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Background: Head and neck cancer (HNC) incidence is on the rise, often diagnosed at late stage and associated with poor prognoses. Risk prediction tools have a potential role in prevention and early detection., Methods: The IARC-ARCAGE European case-control study was used as the model development dataset. A clinical HNC risk prediction model using behavioral and demographic predictors was developed via multivariable logistic regression analyses. The model was then externally validated in the UK Biobank cohort. Model performance was tested using discrimination and calibration metrics., Results: 1926 HNC cases and 2043 controls were used for the development of the model. The development dataset model including sociodemographic, smoking, and alcohol variables had moderate discrimination, with an area under curve (AUC) value of 0.75 (95% CI, 0.74-0.77); the calibration slope (0.75) and tests were suggestive of good calibration. 384 616 UK Biobank participants (with 1177 HNC cases) were available for external validation of the model. Upon external validation, the model had an AUC of 0.62 (95% CI, 0.61-0.64)., Conclusion: We developed and externally validated a HNC risk prediction model using the ARCAGE and UK Biobank studies, respectively. This model had moderate performance in the development population and acceptable performance in the validation dataset. Demographics and risk behaviors are strong predictors of HNC, and this model may be a helpful tool in primary dental care settings to promote prevention and determine recall intervals for dental examination. Future addition of HPV serology or genetic factors could further enhance individual risk prediction., (© 2024 The Author(s). Head & Neck published by Wiley Periodicals LLC.)

Head and neck squamous cell carcinoma (HNSCC) is well known as a serious health problem worldwide, especially in low-income countries or those with limited resources, such as most countries in Latin America. International guidelines cannot always be applied to a population from a large region with specific conditions. This study established a Latin American guideline for care of patients with head and neck cancer and presented evidence of HNSCC management considering availability and oncologic benefit. A panel composed of 41 head and neck cancer experts systematically worked according to a modified Delphi process on (1) document compilation of evidence-based answers to different questions contextualized by resource availability and oncologic benefit regarding Latin America (region of limited resources and/or without access to all necessary health care system infrastructure), (2) revision of the answers and the classification of levels of evidence and degrees of recommendations of all recommendations, (3) validation of the consensus through two rounds of online surveys, and (4) manuscript composition. The consensus consists of 12 sections: Head and neck cancer staging, Histopathologic evaluation of head and neck cancer, Head and neck surgery-oral cavity, Clinical oncology-oral cavity, Head and neck surgery-oropharynx, Clinical oncology-oropharynx, Head and neck surgery-larynx, Head and neck surgery-larynx/hypopharynx, Clinical oncology-larynx/hypopharynx, Clinical oncology-recurrent and metastatic head and neck cancer, Head and neck surgery-reconstruction and rehabilitation, and Radiation therapy. The present consensus established 48 recommendations on HNSCC patient care considering the availability of resources and focusing on oncologic benefit. These recommendations could also be used to formulate strategies in other regions like Latin America countries.

A growing proportion of head and neck cancer (HNC), especially oropharyngeal cancer (OPC), is caused by human papillomavirus (HPV). There are several markers for HPV-driven HNC, one being HPV early antigen serology. We aimed to investigate the diagnostic accuracy of HPV serology and its performance across patient characteristics. Data from the VOYAGER consortium was used, which comprises five studies on HNC from North America and Europe. Diagnostic accuracy, that is, sensitivity, specificity, Cohen's kappa and correctly classified proportions of HPV16 E6 serology, was assessed for OPC and other HNC using p16 INK4a immunohistochemistry (p16), HPV in situ hybridization (ISH) and HPV PCR as reference methods. Stratified analyses were performed for variables including age, sex, smoking and alcohol use, to test the robustness of diagnostic accuracy. A risk-factor analysis based on serology was conducted, comparing HPV-driven to non-HPV-driven OPC. Overall, HPV serology had a sensitivity of 86.8% (95% CI 85.1-88.3) and specificity of 91.2% (95% CI 88.6-93.4) for HPV-driven OPC using p16 as a reference method. In stratified analyses, diagnostic accuracy remained consistent across sex and different age groups. Sensitivity was lower for heavy smokers (77.7%), OPC without lymph node involvement (74.4%) and the ARCAGE study (66.7%), while specificity decreased for cases with <10 pack-years (72.1%). The risk-factor model included study, year of diagnosis, age, sex, BMI, alcohol use, pack-years, TNM-T and TNM-N stage. HPV serology is a robust biomarker for HPV-driven OPC, and its diagnostic accuracy is independent of age and sex. Future research is suggested on the influence of smoking on HPV antibody levels., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Head and neck cancer (HNC) treatments have been based on single or multimodal therapies with surgery, radiotherapy (RT), chemotherapy, and immunotherapy. However, treatment recommendations among countries may differ due to technological/human resources and usual local practices. This scoping review aims to identify, compare, and map the clinical practice guidelines (CPGs) for treating squamous cell carcinoma (SCC) of the oral cavity, oropharynx, and larynx worldwide. A search strategy on global CPGs for HNC was performed by using five electronic databases and grey literature. CPGs were selected for inclusion using EndNote-20 and Rayyan online software. No language or publication date restrictions were applied. The results were analyzed descriptively considering the most updated CPG version. In total, 25 CPGs covering the head and neck region (10), the larynx (7), the oral cavity (5), and the oropharynx (3), were found in 13 geographical regions, and 19 were developed by medical societies from 1996 to 2023. Surgery and RT remain the main modalities for early-stage HNC, with surgery preferred in low-resource countries, and RT in selected cases, especially in the larynx/oropharynx aiming to achieve a cure with organ preservation. Human papillomavirus infection for oropharyngeal SCC is not tested in some Asian countries and there is still no consensus to treat p16-positive cases differently from p16-negative. Recommendations for larynx preservation vary according to facilities in each country, however, individualized choice is emphasized. Inequality across countries/continents is evident, with a similar pattern of recommendations among developed as well as developing ones. No CPGs were found in Latin America as well as Oceania countries, where the incidence of HNC is high and limitations of access to treatment may be encountered.

Head and neck cancer is often diagnosed late and prognosis for most head and neck cancer patients remains poor. To aid early detection, we developed a risk prediction model based on demographic and lifestyle risk factors, human papillomavirus (HPV) serological markers and genetic markers. A total of 10 126 head and neck cancer cases and 5254 controls from five North American and European studies were included. HPV serostatus was determined by antibodies for HPV16 early oncoproteins (E6, E7) and regulatory early proteins (E1, E2, E4). The data were split into a training set (70%) for model development and a hold-out testing set (30%) for model performance evaluation, including discriminative ability and calibration. The risk models including demographic, lifestyle risk factors and polygenic risk score showed a reasonable predictive accuracy for head and neck cancer overall. A risk model that also included HPV serology showed substantially improved predictive accuracy for oropharyngeal cancer (AUC = 0.94, 95% CI = 0.92-0.95 in men and AUC = 0.92, 95% CI = 0.88-0.95 in women). The 5-year absolute risk estimates showed distinct trajectories by risk factor profiles. Based on the UK Biobank cohort, the risks of developing oropharyngeal cancer among 60 years old and HPV16 seropositive in the next 5 years ranged from 5.8% to 14.9% with an average of 8.1% for men, 1.3% to 4.4% with an average of 2.2% for women. Absolute risk was generally higher among individuals with heavy smoking, heavy drinking, HPV seropositivity and those with higher polygenic risk score. These risk models may be helpful for identifying people at high risk of developing head and neck cancer., (© 2023 UICC.)

Background: Although early diagnosis and surgical resection of the tumor have been shown to be the most important predictors of lung cancer survival, long-term survival for surgically-resected early-stage lung cancer remains poor., Aims: In this prospective study we aimed to investigate the survival and prognostic factors of surgically-resected early-stage non-small cell lung cancer (NSCLC) in Central and Eastern Europe., Methods: We recruited 2052 patients with stage I-IIIA NSCLC from 9 centers in Russia, Poland, Serbia, Czech Republic, and Romania, between 2007-2016 and followed them annually through 2020., Results: During follow-up, there were 1121 deaths (including 730 cancer-specific deaths). Median survival time was 4.9 years, and the 5-year overall survival was 49.5%. In the multivariable model, mortality was increased among older individuals (HR for each 10-year increase: 1.31 [95% CI: 1.21-1.42]), males (HR:1.24 [1.04-1.49]), participants with significant weight loss (HR:1.25 [1.03-1.52]), current smokers (HR:1.30 [1.04-1.62]), alcohol drinkers (HR:1.22 [1.03-1.44]), and those with higher stage tumors (HR stage IIIA vs. I: 5.54 [4.10 - 7.48]). However, education, chronic obstructive pulmonary diseases (COPD), and tumor histology were not associated with risk of death. All baseline indicators of smoking and alcohol drinking showed a dose-dependent association with the risk of cancer-specific mortality. This included pack-years of cigarettes smoked (p-trend = 0.04), quantity of smoking (p-trend = 0.008), years of smoking (p-trend = 0.010), gram-days of alcohol drank (p-trend = 0.002), frequency of drinking (p-trend = 0.006), and years of drinking (p-trend = 0.016)., Conclusion: This study shows that the 5-year survival rate of surgically-resected stage I-IIIA NSCLC is still around 50% in Central and Eastern Europe. In addition to non-modifiable prognostic factors, lifetime patterns of smoking and alcohol drinking affected the risk of death and disease progression in a dose-dependent manner in this population., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The COVID-19 pandemic has likely affected the most vulnerable groups of patients and those requiring time-critical access to healthcare services, such as patients with cancer. The aim of this study was to use time trend data to assess the impact of COVID-19 on timely diagnosis and treatment of head and neck cancer (HNC) in the Italian Piedmont region., Methods: This study was based on two different data sources. First, regional hospital discharge register data were used to identify incident HNC in patients ≥18 years old during the period from January 1, 2015, to December 31, 2020. Interrupted time-series analysis was used to model the long-time trends in monthly incident HNC before COVID-19 while accounting for holiday-related seasonal fluctuations in the HNC admissions. Second, in a population of incident HNC patients eligible for recruitment in an ongoing clinical cohort study (HEADSpAcE) that started before the COVID-19 pandemic, we compared the distribution of early-stage and late-stage diagnoses between the pre-COVID-19 and the COVID-19 period., Results: There were 4,811 incident HNC admissions in the 5-year period before the COVID-19 outbreak and 832 admissions in 2020, of which 689 occurred after the COVID-19 outbreak in Italy. An initial reduction of 28% in admissions during the first wave of the COVID-19 pandemic (RR 0.72, 95% CI 0.62-0.84) was largely addressed by the end of 2020 (RR 0.96, 95% CI 0.89-1.03) when considering the whole population, although there were some heterogeneities. The gap between observed and expected admissions was particularly evident and had not completely recovered by the end of the year in older (≥75 years) patients (RR: 0.88, 0.76-1.01), patients with a Romano-Charlson comorbidity index below 2 (RR 0.91, 95% CI: 0.84-1.00), and primary surgically treated patients (RR 0.88, 95% CI 0.80-0.97). In the subgroup of patients eligible for the ongoing active recruitment, we observed no evidence of a shift toward a more advanced stage at diagnosis in the periods following the first pandemic wave., Conclusions: The COVID-19 pandemic has affected differentially the management of certain groups of incident HNC patients, with more pronounced impact on older patients, those treated primarily surgically, and those with less comorbidities. The missed and delayed diagnoses may translate into worser oncological outcomes in these patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Popovic, Fiano, Moirano, Chiusa, Conway, Garzino Demo, Gilardetti, Iorio, Moccia, Ostellino, Pecorari, Ramieri, Ricardi, Riva, Virani and Richiardi.)

Although several oropharyngeal cancer (OPC) susceptibility loci have been identified, most previous studies lacked detailed information on human papillomavirus (HPV) status. We conduct a genome-wide analysis by HPV16 serology status in 4,002 oral cancer cases (OPC and oral cavity cancer (OCC)) and 5,256 controls. We detect four susceptibility loci pointing to a distinct genetic predisposition by HPV status. Our most notable finding in the HLA region, that is now confirmed to be specific of HPV(+)OPC risk, reveal two independent loci with strong protective effects, one refining the previously reported HLA class II haplotype association. Antibody levels against HPV16 viral proteins strongly implicate the protective HLA variants as major determinants of humoral response against L1 capsid protein or E6 oncoprotein suggesting a natural immune response against HPV(+)OPC promoted by HLA variants. This indicates that therapeutic vaccines that target E6 and attenuate viral response after established HPV infections might protect against HPV(+)OPC., (© 2021. The Author(s).)

Recently, ovarian cancer research has evolved considerably because of the emerging recognition that rather than a single disease, ovarian carcinomas comprise several different histotypes that vary by etiologic origin, risk factors, molecular profiles, therapeutic approaches and clinical outcome. Despite significant progress in our understanding of the etiologic heterogeneity of ovarian cancer, as well as important clinical advances, it remains the eighth most frequently diagnosed cancer in women worldwide and the most fatal gynecologic cancer. The International Agency for Research on Cancer and the United States National Cancer Institute jointly convened an expert panel on ovarian carcinoma to develop consensus research priorities based on evolving scientific discoveries. Expertise ranged from etiology, prevention, early detection, pathology, model systems, molecular characterization and treatment/clinical management. This report summarizes the current state of knowledge and highlights expert consensus on future directions to continue advancing etiologic, epidemiologic and prognostic research on ovarian carcinoma., (Published by Oxford University Press 2021.)

Background: Maternal mortality (MM) was persistently high for several decades in Ethiopia though it has declined in recent years. The roles of time-varying elements in this decrease are unknown. Analyzing MM with age-period-cohort analysis will provide evidence to policymakers to re-direct resources towards vulnerable age groups. The aim of this analysis was to determine the role of age effect, period effect and birth cohort effect on the trend of age-specific maternal mortality in Ethiopia., Methods: Age-period-cohort (APC) analysis was applied to examine the effect of age, period and birth cohort on MM in Ethiopia using data from the Ethiopian Demographic and Health Survey (EDHS) from years 2000, 2005, 2011 and 2016. Age-specific maternal mortality rates were calculated using standardized maternal death compared to age-specific population per 100,000 woman-years of exposure and the trend was analyzed., Result: In most age groups, the MM rate decreased in 2015 compared with the previous years except for older women. According to the APC analysis, the age-cohort effect explains the MM rate better than age-period effect. The period effect shows the risk ratio of MM after 2005 decreased compared with before. The cohort effect illustrates women born after 1980 has lower risk ratio compared with the older one., Conclusion: Maternal mortality in Ethiopia declined overall in recent years. However, certain age groups still face high maternal mortality rates. A national policy on MM reduction interventions for the identified high-risk age groups is required., Competing Interests: The authors have declared that no competing interests exist.

Our study aimed to investigate the effect of Pap smear screening on stage at diagnosis of cervical cancer in a heterogeneous population of Thai women. Data was merged from the population-based cancer registry and screening registry based on unique identification numbers from 2006 to 2014. Patients being screened had lower odds to be diagnosed at late stage. After adjustment, married women had reduced risk of late stage cancer compared to single women. Muslim women had almost twice the risk of being diagnosed late stage compared to Buddhist women. The odds of being diagnosed at late stage decreased with increased number of screening. The probability of being diagnosed at late stage increased rapidly among females aged 40 to 55 years. Pap smear screening is a protective factor in diagnosis of late stage cervical cancer. Patients were more likely to be diagnosed at early stage with more frequent screening. For future screening programs, it will be beneficial to shorten screening intervals and take more concern for vulnerable population: women aged between 40 and 55 years, and women who are single or Muslim.

Background: Cervical cancer rates are higher in low-resourced countries than high, partly due to lower rates of screening. Incidence in Thailand is nearly three times higher than in the USA (16.2 vs 6.5 age-standardised incidence), even with Thailand's universal health coverage, which includes screening, suggesting that alternative methods are needed to reduce the burden. We investigated barriers to screening, as well as acceptability of self-collection human papillomavirus (HPV) testing as a primary form of cervical cancer screening among Buddhist and Muslim communities in Southern Thailand., Methods: 267 women from the Buddhist district of Ranot and Muslim district of Na Thawi, Songkhla were recruited to complete a survey assessing knowledge and risk factors of HPV and cervical cancer. Participants were offered an HPV self-collection test with a follow-up survey assessing acceptability. Samples were processed at Prince of Songkhla University and results were returned to participants., Results: 267 women participated in the study (132 Buddhist, 135 Muslim), 264 (99%) self-collecting. 98% reported comfort and ease, and 70% preferred it to doctor-facilitated cytology. The main predictor of prior screening was religion (92% Buddhist vs 73% Muslim reporting prior Pap). After adjustment with multivariate logistic models, Muslim women had an OR of prior Pap of 0.30 compared with Buddhist (95% CI: 0.12 to 0.66)., Conclusions: Self-collection HPV testing was highly acceptable across religious groups, suggesting that it could be beneficial for cervical cancer reduction in this region. Focus should be put into educating women from all backgrounds about the importance of screening to further improve screening rates among Thai women., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: Soy isoflavones have been suggested as epigenetic modulating agents with effects that could be important in carcinogenesis. Hypomethylation of LINE-1 has been associated with head and neck squamous cell carcinoma (HNSCC) development from oral premalignant lesions and with poor prognosis. To determine if neoadjuvant soy isoflavone supplementation could modulate LINE-1 methylation in HNSCC, we undertook a clinical trial., Methods: Thirty-nine patients received 2-3 weeks of soy isoflavone supplements (300 mg/day) orally prior to surgery. Methylation of LINE-1, and 6 other genes was measured by pyrosequencing in biopsy, resection, and whole blood (WB) specimens. Changes in methylation were tested using paired t tests and ANOVA. Median follow up was 45 months., Results: LINE-1 methylation increased significantly after soy isoflavone (P < 0.005). Amount of change correlated positively with days of isoflavone taken (P = 0.04). Similar changes were not seen in corresponding WB samples. No significant changes in tumor or blood methylation levels were seen in the other candidate genes., Conclusion: This is the first demonstration of in vivo increases in tissue-specific global methylation associated with soy isoflavone intake in patients with HNSCC. Prior associations of LINE-1 hypomethylation with genetic instability, carcinogenesis, and prognosis suggest that soy isoflavones maybe potential chemopreventive agents in HNSCC.

Background: The incidence of liver and bile duct cancer continues to rise, especially in Thailand. We aimed to project the trends in incidence of this rare but lethal cancer in southern Thailand in order to determine its future disease burden., Methods: Gender-specific trends in age-standardized incidence rates per 100,000 person-years for hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) cases in Songkhla province of southern Thailand diagnosed between 1989 and 2013 were estimated and projected up to year 2030 using three different modeling techniques: a joinpoint model, an age-period-cohort model, and a modified age-period-cohort model., Results: Of 2,676 liver and bile duct (LBD) cancer cases identified, 73% were males, 51% were aged between 50 and 69 years, and HCC (44.4%) was slightly more common than CCA (38.1%). The models all predicted an increase in the incidence rate of CCA up to 2025 for both sexes whereas the incidence of HCC is expected to decrease among males and stabilize among females. The incidence rates of HCC and CCA among males in 2030 could reach 6.7 and 9.4 per 100,000 person-years, respectively, whereas the expected rates of HCC and CCA among females are expected to be around 1.5 and 3.9 per 100,000 person-years, respectively., Conclusions: The incidence of cholangiocarcinoma is expected to increase in Songkhla and will contribute a larger proportion of LBD cancers in the future. Future public health efforts and research studies should focus on this increasing trend.

Purpose: Prostate cancer is the second most common malignancy among men worldwide, and it poses a significant public health burden that has traditionally been limited mostly to developed countries. However, the burden of the disease is expected to increase, affecting developing countries, including Thailand. We undertook an analysis to investigate current and future trends of prostate cancer in the province of Songkhla, Thailand, using data from the Songkhla Cancer Registry from 1990 to 2013., Methods: Joinpoint regression analysis was used to examine trends in age-adjusted incidence and mortality rates of prostate cancer and provide estimated annual percent change (EAPC) with 95% CIs. Age-period-cohort (APC) models were used to assess the effect of age, calendar year, and birth cohort on incidence and mortality rates. Three different methods (Joinpoint, Nordpred, and APC) were used to project trends from 2013 to 2030., Results: Eight hundred fifty-five cases of prostate cancer were diagnosed from 1990 to 2013 in Songkhla, Thailand. The incidence rates of prostate cancer significantly increased since 1990 at an EAPC of 4.8% (95% CI, 3.6% to 5.9%). Similarly, mortality rates increased at an EAPC of 5.3% (95% CI, 3.4% to 7.2%). The APC models suggest that birth cohort is the most important factor driving the increased incidence and mortality rates of prostate cancer. Future incidence and mortality of prostate cancer are projected to continue to increase, doubling the rates observed in 2013 by 2030., Conclusion: It is critical to allocate resources to provide care for the men who will be affected by this increase in prostate cancer incidence in Songkhla, Thailand, and to design context-appropriate interventions to prevent its increasing burden.

While whole-exome DNA sequencing is the most common technology to study genetic variants in tumors in known exonic regions, RNA-seq is cheaper, covers most of the same exonic regions, and is often more readily available. In this study, we show the utility of mRNA-seq-based variant analysis combined with targeted gene sequencing performed on both tumor and matched blood as an alternative when exome data is unavailable. We use the approach to study expressed variant profiles in the well-characterized University of Michigan (UM) head and neck squamous carcinoma (HNSCC) cohort (n = 36). We found that 441 out of 455 (~97%) identified cancer genes with an expressed variant in the UM cohort also harbor a somatic mutation in TCGA. Fourteen (39%) patients had a germline variant in a cancer-related Fanconi Anemia (FA) pathway gene. HPV-positive patients had more nonsynonymous, rare, and damaging (NRD) variants in those genes than HPV-negative patients. Moreover, the known mutational signatures for DNA mismatch repair and APOBEC activation were attributive to the UM expressed NRD variants, and the APOBEC signature contribution differed by HPV status. Our results provide additional support to certain TCGA findings and suggest an association of expressed variants in FA/DNA repair pathways with HPV-associated HNSCC tumorigenesis. These results will benefit future studies on this and other cohorts by providing the genetic variants of key cancer-related genes.

Background: The northeast has the lowest incidence of breast cancer of all regions in Thailand, although national rates are increasing. The heterogeneity in subnational trends necessitates a comprehensive evaluation of breast cancer incidence trends and projections to provide evidence for future region-specific strategies that may be employed to attenuate this growing burden., Methods: Joinpoint regression and age-period-cohort modeling were used to describe trends from 1988-2012. Data was projected from three separate models to provide a range of estimates of incidence to the year 2030 by age group., Results: Age-standardized rates (ASRs) increased significantly for all women from 1995-2012 by 4.5% per year. Rates for women below age 50 increased by 5.1% per year, while women age 50 years and older increased by 6% per year from 1988-2012. Projected rates show that women age 50 years and older have the largest projected increase in ASRs by 2030 compared to younger women and all women combined., Conclusions: Breast cancer trends in Khon Kaen are presently lower than other regions but are expected to increase and become comparable to other regions by 2030, particularly for women ages 50 years and older.

Background: Breast cancer has the highest incidence in women of all cancers and its burden is expected to continue to increase worldwide, especially in middle-income countries such as Thailand. The southern region of Thailand is unique in that it is comprised of 30% Muslims, whereas the rest of Thailand is 95% Buddhist. Breast cancer incidence and survival differ between these religious groups, but the association between clinical subtype of breast cancer and survival has not yet been assessed., Methods: Here we characterized differences in breast cancer survival with consideration to clinical subtype by religious group (Muslim Thai and Buddhist Thai women). We compared distributions of age, stage and clinical subtype and assessed overall survival by religion., Results: Our findings show that Muslim Thai women with breast cancer are diagnosed at a younger age, at later stages and have shorter overall survival times compared to Buddhist Thai women with breast cancer. We also observe a higher proportion of triple negative tumors characterized in Muslim Thai women., Conclusions: Our findings confirm previous studies that have shown lower survival rates in Muslim Thai women compared to Buddhist women with breast cancer and offer novel information on subtype distribution. To date, this is the first study assessing clinical subtypes in southern Thailand by religious status., Impact: Our findings are critical in providing information on the role of clinical subtype in cancer disparities and provide evidence from the Southeast Asian region for global studies on breast cancer survival., (Copyright © 2018. Published by Elsevier Ltd.)

Objectives: Cervical cancer has posed a serious problem in Thailand for decades. In 2002, a systematic screening program was implemented under universal healthcare coverage for all Thai women. However, there has been little research on how screening affected particular aspects of cervical cancer, such as stage distribution. This screening program has a target group; therefore, it is necessary to assess stage and incidence trends by age of those within and outside the screening target group., Methods: Using trend analysis, we assess in situ and malignant cervical cancers in Northern Thailand to measure changes after implementation of the national screening program., Results: While incidence of malignant cancers is decreasing and incidence of in situ tumors is increasing across all age groups, women above age 60 still experience a high incidence of malignant tumors., Conclusions: The screening program is successful in the target group at downshifting the stage distribution of malignant tumors and reducing incidence of malignant tumors with in situ cases being captured. However, the high incidence of malignant tumors in women over age 60 will continue to be clinically relevant for cervical cancer management until younger generations undergoing screening enter this age group.

The incidence of human papillomavirus (HPV)-related oropharynx cancer has steadily increased over the past two decades and now represents a majority of oropharyngeal cancer cases. Integration of the HPV genome into the host genome is a common event during carcinogenesis that has clinically relevant effects if the viral early genes are transcribed. Understanding the impact of HPV integration on clinical outcomes of head and neck squamous cell carcinoma (HNSCC) is critical for implementing deescalated treatment approaches for HPV + HNSCC patients. RNA sequencing (RNA-seq) data from HNSCC tumors ( n = 84) were used to identify and characterize expressed integration events, which were overrepresented near known head and neck, lung, and urogenital cancer genes. Five genes were recurrent, including CD274 (PD-L1) A significant number of genes detected to have integration events were found to interact with Tp63, ETS, and/or FOX1A. Patients with no detected integration had better survival than integration-positive and HPV - patients. Furthermore, integration-negative tumors were characterized by strongly heightened signatures for immune cells, including CD4 + , CD3 + , regulatory, CD8 + T cells, NK cells, and B cells, compared with integration-positive tumors. Finally, genes with elevated expression in integration-negative specimens were strongly enriched with immune-related gene ontology terms, while upregulated genes in integration-positive tumors were enriched for keratinization, RNA metabolism, and translation. Implications: These findings demonstrate the clinical relevancy of expressed HPV integration, which is characterized by a change in immune response and/or aberrant expression of the integration-harboring cancer-related genes, and suggest strong natural selection for tumor cells with expressed integration events in key carcinogenic genes. Mol Cancer Res; 16(1); 90-102. ©2017 AACR ., (©2017 American Association for Cancer Research.)

In Thailand, five cancer types-breast, cervical, colorectal, liver and lung cancer-contribute to over half of the cancer burden. The magnitude of these cancers must be quantified over time to assess previous health policies and highlight future trajectories for targeted prevention efforts. We provide a comprehensive assessment of these five cancers nationally and subnationally, with trend analysis, projections, and number of cases expected for the year 2025 using cancer registry data. We found that breast (average annual percent change (AAPC): 3.1%) and colorectal cancer (female AAPC: 3.3%, male AAPC: 4.1%) are increasing while cervical cancer (AAPC: -4.4%) is decreasing nationwide. However, liver and lung cancers exhibit disproportionately higher burdens in the northeast and north regions, respectively. Lung cancer increased significantly in northeastern and southern women, despite low smoking rates. Liver cancers are expected to increase in the northern males and females. Liver cancer increased in the south, despite the absence of the liver fluke, a known factor, in this region. Our findings are presented in the context of health policy, population dynamics and serve to provide evidence for future prevention strategies. Our subnational estimates provide a basis for understanding variations in region-specific risk factor profiles that contribute to incidence trends over time., Competing Interests: The authors declare that they have no conflict of interest.

DNA methylation changes with age, and may serve as a biomarker of aging. Cadmium (Cd) modifies cellular processes that promote aging and disrupts methylation globally. Whether Cd modifies aging processes by influencing establishment of age-associated methylation marks is currently unknown. In this pilot study, we characterized methylation profiles in > 450 000 CpG sites in 40 non-smoking women (age 40-80) differentially exposed to environmental Cd from Thailand. Based on specific gravity adjusted urinary Cd, we classified them as high (HE) and low (LE) exposed and age-matched within 5 years. Urinary Cd was defined as below 2 µg/l in the LE group. We predicted epigenetic age (DNAm-age) using two published methods by Horvath and Hannum and examined the difference between epigenetic age and chronologic age (Δage). We assessed differences by Cd exposure using linear mixed models adjusted for estimated white blood cell proportions, BMI, and urinary creatinine. We identified 213 age-associated CpG sites in our population ( P < 10 -4 ). Counterintuitively, the mean Δage was smaller in HE vs. LE (Hannum: 3.6 vs. 7.6 years, P = 0.0093; Horvath: 2.4 vs. 4.5 years, P = 0.1308). The Cd exposed group was associated with changes in methylation ( P < 0.05) at 12, 8, and 20 age-associated sites identified in our population, Hannum, and Horvath. From the results of this pilot study, elevated Cd exposure is associated with methylation changes at age-associated sites and smaller differences between DNAm-age and chronologic age, in contrast to expected age-accelerating effects. Cd may modify epigenetic aging, and biomarkers of aging warrant further investigation when examining Cd and its relationship with chronic disease and mortality.

Objectives: This study was conducted to determine incidence trends of female breast cancer according to age groups and to predict future change in Chiang Mai women through 2028. Method: Data were collected from all hospitals in Chiang Mai in northern Thailand, from 1989 through 2013, and used to investigate effects of age, year of diagnosis (period) and year of birth (cohort) on female breast cancer incidences using an age-period-cohort model. This model features geometric cut trends to predict change by young (<40 years), middle-aged (40-59) and elderly (≥60) age groups. Result: Of 5, 417 female breast cancer patients with a median age of 50 years (interquartile range: 43 to 59 years), 15%, 61% and 24% were young, middle-aged and elderly, respectively. Seventy nine percent of cancer cases in this study were detected at advanced stage. The trend in stage classification showed an increase in percentage of early stage and a decrease in metastatic cancers. Linear trends for cohort and period were not found in young females but were observed in middle-aged and elderly groups. Age-standardized rates (ASR) can be expected to remain stable around 6.8 per 100,000 women-years in young females. In the other age groups, the ASR trends were calculated to increase and reach peaks in 2024 of 120.2 and 138.2 per 100,000 women-years, respectively. Conclusion: Cohort effects or generation-specific effects, such as life style factors and the year of diagnosis (period) might have impacted on increased incidence in women aged over 40 years but not those under 40 years. A budget should be provided for treatment facilities and strategies to detect early stage cancers. The cost effectiveness of screening measures i.e. mammographic screening may need to be reconsidered for women age over 40 years., (Creative Commons Attribution License)

Background: The national cervical cancer screening program in Thailand has been successful in reducing overall burden from this disease. However, evaluation on spatial and temporal scales is needed to assess the efficacy of this program in smaller regions. Here, we geographically assess incidence in a province with a uniquely heterogeneous distribution of lifestyle factors associated with religiosity., Methods: Cervical cancer cases were extracted from the provincial cancer registry from 1989 to 2013. Age-adjusted incidence rates were calculated using population statistics from the census bureau and adjusted to the Segi world standard population. Bayesian hierarchical modelling was employed to spatiotemporally map cervical cancer incidence trends in Songkhla province in 5-year period., Results: Overall, the incidence of cervical cancer decreased in Songkhla province. The three districts with a Muslim population of greater than 70% had consistently lower cervical cancer rates from 1989 to 2013 compared with the rest of the predominantly Buddhist districts. Hotspots of incidence were identified in Sadao, Hat Yai and the juncture of Mueang Songkhla and Singhanakhon in each 5-year period., Conclusions: Distinct cervical cancer incidence trends by religion over time indicate differences in sexual habits, lifestyle and religion-associated culture between Muslims and Buddhists, and suggest divergent risk factor profiles for these groups. The high incidence rates in Sadao and Hat Yai is likely explained by the main road to Malaysia, which runs across these two areas and has frequent commercial sex trade. Female sex workers should be targeted as a vulnerable population for screening efforts to address this continuing burden of cervical cancer., (© The Author 2016. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Background: To better understand the associations between a history of tobacco use and survival outcomes, cigarette use was prospectively surveyed in 687 previously untreated patients with cancer of the oral cavity (n = 271), oropharynx (n = 257), larynx (n = 135), or hypopharynx (n = 24)., Methods: Kaplan-Meier and Cox models explored the associations of tobacco use intensity (packs/day), duration (years of use), and timing before diagnosis with overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS)., Results: Cigarette use duration, timing, and intensity were significant predictors for all outcomes in univariate analysis. Never smoking and pack-years were not significantly associated with outcomes after adjustment for prognostic factors, such as stage, comorbidities, and human papillomavirus (HPV) status, which were strongly associated with clinical outcomes., Conclusion: The findings confirm the association between smoking history and survival and the importance of clinical variables in evaluating smoking as a prognostic factor. Timing, intensity, and duration of cigarette use should be considered with other prognostic factors when considering risk stratification for treatment planning. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1810-1820, 2016., (© 2016 Wiley Periodicals, Inc.)

Purpose: There is substantial heterogeneity within human papillomavirus (HPV)-associated head and neck cancer (HNC) tumors that predispose them to different outcomes; however, the molecular heterogeneity in this subgroup is poorly characterized due to various historical reasons., Experimental Design: We performed unsupervised gene expression clustering on deeply annotated (transcriptome and genome) HPV(+) HNC samples from two cohorts (84 total primary tumors), including 18 HPV(-) HNC samples, to discover subtypes and characterize the differences between subgroups in terms of their HPV characteristics, pathway activity, whole-genome somatic copy number alterations, and mutation frequencies., Results: We identified two distinct HPV(+) subtypes (namely HPV-KRT and HPV-IMU). HPV-KRT is characterized by elevated expression of genes in keratinocyte differentiation and oxidation-reduction process, whereas HPV-IMU has strong immune response and mesenchymal differentiation. The differences in expression are likely connected to the differences in HPV characteristics and genomic changes. HPV-KRT has more genic viral integration, lower E2/E4/E5 expression levels, and higher ratio of spliced to full-length HPV oncogene E6 than HPV-IMU; the subgroups also show differences in copy number alterations and mutations, in particular the loss of chr16q in HPV-IMU and gain of chr3q and PIK3CA mutation in HPV-KRT., Conclusions: Our characterization of two subtypes of HPV(+) HNC tumors provides valuable molecular level information that point to two main carcinogenic paths. Together, these results shed light on stratifications of the HPV(+) HNCs and will help to guide personalized care for HPV(+) HNC patients. Clin Cancer Res; 22(18); 4735-45. ©2016 AACR., Competing Interests: The authors declare there are no potential conflicts of interest., (©2016 American Association for Cancer Research.)

Background: Because immune responses within the tumor microenvironment are important predictors of tumor biology, correlations of types of tumor infiltrating lymphocytes (TILs) with clinical outcomes were determined in 278 patients with head and neck squamous cell carcinoma (HNSCC)., Methods: Infiltrating levels of CD4 (helper T cells), CD8 (cytotoxic/suppressor T cells), FoxP3 (regulatory T cells), CD68 (myeloid-derived suppressor cells,) and CD1a (Langerhans) cells were measured in tissue microarrays (TMAs). Cox models tested associations with patient outcomes after adjusting for all known prognostic factors. Median follow-up was 36.6 months., Results: Higher CD4 and CD8 TIL levels were associated with improved overall survival (OS; hazard ratio [HR] = 0.77; 95% confidence interval [CI]  = 0.65-0.93; p = .005 and HR = 0.77; 95% CI = 0.64-0.94; p = .008, respectively), and relapse-free survival (RFS; p = .03 and .05, respectively). After controlling for prognostic factors, higher CD4 levels predicted improved OS and disease-specific survival (DSS; p = .003 and p = .004, respectively)., Conclusion: The findings suggest that TILs are a significant independent prognostic factor for HNSCC that differ by treatment. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1074-1084, 2016., (© 2016 Wiley Periodicals, Inc.)

Background: As cancer progresses, methylation patterns change to promote the tumorigenic phenotype. However, stability of methylation markers over time and the extent that biopsy samples are representative of larger tumor specimens are unknown. This information is critical for clinical use of such biomarkers., Methods: Ninety-eight patients with tumor specimens from 2 timepoints were measured for DNA methylation in the promoter regions across 4 genes., Results: There were no significant differences in overall methylation of CCNA1 (cyclin A1), NDN (necdin), deleted in colorectal carcinoma (DCC), and cluster of differentiation 1a (CD1A) within paired specimens (p values = .56, .17, .66, and .58, respectively). All genes showed strong correlations between paired specimens across time. Methylation was most consistent for CCNA1 and NDN over time., Conclusion: This report provides the first evidence that methylation markers measured in biopsy samples are representative of gene methylation in later specimens and suggests that biopsy markers could be representative biomarkers for use in defining personalized treatment utilizing epigenetic changes. © 2015 Wiley Periodicals, Head Neck 38: E1325-E1331, 2016., (© 2015 Wiley Periodicals, Inc.)

The adverse health effects of cadmium (Cd) are well known in human populations; however, much of what is known about biological mechanisms of Cd comes from in vitro and animal studies. The adverse health outcomes due to high levels of Cd exposure in the population of Mae Sot, Thailand have been extensively characterized. Here, for the first time, this population is being studied in an epigenetic context. The objective of this study was to characterize the association between DNA methylation markers and Cd exposure, taking into account sex and smoking differences, in an adult population at an increased risk of experiencing adverse health outcomes from high body burden of Cd. One hundred and sixty-nine residents from known exposure areas of Mae Sot, Thailand and one hundred residents from non-exposed areas nearby were surveyed in 2012. Urine and blood samples were collected for measurement of urinary Cd (UCd) and DNA methylation of Cd-related markers (DNMT3B, MGMT, LINE-1, MT2A). UCd levels were 7 times higher in the exposed compared to the unexposed populations (exposed median: 7.4 μg/L, unexposed median: 1.0 μg/L, p < 0.001). MGMT hypomethylation was associated with increasing levels of UCd in the total population. Sex-specific associations included MT2A and DNMT3B hypomethylation in women and LINE-1 hypermethylation in men with increasing UCd. Upon subanalysis, these associations separated by smoking status. In summary, environmental Cd exposure is associated with gene-specific DNA methylation in a sex and smoking dependent manner., Competing Interests: All authors have no competing financial interests Conflict of Interests: All authors have no conflicts of interests, (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: HPV-associated HNSCCs have a distinct etiologic mechanism and better prognosis than those with non-HPV associated HNSCCs. However, even within the each group, there is heterogeneity in survival time. Here, we test the hypothesis that specific candidate gene methylation markers (CCNA1, NDN, CD1A, DCC, p16, GADD45A) are associated with tumor recurrence and survival, in a well-characterized, prospective, cohort of 346 HNSCC patients., Methods: Kaplan-Meier curves were used to estimate survival time distributions. Multivariable Cox Proportional Hazards models were used to test associations between each methylation marker and OST/RPFT after adjusting for known or identified prognostic factors. Stratified Cox models included an interaction term between HPV and methylation marker to test for differences in the associations of the biomarker with OST or RPFT across HPV status., Results: Methylation markers were differentially associated with patient characteristics. DNA hypermethylation of NDN and CD1A was found to be significantly associated with overall survival time (OST) in all HNSCC patients (NDN hazard ratio (HR): 2.35, 95% CI: 1.40-3.94; CD1A HR: 1.31, 95% CI: 1.01-1.71). Stratification by HPV status revealed hypermethylation of CD1A was associated with better OST and recurrence/persistence-free time (RPFT) (OST HR: 3.34, 95% CI: 1.88-5.93; RPFT HR: 2.06, 95% CI: 1.21-3.49), while hypomethylation of CCNA1 was associated with increased RPFT in HPV (+) patients only (HR: 0.31, 95% CI: 0.13-0.74)., Conclusions: This study is the first to describe novel epigenetic alterations associated with survival in an unselected, prospectively collected, consecutive cohort of patients with HNSCC. DNA hypermethylation of NDN and CD1A was found to be significantly associated with increased overall survival time in all HNSCC patients. However, stratification by the important prognostic factor of HPV status revealed the immune marker, CD1A, and the cell cycle regulator, CCNA1 to be associated with prognosis in HPV (+) patients, specifically. Here, we identified novel methylation markers and specific, epigenetic molecular differences associated with HPV status, which warrant further investigation.

Background: Thailand is undergoing an epidemiologic transition, with decreasing incidence of infectious diseases and increasing rates of chronic conditions, including cancer. Breast cancer has the highest incidence rates among females both in the southern region Thailand and throughout Thailand. However, there is a lack of research on the epidemiology of this and other cancers., Methods: Here we use cancer incidence data from the Songkhla Cancer Registry to characterize and analyze the incidence of breast cancer in Southern Thailand. We use joinpoint analysis, age-period-cohort models and nordpred analysis to investigate the incidence of breast cancer in Southern Thailand from 1990 to 2010 and project future trends from 2010 to 2029., Results: We found that age-adjusted breast cancer incidence rates in Southern Thailand increased by almost 300% from 1990 to 2010 going from 10.0 to 27.8 cases per 100,000 person-years. Both period and cohort effects played a role in shaping the increase in incidence. Three distinct incidence projection methods consistently suggested that incidence rates will continue to increase in the future with incidence for women age 50 and above increasing at a higher rate than for women below 50., Conclusions: To date, this is the first study to examine Thai breast cancer incidence from a regional registry. This study provides a basis for future planning strategies in breast cancer prevention and to guide hypotheses for population-based epidemiologic research in Thailand., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Head and neck squamous cell carcinoma (HNSCC) is the eighth most commonly diagnosed cancer in the United States. The risk of developing HNSCC increases with exposure to tobacco, alcohol and infection with human papilloma virus (HPV). HPV-associated HNSCCs have a distinct risk profile and improved prognosis compared to cancers associated with tobacco and alcohol exposure. Epigenetic changes are an important mechanism in carcinogenic progression, but how these changes differ between viral- and chemical-induced cancers remains unknown. CpG methylation at 1505 CpG sites across 807 genes in 68 well-annotated HNSCC tumor samples from the University of Michigan Head and Neck SPORE patient population were quantified using the Illumina Goldengate Methylation Cancer Panel. Unsupervised hierarchical clustering based on methylation identified 6 distinct tumor clusters, which significantly differed by age, HPV status, and three year survival. Weighted linear modeling was used to identify differentially methylated genes based on epidemiological characteristics. Consistent with previous in vitro findings by our group, methylation of sites in the CCNA1 promoter was found to be higher in HPV(+) tumors, which was validated in an additional sample set of 128 tumors. After adjusting for cancer site, stage, age, gender, alcohol consumption, and smoking status, HPV status was found to be a significant predictor for DNA methylation at an additional 11 genes, including CASP8 and SYBL1. These findings provide insight into the epigenetic regulation of viral vs. chemical carcinogenesis and could provide novel targets for development of individualized therapeutic and prevention regimens based on environmental exposures.

Background: Birth by cesarean delivery (CD) as opposed to vaginal delivery (VD) is associated with altered health outcomes later in life, including respiratory disorders, allergies and risk of developing type I diabetes. Epigenetic gene regulation is a proposed mechanism by which early life exposures affect later health outcomes. Previously, type of delivery has been found to be associated with differences in global methylation levels, but the sample sizes have been small. We measured global methylation in a large birth cohort to identify whether type of delivery is associated with epigenetic changes., Methods: DNA was isolated from cord blood collected from the University of Michigan Women's & Children Hospital and bisulfite-converted. The Luminometric Methylation Assay (LUMA) and LINE-1 methylation assay were run on all samples in duplicate., Results: Global methylation data at CCGG sites throughout the genome, as measured by LUMA, were available from 392 births (52% male; 65% CD), and quantitative methylation levels at LINE-1 repetitive elements were available for 407 births (52% male; 64% CD). LUMA and LINE-1 methylation measurements were negatively correlated in this population (Spearman's r = -0.13, p =0.01). LUMA measurements were significantly lower for total CD and planned CD, but not emergency CD when compared to VD (median VD = 74.8, median total CD = 74.4, p = 0.03; median planned CD = 74.2, p = 0.02; median emergency CD = 75.3, p = 0.39). However, this association did not persist when adjusting for maternal age, maternal smoking and infant gender. Furthermore, total CD deliveries, planned CD and emergency CD deliveries were not associated with LINE-1 measurements as compared to VD (median VD = 82.2, median total CD = 81.9, p = 0.19; median planned CD = 81.9, p = 0.19; median emergency CD = 82.1, p = 0.52). This lack of association held when adjusting for maternal age, maternal smoking and infant gender in a multivariable model., Conclusions: Type of delivery was not associated with global methylation in our population, even after adjustment for maternal age, maternal smoking, and infant gender. While type of birth may be associated with later health outcomes, our data suggest that it does not do so through changes in global genomic methylation.

Cancer is a disease that results from the successive accumulation of genetic and epigenetic alterations. Despite intense study, many unanswered questions about the nature of the contribution of epigenetic changes to carcinogenesis remain. In this review, we describe principles of epigenetics as they relate to our current understanding of carcinogenesis. There are a number of in vivo models of specific pathways of carcinogenesis that are very useful for the characterization of epigenetic mechanisms that link environmental exposures or genetic susceptibility and cancer progression. Because epigenetic alterations are thought to be reversible, they offer great promise for treatment of cancer. The use of animal models to evaluate the effects of decitabine and zebularine has elucidated the mechanisms of action and indicated the potential for these types of treatment. Ultimately, the greatest challenge lies in the integration of laboratory and epidemiologic data to best prevent and treat this deadly disease.

The receptor tyrosine kinase c-Met and its ligand, hepatocyte growth factor/scatter factor (HGF/SF), modulate signaling cascades implicated in cellular proliferation, survival, migration, invasion, and angiogenesis. Therefore, dysregulation of HGF/c-Met signaling can compromise the cellular capacity to moderate these activities and can lead to tumorigenesis, metastasis, and therapeutic resistance in various human malignancies. To facilitate studies investigating HGF/c-Met receptor coupling or c-Met signaling events in real time and in living cells and animals, here we describe a genetically engineered reporter where bioluminescence can be used as a surrogate for c-Met tyrosine kinase activity. c-Met kinase activity in cultured cells and tumor xenografts was monitored quantitatively and dynamically in response to the activation or inhibition of the HGF/c-Met signaling pathway. Treatment of tumor-bearing animals with a c-Met inhibitor and the HGF neutralizing antibody stimulated the reporter's bioluminescence activity in a dose-dependent manner and led to a regression of U-87 MG tumor xenografts. Results obtained from these studies provide unique insights into the pharmacokinetics and pharmacodynamics of agents that modulate c-Met activity and validate c-Met as a target for human glioblastoma therapy., (Copyright © 2011 Elsevier Inc. All rights reserved.)