers the 15 million people aged 30-64 years in the 1960, 1970, 1980/1981 and/or 1990 censuses in Denmark, Finland, Iceland, Norway and Sweden, and the 2.8 million incident cancer cases diagnosed in these people in a follow-up until about 2005. The study was undertaken as a cohort study with linkage of individual records based on the personal identity codes used in all the Nordic countries. In the censuses, information on occupation for each person was provided through free text in self-administered questionnaires. The data were centrally coded and computerised in the statistical offices. For the present study, the original occupational codes were reclassified into 53 occupational categories and one group of economically inactive persons. All Nordic countries have a nation-wide registration of incident cancer cases during the entire study period. For the present study the incident cancer cases were classified into 49 primary diagnostic categories. Some categories have been further divided according to sub-site or morphological type. The observed number of cancer cases in each group of persons defined by country, sex, age, period and occupation was compared with the expected number calculated from the stratum specific person years and the incidence rates for the national population. The result was presented as a standardised incidence ratio, SIR, defined as the observed number of cases divided by the expected number. For all cancers combined (excluding non-melanoma skin cancer), the study showed a wide variation among men from an SIR of 0.79 (95% confidence interval 0.66-0.95) in domestic assistants to 1.48 (1.43-1.54) in waiters. The occupations with the highest SIRs also included workers producing beverage and tobacco, seamen and chimney sweeps. Among women, the SIRs varied from 0.58 (0.37-0.87) in seafarers to 1.27 (1.19-1.35) in tobacco workers. Low SIRs were found for farmers, gardeners and teachers. Our study was able to repeat most of the confirmed associations between occupations and cancers. It is known that almost all mesotheliomas are associated with asbestos exposure. Accordingly, plumbers, seamen and mechanics were the occupations with the highest risk in the present study. Mesothelioma was the cancer type showing the largest relative differences between the occupations. Outdoor workers such as fishermen, gardeners and farmers had the highest risk of lip cancer, while the lowest risk was found among indoor workers such as physicians and artistic workers. Studies of nasal cancer have shown increased risks associated with exposure to wood dust, both for those in furniture making and for those exposed exclusively to soft wood like the majority of Nordic woodworkers. We observed an SIR of 1.84 (1.66-2.04) in male and 1.88 (0.90-3.46) in female woodworkers. For nasal adenocarcinoma, the SIR in males was as high as 5.50 (4.60-6.56). Male waiters and tobacco workers had the highest risk of lung cancer, probably attributable to active and passive smoking. Miners and quarry workers also had a high risk, which might be related to their exposure to silica dust and radon daughters. Among women, tobacco workers and engine operators had a more than fourfold risk as compared with the lung cancer risk among farmers, gardeners and teachers. The occupational risk patterns were quite similar in all main histological subtypes of lung cancer. Bladder cancer is considered as one of the cancer types most likely to be related to occupational carcinogens. Waiters had the highest risk of bladder cancer in men and tobacco workers in women, and the low-risk categories were the same ones as for lung cancer. All this can be accounted for by smoking. The second-highest SIRs were among chimney sweeps and hairdressers. Chimney sweeps are exposed to carcinogens such as polycyclic aromatic hydrocarbons from the chimney soot, and hairdressers’ work environment is also rich in chemical agents. Exposure to the known hepatocarcinogens, the Hepatitis B virus and aflatoxin, is rare in the Nordic countries, and a large proportion of primary liver cancers can therefore be attributed to alcohol consumption. The highest risks of liver cancer were seen in occupational categories with easy access to alcohol at the work place or with cultural traditions of high alcohol consumption, such as waiters, cooks, beverage workers, journalists and seamen. The risk of colon cancer has been related to sedentary work. The findings in the present study did not strongly indicate any protective role of physical activity. Colon cancer was one of the cancer types showing the smallest relative variation in incidence between occupational categories. The occupational variation in the risk of female breast cancer (the most common cancer type in the present series, 373 361 cases) was larger, and there was a tendency of physically demanding occupations to show SIRs below unity. Women in occupations which require a high level of education have, on average, a higher age at first child-birth and elevated breast cancer incidence. Women in occupational categories with the highest average number of children had markedly lower incidence. In male breast cancer (2 336 cases), which is not affected by the dominating reproductive factors, there was a suggestion of an increase in risk in occupations characterised by shift work. Night-shift work was recently classified as probably carcinogenic, with human evidence based on breast cancer research. The most common cancer among men in the present cohort was prostate cancer (339 973 cases). Despite the huge number of cases, we were unable to demonstrate any occupation-related risks. The observed small occupational variation could be easily explained by varying PSA test frequency. The Nordic countries are known for equity and free and equal access to health care for all citizens. The present study shows that the risk of cancer, even under these circumstances, is highly dependent on the person’s position in the society. Direct occupational hazards seem to explain only a small percentage of the observed variation – but still a large number of cases – while indirect factors such as life style changes related to longer education and decreasing physical activity become more important. This publication is the first one from the extensive Nordic Occupational Cancer (NOCCA) project. Subsequent studies will focus on associations between specific work-related factors and cancer diseases with the aim to identify exposure-response patterns. In addition to the cancer data demonstrated in the present publication, the NOCCA project produced Nordic Job Exposure Matrix (described in separate articles in this issue of Acta Oncologica) that transforms information about occupational title histories to quantitative estimates of specific exposures. The third essential component is methodological development related to analysis and interpretation of results based on averaged information of exposures and co-factors in the occupational categories. In cases with moderate isolated tobacco or moderate isolated alcohol consumption, the risk attributable to occupational factors and smoking or drinking are of similar magnitude. According to German jurisdiction, a partial compensation of the acquired disability is then justified. In pronounced combined tobacco and alcohol consumption, the non-occupational risk factors increase exponentially and occupational risks attain marginal weight.

Andersen A, Barlow L, Engeland A, Kjaerheim K, Lynge E, Pukkala E. Work-related cancer in the Nordic countries. Scand J Work Environ Health. 1999;25 Suppl 2:1-116.

This report presents 20 years’ of cancer incidence data by occupational group for the Nordic populations. The study covers the 10 million people aged 25-64 years at the time of the 1970 censuses in Denmark, Finland, Norway, and Sweden, and the 1 million incident cancer cases diagnosed among these people during the subsequent 20 years. The project was undertaken as a cohort study with linkage of individual records based on the personal identification numbers used in all the Nordic countries. In the 1970 censuses, information on occupation for each economically active member of the household was provided in free text in self-administered questionnaires. The data were centrally coded and computerized in the statistical offices. Norway, Sweden, and Finland used the Nordic Classification of Occupations, while Denmark used a national coding scheme. However, all the data could be reclassified into 53 occupational groups and 1 group of economically inactive persons. Person-years at risk were accumulated from 1 January 1971 until the date of emigration, date of death or 31 December 1987 in Denmark, 1989 in Sweden, 1990 in Finland, and 1991 in Norway. The 4 countries all had nationwide registration of incident cancer cases during the entire study period. All incident cancer cases during the individual risk periods were included in the analysis. Despite minor differences between the countries, the International Classification of Diseases, 7th revision, formed the core basis for the diagnostic coding in all 4 countries. For the present study the incident cancer cases have been classified into 35 broad diagnostic groups. The observed number of cancer cases in each group of persons defined by country, gender, and occupation was compared with the expected number calculated from the age-, gender-, and period-specific person-years and the incidence rates for the national population. The result has been presented as a standardized incidence ratio (SIR), defined as the observed number of cases divided by the expected number and multiplied by 100. In the tables of this report, all the SIR values for which the upper limit of the 95% confidence interval is below 100 are printed in green and all those for which the lower limit of the confidence interval is above 100 are printed in red. For all cancers combined, the study showed a wide variation among the men, from an SIR of 79 for farmers to 159 for waiters. The occupations with the highest SIR values also included seamen and workers producing beverages and tobacco. Among the women the SIR values varied from 83 for gardeners to 129 for tobacco workers. Low SIR values were found for farmers and teachers. Outdoor workers such as fishermen and gardeners had the highest risk of lip cancer, while the lowest risk was found among indoor workers such as physicians and artistic workers. Almost all pleural cancers are associated with asbestos exposure. Accordingly, plumbers, welders, mechanics, and seamen were the occupations with the highest risk. There was also an excess risk of pleural cancer in the occupational group of technical, chemical, physical, and biological workers, including, among others, engineers and chemists potentially exposed to asbestos. The wood workers included in the present study had the highest risk of nasal cancer. Most studies of nasal cancer have shown increased risks associated with exposure to wood dust, both for those in furniture making and for those exposed exclusively to soft wood. Nickel refinery workers are also known for their high risk of nasal cancer. In the present study they were included in the occupational group of smelting workers. Lung cancer was the most frequent cancer among men in the present study. Tobacco smoking is the major risk factor for this disease, but occupational exposures also play an important role. Waiters and tobacco workers had the highest risk of lung cancer. Miners and quarry workers also had a high risk of lung cancer, which may be related to.

 

 

Kjaerheim K, Martinsen JI, Lynge E, Gunnarsdottir HK, Sparen P, Tryggvadottir L, Weiderpass E, Pukkala E. Effects of occupation on risks of avoidable cancers in the Nordic countries. Eur J Cancer. 2010 Sep;46(14):2545-54. doi: 10.1016/j.ejca.2010.07.038.

Knowledge of cancer risk according to occupational affiliation is an essential part of formatting preventive actions aimed at the adult population. Herein, data on 10 major cancer sites amenable by life style exposures from the Nordic Occupational Cancer Study (NOCCA) are presented. All subjects aged 30-64 years participating in one or more national censuses in Denmark, Finland, Iceland, Norway, or Sweden between 1960 and 1990 were included in the cohort and followed up for cancer from inclusion until 2003/2005 via a linkage with the national cancer registries, and standardised incidence ratios (SIRs) were computed. Variation in risk across occupations was generally larger in men than in women. In men, the most consistent cluster with high risk of numerous cancer types included waiters, cooks and stewards, beverage workers, seamen, and chimney sweeps. Two clusters of occupations with generally low cancer risks were seen in both men and women. The first one comprised farmers, gardeners, and forestry workers, the second one included groups with high education, specifically those in health and pedagogical work. Although cancer risk varies by occupation, only a smaller part of the variation can be attributed to occupational exposures in the strict sense. Preventive measures at the work place are important to avoid established and new occupational health hazards. This study also indicates that the work place in addition should be seen as a useful arena for reaching groups of adults with more or less similar habits and attitudes for general health promotion.

Reijula J, Kjaerheim K, Lynge E, Martinsen JI, Reijula K, Sparén P, Tryggvadottir L, Weiderpass E, Pukkala E. Cancer incidence among waiters: 45 years of follow-up in five Nordic countries. Scand J Public Health. 2015 Mar;43(2):204-11. doi: 10.1177/1403494814565130. Epub 2015 Jan 6.

We identified a cohort of 16,134 male and 81,838 female waiters from Denmark, Finland, Iceland, Norway and Sweden. During the follow-up period from 1961 to 2005, we found that 19,388 incident cancer cases were diagnosed. Standardised incidence ratio (SIR) was defined as the observed number of cancer cases divided by the expected number, based on national age, time period and gender-specific cancer incidence rates in the general population.The SIR of all cancers in waiters, in the five countries combined, was 1.46 (95% CI 1.41-1.51) in men and 1.09 (1.07-1.11) in women. In male waiters, the SIR decreased from 1.79 (1.63-1.96) in 1961-1975, to 1.33 (1.26-1.40) in 1991-2005, but remained stable among women. The SIR among male waiters was highest for cancers in the pharynx (6.11; 95% CI 5.02-7.37), oral cavity (4.91; 95% CI 3.81-6.24) and tongue (4.36; 95% CI 3.13-5.92); and in female waiters, in the larynx (2.17; 95% CI 1.63-2.82), oral cavity (1.96; 95% CI 1.60-2.34) and lung (1.89; 95% CI 1.80-1.99).The risk of cancer among waiters was higher than in the general population. The elevated incidence in some cancer sites can likely be explained by higher alcohol consumption, the prevalence of smoking and occupational exposure to tobacco smoke. Hopefully, the incidence of cancer among waiters will decrease in the future, due to the banning of tobacco smoking in restaurants and bars in the Nordic countries.

Tarvainen L, Suojanen J, Kyyronen P, Lindqvist C, Martinsen JI, Kjaerheim K, Lynge E, Sparen P, Tryggvadottir L, Weiderpass E, Pukkala E. Occupational Risk for Oral Cancer in Nordic Countries. Anticancer Res. 2017 Jun;37(6):3221-3228.

 

To evaluate occupational risk for cancer of the tongue, oral cavity or pharynx after adjustment for alcohol and tobacco use.The data covered 14.9 million people and 28,623 cases of cancer of the tongue, oral cavity and pharynx in the Nordic countries 1961-2005. Alcohol consumption by occupation was estimated based on mortality from liver cirrhosis and incidence of liver cancer. Smoking by occupation was estimated based on the incidence of lung cancer.Only few occupations had relative risks of over 1.5 for cancer of the tongue, oral cavity and pharynx. These occupations included dentists, artistic workers, hairdressers, journalists, cooks and stewards, seamen and waiters.Several occupational categories, including dentists, had an increased relative risk of tongue cancer. This new finding remains to be explained but could be related to occupational chemical exposures, increased consumption of alcohol and tobacco products, or infection with human papilloma virus.

Kjaerheim K, Andersen A. Incidence of cancer among male waiters and cooks: two Norwegian cohorts. Cancer Causes Control. 1993 Sep;4(5):419-26.

Previous occupational survey studies have identified ‘waiter’ and ‘cook’ as possible high risk occupations for cancer. However, few cohort studies have been performed among persons in the restaurant business, and we therefore have analyzed cancer incidence in two cohorts of Norwegian waiters and cooks. The cohorts consisted of skilled male workers, 1,463 waiters and 2,582 cooks, who received their craft certificate between 1958 and 1983. The cohorts were followed from 1959 through 1991. The standardized incidence ratio (SIR) for all causes of cancer was 1.4 (95 percent confidence interval [CI] = 1.2-1.7] for waiters, and 1.1 (CI = 0.9-1.4) for cooks. Cancers of the tongue, mouth, pharynx, larynx, esophagus, and liver were grouped together as alcohol-associated cancers. SIR for these cancers combined was 5.1 (CI = 3.4-7.4) for waiters and 4.2 (CI = 2.2-7.2) for cooks. For lung cancer, SIR was 2.0 (CI = 1.3-2.9) for waiters and 0.7 (CI = 0.2-1.7) for cooks. For alcohol-associated cancers, the analysis carried out according to number of years since first employment showed a larger number of cases than expected for both occupations in all time-periods. The excess of lung cancer cases among waiters appeared after 30 years or more of employment. The study shows that waiters and cooks are at high risk of cancers associated with alcohol consumption, and that waiters, in addition, show high rates for lung cancer. The hypothesis of an occupational lung-cancer risk in cooks was not supported by this study.

 

Kjaerheim K, Martinsen JI, Lynge E, Gunnarsdottir HK, Sparen P, Tryggvadottir L, Weiderpass E, Pukkala E. Effects of occupation on risks of avoidable cancers in the Nordic countries. Eur J Cancer. 2010 Sep;46(14):2545-54. doi: 10.1016/j.ejca.2010.07.038.

Knowledge of cancer risk according to occupational affiliation is an essential part of formatting preventive actions aimed at the adult population. Herein, data on 10 major cancer sites amenable by life style exposures from the Nordic Occupational Cancer Study (NOCCA) are presented. All subjects aged 30-64 years participating in one or more national censuses in Denmark, Finland, Iceland, Norway, or Sweden between 1960 and 1990 were included in the cohort and followed up for cancer from inclusion until 2003/2005 via a linkage with the national cancer registries, and standardised incidence ratios (SIRs) were computed. Variation in risk across occupations was generally larger in men than in women. In men, the most consistent cluster with high risk of numerous cancer types included waiters, cooks and stewards, beverage workers, seamen, and chimney sweeps. Two clusters of occupations with generally low cancer risks were seen in both men and women. The first one comprised farmers, gardeners, and forestry workers, the second one included groups with high education, specifically those in health and pedagogical work. Although cancer risk varies by occupation, only a smaller part of the variation can be attributed to occupational exposures in the strict sense. Preventive measures at the work place are important to avoid established and new occupational health hazards. This study also indicates that the work place in addition should be seen as a useful arena for reaching groups of adults with more or less similar habits and attitudes for general health promotion.

Medicine (Baltimore). 2016 Jul;95(27):e4140. doi: 10.1097/MD.0000000000004140.

The effect of individual and neighborhood socioeconomic status on esophageal cancer survival in working-age patients in Taiwan.

Wu CC1, Chang CM, Hsu TW, Lee CH, Chen JH, Huang CY, Lee CC.

Esophageal cancer is the sixth leading cause of cancer mortality. More than 90% of patients with esophageal cancer in Taiwan have squamous cell carcinoma. Survival of such patients is related to socioeconomic status (SES). We studied the association between SES (individual and neighborhood) and the survival of working-age patients with esophageal cancer in Taiwan. A population-based study was conducted of 4097 patients diagnosed with esophageal cancer between 2002 and 2006. Each was traced for 5 years or until death. Individual SES was defined by enrollee job category. Neighborhood SES was based on household income and dichotomized into advantaged or disadvantaged. Multilevel logistic regression was used to compare the survival rates by SES group after adjustment for possible confounding and risk factors. Hospital and neighborhood SES were used as random effects in multilevel logistic regression. In patients younger than 65 years, 5-year overall survival rates were worst for those with low individual SES living in disadvantaged neighborhoods. After adjustment for patient characteristics, esophageal cancer patients with high individual SES had a 39% lower risk of mortality than those with low individual SES (odds ratio 0.61, 95% confidence interval 0.48-0.77). Patients living in disadvantaged areas with high individual SES were more likely to receive surgery than those with low SES (odds ratio 1.45, 95% confidence interval 1.11-1.89). Esophageal cancer patients with low individual SES have the worst 5-year survival, even with a universal healthcare system. Public health, education, and social welfare programs should address the inequality of esophageal cancer survival.

 

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Nguyen DP, Li J, Tewari AK. Inflammation and prostate cancer: the role of interleukin 6 (IL-6). BJU Int 2014; 113:986-92.

Olimid DA, Simionescu CE, Margaritescu C, Florescu A. Immunoexpression of Ki67 and cyclin D1 in oral squamous carcinomas. Rom J Morphol Embryol 2012;53(3 Suppl):795-8.

Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 2005;121:335–48.

Papatheodorou H, Papanastasiou AD, Sirinian C, Scopa C, Kalofonos HP, Leotsinidis M, et al. Expression patterns of SDF1/CXCR4 in human invasive breast carcinoma and adjacent normal stroma: Correlation with tumor clinicopathological parameters and patient survival. Pathol Res Pract 2014;pii: S0344-0338(14)00185-X.

Purohit V. Can alcohol promote aromatization of androgens to estrogens? A review Alcohol  2000;22: 123–7.

Qian JWenguang XZhiyong WYuntao ZWei H. Hypoxia inducible factor: a potential prognostic biomarker in oral squamous cell carcinoma. Tumour Biol 2016 Epub ahead of print

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Ramoa Pires F, Barreto Ramos A, Coutinho de Oliveira JB, Serra Tavares A, Silva Ribeiro da Luz P et al. Oral squamous cell carcinoma: clinic-pathological features from 346 cases from a single Oral Pathology service during an 8-year period. J Appl Oral Sci 2013;21:460-7.

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Sharma PSaxena SAggarwal P. Trends in the epidemiology of oral squamous cell carcinoma in Western UP: an institutional study. Indian J Dent Res 2010;21:316-9.

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Alam MS, Siddiqui SA, Perween R. Epidemiological profile of head and neck cancer patients in Western Uttar Pradesh and analysis of distributions of risk factors in relation to site of tumor. J Cancer Res Ther. 2017 Jul-Sep;13(3):430-435. doi: 10.4103/0973-1482.180687.

Head and neck cancers (HNCs) are a major form of cancers in India. The spectrum varies from place to place within the country because of significant diversified risk factors.To study, epidemiology and risk factors of HNC patients from Western Uttar Pradesh and to find out the correlation between risk factors and different anatomical regions involved.All patients with histologically confirmed diagnoses of HNC between January 2011 and December 2013 were selected from hospital records. Data regarding age, gender, addiction habits, site of tumor, and other details were obtained from their clinical records, and statistical analysis was done.HNC accounts for 21.2% of total body malignancy and 47% of all malignancies in males and 2.5% in females. Squamous cell carcinoma was the most common histological type (97%). Maximum incidence of HNC (>60%) was in 40-60 year of age. Male:female ratio was 16:1. Oral cancers were most common HNC in patients below 40 year age group, whereas carcinoma oropharynx and larynx were more common in patients above 40 year age group. Tobacco smoking was a most prevalent risk factor for carcinoma oropharynx, larynx, and hypopharynx. Tobacco chewing was a most prevalent risk factor in females, young males, and carcinoma buccal mucosa patients. Habit of tobacco consumption in HNC patients was much higher than their normal counterpart. Alcohols drinking alone was observed in <1% patient as a risk factor. In oral tongue cancer, smoking and tobacco chewing were equally prevalent. Habit of tobacco chewing and alcohol were significantly higher in carcinoma buccal mucosa than other HNC suggesting synergistic effect specific to this site.

McCarthy CE, Field JK, Marcus MW. Age at menopause and hormone replacement therapy as risk factors for head and neck and oesophageal cancer (Review). Oncol Rep. 2017 Oct;38(4):1915-1922. doi: 10.3892/or.2017.5867.

There were ~986,000 cases of head and neck cancer (HNC) and oesophageal cancer diagnosed worldwide in 2012. The incidence of these types of cancer is much higher in males than females, although this disparity decreases in the elderly population, suggesting a role for hormones as a risk factor. This systematic review investigates the potential role of female hormones [age at menopause and use of hormone replacement therapy (HRT)] as risk factors for HNC/oesophageal squamous cell carcinoma (SCC). The electronic databases MEDLINE, Web of Science, EMBASE and Cochrane were searched. Only studies with at least 50 cases of HNC/oesophageal SCC, with data on age at menopause, smoking, alcohol, age and socioeconomic status or educational attainment, were included. The Newcastle Ottawa Scale was used for assessing risk of bias. Eight studies met the inclusion criteria (5 oesophageal SCC, 2 HNC and 1 combined oesophageal SCC and HNC). HRT was shown to reduce the risk of HNC (HR, 0.78; 95% CI, 0.61-0.99) in one study. Our results showed that earlier age at menopause is a risk factor for oesophageal SCC, with women entering menopause at <45 years having double the risk of those entering menopause at age >50 years. Similar, but less striking, results were observed for HNC. HRT was found to reduce the risk of HNC/oesophageal SCC, but the evidence is inconclusive. We, therefore, recommend that consideration should be given to collecting data on reproductive factors and exposure to HRT, as routine practice, in future epidemiological and clinical studies of these cancers. The concept of oestrogen deficiency as a risk for HNC/oesophageal SCC deserves further exploration in future laboratory and clinical studies.

Hashim D, Sartori S, Vecchia C, Serraino D, Maso LD, Negri E, Smith E, Levi F, Boccia S, Cadoni G, Luu HN, Lee YA, Hashibe M, Boffetta P. Hormone factors play a favorable role in female head and neck cancer risk. Cancer Med. 2017 Aug;6(8):1998-2007. doi: 10.1002/cam4.1136.

Due to lower female incidence, estimates of exogenous and endogenous hormonal factors in head and neck cancers (HNCs, comprising cancers of the oral cavity, oropharynx, hypopharynx, and larynx) among women have been inconsistent and unable to account for key HNC risk factors. We pooled data from 11 studies from Europe, North America, and Japan. Analysis included 1572 HNC female cases and 4343 controls. Pooled odds ratios (ORs) estimates and their 95% confidence intervals (CIs) were calculated using multivariate logistic regression models adjusting for tobacco smoking and alcohol drinking. Lower risk was observed in women who used hormone replacement therapy (HRT) (OR = 0.58; 95% CI: 0.34-0.77). Pregnancy (OR = 0.61; 95% CI: 0.42-0.90) and giving birth (OR = 0.59; 95% CI: 0.38-0.90) at <35 years of age were inversely associated with HNCs. An inverse association with HNC was observed with age at start of HRT use (OR = 0.59; 95% CI: 0.39-0.90) for each additional 10 years and with duration of use (OR = 0.87; 95% CI: 0.76-0.99 for every 3 years). Exogenous female hormone use is associated with a nearly twofold risk reduction in female HNCs. The lower female HNC incidence may, in part, be explained by endogenous and exogenous estrogen exposures.

Tarvainen L, Suojanen J, Kyyronen P, Lindqvist C, Martinsen JI, Kjaerheim K, Lynge E, Sparen P, Tryggvadottir L, Weiderpass E, Pukkala E. Occupational Risk for Oral Cancer in Nordic Countries. Anticancer Res. 2017 Jun;37(6):3221-3228.

To evaluate occupational risk for cancer of the tongue, oral cavity or pharynx after adjustment for alcohol and tobacco use.The data covered 14.9 million people and 28,623 cases of cancer of the tongue, oral cavity and pharynx in the Nordic countries 1961-2005. Alcohol consumption by occupation was estimated based on mortality from liver cirrhosis and incidence of liver cancer. Smoking by occupation was estimated based on the incidence of lung cancer. Only few occupations had relative risks of over 1.5 for cancer of the tongue, oral cavity and pharynx. These occupations included dentists, artistic workers, hairdressers, journalists, cooks and stewards, seamen and waiters.Several occupational categories, including dentists, had an increased relative risk of tongue cancer. This new finding remains to be explained but could be related to occupational chemical exposures, increased consumption of alcohol and tobacco products, or infection with human papilloma virus.

Nowosielska-Grygiel J, Owczarek K, Bielińska M, Wacławek M, Olszewski J. Analysis of risk factors for oral cavity and oropharynx cancer in the authors’ own material. Otolaryngol Pol. 2017 Apr 30;71(2):23-28. doi: 10.5604/01.3001.0009.8411.

 

The aim of the study was to analyse the risk factors for oral cavity and oropharynx cancer in peopled examined under the Head and Neck Cancer Awareness Week in 2016, Lodz.In Lodz, 21st September 2016, under the Head and Neck Cancer Awareness Week, 106 people, including 67 women aged 29-77 and 39 men aged 23-84, underwent preventive examinations in the hospital department. Prior to the laryngological examination, the patients were asked to answer questions that referred to their education, medical case history, symptoms, smoking habits with the number of cigarettes per day, alcohol intake, the number of lifetime sexual partners, oral sex engagement, incidents of head and neck cancer in the family history.The major part of the examined patients were women and men with the secondary and high level of education, 47,76% and 35,82%, and 58,97% and 35,91% respectively. The patients were informed by mass media about the planned preventive medical examinations – 80,60% women and 79,49% men. The most common symptoms reported by women were: hoarse voice in 61,19% cases, dysphagia in 32,84% cases and burning sensation and/or pain in the oral cavity in 29,85% cases. The examined male patients mainly showed hoarse voice (46,15%), other symptoms (43,59%) and dysphagia (25,64%). 28,35% women and 28,20% men smoked cigarettes, while passive smokers were 22,38% and 25,64% respectively. Alcohol consumption was reported by 67,16% women and 82,05% men, rather occasionally. Having oral sex was noted in 25,37% women and 38,46% men, mostly with multiple sexual partners. Among the studied patients, 13,43% women and 5,12% men suffered from malignant cancer, including 2,98% women and 2,56% men who reported head and neck carcinoma in the medical interview. On the basis of the interview and ENT examination, 11,94% women and 17,94% men were qualified for the extended oncological diagnostics. Conclussion. The Fourth Head and Neck Cancer Awareness Week shows the increased interest in preventive screening, especially oncological screening, and thus the necessity of such preventive activities in the future.

Javadi P, Sharma A, Zahnd WE, Jenkins WD. Evolving disparities in the epidemiology of oral cavity and oropharyngeal cancers. Cancer Causes Control. 2017 Jun;28(6):635-645. doi: 10.1007/s10552-017-0889-8.

Incidence rates of head and neck cancers (HNC) associated with human papillomavirus (HPVa) infection are increasing while non-HPV-associated (non-HPVa) HNC cancer rates are decreasing. As nearly all sexually active individuals will acquire an HPV infection, it is important to understand epidemiologic trends of HNCs associated with this sexually transmitted disease. We analyzed SEER 9 (1973-2012) and 18 data (2000-2012) for HPVa HNCs (oropharynx area; OP) and non-HPVa (oral cavity area; OC). Incidence rates were examined by gender, race, rurality, geographic location, and time. Joinpoint regression analyses assessed temporal variations. From 1973 to 2012, OC incidence decreased while OP increased, with changes largely driven by males (whose OP rate increased 106.2% vs female decrease of 10.3%). Males consistently had higher rates of both cancer groups across each registry except Alaska, OP rates among blacks changed from significantly above whites to below, and trend analysis indicated significant differences in rates over time by gender, race, and geography. Analysis of SEER 18 found that rates discordantly varied by group and gender across the 18 registries, as did the male/female rate ratio with overall means of 4.7 for OP versus 1.7 for OC (only Alaska and Georgia having overlapping ranges). Our findings indicate that much of the HPVa rate increases were driven by rate increases among males and that there were changing differences in risk between genders, race, and geographic location. The epidemiology of HNCs is complex, with locally relevant factors requiring further research for elucidation of demographic disparities in incidence.

Xu C, Chen YP, Liu X, Tang LL, Chen L, Mao YP, Zhang Y, Guo R, Zhou GQ, Li WF, Lin AH, Sun Y, Ma J. Socioeconomic factors and survival in patients with non-metastatic head and neck squamous cell carcinoma. Cancer Sci. 2017 Jun;108(6):1253-1262. doi: 10.1111/cas.13250.

The effect of socioeconomic factors on receipt of definitive treatment and survival outcomes in non-metastatic head and neck squamous cell carcinoma (HNSCC) remains unclear. Eligible patients (n = 37 995) were identified from the United States Surveillance, Epidemiology and End Results (SEER) database between 2007 and 2012. Socioeconomic factors (i.e., median household income, education level, unemployment rate, insurance status, marital status and residence) were included in univariate/multivariate Cox regression analysis; validated factors were used to generate nomograms for cause-specific survival (CSS) and overall survival (OS), and a prognostic score model for risk stratification. Low- and high-risk groups were compared for all cancer subsites. Impact of race/ethnicity on survival was investigated in each risk group. Marital status, median household income and insurance status were included in the nomograms for CSS and OS, which had higher c-indexes than the 6th edition TNM staging system (all P < 0.001). Based on three disadvantageous socioeconomic factors (i.e., unmarried status, uninsured status, median household income <US $65 394), the prognostic score model generated four risk subgroups with scores of 0, 1, 2 or 3, which had significantly separated CSS/OS curves (all P < 0.001). Low-risk patients (score 0-1) were more likely to receive definitive treatment and obtain better CSS/OS than high-risk patients (score 2-3). Chinese and non-Hispanic black patients with high-risk socioeconomic status had best and poorest CSS/OS, respectively. Therefore, marital status, median household income and insurance status have significance for predicting survival outcomes. Low-risk socioeconomic status and Chinese race/ethnicity confer protective effects in HNSCC.

Perloy A, Maasland DHE, van den Brandt PA, Kremer B, Schouten LJ. Intake of meat and fish and risk of head-neck cancer subtypes in the Netherlands Cohort Study. Cancer Causes Control. 2017 Jun;28(6):647-656. doi: 10.1007/s10552-017-0892-0.

To date, the role of meat and fish intake in head-neck cancer (HNC) etiology is not well understood and prospective evidence is limited. This prompted us to study the association between meat, fish, and HNC subtypes, i.e., oral cavity cancer (OCC), oro- and hypopharyngeal cancer (OHPC), and laryngeal cancer (LC), within the Netherlands Cohort Study (NLCS).In 1986, 120,852 participants (aged 55-69 years) completed a baseline 150-item food frequency questionnaire (FFQ), from which daily meat and fish intake were calculated. After 20.3 years of follow-up, 430 HNC overall (134 OCC, 90 OHPC and 203 LC) cases and 4,111 subcohort members were found to be eligible for case-cohort analysis. Multivariate hazard ratios were calculated using Cox’s proportional hazards model within quartiles of energy-adjusted meat and fish intake.Processed meat intake, but not red meat intake, was positively associated with HNC overall [HR(Q4 vs. Q1) = 1.46, 95% CI 1.06-2.00; ptrend = 0.03]. Among HNC subtypes, processed meat was positively associated with OCC, while no associations were found with OHPC and LC. Fish intake was not associated with HNC risk. Tests for interaction did not reveal statistically significant interaction between meat, fish, and alcohol or smoking on HNC overall risk.In this large cohort study, processed meat intake was positively associated with HNC overall and HNC subtype OCC, but not with OHPC and LC.

 

Bakhtiari S, Mortazavi H, Mehdipour M, Jafarian N, Ranjbari N, Rahmani S. Frequency of Head and Neck Squamous Cell Carcinomas and Related Variables in Southern Iran (Ahvaz City): 10-Year Retrospective Study. Asian Pac J Cancer Prev. 2017 Feb 1;18(2):375-379.

Objective: Squamous cell carcinoma (SCC) is a life threatening lesion but there has been only limited research about its frequency in Iran. The aim of this study was to evaluate the frequency of squamous cell carcinoma of the head and neck in the records of the pathology department of Imam Khomeini hospital in Ahvaz between 2005 and 2015. Methods: The retrospective and cross-sectional study was conducted using 55,708 medical records of cancer throughout the body, accumulated in the pathology department of Imam Khomeini in Ahvaz in the designated period. Information about age, gender, site of involvement, histological characteristics, status of lymph node metastasis, smoking habit, family history, job and education level was extracted and data were analyzed with the Chi-square test with SPSS version 22. Result: Of the total of 55,708 records, 582 patients (1.04%) had head and neck squamous cell carcinomas. The male to female ratio was 2.85. The frequencies in the head, mouth and neck were 28.7%, 22% and 49.3% respectively. Significant relationships between being male and location (neck) (p = 0.002), age (60 to 80 years old) and being a farmer (p = 0.001) was observed. The most important correlated risk factors were: smoking, sunlight exposure, rural residence, job and education level. Conclusion: Head and neck squamous cell carcinomas were found to account for 1.04% of all cancers in Ahvaz, one of the southern provinces of Iran.

Peterson CE, Khosla S, Jefferson GD, Davis FG, Fitzgibbon ML, Freels S, Johnson TP, Hoskins K, Joslin CE. Measures of economic advantage associated with HPV-positive head and neck cancers among non-Hispanic black and white males identified through the National Cancer Database. Cancer Epidemiol. 2017 Jun;48:1-7. doi: 10.1016/j.canep.2017.02.011.

National trends show dramatic increases in the incidence of HPV-related head and neck squamous cell carcinomas (HNSCCs) among black and white males. Using cases identified through the National Cancer Data Base, we assessed factors associated with HPV 16- or 16/18 positive HNSCCs among non-Hispanic black and white males diagnosed in the U.S. between 2009 and 2013.This sample included 21,524 HNSCCs with known HPV status. Adjusted relative risks (RRs) and 95% confidence intervals (CIs) were estimated using log-binomial regression.Compared to those with HPV-negative tumors, male patients diagnosed with HPV-positive HNSCCs were non-Hispanic white, younger at diagnosis, lived in zip-code areas with higher median household income and higher educational attainment, had private health insurance and no reported comorbidities at diagnosis. Although the risk of HPV-positive HNSCCs increased with measures of higher area-level socioeconomic status, the effect was stronger for non-Hispanic black males (RRAdjusted=1.76, 95% CI 1.49-2.09) than for whites (RRAdjusted=1.12, 95% CI 1.08-1.16). The peak age for diagnosis of HPV-positive HNSCCs occurred in those diagnosed at 45-49 years (RRAdjusted=1.57, 95% CI 1.42-1.73). Oropharyngeal tumors were strongly associated with HPV-positivity (RRAdjusted=4.32, 95% CI 4.03-4.63). In the analysis restricted to oropharyngeal anatomic sites, similar patterns persisted.In our analysis, measures of economic advantage were associated with an increased risk of HPV-positive HNSCCs. In order to develop effective interventions, greater understanding of the risk factors for HPV-positive HNSCCs is needed among both high-risk males and their healthcare providers.

Getz KR, Rozek LS, Peterson LA, Bellile EL, Taylor JMG, Wolf GT, Mondul AM. Family history of cancer and head and neck cancer survival. Laryngoscope. 2017 Aug;127(8):1816-1820. doi: 10.1002/lary.26524.

Patients with a family history of cancer may be genetically predisposed to carcinogenesis. This could affect risk of recurrence, second primary tumors, and overall outcomes after treatment of a primary cancer. We evaluated the association between family history of cancer and disease-specific survival in a cohort of patients with primary head and neck squamous carcinoma (HNSCC).

Six hundred and forty-three incident HNSCC patients recruited through the University of Michigan Specialized Program of Research Excellence were followed for up to 5 years for survival. Participants were interviewed about personal and family cancer history, demographic information, and behavioral habits.Cox proportional hazards models were used to estimate the association between family history of cancer in a first-degree relative and disease-specific survival.After multivariable adjustment, we found a nonsignificant inverse association between family history and HNSCC mortality (hazard ratio [HR] = 0.88, 95% confidence interval [CI] 0.57-1.35). This association was stronger and statistically significant among patients who currently both drank alcohol and smoked cigarettes at diagnosis (HR = 0.46, 95% CI = 0.22-0.97); no association was observed among participants who did not both drink and smoke at the time of diagnosis (HR = 1.14, 95% CI = 0.68-1.91; p-interaction = 0.046).Results from this study suggest that having a family history of cancer may be associated with improved disease-specific survival in patients who use tobacco and alcohol. Additional large studies, particularly in populations including nonwhites and women, are needed to confirm or refute the association and to elucidate the genetic factors that may underlie this potential association.

Yakin M, Gavidi RO, Cox B, Rich A. Oral cancer risk factors in New Zealand. N Z Med J. 2017 Mar 3;130(1451):30-38.

Oral cancer constitutes the majority of head and neck cancers, which are the fifth most common malignancy worldwide, accounting for an estimated 984,430 cases in 2012. Between 2000 and 2010, there were 1,916 cases of OSCC in New Zealand with a male to female ratio of 1.85:1, and an age-standardised incidence rate of 42 persons per 1,000,000 population. This article presents an overview of the main risk factors for oral and oropharyngeal cancers and their prevalence in New Zealand. Alcohol consumption is the most prevalent risk factor in New Zealand, followed by tobacco. Given the high prevalence of these two risk factors and their synergistic effect, it is important for doctors and dentists to encourage smoking cessation in smokers and to recommend judicious alcohol intake. Research is needed to determine the prevalence of use of oral preparations of tobacco and water-pipe smoking in New Zealand, especially due to changing demography and increases in migrant populations. UV radiation is also an important risk factor. Further investigations are also needed to determine the prevalence of oral and oropharyngeal cancers attributable to oncogenic HPV infection.

Fakhry C, Westra WH, Wang SJ, van Zante A, Zhang Y, Rettig E, Yin LX, Ryan WR, Ha PK, Wentz A, Koch W, Richmon JD, Eisele DW, D’Souza G. The prognostic role of sex, race, and human papillomavirus in oropharyngeal and nonoropharyngeal head and neck squamous cell cancer. Cancer. 2017 May 1;123(9):1566-1575. doi: 10.1002/cncr.30353.

Human papillomavirus (HPV) is a well-established prognostic marker for oropharyngeal squamous cell cancer (OPSCC). Because of the limited numbers of women and nonwhites in studies to date, sex and racial/ethnic differences in prognosis have not been well explored. In this study, survival differences were explored by the tumor HPV status among 1) patients with OPSCCs by sex and race and 2) patients with nonoropharyngeal (non-OP) head and neck squamous cell cancers (HNSCCs).This retrospective, multi-institution study included OPSCCs and non-OP HNSCCs of the oral cavity, larynx, and nasopharynx diagnosed from 1995 to 2012. Race/ethnicity was categorized as white non-Hispanic, black non-Hispanic, Asian non-Hispanic, and Hispanic of any race. Tumors were centrally tested for p16 overexpression and the presence of HPV by HPV16 DNA and high-risk HPV E6/E7 messenger RNA in situ hybridization. Kaplan-Meier and Cox proportional hazards models were used to evaluate overall survival (OS).The study population included 239 patients with OPSCC and 621 patients with non-OP HNSCC with a median follow-up time of 3.5 years. After adjustments for the tumor HPV status, age, current tobacco use, and stage, the risk of death was lower for women versus men with OPSCC (adjusted hazard ratio, 0.55; P = .04). The results were similar with p16. In contrast, for non-OP HNSCCs, HPV positivity, p16 positivity, and sex were not associated with OS.For OPSCC, there are differences in survival by sex, even after the tumor HPV status has been taken into account. For non-OP HNSCC, the HPV status and the p16 status are not of prognostic significance. Cancer 2017;123:1566-1575. © 2017 American Cancer Society.

Kouyoumdjian FG, Pivnick L, McIsaac KE, Wilton AS, Lofters A, Hwang SW. Cancer prevalence, incidence and mortality in people who experience incarceration in Ontario, Canada: A population-based retrospective cohort study. PLoS One. 2017 Feb 22;12(2):e0171131. doi: 10.1371/journal.pone.0171131. eCollection 2017.

Evidence suggests that many risk factors for cancer are overrepresented in people who experience incarceration, and data on cancer epidemiology are limited for this population. We aimed to describe cancer prevalence, incidence and mortality in adults admitted to provincial custody in Ontario, Canada in 2000.We linked data on 48,166 adults admitted to provincial custody in Ontario in 2000 with Ontario Cancer Registry data to 2012. We calculated cancer prevalence in the 10 years prior to admission to custody in 2000, incidence between 2000 and 2012 and mortality between 2000 and 2011. Standardized for age, we calculated incidence and mortality ratios by sex compared to the general population of Ontario.The 10-year cancer prevalence was 0.4% in men and 0.6% in women at admission to provincial custody in 2000. Between 2000 and 2012, 2.6% of men and 2.8% of women were diagnosed with new cancer. The standardized incidence ratio for cancer was 1.0 (95% CI 0.9-1.0) for men and 0.9 (95% CI 0.7-1.0) for women compared to the general population, and was significantly increased for cervical, head and neck, liver and lung cancers. The standardized mortality ratio was 1.6 (95% CI 1.4-1.7) in men and 1.4 (95% CI 1.0-1.9) in women, and was significantly increased for head and neck, liver, and lung cancers.There is an excess burden of cancer in people who experience incarceration. Cancer prevention should include people who experience incarceration, and the period of incarceration may offer an opportunity for intervention.

Dwojak S, Bhattacharyya N. Racial disparities in preventable risk factors for head and neck cancer. Laryngoscope. 2017 May;127(5):1068-1072. doi: 10.1002/lary.26203.

To demonstrate racial differences in preventable risk behaviors/practices that contribute to head and neck cancer (HNCA).

The Behavioral Risk Factor Surveillance System for 2013 was analyzed. Demographic data were extracted, including age, sex, and race. Social habits considered risk factors for HNCA were also extracted, including alcohol consumption, smoking, and human papillomavirus (HPV) vaccination status. Statistical comparisons were conducted according to race for each risk factor, and additional comparisons were conducted within the American Indian population subgroup for risk factors according to sex.A total of 238.6 million Americans were surveyed. American Indians reported higher rates of binge drinking (19.0%) than whites (17.3%), blacks (12.4%), and Asian Americans (13.1%; P < .001). This rate was significantly higher for American Indian males (23.5%) versus females (13.7%; P < .001). Mean total drinks per month was higher for whites and American Indians (13.5 and 13.5; P < .001). American Indians reported the highest rates of current smoking (28.1%), followed by blacks (20.1%), whites (18.3%), and Asians (10.2%; P < .001). American Indians also reported the highest rates of every day smoking (18.2%), versus whites (13.3%), blacks (13.1%), and Asians (6.1%; P < .001). Rates of HPV vaccination were lowest for American Indians (11.7%), compared to whites (14.6%), blacks (13.6%), and Asians (12%; P = 0.618).There are striking racial disparities in the prevalence of preventable risk factors for HNCA. These data highlight the need for targeted education and prevention programs in particular racial groups.

Meyers TJ, Chang SC, Chang PY, Morgenstern H, Tashkin DP, Rao JY, Cozen W, Mack TM, Zhang ZF. Case-control study of cumulative cigarette tar exposure and lung and upper aerodigestive tract cancers. Int J Cancer. 2017 May 1;140(9):2040-2050. doi: 10.1002/ijc.30632.

The development of comprehensive measures for tobacco exposure is crucial to specify effects on disease and inform public health policy. In this population-based case-control study, we evaluated the associations between cumulative lifetime cigarette tar exposure and cancers of the lung and upper aerodigestive tract (UADT). The study included 611 incident cases of lung cancer; 601 cases of UADT cancers (oropharyngeal, laryngeal and esophageal cancers); and 1,040 cancer-free controls. We estimated lifetime exposure to cigarette tar based on tar concentrations abstracted from government cigarette records and self-reported smoking histories derived from a standardized questionnaire. We analyzed the associations for cumulative tar exposure with lung and UADT cancer, overall and according to histological subtype. Cumulative tar exposure was highly correlated with pack-years among ever smoking controls (Pearson coefficient = 0.90). The adjusted odds ratio (95% confidence limits) for the estimated effect of about 1 kg increase in tar exposure (approximately the interquartile range in all controls) was 1.61 (1.50, 1.73) for lung cancer and 1.21 (1.13, 1.29) for UADT cancers. In general, tar exposure was more highly associated with small, squamous and large cell lung cancer than adenocarcinoma. With additional adjustment for pack-years, positive associations between tar and lung cancer were evident, particularly for small cell and large cell subtypes. Therefore, incorporating the composition of tobacco carcinogens in lifetime smoking exposure may improve lung cancer risk estimation. This study does not support the claim of a null or inverse association between “low exposure” to tobacco smoke and risk of these cancer types.

Adoga AA, Silas OA, Yaro JP, Okwori ET, Iduh AA, Mgbachi CJ. Assessment of the sociodemographic characteristics and efficacy of screening for oral, head and neck potential malignant lesions in apparently healthy adults in Jos Nigeria. Indian J Cancer. 2016 Apr-Jun;53(2):252-255. doi: 10.4103/0019-509X.197713.

This study aims to review our experience with a free oral, HNC-screening program to determine the sociodemographic characteristics of the participants and the effectiveness of this program to improve future programs.In the years of screening, 135 participants presented aged between 21 and 83 years (mean = 47.0; ±15.6) with a male to female ratio of 1.2:1. 32.6% consumed alcohol, and 17.8% were smokers. Smoking (P = 0.04) and alcohol use (P = 0.05) were associated with higher rates of suspicious malignant symptoms. There was no statistical correlation between symptom prevalence and the number of participants requiring immediate consultation for oral, HNC (r = 0.47), and those referred for routine follow-up (r = 0.34). Premalignant and malignant lesions were diagnosed in 5 males aged 44-72 years. 83.7% found the screening program beneficial in increasing their awareness of the disease.This hospital-based screening demonstrates improved awareness among people about oral, HNCs, and survival outcomes on a small scale. A community-based screening with health education to target a larger high-risk population is recommended to encourage individuals to modify high-risk factors and improve outcomes.

Carton M, Barul C, Menvielle G, Cyr D, Sanchez M, Pilorget C, Trétarre B, Stücker I, Luce D; ICARE Study Group. Occupational exposure to solvents and risk of head and neck cancer in women: a population-based case-control study in France. BMJ Open. 2017 Jan 9;7(1):e012833. doi: 10.1136/bmjopen-2016-012833.

Investigation of occupational and environmental CAuses of REspiratory cancers (ICARE), a French population-based case-control study, included 296 squamous cell carcinomas of the head and neck (HNSCC) in women and 775 female controls. Lifelong occupational history was collected. Job-exposure matrices allowed to assess exposure to 5 chlorinated solvents (carbon tetrachloride; chloroform; methylene chloride; perchloroethylene; trichloroethylene), 5 petroleum solvents (benzene; special petroleum product; gasoline; white spirits and other light aromatic mixtures; diesel, fuels and kerosene) and 5 oxygenated solvents (alcohols; ketones and esters; ethylene glycol; diethyl ether; tetrahydrofuran). OR and 95% CIs, adjusted for smoking, alcohol drinking, age and geographical area, were estimated with logistic models.Elevated ORs were observed among women ever exposed to perchloroethylene (OR=2.97, 95% CI 1.05 to 8.45) and trichloroethylene (OR=2.15, 95% CI 1.21 to 3.81). These ORs increased with exposure duration (OR=3.75, 95% CI 0.64 to 21.9 and OR=4.44, 95% CI 1.56 to 12.6 for 10 years or more, respectively). No significantly increased risk of HNSCC was found for occupational exposure to the other chlorinated, petroleum or oxygenated solvents.These findings suggest that exposure to perchloroethylene or trichloroethylene may increase the risk of HNSCC in women. In our study, there is no clear evidence that the other studied solvents are risk factors for HNSCC.

Butler C, Lee YA, Li S, Li Q, Chen CJ, Hsu WL, Lou PJ, Zhu C, Pan J, Shen H, Ma H, Cai L, He B, Wang Y, Zhou X, Ji Q, Zhou B, Wu W, Ma J, Boffetta P, Zhang ZF, Dai M, Hashibe M. Diet and the risk of head-and-neck cancer among never-smokers and smokers in a Chinese population. Cancer Epidemiol. 2017 Feb;46:20-26. doi: 10.1016/j.canep.2016.10.014.

Few studies have been conducted in China to investigate the association between diet and the risk of head-and-neck cancer (HNC). The aim of this study was to determine the relationship between diet and HNC risk in the Chinese population and to examine whether smoking status has any effect on the risk.Our multicenter case-control study included 921 HNC cases and 806 controls. We obtained information on the frequency of both animal- and plant-based food consumption. Unconditional logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (95%CIs).The risk of HNC increased with more frequent consumption of processed meat and fermented foods but decreased with frequent consumption of fruits and vegetables. There was a significant increasing P for trend of 0.006 among smokers who consumed meat and an increased OR among smokers who consumed processed meat (OR 2.95, 95%CI 1.12-7.75). Protective odds ratios for vegetable consumption were observed among smokers only. We also observed protective odds ratios for higher egg consumption among never-smokers (P for trend=0.0.003).Reduced HNC risks were observed for high fruit and vegetable intake, a finding consistent with the results of previous studies. Processed meat intake was associated with an increased risk. The role of dietary factors in HNC in the East Asian population is similar to that in European populations.

Schnelle C, Whiteman DC, Porceddu SV, Panizza BJ, Antonsson A. Past sexual behaviors and risks of oropharyngeal squamous cell carcinoma: a case-case comparison. Int J Cancer. 2017 Mar 1;140(5):1027-1034. doi: 10.1002/ijc.30519.

The incidence of oropharyngeal squamous cell carcinomas (SCCs) is increasing and is believed to reflect changing sexual practices in recent decades. For this case-case comparative study, we collected medical and life-style information and data on sexual behavior from 478 patients treated at the head and neck clinic of a tertiary hospital in Brisbane, Australia. Patients were grouped as (i) oropharyngeal SCC (n = 96), (ii) oral cavity, larynx and hypopharynx SCC (“other HNSCCs,” n = 96), (iii) other SCCs (n = 141), and (iv) other diagnoses (n = 145). We fitted multivariable logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) associated with lifestyle factors and sexual behaviors. Compared to the other three patient groups, the oropharyngeal SCC patients had overall more sexual lifetime partners (kissing, oral sex and sexual intercourse). Oropharyngeal SCC patients were significantly more likely to have ever given oral sex compared to the other three patient groups-93% of oropharyngeal SCC patients, 64% of other HNSCC patients, and 58% of patients with other SCC or other diagnoses. Oropharyngeal SCC patients were significantly more likely to have given oral sex to four or more partners when compared to patients with other HNSCC (odds ratio [OR] 11.9; 95% CI 3.5-40.1), other SCC (OR 16.6; 95% CI 5.3-52.0) or patients with other diagnoses (OR 25.2; 95% CI 7.8-81.7). The very strong associations reported here between oral sex practices and risks of oropharyngeal SCC support the hypothesis that sexually transmitted HPV infections cause some of these cancers.

 

Condon JR, Zhang X, Dempsey K, Garling L, Guthridge S. Trends in cancer incidence and survival for Indigenous and non-Indigenous people in the Northern Territory. Med J Aust. 2016 Nov 21;205(10):454-458.

Age-adjusted incidence rates; rate ratios comparing incidence in NT Indigenous and non-Indigenous populations with that for other Australians; 5-year survival; multivariable Poisson regression of excess mortality.The incidence of most cancers in the NT non-Indigenous population was similar to that for other Australians. For the NT Indigenous population, the incidence of cancer at several sites was much higher (v other Australians: lung, 84% higher; head and neck, 325% higher; liver, 366% higher; cervix, 120% higher). With the exception of cervical cancer (65% decrease), incidence rates in the Indigenous population did not fall between 1991-1996 and 2007-2012. The incidence of several other cancers (breast, bowel, prostate, melanoma) was much lower in 1991-1996 than for other Australians, but had increased markedly by 2007-2012 (breast, 274% increase; bowel, 120% increase; prostate, 116% increase). Five-year survival was lower for NT Indigenous than for NT non-Indigenous patients, but had increased for both populations between 1991-2000 and 2001-2010.The incidence of several cancers that were formerly less common in NT Indigenous people has increased, without a concomitant reduction in the incidence of higher incidence cancers (several of which are smoking-related). The excess burden of cancer in this population will persist until lifestyle risks are mitigated, particularly by reducing the extraordinarily high prevalence of smoking.

 

Shaw R, Beasley N. Aetiology and risk factors for head and neck cancer: United Kingdom National Multidisciplinary Guidelines. J Laryngol Otol. 2016 May;130(S2):S9-S12.

This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. It discusses the aetiology and risk factors for head and neck cancer and the recommended interventions appropriate for each risk factor. Recommendations • Recent evidence synthesis from National Institute for Health and Care Excellence suggests that the following brief interventions for smoking cessation work should be used: ○ Ask smokers how interested they are in quitting (R) ○ If they want to stop, refer them to an intensive support service such as National Health Service Stop Smoking Services (R) ○ If they are unwilling or unable to accept a referral, offer a stop smoking aid, e.g. pharmacotherapy. (R) • Brief interventions are effective for hazardous and harmful drinking. (R) • Specialist interventions are effective in people with alcohol dependence. (R) • Most people with alcohol dependence can undergo medically assisted withdrawal safely at home, after risk assessment. (R) • Management of leukoplakia is not informed by high-level evidence but consensus supports targeted use of biopsy and histopathological assessment. (R) • The management of biopsy proven dysplastic lesions favours: ○ advice to reduce known environmental carcinogens such as tobacco and alcohol (R) ○ surgical excision when the size of the lesions and the patient’s function allows (R) ○ long-term surveillance. (R) • Fanconi anaemia patients should: ○ be followed up in a multidisciplinary specialist Fanconi anaemia clinic (G) ○ have quarterly screening for head and neck squamous cell carcinoma and an aggressive biopsy policy (G) ○ receive prophylactic vaccination against high risk human papilloma virus (G) ○ receive treatment for head and neck squamous cell carcinoma with surgery alone where possible. (G).

Wu YH, Yen CJ, Hsiao JR, Ou CY, Huang JS, Wong TY, Tsai ST, Huang CC, Lee WT, Chen KC, Fang SY, Wu JL, Hsueh WT, Lin FC, Yang MW, Chang JY, Liao HC, Wu SY, Lin CL, Wang YH, Weng YL, Yang HC, Chen YS, Chang JS. A Comprehensive Analysis on the Association between Tobacco-Free Betel Quid and Risk of Head and Neck Cancer in Taiwanese Men. PLoS One. 2016 Oct 25;11(10):e0164937. doi: 10.1371/journal.pone.0164937. eCollection 2016.

Although betel quid (BQ) is an established risk factor of head and neck cancer (HNC), insufficiencies exist in the literature regarding the dose-response, BQ types, HNC sites, and BQ cessation. The current study was conducted to fill these insufficiencies.A hospital-based case-control study was conducted to evaluate the association between BQ and HNC. In-person interview was conducted to collect data on BQ chewing. The current analysis included 487 men newly diagnosed with HNC and 617 male controls who were frequency-matched to the cases by age. The association between BQ and HNC was assessed using multivariable unconditional logistic regression. Ever BQ chewing was associated with an increased HNC risk regardless of the BQ types. A non-linear positive association between BQ and HNC was observed, with a steep rise in HNC risk for the first 5 pack-years or 200,000 minutes of BQ consumption. Every year of BQ cessation was associated with a 2.9% reduction in HNC risk; however, the risk did not reduce to the level of non-BQ chewers even after 20 years of BQ cessation. Eliminating BQ chewing may prevent 51.6% of HNCs, 62.6% of oral cancers, and 41.3% of pharyngeal cancers in Taiwan.Our results supported the positive association between BQ and HNC. BQ cessation is effective in reducing HNC risk and should be encouraged. Because BQ cessation may not reduce the HNC risk to the level of non-BQ chewers, it is important to prevent the initiation of BQ chewing.

Perdomo S, Martin Roa G, Brennan P, Forman D, Sierra MS4. Head and neck cancer burden and preventive measures in Central and South America. Cancer Epidemiol. 2016 Sep;44 Suppl 1:S43-S52. doi: 10.1016/j.canep.2016.03.012.

Central and South America comprise one of the areas characterized by high incidence rates for head and neck cancer. We describe the geographical and temporal trends in incidence and mortality of head and neck cancers in the Central and South American region in order to identify opportunities for intervention on the major identified risk factors: tobacco control, alcohol use and viral infections.We obtained regional- and national-level incidence data from 48 population-based cancer registries in 13 countries and cancer deaths from the WHO mortality database for 18 countries. Age-standardized incidence (ASR) and mortality (ASMR) rates per 100,000 person-years were estimated.Brazil had the highest incidence rates for oral and pharyngeal cancer in the region for both sexes, followed by Cuba, Uruguay and Argentina. Cuba had the highest incidence and mortality rates of laryngeal cancer in the region for males and females. Overall, males had rates about four times higher than those in females. Most countries in the region have implemented WHO recommendations for both tobacco and alcohol public policy control.Head and neck squamous-cell cancer (HNSCC) incidence and mortality rates in the Central and South America region vary considerably across countries, with Brazil, Cuba, French Guyana, Uruguay and Argentina experiencing the highest rates in the region. Males carry most of the HNSCC burden. Improvement and implementation of comprehensive tobacco and alcohol control policies as well as the monitoring of these factors are fundamental to prevention of head and neck cancers in the region.

Chancellor JA, Ioannides SJ, Elwood JM. Oral and oropharyngeal cancer and the role of sexual behaviour: a systematic review. Community Dent Oral Epidemiol. 2016 Sep 19. doi: 10.1111/cdoe.12255.

Following the PRISMA guidelines, we identified observational and interventional studies reporting associations between several different sexual behaviours and OPC or OCC. Study quality was assessed independently by two reviewers using a validated scoring system.

From 513 papers identified, 21, reporting on 20 studies, fulfilled the inclusion criteria. Two cohort studies were rated as moderate quality. The 18 case-control studies were rated as weak; nine comparing people with OPC or OCC to people without cancer, eight comparing HPV-positive to HPV-negative cancer patients and one comparing OPCs to other head and neck cancers. One study was a pooled analysis of seven of the included studies with some additional information. Twelve sexual behaviours were assessed and 69 associations reported. The studies differed in the comparisons made, the sexual behaviours assessed, and how these were reported and categorized, so no quantitative meta-analyses were appropriate. Most studies combined OPC and OCC. Several significantly increased risks were seen with a high number of lifetime sexual partners (nine studies) and with the practice of oral sex (five studies), although two studies found a significant negative association with OCC and ever performing oral sex. Two cohort studies of men and women in homosexual relationships found increases in oral cancer risk, and a cohort study of men married to women who had a history of cervical cancer also showed an increased risk of oral cancers. Results for other sexual behaviours were limited and inconsistent, and these included the following: younger age at first sexual intercourse, number of lifetime oral sex partners, the practice of oral-anal sex, the number of oral-anal sex partners, and ever performing anal sex. Only one study assessed casual sex, never or rare use of a condom and having a sexual partner with a history of genital warts, finding significant associations in the two former behaviours.The current evidence for sexual behaviours being risk factors for oral and oropharyngeal cancer is limited and inconsistent. Evidence suggests that the number of sexual partners and performing oral sex are associated with a greater risk. Furthermore men whose partners have had cervical cancer may have an increased risk. More studies looking at OPC specifically will be useful to determine whether these behaviours are subsite-selective.

Tang L, Hu H, Liu H, Jian C, Wang H, Huang J. Association of nonsteroidal anti-inflammatory drugs and aspirin use and the risk of head and neck cancers: a meta-analysis of observational studies. Oncotarget. 2016 Oct 4;7(40):65196-65207. doi: 10.18632/oncotarget.11239.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, have emerged as the potential chemopreventive agents for a number of cancer types, however, previous studies of head and neck cancers (HNC) have yielded inconclusive results. We performed a meta-analysis of observational studies to quantitatively assess the association between NSAIDs use and the risk for HNC.We searched Pubmed, Embase, Google scholar, and Cochrane library for relevant studies that were published in any language, from January 1980 to April 2016. We pooled the odds ratio (OR) from individual studies and performed subgroup, heterogeneity, and publication bias analyses.A total of eleven studies (eight case-control studies and three cohort studies), involving 370,000 participants and 10,673 HNC cases contributed to this meta-analysis. The results of these studies suggested that neither use of overall NSAIDs (OR=0.95; 95% CI, 0.81-1.11), aspirin (OR=0.93; 95% CI, 0.79-1.10), nor nonsteroidal NSAIDs (OR=0.92; 95% CI, 0.76-1.10) were associated with HNC risk. Similar nonsteroidal results were observed when stratified by HNC sites, study design, sample size, and varied adjustment factors. However, we found significant protective effect of ibuprofen (OR=0.85; 95% CI, 0.72-0.99) and long-term aspirin use (≧5years) (OR=0.75; 95% CI, 0.65-0.85) on HNC risk, with low heterogeneity and publication bias.Our meta-analysis results do not support the hypothesis that overall use of NSAIDs significant reduces the risk of HNC. Whereas, we cannot rule out a modest reduction in HNC risk associated with ibuprofen and long-term aspirin use.

Selmer C, Madsen JC, Torp-Pedersen C, Gislason GH, Faber J. Hyponatremia, all-cause mortality, and risk of cancer diagnoses in the primary care setting: A large population study. Eur J Intern Med. 2016 Dec;36:36-43. doi: 10.1016/j.ejim.2016.07.028.

Hyponatremia has been associated with increased all-cause mortality in hospitalized individuals. In this study we examine the risk of all-cause mortality in primary care subjects with hyponatremia, while also exploring the association with subsequent diagnosis of cancer.Retrospective cohort study on subjects who underwent blood tests, consulting their general practitioner 2000-2012 in Copenhagen, Denmark. Reference range for sodium was 135-145mmol/L, and mild, moderate, and severe hyponatremia were defined as 130-135, 125-129, and <125mmol/L, respectively. Primary outcome was all-cause mortality, and secondary outcomes overall and specific types of cancer diagnoses.Among 625,114 included subjects (mean age 49.9 [SD±18.4] years; 43.5% males), 90,926 (14.5%) deaths occurred. All-cause mortality was increased in mild, moderate, and severe hyponatremia (age-adjusted mortality rates [IRs, incidence rates] 26, 30, and 36 per 1000 person-years (py), respectively and incidence rate ratios [IRRs] 1.81 [95% CI: 1.76-1.85], 2.11 [2.00-2.21], and 2.52 [2.26-2.82], respectively) compared with individuals with normonatremia (IR 14 per 1000 py). For the secondary endpoint an increased level-dependent risk was found with lower sodium levels in relation to cancer overall, head and neck cancers, and pulmonary cancer, with severe hyponatremia associated with the highest IRRs (1.77 [1.39-2.24], 5.24 [2.17-12.63]), and 4.99 [3.49-7.15], respectively).All levels of hyponatremia are associated with all-cause mortality in primary care patients and hyponatremia is linked to an increased risk of being diagnosed with any cancer, particularly pulmonary and head and neck cancers.

Alnuaimi AD, Ramdzan AN, Wiesenfeld D, O’Brien-Simpson NM, Kolev SD, Reynolds EC, McCullough MJ. Candida virulence and ethanol-derived acetaldehyde production in oral cancer and non-cancer subjects. Oral Dis. 2016 Nov;22(8):805-814. doi: 10.1111/odi.12565.

To compare biofilm-forming ability, hydrolytic enzymes and ethanol-derived acetaldehyde production of oral Candida isolated from the patients with oral cancer and matched non-oral cancer.Fungal biofilms were grown in RPMI-1640 medium, and biofilm mass and biofilm activity were assessed using crystal violet staining and XTT salt reduction assays, respectively. Phospholipase, proteinase, and esterase production were measured using agar plate method, while fungal acetaldehyde production was assessed via gas chromatography.Candida isolated from patients with oral cancer demonstrated significantly higher biofilm mass (P = 0.031), biofilm metabolic activity (P < 0.001), phospholipase (P = 0.002), and proteinase (P = 0.0159) activity than isolates from patients with non-oral cancer. High ethanol-derived acetaldehyde-producing Candida were more prevalent in patients with oral cancer than non-oral cancer (P = 0.01). In univariate regression analysis, high biofilm mass (P = 0.03) and biofilm metabolic activity (P < 0.001), high phospholipase (P = 0.003), and acetaldehyde production ability (0.01) were significant risk factors for oral cancer; while in the multivariate regression analysis, high biofilm activity (0.01) and phospholipase (P = 0.01) were significantly positive influencing factors on oral cancer.These data suggest a significant positive association between the ability of Candida isolates to form biofilms, to produce hydrolytic enzymes, and to metabolize alcohol to acetaldehyde with their ability to promote oral cancer development.

Emanuelli E, Alexandre E, Cazzador D, Comiati V, Volo T, Zanon A, Scapellato ML, Carrieri M, Martini A, Mastrangelo G. A case-case study on sinonasal cancer prevention: effect from dust reduction in woodworking and risk of mastic/solvents in shoemaking. J Occup Med Toxicol. 2016 Jul 21;11:35. doi: 10.1186/s12995-016-0124-7. eCollection 2016.

Sinonasal cancers (SNCs) are rare neoplasms, accounting for about 3 % of head and neck cancers, with squamous cell carcinoma (SCC) and adenocarcinoma (ADC) as the most common subtypes. ADCs present strong associations with occupational wood dust exposure. Preventive measures have progressively reduced wood dust concentrations in workplaces but no study has evaluated the effectiveness of such interventions. Few studies indicate associations between ADC and exposure to solvents, which is common in the shoe industry, but this hypothesis still needs confirmation.In a case-case study, we contrasted 32 ADCs against 21 Non-Adenocarcinoma Epithelial Tumors (NAETs) – all recruited from the same clinical setting (Padua’s University Hospital; period 2004-2015) – using questionnaires and clinical records to collect information on potential predictors. Non-occupational factors were age, sex, smoking, allergy and chronic sinusitis. Occupational factors were intensity and frequency of wood dust exposure, protection from wood dust, type of wood (in woodworking); frequency of exposure to leather dust or mastic/solvent (in shoemaking). Odds-ratio (OR), 95 % confidence interval (95 % CI) and two-tail p-values were obtained through stepwise backward logistic regression for each industry, always using as reference patients never employed in either trade and adjusting for non-occupational risk factors.Adjusted OR was 22.5 (95 % CI = 3.50-144; p = 0.001) and 9.37 (95 % CI = 1.29-67.6; p = 0.026), respectively, in patients with low or high degree of protection against wood dust. In the shoe industry, adjusted OR was 1 and 18.8 (95 % CI = 1.29-174; p = 0.030), respectively, in patients with low or high exposure to only mastic/solvent; and 1 and 22.5 (95 % CI = 2.07-244; p = 0.011), respectively, in patients with low or high exposure to only leather dust.The questionnaire used was able to estimate with simple algorithms past exposures in wood and footwear industries. The case-case design considerably increased the validity of this small study. Results in this study were always consistent with the extant literature; this could support reliability of novel findings. In woodworking, respiratory protective equipment and local exhaust ventilation reduced the risk of occupational SNC; in footwear manufacture, where preventive interventions were seldom adopted, SNC risk was significantly greater for high exposure from mastic/solvent and leather dust.

Wu CC, Chang CM, Hsu TW, Lee CH, Chen JH, Huang CY, Lee CC. The effect of individual and neighborhood socioeconomic status on esophageal cancer survival in working-age patients in Taiwan. Medicine (Baltimore). 2016 Jul;95(27):e4140. doi: 10.1097/MD.0000000000004140.

Esophageal cancer is the sixth leading cause of cancer mortality. More than 90% of patients with esophageal cancer in Taiwan have squamous cell carcinoma. Survival of such patients is related to socioeconomic status (SES). We studied the association between SES (individual and neighborhood) and the survival of working-age patients with esophageal cancer in Taiwan. A population-based study was conducted of 4097 patients diagnosed with esophageal cancer between 2002 and 2006. Each was traced for 5 years or until death. Individual SES was defined by enrollee job category. Neighborhood SES was based on household income and dichotomized into advantaged or disadvantaged. Multilevel logistic regression was used to compare the survival rates by SES group after adjustment for possible confounding and risk factors. Hospital and neighborhood SES were used as random effects in multilevel logistic regression. In patients younger than 65 years, 5-year overall survival rates were worst for those with low individual SES living in disadvantaged neighborhoods. After adjustment for patient characteristics, esophageal cancer patients with high individual SES had a 39% lower risk of mortality than those with low individual SES (odds ratio 0.61, 95% confidence interval 0.48-0.77). Patients living in disadvantaged areas with high individual SES were more likely to receive surgery than those with low SES (odds ratio 1.45, 95% confidence interval 1.11-1.89). Esophageal cancer patients with low individual SES have the worst 5-year survival, even with a universal healthcare system. Public health, education, and social welfare programs should address the inequality of esophageal cancer survival.

Sterba KR, Garrett-Mayer E, Carpenter MJ, Tooze JA, Hatcher JL, Sullivan C, Tetrick LA, Warren GW, Day TA, Alberg AJ, Weaver KE. Smoking status and symptom burden in surgical head and neck cancer patients. Laryngoscope. 2017 Jan;127(1):127-133. doi: 10.1002/lary.26159.

Head and neck squamous cell carcinoma (HNSCC) patients who smoke are at risk for poor treatment outcomes. This study evaluated symptom burden and clinical, sociodemographic, and psychosocial factors associated with smoking in surgical patients to identify potential targets for supportive care services.Individuals with HNSCC of the oral cavity, larynx, or pharynx were recruited from two cancer centers and completed questionnaires assessing smoking status (never, former, current/recent), patient characteristics, and symptoms before surgery.

Of the 103 patients enrolled, 73% were male, 52% were stage IV, 41% reported current/recent smoking, and 37% reported former smoking. Current/recent smokers were less likely than former smokers to have adequate finances (53% vs. 89%, P = .001) and be married/partnered (55% vs. 79%, P = .03). Current/recent smokers were also more likely than both former and never smokers to be unemployed (49% vs. 40% and 13%, respectively, all P = .02) and lack health insurance (17% vs. 5% and 13%, respectively, all P ≤.04). Fatalistic beliefs (P = .03) and lower religiosity (P =.04) were more common in current/recent than never smokers. In models adjusted for sociodemographic/clinical factors, current/recent smokers reported more problems than former and never smokers with swallowing, speech, and cough (P ≤.04). Current/recent smokers also reported more problems than never smokers with social contact, feeling ill, and weight loss (P ≤ .02).HNSCC patients reporting current/recent smoking before surgery have high-risk clinical and sociodemographic features that may predispose them to poor postoperative outcomes. Unique symptoms in HNSCC smokers may be useful targets for patient-centered clinical monitoring and intervention.

 

Koyanagi YN, Matsuo K, Ito H, Wakai K, Nagata C, Nakayama T, Sadakane A, Tanaka K, Tamakoshi A, Sugawara Y, Mizoue T, Sawada N, Inoue M, Tsugane S, Sasazuki S; Research Group for the Development and Evaluation of Cancer Prevention Strategies in Japan, Sasazuki S, Tsugane S, Inoue M, Iwasaki M, Otani T, Sawada N, Shimazu T, Yamaji T, Tsuji I, Tsubono Y, Nishino Y, Tamakoshi A, Matsuo K, Ito H, Wakai K, Nagata C, Mizoue T, Tanaka K, Nakayama T, Sadakane A; Research Group for the Development and Evaluation of Cancer Prevention Strategies in Japan. Cigarette smoking and the risk of head and neck cancer in the Japanese population: a systematic review and meta-analysis. Jpn J Clin Oncol. 2016 Jun;46(6):580-95. doi: 10.1093/jjco/hyw027.

Although cigarette smoking is a well-established risk factor for head and neck cancer, the impact of smoking on head and neck cancer might vary among geographic areas. To date, however, no systematic review of cigarette smoking and head and neck cancer in the Japanese population has yet appeared.We conducted a systematic review of previous epidemiological studies for cigarette smoking and head and neck cancer among Japanese. Evaluation of associations was based on the strength of evidence (‘convincing’, ‘probable’, ‘possible’ or ‘insufficient’) and the magnitude of association (‘strong’, ‘moderate’, ‘weak’ or ‘no association’), together with biological plausibility as previously evaluated by the International Agency for Research on Cancer. A meta-analysis was conducted to obtain summary estimates for the overall magnitude of association.We identified five cohort studies and 12 case-control studies. Four of five cohort studies and 11 of 12 case-control studies showed a strong positive association between cigarette smoking and head and neck cancer. Nine of 12 studies indicated a dose-response relationship between cigarette smoking and the risk of head and neck cancer. Meta-analysis of 12 studies indicated that the summary relative risk for ever smokers relative to never smokers was 2.43 (95% confidence interval: 2.09-2.83). Summary relative risks for current and former smokers relative to never smokers were 2.68 (2.08-3.44) and 1.49 (1.05-2.11), respectively.Cigarette smoking is a convincing risk factor for head and neck cancer in the Japanese population.

Woto-Gaye G, M’Farrej MK, Doh K, Thiam I, Touré S, Diop R, Dial C. Human papilloma viruses: other risk factor of head and neck carcinoma. Bull Soc Pathol Exot. 2016 Aug;109(3):160-4. doi: 10.1007/s13149-016-0500-7.

 

Head and neck carcinoma (HNC) occupy the sixth place as the most frequent type of cancer worldwide. Next to alcohol and tobacco intoxication, other risk factors (RF) are suspected, including the human papilloma viruses (HPVs). The aim of this study was to highlight the prevalence of HPVs and histo-epidemiological characteristics of HNC HPV+ in Senegal. This is a prospective, multicenter preliminary study of 18 months (January 1, 2012-June 30, 2014). The cases of HNC histologically confirmed in Senegal were then sent to the bio-pathology department of the Curie Institute in Paris to search HPVs. In the 90 included cases, the PCR technique was successful in 54 cases (60%). HPVs were found in seven cases, that is, a prevalence of 13%. HPVs were associated with 5 cases of hypopharyngeal carcinoma and 2 cases of carcinoma of the oral cavity. Patients with HNC HPV+ had a median age of 42 years against 49 years for HPV-patients. Three patients (42.8%) with HPV+ carcinomas were smokers. Of the 47 HPV-patients, 40 patients (87.1%) had alcohol intoxication and/or smoking. The concept of oral sex was refuted by all our patients. Squamous cell carcinoma was the only histological type found. HPV+ cell carcinoma showed no specific histological appearance. HPVs are another certain RF of HNC in Senegal. The major therapeutic and prognostic impact of HPVinduced cancers requires the systematic search of the viruses by the PCR technique.

Lee PN, Thornton AJ, Hamling JS. Epidemiological evidence on environmental tobacco smoke and cancers other than lung or breast. Regul Toxicol Pharmacol. 2016 Oct;80:134-63. doi: 10.1016/j.yrtph.2016.06.012.

We reviewed 87 epidemiological studies relating environmental tobacco smoke (ETS) exposure to risk of cancer other than lung or breast in never smoking adults. This updates a 2002 review which also considered breast cancer. Meta-analysis showed no significant relationship with ETS for nasopharynx cancer, head and neck cancer, various digestive cancers (stomach, rectum, colorectal, liver, pancreas), or cancers of endometrium, ovary, bladder and brain. For some cancers (including oesophagus, colon, gall bladder and lymphoma) more limited data did not suggest a relationship. An increased cervix cancer risk (RR 1.58, 95%CI 1.29-1.93, n = 17 independent estimates), reducing to 1.29 (95%CI 1.01-1.65) after restriction to five estimates adjusting for HPV infection or sexual activity suggests a causal relationship, as do associations with nasosinus cancer observed in 2002 (no new studies since), and less so kidney cancer (RR 1.33, 95%CI 1.04-1.70, n = 6). A weaker association with total cancer (RR 1.13, 95%CI 1.03-1.35, n = 19) based on heterogeneous data is inconclusive. Inadequate confounder control, recall bias, publication bias, and occasional reports of implausibly large RRs in individual studies contribute to our conclusion that the epidemiological evidence does not convincingly demonstrate that ETS exposure causes any of the cancers studied.

Zaoui K, Doll J, Stiebi P, Federspil P, Plinkert PK, Hess J. Diabetes mellitus as a prognostic marker in oropharyngeal and laryngeal squamous cell carcinoma. HNO. 2016 Jul;64(7):479-86. doi: 10.1007/s00106-016-0177-z.

Recent experimental and clinical studies have provided compelling evidence that diabetes mellitus (DM) is an important risk factor in various cancers, and may affect both pathogenesis and prognosis. Additionally, antidiabetic agents such as metformin exhibit an antitumorigenic effect. However, to date there is insufficient knowledge about the role of DM in the pathogenesis and prognosis of head and neck squamous cell carcinoma (HNSCC).In a retrospective monocentric study including 424 patients with SCC of the oropharynx (OPSCC) or larynx (LaSCC), the impact of DM on clinical and histopathologic parameters was investigated. The authors found a rising incidence of DM among LaSCC patients (<10 % until 2005 and 20 % since 2006) and a significant association between DM and clinical and histopathologic features (age, gender, tumor size, and pathologic grading), which depended on the anatomic site. Moreover, a clear trend toward unfavorable progression-free and overall survival of HNSCC patients with DM upon current treatment modalities was evident.The presented data support a relative increase in patients with DM, particularly for LaSCC. This might have a sustained influence on treatment decisions and management, and should be considered in future clinical trials. A better understanding of the cellular and molecular traits of HNSCC in DM could pave the way for innovative therapeutic strategies in terms of personalized medicine.

Vlastarakos PV, Vassileiou A, Delicha E, Kikidis D, Protopapas D, Nikolopoulos TP. Dietary consumption patterns and laryngeal cancer risk. Ear Nose Throat J. 2016 Jun;95(6):E32-8.

We conducted a case-control study to investigate the effect of diet on laryngeal carcinogenesis. Our study population was made up of 140 participants-70 patients with laryngeal cancer (LC) and 70 controls with a non-neoplastic condition that was unrelated to diet, smoking, or alcohol. A food-frequency questionnaire determined the mean consumption of 113 different items during the 3 years prior to symptom onset. Total energy intake and cooking mode were also noted. The relative risk, odds ratio (OR), and 95% confidence interval (CI) were estimated by multiple logistic regression analysis. We found that the total energy intake was significantly higher in the LC group (p < 0.001), and that the difference remained statistically significant after logistic regression analysis (p < 0.001; OR: 118.70). Notably, meat consumption was higher in the LC group (p < 0.001), and the difference remained significant after logistic regression analysis (p = 0.029; OR: 1.16). LC patients also consumed significantly more fried food (p = 0.036); this difference also remained significant in the logistic regression model (p = 0.026; OR: 5.45). The LC group also consumed significantly more seafood (p = 0.012); the difference persisted after logistic regression analysis (p = 0.009; OR: 2.48), with the consumption of shrimp proving detrimental (p = 0.049; OR: 2.18). Finally, the intake of zinc was significantly higher in the LC group before and after logistic regression analysis (p = 0.034 and p = 0.011; OR: 30.15, respectively). Cereal consumption (including pastas) was also higher among the LC patients (p = 0.043), with logistic regression analysis showing that their negative effect was possibly associated with the sauces and dressings that traditionally accompany pasta dishes (p = 0.006; OR: 4.78). Conversely, a higher consumption of dairy products was found in controls (p < 0.05); logistic regression analysis showed that calcium appeared to be protective at the micronutrient level (p < 0.001; OR: 0.27). We found no difference in the overall consumption of fruits and vegetables between the LC patients and controls; however, the LC patients did have a greater consumption of cooked tomatoes and cooked root vegetables (p = 0.039 for both), and the controls had more consumption of leeks (p = 0.042) and, among controls younger than 65 years, cooked beans (p = 0.037). Lemon (p = 0.037), squeezed fruit juice (p = 0.032), and watermelon (p = 0.018) were also more frequently consumed by the controls. Other differences at the micronutrient level included greater consumption by the LC patients of retinol (p = 0.044), polyunsaturated fats (p = 0.041), and linoleic acid (p = 0.008); LC patients younger than 65 years also had greater intake of riboflavin (p = 0.045). We conclude that the differences in dietary consumption patterns between LC patients and controls indicate a possible role for lifestyle modifications involving nutritional factors as a means of decreasing the risk of laryngeal cancer.

Peterson CE, Khosla S, Chen LF, Joslin CE, Davis FG, Fitzgibbon ML, Freels S, Hoskins K. Racial differences in head and neck squamous cell carcinomas among non-Hispanic black and white males identified through the National Cancer Database (1998-2012). J Cancer Res Clin Oncol. 2016 Aug;142(8):1715-26. doi: 10.1007/s00432-016-2182-8.

Head and neck squamous cell carcinoma (HNSCC) incidence is increasing, and evidence suggests survival disparities between non-Hispanic (nH) black and white males. However, temporal changes in HNSCCs and factors contributing to survival differences have not been examined at the national level.National Cancer Database (NCDB) cases were used to evaluate temporal trends in HNSCC anatomical sites and site groupings (i.e., oral cavity, oropharyngeal, non-oropharyngeal), and to estimate incidence ratios (IRs) comparing nH black and white males in demographic and clinical characteristics.Between 1998 and 2012, 18,443 (11 %) nH black males and 145,611 (89 %) nH white males were diagnosed with HNSCCs. Cases rose from 9094 diagnosed in 1998 to 13,838 in 2012, driven by increases in oropharyngeal tumors, particularly tumors of the tonsil and tongue. Annual percent changes in nH black males and nH white males were 1.93 and 3.17, respectively. Additionally, nH black males had higher incidence of the more aggressive non-oropharyngeal tumors (p < .0001) and distant-stage tumors (76 vs. 64 %, p < .0001). However, nH white males had higher incidence of high-risk HPV types (IRs range from 1.68, 95 % CI 1.50-1.88 in oropharyngeal tumors to 3.03, 95 % CI 1.11-8.25 in non-oropharyngeal tumors).Incidence of oropharyngeal tumors has risen in both nH black and white males. However, nH white males have higher incidence of HPV, and nH black males have higher incidence of more aggressive and advanced HNSCCs. Racial differences in clinical characteristics associated with poorer survival exist, and future studies should determine factors associated with these differences.

 

Moore SC, Lee IM, Weiderpass E, Campbell PT, Sampson JN, Kitahara CM, Keadle SK, Arem H, Berrington de Gonzalez A, Hartge P, Adami HO, Blair CK, Borch KB, Boyd E, Check DP, Fournier A, Freedman ND, Gunter M, Johannson M, Khaw KT, Linet MS, Orsini N, Park Y, Riboli E, Robien K, Schairer C, Sesso H, Spriggs M, Van Dusen R, Wolk A, Matthews CE, Patel AV. Association of Leisure-Time Physical Activity With Risk of 26 Types of Cancer in 1.44 Million Adults. JAMA Intern Med. 2016 Jun 1;176(6):816-25. doi: 10.1001/jamainternmed.2016.1548.

Leisure-time physical activity has been associated with lower risk of heart-disease and all-cause mortality, but its association with risk of cancer is not well understood.To determine the association of leisure-time physical activity with incidence of common types of cancer and whether associations vary by body size and/or smoking.We pooled data from 12 prospective US and European cohorts with self-reported physical activity (baseline, 1987-2004). We used multivariable Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals for associations of leisure-time physical activity with incidence of 26 types of cancer. Leisure-time physical activity levels were modeled as cohort-specific percentiles on a continuous basis and cohort-specific results were synthesized by random-effects meta-analysis. Hazard ratios for high vs low levels of activity are based on a comparison of risk at the 90th vs 10th percentiles of activity. The data analysis was performed from January 1, 2014, to June 1, 2015.Leisure-time physical activity of a moderate to vigorous intensity. A total of 1.44 million participants (median [range] age, 59 [19-98] years; 57% female) and 186 932 cancers were included. High vs low levels of leisure-time physical activity were associated with lower risks of 13 cancers: esophageal adenocarcinoma (HR, 0.58; 95% CI, 0.37-0.89), liver (HR, 0.73; 95% CI, 0.55-0.98), lung (HR, 0.74; 95% CI, 0.71-0.77), kidney (HR, 0.77; 95% CI, 0.70-0.85), gastric cardia (HR, 0.78; 95% CI, 0.64-0.95), endometrial (HR, 0.79; 95% CI, 0.68-0.92), myeloid leukemia (HR, 0.80; 95% CI, 0.70-0.92), myeloma (HR, 0.83; 95% CI, 0.72-0.95), colon (HR, 0.84; 95% CI, 0.77-0.91), head and neck (HR, 0.85; 95% CI, 0.78-0.93), rectal (HR, 0.87; 95% CI, 0.80-0.95), bladder (HR, 0.87; 95% CI, 0.82-0.92), and breast (HR, 0.90; 95% CI, 0.87-0.93). Body mass index adjustment modestly attenuated associations for several cancers, but 10 of 13 inverse associations remained statistically significant after this adjustment. Leisure-time physical activity was associated with higher risks of malignant melanoma (HR, 1.27; 95% CI, 1.16-1.40) and prostate cancer (HR, 1.05; 95% CI, 1.03-1.08). Associations were generally similar between overweight/obese and normal-weight individuals. Smoking status modified the association for lung cancer but not other smoking-related cancers.Leisure-time physical activity was associated with lower risks of many cancer types. Health care professionals counseling inactive adults should emphasize that most of these associations were evident regardless of body size or smoking history, supporting broad generalizability of findings.

Seijas-Tamayo R, Fernández-Mateos J, Adansa Klain JC, Mesía R, Pastor Borgoñón M, Pérez-Ruiz E, Vázquez Fernández S, Salvador Coloma C, Rueda Domínguez A, Taberna M, Martínez-Trufero J, Bonfill Abella T, Vázquez Estévez S, Pollán M, Del Barco Morillo E, Cruz-Hernández JJ. Epidemiological characteristics of a Spanish cohort of patients diagnosed with squamous cell carcinoma of head and neck: distribution of risk factors by tumor location. Clin Transl Oncol. 2016 Nov;18(11):1114-1122.

Head and neck cancer is a highly heterogeneous disease comprising a large number of tumors located in the cervicofacial area. This study aimed to determine the epidemiological characteristics of squamous-cell carcinomas of the head and neck in the Spanish population, and the distribution of risk factors based on tumor locations.A cohort of 459 patients (75 oral cavity, 167 oro-/hypopharyngeal and 217 laryngeal cancers) recruited in 19 hospitals participating in the Spanish head and neck cancer cooperative group were included over 3 years (2012-2014). Epidemiological parameters and risk factors were obtained from a self-administered questionnaire, and tumor characteristics were obtained from clinical records. Multivariate multinomial logistic regression was used to assess factors associated with tumor location.Most patients were males (88.4 %), smokers (95 %) and drinkers (76.5 %). Relative to laryngeal cancer, pharyngeal cancer and oral cancer were more common in women than men (OR 3.58, p = 0.003 and 4.33, p = 0.001, respectively); pharyngeal cancer was more associated with rural environment (OR 1.81, p = 0.007) and weekly alcohol intake (10-140 g: OR 2.53, p = 0.012; 141-280 g: OR 2.47, p = 0.023; >280 g: OR 3.20, p = 0.001) and less associated with pack-years of smoking (21-40 packs: OR 0.46, p = 0.045; 41-70 packs: OR 0.43, p = 0.023; ≥71 packs: OR 3.20, p = 0.015).The distribution of these tumors differs between the sexes, with a higher proportion of oral cavity and pharyngeal tumors in women than in men. Oro-/hypopharyngeal cancers were more strongly associated with rural areas and with alcohol consumption, although less strongly associated with smoking than laryngeal tumors.

Maasland DH, Schouten LJ, Kremer B, van den Brandt PA. Toenail selenium status and risk of subtypes of head-neck cancer: The Netherlands Cohort Study. Eur J Cancer. 2016 Jun;60:83-92. doi: 10.1016/j.ejca.2016.03.003.

There is limited prospective data on the relationship between selenium status and the risk of head-neck cancer (HNC) and HNC subtypes (i.e., oral cavity cancer [OCC], oro-/hypopharyngeal cancer [OHPC] and laryngeal cancer [LC]). Therefore, we investigated the association between toenail selenium, reflecting long-term selenium exposure, and HNC risk within the Netherlands Cohort Study.At baseline, 120,852 participants completed a self-administered questionnaire about diet and other cancer risk factors and were asked to provide toenail clippings. After 20.3 years of follow-up, 294 cases of HNC (95 OCC, 62 OHPC, two oral cavity/pharynx unspecified or overlapping and 135 LC) and 2,164 subcohort members were available for case-cohort analysis using Cox proportional hazards models.Toenail selenium status was statistically significantly associated with a decreased risk of HNC overall (multivariate RR for quartile four versus one: 0.55, 95% confidence interval [CI] 0.37-0.82, P trend = 0.001). The association between toenail selenium and risk of HNC overall was stronger among men than women, but no statistically significant interaction with sex was found. Toenail selenium level was also associated with a decreased risk of all HNC subtypes, with statistically significant associations in OHPC and LC. No statistically significant interaction was found between toenail selenium level and cigarette smoking or alcohol consumption for HNC overall.In this large cohort study, we found an inverse association between toenail selenium level and HNC risk. Among HNC subtypes, this association was strongest for OHPC and LC. Furthermore, the association of toenail selenium status with HNC risk was stronger among men than women.

Shridhar K, Rajaraman P, Koyande S, Parikh PM, Chaturvedi P, Dhillon PK, Dikshit RP. Trends in mouth cancer incidence in Mumbai, India (1995-2009): An age-period-cohort analysis. Cancer Epidemiol. 2016 Jun;42:66-71. doi: 10.1016/j.canep.2016.03.007.

Despite tobacco control and health promotion efforts, the incidence rates of mouth cancer are increasing across most regions in India. Analysing the influence of age, time period and birth cohort on these secular trends can point towards underlying factors and help identify high-risk populations for improved cancer control programmes.We evaluated secular changes in mouth cancer incidence among men and women aged 25-74 years in Mumbai between 1995 and 2009 by calculating age-specific and age-standardized incidence rates (ASR). We estimated the age-adjusted linear trend for annual percent change (EAPC) using the drift parameter, and conducted an age-period-cohort (APC) analysis to quantify recent time trends and to evaluate the significance of birth cohort and calendar period effects.Over the 15-year period, age-standardized incidence rates of mouth cancer in men in Mumbai increased by 2.7% annually (95% CI:1.9 to 3.4), p<0.0001) while rates among women decreased (EAPC=-0.01% (95% CI:-0.02 to -0.002), p=0.03). APC analysis revealed significant non-linear positive period and cohort effects in men, with higher effects among younger men (25-49 years). Non-significant increasing trends were observed in younger women (25-49 years).APC analyses from the Mumbai cancer registry indicate a significant linear increase of mouth cancer incidence from 1995 to 2009 in men, which was driven by younger men aged 25-49 years, and a non-significant upward trend in similarly aged younger women. Health promotion efforts should more effectively target younger cohorts.

Marur S, Forastiere AA. Head and Neck Squamous Cell Carcinoma: Update on Epidemiology, Diagnosis, and Treatment. Mayo Clin Proc. 2016 Mar;91(3):386-96. doi: 10.1016/j.mayocp.2015.12.017.

Squamous cell carcinoma arises from multiple anatomic subsites in the head and neck region. The risk factors for development of cancers of the oral cavity, oropharynx, hypopharynx, and larynx include tobacco exposure and alcohol dependence, and infection with oncogenic viruses is associated with cancers developing in the nasopharynx, palatine, and lingual tonsils of the oropharynx. The incidence of human papillomavirus-associated oropharyngeal cancer is increasing in developed countries, and by 2020, the annual incidence could surpass that of cervical cancer. The treatment for early-stage squamous cell cancers of the head and neck is generally single modality, either surgery or radiotherapy. The treatment for locally advanced head and neck cancers is multimodal, with either surgery followed by adjuvant radiation or chemoradiation as indicated by pathologic features or definitive chemoradiation. For recurrent disease that is not amenable to a salvage local or regional approach and for metastatic disease, chemotherapy with or without a biological agent is indicated. To date, molecular testing has not influenced treatment selection in head and neck cancer. This review will focus on the changing epidemiology, advances in diagnosis, and treatment options for squamous cell cancers of the head and neck, along with data on risk stratification specific to oropharyngeal cancer, and will highlight the direction of current trials.

Al-Jaber A, Al-Nasser L, El-Metwally A. Epidemiology of oral cancer in Arab countries. Saudi Med J. 2016 Mar;37(3):249-55. doi: 10.15537/smj.2016.3.11388.

To review the oral cancer (OC) studies that were conducted in Arab countries with regard to epidemiology, risk factors, and prognosis.A computer-based PubMed literature search was performed to retrieve studies conducted in the Arab world on epidemiology of OC. After screening for exclusion criteria, cross-referencing, and searching local journals, a total of 19 articles were included.Eight prevalence studies found an OC prevalence ranging from 1.8 to 2.13 per 100,000 persons. Oral cancer patients were mostly in their fifth to sixth decade of life, and the incidence in younger age was reported in some Arab countries. Yemenis have an alarming high prevalence of OC among people younger than 45 years. Eleven studies explored determinants or prognosis of OC. Behavioral determinants such as smokeless tobacco (Shamma and Qat), and cigarette smoking were strongly associated with OC. Alcohol drinking and solar radiation exposures were cited as possible risk factors. The most affected sites were tongue, floor of the mouth, and lower lip variations in the affected site were attributed to the socio-cultural behavior of the populations under study. Squamous cell carcinoma was the most frequently detected cancer, and usually patients were in late stages (III and IV) at the time of diagnosis.No solid evidence exists regarding the true OC prevalence/incidence in most Arab countries due to the lack of national cancer registries and population-based studies.

Owczarek K, Jałocha-Kaczka A, Bielińska M, Urbaniak J, Olszewski J. Evaluation of risk factors for oral cavity and oropharynx cancers in patients under the week activity program of head and neck cancers prevention in Lodz. Otolaryngol Pol. 2015;69(6):15-21. doi: 10.5604/00306657.1182713.

The aim of the study was to evaluate risk factors for oral cavity and oropharynx cancers in patients under the week activity program of head and neck cancers prevention in Lodz.104 people reported to preventive examinations under the week activity program of head and neck cancers prevention in Lodz (25-th of September, 2015): 33 women aged 21-68 and 38 men aged 23-71. Before ENT examination, subjects completed the questionnaire, which concerned: the degree of education, source of information about preventive examinations, symptoms, smoking, number of smoked cigarettes, alcohol, number of life sexual partners, number of oral sex partners and family history of head and neck cancers.The analysis showed that people who reported to preventive examination were mostly in the age group of 51-60 and over 60, respectively 71,2% of women and 57,9% of men. Patients were at the age, that predispose to oral cavity and oropharynx cancers. In our own material, 15,9% of women and 23,6% of men have smoked. Most of them have smoked 10-20 cigarettes daily. On the other hand, 40,9% of women and 10,5% of men didn’t consume alcohol. In our study, both women and men had, at life, 1-3 sexual partners the most often, respectively 78,9% and 60,5%. The oral sex was cultivated by 45,5% of women and 60,5% of men, the most often with 1-3 partners, respectively 95,8% and 70,0%. Based on complete ENT examination and the presence of risk factors for oral cavity and oropharynx cancers, 14,4% of patients were qualified to further oncological examinations including: videolaryngostroboscopy, neck ultrasound with fine-needle biopsy, neck CT and HPV test.

Tsai CT, Ho MW, Lin D, Chen HJ, Muo CH, Tseng CH, Su WC, Lin MC, Kao CH. Association of Head and Neck Cancers in Chronic Osteomyelitis: A National Retrospective Cohort Study. Medicine (Baltimore). 2016 Jan;95(3):e2407. doi: 10.1097/MD.0000000000002407.

The aim of study is to determine whether chronic osteomyelitis (COM) is linked to an increased risk of head and neck cancer (HNC).We identify 17,033 patients with osteomyelitis and 68,125 subjects without osteomyelitis during 1996 to 2010 periods. Multivariable Cox proportional hazards regression analysis was used to measure the hazard ratio (HR) of head and neck cancer for the osteomyelitis cohort compared with the comparison cohort.A total of 99 patients in the COM and 228 patients in the comparison cohort developed HNC during an average 5.12 years of follow-up period. The incidence rate of HNC in the COM cohort was 1.51-fold (95% confidence interval [CI]: 1.17-1.95) higher than that in the comparison cohort after adjusting gender, age, urbanization level, monthly income, and comorbidities. In subgroup analysis, younger (less than 45 years-old) and patients without comorbidities have greater risks (adjusted HR: 2.29 [95% CI:1.43-3.66] and 1.74 [95% CI:1.28-2.38] respectively).This study results suggested the association between COM and HNC, particularly in younger population and patients without comorbidities.

Michaud DS, Kelsey KT, Papathanasiou E, Genco CA, Giovannucci E. Periodontal disease and risk of all cancers among male never smokers: an updated analysis of the Health Professionals Follow-up Study. Ann Oncol. 2016 May;27(5):941-7. doi: 10.1093/annonc/mdw028.

Periodontal disease has a direct impact on the immune response and has been linked to several chronic diseases, including atherosclerosis and stroke. Few studies have examined the association between periodontal disease and cancer.A total of 19 933 men reported being never smokers (of cigarette, pipes or cigars) in the Health Professionals’ Follow-up Study. Periodontal disease status and teeth number were self-reported at baseline and during follow-up. All cancers were ascertained during 26 years of follow-up. Cox’s proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) adjusting for risk factors.A 13% increase in total cancer was observed among men reporting periodontitis at baseline, and a 45% increase in risk was observed among men with advanced periodontitis (periodontitis with <17 remaining teeth). Periodontitis was not associated with prostate cancer, colorectal cancer or melanoma, the three most common cancers in this cohort of never smokers, but a 33% increase in risk was observed for smoking-related cancers (lung, bladder, oropharnygeal, esophageal, kidney, stomach and liver cancers; HR = 1.33, 95% CI 1.07-1.65). Men with advanced periodontitis had an HR of 2.57 (95% CI 1.56-4.21; P = 0.0002) for smoking-related cancers, compared with men who did not have periodontitis and had 17 teeth or more. Advanced periodontitis was associated with elevated risks of esophageal and head and neck cancers (HR = 6.29, 95% CI 2.13-18.6; based on five cases with advanced periodontitis) and bladder cancer (HR = 5.06, 95% CI 2.32-11.0; based on nine cases with advanced periodontitis).Advanced periodontitis was associated with a 2.5-fold increase in smoking-related cancers among never smokers. Periodontitis may impact cancer risk through system immune dysregulation. Further studies need to examine the immune impact of advanced periodontitis on cancer, especially for cancers known to be caused by smoking.

Faggons CE, Mabedi C, Shores CG, Gopal S. Review: Head and neck squamous cell carcinoma in sub-Saharan Africa. Malawi Med J. 2015 Sep;27(3):79-87.

Review the literature from 1990 to 2013 to determine known anatomic sites, risk factors, treatments, and outcomes of head and neck squamous cell carcinoma (HNSCC) in sub-Saharan Africa.Using a systematic search strategy, literature pertaining to HNSCC in sub-Saharan Africa was reviewed and patient demographics, anatomic sites, histology, stage, treatment, and outcomes were abstracted. The contributions of human immunodeficiency virus (HIV), human papillomavirus (HPV) and behavioural risk factors to HNSCC in the region were assessed.Of the 342 papers identified, 46 were utilized for review, including 8611 patients. In sub-Saharan Africa, the oropharyngeal/oral cavity was found to be the most common site, with 7750 cases (90% of all cases). Few papers distinguished oropharyngeal from oral cavity, making identification of possible HPV-associated oropharyngeal squamous cell carcinoma (SCC) difficult. SCC of the nasopharynx, nasal cavity, or paranasal sinuses was identified in 410 patients (4.8% of all cases). Laryngeal SCC was found in 385 patients (4.5% of all cases), and only 66 patients (0.8% of all cases) with hypopharyngeal SCC were identified. In 862 patients with data available, 43% used tobacco and 42% used alcohol, and reported use varied widely and was more common in laryngeal SCC than that of the oropharyngeal/oral cavity. Toombak and kola nut use was reported to be higher in patients with HNSCC. Several papers reported HIV-positive patients with HNSCC, but it was not possible to determine HNSCC prevalence in HIV-positive compared to negative patients. Reports of treatment and outcomes were rare.The oropharyngeal/oral cavity was by far the most commonly reported site of HNSCC reported in sub-Saharan Africa. The roles of risk factors in HNSCC incidence in sub-Saharan Africa were difficult to delineate from the available studies, but a majority of patients did not use tobacco and alcohol.

Chu KP, Habbous S, Kuang Q, Boyd K, Mirshams M, Liu FF, Espin-Garcia O, Xu W, Goldstein D, Waldron J, O’Sullivan B, Huang SH, Liu G. Socioeconomic status, human papillomavirus, and overall survival in head and neck squamous cell carcinomas in Toronto, Canada. Cancer Epidemiol. 2016 Feb;40:102-12. doi: 10.1016/j.canep.2015.11.010.

Despite universal healthcare in some countries, lower socioeconomic status (SES) has been associated with worse cancer survival. The influence of SES on head and neck cancer (HNC) survival is of immense interest, since SES is associated with the risk and prognostic factors associated with this disease.Newly diagnosed HNC patients from 2003 to 2010 (n=2124) were identified at Toronto’s Princess Margaret Cancer Centre. Principal component analysis was used to calculate a composite score using neighbourhood-level SES variables obtained from the 2006 Canada Census. Associations of SES with overall survival were evaluated in HNC subsets and by p16 status (surrogate for human papillomavirus).SES score was higher for oral cavity (n=423) and p16-positive oropharyngeal cancer (OPC, n=404) patients compared with other disease sites. Lower SES was associated with worse survival [HR 1.14 (1.06-1.22), p=0.0002], larger tumor staging (p<0.001), current smoking (p<0.0001), heavier alcohol consumption (p<0.0001), and greater comorbidity (p<0.0002), but not with treatment regimen (p>0.20). After adjusting for age, sex, and stage, the lowest SES quintile was associated with the worst survival only for OPC patients [HR 1.66 (1.09-2.53), n=832], primarily in the p16-negative subset [HR 1.63 (0.96-2.79)]. The predictive ability of the prognostic models improved when smoking/alcohol was added to the model (c-index 0.71 vs. 0.69), but addition of SES did not (c-index 0.69).SES was associated with survival, but this effect was lost after accounting for other factors (age, sex, TNM stage, smoking/alcohol). Lower SES was associated with greater smoking, alcohol consumption, comorbidity, and stage.

Maasland DH, van den Brandt PA, Kremer B, Schouten LJ. Body mass index and risk of subtypes of head-neck cancer: the Netherlands Cohort Study. Sci Rep. 2015 Dec 4;5:17744. doi: 10.1038/srep17744.

Low body mass index (BMI) has been associated with risk of head-neck cancer (HNC), but prospective data are scarce. We investigated the association between BMI, BMI at age 20 years and change in BMI during adulthood with risk of HNC and HNC subtypes. 120,852 participants completed a questionnaire on diet and other cancer risk factors, including anthropometric measurements, at baseline in 1986. After 20.3 years of follow-up, 411 HNC (127 oral cavity cancer (OCC), 84 oro-/hypopharyngeal cancer (OHPC), and 197 laryngeal cancer (LC)) cases and 3,980 subcohort members were available for case-cohort analysis using Cox proportional hazards models. BMI at baseline was inversely associated with risk of HNC overall, with a multivariate rate ratio of 3.31 (95% CI 1.40-7.82) for subjects with a BMI < 18.5 kg/m(2), compared to participants with a BMI of 18.5 to 25 kg/m(2). Among HNC subtypes, this association was strongest for OCC and OHPC. The association between BMI at age 20 and HNC risk appeared to be positive. In this large prospective cohort study, we found an inverse association between BMI at baseline and HNC risk. For BMI at age 20, however, a positive rather than inverse association was found.

 

Huang YH, Lee YC, Li Q, Chen CJ, Hsu WL, Lou PJ, Zhu C, Pan J, Shen H, Ma H, Cai L, He B, Wang Y, Zhou X, Ji Q, Zhou B, Wu W, Ma J, Boffetta P, Zhang ZF, Dai M, Hashibe M. Family History of Cancer and Head and Neck Cancer Risk in a Chinese Population. Asian Pac J Cancer Prev. 2015;16(17):8003-8.

This case-control study included 921 cases and 806 controls. Recruitment was from December 2010 to January 2015 in eight centers in East Asia. Controls were matched to cases with reference to sex, 5-year age group, ethnicity, and residence area at each of the centers.We observed an increased risk of head and neck cancer due to first degree family history of head and neck cancer, but after adjustment for tobacco smoking, alcohol drinking and betel quid chewing the association was no longer apparent. The adjusted OR were 1.10 (95% CI=0.80-1.50) for family history of tobacco-related cancer and 0.96 (95%CI=0.75-1.24) for family history of any cancer with adjustment for tobacco, betel quid and alcohol habits. The ORs for having a first-degree relative with HNC were higher in all tobacco/ alcohol subgroups.We did not observe a strong association between family history of head and neck cancer and head and neck cancer risk after taking into account lifestyle factors. Our study suggests that an increased risk due to family history of head and neck cancer may be due to shared risk factors. Further studies may be needed to assess the lifestyle factors of the relatives.

Hettmann A, Demcsák A, Decsi G, Bach Á, Pálinkó D, Rovó L, Nagy K, Takács M, Minarovits J. Infectious Agents Associated with Head and Neck Carcinomas. Adv Exp Med Biol. 2016;897:63-80. doi: 10.1007/5584_2015_5005.

In addition to traditional risk factors such as smoking habits and alcohol consumption, certain microbes also play an important role in the generation of head and neck carcinomas. Infection with high-risk human papillomavirus types is strongly associated with the development of oropharyngeal carcinoma, and Epstein-Barr virus appears to be indispensable for the development of non-keratinizing squamous cell carcinoma of the nasopharynx. Other viruses including torque teno virus and hepatitis C virus may act as co-carcinogens, increasing the risk of malignant transformation. A shift in the composition of the oral microbiome was associated with the development of oral squamous cell carcinoma, although the causal or casual role of oral bacteria remains to be clarified. Conversion of ethanol to acetaldehyde, a mutagenic compound, by members of the oral microflora as well as by fungi including Candida albicans and others is a potential mechanism that may increase oral cancer risk. In addition, distinct Candida spp. also produce NBMA (N-nitrosobenzylmethylamine), a potent carcinogen. Inflammatory processes elicited by microbes may also facilitate tumorigenesis in the head and neck region.

Li S, Lee YC, Li Q, Chen CJ, Hsu WL, Lou PJ, Zhu C, Pan J, Shen H, Ma H, Cai L, He B, Wang Y, Zhou X, Ji Q, Zhou B, Wu W, Ma J, Boffetta P, Zhang ZF, Dai M, Hashibe M. Oral lesions, chronic diseases and the risk of head and neck cancer. Oral Oncol. 2015 Dec;51(12):1082-7. doi: 10.1016/j.oraloncology.2015.10.014.

The aim of our study is to explore the role of the history of oral lesions and chronic diseases on the risk of head and neck cancer in a Chinese population.

Our case-control study included 921 head and neck cancer cases and 806 controls. We obtained medical history information by administering questionnaires to both cases and controls. We used unconditional logistic regression to estimate odds ratios for oral lesions and chronic conditions.Oral submucous fibrosis (OR=24.24, 95% CI=7.39-79.52), oral leukoplakia (OR=4.05, 95% CI=2.44-6.71) and repetitive dental ulcers (OR=5.12, 95% CI=3.17-8.28) increased the risk of HNC. Depression was associated with HNC risk when adjusted for several covariates (OR=2.10, 95% CI=1.06-4.15), but the association was not statistically significant after adjusting for smoking and alcohol drinking (OR=1.53, 95% CI=0.72-3.25). Also, the crude OR suggested an association between diabetes and HNC risk (OR=1.51, 95% CI=1.09-2.11), but it was not significant after adjusting for confounders.Our study reported on strong associations between HNC risk and oral leukoplakia, oral submucous fibrosis, which is consistent with prior research. We also observed repetitive dental ulcer to be associated with HNC risk. Future studies may focus on studying the association between depression and HNC, using medical records or psychological evaluation results to get more accurate information about depression, with careful assessment of tobacco and alcohol history.

Radoï L, Menvielle G, Cyr D, Lapôtre-Ledoux B, Stücker I, Luce D; ICARE Study Group. Population attributable risks of oral cavity cancer to behavioral and medical risk factors in France: results of a large population-based case-control study, the ICARE study. BMC Cancer. 2015 Oct 31;15:827. doi: 10.1186/s12885-015-1841-5.

Population attributable risks (PARs) are useful tool to estimate the burden of risk factors in cancer incidence. Few studies estimated the PARs of oral cavity cancer to tobacco smoking alone, alcohol drinking alone and their joint consumption but none performed analysis stratified by subsite, gender or age. Among the suspected risk factors of oral cavity cancer, only PAR to a family history of head and neck cancer was reported in two studies. The purpose of this study was to estimate in France the PARs of oral cavity cancer to several recognized and suspected risk factors, overall and by subsite, gender and age.We analysed data from 689 oral cavity cancer cases and 3481 controls included in a population-based case-control study, the ICARE study. Unconditional logistic regression models were used to estimate odds ratios (ORs), PARs and 95% confidence intervals (95% CI).The PARs were 0.3% (95% CI -3.9%; +3.9%) for alcohol alone, 12.7% (6.9%-18.0%) for tobacco alone and 69.9% (64.4%-74.7%) for their joint consumption. PAR to combined alcohol and tobacco consumption was 74% (66.5%-79.9%) in men and 45.4% (32.7%-55.6%) in women. Among suspected risk factors, body mass index 2 years before the interview <25 kg.m(-2), never tea drinking and family history of head and neck cancer explained 35.3% (25.7%-43.6%), 30.3% (14.4%-43.3%) and 5.8% (0.6%-10.8%) of cancer burden, respectively. About 93% (88.3%-95.6%) of oral cavity cancers were explained by all risk factors, 94.3% (88.4%-97.2%) in men and only 74.1% (47.0%-87.3%) in women.Our study emphasizes the role of combined tobacco and alcohol consumption in the oral cavity cancer burden in France and gives an indication of the proportion of cases attributable to other risk factors. Most of oral cavity cancers are attributable to concurrent smoking and drinking and would be potentially preventable through smoking or drinking cessation. If the majority of cases are explained by recognized or suspected risk factors in men, a substantial number of cancers in women are probably due to still unexplored factors that remain to be clarified by future studies.

 

Schwingshackl L, Hoffmann G. Adherence to Mediterranean diet and risk of cancer: an updated systematic review and meta-analysis of observational studies. Cancer Med. 2015 Dec;4(12):1933-47. doi: 10.1002/cam4.539.

The aim of the present systematic review and meta-analysis of observational studies was to gain further insight into the effects of adherence to Mediterranean Diet (MD) on overall cancer mortality, incidence of different types of cancer, and cancer mortality risk in cancer survivors. Literature search was performed using the electronic databases PubMed, and EMBASE until 2 July 2015. We included either cohort (for specific tumors only incidence cases were used) or case-control studies. Study specific risk ratios, hazard ratios, and odds ratios (RR/HR/OR) were pooled using a random effect model. The updated review process showed 23 observational studies that were not included in the previous meta-analysis (total number of studies evaluated: 56 observational studies). An overall population of 1,784,404 subjects was included in the present update. The highest adherence score to an MD was significantly associated with a lower risk of all-cause cancer mortality (RR: 0.87, 95% CI 0.81-0.93, I(2) = 84%), colorectal cancer (RR: 0.83, 95% CI 0.76-0.89, I(2) = 56%), breast cancer (RR: 0.93, 95% CI 0.87-0.99, I(2) =15%), gastric cancer (RR: 0.73, 95% CI 0.55-0.97, I(2) = 66%), prostate cancer (RR: 0.96, 95% CI 0.92-1.00, I(2) = 0%), liver cancer (RR: 0.58, 95% CI 0.46-0.73, I(2) = 0%), head and neck cancer (RR: 0.40, 95% CI 0.24-0.66, I(2) = 90%), pancreatic cancer (RR: 0.48, 95% CI 0.35-0.66), and respiratory cancer (RR: 0.10, 95% CI 0.01-0.70). No significant association could be observed for esophageal/ovarian/endometrial/and bladder cancer, respectively. Among cancer survivors, the association between the adherence to the highest MD category and risk of cancer mortality, and cancer recurrence was not statistically significant. The updated meta-analyses confirm a prominent and consistent inverse association provided by adherence to an MD in relation to cancer mortality and risk of several cancer types.

Guercio V, Turati F, La Vecchia C, Galeone C, Tavani A. Allium vegetables and upper aerodigestive tract cancers: a meta-analysis of observational studies. Mol Nutr Food Res. 2016 Jan;60(1):212-22. doi: 10.1002/mnfr.201500587.

To provide updated quantitative overall estimations of the relation between total allium, garlic, and onion intake on the risk of cancer of the upper aerodigestive tract (UADT).We combined data of published observational studies (21 case-control and four cohort studies), using a meta-analytic approach and random effects models. The overall relative risks (RR) and 95% confidence intervals (CIs) for the squamous cell carcinoma of the UADT were 0.79 (95% CI 0.56-1.11) for total allium, 0.74 (95% CI 0.57-0.95) for garlic, and 0.72 (95% CI 0.57-0.91) for onion for the highest versus the lowest consumption. The inverse relation was apparently stronger in case-control studies (RR 0.56, 95% CI 0.38-0.83 for total allium), in Chinese studies (RR 0.67, 95% CI 0.45-0.98 for garlic intake), and for esophageal than for head and neck cancers. Apparently, there was no relation between allium vegetable intake and adenocarcinoma of the esophagus.We found a moderate inverse association between allium vegetable intake and the risk of squamous cell carcinoma of the UADT in case-control studies. The relation was unclear in cohort studies and for adenocarcinoma of the esophagus.

 

Nour A, Joury E, Naja F, Hatahet W, Almanadili A. Diet and the risk of head and neck squamous cell carcinomas in a Syrian population: a case-control study. East Mediterr Health J. 2015 Oct 2;21(9):629-34.

Diet has not been investigated as a potential risk factor for head and neck squamous cell carcinomas in the Syrian Arab Republic. In a hospital-based, unmatched case-control study 108 people with cancer and 105 controls were interviewed about dietary intake using a validated food frequency questionnaire in Arabic. Sociodemographic and health risk behavioural information were collected by a self-completed questionnaire. Adjusting for age, sex, education level, working status and tobacco smoking, the multiple regression analysis showed that low intake of vegetables (OR 3.8; 95% CI: 1.57-9.10), cereal/cereal products (OR 2.6; 95% CI: 1.12-5.99) and high-caffeine beverages (OR 3.2; 95% CI: 1.34-7.43) increased the risk of head and neck squamous cell carcinomas, whereas a low level of fats and oils intake decreased the risk (OR 0.6; 95% CI: 0.24-1.30). These findings should be considered in national health promotion programmes in the Syrian Arab Republic.

Peters ES, Luckett BG, Applebaum KM, Marsit CJ, McClean MD, Kelsey KT. Dairy products, leanness, and head and neck squamous cell carcinoma. Head Neck. 2008 Sep;30(9):1193-205. doi: 10.1002/hed.20846.

As part of a population-based case-control study, we investigated the association of food groups and micronutrients estimated from a validated food frequency questionnaire (FFQ) with the risk of development of head and neck squamous cell carcinoma (HNSCC).Incident cases were accrued through Boston area hospitals from 1999 to 2003, and neighborhood controls were selected and matched by location, age, and sex. There were 504 cases and 717 controls enrolled, who completed the FFQ.We observed a positive association between the consumption of dairy products and HNSCC. The odds of HNSCC in the highest quintile of dairy intake was 1.64 (95% CI: 1.09-2.46), compared with subjects in the lowest quintile. There was a significant association between leanness with HNSCC. The odds of cancer among the leanest subjects was 5.8 (95%CI: 3.2-10.6) compared with a healthy BMI. Finally, intake of animal fat was positively associated with an elevation in cancer risk. The odds of HNSCC for high animal fat intake were 1.50 (0.99-2.27).Our data suggest that consumption of fruits and vegetables is not universally protective for HNSCC and that other food groups and nutrients may influence the risk for developing this disease.

Sapkota A, Hsu CC, Zaridze D, Shangina O, Szeszenia-Dabrowska N, Mates D, Fabiánová E, Rudnai P, Janout V, Holcatova I, Brennan P, Boffetta P, Hashibe M. Dietary risk factors for squamous cell carcinoma of the upper aerodigestive tract in central and eastern Europe. Cancer Causes Control. 2008 Dec;19(10):1161-70. doi: 10.1007/s10552-008-9183-0.

The incidence of squamous cell carcinoma of upper aerodigestive tract (UADT: oral cavity, pharynx, larynx, and esophagus) has been increasing in central and eastern European countries. We investigated the relationship between diet and UADT cancers in these high risk areas.We used data from hospital-based case-control study of 948 UADT cancer cases and 1,228 controls conducted in Romania, Hungary, Poland, Russia, Slovakia, and Czech Republic. Standardized questionnaire were used to collect information on 23 different food items, along with alcohol and tobacco consumptions. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the UADT cancers after adjusting for center, age, sex, tobacco & alcohol intake, and other food groups.Consumption of dairy product was negatively associated with selected UADT cancers: larynx (OR: 0.38, CI: 0.23-0.62) and esophagus (OR: 0.55, CI: 0.33-0.93). While consumption of yellow/orange vegetables were inversely associated with oral/pharyngeal and laryngeal cancer (OR: 0.53, CI: 0.35-0.81 and OR: 0.62, CI: 0.38-1.00, respectively), preserved vegetable was positively associated with oral/pharyngeal and laryngeal cancer risk (p (trend) < 0.01 for both).Specific dietary components may play a role in the development of UADT cancers in the high-risk region of central and eastern Europe.

de Carvalho MF, Dourado MR, Fernandes IB, Araújo CT, Mesquita AT, Ramos-Jorge ML. Head and neck cancer among marijuana users: a meta-analysis of matched case-control studies. Arch Oral Biol. 2015 Dec;60(12):1750-5. doi: 10.1016/j.archoralbio.2015.09.009.

This study performed a systematic review with meta-analysis. Articles were selected from various electronic databases using keywords obtained from the Medical Subject Headings (MeSH). After reading by three reviewers and scoring of methodological quality, six articles (totaling nine case-control studies) were assessed with Comprehensive Meta-Analysis(®) software. The value of effect (odds ratio) was calculated, which represented the chance of developing head and neck cancer between individuals who had smoked marijuana in their lifetime in models controlled for age, gender, race, and tobacco consumption.Approximately 12.6% of cases and 14.3% of controls were marijuana users. The meta-analysis found no association between exposure and disease (OR=1.021; IC 95%=0.912-1.14; p=0.718).

No association between lifetime marijuana use and the development of head and neck cancer was found. The different methods of collection/presentation of results in the selected articles prevented other analyzes from being conducted. Additional studies are needed to assess for long-term effects.

Zhang ZF, Morgenstern H, Spitz MR, Tashkin DP, Yu GP, Marshall JR, Hsu TC, Schantz SP. Marijuana use and increased risk of squamous cell carcinoma of the head and neck. Cancer Epidemiol Biomarkers Prev. 1999 Dec;8(12):1071-8.

Marijuana is the most commonly used illegal drug in the United States. In some subcultures, it is widely perceived to be harmless. Although the carcinogenic properties of marijuana smoke are similar to those of tobacco, no epidemiological studies of the relationship between marijuana use and head and neck cancer have been published. The relationship between marijuana use and head and neck cancer was investigated by a case-control study of 173 previously untreated cases with pathologically confirmed diagnoses of squamous cell carcinoma of the head and neck and 176 cancer-free controls at Memorial Sloan-Kettering Cancer Center between 1992 and 1994. Epidemiological data were collected by using a structured questionnaire, which included history of tobacco smoking, alcohol use, and marijuana use. The associations between marijuana use and head and neck cancer were analyzed by Mantel-Haenszel methods and logistic regression models. Controlling for age, sex, race, education, alcohol consumption, pack-years of cigarette smoking, and passive smoking, the risk of squamous cell carcinoma of the head and neck was increased with marijuana use [odds ratio (OR) comparing ever with never users, 2.6; 95% confidence interval (CI), 1.1-6.6]. Dose-response relationships were observed for frequency of marijuana use/day (P for trend <0.05) and years of marijuana use (P for trend <0.05). These associations were stronger for subjects who were 55 years of age and younger (OR, 3.1; 95% CI, 1.0-9.7). Possible interaction effects of marijuana use were observed with cigarette smoking, mutagen sensitivity, and to a lesser extent, alcohol use. Our results suggest that marijuana use may increase the risk of head and neck cancer with a strong dose-response pattern. Our analysis indicated that marijuana use may interact with mutagen sensitivity and other risk factors to increase the risk of head and neck cancer. The results need to be interpreted with some caution in drawing causal inferences because of certain methodological limitations, especially with regard to interactions.

Berthiller J, Lee YC, Boffetta P, Wei Q, Sturgis EM, Greenland S, Morgenstern H, Zhang ZF, Lazarus P, Muscat J, Chen C, Schwartz SM, Eluf Neto J, Wünsch Filho V, Koifman S, Curado MP, Matos E, Fernandez L, Menezes A, Daudt AW, Ferro G, Brennan P, Hashibe M. Marijuana smoking and the risk of head and neck cancer: pooled analysis in the INHANCE consortium. Cancer Epidemiol Biomarkers Prev. 2009 May;18(5):1544-51. doi: 10.1158/1055-9965.EPI-08-0845.

Marijuana contains carcinogens similar to tobacco smoke and has been suggested by relatively small studies to increase the risk of head and neck cancer (HNC). Because tobacco is a major risk factor for HNC, large studies with substantial numbers of never tobacco users could help to clarify whether marijuana smoking is independently associated with HNC risk.We pooled self-reported interview data on marijuana smoking and known HNC risk factors on 4,029 HNC cases and 5,015 controls from five case-control studies within the INHANCE Consortium. Subanalyses were conducted among never tobacco users (493 cases and 1,813 controls) and among individuals who did not consume alcohol or smoke tobacco (237 cases and 887 controls).The risk of HNC was not elevated by ever marijuana smoking [odds ratio (OR), 0.88; 95% confidence intervals (95% CI), 0.67-1.16], and there was no increasing risk associated with increasing frequency, duration, or cumulative consumption of marijuana smoking. An increased risk of HNC associated with marijuana use was not detected among never tobacco users (OR, 0.93; 95% CI, 0.63-1.37; three studies) nor among individuals who did not drink alcohol and smoke tobacco (OR, 1.06; 95% CI, 0.47-2.38; two studies).Our results are consistent with the notion that infrequent marijuana smoking does not confer a risk of these malignancies. Nonetheless, because the prevalence of frequent marijuana smoking was low in most of the contributing studies, we could not rule out a moderately increased risk, particularly among subgroups without exposure to tobacco and alcohol.

Liang C, McClean MD, Marsit C, Christensen B, Peters E, Nelson HH, Kelsey KT. A population-based case-control study of marijuana use and head and neck squamous cell carcinoma. Cancer Prev Res (Phila). 2009 Aug;2(8):759-68. doi: 10.1158/1940-6207.CAPR-09-0048.

Cannabinoids, constituents of marijuana smoke, have been recognized to have potential antitumor properties. However, the epidemiologic evidence addressing the relationship between marijuana use and the induction of head and neck squamous cell carcinoma (HNSCC) is inconsistent and conflicting. Cases (n = 434) were patients with incident HNSCC disease from nine medical facilities in the Greater Boston, MA area between December 1999 and December 2003. Controls (n = 547) were frequency matched to cases on age (+/-3 years), gender, and town of residence, randomly selected from Massachusetts town books. A questionnaire was adopted to collect information on lifetime marijuana use (decade-specific exposures) and associations evaluated using unconditional logistic regression. After adjusting for potential confounders (including smoking and alcohol drinking), 10 to 20 years of marijuana use was associated with a significantly reduced risk of HNSCC [odds ratio (OR)(10-<20 years versus never users), 0.38; 95% confidence interval (CI), 0.22-0.67]. Among marijuana users moderate weekly use was associated with reduced risk (OR(0.5-<1.5 times versus <0.5 time), 0.52; 95% CI, 0.32-0.85). The magnitude of reduced risk was more pronounced for those who started use at an older age (OR(15-<20 years versus never users), 0.53; 95% CI, 0.30-0.95; OR(> or =20 years versus never users), 0.39; 95% CI, 0.17-0.90; P(trend) < 0.001). These inverse associations did not depend on human papillomavirus 16 antibody status. However, for the subjects who have the same level of smoking or alcohol drinking, we observed attenuated risk of HNSCC among those who use marijuana compared with those who do not. Our study suggests that moderate marijuana use is associated with reduced risk of HNSCC.

Farsi NJ, El-Zein M, Gaied H, Lee YC, Hashibe M, Nicolau B, Rousseau MC. Sexual behaviours and head and neck cancer: A systematic review and meta-analysis. Cancer Epidemiol. 2015 Dec;39(6):1036-46. doi: 10.1016/j.canep.2015.08.010. Epub 2015 Sep 12

Human papillomaviruses (HPV) are associated with head and neck cancers (H&NC). Transmission of HPV to the upper aerodigestive tract occurs plausibly through sexual contact, although epidemiologic evidence on the role of sexual behaviours in H&NC aetiology is inconsistent. We conducted a meta-analysis of studies examining the association between four indicators of sexual behaviours (number of sexual partners and oral sex partners, oral sex practice, and age at first intercourse) and H&NC. Summary odds ratios (OR) and 95% confidence intervals (CI) were estimated using fixed and random effects models for each indicator, contrasting ‘highest’ to ‘lowest’, ‘ever’ to ‘never’, or ‘youngest’ to ‘oldest’ categories. Twenty case-control studies were included out of 3838 identified publications. Using random effects models, summary ORs suggested an increased risk of H&NC for number of sexual partners [OR=1.29, 95% CI: 1.02-1.63] (19 studies) and number of oral sex partners [OR=1.69, 95% CI: 1.00-2.84] (5 studies), whereas no effect was observed with oral sex practice [OR=1.09, 95% CI: 0.88-1.35] (17 studies) and age at first intercourse [OR=1.40, 95% CI: 0.71-2.79] (6 studies). For number of sexual partners and oral sex practice, which were assessed in more studies, we further excluded studies contributing to heterogeneity and those not adjusted for age, sex, smoking, and alcohol consumption. The summary ORs were 0.95 (95% CI: 0.75-1.20) for number of sexual partners and 1.03 (95% CI: 0.84-1.26) for oral sex practice. Our findings highlight that observed associations might be partly attributed to confounding effects of sociodemographic and behavioural factors.

 

 

 

 

 

Heck JE, Berthiller J, Vaccarella S, Winn DM, Smith EM, Shan’gina O, Schwartz SM, Purdue MP, Pilarska A, Eluf-Neto J, Menezes A, McClean MD, Matos E, Koifman S, Kelsey KT, Herrero R, Hayes RB, Franceschi S, Wünsch-Filho V, Fernández L, Daudt AW, Curado MP, Chen C, Castellsagué X, Ferro G, Brennan P, Boffetta P, Hashibe M. Sexual behaviours and the risk of head and neck cancers: a pooled analysis in the International Head and Neck Cancer Epidemiology (INHANCE) consortium. Int J Epidemiol. 2010 Feb;39(1):166-81. doi: 10.1093/ije/dyp350..

We undertook a pooled analysis of four population-based and four hospital-based case-control studies from the International Head and Neck Cancer Epidemiology (INHANCE) consortium, with participants from Argentina, Australia, Brazil, Canada, Cuba, India, Italy, Spain, Poland, Puerto Rico, Russia and the USA. The study included 5642 head and neck cancer cases and 6069 controls. We calculated odds ratios (ORs) of associations between cancer and specific sexual behaviours, including practice of oral sex, number of lifetime sexual partners and oral sex partners, age at sexual debut, a history of same-sex contact and a history of oral-anal contact. Findings were stratified by sex and disease subsite.Cancer of the oropharynx was associated with having a history of six or more lifetime sexual partners [OR = 1.25, 95% confidence interval (CI) 1.01, 1.54] and four or more lifetime oral sex partners (OR = 2.25, 95% CI 1.42, 3.58). Cancer of the tonsil was associated with four or more lifetime oral sex partners (OR = 3.36, 95 % CI 1.32, 8.53), and, among men, with ever having oral sex (OR = 1.59, 95% CI 1.09, 2.33) and with an earlier age at sexual debut (OR = 2.36, 95% CI 1.37, 5.05). Cancer of the base of the tongue was associated with ever having oral sex among women (OR = 4.32, 95% CI 1.06, 17.6), having two sexual partners in comparison with only one (OR = 2.02, 95% CI 1.19, 3.46) and, among men, with a history of same-sex sexual contact (OR = 8.89, 95% CI 2.14, 36.8).Sexual behaviours are associated with cancer risk at the head and neck cancer subsites that have previously been associated with HPV infection.

Chancellor JA, Ioannides SJ, Elwood JM. Oral and oropharyngeal cancer and the role of sexual behaviour: a systematic review. Community Dent Oral Epidemiol. 2016 Sep 19. doi: 10.1111/cdoe.12255.

Following the PRISMA guidelines, we identified observational and interventional studies reporting associations between several different sexual behaviours and OPC or OCC. Study quality was assessed independently by two reviewers using a validated scoring system.From 513 papers identified, 21, reporting on 20 studies, fulfilled the inclusion criteria. Two cohort studies were rated as moderate quality. The 18 case-control studies were rated as weak; nine comparing people with OPC or OCC to people without cancer, eight comparing HPV-positive to HPV-negative cancer patients and one comparing OPCs to other head and neck cancers. One study was a pooled analysis of seven of the included studies with some additional information. Twelve sexual behaviours were assessed and 69 associations reported. The studies differed in the comparisons made, the sexual behaviours assessed, and how these were reported and categorized, so no quantitative meta-analyses were appropriate. Most studies combined OPC and OCC. Several significantly increased risks were seen with a high number of lifetime sexual partners (nine studies) and with the practice of oral sex (five studies), although two studies found a significant negative association with OCC and ever performing oral sex. Two cohort studies of men and women in homosexual relationships found increases in oral cancer risk, and a cohort study of men married to women who had a history of cervical cancer also showed an increased risk of oral cancers. Results for other sexual behaviours were limited and inconsistent, and these included the following: younger age at first sexual intercourse, number of lifetime oral sex partners, the practice of oral-anal sex, the number of oral-anal sex partners, and ever performing anal sex. Only one study assessed casual sex, never or rare use of a condom and having a sexual partner with a history of genital warts, finding significant associations in the two former behaviours.The current evidence for sexual behaviours being risk factors for oral and oropharyngeal cancer is limited and inconsistent. Evidence suggests that the number of sexual partners and performing oral sex are associated with a greater risk. Furthermore men whose partners have had cervical cancer may have an increased risk.