Effect of home-based resistance training on chemotherapy relative dose intensity and tolerability in colon cancer: The FORCE randomized control trial.

BACKGROUND: Many patients with colon cancer cannot fully adhere to postoperative chemotherapy due to dose-limiting toxicities, resulting in lower relative dose intensity (RDI) and potentially compromising overall survival. This study examined whether home-based resistance training (RT) during adjuvant chemotherapy improves RDI and patient-reported toxicities versus usual care (UC) in colon cancer patients. METHODS: Multicenter, randomized control trial (RCT) conducted at community and academic practices. Enrollment of patients receiving postoperative chemotherapy for colon cancer occurred between February 23, 2018, and September 29, 2021; final follow-up was March 21, 2022. Participants were randomized to RT (n = 90) or UC (n = 91) for the duration of chemotherapy. Participants in the RT group engaged in twice weekly home-based progressive RT. At the end of the study, UC was given an online exercise program. RESULTS: Among 181 randomized patients (mean age, 55.2 [SD, 12.8] years, 95 [52.5%] were men), there were no differences in the mean RDI among those in RT (79% [SD, 19%]) and those in UC (82% [SD, 19%]); (mean difference -0.04 [95% confidence interval (CI), -0.09 to 0.02]). Assignment to RT did not significantly reduce the number of moderate/severe symptoms per week across follow-up (relative rate: 0.94 [95% CI, 0.72-1.22]). Additionally, time since randomization did not significantly modify the effect of RT on the overall number of symptoms (p = .06). CONCLUSIONS: Among patients with colon cancer, these results do not support home-based RT as an adjunct to chemotherapy specifically to improve planned treatment intensity.

Randomized Trial of Patient Outreach Approaches to De-implement Outdated Colonoscopy Surveillance Intervals.

BACKGROUND AND AIMS: Guidelines now recommend patients with low-risk adenomas receive colonoscopy surveillance in 7-10 years and those with the previously recommended 5-year interval be re-evaluated. We tested 3 outreach approaches for transitioning patients to the 10-year interval recommendation. METHODS: This was a 3-arm pragmatic randomized trial comparing telephone, secure messaging, and mailed letter outreach. The setting was Kaiser Permanente Northern California, a large integrated healthcare system. Participants were patients 54-70 years of age with 1-2 small (<10 mm) tubular adenomas at baseline colonoscopy, due for 5-year surveillance in 2022, without high-risk conditions, and with access to all 3 outreach modalities. Patients were randomly assigned to the outreach arm (telephone [n = 200], secure message [n = 203], and mailed letter [n = 201]) stratified by age, sex, and race/ethnicity. Outreach in each arm was performed by trained medical assistants (unblinded) communicating in English with 1 reminder attempt at 2-4 weeks. Participants could change their assigned interval to 10 years or continue their planned 5-year interval. RESULTS: Sixty-day response rates were higher for telephone (64.5%) and secure messaging outreach (51.7%) vs mailed letter (31.3%). Also, more patients adopted the 10-year surveillance interval in the telephone (37.0%) and secure messaging arms (32.0%) compared with mailed letter (18.9%) and rate differences were significant for telephone (18.1%; 97.5% confidence interval: 8.3%-27.9%) and secure message outreach (13.1%; 97.5% confidence interval: 3.5%-22.7%) vs mailed letter outreach. CONCLUSIONS: Telephone and secure messaging were more effective than mailed letter outreach for de-implementing outdated colonoscopy surveillance recommendations among individuals with a history of low-risk adenomas in an integrated healthcare setting. (ClinicalTrials.gov, Number: NCT05389397).

The Influence of Dietary Isothiocyanates on the Effectiveness of Mitomycin C and Bacillus Calmette-Guérin in Treating Nonmuscle-Invasive Bladder Cancer.

PURPOSE: Nonmuscle-invasive bladder cancer (NMIBC) has high recurrence rates and is often treated with mitomycin C (MMC) and bacillus Calmette-Guérin (BCG). Their efficacy relies on phase 2 enzyme metabolism and immune response activation, respectively. Dietary isothiocyanates, phytochemicals in cruciferous vegetables, are phase 2 enzyme inducers and immunomodulators, and may impact treatment outcomes. We investigated the modifying effects of cruciferous vegetable and isothiocyanate intake on recurrence risk following MMC or BCG treatment. MATERIALS AND METHODS: Self-reported cruciferous vegetable intake, estimated isothiocyanate intake, and urinary isothiocyanate metabolites were collected from 1158 patients with incident NMIBC in the prospective Be-Well Study. Hazard ratios (HRs) and 95% CIs were calculated from Cox proportional hazards regression models for risk of first recurrences, and random effects Cox shared frailty models for multiple recurrences. RESULTS: Over median follow-up of 23 months, 343 (30%) recurrences occurred. Receipt of MMC and BCG was associated with decreased risks of first recurrence (MMC: HR = 0.58; 95% CI: 0.46-0.73; BCG: HR = 0.66; 95% CI: 0.49-0.88) and multiple recurrences (MMC: HR = 0.55; 95% CI: 0.44-0.68; BCG: HR = 0.72; 95% CI: 0.55-0.95). Patients receiving BCG and having high intake (>2.4 servings/mo), but not low intake, of raw cruciferous vegetables had reduced risk of recurrence (HR: 0.56; 95% CI: 0.36-0.86; P for interaction = .02) and multiple recurrences (HR: 0.51; 95% CI: 0.34-0.77; P for interaction < .001). The inverse association between MMC receipt and recurrence risk was not modified. CONCLUSIONS: For NMIBC patients who receive induction BCG, increasing consumption of raw cruciferous vegetables could be a promising strategy to attenuate recurrence risk.

Comparative effectiveness of treating prenatal depression with counseling versus antidepressants in relation to preterm delivery.

BACKGROUND: Maternal depression during pregnancy is prevalent and has been associated with increased risk of preterm delivery. However, comparative effectiveness of 2 commonly used treatment options, mental health counseling and use of antidepressants, in mitigating the risk of preterm delivery associated with maternal depression remains uncertain. Although antidepressant use has been associated with increased risk of preterm delivery in many previous studies, a direct head-to-head comparison between these 2 treatment options has not been investigated. Thus, the comparative risk-benefit profiles of those 2 treatment options remain unclear. OBJECTIVE: To determine the comparative effectiveness of 2 commonly used options for treating prenatal depression in limiting the risk of preterm delivery associated with maternal depression. STUDY DESIGN: A large prospective cohort study was conducted among 82,170 pregnant women at Kaiser Permanente Northern California, an integrated health care delivery system. Clinically diagnosed depression and its treatments (use of antidepressants and mental health counseling) were identified from the Kaiser Permanente Northern California electronic health record system. Gestational age was also recorded for all deliveries and captured by electronic health records for determining preterm delivery. RESULTS: Using Cox proportional hazards regression incorporating propensity score methodology to ensure comparability between comparison cohorts, relative to those without depression, pregnant women with untreated depression had 41% increased risk of preterm delivery: adjusted hazard ratio=1.41, 95% confidence interval=1.24 to 1.60, confirming increased risk of preterm delivery associated underlying maternal depression. Relative to untreated depression, any mental health counseling was associated with an 18% of reduced risk of preterm delivery: adjusted hazard ratio=0.82 (0.71-0.96). The inverse association showed a dose-response pattern: increased number of counseling visits was associated with greater reduction in preterm delivery risk with 43% reduction in preterm delivery risk associated with 4 or more visits (adjusted hazard ratio=0.57, 95% confidence interval=0.45-0.73). In contrast, use of antidepressants during pregnancy was associated with an additional 31% increased risk of preterm delivery independent of underlying depression: adjusted hazard ratio=1.31, 95% confidence interval=1.06 to 1.61. This positive association also showed a dose-response relationship: a longer duration of use was associated with an even higher risk. CONCLUSION: This study provides much needed evidence regarding the comparative effectiveness of 2 common treatment options for prenatal depression in the context of preterm delivery risk. The results indicate that, to reduce preterm delivery risk due to maternal depression, mental health counseling is more effective. Use of antidepressants may add additional risk of preterm delivery, independent of the underlying depression. The findings provide data for clinicians and pregnant women to make informed and evidence-based treatment decisions that take into account the risks and benefits to both maternal and fetal health.

Gender differences in the association between education and late-life cognitive function in the LifeAfter90 Study: A multiethnic cohort of the oldest-old.

INTRODUCTION: Few studies have examined the relationship between education and cognition among the oldest-old. METHODS: Cognitive assessments were conducted biannually for 803 participants (62.6% women) of LifeAfter90, a longitudinal study of individuals ≥ 90 years old. Gender differences in associations between education (< high school, high school, some college, and ≥ college) and cognition (verbal episodic memory, semantic memory, and executive function) were examined at baseline and longitudinally using linear mixed models. RESULTS: Higher education levels were associated with better cognitive performance at baseline for both men and women. College completion was more strongly associated with better baseline executive function among women. Education-cognition associations for baseline verbal episodic memory and baseline semantic memory did not differ by gender. Education was not associated with a decline in any domain-specific cognitive scores, regardless of gender. DISCUSSION: Education is associated with cognitive function among the oldest-old and varies by gender and cognitive domain at baseline but not over time. HIGHLIGHTS: In the oldest-old, higher education was associated with better cognitive function. College completion was more strongly associated with executive function in women. Education was not associated with cognitive decline after age 90 regardless of gender. Improving education could decrease gaps in cognitive level among older individuals.

Timing and level of educational attainment and late-life cognition in the KHANDLE study.

INTRODUCTION: The timing of educational attainment may modify its effects on late-life cognition, yet most studies evaluate education only at a single time point. METHODS: Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) Study cohort participants (N = 554) reported educational attainment (dichotomized at any college education) at two time points, and we classified them as having low, high, or later-life high educational attainment. Linear mixed-effects models estimated associations between educational attainment change groups and domain-specific cognitive outcomes (z-standardized). RESULTS: Compared to low educational attainment, high (ß= 0.59 SD units; 95% confidence interval [CI]: 0.39, 0.79) and later-life high educational attainment (ß = 0.22; 95% CI: 0.00, 0.44) were associated with higher executive function. Only high educational attainment was associated with higher verbal episodic memory (ß = 0.27; 95% CI: 0.06, 0.48). DISCUSSION: Level and timing of educational attainment are both associated with domain-specific cognition. A single assessment for educational attainment may inadequately characterize protective associations with late-life cognition. HIGHLIGHTS: Few studies have examined both level and timing of educational attainment on cognition. Marginalized populations are more likely to attain higher education in adulthood. Higher educational attainment in late life is also associated with higher cognition.

HbA1c variability associated with dementia risk in people with type 2 diabetes.

INTRODUCTION: Although poor glycemic control is associated with dementia, it is unknown if variability in glycemic control, even in those with optimal glycosylated hemoglobin A1c (HbA1c) levels, increases dementia risk. METHODS: Among 171,964 people with type 2 diabetes, we evaluated the hazard of dementia association with long-term HbA1c variability using five operationalizations, including standard deviation (SD), adjusting for demographics and comorbidities. RESULTS: The mean baseline age was 61 years (48% women). Greater HbA1c SD was associated with greater dementia hazard (adjusted hazard ratio = 1.15 [95% confidence interval: 1.12, 1.17]). In stratified analyses, higher HbA1c SD quintiles were associated with greater dementia hazard among those with a mean HbA1c < 6% (P = 0.0004) or 6% to 8% (P < 0.0001) but not among those with mean HbA1c ≥ 8% (P = 0.42). DISCUSSION: Greater HbA1c variability is associated with greater dementia risk, even among those with HbA1c concentrations at ideal clinical targets. These findings add to the importance and clinical impact of recommendations to minimize glycemic variability. HIGHLIGHTS: We observed a cohort of 171,964 people with type 2 diabetes (mean age 61 years). This cohort was based in Northern California between 1996 and 2018. We examined the association between glycosylated hemoglobin A1c (HbA1c) variability and dementia risk. Greater HbA1c variability was associated with greater dementia hazard. This was most evident among those with normal-low mean HbA1c concentrations.

Environmental and Occupational Exposures and Prognosis in Patients with Non-Muscle Invasive Bladder Cancer in the Be-Well Study.

Bladder cancer is primarily diagnosed as non-muscle invasive bladder cancer (NMIBC) with high recurrence and progression rates. Environmental and occupational exposures to carcinogens are well-known risk factors for developing bladder cancer, yet their effects on prognosis remain unknown. In the Be-Well Study, a population-based prospective cohort study of 1,472 patient with newly diagnosed NMIBC from 2015 to 2019, we examined history of environmental and occupational exposures in relation to tumor stage and grade at initial diagnosis by multivariable logistic regression, and subsequent recurrence and progression by Cox proportional hazards regression. Exposure to environmental and occupational carcinogens was significantly associated with increased risk of progression (HR = 1.79; 95% CI: 1.04, 3.09), specifically increased progression into muscle-invasive disease (HR = 2.28; 95% CI: 1.16, 4.50). Exposure to asbestos and arsenic were associated with increased odds of advanced stage at diagnosis (asbestos: OR = 1.43; 95% CI: 1.11, 1.84; arsenic, OR = 1.27; 95% CI: 1.01, 1.63), and formaldehyde exposure was associated with increased risk of recurrence (HR = 1.38; 95% CI: 1.12, 1.69). Our findings suggest that history of these exposures may benefit current risk stratification systems to tailor clinical care and improve prognosis in patients with NMIBC.

Alcohol consumption and prognosis and survival in breast cancer survivors: The Pathways Study.

BACKGROUND: The impact of alcohol consumption on breast cancer (BC) prognosis remains unclear. METHODS: The authors examined short-term alcohol intake in relation to recurrence and mortality in 3659 women who were diagnosed with stage I-IV BC from 2003 to 2013 in the Pathways Study. Alcohol drinking in the past 6 months was assessed at cohort entry (mean, 2 months postdiagnosis) and 6 months later using a food-frequency questionnaire. Study end points were recurrence and death from BC, cardiovascular disease, and all causes. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using multivariable Cox proportional hazards models. RESULTS: Over an average follow-up of 11.2 years, 524 recurrences and 834 deaths (369 BC-specific and 314 cardiovascular disease-specific) occurred. Compared with nondrinkers (36.9%), drinkers were more likely younger, more educated, and current or past smokers. Overall, alcohol consumption was not associated with recurrence or mortality. However, women with higher body mass index (BMI ≥ 30 kg/m2 ) had lower risk of overall mortality with increasing alcohol consumption for occasional drinking (HR, 0.71; 95% CI, 0.54-0.94) and regular drinking (HR, 0.77; 95% CI, 0.56-1.08) around the time of diagnosis, along with 6 months later, in a dose-response manner (p < .05). Women with lower BMI (<30 kg/m2 ) were not at higher risk of mortality but were at possibly higher, yet nonsignificant, risk of recurrence for occasional drinking (HR, 1.29; 95% CI, 0.97-1.71) and regular drinking (HR, 1.19; 95% CI, 0.88-1.62). CONCLUSIONS: Alcohol drinking around the time of and up to 6 months after BC diagnosis was associated with lower risk of all-cause mortality in obese women. A possible higher risk of recurrence was observed in nonobese women.

Impact of a scalable training program on the quality of colonoscopy performance and risk of postcolonoscopy colorectal cancer.

BACKGROUND AND AIMS: Endoscopist adenoma detection rates (ADRs) vary widely and are associated with patients' risk of postcolonoscopy colorectal cancers (PCCRCs). However, few scalable physician-directed interventions demonstrably both improve ADR and reduce PCCRC risk. METHODS: Among patients undergoing colonoscopy, we evaluated the influence of a scalable online training on individual-level ADRs and PCCRC risk. The intervention was a 30-minute, interactive, online training, developed using behavior change theory, to address factors that potentially impede detection of adenomas. Analyses included interrupted time series analyses for pretraining versus posttraining individual-physician ADR changes (adjusted for temporal trends) and Cox regression for associations between ADR changes and patients' PCCRC risk. RESULTS: Across 21 endoscopy centers and all 86 eligible endoscopists, ADRs increased immediately by an absolute 3.13% (95% confidence interval [CI], 1.31-4.94) in the 3-month quarter after training compared with .58% per quarter (95% CI, .40-.77) and 0.33% per quarter (95% CI, .16-.49) in the 3-year pretraining and posttraining periods, respectively. Posttraining ADR increases were higher among endoscopists with pretraining ADRs below the median. Among 146,786 posttraining colonoscopies (all indications), each 1% absolute increase in screening ADR posttraining was associated with a 4% decrease in their patients' PCCRC risk (hazard ratio, .96; 95% CI, .93-.99). An ADR increase of ≥10% versus <1% was associated with a 55% reduced risk of PCCRC (hazard ratio, .45; 95% CI, .24-.82). CONCLUSIONS: A scalable, online behavior change training intervention focused on modifiable factors was associated with significant and sustained improvements in ADR, particularly among endoscopists with lower ADRs. These ADR changes were associated with substantial reductions in their patients' risk of PCCRC.

Associations Between Childhood Obesity and Pubertal Timing Stratified by Sex and Race/Ethnicity.

Earlier puberty has been associated with numerous adverse mental, emotional, and physical health outcomes. Obesity is a known risk factor for earlier puberty in girls, but research with boys has yielded inconsistent findings. We examined sex- and race/ethnicity-specific associations between childhood obesity and puberty in a multiethnic cohort of 129,824 adolescents born at a Kaiser Permanente Northern California medical facility between 2003 and 2011. We used Weibull regression models to explore associations between childhood obesity and breast development onset (thelarche) in girls, testicular enlargement onset (gonadarche) in boys, and pubic hair development onset (pubarche) in both sexes, adjusting for important confounders. Clear dose-response relationships were observed. Boys with severe obesity had the greatest risk for earlier gonadarche (hazard ratio = 1.23, 95% confidence limit: 1.15, 1.32) and pubarche (hazard ratio = 1.44, 95% confidence limit: 1.34, 1.55), while underweight boys had delayed puberty compared with peers with normal body mass index. A similar dose-response relationship was observed in girls. There were significant interactions between childhood body mass index and race/ethnicity. Childhood obesity is associated with earlier puberty in both boys and girls, and the magnitude of the associations may vary by race/ethnicity. Prevention of childhood obesity may delay pubertal timing and mitigate health risks associated with both conditions.

Metabolic abnormalities and survival among patients with non-metastatic breast cancer.

BACKGROUND: Research on the impact of metabolic abnormalities on breast cancer prognosis is limited by small samples and assessment of laboratory values at a single time point, often prior to cancer diagnosis and treatment. In this population-based cohort, time-updated laboratory values were adjusted for cancer treatment to assess the association between metabolic risk factors (glucose, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides) and breast cancer survival. METHODS: 13,434 women diagnosed with stage I-III breast cancer from 2005-15 at Kaiser Permanente were included. All outpatient fasting glucose, HDL-C, LDL-C, and triglyceride values from diagnosis through 2019 or death were extracted from electronic medical records. Risk of breast cancer-specific mortality was evaluated with Cox proportional hazards models adjusted for metabolic labs, demographics, body mass index, diabetes, dyslipidemia and anti-hypertensive medications, tumor characteristics (stage, ER and HER2 receptor status) and cancer treatment (use of chemotherapy, tamoxifen, and aromatase inhibitors). RESULTS: Mean (SD) age at diagnosis was 62.3 (11.8) years. Over a median follow-up of 8.6 years, 2,876 patients died; 1,080 of breast cancer. Patients with low HDL-C (≤ 45 vs. > 45 mg/dL) had higher breast cancer-specific mortality (HR, 1.77; 95% CI, 1.53-2.05), as did those with elevated fasting glucose (> 99 vs. 60-99 mg/dL) (HR, 1.19; 95% CI, 1.03-1.37). Elevated levels of triglycerides and LDL-C were not associated with breast cancer-specific mortality. CONCLUSIONS: High fasting glucose and low HDL-C evaluated over time after cancer diagnosis were associated with higher breast cancer mortality independent of cancer treatments and changes in other metabolic risk factors. Future studies should address whether pharmacologic or lifestyle treatment of glucose and lipids after breast cancer diagnosis can optimize survival outcomes.

Associations between infant growth and pubertal onset timing in a multiethnic prospective cohort of girls.

BACKGROUND: Early puberty increases risk of adverse health conditions throughout the life course. US girls are experiencing earlier puberty without clear reasons. Studies suggest early life factors, such as infant growth, may influence pubertal timing. We assessed the associations between infant growth and onset of breast development (thelarche), pubic hair development (pubarche), and menarche in girls. METHODS: A prospective cohort of girls born at a Kaiser Permanente Northern California medical facility in 2005-11 was used. Weight-for-age z-scores were calculated at birth and 24 months. Difference in z-scores greater than 0.67 represent rapid "catch-up" growth, less than -0.67 represent delayed "catch-down" growth, and between -0.67 and 0.67 represent "normal" growth. Pubertal onset was measured using clinician-assessed sexual maturity ratings (SMRs) and defined as the age at transition from SMR 1 to SMR 2 + for both thelarche and pubarche. SMR data was collected through June 2020. Menarche was analyzed as a secondary outcome. Weibull and modified Poisson regression models were used. Models were adjusted for potential confounders. RESULTS: There were 15,196 girls included in the study. Approximately 30.2% experienced catch-up growth, 25.8% experienced catch-down growth, and 44% had normal growth. Girls with catch-up growth had increased risk of earlier thelarche (hazard ratio = 1.26, 95% confidence interval (CI): 1.18, 1.35), pubarche (1.38, 95% CI: 1.28, 1.48), and menarche (< 12y, relative risk = 1.52, 95% CI: 1.36, 1.69) compared to those with normal growth, after adjusting for covariates. These associations were partially mediated by childhood body mass index. Catch-down growth was associated with later pubertal onset. CONCLUSIONS: Girls who experience infant catch-up growth have higher risk of earlier pubertal development compared to girls with normal growth and the associations are partially explained by childhood obesity. This information may help clinicians to monitor girls who are at high risk of developing earlier.

Association of Physician Adenoma Detection Rates With Postcolonoscopy Colorectal Cancer.

Importance: Although colonoscopy is frequently performed in the United States, there is limited evidence to support threshold values for physician adenoma detection rate as a quality metric. Objective: To evaluate the association between physician adenoma detection rate values and risks of postcolonoscopy colorectal cancer and related deaths. Design, Setting, and Participants: Retrospective cohort study in 3 large integrated health care systems (Kaiser Permanente Northern California, Kaiser Permanente Southern California, and Kaiser Permanente Washington) with 43 endoscopy centers, 383 eligible physicians, and 735 396 patients aged 50 to 75 years who received a colonoscopy that did not detect cancer (negative colonoscopy) between January 2011 and June 2017, with patient follow-up through December 2017. Exposures: The adenoma detection rate of each patient's physician based on screening examinations in the calendar year prior to the patient's negative colonoscopy. Adenoma detection rate was defined as a continuous variable in statistical analyses and was also dichotomized as at or above vs below the median for descriptive analyses. Main Outcomes and Measures: The primary outcome (postcolonoscopy colorectal cancer) was tumor registry-verified colorectal adenocarcinoma diagnosed at least 6 months after any negative colonoscopy (all indications). The secondary outcomes included death from postcolonoscopy colorectal cancer. Results: Among 735 396 patients who had 852 624 negative colonoscopies, 440 352 (51.6%) were performed on female patients, median patient age was 61.4 years (IQR, 55.5-67.2 years), median follow-up per patient was 3.25 years (IQR, 1.56-5.01 years), and there were 619 postcolonoscopy colorectal cancers and 36 related deaths during more than 2.4 million person-years of follow-up. The patients of physicians with higher adenoma detection rates had significantly lower risks for postcolonoscopy colorectal cancer (hazard ratio [HR], 0.97 per 1% absolute adenoma detection rate increase [95% CI, 0.96-0.98]) and death from postcolonoscopy colorectal cancer (HR, 0.95 per 1% absolute adenoma detection rate increase [95% CI, 0.92-0.99]) across a broad range of adenoma detection rate values, with no interaction by sex (P value for interaction = .18). Compared with adenoma detection rates below the median of 28.3%, detection rates at or above the median were significantly associated with a lower risk of postcolonoscopy colorectal cancer (1.79 vs 3.10 cases per 10 000 person-years; absolute difference in 7-year risk, -12.2 per 10 000 negative colonoscopies [95% CI, -10.3 to -13.4]; HR, 0.61 [95% CI, 0.52-0.73]) and related deaths (0.05 vs 0.22 cases per 10 000 person-years; absolute difference in 7-year risk, -1.2 per 10 000 negative colonoscopies [95%, CI, -0.80 to -1.69]; HR, 0.26 [95% CI, 0.11-0.65]). Conclusions and Relevance: Within 3 large community-based settings, colonoscopies by physicians with higher adenoma detection rates were significantly associated with lower risks of postcolonoscopy colorectal cancer across a broad range of adenoma detection rate values. These findings may help inform recommended targets for colonoscopy quality measures.

Early Screening of African Americans (45-50 Years Old) in a Fecal Immunochemical Test-Based Colorectal Cancer Screening Program.

BACKGROUND & AIMS: Some guidelines recommend starting colorectal cancer (CRC) screening before age 50 years for African Americans, but there are few data on screening uptake and yield in this population. METHODS: We performed a prospective study of fecal immunochemical test (FIT) screening among African American members of the Kaiser Permanente Northern California health plan. We compared data from African American members screened when they were 45-50 years old (early screening group) in 2018 with data from previously unscreened African American, white, Hispanic, and Asian/Pacific Islander health plan members who were 51-56 years old. Screening outreach was performed with mailed FIT kits. Logistic regression models, adjusted for sex, were used to evaluate differences among groups in screening uptake, colonoscopy follow-up of abnormal test results, and test yield. RESULTS: Among 10,232 African Americans in the early screening group who were mailed a FIT, screening was completed by 33.1%. Among the 4% with positive test results, 85.3% completed a follow-up colonoscopy: 57.8% had any adenoma, 33.6% had an advanced adenoma (adenoma with advanced histology or polyp ≥10 mm), and 2.6% were diagnosed with CRC. African Americans in the early screening group were modestly more likely to have completed screening than previously unscreened African Americans, whites, and Hispanics 51-56 years old. The groups did not differ significantly in positive results from the FIT (range, 3.8%-4.6%) and more than 74% received a follow-up colonoscopy after a positive test result. The test yields for any adenoma (range, 56.7%-70.7%), advanced adenoma (range, 20.0%-33.6%), and CRC (range, 0%-7.1%) were similar. CONCLUSIONS: Proportions of African Americans who participated in early (aged 45-50 years) FIT screening and test yield were comparable to those of previously unscreened African Americans, whites, Hispanics, and Asian/Pacific Islanders who were 51-56 years old.

Long-term Risk of Colorectal Cancer and Related Death After Adenoma Removal in a Large, Community-based Population.

BACKGROUND & AIMS: The long-term risks of colorectal cancer (CRC) and CRC-related death following adenoma removal are uncertain. Data are needed to inform evidence-based surveillance guidelines, which vary in follow-up recommendations for some polyp types. Using data from a large, community-based integrated health care setting, we examined the risks of CRC and related death by baseline colonoscopy adenoma findings. METHODS: Participants at 21 medical centers underwent baseline colonoscopies from 2004 through 2010; findings were categorized as no-adenoma, low-risk adenoma, or high-risk adenoma. Participants were followed until the earliest of CRC diagnosis, death, health plan disenrollment, or December 31, 2017. Risks of CRC and related deaths among the high- and low-risk adenoma groups were compared with the no-adenoma group using Cox regression adjusting for confounders. RESULTS: Among 186,046 patients, 64,422 met eligibility criteria (54.3% female; mean age, 61.6 ± 7.1 years; median follow-up time, 8.1 years from the baseline colonoscopy). Compared with the no-adenoma group (45,881 patients), the high-risk adenoma group (7563 patients) had a higher risk of CRC (hazard ratio [HR] 2.61; 95% confidence interval [CI] 1.87-3.63) and related death (HR 3.94; 95% CI 1.90-6.56), whereas the low-risk adenoma group (10,978 patients) did not have a significant increase in risk of CRC (HR 1.29; 95% CI 0.89-1.88) or related death (HR 0.65; 95% CI 0.19-2.18). CONCLUSIONS: With up to 14 years of follow-up, high-risk adenomas were associated with an increased risk of CRC and related death, supporting early colonoscopy surveillance. Low-risk adenomas were not associated with a significantly increased risk of CRC or related deaths. These results can inform current surveillance guidelines for high- and low-risk adenomas.

History of Early Childhood Infections and Acute Lymphoblastic Leukemia Risk Among Children in a US Integrated Health-Care System.

Surrogate measures of infectious exposures have been consistently associated with lower childhood acute lymphoblastic leukemia (ALL) risk. However, recent reports have suggested that physician-diagnosed early-life infections increase ALL risk, thereby raising the possibility that stronger responses to infections might promote risk. We examined whether medically diagnosed infections were related to childhood ALL risk in an integrated health-care system in the United States. Cases of ALL (n = 435) diagnosed between 1994-2014 among children aged 0-14 years, along with matched controls (n = 2,170), were identified at Kaiser Permanente Northern California. Conditional logistic regression was used to estimate risk of ALL associated with history of infections during first year of life and across the lifetime (up to diagnosis). History of infection during first year of life was not associated with ALL risk (odds ratio (OR) = 0.85, 95% confidence interval (CI): 0.60, 1.21). However, infections with at least 1 medication prescribed (i.e., more "severe" infections) were inversely associated with risk (OR = 0.42, 95% CI: 0.20, 0.88). Similar associations were observed when the exposure window was expanded to include medication-prescribed infections throughout the subjects' lifetime (OR = 0.52, 95% CI: 0.32, 0.85).

Effect of Sex, Age, and Positivity Threshold on Fecal Immunochemical Test Accuracy: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Quantitative fecal immunochemical tests (FITs) for hemoglobin are commonly used for colorectal cancer (CRC) screening. We aimed to quantify the change in CRC and advanced adenoma detection and number of positive test results at different positivity thresholds and by sex and age. METHODS: We searched MEDLINE and EMBASE, selecting articles of FIT for CRC detection in asymptomatic adults undergoing screening. We calculated sensitivity and specificity, as well as detected number of cancers, advanced adenomas, and positive test results at positivity thresholds ≤10 µg hemoglobin/g feces, 10 to ≤20 µg/g, 20 to ≤30 µg/g, and >30 µg/g. We also analyzed results from stratified by patient sex, age, and reference standard. RESULTS: Our meta-analysis comprised 46 studies with 2.4 million participants and 6478 detected cancers. Sensitivity for detection of CRC increased from 69% (95% confidence interval [CI], 63%-75%) at thresholds >10 µg/g and ≤20 µg/g to 80% (95% CI, 76%-83%) at thresholds ≤10 µg/g. At these threshold values, sensitivity for detection of advanced adenomas increased from 21% (95% CI, 18%-25%) to 31% (95% CI, 27%-35%), whereas specificity decreased from 94% (95% CI, 93%-96%) to 91% (95% CI, 89%-93%). In 3 studies stratified by sex, sensitivity of CRC detection was 77% in men (95% CI, 75%-79%) and 81% in women (95% CI, 60%-100%) (P = .68). In 3 studies stratified by age groups, sensitivity of CRC detection was 85% for ages 50-59 years (95% CI, 71%-99%) and 73% for ages 60-69 years (95% CI, 71%-75%) (P = .10). All studies with colonoscopy follow-up had similar sensitivity levels for detection of CRC to studies that analyzed 2-year registry follow-up data (74%; 95% CI, 68%-78% vs 75%; 95% CI, 73%-77%). CONCLUSIONS: In a meta-analysis of studies that analyzed detection of CRC and advanced adenomas at different FIT positivity thresholds, we found the sensitivity and specificity of detection to vary with positive cutoff value. It might be possible to decrease positive threshold values for centers with sufficient follow-up colonoscopy resources. More research is needed to precisely establish FIT thresholds for each sex and age subgroup. PROTOCOL: PROSPERO CRD42017068760.

Proton Pump Inhibitor Use and Risk of Gastric, Colorectal, Liver, and Pancreatic Cancers in a Community-Based Population.

INTRODUCTION: Proton pump inhibitors (PPIs) are commonly used for gastrointestinal disorders; given they increase the systemic levels of gastrin, a trophic hormone, there is a concern about their carcinogenicity. This study evaluated the association between PPI use and gastrointestinal cancers. METHODS: We performed a nested case-control study in a large, community-based integrated healthcare setting. Cases were adults with gastric (n = 1,233), colorectal (n = 18,595), liver (n = 2,329), or pancreatic cancers (n = 567). Each case was matched with up to 10 controls by age, sex, race/ethnicity, medical facility, and enrollment duration. The primary exposure was defined as ≥2-year cumulative PPI supply. Data were obtained from pharmacy, cancer registry, and electronic medical record databases. Associations were evaluated using conditional logistic regression and adjusted for multiple confounders. We also evaluated the cancer risks separately by PPI dose, duration of use, and dose and duration. RESULTS: PPI use of ≥2-years was not associated with the risks of gastric (odds ratio [OR]: 1.07, 95% confidence interval [CI]: 0.81-1.42), colorectal (OR: 1.05, 95% CI: 0.99-1.12), liver (OR: 1.14, 95% CI: 0.91-1.43), or pancreatic cancers (OR: 1.22, 95% CI: 0.89-1.67), compared to non-users. In exploratory analyses, elevated cancer risks were primarily restricted to those with ≥10 years of PPI use, but no consistent associations were found for increasing PPI dose and/or duration of use. DISCUSSION: PPI use of ≥2 years was not associated with increased risks of gastrointestinal cancers. The cancer risks associated with PPI use of ≥10 years requires further study.

Caesarean delivery and the risk of atopic dermatitis in children.

BACKGROUND: Caesarean delivery (C-section) may disrupt maternal-infant microbial transfer and alter immune system development and subsequent risk for atopic dermatitis. OBJECTIVE: Investigate the association between C-section and atopic dermatitis by age four and examine potential sources of bias in the relationship in a large cohort study. METHODS: Maternal and child information was collected through Kaiser Permanente Northern California's (KPNC) integrated healthcare system. Data sources included electronic medical records, pharmacy databases, state birth records, and prospectively collected breastfeeding surveys. Children were eligible if they were born in a KPNC or contracting hospital between 2005 and 2014 and had continuous enrolment in the KPNC system for at least four years (n = 173 105). Modified Poisson regression with robust variance estimation was used to estimate the association between C-section and atopic dermatitis overall and when stratified by demographic and labour and delivery characteristics. RESULTS: Although unadjusted analyses showed a positive association between C-section and atopic dermatitis [RR(95%CI): 1.06(1.03, 1.10)], this effect was attenuated towards the null after adjustment [aRR(95%CI): 1.02(0.99, 1.05)]. In stratified analyses, there was evidence that C-section increased atopic dermatitis risk among certain subgroups (eg firstborns, overweight/obese pre-pregnancy BMI), but associations were weak. C-section delivery conditions indicative of the least exposure to maternal microbiome (ie no labour, short interval between membrane rupture and delivery) showed no evidence of association with atopic dermatitis. Estimated associations were not strongly influenced by intrapartum antibiotics, breastfeeding, missing data, or familial factors. CONCLUSION: Caesarean delivery was not associated with atopic dermatitis by age four in this large US cohort. This association did not appear to be biased by intrapartum antibiotics, breastfeeding behaviour, C-section indication, missing covariates, or familial factors.