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SDHApathogenic germline variants (PGVs) are identified in up to 10% of patients with paraganglioma and phaeochromocytoma and up to 30% with wild-type gastrointestinal stromal tumours. MostSDHAPGV carriers present with an apparently sporadic tumour, but often the pathogenic variant has been inherited from parent who has the variant, but has not developed any clinical features. Studies ofSDHAPGV carriers suggest that lifetime penetrance for SDHA-associated tumours is low, particularly when identified outside the context of a family history. Current recommended surveillance forSDHAPGV carriers follows an intensive protocol. With increasing implementation of tumour and germline large panel and whole-genome sequencing, it is likely moreSDHAPGV carriers will be identified in patients with tumours not strongly associated withSDHA,or outside the context of a strong family history. This creates a complex situation about what to recommend in clinical practice considering low penetrance for tumour development, surveillance burden and patient anxiety. An expertSDHAworking group was formed to discuss and consider this situation. This paper outlines the recommendations from this working group for testing and management ofSDHAPGV carriers in clinical practice.

Diabetes and cancer are both common and increasingly prevalent conditions, but emerging epidemiological evidence confirms that the risk of developing a number of common cancers is increased in those with type 2 diabetes. The risk of cancer in type 1 diabetes is less clearly defined, and therefore this review focuses on type 2 diabetes. Emerging evidence also supports an influence of diabetes on outcomes of cancer treatment. However, this relationship is bi-directional, with cancer and its treatment impacting on glucose control, whereas there is also emerging evidence indicating that diabetes care can deteriorate after a cancer diagnosis. Despite these clear links, there is a lack of evidence to guide clinicians in how to manage patients with diabetes during their cancer treatment. Although recent UK guidelines have started to address this, with the development of guidance for the management of hyperglycaemia in cancer, there is a clear need for wider guidance on the management of multi-morbidity during cancer, including diabetes and obesity, to incorporate nutritional management. We have therefore undertaken a narrative review of the evidence of links between type 2 diabetes and cancer incidence and outcomes, and discuss the challenges to diabetes care during cancer treatment.

Context Metastatic medullary thyroid cancer (MTC) is a rare malignancy with minimal treatment options. Many, but not all, MTCs express somatostatin receptors. Objective Our aim was to explore the role of 68Ga-DOTA-somatostatin analogue (SSA) positron emission tomography (PET)/computed tomography (CT) in patients with metastatic MTC and to determine their eligibility for peptide receptor radionuclide therapy (PRRT). Methods We retrospectively identified patients with metastatic MTC who had 68Ga-DOTA-SSA PET/CT at 5 centers. We collected characteristics on contrast-enhanced CT, 68Ga-DOTA-SSA and 18F-FDG PET/CT. The efficacy of PRRT was explored in a subgroup of patients. Kaplan-Meier analysis was used to estimate time to treatment failure (TTF) and overall survival (OS). Results Seventy-one patients were included (10 local recurrence, 61 distant disease). Of the patients with distant disease, 16 (26%) had ≥50% of disease sites with tracer avidity greater than background liver, including 10 (10/61, 16%) with >90%. In 19 patients with contemporaneous contrast-enhanced CT, no disease regions were independently identified on 68Ga-DOTA-SSA PET/CT. Thirty-five patients had an 18F-FDG PET/CT, with 18F-FDG positive/68Ga-DOTA-SSA negative metastases identified in 15 (43%). Twenty-one patients had PRRT with a median TTF of 14 months (95% CI 8-25) and a median OS of 63 months (95% CI 21-not reached). Of the entire cohort, the median OS was 323 months (95% CI 152-not reached). Predictors of poorer OS included a short calcitonin doubling-time (≤24 months), strong 18F-FDG avidity, and age ≥60 years. Conclusions The prevalence of high tumor avidity on 68Ga-DOTA-SSA PET/CT is low in the setting of metastatic MTC; nevertheless, PRRT may still be a viable treatment option in select patients.

Ipilimumab, a monoclonal antibody against CTLA-4, is used in the treatment of melanoma and renal cell cancer. Hypophysitis is one of the more common adverse events, usually presenting with headache, pituitary enlargement and hypopituitarism, mostly ACTH deficiency, which is usually permanent. We describe a series of 3 cases developing pituitary enlargement in keeping with hypophysitis after ipilimumab without any long-term pituitary hormone deficiencies. This illustrates that a comprehensive endocrine assessment is required even when pituitary enlargement is present.

Purpose Ipilimumab, a monoclonal antibody inhibiting CLTA-4, is an established treatment in metastatic melanoma, either alone or in combination with nivolumab, and results in immune mediated adverse events, including endocrinopathy. Hypophysitis is one of the most common endocrine abnormalities. An early recognition of hypophysitis may prevent life threatening consequences of hypopituitarism; therefore, biomarkers to predict which patients will develop hypophysitis would have clinical utility. Recent studies suggested that a decline in TSH may serve as an early marker of IH. This study was aimed at assessing the utility of thyroid function tests in predicting development of hypophysitis. Methods A retrospective cohort study was performed for all patients (n = 308) treated with ipilimumab either as a monotherapy or in combination with nivolumab for advanced melanoma at the Royal Marsden Hospital from 2010 to 2016. Thyroid function tests, other pituitary function tests and Pituitary MRIs were used to identify those with hypophysitis. Results and conclusions Ipilimumab-induced hypophysitis (IH) was diagnosed in 25 patients (8.15%). A decline in TSH was observed in hypophysitis cohort during the first three cycles but it did not reach statistical significance (P = 0.053). A significant fall in FT4 (P P P

Dysregulation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is implicated in human cancer growth and progression. Agents targeting this pathway are associated with hyperglycemia due to interaction with the insulin-glucose regulatory axis. Identifying the predictive factors for hyperglycemia in patients treated with these agents may help direct future management.Clinical characteristics and outcomes of patients treated consecutively with PI3K, AKT, or mTOR inhibitors in the Drug Development Unit, The Royal Marsden (RM) National Health Service (NHS) Foundation Trust, between 2007 and 2012 were recorded. Baseline variables and their association with grade 3 hyperglycemia (Common Terminology Criteria for Adverse Events, version 3.0) were analyzed by using the chi-square test and Fisher exact test for categorical variables and binary logistic regression for continuous variables.A total of 341 patients were treated in 12 phase I trials of PI3K/AKT/mTOR inhibitors, and 298 patients (87.4%) developed hyperglycemia. Hyperglycemia was grade 1 in 217 (72.8%) and grade 2 in 61 (20.5%) patients, respectively. Grade ≥3 hyperglycemia was seen in 6.7% of patients (n = 20). According to the chi-square test, age65 years (p = .03), history of diabetes (p = .003), and treatment with AKT and dual PI3K/mTOR inhibitors (p.0005) predicted the occurrence of grade 3 hyperglycemia. Of 24 patients requiring intervention, 20 received metformin, 2 dietary advice, 1 insulin, and 1 both metformin and insulin. One patient required dose reduction. There were no permanent drug discontinuations, and no hyperglycemia-related dose-limiting toxicities were observed; thus, the recommended phase II dose was not affected by the hyperglycemia observed in our cohort.Hyperglycemia is common in patients treated with PI3K/AKT/mTOR inhibitors; however, it is manageable with conventional treatment. Predictive factors of age, history of diabetes, and administration of AKT and dual PI3K/mTOR inhibitors warrant prospective validation.This study reviewed the clinical data of 341 patients treated in 12 phase I trials of agents targeting phosphatidylinositol3-kinase (PI3), protein kinase B (AKT), and mammalian target of rapamycin (mTOR), as well as dual inhibitors. Hyperglycemia was evident in 87.4% of patients but was ≥grade 3 in just 6.7%. Age65 years, history of diabetes, and treatment with AKT and dual PI3K/mTOR inhibitors were each associated with grade 3 hyperglycemia. Management of patients was uncomplicated, and no permanent drug discontinuations were necessary. Despite the small study size, these findings support continued caution about enrolling patients with a history of diabetes into such trials. However, clinicians may be reassured, pending prospective validation of these results, that significant hyperglycemia is not frequent and, when it occurs, is manageable.

Background ICONIC is a single arm phase 2 trial investigating the safety and efficacy of 4 cycles pre-operative and 4 cycles post-operative FLOT-A in resectable OGA. We report results from the safety run-in phase and early translational biomarker data. Methods Eligible pts were enrolled into the 3 + 3 design dose finding stage. Standard dose FLOT was administered with 10mg/kg iv avelumab q2 weeks (dose level 0). Dose limiting toxicities (DLTs) were assessed for 28d. Biopsies were taken at baseline and post cycle 2. Results At data cut-off (12/4/19) 6 pts were enrolled and completed pre-operative treatment. 1/6 pts experienced a DLT (chest pain during 5FU infusion), and dose level 0 was established as the safe dose for the efficacy stage of the trial. During pre-operative FLOT-A all pts experienced at least one grade 1-2 adverse event (AE), most commonly diarrhoea (5/6 pts), fatigue, nausea, peripheral neuropathy and hypokalaemia (all 4/6 pts); 3/6 pts experienced at least one grade 3-4 AE: neutropenia and elevated liver enzymes (1 pt), thrombotic event (1 pt) and cardiac chest pain (1 pt). 4/6 pts reported any grade chest pain and underwent cardiac work up: 1 episode was due to PE, 1 of likely GI origin and 2 cardiac in nature, which then recurred in one pt who was re-exposed to FLOT without avelumab. 3/6 pts completed 4 cycles pre-operative FLOT-A: 1 pt discontinued avelumab due to diarrhoea, 2 pts discontinued FLOT-A due to cardiac chest pain and switched to a regimen without 5FU. 5 pts have undergone surgery at data cut-off, without unexpected complications. Immunofluorescence shows changes of CD8-, memory- and regulatory T cell infiltrates between baseline and on-treatment biopsies, and detailed results will be presented. Conclusions This is the first data showing that FLOT can be combined with a PD-L1-inhibitor with FLOT-A having a manageable safety profile at dose level 0 (standard dose FLOT + 10mg/kg avelumab). As chest pain of variable aetiologies was observed in 4/6 patients this will be closely monitored and assessed during the efficacy phase. No unexpected complications have been observed during surgery following FLOT-A treatment. Clinical trial identification 2016-003306-13. Legal entity responsible for the study Royal Marsden Hospitals NHS Foundation Trust. Funding Royal Marsden Hospital NHS Foundation Trust Institute of Cancer Research, Merck Pharmaceuticals. Disclosure M. Davidson: Travel / Accommodation / Expenses: Celgene. N. Starling: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Merck; Honoraria (institution): AstraZeneca. I. Chau: Advisory / Consultancy: Eli-Lilly; Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Bayer; Advisory / Consultancy: Roche; Advisory / Consultancy: Merck-Serono; Advisory / Consultancy: Five Prime Therapeutics; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Oncologie International; Advisory / Consultancy: Pierre Fabre; Research grant / Funding (institution): Eli-Lilly; Research grant / Funding (institution): Janssen Cilag; Research grant / Funding (institution): Sanofi Oncology; Research grant / Funding (institution): Merck-Serono; Honoraria (institution): Eli-Lilly. D. Cunningham: Research grant / Funding (institution): Amgen; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Merck-Serono; Research grant / Funding (institution): Medimmune; Research grant / Funding (institution): Merrimack; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Sanofi. D. Morganstein: Advisory / Consultancy: MSD; Advisory / Consultancy: BMS; Advisory / Consultancy: Roche. M.D. Forster: Research grant / Funding (institution): Merck; Honoraria (institution): Merck. M. Gerlinger: Research grant / Funding (institution): Merck; Research grant / Funding (institution): BMS. All other authors have declared no conflicts of interest.

Background 95% of metastatic colorectal cancers (mCRCs) have normal mismatch repair proficient (pMMR) expression and a stable microsatellite phenotype (MSS). As a consequence, checkpoint inhibiting immunotherapy currently plays no role in these tumours. We recently found that RAS/RAF wild type (WT) mCRCs (50% of all CRCs) that first responded to cetuximab and then acquired resistance had converted from an immune-excluded or immune-desert phenotype before treatment to an inflamed phenotype at progression. This progression was characterized by increased CD8+ T cell infiltrates and upregulation of PDL1 and LAG3 immune checkpoints. To assess if the cetuximab induced immune infiltrates can be exploited for therapeutic benefit, the iSCORE trial will treat 25 patients with combined anti-PD1 (nivolumab) and anti-LAG3 (relatlimab) immunotherapy starting ideally within 4 weeks after progression on immunogenic FOLFIRI chemotherapy and cetuximab. Trial design iSCORE is designed to evaluate the efficacy of nivolumab and relatlimab in patients with RAS/RAF WT mCRC who have had radiological response to first line FOLFIRI and cetuximab, but then progressed. Eligible patients will receive nivolumab 480mg and relatlimab 160mg every 4 weeks. The primary endpoint is disease control rate (DCR) at 6 months from treatment initiation. With an A’Hern single stage design for efficacy, 5% significance and a power of 80%, 25 patients would need to be treated and a minimum of 6 would need to be progression free at 6 months in order to support an increase of the DCR at 6 months from Clinical trial identification NCT03867799. Legal entity responsible for the study The Royal Marsden NHS Foundation Trust. Funding The Royal Marsden NHS Foundation Trust, Bristol-Myers Squibb. Disclosure D. Cunningham: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): 4SC; Research grant / Funding (institution): Clovis; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Merck. I. Chau: Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Bayer; Advisory / Consultancy: Roche; Advisory / Consultancy: Merck-Serono; Advisory / Consultancy: Five Prime Therapeutics; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Oncologie International; Advisory / Consultancy: Pierre Fabre; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Janssen-Cilag; Research grant / Funding (institution): Sanofi Oncology; Research grant / Funding (institution): Merck-Serono; Honoraria (self): Eli-Lilly. M. Gerlinger: Research grant / Funding (institution): BMS; Research grant / Funding (institution): Merck KG. N. Starling: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Pfizer; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: BMS; Travel / Accommodation / Expenses: Eli Lilly; Travel / Accommodation / Expenses: Merck; Travel / Accommodation / Expenses: Roche; Honoraria (self): AstraZeneca; Honoraria (self): Eli Lilly; Honoraria (self): Merck; Honoraria (self): Servier; Advisory / Consultancy: Pfizer; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Servier. All other authors have declared no conflicts of interest.

Focusing on the links between diabetes treatment and cancer risk, Daniel Morganstein and Michael Feher discuss the complex clinical needs of patients with diabetes and cancer, and the management of both conditions.

Context Both type 2 diabetes (T2D) and osteoporosis are affected by aging and quite often coexist. Furthermore, the fracture risk in patients with T2D is increased. The aim of this article is to review updated information on osteoporosis and fracture risk in patients with T2D, to discuss the effects of diabetes treatment on bone metabolism, as well as the effect of antiosteoporotic medications on the incidence and control of T2D, and to provide a personalized guide to the optimal management. Evidence acquisition A systematic literature search for human studies was conducted in three electronic databases (PubMed, Cochrane, and EMBASE) until March 2017. Regarding recommendations, we adopted the grading system introduced by the American College of Physicians. Evidence synthesis The results are presented in systematic tables. Healthy diet and physical exercise are very important for the prevention and treatment of both entities. Metformin, sulfonylureas, dipeptidyl peptidase-4 inhibitors, and glucagon-like peptide-1 receptor agonists should be preferred for the treatment of T2D in these patients, whereas strict targets should be avoided for the fear of hypoglycemia, falls, and fractures. Insulin should be used with caution and with careful measures to avoid hypoglycemia. Thiazolidinediones and canagliflozin should be avoided, whereas other sodium-dependent glucose transporter 2 inhibitors are less well-validated options. Insulin therapy is the preferred method for achieving glycemic control in hospitalized patients with T2D and fractures. The treatment and monitoring of osteoporosis should be continued without important amendments because of the presence of T2D. Conclusions Patients with coexisting T2D and osteoporosis should be managed in an optimal way according to scientific evidence.

SummaryContext Checkpoint inhibitors are emerging as important cancer therapies but are associated with a high rate of immune side effects, including endocrinopathy. Objective To determine the burden of thyroid dysfunction in patients with melanoma treated with immune checkpoint inhibitors and describe the clinical course. Design and patients Consecutive patients with melanoma treated with either ipilimumab, nivolumab, pembrolizumab or the combination of ipilimumab and nivolumab were identified. Baseline thyroid function tests were used to exclude those with pre-existing thyroid abnormalities, and thyroid function tests during treatment used to identify those with thyroid dysfunction. Results Rates of overt thyroid dysfunction were in keeping with the published phase 3 trials. Hypothyroidism occurred in 13·0% treated with a programmed death receptor-1 (PD-1) inhibitor and 22·2% with a combination of PD-1 inhibitor and ipilimumab. Transient subclinical hyperthyroidism was observed in 13·0% treated with a PD-1 inhibitor, 15·9% following a PD-1 inhibitor, and 22·2% following combination treatment with investigations suggesting a thyroiditic mechanism rather than Graves’ disease, and a high frequency of subsequent hypothyroidism. Any thyroid abnormality occurred in 23·0% following ipilimumab, 39·1% following a PD-1 inhibitor and 50% following combination treatment. Abnormal thyroid function was more common in female patients. Conclusion Thyroid dysfunction occurs commonly in patients with melanoma treated with immune checkpoint inhibitors, with rates, including subclinical dysfunction, occurring in up to 50%.

TPS4139Background: Peri-operative chemotherapy with 5FU, oxaliplatin and docetaxel (FLOT) is a new standard of care in resectable gastro-oesophageal adenocarcinoma (GOA), however with 3y survival r...

ABSTRACT Neuroendocrine tumors (NETs) are a rare and heterogeneous group of tumors with widely varying morphologies and behaviors. Due to their rarity and heterogeneity, progress in improving their treatment has been slow. However, in recent years there have been advances both in their characterization and in the available treatment options. This review will attempt to address these, with particular reference to pancreatic NETs. Pancreatic NETs are a subset of NETs, previously known as islet cell tumors, which appear to be a distinct biological entity, responding differently to systemic treatments compared with NETs arising elsewhere in the GI tract.

We present a case of a patient with intramyocardial metastases from a carcinoid tumor. These findings were detected using cardiovascular magnetic resonance imaging, with functional metabolic activity analyzed using nuclear imaging and confirmed by histologic findings at surgical biopsy. This case highlights the value of cardiovascular magnetic resonance imaging and the importance of multimodality imaging.

Background Hyponatraemia is a common finding in patients with cancer, and has been shown to be associated with poor prognosis in different settings. We have analysed the impact of severe hyponatraemia in patients with cancer. Methods A retrospective review of all patients admitted to a specialist cancer hospital with a plasma sodium of less than 115 mmol/l and a diagnosis of malignancy was undertaken. Patient and tumour characteristics were analysed as well as impact of hyponatraemia management on overall survival and number of lines of cancer treatment received. Results 57 patients were identified. 84% had advanced Stage 3 or 4 cancer and approximately 85% with data available had symptoms attributable to hyponatraemia. Mean length of hospital stay was 12 days, and overall survival (OS) was 5.1 months. Plasma sodium level corrected in 56% of patients and here OS was 13.6 months compared to 16 days in those whose sodium did not correct (p

Nearly 30% of patients with autoimmune thyroid disease have proteinuria w1x. Membranous glomerulonephritis is the most common finding when thyroid disease is associated with nephrotic range proteinuria. There are only three previous reports of autoimmune thyroid disease and minimal change glomerular disease (MCD). We report the case of a patient in whom Graves’ disease and MCD were diagnosed simultaneously and in whom relapse of the Graves’ disease was invariably accompanied by relapse of MCD.

of lung cancer treatment S.K. Lu1, T. Thay2, S. Popat1 and D.L. Morganstein 1,2 1 Royal Marsden Hospital, London 2 Chelsea and Westminster Hospital, London Background Targeted treatments, such as tyrosine kinase inhibitors, are revolutionizing the treatment of cancer. However multiple endocrine side effects of these treatments are emerging, of which hypothyrodism appears to be the most common. Crizotinib, a multi-targeted small molecule tyrosine kinase inhibitor of ALK and c-met, has been approved by the FDA in 2011 for the treatment of NSCLC patients with a novel oncogenic gene fusion, EML4-ALK and its variants, following early phase trial showing an impressive response rate of 50-60% and median PFS of 10 months. Lowering of testosterone level has been described with crizotinib treatment and increases after interruption of treatment demonstrating a direct causal effect. Here, we report a case of hypogonadism with crizotinib treatment. History A 35 year old man, light ex-smoker, was diagnosed with stage IV adenocarcinoma of the lung in 2011. He progressed despite treatment with conventional chemotherapy. Gene rearrangement the ALK gene at 2p23 was detected by FISH testing. He therefore commenced crizotinib through compassionate supply in May 2012 and continues to be on it at present day and has attained an excellent partial remission. He tolerated the treatment reasonably well except the common known sideeffects including grade 1 rash, nausea, visual disturbance and diarrhoea. Random total testosterone level at baseline was within normal range and monitored at each clinic visit.

Mason and colleagues report that sexual precocity occurred in a 4 year old boy with inadvertent transfer of transdermal testosterone gel.1 We report contamination of blood samples during venepuncture. A patient receiving testosterone replacement treatment had a serum …