NIHR Birmingham Liver Biomedical Research Unit

The liver is the commonest site of metastases in neuroendocrine neoplasias (NENs) and is an independent predictor of poor outcome. Selective internal radiation therapy (SIRT) allows selective delivery of high dose radiation to liver tumours and has shown promise in the management of NENs. We determined the safety and efficacy of SIRT for inoperable liver metastases secondary to NENs. Dose-response and dose-toxicity relationship were assessed. A prospective, multicentre, phase 2 study was conducted. Primary outcomes were objective response rate (ORR) in the treated liver volume according to RECIST 1.1 and mRECIST criteria, incidence and severity of adverse events (AEs) at 6 months. Secondary outcomes were hepatic specific progression free survival, PFS, overall survival (OS), change in quality of life (QoL). Tumour dose-response relationship was derived retrospectively from post therapy yttrium-90 bremsstrahlung single photon emission computed tomography/CT for both the tumour and perfused normal liver. 21 patients were analysed; majority had grade 2 NEN (67%) and were heavily pretreated, 76% having received prior systemic therapy including peptide receptor radiotherapy (33%). ORR by RECIST 1.1 and mRECIST were 14% and 45%, respectively. Median hepatic specific PFS, PFS and OS were 48.1, 13.3 and 49.9 months respectively. Only 3 patients experienced grade 3 AEs; 2 radiation-induced liver disease that resolved without sequelae and one arterial plug migration. No significant deterioration in QoL was observed following SIRT. Dosimetry analysis found a clear tumour dose/response relationship for 3-month ORR. Mean tumour dose in responders was 372Gy versus 173Gy in non-responders (p < 0.001). We identified a threshold tumour absorbed dose of 164Gy for PFS 48.1months compared to 8.8months (HR 0.2, 95%CI 0.05-0.96. p = 0.03). In a prospective study of heavily pretreated patients, we have demonstrated clinical efficacy of SIRT for the management of liver metastases secondary to NENs. A tumour dose-response relationship was demonstrated and a threshold tumour dose for survival outcome. This work lends prospective evidence for personalised dosimetry in NENs.

Ongoing shortages of organs for transplantation have prompted the critical question of which countries have the highest organ donation rates and how each can increase those rates. The existing metric of donors per million population is flawed because it does not sufficiently account for important differences in the underlying population, including age distributions of deaths in the population. We sought to develop a better approach to analyze country-specific data on organ donation, including deaths stratified by age, to allow assessment of performance across the world. We used death data from the World Health Organization and donation data from 17 countries across 3 continents. We calculated age group-stratified organ donation rates as donors per 1000 deaths and estimated each country's potential to increase donation if the age group-specific donation rate mirrored that of the highest-performing country in each age group. There was a 4-fold difference in overall donation rates, with far greater variability within age strata, including a 10-fold difference in donation rates for the oldest age group (70 y and older). The United States showed the greatest potential to increase donations in absolute terms (>8000 increased donors per year), whereas Argentina, Germany, and Hungary had the greatest potential in relative terms. Although countries may have similar overall donation rates, the breakdown within specific age groups varies widely. Examining age-specific donation rates is a necessary step for accurate international comparisons of transplant systems and can enable targeted interventions to augment donation.

Biochemical non-response to ursodeoxycholic acid, as a first-line therapy, is associated with a heightened risk of clinical events in primary biliary cholangitis (PBC). Herein, we determine whether biochemical non-response to second-line therapy in obeticholic acid (OCA) is also predictive of long-term event-free survival. Data were collected from patients who initiated OCA at large, high-volume centres in the UK, Italy, and Canada between August 2017 and 2019, with follow-up continuing until June 2024. Biochemical non-response was defined by POISE criteria. Clinical events were defined as hepatic decompensation, referral for transplantation, hepatocellular carcinoma, or death. Our cohort consisted of 336 patients (29% with cirrhosis), of whom n = 150 (45%) discontinued OCA over 48 months. Over 851 patient-years of OCA use, without the addition of another PBC therapy, n = 230, n = 192, n = 158 and n = 150 patients completed 12, 24, 36 and 48 months follow-up, respectively. Of this cohort, 37%, 48%, 63% and 55% attained biochemical response, with 7%, 14%, 25% and 19% normalising ALP (p < 0.01; all comparisons vs. baseline). Over 4 years, 64 patients experienced a clinical event. Twelve-month biochemical non-response associated with a heightened risk of clinical events (hazard ratio [HR]: 4.50; 95% CI: 1.74-20.23), as did cirrhosis (HR: 20.24, 10.15-40.32), hyperbilirubinaemia (HR: 2.55, 1.71-3.76), hypoalbuminaemia (HR: 0.92, 0.90-0.96) and thrombocytopenia (HR: 0.99, 0.98-0.99). The prognostic utility of biochemical non-response (HR: 3.29, 1.72-14.96) and cirrhosis (HR: 19.67, 5.09-76.08) persisted on multivariable analyses. Biochemical response stratifies risk of clinical events in PBC patients under OCA treatment. Whilst response rates increase over time, discontinuation rates underscore the need for newer treatment paradigms.

ABSTRACTIntroductionCancer is one of the most expensive global health challenges and surgery is needed in most cases. This study aimed to describe out‐of‐pocket payments for cancer surgery across country income groups.MethodsThis was a preplanned secondary analysis from an international prospective cohort study of consecutive patients undergoing cancer surgery in October 2020. Out‐of‐pocket payments (OOPP) to cover most of the cost of cancer surgery were compared across country income groups. Other funding sources were also described as follows: public funds, insurance, or others. A logistic regression model was used to identify variables independently associated with OOPP in low‐ and middle‐income countries.ResultsThere were 24,498 patients included from 1332 hospitals from 108 countries. Overall, 6.4% (1571/24,498) had OOPP to cover most of the cost of their cancer surgery. OOPP rates varied across country income groups: 0.5% (89/16,680) in HICs, 5.7% (272/4784) in UMICs, 38.6% (1008/2614) in LMICs, and 48.1% (202/429) in LICs. Besides the country income, male sex (OR 1.16, 95% CI 1.02–1.32, and p = 0.024) and elective surgery (OR 1.31, 1.04–1.67, and p = 0.022) were associated with OOPP for cancer surgery.DiscussionPatients accessing cancer surgery in LMICs are at an increased risk of catastrophic expenditure. Governments should prevent this by developing health insurance plans that cover elective cancer surgery, possibly involving diverse stakeholders. The interpretation of gender‐related risks demands deeper understanding of the ability to pay out‐of‐pocket and access care.

Born in Bradford (BiB) is a family cohort study with linked routine health records. We calculated the rates of common health conditions and explored differences between White European and South Asian participants. 21 health conditions were identified using diagnostic codes and prescription records extracted from electronic health records. We calculated 2-year period prevalence before recruitment and incidence rates per 1000 person-years were calculated from recruitment to the end of 2021 (or censoring). Age-adjusted Cox proportional hazard models estimated hazard ratios (HR) by ethnicity. The sample included 9,784 mothers, 52% were of South Asian heritage and 48% were White European. The highest prevalence and incidence rates were observed for common mental health disorders and eczema. South Asian women had higher incidence of 14 conditions, including diabetes (HR 3.94 [95% CI 3.15, 4.94]), chronic liver disease (2.98 [2.29, 3.88]) and thyroid disorders (1.87 [1.50, 2.33]), but lower incidence of cancer (0.51 [0.38, 0.68]), other and common mental health disorders (0.56 [0.45, 0.71] and 0.69 [0.64, 0.74] respectively), and other neuromuscular conditions (0.63 [0.49, 0.82]). This study reveals significant differences in the occurrence of several non-communicable health conditions between White European and South Asian women. The observed higher incidence of several conditions in South Asian women, consistent with established knowledge regarding elevated risks for diseases such as diabetes, likely reflects the complex interplay of social, cultural, lifestyle, environmental, and genetic determinants. These findings emphasise the need for culturally sensitive and targeted public health interventions aimed at addressing modifiable risk factors at both the individual and systemic levels to alleviate the burden of long-term health conditions and reduce existing health inequalities.

ObjectivesPrimary sclerosing cholangitis (PSC) is a rare chronic disease that presents challenges to both patients and clinicians. This study aimed to explore the experiences of patients with PSC regarding their disease and healthcare.DesignA series of semi-structured interviews was completed with patients with PSC, including questioning their experiences of living with PSC and its related healthcare.SettingParticipants were recruited from communities in England, Scotland and Wales, with advertisement via PSC Support (UK disease-specific charity support group).Participants18 patients aged between 21 and 72 years were interviewed; 10 were male (56%), and all were of Caucasian ethnicity. Inclusion criteria were as follows: adults, self-identifying as having a diagnosis of PSC, and currently under National Health Service treatment for this disease. Patients with a history of liver transplantation were excluded.ResultsParticipants confirmed the ongoing physical and psychological burden of PSC and its related healthcare. Living with PSC was described as a journey; the timeline of events was important to patients, with particular challenges identified along the way. These included difficulties in obtaining a diagnosis and accessing timely and knowledgeable medical care. Overcoming the unusual combination of uncertainties that PSC presents was of particular concern to participants; these differ from those observed in more common chronic diseases with established treatment pathways. Hidden complexities within chronic illness behaviour in PSC were described, including a noteworthy fragile doctor−patient relationship and dependence on the specialist. These produce additional challenges for the optimal clinical management of such patients by generalists and specialists.ConclusionsThis study complements the existing literature on the ongoing high burden of PSC, with added value from in-depth discussions with patients themselves. Priorities for further work have been identified, including the need for improved risk stratification tools to allow individualised management and prognostication, as well as improving access to knowledgeable care while maintaining a strong doctor–patient relationship.

Low-volume plasma exchange (PLEX) and low-dose steroid improve survival in severe alcoholic hepatitis. We aimed to compare one-year survival of very severe alcoholic hepatitis (VSAH) patients treated with centrifugal PLEX (cPLEX), membrane PLEX (mPLEX) or standard medical treatment (SMT). We retrospectively analyzed survival in consecutive VSAH patients treated at our department from November 2017 to September 2021. PLEX patients received low-volume PLEX along with low-dose steroid (tab. prednisolone 10mg or 20mg daily). To adjust for baseline differences between the three treatment (cPLEX, mPLEX or SMT) groups, propensity score (PS) matching was done. Acute-on-chronic liver failure (ACLF) was defined as per European Association for the Study of the Liver (EASL). The primary study outcome was one-year transplant-free survival of PS-matched VSAH patients treated with cPLEX compared to SMT. Of 101 PLEX-eligible VSAH patients, 30 patients were treated with cPLEX, 21 with mPLEX and 50 with SMT. On comparing 30 PS-matched patients each in the cPLEX group vs. the SMT group, transplant-free survival in the cPLEX group was 86.7% at onemonth, 70% at threemonths and 52.4% at oneyear and in the SMT group was 33.3% at onemonth, 23.3% at threemonths and 16.7% at oneyear with hazard ratio (HR [95%CI]) in favor of the cPLEX group (0.29 [0.15-0.56], p < 0.001). Total 21 patients each (PS-matched) in cPLEX and mPLEX groups were compared and one-year survival was better with cPLEX (0.33 [0.16-0.69], p = 0.001). The sub-group analysis of VSAH (PS-matched cohort) patients with ACLF also showed better survival with cPLEX compared to SMT (0.38 [0.17-0.83], p = 0.003) and compared to mPLEX (0.43 [0.17-0.95], p = 0.03). Better one-year transplant-free survival was noted among PS-matched VSAH patients treated with cPLEX (and low-dose steroid) compared to SMT (without steroid).