Harnessing whole human liver ex situ normothermic perfusion for preclinical AAV vector evaluation.

Developing clinically predictive model systems for evaluating gene transfer and gene editing technologies has become increasingly important in the era of personalized medicine. Liver-directed gene therapies present a unique challenge due to the complexity of the human liver. In this work, we describe the application of whole human liver explants in an ex situ normothermic perfusion system to evaluate a set of fourteen natural and bioengineered adeno-associated viral (AAV) vectors directly in human liver, in the presence and absence of neutralizing human sera. Under non-neutralizing conditions, the recently developed AAV variants, AAV-SYD12 and AAV-LK03, emerged as the most functional variants in terms of cellular uptake and transgene expression. However, when assessed in the presence of human plasma containing anti-AAV neutralizing antibodies (NAbs), vectors of human origin, specifically those derived from AAV2/AAV3b, were extensively neutralized, whereas AAV8- derived variants performed efficiently. This study demonstrates the potential of using normothermic liver perfusion as a model for early-stage testing of liver-focused gene therapies. The results offer preliminary insights that could help inform the development of more effective translational strategies.

Outcomes of patients with gallbladder cancer presenting with acute cholecystitis.

The main purpose of this study is to explore the outcomes of patients found to have gallbladder cancer during investigation and diagnosis of acute cholecystitis. The incidence of primary gallbladder cancer co-existing in acute cholecystitis is not well defined in the literature, with anecdotal reports suggesting that they experience worse outcomes than patients with gallbladder cancer found incidentally. METHODS: A retrospective review of all patients with gallbladder cancer managed at the Canberra Health Service between 1998 and May 2022 were identified and reviewed. RESULTS: A total of 65 patients were diagnosed with primary gallbladder cancer during the study period with a mean age of 70.4 years (SD 11.4, range 59-81.8 years) and a female preponderance (74% versus 26%) with a ratio of 2.8. Twenty (31%) patients presented with acute calculus cholecystitis and were found to have a primary gallbladder cancer. This group of patients were older and predominantly female, but the difference was not statistically significant. The overall 5-year survival in the cohort was 20% (stage 1 63%, stage 2 23%, stage 3 16%, and stage 4 0%). There was no statistically significant difference in survival between those who presented with acute cholecystitis vs other presentations. CONCLUSIONS: A third of the patients with gallbladder cancer presented with acute cholecystitis. There was no statistically significant difference in survival in those with bile spillage during cholecystectomy as well those presenting with acute cholecystitis.

IgG4-related sclerosing cholangitis mimicking cholangiocarcinoma.

A man in his 70s presented to the emergency department with painless obstructive jaundice. Initial blood test results show a predominantly cholestatic picture with elevated tumour markers, and imaging findings are concerning for a pancreatic head neoplasm or cholangiocarcinoma with involvement of the entire common bile duct. The patient underwent staging laparoscopy and biopsies including peritoneal washing, but did not identify any features of malignancy. Immunoglobulin G and immunoglobulin G4 testing were subsequently tested and shown to be elevated. The provisional diagnosis of immunoglobulin G4-related sclerosing cholangitis was made, and steroid treatment was empirically started. Treatment with steroids was successful, with complete resolution of symptoms and abnormal imaging findings and near complete resolution of liver function test results after 1 month.

Long-term ex situ normothermic perfusion of human split livers for more than 1 week.

Current machine perfusion technology permits livers to be preserved ex situ for short periods to assess viability prior to transplant. Long-term normothermic perfusion of livers is an emerging field with tremendous potential for the assessment, recovery, and modification of organs. In this study, we aimed to develop a long-term model of ex situ perfusion including a surgical split and simultaneous perfusion of both partial organs. Human livers declined for transplantation were perfused using a red blood cell-based perfusate under normothermic conditions (36 °C) and then split and simultaneously perfused on separate machines. Ten human livers were split, resulting in 20 partial livers. The median ex situ viability was 125 h, and the median ex situ survival was 165 h. Long-term survival was demonstrated by lactate clearance, bile production, Factor-V production, and storage of adenosine triphosphate. Here, we report the long-term ex situ perfusion of human livers and demonstrate the ability to split and perfuse these organs using a standardised protocol.

Safety of laparoscopic repair of incisional hernias in liver transplant recipients.

INTRODUCTION: Incisional hernia is a common complication following liver transplantation occurring in 5%-34% of patients. Traditionally, open repair was standard due to fear of abdominal adhesions, postoperative complications and lack of experience with laparoscopic techniques. Laparoscopic incisional hernia repair (LIHR) has now become routine in non-transplant patients, with improved postoperative outcomes. In this study, we compared outcomes after laparoscopic and open incisional hernia repair after liver transplantation at a high-volume liver transplant center. METHODS: We performed a retrospective cohort study including all incisional hernia repairs performed on post-liver transplant patients at a major liver transplant center in Australia from 2010 to 2021. Donor, recipient, intraoperative and postoperative variables were collected from the electronic medical record focusing on laparoscopic and open repairs. RESULTS: Between January 2010 and March 2021, 138 patients underwent incisional hernia repair: 40 laparoscopic (29%) and 98 open (71%). No difference in wound infection (2.5% vs. 7.7%, p = .243); wound dehiscence (.00% vs. 2.3%, p = .332) or hernia recurrence (16.3% vs. 23.0%, p = .352) was seen between treatment groups. For larger incisional hernias (>5 cm) we found that a laparoscopic repair reduced length of stay compared to open-repair (3.89 vs. 4.57 days, p = .026). CONCLUSION: Laparoscopic repair of larger incisional hernias reduced postoperative length of hospital stay, whilst potential advantages may include reduced wound complications and hernia recurrence. Importantly, laparoscopic repair did not increase postoperative complication rates and represents a safe technique for repair in this demographic.

Staged versus concurrent native nephrectomy and renal transplantation in patients with autosomal dominant polycystic kidney disease: A systematic review.

BACKGROUND: Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) frequently undergo native nephrectomy before transplantation. The nephrectomy may be a staged procedure or undertaken simultaneously with transplantation. When performed simultaneously, the transplant procedure is more prolonged, involves a larger operative field and incision. There is also a concern of a greater risk of graft loss with simultaneous nephrectomy and transplantation. Moreover, staged surgery may allow nephrectomy to be performed before immunosuppression introduction via a smaller incision or involving a minimally invasive approach. However, staged nephrectomy may require a period of dialysis not otherwise necessary if a transplant and nephrectomy were simultaneous. Moreover, only a single procedure is needed, implying the avoidance of a prior nephrectomy and its attendant morbidity in a patient with chronic renal insufficiency. To account for these issues, this study aims to compare the cumulative morbidity of two-staged procedures versus a single simultaneous approach in term of morbidity and graft outcomes. OBJECTIVES: This study aims to systematically review the literature to determine whether a staged or simultaneous approach to native nephrectomy in ADPKD is the optimal approach in terms of morbidity and graft outcomes. METHODS: A literature search of MEDLINE and EMBASE was conducted to identify published systematic reviews, randomized control trials, case-controlled studies and case studies. Data comparing outcomes of staged and simultaneous nephrectomy for patients undergoing kidney transplantation was extracted and analyzed. The main outcomes analyzed were length of hospitalization, blood loss, operative time, other early postoperative complications and risk of graft thrombosis. Meta-analysis was conducted where appropriate. RESULTS: Seven retrospective cohort studies were included in the review. There was a total of 385 patients included in the analysis, of whom 273 patients underwent simultaneous native nephrectomy and kidney transplantation. Meta-analysis showed an increased cumulative operative time in staged procedures (RR 1.86；95% CI 0.43-3.29 p = 0.01) and increased risk of blood transfusions (RR 2.69; 95% CI 1.92-3.46 p < 0.00001). For the transplant procedure, there were no significant difference in the length of stay (RR 1.03; 95% CI -2.01-4.14 p = 0.52), major postoperative complications (RR 0.02; 95% CI -0.15-0.10 p = 0.74) and vascular thromboses (RR 1.42 95% CI 0.23-8.59 p = 0.7). CONCLUSION: The results suggest that staged nephrectomy followed by kidney transplantation is associated with a longer cumulative operative time and increased cumulative risk of blood transfusions. There is no evidence to suggest that performing a simultaneous nephrectomy and kidney transplant procedure increases the perioperative mortality rate, major postoperative complication rates or risk of vascular thrombosis.

Surgical management of symptomatic right-sided Bochdalek hernias in adults: when is a minimally invasive approach appropriate?

BACKGROUND: Right-sided Bochdalek hernias are uncommon congenital diaphragmatic hernias that can be challenging to manage because they can contain bowel, omentum, kidney or liver. METHODS: We describe our experience at a single centre and integrate this with all reported cases in the literature to evaluate how this rare problem has been managed and when a minimally invasive approach is appropriate. RESULTS: A total of 31 patients were identified, four patients from our institution and 27 case reports from the literature. A minimally invasive approach was utilized in 15 of 31 patients (including two of four at our institution) and was more common if the operation was performed in the elective setting (10/12 versus 4/19). If a bowel resection was required, an open approach was more common (9/17 versus 1/14). The commonest method of repair was a primary suture repair (18/31), and the mesh was used in 13 cases, particularly in the elective setting (9/12 versus 4/19). CONCLUSION: Right-sided Bochdalek hernias are an uncommon and challenging problem. These hernias can contain bowel, kidney and even liver but can still be successfully repaired using minimally invasive techniques, especially in the elective setting and when an emergency bowel resection is not required.

Abdominal wall complications following renal transplantation in adult recipients - factors associated with interventional management in one unit.

BACKGROUND: Abdominal wall surgical site complications following renal transplantation can be challenging to manage. A sub-group of these recipients will require operative management or advanced wound care such as negative pressure wound therapy (NPWT). The aim of this study was to determine if there were any preoperative, intraoperative and postoperative characteristics in our recipients' cohort which were associated with the requirement for such interventions. METHODS: A retrospective review of medical records was performed for all recipients who sustained abdominal wall complications following renal transplantation at our centre from 2006 to 2016. RESULTS: A total of 64/828 recipients (7.7%) had abdominal wall complications. The mean weight for these patients was 84.9 kg (±16.6 kg) and the mean body mass index was 30.2 (±5.1). Forty-five recipients (70%) had a superficial wound dehiscence while nine (14%) had a complete fascial dehiscence. Operative intervention was required in 13/64 patients (20%) and was more likely to be required in the presence of a fascial dehiscence (9/9, 100%) or a wound collection (10/31, 32%) (p < 0.001, p = 0.021). NPWT was used in 17/64 patients (27%) and was more commonly required in patients with diabetes mellitus (10/24, 42%), a complete fascial dehiscence (5/9, 56%) or evidence of infection (16/44, 36%) (p = 0.039, p = 0.034, p = 0.008). CONCLUSIONS: The requirement for either operative management or the use of NPWT in the management of abdominal wall complications following renal transplantation in our experience was more common in recipients with diabetes mellitus, and in the setting of either complete fascial dehiscence, abdominal wall wound collections and/ or infection.