Sargramostim for Prophylactic Management of Gastrointestinal Immune-Related Adverse Events of Immune Checkpoint Inhibitor Therapy for Cancer.

Immune checkpoint inhibitor (ICI) therapy improves outcomes in several cancers. Unfortunately, many patients experience grade 3-4 treatment-related adverse events, including gastrointestinal (GI) toxicities which are common. These GI immune-related adverse events (irAEs) induced by ICIs present significant clinical challenges, require prompt intervention, and result in treatment delays or discontinuations. The treatment for these potentially severe and even fatal GI irAEs which include enterocolitis, severe diarrhea, and hepatitis may interfere with the anti-cancer approach. Sargramostim (glycosylated, yeast-derived, recombinant human GM-CSF) is an agent that has been used in clinical practice for more than 30 years with a well-recognized safety profile and has been studied in many therapeutic areas. The mechanism of action of sargramostim may treat moderate-to-severe GI irAEs without impairing the anti-cancer therapy. Some early data also suggest a potential survival benefit. Through the differentiation/maturation of monocytes, macrophages, and neutrophils and induction of anti-inflammatory T cell responses, GM-CSF aids in GI homeostasis, mucosal healing, and mucosal immunity. GM-CSF knockout mice are susceptible to severe colitis which was prevented with murine GM-CSF administration. For some patients with GI mucosa and immune cell function impairment, e.g., Crohn's disease, sargramostim reduces disease severity. In a prospective, randomized study (ECOG 1608), advanced melanoma patients had a reduction in grade 3-5 GI irAEs and less frequent colonic perforation in the sargramostim plus ipilimumab arm compared to ipilimumab alone. Sargramostim continues to be studied with ICIs for the prophylactic management of irAEs while also potentially providing a survival benefit.

Application of Mendelian randomization to explore the causal role of the human gut microbiome in colorectal cancer.

The role of the human gut microbiome in colorectal cancer (CRC) is unclear as most studies on the topic are unable to discern correlation from causation. We apply two-sample Mendelian randomization (MR) to estimate the causal relationship between the gut microbiome and CRC. We used summary-level data from independent genome-wide association studies to estimate the causal effect of 14 microbial traits (n = 3890 individuals) on overall CRC (55,168 cases, 65,160 controls) and site-specific CRC risk, conducting several sensitivity analyses to understand the nature of results. Initial MR analysis suggested that a higher abundance of Bifidobacterium and presence of an unclassified group of bacteria within the Bacteroidales order in the gut increased overall and site-specific CRC risk. However, sensitivity analyses suggested that instruments used to estimate relationships were likely complex and involved in many potential horizontal pleiotropic pathways, demonstrating that caution is needed when interpreting MR analyses with gut microbiome exposures. In assessing reverse causality, we did not find strong evidence that CRC causally affected these microbial traits. Whilst our study initially identified potential causal roles for two microbial traits in CRC, importantly, further exploration of these relationships highlighted that these were unlikely to reflect causality.

Evaluation of Birth by Cesarean Delivery and Development of Early-Onset Colorectal Cancer.

Importance: The incidence of early-onset colorectal cancer (CRC), diagnosed younger than 50 years of age, has increased worldwide. Gut dysbiosis throughout the life course is hypothesized as a leading mechanism, yet epidemiologic data are limited. Objective: To prospectively examine the association between birth by cesarean delivery and early-onset CRC among offspring. Design, Setting, and Participants: In this population-based, nationwide case-control study in Sweden, adults diagnosed with CRC between 18 and 49 years of age from 1991 to 2017 were identified through the Epidemiology Strengthened by Histopathology Reports in Sweden (ESPRESSO) cohort. Up to 5 general population control individuals without CRC were matched with each case on age, sex, calendar year, and county of residence. Pathology-confirmed end points were linked with the Swedish Medical Birth Register and other national registers. Analyses were conducted from March 2022 through March 2023. Exposure: Birth by cesarean delivery. Main Outcomes and Measures: The primary outcome was development of early-onset CRC in the overall population and by sex. Results: We identified 564 case patients with incident early-onset CRC (mean [SD] age, 32.9 [6.2] years; 284 [50.4%] male) and 2180 matched controls (mean [SD] age, 32.7 [6.3] years; 1104 [50.6%] male). Compared with vaginal delivery, birth by cesarean delivery was not associated with early-onset CRC in the overall population (adjusted odds ratio [aOR], 1.28; 95% CI, 0.91-1.79) after multivariable adjustment for matching and maternal and pregnancy-related factors. A positive association was found for females (aOR, 1.62; 95% CI, 1.01-2.60), but there was no association for males (aOR, 1.05; 95% CI, 0.64-1.72). Conclusions and Relevance: In this nationwide, population-based case-control study, birth by cesarean delivery was not associated with early-onset CRC compared with birth by vaginal delivery in the overall population in Sweden. However, females born by cesarean delivery had greater odds of early-onset CRC compared with individuals born through vaginal delivery. This finding suggests that early-life gut dysbiosis may contribute to early-onset CRC in females.

Genetic Predictors for Fecal Propionate and Butyrate-Producing Microbiome Pathway Are Not Associated with Colorectal Cancer Risk: A Mendelian Randomization Analysis.

BACKGROUND: Mechanistic data indicate the benefit of short-chain fatty acids (SCFA) produced by gut microbial fermentation of fiber on colorectal cancer, but direct epidemiologic evidence is limited. A recent study identified SNPs for two SCFA traits (fecal propionate and butyrate-producing microbiome pathway PWY-5022) in Europeans and showed metabolic benefits. METHODS: We conducted a two-sample Mendelian randomization analysis of the genetic instruments for the two SCFA traits (three SNPs for fecal propionate and nine for PWY-5022) in relation to colorectal cancer risk in three large European genetic consortia of 58,131 colorectal cancer cases and 67,347 controls. We estimated the risk of overall colorectal cancer and conducted subgroup analyses by sex, age, and anatomic subsites of colorectal cancer. RESULTS: We did not observe strong evidence for an association of the genetic predictors for fecal propionate levels and the abundance of PWY-5022 with the risk of overall colorectal cancer, colorectal cancer by sex, or early-onset colorectal cancer (diagnosed at <50 years), with no evidence of heterogeneity or pleiotropy. When assessed by tumor subsites, we found weak evidence for an association between PWY-5022 and risk of rectal cancer (OR per 1-SD, 0.95; 95% confidence intervals, 0.91-0.99; P = 0.03) but it did not surpass multiple testing of subgroup analysis. CONCLUSIONS: Genetic instruments for fecal propionate levels and the abundance of PWY-5022 were not associated with colorectal cancer risk. IMPACT: Fecal propionate and PWY-5022 may not have a substantial influence on colorectal cancer risk. Future research is warranted to comprehensively investigate the effects of SCFA-producing bacteria and SCFAs on colorectal cancer risk.

Prediagnostic Vitamin D Status and Colorectal Cancer Survival by Vitamin D Binding Protein Isoforms in US Cohorts.

CONTEXT: Lower 25-hydroxyvitamin D (25(OH)D) levels have consistently been associated with higher mortality among participants with colorectal cancer (CRC). OBJECTIVE: To investigate whether the association between 25(OH)D and CRC mortality differs according to vitamin D binding protein (also known as Gc) isoforms. METHODS: We examined the association between prediagnostic 25(OH)D levels and overall and CRC-specific mortality among participants with CRC within 2 prospective US cohorts. Cox proportional hazards regression was used to estimate the hazard ratios (HRs) and 95% CIs. RESULTS: 588 participants with CRC were observed until the date of death or last follow-up (2018), whichever came first. Deficient vs sufficient 25(OH)D concentrations (<30 vs ≥50 nmol/L) were associated with higher overall mortality (HR 2.06; 95% CI 1.34-3.18) but not with CRC-specific mortality (HR 1.51; 95% CI 0.75-3.07). The HRs for overall mortality comparing deficient vs sufficient concentrations were 2.43 (95% CI 1.26-4.70) for those with the Gc1-1 isoform (rs4588 CC) and 1.63 (95% CI 0.88-3.02) for those with the Gc1-2 or Gc2-2 (rs4588 CA or AA) isoform (P for interaction = .54). The HRs for CRC-specific mortality were 1.18 (95% CI 0.27-5.14) for those with the Gc1-1 isoform and 1.41 (95% CI 0.62-3.24) for those with the Gc1-2 or Gc2-2 isoform (P for interaction = .94). CONCLUSION: In these 2 US cohorts, we found that lower 25(OH)D levels were associated with higher overall mortality, but this association did not differ by Gc isoforms.

Endoscopic Screening and Risk of Colorectal Cancer according to Type 2 Diabetes Status.

Current recommendations for colorectal cancer screening have not accounted for type 2 diabetes (T2D) status. It remains unknown whether the colorectal cancer-preventive benefit of endoscopic screening and the recommended age for screening initiation differ by T2D. Among 166,307 women (Nurses' Health Study I and II, 1988-2017) and 42,875 men (Health Professionals Follow-up Study, 1988-2016), endoscopic screening and T2D diagnosis were biennially updated. We calculated endoscopic screening-associated hazard ratios (HR) and absolute risk reductions (ARR) for colorectal cancer incidence and mortality according to T2D, and age-specific colorectal cancer incidence according to T2D. During a median of 26 years of follow-up, we documented 3,457 colorectal cancer cases and 1,129 colorectal cancer deaths. Endoscopic screening was associated with a similar HR of colorectal cancer incidence in the T2D and non-T2D groups (P-multiplicative interaction = 0.57). In contrast, the endoscopic screening-associated ARR for colorectal cancer incidence was higher in the T2D group (2.36%; 95% CI, 1.55%-3.13%) than in the non-T2D group (1.73%; 95% CI, 1.29%-2.16%; P-additive interaction = 0.01). Individuals without T2D attained a 10-year cumulative risk of 0.35% at the benchmark age of 45 years, whereas those with T2D reached this threshold risk level at the age of 36 years. Similar results were observed for colorectal cancer mortality. In conclusion, the absolute benefit of endoscopic screening for colorectal cancer prevention may be substantially higher for individuals with T2D compared with those without T2D. Although T2D is comparatively rare prior to the fifth decade of life, the rising incidence of young-onset T2D and heightened colorectal cancer risk associated with T2D support the consideration of earlier endoscopic screening in individuals with T2D. PREVENTION RELEVANCE: The endoscopic screening-associated ARRs for colorectal cancer incidence and mortality were higher for individuals with T2D than those without T2D. Endoscopic screening confers a greater benefit for colorectal cancer prevention among T2D individuals, who may also benefit from an earlier screening than the current recommendation.

A Multicenter Study of Left Ventricular Assist Device-Related Gastrointestinal Bleeding.

INTRODUCTION: Continuous left ventricular assist devices (LVADs) offer hemodynamic support in advanced and decompensated heart failure but are often complicated by gastrointestinal bleeding (GIB) in medically fragile patients. METHODS: We performed a retrospective analysis of 475 consecutive patients who underwent LVAD implantation at the Massachusetts General Hospital and Tufts Medical Center from 2008 to 2019 and identified 128 patients with clinically significant GIB. Clinical characteristics of each bleeding event, including procedures and interventions, were recorded. We examined LVAD patients with overt and occult presentations to determine diagnostic endoscopic yield and analyzed predictors of recurrent GIB. RESULTS: We identified 128 unique patients with LVAD implantation complicated by GIB. No significant difference was observed based on study center, underlying cardiomyopathy, race/ethnicity, serum indices, and medications used. Overt bleeders presented more commonly during LVAD implantation admission ( P = 0.001) than occult bleeders. Occult bleed presentations had only 1 lower and no middle GI bleed source identified, despite similar workups to overt bleeds. Destination therapy (e.g., among nontransplant candidates) LVAD implantation (odds ratio 2.38, 95% confidence interval 1.05-5.58) and a history of GIB (odds ratio 3.85, 95% confidence interval 1.29-12.7) were independently associated with an increased risk of recurrent GIB-related hospitalization. DISCUSSION: Our findings confirm a high rate of GIB, especially in destination LVAD patients, and show a low diagnostic yield for colonoscopy and middle GI bleed assessments in LVAD patients with occult bleeds. Overt bleeding was more common and associated with vascular malformations. Although endoscopic interventions stopped active hemorrhage, GIB often recurred.

Association of Proton Pump Inhibitor Use With All-Cause and Cause-Specific Mortality.

BACKGROUND & AIMS: The use of proton pump inhibitors (PPIs) has increased rapidly in the past 2 decades. Concerns about the regular use of PPIs contributing to mortality have been raised. METHODS: We conducted a prospective cohort study using data collected from the Nurses' Health Study (2004-2018) and the Health Professionals Follow-up Study (2004-2018). Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% CIs for mortality according to PPI use. We used a modified lag-time approach to minimize reverse causation (ie, protopathic bias). RESULTS: Among 50,156 women and 21,731 men followed for 831,407 person-years and a median of 13.8 years, we documented 22,125 deaths, including 4592 deaths from cancer, 5404 from cardiovascular diseases, and 12,129 deaths from other causes. Compared with nonusers of PPIs, PPI users had significantly higher risks of all-cause mortality (HR, 1.19; 95% CI, 1.13-1.24) and mortality due to cancer (HR, 1.30; 95% CI, 1.17-1.44), cardiovascular diseases (HR, 1.13; 95% CI, 1.02-1.26), respiratory diseases (HR, 1.32; 95% CI, 1.12-1.56), and digestive diseases (HR, 1.50; 95% CI, 1.10-2.05). Upon applying lag times of up to 6 years, the associations were attenuated and no longer statistically significant (all-cause: HR, 1.04; 95% CI, 0.97-1.11; cancer: HR, 1.07; 95% CI, 0.89-1.28; cardiovascular diseases: HR, 0.94; 95% CI, 0.81-1.10; respiratory diseases: HR, 1.20; 95% CI, 0.95-1.50; digestive diseases: HR, 1.38; 95% CI, 0.88-2.18). Longer duration of PPI use did not confer higher risks for all-cause and cause-specific mortality. CONCLUSIONS: After accounting for protopathic bias, PPI use was not associated with higher risks of all-cause mortality and mortality due to major causes.

Antibiotic Therapy and Risk of Early-Onset Colorectal Cancer: A National Case-Control Study.

INTRODUCTION: Antibiotic use has emerged as a risk factor for colorectal neoplasia and is hypothesized as a contributor to the rising incidence of colorectal cancer under age 50 years or early-onset colorectal cancer (EOCRC). However, the impact of antibiotic use and risk of EOCRC is unknown. METHODS: We conducted a population-based case-control study of CRC among individuals aged ≥18 years in the Epidemiology Strengthened by histoPathology Reports in Sweden (ESPRESSO) cohort (2006-2016). The primary outcome was EOCRC. A secondary outcome was CRC at any age. Incident CRC was pathologically confirmed, and for each, up to 5 population-based controls were matched on age, sex, county of residence, and calendar year. We assessed prescriptions until 6 months before CRC diagnosis. Conditional logistic regression was used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). RESULTS: We identified 54,804 cases of CRC (2,557 EOCRCs) and 261,089 controls. Compared with none, previous antibiotic use was not associated with EOCRC risk after adjustment for potential confounders (aOR 1.06, 95% CI: 0.96, 1.17) with similarly null findings when stratified by anatomic tumor site. In contrast, previous antibiotic use was weakly associated with elevated risk for CRC at any age (aOR 1.05, 95% CI: 1.02, 1.07). A potential but modest link between broad-spectrum antibiotic use and EOCRC was observed (aOR 1.13, 95% CI: 1.02, 1.26). DISCUSSION: We found no conclusive evidence that antibiotics are associated with EOCRC risk. Although antibiotic use was weakly associated with risk of CRC at any age, the magnitude of association was modest, and the study period was relatively short.

Symptom clusters: Revisiting the concept in nursing care for cancer patients.

BACKGROUND: Studies on symptom clusters among cancer patients have been conducted intensively. However, the concept seems not to be well defined, hindering its utilization in clinical practice. AIM: The aim of this paper is to reconceptualize symptom cluster and discuss areas of future research. RESULTS: A cluster of symptoms should not be viewed as simply as a group of symptoms appearing together. It should be clinically relevant, and symptom members should be interactive or have a mutual etiology. A cluster is declared as stable if its "quality" or "nature" is remained instead of merely having the same number of symptoms. Importantly, each symptom cluster should have a sentinel symptom. The sentinel symptom could be the one that predicts the presence of the cluster or could be the one that significantly interacts with other symptoms. The search for symptom clusters, which are common among various patient groups, might be helpful in some aspects. However, to better understand them, symptom clusters should be examined in specific populations. CONCLUSION: The nature of the relationship between symptom members, clinical relevance, sentinel symptom, stability, and prevalence are important features of a symptom cluster. More explorations into these properties by future studies are suggested.

Association Between the Sulfur Microbial Diet and Risk of Colorectal Cancer.

Importance: Sulfur-metabolizing bacteria that reduce dietary sulfur to hydrogen sulfide have been associated with colorectal cancer (CRC). However, there are limited studies investigating the association between diet and sulfur-metabolizing bacteria in the development of CRC. Objective: To develop a dietary score that correlates with gut sulfur-metabolizing bacteria and to examine its association with CRC risk. Design, Setting, and Participants: This prospective cohort study included data from the Health Professionals Follow-up Study (1986-2014), Nurses' Health Study (1984-2016), and Nurses' Health Study II (1991-2017). Participants were US male health professionals and female registered nurses who were free of inflammatory bowel disease and cancer at baseline, with a subsample of participants who provided stool samples from 2012 to 2014. Statistical analysis was conducted from September 1, 2020, to June 1, 2021. Exposure: A dietary pattern, assessed by a food-frequency questionnaire, that most correlated with 43 sulfur-metabolizing bacteria identified through taxonomic and functional profiling of gut metagenome data. Main Outcomes and Measures: Incident CRC. Results: Among 214 797 participants comprising 46 550 men (mean [SD] age at baseline, 54.3 [9.7] years) and 168 247 women (mean [SD] age at baseline, 43.0 [9.2] years), 3217 incident cases of CRC (1.5%) were documented during 5 278 048 person-years of follow-up. The sulfur microbial diet, developed in a subsample of 307 men (mean [SD] age, 70.5 [4.3] years) and 212 women (mean [SD] age, 61.0 [3.8] years), was characterized by high intakes of low-calorie beverages, french fries, red meats, and processed meats and low intakes of fruits, yellow vegetables, whole grains, legumes, leafy vegetables, and cruciferous vegetables. After adjustment for other risk factors, greater adherence to the sulfur microbial diet was associated with an increased risk of CRC, with a hazard ratio (HR) of 1.27 (95% CI, 1.12-1.44) comparing the highest vs the lowest quintile of the diet score (linear trend of diet score quintiles; P < .001 for trend). When assessed by anatomical subsites, greater adherence to the sulfur microbial diet was positively associated with distal CRC (HR, 1.25; 95% CI, 1.05-1.50; P = .02 for trend) but not proximal colon cancer (HR, 1.13; 95% CI, 0.93-1.39; P = .19 for trend). Conclusions and Relevance: Adherence to the sulfur microbial diet was associated with an increased risk of CRC, suggesting a potential mediating role of sulfur-metabolizing bacteria in the associaton between diet and CRC. Further research is needed to confirm these findings and to determine the underlying mechanisms.

Regular Use of Proton Pump Inhibitor and the Risk of Inflammatory Bowel Disease: Pooled Analysis of 3 Prospective Cohorts.

BACKGROUND & AIMS: Proton pump inhibitors (PPIs) have a major impact on gut microbiome and immune function, which in turn, may increase the risk of inflammatory bowel disease (IBD). Our aim in this study was to evaluate PPI use and subsequent risk of IBD and subtypes (ie, Crohn's disease and ulcerative colitis). METHODS: This was a pooled analysis of the Nurses' Health Study (NHS, n = 82,869), NHS II (n = 95,141), and UK Biobank (n = 469,397). We included participants with information on personal use of PPIs and free of IBD or cancer at baseline. We evaluated hazard ratios and 95% confidence intervals (CIs) with Cox regression adjusting for lifestyle factors, PPI indications, comorbidities, and other medications. RESULTS: We documented 271 cases of IBD (median follow-up, 12 years) in the pooled NHS cohorts and 1419 cases (median follow-up, 8.1 years) in the UK Biobank. For both pooled NHS cohorts and UK Biobank, regular use of PPIs consistently showed a significantly positive association with IBD, Crohn's disease, and ulcerative colitis risk. Combined analyses of 3 cohorts showed that regular PPI users had an increased risk of IBD as compared with nonusers (hazard ratio, 1.42; 95% CI, 1.22-1.65; number needed to harm, 3770; 95% CI, 3668-4369). Direct comparison with H2 receptor antagonist, a less potent acid suppressor, showed that PPI use was also associated with higher IBD risk (hazard ratio, 1.38; 95% CI, 1.16-1.65). CONCLUSIONS: Regular use of PPIs was associated with an increased risk of IBD and its subtypes. The findings should be interpreted with caution because the absolute risk was low and the clinical benefits of PPIs are substantial.

The Sulfur Microbial Diet and Risk of Colorectal Cancer by Molecular Subtypes and Intratumoral Microbial Species in Adult Men.

INTRODUCTION: We recently described the sulfur microbial diet, a pattern of intake associated with increased gut sulfur-metabolizing bacteria and incidence of distal colorectal cancer (CRC). We assessed whether this risk differed by CRC molecular subtypes or presence of intratumoral microbes involved in CRC pathogenesis (Fusobacterium nucleatum and Bifidobacterium spp.). METHODS: We performed Cox proportional hazards modeling to examine the association between the sulfur microbial diet and incidence of overall and distal CRC by molecular and microbial subtype in the Health Professionals Follow-Up Study (1986-2012). RESULTS: We documented 1,264 incident CRC cases among 48,246 men, approximately 40% of whom had available tissue data. After accounting for multiple hypothesis testing, the relationship between the sulfur microbial diet and CRC incidence did not differ by subtype. However, there was a suggestion of an association by prostaglandin synthase 2 (PTGS2) status with a multivariable adjusted hazard ratio for highest vs lowest tertile of sulfur microbial diet scores of 1.31 (95% confidence interval: 0.99-1.74, Ptrend = 0.07, Pheterogeneity = 0.04) for PTGS2-high CRC. The association of the sulfur microbial diet with distal CRC seemed to differ by the presence of intratumoral Bifidobacterium spp. with an adjusted hazard ratio for highest vs lowest tertile of sulfur microbial diet scores of 1.65 (95% confidence interval: 1.14-2.39, Ptrend = 0.01, Pheterogeneity = 0.03) for Bifidobacterium-negative distal CRC. We observed no apparent heterogeneity by other tested molecular markers. DISCUSSION: Greater long-term adherence to the sulfur microbial diet could be associated with PTGS2-high and Bifidobacterium-negative distal CRC in men. Additional studies are needed to further characterize the role of gut microbial sulfur metabolism and CRC.

The Sulfur Microbial Diet Is Associated With Increased Risk of Early-Onset Colorectal Cancer Precursors.

BACKGROUND & AIMS: Diet may contribute to the increasing incidence of colorectal cancer (CRC) before age 50 (early-onset CRC). Microbial metabolism of dietary sulfur produces hydrogen sulfide (H2S), a gastrointestinal carcinogen that cannot be easily measured at scale. As a result, evidence supporting its role in early neoplasia is lacking. METHODS: We evaluated long-term adherence to the sulfur microbial diet, a dietary index defined a priori based on increased abundance of 43 bacterial species involved with sulfur metabolism, with risk of CRC precursors among 59,013 individuals who underwent lower endoscopy in the Nurses' Health Study II (1991-2015), a prospective cohort study with dietary assessment every 4 years through validated food frequency questionnaires and an assessment of dietary intake during adolescence in 1998. The sulfur microbial diet was characterized by intake high in processed meats, foods previously linked to CRC development, and low in mixed vegetables and legumes. Multivariable logistic regression for clustered data was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: We documented 2911 cases of early-onset adenoma. After adjusting for established risk factors, higher sulfur microbial diet scores were associated with increased risk for early-onset adenomas (ORquartile [Q]4 vs Q1, 1.31; 95% CI, 1.10-1.56, Ptrend = .02), but not serrated lesions. Compared with the lowest, women in the highest quartile of sulfur microbial diet scores had significantly increased risk of early-onset adenomas with greater malignant potential (ORQ4 vs Q1, 1.65 for villous/tubulovillous histology; 95% CI, 1.12-2.43; Ptrend = .04). Similar trends for early-onset adenoma were observed based on diet consumed during adolescence. In contrast, no clear association for adenomas was identified after age 50. CONCLUSIONS: Our findings in a cohort of young women support a role for dietary interactions with gut sulfur-metabolizing bacteria in early-onset colorectal carcinogenesis, possibly beginning in adolescence.

Irreducible Traumatic Radial Head Dislocation Due to Annular Ligament Interposition in a Child with Ulnar Plastic Deformation: A Case Report.

BACKGROUND: The traumatic dislocation of the radial head in children is commonly treated by closed reduction. Sometimes, however, this strategy of treatment may not be effective due to the location of soft tissues in the radio-shoulder joint. The literature presents a few cases of the irreducible radial head dislocation with ulnar plastic deformation. Because it is a relatively rare condition, such a traumatic dislocation can be easily missed. Neglected injuries can lead to unwanted complications and unpredictable surgical outcomes. CASE PRESENTATION: This study presents a relatively rare case of traumatic radial head dislocation with ulnar plastic deformation in a 3-year-old child, which was successfully treated by open reduction. The examined case did not require osteotomy and ligamentous reconstruction. The initial attempt of closed reduction failed due to annular ligament interposition, which has been detected on MRI. After 3 months of treatment, the range of motion of the operated arm gradually improved. At the 6-month follow-up, the Mayo elbow-performance score indicated an excellent treatment outcome. CONCLUSIONS: The delayed treatment of radial head dislocation with ulnar plastic deformation can hinder the supination and pronation of the forearm, resulting in elbow/forearm deformity. The earlier this condition is detected, the easier it will be to treat it and the better the treatment outcome will be. The examined case of irreversible traumatic dislocation, successfully treated by open reduction, may help to treat radial head dislocation better.

Association of Screening Lower Endoscopy With Colorectal Cancer Incidence and Mortality in Adults Older Than 75 Years.

IMPORTANCE: Evidence indicates that screening for colorectal cancer (CRC) beginning at 50 years of age can detect early-stage CRC and premalignant neoplasms (eg, adenomas) and thus prevent CRC-related mortality. At present, the US Preventive Services Task Force recommends continuing CRC screening until 75 years of age and individualized decision-making for adults older than 75 years, while accounting for a patient's overall health and screening history. However, scant data exist to support these recommendations. OBJECTIVE: To examine the association of lower gastrointestinal tract screening endoscopy with the risk of CRC incidence and CRC-related mortality in older US adults. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study of health care professionals in the US included data from the Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS) from January 1, 1988, through January 31, 2016, for the HPFS and June 30, 2016, for the NHS. Data were analyzed from May 8, 2019, to July 9, 2020. EXPOSURES: History of screening sigmoidoscopy or colonoscopy (routine/average risk or positive family history) to 75 years of age and after 75 years of age, assessed every 2 years. MAIN OUTCOMES AND MEASURES: Incidence of CRC and CRC-related mortality confirmed by National Death Index, medical records, and pathology reports. RESULTS: Among 56 374 participants who reached 75 years of age during follow-up (36.8% men and 63.2% women), 661 incident CRC cases and 323 CRC-related deaths were documented. Screening endoscopy after 75 years of age was associated with reduced risk of CRC incidence (multivariable hazard ratio [HR], 0.61; 95% CI, 0.51-0.74) and CRC-related mortality (HR, 0.60; 95% CI, 0.46-0.78), regardless of screening history. The HR comparing screening with nonscreening after 75 years of age was 0.67 (95% CI, 0.50-0.89) for CRC incidence and 0.58 (95% CI, 0.38-0.87) for CRC-related mortality among participants who underwent screening endoscopy before 75 years of age, and 0.51 (95% CI, 0.37-0.70) for CRC incidence and 0.63 (95% CI, 0.43-0.93) for CRC-related mortality among participants without a screening history. However, screening endoscopy after 75 years of age was not associated with risk reduction in CRC death among participants with cardiovascular disease (HR, 1.18; 95% CI, 0.59-2.35) or significant comorbidities (HR, 1.17; 95% CI, 0.57-2.43). CONCLUSIONS AND RELEVANCE: In this cohort study, endoscopy among individuals older than 75 years was associated with lower risk of CRC incidence and CRC-related mortality. These data support continuation of screening after 75 years of age among individuals without significant comorbidities.

Overview of the Microbiome Among Nurses study (Micro-N) as an example of prospective characterization of the microbiome within cohort studies.

A lack of prospective studies has been a major barrier for assessing the role of the microbiome in human health and disease on a population-wide scale. To address this significant knowledge gap, we have launched a large-scale collection targeting fecal and oral microbiome specimens from 20,000 women within the Nurses' Health Study II cohort (the Microbiome Among Nurses study, or Micro-N). Leveraging the rich epidemiologic data that have been repeatedly collected from this cohort since 1989; the established biorepository of archived blood, urine, buccal cell, and tumor tissue specimens; the available genetic and biomarker data; the cohort's ongoing follow-up; and the BIOM-Mass microbiome research platform, Micro-N furnishes unparalleled resources for future prospective studies to interrogate the interplay between host, environmental factors, and the microbiome in human health. These prospectively collected materials will provide much-needed evidence to infer causality in microbiome-associated outcomes, paving the way toward development of microbiota-targeted modulators, preventives, diagnostics and therapeutics. Here, we describe a generalizable, scalable and cost-effective platform used for stool and oral microbiome specimen and metadata collection in the Micro-N study as an example of how prospective studies of the microbiome may be carried out.

Aspirin Use and Risk of Colorectal Cancer Among Older Adults.

IMPORTANCE: Although aspirin is recommended for the prevention of colorectal cancer (CRC) among adults aged 50 to 59 years, recent data from a randomized clinical trial suggest a lack of benefit and even possible harm among older adults. OBJECTIVE: To examine the association between aspirin use and the risk of incident CRC among older adults. DESIGN, SETTING, AND PARTICIPANTS: A pooled analysis was conducted of 2 large US cohort studies, the Nurses' Health Study (June 1, 1980-June 30, 2014) and Health Professionals Follow-up Study (January 1, 1986-January 31, 2014). A total of 94 540 participants aged 70 years or older were included and followed up to June 30, 2014, for women or January 31, 2014, for men. Participants with a diagnosis of any cancer, except nonmelanoma skin cancer, or inflammatory bowel disease were excluded. Statistical analyses were conducted from December 2019 to October 2020. MAIN OUTCOMES AND MEASURES: Cox proportional hazards models were used to calculate multivariable adjusted hazard ratios (HRs) and 95% CIs for incident CRC. RESULTS: Among the 94 540 participants (mean [SD] age, 76.4 [4.9] years for women, 77.7 [5.6] years for men; 67 223 women [71.1%]; 65 259 White women [97.1%], 24 915 White men [96.0%]) aged 70 years or older, 1431 incident cases of CRC were documented over 996 463 person-years of follow-up. After adjustment for other risk factors, regular use of aspirin was associated with a significantly lower risk of CRC at or after age 70 years compared with nonregular use (HR, 0.80; 95% CI, 0.72-0.90). However, the inverse association was evident only among aspirin users who initiated aspirin use before age 70 years (HR, 0.80; 95% CI, 0.67-0.95). In contrast, initiating aspirin use at or after 70 years was not significantly associated with a lower risk of CRC (HR, 0.92; 95% CI, 0.76-1.11). CONCLUSIONS AND RELEVANCE: Initiating aspirin at an older age was not associated with a lower risk of CRC in this pooled analysis of 2 cohort studies. In contrast, those who used aspirin before age 70 years and continued into their 70s or later had a reduced risk of CRC.

Association of Inflammatory and Insulinemic Potential of Diet and Lifestyle with Risk of Hepatocellular Carcinoma.

BACKGROUND: We prospectively examined the extent to which greater inflammatory and insulinemic potential of diet and lifestyle are associated with the risk of developing hepatocellular carcinoma (HCC) in two nationwide cohorts. METHODS: Five kinds of pattern scores, including the empirical dietary inflammatory pattern (EDIP), empirical dietary index for hyperinsulinemia (EDIH) and insulin resistance (EDIR), empirical lifestyle pattern score for hyperinsulinemia (ELIH) and insulin resistance (ELIR) were calculated. Multivariable hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox regression. RESULTS: After an average follow-up of 25.6 years among 119,316 participants, 142 incident HCC cases were documented. Higher adherence to EDIP (HR by comparing extreme tertiles: 2.03; 95% CI, 1.31-3.16; P trend = 0.001), EDIH (HR, 1.61; 95% CI, 1.06-2.43; P trend = 0.02), and EDIR (HR, 1.62; 95% CI: 1.08-2.42; P trend = 0.02) was associated with increased risk of HCC. Likewise, participants with higher scores of ELIH (HR, 1.89; 95% CI, 1.25-2.87; P trend = 0.001) and ELIR (HR, 2.05; 95% CI, 1.34-3.14, P trend = 0.0004) had higher risk of developing HCC. Additional adjustment for diabetes mellitus and/or body mass index attenuated the magnitude of the associations, indicating that diabetes and/or adiposity may partly mediate the association of these patterns with HCC risk. CONCLUSIONS: Our findings suggest that inflammation and insulin resistance/hyperinsulinemia are potential mechanisms linking dietary or lifestyle factors and HCC development. IMPACT: Inflammation and insulin resistance/hyperinsulinemia may partly mediate the association of diet and other lifestyles with HCC development, and interventions to reduce the adverse effect of pro-inflammatory and hyperinsulinemic diet and lifestyle may reduce HCC risk.