Stable liver graft post anti-PD1 therapy as a bridge to transplantation in an adolescent with hepatocellular carcinoma.

BACKGROUND: Immunotherapy, specifically immune checkpoint inhibitors (ICIs), including anti-programmed cell death 1 (anti-PD1), has recently received clinical approval for the treatment of adult hepatocellular carcinoma (HCC). However, the safety and efficacy of ICIs prior to solid organ transplant are unknown, especially in pediatrics. Safety reports are variable in adults, with some series describing subsequent allograft rejection and loss while others report successful transplants without allograft rejection.As ICIs stimulate the immune system by blocking the interaction between PD1 and the ligand-receptor pair programmed cell death-ligand 1 (PDL1), the downstream effects of T-cell activation increase the risk of graft rejection. METHODS: Here, we present a case of an adolescent with moderately differentiated non-fibrolamellar HCC treated with pembrolizumab, an anti-PD1 therapy, who subsequently underwent successful orthotopic liver transplantation (OLT). RESULTS: Our patient received an OLT 138 days from the last pembrolizumab dose with graft preservation. The patient has no evidence of recurrent disease or any episode of allograft rejection 48 months post OLT. Staining of tumor and normal tissues from longitudinal specimens finds PDL1 positive Kupffer cells present in normal liver and peritumoral areas with no changes post anti-PD1 therapy. In contrast, tumor cells were negative for PDL1. CONCLUSION: This case represents a basis for optimism in potential use of anti-PD1 therapy in liver transplant candidates and supports further investigation of immune checkpoint inhibitors use in this unique patient population.

Risk Factors for 30-Day Unplanned Readmission After Hepatectomy: Analysis of 438 Pediatric Patients from the ACS-NSQIP-P Database.

BACKGROUND: Hepatic resections are uncommon in children. Most studies reporting complications of these procedures and risk factors associated with unplanned readmissions are limited to retrospective data from single centers. We investigated risk factors for 30-day unplanned readmission after hepatectomy in children using the American College of Surgeons National Surgical Quality Improvement-Pediatric database. METHODS: The database was queried for patients aged 0-18 years who underwent hepatectomy for the treatment of liver lesions from 2012 to 2018. Chi-squared tests were performed to evaluate for potential risk factors for unplanned readmissions. A multivariate regression analysis was performed to identify independent predictors for unplanned 30-day readmissions. RESULTS: Among 438 children undergoing hepatectomy, 64 (14.6%) had unplanned readmissions. The median age of the hepatectomy cohort was 1 year (0-17); 55.5% were male. Patients readmitted had significantly higher rates of esophageal/gastric/intestinal disease (26.56% vs. 14.97%; p=0.022), current cancer (85.94% vs. 75.67%; p=0.012), and enteral and parenteral nutritional support (31.25% vs. 17.65%; p=0.011). Readmitted patients had significantly higher rates of perioperative blood transfusion (67.19% vs. 52.41%; p=0.028), organ/space surgical site infection (10.94% vs. 1.07%; p<.001), sepsis (15.63% vs. 3.74%; p<.001), and total parenteral nutrition at discharge (9.09% vs. 2.66%; p=0.041). Organ/space surgical site infection was an independent risk factor for unplanned readmission (OR=9.598, CI [2.070-44.513], p=0.004) by multivariable analysis. CONCLUSION: Unplanned readmissions after liver resection are frequent in pediatric patients. Organ/space surgical site infections may identify patients at increased risk for unplanned readmission. Strategies to reduce these complications may decrease morbidity and costs associated with unplanned readmissions.

Transient-mixed Chimerism With Nonmyeloablative Conditioning Does Not Induce Liver Allograft Tolerance in Nonhuman Primates.

BACKGROUND: Although short-term outcomes for liver transplantation have improved, patient and graft survival are limited by infection, cancer, and other complications of immunosuppression. Rapid induction of tolerance after liver transplantation would decrease these complications, improving survival and quality of life. Tolerance to kidneys, but not thoracic organs or islets, has been achieved in nonhuman primates and humans through the induction of transient donor chimerism. Since the liver is considered to be tolerogenic, we tested the hypothesis that the renal transplant transient chimerism protocol would induce liver tolerance. METHODS: Seven cynomolgus macaques received immune conditioning followed by simultaneous donor bone marrow and liver transplantation. The more extensive liver surgery required minor adaptations of the kidney protocol to decrease complications. All immunosuppression was discontinued on postoperative day (POD) 28. Peripheral blood chimerism, recipient immune reconstitution, liver function tests, and graft survival were determined. RESULTS: The level and duration of chimerism in liver recipients were comparable to those previously reported in renal transplant recipients. However, unlike in the kidney model, the liver was rejected soon after immunosuppression withdrawal. Rejection was associated with proliferation of recipient CD8 T effector cells in the periphery and liver, increased serum interleukin (IL)-6 and IL-2, but peripheral regulatory T cell (Treg) numbers did not increase. Antidonor antibody was also detected. CONCLUSIONS: These data show the transient chimerism protocol does not induce tolerance to livers, likely due to greater CD8 T cell responses than in the kidney model. Successful tolerance induction may depend on greater control or deletion of CD8 T cells in this model.

COVID-19 Associated Hepatitis Complicating Recent Living Donor Liver Transplantation.

We present a case of COVID-19 hepatitis in a living donor liver allograft recipient whose donor subsequently tested positive for COVID-19. The patient is a female infant with biliary atresia (failed Kasai procedure). She recovered well, with improving liver function tests for 4 days. On post-operative day (POD) 4 the patient developed respiratory distress and fever. COVID-19 testing (polymerase chain reaction) was positive. Liver function tests increased approximately 5-fold. Liver biopsy showed moderate acute hepatitis with prominent clusters of apoptotic hepatocytes and associated cellular debris. Lobular lymphohistiocytic inflammation was noted. Typical portal features of mild to moderate acute cellular rejection were also noted.

Exploring Medical Students' Perceptions of Organ Procurement: Need for a Formalized Medical Student Curriculum.

OBJECTIVE: We evaluated the medical student experience with a deceased-donor multiorgan procurement program at a single center. The program provided the opportunity to assist with organ procurement, but no formal curriculum was offered. DESIGN, SETTING, PARTICIPANTS: In 2018, medical students who registered for the program between 2014 and 2017 completed a voluntary survey about the experience and its impact on surgery interest and organ donation knowledge and advocacy. RESULTS: Of 139 respondents, 53.3% (N = 74) of students participated in at least one procurement. The experience was resoundingly positive: 81.7% (N = 58) believed it exceeded expectations, with less than one-third missing class and only 4.3% (N = 3) reporting a negative impact on academics. Although 60.6% (N = 43) students studied prior to procurement, 57.8% (N = 41) expressed the need for increased preparation. Preferred learning modalities included videos, discussion with the transplant fellows, and focused anatomy overview. Following participation, 53.5% (N = 38) of students had increased interest in pursuing an acting internship and career in surgery. However, participation was not associated with improved familiarity with organ donation concepts or advocacy. CONCLUSIONS: Adding a structured curriculum may turn medical students from passive observers into active learners, maximizing the educational value of procurement and better equipping future providers to promote organ donation.

Liver atrophy and regeneration in noncirrhotic portal vein thrombosis: Effect of surgical shunts.

The goal of the study is to characterize the relationship between portal vein thrombosis (PVT) and hepatic atrophy in patients without cirrhosis and the effect of various types of surgical shunts on liver regeneration and splenomegaly. Patients without cirrhosis with PVT suffer from presinusoidal portal hypertension, and often hepatic atrophy is a topic that has received little attention. We hypothesized that patients with PVT have decreased liver volumes, and shunts that preserve intrahepatic portal flow enhance liver regeneration. Sixty-four adult and pediatric patients with PVT who underwent surgical shunt placement between 1998 and 2011 were included in a retrospective study. Baseline liver volumes from adult patients were compared with standard liver volume (SLV) as well as a group of healthy controls undergoing evaluation for liver donation. Clinical assessment, liver function tests, and liver and spleen volumes from cross-sectional imaging were compared before and after surgery. A total of 40 patients received portal flow-preserving shunts (32 mesoportal and 8 selective splenorenal), whereas 24 received portal flow-diverting shunts (16 nonselective splenorenal and 8 mesocaval). Baseline adult liver volumes were 26% smaller than SLV (1248 versus 1624 cm3 ; P = 0.02) and 20% smaller than the control volumes (1248 versus 1552 cm3 ; P = 0.02). Baseline adult spleen volumes were larger compared with controls (1258 versus 229 cm3 ; P < 0.001). Preserving shunts were associated with significant increase in liver volumes (886 versus 1131 cm3 ; P = 0.01), whereas diverting shunts were not. Diverting shunts significantly improved splenomegaly. In conclusion, we have demonstrated that patients without cirrhosis with PVT have significant liver atrophy and splenomegaly. Significant liver regeneration was achieved after portal flow-preserving shunts. Liver Transplantation 24 881-887 2018 AASLD.

Durable Clinical and Immunologic Advantage of Living Donor Liver Transplantation in Children.

BACKGROUND: Despite high survival in pediatric living donor liver transplantation (LDLT), only 10% of liver transplants in children in the United States are from living donors, reflecting reluctance to embrace this approach. In addition to optimal timing and graft quality, LDLT may offer immunologic benefit because most donors are haploidentical parents. We sought to quantify the benefit of LDLT compared to deceased donor liver transplantation (DDLT) using granular clinical and immunologic outcomes over the long term. METHODS: A retrospective cohort of children (age <18 years) surviving 1 year or longer posttransplant was evaluated to determine the impact of donor type on graft survival and immunologic outcomes. RESULTS: Two hundred forty-one children (177 DDLT and 64 LDLT) were assessed. In multivariable analysis, LDLT was associated with a lower rate of acute cellular rejection (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.29-0.98; P = 0.04), a lower rate of chronic rejection (HR, 0.12; 95% CI, 0.03-0.56; P = 0.007), better graft survival on monotherapy immunosuppression at 3 years posttransplant (87.7% vs 46.7%; odds ratio, 7.41; 95% CI, 2.80-19.66; P < 0.001), and a lower rate of graft loss (HR, 0.29; 95% CI, 0.10-0.88; P = 0.03). Graft type was not an independent predictor of posttransplant mortality (LDLT HR, 0.57; 95% CI, 0.16-2.01; P = 0.38). Maternal graft LDLT was associated with a lower rate of acute cellular rejection (HR, 0.13; 95% CI, 0.03-0.64; P = 0.01) and posttransplant lymphoproliferative disorder (HR, 0.04; 95% CI, 0.004-0.44; P = 0.008) compared with paternal grafts. CONCLUSIONS: This study demonstrates the potential benefit of LDLT, particularly with maternal grafts, for pediatric liver transplant recipients on multiple clinical parameters over long-term follow-up.

Ex vivo excision of retroperitoneal soft tissue tumors: A case report.

Ganglioneuromas are slow growing, clinically silent benign tumors for which surgery is considered to be the standard treatment. However, surgical excision in cases where surrounding structures are involved can be challenging. The present study reports a novel technique of ex vivo excision for the management of a retroperitoneal ganglioneuroma in a 21-year old patient, that appeared to be inoperable using standard surgical resection. Preoperative investigations revealed a large tumor with encasement of the origins of the superior mesenteric artery (SMA) and bilateral renal arteries. Initially, to prevent the need to explant the liver, the distal SMA (with takeoff of the replaced common hepatic artery) was anastomosed to the splenic artery. The bulk of the tumor along with the bilateral kidneys was mobilized from the retroperitoneum, and the aorta and inferior vena cava (IVC) were cross-clamped above and below the tumor and divided. The two kidneys were dissected free of the tumor at the back-table and were auto-transplanted in a standard technique following the reconstruction of the aorta and IVC. The patient tolerated surgery well and a one-year postoperative follow-up did not show any sign of tumor recurrence. Although technically demanding, ex vivo resection and auto-transplantation of the involved organs can be introduced as a final option for the treatment of tumors that are un-resectable using standard surgical techniques.

Expanding the Margins: High Volume Utilization of Marginal Liver Grafts Among >2000 Liver Transplants at a Single Institution.

OBJECTIVE: Marginal livers (ML) have been used to expand the donor pool. National utilization of MLs is variable, and in some centers, they are never used. We examined the outcomes of MLs in the largest single center series of MLs used to date and compared outcomes to standard (SL) and living donor (LD) livers. METHODS: Analysis of a prospectively maintained database of all liver transplants performed at our institution from 1998 to 2016. ML grafts were defined as livers from donors >70, livers discarded regionally and shared nationally, livers with cold ischemic time >12 hours, livers from hepatitis C virus positive donors, livers from donation after cardiac death donors, livers with >30% steatosis, and livers split between 2 recipients. RESULTS: A total of 2050 liver transplant recipients were studied, of these 960 (46.8%) received ML grafts. ML recipients were more likely to have lower MELDs and have hepatocellular carcinoma. Most MLs used were from organs turned down regionally and shared nationally (69%) or donors >70 (22%). Survival of patients receiving MLs did not significantly differ from patients receiving SL grafts (P = 0.08). ML and SL recipients had worse survival than LDs (P < 0.01). Despite nearly half of our recipients receiving MLs, overall survival was significantly better than national survival over the same time period (P = 0.04). Waitlist mortality was significantly lower in our series compared with national results (19% vs 24.0%, P < 0.0001). CONCLUSIONS: Outcomes of recipients of ML grafts are comparable to SL transplants. Despite liberal use of these grafts, we have been able to successfully reduce waitlist mortality while exceeding national post-transplant survival metrics.

Recurrence After Liver Transplantation for Hepatocellular Carcinoma: A New MORAL to the Story.

OBJECTIVE: We sought to develop a "Model Of Recurrence After Liver transplant" (MORAL) for hepatocellular carcinoma (HCC). BACKGROUND: The Milan criteria are used to allocate livers to patients with HCC requiring liver transplantation (LT) but do not include objective measures of tumor biology. Biological markers including the neutrophil-lymphocyte ratio (NLR) and alpha-fetoprotein (AFP) have been associated with recurrence risk. METHODS: Prospective cohort study of adults undergoing LT for HCC between January 2001 and December 2012. RESULTS: A total of 339 patients were included. On multivariable Cox regression analysis, 3 preoperatively available factors were independent predictors of worse recurrence-free survival (RFS), namely, an NLR ≥ 5 (P < 0.0001, hazard ratio, HR: 6.2), AFP > 200 (P < 0.0001, HR: 3.8), and Size >3 cm (P < 0.001, HR: 3.2). The Pre-MORAL score was constructed from the hazard ratios and assigning patients points in an additive fashion, with a minimum of 0 points (no factors) and a maximum of 13 points (all 3 factors). The highest risk patients in the Pre-MORAL had a 5-year RFS of 17.9% compared with 98.6% for the low risk group (P < 0.0001). The post-MORAL was constructed similarly using the 4 postoperatively available independent predictors of worse RFS, grade 4 HCC's (P < 0.0001, HR: 5.6), vascular invasion (P = 0.019, HR: 2.0), size >3 cm (P < 0.0001, HR: 3.2) and number >3 (P = 0.048, HR: 1.8). The pre- and post-MORAL were superior to Milan at predicting recurrence with c-statistics of 0.82 and 0.87, compared with 0.63, respectively. We then combined the scores to produce a combo-MORAL, with a c-statistic of 0.91 for predicting recurrence. CONCLUSIONS: The MORAL score provides a simple, highly accurate tool for predicting recurrence and risk-stratification pre- and postoperatively.

Leaning to the Left: Increasing the Donor Pool by Using the Left Lobe, Outcomes of the Largest Single-center North American Experience of Left Lobe Adult-to-adult Living Donor Liver Transplantation.

OBJECTIVE: Centers offering adult living donor liver transplantation (LDLT) mostly use right lobe grafts due to fears of providing recipients with insufficient hepatic volume, and the technical challenges presented by using left lobe grafts (LLGs). LLGs therefore represent approximately 5% of adult LDLTs performed in the United States. Here we present the largest North American experience with the use of LLG for adult LDLT. METHODS: Analysis of a prospectively maintained database of LDLTs performed from 1998 to 2015 at our institution. RESULTS: A total of 214 adult LDLTs were studied. Fifty-six patients (26%) received LLG. LLG recipients were more likely to be women, had significantly lower BMI, graft weight, and graft-weight-recipient-weight ratios (P < 0.05 for all). There were no significant differences in vascular or biliary complication between the groups. No significant differences existed in patient or graft survival at 1, 3, and 5 years (P = 0.747 and P = 0.398 respectively). Despite significantly increased risk of small-for-size syndrome in LLG, there was no increased risk of retransplant within 90-days or perioperative mortality in LLG recipients (P = 0.308 and P = 0.932 respectively). Graft type did not predict patient or graft outcomes on regression analysis (P = 0.857 and 0.399 respectively). CONCLUSIONS: Despite smaller graft sizes, outcomes of adult LDLT using LLG are comparable to right lobe grafts transplants. Left lobes can provide an important resource in an era of severe organ shortages, and these data should serve to allay the concerns of the transplant community in the United States.

Standing the test of time: outcomes of a decade of prioritizing patients with hepatocellular carcinoma, results of the UNOS natural geographic experiment.

UNLABELLED: Priority is given to patients with hepatocellular carcinoma (HCC) to receive liver transplants, potentially causing significant regional disparities in organ access and possibly outcomes in this population. Our aim was to assess these disparities by comparing outcomes in long waiting time regions (LWTR, regions 5 and 9) and short waiting time regions (SWTR regions 3 and 10) by analyzing the United Network for Organ Sharing (UNOS) database. We analyzed 6,160 HCC patients who received exception points in regions 3, 5, 9, and 10 from 2002 to 2012. Data from regions 5 and 9 were combined and compared to data from regions 3 and 10. Survival was studied in three patient cohorts: an intent-to-treat cohort, a posttransplant cohort, and a cohort examining overall survival in transplanted patients only (survival from listing to last posttransplant follow-up). Multivariate analysis and log-rank testing were used to analyze the data. Median time on the list in the LWTR was 7.6 months compared to 1.6 months for SWTR, with a significantly higher incidence of death on the waiting list in LWTR than in SWTR (8.4% versus 1.6%, P < 0.0001). Patients in the LWTR were more likely to receive loco-regional therapy, to have T3 tumors at listing, and to receive expanded-criteria donor (ECD) or donation after cardiac death (DCD) grafts than patients in the SWTR (P < 0.0001 for all). Survival was significantly better in the LWTR compared to the SWTR in all three cohorts (P < 0.0001 for all three survival points). Being listed/transplanted in an SWTR was an independent predictor of poor patient survival on multivariate analysis (P < 0.0001, hazard ratio = 1.545, 95% confidence interval 1.375-1.736). CONCLUSION: This study provides evidence that expediting patients with HCC to transplant at too fast a rate may adversely affect patient outcomes.

Reversal of age-related thymic involution by an LHRH agonist in miniature swine.

UNLABELLED: BACKGROUND AND AIMS OF STUDY: We have previously demonstrated a requirement for the presence of a juvenile thymus for the induction of transplantation tolerance to renal allografts by a short-course of calcineurin inhibition in miniature swine. We have also shown that aged, involuted thymi can be rejuvenated when transplanted as vascularized thymic lobes into juvenile swine recipients. The present studies were aimed at elucidating the extrinsic factors facilitating this restoration of function in the aged thymus. In particular, we tested the impact of sex steroid blockade by Luteinizing Hormone-Releasing Hormone (LHRH). MATERIALS AND METHODS: 30 naive animals (25 males and 5 females) were used for measurement of serum testosterone levels. 3 mature male pigs (aged at 22, 22 and 29 months old) were used to test the effects of Lupron (LHRH analog) injection at 45 mg (per 70-80 kg body weight) as a 3-month depot on testosterone levels and thymic rejuvenation. Thymic rejuvenation was assessed by histology, flow cytometric analysis, morphometric analysis and TREC assays. RESULTS: Hormonal alterations were induced by Lupron and resulted in macroscopic and histologic regeneration of the thymus of aged animals within 2 months, as evidenced by restoration of juvenile thymus architecture and increased cellularity. Two animals that were evaluated for TREC both showed increased levels in the periphery following Lupron treatment. CONCLUSION: Treatment of aged animals with Lupron leads to thymic rejuventaion in adult miniature swine. This result could expand the applicability of thymus-dependent tolerance-inducing regimens to adult recipients.

John Jones, M.D.: pioneer, patriot, and founder of American surgery.

John Jones was a pioneer of American Surgery. Born in Long Island, New York in 1729, he received his medical degree in France from the University of Rheims. He returned to the colonies and helped to establish the medical school that would later become Columbia University's College of Physicians and Surgeons where he was appointed the first Professor of Surgery in the New World. He used his position to assert that surgeons trained in America should be familiar with all facets of medicine and not be mere technicians. Before the outbreak of the American Revolution, he wrote a surgical field manual, which was the first medical text published in America. A believer in the principles of the American Revolution, he would go on to count Benjamin Franklin and George Washington as his patients. Despite achieving many firsts in American medicine, his influence on surgical training is his most enduring legacy.

Porcine CFSE mixed lymphocyte reaction and PKH-26 cell-mediated lympholysis assays.

UNLABELLED: Mixed lymphocyte reaction (MLR) and cell-mediated lympholysis (CML) are widely used to assess T cell responses. A major limitation of the traditional MLR and CML assays is that they require radioisotope labeling with (3)H for MLR and (51)Cr for CML, thereby limiting their use to laboratories with the capabilities to deal safely with these materials. Recently, flow cytometry with CFSE labeling has been used to detect cell division in rodent and human assays, and flow cytometry with PKH-26 labeling has been used to study cytotoxicity in murine models. Partially inbred miniature swine provide a unique large animal preclinical model for experimental transplantation, helping to bridge the gap between rodent and clinical studies. In this study, we modified the reported CFSE and PKH-26 labeling procedures for use with porcine cells, and established that these radioactive-free MLR and CML assays are comparable to traditional radioactive CML and MLR assays for assessing immunologic responses in miniature swine. To our knowledge, this is the first report that has directly compared the traditional CML/MLR with radiation-free CML/MLR in MHC-defined swine models. OBJECTIVE: The aim of this study is to establish non-radiolabeled CSFE and PKH-26 labeling procedures for flow cytometry based CML/MLR assays that are comparable to radioactive CML/MLR assays in preclinical large animals.

Role of persistence of antigen and indirect recognition in the maintenance of tolerance to renal allografts.

BACKGROUND: We have previously shown that a 12-day treatment with cyclosporine A (CyA) facilitates induction of tolerance to class-I disparate kidneys, as demonstrated by acceptance of second, donor-matched kidneys without immunosuppression. In the present study, we have examined 1) the duration of tolerance in the absence of donor antigen and 2) the pathway of antigen recognition determining maintenance or loss of tolerance. METHODS: Seventeen miniature swine received class-I mismatched kidneys with 12 days of CyA, and received second donor-matched kidneys without immunosuppression at 0, 1, 3, or 4 months after nephrectomy of the primary graft. Five were sensitized 6 weeks after nephrectomy of the primary graft, three with donor-matched skin grafts, and two with donor class-I peptides to eliminate direct pathway involvement. In addition, two long-term tolerant animals received class-I peptides. RESULTS: Rejection of second grafts required at least a 3 month absence of donor antigen. Although donor-matched skin grafts in animals tolerant to kidneys induced antidonor cytotoxic T lymphocyte responses, second renal transplants revealed no evidence of sensitization. In contrast, immunization of recipients with donor class-I peptides after nephrectomy of the primary graft led to loss of tolerance at both T-cell and B-cell levels, as evidenced by rejection of the second graft in 5 days and development of antidonor immunoglobulin G. Peptide immunization of long-term tolerant in recipients bearing long-term renal grafts did not break tolerance. CONCLUSIONS: These data indicate that the renal allograft is required for the indefinite maintenance of tolerance, that indirect antigen presentation is capable of breaking tolerance, and that in tolerant animals, direct antigen presentation may suppress rejection, allowing tolerance to persist.