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.

Impact of adjuvant therapy in patients with invasive intraductal papillary mucinous neoplasms of the pancreas: an international multicenter cohort study.

BACKGROUND: Adjuvant therapy prolongs survival in patients with pancreatic ductal adenocarcinoma. However, no clear guidelines are available regarding the oncologic effects of adjuvant therapy (AT) in resected invasive intraductal papillary mucinous neoplasms (IPMN). The aim was to investigate the potential role of AT in patients with resected invasive IPMN. MATERIALS AND METHODS: From 2001 to 2020, 332 patients with invasive pancreatic IPMN were retrospectively reviewed in 15 centres in eight countries. Propensity score-matched and stage-matched survival analyses were conducted. RESULTS: A total of 289 patients were enroled in the study after exclusion (neoadjuvant therapy, unresectable disease, uncertain AT status, and stage IV). A total of 170 patients were enroled in a 1:1 propensity score-matched analysis according to the covariates. In the overall cohort, disease-free survival was significantly better in the surgery alone group than in the AT group ( P =0.003), but overall survival (OS) was not ( P =0.579). There were no significant differences in OS in the stage-matched analysis between the surgery alone and AT groups (stage I, P =0.402; stage II, P =0.179). AT did not show a survival benefit in the subgroup analysis according to nodal metastasis (N0, P =0.481; N+, P =0.705). In multivariate analysis, node metastasis (hazard ratio, 4.083; 95% CI, 2.408-6.772, P <0.001), and cancer antigen 19-9 greater than or equal to 100 (hazard ratio, 2.058; 95% CI, 1.247-3.395, P =0.005) were identified as adverse prognostic factors in resected invasive IPMN. CONCLUSION: The current AT strategy may not be recommended to be performed with resected invasive IPMN in stage I and II groups, unlike pancreatic ductal adenocarcinoma. Further investigations of the potential role of AT in invasive IPMN are recommended.

Cerebrospinal fluid liver pseudocyst: A bizarre long-term complication of ventriculoperitoneal shunt: A case report.

BACKGROUND: Ventriculoperitoneal (VP) shunt placement has become a standard of care procedure in managing hydrocephalus for drainage and absorption of cerebrospinal fluid (CSF) into the peritoneum. Abdominal pseudocysts containing CSF are the common long-term complication of this frequently performed procedure, mainly because VP shunts have significantly prolonged survival. Of these, liver CSF pseudocysts are rare entities that may cause shunt dysfunction, affect normal organ function, and therefore pose therapeutic challenges. CASE SUMMARY: A 49-year-old man with history of congenital hydrocephalus status post bilateral VP shunt placement presented with progressively worsening dyspnea on exertion, abdominal discomfort/distention. Abdominal computed tomography (CT) scan revealed a large CSF pseudocyst in the right hepatic lobe with the tip of VP shunt catheter into the hepatic cyst cavity. Patient underwent robotic laparoscopic cyst fenestration with a partial hepatectomy, and repositioning of VP shunt catheter to the right lower quadrant of the abdomen. Follow-up CT demonstrated a significant reduction in hepatic CSF pseudocyst. CONCLUSION: A high index of clinical suspicion is required for early detection of liver CSF pseudocysts since their presentation is often asymptomatic and cunning early in the course. Late-stage liver CSF pseudocysts could have adverse outcomes on the treatment course of hydrocephalus as well as on hepatobiliary dysfunction. There is paucity of data to define the management of liver CSF pseudocyst in current guidelines due to rare nature of this entity. The reported occurrences have been managed by laparotomy with debridement, paracentesis, radiological imaging guided fluid aspiration and laparoscopic-associated cyst fenestration. Robotic surgery is an additional minimally invasive option in the management of hepatic CSF pseudocyst; however, its use is limited by lack of widespread availability and cost of surgery.

The Microbiome and Metabolomic Profile of the Transplanted Intestine with Long-Term Function.

We analyzed the fecal microbiome by deep sequencing of the 16S ribosomal genes and the metabolomic profiles of 43 intestinal transplant recipients to identify biomarkers of graft function. Stool samples were collected from 23 patients with stable graft function five years or longer after transplant, 15 stable recipients one-year post-transplant and four recipients with refractory rejection and graft loss within one-year post-transplant. Lactobacillus and Streptococcus species were predominant in patients with stable graft function both in the short and long term, with a microbiome profile consistent with the general population. Conversely, Enterococcus species were predominant in patients with refractory rejection as compared to the general population, indicating profound dysbiosis in the context of graft dysfunction. Metabolomic analysis demonstrated significant differences between the three groups, with several metabolites in rejecting recipients clustering as a distinct set. Our study suggests that the bacterial microbiome profile of stable intestinal transplants is similar to the general population, supporting further application of this non-invasive approach to identify biomarkers of intestinal graft function.

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.

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.

Graft Versus Host Disease After Intestinal Transplantation: A Single-center Experience.

BACKGROUND: Graft versus host disease (GVHD) is an uncommon but highly morbid complication of intestinal transplantation (ITx). In this study, we reviewed our 17-y experience with GVHD focusing on factors predicting GVHD occurrence and survival. METHODS: Retrospective review of 271 patients who received 1 or more ITx since program inception in 2003 with survival analysis using Cox proportional hazard modeling. RESULTS: Of 271 patients, 28 developed GHVD 34 (18-66) d after ITx presenting with rash or rash with fever in 26, rectosigmoid disease in 1, and hemolysis in 1; other sites, mainly rectosigmoid colon, were involved in 13. Initial skin biopsy demonstrated classic findings in 6, compatible findings in 14, and no abnormalities in 2. Additional sites of GVHD later emerged in 14. Of the 28 patients, 16 died largely from sepsis, the only independent hazard for death (hazard ratio [HR], 37.4181; P = 0.0008). Significant (P < 0.0500) independent hazards for occurrence of GVHD in adults were pre-ITx functional intestinal failure (IF) (HR, 15.2448) and non-IF diagnosis (HR, 20.9952) and early post-ITx sirolimus therapy (HR, 0.0956); independent hazards in children were non-IF diagnosis (HR, 4.3990), retransplantation (HR, 4.6401), donor:recipient age ratio (HR, 7.3190), and graft colon omission (HR, 0.1886). Variant transplant operation was not an independent GVHD hazard. CONCLUSIONS: Initial diagnosis of GVHD after ITx remains largely clinical, supported but not often confirmed by skin biopsy. Although GVHD risk is mainly recipient-driven, changes in donor selection and immunosuppression practice may reduce incidence and improve survival.

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.

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.

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.

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.

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.