Optimising inflammatory bowel disease surveillance and dysplasia management-Where do we stand?

Patients with longstanding extensive colitis are at an increased risk of developing colorectal cancer (CRC), and are therefore enrolled into colonoscopy screening programmes with the aim of detecting pre-cancerous dysplastic change. However, current surveillance programs face multiple limitations relating to low levels of patient enrolment, missed lesions resulting in interval cancers, and uncertainties in the management of dysplasia. Patient counselling regarding the endoscopic and surgical management options of dysplastic lesions can prove particularly challenging, due to the variable risk of progression to cancer. In this review, we discuss the histopathological diagnosis of inflammatory bowel disease (IBD)-associated dysplasia, describe the techniques to maximise dysplasia detection, and present a standardised multi-disciplinary approach to managing patients with dysplasia. The challenges presented by this patient cohort highlight the clear clinical need for further research into the development and validation of non-invasive markers of CRC risk in IBD patients undergoing surveillance.

Predicting Colorectal Cancer Occurrence in IBD.

Patients with colonic inflammatory bowel disease (IBD) are at an increased risk of developing colorectal cancer (CRC), and are therefore enrolled into a surveillance programme aimed at detecting dysplasia or early cancer. Current surveillance programmes are guided by clinical, endoscopic or histological predictors of colitis-associated CRC (CA-CRC). We have seen great progress in our understanding of these predictors of disease progression, and advances in endoscopic technique and management, along with improved medical care, has been mirrored by the falling incidence of CA-CRC over the last 50 years. However, more could be done to improve our molecular understanding of CA-CRC progression and enable better risk stratification for patients with IBD. This review summarises the known risk factors associated with CA-CRC and explores the molecular landscape that has the potential to complement and optimise the existing IBD surveillance programme.

Gaps in knowledge and future directions for the use of faecal microbiota transplant in the treatment of inflammatory bowel disease.

Faecal microbiota transplant (FMT) has now been established into clinical guidelines for the treatment of recurrent and refractory Clostridioides difficile infection (CDI). Its therapeutic application in inflammatory bowel disease (IBD) is currently at an early stage. To date, there have been four randomized controlled trials for FMT in IBD and a multitude of observational studies. However, significant gaps in our knowledge regarding optimum methods for FMT preparation, technical aspects and logistics of its administration, as well as mechanistic underpinnings, still remain. In this article, we aim to highlight these gaps by reviewing evidence and making key recommendations on the direction of future studies in this field. In addition, we provide an overview of the current evidence of potential mechanisms of FMT in treating IBD.

STOP-Colitis pilot trial protocol: a prospective, open-label, randomised pilot study to assess two possible routes of faecal microbiota transplant delivery in patients with ulcerative colitis.

INTRODUCTION: Imbalance of the gut microbiome is key to the pathogenesis of ulcerative colitis (UC). Faecal microbiota transplant (FMT) is the transfer of homogenised and filtered faeces from a healthy individual to the gastrointestinal tract of a patient with disease. Published datasets show a positive signal for the use of FMT to treat UC, but the optimal route and dose of FMT remain unanswered. METHODS AND ANALYSIS: This prospective, multi-centre open-label, randomised pilot study will assess two possible routes of FMT delivery, via the nasogastric (NG) route or by delivery to the COLON, in 30 patients with active UC recruited from three sites in the UK. Stool will be collected from healthy screened donors, processed, frozen and stored under a Medicines and Healthcare products Regulatory Agency (MHRA) "specials" manufacturing licence held at the University of Birmingham Microbiome Treatment Centre. Thawed FMT samples will be administered to patients either via eight nasogastric infusions given initially over 4 days starting on the day of randomisation, and then again for 4 days in week 4 for foregut delivery (total of 240 g of stool) or via one colonoscopic infusion followed by seven weekly enemas according to the hindgut protocol (total of 360 g of stool). Patients will be followed up weekly for 8 weeks, and then at 12 weeks. The aims of this pilot study are (1) to determine which FMT administration route (NG or COLON) should be investigated in a randomised double-blind, placebo-controlled trial and (2) to determine if a full randomised controlled trial is feasible. The primary outcome will be a composite assessment of both qualitative and quantitative data based on efficacy (clinical response), acceptability and safety. At the end of the pilot study, decisions will be made regarding the feasibility of a full randomised double-blind, placebo-controlled trial and, if deemed feasible, which route of administration should be used in such a study. ETHICS AND DISSEMINATION: Ethical approval for this study has been obtained from the East Midlands-Nottingham Research Ethics Committee (REC 17/EM/0274). At the end of the study, findings will be reported at national and international gastroenterology meetings and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN74072945.

Early efficacy of and toxicity from lutetium-177-DOTATATE treatment in patients with progressive metastatic NET.

OBJECTIVE: Lutetium-177 DOTA-D-Phe1-Tyr3-octreotide (Lu-DOTATATE) is a treatment option for patients with well-differentiated metastatic neuroendocrine tumours. Our centre started administering this therapy in 2012. The aim of this study was therefore to analyse the first cohort of patients treated with Lu-DOTATATE to determine its early efficacy and toxicity. PATIENTS AND METHODS: We retrospectively analysed patient, tumour and treatment characteristics, end-of-treatment outcome, time to progression and toxicity in 79 consecutive patients treated with Lu-DOTATATE who had progressive NET according to Response Evaluation Criteria in Solid Tumours criteria. Follow-up time was 12-40 months. Study of Kaplan-Meier plots, analysis of time to progression and multiple regression analysis of factors predictive of time to progression were performed. RESULTS: At end-of-treatment radiological restaging, 13% of patients were found to have partial response and 64% to have stable disease; 23% of patients progressed through treatment. Overall, 47% of patients demonstrated a reduction in chromogranin A levels. The overall estimated median time to progression from the start of treatment was 28 months for the entire cohort and 31, 30 and 5 months for those with partial response, stable disease and progressive disease, respectively. On multivariate regression analysis, higher grade of tumour was found to be significantly associated with shorter progression-free survival. Three patients experienced grade 1 haematotoxicity, five grade 1 nephrotoxicity and one grade 2 nephrotoxicity. CONCLUSION: Early outcomes of patients treated with Lu-DOTATATE are similar to those in previously published series in terms of end-of-treatment efficacy and toxicity. This provides further evidence that this is a safe and efficacious form of treatment for patients with progressive metastatic neuroendocrine tumours.

The Impact of Radiological Response to Peptide Receptor Radionuclide Therapy on Overall Survival in Patients With Metastatic Midgut Neuroendocrine Tumors.

PURPOSE OF THE REPORT: Peptide receptor radionuclide therapy (PRRT) is an effective treatment for advanced neuroendocrine tumors (NET); however, long-term survival data are scarce. The aim of this study is to determine long-term survival in patients with metastatic midgut NET, according to response to PRRT. PATIENTS AND METHODS: One hundred thirty-three consecutive patients with progressive metastatic midgut NET underwent PRRT. Response at 1 year post PRRT was classified as partial response, stable disease, disease progression, or death. Survival was assessed according to response to PRRT, and predictors of overall survival (OS) and progression-free survival (PFS) were identified. RESULTS: At 1 year post PRRT, 9% had partial response, 50.4% stable disease, 10.5% disease progression, and 30.1% were dead. The OS was 33.5, and PFS was 28.5 months. Predictors of disease progression/death were chromogranin A greater than 10 ULN (OR, 4.6; P = 0.007) and hepatic tumor load greater than 50% (OR, 5; P = 0.004). There was no difference in OS between patients with partial response and those with stable disease post PRRT. In multivariate Cox regression, predictors of OS were number of PRRT cycles (HR, 0.33; P < 0.0005), hepatic tumor load greater than 50% (HR, 3.46; P = 0.01), and outcome at 1 year post PRRT (HR, 21.37; P < 0.0005). Predictors of PFS were number of PRRT cycles (HR, 0.39; P < 0.0005), previous resection of liver metastases (HR, 3.56; P = 0,023), and hepatic tumor load greater than 50% (HR, 3.06; P < 0.0005). CONCLUSIONS: Patients with progressive metastatic midgut NET who achieved stable disease at 1 year post PRRT had similar OS with those with partial response. Hepatic tumor burden was a strong predictor of response to PRRT, PFS, and OS.