Initial Experience With Robotic Liver Resection in the United States.

BACKGROUND: This study's aim was to show the feasibility and safety of robotic liver resection (RLR) even without extensive experience in major laparoscopic liver resection (LLR). METHODS: A single center, retrospective analysis was performed for consecutive liver resections for solid liver tumors from 2014 to 2022. RESULTS: The analysis included 226 liver resections, comprising 127 (56.2%) open surgeries, 28 (12.4%) LLR, and 71 (31.4%) RLR. The rate of RLR increased and that of LLR decreased over time. In a comparison between propensity score matching-selected open liver resection and RLR (41:41), RLR had significantly less blood loss (384 ± 413 vs 649 ± 646 mL, P = .030) and shorter hospital stay (4.4 ± 3.0 vs 6.4 ± 3.7 days, P = .010), as well as comparable operative time (289 ± 123 vs 290 ± 132 mins, P = .954). A comparison between LLR and RLR showed comparable perioperative outcomes, even with more surgeries with higher difficulty score included in RLR (5.2 ± 2.7 vs 4.3 ± 2.5, P = .147). The analysis of the learning curve in RLR demonstrated that blood loss, conversion rate, and complication rate consistently improved over time, with the case number required to achieve the learning curve appearing to be 60 cases. CONCLUSIONS: The findings suggest that RLR is a feasible, safe, and acceptable platform for liver resection, and that the safe implementation and dissemination of RLR can be achieved without solid experience of LLR.

'Burn and Push' technique: A novel robotic liver parenchymal transection technique.

BACKGROUND: Liver parenchymal transection during robotic liver resection (RLR) remains a significant challenge due to the limited range of specialised instruments. This study introduces our 'Burn and Push' technique as a novel approach to address these challenges. METHODS: A retrospective analysis was conducted on 20 patients who underwent RLR using the 'Burn and Push' technique at Virginia Commonwealth University Health System from November 2021 to August 2023. The study evaluated peri- and post-operative outcomes. RESULTS: The median operation time was 241.5 min (range, 90-620 min), and the median blood loss was 100 mL (range, 10-600 mL). Major complications occurred in one case, with no instances of postoperative bleeding, bile leak, or liver failure. CONCLUSIONS: The 'Burn and Push' technique is a viable and efficient alternative for liver parenchymal transection in RLR. Further research with larger sample sizes and consideration of the learning curve is necessary to validate these findings.

Inflammatory and hypoxic stress-induced islet exosomes released during isolation are associated with poor transplant outcomes in islet autotransplantation.

Islets experience enormous stress during the isolation process, leading to suboptimal endocrine function after total pancreatectomy with islet autotransplantation (TPIAT). Our investigation focused on inducing isolation stress in islets ex vivo, where proinflammatory cytokines and hypoxia prompted the release of stress exosomes (exoS) sized between 50 and 200 nm. Mass spectrometry analysis revealed 3 distinct subgroups of immunogenic proteins within these exoS: damage-associated molecular patterns (DAMPs), chaperones, and autoantigens. The involvement of endosomal-sorting complex required for transport proteins including ras-associated binding proteins7A, ras-associated binding protein GGTA, vacuolar protein sorting associated protein 45, vacuolar protein sorting associated protein 26B, and the tetraspanins CD9 and CD63, in exoS biogenesis was confirmed through immunoblotting. Next, we isolated similar exoS from the islet infusion bags of TPIAT recipients (N = 20). The exosomes from infusion bags exhibited higher DAMP (heat shock protein family A [Hsp70] member 1B and histone H2B) levels, particularly in the insulin-dependent TPIAT group. Additionally, elevated DAMP protein levels in islet infusion bag exosomes correlated with increased insulin requirements (P = .010) and higher hemoglobin A1c levels 1-year posttransplant. A deeper exploration into exoS functionality revealed their potential to activate monocytes via the toll-like receptor 3/7: DAMP axis. This stimulation resulted in the induction of inflammatory phenotypes marked by increased levels of CD68, CD80, inducible nitric oxide synthase, and cyclooxygenase-2. This activation mechanism may impact the successful engraftment of transplanted islets.

Domino Liver Transplantation for Unresectable Colon Cancer Liver Metastasis From a Donor With Heterozygous Familial Hyperlipidemia: A Case Report.

Liver transplantation (LT) is a potential curative treatment for unresectable colorectal cancer liver metastasis (CRLM). Familial hypercholesterolemia (FH) is an inherited condition characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels. Liver transplantation is offered for selected cases, and an explanted liver can be used as a domino graft. We report the first report of domino LT for unresectable CRLM using a liver from a patient with heterozygous FH. The domino donor was a 30-year-old female with a history of heterozygous FH. She had failed medical therapies for FH, including plasmapheresis; therefore, she underwent living donor LT as a treatment for FH. The explanted liver was transplanted to the domino recipient. She has been doing well with normal LDL-C levels. The domino recipient was a 44-year-old female with a history of stage 4 sigmoid cancer with liver metastases, for which she underwent laparoscopic sigmoid colectomy and right hepatectomy. She developed unresectable lesions in the remnant left lobe, which were controlled well with chemotherapy; therefore, she underwent domino LT. She is doing well without recurrence at the 31-month follow-up. Domino LT from a donor with heterozygous FH is feasible for strictly selected patients with unresectable CRLM.

Liver transplantation for post-COVID-19 cholangiopathy: A case series.

BACKGROUND: Post-COVID-19 cholangiopathy is an emerging cholestatic liver disease observed in patients recovering from severe COVID-19 infection. Its prognosis is poor, necessitating liver transplantation in some cases. This study aimed to investigate the outcomes of liver transplantation for post-COVID-19 cholangiopathy. METHODS: Seven patients who underwent liver transplantation for post-COVID-19 cholangiopathy at three institutions between 2020 and 2022 were included in this retrospective multi-center case series. RESULTS: At the time of initial COVID-19 infection, all patients developed acute respiratory distress syndrome, and six patients (86%) required ICU admission. Median time intervals from the initial COVID-19 diagnosis to the diagnosis of post-COVID-19 cholangiopathy and liver transplantation were 4 and 12 months, respectively. Four patients underwent living donor liver transplantation, and three patients underwent deceased donor liver transplantation. The median MELD score was 22 (range, 10-38). No significant intraoperative complications were observed. The median ICU and hospital stays were 2.5 and 12.5 days, respectively. One patient died due to respiratory failure 5 months after liver transplantation. Currently, the patient and graft survival rate is 86% at a median follow-up of 11 months. CONCLUSIONS: Liver transplantation is a viable option for patients with post-COVID-19 cholangiopathy with acceptable outcome. Timely identification of this disease and appropriate management, including evaluation for liver transplantation, are essential.

Exosomes in transplantation: Role in allograft rejection, diagnostic biomarker, and therapeutic potential.

Exosomes are 50-200 nm-sized extracellular vesicles that are secreted by cells to transfer signals and communicate with other cells. Recent research has revealed that allograft-specific exosomes containing proteins, lipids, and genetic materials are released into circulation post-transplantation which are powerful indicators of graft failure in solid-organ and tissue transplantations. The macromolecular content of exosomes released by the allograft and the immune cells serve as potential biomarkers for assessing the function and the acceptance/rejection status of the transplanted grafts. Identifying these biomarkers could aid in the development of therapeutic strategies to improve graft longevity. Exosomes can be used to deliver therapeutic agonists/antagonists to grafts and prevent rejection. Inducing long-term graft tolerance has been demonstrated in many studies using exosomes from immunomodulatory cells such as immature DCs, T regulatory cells, and MSCs. The use of graft-specific exosomes for targeted drug therapy has the potential to reduce the unwanted side effects of immunosuppressive drugs. Overall, in this review, we have explored the critical role of exosomes in the recognition and cross-presentation of donor organ-specific antigens during allograft rejection. Additionally, we have discussed the potential of exosomes as a biomarker for monitoring graft function and damage, as well as their potential therapeutic applications in mitigating allograft rejection.

Single incision simultaneous liver kidney transplantation: Feasibility and outcomes.

BACKGROUND: Traditionally, simultaneous liver kidney transplantation (SLK) has been performed using a subcostal incision for the liver allograft and a lower abdominal incision for kidney transplantation (dual incision, DI). At our institution, we performed SLK using a single subcostal incision (SI). The aim of this study was to report the outcomes of single versus dual incisions for SLK. METHODS: A retrospective cohort study of consecutive SLK procedures performed at our center from January 2015 to April 2021 was performed. The demographic characteristics, complications, intraoperative findings, and complications after SI and DI were statistically compared. RESULTS: A total 37 SLK were performed (19 DI and 18 SI). The age and indications for transplantation were comparable between the two groups. Patient in SI group had significantly higher MELD score (27.0 ± 1.5 vs. 31.7 ± 1.5, p = .038). The cold ischemic time of kidney transplantation (599 ± 26 min vs. 447 ± 27 min, p < .001) and the total surgical time (508 ± 21 min vs. 423 ± 22 min, p = .008) were significantly shorter in the SI group. The incidence of complications and post-transplant kidney function was comparable between the groups. A slightly higher incidence of surgical site complications was noted in the DI group without any statistically significance (p = .178). CONCLUSIONS: Single-subcostal incision SLK is technically feasible and has comparable outcomes to dual-incision SLK. SI was associated with shorter cold ischemic time for kidney transplant, as well as shorter overall operative time.

Assessment of Culture/Preservation Conditions of Human Islets for Transplantation.

Islet culture before clinical transplantation has been adopted by various centers, but its effect on the survival and function of islets relative to the culture conditions and media needs further assessment. Human islets were cultured or preserved under four different conditions and three media options. Parameters such as recovery, viability, function, islet damage, and gene expressions for markers of hypoxia, and inflammation were assessed after 48-h culture or preservation. Preservation of islets was performed at 4°C in Connaught's Medical Research Lab (CMRL) and University of Wisconsin (UW) media. Islets were cultured at 22°C, 37°C, and 37°C-22°C in CMRL and PRODO culture media. Islets preserved in UW solution had visually good morphology and exhibited higher recovery with less islet damage compared with the rest of the groups, whereas islets preserved in CMRL at 4°C resulted in poor morphology, recovery, viability, and function compared with the rest of the treatment conditions. Culture at 22°C and 37°C demonstrated an increase in the expression of inflammatory and hypoxia-related genes. In conclusion, islets preserved at 4°C in UW solution showed the best overall outcomes after 48 h compared with islets cultured at 22°C, 37°C, or 37°C-22°C in PRODO. Advancement in islet culture media is warranted to reduce inflammatory gene activation and improve recovery of islets for transplantation.

Purification and Isolation of Hepatic Stellate Cells.

Quiescent human hepatic stellate cells (HSCs) serve as important reservoirs of fat-soluble vitamins in the body, namely vitamin A. In an activated form, HSCs are the drivers of fibrosis following chronic liver injury. In non-alcoholic steatohepatitis (NASH) specifically, activated HSCs are drivers of induction and progression of fibrogenesis. Isolation and purification of HSCs from donor liver samples provides an avenue to study HSCs and their fibrotic capabilities. Manual and chemical digestion of donor liver via dissection and Pronase, collagenase, and DNAse treatment creates a suspension of non-parenchymal liver cells. Quiescent HSCs can be further isolated from this suspension by density-gradient centrifugation in a 6%, 8%, 12%, and 15% arabinogalactan medium. After collection of HSCs from the low-density layers of the gradient, they can be grown on uncoated plastic. Rodent HSCs can also be isolated via density-gradient centrifugation. To isolate activated HSCs, liver tissue explants or established immortalized HSC lines can be utilized. Here, we described protocols for isolation of human and rodent HSCs.

A comparison of the inflammatory response following autologous compared with allogenic islet cell transplantation.

BACKGROUND: The initial response to islet transplantation and the subsequent acute inflammation is responsible for significant attrition of islets following both autologous and allogenic procedures. This multicentre study compares this inflammatory response using cytokine profiles and complement activation. METHODS: Inflammatory cytokine and complement pathway activity were examined in two cohorts of patients undergoing total pancreatectomy followed either by autologous (n=11) or allogenic (n=6) islet transplantation. Two patients who underwent total pancreatectomy alone (n=2) served as controls. RESULTS: The peak of cytokine production occurred immediately following induction of anaesthesia and during surgery. There was found to be a greater elevation of the following cytokines: TNF-alpha (P<0.01), MCP-1 (P=0.0013), MIP-1α (P=0.001), MIP-1ß (P=0.00020), IP-10 (P=0.001), IL-8 (P=0.004), IL-1α (P=0.001), IL-1ra (0.0018), IL-10 (P=0.001), GM-CSF (P=0.001), G-CSF (P=0.0198), and Eotaxin (P=0.01) in the allogenic group compared to autografts and controls. Complement activation and consumption was observed in all three pathways, and there were no significant differences in between the groups although following allogenic transplantation ∆IL-10 and ∆VEGF levels were significantly elevated those patients who became insulin-independent compared with those who were insulin-dependent. CONCLUSIONS: The cytokine profiles following islet transplantation suggests a significantly greater acute inflammatory response following allogenic islet transplantation compared with auto-transplantation although a significant, non-specific inflammatory response occurs following both forms of islet transplantation.

The demise of islet allotransplantation in the United States: A call for an urgent regulatory update.

Islet allotransplantation in the United States (US) is facing an imminent demise. Despite nearly three decades of progress in the field, an archaic regulatory framework has stymied US clinical practice. Current regulations do not reflect the state-of-the-art in clinical or technical practices. In the US, islets are considered biologic drugs and "more than minimally manipulated" human cell and tissue products (HCT/Ps). In contrast, across the world, human islets are appropriately defined as "minimally manipulated tissue" and not regulated as a drug, which has led to islet allotransplantation (allo-ITx) becoming a standard-of-care procedure for selected patients with type 1 diabetes mellitus. This regulatory distinction impedes patient access to islets for transplantation in the US. As a result only 11 patients underwent allo-ITx in the US between 2016 and 2019, and all as investigational procedures in the settings of a clinical trials. Herein, we describe the current regulations pertaining to islet transplantation in the United States. We explore the progress which has been made in the field and demonstrate why the regulatory framework must be updated to both better reflect our current clinical practice and to deal with upcoming challenges. We propose specific updates to current regulations which are required for the renaissance of ethical, safe, effective, and affordable allo-ITx in the United States.

Outcomes of Islet Autotransplantation in Chronic Pancreatitis Patients with Complete Acinar Atrophy.

Total pancreatectomy with islet autotransplantation (TPIAT) is a promising treatment for refractory chronic pancreatitis (CP). Pathological features of CP include progressive fibrosis in pancreas parenchyma, atrophy, and/or ductal occlusion. Complete acinar atrophy (CAA) caused by chronic fibrosis and necroinflammation results in exocrine sufficiency and may influence islet isolation characteristics during TPIAT. In this analysis of patients who underwent TPIAT at our center, we compared transplant outcomes among those with CAA (n = 5) vs non-acinar atrophy (NAA; matching controls, n = 36). Data were analyzed using one-way analysis of variance with Bonferroni post hoc test or Student's t test. Pancreas digestion was longer in CAA than in NAA cases (18.6 vs 14.6 min) despite a lower pancreas weight (55.2 vs 91.2 g). Obtained tissue volume was 1.0 ml in the CAA group and 12.1 ml in the NAA group. Both groups had similar islet viability (96%) and islet dose (CAA, 3,391 IEQ/kg; NAA, 4141.1 IEQ/kg). During islet infusion, serum cytokine (IL-6, IL-8, and MCP-1) levels and plasma hsa-miR-375 levels were lower in the CAA group than in the NAA group, but not significantly. Serum tumor necrosis factor α levels at 3 h after infusion were significantly higher in CAA group than in NAA group. After TPIAT, the metabolic outcomes of the CAA group were comparable with that of the NAA group. Narcotics usage decreased significantly over 24 months in both groups, with the CAA group reporting being pain free at 12 months. Complete atrophy of acinar cells of pancreas did not significantly impact islet yield or endocrine function after TPIAT.

Management of hepatic artery aneurysm: A case series.

Hepatic artery aneurysms are rare, but their diagnosis is important because of high mortality and complications. Common risk factors for developing these aneurysms include hypertension, vascular disease, pancreatitis, diabetes, tobacco use, autoimmune diseases, and previous transplantation. Frequent imaging for trauma and tumor surveillance has increased the incidence of naive hepatic aneurysms. These aneurysms can be difficult to manage, and it can be challenging to decide the correct treatment modality for the patient. Hereby, we present four cases of hepatic artery aneurysm and discuss various treatment options. Patient 1 suffered from a proper and right hepatic artery aneurysm discovered incidentally; repaired with an endovascular intervention later complicated by an endoleak which was further managed by another stenting. Patient 2 had a common hepatic artery aneurysm followed with serial imaging without any intervention. Patient 3 had a hepatic artery aneurysm and liver mass diagnosed concurrently. The patient underwent an open surgical repair of his aneurysm with graft and liver resection which was complicated later with rupture of aneurysm followed by surgical bypass repair. Patient 4 suffered from a large hepatic artery aneurysm causing bile duct compression. Her aneurysm was repaired open with splenic artery grafting. Patients were managed from careful observation to surgery with different outcomes.

The role of total pancreatectomy with islet autotransplantation in the treatment of chronic pancreatitis: A report from the International Consensus Guidelines in chronic pancreatitis.

BACKGROUND: Advances in our understanding of total pancreatectomy with islet autotransplantation (TPIAT) have been made. We aimed to define indications and outcomes of TPIAT. METHODS: Expert physician-scientists from North America, Asia, and Europe reviewed the literature to address six questions selected by the writing group as high priority topics. A consensus was reached by voting on statements generated from the review. RESULTS: Consensus statements were voted upon with strong agreement reached that (Q1) TPIAT may improve quality of life, reduce pain and opioid use, and potentially reduce medical utilization; that (Q3) TPIAT offers glycemic benefit over TP alone; that (Q4) the main indication for TPIAT is disabling pain, in the absence of certain medical and psychological contraindications; and that (Q6) islet mass transplanted and other disease features may impact diabetes mellitus outcomes. Conditional agreement was reached that (Q2) the role of TPIAT for all forms of CP is not yet identified and that head-to-head comparative studies are lacking, and that (Q5) early surgery is likely to improve outcomes as compared to late surgery. CONCLUSIONS: Agreement on TPIAT indications and outcomes has been reached through this working group. Further studies are needed to answer the long-term outcomes and maximize efforts to optimize patient selection.

Pilot study: deficiency of mannose-binding lectin-dependent lectin pathway, a novel modulator in outcome from pancreatic islet auto-transplantation.

BACKGROUND: Numerous factors influence pancreatic islet survival following auto-transplantation. Of these, the host immune response in the early peri-operative period is one of the most important. In this study we investigated the role of the mannose-binding lectin (MBL)-dependent pathway in a group of total pancreatectomy (TP) islet auto-transplantation (TPIAT) patients and classified them as competent or deficient in MBL activity. Complement pathway activities, MBL protein and inflammatory cytokine concentrations were evaluated from eleven pancreatic islet auto-transplant patients from two institutions. METHODS: Eleven patients from two institutions were prospectively recruited. Serum was screened at different time points for 29 different cytokines and compared according to their MBL deficient or competent status. Twelve patients from previous TPIAT patients also underwent screening of MBL pathway activity. RESULTS: A total nine of twenty three patients (39%) were MBL pathway deficient. MCP-1, IL-7 and IL-1a concentrations were significantly lower in the MBL deficient cohort compared to the normal MBL group (P=0.0237, 0.0001 and 0.0051 respectively). IL-6 and IL-8 concentrations were significantly raised in the normal MBL group. MBL functional activity was lower in insulin-independent group compared to the insulin-dependent group. CONCLUSIONS: Complement activation is an important, possibly damaging response during intra-portal islet infusion. MBL pathway deficiency appears common in this population and the cytokine response was attenuated in MBL pathway deficient patients. Therapeutic MBL pathway blockade during and following islet auto-transplantation (IAT) may improve islet survival and function and thereby clinical outcome.

Anti-inflammatory Approach With Early Double Cytokine Blockade (IL-1ß and TNF-α) Is Safe and Facilitates Engraftment in Islet Allotransplantation.

BACKGROUND: The approach to reducing nonspecific inflammation after islet allotransplantation has been designed to improve engraftment, typically using 1 agent. We report results with the use of combination inflammatory blockade consisting of anti-interleukin (IL)-1ß and tumor necrosis factor (TNF)-α. METHODS: Nine patients underwent islet allotransplantation under a prospective research protocol using double cytokine blockade with anti-TNF-α (etanercept, d 0, 3, 7, 10) and IL-1ß (anakinra, d 0-7) at the time of each islet infusion. The primary endpoint, assessed 2 years after the last islet transplant, was the elimination of severe hypoglycemic events and hypoglycemia unawareness, with proper glycemic control, and detectable serum C-peptide. RESULTS: No thrombotic events or infectious complications were associated with combined IL-1ß and TNF-α blockade. Six patients became insulin independent, 2 had partial function, and 1 had primary nonfunction. After 24-month follow-up, 6 of 9 patients had excellent glycemic control, hemoglobin A1c ≤6.5%, and no episodes of hypoglycemia unawareness. Eight patients developed HLA alloantibodies at various time points (class 1, 5; class 2, 6), with enhanced T-cell alloreactivity. One patient retained good graft function despite having anti-glutamic acid decarboxylase 65 antibodies. CONCLUSIONS: The use of double cytokine blockade is safe, with reduction of inflammation at transplantation and presumably with better engraftment. However, it does not influence later islet loss from T-cell-mediated autoimmunity and alloimmunity, which require other strategies to maintain long-term islet function.

The impact of surgical complications on the outcome of total pancreatectomy with islet autotransplantation.

Total pancreatectomy with islet autotransplantation is a promising treatment for refractory chronic pancreatitis. We analyzed postoperative complications in 83 TPIAT patients and their impact on islet graft function. We examined patient demographics, preoperative risk factors, intraoperative variables, and 30- and 90-day postoperative morbidity and mortality. Daily insulin requirement, HbA1c, C-peptide levels, and narcotic requirements were analyzed before and after surgery. Adverse events were recorded, with postoperative complications graded according to the Clavien-Dindo classification. There was no mortality in this patient group. Postoperative complications occurred in 38 patients (45.7%). Patients with postoperative complications were readmitted significantly more often within 30 days (p = 0.01) and 90 days posttransplant (p < 0.0003) and had a significantly longer hospital stay (p = 0.004) and intensive care unit stay (p = 0.001). Insulin dependence and graft function assessed by HbA1c, C-Peptide and insulin requirements did not differ significantly by these complications. Postoperative complications after TPIAT are associated with longer hospital and intensive care unit stay and with readmission; however, the surgical complications do not affect islet graft function.