Debra Sudan

Radiochemotherapy and Transplantation Allow Long‐Term Survival For Nonresectable Hilar Cholangiocarcinoma

Results of liver transplantation in the treatment of cholangiocarcinoma have been poor as a result of the high incidence of locoregional dissemination and tumor recurrence. This study evaluates the effect of neoadjuvant chemoradiation therapy combined with orthotopic liver transplantation in a carefully selected group of patients with hilar cholangiocarcinoma.

Natural History of Pediatric Intestinal Failure: Initial Report from the Pediatric Intestinal Failure Consortium

OBJECTIVE To characterize the natural history of intestinal failure (IF) among 14 pediatric centers during the intestinal transplantation era. STUDY DESIGN The Pediatric Intestinal Failure Consortium performed a retrospective analysis of clinical and outcome data for a multicenter cohort of infants with IF. Entry criteria included infants <12 months receiving parenteral nutrition (PN) for >60 continuous days. Enteral autonomy was defined as discontinuation of PN for >3 consecutive months. Values are presented as median (25th, 75th percentiles) or as number (%). RESULTS 272 infants with a gestational age of 34 weeks (30, 36) and birth weight of 2.1 kg (1.2, 2.7) were followed for 25.7 months (11.2, 40.9). Residual small bowel length in 144 patients was 41 cm (25.0, 65.5). Diagnoses were necrotizing enterocolitis (71, 26%), gastroschisis (44, 16%), atresia (27, 10%), volvulus (24, 9%), combinations of these diagnoses (46, 17%), aganglionosis (11, 4%), and other single or multiple diagnoses (48, 18%). Prescribed medications included oral antibiotics (207, 76%), H2 blockers (187, 69%), and proton pump inhibitors (156, 57%). Enteral feeding approaches varied among centers; 19% of the cohort received human milk. The cohort experienced 8.9 new catheter-related blood stream infections per 1000 catheter days. The cumulative incidences for enteral autonomy, death, and intestinal transplantation were 47%, 27%, and 26%, respectively. Enteral autonomy continued into the fifth year after study entry. CONCLUSIONS Children with IF endure significant mortality and morbidity. Enteral autonomy may require years to achieve. Improved medical, nutritional, and surgical management may reduce time on PN, mortality, and need for transplantation.

Hedgehog pathway activation and epithelial-to-mesenchymal transitions during myofibroblastic transformation of rat hepatic cells in culture and cirrhosis

Myofibroblastic hepatic stellate cells (MF-HSC) are derived from quiescent hepatic stellate cells (Q-HSC). Q-HSC express certain epithelial cell markers and have been reported to form junctional complexes similar to epithelial cells. We have shown that Hedgehog (Hh) signaling plays a key role in HSC growth. Because Hh ligands regulate epithelial-to-mesenchymal transition (EMT), we determined whether Q-HSC express EMT markers and then assessed whether these markers change as Q-HSC transition into MF-HSC and whether the process is modulated by Hh signaling. Q-HSC were isolated from healthy livers and cultured to promote myofibroblastic transition. Changes in mRNA and protein expression of epithelial and mesenchymal markers, Hh ligands, and target genes were monitored in HSC treated with and without cyclopamine (an Hh inhibitor). Studies were repeated in primary human HSC and clonally derived HSC from a cirrhotic rat. Q-HSC activation in vitro (culture) and in vivo (CCl(4)-induced cirrhosis) resulted in decreased expression of Hh-interacting protein (Hhip, an Hh antagonist), the EMT inhibitors bone morphogenic protein (BMP-7) and inhibitor of differentiation (Id2), the adherens junction component E-cadherin, and epithelial keratins 7 and 19 and increased expression of Gli2 (an Hh target gene) and mesenchymal markers, including the mesenchyme-associated transcription factors Lhx2 and Msx2, the myofibroblast marker alpha-smooth muscle actin, and matrix molecules such as collagen. Cyclopamine reverted myofibroblastic transition, reducing mesenchymal gene expression while increasing epithelial markers in rodent and human HSC. We conclude that Hh signaling plays a key role in transition of Q-HSC into MF-HSC. Our findings suggest that Q-HSC are capable of transitioning between epithelial and mesenchymal fates.

Everolimus With Reduced Tacrolimus Improves Renal Function in De Novo Liver Transplant Recipients: A Randomized Controlled Trial

In a prospective, multicenter, open‐label study, de novo liver transplant patients were randomized at day 30±5 to (i) everolimus initiation with tacrolimus elimination (TAC Elimination) (ii) everolimus initiation with reduced‐exposure tacrolimus (EVR+Reduced TAC) or (iii) standard‐exposure tacrolimus (TAC Control). Randomization to TAC Elimination was terminated prematurely due to a higher rate of treated biopsy‐proven acute rejection (tBPAR). EVR+Reduced TAC was noninferior to TAC Control for the primary efficacy endpoint (tBPAR, graft loss or death at 12 months posttransplantation): 6.7% versus 9.7% (−3.0%; 95% CI −8.7, 2.6%; p<0.001 for noninferiority [12% margin]). tBPAR occurred in 2.9% of EVR+Reduced TAC patients versus 7.0% of TAC Controls (p = 0.035). The change in adjusted estimated GFR from randomization to month 12 was superior with EVR+Reduced TAC versus TAC Control (difference 8.50 mL/min/1.73 m2, 97.5% CI 3.74, 13.27 mL/min/1.73 m2, p<0.001 for superiority). Drug discontinuation for adverse events occurred in 25.7% of EVR+Reduced TAC and 14.1% of TAC Controls (relative risk 1.82, 95% CI 1.25, 2.66). Relative risk of serious infections between the EVR+Reduced TAC group versus TAC Controls was 1.76 (95% CI 1.03, 3.00). Everolimus facilitates early tacrolimus minimization with comparable efficacy and superior renal function, compared to a standard tacrolimus exposure regimen 12 months after liver transplantation.

Isolated intestinal transplantation for intestinal failure

OBJECTIVE:Parenteral nutrition sustains life in patients with intestinal failure. However, some experience life-threatening complications from parenteral nutrition, and in these individuals intestinal transplantation may be lifesaving.METHODS:This is a retrospective review of 28 consecutive isolated small bowel transplants performed in eight adults and 20 children between December 1993 and June 1998 at the University of Nebraska Medical Center.RESULTS:The 1-yr patient and graft survivals were 93% and 71%, respectively. The causes of graft loss were hyperacute rejection (n = 1), acute rejection (n = 5), vascular thrombosis (n = 1), and patient death (n = 1). The median length of time required until full enteral nutrition was 27 days. All 28 patients have experienced acute rejection of their small bowel grafts and rejection led to graft failure in five. Jaundice and/or hepatic fibrosis was present preoperatively in 17 of the 28 recipients and hyperbilirubinemia was completely reversed in all patients with functional grafts within 4 months of transplantation. Three patients developed posttransplant lymphoproliferative disease (11%). Three recipients developed cytomegalovirus enteritis and all were successfully treated.CONCLUSIONS:Patient survival after intestinal transplantation is comparable to parenteral nutrition for patients with intestinal failure. Better immunosuppressive regimens are needed to decrease the risk of graft loss from acute rejection. The incidence of posttransplant lymphoproliferative disorder is higher after intestinal transplantation than after other solid organ transplants and the risk of cytomegalovirus enteritis is low with the use of cytomegalovirus seronegative donors. Liver dysfunction in the absence of established cirrhosis can be reversed.

Comparison of intestinal lengthening procedures for patients with short bowel syndrome.

Objective:Review the clinical results of 24 years of intestinal lengthening procedures at one institution. Methods:Retrospective review of a single center experience comparing the outcome of 2 intestinal lengthening procedures (Bianchi and serial transverse enteroplasty [STEP]) in terms of survival, total parenteral nutrition (TPN) weaning, and complications. Results:Sixty-four patients, including 14 adults, underwent 43 Bianchi and 34 STEP procedures between 1982 and 2007. Three patients had prior isolated liver transplants. The median (range) remnant bowel length before first lengthening was 45 (11-150) cm overall; (Bianchi = 44 cm, STEP = 45 cm) and 68 (20-250) cm after lengthening; (Bianchi = 68 cm, STEP = 65 cm). Actual survival is 91% overall (Bianchi 88%, STEP 95%) with median follow-up of 3.8 years (Bianchi = 5.9 years, STEP = 1.7 years). Average enteral caloric intake in pediatric patients was 15 kcal/kg before lengthening and 85 kcal/kg at 1 year after lengthening. Sixty-nine percent of patients are off TPN at most recent follow-up, including 8 who were weaned from TPN after intestinal transplantation. Liver disease (when present) was reversed in 80%. Surgical complications occurred in 10%, more commonly requiring reoperation after Bianchi than STEP. Intestinal transplantation salvage was required in 14% at a median of 2.9 years (range = 8 months to 20.7 years) after lengthening. Conclusions:Surgical lengthening with both Bianchi and STEP procedures results in improvement in enteral nutrition, reverses complications of TPN and avoids intestinal transplantation in the majority with few surgical complications. Intestinal transplantation can salvage most patients who later develop life-threatening complications or fail to wean TPN.

Low-Dose Chemotherapy for Epstein-Barr Virus–Positive Post-Transplantation Lymphoproliferative Disease in Children After Solid Organ Transplantation

PURPOSE To evaluate the efficacy of a low-dose chemotherapy regimen in children with Epstein-Barr virus (EBV) -positive, post-transplantation lymphoproliferative disease (PTLD) after organ transplantation who have experienced failure with front-line therapy for PTLD. PATIENTS AND METHODS Eligible patients received cyclophosphamide (600 mg/m2 intravenous for 1 day) and prednisone (2 mg/kg orally for 5 days) every 3 weeks for six cycles. RESULTS Thirty-six patients treated on study were assessable for analyses. Front-line therapies for PTLD before study entry included immune suppression reduction or withdrawal (n = 36), antiviral therapy (n = 33), surgical resection (n = 8), rituximab (n = 2), and interferon alfa (n = 1). Reasons for failure of front-line therapy included progressive disease (PD; n = 33) and persistent disease with concurrent allograft rejection (n = 3). Thirty patients (83%) had stage III to IV disease, 92% had extranodal disease, and 75% had > or = three sites of disease. The overall response rate was 83% (75% complete response + 8% partial response). The relapse rate was 19%, with only one of five relapsed patients alive and disease-free. Four patients presented with fulminant, disseminated PTLD; only one of these four patients achieved a response, and all four died of PD. Two patients died of treatment-related toxicity. Three patients (8%) experienced allograft loss, but two of the three patients are alive and disease-free after a second transplantation. The 2-year overall, relapse-free, and failure-free (without PTLD and with functioning original allograft) survival rates were 73%, 69%, and 67%, respectively. CONCLUSION This low-dose chemotherapy regimen is effective for children with EBV-positive, nonfulminant PTLD who have experienced treatment failure with front-line therapy, and this study represents the largest series of PTLD patients treated prospectively with a uniform chemotherapy regimen.

Inflammatory Bowel Disease After Liver Transplantation: Risk Factors for Recurrence and De Novo Disease

Inflammatory bowel disease (IBD) is associated with primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) and can recur or develop de novo after orthotopic liver transplantation (OLT). The aim of this study was to investigate the incidence and severity of IBD after liver transplantation and to perform a multivariate analysis for possible risk factors. In this retrospective study, 91 patients transplanted for PSC or AIH, without prior colectomy, were included. Sixty patients were transplanted for PSC, 31 for AIH. IBD activity before and after OLT and other possible risk factors were analysed in a multivariate model. Forty‐nine patients (54%) had IBD before OLT. Forty patients (44%) had active IBD after transplantation: recurrence in 32 and de novo in 8. Cumulative risk for IBD after OLT was 15, 39 and 54% after 1, 5 and 10 years, respectively. In 59% of patients with IBD prior to OLT the disease was more active after transplantation. Risk factors for recurrent disease were: symptoms at time of OLT, short interval of IBD before OLT and use of tacrolimus. 5‐aminosalicylates were protective. A cytomegalovirus positive donor/negative recipient combination increased the risk for de novo IBD.

Collaborative strategies to reduce mortality and morbidity in patients with chronic intestinal failure including those who are referred for small bowel transplantation.

Intestinal transplant wait-list mortality is higher than for other organ transplants. The objective of this workshop was to identify the main problems contributing to high mortality in adults and children candidates for intestinal transplantation and provide recommendations on how to correct them. Outcome. To facilitate this, 63 relevant articles identified from the medical literature from 1987 to 2007 were reviewed. Consensus was achieved on several important definitions relevant to this review. For children and adults on parenteral nutrition (PN) the main mortality risk factors were identified as were the main risks of mortality for those on the waiting list for intestinal transplants. Recommendations. (1) Primary care givers managing intestinal failure patients should establish a link with an intestinal failure programs early and collaboration with intestinal failure programs should be initiated for patients whose PN requirements are anticipated to be more than 50% 3 months after initiating PN; (2) intestinal failure programs should include both intestinal rehabilitation and intestinal transplantation or have active collaborative relationships with centers performing intestinal transplantation; (3) National registries for intestinal failure patients should be established and organizations that provide home PN solutions should be expected to participate. Conclusion. There are many unresolved issues in adults and children with PN dependent intestinal failure. To address these, a key recommendation of this group is to establish national intestinal failure databases that can support multicenter studies and lead to the adoption of universally accepted standards of patient care with the goal of improving outcomes in all long-term intestinal failure patients including those requiring intestinal transplantation.

A multidisciplinary approach to the treatment of intestinal failure

Intestinal failure is most commonly treated by the administration of total parenteral nutrition (TPN). In some patients, however, surgical therapy may increase the ability to use the intestine for nutrition and thereby decrease the complications of TPN therapy. A multidisciplinary comprehensive intestinal failure program was initiated at the University of Nebraska Medical Center in October 2000. Here we describe the surgical approaches to patients with short bowel syndrome and the subsequent impact on the need for TPN and on survival. Fifty patients (children = 30, adults = 20) underwent surgical procedures to restore intestinal continuity (n = 5), repair enterocutaneous fistulas (n = 5), resect dysmotile or strictured/obstructed bowel segments or mesenteric desmoid tumors (n = 7), stricturoplasty (n = 2), Bianchi tapering and lengthening (n = 20), serial transverse enteroplasty (n = 8), and other operations (n = 8). Of these 50 patients, three patients did not require TPN after surgical intervention and seven had remnant small bowel anatomy that precluded TPN weaning (e.g., end duodenostomy) and were listed for transplantation or continued on full TPN support. Of the 40 remaining patients, most received the majority of calories fromTPNat the time of referral, i.e., mean calories fromTPN _ 90%. Subsequent to the surgical and medical therapy, 26 (65%) have been completely weaned off TPN. In addition, 10 had substantial decreases in their TPN requirements (i.e., from 85% of calories from TPN at onset decreased to a median 35% of required calories at most recent follow-up). Four patients remained on the same amount of TPN support. Four of the seven patients listed for transplantation underwent successful transplantation. Despite the complications of short bowel syndrome, 86% (n = 43) of the patients are alive and well at a mean follow-up of 2 years. Patient deaths occurred primarily in those listed or eligible for transplantation and were related to advanced liver disease (n = 3), gastrointestinal hemorrhage (n = 1), or line sepsis (n = 1). Two other patients died, one from influenza A infection and one from unknown cause at home, months after complete discontinuation of TPN. In this series of patients with short bowel syndrome, surgical intervention led to weaning or discontinuation of TPN support in 85% of patients. An organized multidisciplinary approach to the patient with short bowel syndrome is recommended.