Associations between eosinophils and cancer risk in the UK Biobank.

Eosinophils exhibit anti-tumor cytotoxic responses in the tumor microenvironment and may contribute to tumor immunosurveillance. To assess the relationship between circulating eosinophils and cancer risk, we analyzed data from 443,542 adults aged 38-73 in the UK Biobank, who were initially cancer-free, had over a year of follow-up, and baseline white blood cell count measurements. Using multivariable Cox regression, we estimated hazard ratios (aHR) and 95% confidence intervals (95%CI) for each quartile increase in absolute eosinophil count (AEC) across 58 cancer types, adjusting for relevant confounders. During a median follow-up of 5.8 years, 22,747 incident cancer cases were diagnosed. We observed an inverse association, which met Bonferroni significance, between AEC and overall cancer risk (aHR, 95%CI 0.97, 0.95-0.98). Notably, 16 cancer types showed borderline associations (p <.05) with AEC, with 12 types displaying an inverse relationship. These included four hematologic cancers (acute and other myeloid leukemia, other lymphocytic leukemia, and chronic lymphocytic leukemia/small lymphocytic lymphoma; aHR range; 0.58-0.87) and eight nonhematologic cancers (melanoma and nose/middle ear, soft tissue/heart, gum/other mouth, tongue, lung, colon, and breast cancers; aHR range: 0.65-0.95). Higher AEC showed a borderline significant association with increased risk for intrahepatic bile duct cancer, Hodgkin lymphoma, diffuse large B-cell lymphoma, and chronic myeloid leukemia (aHR range: 1.13-1.42). Our study, the largest to date, provides insights into the relationship between blood eosinophils and a comprehensive list of incident cancers. The inverse association between AEC and overall cancer risk suggests a protective role for eosinophils in tumor surveillance.

Cancer Mortality Among Solid Organ Transplant Recipients in the United States During 1987-2018.

BACKGROUND: Solid organ transplant recipients (ie, "recipients") have elevated cancer risk and reduced survival after a cancer diagnosis. Evaluation of cancer mortality among recipients can facilitate improved outcomes from cancers arising before and after transplantation. METHODS: We linked the US transplant registry to the National Death Index to ascertain the causes of 126 474 deaths among 671 127 recipients (1987-2018). We used Poisson regression to identify risk factors for cancer mortality and calculated standardized mortality ratios to compare cancer mortality in recipients with that in the general population. Cancer deaths verified with a corresponding cancer diagnosis from a cancer registry were classified as death from pretransplant or posttransplant cancers. RESULTS: Thirteen percent of deaths were caused by cancer. Deaths from lung cancer, liver cancer, and non-Hodgkin lymphoma (NHL) were the most common. Heart and lung recipients had the highest mortality for lung cancer and NHL, whereas liver cancer mortality was highest among liver recipients. Compared with the general population, cancer mortality was elevated overall (standardized mortality ratio 2.33; 95% confidence interval, 2.29-2.37) and for most cancer sites, with large increases from nonmelanoma skin cancer (23.4, 21.5-25.5), NHL (5.17, 4.87-5.50), kidney cancer (3.40, 3.10-3.72), melanoma (3.27, 2.91-3.68), and, among liver recipients, liver cancer (26.0, 25.0-27.1). Most cancer deaths (93.3%) were associated with posttransplant cancer diagnoses, excluding liver cancer deaths in liver recipients (of which all deaths were from pretransplant diagnoses). CONCLUSIONS: Improved posttransplant prevention or screening for lung cancer, NHL, and skin cancers and management of liver recipients with prior liver cancer may reduce cancer mortality among recipients.

IFNL4 Genotypes and Risk of Childhood Burkitt Lymphoma in East Africa.

Interferon lambda 4 (IFN-λ4) is a novel type-III interferon that can be expressed only by carriers of the genetic variant rs368234815-dG within the first exon of the IFNL4 gene. Genetic inability to produce IFN-λ4 (in carriers of the rs368234815-TT/TT genotype) has been associated with improved clearance of hepatitis C virus (HCV) infection. The IFN-λ4-expressing rs368234815-dG allele (IFNL4-dG) is most common (up to 78%) in West sub-Saharan Africa (SSA), compared to 35% of Europeans and 5% of individuals from East Asia. The negative selection of IFNL4-dG outside Africa suggests that its retention in African populations could provide survival benefits, most likely in children. To explore this hypothesis, we conducted a comprehensive association analysis between IFNL4 genotypes and the risk of childhood Burkitt lymphoma (BL), a lethal infection-associated cancer most common in SSA. We used genetic, epidemiologic, and clinical data for 4,038 children from the Epidemiology of Burkitt Lymphoma in East African Children and Minors (EMBLEM) and the Malawi Infections and Childhood Cancer case-control studies. Generalized linear mixed models fit with the logit link controlling for age, sex, country, P. falciparum infection status, population stratification, and relatedness found no significant association between BL risk and 3 coding genetic variants within IFNL4 (rs368234815, rs117648444, and rs142981501) and their combinations. Because BL occurs in children 6-9 years of age who survived early childhood infections, our results suggest that additional studies should explore the associations of IFNL4-dG allele in younger children. This comprehensive study represents an important baseline in defining the health effects of IFN-λ4 in African populations.

Immune-related conditions and cancer-specific mortality among older adults with cancer in the United States.

Immunity may play a role in preventing cancer progression. We studied associations of immune-related conditions with cancer-specific mortality among older adults in the United States. We evaluated 1 229 443 patients diagnosed with 20 common cancer types (age 67-99, years 1993-2013) using Surveillance Epidemiology and End Results-Medicare data. With Medicare claims, we ascertained immune-related medical conditions diagnosed before cancer diagnosis (4 immunosuppressive conditions [n = 3380 affected cases], 32 autoimmune conditions [n = 155 766], 3 allergic conditions [n = 101 366]). For each cancer site, we estimated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for cancer-specific mortality associated with each condition, applying a Bonferroni cutoff for significance (P < 5.1 × 10-5 ). Bayesian metaanalysis methods were used to detect patterns across groups of conditions and cancers. We observed 21 associations with cancer-specific mortality at the Bonferroni threshold. Increased cancer-specific mortality was observed with rheumatoid arthritis for patients with melanoma (aHR 1.51, 95% CI 1.31-1.75) and breast cancer (1.24, 1.15-1.33)), and with hemolytic anemia for bladder cancer (2.54, 1.68-3.82). Significant inverse associations with cancer-specific mortality were observed for allergic rhinitis (range of aHRs: 0.84-0.94) and asthma (0.83-0.95) for cancers of the lung, breast, and prostate. Cancer-specific mortality was nominally elevated in patients with immunosuppressive conditions for eight cancer types (aHR range: 1.27-2.36; P-value range: 7.5 × 10-5 to 3.1 × 10-2 ) and was strongly associated with grouped immunosuppressive conditions using Bayesian metaanalyses methods. For older patients with several cancer types, certain immunosuppressive and autoimmune conditions were associated with increased cancer-specific mortality. In contrast, inverse associations with allergic conditions may reflect enhanced immune control of cancer.

Risk factors for acute mental health symptoms and tobacco initiation in Coast Guard Responders to the Deepwater Horizon oil spill.

Acute mental health symptoms experienced during oil spill response work are understudied, especially among nonlocal responders. We assessed potential risk factors for acute mental health symptoms and tobacco initiation among U.S. Coast Guard responders to the 2010 Deepwater Horizon (DWH) oil spill who completed a deployment exit survey. Cross-sectional associations among responder characteristics, deployment-related stressors (deployment duration, timing, crude oil exposure, physical symptoms, injuries), and professional help-seeking for stressors experienced with concurrent depression/anxiety and tobacco initiation were examined. Log-binomial regression was used to calculate adjusted prevalence ratios (aPRs) and 95% confidence intervals. Sensitivity analyses excluded responders with a history of mental health conditions using health encounter data from the Military Health System Data Repository. Of the 4,855 responders, 75.5% were deployed from nonlocal/non-Gulf home stations, 5.8% reported concurrent depression and anxiety, and 2.8% reported the initiation of any tobacco product during oil spill response. Self-report of concurrent depression and anxiety was more prevalent among female responders and positively associated with longer deployments, crude oil exposure via inhalation, physical symptoms and injuries, and professional help-seeking during deployment, aPRs = 1.54-6.55. Tobacco initiation was inversely associated with older age and officer rank and positively associated with deployment-related stressors and depression/anxiety during deployment, aPRs = 1.58-4.44. Associations remained robust after excluding responders with a history of mental health- and tobacco-related health encounters up to 3 years before deployment. Depression, anxiety, and tobacco initiation were cross-sectionally associated with oil spill response work experiences among DWH responders, who largely originated outside of the affected community.

Associations of Inflammatory Bowel Disease and Subsequent Cancers in a Population-Based Study of Older Adults in the United States.

Background: Cancer risk is elevated in patients with inflammatory bowel disease (IBD). A comprehensive investigation of cancer risk in older patients (≥66 years of age) is needed, because this understudied population is at high risk. Methods: We performed a case-control study using Surveillance Epidemiology and End Results-Medicare data including 1 986 735 incident cancer cases (aged 66-99 years; diagnosed 1992-2015) and 200 000 controls matched by sex, age, race and ethnicity, and selection year. IBD was identified by ulcerative colitis (UC) or Crohn's disease (CD) diagnosis codes. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated with logistic regression, adjusting for potential confounders. For colorectal cancers, we further adjusted for screening rates. We assessed confounding by medication exposure among patients with prescription drug coverage. Results: IBD, CD, and UC were present in 0.8%, 0.3%, and 0.5% in both cancer cases and non-cancer controls. Of 51 cancers examined, IBD was statistically significantly associated with cancers of the small intestine (OR = 2.55, 95% CI = 2.15 to 3.01), intrahepatic (OR = 1.92, 95% CI = 1.47 to 2.51) and extrahepatic bile ducts (OR = 1.75, 95% CI = 1.38 to 2.22), rectum (OR = 1.61, 95% CI = 1.36 to 1.90), and colon (OR = 1.21, 95% CI = 1.10 to 1.33). CD was associated with cancers of the small intestine (OR = 4.55, 95% CI = 3.65 to 5.67), and UC was associated with cancers of the intrahepatic bile ducts (OR = 1.87, 95% CI = 1.34 to 2.61), rectum (OR = 1.80, 95% CI = 1.47 to 2.20), and colon (OR = 1.28, 95% CI = 1.14 to 1.43). After adjusting for medication exposure, IBD was not statistically significantly associated with lung cancer, melanoma, diffuse large B-cell lymphoma, and myelodysplastic syndrome. Conclusions: In this large study among older adults (≥66 years of age), IBD was positively associated with gastrointestinal cancers. Associations with extraintestinal cancers may reflect the effect of immunosuppressive medications.

Succinate Dehydrogenase Subunit B (SDHB) Is Expressed in Neurofibromatosis 1-Associated Gastrointestinal Stromal Tumors (Gists): Implications for the SDHB Expression Based Classification of Gists.

Gastrointestinal Stromal Tumor (GIST) is the most common mesenchymal tumor of the digestive tract. GISTs develop with relatively high incidence in patients with Neurofibromatosis-1 syndrome (NF1). Mutational activation of KIT or PDGFRA is believed to be a driving force in the pathogenesis of familial and sporadic GISTs. Unlike those tumors, NF1-associated GISTs do not have KIT or PGDFRA mutations. Similarly, no mutational activation of KIT or PDGFRA has been identified in pediatric GISTs and in GISTs associated with Carney Triad and Carney-Stratakis Syndrome. KIT and PDGFRA-wild type tumors are expected to have lesser response to imatinib treatment. Recently, Carney Triad and Carney-Stratakis Syndrome -associated GISTs and pediatric GISTs have been shown to have a loss of expression of succinate dehydrogenase subunit B (SDHB), a Krebs cycle/electron transport chain interface protein. It was proposed that GISTs can be divided into SDHB- positive (type 1), and SDHB-negative (type 2) tumors because of similarities in clinical features and response to imatinib treatment. In this study, SDHB expression was examined immunohistochemically in 22 well-characterized NF1-associated GISTs. All analyzed tumors expressed SDHB. Based on SDHB-expression status, NF1-associated GISTs belong to type 1 category; however, similarly to SDHB type 2 tumors, they do not respond well to imatinib treatment. Therefore, a simple categorization of GISTs into SDHB-positive and-negative seems to be incomplete. A classification based on both SDHB expression status and KIT and PDGFRA mutation status characterize GISTs more accurately and allow subdivision of SDHB-positive tumors into different clinico-genetic categories.