Predictors of recurrence following laparoscopic minor hepatectomy for hepatocellular carcinoma in the UK.

AIMS: Minor hepatectomy, which is increasingly carried out laparoscopically (LLR), is a cornerstone of curative treatment for hepatocellular carcinoma (HCC). The majority of relevant publications however originate from regions with endemic viral hepatitis. Although the incidence of HCC in the UK is increasing, little is known about outcomes following LLR. METHODS: Consecutive patients undergoing minor (involving ≤2 segments) LLR or open resection (OLR) at our institute between 2014 and 2021 were compared. Selection from a plethora of factors potentially impacting on overall (OS) and disease free survival (DFS) was optimised with Lasso regression. To enable analysis of patients having repeat resection, multivariate frailty modelling was utilised to calculate hazard ratios (HR). RESULTS: The analysis of 111 liver resections included 55 LLR and 56 OLR. LLR was associated with a shorter hospital stay (5 ± 2 vs. 7 ± 2 days; p < 0.001) and a lower comprehensive complication index (4.43 vs. 9.96; p = 0.006). Mean OS (52.3 ± 2.3 vs. 49.9 ± 3.0 months) and DFS (33.9 ± 3.4 vs. 36.5 ± 3.6 months; p = 0.59) were comparable between LLR and OLR, respectively (median not reached). Presence of mixed cholangiocarcinoma/HCC, satellite lesions and AFP level predicted OS and DFS. In addition tumour size was predictive of DFS. CONCLUSIONS: In the studied population minor LLR was associated with shorter hospital stay and fewer complications while offering non-inferior long-term outcomes. A number of predictors for disease free survival have been elucidated that may aid in identifying patients with a high risk of disease recurrence and need for further treatment.

Safety and efficacy of irreversible electroporation treatment in hepatobiliary and pancreatic tumours: a single-centre experience.

AIM: To report initial experience with irreversible electroporation (IRE) in a single tertiary oncology centre and to describe its role in the management of liver and pancreatic tumours. MATERIALS AND METHODS: The present study was a retrospective review of the technical success rate, complications, and treatment efficacy of patients who had undergone IRE treatment for hepatobiliary and pancreatic tumours between February 2014 to January 2020. The patients were divided into two cohorts: first 30 patients (cohort A) and subsequent 70 patients (cohort B) after a change in protocol. RESULTS: One hundred IRE procedures (n=69 liver lesions; n=28 pancreatic lesions, n=3 nodal disease) were reviewed. The overall technical success rate was 99%. Early and immediate complications were 4% and 3%, respectively. In cohort A, the complete tumour ablation rate was 65% (13/20) for hepatic tumours, 20% (1/5) for locally advanced pancreatic adenocarcinoma, 50% (2/4) for pancreatic neuroendocrine tumours, and 0% (0/1) for nodal metastasis. For cohort B, the rate improved to 87.76% (43/49) for hepatic tumours, 28.57% (4/14) for locally advanced pancreatic adenocarcinoma, 80% (4/5) for pancreatic neuroendocrine, and 50% (1/2) for nodal metastasis. After the initial cohort A, cohort B showed a significant increase in the initial complete ablation rate in hepatic tumours (p=0.028). CONCLUSION: IRE is a complex technique with a steep learning curve. It is safe, effective, and is valuable in the treatment of liver tumours that are unsuitable or considered high risk for conventional thermal ablation. Its role in the management of pancreatic tumours is less clear and requires larger studies.

Short- and long-term mortality after liver transplantation in patients with and without hepatocellular carcinoma in the UK.

BACKGROUND: The increasing demand for liver transplantation has led to considerable changes in characteristics of donors and recipients. This study evaluated the short- and long-term mortality of recipients with and without hepatocellular carcinoma (HCC) in the UK between 1997 and 2016. METHODS: First-time elective adult liver transplant recipients in the UK were identified and four successive eras of transplantation were compared. Hazard ratios (HRs) comparing the impact of era on short-term (first 90 days) and longer-term (from 90 days to 5 years) mortality were estimated, with adjustment for recipient and donor characteristics. RESULTS: Some 1879 recipients with and 7661 without HCC were included. There was an increase in use of organs donated after circulatory death (DCD), from 0 per cent in era 1 to 35·2 per cent in era 4 for recipients with HCC, and from 0·2 to 24·1 per cent for non-HCC recipients. The 3-year mortality rate decreased from 28·3 per cent in era 1 to 16·9 per cent in era 4 (adjusted HR 0·47, 95 per cent c.i. 0·35 to 0·63) for recipients with HCC, and from 20·4 to 9·3 per cent (adjusted HR 0·44, 0·36 to 0·53) for those without HCC. Comparing era 4 with era 1, improvements were more marked in short-term than in long-term mortality, both for recipients with HCC (0-90 days: adjusted HR 0·20, 0·10 to 0·39; 90 days to 5 years: adjusted HR 0·52, 0·35 to 0·75; P = 0·043) and for non-HCC recipients (0-90 days: adjusted HR 0·32, 0·24 to 0·42; 90 days to 5 years: adjusted HR 0·52, 0·40 to 0·67; P = 0·024). CONCLUSION: In the past 20 years, the mortality rate after liver transplantation has more than halved, despite increasing use of DCD donors. Improvements in overall survival can be explained by decreases in short-term and longer-term mortality.

ANTECEDENTES: La creciente demanda de trasplante hepático ha determinado cambios considerables en las características de los donantes y receptores. En este estudio, se evaluó la mortalidad a corto y a largo plazo de los receptores de trasplante hepático por carcinoma hepatocelular (hepatocelular carcinoma, HCC) y no-HCC en el Reino Unido entre 1997 y 2016. MÉTODOS: Se identificaron los receptores adultos de un primer trasplante hepático electivo en el Reino Unido y se compararon cuatro eras sucesivas de trasplante. Se estimaron los cocientes de riesgos instantáneos ajustados (adjusted hazard ratio, aHR) que comparaban el impacto de la era en la mortalidad a corto plazo (primeros 90 días) y a largo plazo (de 90 días a 5 años) ajustando por las características del receptor y del donante. RESULTADOS: Se incluyeron 1.879 receptores HCC y 7.661 receptores no-HCC. Hubo un aumento en el uso de donantes después de parada cardíaca (donors following circulatory death, DCD) del 0% en la era 1 al 35,2% en la era 4 para los receptores HCC y del 0,2% al 24,1% para los receptores no-HCC. La mortalidad a los 3 años disminuyó de 28,3% en la era 1 a 16,9% en la era 4 (aHR 0,47, i.c. del 95% 0,35-0,63) para receptores HCC y de 20,4% a 9,3% (aHR 0,44, 0,36-0,53) para receptores no-HCC. Comparando la era 1 y la era 4, las mejoras en la mortalidad a corto plazo fueron más marcadas que en la mortalidad a largo plazo, tanto para receptores HCC (aHR 0-90 días 0,20, 0,10-0,39; 90 días-5 años 0,52, 0,35-0,75; P =舁0,04) como para receptores no-HCC (aHR 0-90 días 0,32, 0,24-0,42; 90 días-5 años 0,52, 0,40-0,67; P =舁0,02). CONCLUSIÓN: En los últimos 20 años, la mortalidad después del trasplante de hígado se ha reducido a más de la mitad, a pesar del uso cada vez mayor de donantes DCD. Las mejoras en la supervivencia global pueden explicarse por la disminución de la mortalidad a corto y largo plazo.

Liver transplantation outcomes after transarterial chemotherapy for hepatocellular carcinoma.

BACKGROUND: Transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC) awaiting liver transplantation is widespread, although evidence that it improves outcomes is lacking and there exist concerns about morbidity. The impact of TACE on outcomes after transplantation was evaluated in this study. METHODS: Patients with HCC who had liver transplantation in the UK were identified, and stratified according to whether they received TACE between 2006 and 2016. Cox regression methods were used to estimate hazard ratios (HRs) for death and graft failure after transplantation adjusted for donor and recipient characteristics. RESULTS: In total, 385 of 968 patients (39·8 per cent) received TACE. Five-year patient survival after transplantation was similar in those who had or had not received TACE: 75·2 (95 per cent c.i. 68·8 to 80·5) and 75·0 (70·5 to 78·8) per cent respectively. After adjustment for donor and recipient characteristics, there were no differences in mortality (HR 0·96, 95 per cent c.i. 0·67 to 1·38; P = 0·821) or graft failure (HR 1·01, 0·73 to 1·40; P = 0·964). The number of TACE treatments (2 or more versus 1: HR 0·97, 0·61 to 1·55; P = 0·903) or the time of death after transplantation (within or after 90 days; P = 0·291) did not alter the outcome. The incidence of hepatic artery thrombosis was low in those who had or had not received TACE (1·3 and 2·4 per cent respectively; P = 0·235). CONCLUSION: TACE delivered to patients with HCC before liver transplant did not affect complications, patient death or graft failure after transplantation.

ANTECEDENTES: La quimioembolización transarterial (transarterial chemoembolization, TACE) en pacientes con carcinoma hepatocelular (hepatocellular carcinoma, HCC) se utiliza como puente al trasplante hepático, aunque falta evidencia de que mejore los resultados y la morbilidad relacionada es motivo de preocupación. En este estudio se evaluó el impacto de la TACE en los resultados tras el trasplante para analizar las complicaciones. MÉTODOS: Se identificaron los receptores de trasplante hepático por HCC en el Reino Unido y se estratificaron según si habían recibido TACE entre 2006 y 2016. Se utilizó el método de regresión de Cox para estimar los cocientes de riesgos instantáneos (hazard ratio, HR) para la mortalidad post-trasplante y el fallo del injerto ajustados por las características del donante y del receptor. RESULTADOS: En total, 385 (39,8%) de 968 pacientes recibieron TACE, observándose similar supervivencia del paciente a los 5 años después del trasplante: 75,2% (i.c. del 95%: 68,8% a 80,5%) con TACE y 75,0% (70,5% a 78,8 %) sin TACE. Después de ajustar según las características del donante y del receptor, no hubo diferencias en la mortalidad (HR: 0,96, 0,67 a 1,38; P = 0,82) o en el fallo del injerto (HR: 1,01, 0,73 a 1,40; P = 0,96). El número de tratamientos con TACE (≥ 2 tratamientos TACE HR: 0,97, 0,61 a 1,55; P = 0,90) o el período de tiempo después del trasplante (mortalidad del paciente antes o después de 90 días; P = 0,29) no alteró el resultado. La incidencia de trombosis de la arteria hepática fue baja en aquellos que recibieron TACE o no (1,3% y 2,5%, respectivamente; P = 0,23). El fallo del injerto debido a eventos oclusivos fue similar en el grupo de pacientes que recibieron TACE (8,0% o 11/137) o que no la recibieron (6,7% o 5/75) TACE (P = 0,74). CONCLUSIÓN: La administración de TACE en pacientes con HCC antes del trasplante hepático no influyó en las complicaciones post-trasplante, la mortalidad del paciente o el fallo del injerto.

Safety and Efficacy of Inferior Vena Cava Reconstruction During Hepatic Resection.

BACKGROUND AND AIMS: Patients with liver tumors involving the inferior vena cava have a poor outcome without surgery. Liver resection en bloc with inferior vena cava resection and reconstruction is now performed in many centers. The purpose of this study is to investigate the safety and efficacy of inferior vena cava reconstruction during hepatic resection. MATERIALS AND METHODS: A review of 12 centers reporting 240 patients with combined hepatectomy and inferior vena cava resection and reconstruction for malignant tumors was performed. Sample size, patient characteristics, histological type of the tumor, method of reconstruction, complications, and long-term survival (1-, 2-, and 5-year survival) were evaluated. RESULTS: A total of 240 patients from 12 institutions (male 58%) with mean age 54 years underwent combined liver resection and inferior vena cava resection and reconstruction for colorectal liver metastases (43%), cholangiocarcinomas (26%), hepatocellular carcinomas (19%), leiomyosarcomas (4%), and other tumors (7.9%). Reconstruction included primary closure (35.8%), patch repair (13.3%), or interposition graft (50.8%) In-hospital mortality was 6.25% and overall morbidity was 42.1%. 1- and 10-year survival rates were 79.7% and 28.9%, respectively. CONCLUSION: Tumors arising in or extending to inferior vena cava that require liver resection should be considered for surgery as it can be performed with an acceptable mortality and morbidity in centers with liver transplantation and hepato-pancreato-biliary facilities.

Case Report of Multiple Bilobar Hepatic Arterio-Portal Fistulas Post-Liver Transplantation Managed Conservatively.

Multiple intrahepatic arterio-portal fistulas are rare. The majority are isolated and occur secondary to liver trauma including iatrogenic interventions such as liver biopsy. Post-liver transplantation 18 cases have been reported, all secondary to an interventional radiological procedure. We report multiple bi-lobar arterio-portal fistulas in a liver transplant recipient recognized 1 year after transplantation. The donor died due to intracerebral bleeding following blunt head and abdominal trauma. In the present case, the etiology is not very clear. The patient was managed conservatively and to date has not required intervention.

Successful endoscopic management of a persistent bronchobiliary fistula with Histoacryl®/Lipiodol® mixture.

Introduction A bronchobiliary fistula (BBF) following liver directed therapy (resection/ablation) is a rare complication in which an abnormal communication between the biliary tract and bronchial tree is formed. This case report describes the successful management of a persistent BBF following multiple liver wedge resections and microwave ablation in a patient with a metastatic neuroendocrine tumour of the terminal ileum. Case history A 69-year-old man presented with unexplained weight loss and was subsequently diagnosed with a neuroendocrine tumour of the terminal ileum and liver metastasis. Following elective right hemicolectomy and multiple bilobar liver wedge resections combined with liver microwave ablation, he developed an early bile leak. A month later, a right subphrenic collection was identified and four months following surgery, biloptysis was noted. Numerous attempts with endoscopic retrograde biliary drainage (ERBD) failed to achieve sufficient drainage. The patient was treated successfully with endoscopic injection of a mixture of Histoacryl® glue (B Braun, Sheffield, UK) and Lipiodol® (Guerbet, Solihull, UK). There was no evidence of the BBF one year following intervention. Conclusions This novel approach for persistent BBF management using endoscopic Histoacryl® glue embolisation of the fistula tract should be considered either as an adjunct to ERBD or when biliary tract decompression by drainage and/or sphincterotomy fails, prior to proceeding with surgical interventions.

Liver transplantation in children: state of the art and future perspectives.

In this review, we provide a state of the art of liver transplantation in children, as the procedure is now carried out for more than 30 years and most of our paediatric colleagues are managing these patients jointly with liver transplant centres. Our goal for this article is to enhance the understanding of the liver transplant process that a child and his family goes through while explaining the surgical advances and the associated complications that could happen in the immediate or long-term follow-up. We have deliberately introduced the theme that 'liver transplant is a disease' and 'not a cure', to emphasise the need for adherence with immunosuppression, a healthy lifestyle and lifelong medical follow-up.

Congenital portosystemic venous shunt.

Congenital portosystemic venous shunts are rare developmental anomalies resulting in diversion of portal flow to the systemic circulation and have been divided into extra- and intrahepatic shunts. They occur during liver and systemic venous vascular embryogenesis and are associated with other congenital abnormalities. They carry a higher risk of benign and malignant liver tumors and, if left untreated, can result in significant medical complications including systemic encephalopathy and pulmonary hypertension. CONCLUSION: This article reviews the various types of congenital portosystemic shunts and their anatomy, pathogenesis, symptomatology, and timing and options of treatment. What is Known: • The natural history and basic management of this rare congenital anomaly are presented. What is New: • This paper is a comprehensive review; highlights important topics in pathogenesis, clinical symptomatology, and treatment options; and proposes an algorithm in the management of congenital portosystemic shunt disease in order to provide a clear idea to a pediatrician. An effort has been made to emphasize the indications for treatment in the children population and link to the adult group by discussing the consequences of lack of treatment or delayed diagnosis.

Subunit composition of respiratory chain complex 1 and its responses to oxygen in mitochondria from human donor livers.

OBJECTIVE: Donor liver function in transplantation is defined by mitochondrial function and the ability of mitochondria to recover from the sequence of warm and/or cold ischemia. Mitochondrial resilience maybe related to assembly and- subunit composition of Complex 1. The aim of this study was to determine if Complex 1 subunit composition was different in donor livers of varying quality and whether oxygen exposure had any effect. RESULTS: Five human livers not suitable for transplant were split. One half placed in cold static storage and the other half exposed to 40% oxygen for 2 h. Protein was extracted for western blot. Membranes were probed with antibodies against ß-actin and the following subunits of Complex 1: MTND1, NDUFA10, NDUFB6 and NDUFV2. No difference in steady state Complex 1 subunit composition was demonstrated between donor livers of varying quality, in terms of steatosis or mode of donation. Neither did exposure to oxygen influence Complex 1 subunit composition. This small observational study on subunit levels suggest that Complex 1 is fully assembled as no degradation of subunits associated with the different parts of the enzyme was seen.

Improving the Diagnostic Criteria for Primary Liver Graft Nonfunction in Adults Utilizing Standard and Transportable Laboratory Parameters: An Outcome-Based Analysis.

Current diagnostic criteria for primary nonfunction (PNF) of liver grafts are based on clinical experience rather than statistical methods. A retrospective, single-center study was conducted of all adults (n = 1286) who underwent primary liver transplant (LT) 2000-2008 in our center. Laboratory variables during the first post LT week were analyzed. Forty-two patients (3.7%) had 2-week graft failure. Transplant albumin, day-1 aspartate aminotransferase (AST), day-1 lactate, day-3 bilirubin, day-3 international normalized ratio (INR), and day-7 AST were independently associated with PNF on multivariate logistic regression. PNF score =(0.000280*D1AST)+ (0.361*D1 Lactate)+(0.00884*D3 Bilirubin)+(0.940*D3 INR)+(0.00153*D7 AST)-(0.0972*TxAlbumin)-4.5503. Receiver operating curve analysis showed the model area under receiver operating curve (AUROC) of 0.912 (0.889-0.932) was superior to the current United Kingdom (UK) PNF criteria of 0.669 (0.634-0.704, p < 0.0001). When applied to a validation cohort (n = 386, 34.4% patients), the model had AUROC of 0.831 (0.789-0.867) compared to the UK early graft dysfunction criteria of 0.674 (0.624-0.721). The new model performed well after exclusion of patients with marginal grafts and when modified to include variables from the first three post-LT days only (AUROC of 0.818, 0.776-0.856, p = 0.001). This model is superior to the current UK PNF criteria and is based on statistical methods. The model is also applicable to recipients of all types of grafts (marginal and nonmarginal).

Late cytomegalovirus infection in children: High incidence of allograft rejection and hepatitis in donor negative and seropositive liver transplant recipients.

The complications and outcome associated with late CMV infection and disease on the graft are poorly characterized in PLT recipients. We studied the overall incidence, risk factors, and outcome of late CMV infection and disease (infection 6 months after transplant) in 180 PLT recipients admitted between 2008 and 2011 at the King's College Hospital. Antiviral prophylaxis of intravenous ganciclovir was given only to the D+R- group starting at day 7 post-transplant. The remaining groups (D-R+, D+R+, and D-R-) received pre-emptive therapy when they have CMV viremia above cut-off value and treatment for symptomatic CMV infection. The overall incidence of late CMV infection and disease was 9.4% (19/180) and 14.5% (19/130) in D+R-, D-R+, D+R- groups. The D-R+ group had the highest incidence of hepatitis (37.5%) and significantly increased incidence of CMV disease, and single and multiple acute rejection episodes when compared to the D+R- group, which received prophylaxis. The late CMV infection and disease in pediatric LT recipients was comparable to adult LT recipients despite variable duration of antiviral prophylaxis. Our results show that D-R+ group had highest rate of hepatitis and rejection episodes, associated with high morbidity, and should be considered for antiviral prophylaxis.

Primum Non Nocere: Organ Donation After Electrocution and Transplantation of Electricity-Damaged Livers: Report of 2 Cases.

Liver transplantation remains the treatment of choice for patients with end-stage liver disease. However, allograft availability continues to be a problem, and extending the criteria for organ acceptance is key. Deceased donors after electrical accidents, as well as electricity-traumatized allografts, are not common but should be considered suitable. This study describes 2 cases of heart-beating organ donors with electrical injury to the liver. In 1 case, the electric shock was the cause of death; in the second case, the injury was caused by defibrillation at organ procurement. Both allografts had sustained sizeable electrical injury, and both resulted in excellent early posttransplant outcomes. These cases demonstrate that electrocution is not a contraindication to donation and that electricity-traumatized allografts may remain transplantable after careful assessment. Education of all staff in the management of such donors can optimize utility of such allografts.

Liver Transplantation After Ex Vivo Normothermic Machine Preservation: A Phase 1 (First-in-Man) Clinical Trial.

The number of donor organs suitable for liver transplantation is restricted by cold preservation and ischemia-reperfusion injury. We present the first patients transplanted using a normothermic machine perfusion (NMP) device that transports and stores an organ in a fully functioning state at 37°C. In this Phase 1 trial, organs were retrieved using standard techniques, attached to the perfusion device at the donor hospital, and transported to the implanting center in a functioning state. NMP livers were matched 1:2 to cold-stored livers. Twenty patients underwent liver transplantation after NMP. Median NMP time was 9.3 (3.5-18.5) h versus median cold ischaemia time of 8.9 (4.2-11.4) h. Thirty-day graft survival was similar (100% NMP vs. 97.5% control, p = 1.00). Median peak aspartate aminotransferase in the first 7 days was significantly lower in the NMP group (417 IU [84-4681]) versus (902 IU [218-8786], p = 0.03). This first report of liver transplantation using NMP-preserved livers demonstrates the safety and feasibility of using this technology from retrieval to transplantation, including transportation. NMP may be valuable in increasing the number of donor livers and improving the function of transplantable organs.

Meta-analysis of benefits of portal-superior mesenteric vein resection in pancreatic resection for ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma has a poor prognosis without surgery. No standard treatment has yet been accepted for patients with portal-superior mesenteric vein (PV-SMV) infiltration. The present meta-analysis aimed to compare the results of pancreatic resection with PV-SMV resection for suspected infiltration with the results of surgery without PV-SMV resection. METHODS: A systematic search was performed of PubMed, Embase and the Cochrane Library in accordance with PRISMA guidelines from the time of inception to 2013. The inclusion criteria were comparative studies including patients who underwent pancreatic resection with or without PV-SMV resection. One, 3- and 5-year survival were the primary outcomes. RESULTS: Twenty-seven studies were identified involving a total of 9005 patients (1587 in PV-SMV resection group). Patients undergoing PV-SMV resection had an increased risk of postoperative mortality (risk difference (RD) 0.01, 95 per cent c.i. 0.00 to 0.03; P = 0.2) and of R1/R2 resection (RD 0.09, 0.06 to 0.13; P < 0.001) compared with those undergoing standard surgery. One-, 3- and 5-year survival were worse in the PV-SMV resection group: hazard ratio 1.23 (95 per cent c.i. 1.07 to 1.43; P = 0.005), 1.48 (1.14 to 1.91; P = 0.004) and 3.18 (1.95 to 5.19; P < 0.001) respectively. Median overall survival was 14.3 months for patients undergoing pancreatic resection with PV-SMV resection and 19.5 months for those without vein resection (P = 0.063). Neoadjuvant therapies recently showed promising results. CONCLUSION: This meta-analysis showed increased postoperative mortality, higher rates of non-radical surgery and worse survival after pancreatic resection with PV-SMV resection. This may be related to more advanced disease in this group.

Modification of human islet preparation: an effective approach to improve graft outcome after islet transplantation?

Revascularisation of transplanted islets is an essential prerequisite for graft survival and function. However, current islet isolation procedures deprive the islets of endothelial tubulets. This may have a detrimental effect on the revascularisation process of islets following transplantation. We hypothesise that modification of the isolation procedure that preserves islet endothelial vessels may improve the islet revascularisation process following transplantation. Here, we present a modified islet isolation method by which a substantial amount of endothelial cells still attached to the islets could be preserved. The islets with preserved endothelial cells isolated by this method were revascularised within 3 days, not observed in islets isolated by standard methods. Further, we observed that grafts of islets isolated by standard methods had more patches of dead tissue than islet grafts obtained by the modified method, indicating that attached endothelial cells may play an important role in the islet revascularisation process and potentially help to improve the transplantation outcome.

Outcomes for adults with type 1 diabetes referred with severe hypoglycaemia and/or referred for islet transplantation to a specialist hypoglycaemia service.

Islet transplantation alone (ITA) is indicated for patients with type 1 diabetes (T1D) with disabling severe hypoglycaemia (SH) despite optimised medical therapy. We examined outcomes for patients referred to an islet transplant unit with recurrent SH. Retrospective case note audit of 45 patients with ≥1 SH per year who were referred to our ITA unit between 2009-2012; 36 patients attended follow-up appointments. The cohort was 52.8% male, mean (± SD) age 43.9 (± 11.4) years, and duration of diabetes 26.5 (± 12.9) years. Baseline HbA1c was 8.3% (± 1.7) (67.2 mmol/mol), median (IQR) frequency of SH was 6.0 (2.0-24.0) per/patient/year and 83.3% had impaired awareness of hypoglycaemia (IAH). 80.6% of patients were referred from other secondary diabetes services, 22.2% had completed structured education, and 30.6% were using continuous subcutaneous insulin infusion (CSII). Seventeen patients were optimised with conventional therapy; SH reduced from 2.0 (1.5-9.0) to 0.0 (0.0-0.5) episodes/patient/year; p<0.001, and there was concurrent improvement in HbA1c (8.1-7.7%; 65.0 vs. 60.7 mmol/mol; p=0.072). Ten patients were listed for transplantation as they were not optimised despite structured education, CSII, and continuous glucose monitoring (CGM). The remaining 9 had a reduction in SH [7.0 (4.8-40.5) to 4.0 (2.5-6.3) episodes/patient/year; p=0.058] and either left the service (n=5) or are still being optimised (n=4). In conclusion, 47.2% of patients presenting with problematic hypoglycaemia resolved with optimal medical therapy, with a further 25% achieving clinically relevant improvement, however 27.8% required transplantation despite access to all therapies. Provision of expertise in hypoglycaemia management is essential to focus limited transplant resources on those who need it most.

Review article: liver transplantation for hepatocellular carcinoma - a critical appraisal of the current worldwide listing criteria.

BACKGROUND: Liver transplantation (LT) plays an important role in the management of patients with hepatocellular carcinoma (HCC). Although early results following LT for HCC were poor, since the introduction of the Milan criteria in 1996 morphological criteria have since been well established. Thereafter, various expansions of the Milan criteria were introduced worldwide. Listing criteria for LT for HCC in the United Kingdom (UK) initially conformed to the Milan criteria but were re-defined in 2009 by expansion of the Milan criteria. AIMS: To look at the evidence in literature on listing criteria and management of HCC worldwide in comparison with the UK. Secondly, we aim to review worldwide vs. UK literature on prioritisation models, loco-regional therapy protocols and role of alpha-fetoprotein (AFP) in LT for HCC. METHODS: An electronic literature search with Medline was carried out to identify articles related to LT for HCC. RESULTS: Although various expansions of the Milan criteria have been described, they remain the gold standard against which other criteria are measured. The UK criteria are an expansion of the Milan criteria that go beyond Milan and University of California, San Francisco (UCSF) criteria. The current UK listing criteria for LT for HCC when compared to the worldwide criteria have a worse survival benefit (projected 5-year survival between 35-50%) when plotted on the metroticket calculator. CONCLUSIONS: In keeping with most transplant centres worldwide, the UK have adopted expansions to Milan to allow more patients to benefit from LT. However, currently, as it stands the UK criteria when plotted in the modification of the Metroticket model project worse survival that would seem unjustified.

Hemagglutinin stalk-based universal vaccine constructs protect against group 2 influenza A viruses.

Current influenza virus vaccines contain H1N1 (phylogenetic group 1 hemagglutinin), H3N2 (phylogenetic group 2 hemagglutinin), and influenza B virus components. These vaccines induce good protection against closely matched strains by predominantly eliciting antibodies against the membrane distal globular head domain of their respective viral hemagglutinins. This domain, however, undergoes rapid antigenic drift, allowing the virus to escape neutralizing antibody responses. The membrane proximal stalk domain of the hemagglutinin is much more conserved compared to the head domain. In recent years, a growing collection of antibodies that neutralize a broad range of influenza virus strains and subtypes by binding to this domain has been isolated. Here, we demonstrate that a vaccination strategy based on the stalk domain of the H3 hemagglutinin (group 2) induces in mice broadly neutralizing anti-stalk antibodies that are highly cross-reactive to heterologous H3, H10, H14, H15, and H7 (derived from the novel Chinese H7N9 virus) hemagglutinins. Furthermore, we demonstrate that these antibodies confer broad protection against influenza viruses expressing various group 2 hemagglutinins, including an H7 subtype. Through passive transfer experiments, we show that the protection is mediated mainly by neutralizing antibodies against the stalk domain. Our data suggest that, in mice, a vaccine strategy based on the hemagglutinin stalk domain can protect against viruses expressing divergent group 2 hemagglutinins.