Robotic Hepaticojejunostomy for Late Anastomotic Biliary Stricture After Liver Transplantation: Technical Description and Case Series.

Biliary strictures after liver transplantation are common and when refractive to endoscopic and percutaneous intervention require surgical revision. Robotic technology facilitates minimally invasive biliary reconstruction and has not previously been described after liver transplantation. Robotic biliary revisions were retrospectively compared to all the historical open cases over a time period from May 2013 to October 2020. During the study period there were 3 robotic and 4 open surgical biliary revisions with a follow-up of at least 6months. All cases were hepaticojejunostomies for late choledocho-choledochostomy anastomotic strictures presenting > 4 weeks after transplant and refractive to at least 3 endoscopic and/or percutaneous interventions. Median (range) case time was longer in the robotic group, 373 minutes (286-373) compared to open group, 280 minutes (163-321). The median length of stay was shorter in the robotic group, 4 days (1--4) compared to open group 7 days (4-10). Morbidity included 2 wound infections in the open group (grade II), 1 infected hematoma in the robotic group (grade Ilia), and 1 bile leak on the open group (grade Ilia). There was no biliary stricture recurrence or mortality in either group. Robotic biliary revision is a safe alternative to traditional open biliary revision for refractive biliary strictures after liver transplantation.

Improving safety of robotic major hepatectomy with extrahepatic inflow control and laparoscopic CUSA parenchymal transection: technical description and initial experience.

BACKGROUND: Blood loss is a major determinant of outcomes following hepatectomy. Robotic technology enables hepatobiliary surgeons to mimic open techniques for inflow control and parenchymal transection during major hepatectomy, increasing the ability to minimize blood loss and perform safe liver resections. METHODS: Initial experience of 20 consecutive major robotic hepatectomies from November 2018 to July 2020 at two co-located institutions was reviewed. All cases were performed with extrahepatic inflow control and parenchymal transection with the laparoscopic cavitron ultrasonic surgical aspirator (CUSA), and a technical description is illustrated. Clinical characteristics, operative data, and surgical outcomes were retrospectively analyzed. RESULTS: The median (range) patient age was 58 years (20-76) and the majority of 14 (70%) patients were ASA III-IV. There were 12 (60%) resections for malignancy and the median tumor size was 6.2 cm (1.2-14.6). Right or extended right hepatectomy was the most common procedure (12 or 60% of cases). There were 7 (35%) left or extended left hepatectomies and 1 (5%) central hepatectomy. The median operative time was 420 (177-622) minutes. Median estimated blood loss was 300 mL (25-800 mL). One (5%) case was converted to open. Two (10%) patients required blood transfusion. The median length of stay was 3 (1-6) days. Major complications included 1 (5%) Clavien-Dindo IIIa bile leak requiring percutaneous drainage placement. There was no 90-day mortality. CONCLUSION: Advanced techniques to reduce blood loss in robotic hepatectomy may optimize safety and minimize morbidity in these complex minimally invasive procedures.

CD69+ resident memory T cells are associated with graft-versus-host disease in intestinal transplantation.

Graft-versus-host disease (GvHD) is a common, morbid complication after intestinal transplantation (ITx) with poorly understood pathophysiology. Resident memory T cells (TRM ) are a recently described CD69+ memory T cell subset localizing to peripheral tissue. We observed that T effector memory cells (TEM ) in the blood increase during GvHD and hypothesized that they derive from donor graft CD69+TRM migrating into host blood and tissue. To probe this hypothesis, graft and blood lymphocytes from 10 ITx patients with overt GvHD and 34 without were longitudinally analyzed using flow cytometry. As hypothesized, CD4+ and CD8+CD69+TRM were significantly increased in blood and grafts of GvHD patients, alongside higher cytokine and activation marker expression. The majority of CD69+TRM were donor derived as determined by multiplex immunostaining. Notably, CD8/PD-1 was significantly elevated in blood prior to transplantation in patients who later had GvHD, and percentages of HLA-DR, CD57, PD-1, and naïve T cells differed significantly between GvHD patients who died vs. those who survived. Overall, we demonstrate that (1) there were significant increases in TEM at the time of GvHD, possibly of donor derivation; (2) donor TRM in the graft are a possible source; and (3) potential biomarkers for the development and prognosis of GvHD exist.

Type 3 innate lymphoid cells are associated with a successful intestinal transplant.

Although innate lymphoid cells (ILCs) play fundamental roles in mucosal barrier functionality and tissue homeostasis, ILC-related mechanisms underlying intestinal barrier function, homeostatic regulation, and graft rejection in intestinal transplantation (ITx) patients have yet to be thoroughly defined. We found protective type 3 NKp44+ ILCs (ILC3s) to be significantly diminished in newly transplanted allografts, compared to allografts at 6 months, whereas proinflammatory type 1 NKp44- ILCs (ILC1s) were higher. Moreover, serial immunomonitoring revealed that in healthy allografts, protective ILC3s repopulate by 2-4 weeks postoperatively, but in rejecting allografts they remain diminished. Intracellular cytokine staining confirmed that NKp44+ ILC3 produced protective interleukin-22 (IL-22), whereas ILC1s produced proinflammatory interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). Our findings about the paucity of protective ILC3s immediately following transplant and their repopulation in healthy allografts during the first month following transplant were confirmed by RNA-sequencing analyses of serial ITx biopsies. Overall, our findings show that ILCs may play a key role in regulating ITx graft homeostasis and could serve as sentinels for early recognition of allograft rejection and be targets for future therapies.

Rejection of intestinal allotransplants is driven by memory T helper type 17 immunity and responds to infliximab.

Intestinal transplantation (ITx) can be life-saving for patients with advanced intestinal failure experiencing complications of parenteral nutrition. New surgical techniques and conventional immunosuppression have enabled some success, but outcomes post-ITx remain disappointing. Refractory cellular immune responses, immunosuppression-linked infections, and posttransplant malignancies have precluded widespread ITx application. To shed light on the dynamics of ITx allograft rejection and treatment resistance, peripheral blood samples and intestinal allograft biopsies from 51 ITx patients with severe rejection, alongside 37 stable controls, were analyzed using immunohistochemistry, polychromatic flow cytometry, and reverse transcription-PCR. Our findings inform both immunomonitoring and treatment. In terms of immunomonitoring, we found that while ITx rejection is associated with proinflammatory and activated effector memory T cells in the blood, evidence of treatment efficacy can only be found in the allograft itself, meaning that blood-based monitoring may be insufficient. In terms of treatment, we found that the prominence of intra-graft memory TNF-α and IL-17 double-positive T helper type 17 (Th17) cells is a leading feature of refractory rejection. Anti-TNF-α therapies appear to provide novel and safer treatment strategies for refractory ITx rejection; with responses in 14 of 14 patients. Clinical protocols targeting TNF-α, IL-17, and Th17 warrant further testing.

De novo hepatocellular carcinoma 18 years after liver and small bowel transplantation in a one-year-old pediatric patient.

De novo HCC following transplantation in a child is a rare occurrence. Even within the adult liver transplantation population, there are a limited number of published cases. In this report, we present a case of de novo HCC found in a child, post-multivisceral transplantation. A 19-year-old boy, at the age of one, received liver and small bowel transplantation due to short gut syndrome secondary to midgut volvulus and total parenteral nutrition-associated liver disease. Eighteen years later, he was found to have a large mass involving the right hepatic dome consistent with HCC. To the best of our knowledge, this is the second reported case after gut transplantation and the third case post-liver transplantation in the pediatric population.

Anti-plasma cell treatment in refractory autoimmune hemolytic anemia in a child with multivisceral transplant.

BACKGROUND: Warm-antibody AIHA is known to complicate solid organ (SOT) and HSCT, the disease maybe refractory to standard therapy. Immunosuppressive therapies as well as IVIG, and rituximab have been the main stay of treatment. Over the past decade, B-lymphocyte targeted, anti-CD-20 antibody has been recognized in the treatment of autoimmune diseases and utilized in AIHA. Bortezomib, a proteasome inhibitor that causes apoptosis of plasma cells, is an appealing targeted therapy in secondary AIHA and has demonstrated efficacy in HSCT patients. From our experience, we advocate for early targeted therapy that combines B cell with plasma cell depletion. CASE REPORT: We describe a 4-year-old-girl with stage III neuroblastoma, complicated with intestinal necrosis needing multivisceral transplant developed warm AIHA 1-year after transplantation, and following an adenovirus infection. She received immunoglobulin therapy, rituximab, sirolimus, plasmapheresis, and long-term prednisolone with no sustained benefit while developing spinal fractures related to the latter therapy. She received bortezomib for intractable AIHA in combination with rituximab with no appreciable adverse effects. Three years later the child remains in remission with normal reticulocyte and recovered B cells. In the interim, she required chelation therapy for iron overload related to blood transfusion requirement during the treatment of AIHA. CONCLUSION: We propose early targeted anti-plasma cell therapy with steroid burst, IVIG, rituximab, and possible plasmapheresis may reduce morbidity in secondary refractory w-AIHA.

Efficacy and feasibility of ruxolitinib in chronic steroid-refractory GVHD in a pediatric intestine transplant.

Acute graft-versus-host disease (GvHD) has been a clinical problem in solid organ transplant that includes intestine due to the donor lymphoid tissue mass which accompanies the intestinal component of the graft. We report a case that demonstrated the efficacy and feasibility of ruxolitinib a JAK 1/2 inhibitor in the treatment of chronic steroid-refractory GVHD (SR-GVHD). The child developed SR-GVHD following a composite intestine transplant (small bowel, colon, liver, and pancreas). And after receiving ruxolitinib 1.25 mg (0.15 mg/kg/dose) per gastric tube (G-tube) daily, the child appeared to have improved skin rash and sigmoidoscopy was negative. Nonetheless, we encourage close monitoring of hematologic and infectious adverse effect during dose escalation, and individualizing patient maximum effective dose with the least adverse effect possible. We stress the importance of early diagnosis and hyper-alertness of GVHD in intestinal transplant patients.

Factors Associated With 5- and 10-Year Survival After Intestinal Transplantation in Infants and Children.

OBJECTIVES: Intestinal transplantation is an option for permanent intestinal failure with parenteral nutrition intolerance. We sought to determine long-term intestinal graft survival in pediatric patients at our center and to identify factors influencing survival. METHODS: Retrospective chart review of 86 patients transplanted between 2003 and 2013, targeting potential explanatory variables related to demographics, perioperative factors, and postoperative complications. RESULTS: Intestinal graft survival was 71% and 65% after 5 and 10 years, respectively. Five-year graft survival was attained in 79% of patients with a history of anatomic intestinal failure compared with 45% with functional intestinal failure (P = 0.0055). Compared with nonsurvival, 5-year graft survival was also associated with reduced incidences of graft-versus-host disease (2% vs 16%, P = 0.0237), post-transplant lymphoproliferative disorder (3% vs 24%, P = 0.0067), and de novo donor-specific antibodies (19% vs 57%, P = 0.0451) plus a lower donor-recipient weight ratio (median 0.727 vs 0.923, P = 0.0316). Factors not associated with 5-year intestinal graft survival included graft rejection of any severity and inclusion of a liver graft. Factors associated with graft survival at 10 years were similar to those at 5 years. CONCLUSIONS: In our experience, outcomes in pediatric intestinal transplantation have improved substantially for anatomic but not functional intestinal failure. Graft survival depends on avoidance of severe infectious and immunological complications including GVHD, whereas inclusion of a liver graft provides no obvious survival benefit. Reduced success with functional intestinal failure may reflect inherently increased susceptibility to complications in this group.

Long-term survival in visceral transplant recipients in the new era: A single-center experience.

There is a paucity of data on long-term outcomes following visceral transplantation in the contemporary era. This is a single-center retrospective analysis of all visceral allograft recipients who underwent transplant between November 2003 and December 2013 with at least 3-year follow-up data. Clinical data from a prospectively maintained database were used to assess outcomes including patient and graft survival. Of 174 recipients, 90 were adults and 84 were pediatric patients. Types of visceral transplants were isolated intestinal transplant (56.3%), combined liver-intestinal transplant (25.3%), multivisceral transplant (16.1%), and modified multivisceral transplant (2.3%). Three-, 5-, and 10-year overall patient survival was 69.5%, 66%, and 63%, respectively, while 3-, 5-, and 10-year overall graft survival was 67%, 62%, and 61%, respectively. In multivariable analysis, significant predictors of survival included pediatric recipient (P = .001), donor/recipient weight ratio <0.9 (P = .008), no episodes of severe acute rejection (P = .021), cold ischemia time <8 hours (P = .014), and shorter hospital stay (P = .0001). In conclusion, visceral transplantation remains a good option for treatment of end-stage intestinal failure with parenteral nutritional complications. Proper graft selection, shorter cold ischemia time, and improvement of immunosuppression regimens could significantly improve the long-term survival.

Successful long-term outcome after combined hematopoietic stem cell transplantation and small bowel transplantation: A case report and review of the literature.

Combining HSCT with SOT is an unusual and challenging undertaking given the complexities of immune modulation, the need to balance comorbidities, and the cumulative potential for complications. Early life-threatening complications include infections and related effects, graft rejection, and GVHD can be expected to be increased especially if the HSCT is indicated for high-risk cases such as individuals with severe combined immune deficiency and SOT that includes an intestine graft. Herein, we report such a case. Our patient is unique as a long-term survivor. We review the literature and the features of our case, especially the timing of transplants and human leukocyte antigen matching for HSCT that resulted in a successful outcome and discuss how this may be applied to others in the future.

Donor-specific antibody management in intestine transplantation: hope for improving the long-term durability of the intestine allograft?

PURPOSE OF REVIEW: In this review, we appraise the current status of donor-specific antibody (DSA) monitoring and treatment in the literature and highlight the current challenges in DSA management for the intestine transplant community. RECENT FINDINGS: Sensitizing events are common in patients referred for intestinal transplant, as these patients universally are repeatedly exposed to immune activation and inflammatory events. Both preformed and de novo DSA have been shown to increase rejection and graft loss in intestine recipients. Avoidance of preformed DSA with the use of virtual crossmatch (VXM) and antibody monitoring protocols to detect and treat de novo DSA may improve intestine transplant outcomes. There is no consensus on the clinical and pathologic criteria that are required to diagnose antibody-mediated rejection (AMR) in the intestine recipient. Therefore, many clinicians treat AMR based on the coincidence of DSA and acute biopsy-proven rejection. Inclusion of the liver in the intestine allograft appears to be immunologically protective in the setting of DSA with improved outcomes and a higher rate of preformed DSA clearance. Critically, DSA has been linked to chronic rejection and poor long-term outcomes in the intestine recipient. SUMMARY: On the basis of increasing evidence in the intestine transplant literature, it appears that avoidance of preformed DSA and aggressive monitoring and treatment of de novo DSA is a key to long-term survival following intestine transplantation.

Visceral transplantation in patients with intestinal-failure associated liver disease: Evolving indications, graft selection, and outcomes.

Intestinal failure (IF)-associated liver disease (IFALD) is widely recognized as a lethal complication of long-term parenteral nutrition. The pathophysiology of IFALD is poorly understood but appears to be multifactorial and related to the inflammatory state in the patient with IF. Visceral transplant for IFALD includes variants of intestine, liver, or combined liver-intestine allografts. Graft selection for an individual patient depends on the etiology of IF, abdominal and vascular anatomy, severity of IFALD, and potential for intestinal rehabilitation. The past decade has witnessed dramatic improvement in the management of IFALD, principally due to improved lipid emulsion formulations and the multidisciplinary care of the patient with IF. As the recognition and treatment of IFALD continue to improve, the requirement of liver-inclusive visceral grafts appears to be decreasing, representing a paradigm shift in the care of the patient with IF. This review highlights the current indications, graft selection, and outcomes of visceral transplantation for IFALD.

Impact of early reoperation on graft survival after liver transplantation: Univariate and multivariate analysis.

BACKGROUND: Data on rate, risk factors, and consequences of early reoperation after liver transplantation are still limited. STUDY DESIGN: Single-center retrospective analysis of data of 428 patients, who underwent liver transplantation in period between January 2009 and December 2014. Univariate and multivariate analysis were used to study the risk factors of early reoperation and its impact on graft survival. RESULTS: Of 428 patients, 74 (17.3%) underwent early reoperation. Of them, 46 (62.2%) underwent reoperation within the first week and 28 (37.8%) underwent reoperation later than 1 week after transplantation. With multivariate analysis, significant risk factors of early reoperation included pretransplant ICU admission, previous abdominal surgery and diabetes. Early reoperation itself was not found to be an independent predictor of graft loss. However, early reoperation later than 7 days from transplant was found to be independent predictor of graft loss (odds ratio [OR] = 5.125; 95% CI, 1.358-19.552; P = .016). In our series, other independent predictors of graft loss were MELD score (P = .010) and operative time (P = .048). CONCLUSIONS: This analysis demonstrates that early reoperations later than a week appear to negatively impact the graft survival. The timing of early reoperation should be a focus of additional studies.

World's smallest combined en bloc liver-pancreas transplantation.

We present a case of a 2-year-old child who underwent a combined en bloc liver and pancreas transplant following complications of WRS. WRS is characterized clinically through infantile insulin-dependent diabetes mellitus, neutropenia, recurrent infections, propensity for liver failure following viral infections, bone dysplasia, and developmental delay. Usually, death occurs from fulminant liver and concomitant kidney failure. Few cases with WRS are reported in the literature, mostly from consanguineous parents. To the best of our knowledge, combined en bloc liver and pancreas transplant has not been performed in small children.

The impact of intercenter sharing on the outcomes of pediatric split liver transplantation.

BACKGROUND: Split liver transplantation allows for expansion of the pool of organs available for pediatric liver transplantation. The impact of sharing segments of the same liver between centers has not been studied. STUDY DESIGN: Retrospective analysis of 24 pediatric split liver transplant cases in a recent cohort. We evaluated the outcomes of pediatric recipients who shared organs with adult patients in our own center (group A) compared to recipients who shared organs with adult patients in other centers. (group B). RESULTS: One-, 3-, and 5-year graft survival for group A was 100%, 100%, and 100% vs 83%, 71%, and 57% for group B (P = .039). Postoperative complications included biliary complications (41.7% in group A vs 50% in group B, P = .682), vascular complications (8.3% in group A vs 41.7% in group B, P = .059), and postoperative bleeding (16.7% in group A vs 25% in group B, P = .615). High-grade Clavien-Dindo complications were 0% in group A vs 33.3% in group B, P = .028. CONCLUSIONS: Organ sharing between centers appears to be associated with significantly poorer graft survival. Possible explanations include greater procurement-related injury or suboptimal vessel distribution. Future larger studies focused on this area may be helpful to formulate policy considerations.

Modified technique for aortic cross-clamping during liver donor procurement.

Undue tension on the donor vessels during organ procurement is associated with intimal dissection, which can form the nidus for the thrombosis of the hepatic artery (HA) and graft loss. According to the US OPTN database, 143 grafts were discarded in the last 15 yr due to vascular damage during procurement. The most common technique to expose the supraceliac aorta is dissection between the left lateral segment of the liver and the esophagus-stomach. In obese donors, due to restricted space and in pediatric donors where the vessels are very delicate and this space is very small, the replaced or accessory left HA(R/A LHA) is prone to damage if approached conventionally. We describe a technique for the exposure of the supraceliac aorta in which the aorta is approached from the left side behind the gastroesophageal junction that does not require division of the gastrohepatic ligament. From May 2007 to May 2013, 104 liver procurements were performed. Eighty-nine (85.6%) were adults, and 15 (14.4%) were pediatric donors. Twenty-three (22.1%) had R/A LHA. No donor organ suffered any damage. One adult recipient with R/A LHA suffered HA thrombosis not related to it. In summary, this technical modification offers improved safety during cadaveric procurement and increases the ease.

Minimally Invasive Robotic Techniques for Hepatocellular Carcinoma Resection: How I Do It.

The adoption of minimally invasive techniques for hepatocellular resection has progressively increased in North America. Cumulative evidence has demonstrated improved surgical outcomes in patients who undergo minimally invasive hepatectomy. In this review, the authors' approach and methodology to minimally invasive robotic liver resection for hepatocellular carcinoma is discussed.