Background While it is well established that perioperative use of oral nutrition supplement (ONS) improves nutrition status among severely malnourished surgical cancer patients, the evidence requires further substantiation for non-severely malnourished patients with cancer. This protocol paper presents the rationale and design of a randomised controlled trial to evaluate the effectiveness of preoperative as well as an extended 90-day postoperative use of ONS on nutritional and clinical outcomes among patients undergoing elective surgery for breast and colorectal cancer. Methods Patients with primary breast and colorectal cancer undergoing elective surgery are recruited from two tertiary hospitals. Eligible patients are assigned into one of the three intervention arms: (i) Group SS will receive ONS in addition to their normal diet up to 14 days preoperatively and postoperatively up to discharge; (ii) Group SS-E will receive ONS in addition to their normal diet up to 14 days preoperatively, postoperatively up to discharge and for an extended 90 days after discharge; and (iii) Group DS will receive ONS in addition to their normal diet postoperatively up to discharge from the hospital. The ONS is a standard formula fortified with lactium to aid in sleep for recovery. The primary endpoints include changes in weight, body mass index (BMI), serum albumin and prealbumin levels, while secondary endpoints are body composition (muscle and fat mass), muscle strength (handgrip strength), energy and protein intake, sleep quality, haemoglobin, inflammatory markers (transferrin, high sensitivity C-reactive protein, interleukin-6), stress marker (saliva cortisol), length of hospital stay and postoperative complication rate. Discussion This trial is expected to provide evidence on whether perioperative supplementation in breast and colorectal cancer patients presenting with high BMI and not severely malnourished but undergoing the stress of surgery would be beneficial in terms of nutritional and clinical outcomes. Trial registration ClinicalTrial.gov NCT04400552. Registered on 22 May 2020, retrospectively registered

Background Cutaneous immune-related adverse events (cirAEs) are a common sideeffect of immune checkpoint inhibitors (ICIs). However, prior work examining these toxicities in detail has considered only the fraction of events evaluated by dermatologists. Associations between dermatology referral, cirAE treatment and survival outcomes remain underexplored across care settings. Objectives To comprehensively categorize cirAE patterns among all patients treated with immunotherapy at our institution, and to evaluate: (i) the effect of dermatology referral on cirAE treatment and (ii) the impact of cirAE treatment on survival. Methods This was a retrospective cohort analysis of patients with cancer who initiated ICI therapy between 1 January 2016 and 8 March 2019 and developed one or more cirAEs, as screened for using International Classification of Diseases 10th revision codes and confirmed via manual chart review (n = 358). All relevant information documented prior to 31 March 2020 was included. Results CirAEs evaluated by dermatologists were significantly more likely to be treated than cirAEs that were not referred (odds ratio 6Á08, P < 0Á001). Patients who received any cirAE treatment had improved progression-free survival [hazard ratio (HR) 0Á59, P = 0Á001] and overall survival (HR 0Á58, P = 0Á007) compared with those who did not. Conclusions CirAEs evaluated by dermatologists were significantly more likely to be treated than cirAEs that were not referred, and patients who received any treatment for a cirAE had improved survival outcomes.What is already known about this topic?• Cutaneous immune-related adverse events (cirAEs) are common among patients on immune checkpoint inhibitor (ICI) therapy, occurring in up to one-third of ICI monotherapy recipients.• Despite the prevalence of cirAEs, the relationships between dermatology referral, cirAE treatment and survival outcomes remain underexplored.What does this study add?• CirAEs evaluated by dermatologists were significantly more likely to be treated than cirAEs that were not referred, and patients who received treatment had improved survival.• Our findings underscore the vital role of dermatologists in oncological care and suggest that closer collaboration between oncologists and dermatologists may be valuable in supporting comprehensive cirAE treatment.

In this issue of BJD, Hibler and Markova present a patient with metastatic cancer receiving ipilimumab and nivolumab who developed a severe drug hypersensitivity reaction with elevated interleukin (IL)-6 following antibiotic initiation for infection, with subsequent successful hypersensitivity treatment using tocilizumab (anti-IL-6 receptor monoclonal antibody). 1 Cutaneous immune-related adverse events (cirAEs) like the drug hypersensitivity described represent one of the most common side-effects of immune checkpoint inhibition (ICI) therapy, emerging in more than a third of patients on monotherapy, and nearly three-quarters of those receiving combination therapies. 2,3 Although many cirAEs are self-limited and can be palliated with topical approaches, a substantial proportion are more severe, necessitating consideration of systemic immunosuppression and/or ICI suspension. 2-4 Importantly, severe (grade 3-4) cirAEs are nearly twice as likely among patients on combined ICI regimens, manifesting in 5-10% of treated patients. 2 As combination approaches continue to be explored in a greater range of cancer types, the number of severe cirAEs requiring treatment will continue to rise. 3 Despite the growing prevalence of cirAEs, the immunological context of these heterogeneous reactions remains poorly understood. Few patients are referred to dermatology (1 5%), and even fewer (~5%) undergo biopsy or serological testing, limiting characterization of immunohistochemical features. 4 Current treatment paradigms reflect this paucity of data, with current guidelines for moderate-to-severe cirAEs revolving around high doses of systemic corticosteroids. 3 As Hibler and Markova appropriately assert, 1 this approach may be suboptimal given manifold sequelae and variable efficacy of corticosteroids and the potential attenuation of antitumour responses. 1,2,5 Although the scope of these effects remains underexplored for the full spectrum of cirAEs, systemic corticosteroid use has been shown to reduce progression-free survival when used at ICI start and for selected non-cirAEs. 2,5 As cirAEs appear to confer survival benefit to patients with certain cancer types (i.e. melanoma, nonsmall cell lung cancer), developing tailored strategies to manage these toxicities will be imperative to enhance outcomes. 4,6 Although studies evaluating targeted approaches to cirAE and non-cirAE management have been limited, emerging work illuminates several promising therapeutic targets. 4,7

factors collected at baseline, and histological confirmation of all cases included in the analyses. One of the limitations of our analysis is that information about OCs/MHT was self-reported, and we did not collect information on specific doses or formulations. Repeatability analyses showed very high agreement for age at menarche, menopausal status, age at menopause, parity, OC and MHT use, 8 however, which would indicate that any error is likely to be small. Women may have experienced menopause, or commenced or ceased MHT treatment during follow-up, leading to potential misclassification of exposure. To assess the effect of potential misclassification we re-classified premenopausal women who were aged 50 years or more at baseline as postmenopausal (n = 1510; 7.2%); the effect estimate was attenuated towards the null.In summary, our findings do not support an association between either reproductive factors or MHT use and melanoma. We report a modest association between long duration of OC use and invasive melanoma, and while we found no conclusive evidence of detection bias or confounding to explain the findings, we counsel cautious interpretation until further studies, with information on dose and formulation of OCs, have explored these associations.