Differential Requirements for eIF4E Dose in Normal Development and Cancer.

eIF4E, the major cap-binding protein, has long been considered limiting for translating the mammalian genome. However, the eIF4E dose requirement at an organismal level remains unexplored. By generating an Eif4e haploinsufficient mouse, we found that a 50% reduction in eIF4E expression, while compatible with normal development and global protein synthesis, significantly impeded cellular transformation. Genome-wide translational profiling uncovered a translational program induced by oncogenic transformation and revealed a critical role for the dose of eIF4E, specifically in translating a network of mRNAs enriched for a unique 5' UTR signature. In particular, we demonstrate that the dose of eIF4E is essential for translating mRNAs that regulate reactive oxygen species, fueling transformation and cancer cell survival in vivo. Our findings indicate eIF4E is maintained at levels in excess for normal development that are hijacked by cancer cells to drive a translational program supporting tumorigenesis.

Ribosomal Proteins Regulate MHC Class I Peptide Generation for Immunosurveillance.

The MHC class I antigen presentation system enables T cell immunosurveillance of cancers and viruses. A substantial fraction of the immunopeptidome derives from rapidly degraded nascent polypeptides (DRiPs). By knocking down each of the 80 ribosomal proteins, we identified proteins that modulate peptide generation without altering source protein expression. We show that 60S ribosomal proteins L6 (RPL6) and RPL28, which are adjacent on the ribosome, play opposite roles in generating an influenza A virus-encoded peptide. Depleting RPL6 decreases ubiquitin-dependent peptide presentation, whereas depleting RPL28 increases ubiquitin-dependent and -independent peptide presentation. 40S ribosomal protein S28 (RPS28) knockdown increases total peptide supply in uninfected cells by increasing DRiP synthesis from non-canonical translation of "untranslated" regions and non-AUG start codons and sensitizes tumor cells for T cell targeting. Our findings raise the possibility of modulating immunosurveillance by pharmaceutical targeting ribosomes.

Weight management and physical activity throughout the cancer care continuum.

Mounting evidence suggests that weight management and physical activity (PA) improve overall health and well being, and reduce the risk of morbidity and mortality among cancer survivors. Although many opportunities exist to include weight management and PA in routine cancer care, several barriers remain. This review summarizes key topics addressed in a recent National Academies of Science, Engineering, and Medicine workshop entitled, "Incorporating Weight Management and Physical Activity Throughout the Cancer Care Continuum." Discussions related to body weight and PA among cancer survivors included: 1) current knowledge and gaps related to health outcomes; 2) effective intervention approaches; 3) addressing the needs of diverse populations of cancer survivors; 4) opportunities and challenges of workforce, care coordination, and technologies for program implementation; 5) models of care; and 6) program coverage. While more discoveries are still needed for the provision of optimal weight-management and PA programs for cancer survivors, obesity and inactivity currently jeopardize their overall health and quality of life. Actionable future directions are presented for research; practice and policy changes required to assure the availability of effective, affordable, and feasible weight management; and PA services for all cancer survivors as a part of their routine cancer care. CA Cancer J Clin 2018;68:64-89. © 2017 American Cancer Society.

Gender Trends in Authorship of Gastroenterology Randomized Controlled Trial Literature.

INTRODUCTION: We describe female authorship trends in gastroenterology (GI) randomized controlled trial literature as a novel focus on gender bias in academic GI. METHODS: Using a systematic PubMed search, we extracted GI randomized controlled trial reports published from 2011 to 2022. We describe time trends in proportions of females among first and last authors overall and within GI subspecialties and high-impact journals. RESULTS: The proportion of females increased from 25.4% to 36.8% and from 14.3% to 24.8% among first and last authors, respectively. Smaller increases in female authorship occurred in most subgroups, although there were proportionately fewer females among authors in high-impact journals and advanced therapeutic endoscopy publications. DISCUSSION: Over the past decade, female authorship in GI RCT reports has increased. However, female representation, particularly among senior authors and in high-impact journals, remains significantly lower. Despite recent improvements, female still constitutes a minority of the authors of original GI RCTs.

Understanding health behaviors that modify the risk for obesity in ADHD.

OBJECTIVE: Research provides support for the associated risk of inadequate sleep duration, limited physical activity, and excessive media use in attention-deficit/hyperactivity disorder (ADHD) and obesity. The present study aims to (1) examine the association between ADHD and overweight or obese status (OW/OB); (2) comprehensively examine sleep duration, physical activity, and media use as potential moderators of OW/OB; and (3) examine the moderating effects of these health behaviors cross-sectionally by comparing medicated youth with ADHD, unmedicated youth with ADHD, and youth without ADHD. METHODS: Data were acquired from the 2018 and 2019 National Survey of Children's Health, a nationally representative survey of caregivers conducted across the United States. The current study used data for youth 11-17 years old with a final sample size of 26,644. Hours of sleep, physical activity, and media use per day were dichotomized based on national recommendation guidelines for each health behavior (i.e., either meeting or not meeting guidelines). RESULTS: The OW/OB prevalence rate was 7% greater among unmedicated youth with ADHD than among medicated youth with ADHD. Medicated youth with ADHD and peers without ADHD had similar OW/OB rates. Among medicated youth with ADHD, physical activity, sleep duration, and media use did not contribute to OW/OB risk after controlling for family poverty level. However, among unmedicated youth with ADHD, meeting sleep duration guidelines was linked to a lower OW/OB risk. CONCLUSION: Overall, findings suggest that clinical providers and parents may wish to prioritize improved sleep duration in the management of OW/OB risk in youth with ADHD.

Systematic review and meta analysis of psychological interventions to prevent or treat pediatric chronic disease in rural communities.

OBJECTIVE: The purpose of this systematic review and meta-analysis was to examine the effectiveness of psychological interventions at improving physical or mental health outcomes for youth living in rural communities who have, or are at-risk for, any chronic medical condition in comparison to control interventions conducted in rural communities. METHODS: Following prospective registration (OSF.IO/7TDQJ), 7 databases were searched through July 1, 2023. Studies were included if they were a randomized control trial of a psychological intervention conducted with youth living in a rural area who had, or were at-risk for, a chronic medical condition. Risk of bias was assessed with the Cochrane risk of bias version 2 tool. A qualitative synthesis and meta-analysis were conducted. RESULTS: 15 studies met inclusion criteria. Obesity studies (n = 13) primarily focused on body mass index metrics, with limited significant findings across studies. Asthma treatment interventions (n = 2) showed no impact on hospitalizations. 3 studies evaluated mental health outcomes with no significant group differences observed. We meta-analytically analyzed 9 studies that evaluated body mass index z-scores and identified an overall null effect (Hedge's g = 0.01, 95% CI [-0.07, 0.09], p = .85). CONCLUSIONS: Most included studies focused on pediatric obesity, and there was a limited range of health outcomes reported. Compared to controls, minimal significant improvements in health outcomes were identified for psychological interventions for youth living in rural communities. Future efforts may benefit from situating this work more systematically within a health disparities framework with a focus on understanding mechanisms of disparities and translating this work into interventions and policy changes.

Post-diagnostic health behaviour scores and risk of prostate cancer progression and mortality.

BACKGROUND: Individual behaviours are associated with prostate cancer (PC) progression. Behavioural scores, comprised of multiple risk factors, allow assessment of the combined impact of multiple behaviours. METHODS: We examined the association between six a priori scores and risk of PC progression and mortality among 2156 men with PC in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) cohort: two scores developed based on the PC survivorship literature ('2021 Score [+ Diet]'); a score developed based on pre-diagnostic PC literature ('2015 Score'); and three scores based on US recommendations for cancer prevention ('WCRF/AICR Score') and survival ('ACS Score [+ Alcohol]'). Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for progression and PC mortality via parametric survival models (interval censoring) and Cox models, respectively. RESULTS: Over a median (IQR) of 6.4 (1.3, 13.7) years, we observed 192 progression and 73 PC mortality events. Higher (i.e., healthier) 2021 Score + Diet and WCRF/AICR Scores were inversely associated with risk of PC progression (2021 + Diet: HRcontinuous = 0.76, 95% CI: 0.63-0.90. WCRF/AICR: HRcontinuous = 0.83, 95% CI: 0.67-1.02) and mortality (2021 + Diet: HRcontinuous = 0.65, 95% CI: 0.45-0.93. WCRF/AICR: HRcontinuous = 0.71; 95% CI: 0.57-0.89). The ACS Score + Alcohol was only associated with progression (HRcontinuous = 0.89, 95% CI: 0.81-0.98) while the 2021 Score was only associated with PC mortality (HRcontinuous = 0.62, 95% CI: 0.45-0.85). The 2015 was not associated with PC progression or mortality. CONCLUSION: Findings strengthen the evidence that behavioural modifications following a prostate cancer diagnosis may improve clinical outcomes.

KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors.

BACKGROUND: No therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRASG12C. METHODS: We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. RESULTS: A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma. CONCLUSIONS: Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).

The effects of exercise and diet on oxidative stress and telomere length in breast cancer survivors.

PURPOSE: Cancer and its treatments accelerate biological aging. This analysis tested the hypothesis that exercise and diet reduce oxidative stress and prevent telomere shortening in breast cancer survivors. METHODS: In a 2 × 2 factorial design, 342 breast cancer survivors who were insufficiently physically active and had overweight or obesity at enrollment were randomized to one of four treatment groups for 52 weeks: control, exercise alone, diet alone, or exercise plus diet. The endpoints of this analysis were the change from baseline to week 52 in 8-iso-prostaglandin F2α (8-iso-PGF2α) and lymphocyte telomere length. RESULTS: Baseline telomere length was shorter than age-adjusted normative values (median difference: - 1.8 kilobases; 95% CI - 2.4, - 1.1); equivalent to 21 years (95% CI 17, 25) of accelerated chronological aging. Compared to control, exercise alone did not change 8-iso-PGF2α [9.9%; 95% confidence interval (CI) - 1.0, 20.8] or telomere length (13.8%; 95% CI - 15.6, 43.3). Compared to control, diet alone was associated with reduced 8-iso-PGF2α (- 10.5%; 95% CI - 19.5, - 1.5) but did not change telomere length (12.1%; 95% CI - 17.2, 41.3). Compared to control, exercise plus diet was associated with reduced 8-iso-PGF2α (- 9.8%; 95% CI - 18.7, - 0.9) but did not change telomere length (- 8.5%; 95% CI - 32.1, 15.2). Change in 8-iso-PGF2α did not correlate with change in telomere length (r = 0.07; 95% CI - 0.07, 0.20). CONCLUSION: In breast cancer survivors, diet alone or exercise plus diet were associated with reduced oxidative stress but did not change telomere length. This analysis may inform future trials that aim to optimize healthy aging in cancer survivors.

Advancing More Equitable Care Through the Development of a Health Equity Report Card.

The root causes of racial disparities in access to optimal cancer care and related cancer outcomes are complex, multifactorial, and not rooted in biology. Contributing factors to racial disparities in care delivery include implicit and explicit bias, lack of representation of people of color in the oncology care and research workforce, and homogenous research participants that are not representative of the larger community. Systemic and structural barriers include policies leading to lack of insurance and underinsurance, costs of cancer treatment and associated ancillary costs of care, disparate access to clinical trials, and social determinants of health, including exposure to environmental hazards, access to housing, childcare, and economic injustices. To address these issues, ACS CAN, NCCN, and NMQF convened the Elevating Cancer Equity (ECE) initiative. The ECE Working Group developed the Health Equity Report Card (HERC). In this manuscript, we describe the process taken by the ECE Working Group to develop the HERC recommendations, the strategies employed by NCCN to develop an implementation plan and scoring methodology for the HERC, and next steps to pilot the HERC tool in practice settings.

Sotorasib for previously treated colorectal cancers with KRASG12C mutation (CodeBreaK100): a prespecified analysis of a single-arm, phase 2 trial.

BACKGROUND: Sotorasib, a specific, irreversible KRASG12C protein inhibitor, has shown monotherapy clinical activity in KRASG12C-mutated solid tumours, including colorectal cancer, in the CodeBreaK100 phase 1 trial. We aimed to investigate the activity and safety of sotorasib in phase 2 of the trial. METHODS: In this single-arm, phase 2 trial, adult patients with KRASG12C-mutated advanced solid tumours were enrolled, from 59 medical centres in 11 countries, if they were aged 18 years or older, had at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, and had an Eastern Cooperative Oncology Group performance status of 1 or lower. Only data for patients with colorectal cancer, enrolled at 33 medical centres in nine countries, are presented from this basket trial. To be enrolled, the patients had to have progressed after receiving fluoropyrimidine, oxaliplatin, and irinotecan treatment. These patients were administered 960 mg sotorasib orally once per day until disease progression, development of unacceptable side-effects, withdrawal of consent, or death. The primary endpoint was objective response (complete or partial response) as assessed by blinded independent central review. Response was evaluated in patients who received at least one dose of sotorasib and had at least one measurable lesion at baseline; safety was evaluated in patients who received at least one dose of sotorasib. This analysis is a prespecified analysis triggered by the phase 2 colorectal cancer cohort. This study is registered with ClinicalTrials.gov, NCT03600883, and is active but no longer recruiting. FINDINGS: On March 1, 2021, at data cutoff, 62 patients with KRASG12C-mutant colorectal cancer had been enrolled between Aug 14, 2019, and May 21, 2020, and had received at least one dose of sotorasib monotherapy. Objective response was observed in six (9·7%, 95% CI 3·6-19·9) of 62 patients, all with partial response. Treatment-related adverse events at grade 3 occurred in six (10%) patients, the most common of which was diarrhoea (two [3%] of 62 patients), and at grade 4 occurred in one (2%) patient (blood creatine phosphokinase increase); no fatal events were recorded. Serious treatment-related adverse events occurred in two (3%) patients (back pain and acute kidney injury). INTERPRETATION: Although the 9·7% overall response rate did not reach the benchmark, oral administration of sotorasib once per day showed modest anti-tumour activity and manageable safety in these heavily pretreated chemorefractory patients. Sotorasib is under evaluation in combination with other therapeutics to increase potential activity and overcome potential resistance mechanisms. FUNDING: Amgen.

Post-diagnostic health behaviour scores in relation to fatal prostate cancer.

BACKGROUND: Individual health behaviours have been associated with fatal prostate cancer (PCa). Their combined association with fatal PCa after diagnosis is unknown. METHODS: This prospective cohort included 4518 men diagnosed with nonmetastatic PCa from the Health Professionals Follow-up Study. Exposures included a three-factor score integrating post-diagnostic fatal PCa risk factors ("2021 PCa Behaviour Score"), six-factor score integrating incident aggressive PCa risk factors ("2015 PCa Behaviour Score"), and two scores integrating recommendations for cancer prevention and survival, respectively. Multivariable Cox models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for fatal PCa. RESULTS: Over a median 10.2 years, we observed 219 PCa deaths. Each additional point of one of the PCa-specific health behaviour scores (2015 PCa Behaviour Score) was associated with a 19% reduced fatal PCa risk (HR: 0.81, 95%CI: 0.68-0.97). The 2021 PCa Behaviour Score and scores integrating national recommendations were not associated with fatal PCa. CONCLUSIONS: While a PCa-specific health behaviour score was associated with a reduced risk of fatal PCa, we did not otherwise observe strong evidence of associations between post-diagnostic scores and fatal PCa. Avoiding tobacco, healthy body size, and physical activity may decrease PCa death risk, but further research is needed to inform cancer survivorship recommendations.

Robust Response to Futibatinib in a Patient With Metastatic FGFR-Addicted Cholangiocarcinoma Previously Treated Using Pemigatinib.

Futibatinib is a novel FGFR inhibitor currently under investigation as a second-line treatment for locally advanced or metastatic cholangiocarcinoma harboring FGFR2 gene fusions and rearrangements. As FGFR-targeted therapies move into the frontline setting, sequencing of these drugs remains undetermined. To date, no study has investigated the use of futibatinib in the context of pemigatinib resistance. We describe a 50-year-old woman with metastatic FGFR-aberrant intrahepatic cholangiocarcinoma who showed a robust response to futibatinib for 23.6 months, having previously benefited from pemigatinib. Futibatinib was safely used despite her history of decompensated cirrhosis and significant cytopenias. We observed a reduction in CA 19-9 level and a partial radiographic response on futibatinib. Serial next-generation sequencing and cell-free DNA testing proved crucial to making appropriate treatment decisions.

Latent profiles of the feeding practices of caregivers of rural children with overweight and obesity and associations with child eating behaviors.

Previous research has shown that food parenting practices, which vary within the context of sociocultural factors, are associated with child weight, eating behaviors, and body dissatisfaction. While parents typically engage in multiple food parenting practices, few studies have examined what subgroups or combinations of food parenting practices are associated with child health outcomes and sociocultural factors. The current study examined profiles of food parenting practices among school-age children with overweight/obesity (OW/OB) from rural communities and examined how they may be associated with sociocultural factors, child-eating habits, and health outcomes. The study included 270 children with OW/OB aged 8-12 (Mage = 10.36 years) and their caregivers. Caregivers completed a measure assessing perceptions of their feeding practices and sociocultural questionnaires. Children completed measures assessing disordered eating habits, weight control behaviors, and body dissatisfaction. Weight status was measured for caregivers and children with height and weight measurements. Latent variable mixture modeling (LVMM) was conducted. Three profiles emerged: (a) Lower Parental Involvement, (b) Higher Parental Involvement, and (c) Mixed Parental Involvement. Lower family income and non-White child race were related to membership in the "Higher Parental Involvement" profile. After controlling for income and child race, children in the "Mixed Parental Involvement" profile reported significantly higher body dissatisfaction than children in the "Lower Parental Involvement" profile. There are subgroups of caregivers of rural children with OW/OB that demonstrate various patterns of parent feeding practices, and these subgroups differ by income, race, and child body dissatisfaction. Future research should consider how caregiver-specific feeding practices may impact child eating behaviors and their body image development, as well as the impact cultural factors may have on parent feeding practices.

Prevalence of raised body mass index in paediatric sickle cell disease.

AIM: Children with sickle cell disease (SCD) have historically weighed less than their healthy peers. More recently, a retrospective chart review from six institutions in New England reported nearly one-quarter of children and adolescents with SCD had raised body mass index (BMI). This study aimed to examine rates of children with SCD with raised BMI in Mississippi compared to state and national norms and assess the correlation between haemoglobin and BMI. METHODS: A retrospective chart review of paediatric patients with SCD at the University of Mississippi Medical Center (UMMC) was conducted using data from the most recent clinic visit. Mississippi and national weight status estimates for youth 10-17 years were obtained from the 2016-2017 National Survey of Children's Health. RESULTS: For youth 10-17 years with SCD (n = 345), 21.4.% of children with SS/Sß° and 36.1% with SC/Sß+ had raised BMI compared to Mississippi and national rates, 39.2 and 31%, respectively. The prevalence of children with raised BMI with SC/Sß+ did not differ from state and national rates, while children with SS/Sß° were half as likely as their Mississippi peers to have raised BMI. Haemoglobin levels were different among children with SCD who had low BMI (8.80 g/dL), average BMI (9.2 g/dL) and raised BMI (10.5 g/dL) (P < 0.001). CONCLUSIONS: Children with SCD evaluated at UMMC have similar rates of raised BMI compared to state and national norms. Children with raised BMI have higher mean haemoglobin levels compared to children with SCD with low or average BMI. IMPLICATIONS AND CONTRIBUTION: Historically, patients with SCD have been underweight and normal weight. Our paediatric and adolescent patients with SCD now have prevalence rates of raised BMI that approach state and national rates. Further work must be done to determine whether this reflects healthier children with SCD or raises concerns about life-style-related comorbidities.

Prophylactic Radiotherapy for Prevention of Heterotopic Ossification After Periacetabular Fractures: A Review of Efficacy and Associated Conditions.

Prophylactic radiotherapy (XRT) is a commonly used treatment to decrease heterotopic ossification (HO) in patients with traumatic hip injuries. We conducted a retrospective review of patients at risk for HO who underwent XRT. Of the patients reviewed, 27.3% developed radiographic HO, 11.2% developed symptoms, and 2.0% required resection surgery. Patients were divided into primary (n = 71) and secondary prophylaxis (n = 27) cohorts. In the primary group, 25.0% developed radiographic HO, 5.6% developed symptoms, and 0 required surgery. In the secondary cohort, 33.3% of patients developed new radiographic HO, and 25.9% were symptomatic: four had a Brooker score of 3, and three had a score of 4 (p = 0.03), and 7.4% required surgical resection. (Journal of Surgical Orthopaedic Advances 31(2):113-118, 2022).

Addition of ramucirumab or merestinib to standard first-line chemotherapy for locally advanced or metastatic biliary tract cancer: a randomised, double-blind, multicentre, phase 2 study.

BACKGROUND: Biliary tract cancers are aggressive, rare, gastrointestinal malignancies with a poor prognosis; approximately half of patients with these cancers survive for less than 1 year after diagnosis with advanced disease. We aimed to evaluate the efficacy and safety of ramucirumab or merestinib in addition to first-line cisplatin-gemcitabine in patients with locally advanced or metastatic biliary tract cancer. METHODS: We did a randomised, double-blind, phase 2 study at 81 hospitals across 18 countries. We enrolled patients with histologically or cytologically confirmed, non-resectable, recurrent, or metastatic biliary tract adenocarcinoma, who were treatment-naive, aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 0 or 1, estimated life expectancy of 3 months or more, and measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1. Eligible participants were randomly assigned (2:1:2:1) to receive either intravenous ramucirumab 8 mg/kg or placebo (on days 1 and 8 in 21-day cycles) or oral merestinib 80 mg or placebo (once daily) until disease progression, unacceptable toxicity, death, or patient or investigator request for discontinuation. All participants received intravenous cisplatin 25 mg/m2 and gemcitabine 1000 mg/m2 (on days 1 and 8 in 21-day cycles), for a maximum of eight cycles. Randomisation was done by an interactive web response system using a permuted block method (blocks of six) and was stratified by primary tumour site, geographical region, and presence of metastatic disease. Participants, investigators, and the study funder were masked to treatment assignment within the intravenous and oral groups. The primary endpoint was investigator-assessed progression-free survival (in the intention-to-treat population). The safety analysis was done in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT02711553, and long-term follow-up is ongoing. FINDINGS: Between May 25, 2016, and Aug 8, 2017, 450 patients were assessed for eligibility and 309 (69%) were enrolled and randomly assigned to ramucirumab (n=106), merestinib (n=102), or pooled placebo (n=101); 306 received at least one dose of study treatment. The median follow-up time for progression-free survival at data cutoff (Feb 16, 2018) was 10·9 months (IQR 8·1-14·1). Median progression-free survival was 6·5 months (80% CI 5·7-7·1) in the ramucirumab group, 7·0 months (6·2-7·1) in the merestinib group, and 6·6 months (5·6-6·8) in the pooled placebo group (ramucirumab vs placebo hazard ratio 1·12 [80% CI 0·90-1·40], two-sided stratified p=0·48; merestinib vs placebo 0·92 [0·73-1·15], two-sided stratified p=0·64). The most common grade 3 or worse adverse events were neutropenia (51 [49%] of 104 patients in the ramucirumab group; 48 [47%] of 102 in the merestinib group; and 33 [33%] of 100 in the pooled placebo group), thrombocytopenia (36 [35%]; 19 [19%]; and 17 [17%]), and anaemia (28 [27%]; 16 [16%]; and 19 [19%]). Serious adverse events occurred in 53 (51%) patients in the ramucirumab group, 56 (55%) in the merestinib group, and 48 (48%) in the pooled placebo group. Treatment-related deaths (deemed related by the investigator) occurred in one (1%) of 104 patients in the ramucirumab group (cardiac arrest) and two (2%) of 102 patients in the merestinib group (pulmonary embolism [n=1] and sepsis [n=1]). INTERPRETATION: Adding ramucirumab or merestinib to first-line cisplatin-gemcitabine was well tolerated, with no new safety signals, but neither improved progression-free survival in patients with molecularly unselected, locally advanced or metastatic biliary tract cancer. The role of these targeted inhibitors remains investigational, highlighting the need for further understanding of biliary tract malignancies and the contribution of molecular selection. FUNDING: Eli Lilly and Company.

A randomized trial of exercise and diet on health-related quality of life in survivors of breast cancer with overweight or obesity.

BACKGROUND: Obesity is a chronic, relapsing, and progressive disease; it is associated with poor health-related quality of life (HRQOL) in survivors of breast cancer. METHODS: In this 2 × 2 factorial trial, 351 survivors of breast cancer with overweight or obesity were randomized to 1 of 4 treatment groups for 52 weeks: control, exercise alone, diet alone, or exercise plus diet. HRQOL end points were measured at baseline and at week 52 using the 36-Item Medical Outcomes Survey-Short Form (SF-36). Repeated measures analysis of covariance quantified the estimated treatment difference (ETD). RESULTS: At baseline, participants had a mean (SD) age of 59.4 years (8.7), body mass index of 34.0 kg/m2 (5.9), and 71 participants (20.2%) self-reported fair or poor general health. After 52 weeks, compared with control, the exercise plus diet improved the physical health summary score (ETD: 5.39; 95% CI, 0.55-10.22); exercise alone (ETD: -1.91; 95% CI, -6.60 to 2.79) and diet alone (ETD: 3.16; 95% CI, -1.52 to 7.83) did not change the physical health summary score. Compared with control, exercise alone (ETD: -0.27; 95% CI, -6.60 to 2.79), diet alone (ETD: 3.25; 95% CI, -1.41 to 7.91), and the exercise plus diet (ETD: 1.75; 95% CI, -2.90 to 6.39) did not change the mental health summary score. Exercise alone did not impact any HRQOL subscale; diet alone improved the vitality subscale; exercise plus diet improved the physical functioning, role-physical and vitality subscales. CONCLUSION: In survivors of breast cancer with overweight or obesity, exercise plus diet improved select HRQOL end points at week 52.

Your Path to Transplant: A randomized controlled trial of a tailored expert system intervention to increase knowledge, attitudes, and pursuit of kidney transplant.

Individually tailoring education over time may help more patients, especially racial/ethnic minorities, get waitlisted and pursue deceased and living donor kidney transplant (DDKT and LDKT, respectively). We enrolled 802 patients pursuing transplant evaluation at the University of California, Los Angeles Transplant Program into a randomized education trial. We compared the effectiveness of Your Path to Transplant (YPT), an individually tailored coaching and education program delivered at 4 time points, with standard of care (SOC) education on improving readiness to pursue DDKT and LDKT, transplant knowledge, taking 15 small transplant-related actions, and pursuing transplant (waitlisting or LDKT rates) over 8 months. Survey outcomes were collected prior to evaluation and at 4 and 8 months. Time to waitlisting or LDKT was assessed with at least 18 months of follow-up. At 8 months, compared to SOC, the YPT group demonstrated increased LDKT readiness (47% vs 33%, P = .003) and transplant knowledge (effect size [ES] = 0.41, P < .001). Transplant pursuit was higher in the YPT group (hazard ratio: 1.44, 95% confidence interval: 1.15-1.79, P = .002). A focused, coordinated education effort can improve transplant-seeking behaviors and waitlisting rates. ClinicalTrials.gov registration: NCT02181114.