Publications by authors named "Stephen M Schwartz"

274 Publications

Infection with Human Papilloma Virus (HPV) and risk of subsites within the oral cancer.

Cancer Epidemiol 2021 Sep 9;75:102020. Epub 2021 Sep 9.

Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy; Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY, USA. Electronic address:

Background: The aim of this study was to investigate the relationship between high-risk genotypes of Human Papilloma Virus (HPV) and cancer of different subsites of the oral cavity.

Material And Methods: A pooled analysis of five studies included on the International Head and Neck Cancer Epidemiology (INHANCE) Consortium was conducted. HPV 16 and HPV 18 were considered. Adjusted odds ratios (ORs) and corresponding 95 % confidence intervals (CIs) for HPV and each oral cavity subsites were simultaneously estimated using multinomial logistic regression models.

Results: The analysis included 1157 cases and 3272 controls. This study showed a slightly higher prevalence of HPV infection among oral cancer cases than controls. In particular, an increased risk of other and not otherwise specified (NOS) sites within the oral cavity, oral tongue, palate and floor of mouth cancer was observed for overall HPV16 positivity (OR = 1.66, 95 % CI: 1.01-2.72; OR = 1.97, 95 % CI: 1.36-2.85; OR = 2.48, 95 % CI: 1.50-4.11; OR = 2.71, 95 % CI: 1.06-6.95, respectively). In particular, HPV16E7 was related to cancer of floor of mouth, oral cavity NOS and palate (OR = 2.71, 95 % CI: 1.06-6.95; OR = 3.32, 95 % CI:1.53-7.19; OR = 3.34, 95 % CI:1.38-8.06). Results were inconsistent for HPV18 due to low prevalence of infection.

Conclusion: Our study suggests that HPV16 infection may increase the risk of developing floor of mouth, gum, tongue, and palate cancers.

Clinical Relevance: Subjects with HPV infection have a higher risk of cancer from all sites of the oral cavity.
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http://dx.doi.org/10.1016/j.canep.2021.102020DOI Listing
September 2021

Identification of 22 susceptibility loci associated with testicular germ cell tumors.

Nat Commun 2021 07 23;12(1):4487. Epub 2021 Jul 23.

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Testicular germ cell tumors (TGCT) are the most common tumor in young white men and have a high heritability. In this study, the international Testicular Cancer Consortium assemble 10,156 and 179,683 men with and without TGCT, respectively, for a genome-wide association study. This meta-analysis identifies 22 TGCT susceptibility loci, bringing the total to 78, which account for 44% of disease heritability. Men with a polygenic risk score (PRS) in the 95 percentile have a 6.8-fold increased risk of TGCT compared to men with median scores. Among men with independent TGCT risk factors such as cryptorchidism, the PRS may guide screening decisions with the goal of reducing treatment-related complications causing long-term morbidity in survivors. These findings emphasize the interconnected nature of two known pathways that promote TGCT susceptibility: male germ cell development within its somatic niche and regulation of chromosomal division and structure, and implicate an additional biological pathway, mRNA translation.
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http://dx.doi.org/10.1038/s41467-021-24334-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8302763PMC
July 2021

Cancer mortality in a population-based cohort of American Indians - The strong heart study.

Cancer Epidemiol 2021 Jul 19;74:101978. Epub 2021 Jul 19.

MedStar Health Research Institute, 6525 Belcrest Road, Suite 700, Hyattsville, MD, 20782, USA; Georgetown, Howard Universities Center for Clinical and Translational Research, Washington, DC, 2000, USA. Electronic address:

Background: Cancer mortality among American Indian (AI) people varies widely, but factors associated with cancer mortality are infrequently assessed.

Methods: Cancer deaths were identified from death certificate data for 3516 participants of the Strong Heart Study, a population-based cohort study of AI adults ages 45-74 years in Arizona, Oklahoma, and North and South Dakota. Cancer mortality was calculated by age, sex and region. Cox proportional hazards model was used to assess independent associations between baseline factors in 1989 and cancer death by 2010.

Results: After a median follow-up of 15.3 years, the cancer death rate per 1000 person-years was 6.33 (95 % CI 5.67-7.04). Cancer mortality was highest among men in North/South Dakota (8.18; 95 % CI 6.46-10.23) and lowest among women in Arizona (4.57; 95 % CI 2.87-6.92). Factors independently associated with increased cancer mortality included age, current or former smoking, waist circumference, albuminuria, urinary cadmium, and prior cancer history. Factors associated with decreased cancer mortality included Oklahoma compared to Dakota residence, higher body mass index and total cholesterol. Sex was not associated with cancer mortality. Lung cancer was the leading cause of cancer mortality overall (1.56/1000 person-years), but no lung cancer deaths occurred among Arizona participants. Mortality from unspecified cancer was relatively high (0.48/100 person-years; 95 % CI 0.32-0.71).

Conclusions: Regional variation in AI cancer mortality persisted despite adjustment for individual risk factors. Mortality from unspecified cancer was high. Better understanding of regional differences in cancer mortality, and better classification of cancer deaths, will help healthcare programs address cancer in AI communities.
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http://dx.doi.org/10.1016/j.canep.2021.101978DOI Listing
July 2021

Utilization of Systemic Therapy in Patients With Cancer Near the End of Life in the Pre- Versus Postimmune Checkpoint Inhibitor Eras.

JCO Oncol Pract 2021 May 19:OP2001050. Epub 2021 May 19.

Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA.

Purpose: Systemic therapy use in the last 30 days of life (DOL) for patients with advanced cancer is a low-value medical practice. We hypothesized that systemic therapy use in the last 30 DOL increased after approval of antiprogrammed cell death protein 1 immune checkpoint inhibitors (ICIs) and has contributed to increased health care utilization and spending.

Methods: We investigated the change in prevalence of systemic therapy use in the last 30 DOL among patients with advanced solid tumors in the 4 years before and after antiprogrammed cell death protein 1 ICI approval in 2014. We used cases from the Western Washington Cancer Surveillance System linked to commercial and Medicare insurance. We calculated the difference in prevalence between the pre- and post-ICI periods. We also calculated the annual prevalence of any systemic therapy and ICI use in the last 30 DOL and measured health care utilization (emergency department visits and hospitalizations) and costs during the last 30 DOL.

Results: Eight thousand eight hundred seventy-one patients (median age 73 years) were included; 34% and 66% in the pre-and post-ICI period, respectively. Systemic therapy use in the last 30 DOL was lower in the post-ICI versus pre-ICI period (12.4% 14.4%; difference -2.0% [95% CI, -3.5 to -0.5]). The annual prevalence of systemic therapy use in the last 30 DOL also declined, although ICI use rose. Patients treated with ICIs in last 30 DOL had more emergency department visits, hospitalizations, and higher costs.

Conclusion: Systemic therapy use in the last 30 DOL was lower in the period after ICI approval. However, ICI use rose over time and had higher utilization and costs in the last 30 DOL. Systemic therapy use in the last 30 DOL warrants monitoring, especially as more ICI indications are approved.
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http://dx.doi.org/10.1200/OP.20.01050DOI Listing
May 2021

Genetically Inferred Telomere Length and Testicular Germ Cell Tumor Risk.

Cancer Epidemiol Biomarkers Prev 2021 06 18;30(6):1275-1278. Epub 2021 Mar 18.

Division of Cancer Epidemiology and Genetics, NCI, Rockville, Maryland.

Background: Studies evaluating the association between peripheral blood leukocyte telomere length (LTL) and testicular germ cell tumor (TGCT) risk have produced conflicting results.

Methods: Using available genotype data from the Testicular Cancer Consortium (TECAC), polygenic risk score and Mendelian randomization analyses of genetic variants previously associated with LTL were used to assess potential etiologic associations between telomere length and TGCT risk.

Results: Genetically inferred telomere length was not associated with TGCT risk among 2,049 cases and 6,921 controls with individual-level genotype data (OR, 1.02; 95% confidence interval, 0.97-1.07). Mendelian randomization analyses using summary statistic data further indicated no evidence for an association between telomere length and TGCT risk among all available TECAC participants (3,558 cases and 13,971 controls).

Conclusions: Our analyses in the largest molecular genetic testicular cancer study to date provide no evidence for an association between genetically inferred peripheral blood LTL and TGCT risk.

Impact: The lack of evidence for an overall association indicates that peripheral blood LTL is likely not a strong biomarker for TGCT risk.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172526PMC
June 2021

Correction: Incorporating Breast Cancer Recurrence Events Into Population-Based Cancer Registries Using Medical Claims: Cohort Study.

JMIR Cancer 2020 Sep 24;6(2):e23821. Epub 2020 Sep 24.

Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.

[This corrects the article DOI: 10.2196/18143.].
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http://dx.doi.org/10.2196/23821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545323PMC
September 2020

Alcohol drinking and head and neck cancer risk: the joint effect of intensity and duration.

Br J Cancer 2020 10 24;123(9):1456-1463. Epub 2020 Aug 24.

Institute of Oncology and Radiobiology, Havana, Cuba.

Background: Alcohol is a well-established risk factor for head and neck cancer (HNC). This study aims to explore the effect of alcohol intensity and duration, as joint continuous exposures, on HNC risk.

Methods: Data from 26 case-control studies in the INHANCE Consortium were used, including never and current drinkers who drunk ≤10 drinks/day for ≤54 years (24234 controls, 4085 oral cavity, 3359 oropharyngeal, 983 hypopharyngeal and 3340 laryngeal cancers). The dose-response relationship between the risk and the joint exposure to drinking intensity and duration was investigated through bivariate regression spline models, adjusting for potential confounders, including tobacco smoking.

Results: For all subsites, cancer risk steeply increased with increasing drinks/day, with no appreciable threshold effect at lower intensities. For each intensity level, the risk of oral cavity, hypopharyngeal and laryngeal cancers did not vary according to years of drinking, suggesting no effect of duration. For oropharyngeal cancer, the risk increased with durations up to 28 years, flattening thereafter. The risk peaked at the higher levels of intensity and duration for all subsites (odds ratio = 7.95 for oral cavity, 12.86 for oropharynx, 24.96 for hypopharynx and 6.60 for larynx).

Conclusions: Present results further encourage the reduction of alcohol intensity to mitigate HNC risk.
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http://dx.doi.org/10.1038/s41416-020-01031-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592048PMC
October 2020

Incorporating Breast Cancer Recurrence Events Into Population-Based Cancer Registries Using Medical Claims: Cohort Study.

JMIR Cancer 2020 Aug 17;6(2):e18143. Epub 2020 Aug 17.

Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.

Background: There is a need for automated approaches to incorporate information on cancer recurrence events into population-based cancer registries.

Objective: The aim of this study is to determine the accuracy of a novel data mining algorithm to extract information from linked registry and medical claims data on the occurrence and timing of second breast cancer events (SBCE).

Methods: We used supervised data from 3092 stage I and II breast cancer cases (with 394 recurrences), diagnosed between 1993 and 2006 inclusive, of patients at Kaiser Permanente Washington and cases in the Puget Sound Cancer Surveillance System. Our goal was to classify each month after primary treatment as pre- versus post-SBCE. The prediction feature set for a given month consisted of registry variables on disease and patient characteristics related to the primary breast cancer event, as well as features based on monthly counts of diagnosis and procedure codes for the current, prior, and future months. A month was classified as post-SBCE if the predicted probability exceeded a probability threshold (PT); the predicted time of the SBCE was taken to be the month of maximum increase in the predicted probability between adjacent months.

Results: The Kaplan-Meier net probability of SBCE was 0.25 at 14 years. The month-level receiver operating characteristic curve on test data (20% of the data set) had an area under the curve of 0.986. The person-level predictions (at a monthly PT of 0.5) had a sensitivity of 0.89, a specificity of 0.98, a positive predictive value of 0.85, and a negative predictive value of 0.98. The corresponding median difference between the observed and predicted months of recurrence was 0 and the mean difference was 0.04 months.

Conclusions: Data mining of medical claims holds promise for the streamlining of cancer registry operations to feasibly collect information about second breast cancer events.
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http://dx.doi.org/10.2196/18143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459434PMC
August 2020

An Evaluation of the Utility of Big Data to Supplement Cancer Treatment Information: Linkage Between IQVIA Pharmacy Database and the Surveillance, Epidemiology, and End Results Program.

J Natl Cancer Inst Monogr 2020 05;2020(55):72-81

National Cancer Institute, Bethesda, MD.

Oral anticancer medications (OAMs) are increasingly utilized. We evaluated the representativeness and completeness of IQVIA, a large aggregator of pharmacy data, for breast cancer, colon cancer, chronic myeloid leukemia, and myeloma cases diagnosed in six Surveillance, Epidemiology, and End Results Program (SEER) registries between 2007 and 2011. Patient's SEER and SEER-Medicare data were linked and compared with IQVIA pharmacy data from 2006 to 2012 for specific OAMs. Overall, 67.6% of SEER cases had a pharmacy claim in IQVIA during the treatment assessment window. This varied by location, race and ethnicity, and insurance status. IQVIA consistently identified fewer cases who received an OAM of interest than SEER-Medicare. The difference was least pronounced for breast cancer agents and most pronounced for myeloma agents. The IQVIA pharmacy database included a large portion of persons in the SEER areas. Future studies should assess receipt of OAMs for other cancer sites and in different SEER registries.
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http://dx.doi.org/10.1093/jncimonographs/lgz036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868033PMC
May 2020

Sonic Hedgehog upregulation does not enhance the survival and engraftment of stem cell-derived cardiomyocytes in infarcted hearts.

PLoS One 2020 16;15(1):e0227780. Epub 2020 Jan 16.

Department of Pathology, Center for Cardiovascular Biology, and Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, United States of America.

The engraftment of human stem cell-derived cardiomyocytes (hSC-CMs) is a promising treatment for remuscularizing the heart wall post-infarction, but it is plagued by low survival of transplanted cells. We hypothesize that this low survival rate is due to continued ischemia within the infarct, and that increasing the vascularization of the scar will ameliorate the ischemia and improve hSC-CM survival and engraftment. An adenovirus expressing the vascular growth factor Sonic Hedgehog (Shh) was injected into the infarcted myocardium of rats immediately after ischemia/reperfusion, four days prior to hSC-CM injection. By two weeks post-cell injection, Shh treatment had successfully increased capillary density outside the scar, but not within the scar. In addition, there was no change in vessel size or percent vascular volume when compared to cell injection alone. Micro-computed tomography revealed that Shh failed to increase the number and size of larger vessels. It also had no effect on graft size or heart function when compared to cell engraftment alone. Our data suggests that, when combined with the engraftment of hSC-CMs, expression of Shh within the infarct scar and surrounding myocardium is unable to increase vascularization of the infarct scar, and it does not improve survival or function of hSC-CM grafts.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227780PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964843PMC
April 2020

Dietary glycaemic index, glycaemic load and head and neck cancer risk: a pooled analysis in an international consortium.

Br J Cancer 2020 03 13;122(6):745-748. Epub 2020 Jan 13.

Department of Clinical Sciences and Community Health, Università degli Studi di Milano, via Venezian, 1, 20133, Milano, Italy.

High dietary glycaemic index (GI) and glycaemic load (GL) may increase cancer risk. However, limited information was available on GI and/or GL and head and neck cancer (HNC) risk. We conducted a pooled analysis on 8 case-control studies (4081 HNC cases; 7407 controls) from the International Head and Neck Cancer Epidemiology (INHANCE) consortium. We estimated the odds ratios (ORs) and 95% confidence intervals (CIs) of HNC, and its subsites, from fixed- or mixed-effects logistic models including centre-specific quartiles of GI or GL. GI, but not GL, had a weak positive association with HNC (OR = 1.16; 95% CI = 1.02-1.31). In subsites, we found a positive association between GI and laryngeal cancer (OR = 1.60; 95% CI = 1.30-1.96) and an inverse association between GL and oropharyngeal cancer (OR = 0.78; 95% CI = 0.63-0.97). This pooled analysis indicates a modest positive association between GI and HNC, mainly driven by laryngeal cancer.
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http://dx.doi.org/10.1038/s41416-019-0702-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078183PMC
March 2020

The association between HIV infection and cervical cancer presentation and survival in Uganda.

Gynecol Oncol Rep 2020 Feb 19;31:100516. Epub 2019 Nov 19.

Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, PO Box 19024, Seattle, WA 98109, USA.

Our objective was to determine how HIV infection impacts cervical cancer stage at presentation and overall survival (OS) among Ugandan women. This was a prospective study of 149 women diagnosed with cervical cancer from 2013 to 2015 at the Uganda Cancer Institute. Poisson regression models were fit to calculate prevalence ratios (PR) for the association between HIV infection and late stage at cancer diagnosis. The association between HIV infection and OS after cervical cancer diagnosis was evaluated using Cox proportional hazards models. The cohort included 53 HIV-positive and 96 HIV-negative participants. Median age at diagnosis was 44 years for HIV-positive and 54 years for HIV-negative participants. Seventy-seven percent of HIV-positive participants received antiretroviral therapy. Median baseline CD4 count was 373 cells/mm3 for HIV-positive participants versus 926 cells/mm3 for HIV-negative participants. Thirty-two percent of HIV-positive participants were diagnosed with late stage cervical cancer (III-IV) versus 39% of HIV-negative participants. No association was found between late stage at cancer diagnosis and HIV infection (PR adjusted for age, parity and transport cost 1.0, 95%CI 0.6-1.8). Most women presenting for care received cancer treatment, though almost half who received radiotherapy did not complete treatment. The median OS was 13.7 months for HIV-positive participants and 24.3 months for HIV-negative participants. After adjusting for age and stage, HIV infection was weakly associated with OS (HR 1.3, 95%CI 0.8-2.2). In Uganda, cervical cancer is often incompletely treated and survival remains poor. HIV infection was not associated with cervical cancer stage at diagnosis, but may be weakly associated with shorter survival.
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http://dx.doi.org/10.1016/j.gore.2019.100516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921151PMC
February 2020

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

Oral Oncol 2020 01 10;100:104487. Epub 2019 Dec 10.

Section of Otolaryngology -- Head & Neck Surgery, Cumming School of Medicine, University of Calgary, 3330 Hospital Dr NW, Calgary Alberta, Canada.

Objectives: 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.

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.
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http://dx.doi.org/10.1016/j.oraloncology.2019.104487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386199PMC
January 2020

Risk Prediction Models for Head and Neck Cancer in the US Population From the INHANCE Consortium.

Am J Epidemiol 2020 04;189(4):330-342

Head and neck cancer (HNC) risk prediction models based on risk factor profiles have not yet been developed. We took advantage of the large database of the International Head and Neck Cancer Epidemiology (INHANCE) Consortium, including 14 US studies from 1981-2010, to develop HNC risk prediction models. Seventy percent of the data were used to develop the risk prediction models; the remaining 30% were used to validate the models. We used competing-risk models to calculate absolute risks. The predictors included age, sex, education, race/ethnicity, alcohol drinking intensity, cigarette smoking duration and intensity, and/or family history of HNC. The 20-year absolute risk of HNC was 7.61% for a 60-year-old woman who smoked more than 20 cigarettes per day for over 20 years, consumed 3 or more alcoholic drinks per day, was a high school graduate, had a family history of HNC, and was non-Hispanic white. The 20-year risk for men with a similar profile was 6.85%. The absolute risks of oropharyngeal and hypopharyngeal cancers were generally lower than those of oral cavity and laryngeal cancers. Statistics for the area under the receiver operating characteristic curve (AUC) were 0.70 or higher, except for oropharyngeal cancer in men. This HNC risk prediction model may be useful in promoting healthier behaviors such as smoking cessation or in aiding persons with a family history of HNC to evaluate their risks.
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http://dx.doi.org/10.1093/aje/kwz259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274188PMC
April 2020

Age at start of using tobacco on the risk of head and neck cancer: Pooled analysis in the International Head and Neck Cancer Epidemiology Consortium (INHANCE).

Cancer Epidemiol 2019 12 3;63:101615. Epub 2019 Oct 3.

Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.

Background: Tobacco use is a well-established risk factor for head and neck cancer (HNC). However, less is known about the potential impact of exposure to tobacco at an early age on HNC risk.

Methods: We analyzed individual-level data on ever tobacco smokers from 27 case-control studies (17,146 HNC cases and 17,449 controls) in the International Head and Neck Cancer Epidemiology (INHANCE) consortium. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using random-effects logistic regression models.

Results: Without adjusting for tobacco packyears, we observed that younger age at starting tobacco use was associated with an increased HNC risk for ever smokers (OR: 1.64, 95% CI: 1.35, 1.97). However, the observed association between age at starting tobacco use and HNC risk became null after adjusting for tobacco packyears (OR: 0.97, 95% CI: 0.80, 1.19). In the stratified analyses on HNC subsites by tobacco packyears or years since quitting, no difference in the association between age at start and HNC risk was observed.

Conclusions: Results from this pooled analysis suggest that increased HNC risks observed with earlier age at starting tobacco smoking are largely due to longer duration and higher cumulative tobacco exposures.
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http://dx.doi.org/10.1016/j.canep.2019.101615DOI Listing
December 2019

Cross-registry neural domain adaptation to extract mutational test results from pathology reports.

J Biomed Inform 2019 09 8;97:103267. Epub 2019 Aug 8.

Division of Biomedical Informatics, Dept. of Internal Medicine, University of Kentucky, USA; Computer Science Department, University of Kentucky, USA. Electronic address:

Objective: We study the performance of machine learning (ML) methods, including neural networks (NNs), to extract mutational test results from pathology reports collected by cancer registries. Given the lack of hand-labeled datasets for mutational test result extraction, we focus on the particular use-case of extracting Epidermal Growth Factor Receptor mutation results in non-small cell lung cancers. We explore the generalization of NNs across different registries where our goals are twofold: (1) to assess how well models trained on a registry's data port to test data from a different registry and (2) to assess whether and to what extent such models can be improved using state-of-the-art neural domain adaptation techniques under different assumptions about what is available (labeled vs unlabeled data) at the target registry site.

Materials And Methods: We collected data from two registries: the Kentucky Cancer Registry (KCR) and the Fred Hutchinson Cancer Research Center (FH) Cancer Surveillance System. We combine NNs with adversarial domain adaptation to improve cross-registry performance. We compare to other classifiers in the standard supervised classification, unsupervised domain adaptation, and supervised domain adaptation scenarios.

Results: The performance of ML methods varied between registries. To extract positive results, the basic convolutional neural network (CNN) had an F1 of 71.5% on the KCR dataset and 95.7% on the FH dataset. For the KCR dataset, the CNN F1 results were low when trained on FH data (Positive F1: 23%). Using our proposed adversarial CNN, without any labeled data, we match the F1 of the models trained directly on each target registry's data. The adversarial CNN F1 improved when trained on FH and applied to KCR dataset (Positive F1: 70.8%). We found similar performance improvements when we trained on KCR and tested on FH reports (Positive F1: 45% to 96%).

Conclusion: Adversarial domain adaptation improves the performance of NNs applied to pathology reports. In the unsupervised domain adaptation setting, we match the performance of models that are trained directly on target registry's data by using source registry's labeled data and unlabeled examples from the target registry.
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http://dx.doi.org/10.1016/j.jbi.2019.103267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736690PMC
September 2019

Joint effects of intensity and duration of cigarette smoking on the risk of head and neck cancer: A bivariate spline model approach.

Oral Oncol 2019 07 17;94:47-57. Epub 2019 May 17.

International Agency for Research on Cancer, Lyon, France.

Objectives: This study aimed at re-evaluating the strength and shape of the dose-response relationship between the combined (or joint) effect of intensity and duration of cigarette smoking and the risk of head and neck cancer (HNC). We explored this issue considering bivariate spline models, where smoking intensity and duration were treated as interacting continuous exposures.

Materials And Methods: We pooled individual-level data from 33 case-control studies (18,260 HNC cases and 29,844 controls) participating in the International Head and Neck Cancer Epidemiology (INHANCE) consortium. In bivariate regression spline models, exposures to cigarette smoking intensity and duration (compared with never smokers) were modeled as a linear piecewise function within a logistic regression also including potential confounders. We jointly estimated the optimal knot locations and regression parameters within the Bayesian framework.

Results: For oral-cavity/pharyngeal (OCP) cancers, an odds ratio (OR) >5 was reached after 30 years in current smokers of ∼20 or more cigarettes/day. Patterns of OCP cancer risk in current smokers differed across strata of alcohol intensity. For laryngeal cancer, ORs >20 were found for current smokers of ≥20 cigarettes/day for ≥30  years. In former smokers who quit ≥10  years ago, the ORs were approximately halved for OCP cancers, and ∼1/3 for laryngeal cancer, as compared to the same levels of intensity and duration in current smokers.

Conclusion: Referring to bivariate spline models, this study better quantified the joint effect of intensity and duration of cigarette smoking on HNC risk, further stressing the need of smoking cessation policies.
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http://dx.doi.org/10.1016/j.oraloncology.2019.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7117823PMC
July 2019

Validity of Natural Language Processing for Ascertainment of and Test Results in SEER Cases of Stage IV Non-Small-Cell Lung Cancer.

JCO Clin Cancer Inform 2019 05;3:1-15

Fred Hutchinson Cancer Research Center, Seattle, WA.

Purpose: SEER registries do not report results of epidermal growth factor receptor () and anaplastic lymphoma kinase () mutation tests. To facilitate population-based research in molecularly defined subgroups of non-small-cell lung cancer (NSCLC), we assessed the validity of natural language processing (NLP) for the ascertainment of EGFR and ALK testing from electronic pathology (e-path) reports of NSCLC cases included in two SEER registries: the Cancer Surveillance System (CSS) and the Kentucky Cancer Registry (KCR).

Methods: We obtained 4,278 e-path reports from 1,634 patients who were diagnosed with stage IV nonsquamous NSCLC from September 1, 2011, to December 31, 2013, included in CSS. We used 855 CSS reports to train NLP systems for the ascertainment of and test status (reported not reported) and test results (positive negative). We assessed sensitivity, specificity, and positive and negative predictive values in an internal validation sample of 3,423 CSS e-path reports and repeated the analysis in an external sample of 1,041 e-path reports from 565 KCR patients. Two oncologists manually reviewed all e-path reports to generate gold-standard data sets.

Results: NLP systems yielded internal validity metrics that ranged from 0.95 to 1.00 for and test status and results in CSS e-path reports. NLP showed high internal accuracy for the ascertainment of and in CSS patients-F scores of 0.95 and 0.96, respectively. In the external validation analysis, NLP yielded metrics that ranged from 0.02 to 0.96 in KCR reports and F scores of 0.70 and 0.72, respectively, in KCR patients.

Conclusion: NLP is an internally valid method for the ascertainment of and test information from e-path reports available in SEER registries, but future work is necessary to increase NLP external validity.
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http://dx.doi.org/10.1200/CCI.18.00098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874053PMC
May 2019

An update on clonality: what smooth muscle cell type makes up the atherosclerotic plaque?

F1000Res 2018 21;7. Epub 2018 Dec 21.

Center for Developmental Biology and Regenerative Medicine, Seattle Children's Hospital Research Institute, Seattle, WA, 98112, USA.

Almost 50 years ago, Earl Benditt and his son John described the clonality of the atherosclerotic plaque. This led Benditt to propose that the atherosclerotic lesion was a smooth muscle neoplasm, similar to the leiomyomata seen in the uterus of most women. Although the observation of clonality has been confirmed many times, interest in the idea that atherosclerosis might be a form of neoplasia waned because of the clinical success of treatments for hyperlipemia and because animal models have made great progress in understanding how lipid accumulates in the plaque and may lead to plaque rupture. Four advances have made it important to reconsider Benditt's observations. First, we now know that clonality is a property of normal tissue development. Second, this is even true in the vessel wall, where we now know that formation of clonal patches in that wall is part of the development of smooth muscle cells that make up the tunica media of arteries. Third, we know that the intima, the "soil" for development of the human atherosclerotic lesion, develops before the fatty lesions appear. Fourth, while the cells comprising this intima have been called "smooth muscle cells", we do not have a clear definition of cell type nor do we know if the initial accumulation is clonal. As a result, Benditt's hypothesis needs to be revisited in terms of changes in how we define smooth muscle cells and the quite distinct developmental origins of the cells that comprise the muscular coats of all arterial walls. Finally, since clonality of the lesions is real, the obvious questions are do these human tumors precede the development of atherosclerosis, how do the clones develop, what cell type gives rise to the clones, and in what ways do the clones provide the soil for development and natural history of atherosclerosis?
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http://dx.doi.org/10.12688/f1000research.15994.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305222PMC
March 2019

Understanding care and outcomes in adolescents and young adult with Cancer: A review of the AYA HOPE study.

Pediatr Blood Cancer 2019 01 7;66(1):e27486. Epub 2018 Oct 7.

Outcomes Research Branch, Healthcare Delivery Research Program, Division of Cancer Control and Population Science, National Cancer Institute, Rockville, Maryland.

Historically, adolescents and young adults (AYA) diagnosed with cancer have been an understudied population, and their unique care experiences, needs, and outcomes were not well understood. Thus, 10 years ago, the National Cancer Institute supported the fielding of the Adolescent and Young Adult Health Outcomes and Patient Experiences (AYA HOPE) study to address this gap. We recruited individuals diagnosed at ages 15 to 39 with germ cell, Hodgkin and non-Hodgkin lymphoma, acute lymphoblastic leukemia, and sarcoma from Surveillance, Epidemiology, and End Results cancer registries into the first multicenter population-based study of medical care, physical, and mental health outcomes for AYAs with cancer in the United States. This review of the 17 published manuscripts showed low awareness of clinical trials and substantial impact of cancer on financial burden, education and work, relationships and family planning, and physical and mental health. It highlights the feasibility of a longitudinal population-based study and key lessons learned for research on AYAs with cancer in and beyond the United States.
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http://dx.doi.org/10.1002/pbc.27486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239374PMC
January 2019

Human Organ-Specific Endothelial Cell Heterogeneity.

iScience 2018 Jun 9;4:20-35. Epub 2018 May 9.

Department of Bioengineering, University of Washington, Seattle, WA, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA; Kidney Research Institute, University of Washington, Seattle, WA, USA. Electronic address:

The endothelium first forms in the blood islands in the extra-embryonic yolk sac and then throughout the embryo to establish circulatory networks that further acquire organ-specific properties during development to support diverse organ functions. Here, we investigated the properties of endothelial cells (ECs), isolated from four human major organs-the heart, lung, liver, and kidneys-in individual fetal tissues at three months' gestation, at gene expression, and at cellular function levels. We showed that organ-specific ECs have distinct expression patterns of gene clusters, which support their specific organ development and functions. These ECs displayed distinct barrier properties, angiogenic potential, and metabolic rate and support specific organ functions. Our findings showed the link between human EC heterogeneity and organ development and can be exploited therapeutically to contribute in organ regeneration, disease modeling, as well as guiding differentiation of tissue-specific ECs from human pluripotent stem cells.
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http://dx.doi.org/10.1016/j.isci.2018.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6147238PMC
June 2018

Sleep apnea and subsequent cancer incidence.

Cancer Causes Control 2018 Oct 17;29(10):987-994. Epub 2018 Aug 17.

Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA.

Purpose: In vitro and animal models suggest that the physiological effects of sleep apnea could contribute to cancer risk, yet epidemiologic studies have been inconsistent.

Methods: We identified a cohort of adults diagnosed with sleep apnea between 2005 and 2014 using regional administrative databases. Linking this cohort to a population-based cancer registry, we identified first incident cancers diagnosed after sleep apnea diagnosis through 2015. We calculated age-sex standardized cancer incidence ratios (SIRs) to compare the observed number of cancers among those with sleep apnea with expected population estimates over a comparable period.

Results: Among 34,402 individuals with sleep apnea, 1,575 first incident cancers were diagnosed during follow-up (mean ± SD; 5.3 ± 2.0 years). Compared to the general population, cancer incidence (SIR 1.26, 95% CI 1.20-1.32) was elevated among sleep apnea patients. We observed significantly elevated incidence for kidney (SIR 2.24, 95% CI 1.82-2.72), melanoma (SIR 1.71, 95% CI 1.42-2.03), breast (SIR 1.43, 95% CI 1.76-2.00), and corpus uteri (SIR 2.80, 95% CI 2.24-2.47) while risk for lung (SIR 0.66, 95% CI 0.54-0.79) and colorectal cancer (SIR 0.71, 95% CI 0.56-0.89) was lower.

Conclusion: These findings suggest an elevated cancer burden, particularly at certain sites, among individuals with diagnosed sleep apnea. Results should be interpreted with caution due to unmeasured confounders (e.g., BMI, diabetes).
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http://dx.doi.org/10.1007/s10552-018-1073-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162141PMC
October 2018

HLA and KIR Associations of Cervical Neoplasia.

J Infect Dis 2018 11;218(12):2006-2015

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda.

Background: Cervical cancer is the fourth most common cancer in women, and we recently reported human leukocyte antigen (HLA) alleles showing strong associations with cervical neoplasia risk and protection. HLA ligands are recognized by killer immunoglobulin-like receptors (KIRs) expressed on a range of immune cell subsets, governing their proinflammatory activity. We hypothesized that the inheritance of particular HLA-KIR combinations would increase cervical neoplasia risk.

Methods: Here, we used HLA and KIR dosages imputed from single-nucleotide polymorphism genotype data from 2143 cervical neoplasia cases and 13858 healthy controls of European decent.

Results: The following 4 novel HLA alleles were identified in association with cervical neoplasia, owing to their linkage disequilibrium with known cervical neoplasia-associated HLA-DRB1 alleles: HLA-DRB3*9901 (odds ratio [OR], 1.24; P = 2.49 × 10-9), HLA-DRB5*0101 (OR, 1.29; P = 2.26 × 10-8), HLA-DRB5*9901 (OR, 0.77; P = 1.90 × 10-9), and HLA-DRB3*0301 (OR, 0.63; P = 4.06 × 10-5). We also found that homozygosity of HLA-C1 group alleles is a protective factor for human papillomavirus type 16 (HPV16)-related cervical neoplasia (C1/C1; OR, 0.79; P = .005). This protective association was restricted to carriers of either KIR2DL2 (OR, 0.67; P = .00045) or KIR2DS2 (OR, 0.69; P = .0006).

Conclusions: Our findings suggest that HLA-C1 group alleles play a role in protecting against HPV16-related cervical neoplasia, mainly through a KIR-mediated mechanism.
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http://dx.doi.org/10.1093/infdis/jiy483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6217726PMC
November 2018

The mutational landscape of recurrent versus nonrecurrent human papillomavirus-related oropharyngeal cancer.

JCI Insight 2018 07 26;3(14). Epub 2018 Jul 26.

Departments of Otolaryngology, University of Washington School of Medicine, Seattle, Washington, USA.

Background: Human papillomavirus-related (HPV-related) oropharyngeal squamous cell carcinomas (OPSCCs) have an excellent response rate to platinum-based chemoradiotherapy. Genomic differences between primary HPV-related OPSCCs that do or do not recur are unknown. Furthermore, it is unclear if HPV-related OPSCCs that recur share a genomic landscape with HPV-negative head and neck cancers (HNCs).

Methods: We utilized whole exome sequencing to analyze somatic nucleotide (SNVs) and copy number variants (CNVs) among a unique set of 51 primary HPV-related OPSCCs, including 35 that did not recur and 16 that recurred. We evaluated 12 metachronous recurrent OPSCCs (7 with paired primary OPSCCs) and 33 primary HPV-unrelated oral cavity and OPSCCs.

Results: KMT2D was the most frequently mutated gene among primary HPV-related OPSCCs (n = 51; 14%) and among metachronous recurrent OPSCCs (n = 12; 42%). Primary HPV-related OPSCCs that recurred shared a genomic landscape with primary HPV-related OPSCCs that did not recur. However, TSC2, BRIP1, NBN, and NFE2L2 mutations occurred in primary OPSCCs that recurred but not in those that did not recur. Moreover, primary HPV-related OPSCCs that recur harbor features of HPV-unrelated HNCs, notably including MAPK, JAK/STAT, and differentiation signaling pathway aberrations. Metachronous recurrent OPSCCs shared a genomic landscape with HPV-unrelated HNCs, including a high frequency of TP53, CASP8, FAT1, HLA-A, AJUBA, and NSD1 genomic alterations.

Conclusion: Overall, primary HPV-related OPSCCs that recur share a genomic landscape with nonrecurrent OPSCCs. Metachronous recurrent OPSCCs share genomic features with HPV-negative HNCs. These data aim to guide future deescalation endeavors and functional experiments.

Funding: This study is supported by the American Cancer Society (RSG TBG-123653), funding support for RAH (T32DC00018, Research Training in Otolaryngology, University of Washington), funds to EM from Seattle Translational Tumor Research (Fred Hutchinson Cancer Research Center), and center funds from the Fred Hutchinson Cancer Research Center to EM. UD is supported by the Department of Veterans Affairs, Biomedical Laboratory Research and Development (BLR&D), grant IO1-oo23456, and funds from the Pittsburgh Foundation and PNC Foundation.
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http://dx.doi.org/10.1172/jci.insight.99327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6124437PMC
July 2018

Racial differences in the relationship between tobacco, alcohol, and the risk of head and neck cancer: pooled analysis of US studies in the INHANCE Consortium.

Cancer Causes Control 2018 Jul 14;29(7):619-630. Epub 2018 May 14.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.

There have been few published studies on differences between Blacks and Whites in the estimated effects of alcohol and tobacco use on the incidence of head and neck cancer (HNC) in the United States. Previous studies have been limited by small numbers of Blacks. Using pooled data from 13 US case-control studies of oral, pharyngeal, and laryngeal cancers in the International Head and Neck Cancer Epidemiology Consortium, this study comprised a large number of Black HNC cases (n = 975). Logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) for several tobacco and alcohol consumption characteristics. Blacks were found to have consistently stronger associations than Whites for the majority of tobacco consumption variables. For example, compared to never smokers, Blacks who smoked cigarettes for > 30 years had an OR 4.53 (95% CI 3.22-6.39), which was larger than that observed in Whites (OR 3.01, 95% CI 2.73-3.33; p < 0.0001). The ORs for alcohol use were also larger among Blacks compared to Whites. Exclusion of oropharyngeal cases attenuated the racial differences in tobacco use associations but not alcohol use associations. These findings suggest modest racial differences exist in the association of HNC risk with tobacco and alcohol consumption.
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http://dx.doi.org/10.1007/s10552-018-1026-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626318PMC
July 2018

THE AUTHORS REPLY.

Am J Epidemiol 2017 09;186(5):625-626

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

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http://dx.doi.org/10.1093/aje/kwx212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279081PMC
September 2017

Defining the genetic susceptibility to cervical neoplasia-A genome-wide association study.

PLoS Genet 2017 08 14;13(8):e1006866. Epub 2017 Aug 14.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States of America.

A small percentage of women with cervical HPV infection progress to cervical neoplasia, and the risk factors determining progression are incompletely understood. We sought to define the genetic loci involved in cervical neoplasia and to assess its heritability using unbiased unrelated case/control statistical approaches. We demonstrated strong association of cervical neoplasia with risk and protective HLA haplotypes that are determined by the amino-acids carried at positions 13 and 71 in pocket 4 of HLA-DRB1 and position 156 in HLA-B. Furthermore, 36% (standard error 2.4%) of liability of HPV-associated cervical pre-cancer and cancer is determined by common genetic variants. Women in the highest 10% of genetic risk scores have approximately >7.1% risk, and those in the highest 5% have approximately >21.6% risk, of developing cervical neoplasia. Future studies should examine genetic risk prediction in assessing the risk of cervical neoplasia further, in combination with other screening methods.
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http://dx.doi.org/10.1371/journal.pgen.1006866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5570502PMC
August 2017

Breast-cancer-specific mortality in patients treated based on the 21-gene assay: a SEER population-based study.

NPJ Breast Cancer 2016 8;2:16017. Epub 2016 Jun 8.

Genomic Health, Inc., Redwood City, CA, USA.

The 21-gene Recurrence Score assay is validated to predict recurrence risk and chemotherapy benefit in hormone-receptor-positive (HR+) invasive breast cancer. To determine prospective breast-cancer-specific mortality (BCSM) outcomes by baseline Recurrence Score results and clinical covariates, the National Cancer Institute collaborated with Genomic Health and 14 population-based registries in the the Surveillance, Epidemiology, and End Results (SEER) Program to electronically supplement cancer surveillance data with Recurrence Score results. The prespecified primary analysis cohort was 40-84 years of age, and had node-negative, HR+, HER2-negative, nonmetastatic disease diagnosed between January 2004 and December 2011 in the entire SEER population, and Recurrence Score results (=38,568). Unadjusted 5-year BCSM were 0.4% (=21,023; 95% confidence interval (CI), 0.3-0.6%), 1.4% (=14,494; 95% CI, 1.1-1.7%), and 4.4% (=3,051; 95% CI, 3.4-5.6%) for Recurrence Score <18, 18-30, and ⩾31 groups, respectively (<0.001). In multivariable analysis adjusted for age, tumor size, grade, and race, the Recurrence Score result predicted BCSM (<0.001). Among patients with node-positive disease (micrometastases and up to three positive nodes; =4,691), 5-year BCSM (unadjusted) was 1.0% (=2,694; 95% CI, 0.5-2.0%), 2.3% (=1,669; 95% CI, 1.3-4.1%), and 14.3% (=328; 95% CI, 8.4-23.8%) for Recurrence Score <18, 18-30, ⩾31 groups, respectively (<0.001). Five-year BCSM by Recurrence Score group are reported for important patient subgroups, including age, race, tumor size, grade, and socioeconomic status. This SEER study represents the largest report of prospective BCSM outcomes based on Recurrence Score results for patients with HR+, HER2-negative, node-negative, or node-positive breast cancer, including subgroups often under-represented in clinical trials.
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http://dx.doi.org/10.1038/npjbcancer.2016.17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515329PMC
June 2016
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