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Patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck have few treatment options and poor prognosis. Nivolumab significantly improved survival of this patient population when compared with standard single-agent therapy of investigator's choice in Checkmate 141; here we report the effect of nivolumab on patient-reported outcomes (PROs). CheckMate 141 was a randomised, open-label, phase 3 trial in patients with recurrent or metastatic squamous cell carcinoma of the head and neck who progressed within 6 months after platinum-based chemotherapy. Patients were randomly assigned (2:1) to nivolumab 3 mg/kg every 2 weeks (n=240) or investigator's choice (n=121) of methotrexate (40–60 mg/m2 of body surface area), docetaxel (30–40 mg/m2), or cetuximab (250 mg/m2 after a loading dose of 400 mg/m2) until disease progression, intolerable toxicity, or withdrawal of consent. On Jan 26, 2016, the independent data monitoring committee reviewed the data at the planned interim analysis and declared overall survival superiority for nivolumab over investigator's choice therapy (primary endpoint; described previously). The protocol was amended to allow patients in the investigator's choice group to cross over to nivolumab. All patients not on active therapy are being followed for survival. As an exploratory endpoint, PROs were assessed at baseline, week 9, and every 6 weeks thereafter using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire–Core 30 (QLQ-C30), the EORTC head and neck cancer-specific module (EORTC QLQ-H&N35), and the three-level European Quality of Life–5 Dimensions (EQ-5D) questionnaire. Differences within and between treatment groups in PROs were analysed by ANCOVA among patients with baseline and at least one other assessment. All randomised patients were included in the time to clinically meaningful deterioration analyses. Median time to clinically meaningful deterioration was analysed by Kaplan-Meier methods. CheckMate 141 was registered with ClinicalTrials.org, number NCT02105636. Patients were enrolled between May 29, 2014, and July 31, 2015, and subsequently 361 patients were randomly assigned to receive nivolumab (n=240) or investigator's choice (n=121). Among them, 129 patients (93 in the nivolumab group and 36 in the investigator's choice group) completed any of the PRO questionnaires at baseline and at least one other assessment. Treatment with nivolumab resulted in adjusted mean changes from baseline to week 15 ranging from −2·1 to 5·4 across functional and symptom domains measured by the EORTC QLQ-C30, with no domains indicating clinically meaningful deterioration. By contrast, eight (53%) of the 15 domains in the investigator's choice group showed clinically meaningful deterioration (10 points or more) at week 15 (change from baseline range, −24·5 to 2·4). Similarly, on the EORTC QLQ-H&N35, clinically meaningful worsening at week 15 was seen in no domains in the nivolumab group and eight (44%) of 18 domains in the investigator's choice group. Patients in the nivolumab group had a clinically meaningful improvement (according to a difference of 7 points or greater) in adjusted mean change from baseline to week 15 on the EQ-5D visual analogue scale, in contrast to a clinically meaningful deterioration in the investigator's choice group (7·3 vs −7·8). Differences between groups were significant and clinically meaningful at weeks 9 and 15 in favour of nivolumab for role functioning, social functioning, fatigue, dyspnoea, and appetite loss on the EORTC QLQ-C30 and pain and sensory problems on the EORTC QLQ-H&N35. Median time to deterioration was significantly longer with nivolumab versus investigator's choice for 13 (37%) of 35 domains assessed across the three questionnaires. In this exploratory analysis of CheckMate 141, nivolumab stabilised symptoms and functioning from baseline to weeks 9 and 15, whereas investigator's choice led to clinically meaningful deterioration. Nivolumab delayed time to deterioration of patient-reported quality-of-life outcomes compared with single-agent therapy of investigator's choice in patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck. In view of the major unmet need in this population and the importance of maintaining or improving quality of life for patients with recurrent or metastatic squamous cell carcinoma of the head and neck, these data support nivolumab as a new standard-of-care option in this setting. Bristol-Myers Squibb.

WHO recommends hospital-based treatment for young infants aged 0–59 days with clinical signs of possible serious bacterial infection, but most families in resource-poor settings cannot accept referral. We aimed to assess whether use of simplified antibiotic regimens to treat young infants with clinical signs of severe infection was as efficacious as an injectable procaine benzylpenicillin–gentamicin combination for 7 days for situations in which hospital referral was not possible. In a multisite open-label equivalence trial in DR Congo, Kenya, and Nigeria, community health workers visited all newborn babies at home, identifying and referring unwell young infants to a study nurse. We stratified young infants with clinical signs of severe infection whose parents did not accept referral to hospital by age (0–6 days and 7–59 days), and randomly assigned each individual within these strata to receive one of the four treatment regimens. Randomisation was stratified by age group of infants. An age-stratified randomisation scheme with block size of eight was computer-generated off-site at WHO. The outcome assessor was masked. We randomly allocated infants to receive injectable procaine benzylpenicillin–gentamicin for 7 days (group A, reference group); injectable gentamicin and oral amoxicillin for 7 days (group B); injectable procaine benzylpenicillin–gentamicin for 2 days, then oral amoxicillin for 5 days (group C); or injectable gentamicin for 2 days and oral amoxicillin for 7 days (group D). Trained health professionals gave daily injections and the first dose of oral amoxicillin. Our primary outcome was treatment failure by day 8 after enrolment, defined as clinical deterioration, development of a serious adverse event (including death), no improvement by day 4, or not cured by day 8. Independent outcome assessors, who did not know the infant's treatment regimen, assessed study outcomes on days 4, 8, 11, and 15. Primary analysis was per protocol. We used a prespecified similarity margin of 5% to assess equivalence between regimens. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12610000286044. In Kenya and Nigeria, we started enrolment on April 4, 2011, and we enrolled the necessary number of young infants aged 7 days or older from Oct 17, 2011, to April 30, 2012. At these sites, we continued to enrol infants younger than 7 days until March 29, 2013. In DR Congo, we started enrolment on Sept 17, 2012, and continued until June 28, 2013. We randomly assigned 3564 young infants to either group A (n=894), group B (n=884), group C (n=896), or group D (n=890). We excluded 200 randomly assigned infants, who did not fulfil the predefined criteria of adherence to treatment and adequate follow-up. In the per-protocol analysis, 828 infants were included in group A, 826 in group B, 862 in group C, and 848 in group D. 67 (8%) infants failed treatment in group A compared with 51 (6%) infants in group B (risk difference −1·9%, 95% CI −4·4 to 0·1), 65 (8%) in group C (−0·6%, −3·1 to 2·0), and 46 (5%) in group D (−2·7%, −5·1 to 0·3). Treatment failure in groups B, C, and D was within the similarity margin compared with group A. During the 15 days after random allocation, 12 (1%) infants died in group A, compared with ten (1%) infants in group B, 20 (2%) infants in group C, and 11 (1%) infants in group D. An infant in group A had a serious adverse event other than death (injection abscess). The three simplified regimens were as effective as injectable procaine benzylpenicillin–gentamicin for 7 days on an outpatient basis in young infants with clinical signs of severe infection, without signs of critical illness, and whose caregivers did not accept referral for hospital admission. Bill & Melinda Gates Foundation grant to WHO.

Anorexia is experienced by most people with lung cancer during the course of their disease and treatment. Anorexia reduces response to chemotherapy and the ability of patients to cope with, and complete their treatment leading to greater morbidity, poorer prognosis and outcomes. Despite the significant importance of cancer-related anorexia, current therapies are limited, have marginal benefits and unwarranted side effects. In this multi-site, randomised, double blind, placebo controlled, phase II trial, participants will be randomly assigned (1:1) to receive once-daily oral dosing of 100mg of anamorelin HCl or matched placebo for 12 weeks. Participants can then opt into an extension phase to receive blinded intervention for another 12 weeks (weeks 13–24) at the same dose and frequency. Adults (≥18 years) with small cell lung cancer (SCLC); newly diagnosed with planned systemic therapy OR with first recurrence of disease following a documented disease-free interval ≥6 months, AND with anorexia (i.e., ≤ 37 points on the 12-item Functional Assessment of Anorexia Cachexia Treatment (FAACT A/CS) scale) will be invited to participate. Primary outcomes are safety, desirability and feasibility outcomes related to participant recruitment, adherence to interventions, and completion of study tools to inform the design of a robust Phase III effectiveness trial. Secondary outcomes are the effects of study interventions on body weight and composition, functional status, nutritional intake, biochemistry, fatigue, harms, survival and quality of life. Primary and secondary efficacy analysis will be conducted at 12 weeks. Additional exploratory efficacy and safety analyses will also be conducted at 24 weeks to collect data over longer treatment duration. The feasibility of economic evaluations in Phase III trial will be assessed, including the indicative costs and benefits of anamorelin for SCLC to the healthcare system and society, the choice of methods for data collection and the future evaluation design. Trial registration. The trial has been registered with the Australian New Zealand Clinical Trials Registry [ACTRN12622000129785] and approved by the South Western Sydney Local Health District Human Research Ethics Committee [2021/ETH11339]. https://clin.larvol.com/trial-detail/ACTRN12622000129785 .

Twenty-one adult patients were randomised to receive ghrelin on days 1 and 8 and placebo on days 4 and 11 or vice versa, given intravenously over a 60-min period before lunch: 10 received 2  μ g kg −1 (lower-dose) ghrelin; 11 received 8  μ g kg −1 (upper-dose) ghrelin. Active and total ghrelin, growth hormone (GH), and insulin-like growth factor 1 levels were monitored at baseline (4–5 days before day 1), during treatment days, and at end of study (day 17/18). Drug-related adverse events (assessed by NCI-CTC-toxicity criteria and cardiac examination) did not differ between ghrelin and placebo. No grade 3/4 toxicity or stimulation of tumour growth was observed. The peak increase of GH, a biological marker of ghrelin action, was 25 ng ml −1 with lower-dose and 42 ng ml −1 with upper-dose ghrelin. Morning fasting total ghrelin levels were higher ( P <0.05) for upper-dose patients at end of study (3580 pg ml −1 ) than at baseline (990 pg ml −1 ). Insulin-like growth factor 1 levels did not change. At day 8, 81% of patients preferred ghrelin to placebo as against 63% at the end of study. Nutritional intake and eating-related symptoms, measured to explore preliminary efficacy, did not differ between ghrelin and placebo. Ghrelin is well tolerated and safe in patients with advanced cancer. For safety, tolerance, and patients' preference for treatment, no difference was observed between the lower- and upper-dose group.

Purpose Cancer anorexia-cachexia syndrome (CACS) is common in advanced cancer patients and associated with weight loss, fatigue, impaired quality of life (QoL), and poor prognosis. The goal of this project was to identify the most responsive items from two QoL measures in the ROMANA 2 (NCT01387282) phase III global study evaluating anamorelin HCl in the treatment of non-small cell lung cancer (NSCLC) cachexia: the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and the Functional Assessment of Anorexia/Cachexia Therapy (FAACT). Methods In the ROMANA 2 trial, 477 patients with unresectable stage III or IV NSCLC and cachexia were to be enrolled and randomized (2:1) to receive anamorelin HCl or placebo once daily for 12 weeks. All 203 patients who reached the week 12 visit at the time of data analysis were included. Co-primary endpoints were change from baseline in lean body mass and handgrip strength. QoL was a secondary outcome with FACIT-F and FAACT questionnaires administered at baseline and at weeks 3, 6, 9, and 12. Results Two 4-item scales (fatigue/activity and appetite/eating) from the FACIT-F and FAACT questionnaires, respectively, demonstrated good internal consistency reliability, validity, and responsiveness (also referred to as the Simplified Evaluation of Fatigue (SEF) and Simplified Evaluation of Appetite (SEA), respectively). The estimated important difference for each scale was 1–2 points. Conclusions These brief scales provide the psychometric properties necessary to promote future research in NSCLC patients with CACS. Additional work should examine the clinical utility of these scales and their impact on treatment decision-making.

Background Because the extant literature suggests wine increases appetite, this study sought to determine whether this effect could be observed in advanced cancer patients with appetite loss. Methods Advanced cancer patients with self-reported loss of appetite were randomly assigned to white wine with ≤15 % alcohol content twice a day for 3–4 weeks versus a nutritional supplement, such as Boost® or Ensure®. Patients assigned to wine were encouraged to also take a nutritional supplement, whereas patients assigned to the nutritional supplement arm were told to abstain completely from alcohol. Patient-reported outcomes were captured with a validated questionnaire to assess the primary endpoint of appetite improvement. Results A total of 141 patients (118 evaluable) were enrolled. Twenty-eight patients (48 %) in the wine arm reported an improvement in appetite at some point during the treatment period, whereas 22 patients (37 %) assigned to the nutritional supplement arm also reported improvement ( p  = 0.35). Other appetite-related questions and questionnaire items showed no statistically significant differences between treatment arms. In both arms, approximately 9 % of patients achieved weight stability ( p  = 0.98); median survival was not statistically different. Both interventions were well tolerated. Conclusion As prescribed in this trial, wine does not improve appetite or weight in advanced cancer patients.

Purpose The purpose of the study was to determine the effectiveness of megestrol acetate (MA) and olanzapine (OLN) for the treatment of cancer-related anorexia (CRA). Methods Eighty adult patients with advanced gastrointestinal cancer or lung cancer (stages III and IV) with CRA (loss of appetite and greater than or equal to 5% loss of preillness stable weight) were randomized to receive daily MA or MA plus OLN for a period of 8 weeks. Patients were assessed weekly using the M.D. Anderson Symptom Inventory with specific measurement of weight, appetite, nausea, and quality of life (QOL) measures. Results For the 37 patients receiving MA, 15 patients had a greater than or equal to 5% weight gain, 2 patients had an appetite improvement, 3 patients had an improvement in nausea, and 5 patients had an improvement in QOL at both 4 and 8 weeks. For the 39 patients receiving MA plus OLN, 33 patients had a greater than or equal to 5% weight gain, 25 patients had an appetite improvement, 21 patients had an improvement in nausea, and 23 patients had an improvement in QOL at both 4 and 8 weeks, and there was an improvement in general activity, mood, work, walking, and enjoyment at 8 weeks. There were no grade III or IV treatment-related toxicities in patients receiving MA or the combination of MA plus OLN. Conclusions The combination of MA and OLN appears to be an effective intervention for patients with CRA.

The recovered possess the key to overcoming anorexia. Although individual sufferers do not know how the affliction takes hold, piecing their stories together reveals two accidental afflictions. One is that activity disorders—dieting, exercising, healthy eating—start as virtuous practices, but become addictive obsessions. The other affliction is a developmental disorder, which also starts with the virtuous—those eager for challenge and change. But these overachievers who seek self-improvement get a distorted life instead. Knowing anorexia from inside, the recovered offer two watchwords on helping those who suffer. One is \"negotiate,\" to encourage compromise, which can aid recovery where coercion fails. The other is \"balance,\" for the ill to pursue mind-with-body activities to defuse mind-over-body battles.

IntroductionCancer-related anorexia is the loss of appetite or desire to eat in patients with cancer. Although treatments for cancer-related anorexia do exist, patients have sought complementary and alternative medicine including herbal remedies, due to safety concerns. Sipjeondaebo-tang is one among other popular herbal medicines that are beneficial to management of anorexia in Korea. The purpose of this study is to examine the feasibility for a full randomised clinical trial of Sipjeondaebo-tang for cancer-related anorexia.Methods and analysisThis study is a randomised, double-blinded and placebo-controlled trial of Sipjeondaebo-tang. For the study, 40 patients with cancer, aged 20–80 years, who reported anorexia, will be recruited. The participants will receive either 3 g of Sipjeondaebo-tang or a placebo, 3 times a day for 4 weeks. The primary end point is a change in the anorexia/cachexia subscale (A/CS) of Functional Assessment of Anorexia/Cachexia Therapy (FAACT). The secondary end points include changes in the visual analogue scale (VAS) of appetite, cortisol and ghrelin. The outcomes will be measured on every visit. Each participant will visit once a week during 4 weeks.Ethics and disseminationThe present study has been approved by the Institutional Review Board of the Dunsan Korean Medicine Hospital of Daejeon University (reference DJDSKH-15-03-2 (V.2.0)). The results will be disseminated in a peer-reviewed journal and scientific conference.Trial registration numberNCT02468141; Pre-results.

The aquatic environment and the associated fish assemblages are being exposed to an increasing amount of microplastics. Despite the high number of publications on the presence of microplastics in fish, little is known about their uptake, translocation and accumulation within fish organs. Experimental studies on the detection and effects of pristine microplastics in fish have shown controversial and ambiguous results, respectively. Here, we conducted two experiments to detect and assess the impacts of dietary exposure of Danio rerio to different types of pristine microplastics. Our results show that D. rerio recognizes plastic particles as inedible materials but ingests them when mixed with food or fish oil. Accidental ingestion occurs in fish exposed to relatively small (1–5 µm) microplastic particles without associated food or fish oil. Additionally, D. rerio effectively eliminated pristine microplastics 24 h after ingestion; however, retention time was associated with increasing particle size and the intake of additional meals. Clinical signs, such as anorexia and lethargy, are present in fish fed relatively large microplastics (120–220 µm). The ingestion of microplastics does not induce any histopathological changes. To the best of our knowledge, we are able, for the first time, to fully demonstrate the uptake and translocation of plastic microbeads using confocal microscopy. Our results question the findings of previous studies on the detection and effects of pristine microplastics in fish and state that inaccurate interpretations of the histological findings regarding microplastics in fish organs is a prevalent flaw in the current scientific literature.