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PURPOSE: Obesity increases the risk of cancer recurrence and death in survivors of breast cancer. This study tested the hypothesis that exercise alone, diet alone, and the combination of exercise plus diet reduce body weight and improve body composition in survivors of breast cancer. METHODS: In this 2×2 factorial trial, 351 survivors of breast cancer with overweight or obesity were randomized to one of four treatment groups for 52 weeks: control, exercise alone, diet alone, or exercise plus diet. Endpoints included body weight and body composition measured by dual-energy x-ray absorptiometry. RESULTS: After 52 weeks, compared with control, diet alone [−5.39 kg (95% CI: −7.24, −3.55); −6.0% (95% CI: −8.0, −3.9)] and exercise plus diet [−6.68 kg (95% CI: −8.46, −4.90); −7.4% (95% CI: −9.4, −5.4)] reduced body weight; exercise alone did not change body weight. Compared with control, diet alone [−3.59 kg (95% CI: −5.00, −2.17)] and exercise plus diet [−4.28 kg (95% CI: −5.71, −2.84)] reduced fat mass; exercise alone did not change fat mass. Compared with control, diet alone [−0.82 kg (95% CI: −1.50, −0.15)] and exercise plus diet [−1.24 kg (95% CI: −1.92, −0.56)] reduced lean mass; exercise alone did not change lean mass. Compared with control, exercise alone, diet alone, and exercise plus diet did not change bone mineral density. CONCLUSION: In survivors of breast cancer with overweight or obesity, diet alone or diet plus exercise produced clinically meaningful weight loss at week 52. The majority of weight loss was fat mass.

The NCCN Guidelines for Survivorship are intended to help healthcare professionals working with cancer survivors to ensure that each survivor’s complex and varied needs are addressed. The Guidelines provide screening, evaluation, and treatment recommendations for consequences of adult-onset cancer and its treatment; recommendations to help promote healthful lifestyle behaviors, weight management, and immunizations in survivors; and a framework for care coordination. This article summarizes the recommendations regarding employment and return to work for cancer survivors that were added in the 2021 version of the NCCN Guidelines.

Eye contact enhances memory for spoken words. The present research examined if a similar effect occurs when one observes rather than experiences eye contact, and whether the effect extends to situa...

Background The mechanism by which immune cells regulate metastasis is unclear. Understanding the role of immune cells in metastasis will guide the development of treatments improving patient survival. Methods We used syngeneic orthotopic mouse tumour models (wild-type, NOD/scid and Nude), employed knockout (CD8 and CD4) models and administered CXCL4. Tumours and lungs were analysed for cancer cells by bioluminescence, and circulating tumour cells were isolated from blood. Immunohistochemistry on the mouse tumours was performed to confirm cell type, and on a tissue microarray with 180 TNBCs for human relevance. TCGA data from over 10,000 patients were analysed as well. Results We reveal that intratumoral immune infiltration differs between metastatic and non-metastatic tumours. The non-metastatic tumours harbour high levels of CD8+ T cells and low levels of platelets, which is reverse in metastatic tumours. During tumour progression, platelets and CXCL4 induce differentiation of monocytes into myeloid-derived suppressor cells (MDSCs), which inhibit CD8+ T-cell function. TCGA pan-cancer data confirmed that CD8lowPlatelethigh patients have a significantly lower survival probability compared to CD8highPlateletlow. Conclusions CD8+ T cells inhibit metastasis. When the balance between CD8+ T cells and platelets is disrupted, platelets produce CXCL4, which induces MDSCs thereby inhibiting the CD8+ T-cell function.

Background Quinacrine plus a fluoropyrimidine has in vivo efficacy against metastatic colorectal cancer (mCRC). This phase 1b trial evaluated the combination of quinacrine plus capecitabine in patients with treatment-refractory mCRC. Patients and Methods Using a modified Simon accelerated titration design, adults with treatment-refractory mCRC were treated with capecitabine 1000 mg/m2 twice daily for 14/21-day cycle, and escalating doses of quinacrine 100 mg daily, 100 mg twice daily, and 200 mg twice daily for 21 days. The primary endpoint was identifying the maximum tolerated dose, determining tolerability and safety. In an expansion cohort, it was overall response rate and time to tumor progression (TTP). Results Ten patients (median age of 60 years) were treated in phase 1b. The first 2 quinacrine dosing levels were well tolerated. Dose-limiting toxicities were seen in 3 patients treated with quinacrine 200 mg twice daily. Five additional patients tolerated quinacrine 100 mg twice daily without further dose-limiting toxicities, thus establishing the maximum tolerated dose. Seven additional expansion-cohort patients enrolled onto the study before quinacrine manufacturing ceased within the United States. Five patients experienced stable disease, 1 partial response, and 10 disease progression. Median TTP overall was 2.12 months and median overall survival 5.22 months for the 17 patients. Conclusion Capecitabine and quinacrine can be safely administered at the maximum tolerated dose of capecitabine 1000 mg/m2 by mouth twice daily on days 1-14 and quinacrine 100 mg by mouth twice daily on days 1-21 of a 21-day cycle in mCRC patients. Although the expansion study was halted early, TTP was in line with other studies of refractory mCRC, suggesting activity of this regimen in heavily pretreated patients.

Oxaliplatin-induced immune thrombocytopenia is a rare manifestation of oxaliplatin hypersensitivity, presenting as an acute onset of severe thrombocytopenia after oxaliplatin administration. No standard therapeutic approach outside of permanent discontinuation of oxaliplatin exists. Here, we present a case of oxaliplatin-induced immune thrombocytopenia occurring after oxaliplatin retreatment for metastatic colon cancer. Possible mechanisms of disease and approach to treatment are discussed.

Objective The objectives were to identify profiles of school-age children with overweight and obesity (OW/OB) from rural counties based on patterns of diet, activity, and sleep, to examine demographic predictors, and to examine whether profiles were differentially associated with psychosocial functioning. Methods Participants included 163 children (Mage = 9.8) and parents. Children wore accelerometers to assess physical activity and sleep duration. Consumption of fruits and vegetables (F/V) and sugar-sweetened beverages (SSB) was assessed with a food frequency questionnaire. Self-report of emotional, social, and academic health-related quality of life (HRQOL), peer victimization, social skills, and social problem behaviors was collected, as well as parent-report of HRQOL. Latent variable mixture modeling (LVMM) was conducted. Results Sleep did not significantly contribute to profile differentiation and was removed. Four profiles emerged: (a) Low F/V + Low SSB + Low activity, (b) Low F/V + Low SSB + Moderate activity, (c) High F/V + High SSB + Low activity, and (d) Moderate F/V + Moderate SSB + High activity. Older children were more likely to be in profile 1. After controlling for child age, parents of children in profile 1 reported significantly lower child social HRQOL than parents of children in profiles 2 and 4. Children in profile 4 reported experiencing significantly lower victimization than those in profile 3. Conclusions There are subgroups of rural children with OW/OB that engage in various combinations of healthy and unhealthy behaviors. LVMM has the potential to inform future interventions and identify needs of groups of children with OW/OB.

PURPOSE: Perceiving positive life changes (“benefit finding”) is thought to promote better adjustment after cancer, yet is poorly understood among colorectal cancer (CRC) patients. We characterized benefit finding and examined its relationship to demographic/medical factors, change over time, and association with distress. METHODS: CRC outpatients (N=133, 50% metastatic) completed self-report measures (demographic/medical factors, benefit finding, distress) at baseline and 6-months later. Wilcoxon Rank-Sum (Kruskal Wallis) tests or Spearman correlations tested associations between benefit finding and demographic/medical factors. Linear regressions assessed (1) change in benefit finding over time and whether this differed by demographic/medical factors, and (2) association between benefit finding and distress and whether this changed over time. RESULTS: Benefit finding was common among patients with CRC, with highest rated items reflecting gratitude, acceptance, and stronger family relationships. Women and racial minorities reported greater benefit finding than men (p

Background Metastatic high-grade neuroendocrine neoplasms (G3NENs) have limited treatment options after progression on platinum-based therapy. We addressed the role of Pembrolizumab in patients with previously treated metastatic G3NENs. Methods Two open-label, phase 2 studies enrolled patients with G3NEN (Ki-67 > 20%) to receive Pembrolizumab at 200 mg I.V. every 3 weeks. Radiographic evaluation was conducted every 9 weeks with overall response rate as the primary endpoint. Results Between November 2016 and May 2018, 29 patients (13 males/16 females) with G3NENs were enrolled. One patient (3.4%) had an objective response and an additional six patients (20.7%) had stable disease, resulting in a disease control rate of 24.1%. Disease control rate (DCR) at 18 weeks was 10.3% (3/29). There was no difference in the DCR, PFS or OS between the PD-L1-negative and -positive groups (p 0.56, 0.88 and 0.55, respectively). Pembrolizumab was well tolerated with only 9 grade 3, and no grade 4 events considered drug-related. Conclusions Pembrolizumab can be safely administered to patients with G3NENs but has limited activity as a single agent. Successful completion of our trials suggest studies in G3NENs are feasible and present an unmet need. Further research to identify active combination therapies should be considered. Clinical trial registration number NCT02939651 (10/20/2016).

Purpose: This randomized, multicenter, open-label, phase Ib/II study assessed durvalumab and tremelimumab in combination or as monotherapy for chemotherapy-refractory gastric cancer or gastroesophageal junction (GEJ) cancer. Patients and Methods: Second-line patients were randomized 2:2:1 to receive durvalumab plus tremelimumab (arm A), or durvalumab (arm B) or tremelimumab monotherapy (arm C), and third-line patients received durvalumab plus tremelimumab (arm D). A tumor-based IFNγ gene signature was prospectively evaluated as a potential predictive biomarker in second- and third-line patients receiving the combination (arm E). The coprimary endpoints were objective response rate and progression-free survival (PFS) rate at 6 months. Results: A total of 113 patients were treated: 6 in phase Ib and 107 (arm A, 27; arm B, 24; arm C, 12; arm D, 25; arm E, 19) in phase II. Overall response rates were 7.4%, 0%, 8.3%, 4.0%, and 15.8% in the five arms, respectively. PFS rates at 6 months were 6.1%, 0%, 20%, 15%, and 0%, and 12-month overall survival rates were 37.0%, 4.6%, 22.9%, 38.8%, and NA, respectively. Treatment-related grade 3/4 adverse events were reported in 17%, 4%, 42%, 16%, and 11% of patients, respectively. Conclusions: Response rates were low regardless of monotherapy or combination strategies. No new safety signals were identified. Including use of a tumor-based IFNγ signature and change in baseline and on-treatment circulating tumor DNA are clinically feasible and may be novel strategies to improve treatment response in this difficult-to-treat population.

Background Pediatric obesity is a critical public health issue. Augmenting care in multidisciplinary pediatric obesity clinics with innovative evidence-based technology to improve weight status and health outcomes is needed. Objective This study describes the design and methods of an open trial pilot study to examine a remote patient monitoring system (RPMS) for children aged 8-17 years who are receiving treatment in a multidisciplinary pediatric obesity clinic. Methods Participants will include 45 youth with obesity and their parents. Families will receive standard care in the clinic and the RPMS for 3 months. The RPMS consists of a tablet, weight scale, and pedometer. The system provides daily educational content and involves the use of the pedometer and weekly weigh-ins. Children and parents will complete baseline, posttreatment (month 3), and follow-up assessments (month 6). The primary aim of the study is to examine feasibility and satisfaction with the RPMS and assess its initial effectiveness. Results We hypothesize high feasibility and satisfaction, with rates over 75%. Furthermore, after RPMS treatment, children will exhibit improved weight status, health outcomes, dietary intake, physical activity, health-related quality of life, self-efficacy, and home-food environment compared to before treatment. These gains are expected to persist at follow-up. Conclusions This study is novel in that it is the first to design, implement, and examine an RPMS in a pediatric obesity clinic. If the RPMS is feasible, effective, and easily accessible, it may prove to be a practical, acceptable, and cost-effective weight management treatment for youth seeking treatment for severe obesity. Trial Registration ClinicalTrials.gov NCT04029597; https://clinicaltrials.gov/ct2/show/NCT04029597 International Registered Report Identifier (IRRID) DERR1-10.2196/29858

The c-Myc oncogene drives malignant progression and induces robust anabolic and proliferative programmes leading to intrinsic stress. The mechanisms enabling adaptation to MYC-induced stress are not fully understood. Here we reveal an essential role for activating transcription factor 4 (ATF4) in survival following MYC activation. MYC upregulates ATF4 by activating general control nonderepressible 2 (GCN2) kinase through uncharged transfer RNAs. Subsequently, ATF4 co-occupies promoter regions of over 30 MYC-target genes, primarily those regulating amino acid and protein synthesis, including eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), a negative regulator of translation. 4E-BP1 relieves MYC-induced proteotoxic stress and is essential to balance protein synthesis. 4E-BP1 activity is negatively regulated by mammalian target of rapamycin complex 1 (mTORC1)-dependent phosphorylation and inhibition of mTORC1 signalling rescues ATF4-deficient cells from MYC-induced endoplasmic reticulum stress. Acute deletion of ATF4 significantly delays MYC-driven tumour progression and increases survival in mouse models. Our results establish ATF4 as a cellular rheostat of MYC activity, which ensures that enhanced translation rates are compatible with survival and tumour progression.

OBJECTIVE: The objective of this scoping review is to map the available literature on school-based obesity prevention programs in rural communities. INTRODUCTION: Significant health disparities are associated with childhood obesity, and these disparities disproportionately affect children in disadvantaged communities, such as rural areas. Youth in rural areas are 26% more likely to be obese than youth in urban communities. To combat obesity in children, schools have become an avenue for educating children about the importance of healthy diet and physical activity. Although many school-based obesity prevention programs have been implemented in recent years, more information is needed on programs in rural communities. INCLUSION CRITERIA: This scoping review will consider studies that include children 5 to 18 years of age who are enrolled in elementary, middle or high school in a rural setting and that investigate school-based obesity prevention programs. Studies that include children who are in non-rural areas, who are home-schooled, who are in an alternative setting (e.g. juvenile detention) or who are hospitalized will be excluded. Studies published in English since 1990 will be included. METHODS: Multiple databases will be searched, including PubMed, CINAHL, ERIC, Embase, Scopus and Academic Search Premier. Trials registers and gray literature will also be searched. After screening the titles and abstracts of identified citations, potentially relevant studies will be retrieved in full. Data will be extracted by independent reviewers and presented in a diagrammatic or tabular form, accompanied by a narrative summary.

Esophageal cancer is the sixth leading cause of cancer-related deaths worldwide. Squamous cell carcinoma is the most common histology in Eastern Europe and Asia, and adenocarcinoma is most common in North America and Western Europe. Surgery is a major component of treatment of locally advanced resectable esophageal and esophagogastric junction (EGJ) cancer, and randomized trials have shown that the addition of preoperative chemoradiation or perioperative chemotherapy to surgery significantly improves survival. Targeted therapies including trastuzumab, ramucirumab, and pembrolizumab have produced encouraging results in the treatment of patients with advanced or metastatic disease. Multidisciplinary team management is essential for all patients with esophageal and EGJ cancers. This selection from the NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers focuses on recommendations for the management of locally advanced and metastatic adenocarcinoma of the esophagus and EGJ.

The NCCN Guidelines for Survivorship provide screening, evaluation, and treatment recommendations for consequences of cancer and cancer treatment to aid healthcare professionals who work with survivors of adult-onset cancer. Guidance is also provided to help promote physical activity, weight management, and proper immunizations in survivors and to facilitate care coordination to ensure that all needs are addressed. These NCCN Insights summarize some of the topics discussed by the NCCN Survivorship Panel during the 2019 update of the guidelines, including the survivorship population addressed, ways to improve care coordination, and pain management.

The incidence and death rates of hepatocellular carcinoma (HCC) are rising. For more than a decade, the multikinase inhibitor sorafenib was the only U.S. Food and Drug Administration (FDA)–approved systemic therapy for HCC. However, since 2017, five additional agents have been approved in the first- or second-line setting. Although this represents an incredible victory for the field, there are no clear guidelines for agent selection on the basis of either patient or tumor characteristics. Here, we review the available systemic therapy options for advanced HCC and reported clinical data for each. We outline each agent’s unique toxicity profile, potential impact on patient quality of life, monitoring recommendations, and supportive strategies. Last, we review molecular and immunologic classifications of HCC as well as preclinical data that may serve as a basis for future biomarker enriched clinical trials to enable precision oncology care in HCC.

Sickle cell disease (SCD) is associated with pain and decreased health-related quality of life (HRQOL). Coping strategies influence pain but have not been evaluated as mediating the relation between pain and HRQOL in pediatric SCD. The current study examined whether pain-related coping mediates the association between pain and HRQOL in children and adolescents with SCD. In total, 104 children and adolescents 8 to 18 years of age (Mage=12.93 y) with SCD attending outpatient clinics completed pain intensity, HRQOL, and pain-related coping measures. Multiple mediation analyses were used to examine whether pain-related coping mediated the pain and HRQOL relation and whether types of coping (ie, approach, emotion-focused avoidance, problem-focused avoidance) were independent mediators. Total indirect effects for models examining physical and psychosocial HRQOL were not significant. After controlling for covariates, emotion-focused avoidance significantly mediated the association between pain and physical HRQOL (effect: -0.023; bootstrapped SE: 0.018; 95% confidence interval: -0.0751, -0.0003) but not the pain and psychosocial HRQOL relation. Approach and problem-focused avoidance were not significant mediators. Coping with pain in pediatric SCD is an important avenue for clinical intervention and additional research. Among children with SCD reporting high pain intensity, interventions should emphasize negative impacts of emotion-focused avoidance coping and integrate other empirically supported coping strategies to improve HRQOL.

OBJECTIVES: Examine racial differences in disordered eating and parental feeding in youth with obesity. METHODS: A diverse sample of 131 treatment-seeking youth (M(age) = 12.84 years; Range(age) = 8–18 years; 65.6% African American, 34.4% Caucasian) with obesity (M(BMIz) = 2.60) completed a disordered eating questionnaire; parents completed a questionnaire about feeding practices. RESULTS: No significant differences in disordered eating between African American and Caucasian youth emerged. Significant differences were found on parent feeding where parents of African American children endorsed more frequent use of pressure to eat, including ensuring and monitoring enough is eaten. CONCLUSIONS: Generally, comparisons of disordered eating and parent feeding practices between African American and Caucasian youth with obesity were not significant. Racial differences on some aspects of parental feeding practices were found. Future research should identify cultural factors impacting these differences. Clinical implications include providing culturally sensitive psychoeducation and interventions to address unhealthy feeding practices in diverse families.

Background The purpose of this nonrandomized, open-label, phase I study (NCT01285037) was to evaluate the safety and tolerability of merestinib, an oral antiproliferative and antiangiogenic kinase inhibitor, and to determine a recommended phase II dose and schedule for patients with advanced cancer. Materials and Methods This was a multicenter, nonrandomized, open-label, phase I study of oral merestinib consisting of six parts: dose escalation (part A), followed by a four-cohort dose-confirmation study (part B) and subsequently a four-part dose expansion and combination safety testing of merestinib with standard doses of cetuximab (part C), cisplatin (part D), gemcitabine and cisplatin (part E), and ramucirumab (part F) in patients with specific types of advanced cancers. Safety, tolerability, antitumor activity, and pharmacokinetics were evaluated in all cohorts. Results The dose escalation, confirmation, and expansion results support the dosing of merestinib at 120 mg once daily, based on acceptable exposure and safety at this dose. One complete response was observed in a patient with cholangiocarcinoma, and three patients with cholangiocarcinoma achieved a partial response. Overall, 60 (32%) of the 186 patients enrolled in the study had a best response of stable disease. Conclusion This study demonstrates that merestinib has a tolerable safety profile and potential anticancer activity and warrants further clinical investigation. Implications for Practice Merestinib treatment in patients with advanced cancer demonstrated an acceptable safety profile and potential antitumor activity, supporting its future development in specific disease populations as a monotherapy and/or in combination with other therapies.

Summary Background VEGF and VEGF receptor 2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. We aimed to assess whether the addition of ramucirumab, a VEGFR-2 antagonist monoclonal antibody, to first-line chemotherapy improves outcomes in patients with metastatic gastric or gastro-oesophageal junction adenocarcinoma. Methods For this double-blind, randomised, placebo-controlled, phase 3 trial done at 126 centres in 20 countries, we recruited patients aged 18 years or older with metastatic, HER2-negative gastric or gastro-oesophageal junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate organ function. Eligible patients were randomly assigned (1:1) with an interactive web response system to receive cisplatin (80 mg/m2, on the first day) plus capecitabine (1000 mg/m2, twice daily for 14 days), every 21 days, and either ramucirumab (8 mg/kg) or placebo on days 1 and 8, every 21 days. 5-Fluorouracil (800 mg/m2 intravenous infusion on days 1–5) was permitted in patients unable to take capecitabine. The primary endpoint was investigator-assessed progression-free survival, analysed by intention to treat in the first 508 patients. We did a sensitivity analysis of the primary endpoint, including a central review of CT scans. Overall survival was a key secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT02314117. Findings Between Jan 28, 2015, and Sept 16, 2016, 645 patients were randomly assigned to receive ramucirumab plus fluoropyrimidine and cisplatin (n=326) or placebo plus fluoropyrimidine and cisplatin (n=319). Investigator-assessed progression-free survival was significantly longer in the ramucirumab group than the placebo group (hazard ratio [HR] 0·753, 95% CI 0·607–0·935, p=0·0106; median progression-free survival 5·7 months [5·5–6·5] vs 5·4 months [4·5–5·7]). A sensitivity analysis based on central independent review of the radiological images did not corroborate the investigator-assessed difference in progression-free survival (HR 0·961, 95% CI 0·768–1·203, p=0·74). There was no difference in overall survival between groups (0·962, 0·801–1·156, p=0·6757; median overall survival 11·2 months [9·9–11·9] in the ramucirumab group vs 10·7 months [9·5–11·9] in the placebo group). The most common grade 3–4 adverse events were neutropenia (85 [26%] of 323 patients in the ramucirumab group vs 85 [27%] of 315 in the placebo group), anaemia (39 [12%] vs 44 [14%]), and hypertension (32 [10%] vs 5 [2%]). The incidence of any-grade serious adverse events was 160 (50%) of 323 patients in the ramucirumab group and 149 (47%) of 315 patients in the placebo group. The most common serious adverse events were vomiting (14 [4%] in the ramucirumab group vs 21 [7%] in the placebo group) and diarrhoea (11 [3%] vs 19 [6%]). There were seven deaths in each group, either during study treatment or within 30 days of discontinuing study treatment, which were the result of treatment-related adverse events. In the ramucirumab group, these adverse events were acute kidney injury, cardiac arrest, gastric haemorrhage, peritonitis, pneumothorax, septic shock, and sudden death (n=1 of each). In the placebo group, these adverse events were cerebrovascular accident (n=1), multiple organ dysfunction syndrome (n=2), pulmonary embolism (n=2), sepsis (n=1), and small intestine perforation (n=1). Interpretation Although the primary analysis for progression-free survival was statistically significant, this outcome was not confirmed in a sensitivity analysis of progression-free survival by central independent review, and did not improve overall survival. Therefore, the addition of ramucirumab to cisplatin plus fluoropyrimidine chemotherapy is not recommended as first-line treatment for this patient population. Funding Eli Lilly and Company.

Focused Abdominal Sonography for Trauma (FAST) examination has long been proven useful in the management of adult trauma patients, however, its utility in pediatric trauma patients is not as proven. Our goal was to evaluate the utility of a FAST examination in predicting the success or failure of nonoperative management (NOM) of blunt liver and/or spleen (BLSI) in the pediatric trauma population.A retrospective analysis of a prospective observational study of patients younger than 18 years presenting with BLSI to one of ten Level I pediatric trauma centers between April 2013 and January 2016. 1,008 patients were enrolled and 292 had a FAST examination recorded. We analyzed failure of NOM of BLSI in the pediatric trauma population. We then compared FAST examination alone or in combination with the pediatric age adjusted shock index (SIPA) as it relates to success of NOM of BLSI.Focused Abdominal Sonography for Trauma examination had a negative predictive value (NPV) of 97% and positive predictive value (PPV) of 13%. The odds ratio of failing with a positive FAST examination was 4.9 and with a negative FAST was 0.20. When combined with SIPA, a positive FAST examination and SIPA had a PPV of 17%, and an odds ratio for failure of 4.9. The combination of negative FAST and SIPA had an NPV of 96%, and the odds ratio for failure was 0.20.Negative FAST is predictive of successful NOM of BLSI. The addition of a positive or negative SIPA score did not affect the PPV or NPV significantly. Focused Abdominal Sonography for Trauma examination may be useful clinically in determining which patients are not at risk for failure of NOM of BLSI and do not require monitoring in an intensive care setting.Prognostic study, level IV; therapeutic/care management, level IV.

This review highlights the etiology, assessment, and management of unintentional weight loss in patients with pancreatic cancer and provides recommendations for best supportive care., Unintentional weight loss in patients with pancreatic cancer is highly prevalent and contributes to low therapeutic tolerance, reduced quality of life, and overall mortality. Weight loss in pancreatic cancer can be due to anorexia, malabsorption, and/or cachexia. Proper supportive care can stabilize or reverse weight loss in patients and improve outcomes. We review the literature on supportive care relevant to pancreatic cancer patients, and offer evidence‐based recommendations that include expert nutritional assessment, counseling, supportive measures to ensure adequate caloric intake, pancreatic enzyme supplementation, nutritional supplement replacement, orexigenic agents, and exercise. Pancreatic Cancer Action Network‐supported initiatives will spearhead the dissemination and adoption of these best supportive care practices. Implications for Practice. Weight loss in pancreatic cancer patients is endemic, as 85% of pancreatic cancer patients meet the classic definition of cancer cachexia. Despite its significant prevalence and associated morbidity, there is no established approach to this disease entity. It is believed that this is due to an important knowledge gap in understanding the underlying biology and lack of optimal treatment approaches. This article reviews the literature regarding pancreas cancer‐associated weight loss and establishes a new framework from which to view this complex clinical problem. An improved approach and understanding will help educate clinicians, improve clinical care, and provide more clarity for future clinical investigation.

BACKGROUND: Overactivation of human epidermal growth factor receptor 3 (HER3) triggers multiple intracellular pathways resulting in tumor cell survival. This Phase 1 study assessed the safety, efficacy, and pharmacokinetics (PK) of seribantumab, a fully human anti-HER3 monoclonal antibody.METHODS: Adult patients with advanced or refractory solid tumors were treated in six dose cohorts of seribantumab: 3.2, 6, 10, 15, or 20 mg/kg weekly, or 40 mg/kg loading dose followed by 20 mg/kg weekly maintenance dose (40/20 mg/kg) using a modified 3+3 dose escalation strategy with cohort expansion. Primary objectives were identification of a recommended Phase 2 dose (RP2D) and determination of objective response rate. Secondary objectives were assessment of safety, dose-limiting toxicities, and PK.RESULTS: Forty-four patients (26 dose escalation; 18 dose expansion) were enrolled. Seribantumab monotherapy was well tolerated with most adverse events being transient and mild to moderate (grade 1 or 2) in severity; maximum tolerated dose was not reached. The highest dose, 40/20 mg/kg, was identified as RP2D. Best response was stable disease, achieved by 24% and 39% of patients during the dose escalation and expansion portions of the study, respectively. Seribantumab terminal half-life was ≈100 hours; steady state concentrations were reached after 3–4 weekly doses. CONCLUSIONS: Seribantumab monotherapy was well tolerated across all dose levels. Safety and PK data from this study support further seribantumab investigations in genomically defined populations. CLINICAL TRIAL REGISTRATION: NCT00734305.DATE OF REGISTRATION: August 12, 2008.

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.

Background In 1999, type 2 diabetes mellitus (T2DM) was identified as an emerging epidemic in youth, and racial and ethnic minority youth were identified with high risk. Two decades later, no gold standard T2DM prevention intervention has been established for this population. Objective This study tests the efficacy of a telehealth diabetes prevention intervention for African American (AA) families with children with risk for T2DM. Concurrently, investigators aim to evaluate an implementation strategy for the uptake of the intervention by the University of Mississippi Medical Center’s (UMMC) pediatric weight management clinic. Methods This single-arm trial will enroll 20 parents with overweight or obesity of children (8-11 years) with overweight or obesity, both of whom are at risk for T2DM. Parents will meet in small groups (5 parents per group) weekly for 11 weeks and then monthly for 4 monthly maintenance sessions via videoconference using Wi-Fi–enabled iPads with cellular connectivity. The intervention will be adapted from the National Diabetes Prevention Program and Power to Prevent, a diabetes prevention program tailored for AA families. The same lifestyle intervention facilitated by a racially concordant lifestyle coach trained in the Diabetes Prevention Program will be delivered to all groups (n=4). Participants will be recruited in-person during patient encounters at the UMMC’s pediatric weight management clinic. Sessions will consist of dietary and physical activity behavior change strategies facilitated using problem-solving and goal-setting skills. The implementation strategy has 2 targets: the pediatric weight management clinic site and clinical team and parents of children at risk for T2DM engaged in intensive obesity treatment to prevent T2DM. The multifaceted implementation protocol includes 4 discrete strategies: creating a new clinical team, changing the service site, intervening with families, and promoting organizational readiness for change. Results Recruitment and enrollment began in December 2020, and the intervention is scheduled to be delivered to the first cohort of parents in March 2021. The results are expected to be submitted for publication beginning in November 2021 through 2022. The primary outcome measure for the pilot trial will include changes from baseline to 12 and 30 weeks in the child BMI z score and parent BMI. The implementation evaluation will include multiple measures of feasibility, acceptability, appropriateness, fidelity, and efficacy. This protocol was approved by the UMMC’s Institutional Review Board (#2020V0249). Conclusions The proposed intervention approach is supported by the scientific literature and is scalable given the current and future health care subsidies for telehealth. Findings from this pilot trial will begin to address critical barriers to defining a gold standard lifestyle intervention for AA families with children at risk for T2DM. If effective, the intervention could be feasibly disseminated to treat obesity and prevent T2DM in high-risk AA pediatric populations. International Registered Report Identifier (IRRID) PRR1-10.2196/25699

PURPOSE Performance status (PS) is a subjective assessment of patients' overall health. Quantification of physical activity using a wearable tracker (Fitbit Charge [FC]) may provide an objective measure of patient's overall PS and treatment tolerance. MATERIALS AND METHODS Patients with colorectal cancer were prospectively enrolled into two cohorts (medical and surgical) and asked to wear FC for 4 days at baseline (start of new chemotherapy [± 4 weeks] or prior to curative resection) and follow-up (4 weeks [± 2 weeks] after initial assessment in medical and postoperative discharge in surgical cohort). Primary end point was feasibility, defined as 75% of patients wearing FC for at least 12 hours/d, 3 of 4 assigned days. Mean steps per day (SPD) were correlated with toxicities of interest (postoperative complication or ≥ grade 3 toxicity). A cutoff of 5,000 SPD was selected to compare outcomes. RESULTS Eighty patients were accrued over 3 years with 55% males and a median age of 59.5 years. Feasibility end point was met with 68 patients (85%) wearing FC more than predefined duration and majority (91%) finding its use acceptable. The mean SPD count for patients with PS 0 was 6,313, and for those with PS 1, it was 2,925 (122 and 54 active minutes, respectively) ( P = .0003). Occurrence of toxicity of interest was lower among patients with SPD > 5,000 (7 of 33, 21%) compared with those with SPD < 5,000 (14 of 43, 32%), although not significant ( P = .31). CONCLUSION Assessment of physical activity with FC is feasible in patients with colorectal cancer and well-accepted. SPD may serve as an adjunct to PS assessment and a possible tool to help predict toxicities, regardless of type of therapy. Future studies incorporating FC can standardize patient assessment and help identify vulnerable population.

Background Diet and exercise may be associated with quality of life and survival in men with prostate cancer. Objective This study aimed to determine the feasibility and acceptability of a remotely delivered web-based behavioral intervention among men with prostate cancer. Methods We conducted a multi-site 4-arm pilot randomized controlled trial of a 3-month intervention (TrueNTH Community of Wellness). Eligibility included self-reported prostate cancer diagnosis, having a personal device that connected to the internet, age ≥18 years, and ability to read English and receive text messages and emails. Men receiving chemotherapy or radiation, or those who reported contraindications to exercise, could participate with physician clearance. Participants were randomized (1:1:1:1) to additive intervention levels: website; website and personalized diet and exercise prescription; website, personalized prescription, Fitbit, and text messages; and website, personalized prescription, Fitbit, text messages, and 2 30-minute phone calls—one with an exercise trainer and one with a registered dietician. Primary outcomes were feasibility (accrual and attrition) and acceptability (survey data and website use). We described self-reported diet and exercise behavior at the time of enrollment, 3 months, and 6 months as secondary outcomes. Results In total, 202 men consented and were randomized between August 2017 and September 2018 (level 1: 49, level 2: 51, level 3: 50, level 4: 52). A total of 160 men completed the onboarding process and were exposed to their randomly assigned intervention (38, 38, 42, and 42 in levels 1, 2, 3, and 4, respectively). The follow-up rate was 82.7% (167/202) at 3 months and 77.2% (156/202) at 6 months. Participants had a median age of 70 years and were primarily White and college educated. Website visit frequency over the 3-month intervention period increased across levels (median: 2, 9, 11, and 16 visits for levels 1, 2, 3, and 4, respectively). Most were satisfied or very satisfied with the intervention (20/39, 51%; 27/42, 64%; 23/44, 52%; and 27/42, 64% for levels 1, 2, 3, and 4, respectively). The percentage of men who reported being very satisfied was highest among level 4 participants (10/42, 24% vs 4/39, 10%; 5/42, 12%; and 5/44, 11% for levels 1, 2, and 3, respectively). Dissatisfaction was highest in level 1 (5/39, 13% vs 1/42, 2%; 3/44, 7%; and 2/42, 5% for levels 2, 3, and 4, respectively). We observed small improvements in diet and physical activity at 3 months among men in level 4 versus those in level 1. Conclusions A web-based, remotely delivered, tailored behavioral intervention for men with prostate cancer is feasible. Future studies are warranted to increase the effect of the intervention on patient behavior while maintaining sustainability and scalability as well as to design and implement interventions for more diverse populations. Trial Registration ClinicalTrials.gov NCT03406013; http://clinicaltrials.gov/ct2/show/NCT03406013

Purpose of Review This study aimed to summarize evidence published between 1999 and June 2020 examining diet and lifestyle after prostate cancer (PC) diagnosis in relation to risk of biochemical recurrence, PC progression, and PC-specific mortality. Recent Findings Secondary prevention is an important research area in cancer survivorship. A growing number of studies have reported associations between post-diagnostic modifiable behaviors and risk of PC outcomes. Summary Evidence on modifiable lifestyle factors and PC remains limited. Where multiple studies exist, findings are often mixed. However, studies consistently suggest that smoking and consumption of whole milk/high-fat dairy are associated with higher risk of PC recurrence and mortality. In addition, physical activity and ½ to 1 glass of red wine/day have been associated with lower risk of recurrence and PC-specific mortality. Greater inclusion of racially/ethnically diverse groups in future research is necessary to understand these relationships in populations most impacted by adverse PC outcomes.

Background: Patients with esophageal cancer (EC) have high rates of malnutrition due to tumor location and treatment-related toxicity. Various strategies are used to improve nutritional status in patients with EC including oral and enteral support. Methods: We conducted a retrospective analysis to determine the impact of malnutrition and prophylactic feeding jejunostomy tube (FJT) placement on toxicity and outcomes in patients with localized EC who were treated with neoadjuvant chemoradiation therapy (nCRT) followed by esophagectomy. Results: We identified 125 patients who were treated with nCRT between 2002 and 2014. Weight loss and hypoalbuminemia occurred frequently during nCRT and were associated with multiple adverse toxicity outcomes including hematologic toxicity, nonhematologic toxicity, grade &ge, 3 toxicity, and hospitalizations. After adjusting for relevant covariates including the specific nCRT chemotherapy regimen received and the onset of toxicity, there were no significant associations between hypoalbuminemia, weight loss, or FJT placement and relapse-free survival (RFS) or overall survival (OS). FJT placement was associated with less weight loss during nCRT (p = 0.003) but was not associated with reduced toxicity or improved survival. Conclusions: Weight and albumin loss during nCRT for EC are important factors relating to treatment toxicity but not RFS or OS. While pretreatment FJT placement may reduce weight loss, it may not impact treatment tolerance or survival.

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 KRAS(G12C). 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.)

PurposePost-diagnostic coffee and tea consumption and prostate cancer progression is understudied.MethodsWe examined 1,557 men from the Cancer of the Prostate Strategic Urologic Research Endeavor who completed a food frequency questionnaire a median of 28months post-diagnosis. We estimated associations between post-diagnostic coffee (total, caffeinated, decaffeinated) and tea (total, non-herbal, herbal) and risk of prostate cancer progression (recurrence, secondary treatment, bone metastases, or prostate cancer death) using Cox proportional hazards regression. We also examined whether smoking (current, former, never) modified these associations.ResultsWe observed 167 progression events (median follow-up 9years). Higher coffee intake was associated with higher risk of progression among current smokers (n = 95). The hazard ratio (HR) [95% confidence interval (CI)] for 5 vs 0 cups/day of coffee was 0.5 (CI 0.2, 1.7) among never smokers, but 4.5 (CI 1.1, 19.4) among current smokers (p-interaction: 0.001). There was no association between total coffee intake and prostate cancer progression among never and former smokers. However, we observed an inverse association between decaffeinated coffee (cups/days) and risk of prostate cancer progression in these men (HR > 0 to

Objective To comprehensively examine the behavioral phenotypes of children with and without executive function (EF) impairments in a clinical sample of youth with obesity. Methods Youth aged 8 to 17 years (Mean age = 12.97) attending a medical clinic for obesity and their caregivers (N = 195 dyads) completed a battery of behavioral questionnaires. Caregiver-proxy report of EF was assessed using the Behavior Rating Inventory of Executive Function. Latent Class Analysis was conducted to identify EF groupings. Analysis of variance and chi-square tests were conducted to examine associations between EF groups and behavioral phenotypes. Results Four latent classes of EF impairment were identified (No/Low Impairment; Behavioral Regulation Impairment; Metacognition Impairment; Global Impairment). There was an overall positive pattern of associations between these EF groups and behavioral/emotional symptoms, such that behavioral/emotional symptoms tended to increase with EF impairment. Conclusions Children with obesity and EF impairment demonstrate a dysregulated behavioral phenotype ranging from internalizing to externalizing behavioral and weight-related symptoms. This phenotype framework may be clinically beneficial for utilizing screening/assessment results to develop, tailor, and/or match treatment approaches in pediatric obesity.

Background Exercise and a healthy diet can improve the quality of life and prognosis of prostate cancer survivors, but there have been limited studies on the feasibility of web-based lifestyle interventions in this population. Objective This study aims to develop a data-driven grounded theory of web-based engagement by prostate cancer survivors based on their experience in the Community of Wellness, a 12-week randomized clinical trial designed to support healthy diet and exercise habits. Methods TrueNTH’s Community of Wellness was a four-arm pilot study of men with prostate cancer (N=202) who received progressive levels of behavioral support (level 1: website; level 2: website with individualized diet and exercise recommendations; level 3: website with individualized diet and exercise recommendations, Fitbit, and text messages; and level 4: website with individualized diet and exercise recommendations, Fitbit and text messages, and separate phone calls with an exercise trainer and a registered dietitian). The primary aim of the study is to determine the feasibility and estimate the effects on behaviors (results reported in a separate paper). Following the 12-week intervention, we invited participants to participate in 4 focus groups, one for each intervention level. In this report, we used grounded theory analyses including open, axial, and selective coding to generate codes and themes from the focus group transcripts. Categories were refined across levels using embodied categorization and constant comparative methods. Results In total, 20 men with prostate cancer participated in the focus groups: 5, 4, 5, and 6 men in levels 1, 2, 3, and 4, respectively. Participants converged on 5 common factors influencing engagement with the intervention: environment (home environment, competing priorities, and other lifestyle programs), motivation (accountability and discordance experienced within the health care system), preparedness (technology literacy, health literacy, trust, and readiness to change), program design (communication, materials, and customization), and program support (education, ally, and community). Each of these factors influenced the survivors’ long-term impressions and habits. We proposed a grounded theory associating these constructs to describe the components contributing to the intuitiveness of a web-based lifestyle intervention. Conclusions These analyses suggest that web-based lifestyle interventions are more intuitive when we optimize participants’ technology and health literacy; tailor interface design, content, and feedback; and leverage key motivators (ie, health care providers, family members, web-based coach) and environmental factors (ie, familiarity with other lifestyle programs). Together, these grounded theory–based efforts may improve engagement with web-based interventions designed to support prostate cancer survivorship.

Purpose: The recombinant fusion protein ipafricept blocks Wnt signaling, and in combination with gemcitabine and nab-paclitaxel caused tumor regression in xenografts. This phase Ib study evaluated the combination of ipafricept with nab-paclitaxel + gemcitabine in patients with untreated metastatic pancreatic adenocarcinoma (mPDAC). Patients and Methods: Dose escalation started with standard dose nab-paclitaxel + gemcitabine and ipafricept (3.5 mg/kg days 1, 15). Because of fragility fractures seen with different anti-Wnt agents, following cohorts had ≥6 patients treated with ipafricept 3 to 5 mg/kg on day 1, and included bone marker monitoring and prophylactic bisphosphonates as indicated. On the basis of preclinical data, sequential dosing was evaluated in cohort 4 (ipafricept day 1 followed nab-paclitaxel + gemcitabine day 3). Objectives included safety, MTD, recommended phase II dose, pharmacokinetics, immunogenicity, pharmacodynamics, and efficacy. Results: A total of 26 patients were enrolled, five in cohort 1 and seven each in cohorts 2–4. ipafricept-related adverse events (AEs) of any grade included fatigue, nausea, vomiting, anorexia, and pyrexia. ipafricept-related AEs grade ≥3 included two events of aspartate aminotransferase elevation, and one each of nausea, rash, vomiting, and leucopenia. No dose-limiting toxicities or fragility fractures were observed. Nine patients (34.6%) had partial response, 12 (46.2%) stable disease as best response, with clinical benefit rate of 81%. Median progression-free survival was 5.9 m [95% confidence interval (CI), 3.4–18.4], median overall survival was 9.7 m (95% CI, 7.0–14). The study was terminated by the sponsor due to bone-related toxicity within this therapeutic program and concerns for commercial viability. One patient remains on therapy under compassionate use. Conclusions: Ipafricept can be administered with nab-paclitaxel + gemcitabine with reasonable tolerance. Wnt pathway remains a therapeutic target of interest in mPDAC.

Purpose: The safety and preliminary efficacy of MEDI1873, an agonistic IgG1 fusion protein targeting glucocorticoid-induced TNF receptor–related protein (GITR), were evaluated in an open-label, first-in-human, phase I, dose escalation study in previously treated patients with advanced solid tumors. Patients and Methods: Two single-patient cohorts at 1.5 and 3 mg i.v. were followed by 3+3 dose escalation in six cohorts at 7.5, 25, 75, 250, 500, and 750 mg, all every 2 weeks, for up to 52 weeks. Primary endpoints were safety and tolerability, dose-limiting toxicities (DLT), and MTD. Secondary endpoints included antitumor activity, pharmacokinetics, immunogenicity, and pharmacodynamics. Results: Forty patients received MEDI1873. Three experienced DLTs: grade 3 worsening tumor pain (250 mg); grade 3 nausea, vomiting, and headache (500 mg); and grade 3 non-ST segment elevation myocardial infarction (750 mg). An MTD was not reached and treatment was well tolerated up to 500 mg. Most common treatment-related adverse events were headache (25%), infusion-related reaction (17.5%), and decreased appetite (17.5%). MEDI1873 exposure was dose proportional. Antidrug–antibody incidence was low. MEDI1873 increased peripheral CD4+ effector memory T-cell proliferation as well as cytokines associated with effector T-cell activation at dose levels ≥75 mg. The best response was stable disease (SD) in 17 patients (42.5%), including 1 unconfirmed partial response. Eight patients (20.0%) had SD ≥24 weeks. Conclusions: MEDI1873 showed acceptable safety up to 500 mg i.v. every 2 weeks with pharmacodynamics activity, and prolonged SD in some patients. However, further development is not planned because of lack of demonstrated tumor response.

Oxidative stress is widely known to be a major contributor in the pathogenesis of dry eye disease (DED). 4-Hydroxynonenal (4-HNE), a well-known byproduct frequently measured as an indicator of oxidative stress-induced lipid peroxidation, has been shown to be elevated in both human and murine corneal DED samples. This study aims to investigate if 4-HNE is responsible for the oxidative stress in human corneal epithelial cells (HCECs) and explores the underlying mechanism by which it confers its effects. SV40-immortalized HCECs were cultured in minimum essential media (MEM) with 1% penicillin/streptomycin and 10% fetal bovine serum. HCECs were exposed to media with or without 4-HNE and cell culture supernatants were collected at 4 and 24 h. Cellular reactive oxygen species (ROS) measurement was performed using a 2′,7′-dichlorofluorescein diacetate (DCFDA) assay kit according to the manufacturer’s instructions. Protein levels of antioxidant enzymes copper/zinc superoxide dismutase 1 (SOD1) and NAD(P)H quinone dehydrogenase 1 (NQO1) were analyzed by Western blot. NF-κB activation and expression of IL-6 and IL-8 were measured using an NF-κB p65 Total SimpleStep ELISA Kit and Proteome Profiler Human Cytokine Array Kit. Cell viability was evaluated by LDH cytotoxicity assay. Treatment with 4-HNE decreased cell viability of HCECs. Band intensities corresponding to levels of ROS production showed a significant increase in ROS generation after treatment with 4-HNE. 4-HNE decreased SOD1 levels and upregulated NQO1 expression in HCECs. A significant increase in activation of NF-κB and production of pro-inflammatory cytokines IL-6 and IL-8 was observed after treatment with 4-HNE. Exposure to N-acetylcysteine (NAC), an antioxidant and ROS scavenger, antagonized the oxidative effects of 4-HNE on HCECs. 4-HNE induces oxidative stress in corneal epithelial cells by increasing levels of ROS generation and modifying the expression of antioxidant enzyme levels, decreasing cell viability of HCECs in vitro. This study demonstrates a potential pathway by which 4-HNE functions to confer its detrimental effects and provides a new therapeutic target for the treatment of DED.

Gallbladder cancer (GBC) and cholangiocarcinoma (CCA) are rare entities with relatively poor prognoses. We compared treatment outcomes of definitive resection with or without neoadjuvant therapy in GBC and CCA patients.All non-metastatic GBC and CCA patients at a single institution who underwent definitive resection from 1992-2016 were analyzed. We compared overall survival (OS), locoregional failure (LRF) and distant failure (DF) in patients who received neoadjuvant therapy (chemotherapy and/or radiation) versus those who did not receive neoadjuvant treatment. OS was analyzed using the Kaplan-Meier method and log rank tests. Cox proportional hazard models were used to analyze time to recurrence.Out of 128 patients, 90 had GBC and 38 had CCA, 25 patients (27%) among GBC and 8 patients (21%) with CCA were T3, T4 or node positive. Overall, 52 (40%) GBC and 25 (20%) CCA patients received neoadjuvant treatment, chemotherapy alone 60 patients (47%) or radiation with or without chemotherapy 17 patients (13%). Chemotherapy was single agent in 44 patients (34%) and multi-agent in 25 (20%). The median OS for GBC patients was 3.1 years with 2.6 years for no neoadjuvant group and 3.1 years for neoadjuvant group (P=0.6786). Median OS was 2.6 years for CCA patients, 3.6 years for no neoadjuvant therapy versus 2.0 years for neoadjuvant group (P=0.1613). There was a trend towards increased DF in patients with CCA and GBC receiving neoadjuvant therapy: HR 2.74, 95% CI, 0.73-10.3, P=0.14 and 0.92, 95% CI, 0.44-1.93, P=0.82 respectively. The hazard ratio for time to LRF in CCA patients receiving neoadjuvant treatment was 3.17, 95% CI, 0.62-16.31, P=0.16 whereas HR was 0.15, 95% CI, 0.10-1.76, P=0.23 for GBC patients. Among GBC patients, the pattern of first failure was locoregional in 8 (10%) having 3 LRF in neoadjuvant group (2 with chemotherapy, 1 with CRT, 0 with RT alone) as compared to 5 in adjuvant group. Among 28 (35%) patients with DF first, 15 patients received neoadjuvant therapy versus 13 patients in non-neoadjuvant group. In CCA patients, LRF occurred first in 6 patients receiving neoadjuvant treatment (3 with chemotherapy, 1 with CRT, 2 with RT alone) as compared to 2 patients who were treated with non-neoadjuvant CRT. DF was the first site of failure in 9 patients treated with neoadjuvant CRT (8 with chemotherapy, 0 with CRT and 1 with RT alone) as compared to 4 patients without neoadjuvant treatment.In this retrospective data set, a trend towards better survival was seen in adjuvantly treated CCA patients, but not in GBC patients. Recurrence patterns also appear different among the two, which might be attributed to treatment modality used, patient selection or unmeasured factors.Gallbladder cancer (GBC); cholangiocarcinoma (CCA); neoadjuvant; resection; chemoradiation; chemotherapy.

Objective To assess the clinical findings and microbiology investigations in patients with suspected infectious posterior segment uveitis (PSU). Design Retrospective case study. Methods Between January and December 2014, medical records of 270 patients with PSU were reviewed. Baseline ocular examination, presumed and final diagnoses, microbiology investigations from aqueous or vitreous fluid, and peripheral blood were reviewed. Results Infectious PSU was suspected in 28 patients among 270 PSU cases (10.4%, 28/270), and 11 cases were of infectious origin (4.1%, 11/270). Six patients were immunocompromised: 5 patients in the confirmed infectious PSU group (45.5%, 5/11) and 1 in the confirmed noninfectious group (5.9%, 1/17; p = 0.002). Initial visual acuity was 1.8 ± 0.35 logMAR and 0.9 ± 0.23 logMAR for patients with confirmed infectious and noninfectious PSU, respectively (p = 0.04). Anterior chamber reaction was worse in patients with confirmed infectious PSU (1.8 ± 0.49) than confirmed noninfectious cases (0.5 ± 0.1; p = 0.003). The frequency of chorioretinitis among patients with confirmed infectious and noninfectious PSU is 54.5% (6/11) and 11.8% (2/17; p = 0.03), respectively. Onset of confirmed infectious uveitis was more acute (≤6 weeks in duration) than noninfectious cases (p = 0.0015). Among the 11 patients with positive blood culture or serology, 6 had anterior and vitreous chamber fluid analysis. The rate of positive cultures and PCR is 16.7% (1/6) for aqueous humour and 50% (3/6) for vitreous samples. Conclusions Clinical features more suggestive of infectious PSU include immunosuppression, worse initial visual acuity, acute onset, worse anterior chamber reaction, and chorioretinitis. Further studies are needed to enhance the diagnostic yields of aqueous and vitreous fluid analyses.

Objective To determine if a less labor-intensive video-based program for teaching car seat installation can be as effective as the traditional didactic lecture component. Methods This is a randomized controlled trial of caregivers seeking car seat education. Caregivers were assigned to didactic or video-based social learning classes. The didactic class involved live lecture; the social learning class included a brief lecture and the video, Simple Steps to Child Passenger Safety, utilizing social learning principles. Proficiency in child passenger safety was evaluated pre- and post-class via: (1) 5-question confidence assessment; (2) 15-question knowledge test; and (3) 5-part car seat installation demonstration. Data were analyzed to compare post-class assessment scores between teaching modalities using pre-test scores as covariates, and correlation of participant confidence and knowledge with installation ability. Results 526 individuals registered and were randomized. A total of 213 arrived for class with 103 randomized to didactic teaching and 111 to social learning. Didactics and social learning groups showed similar increases in post-class confidence, knowledge, and installation ability. In the pre-class assessment, 16% of participants in each group installed the car seat correctly. After controlling for baseline installation ability, correct post-class car seat installation did not vary between groups (mean difference = 0.001; p = 0.964). Among participants with high scores on the knowledge assessment, only 57% could demonstrate correct car seat installation (rs = 0.160, p = 0.023). Conclusion Video-based social learning methodology, which requires less time and resources, was as effective in teaching child passenger safety as didactic lecture. Both teaching methods significantly improved proficiency in child passenger restraint. Car seat installation knowledge is only weakly correlated with proper installation ability and proper installation remains a challenge, even after education.

Dry Eye Disease (DED) is a very common disorder that can result in severe disability and vision loss. Although the pathogenesis of DED is not fully understood, hyperosmolarity, inflammation, and tear film instability are recognized as hallmarks of DED. Recently, Nucleoside Reverse Transcriptase Inhibitors (NRTIs), a class of medication used to treat HIV, have been shown to inhibit inflammation in a mouse model of retinal atrophy. In this study, we investigated whether Zidovudine (AZT) can inhibit human corneal epithelial cell (HCEC) inflammatory responses under hyperosmotic conditions. HCECs were cultured in hyperosmotic media containing AZT. Cell viability, cytokine production, and reactive oxygen species (ROS) production were measured. We found that AZT decreased nuclear factor kappa B (NF-κB) and Interleukin-6 (IL-6) levels, increased Superoxide Dismutase 1 (SOD1) production, decreased ROS production, and increased cell viability. These results support the novel use of AZT in the reduction of ocular surface inflammation and the promotion of corneal health in the context of DED.

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.

OBJECTIVE To examine initial outcomes of an 8-week Healthy-Lifestyle Intervention Program (HIP) which included children's participation in a daily summer camp along with parents' participation in a parenting program focused on overweight/obesity. METHODS Using a nonrandomized pilot trial design, 16 children (M child age = 6.42 yr; 81% male; 100% Latino) classified as overweight/obese and their mothers completed 3 assessments (baseline, posttreatment, and 6-8 mo follow-up). RESULTS Children who completed HIP experienced significant decreases in their body mass index z-scores (primary outcome) from baseline to posttreatment (d = -1.11) with such decreases being moderately maintained at follow-up (d = -0.64). In terms of secondary outcomes, HIP was effective in improving and maintaining healthy habits in both children and mothers and children's nutritional knowledge and fitness. Objective food data showed that children's dietary intake during HIP improved. High attendance and satisfaction were reported for families who completed HIP. CONCLUSION This pilot treatment development study shows that a family lifestyle intervention conducted in a summer camp setting that targets both children and parents is a promising option for addressing pediatric obesity in young children.

Many cancer survivors experience menopausal symptoms, including female survivors taking aromatase inhibitors or with a history of oophorectomy or chemotherapy, and male survivors who received or are receiving androgen-ablative therapies. Sexual dysfunction is also common in cancer survivors. Sexual dysfunction and menopause-related symptoms can increase distress and have a significant negative impact on quality of life. This portion of the NCCN Guidelines for Survivorship provide recommendations for screening, evaluation, and treatment of sexual dysfunction and menopausal symptoms to help healthcare professionals who work with survivors of adult-onset cancer in the posttreatment period.

Purpose: mTOR regulates many normal physiological processes and when hyperactive can drive numerous cancers and human diseases. However, it is very challenging to detect and quantify mTOR signaling noninvasively in clinically relevant animal models of disease or man. We hypothesized that a nuclear imaging tool measuring intracellular mTOR activity could address this unmet need. Experimental Design: Although the biochemical activity of mTOR is not directly amenable to nuclear imaging probe development, we show that the transferrin receptor can be used to indirectly measure intracellular changes in mTOR activity. Results: After verifying that the uptake of radiolabeled transferrin (the soluble ligand of the transferrin receptor) is stimulated by active mTORC1 in vitro, we showed that 89Zr-labeled transferrin (Tf) can measure mTORC1 signaling dynamics in normal and cancerous mouse tissues with PET. Finally, we show that 89Zr-Tf can detect the upregulation of mTORC1 by tumor cells to escape the antitumor effects of a standard-of-care antiandrogen, which is to our knowledge the first example of applying PET to interrogate the biology of treatment resistant cancer. Conclusions: In summary, we have developed the first quantitative assay to provide a comprehensive measurement of mTOR signaling dynamics in vivo, in specific normal tissues, and during tumor development in genetically engineered animal models using a nuclear imaging tool that is readily translatable to man. Clin Cancer Res; 23(12); 3045–52. ©2016 AACR.

Purpose Children with blunt liver or spleen injury (BLSI) requiring early transfusion may present without hypotension despite significant hypovolemia. This study sought to determine the relationship between early transfusion in pediatric BLSI and hypotension. Methods Secondary analysis of a 10-institution prospective observational study was performed of patients 18years and younger presenting with BLSI. Patients with central nervous system (CNS) injury were excluded. Children receiving blood transfusion within 4h of injury were evaluated. Time to first transfusion, vital signs, and physical exams were analyzed. Patients with hypotension were compared to those without hypotension. Results Of 1008 patients with BLSI, 47 patients met inclusion criteria. 22 (47%) had documented hypotension. There was no statistical difference in median time to first transfusion for those with or without hypotension (2h vs. 2.5h, p =0.107). The hypotensive group was older (median 15.0 versus 9.5years; p =0.007). Median transfusion volume in the first 24h was 18.2mL/kg (IQR: 9.6, 25.7) for those with hypotension and 13.9mL/kg (IQR: 8.3, 21.0) for those without ( p =0.220). Mortality was 14% (3/22) in children with hypotension and 0% (0/25) in children without hypotension. Conclusion Hypotension occurred in less than half of patients requiring early transfusion following pediatric BLSI suggesting that hypotension does not consistently predict the need for early transfusion. Type of study Secondary analysis of a prospective observational study. Level of evidence Level IV cohort study.

Introduction: The blockade of HER2 signaling has significantly improved the outlook for esophagogastric cancer patients. However, targeting HER2 still remains challenging due to complex biology of this receptor in gastric and esophageal cancers.Areas covered: Here, we review complex HER2 biology, current methods of HER2 testing and tumor heterogeneity of gastroesophageal cancer. Ongoing and completed clinical research data are discussed.Expert opinion: HER2 overexpression is a validated target in gastroesophageal cancer, with therapeutic implications resulting in prolonged survival when inhibited in the front-line setting. With standardized HER2 testing in gastro-esophageal cancer, the ongoing trials are testing newer agents and combinations including combination of anti-HER2 antibodies with immunotherapy. Clonal heterogeneity and emergence of resistance will challenge our approach to treating these patients beyond the frontline settings.

Nonoperative management (NOM) is standard of care for most pediatric blunt liver and spleen injuries (BLSI); only 5% of patients fail NOM in retrospective reports. No prospective studies examine failure of NOM of BLSI in children. The aim of this study was to determine the frequency and clinical characteristics of failure of NOM in pediatric BLSI patients.A prospective observational study was conducted on patients 18 years or younger presenting to any of 10 Level I pediatric trauma centers April 2013 and January 2016 with BLSI on computed tomography. Management of BLSI was based on the Arizona-Texas-Oklahoma-Memphis-Arkansas Consortium pediatric guideline. Failure of NOM was defined as needing laparoscopy or laparotomy.A total of 1008 patients met inclusion; 499 (50%) had liver injury, 410 (41%) spleen injury, and 99 (10%) had both. Most patients were male (n = 624; 62%) with a median age of 10.3 years (interquartile range, 5.9, 14.2). A total of 69 (7%) underwent laparotomy or laparoscopy, but only 34 (3%) underwent surgery for spleen or liver bleeding. Other (nonexclusive) operations were for 21 intestinal injuries; 15 hematoma evacuations, washouts, or drain placements; 9 pancreatic injuries; 5 mesenteric injuries; 3 diaphragm injuries; and 2 bladder injuries. Patients who failed were more likely to receive blood (52 of 69 vs. 162 of 939; p0.001) and median time from injury to first blood transfusion was 2.3 hours for those who failed versus 5.9 hours for those who did not (p = 0.002). Overall mortality rate was 24% (8 of 34) in those who failed NOM due to bleeding.NOM fails in 7% of children with BLSI, but only 3% of patients failed for bleeding due to liver or spleen injury. For children failing NOM due to bleeding, the mortality was 24%.Therapeutic study, level II.

Objective The aim of this study was to evaluate the visual outcome, uveitis control, and complications following cataract surgery for intraocular lens (IOL) implantation in patients with a known diagnosis of uveitis. Design The study was a retrospective interventional case series. Participants We reviewed 98 patients (137 eyes) with adult uveitis undergoing cataract surgery with foldable acrylic posterior chamber IOL implantation between 2003 and 2013 in 2 uveitis practices. Methods Best-corrected visual acuity (BCVA) and uveitis grade (Standardized Uveitis Nomenclature criteria) were measured at 1 month preoperatively, at postoperative week 1, and at postoperative months 1, 6, and 12. The main outcome measures were mean change in postoperative BCVA, uveitis grade, and complications. Results Of the eyes studied, 84% had grade 0–0.5 anterior uveitis at postoperative week 1 and maintained uveitis control (77% grade 0; 19% grade 0.5 anterior uveitis) at 1 year postoperatively. None of the patients had active intermediate or posterior uveitis at any time point. Mean BCVA improved from 0.71 ± 0.38 logMAR preoperatively to 0.37 ± 0.36 at 6 months ( p p = 0.01) p ostoperatively. Of the study participants, 30% had preoperative complications related to uveitis, including epiretinal membrane (12%), cystoid macular edema (12%), and glaucoma (5.8%); 46% of patients had small pupils as a result of posterior synechiae. Postoperative vision-limiting complications included posterior capsule opacification (18%), epiretinal membrane (9.0%), and cystoid macular edema (8.8%). Of the eyes studied, 5.8% underwent Nd:YAG capsulotomy. Conclusions Cataract surgery with acrylic posterior-chamber IOL implantation is effective at improving visual acuity in patients with uveitis. Uveitis was well controlled in the majority of our study patients for 12 months after cataract surgery. The most frequent vision-limiting postoperative complication was posterior capsule opacification, which was treatable with Nd:YAG capsulotomy.

A pilot trial of low-carbohydrate diet after definitive treatment for localized prostate cancer stopped early owing to futility but provides intriguing results in secondary analyses. The study offers an important opportunity to highlight caveats in data interpretation and to consider requirements for successful future research on dietary interventions in men with prostate cancer.