Background Immune check point inhibitors (ICPis) have transformed the treatment landscape for several cancers, but at the cost of triggering ICPi-induced colitis which resembles some aspects of IBD. Diagnosis is often made by symptoms, or by identifying endoscopic features of colitis. Little is known about histological findings in the absence of macroscopic disease. Furthermore, first-line management strategies beyond the use of systemic corticosteroids have not been explored. Our aim was to assess the incidence of microscopic inflammation in patients with ICPi-diarrhoea, and report our experience of treating two such patients with beclomethasone diproprionate (Clipper). Methods Electronic records of patients with advanced melanoma and ICPi- diarrhoea/colitis at the Royal Marsden Hospital (RMH) and Guy’s and St Thomas’ Hospital (GSTT) between 2011–2016, were retrospectively reviewed. Endoscopic, histological and clinical outcome data was recorded for patients who underwent flexible sigmoidoscopy and had colonic biopsies taken regardless of macroscopic findings. Two symptomatic patients (one treated with anti-PD-1, and another on combination -anti-PD-1/anti-CTLA-4 therapy) with isolated microscopic disease were managed with 5 mg Clipper, once a day, for 4 weeks. Endoscopic, histological and clinical outcomes were recorded 6 weeks after completion of therapy. Results A total of 63 flexible sigmoidoscopies were performed in 59 patients with ICPi diarrhoea/colitis. Microscopic inflammation with normal macroscopic appearances were recorded in 22% of cases. 6 patients were prescribed anti-CTLA-4, 4 anti-PD-1, and 4 combination therapy. Histological features that were distinct from conventional microscopic colitis were recorded in the majority of patients (10/14), which included acute and chronic inflammation, architectural distortion, crypt abscess formation and neutrophil infiltration. Four patients had changes consistent with conventional microscopic colitis (2 lymphocytic colitis, 2 collagenous colitis). Clipper induced clinical remission within 7 days, and histological remission by week 6 in both patients with ICPi-induced microscopic inflammation. There was no treatment associated adverse events. Conclusion Microscopic inflammation in the absence of macroscopic features of colitis is a common finding in ICPi-induced diarrhoea, justifying the routine practice of performing colonic biopsies even when endoscopy is normal. Our favourable clinical experience of using Clipper in 2 patients with microscopic inflammation merit further investigation in appropriately controlled clinical trials.

Background Immune checkpoint inhibitors (CPI) against lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) are a novel therapeutic breakthrough in an increasing number of malignancies. CPI induced acute liver injury (ALI) is the second most frequently encountered organ toxicity occurring in up to 30% patients. There are no reported data on ALI disease pathogenesis, clinical evolution and outcome of patients treated with CPI therapy. Our multicentre cohort study evaluated clinico-pathological aspects of CPI-induced ALI. Method A retrospective analysis was performed of patients with CPI induced ALI presenting to 6 UK oncology centres between 2013 and 2017. Indices of acute liver injury, treatment related complications and outcome were recorded. Severity scoring of liver injury was based on Common Terminology Criteria for Adverse Events (ALI grade 1–4). Results 65% (36/57) patients received ipilimumab +pembrolizumab or nivolumab (combo group) and 35% (21/57) pembrolizumab or nivolumab alone (mono group). Median treatment duration to development of ALI was 96 days in the mono and 22 days in the combo group. All patients presented with acute elevations in transaminases (ALT 325 [155–543], ALP 111 [72–250]). Immungolulins and autoantibodies were normal. One patient developed acute synthetic dysfunction with no encephalopathy (Bilirubin 64, INR 1.5). 79% received steriods (mean dose:1.3 mg/kg); 34% MMF. Steroid refractory ALI was treated with anti-thymocyte globulin (ATG) in 4 patients. Pathological findings (n=6 liver biopsies) revealed lobular hepatitis and myelo-lymphoid cell infiltrate/aggregates (CD3+,CD8+,CD68+). Patients with severe, refractory (grade 4) ALI had signifcant reductions in circulating lymphocytes/monocytes. 63% (n=35) had a temporal association between recent infection and ALI. 15% (n=8) had colitis prior to onset of ALI. Anti-TNF-a administration for colitis was not associated with more severe ALI. 21% (n=11) developed bacterial infections. Fungal sepsis (aspergillus) occurred in all ATG (n=4) treated patients. Overall 14 patients died with 93% (n=13) due to disease progression and 7% (n=1) due to immunotherapy related neuropathy. All deaths due to progressive disease were in patients with grade 3–4 ALI. Acturial median survival was significantly lower in grade 3–4 (14.5 months) vs grade 1–2 (25 months) liver injury. Conclusion Our data report on the largest cohort of CPI induced ALI identifying disease evolution, markers of disease severity and strong correlation with increased morbidity and mortality. Further research is required to delineate triggers and pathogenesis of CPI induced ALI in order to develop calibrated therapies to ameliorate liver injury.

Background Agreement on the utility of imaging follow-up in patients with high-risk melanoma is lacking. A UK consensus statement recommends a surveillance schedule of CT or positron-emission tomography-CT and MRI brain (every 6 months for 3 years, then annually in years 4 and 5) as well as clinical examination for high-risk resected Stages II and III cutaneous melanoma. Our aim was to assess patterns of relapse and whether imaging surveillance could be of clinical benefit. Patients and methods A retrospective study of patients enrolled between July 2013 and June 2015 from three UK tertiary cancer centres followed-up according to this protocol was undertaken. We evaluated time-to-recurrence (TTR), recurrence-free survival (RFS), method of detection and characteristics of recurrence, treatment received and overall survival (OS). Results A total of 173 patients were included. Most (79%) had treated Stages IIIB and IIIC disease. With a median follow-up of 23.3 months, 82 patients (47%) had relapsed. Median TTR was 10.1 months and median RFS was 21.2 months. The majority of recurrences (66%) were asymptomatic and detected by scheduled surveillance scan. Fifty-six (68%) patients recurred with Stage IV disease, with a median OS of 25.3 months; 26 (31.7%) patients had a locoregional recurrence, median OS not reached (P=0.016). Patients who underwent surgery at recurrence for either Stage III (27%) or IV (18%) disease did not reach their median OS. The median OS for the 33 patients (40%) who received systemic therapy was 12.9 months. Conclusion Imaging appears to reliably detect subclinical disease and identify patients suitable for surgery, conferring favourable outcomes. The short median TTR provides rationale to intensify imaging schedule in the first year of surveillance. The poor OS of patients treated with systemic therapy probably reflects the relatively inferior treatment options during this time and requires further evaluation in the current era.