The positive impact of the COVID 19 pandemic on organ utilisation in liver transplantation.

Background: As the world recovers from the aftermath of devastating waves of an outbreak, the ongoing Coronavirus disease 2019 pandemic has presented a unique perspective to the transplantation community of ''organ utilisation'' in liver transplantation, a poorly defined term and ongoing hurdle in this field. To this end, we report the key metrics of transplantation activity from a high-volume liver transplantation centre in the United Kingdom over the past two years. Methods: Between March 2019 and February 2021, details of donor liver offers received by our centre from National Health Service Blood & Transplant, and of transplantation were reviewed. Differences in the activity before and after the outbreak of the pandemic, including short term post-transplant survival, have been reported. Results: The pandemic year at our centre witnessed a higher utilisation of Donation after Cardiac Death livers (80.4% vs. 58.3%, p = 0.016) with preserved United Kingdom donor liver indices and median donor age (2.12 vs. 2.02, p = 0.638; 55 vs. 57 years, p = 0.541) when compared to the pre-pandemic year. The 1- year patient survival rates for recipients in both the periods were comparable. The pandemic year, that was associated with increased utilisation of Donation after Cardiac Death livers, had an ischaemic cholangiopathy rate of 6%. Conclusions: The pressures imposed by the pandemic led to increased utilisation of specific donor livers to meet patient needs and minimise the risk of death on the waiting list, with apparently preserved early post-transplant survival. Optimum organ utilisation is a balancing act between risk and benefit for the potential recipient, and technologies like machine perfusion may allow surgeons to increase utilisation without compromising patient outcomes.

Patient-derived precision cut tissue slices from primary liver cancer as a potential platform for preclinical drug testing.

BACKGROUND: The exploitation of anti-tumour immunity, harnessed through immunomodulatory therapies, has fundamentally changed the treatment of primary liver cancer (PLC). However, this has posed significant challenges in preclinical research. Novel immunologically relevant models for PLC are urgently required to improve the translation from bench to bedside and back, explore and predict effective combinatorial therapies, aid novel drug discovery and develop personalised treatment modalities. METHODS: We used human precision-cut tissue slices (PCTS) derived from resected tumours to create a patient-specific immunocompetent disease model that captures the multifaceted and intricate heterogeneity of the tumour and the tumour microenvironment. Tissue architecture, tumour viability and treatment response to single agent and combination therapies were assessed longitudinally over 8 days of ex vivo culture by histological analysis, detection of proliferation/cell death markers, ATP content via HPLC. Immune cell infiltrate was assessed using PCR and immunofluorescence. Checkpoint receptor expression was quantified via Quantigene RNA assay. FINDINGS: After optimising the culture conditions, PCTS maintained the original tissue architecture, including tumour morphology, stroma and tumour-infiltrated leukocytes. Moreover, PCTS retained the tumour-specific immunophenotype over time, suggesting the utility of PCTS to investigate immunotherapeutic drug efficacy and identify non-responsiveness. INTERPRETATION: Here we have characterised the PCTS model and demonstrated its effectiveness as a robust preclinical tool that will significantly support the development of successful (immuno)therapeutic strategies for PLC. FUNDING: Foundation for Liver Research, London.

Satellite liver transplant centres significantly improve transplant assessment outcomes for patients with chronic liver disease but not hepatocellular carcinoma: a retrospective cohort study.

Introduction: Liver transplantation (LT) remains integral to the management of end-stage chronic liver disease (CLD). However, referral thresholds and assessment pathways remain poorly defined. Distance from LT centre has been demonstrated to impact negatively on patient outcomes resulting in the development of satellite LT centres (SLTCs). We aimed to evaluate the impact of SLTCs on LT assessment in patients with CLD and hepatocellular carcinoma (HCC). Methods: A retrospective cohort study was undertaken including all patients with CLD or HCC assessed for LT at King's College Hospital (KCH) between October 2014 and October 2019. Referral location, social, demographic, clinical and laboratory data were collected. Univariable and multivariable analyses (MVA) were performed to assess the impact of SLTCs on patients being accepted as LT candidates and contraindications being identified. Results: 1102 and 240 LT assessments were included for patients with CLD and HCC, respectively. MVA demonstrated significant associations with; patients living greater than 60 min from KCH/SLTCs and LT candidacy acceptance in CLD, and less deprived patients and LT candidacy acceptance in HCC. However, neither variable was associated with identification of LT contraindications. MVA demonstrated that referrals from SLTCs were more likely to result in acceptance of LT candidacy and less likely to result in a contraindication being identified in CLD. However, such associations were not demonstrated in HCC. Conclusion: SLTCs improve LT assessment outcomes in CLD but not HCC reflecting the standardised HCC referral pathway. Developing a formal regional LT assessment pathway across the UK would improve equity of access to transplantation.

Outcomes after liver transplantation using deceased after circulatory death donors: A comparison of outcomes in the UK and the US.

BACKGROUND AND AIMS: Identifying international differences in utilization and outcomes of liver transplantation (LT) after donation after circulatory death (DCD) donation provides a unique opportunity for benchmarking and population-level insight. METHODS: Adult (≥18 years) LT data between 2008 and 2018 from the UK and US were used to assess mortality and graft failure after DCD LT. We used time-dependent Cox-regression methods to estimate hazard ratios (HR) for risk-adjusted short-term (0-90 days) and longer-term (90 days-5 years) outcomes. RESULTS: One-thousand five-hundred-and-sixty LT receipts from the UK and 3426 from the US were included. Over the study period, the use of DCD livers increased from 15.7% to 23.9% in the UK compared to 5.1% to 7.6% in the US. In the UK, DCD donors were older (UK:51 vs. US:33 years) with longer cold ischaemia time (UK: 437 vs. US: 333 min). Recipients in the US had higher Model for End-stage Liver Disease (MELD) scores, higher body mass index, higher proportions of ascites, encephalopathy, diabetes and previous abdominal surgeries. No difference in the risk-adjusted short-term mortality or graft failure was observed between the countries. In the longer-term (90 days-5 years), the UK had lower mortality and graft failure (adj.mortality HR:UK: 0.63 (95% CI: 0.49-0.80); graft failure HR: UK: 0.72, 95% CI: 0.58-0.91). The cumulative incidence of retransplantation was higher in the UK (5 years: UK: 11.9% vs. 4.6%; p < .001). CONCLUSIONS: For those receiving a DCD LT, longer-term post-transplant outcomes in the UK are superior to the US, however, significant differences in recipient illness, graft quality and access to retransplantation were seen between the two countries.

Immediate surgery compared with short-course neoadjuvant gemcitabine plus capecitabine, FOLFIRINOX, or chemoradiotherapy in patients with borderline resectable pancreatic cancer (ESPAC5): a four-arm, multicentre, randomised, phase 2 trial.

BACKGROUND: Patients with borderline resectable pancreatic ductal adenocarcinoma have relatively low resection rates and poor survival despite the use of adjuvant chemotherapy. The aim of our study was to establish the feasibility and efficacy of three different types of short-course neoadjuvant therapy compared with immediate surgery. METHODS: ESPAC5 (formerly known as ESPAC-5f) was a multicentre, open label, randomised controlled trial done in 16 pancreatic centres in two countries (UK and Germany). Eligible patients were aged 18 years or older, with a WHO performance status of 0 or 1, biopsy proven pancreatic ductal adenocarcinoma in the pancreatic head, and were staged as having a borderline resectable tumour by contrast-enhanced CT criteria following central review. Participants were randomly assigned by means of minimisation to one of four groups: immediate surgery; neoadjuvant gemcitabine and capecitabine (gemcitabine 1000 mg/m2 on days 1, 8, and 15, and oral capecitabine 830 mg/m2 twice a day on days 1-21 of a 28-day cycle for two cycles); neoadjuvant FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, folinic acid given according to local practice, and fluorouracil 400 mg/m2 bolus injection on days 1 and 15 followed by 2400 mg/m2 46 h intravenous infusion given on days 1 and 15, repeated every 2 weeks for four cycles); or neoadjuvant capecitabine-based chemoradiation (total dose 50·4 Gy in 28 daily fractions over 5·5 weeks [1·8 Gy per fraction, Monday to Friday] with capecitabine 830 mg/m2 twice daily [Monday to Friday] throughout radiotherapy). Patients underwent restaging contrast-enhanced CT at 4-6 weeks after neoadjuvant therapy and underwent surgical exploration if the tumour was still at least borderline resectable. All patients who had their tumour resected received adjuvant therapy at the oncologist's discretion. Primary endpoints were recruitment rate and resection rate. Analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN, 89500674, and is complete. FINDINGS: Between Sept 3, 2014, and Dec 20, 2018, from 478 patients screened, 90 were randomly assigned to a group (33 to immediate surgery, 20 to gemcitabine plus capecitabine, 20 to FOLFIRINOX, and 17 to capecitabine-based chemoradiation); four patients were excluded from the intention-to-treat analysis (one in the capecitabine-based chemoradiotherapy withdrew consent before starting therapy and three [two in the immediate surgery group and one in the gemcitabine plus capecitabine group] were found to be ineligible after randomisation). 44 (80%) of 55 patients completed neoadjuvant therapy. The recruitment rate was 25·92 patients per year from 16 sites; 21 (68%) of 31 patients in the immediate surgery and 30 (55%) of 55 patients in the combined neoadjuvant therapy groups underwent resection (p=0·33). R0 resection was achieved in three (14%) of 21 patients in the immediate surgery group and seven (23%) of 30 in the neoadjuvant therapy groups combined (p=0·49). Surgical complications were observed in 29 (43%) of 68 patients who underwent surgery; no patients died within 30 days. 46 (84%) of 55 patients receiving neoadjuvant therapy were available for restaging. Six (13%) of 46 had a partial response. Median follow-up time was 12·2 months (95% CI 12·0-12·4). 1-year overall survival was 39% (95% CI 24-61) for immediate surgery, 78% (60-100) for gemcitabine plus capecitabine, 84% (70-100) for FOLFIRINOX, and 60% (37-97) for capecitabine-based chemoradiotherapy (p=0·0028). 1-year disease-free survival from surgery was 33% (95% CI 19-58) for immediate surgery and 59% (46-74) for the combined neoadjuvant therapies (hazard ratio 0·53 [95% CI 0·28-0·98], p=0·016). Three patients reported local disease recurrence (two in the immediate surgery group and one in the FOLFIRINOX group). 78 (91%) patients were included in the safety set and assessed for toxicity events. 19 (24%) of 78 patients reported a grade 3 or worse adverse event (two [7%] of 28 patients in the immediate surgery group and 17 [34%] of 50 patients in the neoadjuvant therapy groups combined), the most common of which were neutropenia, infection, and hyperglycaemia. INTERPRETATION: Recruitment was challenging. There was no significant difference in resection rates between patients who underwent immediate surgery and those who underwent neoadjuvant therapy. Short-course (8 week) neoadjuvant therapy had a significant survival benefit compared with immediate surgery. Neoadjuvant chemotherapy with either gemcitabine plus capecitabine or FOLFIRINOX had the best survival compared with immediate surgery. These findings support the use of short-course neoadjuvant chemotherapy in patients with borderline resectable pancreatic ductal adenocarcinoma. FUNDING: Cancer Research UK.

A Multicenter, Randomized, Double-Blinded, Clinical Trial Comparing Cattell-Warren and Blumgart Anastomoses Following Partial Pancreatoduodenectomy: PANasta Trial.

Whether a Blumgart anastomosis (BA) is superior to Cattell-Warren anastomosis (CWA) in terms of postoperative pancreatic fistula (POPF) following pancreatoduodenectomy. Importance: Complications driven by POPF following pancreatic cancer resection may hinder adjuvant therapy, shortening survival. BA may reduce complications compared to CWA, improving the use of adjuvant therapy and prolonging survival. Methods: A multicenter double-blind, controlled trial of patients undergoing resection for suspected pancreatic head cancer, randomized during surgery to a BA or CWA, stratified by pancreatic consistency and duct diameter. The primary end point was POPF, and secondary outcome measures were adjuvant therapy use, specified surgical complications, quality of life, and survival from the date of randomization. For a 10% POPF reduction, 416 patients were required, 208 per arm (two-sided α = 0·05; power = 80%). Results: Z-score at planned interim analysis was 0.474 so recruitment was held to 238 patients; 236 patients were analyzed (112 BA and 124 CWA). No significant differences in POPF were observed between BA and CWA, odds ratio (95% confidence interval [CI]) 1·04 (0.58-1.88), P = 0.887, nor in serious adverse events. Adjuvant therapy was delivered to 98 (62%) of 159 eligible patients with any malignancy; statistically unrelated to arm or postoperative complications. Twelve-month overall survival, hazard ratio (95% CI), did not differ between anastomoses; BA 0.787 (0.713-0.868) and CWA 0.854 (0.792-0.921), P = 0.266, nor for the 58 patients with complications, median (IQR), 0.83 (0.74-0.91) compared to 101 patients without complications 0.82 (0.76-0.89) (P = 0.977). Conclusions: PANasta represents the most robust analysis of BA versus CWA to date.

Diagnostic features and management options for duodenal neuroendocrine neoplasms: a retrospective, multi-centre study.

Duodenal neuroendocrine neoplasms (dNENs) are rare neoplasms but their incidence is on the rise. They are classified into 5 sub-types but there remains much heterogeneity in behaviour in particular of non-functioning dNENs. To retrospectively analyse outcomes for all types of dNENs, and highlight prognostic factors associated with worse outcome. 102 (57 m/45f.) patients were identified with mean age at diagnosis 62 (range 32-87) years. The majority were non-functioning tumours 87/102 and median size was 10 mm (range 0.9-130 mm). 83 patients had Stage I or II disease, of which 17 underwent endoscopic resection with R1 rate of 45% and complication rate 12%. 36 patients were kept under endoscopic surveillance. There were 11 deaths of which 4 were disease related. Age and Ki67 > 20% were associated with worse OS in all dNENs. In non-functioning dNENs Ki67 > 3% was a predictor of lymph nodes metastases with OR 18.2 (2.54-13) (p < 0.005) in univariate analyses and liver metastases with OR 6.79 (1.56-29.5) (p < 0.05) in the multivariate analysis. Lesions 11-20 mm in size had OR 11.1 (1.16-106) compared to lesions < 11 mm for the prediction of lymph node metastases in the multivariate analysis (p < 0.05). ROC analysis of size of non-functioning dNENs to predict LN metastases found < 15 mm had an AUROC of 0.9 (0.81-0.99) with a sensitivity of 85% and specificity of 88%. dNENs are increasing in incidence, however low grade and smaller lesions have an indolent course and the role of endoscopic resection and active surveillance needs to be reviewed.

Low utilization of adult-to-adult LDLT in Western countries despite excellent outcomes: International multicenter analysis of the US, the UK, and Canada.

BACKGROUND & AIMS: Adult-to-adult living donor liver transplantation (LDLT) offers an opportunity to decrease the liver transplant waitlist and reduce waitlist mortality. We sought to compare donor and recipient characteristics and post-transplant outcomes after LDLT in the US, the UK, and Canada. METHODS: This is a retrospective multicenter cohort-study of adults (≥18-years) who underwent primary LDLT between Jan-2008 and Dec-2018 from three national liver transplantation registries: United Network for Organ Sharing (US), National Health Service Blood and Transplantation (UK), and the Canadian Organ Replacement Registry (Canada). Patients undergoing retransplantation or multi-organ transplantation were excluded. Post-transplant survival was evaluated using the Kaplan-Meier method, and multivariable adjustments were performed using Cox proportional-hazards models with mixed-effect modeling. RESULTS: A total of 2,954 living donor liver transplants were performed (US: n = 2,328; Canada: n = 529; UK: n = 97). Canada has maintained the highest proportion of LDLT utilization over time (proportion of LDLT in 2008 - US: 3.3%; Canada: 19.5%; UK: 1.7%; p <0.001 - in 2018 - US: 5.0%; Canada: 13.6%; UK: 0.4%; p <0.001). The 1-, 5-, and 10-year patient survival was 92.6%, 82.8%, and 70.0% in the US vs. 96.1%, 89.9%, and 82.2% in Canada vs. 91.4%, 85.4%, and 66.7% in the UK. After adjustment for characteristics of donors, recipients, transplant year, and treating transplant center as a random effect, all countries had a non-statistically significantly different mortality hazard post-LDLT (Ref US: Canada hazard ratio 0.53, 95% CI 0.28-1.01, p = 0.05; UK hazard ratio 1.09, 95% CI 0.59-2.02, p = 0.78). CONCLUSIONS: The use of LDLT has remained low in the US, the UK and Canada. Despite this, long-term survival is excellent. Continued efforts to increase LDLT utilization in these countries may be warranted due to the growing waitlist and differences in allocation that may disadvantage patients currently awaiting liver transplantation. LAY SUMMARY: This multicenter international comparative analysis of living donor liver transplantation in the United States, the United Kingdom, and Canada demonstrates that despite low use of the procedure, the long-term outcomes are excellent. In addition, the mortality risk is not statistically significantly different between the evaluated countries. However, the incidence and risk of retransplantation differs between the countries, being the highest in the United Kingdom and lowest in the United States.

Human Immunocompetent Model of Neuroendocrine Liver Metastases Recapitulates Patient-Specific Tumour Microenvironment.

Neuroendocrine liver metastases (LM-NEN) develop in a considerable proportion of patients with gastroenteropancreatic neuroendocrine neoplasms. There is a paucity of experimental models that accurately recapitulate this complex metastatic human liver microenvironment precluding scientific and clinical advancements. Here, we describe the development of a novel personalised immunocompetent precision cut tumour slice (PCTS) model for LM-NEN using resected human liver tissue. The histological assessment throughout the culture demonstrated that slices maintain viability for at least 7 days and retain the cellular heterogeneity of the original tumour. Essential clinical features, such as patient-specific histoarchitecture, tumour grade, neuroendocrine differentiation and metabolic capacity, are preserved in the slices. The PCTS also replicate the tumor-specific immunological profile as shown by the innate and adaptive immunity markers analysis. Furthermore, the study of soluble immune checkpoint receptors in the culture supernatants proves that these immunomodulators are actively produced by LM-NEN and suggests that this process is epithelium-dependent. This model can be employed to investigate these pathways and provides a powerful platform for mechanistic, immunological and pre-clinical studies.

Time-varying Comparison of All-cause Mortality After Liver Transplantation Between Recipients With and Without Hepatocellular Carcinoma: A Population-based Cohort Study Using the United Kingdom Liver Transplant Registry.

BACKGROUND: Accurately identifying time-varying differences in the hazard of all-cause mortality after liver transplantation (LT) between recipients with and without hepatocellular carcinoma (HCC) may inform patient selection and organ allocation policies as well as post-LT surveillance protocols. METHODS: A UK population-based study was carried out using 9586 LT recipients. The time-varying association between HCC and post-LT all-cause mortality was estimated using an adjusted flexible parametric model (FPM) and expressed as hazard ratios (HRs). Differences in this association by transplant year were then investigated. Non-cancer-specific mortality was compared between HCC and non-HCC recipients using an adjusted subdistribution hazard model. RESULTS: The HR comparing HCC recipients with non-HCC recipients was below one immediately after LT (1-mo HR = 0.76; 95% confidence interval [CI], 0.59-0.99; P = 0.044). The HR then increased sharply to a maximum at 1.3 y (HR = 2.07; 95% CI, 1.70-2.52; P < 0.001) before decreasing. The hazard of death was significantly higher in HCC recipients than in non-HCC recipients between 4 mo and 7.4 y post-LT. There were no notable differences in the association between HCC and the post-LT hazard of death by transplant year. The estimated non-cancer-specific subdistribution HR for HCC was 0.93 (95% CI, 0.80-1.09; P = 0.390) and not found to vary over time. CONCLUSIONS: FPMs can provide a more precise comparison of post-LT hazards of mortality between HCC and non-HCC patients. The results provide further evidence that some HCC patients have extra-hepatic spread at the time of LT, which has implications for optimal post-LT surveillance protocols.

USP25 promotes pathological HIF-1-driven metabolic reprogramming and is a potential therapeutic target in pancreatic cancer.

Deubiquitylating enzymes (DUBs) play an essential role in targeted protein degradation and represent an emerging therapeutic paradigm in cancer. However, their therapeutic potential in pancreatic ductal adenocarcinoma (PDAC) has not been explored. Here, we develop a DUB discovery pipeline, combining activity-based proteomics with a loss-of-function genetic screen in patient-derived PDAC organoids and murine genetic models. This approach identifies USP25 as a master regulator of PDAC growth and maintenance. Genetic and pharmacological USP25 inhibition results in potent growth impairment in PDAC organoids, while normal pancreatic organoids are insensitive, and causes dramatic regression of patient-derived xenografts. Mechanistically, USP25 deubiquitinates and stabilizes the HIF-1α transcription factor. PDAC is characterized by a severely hypoxic microenvironment, and USP25 depletion abrogates HIF-1α transcriptional activity and impairs glycolysis, inducing PDAC cell death in the tumor hypoxic core. Thus, the USP25/HIF-1α axis is an essential mechanism of metabolic reprogramming and survival in PDAC, which can be therapeutically exploited.

Liver transplantation for HCC: validation of prognostic power of the RETREAT score for recurrence in a UK cohort.

BACKGROUND: The Risk Estimation of Tumor Recurrence After Transplant (RETREAT) score as a prognostic index for recurrence has been reported previously and has not been validated outside the USA. Our study has validated the score in a single center UK cohort of patients being transplanted for HCC. METHODS: LT for HCC between 2008 and 2018 at our center were analyzed. Recurrence-free survival (RFS) was compared by the RETREAT score and validated using Net Reclassification Improvement (NRI) by comparing it to Milan criteria. RESULTS: 346 adult HCC patients were transplanted of whom 313 were included. 28 (8.9%) had a recurrence. Summation of largest diameter and total number of viable tumors (HR = 1.19, p < 0.001), micro-/macro-vascular invasion (HR = 3.74, p = 0.002) and AFP>20 ng/ml (HR = 3.03, p = 0.005) were associated with recurrence on multivariate analysis. RFS decreased with increasing RETREAT score (log-rank p = 0.016). RETREAT performed better than Milan with significant NRI at 1- and 2-years post-transplant (0.43 (p = 0.004) and 0.38 (p = 0.03) respectively). CONCLUSION: LT outcomes using the revised UK criteria are equivalent to Milan criteria. Further, RETREAT score was validated as a prognostic index for the first time in a UK cohort and may assist risk stratification, selection for adjuvant therapies and guide surveillance.

A coordinated national UK liver transplant program response, prioritizing waitlist recipients with the highest need, provided excellent outcomes during the first wave of the COVID-19 pandemic.

INTRODUCTION: Healthcare provision has been severely affected by COVID-19, with specific challenges in organ transplantation. Here, we describe the coordinated response to, and outcomes during the first wave, across all UK liver transplant (LT) centers. METHODS: Several policy changes affecting the liver transplant processes were agreed upon. These included donor age restrictions and changes to offering. A "high-urgency" (HU) category was established, prioritizing only those with UKELD > 60, HCC reaching transplant criteria, and others likely to die within 90 days. Outcomes were compared with the same period in 2018 and 2019. RESULTS: The retrieval rate for deceased donor livers (71% vs. 54%; P < .0001) and conversion from offer to completed transplant (63% vs. 48%; P < .0001) was significantly higher. Pediatric LT activity was maintained; there was a significant reduction in adult (42%) and total (36%) LT. Almost all adult LT were super-urgent (n = 15) or HU (n = 133). We successfully prioritized those with highest illness severity with no reduction in 90-day patient (P = .89) or graft survival (P = .98). There was a small (5% compared with 3%; P = .0015) increase in deaths or removals from the waitlist, mainly amongst HU cohort. CONCLUSIONS: We successfully prioritized LT recipients in highest need, maintaining excellent outcomes, and waitlist mortality was only marginally increased.

Liver Transplantation for Biliary Atresia in Adulthood: Single-Centre Surgical Experience.

BACKGROUND: Biliary atresia (BA) is the most common indicator for liver transplant (LT) in children, however, approximately 22% will reach adulthood with their native liver, and of these, half will require transplantation later in life. The aim of this study was to analyse the surgical challenges and outcomes of patients with BA undergoing LT in adulthood. METHODS: Patients with BA requiring LT at the age of 16 or older in our unit between 1989 and 2020 were included. Pretransplant, perioperative variables and outcomes were analysed. Pretransplant imaging was reviewed to assess liver appearance, spontaneous visceral portosystemic shunting (SPSS), splenomegaly, splenic artery (SA) size, and aneurysms. RESULTS: Thirty-four patients who underwent LT for BA fulfilled the inclusion criteria, at a median age of 24 years. The main indicators for LT were synthetic failure and recurrent cholangitis. In total, 57.6% had significant enlargement of the SA, 21% had multiple SA aneurysm, and SPSS was present in 72.7% of the patients. Graft and patient survival at 1, 5, and 10 years was 97.1%, 91.2%, 91.2% and 100%, 94%, 94%, respectively Conclusions: Good outcomes after LT for BA in young patients can be achieved with careful donor selection and surgery to minimise the risk of complications. Identification of anatomical variants and shunting are helpful in guiding attitude at the time of transplant.

Impact of SARS-CoV-2 pandemic on pancreatic cancer services and treatment pathways: United Kingdom experience.

INTRODUCTION: The SARS-CoV-2 pandemic presented healthcare providers with an extreme challenge to provide cancer services. The impact upon the diagnostic and treatment capacity to treat pancreatic cancer is unclear. This study aimed to identify national variation in treatment pathways during the pandemic. METHODS: A survey was distributed to all United Kingdom pancreatic specialist centres, to assess diagnostic, therapeutic and interventional services availability, and alterations in treatment pathways. A repeating methodology enabled assessment over time as the pandemic evolved. RESULTS: Responses were received from all 29 centres. Over the first six weeks of the pandemic, less than a quarter of centres had normal availability of diagnostic pathways and a fifth of centres had no capacity whatsoever to undertake surgery. As the pandemic progressed services have gradually improved though most centres remain constrained to some degree. One third of centres changed their standard resectable pathway from surgery-first to neoadjuvant chemotherapy. Elderly patients, and those with COPD were less likely to be offered treatment during the pandemic. CONCLUSION: The COVID-19 pandemic has affected the capacity of the NHS to provide diagnostic and staging investigations for pancreatic cancer. The impact of revised treatment pathways has yet to be realised.

Perihilar Cholangiocarcinoma - Novel Benchmark Values for Surgical and Oncological Outcomes From 24 Expert Centers.

OBJECTIVE: The aim of this study was to define robust benchmark values for the surgical treatment of perihilar cholangiocarcinomas (PHC) to enable unbiased comparisons. BACKGROUND: Despite ongoing efforts, postoperative mortality and morbidity remains high after complex liver surgery for PHC. Benchmark data of best achievable results in surgical PHC treatment are however still lacking. METHODS: This study analyzed consecutive patients undergoing major liver surgery for PHC in 24 high-volume centers in 3 continents over the recent 5-year period (2014-2018) with a minimum follow-up of 1 year in each patient. Benchmark patients were those operated at high-volume centers (≥50 cases during the study period) without the need for vascular reconstruction due to tumor invasion, or the presence of significant co-morbidities such as severe obesity (body mass index ≥35), diabetes, or cardiovascular diseases. Benchmark cutoff values were derived from the 75th or 25th percentile of the median values of all benchmark centers. RESULTS: Seven hundred eight (39%) of a total of 1829 consecutive patients qualified as benchmark cases. Benchmark cut-offs included: R0 resection ≥57%, postoperative liver failure (International Study Group of Liver Surgery): ≤35%; in-hospital and 3-month mortality rates ≤8% and ≤13%, respectively; 3-month grade 3 complications and the CCI: ≤70% and ≤30.5, respectively; bile leak-rate: ≤47% and 5-year overall survival of ≥39.7%. Centers operating mostly on complex cases disclosed better outcome including lower post-operative liver failure rates (4% vs 13%; P = 0.002). Centers from Asia disclosed better outcomes. CONCLUSION: Surgery for PHC remains associated with high morbidity and mortality with now the availability of benchmark values covering 21 outcome parameters, which may serve as key references for comparison in any future analyses of individuals, group of patients or centers.

The Impact of 68Gallium DOTA PET/CT in Managing Patients With Sporadic and Familial Pancreatic Neuroendocrine Tumours.

Objective: Pancreatic neuroendocrine tumours (panNETs) arise sporadically or as part of a genetic predisposition syndrome. CT/MRI, endoscopic ultrasonography and functional imaging using Octreoscan localise and stage disease. This study aimed to evaluate the complementary role of 68Gallium (68Ga)-DOTA PET/CT in managing patients with panNETs. Design: A retrospective study conducted across three tertiary UK NET referral centres. Methods: Demographic, clinical, biochemical, cross-sectional and functional imaging data were collected from patients who had undergone a 68Ga-DOTA PET/CT scan for a suspected panNET. Results: We collected data for 183 patients (97 male): median (SD) age 63 (14.9) years, 89.1 vs. 9.3% (n=163 vs. 17) alive vs. dead (3 data missing), 141 sporadic vs. 42 familial (MEN1, n=36; 85.7%) panNETs. Non-functional vs. functional tumours comprised 73.2 vs. 21.3% (n=134 vs. 39) (10 missing). Histological confirmation was available in 89% of individuals (n=163) but tumour grading (Ki67 classiifcation) was technically possible only in a smaller cohort (n=143): grade 1, 50.3% (n=72); grade 2, 46.2% (n=66) and grade 3, 3.5% (n=5) (40 histopathological classification either not technically feasible or biopsy not perfomed). 60.1% (n=110) were localised, 14.2% (n=26) locally advanced and 23.5% (n=43) metastatic (4 missing). 224 68Ga-DOTA PET/CT scans were performed in total for: diagnosis/staging 40% (n=88), post-operative assessment/clinical surveillance 53% (n=117) and consideration of peptide receptor radionuclide therapy (PRRT) 8% (n=17) (2 missing). PET/CT results confirmed other imaging findings (53%), identified new disease sites (28.5%) and excluded suspected disease (5%). Overall, 68Ga-DOTA PET/CT imaging findings provided additional information in 119 (54%) patients and influenced management in 85 (39%) cases. Conclusion: 68Ga-DOTA PET/CT imaging more accurately stages and guides treatment in patients with sporadic/familial panNETs with newly diagnosed/recurrent disease.

Margin ACcentuation for resectable Pancreatic cancer using Irreversible Electroporation - Results from the MACPIE-I study.

INTRODUCTION: Margin accentuation (MA) using Irreversible electroporation (IRE) offers an unique opportunity to reduce the R1 resections in resectable pancreatic cancer (RPC). This study aims to assess the rate of margin positivity using IRE for MA during pancreaticoduodenectomy (PD) for resectable pancreatic head tumours. MATERIALS AND METHODS: Following ethical approval, MA using IRE was carried out in 20 consecutive patients to posterior and superior mesenteric vein (SMV) margin, and the pancreatic neck, prior to the PD resection. The control group (non-IRE; n = 91) underwent PD without MA over the study period, March 2018 to March 2020. RESULTS: There was no difference between the two groups in terms of patients' age, gender, pre-op biliary drainage, site of malignancy or pre-operative TNM stage. The overall margin positive rate for IRE group was lesser (35.0%) when compared to non-IRE group (51.6%; p = 0.177), with significantly less posterior pancreatic margin positivity (5.0% vs. 25.3%; p = 0.046). When only treated margins (SMA margin excluded) were compared, the IRE group had significantly lower margin positive rates (20.0% vs. 51.6%; p = 0.013). There was no difference between the two groups in terms of intra- or post-operative complications. With a median follow-up of 15.6 months, the median DFS and OS for IRE and non-IRE groups were 17 and 18 months (p = 0.306) and 19 and 22 months (p = 0.227) respectively. CONCLUSION: Our pilot study confirms the safety of MA using IRE for RPC, with reduction in margin positivity. These results as a proof of concept are promising and need further validation with a randomised controlled trial.