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Immunotherapy is now the standard of care for advanced hepatocellular carcinoma (HCC), yet many patients fail to respond. A major unmet goal is the boosting of T-cells with both strong HCC reactivity and the protective advantages of tissue-resident memory T-cells (T RM ). Here, we show that higher intratumoural frequencies of γδ T-cells, which have potential for HLA-unrestricted tumour reactivity, associate with enhanced HCC patient survival. We demonstrate that γδ T-cells exhibit bona fide tissue-residency in human liver and HCC, with γδT RM showing no egress from hepatic vasculature, persistence for >10 years and superior anti-tumour cytokine production. The Vγ9Vδ2 T-cell subset is selectively depleted in HCC but can efficiently target HCC cell lines sensitised to accumulate isopentenyl-pyrophosphate by the aminobisphosphonate Zoledronic acid. Aminobisphosphonate-based expansion of peripheral Vγ9Vδ2 T-cells recapitulates a T RM  phenotype and boosts cytotoxic potential. Thus, our data suggest more universally effective HCC immunotherapy may be achieved by combining aminobisphosphonates to induce Vγ9Vδ2T RM capable of replenishing the depleted pool, with additional intratumoural delivery to sensitise HCC to Vγ9Vδ2T RM -based targeting. Many cancer immune therapy approaches depend on an HLA-restricted neoantigen-specific T cell response. AUs show here that Zoledronic acid can expand, and induce tumour recognition by, a population of tissue resident memory gamma-delta T cells associated with an efficient anti-tumour immune response in hepatocellular carcinoma.

Determining divergent metabolic requirements of T cells, and the viruses and tumours they fail to combat, could provide new therapeutic checkpoints. Inhibition of acyl-CoA:cholesterol acyltransferase (ACAT) has direct anti-carcinogenic activity. Here, we show that ACAT inhibition has antiviral activity against hepatitis B (HBV), as well as boosting protective anti-HBV and anti-hepatocellular carcinoma (HCC) T cells. ACAT inhibition reduces CD8 +  T cell neutral lipid droplets and promotes lipid microdomains, enhancing TCR signalling and TCR-independent bioenergetics. Dysfunctional HBV- and HCC-specific T cells are rescued by ACAT inhibitors directly ex vivo from human liver and tumour tissue respectively, including tissue-resident responses. ACAT inhibition enhances in vitro responsiveness of HBV-specific CD8 + T cells to PD-1 blockade and increases the functional avidity of TCR-gene-modified T cells. Finally, ACAT regulates HBV particle genesis in vitro, with inhibitors reducing both virions and subviral particles. Thus, ACAT inhibition provides a paradigm of a metabolic checkpoint able to constrain tumours and viruses but rescue exhausted T cells, rendering it an attractive therapeutic target for the functional cure of HBV and HBV-related HCC. Shared metabolic pathways could allow simultaneous manipulation of T cells, viruses and tumours. Here the authors show targeting cholesterol esterification restrains hepatitis B in vitro, whilst bolstering exhausted antigen-specific T cell responses from human liver and hepatocellular carcinoma.

Background Acute-on-chronic liver failure (ACLF) is a severe complication of cirrhosis and is defined by organ failure and high rates of short-term mortality. Patients with ACLF are managed with multiorgan support in the intensive care unit (ICU). Currently, it is unclear when this supportive care becomes futile, particularly in patients who are not candidates for liver transplant. The aim of this study was to determine whether the currently available prognostic scores can identify patients with ACLF in whom prolonged ICU care is likely to be futile despite maximal treatment efforts. Methods Data of 202 consecutive patients with ACLF admitted to the ICU at the Royal Free Hospital London between 2005 and 2012 were retrospectively analyzed. Prognostic scores for chronic liver diseases, such as Child-Pugh, Model for End-Stage Liver Disease (MELD), European Foundation for the study of chronic liver failure (CLIF-C) organ failure (OF), and CLIF-C ACLF, were calculated 48 hours after ICU admission and correlated with patient outcome after 28 days. Results The CLIF-C ACLF score, compared with all other scores, most accurately predicted 28-day mortality, with an area under the receiver operator characteristic of 0.8 (CLIF-C OF, 0.75; MELD, 0.68; Child-Pugh, 0.66). A CLIF-C ACLF score cutoff ≥ 70 identified patients with a 100% mortality within 28 days. These patients had elevated inflammatory parameters representing a systemic inflammatory response, most often renal failure, compared with patients below this cutoff. Conclusions Patients with ACLF and high CLIF-C ACLF score (≥ 70) after 48 hours of intensive care may reach a threshold of futility for further ongoing intensive support. The best treatment options in this scenario remain to be determined but may include palliative care.

Background Advanced hepatocellular carcinoma (HCC) is commonly diagnosed using non-invasive radiological criteria (NIRC) defined by the European Association for the Study of the Liver or the American Association for the Study of Liver Diseases. In 2017, The National Institute for Clinical Excellence mandated histological confirmation of disease to authorise the use of sorafenib in the UK. Methods This was a prospective multicentre audit in which patients suitable for sorafenib were identified at multidisciplinary meetings. The primary analysis cohort (PAC) was defined by the presence of Child-Pugh class A liver disease and performance status 0–2. Clinical, radiological and histological data were reported locally and collected on a standardised case report form. Results Eleven centres reported 418 cases, of which 361 comprised the PAC. Overall, 76% had chronic liver disease and 66% were cirrhotic. The diagnostic imaging was computed tomography in 71%, magnetic resonance imaging in 27% and 2% had both. Pre-existing histology was available in 45 patients and 270 underwent a new biopsy, which confirmed HCC in 93.4%. Alternative histological diagnoses included cholangiocarcinoma (CC) and combined HCC-CC. In cirrhotic patients, NIRC criteria had a sensitivity of 65.4% and a positive predictive value of 91.4% to detect HCC. Two patients (0.7%) experienced mild post-biopsy bleeding. Conclusion The diagnostic biopsy is safe and feasible for most patients eligible for systemic therapy

Background Stereotactic ablative radiotherapy (SABR) has emerged as a new treatment modality for hepatocellular carcinoma (HCC). Evaluation of tumour responses following SABR are currently based on conventional radiological criteria used for locoregional therapies. Whether these criteria accurately reflect tumour responses following SABR remains unknown. In this study, we provide a direct comparison of post-SABR radiological evaluation and explant histology for patients with HCC who underwent bridging SABR prior to liver transplantation. Methods Patients with HCC who received SABR as bridging therapy prior to liver transplantation (January 2016-December 2022) in a large UK liver transplant centre were included. Post-SABR imaging was reported by two specialist hepato-pancreato-biliary radiologists, and histological examination of the explanted liver was performed by experienced liver histopathologists. Results Six patients with residual active HCC received SABR as bridging therapy prior to undergoing liver transplantation in our cohort. Of five patients with viable HCC detected on explant histology, recent radiological evaluation using LI-RADS treatment response criteria had suggested no evidence of residual active HCC for three patients, difficulty delineating residual disease from post-radiotherapy changes for one patient, and accurately identified viable tumour in one patient. Conclusion In our case series conventional radiological criteria underestimated HCC tumour viability following SABR compared to explant histology. As the role for SABR expands in the management of HCC, caution is needed with radiological interpretation of HCC responses to radiotherapy using standard LI-RADS criteria. Prospective study in a larger cohort is required to identify radiological criteria capable of more conclusively evaluating HCC responses to SABR.

IntroductionAntibiotic therapy is routinely used to eradicate Helicobacter pylori (Hp) infection, but emerging antibiotic resistance is a considerable concern. This study aimed to determine the prevalence of antibiotic resistance in high-risk patients undergoing upper gastrointestinal (GI) endoscopy and to identify potential predictive factors.MethodsThe retrospective study cohort comprised of all patients with recurrent/previous Hp infection undergoing upper GI endoscopy at the Royal Free Hospital (RFH), London between 2009 and 2019. Demographic, clinical, socioeconomic data and self-reported ethnic origin were retrieved from the medical records. Deprivation scores were based on postcode using the 2019 English Indices of Deprivation and decile rankings. The results of gastro/duodenal biopsy microscopy, culture and sensitivity testing were retrieved.ResultsA total of 408 patients (60% female, mean±1SD age 40.9±20.8 yr) were included; 118 (28.9%) were Hp culture positive while 290 were culture negative. There were no age or sex differences between the two cohorts; significantly fewer Hp positive patients were Caucasian (28% vs. 43%; p=0.039) and significantly more were classified as deprived (68% vs. 57%; p=0.031). Non-Caucasian origin (p=0.040) and greater deprivation (p=0.031) were significant independent predictors of Hp infection. Antibiotic resistance profiles were available in 115 patients; of these eight were fully sensitive but 107 (93.0%) exhibited antibiotic resistance, most commonly to metronidazole (100/111;90.1%) or clarithromycin (82/115;71.3%) or both (75/111;67.6%); resistance was also observed to tetracycline (3/113; 2.7%); amoxicillin (9/108; 8.3%); levofloxacin (20/111;18.0%) and rifabutin (8/26;30.8%). Overall, 81/107 (68.6%) cultures exhibited resistance to two or more antibiotics. Older age (p=0.009), greater deprivation (p=0.002), Caucasian origin (p=0.027) and use of PPIs (p=0.030) were significant independent predictors of antibiotic resistance but the number of failed eradication episodes was not.ConclusionNon-Caucasian origin and greater deprivation were identified as independent risk factors for the development of Hp infection while Caucasian origin, greater deprivation, older age and use of PPIs were independent risk factors for the development of antibiotic resistance. High levels of resistance were observed to the commonly used first and second line antibiotics in the majority of culture positive patients. In consequence wider use of culture and sensitivity testing of gastric biopsies in Hp positive patients should be advocated.

IntroductionAcute upper gastrointestinal bleeding (AUGIB) is a common complication of peptic ulcer disease (PUD) defined as not only peptic ulceration but also erosive gastritis and duodenitis, Helicobacter pylori (H. pylori) infection is the major cause of PUD. NICE guidelines recommend that patients identified with PUD should be tested and treated for H pylori if infected. Post-eradication testing is mandated to confirm successful eradication. The aim of this study was to determine compliance with national guidelines for the management of H. pylori in those with PUD-associated AUGIB.MethodsRetrospective data were collected on all patients presenting to the Royal Free Hospital, London, with non-variceal AUGIB between 1 January and 31 December 2017. Prospective data were collected between 1 February and 1 April 2018. Compliance with guidelines was judged using predetermined criteria and classified as: poor (<67% compliance); moderate (67–75%); good (>75%); or excellent (>90%).ResultsA total of 203 patients presented with non-variceal AUGIB during 2017, of whom 148 underwent endoscopy. Sixty-seven of those endoscoped met criteria for H. pylori testing but only 35 (52.2%) were investigated despite an absence of active bleeding or high-risk stigmata (compliance poor) (table 1). Of the 32 cases not tested, 22 exhibited overt ulceration at endoscopy, with the remaining cases demonstrating erosive changes. Four of the 55 non-endoscoped patients were tested for H pylori by other means. Overall, 15 (38.5%) of the 39 patients investigated tested positive for H pylori; 14 (93.3%) were prescribed eradication therapy (compliance excellent) while a further five patients were treated empirically. Of the 19 treated patients, only nine (47.4%) underwent post-eradication testing (compliance poor); all however tested negative. Prospective compliance rates in 36 patients exhibited similar poor compliance although samples were small (table 1).Abstract PTU-066 Table 1Management of H. pylori and compliance with associated NICE guidelines Management Step NICE Guideline Study Eligible (n) Performed (n) Compliance (%) Endoscopic detection Test for H. pylori if evidence of PUD R 67 35 Poor (52.2%) P 9 5 Poor (55.6%) Eradication therapy Offer those testing positive eradication therapy R 15 14 Excellent (93.3%) P 3 2 Poor (66.7%) Post-Eradication Testing Re-test using a C13 urea breath test. R 19 8 Poor (42.1%) P 2 0 Poor (0%) R = Retrospective, P = ProspectiveConclusionApproximately 50% of patients presenting with AUGIB with endoscopic features of PUD were not tested for H. pylori. Almost 40% of those who were tested were infected. Post-eradication investigation rates were particularly low. No clear explanation for this level of non-compliance with guidelines is apparent but enforcement is clearly warranted.

Purpose of Review Previous perceptions of cirrhosis as a hypocoagulable state have resulted in empirical blood product transfusions prior to invasive procedures. We evaluate procedure-related bleeding risks in patients with cirrhosis, assess the utility of conventional and newer global coagulation tests, and explore evidence surrounding prophylactic transfusion strategies. Recent Findings Recent literature supports the concept of a rebalanced, albeit fragile, haemostasis equilibrium in cirrhosis, with a potential hypercoagulable tendency in stable patients. Standard coagulation tests provide a poor reflection of bleeding risks and yet are relied upon for transfusion thresholds. Consequently, a sizeable proportion of patients receive unnecessary blood products. The role of viscoelastic tests to guide transfusions requires further evaluation. Summary In stable cirrhotic patients, procedure-related bleeding rates appear low. Prophylactic transfusion strategies based on arbitrary thresholds lack evidence of clinical benefit. There is a pressing need for point-of-care coagulation tests that represent the complex coagulopathy of cirrhosis and well-powered randomised controlled trials to develop evidence-based pre-procedure transfusion guidelines.

More effective immunotherapeutic strategies are urgently needed for hepatocellular carcinoma (HCC). Gamma delta (γδ) T cells are attractive candidates for cancer immunotherapy with potential for HLA-unrestricted tumour reactivity. In this thesis, I characterise the phenotypic and functional profiles of tissue-resident memory (TRM) Vδ1 and Vδ2 T cells in human liver, examine their potential contributions to immunosurveillance in HCC, and explore therapeutic strategies to enhance the anti-tumour potential of Vγ9Vδ2 TRM cells for immunotherapy for HCC. I find that Vδ1 and Vδ2 T cells exhibit a bona fide TRM phenotype in human liver (CD69+CD49a+ and/or CD103+) with increased expression of the liver-homing chemokine receptors CXCR6 and CXCR3. Vδ1 and Vδ2 TRM cells show no egress from hepatic vasculature, demonstrate long-lived persistence in the liver for over a decade, and display superior anti-tumour cytokine production. Higher intratumoural γδ T cell counts in HCC are associated with smaller tumour size and longer patient survival. Vδ1 T cells display a more activated phenotype in HCC, while Vγ9Vδ2 T cells appear selectively depleted but maintain high IFN-γ production and equivalent capabilities to acquire an intratumoural γδ TRM phenotype. I demonstrate that intrahepatic and intratumoural Vγ9Vδ2 TRM cells efficiently target HCC cell lines (HepG2 or HuH7) sensitised to accumulate isopentenyl-pyrophosphate by the aminobisphosphonate Zoledronic acid (ZOL). In vitro expansion of blood Vγ9Vδ2 T cells using ZOL and IL-2 recapitulates a de novo TRM phenotype with enhanced cytotoxic potential. Using an in vivo murine model, adoptive cell transfer of ZOL-expanded Vγ9Vδ2 T cells combined with intratumoural ZOL sensitisation induces the greatest HepG2 tumour regression. In conclusion, intrahepatic γδ TRM cells demonstrate beneficial and long-lived immunotherapeutic properties. Future trials could explore a dual immunotherapeutic strategy using aminobisphosphonates to induce Vγ9Vδ2 TRM cells capable of replenishing the depleted pool in HCC, with additional intra-tumoral delivery of aminobisphosphonates to sensitise HCC for more efficient Vγ9Vδ2 TRM based targeting.

IntroductionRecent literature supports the paradigm of a rebalanced, although fragile, haemostasis equilibrium in compensated cirrhosis, poorly reflected by standard coagulation tests. We performed thromboelastography (TEG) to evaluate the global haemostatic profile of patients with stable decompensated cirrhosis, assessing for correlation with liver disease severity. We examined whether portal venous blood displayed an increased pro-thrombotic profile in comparison to peripheral and hepatic venous blood, potentially contributing to the high incidence of portal venous thrombosis in cirrhosis.Methods18 cirrhotic patients undergoing transjugular intrahepatic portosystemic shunt procedures for refractory ascites or previous variceal bleeding were prospectively studied. Exclusion criteria included recent anticoagulation, infection or variceal bleeding (within two weeks), haematological disorders, or splanchnic venous thrombosis. Reaction time (R), kinetic time (K), alpha-angle, and maximum amplitude (MA) were measured in citrated portal, hepatic and peripheral venous blood using TEG Haemostasis Analyser 5000. Correlations were assessed with platelet count, prothrombin time (PT), international normalised ratio (INR), activated partial thromboplastin time (APTT), fibrinogen concentration; and evaluated against liver disease severity scores. Statistical analysis was performed using SPSSv24.ResultsPatients were predominantly male (61%), with Child Pugh B cirrhosis (89%), mean MELD score 11.6±3.6. A frequent hypercoagulable profile was demonstrated (shortened R-time in 89% of patients, shortened K-time in 69%, increased alpha-angle in 81%), despite a prolonged INR, PT, APTT in 56–61% of patients. R-time (reflecting soluble clotting factors concentration) did not significantly correlate with INR or PT. MA (associated with platelet number/function) was normal in 83% of patients, despite thrombocytopenia present in 56%. Portal venous blood displayed a comparable TEG profile to peripheral and hepatic venous blood. The MA parameter of TEG demonstrated the strongest correlation with UKELD (r=-0.7, p=0.001) and MELD (r=-0.6, p=0.02) scores.ConclusionOur cohort of decompensated cirrhotic patients displayed an overall hypercoagulable TEG profile, despite co-existing thrombocytopenia and a prolonged INR, PT and APTT, demonstrating poor representation of the global haemostatic profile by standard coagulation tests. TEG in peripheral venous blood accurately reflected the haemostatic profile of portal venous blood. TEG parameters correlated with liver disease severity scores in spite of poor representation by INR within these scores, thus the potential benefit of utilising TEG for liver disease severity assessment in routine clinical practice warrants further evaluation.