Outcomes from a 12-Week, Open-Label, Multicenter Clinical Trial of Teduglutide in Pediatric Short Bowel Syndrome

Objective To determine safety and pharmacodynamics/efficacy of teduglutide in children with intestinal failure associated with short bowel syndrome (SBS-IF). Study design This 12-week, open-label study enrolled patients aged 1-17 years with SBS-IF who required parenteral nutrition (PN) and showed minimal or no advance in enteral nutrition (EN) feeds. Patients enrolled sequentially into 3 teduglutide cohorts (0.0125 mg/kg/d [n = 8], 0.025 mg/kg/d [n = 14], 0.05 mg/kg/d [n = 15]) or received standard of care (SOC, n = 5). Descriptive summary statistics were used. Results All patients experienced ≥1 treatment-emergent adverse event; most were mild or moderate. No serious teduglutide-related treatment-emergent adverse events occurred. Between baseline and week 12, prescribed PN volume and calories (kcal/kg/d) changed by a median of −41% and −45%, respectively, with 0.025 mg/kg/d teduglutide and by −25% and −52% with 0.05 mg/kg/d teduglutide. In contrast, PN volume and calories changed by 0% and −6%, respectively, with 0.0125 mg/kg/d teduglutide and by 0% and −1% with SOC. Per patient diary data, EN volume increased by a median of 22%, 32%, and 40% in the 0.0125, 0.025, and 0.05 mg/kg/d cohorts, respectively, and by 11% with SOC. Four patients achieved independence from PN, 3 in the 0.05 mg/kg/d cohort and 1 in the 0.025 mg/kg/d cohort. Study limitations included its short-term, open-label design, and small sample size. Conclusions Teduglutide was well tolerated in pediatric patients with SBS-IF. Teduglutide 0.025 or 0.05 mg/kg/d was associated with trends toward reductions in PN requirements and advancements in EN feeding in children with SBS-IF

Intestinal Perforation Following Ileoscopy Through a Prolapsed Stoma in an Pediatric Intestinal Transplant Recipient With an Unrecognized Parastomal Hernia.

Ileoscopy with mucosal biopsy is fundamental in the management and surveillance of inflammatory bowel disease patients and intestinal transplant recipients. There is a paucity of data describing the risks of ileoscopy in the presence of a prolapsed stoma. Parastomal hernias are frequently associated with prolapsed stomas. We report the first case of perforation during ileoscopy in the setting of a prolapsed stoma and unrecognized parastomal hernia. Recognition of parastomal hernia associated with stoma prolapse is of paramount importance in patients undergoing ileoscopy as it may increase the risk of perforation

Non‐HLA AT1R antibodies are highly prevalent after pediatric intestinal transplantation

The role of angiotensin II type-1 receptor (AT1R) antibodies in intestinal transplantation (ITx) is unclear. The aims were 1) to identify the prevalence of AT1R antibodies in pediatric ITx, compared to pediatric intestinal failure (IF), and 2) to determine whether AT1R antibodies were associated with graft dysfunction. 46 serum samples from 25 ITx patients (3 isolated ITx, 22 liver-inclusive ITx) were collected during routine visits >6 months apart and during episodes of graft dysfunction as a result of infectious enteritis or rejection. For comparison, samples were collected from 7 IF control patients. AT1R antibodies were considered positive for levels >17 U/mL. The median (range) AT1R antibody level for ITx patients was 40.0 U/mL (7.2-40.0), compared to 7.0 U/mL (5.7-40.0) for IF patients (p = .02). There was a trend toward higher prevalence of AT1R antibodies in ITx compared with IF patients (68% versus 29%, p = .09). Among ITx patients, the prevalence of AT1R antibodies was not different between periods of active graft dysfunction and normal health (83% versus 67%, p = .31). For 16 patients with >2 samples, AT1R antibodies remained positive in 67% cases, developed in 14% cases, disappeared in 10% cases, and remained negative in 10% cases. The changes in AT1R antibodies did not correlate with de/sensitizing events. This is the first study of AT1R antibodies in pediatric ITx. AT1R antibodies are highly prevalent after ITx and may be triggered by immune activation associated with the transplant. However, their pathogenicity and clinical utility remain in question

Characterization of T cell immunophenotypes in intestinal transplantation: A pilot study

Immunophenotyping of peripheral blood mononuclear cells has been shown to be a useful, non-invasive method of predicting acute cellular rejection (ACR) following intestinal transplantation (ITx). Our objectives were to characterize differences in the T cell immunophenotype of ITx recipients in peripheral blood samples (1) collected late versus early after ITx and (1) associated with episodes of ACR and infectious enteritis. An IRB-approved, cross-sectional study of ITx recipients was performed. Peripheral blood samples were collected during normal visits and episodes of allograft dysfunction. A total of 38 patients were included in the analysis: 31 ITx recipients (87% liver-inclusive allografts) and 7 intestinal failure control patients. Of the ITx patients, 26 patients were pediatric patients (<21 years). A total of 70 samples were analyzed from ITx recipients, including 51 during normal visits and 19 during episodes of allograft dysfunction (median of 2 samples per patient; range of 1-6 samples per patient). In the late (n = 32) versus early post-ITx (n = 19) normal samples, there was a significantly higher percentage of central memory CD4 T cells (p = .001). In the ACR (n = 5) versus infectious enteritis (n = 14) samples, there was a higher percentage of CD8 T cells expressing HLA-DR (p = .002), CD57 (p < .001), and KLRG1 (p < .001) and a higher percentage of CD4 T cells expressing CD57 (p = .03). Additional studies are needed with larger cohorts to validate these changes in the T cell immunophenotype. Further elucidating T cell immunophenotypes in ITx will lead to a better understanding of immune mechanisms of allograft dysfunction, identification of potential biomarkers in ITx, and optimized selection of immunosuppressive therapies

The evolution of liver transplantation during 3 decades: analysis of 5347 consecutive liver transplants at a single center.

ObjectiveTo analyze a 28-year single-center experience with orthotopic liver transplantation (OLT) for patients with irreversible liver failure.BackgroundThe implementation of the model for end-stage liver disease (MELD) in 2002 represented a fundamental shift in liver donor allocation to recipients with the highest acuity, raising concerns about posttransplant outcome and morbidity.MethodsOutcomes and factors affecting survival were analyzed in 5347 consecutive OLTs performed in 3752 adults and 822 children between 1984 and 2012, including comparisons of recipient and donor characteristics, graft and patient outcomes, and postoperative morbidity before (n = 3218) and after (n = 2129) implementation of the MELD allocation system. Independent predictors of survival were identified.ResultsOverall, 1-, 5-, 10-, and 20-year patient and graft survival estimates were 82%, 70%, 63%, 52%, and 73%, 61%, 54%, 43%, respectively. Recipient survival was best in children with biliary atresia and worst in adults with malignancy. Post-MELD era recipients were older (54 vs 49, P < 0.001), more likely to be hospitalized (50% vs 47%, P = 0.026) and receiving pretransplant renal replacement therapy (34% vs 12%, P < 0.001), and had significantly greater laboratory MELD scores (28 vs 19, P < 0.001), longer wait-list times (270 days vs 186 days, P < 0.001), and pretransplant hospital stays (10 days vs 8 days, P < 0.001). Despite increased acuity, post-MELD era recipients achieved superior 1-, 5-, and 10-year patient survival (82%, 70%, and 65% vs 77%, 66%, and 58%, P < 0.001) and graft survival (78%, 66%, and 61% vs 69%, 58%, and 51%, P < 0.001) compared with pre-MELD recipients. Of 17 recipient and donor variables, era of transplantation, etiology of liver disease, recipient and donor age, prior transplantation, MELD score, hospitalization at time of OLT, and cold and warm ischemia time were independent predictors of survival.ConclusionsWe present the world's largest reported single-institution experience with OLT. Despite increasing acuity in post-MELD era recipients, patient and graft survival continues to improve, justifying the "sickest first" allocation approach

The evolution of liver transplantation during 3 decades: analysis of 5347 consecutive liver transplants at a single center.

ObjectiveTo analyze a 28-year single-center experience with orthotopic liver transplantation (OLT) for patients with irreversible liver failure.BackgroundThe implementation of the model for end-stage liver disease (MELD) in 2002 represented a fundamental shift in liver donor allocation to recipients with the highest acuity, raising concerns about posttransplant outcome and morbidity.MethodsOutcomes and factors affecting survival were analyzed in 5347 consecutive OLTs performed in 3752 adults and 822 children between 1984 and 2012, including comparisons of recipient and donor characteristics, graft and patient outcomes, and postoperative morbidity before (n = 3218) and after (n = 2129) implementation of the MELD allocation system. Independent predictors of survival were identified.ResultsOverall, 1-, 5-, 10-, and 20-year patient and graft survival estimates were 82%, 70%, 63%, 52%, and 73%, 61%, 54%, 43%, respectively. Recipient survival was best in children with biliary atresia and worst in adults with malignancy. Post-MELD era recipients were older (54 vs 49, P < 0.001), more likely to be hospitalized (50% vs 47%, P = 0.026) and receiving pretransplant renal replacement therapy (34% vs 12%, P < 0.001), and had significantly greater laboratory MELD scores (28 vs 19, P < 0.001), longer wait-list times (270 days vs 186 days, P < 0.001), and pretransplant hospital stays (10 days vs 8 days, P < 0.001). Despite increased acuity, post-MELD era recipients achieved superior 1-, 5-, and 10-year patient survival (82%, 70%, and 65% vs 77%, 66%, and 58%, P < 0.001) and graft survival (78%, 66%, and 61% vs 69%, 58%, and 51%, P < 0.001) compared with pre-MELD recipients. Of 17 recipient and donor variables, era of transplantation, etiology of liver disease, recipient and donor age, prior transplantation, MELD score, hospitalization at time of OLT, and cold and warm ischemia time were independent predictors of survival.ConclusionsWe present the world's largest reported single-institution experience with OLT. Despite increasing acuity in post-MELD era recipients, patient and graft survival continues to improve, justifying the "sickest first" allocation approach