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Background: Survivors of rectal cancer experience persistent bowel dysfunction after treatments. Dietary interventions may be an effective approach for symptom management and posttreatment diet quality. SWOG S1820 was a pilot randomized trial of the Altering Intake, Managing Symptoms in Rectal Cancer (AIMS‐RC) intervention for bowel dysfunction in survivors of rectal cancer. Methods: Ninety‐three posttreatment survivors were randomized to the AIMS‐RC group (N = 47) or the Healthy Living Education attention control group (N = 46) after informed consent and completion of a prerandomization run‐in. Outcome measures were completed at baseline and at 18 and 26 weeks postrandomization. The primary end point was total bowel function score, and exploratory end points included low anterior resection syndrome (LARS) score, quality of life, dietary quality, motivation, self‐efficacy, and positive/negative affect. Results: Most participants were White and college educated, with a mean age of 55.2 years and median time since surgery of 13.1 months. There were no statistically significant differences in total bowel function score by group, with the AIMS‐RC group demonstrating statistically significant improvements in the exploratory end points of LARS (p =.01) and the frequency subscale of the bowel function index (p =.03). The AIMS‐RC group reported significantly higher acceptability of the study. Conclusions: SWOG S1820 did not provide evidence of benefit from the AIMS‐RC intervention relative to the attention control. Select secondary end points did demonstrate improvements. The study was highly feasible and acceptable for participants in the National Cancer Institute Community Oncology Research Program. Findings provide strong support for further refinement and effectiveness testing of the AIMS‐RC intervention. In this feasibility and preliminary efficacy randomized trial, the Altering Intake, Managing Symptoms in Rectal Cancer (AIMS‐RC) diet modification intervention did not significantly improve total bowel function among survivors of rectal cancer but demonstrated improvements in the frequency of bowel movements and low anterior resection syndrome. SWOG S1820 and the AIMS‐RC intervention were highly feasible and acceptable for participants enrolled via the National Cancer Institute Community Oncology Research Program. [ABSTRACT FROM AUTHOR]

Objective: Loss‐of‐function variants in SCN1A cause Dravet syndrome, the most common genetic developmental and epileptic encephalopathy (DEE). However, emerging evidence suggests separate entities of SCN1A‐related disorders due to gain‐of‐function variants. Here, we aim to refine the clinical, genetic, and functional electrophysiological features of a recurrent p.R1636Q gain‐of‐function variant, identified in four individuals at a single center. Methods: Individuals carrying the recurrent SCN1A p.R1636Q variant were identified through diagnostic testing. Whole cell voltage‐clamp electrophysiological recording in HEK‐293 T cells was performed to compare the properties of sodium channels containing wild‐type Nav1.1 or Nav1.1‐R1636Q along with both Navβ1 and Navβ2 subunits, including response to oxcarbazepine. To delineate differences from other SCN1A‐related epilepsies, we analyzed electronic medical records. Results: All four individuals had an early onset DEE characterized by focal tonic seizures and additional seizure types starting in the first few weeks of life. Electrophysiological analysis showed a mixed gain‐of‐function effect with normal current density, a leftward (hyperpolarized) shift of steady‐state inactivation, and slower inactivation kinetics leading to a prominent late sodium current. The observed functional changes closely paralleled effects of pathogenic variants in SCN3A and SCN8A at corresponding positions. Both wild type and variant exhibited sensitivity to block by oxcarbazepine, partially correcting electrophysiological abnormalities of the SCN1A p.R1636Q variant. Clinically, a single individual responded to treatment with oxcarbazepine. Across 51 individuals with SCN1A‐related epilepsies, those with the recurrent p.R1636Q variants had the earliest ages at onset. Significance: The recurrent SCN1A p.R1636Q variant causes a clinical entity with a wider clinical spectrum than previously reported, characterized by neonatal onset epilepsy and absence of prominent movement disorder. Functional consequences of this variant lead to mixed loss and gain of function that is partially corrected by oxcarbazepine. The recurrent p.R1636Q variant represents one of the most common causes of early onset SCN1A‐related epilepsies with separate treatment and prognosis implications. [ABSTRACT FROM AUTHOR]

Aim: To summarize quality of life (QoL) and its determinants, including disease severity, in individuals with developmental and epileptic encephalopathies (DEEs) through a tailored questionnaire. Method: A questionnaire containing 89 items addressing demographic characteristics, genetic diagnosis, clinical features, and QoL was distributed to primary caregivers of individuals with DEEs through patient advocacy organizations. Composite scores were generated from the mean values of QoL items, grouped into domain scores. Results: Out of 176 received responses, the most common genetic diagnoses reported were SCN2A (n=42/173, 24%), SLC6A1 (n=28/173, 16%), SCN1A (n=22/173, 13%), and KCNQ2 (n=21/173, 12%). Composite QoL scores centered around a mean score of 61.67 of 100 (SD 17.10). QoL scores were strongly associated with the number of days minimally disrupted by seizures, medication side effects, genetic diagnosis, and community type. The mean QoL scores for individuals with DEEs was significantly lower than for individuals with Rett syndrome, cerebral palsy, autism spectrum disorder, and Down syndrome. Interpretation: QoL in DEEs can be assessed through a standardized instrument. QoL only partially overlaps with objective measurements of disease severity and may represent an independent outcome measure in precision medicine trials. [ABSTRACT FROM AUTHOR]

Background: Arginine starvation depletes the micronutrients required for DNA synthesis and interferes with both thymidylate synthetase activity and DNA repair pathways in preclinical models of hepatocellular carcinoma (HCC). Pegylated arginine deiminase (ADI‐PEG 20), an arginine degrader, potentiates the cytotoxic activity of platinum and pyrimidine antimetabolites in HCC cellular and murine models. Methods: This was a global, multicenter, open‐label, single‐arm, phase 2 trial of ADI‐PEG 20 and modified 5‐fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) in patients who had HCC with Child‐Pugh A cirrhosis and disease progression on ≥2 prior lines of treatment. The primary objective was the objective response rate assessed according to Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary objectives were to estimate progression‐free survival, overall survival, safety, and tolerability. Eligible patients were treated with mFOLFOX6 intravenously biweekly at standard doses and ADI‐PEG‐20 intramuscularly weekly at 36 mg/m2. Results: In total, 140 patients with advanced HCC were enrolled. The median patient age was 62 years (range, 30‐85 years), 83% of patients were male, 76% were of Asian race, 56% had hepatitis B viremia, 10% had hepatitis C viremia, 100% had received ≥2 prior lines of systemic therapy, and 39% had received ≥3 prior lines of systemic therapy. The objective response rate was 9.3% (95% confidence interval [CI], 5.0%‐15.4%), with a median response duration of 10.2 months (95% CI, 5.8 months to not reached). The median progression‐free survival was 3.8 months (95% CI, 1.8‐6.3 months), and the median overall survival was 14.5 months (95% CI, 13.6‐20.9 months). The most common grade ≥3 treatment‐related events were neutropenia (32.9%), white blood cell count decrease (20%), platelet count decrease (19.3%), and anemia (9.3%). Conclusions: Concurrent mFOLFOX6 plus ADI‐PEG 20 exhibited limited antitumor activity in patients with treatment‐refractory HCC. The study was terminated early, and no further evaluation of the combination will be pursued. Lay Summary: Arginine is an important nutrient for hepatocellular carcinoma (HCC).The depletion of arginine with pegylated arginine deiminase (ADI‐PEG 20), an arginine degrader, appeared to make chemotherapy (FOLFOX) work better in animal models of HCC and in patients with HCC on an early phase clinical trial.To formally test this hypothesis in the clinical setting, a large, global, phase 2 clinical trial was conducted of ADI‐PEG 20 and FOLFOX in the treatment of patients with refractory HCC.The study showed limited activity of ADI‐PEG 20 and FOLFOX in advanced HCC and was stopped early. Despite high‐level preclinical and early phase clinical data suggesting a potentiating effect of arginine depletion on 5‐fluorouracil, leucovorin, and oxaliplatin (FOLFOX) anticancer activity in hepatocellular carcinoma, a global, single‐arm, phase 2 study of pegylated arginine deiminase (ADI‐PEG 20) plus FOLFOX in patients with hepatocellular carcinoma who progressed on 2 lines of systemic therapy failed to meet its primary end point. There is no role for the combination of AGI‐PEG 20 and FOLFOX in advanced hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Background: Body weight is associated with colorectal cancer (CRC) risk and survival, but to the authors' knowledge, the impact of long-term postdiagnostic weight change is unclear. Herein, the authors investigated whether weight change over the 5 years after a diagnosis of CRC is associated with survival.Methods: CRC cases diagnosed from 1997 to 2008 were identified through 4 population-based cancer registry sites. Participants enrolled within 2 years of diagnosis and reported their height and weight 2 years prior. Follow-up questionnaires were administered approximately 5 years after diagnosis. Associations between change in weight (in kg) or body mass index (BMI) with overall and CRC-specific survival were estimated using Cox regression analysis adjusted for age, sex, American Joint Committee on Cancer stage of disease, baseline BMI, nonsteroidal anti-inflammatory drug use, smoking, time between diagnosis and enrollment, and study site.Results: At the 5-year postdiagnostic survey, 2049 participants reported higher (53%; median plus 5 kg), unchanged (12%), or lower (35%; median -4 kg) weight. Over a median of 5.1 years of subsequent follow-up (range, 0.3-9.9 years), 344 participants died (91 of CRC). Long-term weight loss (per 5 kg) was found to be associated with poorer overall survival (hazard ratio, 1.13; 95% confidence interval, 1.07-1.21) and CRC-specific survival (hazard ratio, 1.25; 95% confidence interval, 1.13-1.39). Significantly lower survival was similarly observed for relative weight loss (>5% vs ≤5% change), BMI reduction (per 1 unit), or BMI category change (overweight to normal vs remaining overweight).Conclusions: Weight loss 5 years after a diagnosis of CRC was found to be significantly associated with decreased long-term survival, suggesting the importance of avoiding weight loss in survivors of CRC. Future research should attempt to further evaluate this association, accounting for whether this weight change was intentional or represents a marker of declining health. Cancer 2017;123:4701-4708. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Lynch syndrome confers a hereditary predisposition to colorectal and other cancers. Universal tumor screening (UTS) for Lynch syndrome is recommended by several professional societies, but the implementation can be complex. This article describes the evaluation, process development, and initiation of Lynch syndrome UTS at a tertiary referral cancer center.Methods: A multidisciplinary team developed the new process design. Issues in 5 themes were noted: timing, funding, second-opinion patients, result processing, and the role of genetics providers. A committee approach was used to examine each issue for process-improvement development.Results: The issues related to testing were addressed individually for the successful implementation of UTS at the institutional level. In the conventional-care period, 9 of 30 cases (30%) received Lynch syndrome screening, and 4 cases were referred to medical genetics. During the 6 months following the implementation of UTS, 32 of 44 patients (73%) received Lynch syndrome screening. The 13 unscreened patients all had identified reasons for nonscreening (eg, financial limitations). Ten patients were referred to medical genetics, which identified no new cases of Lynch syndrome, but a low-risk adenomatous polyposis coli (APC) variant was detected in 1 individual.Conclusions: The implementation of effective Lynch syndrome UTS can feasibly alter practice at the institutional level. This experience with the assessment and management of issues relevant to the successful implementation of a new clinical care paradigm based on emerging technology has implications for the uptake of advances across molecular oncology into clinical practice, and this is highly relevant in the current era of rapidly evolving genomic technology. [ABSTRACT FROM AUTHOR]