Significant association between host transcriptome‐derived HPV oncogene E6* influence score and carcinogenic pathways, tumor size, and survival in head and neck cancer

BackgroundHuman 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.MethodsWe 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.ResultsFor 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.ConclusionsHPV 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.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156432/2/hed26244.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156432/1/hed26244_am.pd

Childhood cancer incidence and survival in Thailand: A comprehensive population‐based registry analysis, 1990–2011

BackgroundSoutheast 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 children for a short period of time. This comprehensive multisite study examined childhood cancer incidence and survival rates in Thailand across all International Classification of Childhood Cancer (ICCC) groups over a 20‐year period.MethodsCancer cases diagnosed in children ages 0‐19 years (n = 3574) from 1990 to 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 (ASRs) 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).ResultsThe ASR 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 < 0.01). The top three cancer groups were leukemias, brain tumors, and lymphomas. The 5‐year survival for all childhood cancers significantly improved from 39.4% in 1990–2000 to 47.2% in 2001–2011 (P < 0.01).ConclusionsBoth childhood cancer incidence and survival rates have increased, suggesting improvement in the health care system as more cases are identified and treated. Analyzing childhood cancer trends in low‐ and middle‐income countries can improve understanding of cancer etiology and pediatric health care disparities.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146559/1/pbc27428_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146559/2/pbc27428.pd

Prediction of survival of HPV16-negative, p16-negative oral cavity cancer patients using a 13-gene signature: A multicenter study using FFPE samples

Objectives: To WA 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. Materials and Methods: 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. Results: 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. Conclusions: 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

Dietary Fiber, Whole Grains, and Head and Neck Cancer Prognosis: Findings from a Prospective Cohort Study

No studies, to date, have examined the relationship between dietary fiber and recurrence or survival after head and neck cancer diagnosis. The aim of this study was to determine whether pretreatment intake of dietary fiber or whole grains predicted recurrence and survival outcomes in newly diagnosed head and neck cancer (HNC) patients. This was a prospective cohort study of 463 participants baring a new head and neck cancer diagnosis who were recruited into the study prior to the initiation of any cancer therapy. Baseline (pre-treatment) dietary and clinical data were measured upon entry into the study cohort. Clinical outcomes were ascertained at annual medical reviews. Cox proportional hazard models were fit to examine the relationships between dietary fiber and whole grain intakes with recurrence and survival. There were 112 recurrence events, 121 deaths, and 77 cancer-related deaths during the study period. Pretreatment dietary fiber intake was inversely associated with risk of all-cause mortality (hazard ratio (HR): 0.37, 95% confidence interval (CI): 0.14&ndash;0.95, ptrend = 0.04). No statistically significant associations between whole grains and prognostic outcomes were found. We conclude that higher dietary fiber intake, prior to the initiation of treatment, may prolong survival time, in those with a new HNC diagnosis

The association between inflammatory biomarkers and statin use among patients with head and neck squamous cell carcinoma

BackgroundTumor-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.MethodsStatin 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.ResultsWe 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.ConclusionsStatins may influence TILs in HPV-positive patients. This may be the mechanism through which they improve prognosis in HPV-positive HNSCC patients.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/172261/1/hed27040.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/172261/2/hed27040_am.pd

Statin use and head and neck squamous cell carcinoma outcomes

Head and neck squamous cell carcinoma (HNSCC) is a morbid cancer with poor outcomes. Statins possess anticancer properties such as immunomodulatory and anti‐inflammatory effects. The objective of our 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 to 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 1638 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 nonstatistically 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.What’s new?For certain cancer types, statin medications reduce the risk of disease development and death, possibly owing to the immune‐modifying or cholesterol‐lowering effects of statins. Whether head and neck squamous cell carcinoma (HNSCC) is among these cancers affected by statins remains unclear. In this study of more than 1600 HNSCC patients, statin use was associated with a reduced overall mortality rate in all patients and with a reduced rate of disease‐specific mortality and disease recurrence specifically among patients with human papillomavirus‐positive tumors. Inverse associations were also observed between statin use and recurrence among participants with disease located in the oropharynx.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/167065/1/ijc33441.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/167065/2/ijc33441_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/167065/3/ijc33441-sup-0001-Tables.pd

Childhood cancer incidence and survival in Thailand: A comprehensive population-based registry analysis, 1990–2011

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 children for a short period of time. This comprehensive multisite 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 = 3574) from 1990 to 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 (ASRs) 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 ASR 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 \u3c 0.01). The top three cancer groups were leukemias, brain tumors, and lymphomas. The 5-year survival for all childhood cancers significantly improved from 39.4% in 1990–2000 to 47.2% in 2001–2011 (P \u3c 0.01). Conclusions: Both childhood cancer incidence and survival rates have increased, suggesting improvement in the health care system as more cases are identified and treated. Analyzing childhood cancer trends in low- and middle-income countries can improve understanding of cancer etiology and pediatric health care disparities

Tumor infiltrating lymphocytes after neoadjuvant IRX-2 immunotherapy in oral squamous cell carcinoma: Interim findings from the INSPIRE trial.

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/mm 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. (NCT02609386)

Assessment the effect of vitamin D supplementation on plasma vitamin D levels, inflammation, and oxidative stress biomarkers based on vitamin D receptor genetic variation in breast cancer survivors: a protocol for clinical trial

Abstract 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/27153http://deepblue.lib.umich.edu/bitstream/2027.42/174041/1/41043_2021_Article_272.pd