NCI SEER-Linked Virtual Tissue Repository Pilot.

BACKGROUND: The Surveillance, Epidemiology, and End Results (SEER) Program with the National Cancer Institute tested whether population-based cancer registries can serve as honest brokers to acquire tissue and data in the SEER-Linked Virtual Tissue Repository (VTR) Pilot. METHODS: We collected formalin-fixed, paraffin-embedded tissue and clinical data from patients with pancreatic ductal adenocarcinoma (PDAC) and breast cancer (BC) for two studies comparing cancer cases with highly unusual survival (≥5 years for PDAC and ≤30 months for BC) to pair-matched controls with usual survival (≤2 years for PDAC and ≥5 years for BC). Success was defined as the ability for registries to acquire tissue and data on cancer cases with highly unusual outcomes. RESULTS: Of 98 PDAC and 103 BC matched cases eligible for tissue collection, sources of attrition for tissue collection were tissue being unavailable, control paired with failed case, second control that was not requested, tumor necrosis ≥20%, and low tumor cellularity. In total, tissue meeting the study criteria was obtained for 70 (71%) PDAC and 74 (72%) BC matched cases. For patients with tissue received, clinical data completeness ranged from 59% for CA-19-9 after treatment to >95% for margin status, whether radiation therapy and chemotherapy were administered, and comorbidities. CONCLUSIONS: The VTR Pilot demonstrated the feasibility of using SEER cancer registries as honest brokers to provide tissue and clinical data for secondary use in research. Studies using this program should oversample by 45% to 50% to obtain sufficient sample size and targeted population representation and involve subspecialty matter expert pathologists for tissue selection.

Human Papillomavirus and Rising Oropharyngeal Cancer Incidence in the United States.

PURPOSE: Recent increases in incidence and survival of oropharyngeal cancers in the United States have been attributed to human papillomavirus (HPV) infection, but empirical evidence is lacking. PATIENTS AND METHODS: HPV status was determined for all 271 oropharyngeal cancers (1984-2004) collected by the three population-based cancer registries in the Surveillance, Epidemiology, and End Results (SEER) Residual Tissue Repositories Program by using polymerase chain reaction and genotyping (Inno-LiPA), HPV16 viral load, and HPV16 mRNA expression. Trends in HPV prevalence across four calendar periods were estimated by using logistic regression. Observed HPV prevalence was reweighted to all oropharyngeal cancers within the cancer registries to account for nonrandom selection and to calculate incidence trends. Survival of HPV-positive and HPV-negative patients was compared by using Kaplan-Meier and multivariable Cox regression analyses. RESULTS: HPV prevalence in oropharyngeal cancers significantly increased over calendar time regardless of HPV detection assay (P trend < .05). For example, HPV prevalence by Inno-LiPA increased from 16.3% during 1984 to 1989 to 71.7% during 2000 to 2004. Median survival was significantly longer for HPV-positive than for HPV-negative patients (131 v 20 months; log-rank P < .001; adjusted hazard ratio, 0.31; 95% CI, 0.21 to 0.46). Survival significantly increased across calendar periods for HPV-positive (P = .003) but not for HPV-negative patients (P = .18). Population-level incidence of HPV-positive oropharyngeal cancers increased by 225% (95% CI, 208% to 242%) from 1988 to 2004 (from 0.8 per 100,000 to 2.6 per 100,000), and incidence for HPV-negative cancers declined by 50% (95% CI, 47% to 53%; from 2.0 per 100,000 to 1.0 per 100,000). If recent incidence trends continue, the annual number of HPV-positive oropharyngeal cancers is expected to surpass the annual number of cervical cancers by the year 2020. CONCLUSION: Increases in the population-level incidence and survival of oropharyngeal cancers in the United States since 1984 are caused by HPV infection.

Tobacco use profiles by respiratory disorder status for adults in the wave 1-wave 4 population assessment of tobacco and health (PATH) study.

Limited evidence exists on the association between electronic nicotine delivery systems (ENDS) and chronic respiratory disorders. This study examines the association of combustible tobacco and ENDS use with chronic respiratory disorders among US adults. Public-use data from the Population Assessment of Tobacco and Health (PATH) Study Wave 1 (2013-2014), Wave 2 (2014-2015), Wave 3 (2015-2016), and Wave 4 (2016-2018) were pooled. Analyses focused on adults with W1-W4 respiratory disorder data and current tobacco use at W4, as well as youth entering the adult cohort at W2 through W4 (N = 26,072). We fit weighted multivariable logistic regression models for each respiratory outcome (asthma, COPD, bronchitis) using W4 longitudinal weights. Cigarette smokers (adjusted odds ratio [AOR] = 0.8, 95 % CI 0.7-0.9) were less likely to report an asthma diagnosis (p = 0.013). In contrast, ENDS users (AOR = 6.5, 95 % CI 3.7-11.5), cigarette smokers (AOR = 6.1, 95 % CI 4.0-9.1), dual users of cigarettes and ENDS (AOR = 5.4, 95 % CI 3.4-8.7), current users of non-cigarette combustible, smokeless, and polytobacco products (AOR = 4.4, 95 % CI 3.1-6.4), and former users of any product (AOR = 3.0, 95 % CI 1.9-4.7) had significantly elevated odds of reporting a diagnosis of COPD (p < 0.001). Similar patterns to COPD were observed for bronchitis (p < 0.001). Current and former tobacco use, including ENDS, were significantly associated with prevalence of self-reported COPD and bronchitis after controlling for demographic and psychosocial confounders.

Characteristics of the MACS/WIHS Combined Cohort Study: Opportunities for Research on Aging With HIV in the Longest US Observational Study of HIV.

In 2019, the National Institutes of Health combined the Multicenter AIDS Cohort Study (MACS) and the Women's Interagency HIV Study (WIHS) into the MACS/WIHS Combined Cohort Study (MWCCS). In this paper, participants who made a study visit during October 2018-September 2019 (targeted for MWCCS enrollment) are described by human immunodeficiency virus (HIV) serostatus and compared with people living with HIV (PLWH) in the United States. Participants include 2,115 women and 1,901 men with a median age of 56 years (interquartile range, 48-63); 62% are PLWH. Study sites encompass the South (18%), the Mid-Atlantic/Northeast (45%), the West Coast (22%), and the Midwest (15%). Participant race/ethnicity approximates that of PLWH throughout the United States. Longitudinal data and specimens collected for 35 years (men) and 25 years (women) were combined. Differences in data collection and coding were reviewed, and key risk factor and comorbidity data were harmonized. For example, recent use of alcohol (62%) and tobacco (28%) are common, as are dyslipidemia (64%), hypertension (56%), obesity (42%), mildly or severely impaired daily activities (31%), depressive symptoms (28%), and diabetes (22%). The MWCCS repository includes serum, plasma, peripheral blood mononuclear cells, cell pellets, urine, cervicovaginal lavage samples, oral samples, B-cell lines, stool, and semen specimens. Demographic differences between the MACS and WIHS can confound analyses by sex. The merged MWCCS is both an ongoing observational cohort study and a valuable resource for harmonized longitudinal data and specimens for HIV-related research.

Pathology Laboratory Policies and Procedures for Releasing Diagnostic Tissue for Cancer Research.

CONTEXT.­: The Surveillance, Epidemiology, and End Results (SEER) cancer registry program is currently evaluating the use of archival, diagnostic, formalin-fixed, paraffin-embedded (FFPE) tissue obtained through SEER cancer registries, functioning as honest brokers for deidentified tissue and associated data. To determine the feasibility of this potential program, laboratory policies for sharing tissue for research needed to be assessed. OBJECTIVE.­: To understand the willingness of pathology laboratories to share archival diagnostic tissue for cancer research and related policies. DESIGN.­: Seven SEER registries administered a 27-item questionnaire to pathology laboratories within their respective registry catchment areas. Only laboratories that processed diagnostic FFPE specimens and completed the questionnaire were included in the analysis. RESULTS.­: Of the 153 responding laboratories, 127 (83%) responded that they process FFPE specimens. Most (n = 88; 69%) were willing to share tissue specimens for research, which was not associated with the number of blocks processed per year by the laboratories. Most laboratories retained the specimens for at least 10 years. Institutional regulatory policies on sharing deidentified tissue varied considerably, ranging from requiring a full Institutional Review Board review to considering such use exempt from Institutional Review Board review, and 43% (55 of 127) of the laboratories did not know their terms for sharing tissue for research. CONCLUSIONS.­: This project indicated a general willingness of pathology laboratories to participate in research by sharing FFPE tissue. Given the variability of research policies across laboratories, it is critical for each SEER registry to work with laboratories in their catchment area to understand such policies and state legislation regulating tissue retention and guardianship.

Patterns of de-novo metastasis and breast cancer-specific mortality by race and molecular subtype in the SEER population-based dataset.

PURPOSE: To examine patterns of de-novo metastases (mets) and association with breast cancer-specific mortality across subtypes and racial groups. METHODS: Non-Hispanic (NH) Black and NH-White patients ages 40 years and older with primary breast cancer (BC) between 2010 and 2015 were examined. Multilevel logistic regression and Cox proportional hazards models were used to assess (1) odds of de-novo mets to specific sites by subtype, and (2) association of subtype with risk of BC mortality among patients with de-novo mets by race. RESULTS: A total of 204,941 BC patients were included in analysis. The most common de-novo mets site was to the bone, and overall prevalence of de-novo mets was higher among NH-Black (6.4%) versus NH-White (4.1%) patients. The odds of de-novo mets to any site were lower for TNBC (OR 0.68, 95% CI 0.62-0.73) and HR+/HER2- (OR 0.50, 95% CI 0.47-0.53) subtypes, but higher for HR-/HER2+ (OR 1.16, 95% CI 1.06-1.28) relative to HR+/HER2+ . De-novo mets to the brain only was associated with the highest mortality risk across all subtypes, ranging from a 13-fold increase (hazard ratio 13.45, 95% CI 5.03-35.96) for HR-/HER2+ to a 39-fold increase (hazard ratio 39.04, 95% CI 26.2-58.14) for HR+/HER2-. CONCLUSION: Site and fatality of de-novo mets vary by subtype and by race. This information may help improve risk stratification and post-diagnostic surveillance to ultimately reduce BC mortality.

Hepatocellular Carcinoma Survival by Etiology: A SEER-Medicare Database Analysis.

In the United States, hepatocellular carcinoma (HCC) survival varies with tumor characteristics, patient comorbidities, and treatment. The effect of HCC etiology on survival is less clearly defined. The relationship between HCC etiology and mortality was examined using Surveillance, Epidemiology, and End Results-Medicare data. In a cohort of 11,522 HCC cases diagnosed from 2000 through 2014, etiologies were identified from Medicare data, including metabolic disorders (32.9%), hepatitis C virus (8.2%), alcohol (4.7%), hepatitis B virus (HBV, 2.1%), rare etiologies (0.9%), multiple etiologies (26.7%), and unknown etiology (24.4%). After adjusting for demographics, tumor characteristics, comorbidities and treatment, hazard ratios (HRs) and survival curves by HCC etiology were estimated using Cox proportional hazard models. Compared with HBV-related HCC cases, higher mortality was observed for those with alcohol-related HCC (HR 1.49; 95% confidence interval [95% CI] 1.25-1.77), metabolic disorder-related HCC (HR 1.25; 95% CI 1.07-1.47), and multiple etiology-related HCC (HR 1.25; 95% CI 1.07-1.46), but was not statistically significant for hepatitis C virus-related, rare disorder-related, and HCC of unknown etiology. For all HCC etiologies, there was short median survival ranging from 6.1 months for alcohol to 10.3 months for HBV. Conclusion: More favorable survival was seen with HBV-related HCC. To the extent that HCC screening is more common among persons with HBV infection compared to those with other etiologic risk factors, population-based HCC screening, applied evenly to persons across all HCC etiology categories, could shift HCC diagnosis to earlier stages, when cases with good clinical status are more amenable to curative therapy.

The association between etiology of hepatocellular carcinoma and race-ethnicity in Florida.

BACKGROUND AND AIM: The incidence of hepatocellular carcinoma (HCC) has risen considerably in the US since 1980. The main causes include metabolic disorders (NAFLD, diabetes, obesity, metabolic syndrome), alcohol-related disease (ALD) and hepatitis C and B virus infections (HCV, HBV). Etiology-specific HCC incidence rates by detailed race-ethnicity are needed to improve HCC control and prevention efforts. METHODS: All HCC cases diagnosed in Florida during 2014-2015 were linked to statewide hospital discharge data to determine etiology. Age-specific and age-adjusted rates were used to assess the intersection between etiology and detailed racial-ethnicities, including White, African American, Afro-Caribbean, Asian, Cuban, Puerto Rican and Continental Hispanic (Mexican, South and Central American). RESULTS: Of 3666 HCC cases, 2594 matched with discharge data. HCV was the leading cause of HCC among men and women (50% and 43% respectively), followed by metabolic disorders (25% and 37%) and ALD (16% and 9%). Puerto Rican and African American men had the highest HCV-HCC rates, 7.9 and 6.3 per 100 000 respectively. Age-specific rates for HCV-HCC peaked among baby boomers (those born in 1945-1965). Metabolic-HCC rates were highest among populations above age 70 and among Continental Hispanics. Afro-Caribbean men had high rates of HBV-HCC, whereas Puerto Rican men had high ALD-HCC. CONCLUSIONS: HCC etiology is associated with specific race/ethnicity. While HCV-related HCC rates are projected to decrease soon, HCC will continue to affect Hispanics disproportionately, based on higher rates of metabolic-HCC (and ALD-HCC) among Continental Hispanics, who demographically represent 80% of all US Hispanics. Multifaceted approaches for HCC control and prevention are needed.

Lower rates of cancer and all-cause mortality in an Adventist cohort compared with a US Census population.

BACKGROUND: Previous research suggests that Adventists, who often follow vegetarian diets, live longer and have lower risks for many cancers than others, but there are no national data and little published comparative data for black subjects. METHODS: This study compared all-cause mortality and cancer incidence between the nationally inclusive Adventist Health Study 2 (AHS-2) and nonsmokers in US Census populations: the National Longitudinal Mortality Study (NLMS) and its Surveillance, Epidemiology, and End Results substudy. Analyses used proportional hazards regression adjusting for age, sex, race, cigarette smoking history, and education. RESULTS: All-cause mortality and all-cancer incidence in the black AHS-2 population were significantly lower than those for the black NLMS populations (hazard ratio [HR] for mortality, 0.64; 95% confidence interval [CI], 0.59-0.69; HR for incidence, 0.78; 95% CI, 0.68-0.88). When races were combined, estimated all-cause mortality was also significantly lower in the AHS-2 population at the age of 65 years (HR, 0.67; 95% CI, 0.64-0.69) and at the age of 85 years (HR, 0.78; 95% CI, 0.75-0.81), as was cancer mortality; this was also true for the rate of all incident cancers combined (HR, 0.70; 95% CI, 0.67-0.74) and the rates of breast, colorectal, and lung cancers. Survival curves confirmed the mortality results and showed that among males, AHS-2 blacks survived longer than white US subjects. CONCLUSIONS: Substantially lower rates of all-cause mortality and cancer incidence among Adventists have implications for the effects of lifestyle and perhaps particularly diet on the etiology of these health problems. Trends similar to those seen in the combined population are also found in comparisons of black AHS-2 and NLMS subjects.

Are associations between psychosocial stressors and incident lung cancer attributable to smoking?

PURPOSE: To learn whether reported associations between major psychosocial stressors and lung cancer are independent of smoking history. METHODS: Subjects were at least 25 years old and without lung cancer at enrollment in the United States Census Bureau's National Longitudinal Mortality Survey in 1995-2008. Follow-up via Surveillance Epidemiology and End Results and National Death Index continued until lung cancer diagnosis, death, or December 2011. Involuntary unemployment, widowhood, and divorce, stratified by sex, were tested for association with subsequent lung cancer using proportional hazards regression for competing risks. Smoking status, years smoked, cigarettes per day, and years since quitting were imputed when missing. RESULTS: At enrollment, subjects (n = 100,733, 47.4% male, age 49.1(±15.8) years) included 17.6% current smokers, 23.5% former smokers. Of men and women, respectively, 11.3% and 15.0% were divorced/separated, 2.9% and 11.8% were widowed, and 2.9% and 2.3% were involuntarily unemployed. Ultimately, 667 subjects developed lung cancer; another 10,071 died without lung cancer. Adjusted for age, education, and ancestry, lung cancer was associated with unemployment, widowhood, and divorce/separation in men but not women. Further adjusted for years smoked, cigarettes per day, and years since quitting, none of these associations was significant in either sex. CONCLUSIONS: Once smoking is accounted for, psychosocial stressors in adulthood do not independently promote lung cancer. Given their increased smoking behavior, persons experiencing stressors should be referred to effective alternatives to smoking and to support for smoking cessation.

Does socioeconomic status account for racial and ethnic disparities in childhood cancer survival?

BACKGROUND: For many childhood cancers, survival is lower among non-Hispanic blacks and Hispanics in comparison with non-Hispanic whites, and this may be attributed to underlying socioeconomic factors. However, prior childhood cancer survival studies have not formally tested for mediation by socioeconomic status (SES). This study applied mediation methods to quantify the role of SES in racial/ethnic differences in childhood cancer survival. METHODS: This study used population-based cancer survival data from the Surveillance, Epidemiology, and End Results 18 database for black, white, and Hispanic children who had been diagnosed at the ages of 0 to 19 years in 2000-2011 (n = 31,866). Black-white and Hispanic-white mortality hazard ratios and 95% confidence intervals, adjusted for age, sex, and stage at diagnosis, were estimated. The inverse odds weighting method was used to test for mediation by SES, which was measured with a validated census-tract composite index. RESULTS: Whites had a significant survival advantage over blacks and Hispanics for several childhood cancers. SES significantly mediated the race/ethnicity-survival association for acute lymphoblastic leukemia, acute myeloid leukemia, neuroblastoma, and non-Hodgkin lymphoma; SES reduced the original association between race/ethnicity and survival by 44%, 28%, 49%, and 34%, respectively, for blacks versus whites and by 31%, 73%, 48%, and 28%, respectively, for Hispanics versus whites ((log hazard ratio total effect - log hazard ratio direct effect)/log hazard ratio total effect). CONCLUSIONS: SES significantly mediates racial/ethnic childhood cancer survival disparities for several cancers. However, the proportion of the total race/ethnicity-survival association explained by SES varies between black-white and Hispanic-white comparisons for some cancers, and this suggests that mediation by other factors differs across groups.

Association Between Socioeconomic Status and Tumor Grade Among Black Men with Prostate Cancer.

BACKGROUND: Prostate cancer affects black men disproportionately. Black men have an increased incidence of prostate cancer diagnoses at earlier ages and higher grade as indicated by Gleason score, compared to other races. This study investigates the impact of socioeconomic status (SES) on prostate cancer tumor grade among black men. METHODS: Black men with a prostate cancer diagnosis during 1973-2011 were examined using individual-level data from the SEER NLMS database. Logistic regression model estimated the likelihood of receiving a diagnosis of high versus low grade prostate cancer based on self-reported SES status at the time of diagnosis. RESULTS: Men who completed high school only were statistically significantly more likely to have a higher prostate cancer grade than those with a bachelor's degree or higher. However, there was no dose-response effect across educational strata. Retirees were 30% less likely to have higher grade tumors compared to those who were employed. CONCLUSIONS: SES differences among black men did not fully explain the high grade of prostate cancer. Further research is needed on the biology of the disease and to assess access to medical care and prostate health education, discrimination, stress exposures, and social norms that might contribute to the aggressiveness of prostate cancer among black men.

Racial/ethnic disparities in de novo metastases sites and survival outcomes for patients with primary breast, colorectal, and prostate cancer.

Racial disparities in cancer mortality still exist despite improvements in treatment strategies leading to improved survival for many cancer types. In this study, we described race/ethnic differences in patterns of de novo metastasis and evaluated the association between site of de novo metastasis and breast, prostate, and colorectal cancer mortality. Data were obtained from the Surveillance Epidemiology and Ends Results (SEER) database from 2010 to 2013 and included 520,147 patients ages ≥40 years with primary diagnosis of breast, colorectal, or prostate cancer. Site and frequency of de novo metastases to four sites (bone, brain, liver, and lung) were compared by race/ethnicity using descriptive statistics, and survival differences examined using extended Cox regression models in SAS 9.4. Overall, non-Hispanic (NH) Blacks (11%) were more likely to present with de novo metastasis compared with NH-Whites (9%) or Hispanics (10%). Among patients with breast cancer, NH-Blacks were more likely to have metastasis to the bone, (OR: 1.25, 95% CI: 1.15-1.37), brain (OR: 2.26, 95% CI: 1.57-3.25), or liver (OR: 1.62, 95% CI: 1.35-1.93), while Hispanics were less likely to have metastasis to the liver (OR: 0.76, 95% CI: 0.60-0.97) compared with NH-Whites. Among patients with prostate cancer, NH-Blacks (1.39, 95% CI: 1.31-1.48) and Hispanics (1.39, 95% CI: 1.29-1.49) were more likely to have metastasis to the bone. Metastasis to any of the four sites evaluated increased overall mortality by threefold (for breast cancer and metastasis to bone) to 17-fold (for prostate cancer and metastasis to liver). Racial disparities in mortality remained after adjusting for metastasis site in all cancer types evaluated. De novo metastasis is a major contributor to cancer mortality in USA with racial differences in the site, frequency, and associated survival.

Association of Cigarette, Cigar, and Pipe Use With Mortality Risk in the US Population.

Importance: Tobacco products have changed in recent years. Contemporary mortality risk estimates of combustible tobacco product use are needed. Objective: To investigate the mortality risks associated with current and former use of cigars, pipes, and cigarettes. Design, Setting, and Participants: The National Longitudinal Mortality Study is a longitudinal population-based, nationally representative health survey with mortality follow-up that includes demographic and other information from the Current Population Survey, tobacco product use information from the Tobacco Use Supplement, and mortality data from the National Death Index. In this study, participants provided tobacco use information at baseline in surveys starting from 1985 and were followed for mortality through the end of 2011. The study includes 357 420 participants who reported exclusively using cigar, pipes, or cigarettes or reported never using any type of tobacco product. Exposures: Current or former exclusive use of any cigar (little cigar, cigarillos, large cigar), traditional pipe, or cigarette and never tobacco use. Information on current daily and nondaily use was also collected. Estimates adjusted for age, sex, race/ethnicity, education, and survey year. Main Outcomes and Measures: All-cause and cause-specific mortality as identified as the primary cause of death from death certificate information. Results: Of the 357 420 persons included in the analysis, the majority of current and former cigar and pipe smokers were male (79.3%-98.0%), and smokers were more evenly divided by sex (46% of current daily smokers were male). There were 51 150 recorded deaths during follow-up. Exclusive current cigarette smokers (hazard ratio [HR], 1.98; 95% CI, 1.93-2.02) and exclusive current cigar smokers (HR, 1.20; 95% CI, 1.03-1.38) had higher all-cause mortality risks than never tobacco users. Exclusive current cigarette smokers (HR, 4.06; 95% CI, 3.84-4.29), exclusive current cigar smokers (HR, 1.61; 95% CI, 1.11-2.32), and exclusive current pipe smokers (HR, 1.58; 95% CI, 1.05-2.38) had an elevated risk of dying from a tobacco-related cancer (including bladder, esophagus, larynx, lung, oral cavity, and pancreas). Among current nondaily cigarette users, statistically significant associations were observed with deaths from lung cancer (HR, 6.24; 95% CI, 5.17-7.54), oral cancer (HR, 4.62; 95% CI, 1.84-11.58), circulatory death (HR, 1.43; 95% CI, 1.30-1.57), cardiovascular death (HR, 1.24; 95% CI, 1.11-1.39), cerebrovascular death (stroke) (HR, 1.39; 95% CI, 1.12-1.74), and chronic obstructive pulmonary disease (HR, 7.66; 95% CI, 6.09-9.64) as well as for daily smokers. Conclusions and Relevance: This study provides further evidence that exclusive use of cigar, pipes, and cigarettes each confers significant mortality risks.

Cancer burden attributable to cigarette smoking among HIV-infected people in North America.

OBJECTIVE: With combination-antiretroviral therapy, HIV-infected individuals live longer with an elevated burden of cancer. Given the high prevalence of smoking among HIV-infected populations, we examined the risk of incident cancers attributable to ever smoking cigarettes. DESIGN: Observational cohort of HIV-infected participants with 270 136 person-years of follow-up in the North American AIDS Cohort Collaboration on Research and Design consortium. Among 52 441 participants, 2306 were diagnosed with cancer during 2000-2015. MAIN OUTCOME MEASURES: Estimated hazard ratios and population-attributable fractions (PAF) associated with ever cigarette smoking for all cancers combined, smoking-related cancers, and cancers that were not attributed to smoking. RESULTS: People with cancer were more frequently ever smokers (79%) compared with people without cancer (73%). Adjusting for demographic and clinical factors, cigarette smoking was associated with increased risk of cancer overall [hazard ratios = 1.33 (95% confidence interval: 1.18-1.49)]; smoking-related cancers [hazard ratios = 2.31 (1.80-2.98)]; lung cancer [hazard ratios = 17.80 (5.60-56.63)]; but not nonsmoking-related cancers [hazard ratios = 1.12 (0.98-1.28)]. Adjusted PAFs associated with ever cigarette smoking were as follows: all cancers combined, PAF = 19% (95% confidence interval: 13-25%); smoking-related cancers, PAF = 50% (39-59%); lung cancer, PAF = 94% (82-98%); and nonsmoking-related cancers, PAF = 9% (1-16%). CONCLUSION: Among HIV-infected persons, approximately one-fifth of all incident cancer, including half of smoking-related cancer, and 94% of lung cancer diagnoses could potentially be prevented by eliminating cigarette smoking. Cigarette smoking could contribute to some cancers that were classified as nonsmoking-related cancers in this report. Enhanced smoking cessation efforts targeted to HIV-infected individuals are needed.

Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: A population-based study in SEER-Medicare.

OBJECTIVES: Intrahepatic (ICC) and extrahepatic (ECC) cholangiocarcinomas are rare tumors that arise from the epithelial cells of the bile ducts, and the etiology of both cancer types is poorly understood. Thus, we utilized the Surveillance, Epidemiology, and End Results (SEER)-Medicare resource to examine risk factors and novel preexisting medical conditions that may be associated with these cancer types. METHODS: Between 2000 and 2011, 2,092 ICC and 2,981 ECC cases and 323,615 controls were identified using the SEER-Medicare database. Logistic regression was used to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Non-alcoholic fatty liver disease was associated with approximately 3-fold increased risks of ICC (OR = 3.52, 95% CI: 2.87-4.32) and ECC (OR = 2.93, 95% CI: 2.42-3.55). Other metabolic conditions, including obesity and type 2 diabetes, were also associated with increased risks of both cancer types. Smoking was associated with a 46% and 77% increased ICC and ECC risk, respectively. Several autoimmune/inflammatory conditions, including type 1 diabetes and gout, were associated with increased risks of ICC/ECC. As anticipated, viral hepatitis, alcohol-related disorders, and bile duct conditions were associated with both cancer types. However, thyrotoxicosis and hemochromatosis were associated with an increased risk of ICC but not ECC, but did not remain significantly associated after Bonferroni correction. CONCLUSIONS: In this study, risk factors for ICC and ECC were similar, with the exceptions of thyrotoxicosis and hemochromatosis. Notably, metabolic conditions were associated with both cancer types. As metabolic conditions are increasing in prevalence, these could be increasingly important risk factors for both types of cholangiocarcinoma.

Expression of the scaffold connector enhancer of kinase suppressor of Ras 1 (CNKSR1) is correlated with clinical outcome in pancreatic cancer.

BACKGROUND: Despite the near universal occurrence of activating codon 12 KRAS somatic variants in pancreatic cancer, there is considerable heterogeneity in the molecular make-up, MAPK/ERK pathway activation states, and clinical outcome in this disease. We analyzed the expression levels of CNKSR1, a scaffold that influences MAPK/ERK pathway activity, in clinical pancreas cancer specimens and their impact on survival of patients with pancreatic cancer. METHODS: Immunohistochemical staining for CNKSR1 expression was performed on 120 specimens from three independent pancreatic cancer tissue registries, phospho-ERK levels were measured in 86 samples. Expression was divided into CNKSR1 low and CNKSR1 high and correlated with clinicopathological variables including overall survival using multivariate Cox proportional hazard ratio models. RESULTS: CNKSR1 expression was increased in tumors compared to matched normal uninvolved resection specimens (p = 0.004). 28.3% (34/120) of patient specimens stained as CNKSR1 low compared to 71.7% (86/120) of specimens which stained as CNKSR1 high. High CNKSR1 expression was more prevalent in low grade tumors (p = 0.04). In multivariate analysis, low CNKSR1 expression status was independently correlated with decreased overall survival (HR = 2.146; 95% CI 1.34 to 3.43). When stratifying primary, non-metastatic tumor biopsies by CNKSR1 expression, resection was associated with improved survival in patients with high CNKSR1 expression (p < 0.0001) but not low CNKSR1 expression (p = 0.3666). Pancreatic tumors with nuclear in addition to cytoplasmic CNKSR1 staining (32/107) showed increased nuclear phospho-ERK expression compared to tumor with cytoplasmic CNKSR1 staining only (p = 0.017). CONCLUSION: CNKSR1 expression is increased in pancreatic tissue specimens and was found to be an independent prognostic marker of overall survival. CNKSR1 may help to identify patient subgroups with unfavorable tumor biology in order to improve risk stratification and treatment selection. Cellular distribution of CNKSR1 was correlated with nuclear pERK expression.

A longitudinal study of smokeless tobacco use and mortality in the United States.

Few studies in the United States have examined longitudinally the mortality risks associated with use of smokeless tobacco (SLT). The sample of our study was composed of participants from the National Longitudinal Mortality Study who completed a single Tobacco Use Supplement to the Current Population Survey between the years 1985 and 2011. Using survival methods, SLT use at the baseline survey was examined as a predictor of all-cause mortality and cause-specific mortalities in models that excluded individuals who had ever smoked cigarettes, cigars or used pipes (final n = 349,282). The participants had median and maximum follow-up times of 8.8 and 26.3 years, respectively. Regression analyses indicated that compared to the never tobacco users, the current SLT users did not have elevated mortality risks from all cancers combined, the digestive system cancers and cerebrovascular disease. However, current SLT users had a higher mortality risk for coronary heart disease (CHD) [hazard ratio (HR) (95% CI) = 1.24 (1.05, 1.46)] relative to never tobacco users. In a separate model, the elevated risk for CHD mortality corresponded to the use of moist snuff [HR (95% CI) = 1.30 (1.03, 1.63)]. The associations with CHD mortality could be attributed to long-term nicotine exposure, other SLT constituents (e.g., metals) or the confounding effects of CHD risk factors not accounted for in our study. The study's findings contribute to the ongoing dialogue on tobacco harm reduction and the US FDA's evaluation of Modified Risk Tobacco Product applications submitted by American SLT manufacturers.

Primary Breast Lymphoma in the United States: 1975-2013.

Background: Primary breast lymphoma (PBL) has gained attention with the description of breast implant-associated anaplastic large cell lymphoma (ALCL). Less is known about PBL incidence, treatment, and survival by lymphoma subtype. Methods: The Surveillance, Epidemiology, and End Results (SEER) registry database was queried for patients with PBL as first malignancy, with attention to non-Hodgkin Lymphoma PBL subtypes: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, marginal zone lymphoma (MZL), and ALCL. Incidence was estimated by age and subtype with joinpoint analyses, along with initial local therapy. Five-year relative and overall survival estimates were compared using z and two-sided log-rank tests. Results: PBL incidence (per 1 000 000 women) increased from 0.66 (1975-1977) to 2.96 (2011-2013) with an annual percentage change (APC) of 5.3% (95% confidence interval [CI] = 3.8% to 6.9%, P < .001) from 1975 to 1999 and no statistically significant change thereafter. Incidence continues to increase for women younger than age 50 years (APC = 2.8%, 95% CI = 1.0% to 4.6%, P = .003) and for ALCL-PBL (APC = 11.8%, 95% CI = 0.2% to 24.9%, P = .047) and MZL-PBL (APC = 2.3%, 95% CI = -0.2% to 4.9%, P = .07), with the latter increasing significantly from 1995 to 2013 (APC = 7.5%, 95% CI = 3.4% to 11.8%, P = .001). Surgery and surgery with radiation declined from 2000 to 2013 as initial local therapy for PBL. Five-year relative survival for PBL improved markedly over four decades and was superior for stage I DLBCL-PBL and stage I follicular PBL than for corresponding systemic presentations. Conclusions: PBL has increased in incidence over the last four decades and continues to increase for younger women and for some subtypes. The rise in imaging and procedures to the breast might enhance diagnostic sensitivity for PBL. Further study of the etiologies of PBL is needed.