Imperial College London

ProfessorRobertGoldin

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

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Department of Digestive DiseasesQueen Elizabeth the Queen Mother Wing (QEQM)St Mary's Campus

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Publications

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504 results found

Pinato DJ, D'Alessio A, Fulgenzi CAM, Schlaak AE, Celsa C, Killmer S, Blanco JM, Ward C, Stikas C-V, Openshaw MR, Acuti N, Nteliopoulos G, Balcells C, Keun HC, Goldin RD, Ross PJ, Cortellini A, Thomas R, Young AM, Danckert N, Tait P, Marchesi JR, Bengsch B, Sharma Ret al., 2024, Safety and preliminary efficacy of pembrolizumab following trans-arterial chemoembolization for hepatocellular carcinoma: the PETAL phase Ib study., Clin Cancer Res

BACKGROUND: TACE may prime adaptive immunity and enhance immunotherapy efficacy. PETAL evaluated safety, preliminary activity of TACE plus pembrolizumab and explored mechanisms of efficacy. METHODS: Patients with liver-confined HCC were planned to receive up to 2 rounds of TACE followed by pembrolizumab 200 mg every 21 days commencing 30-days post-TACE until disease progression or unacceptable toxicity for up to 1 year. Primary endpoint was safety, 21-days dose-limiting toxicities (DLT) from pembrolizumab initiation. Secondary endpoints included progression-free survival (PFS) and evaluation of tumour and host determinants of response. RESULTS: Fifteen patients were included in the safety and efficacy population: 73% had non-viral cirrhosis, median age was 72 years. Child-Pugh (CP) class was A in 14 patients. Median tumour size was 4 cm. Ten patients (67%) received pembrolizumab after 1 TACE, 5 patients after 2 (33%). Pembrolizumab yielded no synergistic toxicity nor DLTs post-TACE. Treatment-related adverse events occurred in 93% of patients most commonly skin rash (40%), fatigue and diarrhoea (27%). After a median follow-up of 38.5 months, objective response rate (ORR) 12 weeks post-TACE was 53%. PFS rate at 12 weeks was 93% and median PFS was 8.95 months (95%CI 7.30-NA). Median duration of response was 7.3 months (95%CI: 6.3-8.3). Median OS was 33.5 months (95%CI: 11.6-NA). Dynamic changes in peripheral T-cell subsets, circulating tumour DNA, serum metabolites and in stool bacterial profiles highlight potential mechanisms of action of multi-modal therapy. CONCLUSIONS: TACE plus pembrolizumab was tolerable with no evidence of synergistic toxicity, encouraging further clinical development of immunotherapy alongside TACE.

Journal article

Gudd C, Mitchell E, Atkinson S, Mawhin M-A, Turajlic S, Larkin J, Thursz M, Goldin R, Powell N, Antoniades C, Woollard K, Possamai L, Triantafyllou Eet al., 2024, Therapeutic inhibition of monocyte recruitment prevents checkpoint inhibitor-induced hepatitis, Journal for ImmunoTherapy of Cancer, ISSN: 2051-1426

Journal article

Ma J, Al Moussawi K, Lou H, Chan HF, Wang Y, Chadwick J, Phetsouphanh C, Slee EA, Zhong S, Leissing TM, Roth A, Qin X, Chen S, Yin J, Ratnayaka I, Hu Y, Louphrasitthiphol P, Taylor L, Bettencourt PJG, Muers M, Greaves DR, McShane H, Goldin R, Soilleux EJ, Coleman ML, Ratcliffe PJ, Lu Xet al., 2024, Deficiency of factor-inhibiting HIF creates a tumor-promoting immune microenvironment, Proceedings of the National Academy of Sciences of USA, Vol: 121, ISSN: 0027-8424

Hypoxia signaling influences tumor development through both cell-intrinsic and -extrinsic pathways. Inhibiting hypoxia-inducible factor (HIF) function has recently been approved as a cancer treatment strategy. Hence, it is important to understand how regulators of HIF may affect tumor growth under physiological conditions. Here we report that in aging mice factor-inhibiting HIF (FIH), one of the most studied negative regulators of HIF, is a haploinsufficient suppressor of spontaneous B cell lymphomas, particular pulmonary B cell lymphomas. FIH deficiency alters immune composition in aged mice and creates a tumor-supportive immune environment demonstrated in syngeneic mouse tumor models. Mechanistically, FIH-defective myeloid cells acquire tumor-supportive properties in response to signals secreted by cancer cells or produced in the tumor microenvironment with enhanced arginase expression and cytokine-directed migration. Together, these data demonstrate that under physiological conditions, FIH plays a key role in maintaining immune homeostasis and can suppress tumorigenesis through a cell-extrinsic pathway.

Journal article

Duran I, Pombo J, Sun B, Gallage S, Kudo H, McHugh D, Bousset L, Barragan Avila JE, Forlano R, Manousou P, Heikenwalder M, Withers DJ, Vernia S, Goldin RD, Gil Jet al., 2024, Detection of senescence using machine learning algorithms based on nuclear features, Nature Communications, Vol: 15, Pages: 1-20, ISSN: 2041-1723

Cellular senescence is a stress response with broad pathophysiological implications. Senotherapies can induce senescence to treat cancer or eliminate senescent cells to ameliorate ageing and age-related pathologies. However, the success of senotherapies is limited by the lack of reliable ways to identify senescence. Here, we use nuclear morphology features of senescent cells to devise machine-learning classifiers that accurately predict senescence induced by diverse stressors in different cell types and tissues. As a proof-of-principle, we use these senescence classifiers to characterise senolytics and to screen for drugs that selectively induce senescence in cancer cells but not normal cells. Moreover, a tissue senescence score served to assess the efficacy of senolytic drugs and identified senescence in mouse models of liver cancer initiation, ageing, and fibrosis, and in patients with fatty liver disease. Thus, senescence classifiers can help to detect pathophysiological senescence and to discover and validate potential senotherapies.

Journal article

McGenity C, Randell R, Bellamy C, Burt A, Cratchley A, Goldin R, Hubscher SG, Neil DAH, Quaglia A, Tiniakos D, Wyatt J, Treanor Det al., 2024, Survey of liver pathologists to assess attitudes towards digital pathology and artificial intelligence, Journal of Clinical Pathology, Vol: 77, Pages: 27-33, ISSN: 0021-9746

Aims: A survey of members of the UK Liver Pathology Group (UKLPG) was conducted, comprising consultant histopathologists from across the UK who report liver specimens and participate in the UK National Liver Pathology External Quality Assurance scheme. The aim of this study was to understand attitudes and priorities of liver pathologists towards digital pathology and artificial intelligence (AI).Methods: The survey was distributed to all full consultant members of the UKLPG via email. This comprised 50 questions, with 48 multiple choice questions and 2 free-text questions at the end, covering a range of topics and concepts pertaining to the use of digital pathology and AI in liver disease.Results: Forty-two consultant histopathologists completed the survey, representing 36% of fully registered members of the UKLPG (42/116). Questions examining digital pathology showed respondents agreed with the utility of digital pathology for primary diagnosis 83% (34/41), second opinions 90% (37/41), research 85% (35/41) and training and education 95% (39/41). Fatty liver diseases were an area of demand for AI tools with 80% in agreement (33/41), followed by neoplastic liver diseases with 59% in agreement (24/41). Participants were concerned about AI development without pathologist involvement 73% (30/41), however, 63% (26/41) disagreed when asked whether AI would replace pathologists.Conclusions: This study outlines current interest, priorities for research and concerns around digital pathology and AI for liver pathologists. The majority of UK liver pathologists are in favour of the application of digital pathology and AI in clinical practice, research and education.

Journal article

Forlano R, Stanic T, Jayawardana S, Mullish BH, Yee M, Mossialos E, Goldin R, Petta S, Tsochatzis E, Thursz M, Manousou Pet al., 2024, A prospective study on the prevalence of MASLD in people with type-2 diabetes in the community. Cost effectiveness of screening strategies, Liver International, Vol: 44, Pages: 61-71, ISSN: 1478-3223

Background and AimsAs screening for the liver disease and risk-stratification pathways are not established in patients with type-2 diabetes mellitus (T2DM), we evaluated the diagnostic performance and the cost-utility of different screening strategies for MASLD in the community.MethodsConsecutive patients with T2DM from primary care underwent screening for liver diseases, ultrasound, ELF score and transient elastography (TE). Five strategies were compared to the standard of care: ultrasound plus abnormal liver function tests (LFTs), Fibrosis score-4 (FIB-4), NAFLD fibrosis score, Enhanced liver fibrosis test (ELF) and TE. Standard of care was defined as abnormal LFTs prompting referral to hospital. A Markov model was built based on the fibrosis stage, defined by TE. We generated the cost per quality-adjusted life year (QALY) gained and calculated the incremental cost-effectiveness ratio (ICER) over a lifetime horizon.ResultsOf 300 patients, 287 were included: 64% (186) had MASLD and 10% (28) had other causes of liver disease. Patients with significant fibrosis, advanced fibrosis, and cirrhosis due to MASLD were 17% (50/287), 11% (31/287) and 3% (8/287), respectively. Among those with significant fibrosis classified by LSM≥8.1 kPa, false negatives were 54% from ELF and 38% from FIB-4. On multivariate analysis, waist circumference, BMI, AST levels and education rank were independent predictors of significant and advanced fibrosis. All the screening strategies were associated with QALY gains, with TE (148.73 years) having the most substantial gains, followed by FIB-4 (134.07 years), ELF (131.68 years) and NAFLD fibrosis score (121.25 years). In the cost-utility analysis, ICER was £2480/QALY for TE, £2541.24/QALY for ELF and £2059.98/QALY for FIB-4.ConclusionScreening for MASLD in the diabetic population in primary care is cost-effective and should become part of a holistic assessment. However, traditional screenin

Journal article

Lo J, Cozzetto D, Alexander J, Danckert N, Madgwick M, Knox N, Sieh J, Olbei M, Liu Z, Ibraheim H, Miguens Blanco J, Kudo H, Castro Seoane R, Possamai L, Goldin R, Marchesi J, Korcsmaros T, Lord G, Powell Net al., 2023, Immune checkpoint inhibitor-induced colitis is mediated by polyfunctional lymphocytes and dependent on IL23 and IFNg, Nature Communications, Vol: 14, ISSN: 2041-1723

Immune checkpoint inhibitors (CPIs) are a relatively newly licenced cancer treatment, which make a once previously untreatable disease now amenable to a potential cure. Combination regimens of anti-CTLA4 and anti-PD-1 show enhanced efficacy but are prone to off-target immune-mediated tissue injury, particularly at the barrier surfaces. To probe the impact of immune checkpoints on intestinal homoeostasis, mice are challenged with anti-CTLA4 and anti-PD-1 immunotherapy and manipulation of the intestinal microbiota. The immune profile of the colon of these mice with CPI-colitis is analysed using bulk RNA sequencing, single-cell RNA sequencing and flow cytometry. CPI-colitis in mice is dependent on the composition of the intestinal microbiota and by the induction of lymphocytes expressing interferon-γ (IFNγ), cytotoxicity molecules and other pro-inflammatory cytokines/chemokines. This pre-clinical model of CPI-colitis could be attenuated following blockade of the IL23/IFNγ axis. Therapeutic targeting of IFNγ-producing lymphocytes or regulatory networks, may hold the key to reversing CPI-colitis.

Journal article

Parker R, Allison M, Anderson S, Aspinall R, Bardell S, Bains V, Buchanan R, Corless L, Davidson I, Dundas P, Fernandez J, Forrest E, Forster E, Freshwater D, Gailer R, Goldin R, Hebditch V, Hood S, Jones A, Lavers V, Lindsay D, Maurice J, Mcdonagh J, Morgan S, Nurun T, Oldroyd C, Oxley E, Pannifex S, Parsons G, Phillips T, Rainford N, Rajoriya N, Richardson P, Ryan J, Sayer J, Smith M, Srivastava A, Stennett E, Towey J, Vaziri R, Webzell I, Wellstead A, Dhanda A, Masson Set al., 2023, Quality standards for the management of alcohol-related liver disease: consensus recommendations from the British Association for the Study of the Liver and British Society of Gastroenterology ARLD special interest group, BMJ Open Gastroenterology, Vol: 10, ISSN: 2054-4774

Objective Alcohol-related liver disease (ALD) is the most common cause of liver-related ill health and liver-related deaths in the UK, and deaths from ALD have doubled in the last decade. The management of ALD requires treatment of both liver disease and alcohol use; this necessitates effective and constructive multidisciplinary working. To support this, we have developed quality standard recommendations for the management of ALD, based on evidence and consensus expert opinion, with the aim of improving patient care.Design A multidisciplinary group of experts from the British Association for the Study of the Liver and British Society of Gastroenterology ALD Special Interest Group developed the quality standards, with input from the British Liver Trust and patient representatives.Results The standards cover three broad themes: the recognition and diagnosis of people with ALD in primary care and the liver outpatient clinic; the management of acutely decompensated ALD including acute alcohol-related hepatitis and the posthospital care of people with advanced liver disease due to ALD. Draft quality standards were initially developed by smaller working groups and then an anonymous modified Delphi voting process was conducted by the entire group to assess the level of agreement with each statement. Statements were included when agreement was 85% or greater. Twenty-four quality standards were produced from this process which support best practice. From the final list of statements, a smaller number of auditable key performance indicators were selected to allow services to benchmark their practice and an audit tool provided.Conclusion It is hoped that services will review their practice against these recommendations and key performance indicators and institute service development where needed to improve the care of patients with ALD.

Journal article

Clift AK, Drymousis P, von Roon A, Humphries A, Goldin R, Bomanji J, Leaman S, Wasan H, Habib N, Frilling Aet al., 2023, Management of small bowel neuroendocrine tumours: 10 years' experience at a tertiary referral centre, Cancers, Vol: 15, ISSN: 2072-6694

Background: Neuroendocrine tumours (NET) arising from the small bowel are clinically challenging and are often diagnosed at advanced stages. Disease control with surgery alone can be demanding. Multimodal treatment concepts integrating surgery and non-surgical modalities could be of benefit. Method: Retrospective review of consecutive adult patients with SB NET treated at Imperial College Healthcare NHS Trust between 1 January 2010 and 31 December 2019. Data regarding clinicopathological characteristics, treatments, and disease trajectory were extracted and summarised. Overall and progression/recurrence-free survival were estimated at 5 and 10 years. Results: 154 patients were identified, with a median age of 64 years (range 33–87); 135/154 (87.7%) had stage III/IV disease at diagnosis. Surgery was used in 125 individuals (81.2%), typically with either segmental small bowel resection (60.8%) or right hemicolectomy (33.6%) and mesenteric lymphadenectomy for the primary tumour. Systemic and/or liver-directed therapies were used in 126 (81.8%); 60 (47.6%) had more than one line of non-surgical treatment. Median follow-up was 67.2 months (range 3.1–310.4); overall survival at 5 and 10 years was 91.0% (95% CI: 84.9–94.7%) and 82.5% (95% CI: 72.9–88.9%), respectively. Imaging-based median progression-free survival was 42.7 months (95% CI: 24.7 to 72.4); 5-year progression-free survival was 63.4% (95% CI: 55.0–70.6%); 10-year progression-free survival was 18.7% (95% CI: 12.4–26.1). Nineteen patients (12.3%) reached 10 years follow-up without disease recurrence and therefore were considered cured. Conclusions: Most patients with SB NET present in a metastasised stage. Multimodal treatment concepts may be associated with excellent clinical outcomes. Future work should explore optimal approaches to treatment sequencing and patient selection.

Journal article

McGlone ER, Siebert M, Dore M, Hope DCD, Davies I, Owen B, Khoo B, Goldin R, Carling D, Bloom S, Le Gall M, Tan TM-Met al., 2023, Sleeve gastrectomy causes weight-loss independent improvements in hepatic steatosis, Liver International, Vol: 43, Pages: 1890-1900, ISSN: 1478-3223

Background and AimsSleeve gastrectomy (VSG) leads to improvement in hepatic steatosis, associated with weight loss. The aims of this study were to investigate whether VSG leads to weight-loss independent improvements in liver steatosis in mice with diet-induced obesity (DIO); and to metabolically and transcriptomically profile hepatic changes in mice undergoing VSG.MethodsMice with DIO were treated with VSG, sham surgery with subsequent food restriction to weight-match to the VSG group (Sham-WM), or sham surgery with return to unrestricted diet (Sham-Ad lib). Hepatic steatosis, glucose tolerance, insulin and glucagon resistance, and hepatic transcriptomics were investigated at the end of the study period and treatment groups were compared with mice undergoing sham surgery only (Sham-Ad lib).ResultsVSG led to much greater improvement in liver steatosis than Sham-WM (liver triglyceride mg/mg 2.5 ± 0.1, 2.1 ± 0.2, 1.6 ± 0.1 for Sham-AL, Sham-WM and VSG respectively; p = 0.003). Homeostatic model assessment of insulin resistance was improved following VSG only (51.2 ± 8.8, 36.3 ± 5.3, 22.3 ± 6.1 for Sham-AL, Sham-WM and VSG respectively; p = 0.03). The glucagon-alanine index, a measure of glucagon resistance, fell with VSG but was significantly increased in Sham-WM (9.8 ± 1.7, 25.8 ± 4.6 and 5.2 ± 1.2 in Sham Ad-lib, Sham-WM and VSG respectively; p = 0.0003). Genes downstream of glucagon receptor signalling which govern fatty acid synthesis (Acaca, Acacb, Me1, Acly, Fasn and Elovl6) were downregulated following VSG but upregulated in Sham-WM.ConclusionsChanges in glucagon sensitivity may contribute to weight-loss independent improvements in hepatic steatosis following VSG.

Journal article

Calvisi D, Boulter L, Vaquero J, Saborowski A, Fabris LM, Rodrigues P, Coulouarn CE, Castro R, Segatto O, Raggi C, van der Laan LJW, Carpino G, Goeppert B, Roessler SJ, Kendall T, Evert M, Gonzalez-Sanchez EW, Valle J, Vogel A, Bridgewater JJ, Borad MJ, Gores GR, Roberts L, Marin JJGB, Andersen J, Alvaro D, Forner AM, Banales J, Cardinale V, Macias RIR, Vicent S, Chen X, Braconi C, Verstegen MMA, Fouassier L, Roberts L, Scheiter A, Selaru FM, Evert K, Utpatel K, Broutier L, Cadamuro M, Huch M, Goldin R, Gradilone SA, Saito Yet al., 2023, Criteria for preclinical models of cholangiocarcinoma: scientific and medical relevance, Nature Reviews Gastroenterology & Hepatology, Vol: 20, Pages: 462-480, ISSN: 1759-5053

Cholangiocarcinoma (CCA) is a rare malignancy that develops at any point along the biliary tree. CCA has a poor prognosis, its clinical management remains challenging, and effective treatments are lacking. Therefore, preclinical research is of pivotal importance and necessary to acquire a deeper understanding of CCA and improve therapeutic outcomes. Preclinical research involves developing and managing complementary experimental models, from in vitro assays using primary cells or cell lines cultured in 2D or 3D to in vivo models with engrafted material, chemically induced CCA or genetically engineered models. All are valuable tools with well-defined advantages and limitations. The choice of a preclinical model is guided by the question(s) to be addressed; ideally, results should be recapitulated in independent approaches. In this Consensus Statement, a task force of 45 experts in CCA molecular and cellular biology and clinicians, including pathologists, from ten countries provides recommendations on the minimal criteria for preclinical models to provide a uniform approach. These recommendations are based on two rounds of questionnaires completed by 35 (first round) and 45 (second round) experts to reach a consensus with 13 statements. An agreement was defined when at least 90% of the participants voting anonymously agreed with a statement. The ultimate goal was to transfer basic laboratory research to the clinics through increased disease understanding and to develop clinical biomarkers and innovative therapies for patients with CCA.

Journal article

Pinato DJ, Kaneko T, DAlessio A, Forner A, Fessas P, Minguez B, Giannini EG, Grillo F, Díaz A, Mauri FA, Fulgenzi CAM, Pria AD, Goldin RD, Pieri G, Toniutto P, Avellini C, Plaz Torres MC, Akarca AU, Marafioti T, Bhoori S, Miró JM, Bower M, Bräu N, Mazzaferro Vet al., 2023, Integrated phenotyping of the anti-cancer immune response in HIV-associated hepatocellular carcinoma, JHEP Reports, Vol: 5, Pages: 1-11, ISSN: 2589-5559

Background & AimsHIV-seropositivity shortens survival in patients with hepatocellular carcinoma (HCC). Whilst risk factors for HCC including Hepatitis C virus infection can influence T-cell phenotype, it is unknown whether HIV can influence functional characteristics of the T-cell infiltrate.MethodsFrom the Liver Cancer in HIV biorepository, we derived 129 samples of transplanted (76%) or resected (20%) HCC in 8 European and North American centres. We profiled intra and peri-tumoural tissue to evaluate regulatory CD4+/FOXP3+ and immune-exhausted CD8+/PD1+ T-cells in HIV+ (n=66) and HIV- (n=63) samples. We performed targeted transcriptomics and T-cell receptor sequencing in a restricted subset of samples evaluated in relationship with HIV status. We correlated immuno-pathologic features with patients’ characteristics including markers of HIV infection.ResultsOf the 66 HIV+ patients, 83% were Hepatitis C virus co-infected with an undetectable HIV viral load (51%) and a median blood CD4+ cell count of 430 cells/mm3 (range 15-908). HIV+ patients were compared with HIV- controls with similar staging characteristics including Barcelona Clinic Liver Cancer (BCLC) stage A-B (86% vs. 83%, p=0.16), <3 nodules (90% vs 83%, p=0.3) and median alfa-fetoprotein (AFP) values (10.9 vs. 12.8 ng/ml, p=0.72). HIV+ samples had higher PD-L1 expression rates in tumour tissue (51% vs 8% p<0.0001) and displayed a denser intra-tumoral CD4+/FOXP3+ (p<0.0001), CD8+/PD1+ (p<0.0001), with lower total peri-tumoral CD4+ (p<0.0001) and higher peri-tumoral CD8+/PD1+ (p<0.0001). Gene set analysis revealed HIV+ cases to have evidence of dysregulated adaptive and innate immunity. Tumour infiltrating lymphocyte clonality was not influenced by HIV status.ConclusionsHIV-associated HCC harbours a profoundly immune-exhausted tumour microenvironment, warranting prospective testing of immunotherapy in this treatment-deprived patient population.

Journal article

Perez-Ternero C, Li W, Aubdool A, Goldin R, Alazawi W, Hobbs Aet al., 2023, C-type natriuretic peptide protects against the development of non-alcoholic steatohepatitis and portal hypertension, 19th World Congress of Basic and Clinical Pharmacology (WCP), Publisher: WILEY, Pages: 6-7, ISSN: 0007-1188

Conference paper

Miller P, Akama-Garren EH, Owen RP, Demetriou C, Carroll TM, Slee E, Al Moussawi K, Ellis M, Goldin R, O'Neill E, Lu Xet al., 2023, p53 inhibitor iASPP is an unexpected suppressor of KRAS and inflammation-driven pancreatic cancer, Cell Death and Differentiation, Vol: 30, Pages: 1619-1635, ISSN: 1350-9047

Oncogenic KRAS activation, inflammation and p53 mutation are key drivers of pancreatic cancer (PC) development. Here we report iASPP, an inhibitor of p53, as a paradoxical suppressor of inflammation and oncogenic KRASG12D-driven PC tumorigenesis. iASPP suppresses PC onset driven by KRASG12D alone or KRASG12D in combination with mutant p53R172H. iASPP deletion limits acinar-to-ductal metaplasia (ADM) in vitro but accelerates inflammation and KRASG12D-induced ADM, pancreatitis and PC tumorigenesis in vivo. KRASG12D/iASPPΔ8/Δ8 tumours are well-differentiated classical PCs and their derivative cell lines form subcutaneous tumours in syngeneic and nude mice. Transcriptomically, either iASPP deletion or p53 mutation in the KRASG12D background altered the expression of an extensively overlapping gene set, comprised primarily of NF-κB and AP1-regulated inflammatory genes. All these identify iASPP as a suppressor of inflammation and a p53-independent oncosuppressor of PC tumorigenesis.

Journal article

Yong KK, He Y, Cheung HCA, Sriskandarajah R, Jenkins W, Goldin R, Beg Set al., 2023, Rationalising the use of specimen pots following colorectal polypectomy: a small step towards greener endoscopy, Frontline Gastroenterology, Vol: 14, Pages: 295-299, ISSN: 2041-4137

Aims In this study, we aim to determine whether combining multiple small colorectal polyps within a single specimen pot can reduce carbon footprint, without an associated deleterious clinical impact.Methods This was a retrospective observational study of colorectal polyps resected during 2019, within the Imperial College Healthcare Trust. The numbers of pots for polypectomy specimens were calculated and corresponding histology results were extracted. We modelled the potential reduction in carbon footprint if all less than 10 mm polyps were sent together and the number of advanced lesions we would not be able to locate if we adopted this strategy. Carbon footprint was estimated based on previous study using a life-cycle assessment, at 0.28 kgCO2e per pot.Results A total of 11 781 lower gastrointestinal endoscopies were performed. There were 5125 polyps removed and 4192 pots used, equating to a carbon footprint of 1174 kgCO2e. There were 4563 (89%) polyps measuring 0–10 mm. 6 (0.1%) of these polyps were cancers, while 12 (0.2%) demonstrated high-grade dysplasia. If we combined all small polyps in a single pot, total pot usage could be reduced by one-third (n=2779).Conclusion A change in practice by placing small polyps collectively in one pot would have resulted in reduction in carbon footprint equivalent to 396 kgCO2e (emissions from 982 miles driven by an average passenger car). The reduction in carbon footprint from judicious use of specimen pots would be amplified with a change in practice on a national level.Data availability statementData are available on reasonable request.

Journal article

Alexander J, Posma J, Scott A, Poynter L, Mason S, Herendi L, Roberts L, McDonald J, Cameron S, Darzi A, Goldin R, Takats Z, Marchesi J, Teare J, Kinross Jet al., 2023, Pathobionts in the tumour microbiota predict survival following resection for colorectal cancer, Microbiome, Vol: 11, Pages: 1-14, ISSN: 2049-2618

Background and aimsThe gut microbiota is implicated in the pathogenesis of colorectal cancer (CRC). We aimed to map the CRC mucosal microbiota and metabolome and define the influence of the tumoral microbiota on oncological outcomes.MethodsA multicentre, prospective observational study was conducted of CRC patients undergoing primary surgical resection in the UK (n = 74) and Czech Republic (n = 61). Analysis was performed using metataxonomics, ultra-performance liquid chromatography-mass spectrometry (UPLC-MS), targeted bacterial qPCR and tumour exome sequencing. Hierarchical clustering accounting for clinical and oncological covariates was performed to identify clusters of bacteria and metabolites linked to CRC. Cox proportional hazards regression was used to ascertain clusters associated with disease-free survival over median follow-up of 50 months.ResultsThirteen mucosal microbiota clusters were identified, of which five were significantly different between tumour and paired normal mucosa. Cluster 7, containing the pathobionts Fusobacterium nucleatum and Granulicatella adiacens, was strongly associated with CRC (PFDR = 0.0002). Additionally, tumoral dominance of cluster 7 independently predicted favourable disease-free survival (adjusted p = 0.031). Cluster 1, containing Faecalibacterium prausnitzii and Ruminococcus gnavus, was negatively associated with cancer (PFDR = 0.0009), and abundance was independently predictive of worse disease-free survival (adjusted p = 0.0009). UPLC-MS analysis revealed two major metabolic (Met) clusters. Met 1, composed of medium chain (MCFA), long-chain (LCFA) and very long-chain (VLCFA) fatty acid species, ceramides and lysophospholipids, was negatively associated with CRC (PFDR = 2.61 × 10−11); Met 2, composed of phosphatidylcholine species, nucleosides and amino acids, was strongly associated with CRC (PFDR&

Journal article

Abbassi-Ghadi N, Antonowicz SS, McKenzie JS, Kumar S, Huang J, Jones EA, Strittmatter N, Petts G, Kudo H, Court S, Hoare JM, Veselkov K, Goldin R, Takáts Z, Hanna GBet al., 2023, Data from &lt;i&gt;De Novo&lt;/i&gt; Lipogenesis Alters the Phospholipidome of Esophageal Adenocarcinoma

<jats:p>&lt;div&gt;Abstract&lt;p&gt;The incidence of esophageal adenocarcinoma is rising, survival remains poor, and new tools to improve early diagnosis and precise treatment are needed. Cancer phospholipidomes quantified with mass spectrometry imaging (MSI) can support objective diagnosis in minutes using a routine frozen tissue section. However, whether MSI can objectively identify primary esophageal adenocarcinoma is currently unknown and represents a significant challenge, as this microenvironment is complex with phenotypically similar tissue-types. Here, we used desorption electrospray ionization-MSI (DESI-MSI) and bespoke chemometrics to assess the phospholipidomes of esophageal adenocarcinoma and relevant control tissues. Multivariate models derived from phospholipid profiles of 117 patients were highly discriminant for esophageal adenocarcinoma both in discovery (AUC = 0.97) and validation cohorts (AUC = 1). Among many other changes, esophageal adenocarcinoma samples were markedly enriched for polyunsaturated phosphatidylglycerols with longer acyl chains, with stepwise enrichment in premalignant tissues. Expression of fatty acid and glycerophospholipid synthesis genes was significantly upregulated, and characteristics of fatty acid acyls matched glycerophospholipid acyls. Mechanistically, silencing the carbon switch &lt;i&gt;ACLY&lt;/i&gt; in esophageal adenocarcinoma cells shortened glycerophospholipid chains, linking &lt;i&gt;de novo&lt;/i&gt; lipogenesis to the phospholipidome. Thus, DESI-MSI can objectively identify invasive esophageal adenocarcinoma from a number of premalignant tissues and unveils mechanisms of phospholipidomic reprogramming.&lt;/p&gt;Significance:&lt;p&gt;These results call for accelerated diagnosis studies using DESI-MSI in the upper gastrointestinal endoscopy suite, as well as functional studies to determine how polyunsaturated phosphatidylglycerols contribute to

Other

Abbassi-Ghadi N, Antonowicz SS, McKenzie JS, Kumar S, Huang J, Jones EA, Strittmatter N, Petts G, Kudo H, Court S, Hoare JM, Veselkov K, Goldin R, Takáts Z, Hanna GBet al., 2023, Supplementary Data from &lt;i&gt;De Novo&lt;/i&gt; Lipogenesis Alters the Phospholipidome of Esophageal Adenocarcinoma

<jats:p>&lt;p&gt;The Supplementary information file contains: (i) Supplementary Methods, concerning PCR primers, antibodies and explanation of the chemometric approach. (ii) Supplementary Figures 1-4, which provide extended data for the multivariable models of Figure 2 and 3, MS/MS analyses, and further gene expression data supporting Figure 5. (iii) Supplementary Tables 1-4, which provide demographics of the cohorts and univariate lipid analyses from Cohort 1 and 2.&lt;/p&gt;</jats:p>

Other

Abbassi-Ghadi N, Antonowicz SS, McKenzie JS, Kumar S, Huang J, Jones EA, Strittmatter N, Petts G, Kudo H, Court S, Hoare JM, Veselkov K, Goldin R, Takáts Z, Hanna GBet al., 2023, Data from &lt;i&gt;De Novo&lt;/i&gt; Lipogenesis Alters the Phospholipidome of Esophageal Adenocarcinoma

<jats:p>&lt;div&gt;Abstract&lt;p&gt;The incidence of esophageal adenocarcinoma is rising, survival remains poor, and new tools to improve early diagnosis and precise treatment are needed. Cancer phospholipidomes quantified with mass spectrometry imaging (MSI) can support objective diagnosis in minutes using a routine frozen tissue section. However, whether MSI can objectively identify primary esophageal adenocarcinoma is currently unknown and represents a significant challenge, as this microenvironment is complex with phenotypically similar tissue-types. Here, we used desorption electrospray ionization-MSI (DESI-MSI) and bespoke chemometrics to assess the phospholipidomes of esophageal adenocarcinoma and relevant control tissues. Multivariate models derived from phospholipid profiles of 117 patients were highly discriminant for esophageal adenocarcinoma both in discovery (AUC = 0.97) and validation cohorts (AUC = 1). Among many other changes, esophageal adenocarcinoma samples were markedly enriched for polyunsaturated phosphatidylglycerols with longer acyl chains, with stepwise enrichment in premalignant tissues. Expression of fatty acid and glycerophospholipid synthesis genes was significantly upregulated, and characteristics of fatty acid acyls matched glycerophospholipid acyls. Mechanistically, silencing the carbon switch &lt;i&gt;ACLY&lt;/i&gt; in esophageal adenocarcinoma cells shortened glycerophospholipid chains, linking &lt;i&gt;de novo&lt;/i&gt; lipogenesis to the phospholipidome. Thus, DESI-MSI can objectively identify invasive esophageal adenocarcinoma from a number of premalignant tissues and unveils mechanisms of phospholipidomic reprogramming.&lt;/p&gt;Significance:&lt;p&gt;These results call for accelerated diagnosis studies using DESI-MSI in the upper gastrointestinal endoscopy suite, as well as functional studies to determine how polyunsaturated phosphatidylglycerols contribute to

Other

Abbassi-Ghadi N, Antonowicz SS, McKenzie JS, Kumar S, Huang J, Jones EA, Strittmatter N, Petts G, Kudo H, Court S, Hoare JM, Veselkov K, Goldin R, Takáts Z, Hanna GBet al., 2023, Supplementary Data from &lt;i&gt;De Novo&lt;/i&gt; Lipogenesis Alters the Phospholipidome of Esophageal Adenocarcinoma

<jats:p>&lt;p&gt;The Supplementary information file contains: (i) Supplementary Methods, concerning PCR primers, antibodies and explanation of the chemometric approach. (ii) Supplementary Figures 1-4, which provide extended data for the multivariable models of Figure 2 and 3, MS/MS analyses, and further gene expression data supporting Figure 5. (iii) Supplementary Tables 1-4, which provide demographics of the cohorts and univariate lipid analyses from Cohort 1 and 2.&lt;/p&gt;</jats:p>

Other

Akama-Garren EHH, Miller P, Carroll TMM, Tellier M, Sutendra G, Buti L, Zaborowska J, Goldin RDD, Slee E, Szele FGG, Murphy S, Lu Xet al., 2023, Regulation of immunological tolerance by the p53-inhibitor iASPP, Cell Death and Disease, Vol: 14, ISSN: 2041-4889

Maintenance of immunological homeostasis between tolerance and autoimmunity is essential for the prevention of human diseases ranging from autoimmune disease to cancer. Accumulating evidence suggests that p53 can mitigate phagocytosis-induced adjuvanticity thereby promoting immunological tolerance following programmed cell death. Here we identify Inhibitor of Apoptosis Stimulating p53 Protein (iASPP), a negative regulator of p53 transcriptional activity, as a regulator of immunological tolerance. iASPP-deficiency promoted lung adenocarcinoma and pancreatic cancer tumorigenesis, while iASPP-deficient mice were less susceptible to autoimmune disease. Immune responses to iASPP-deficient tumors exhibited hallmarks of immunosuppression, including activated regulatory T cells and exhausted CD8+ T cells. Interestingly, iASPP-deficient tumor cells and tumor-infiltrating myeloid cells, CD4+, and γδ T cells expressed elevated levels of PD-1H, a recently identified transcriptional target of p53 that promotes tolerogenic phagocytosis. Identification of an iASPP/p53 axis of immune homeostasis provides a therapeutic opportunity for both autoimmune disease and cancer.

Journal article

Jambulingam N, Forlano R, Preston B, Mullish BH, Portone G, Baheer Y, Yee M, Goldin R, Thursz M, Manousou Pet al., 2023, Metabolic profile reflects stages of fibrosis in patients with non-alcoholic fatty liver disease, International Journal of Molecular Sciences, Vol: 24, Pages: 1-12, ISSN: 1422-0067

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease worldwide, with fibrosis stage being the main predictor for clinical outcomes. Here, we present the metabolic profile of NAFLD patients with regards to fibrosis progression. We included all consecutive new referrals for NAFLD services between 2011 and 2019. Demographic, anthropometric and clinical features and noninvasive markers of fibrosis were recorded at baseline and at follow-up. Significant and advanced fibrosis were defined using liver stiffness measurement (LSM) as LSM ≥ 8.1 kPa and LSM ≥ 12.1 kPa, respectively. Cirrhosis was diagnosed either histologically or clinically. Fast progressors of fibrosis were defined as those with delta stiffness ≥ 1.03 kPa/year (25% upper quartile of delta stiffness distribution). Targeted and untargeted metabolic profiles were analysed on fasting serum samples using Proton nuclear magnetic resonance (1H NMR). A total of 189 patients were included in the study; 111 (58.7%) underwent liver biopsy. Overall, 11.1% patients were diagnosed with cirrhosis, while 23.8% were classified as fast progressors. A combination of metabolites and lipoproteins could identify the fast fibrosis progressors (AUROC 0.788, 95% CI: 0.703–0.874, p < 0.001) and performed better than noninvasive markers. Specific metabolic profiles predict fibrosis progression in patients with nonalcoholic fatty liver disease. Algorithms combining metabolites and lipids could be integrated in the risk-stratification of these patients.

Journal article

Naik SN, Forlano R, Manousou P, Goldin R, Angelini EDet al., 2023, Fibrosis severity scoring on Sirius red histology with multiple-instance deep learning, Biological Imaging, Vol: 3, ISSN: 2633-903X

Non-alcoholic fatty liver disease (NAFLD) is now the leading cause of chronic liver disease, affecting approximately 30% of people worldwide. Histopathology reading of fibrosis patterns is crucial to diagnosing NAFLD. In particular, separating mild from severe stages corresponds to a critical transition as it correlates with clinical outcomes. Deep Learning for digitized histopathology whole-slide images (WSIs) can reduce high inter- and intra-rater variability. We demonstrate a novel solution to score fibrosis severity on a retrospective cohort of 152 Sirius-Red WSIs, with fibrosis stage annotated at slide level by an expert pathologist. We exploit multiple instance learning and multiple-inferences to address the sparsity of pathological signs. We achieved an accuracy of 78:98 ± 5:86%, an F1 score of 77:99 ± 5:64%, and an AUC of 0:87 ± 0:06. These results set new state-of-the-art benchmarks for this application.

Journal article

Imrie H, Viswambharan H, Haywood NJ, Bridge K, Yuldasheva NY, Galloway S, Simmons KJ, Cubbon RM, Sukumar P, Watt NT, Lichtenstein L, Wyatt J, Kudo H, Goldin R, Rode B, Wheatcroft SB, Kearney MTet al., 2022, Cixutumumab reveals a critical role for IGF-1 in adipose and hepatic tissue remodelling during the development of diet-induced obesity, Adipocyte, Vol: 11, Pages: 366-378, ISSN: 2162-3945

High fat diet (HFD)-induced obesity leads to perturbation in the storage function of white adipose tissue (WAT) resulting in deposition of lipids in tissues ill-equipped to deal with this challenge. The role of insulin like growth factor-1 (IGF-1) in the systemic and organ-specific responses to HFD is unclear. Using cixutumumab, a monoclonal antibody that internalizes and degrades cell surface IGF-1 receptors (IGF-1 R), leaving insulin receptor expression unchanged we aimed to establish the role of IGF-1 R in the response to a HFD. Mice treated with cixutumumab fed standard chow developed mild hyperinsulinemia with no change in WAT. When challenged by HFD mice treated with cixutumumab had reduced weight gain, reduced WAT expansion, and reduced hepatic lipid vacuole formation. In HFD-fed mice, cixutumumab led to reduced levels of genes encoding proteins important in fatty acid metabolism in WAT and liver. Cixutumumab protected against blunting of insulin-stimulated phosphorylation of Akt in liver of HFD fed mice. These data reveal an important role for IGF-1 R in the WAT and hepatic response to short-term nutrient excess. IGF-1 R inhibition during HFD leads to a lipodystrophic phenotype with a failure of WAT lipid storage and protection from HFD-induced hepatic insulin resistance.

Journal article

Gilbert A, Homer V, Brock K, Korsgen S, Geh I, Hill J, Gill T, Hainsworth P, Tutton M, Khan J, Robinson J, Steward M, Cunningham C, Kaur M, Magill L, Russell A, Quirke P, West NP, Sebag-Montefiore D, Bach SP, Beveridge A, Levy B, Handley K, Brown G, Antonio P, Vince A, Hilken N, Sidile C, Wilcockson A, Peto R, Crosby T, Moran B, Olliff J, Ashok K, Slawik S, Smethurst A, Sripadam R, Tagore V, Terlizzo M, Philip B, Davies R, Dodd S, Essapen S, Nisar P, Stewart A, Trickett J, Ashish B, Billings P, Chandran P, Corr C, Favill E, Gollins S, Marsh P, Maw A, Neupane R, Rajagopal R, Cooper R, Griffith J, Hatfield P, Lowe A, Ostrowski J, Robinson J, Simpson R, Adams R, Bleehen R, Davies M, Morgan M, Boone D, Lacey N, Seddon I, Sizer B, Stunell H, Wu S, Hadaki M, Blunt D, Cleator S, Darzi A, Goldin R, Ziprin P, Dobson M, Pitt M, Susnerwala S, Williamson D, Howarth G, Lee S, Wright P, Hoare T, Horgan A, McDonald F, Needham S, Scott J, Simmons T, Biswas D, Hernon J, Kapur G, Kapur S, Sington J, Speakman C, Stebbings W, Williams S, Adusumalli M, Agarwal A, Borowski D, Garg D, Gill T, Hegab M, Hobday C, Rao V, Shrimankar J, Tabaqchali M, Wilson D, Jones O, Mortensen N, Slater A, Szuts A, Wang L, Warren B, Weaver A, Ahmad M, Alexander J, Flubacher M, Tarver D, Baluch S, Beable R, Cowlishaw D, Higginson A, Vogiatzis P, Cruickshank N, Joy H, Peake D, Zanetto U, Saunders M, Sun-Myint A, Sripadam R, Cooper R, Hatfield P, Teo M, Allan A, Geh I, Glaholm J, Goldstein M, Hejmadi R, Langman G, Morton D, Nelson C, Tattersall D, Falk S, Longman R, Roach H, Shabbir J, Shelley-Fraser G, Thomas M, Cripps N, Haba Y, Harris G, Hookway M, Simson J, Skull A, Umar Tet al., 2022, Quality-of-life outcomes in older patients with early-stage rectal cancer receiving organ-preserving treatment with hypofractionated short-course radiotherapy followed by transanal endoscopic microsurgery (TREC): non-randomised registry of patients unsuitable for total mesorectal excision, The Lancet Healthy Longevity, Vol: 3, Pages: e825-e838, ISSN: 2666-7568

BackgroundOlder patients with early-stage rectal cancer are under-represented in clinical trials and, therefore, little high-quality data are available to guide treatment in this patient population. The TREC trial was a randomised, open-label feasibility study conducted at 21 centres across the UK that compared organ preservation through short-course radiotherapy (SCRT; 25 Gy in five fractions) plus transanal endoscopic microsurgery (TEM) with standard total mesorectal excision in adults with stage T1–2 rectal adenocarcinoma (maximum diameter ≤30 mm) and no lymph node involvement or metastasis. TREC incorporated a non-randomised registry offering organ preservation to patients who were considered unsuitable for total mesorectal excision by the local colorectal cancer multidisciplinary team. Organ preservation was achieved in 56 (92%) of 61 non-randomised registry patients with local recurrence-free survival of 91% (95% CI 84–99) at 3 years. Here, we report acute and long-term patient-reported outcomes from this non-randomised registry group.MethodsPatients considered by the local colorectal cancer multidisciplinary team to be at high risk of complications from total mesorectal excision on the basis of frailty, comorbidities, and older age were included in a non-randomised registry to receive organ-preserving treatment. These patients were invited to complete questionnaires on patient-reported outcomes (the European Organisation for Research and Treatment of Cancer Quality of Life [EORTC-QLQ] questionnaire core module [QLQ-C30] and colorectal cancer module [QLQ-CR29], the Colorectal Functional Outcome [COREFO] questionnaire, and EuroQol-5 Dimensions-3 Level [EQ-5D-3L]) at baseline and at months 3, 6, 12, 24, and 36 postoperatively. To aid interpretation, data from patients in the non-randomised registry were compared with data from those patients in the TREC trial who had been randomly assigned to organ-preserving therapy, and an additional reference c

Journal article

Al Moussawi K, Chung K, Carroll TM, Osterburg C, Smirnov A, Lotz R, Miller P, Dedeic Z, Zhong S, Oti M, Kouwenhoven EN, Asher R, Goldin R, Tellier M, Murphy S, Zhou H, Dotsch V, Lu Xet al., 2022, Mutant Ras and inflammation-driven skin tumorigenesis is suppressed via a JNK-iASPP-AP1 axis, Cell Reports, Vol: 41, Pages: 1-28, ISSN: 2211-1247

Concurrent mutation of a RAS oncogene and the tumor suppressor p53 is common in tumorigenesis, and inflammation can promote RAS-driven tumorigenesis without the need to mutate p53. Here, we show, using a well-established mutant RAS and an inflammation-driven mouse skin tumor model, that loss of the p53 inhibitor iASPP facilitates tumorigenesis. Specifically, iASPP regulates expression of a subset of p63 and AP1 targets, including genes involved in skin differentiation and inflammation, suggesting that loss of iASPP in keratinocytes supports a tumor-promoting inflammatory microenvironment. Mechanistically, JNK-mediated phosphorylation regulates iASPP function and inhibits iASPP binding with AP1 components, such as JUND, via PXXP/SH3 domain-mediated interaction. Our results uncover a JNK-iASPP-AP1 regulatory axis that is crucial for tissue homeostasis. We show that iASPP is a tumor suppressor and an AP1 coregulator.

Journal article

Forlano R, Stanic T, Jayawardana S, Mullish B, Yee M, Mossialos E, Goldin R, Petta S, Tsochatzis E, Thursz M, Manousou Pet al., 2022, Clinical and cost-effectiveness analysis of community-based screening strategies for non-alcoholic fatty liver disease in patients with type-2 diabetes mellitus

<jats:title>Abstract</jats:title> <jats:p>Background &amp; Aims: We investigated the prevalence of non-alcoholic fatty liver disease(NAFLD) in patients with type 2 diabetes mellitus(T2DM) in primary care and developed a risk-stratification pathway. We also assessed the cost-utility of different screening strategies for NAFLD in the diabetic community.Methods Consecutive T2DM patients underwent screening for liver diseases, including liver stiffness measurement(LSM). Binary logistic was used to predict factors associated with significant fibrosis. We used independent predictors of significant and advanced fibrosis to generate a predictive score for this population (BIMAST),and validated it internally and externally. Five screening strategies were compared against standard of care (SOC): BIMAST score, ultrasound plus abnormal liver function tests, FIB-4, NAFLD fibrosis score, and fibroscan. A Markov model was built upon four health states based on fibrosis status. We generated the cost per quality-adjusted life year(QALY) gained and calculated the incremental cost-effectiveness ratio (ICER) in the base-case analysis conducted over a lifetime horizon.Results Among 300 patients enrolled (287 included), 64% (186) had NAFLD and 10% (28) other causes of liver disease. Patients with significant fibrosis, advanced fibrosis, and cirrhosis due to NAFLD accounted for 17% (50/287), 11% (31/287), and 3% (8/287), respectively. BIMAST score validation showed an excellent diagnostic performance in primary care improving false negatives from 38–10% compared to FIB-4. In the cost-utility analysis, ICER was £2,337.92/QALY for BIMAST and £2,480/QALY for fibroscan. When transition probabilities, utilities, screening effect, and cost inputs were modified, we found a &gt; 99% probability of NAFLD screening tests being cost-effective compared to SOC in all evaluated scenarios.Conclusion Screening for NAFLD in diabetic patient

Journal article

McPherson S, Armstrong MJ, Cobbold JF, Corless L, Anstee QM, Aspinall RJ, Barclay ST, Brennan PN, Cacciottolo TM, Goldin RD, Hallsworth K, Hebditch V, Jack K, Jarvis H, Johnson J, Li W, Mansour D, McCallum M, Mukhopadhya A, Parker R, Ross V, Rowe IA, Srivastava A, Thiagarajan P, Thompson A, Tomlinson J, Tsochatzis EA, Yeoman A, Alazawi Wet al., 2022, Quality standards for the management of non-alcoholic fatty liver disease (NAFLD): consensus recommendations from the British Association for the Study of the Liver and British Society of Gastroenterology NAFLD Special Interest Group, The Lancet Gastroenterology & Hepatology, Vol: 7, Pages: 755-769, ISSN: 2468-1253

Non-alcoholic fatty liver disease (NAFLD) is common, affecting approximately 25% of the general population. The evidence base for the investigation and management of NAFLD is large and growing, but there is currently little practical guidance to support development of services and delivery of care. To address this, we produced a series of evidence-based quality standard recommendations for the management of NAFLD, with the aim of improving patient care. A multidisciplinary group of experts from the British Association for the Study of the Liver and British Society of Gastroenterology NAFLD Special Interest Group produced the recommendations, which cover: management of people with, or at risk of, NAFLD before the gastroenterology or liver clinic; assessment and investigations in secondary care; and management in secondary care. The quality of evidence for each recommendation was evaluated by the Grading of Recommendation Assessment, Development and Evaluation tool. An anonymous modified Delphi voting process was conducted individually by each member of the group to assess the level of agreement with each statement. Statements were included when agreement was 80% or greater. From the final list of statements, a smaller number of auditable key performance indicators were selected to allow services to benchmark their practice. It is hoped that services will review their practice against our recommendations and key performance indicators and institute service development where needed to improve the care of patients with NAFLD.

Journal article

Hong AS, Sarwar N, Goldin RD, Dhar A, Possamai LAet al., 2022, Pembrolizumab-Induced Pancreatic Exocrine Insufficiency Complicated by Severe Hepatic Steatosis, Cureus, Vol: 14, ISSN: 2168-8184

Anti-programmed death receptor-1 (anti-PD-1) monoclonal antibodies (mAbs) are used to treat an increasing range of cancers. However, the distinct toxicity profile of immune-related adverse events (irAEs) is a frequent drawback of their clinical application. Among the more common irAEs are hepatitis and colitis, which are diagnosed and graded in patients based on elevated serum liver enzyme levels and increased stool frequency, respectively, and both of which often require treatment with high-dose corticosteroids. Herein, we describe the case of a patient who developed severe transaminase elevation and diarrhoea due to an unusual irAE, which was successfully treated without corticosteroids.

Journal article

Vergis N, Patel VC, Bogdanowicz K, Czyzewska-Khan J, Keshinro R, Fiorentino F, Day E, Middleton P, Atkinson S, Cross M, Babalis D, Foster N, Quaglia A, Lloyd J, Goldin RD, Rosenberg W, Parker R, Richardson P, Masson S, Whitehouse G, Sieberhagen C, Patch D, Dhanda A, Lord E, Forrest E, Naoumov N, Thursz Met al., 2022, Il-1beta Signal Inhibition in acute alcoholic hepatitis: a multicentre, randomised, double-blind, placebo-controlled phase 2 trial of canakinumab therapy (ISAIAH), Publisher: ELSEVIER, Pages: S34-S35, ISSN: 0168-8278

Conference paper

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