Elaine Y. Cheng

Prevalence and clinical impact of donor-specific alloantibody among intestinal transplant recipients.

Background Rejection remains the leading cause of allograft loss, and a major barrier to improving long-term outcomes after intestinal transplantation. Our aim is to define the prevalence and investigate the role of donor-specific antibody (DSA) on intestinal graft outcomes. Methods The study includes 109 transplants performed in 95 recipients at a single center. Patients were screened for DSA pretransplant, monitored regularly posttransplant and when clinically indicated using the single-antigen bead Luminex assay. Standard induction immunosuppression was with interleukin-2 receptor antagonists, and antithymocyte globulin in high-risk recipients. Maintenance regimens were tacrolimus-based. Results Pretransplant DSA was detected in 12 (11%) recipients with 50% continuing to have circulating antibodies posttransplant. An additional 24 (25%) patients developed de novo DSA, and of these, 71% had persistent antibodies. Recipients with preformed DSA demonstrated elevated risks of early graft failure, whereas those with de novo DSA experienced accelerated graft loss once DSA was detected, reaching a 28% failure rate within 2 years. HLA-DQ mismatch is a significant risk factor for de novo DSA emergence, whereas the persistence of antibodies is predicted by DSA strength and specificity. Although inclusion of the liver in the intestinal allograft imparts an immunological advantage against rejection-related graft loss, this protective effect was lost among recipients with persistent DSA. Conclusions The presence of DSA is associated with inferior graft outcomes among intestinal transplant recipients. An enhanced understanding of the mechanisms by which DSA causes allograft injury, and effective strategies targeting humoral immune reactivity are needed to improve long-term intestinal graft outcomes.

Evaluation of Patients With Hepatocellular Carcinomas That Do Not Produce α-Fetoprotein

Importance Serum &agr;-fetoprotein (AFP) is a biomarker for hepatocellular carcinomas (HCCs) associated with a more aggressive tumor phenotype and inferior outcomes after a liver transplant (LT). Data on the outcomes for patients with HCCs that do not produce AFP are limited. Objective To compare characteristics and outcomes among LT recipients with radiographically apparent HCC lesions with AFP-producing tumors or with tumors that do not produce AFP (hereafter referred to as non-AFP–producing tumors), and to identify factors influencing recurrence in LT recipients with non-AFP–producing tumors. Design, Setting, and Participants Retrospective analysis at a university transplant center of 665 adults with HCC who underwent an LT during the period from 1989 to 2013. Of the 665 LT recipients, 457 (68.7%) had AFP-producing tumors, and 208 (31.3%) had non-AFP–producing tumors (the maximum AFP level before an LT was ⩽10 ng/mL). Dates of study analysis were from August 2015 to June 2016. Intervention Liver transplant. Main Outcomes and Measures Recurrence-free survival and recurrence rates. Results Patients with non-AFP–producing tumors had radiographic tumor characteristics similar to those of patients with AFP-producing tumors, but, pathologically, they had fewer lesions (25% vs 35% with >2 lesions; P = .03), smaller cumulative tumor diameters (4.2 vs 5.0 cm; P = .02), fewer microvascular (17% vs 22%) and macrovascular (2% vs 9%) invasions (P < .001), and fewer poorly differentiated tumors (15% vs 28%; P < .001). Patients with non-AFP–producing tumors also had significantly superior recurrence-free survival at 1, 3, and 5 years (88%, 74%, and 67% vs 76%, 59%, and 51%, respectively; P = .002) and lower 5-year recurrence rates (8.8% vs 22%; P < .001) than patients with AFP-producing tumors. When stratified by radiologic Milan criteria, 5-year survival was better, and recurrence lowest, among patients with non-AFP–producing tumors within the Milan criteria (71% survival and 6% recurrence), and survival was worse, and recurrence highest, for patients with AFP-producing tumors outside the Milan criteria (40% survival and 42% recurrence; P < .001). Significant predictors of recurrence among patients with non-AFP–producing tumors include radiologic (>2 tumors [HR, 4.98; 95% CI, 1.72-14.4; P = .003]; cumulative diameter [1.70 per log SD; 1.12-2.59; P < .001]; outside the Milan criteria [10.0; 3.7-33.3; P < .001) and pathologic factors (>2 tumors [4.39; 1.32-14.6; P = .02]; cumulative diameter [2.32 per log SD; 1.43-3.77; P = .001]; microvascular [3.07; 1.02-9.24; P = .05] and macrovascular invasion [8.75; 2.15-35.6; P = .002]). Conclusions and Relevance Nearly one-third of patients with radiographically apparent HCC have non-AFP–producing tumors that have more favorable pathologic characteristics, lower posttransplant recurrence, and superior survival compared with patients with AFP-producing tumors. Posttransplant HCC recurrence for patients with non-AFP–producing tumors is predicted by important radiologic and pathologic factors, and is negligible for patients within the Milan criteria. Stratifying patients by AFP status in addition to radiological criteria may improve the selection process for and the prioritization of transplant candidates.

Paritaprevir/ritonavir/ombitasvir and dasabuvir for the treatment of chronic hepatitis C virus infection.

Introduction: The use of direct-acting antiviral (DAA) agents against chronic hepatitis C virus (HCV) infections can result in the successful treatment of nearly all patients. Effective antiviral treatments can prevent the progression to cirrhosis and hepatocellular malignancy, and decrease liver-related morbidity and mortality. Areas covered: Paritaprevir–ritonavir–ombitasvir and dasabuvir (PrOD), with or without ribavirin, is an all-oral regimen approved for the treatment of HCV genotype 1 infections, including patients with compensated cirrhosis. Phase 2 and 3 clinical trials demonstrated the safety and efficacy of this regimen in HCV genotype 1-infected patients who are treatment-naïve and those who have failed peginterferon/ribavirin therapy. Additional studies evaluated the use of PrOD with or without ribavirin among special populations, including patients co-infected with human immunodeficiency virus-1 and HCV, liver transplant recipients with HCV recurrence, and patients with severe renal impairment. Additionally, the combination of paritaprevir-ritonavir-ombitasvir plus ribavirin is found to be highly efficacious, and is now approved in the US, for the treatment of HCV genotype 4 infections. Expert opinion: The availability and use of interferon-free DAA combination regimens has resulted in a major paradigm shift in the treatment of HCV. PrOD, with or without ribavirin, is an effective, safe and tolerable treatment option.

Liver Transplantation for Pediatric Hepatoblastoma and Hepatocellular Carcinoma: Out of the Unknown

Withadvances inchemotherapy, surgical treatment, andpostoperative care, the prognosis for children with hepatoblastoma (HBL) has improved significantly during the past 3 decades. The combined use of liver transplantation and chemotherapy isnowthepreferred treatment option for unresectableHBL.1 Inpediatric patientswithhepatocellular carcinoma (HCC), transplantationhasbeenassociatedwith improved disease-free survival compared with conventional treatment with chemotherapy and resection, particularly in children with advanced-stage tumors or chronic underlying liver disease.2 In this issue of JAMA Surgery, Pham et al3 report excellent long-term outcomes at their center after liver transplantation for childhood HBL and HCC, with 5-year disease-free survival rates of 82% and 78%, respectively. Similar to other published reports in the literature, this study is limited by its retrospective nature and the small numbers of patients. The authors proposed several risk factors associated with tumor recurrence after transplantation, but proper multivariable analysis was not performed. Furthermore, patient selection protocols can vary from one transplant center to another, which may lead to notable differences in observed outcomes. The Pediatric Liver Unresectable Tumor Observatory (PLUTO) registry was initiated in 2006 by the International Childhood Liver Tumors Strategy Group (SIOPEL) and now contains prospectively collected data on more than 200 pediatric patients who have undergone transplant for unresectable liver tumors in 79 centers around the world. The primary objectives of the registry are (1) to fully define the indications for liver transplantation in the treatment of pediatric liver tumors, (2) to identify the optimal timing for transplantation, (3) to define the role of pretransplant and posttransplant chemotherapy, and (4) to determine the best strategy for immunosuppression.4 An interim report of the registry5 has demonstrated an expected long-term survival rate of approximately 90% after liver transplantation for unresectable HBL. For children with HCC in the setting of underlying liver disease, liver transplantation produces excellent long-term survival and cure rates, even without the use of chemotherapy. In pediatric patients without chronic liver disease who develop unresectable HCC tumors, Related article page 1150 Research Original Investigation Survival in ChildrenWith Hepatoblastoma and Hepatocellular Cancer

The impact of antibodies and virtual crossmatching on intestinal transplant outcomes

Purpose of review Sensitization to human leukocyte antigens (HLAs) limits access to potential donors and contributes to inferior graft survival after transplantation. In this article, we will review the effects of HLA-specific antibodies on intestinal transplant outcomes, and discuss considerations in the monitoring and treatment of anti-HLA antibodies. Recent findings Only a handful of studies has investigated the effects of donor-specific anti-HLA antibodies (DSAs) on intestinal allograft outcomes. Most have reported associations between DSA presence and rejection-related graft failure. The evolution of antibody detection methods and improvements in crossmatch testing have allowed for a systematic approach to the broadly sensitized transplant candidate, and facilitated the identification of compatible organ donors. The virtual crossmatch can be used to aid in organ allocation and avoid transplantation across preformed DSA. However, much remains unknown about the mechanisms of antibody-mediated injury in the intestinal graft, and the effectiveness of current therapies against DSA has yet to be established. Summary On the basis of available data, we will provide recommendations for the testing and management of DSA among intestinal transplant recipients. The precise management protocol should be tailored to each individual based on immunologic risk as well as clinical status.

Obliterative portal venopathy: A histopathologic finding associated with chronic antibody-mediated rejection in pediatric liver allografts

The significance of post‐transplant HLA DSA and chronic AMR in LT is an emerging field of study. Although OPV has previously been described as a histopathologic finding in DSA‐positive adult LT recipients, it was not included in the recent Banff criteria for chronic AMR. Our aim was to describe the association between OPV and chronic AMR in pediatric LT recipients. A retrospective review of 67 liver biopsies performed between November 2014 and April 2016 in 45 pediatric LT recipients identified four patients with OPV. Clinical status, liver biochemistry, the presence of DSA, and available non‐HLA antibody testing, as well as histopathologic features of chronic AMR, were assessed. All four patients with OPV had class II DSA and histopathologic features of chronic AMR based on the Banff criteria. Two patients were noted to have non‐HLA antibodies. Three patients are undergoing treatment with IVIG but have persistent DSA. Two patients have graft failure and are awaiting retransplantation. In conclusion, OPV is a histopathologic finding associated with chronic AMR in pediatric LT recipients. Further studies are needed to elucidate whether OPV is reversible and/or amenable to medical therapy.

Clinical characteristics and outcomes of PTLD following intestinal transplantation

Post‐transplant lymphoproliferative disease (PTLD) has the highest incidence following intestinal transplantation (ITx). Our center has seen a recent increase in PTLD. Our aim was to review a single‐center PTLD experience with a focus on clinical characteristics and outcomes. We completed a retrospective review of biopsy‐proven PTLD cases using a prospectively maintained database of 115 ITx recipients transplanted between 1991 and 2014. Nineteen (17%) ITx recipients developed 25 PTLD cases during a median follow‐up time of 6.4 (1.6‐14.6) years. The incidence of early PTLD was 6% (n = 7). There was a trend toward increased risk of PTLD in children compared with adults (P = .11) and a significantly increased risk of PTLD in re‐ITx compared with primary ITx recipients (P = .03). Most PTLD cases were diagnosed between 2010 and 2014 (n = 14). All early PTLD cases were EBV+ on in situ hybridization. Overall graft and patient survival are 68% and 74%, respectively. Second episodes of PTLD were diagnosed in 43% of surviving pediatric patients. Our program has a low incidence of early PTLD with overall excellent graft and patient survival following diagnosis. However, we have also seen a rising incidence of late PTLD. The cause of the increase is unknown as no major changes in immunosuppression protocols have occurred since 1999.

Recurrence of Disease After Liver Transplantation in the Pediatric Population

Disease relapse after liver transplantation occurs infrequently in the pediatric population, and the spectrum of recurrent conditions differs from that which is seen in adults. Chemotherapy followed by liver transplantation as primary treatment for hepatic malignancies such as hepatoblastoma and hepatocellular carcinoma yields excellent outcomes with low recurrence rates, even in the presence of locally advanced tumors. End-stage liver disease secondary to hepatitis C viral infections is an uncommon indication for liver transplantation in pediatric patients, but the rates of recurrent viremia and retransplantation appear similar to adult recipients with hepatitis C. The posttransplant management of children with disorders of immune regulation (such as autoimmune hepatitis) is particularly challenging, as they often require a greater degree of immunosuppression and yet are at elevated risk for disease relapse. The return of cholestasis has also been reported for liver transplant recipients with specific types of biliary diseases, such as primary sclerosing cholangitis, progressive familial intrahepatic cholestasis subtype 2, or sclerosing cholangitis associated with the multisystem disorder Langerhans cell histiocytosis.