Publications
473 results found
Pinato DJ, Kaneko T, DAlessio A, et 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.
Miller P, Akama-Garren EH, Owen RP, et al., 2023, p53 inhibitor iASPP is an unexpected suppressor of KRAS and inflammation-driven pancreatic cancer., Cell Death Differ, Vol: 30, Pages: 1619-1635
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.
Yong KK, He Y, Cheung HCA, et 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.
Abbassi-Ghadi N, Antonowicz SS, McKenzie JS, et al., 2023, Data from <i>De Novo</i> Lipogenesis Alters the Phospholipidome of Esophageal Adenocarcinoma
<jats:p><div>Abstract<p>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 <i>ACLY</i> in esophageal adenocarcinoma cells shortened glycerophospholipid chains, linking <i>de novo</i> 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.</p>Significance:<p>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
Abbassi-Ghadi N, Antonowicz SS, McKenzie JS, et al., 2023, Supplementary Data from <i>De Novo</i> Lipogenesis Alters the Phospholipidome of Esophageal Adenocarcinoma
<jats:p><p>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.</p></jats:p>
Abbassi-Ghadi N, Antonowicz SS, McKenzie JS, et al., 2023, Data from <i>De Novo</i> Lipogenesis Alters the Phospholipidome of Esophageal Adenocarcinoma
<jats:p><div>Abstract<p>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 <i>ACLY</i> in esophageal adenocarcinoma cells shortened glycerophospholipid chains, linking <i>de novo</i> 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.</p>Significance:<p>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
Abbassi-Ghadi N, Antonowicz SS, McKenzie JS, et al., 2023, Supplementary Data from <i>De Novo</i> Lipogenesis Alters the Phospholipidome of Esophageal Adenocarcinoma
<jats:p><p>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.</p></jats:p>
Akama-Garren EHH, Miller P, Carroll TMM, et al., 2023, Regulation of immunological tolerance by the p53-inhibitor iASPP, CELL DEATH & DISEASE, Vol: 14, ISSN: 2041-4889
Jambulingam N, Forlano R, Preston B, et 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.
McGenity C, Randell R, Bellamy C, et al., 2023, Survey of liver pathologists to assess attitudes towards digital pathology and artificial intelligence, Journal of Clinical Pathology, 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.
Imrie H, Viswambharan H, Haywood NJ, et 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.
Gilbert A, Homer V, Brock K, et 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
Al Moussawi K, Chung K, Carroll TM, et 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.
Forlano R, Stanic T, Jayawardana S, et 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 & 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 > 99% probability of NAFLD screening tests being cost-effective compared to SOC in all evaluated scenarios.Conclusion Screening for NAFLD in diabetic patient
McPherson S, Armstrong MJ, Cobbold JF, et 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.
Hong AS, Sarwar N, Goldin RD, et 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.
D'Alessio A, Pai M, Spalding D, et al., 2022, PRIME-HCC: phase Ib study of neoadjuvant ipilimumab and nivolumab prior to liver resection for hepatocellular carcinoma, International Liver Congress, Publisher: ELSEVIER, Pages: S108-S109, ISSN: 0168-8278
Vergis N, Hall I, Arthurs C, et al., 2022, In severe alcohol-related hepatitis, hepatocyte ballooning correlates with expression of p16 and components of a secretory phenotype that has been associated with cellular senescence, International Liver Congress, Publisher: ELSEVIER, Pages: S132-S132, ISSN: 0168-8278
Vergis N, Patel VC, Bogdanowicz K, et 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
D'Alessio A, Pai M, Spalding D, et al., 2022, Preliminary results from a phase Ib study of neoadjuvant ipilimumab plus nivolumab prior to liver resection for hepatocellular carcinoma: The PRIME-HCC trial., Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0732-183X
Habboub N, Forlano R, Goldin R, et al., 2022, EXAMINING THE CORRELATION OF HISTOLOGICAL FEATURES OF NAFLD WITH A POLYMETABOLIC RISK SCORE FOR PREDICTING PATIENTS WITH NAFLD, GASTROENTEROLOGY, Vol: 162, Pages: S1271-S1271, ISSN: 0016-5085
Arjmand A, Tsakai O, Christou V, et al., 2022, Ensemble convolutional neural network classification for pancreatic steatosis assessment in biopsy images, Information, Vol: 13, Pages: 1-21, ISSN: 2078-2489
Non-alcoholic fatty pancreas disease (NAFPD) is a common and at the same time not extensively examined pathological condition that is significantly associated with obesity, metabolic syndrome, and insulin resistance. These factors can lead to the development of critical pathogens such as type-2 diabetes mellitus (T2DM), atherosclerosis, acute pancreatitis, and pancreatic cancer. Until recently, the diagnosis of NAFPD was based on noninvasive medical imaging methods and visual evaluations of microscopic histological samples. The present study focuses on the quantification of steatosis prevalence in pancreatic biopsy specimens with varying degrees of NAFPD. All quantification results are extracted using a methodology consisting of digital image processing and transfer learning in pretrained convolutional neural networks for the detection of histological fat structures. The proposed method is applied to 20 digitized histological samples, producing an 0.08% mean fat quantification error thanks to an ensemble CNN voting system and 83.3% mean Dice fat segmentation similarity compared to the semi-quantitative estimates of specialist physicians.
Forrest E, Goldin R, 2022, Letter: the value of quality liver biopsy before initiation of corticosteroids for severe alcoholic hepatitis-authors' reply, ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Vol: 55, Pages: 1072-1072, ISSN: 0269-2813
Muhammed A, D'Alessio A, Enica A, et al., 2022, Predictive biomarkers of response to immune checkpoint inhibitors in hepatocellular carcinoma, EXPERT REVIEW OF MOLECULAR DIAGNOSTICS, Vol: 22, Pages: 253-264, ISSN: 1473-7159
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Atkinson SR, Aly M, Remih K, et al., 2022, Serum keratin 19 (CYFRA21-1) is a prognostic biomarker in severe alcoholic hepatitis, LIVER INTERNATIONAL, Vol: 42, Pages: 1049-1057, ISSN: 1478-3223
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Lo J, Cozzetto D, Madgwick M, et al., 2022, Immune checkpoint inhibitor-induced colitis is mediated by polyfunctional lymphocytes and is dependent on the IL23/IFNg axis, Publisher: Research Square
Immune checkpoint inhibitors (CPIs) have revolutionised cancer treatment, with previously untreatable disease now amenable to potential cure. Combination regimens of anti-CTLA-4 and anti-PD-1 show enhanced efficacy but are prone to off-target immune-mediated tissue injury, particularly at the barrier surfaces. CPI-induced colitis is a common and serious complication. To probe the impact of immune checkpoints on intestinal homeostasis, mice were challenged with combination anti-CTLA-4/anti-PD-1 immunotherapy and manipulation of the intestinal microbiota. Colonic immune responses were profiled using bulk and single-cell RNA-sequencing and flow cytometry. CPI-colitis was dependent on the composition of the intestinal microbiota and was characterized by remodelling of mucosal lymphocytes with induction of polyfunctional lymphocyte responses characterized by increased expression of interferon-γ (IFNγ), other pro-inflammatory cytokines/chemokines (Il22, Il17a Ccl3, Ccl4 and Ccl9), cytotoxicity molecules (Gzmb, Gzma, Prf1, Nkg7) and the chemokine receptor Cxcr6. In comparison with mucosal lymphocytes in the steady state, polyfunctional lymphocytes from both CD4+ and CD8+ lineages upregulated costimulatory molecules and checkpoint molecules in CPI-colitis, indicating that these cells are tightly regulated. CPI-colitis was attenuated following depletion of effector lymphocytes or following blockade of the IL23/IFNγ axis. This study provides new mechanistic insights into CPI-colitis, identifying polyfunctional, cytotoxic lymphocytes as key mediators of disease. Therapeutic targeting of their effector response or regulatory networks, including the IL23/IFNγ axis likely holds the key to preventing and reversing CPI-colitis.
Forlano R, Mullish BH, Dhar A, et al., 2021, Liver function tests and metabolic-associated fatty liver disease: Changes in upper normal limits, does it really matter?, World Journal of Hepatology, Vol: 13, Pages: 2104-2112, ISSN: 1948-5182
BACKGROUND: Metabolic-associated fatty liver disease (MAFLD) is the commonest cause of abnormal liver function tests (LFTs). Current upper normal of limit (UNL) of LFTs was derived from a “healthy” population, where undiagnosed MAFLD and viral hepatitis might be suspected.AIM :To evaluated potential implications of changes in UNL of alanine aminotrans-ferase (ALT) in MAFLD.METHODS:We retrospectively assessed consecutive first referrals with a diagnosis of MAFLD from 2010 to 2017. The conventional UNL of ALT was 45 IU/L for men and 34 IU/L for women, while a low UNL of ALT was 30 IU/L for men and 19 IU/L for women. The UNL of aspartate aminotransferase (AST) was 40 IU/L.RESULTS:Total 436 patients were enrolled; of these, 288 underwent liver biopsy. Setting a lower UNL reduced the percentage of those with significant disease despite normal ALT; specifically, patients with advanced fibrosis (F ≥ F3) or definite “metabolic-associated steato-hepatitis (MASH)” (NAS ≥ 5) within normal ALT decreased from 10% to 1% and from 28% to 4% respectively. However, the proportion of those with elevated ALT and no evidence of advanced fibrosis or “definite MASH” increased from 39% to 47% and from 3% to 19%. Overall, LFTs performed poorly in distinguishing “definite MASH” from simple steatosis (receiver operating characteristic areas under the curves 0.59 for ALT and 0.55 for AST).CONCLUSION:Liver function tests might both under- and overestimate MASH-related liver disease. Reducing the UNL might not be beneficial and imply an increase in healthcare burden. Risk stratification in MAFLD should rely on a combination of risk factors, not on LFTs alone.
Maclean D, Tsakok M, Gleeson F, et al., 2021, Comprehensive Imaging Characterization of Colorectal Liver Metastases, FRONTIERS IN ONCOLOGY, Vol: 11, ISSN: 2234-943X
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Strittmatter N, Kanvatirth P, Inglese P, et al., 2021, Holistic characterization of a salmonella typhimurium infection model using integrated molecular imaging., Journal of the American Society for Mass Spectrometry, Vol: 32, Pages: 2791-2802, ISSN: 1044-0305
A more complete and holistic view on host-microbe interactions is needed to understand the physiological and cellular barriers that affect the efficacy of drug treatments and allow the discovery and development of new therapeutics. Here, we developed a multimodal imaging approach combining histopathology with mass spectrometry imaging (MSI) and same section imaging mass cytometry (IMC) to study the effects of Salmonella Typhimurium infection in the liver of a mouse model using the S. Typhimurium strains SL3261 and SL1344. This approach enables correlation of tissue morphology and specific cell phenotypes with molecular images of tissue metabolism. IMC revealed a marked increase in immune cell markers and localization in immune aggregates in infected tissues. A correlative computational method (network analysis) was deployed to find metabolic features associated with infection and revealed metabolic clusters of acetyl carnitines, as well as phosphatidylcholine and phosphatidylethanolamine plasmalogen species, which could be associated with pro-inflammatory immune cell types. By developing an IMC marker for the detection of Salmonella LPS, we were further able to identify and characterize those cell types which contained S. Typhimurium.
Vergis N, Patel V, Bogdanowicz K, et al., 2021, IL-1 Signal Inhibition In Alcoholic Hepatitis (ISAIAH): a study protocol for a multicentre, randomised, placebo controlled trial to explore the potential benefits of canakinumab in the treatment of alcoholic hepatitis, Trials, Vol: 22, Pages: 1-16, ISSN: 1745-6215
Background: Alcohol consumption causes a spectrum of liver abnormalities and leads to over 3 million deaths per year. Alcoholic hepatitis (AH) is a florid presentation of alcoholic liver disease characterized by liver failure in the context of recent and heavy alcohol consumption. The aim of this study is to explore the potential benefits of the IL-1β antibody, Canakinumab, in the treatment of AH.Methods: This is multicentre, double-blind, randomised placebo-controlled trial. Participants will be diagnosed with AH using clinical criteria. Liver biopsy will then confirm that all histological features of AH are present. Up to 58 participants will be recruited into two groups from 15 centres in the United Kingdom. Patients will receive an infusion of Canakinumab or matched placebo by random 1:1 allocation. The primary outcome is reduction in lobular inflammation, comparing histological appearances at baseline with appearances at 28 days. Patients with evidence of ongoing disease activity will receive a second infusion of Canakinumab or placebo. Participants will be followed up for 90 days. Secondary outcomes include mortality and change in MELD score at 90 days. Discussion: This phase II study will explore the benefits of the IL-1β antibody, canakinumab, in the treatment of AH to provide proof of concept that inhibition of IL-1β signaling may improve histology and survival for patients with AH. Trial registration: Prospectively registered with EudraCT 2017-003724-79.
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