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Tumor-infiltrating lymphocytes (TILs) and cytokines are associated with prognosis among patients with head and neck squamous cell carcinoma (HNSCC). Statins (cholesterol-lowering drugs) may improve HNSCC prognosis, particularly in human papillomavirus (HPV)-positive cases, but the mechanism remains unclear.Statin use was collected from medical records for HNSCC cases (2008-2014). TILs were counted in tumor tissue, and a total weighted score (TILws) was created. Cytokines were measured in blood. The associations between statins and biomarkers were estimated using logistic (biomarker categories:median, ≥median) and linear regression models (log-transformed continuous biomarkers) adjusted for age, smoking, and comorbidities.We observed a positive association between statins and TILs among HPV-positive patients (TILws odds ratio [OR] = 2.80; 95% CI = 1.03-7.61), but no association among HPV-negative patients. We observed no association between statins and cytokines.Statins may influence TILs in HPV-positive patients. This may be the mechanism through which they improve prognosis in HPV-positive HNSCC patients.

This study assessed the associations between blood and urine levels of toxic metals; cadmium (Cd) and lead (Pb), and methylation levels of the LINE-1 gene among e-waste and control populations in Ghana. The study enrolled 100 male e-waste workers and 51 all-male non-e-waste workers or controls. The concentrations of Cd and Pb were measured in blood and urine using inductively coupled plasma mass spectrometry, while LINE1 methylation levels were assessed by pyrosequencing of bisulfite-converted DNA extracted from whole blood. Single and multiple metals linear regression models were used to determine the associations between metals and LINE1 DNA methylation. Blood lead (BPb) and urine lead (UPb) showed higher median concentrations among the e-waste workers than the controls (76.82 µg/L vs 40.25 µg/L, p ≤ 0.001; and 6.89 µg/L vs 3.43 µg/L, p ≤ 0.001, respectively), whereas blood cadmium (BCd) concentration was lower in the e-waste workers compared to the controls (0.59 µg/L vs 0.81 µg/L, respectively, p = 0.003). There was no significant difference in LINE1 methylation between the e-waste and controls (85.16 ± 1.32% vs 85.17 ± 1.11%, p = 0.950). In our single metal linear regression models, BPb was significantly inversely associated with LINE1 methylation in the control group (βBPb = − 0.027, 95% CI − 0.045, − 0.010, p = 0.003). In addition, a weak association between BPb and LINE1 was observed in the multiple metals analysis in the e-waste worker group (βBPb = − 0.005, 95% CI − 0.011, 0.000, p = 0.058). Continuous Pb exposure may interfere with LINE1 methylation, leading to epigenetic alterations, thus serving as an early epigenetic marker for future adverse health outcomes.

BACKGROUND: Tumor infiltrating lymphocytes (TILs) aid in informing treatment for head and neck squamous cell carcinoma (HNSCC). Nevertheless, little is known about the role of diet on TILs. METHODS: Immunohistologic expression of CD4, CD8, CD68, CD103, CD104 and FOXP3 were assessed in tissue microarrays from 233 previously untreated HNSCC patients. Associations between these markers and pre-treatment dietary patterns were evaluated using linear regression. Associations between baseline serum carotenoids, tocopherols and TILs were assessed using logistic regression. Cox models evaluated the association between diet and TILs on overall and recurrence-free survival. RESULTS: Consumption of a Western dietary pattern was associated with lower CD8+ and FOXP3+ infiltrates (p-value:0.03 and 0.02, respectively). Multivariable logistic regression models demonstrated significantly higher CD8+ (OR:2.21;p-value:0.001) and FOXP3+ (OR:4.26;p-value

Background Human papillomavirus (HPV) oncogenes E6, E7, and shorter isoforms of E6 (E6*) are known carcinogenic factors in head and neck squamous cell carcinoma (HNSCC). Little is known regarding E6* functions. Methods We analyzed RNA-seq data from 68 HNSCC HPV type 16-positive tumors to determine host genes and pathways associated with E6+E7 expression (E6E7) or the percent of full-length E6 (E6%FL). Influence scores of E6E7 and E6%FL were used to test for associations with clinical variables. Results For E6E7, we recapitulated all major known affected pathways and revealed additional pathways. E6%FL was found to affect mitochondrial processes, and E6%FL influence score was significantly associated with overall survival and tumor size. Conclusions HPV E6E7 and E6* result in extensive, dose-dependent compensatory effects and dysregulation of key cancer pathways. The switch from E6 to E6* promotes oxidative phosphorylation, larger tumor size, and worse prognosis, potentially serving as a prognostic factor for HPV-positive HNSCC.

We investigated whether plasma oxidative stress and apoptotic biomarkers were associated with the VDR polymorphisms in breast cancer survivors supplemented with vitamin D3. Two hundred fourteen breast cancer survivors received 4000 IU of vitamin D3 daily for 12 weeks. Linear regression was used to analyze whether the effect of vitamin D3 supplementation on response variables was associated with the selected VDR single nucleotide polymorphisms executing by 'association' function in the R package 'SNPassoc'. Linear regression analyses adjusted for age, BMI and on-study plasma 25(OH)D changes indicated that the aa genotype of the ApaI [codominant model (aa vs. AA): -0.21 (-0.39 to -0.03); recessive model (aa vs. AA and Aa): -0.20 (-0.37 to -0.03)] and bb genotypes of the BsmI [recessive model (bb vs. BB and Bb): -0.20 (-0.39 to -0.01)] on VDR were associated with greater decrease in plasma Bcl2. Our findings indicated that, the Ff genotype of FokI was accompanied by higher increase in plasma MDA levels [codominant model (Ff vs. FF): 0.64 (0.18-1.11); dominant model (ff and Ff vs. FF): 0.52 (0.09-0.05)]. This observed association was not remained statistically significant after correction for multiple testing. Haplotype score analyses revealed statistically significant association between the FokI BsmI ApaI haplotype and circulating MDA changes (P-value for global score = 0.001) after false-discovery rate correction. Our study suggests that genetic variations in the VDR do not powerfully modify the effects of vitamin D3 intake on biomarkers associated with antioxidant activity, oxidative stress and apoptosis in breast cancer survivors.

BACKGROUND: The associations between specific types of fat and head and neck squamous cell carcinoma (HNSCC) recurrence and mortality rates have not yet been examined. OBJECTIVES: The purpose of this study was to determine how intakes of various fat subtypes before cancer treatment are associated with recurrence and mortality in adults diagnosed with HNSCC. METHODS: This was a secondary analysis longitudinal cohort study of data collected from 476 newly diagnosed patients with HNSCC. Patients completed baseline FFQs and epidemiologic health surveys. Recurrence and mortality events were collected annually. Fat intakes examined included long-chain fatty acids (LCFAs), unsaturated fatty acids (FAs), PUFAs, ω-3 (n–3) PUFAs, ω-6 (n–6) PUFAs, MUFAs, animal fats, vegetable fats, saturated FAs, and trans fats. Associations between fat intake (categorized into tertiles) and time to event were tested using multivariable Cox proportional hazards models, adjusting for age, sex, smoking status, human papillomavirus status, tumor site, cancer stage, and total caloric intake. Intake of fats was compared with the lowest tertile. RESULTS: During the study period, there were 115 recurrent and 211 death events. High LCFA intake was associated with a reduced all-cause mortality risk (HR: 0.55; 95% CI: 0.34, 0.91; P-trend = 0.02). High unsaturated FA intake was associated with a reduced all-cause mortality risk (HR: 0.62; 95% CI: 0.40, 0.97; P-trend = 0.04) and HNSCC-specific mortality risk (HR: 0.51; 95% CI: 0.29, 0.90; P-trend = 0.02). High intakes of ω-3 PUFAs (HR: 0.56; 95% CI: 0.35, 0.91; P-trend = 0.02) and ω-6 PUFAs (HR: 0.57; 95% CI: 0.34, 0.94; P-trend = 0.02) were significantly associated with a reduced all-cause mortality risk. There were no significant associations between other fat types and recurrence or mortality risk. CONCLUSIONS: In this prospective survival cohort of 476 newly diagnosed patients with HNSCC, our data suggest that HNSCC prognosis may vary depending on the fat types consumed before cancer treatment. Clinical intervention trials should test these associations.

Aberrant global DNA methylation status is a known biomarker for increased disease risk, especially cancer. There is little published data on the association between toxic and essential metal mixtures and global DNA methylation in electronic waste (e-waste) workers. We aimed to establish the association between toxic and essential metals in blood and the effect of their interactions on global DNA methylation among e-waste recyclers and a reference group in Ghana. We used ICP-MS to measure the level of five metals (Se, Zn, Mn, Cd, and Pb) in the blood of 100 e-waste workers and 51 controls. We quantified blood DNA methylation levels of LINE-1 as an indicator of global DNA methylation. Cd, Mn, and Se levels were significantly higher in the reference group than in e-waste workers. Only Pb was significantly higher in the e-waste workers compared to the controls. Our linear regression analysis results showed a significant inverse association between Zn and LINE-1 DNA methylation (β

Background Both human genes and environmental exposures, due to complex interplay, play important role in the cancer etiology. Vitamin D is associated with a reduced risk of incidence and mortality of several human cancers. This study will aim to investigate the possible effects of individual polymorphisms in vitamin D receptor (VDR) as well as effects of VDR haplotypes on response to vitamin D supplementation in breast cancer survivors. Methods This is an interventional study in which the effects of vitamin D supplementation on plasma vitamin D levels, inflammatory and antioxidant biomarkers and factors associated with cell proliferation, differentiation, damage, and apoptosis will be investigated stratified by variations in VDR genotype. The present study will be conducted on breast cancer survivors referred to the Shohadaye Tajrish hospital and its associated clinics. One hundred ninety-eight breast cancer survivors will receive 4000 IU of vitamin D3 daily for 12 weeks. VDR Fok1, ApaI, TaqI, BsmI, and Cdx-2 genotype will be determined at the end of the study and responses to vitamin D supplements (inflammatory, antioxidant, cell proliferation, differentiation, damage, and apoptosis biomarkers) will be compared between the three subgroups of each VDR polymorphism as well as different VDR haplotype categories. Discussion Genetic variation is a fundamental factor influencing individuals’ divergent responses to diet, nutritional status, metabolic response, and diet-related health disorders. Furthermore, studies of gene and environment interactions will provide a precise and accurate assessments of individuals’ dietary requirements by considering both the genetic and environmental aspects simultaneously. The results of the current study, to some extent, will highlight the discrepancies existing in the findings of different studies regarding vitamin D, VDR, and cancer by considering both the genetic and environmental aspects simultaneously. If responses to vitamin D supplementation could be modified by VDR SNPs, determining the distribution of VDR polymorphisms in both breast cancer survivors and healthy populations will provide a new insight into the vitamin D requirements of individuals to prevent cancer and its related mortality based on their genotypes. Trial registration This trial has been registered on Iranian Registry of Clinical Trials (IRCT) under the identification code: IRCT2017091736244N1, registration date: 2017-11-10, http://www.irct.ir/trial/27153

No studies, to date, have scrutinized the role of

Dietary intake is understood to contribute to nutrition impact symptoms (NIS) in patients with head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to evaluate the performance of four a priori-defined diet quality indices on the presence of NIS 1 year following diagnosis using data on 323 participants from the University of Michigan Head and Neck Specialized Program of Research Excellence (UM-SPORE). Pretreatment dietary intake was measured before treatment initiation using a food frequency questionnaire. NIS were measured along seven subdomains. Multivariable binary logistic regression models were constructed to evaluate relationships between pretreatment scores on a priori-defined diet quality indices (AHEI-2010, aMED, DASH, and a low-carbohydrate score) and the presence of individual symptoms in addition to a composite “symptom summary score” 1-year postdiagnosis. There were several significant associations between different indices and individual NIS. For the symptom summary score, there were significant inverse associations observed for aMED (ORQ5-Q1: 0.36, 95% CI: 0.14–0.88, ptrend = 0.04) and DASH (ORQ5-Q1: 0.38, 95% CI: 0.15–0.91, ptrend = 0.02) and the presence of NIS 1-year postdiagnosis. Higher adherence to the aMED and DASH diet quality indices before treatment may reduce NIS burden at 1-year postdiagnosis.

PURPOSE Head and neck cancer is the sixth most common cancer in the world, and the largest burden occurs in developing countries. Although the primary risk factors have been well characterized, little is known about temporal trends in head and neck cancer across Thailand. METHODS Head and neck squamous cell carcinoma (HNSCC) occurrences diagnosed between 1990 and 2014 were selected by International Classification of Diseases (10th revision; ICD10) code from the Songkhla, Lampang, Chiang Mai, and Khon Kaen cancer registries and the US SEER program for oral cavity (ICD10 codes 00, 03-06), tongue (ICD10 codes 01-02), pharynx (ICD10 codes 09-10, 12-14), and larynx (ICD10 code 32). The data were analyzed using R and Joinpoint regression software to determine age-standardized incidence rates and trends of annual percent change (APC). Incidence rates were standardized using the Segi (1960) population. Stratified linear regression models were conducted to assess temporal trends in early-onset HNSCC across 20-year age groups. RESULTS Although overall HNSCC rates are decreasing across all registries, subsite analyses demonstrate consistent decreases in both larynx and oral cavity cancers but suggest increases in tongue cancers among both sexes in the United States (APCmen, 2.36; APCwomen, 0.77) and in pharyngeal cancer in Khon Kaen and US men (APC, 2.1 and 2.23, respectively). Age-stratified APC analyses to assess young-onset (< 60 years old) trends demonstrated increased incidence in tongue cancer in Thailand and the United States as well as in pharyngeal cancers in Khon Kaen men age 40 to 59 years and US men age 50 to 59 years. CONCLUSION Although overall trends in HNSCC are decreasing across both Thailand and the United States, there is reason to believe that the etiologic shift to oropharyngeal cancers in the United States may be occurring in Thailand.

We investigated how vitamin D receptor (VDR) allelic variants affect breast cancer survivors’ responses to vitamin D3 supplementation to increase circulating 25-hydroxy vitamin D (25(OH)D) levels. ...

Head and neck squamous cell carcinoma (HNSCC) is a morbid cancer with poor outcomes. Statins possess anti-cancer properties such as immunomodulatory and anti-inflammatory effects. The objective of this study is to identify the association between statin use among untreated HNSCC patients and overall death, disease-specific death and recurrence. HNSCC patients were recruited to participate in the University of Michigan Head and Neck Cancer Specialized Program of Research Excellence (SPORE) from 2003-2014. Statin use data were collected through medical record review. Participants were considered a statin user if they used a statin at or after diagnosis. Outcome data were collected through medical record review, Social Security Death Index or LexisNexis. Our analytic cohort included 1,638 participants. Cox proportional hazard models were used to estimate the association between ever statin use and HNSCC outcomes. Statin use was seen in 36.0% of participants. We observed a statistically significant inverse association between ever using a statin and overall death (HR=0.75, 95%CI=0.63-0.88) and HNSCC-specific death (HR=0.79, 95%CI=0.63-0.99) and a non-statistically significant inverse association for recurrence (HR=0.85, 95%CI=0.70-1.04). When investigating the association between statin use and HNSCC outcomes utilizing interaction terms between statin use and human papillomavirus (HPV), statistically significant interactions for HNSCC-specific death and recurrence were identified (HNSCC-specific death: HPV-positive HR=0.41, 95%CI=0.21-0.84; HPV-negative HR=1.04, 95%CI=0.71-1.51; p-int-0.02; recurrence: HPV-positive HR=0.49, 95%CI=0.29-0.84; HPV-negative HR=1.03, 95%CI=0.74-1.43; p-int-0.02). Statin use may be protective for adverse outcomes in HNSCC patients, particularly those with HPV-positive disease. If true, these findings could have a meaningful impact on tertiary prevention for this cancer. This article is protected by copyright. All rights reserved.

Background Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide, with human papillomavirus (HPV)-related HNSCC rising to concerning levels. Extensive clinical, genetic and epigenetic differences exist between HPV-associated HNSCC and HPV-negative HNSCC, which is often linked to tobacco use. However, 5-hydroxymethylation (5hmC), an oxidative derivative of DNA methylation and its heterogeneity among HNSCC subtypes, has not been studied. Results We characterized genome-wide 5hmC profiles in HNSCC by HPV status and subtype in 18 HPV(+) and 18 HPV(−) well-characterized tumors. Results showed significant genome-wide hyper-5hmC in HPV(−) tumors, with both promoter and enhancer 5hmC able to distinguish meaningful tumor subgroups. We identified specific genes whose differential expression by HPV status is driven by differential hydroxymethylation. CDKN2A (p16), used as a key biomarker for HPV status, exhibited the most extensive hyper-5hmC in HPV(+) tumors, while HPV(−) tumors showed hyper-5hmC in CDH13, TIMP2, MMP2 and other cancer-related genes. Among the previously reported two HPV(+) subtypes, IMU (stronger immune response) and KRT (more keratinization), the IMU subtype revealed hyper-5hmC and up-regulation of genes in cell migration, and hypo-5hmC with down-regulation in keratinization and cell junctions. We experimentally validated our key prediction of higher secreted and intracellular protein levels of the invasion gene MMP2 in HPV(−) oral cavity cell lines. Conclusion Our results implicate 5hmC in driving differences in keratinization, cell junctions and other cancer-related processes among tumor subtypes. We conclude that 5hmC levels are critical for defining tumor characteristics and potentially used to define clinically meaningful cancer patient subgroups.

This study assessed the associations between blood and urine levels of toxic metals; cadmium (Cd) and lead (Pb), and methylation levels of the LINE-1 gene among e-waste and control populations in Ghana.The study enrolled 100 male e-waste workers and 51 all-male non-e-waste workers or controls. The concentrations of Cd and Pb were measured in blood and urine using inductively coupled plasma mass spectrometry, while LINE1 methylation levels were assessed by pyrosequencing of bisulfite-converted DNA extracted from whole blood. Single and multiple metals linear regression models were used to determine the associations between metals and LINE1 DNA methylation.Blood lead (BPb) and urine lead (UPb) showed higher median concentrations among the e-waste workers than the controls (76.82 µg/L vs 40.25 µg/L, p ≤ 0.001; and 6.89 µg/L vs 3.43 µg/L, p ≤ 0.001, respectively), whereas blood cadmium (BCd) concentration was lower in the e-waste workers compared to the controls (0.59 µg/L vs 0.81 µg/L, respectively, p = 0.003). There was no significant difference in LINE1 methylation between the e-waste and controls (85.16 ± 1.32% vs 85.17 ± 1.11%, p = 0.950). In our single metal linear regression models, BPb was significantly inversely associated with LINE1 methylation in the control group (βContinuous Pb exposure may interfere with LINE1 methylation, leading to epigenetic alterations, thus serving as an early epigenetic marker for future adverse health outcomes.

Background: Electronic waste recycling processes such as dismantling with rudimentary tools and open-air burning result in the release of several toxic chemicals into the environment. Exposure to these toxic chemical mixtures has been associated with many adverse health outcomes affecting respiratory, cardiovascular, neurological, and reproductive systems. DNA methylation has been associated with exposure to toxic chemicals, including heavy metals in several epidemiological studies. DNA methylation profile due to exposure to toxic chemicals among e-waste recyclers has not been studied.Objective: This study assessed the associations between blood and urine levels of heavy metals; cadmium (Cd), lead (Pb), and arsenic (As) and methylation levels of the LINE1 gene among e-waste and control populations in Ghana.Methods: The study enrolled 100 male e-waste workers and 51 all-male non e-waste workers or controls. Body burden of Cd, Pb and As was measured in blood and urine using Inductively Coupled Plasma Mass Spectrometry, while LINE1 methylation levels were assessed by pyrosequencing of bisulfite-converted DNA extracted from whole blood.Results: There was no significant difference in LINE1 methylation between the e-waste and the non e-waste workers (85.16% ±1.32 vs 85.17% ±1.11, p = 0.950). However, CpG1 showed significantly lower mean methylation among controls, compared to e-waste workers (81.70% ±1.86 vs 82.48% ±2.20, p = 0.034). In linear regression models, blood lead (B-Pb) level was significantly inversely associated with overall LINE1 methylation (β = -0.004; 95%CI: -0.008, -0.0003; p = 0.034). Among e-waste recyclers, collectors showed significantly reduced LINE1 methylation levels (β = -0.889; 95%CI: -1.757, -0.021; p = 0.045). Conclusion: Continuous exposure to Pb may interfere with LINE1 methylation leading to epigenetic alteration, thus serve as an early epigenetic marker for future adverse health outcomes.

Background While nasopharyngeal carcinoma (NPC) is rare in non-endemic regions such as the North America, endemic countries, such as Thailand, continue to struggle with high incidence and mortality rates. NPC has a complex etiology that varies by histological subtype. Methods NPC cases (1990-2014) were identified using the International Classification of Diseases for Oncology (ICD-O) code C11 from the Chiang Mai, Khon Kaen, Lampang, and Songkhla cancer registries and compared to Asian/Pacific Islanders (A/PI) from the US SEER program. Age-standardized incidence rates and changes in annual percent change (APC) for overall and subtype specific NPC were assessed using R and Joinpoint. Kaplan Meier curves were generated in SAS to evaluate differences in survival by sex, year of diagnosis and histological subtype. Five-year relative survival estimates were calculated between 2000-2014. Results Non-keratinizing NPC predominated across all registries except Songkhla, where the keretinizing subtype made up ~60% of all reported cases. Incidence of keratinizing NPC significantly decreased among Chiang Mai males between 1996 and 2014 (APC:-13.0 [95%CI:-16.2, -9.6]), Songkhla females (APC:-4.0 [95%CI: -7.4, -0.5]) and males between 2006 and 2014 (APC:-15.5 [95%CI:-25.0, -4.7]), as well as A/PI females (APC:-5.1 [95%CI:-6,7, -3.4]) and males (APC: -4.8 [95%CI:-5.9, -3.7]). Non-keratinizing NPC increased among Songkhla males (APC:4.3 [95%CI:1.8, 6.9]). The keratinizing subtype exhibited the worst survival, while the non-keratinizing undifferentiated subtype had the best survival. Although US A/PI had the highest 5-year relative survival estimates, among the Thai registries Chiang Mai had the best and Lampang the worst survival. Conclusion Although US A/PIs exhibited similar rates of NPC as seen in the endemic Thai population, improved tobacco control has led to a decrease in keratinizing NPC incidence irrespective of geography. Additionally, while challenges associate with access to care may still exist among rural Thais, chemoradiation was shown to confer a survival benefit in non-keratinizing NPC treatment.

Objectives:\ud \ud To test the performance of an oral cancer prognostic 13-gene signature for the prediction of survival of patients diagnosed with HPV-negative and p16-negative oral cavity cancer.\ud Materials and Methods:\ud \ud Diagnostic formalin-fixed paraffin-embedded oral cavity cancer tumor samples were obtained from the Fred Hutchinson Cancer Research Center/University of Washington, University of Calgary, University of Michigan, University of Utah, and seven ARCAGE study centers coordinated by the International Agency of Research on Cancer. RNA from 638 Human Papillomavirus (HPV)-negative and p16-negative samples was analyzed for the 13 genes using a NanoString assay. Ridge-penalized Cox regressions were applied to samples randomly split into discovery and validation sets to build models and evaluate the performance of the 13-gene signature in predicting 2-year oral cavity cancer-specific survival overall and separately for patients with early and late stage disease.\ud Results:\ud \ud Among AJCC stage I/II patients, including the 13-gene signature in the model resulted in substantial improvement in the prediction of 2-year oral cavity cancer-specific survival. For models containing age and sex with and without the 13-gene signature score, the areas under the Receiver Operating Characteristic Curve (AUC) and partial AUC were 0.700 vs. 0.537 (p < 0.001), and 0.046 vs. 0.018 (p < 0.001), respectively. Improvement in predicting prognosis for AJCC stage III/IV disease also was observed, but to a lesser extent.\ud Conclusions:\ud \ud If confirmed using tumor samples from a larger number of early stage oral cavity cancer patients, the 13-gene signature may inform personalized treatment of early stage HPV-negative and p16-negative oral cavity cancer patients.

IMPORTANCE: Biomarkers that reflect prognosis and cellular immunity in patients with head and neck squamous cell carcinoma (HNSCC) are a prerequisite for improving individualized treatment that limits the intensity and morbidity of conventional treatment and may be useful in the introduction of new immunotherapy regimens. OBJECTIVE: To determine if specific classes of tumor-infiltrating lymphocytes (TILs) in pretreatment biopsy specimens have prognostic value for outcomes in a large training and validation cohort of patients with HNSCC. DESIGN, SETTING, AND PARTICIPANTS: In this prospective, epidemiologic study with a median follow-up of 47.5 months, in 464 previously untreated patients with available tissue for construction of tissue microarray, HNSCC disease sites included oral cavity (228), oropharynx (147), larynx (74), and hypopharynx (15). The training cohort consisted of 241 patients and the validation cohort consisted of 223 patients. Overall tumor stage was I (55), II (69), III (71), or IV (269). Patients were enrolled between November 2008 to October 2014. Data were analyzed between October 2018 to April 2019. MAIN OUTCOMES AND MEASURES: Semiquantitative levels of CD4, CD8, and FoxP3 lymphocytes were assessed by immunohistologic analysis and correlations with clinical prognostic factors, initial treatment modality, and overall survival (OS) and disease-specific (DSS) survival were determined. A principal component analysis was performed to generate a combined TIL-weighted sum score (TIL(ws)). RESULTS: Of the 464 participants, 135 (29%) were women; mean (SD) age was 61.1 (11.8) years. Higher CD8 counts were associated with improved OS in both training and validation sets (HR, 0.94; 95% CI, 0.90-0.98; and HR, 0.97; 95% CI, 0.95-0.99, respectively). Higher TIL(ws) levels were associated with improved OS and DSS in both the training set (HR, 0.91; 95% CI, 0.86-0.96; and HR, 0.93; 95% CI, 0.87-0.99, respectively) and validation set (HR, 0.96; 95% CI, 0.93-0.99; and HR, 0.94; 95% CI, 0.89-0.99, respectively). A multivariable Cox model controlling for batch, age, clinical stage, disease site, comorbidities, HPV status, and smoking, showed that higher TIL(ws) levels were associated with improved OS and DSS (HR, 0.94; 95% CI, 0.92-0.97; and HR, 0.94; 95% CI, 0.90-0.98, respectively). When grouped by treatment (surgery vs chemoradiation) and tested for interaction, treatment was found to be an effect modifier for CD4 levels and OS. Low CD4 levels were showed greater association with decreased survival in the chemoradiation cohort than the surgery cohort. CONCLUSIONS AND RELEVANCE: The findings from this large cohort study suggest that levels of TILs are an independent prognostic factor in patients with HNSCC. Subsets of TILs and combined TIL scores may be clinically useful predictive and prognostic factors.

We investigated whether vitamin D receptor (VDR) polymorphisms were associated with cancer biomarkers, i.e., E-cadherin, matrix metallopeptidase 9 (MMP9), interferon &beta, (IFN&beta, ), soluble intercellular adhesion molecule-1 (s-ICAM-1), soluble vascular cell adhesion molecule-1 (s-VCAM-1), tumor necrosis factor&alpha, (TNF&alpha, ), interleukin 6 (IL6), plasminogen activator inhibitor-1(PAI-1), and human high sensitivity C-reactive protein (hs-CRP), among breast cancer survivors who received vitamin D3 supplementation. In a single-arm non-randomized pre- and post trial, 176 breast cancer survivors who had completed treatment protocol including surgery, radio and chemotherapy were enrolled in the study and received 4000 IU of vitamin D3 daily for 12 weeks. The association between the VDR SNPs (ApaI, TaqI, FokI, BsmI and Cdx2) and response variable changes was assessed using linear regression, utilizing the &ldquo, association&rdquo, function in the R package &ldquo, SNPassoc&rdquo, We observed that women with AA and GA [codominant model (AA compared to GG) and (GA compared to GG), dominant model (AA &amp, GA compared to GG)] genotypes of Cdx2 showed higher increase in plasma MMP9 levels compared to the GG category. In addition, carriers of BsmI bb showed greater decrease in circulating TNF&alpha, levels after vitamin D3 supplementation [recessive model (bb compared to BB &amp, Bb]. Likewise, significant associations were identified between haplotypes of VDR polymorphisms and on-study plasma MMP9 changes. However, our results indicate that VDR genetic polymorphisms were not associated with longitudinal changes in the remaining cancer biomarkers. Overall, our findings suggest that changes in certain inflammatory biomarkers in breast cancer survivors with low plasma 25(OH)D levels, supplemented with vitamin D3, may depend on VDR SNPs and haplotypes.

Background The incidence of nasopharyngeal carcinoma (NPC) has been historically low in the United States. Although etiological factors differ by histological subtype, Epstein-Barr virus is accepted as the primary risk factor for nonkeratinizing NPC. In light of the changing epidemiology of viral-associated cancers, it is important to evaluate the temporal incidence of NPC in the United States. Methods Incidence and survival data from 1973 through 2015 were obtained from the Surveillance, Epidemiology, and End Results program. Stratified analyses were conducted to assess temporal trends in NPC by histological subtype, sex, and race. The data were analyzed using SAS and Joinpoint Regression Software to determine age-adjusted incidence rates, determine trends in the annual percent change, and calculate 5-year relative survival estimates and Kaplan-Meier curves. Results Although overall NPC incidence is decreasing in the United States, the nonkeratinizing differentiated subtype is starkly increasing, with an annual percent change of approximately 4% among white males (95% CI, 2.5%-5.2%), white females (95% CI, 1.9%-6.2%), and black males (95% CI, 2.0%, 5.7%); 2.7% among black females (95% CI, 0.8%, 4.6%); and 1.8% among women in the "other" race category (95% CI, 0.4%-3.3%). Racial disparities were noted, with 32% of nonkeratinizing NPC cases among blacks occurring before the age of 40 years. In addition, black males displayed consistently worse survival across all histological subtypes, whereas individuals in the "other" race category, particularly females, experienced the highest 5-year relative survival estimates. Conclusions The current results indicate that the Epstein-Barr virus-related, differentiated NPC subtype is increasing across all sexes and races in the United States, with distinct incidence and survival disparities among blacks.

Objectives IRX-2 is a primary-cell-derived immune-restorative consisting of multiple human cytokines that act to overcome tumor-mediated immunosuppression and provide an in vivo tumor vaccination to increase tumor infiltrating lymphocytes (TILs). A randomized phase II trial was conducted of the IRX regimen 3 weeks prior to surgery consisting of an initial dose of cyclophosphamide followed by 10 days of regional perilymphatic IRX-2 cytokine injections and daily oral indomethacin, zinc and omeprazole (Regimen 1) compared to the identical regimen without IRX-2 cytokines (Regimen 2). Methods A total of 96 patients with previously untreated, stage II-IV oral cavity SCC were randomized 2:1 to experimental (1) or control (2) regimens (64:32). Paired biopsy and resection specimens from 62 patients were available for creation of tissue microarray (n = 39), and multiplex immunohistology (n = 54). Increases in CD8+ TIL infiltrate scores of at least 10 cells/mm2 were used to characterize immune responders (IR). Results Regimen 1 was associated with significant increases in CD8+ infiltrates (p = 0.01) compared to Regimen 2. In p16 negative cancers (n = 26), significant increases in CD8+ and overall TILs were evident in Regimen 1 (p = 0.004, and 0.04 respectively). IRs were more frequent in Regimen 1 (74% vs 31%, p = 0.01). Multiplex immunohistology for PD-L1 expression confirmed an increase in PD-L1 H score for Regimen 1 compared to Regimen 2 (p = 0.11). Conclusions The findings demonstrate significant increases in TILs after perilymphatic IRX-2 injections. Three quarters of patients showed significant immune responses to IRX-2. (NCT 02609386).

Background Human papillomavirus (HPV) is etiologically linked to increasing oropharyngeal squamous cell carcinoma (OPSCC) rates in the Western world. However, the role of HPV in Southeast Asia, a high incidence region, hasn't been assessed. Methods 96 formalin-fixed, paraffin-embedded (FFPE) tissue blocks and corresponding patient data were obtained from Srinagarind Hospital, Thailand from 2012−2017. DNA from areas of 70 %+ cellularity were genotyped using polymerase chain reaction (PCR) and stained for p16, a surrogate marker for HPV. Inverse probability weights based on data from the hospital-based cancer registry were used in statistical analyses. Adjusted linear regression was used to assess changes in OPSCC HPV prevalence and conduct projections. Kaplan-Meier and Cox proportional hazard models were used to determine HPV-specific survival differences. Results 14 patients exhibited monoinfection with HPV16, two with HPV18 and one was HPV16/18 coinfected. PCR results were in agreement with p16 staining. On average, HPV + patients were more likely to have tonsil cancer (p-value:0.002). HPV prevalence increased by 2% annually (pvalue: 0.01), from 16 % in 2012 to 26 % in 2017. At the current rate, OPSCC HPV positivity will exceed 50 % by 2030. HPV positivity was shown to be protective in Kaplan-Meier (log-rank p = 0.02) and sex, age and stage adjusted Cox models (HR:0.34 [95 %CI:0.22, 0.52]). Conclusion Given the increased prevalence and similarities in presentation of HPV + OPSCC to those observed in Western countries, the data suggest the adaptation of p16 staining and subsequent restaging of OPSCC tumors as suggested by the American Joint Committee on Cancer in Southeast Asia.

Background: Tumor infiltrating lymphocytes (TILs) have recently emerged as an important factor in informing treatment decisions for head and neck squamous cell carcinoma (HNSCC). Nevertheless, little is known about the role of modifiable risk factors, such as diet, on TILs. Methods: Immunohistologic expression of CD4, CD8, CD68, CD103, CD104 and FOXP3 were assessed in tissue microarrays from 233 previously untreated HNSCC patients. Associations between these markers and pre-treatment dietary patterns were then evaluated using linear regression models. Logistic regression models assessing the associations between baseline serum carotenoids, tocopherols and TILs were conducted on a smaller subset of 70 patients. Cox proportional hazard models were used to evaluate the joint association between diet and TILs on overall and recurrence free survival. Results: High intake of a Western dietary pattern decreased CD8+ and FOXP3+ infiltrates after adjustment for age, sex and batch (p-value: 0.03 and 0.02, respectively). Multivariate logistic regression models demonstrated significant increases in CD8+ (OR: 2.21; p-value: 0.001) and FOXP3+ (OR: 4.26; p-value: Conclusion: Dietary patterns and serum carotenoids may play an important role in modifying TILs, and ultimately, outcome after diagnosis with HNSCC. The results of this study could inform dietary interventions among high risk individuals in an attempt to moderate risk and improve HNSCC prognosis. Citation Format: Ilona Argirion, Anna E. Arthur, Katie R. Zarins, Emily Bellile, Lahin Amlani, Jeremy M. Taylor, Greg T. Wolf, Jonathan McHugh, Ariane Nguyen, Alison M. Mondul, Laura S. Rozek, The University of Michigan Head and Neck SPORE Program. Pretreatment diet, serum carotenoids and tocopherols influence tumor immune response in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4644.

Background: The purpose of this study is to examine the association between statin use and head and neck squamous cell carcinoma (HNSCC) outcomes: overall death, HNSCC-specific death and recurrence. Statins possess anti-cancer properties such as anti-inflammatory and immunomodulatory effects, and have been found to be protective against cancer risk and mortality across various cancer sites. However, little research has been done examining the association between statin use and HNSCC outcomes. Methods: Incident HNSCC patients (n=1,843) were recruited through the University of Michigan Rogel Cancer Center to participate in the University of Michigan Head and Neck Cancer Specialized Program of Research Excellence (SPORE) from 2003-2014. Statin data were collected retrospectively from SPORE participants through medical record review. Participants were identified as being a statin user if they had used a statin at or after diagnosis. Outcome data were also collected through medical record review as well as Social Security Death Master File and LexisNexis. Our analytic cohort included 1,642 SPORE participants who had information on both statin use and HNSCC outcomes. Cox proportional hazard models were used to estimate the association between ever statin use and HNSCC outcomes. The following factors were considered as potential confounders; age, gender, race, comorbidities, smoking status, body mass index (BMI) and education. All estimates presented are from the final multivariable models which included age, comorbidities and BMI as only these variables changed the point estimate by >10%. Results: 35.9% of participants were ever statin users. Overall, we observed a statistically significant inverse association between ever using a statin and both overall death (HR=0.74, 95%CI=0.63-0.88) and HNSCC-specific death (HR=0.79, 95%CI=0.63-0.99). We observed an inverse association with recurrence, although it was not statistically significant (HR=0.85, 95%CI=0.70-1.04). We observed a statistically significant interaction such that the inverse associations for HNSCC-specific death and recurrence were restricted to patients with human papillomavirus (HPV) positive disease (HNSCC-specific death: HPV+ HR=0.43, 95%CI=0.21-0.86; HPV- HR=1.02, 95%CI=0.71-1.47; p-int-0.02; recurrence: HPV+ HR=0.50, 95%CI=0.30-0.86; HPV- HR=1.02, 95%CI=0.74-1.41; p-int-0.02); statins were inversely associated with overall death in both HPV positive and negative patients. Analyses stratified by disease site supported the HPV interaction; the strongest inverse association was observed for oropharyngeal cancers. Conclusion: Our findings from this large, prospective study demonstrate that statin use may be protective for adverse outcomes in HNSCC patients, particularly those with HPV positive disease. If true, these findings could have a meaningful impact on tertiary prevention for this cancer, which currently has unacceptably low survival rates. Citation Format: Kayla R. Getz, Emily Bellile, Katie Zarins, Steven Chinn, Jeremy Taylor, Laura Rozek, Gregory Wolf, Alison Mondul. Statin use and head and neck cancer outcomes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3391.

OBJECTIVES: Use of diet quality indices has become increasingly common. However, there are no studies, to date, that have examined the relationship of a priori indices with prognostic outcomes in the head and neck squamous cell carcinoma (HNSCC) population. The purpose of this analysis was to examine associations between diet quality in the first two years after diagnosis and mortality in a sample of HNSCC patients. METHODS: This was a secondary analysis of 396 newly diagnosed HNSCC patients recruited from the University of Michigan Head and Neck Specialized Programs of Research Excellence longitudinal cohort study. Participants completed food frequency questionnaires (FFQs) and health surveys at the time of diagnosis, 1-year post-diagnosis (n = 341), and 2-years post-diagnosis (n = 217). Cox Proportional Hazards models assessed associations between diet quality index score (categorized as quintiles and modeled as a time-varying covariate), all-cause-, and cancer-specific mortality. The indices chosen for examination included the Alternative Mediterranean Diet Index (aMED), Alternate Healthy Eating Index-2010 (AHEI-2010), Dietary Approaches to Stop Hypertension (DASH), and a ketogenic diet index. All models adjusted for age, sex, BMI, HPV-status, tumor site, stage, education, smoking, drinking, and total calorie intake (modeled as time-varying). RESULTS: There were 105 total deaths and 67 cancer-related deaths, during a median follow-up time of 3 years. Higher aMED and AHEI-2010 scores were significantly inversely associated with all-cause (HR(aMED) 0.33, 95% CI: 0.18–0.59, p(t)(rend)

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.

BackgroundCervical 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.Methods267 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.Results267 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).ConclusionsSelf-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.

Purpose: Incidence of nasopharyngeal carcinoma (NPC) is highly geographically variable and historically rare in the US. While etiological factors differ by histological subtype, Epstein-Barr virus (EBV) is generally accepted as the primary risk factor for non-keratinizing NPC. In light of the changing epidemiology of HPV-associated oropharyngeal cancer, it is important to evaluate temporal incidence of NPC in the US. Methods: Incidence and survival data from 1973-2015 were obtained from the Surveillance, Epidemiology and End Results (SEER) Program. Stratified analyses were conducted to assess temporal trends in NPC by histological subtype, sex and race. The data were analyzed using SAS 9.4 and Joinpoint Regression Software to determine age-adjusted incidence rates, trends in annual percent change (APC) as well as calculate 5-year relative survival estimates and Kaplan-Meier curves. Results: Although overall NPC incidence is decreasing in the US, the non-keratinizing differentiated subtype appears to be starkly increasing with an APC of approximately 4% among white males (95%CI: 2.5, 5.2), white females (95%CI: 1.9, 6.2), and black males (95%CI: 2.0, 5.7), 2.7% among black females (95%CI: 0.8, 4.6) and 1.8% among women of other race (95%CI: 0.4, 3.3). When compared to other histological subtypes, patients with keratinizing squamous cell carcinoma had the worst survival (log rank p Conclusions: Although NPC remains relatively rare in the overall US population, there is evidence to suggest that the EBV-related differentiated subtype is increasing across all genders and races. Citation Format: Ilona Argirion, Katie R. Zarins, Julie J. Ruterbusch, Patravoot Vatanasapt, Hutcha Sriplung, Erlene K. Seymour, Laura S. Rozek. Increasing incidence of EBV-related nasopharyngeal carcinoma in the United States [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4192.

Infection with high-risk HPV, or human papillomavirus, has been shown to be a risk factor for head and neck squamous cell carcinoma (HNSCC) development in addition to the classical risk factors of tobacco and alcohol usage. Previous studies have identified epigenetic differences between these two classes of HNSCC, including DNA methylation, histone modifications and non-coding RNAs. 5-hydroxymethylation (5hmC) is an oxidative derivative of 5-methylcytosine (5mC) and is depleted in human cancers of many different origins. However, the roles of 5hmC in HNSCC is still unknown. Our study is the first to characterize 5hmC in HNSCC, which we profiled in 18 HPV(+) and 18 HPV(-) HNSCC tumors. Since previous studies found higher levels of 5hmC in more differentiated cells and lower levels in stem-like cells, we hypothesized an overall higher 5hmC level in HPV(-) tumors, which tend to be more differentiated in nature. Consistent with our hypothesis, results showed significant hyper-hydroxymethylation in HPV(-) tumors, and detected multiple cancer-related genes with hyper-hydroxymethylation in either HPV(+) and HPV(-) tumors. For example, CDKN2A (p16) and MTAP were the most hyper-methylated genes in HPV(+) tumors, while 5hmC levels of HPV(-) tumors were particularly high in CDH13, TIMP2, and BCAR1. We found that the two HPV(+) subtypes defined by Zhang et al., IMU (heightened immune response, more mesenchymal differentiation) and KRT (more keratinization, more likely viral integration), explained a high level of heterogeneity in 5hmC levels at promoter and enhancer regions. By testing for genes and pathways that demonstrate concordant changes in gene expression and 5hmC levels, we found that keratinocyte differentiation, cell-cell adhesion and adherens junction pathways are both up-regulated and have hyper-hydroxymethylation in HPV(-) tumors. Using predicted enhancers of epidermal keratinocytes, we found a much higher portion of hydroxymethylated regions fall in enhancer regions for HPV(-) samples compared with HPV(+) samples. The higher differential 5hmC in enhancer regions was further validated by stronger histone marks of H3K4me1 and H3K27ac in HPV(-) tumors. Since some of these enhancers can be linked to differentially expressed target genes, this result indicates that the enhancer hydryoxymethylation in HNSCC could also play an important role in downstream gene regulation. We hope that this study could partially explain the different mechanisms and cast light on potential targeted therapies in HNSCC both based on HPV status and different HPV(+) subtypes. Citation Format: Siyu Liu, Katie Zarins, Evan Fernandez, Laura Rozek, Maureen Sartor. 5-hydroxymethylation captures the heterogeneity in keratinization and cytoskeletal rearrangement processes in head & neck cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4325.

OBJECTIVES: Interactions of human genes and environmental exposures play a crucial role in cancer etiology and prognosis. We investigated whether response to vitamin D3 supplementation in terms of plasma oxidative stress (OS) and apoptotic biomarkers were mediated by the vitamin D receptor (VDR) single-nucleotide polymorphisms (SNPs) among breast cancer survivors. METHODS: Two hundred and fourteen women who were diagnosed with breast cancer (invasive or in situ) and had completed all treatment regimens received 4000 IU of vitamin D3 daily for 12 weeks. Anthropometric, dietary, sun exposure, physical activity, as well as laboratory assessments including plasma superoxide dismutase (SOD), total antioxidant capacity (TAC), malondialdehyde (MDA), 8-hydroxy-2′-deoxyguanosine (8-OHdG), and Bcl2 were performed at enrolment and post-intervention. VDR genotyping was performed at ApaI, TaqI, FokI, BsmI, and Cdx-2. Linear regression was used to analyze whether the effect of vitamin D3 supplementation on response variables was modulated by the selected VDR SNPs. RESULTS: Linear regression analysis adjusted for age, BMI, on-study plasma 25(OH)D changes, and baseline circulating 25(OH)D indicated that the AA genotype of the ApaI on VDR was associated with greater increase and decrease in plasma Bcl2 [0.21, 95% Confidence Interval (CI) (0.03, 0.39)] and MDA [−0.68, 95% CI (−1.35, −0.02)] compared to aa respectively. This association did not remain statistically significant after correction for multiple testing. Overall, we found no statistically significant interaction of the VDR SNPs and inferred haplotypes with the circulating OS and apoptotic biomarkers except for the FokI BsmI ApaIhaplotype and circulating MDA (p-value for global score = 0.02) after multiple testing correction. CONCLUSIONS: Our findings indicate a weak interaction between the VDR haplotypes and responses of plasma OS and apoptotic biomarkers to vitamin D3 supplementation. However, further assessments of additional genes and biomarkers with longer intervention periods may further explain the complex interplay between genes and nutrients. FUNDING SOURCES: Cancer Research Center, National Nutrition and Food Technology Research Institute, and the Endocrine Research Center of Shahid Beheshti University of Medical Sciences.

BACKGROUND: Southeast Asia is undergoing a transition from infectious to chronic diseases, including a dramatic increase in adult cancers. Childhood cancer research in Thailand has focused predominantly on leukemias and lymphomas or only examined a short period of time. This comprehensive multi-site study examined childhood cancer incidence and survival rates in Thailand across all international classification of childhood cancer (ICCC) groups over a 20-year period. METHODS: Cancer cases diagnosed in children ages 0–19 years (n=3,574) from 1990–2011 were extracted from five provincial population-based Thai registries, covering approximately 10% of the population. Descriptive statistics of the quality of the registries were evaluated. Age-standardized incidence rates were calculated using the Segi world standard population, and relative survival was computed using the Kaplan-Meier method. Changes in incidence and survival were analyzed using Joinpoint Regression and reported as annual percent changes (APC). RESULTS: The age-standardized incidence rate of all childhood cancers during the study period was 98.5 per million person-years with 91.0 per million person-years in 1990–2000 and 106.2 per million person-years in 2001–2011. Incidence of all childhood cancers increased significantly (APC=1.2%, p