Diabetes and gastric cancer incidence and mortality in the Asia Cohort Consortium: A pooled analysis of more than a half million participants.

BACKGROUND: Evidence suggests a possible link between diabetes and gastric cancer risk, but the findings remain inconclusive, with limited studies in the Asian population. We aimed to assess the impact of diabetes and diabetes duration on the development of gastric cancer overall, by anatomical and histological subtypes. METHODS: A pooled analysis was conducted using 12 prospective studies included in the Asia Cohort Consortium. Among 558 981 participants (median age 52), after a median follow-up of 14.9 years and 10.5 years, 8556 incident primary gastric cancers and 8058 gastric cancer deaths occurred, respectively. Cox proportional hazard regression models were used to estimate study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) and pooled using random-effects meta-analyses. RESULTS: Diabetes was associated with an increased incidence of overall gastric cancer (HR 1.15, 95% CI 1.06-1.25). The risk association did not differ significantly by sex (women vs men: HR 1.31, 95% CI 1.07-1.60 vs 1.12, 1.01-1.23), anatomical subsites (noncardia vs cardia: 1.14, 1.02-1.28 vs 1.17, 0.77-1.78) and histological subtypes (intestinal vs diffuse: 1.22, 1.02-1.46 vs 1.00, 0.62-1.61). Gastric cancer risk increased significantly during the first decade following diabetes diagnosis (HR 4.70, 95% CI 3.77-5.86), and decreased with time (nonlinear p < .01). Positive associations between diabetes and gastric cancer mortality were observed (HR 1.15, 95% CI 1.03-1.28) but attenuated after a 2-year time lag. CONCLUSION: Diabetes was associated with an increased gastric cancer incidence regardless of sex, anatomical subsite, or subtypes of gastric cancer. The risk of gastric cancer was particularly high during the first decade following diabetes diagnosis.

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.

White Blood Cell Count, Neutrophil-to-Lymphocyte Ratio, and Incident Cancer in the UK Biobank.

BACKGROUND: The peripheral white blood cell (WBC) and neutrophil-to-lymphocyte ratio (NLR) reflect levels of inflammation and adaptive immunity. They are associated with cancer prognosis, but their associations with cancer incidence are not established. METHODS: We evaluated 443,540 cancer-free adults in the UK Biobank with data on total WBC and its subsets, follow-up starting one year after baseline. Cox regression was used to estimate hazard ratios (HRs) per quartile of WBC or NLR for incidence of 73 cancer types. RESULTS: 22,747 incident cancers were diagnosed during a median of 6.9 years of follow-up. WBC was associated with risk of cancer overall (HR 1.05, 95%CI 1.03-1.06), chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL: 2.79, 2.45-3.18), lung cancer (1.14, 1.08-1.20), and breast cancer (1.05-1.02-1.08). NLR was positively associated with cancer overall (HR 1.03, 95%CI 1.02-1.04, per quartile) and kidney cancer (1.16, 1.07-1.25), and inversely with CLL/SLL (0.38, 0.33-0.42). CONCLUSIONS: High WBC or NLR may reflect excessive inflammatory status, promoting development of some cancers. Conversely, low NLR indicates a relative rise in lymphocytes, which could reflect an increase in circulating premalignant cells before CLL/SLL diagnosis. Peripheral WBC and NLR, in combination with other clinical information or biomarkers, may be useful tools for cancer risk stratification. IMPACT: Elevated levels of white blood cells or an increased neutrophil-to-lymphocyte ratio may indicate an overly active inflammatory response, potentially contributing to the eventual onset of certain types of cancer.

The Cancer Spectrum Theory.

SUMMARY: Biological characteristics of tumors are heterogeneous, forming spectra in terms of several factors such as age at onset, anatomic spatial localization, tumor subtyping, and the degree of tumor aggressiveness (encompassing a neoplastic property spectrum). Instead of blindly using dichotomized approaches, the application of the multicategorical and continuous analysis approaches to detailed cancer spectrum data can contribute to a better understanding of the etiology of cancer, ultimately leading to effective prevention and precision oncology. We provide examples of cancer spectra and emphasize the importance of integrating the cancer spectrum theory into large-scale population cancer research.

Family history and gastric cancer incidence and mortality in Asia: a pooled analysis of more than half a million participants.

BACKGROUND: The family history of gastric cancer holds important implications for cancer surveillance and prevention, yet existing evidence predominantly comes from case-control studies. We aimed to investigate the association between family history of gastric cancer and gastric cancer risk overall and by various subtypes in Asians in a prospective study. METHODS: We included 12 prospective cohorts with 550,508 participants in the Asia Cohort Consortium. Cox proportional hazard regression was used to estimate study-specific adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between family history of gastric cancer and gastric cancer incidence and mortality, then pooled using random-effects meta-analyses. Stratified analyses were performed for the anatomical subsites and histological subtypes. RESULTS: During the mean follow-up of 15.6 years, 2258 incident gastric cancers and 5194 gastric cancer deaths occurred. The risk of incident gastric cancer was higher in individuals with a family history of gastric cancer (HR 1.44, 95% CI 1.32-1.58), similarly in males (1.44, 1.31-1.59) and females (1.45, 1.23-1.70). Family history of gastric cancer was associated with both cardia (HR 1.26, 95% CI 1.00-1.60) and non-cardia subsites (1.49, 1.35-1.65), and with intestinal- (1.48, 1.30-1.70) and diffuse-type (1.59, 1.35-1.87) gastric cancer incidence. Positive associations were also found for gastric cancer mortality (HR 1.30, 95% CI 1.19-1.41). CONCLUSIONS: In this largest prospective study to date on family history and gastric cancer, a familial background of gastric cancer increased the risk of gastric cancer in the Asian population. Targeted education, screening, and intervention in these high-risk groups may reduce the burden of gastric cancer.

Autoimmune disease and the risk of anal cancer in the US population aged 66 years and over.

BACKGROUND: In the United States, anal squamous cell carcinoma rates have increased rapidly, particularly among women 50 or older than 66 years of age. As immunosuppression is associated with increased risk, autoimmune conditions may be associated with greater risk of anal squamous cell carcinoma. METHODS: We conducted a population-based, case-control study using Surveillance, Epidemiology, and End Results-Medicare data (2000-2017). Anal squamous cell carcinoma cases (n = 4505) were matched to 200 000 cancer-free controls. Using multivariable logistic regression, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) for associations between 47 autoimmune conditions diagnosed before selection, identified using Medicare claims, and anal squamous cell carcinoma. The Bonferroni threshold was used to correct for multiple comparisons. Population attributable fractions were calculated for conditions nominally associated with anal squamous cell carcinoma. RESULTS: In total, 18% of anal squamous cell carcinoma cases and 15% of cancer-free controls had a diagnosed autoimmune condition. Any autoimmune condition was associated with an increased risk of anal squamous cell carcinoma (OR = 1.11, 95% CI = 1.02 to 1.21; population attributable fraction = 1.8%). Anal squamous cell carcinoma was associated with systemic lupus erythematosus (OR = 1.79, 95% CI = 1.32 to 2.42; population attributable fraction = 0.4%) and nominally associated (P < .05) with sarcoidosis (OR = 2.09, 95% CI = 1.30 to 3.37; population-attributable fraction = 0.2%) and psoriasis (OR = 1.28, 95% CI = 1.06 to 1.56; population attributable fraction = 0.5%). Stratified by sex, only women showed statistically significant associations for systemic lupus erythematosus (OR = 1.97, 95% CI = 1.46 to 2.68). Statistically significant interaction was observed by sex for psoriasis (men vs women: OR = 1.68 [95% CI = 1.03 to 4.28] vs OR = 1.12 [95% CI = 0.88 to 1.43]) and polymyalgia rheumatica (OR = 0.33 [95% CI = 0.12 to 0.89] vs OR = 0.99 [95% CI = 0.75 to 1.30]). CONCLUSION: Systemic lupus erythematosus, sarcoidosis, and psoriasis were associated with a moderately increased risk of anal squamous cell carcinoma. Given these conditions' rarity and moderate associations with anal squamous cell carcinoma, autoimmune diseases cannot explain the rising trend in this disease.

Reproductive factors, hormonal interventions, and gastric cancer risk in the Stomach cancer Pooling (StoP) Project.

BACKGROUND: Gastric cancer incidence is higher in men, and a protective hormone-related effect in women is postulated. We aimed to investigate and quantify the relationship in the Stomach cancer Pooling (StoP) Project consortium. METHODS: A total of 2,084 cases and 7,102 controls from 11 studies in seven countries were included. Summary odds ratios (ORs) and 95% confidence intervals (CIs) assessing associations of key reproductive factors and menopausal hormone therapy (MHT) with gastric cancer were estimated by pooling study-specific ORs using random-effects meta-analysis. RESULTS: A duration of fertility of ≥ 40 years (vs. < 20), was associated with a 25% lower risk of gastric cancer (OR = 0.75; 95% CI: 0.58-0.96). Compared with never use, ever, 5-9 years and ≥ 10 years use of MHT in postmenopausal women, showed ORs of 0.73 (95% CI: 0.58-0.92), 0.53 (95% CI: 0.34-0.84) and 0.71 (95% CI: 0.50-1.00), respectively. The associations were generally similar for anatomical and histologic subtypes. CONCLUSION: Our results support the hypothesis that reproductive factors and MHT use may lower the risk of gastric cancer in women, regardless of anatomical or histologic subtypes. Given the variation in hormones over the lifespan, studies should address their effects in premenopausal and postmenopausal women. Furthermore, mechanistic studies may inform potential biological processes.

Impact of overweight and obesity on US renal cell carcinoma incidence trends (1995-2018).

In the United States, renal cell carcinoma (RCC) incidence and the prevalence of obesity, an established risk factor for RCC, have been increasing for several decades. RCC is more common among older individuals. We sought to quantify the contribution of excess adiposity to the rising incidence of RCC among individuals 60 years or older. National Institutes of Health-American Association of Retired Persons Diet and Health Study data (n = 453 859 participants, enrolled in 1995-1996, age at enrollment 50-71 years) were used to estimate multivariable-adjusted hazard ratios (HRs) for RCC across body mass index categories and HRs associated with smoking. Population attributable fractions (PAFs) were calculated using estimated HRs and annual overweight/obesity prevalence from the National Health Interview Survey (1985-2008). PAF estimates were combined with RCC incidence from Surveillance, Epidemiology and End Results-13 to calculate annual percent changes in RCC incidence attributable (and unrelated) to overweight/obesity. We found that between 1995 and 2018, among individuals aged 60 years and older, PAF for overweight/obesity increased from 18% to 29% for all RCCs. In comparison, the PAF for smoking declined from 12% to 9%. RCC incidence increased 1.8% per year (95% confidence interval [CI] 1.5%-2.1%) overall, while RCC incidence attributable to overweight/obesity increased 3.8% per year (95%CI 3.5%-4.2%) and RCC incidence unrelated to overweight/obesity increased 1.2% per year (95% CI 0.9%-1.4%). In conclusion, overweight/obesity appears to have contributed importantly to the rising incidence of RCC in the United States since the mid-1990s. Public health interventions focused on reducing overweight and obesity could help substantially in curbing this trend.

Identification of anti-Helicobacter pylori antibody signatures in gastric intestinal metaplasia.

BACKGROUND: Chronic Helicobacter pylori infection may induce gastric intestinal metaplasia (IM). We compared anti-H. pylori antibody profiles between IM cases and non-atrophic gastritis (NAG) controls. METHODS: We evaluated humoral responses to 1528 H. pylori proteins among a discovery set of 50 IM and 50 NAG using H. pylori protein arrays. Antibodies with ≥ 20% sensitivity at 90% specificity for either group were selected and further validated in an independent set of 100 IM and 100 NAG using odds ratios (OR). A validated multi-signature was evaluated using the area under the receiver operating characteristics curve (AUC) and net reclassification improvement (NRI). RESULTS: Sixty-two immunoglobulin (Ig) G and 11 IgA antibodies were detected in > 10%. Among them, 22 IgG and 6 IgA antibodies were different between IM and NAG in the discovery set. Validated antibodies included 11 IgG (anti-HP1177/Omp27/HopQ [OR = 8.1, p < 0.001], anti-HP0547/CagA [4.6, p < 0.001], anti-HP0596/Tipα [4.0, p = 0.002], anti-HP0103/TlpB [3.8, p = 0.001], anti-HP1125/PalA/Omp18 [3.1, p = 0.001], anti-HP0153/RecA [0.48, p = 0.03], anti-HP0385 [0.41, p = 0.006], anti-HP0243/TlpB [0.39, p = 0.016], anti-HP0371/FabE [0.37, p = 0.017], anti-HP0900/HypB/AccB [0.35, p = 0.048], and anti-HP0709 [0.30, p = 0.003]), and 2 IgA (anti-HP1125/PalA/Omp18 [2.7, p = 0.03] and anti-HP0596/Tipα [2.5, p = 0.027]). A model including all 11 IgG antibodies (AUC = 0.81) had better discriminated IM and NAG compared with an anti-CagA only (AUC = 0.77) model (NRI = 0.44; p = 0.001). CONCLUSIONS: Our study represents the most comprehensive assessment of anti-H. pylori antibody profiles in IM. The target antigens for these novel antibodies may act together with CagA in the progression to IM. Along with other biomarkers, specific H. pylori antibodies may identify IM patients, who would benefit from surveillance.

The Association of Serum High-Sensitivity C-Reactive Protein Level With the Risk of Site-Specific Cancer Mortality: The Health Examinees (HEXA) Study Cohort.

Few studies have investigated the association between high-sensitivity C-reactive protein (hsCRP) level and site-specific cancer mortality. In this study, we aimed to examine the associations of hsCRP with overall and site-specific cancer mortality among South Koreans using data on the Health Examinees (HEXA) Study cohort (41,070 men and 81,011 women aged ≥40 years). We obtained mortality information from the National Statistical Office of Korea, which provided the dates and causes of all deaths occurring through December 31, 2015, by linking mortality data with each participant's unique national identifier. Cox proportional hazards and restricted cubic spline models were used to assess the association between hsCRP and cancer mortality with adjustment for covariates. An analysis of site-specific cancer mortality was focused on 5 major cancers (lung, liver, gastric, colorectal, and breast/prostate). Median hsCRP levels were 0.77 mg/L and 0.59 mg/L for men and women, respectively. A dose-response association between hsCRP and overall cancer mortality was observed in men but disappeared in women after exclusion of deaths occurring in the first 1 or 2 years of follow-up. Elevated hsCRP levels increased the risks of lung, liver, and gastric cancer mortality in men, but the risks of colorectal and breast cancer mortality were not increased. The dose-response association between hsCRP and cancer mortality was observed differently depending on site-specific cancer mortality by sex.

Renal Parenchymal Leiomyoma Mimicking Renal Cell Carcinoma: A Case Report.

BACKGROUND: Renal leiomyoma is a challenging diagnostic and therapeutic condition. Given that 90% of leiomyomas originate from the renal capsule, leiomyoma presenting as a renal parenchymal mass is extraordinarily rare. CASE PRESENTATION: Herein, we report the clinical and imaging features of a patient with renal leiomyoma occurring in the renal parenchyma and mimicking renal cell carcinoma. We also review the clinical, imaging, and histological features of renal leiomyoma. CONCLUSION: An initial partial, simple or radical nephrectomy according to tumor size and patient's underlying condition is suitable for larger, heterogeneous, and non-peripherally located tumors, even if they demonstrate hypointensity on T1- and T2-weighted images, considering the possibility of other diagnoses.

Frequent low dose alcohol intake increases gastric cancer risk: the Health Examinees-Gem (HEXA-G) study.

OBJECTIVE: Epidemiological studies indicate that alcohol increases gastric cancer (GC) risk, yet most studies have focused on heavy alcohol intake, leaving other factors understudied. A comprehensive investigation of the effects of the frequency and amount of alcohol intake may help elucidate the GC risk associated with drinking behavior. METHODS: The Health Examinees-Gem (HEXA-G) study, a community-based large-scale prospective cohort study, enrolled Korean adults 40-69 years of age between the years 2004 and 2013. Incident GC cases were identified through linkage to Korea Central Cancer Registry data until December 31, 2017. Self-reported questionnaires were used to survey alcohol consumption-related factors (duration, frequency, amount, and type of alcoholic beverages). The frequency and amount of alcohol consumption were combined to explore GC risk according to 4 drinking patterns: "infrequent-light", "frequent-light", "infrequent-heavy", and "frequent-heavy". We used Cox proportional hazard models to estimate the adjusted hazard ratios (HRs) and 95% confidence intervals (CIs), and investigate the relationship between alcohol intake and GC incidence. RESULTS: A total of 128,218 participants were included in the analysis. During an average follow-up period of 8.6 years, 462 men and 385 women were diagnosed with GC. In men, current drinkers showed a 31% greater risk of GC than non-drinkers (HR 1.31, 95% CI 1.03-1.66), whereas no significant association was observed in women. In men, GC risk was associated with a higher frequency (P trend 0.02) and dose of ethanol intake in grams (P trend 0.03). In men, the "frequent-light" (≥5 times/week and <40 g ethanol/day) drinking pattern was associated with a 46% greater risk of GC (HR 1.46, 95% CI 1.02-2.07) than the "infrequent-light" pattern (<5 times/week and <40 g ethanol/day). CONCLUSIONS: This study suggests that frequent intake of alcohol, even in low quantities per session, increases GC risk. Further research is warranted to evaluate the relationship between alcohol and GC in detail.

Obesity at early adulthood increases risk of gastric cancer from the Health Examinees-Gem (HEXA-G) study.

Emerging evidence has indicated a possible link between obesity in early life with subsequent cancer risks, but its association with gastric cancer remains unknown. This study aimed to investigate the association of obesity at ages 18-20 and 35 with the later risk of gastric cancer among the Korean population. Included were 122,724 individuals who participated in the large-scale prospective cohort study, the Health Examinees-Gem (HEXA-G) study, during 2004-2017. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for gastric cancer risk associated with body mass index (BMI) at ages 18-20 and 35 years. During a mean follow-up period of 8.6±2.1 years, a total 927 gastric cancer cases (531 men and 396 women) were identified. When compared to normal BMI (18.5-23.0 kg/m2), obesity (BMI ≥30 kg/m2) at age 35 was significantly associated with increased risk of gastric cancer later in life among total participants (HR 1.94, 95% CI 1.26-2.97, p 0.01). When analyzed separately by sex, obesity at 35 years of age was significantly associated with increased risk of gastric cancer among both men (HR 1.79, 95% CI 1.02-3.13, p 0.05) and women (HR 2.35, 95% CI 1.21-4.60, p 0.02). No significant associations were found for obesity at late adolescence in both men and women. Our findings suggest that obesity in early adulthood may be associated with an increased risk of gastric cancer. The results may aid in understanding the etiology of GC in a population with a divergent trend of gastric cancer.

Associations Between Autoimmune Conditions and Gastric Cancer Risk Among Elderly Adults in the United States.

INTRODUCTION: Pernicious anemia (PA) is a risk factor for gastric cancer. Other autoimmune conditions may also contribute. METHODS: In a case-control study, we evaluated 47 autoimmune conditions among 39,125 gastric cancers and 200,000 cancer-free controls. RESULTS: Six conditions were associated with increased gastric cancer risk (range of adjusted odds ratios: 1.28-1.93, P < 0.05): PA, membranous nephropathy, primary biliary cirrhosis, pure red cell aplasia, primary sclerosing cholangitis, and Graves disease. PA was associated with 8 other autoimmune conditions (adjusted odds ratios: 1.57-4.54, P < 0.05). DISCUSSION: Autoimmune conditions associated with gastric cancer or PA may reflect effects of autoimmune gastritis or other carcinogenic pathways.

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.

Circulating Inflammation Markers and Pancreatic Cancer Risk: A Prospective Case-Cohort Study in Japan.

BACKGROUND: Previous prospective studies of associations between circulating inflammation-related molecules and pancreatic cancer risk have included limited numbers of markers. METHODS: We conducted a case-cohort study nested within the Japan Public Health Center-based Prospective Study Cohort II. We selected a random subcohort (n = 774) from a total of 23,335 participants aged 40 to 69 years who returned a questionnaire and provided blood samples at baseline. During the follow-up period from 1993 to 2010, we identified 111 newly diagnosed pancreatic cancer cases, including one case within the subcohort. Plasma concentrations of 62 inflammatory markers of chemokines, cytokines, and growth factors were measured by a Luminex fluorescent bead-based assay. Cox regression models were applied to estimate HR and 95% confidence intervals (CI) for pancreatic cancer risk for quartiles of marker levels adjusted for potential confounders. RESULTS: The HR (95% CI) for the highest versus the lowest category of C-C motif ligand chemokine 8/monocyte chemoattractant protein 2 (CCL8/MCP2) was 2.03 (1.05-3.93; P trend = 0.048). After we corrected for multiple comparisons, none of the examined biomarkers were associated with pancreatic cancer risk at P-value <0.05. CONCLUSIONS: We found no significant associations between 62 inflammatory markers and pancreatic cancer risk. IMPACT: The suggestive association with circulating levels of leukocyte recruiting cytokine CCL8/MCP2 may warrant further investigation.

Circulating immune- and inflammation-related biomarkers and early-stage noncardia gastric cancer risk.

BACKGROUND: In Helicobacter pylori-driven gastric cancer, mucosal colonization induces chronic inflammation that may variably progress to cancer. Prospective studies of circulating inflammation-related proteins have suggested weak associations with gastric cancer risk. To assess potential utility as a screening tool in clinical settings, we examined circulating levels of a wide range of key inflammation molecules for associations with early-stage gastric cancer. METHODS: We used pretreatment EDTA plasma from 239 individuals with early-stage noncardia gastric cancer (203 stage I and 36 stage II) and 256 age-frequency-matched H. pylori-seropositive cancer-free controls within the Hospital-based Epidemiologic Research Program at Aichi Cancer Center. Levels of 92 biomarkers were measured by proximity extension assays using Olink's Proseek Immuno-oncology Panel. Odds ratios (ORs) for association with gastric cancer risk were calculated for quantiles (two to four categories) of each biomarker from unconditional logistic regression models, adjusted for age, sex, smoking and alcohol consumption. Two-sided P values <0.05 were considered as significant. The false discovery rate (FDR) was used to correct for multiple comparisons. RESULTS: Of 83 evaluable biomarkers, lower levels of TNFRSF12A (per quartile OR, 0.82; nominal P-trend = 0.02) and ADGRG1 (per quartile OR, 0.84; nominal P-trend = 0.03) were associated with early-stage gastric cancer but were not statistically significant after FDR correction. CONCLUSION: Our study did not identify any inflammation-related biomarkers that may be useful for early disease detection. To date, this is the first assessment of circulating inflammation-related proteins in early-stage gastric cancer. Given the complex inflammation processes preceding malignant transformation, further investigation of other biomarkers is warranted.

Urinary estrogen metabolites and gastric cancer risk among postmenopausal women.

BACKGROUND: The overall incidence of gastric cancer in women is half that in men for most global populations. Sex hormone pathways may be involved in carcinogenesis and estrogens have been postulated to protect women against gastric cancer. AIM: To evaluate associations of gastric cancer with estrogen metabolites in postmenopausal women. METHODS AND RESULTS: We performed an analysis of 233 gastric cancer cases and 281 age-matched controls from three prospective cohorts and two case-control studies of early-stage gastric cancer, mainly conducted in high-risk Asian populations. Fifteen estrogen-parent (estrone and estradiol) and -metabolite analytes (2-hydroxyestrone, 2-hydroxyestradiol, 2-hydroxyestrone-3-methyl ether, 4-hydroxyestrone; 4-methoxyestrone, 4-methoxyestradiol, 2-methoxyestrone, 2-methoxyestradiol, estriol, 16α-hydroxyestrone, 16-ketoestradiol, 16-epiestriol, and 17-epiestriol) were measured in spot urines using liquid chromatography-tandem mass spectrometry. Odds ratios for association with each marker were estimated by logistic regression. Heterogeneity was assessed by Cochran's Q test. Study-specific odds ratios were pooled by fixed-effects meta-analysis. Urinary levels of estrogen-related molecules were not associated with gastric cancer (adjusted odds ratios ranged from 0.87 to 1.27; p-values >.05), with low between-study heterogeneity (p-values >.1) for all but two metabolites (2-hydroxyestrone-3-methyl ether and 2-methoxyestradiol). CONCLUSION: To date, this is the first comprehensive assessment of endogenous estrogens with gastric cancer risk in women. Estrogens do not appear to have an etiologic role in gastric cancer risk among postmenopausal women. Given the complex network of sex steroid hormones and their extreme variation over the lifespan, further evaluation of this hypothesis is warranted.

Association of Antiparietal Cell and Anti-Intrinsic Factor Antibodies With Risk of Gastric Cancer.

IMPORTANCE: Autoimmune gastritis is an alternative cause of gastric carcinogenesis. This cause may be gaining importance with declining prevalence of chronic Helicobacter pylori infection. OBJECTIVE: To determine the association of prediagnostic autoantibodies to gastric mucosa with gastric cancer (GC) risk. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used nested GC case-control analyses within separate Finnish cohorts of women of reproductive age (Finnish Maternity Cohort [FMC]; born 1938-1989) and older men (Alpha-Tocopherol, Beta-Carotene Cancer Prevention [ATBC] Study; born 1916-1939). There were 529 and 457 matched pairs from the FMC and ATBC Study, respectively, with mean participant ages of 30.5 and 57.5 years and medians of 17 and 11 years from baseline to cancer diagnosis. Data analyses were performed between August 2019 and November 2020. EXPOSURES: Antiparietal cell antibodies (APCAs), anti-intrinsic factor antibodies, and anti-H pylori antibodies were measured in baseline serum using immunoassays. MAIN OUTCOMES AND MEASURES: Autoantibody associations were estimated by odds ratios (ORs) and 95% CIs. RESULTS: Of the 529 control participants in the FMC and 457 control participants in the ATBC Study, 53 (10%) women and 35 (7.7%) men were APCA seropositive, respectively, whereas 146 (28%) women and 329 (72%) men were H pylori seropositive. In the FMC, APCA seropositivity was statistically significantly associated with GC risk among H pylori-seronegative women (OR, 5.52; 95% CI, 3.16-9.64) but not H pylori-seropositive women (OR, 1.29; 95% CI, 0.64-2.60; P for interaction = .002). The APCA association with H pylori seronegativity was strongest for tumors in the fundus and corpus (OR, 24.84; 95% CI, 8.49-72.72). In the ATBC Study, APCA seropositivity was not associated with GC among either H pylori-seronegative men (OR, 0.99; 95% CI, 0.32-3.04) or H pylori-seropositive men (OR, 1.06; 95% CI, 0.60-1.88). In both cohorts, anti-intrinsic factor antibody seroprevalence was less than 2% among cases as well as controls and not statistically associated with GC risk. CONCLUSIONS AND RELEVANCE: Results of this cohort study demonstrate that autoantibody positivity may reflect subclinical autoimmune gastritis in younger women. The findings among young females and corpus subsite align with increasing cancer incidence trends for these groups. Stronger autoimmune associations in H pylori-seronegative individuals support a model of autoimmune gastritis replacing H pylori as the driving factor.

Association between long-term exposure to particulate matter and childhood cancer: A retrospective cohort study.

BACKGROUND: Although particulate matter is a known carcinogen, its association with childhood cancer is inconclusive. The present study aimed to examine the association between long-term exposure to particulate matter and childhood cancer. METHODS: A retrospective cohort was constructed from the claims database of the Korea National Health Insurance Service, including children born in seven metropolitan cities in Korea between 2002 and 2012. Monthly mean concentrations of particulate matter with aerodynamic diameter <10 µm (PM10) and other air pollutants (NO2, SO2, CO, and O3) were calculated using data from the AirKorea. Monthly mean concentrations of particulate matter with aerodynamic diameter <2.5 µm (PM2.5) were estimated based on a data fusion approach. Cumulative exposure was assessed by averaging the monthly concentrations accounting for the residential mobility of the children. The occurrence of cancer was identified by the appearance of diagnosis codes in the claims database. Hazard ratios (HR) and 95% confidence intervals (95% CI) were calculated using Cox proportional regression, adjusting for potential confounders and O3 concentrations. RESULTS: During the study period, 1,725 patients were newly diagnosed with cancer among 1,261,855 children. HR of all cancers per 10 µg/m3 increment in annual mean concentrations of PM2.5 and PM10 were 3.02 (95% CI: 1.63, 5.59) and 1.04 (0.74, 1.45), respectively. CONCLUSION: PM2.5 exposure was positively associated with childhood cancer in a large retrospective cohort with exposure assessment accounting for residential mobility.