Jean F. Botha

Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers.

BACKGROUND & AIMS Excellent single-center outcomes of neoadjuvant chemoradiation and liver transplantation for unresectable perihilar cholangiocarcinoma caused the United Network of Organ Sharing to offer a standardized model of end-stage liver disease (MELD) exception for this disease. We analyzed data from multiple centers to determine the effectiveness of this treatment and the appropriateness of the MELD exception. METHODS We collected and analyzed data from 12 large-volume transplant centers in the United States. These centers met the inclusion criteria of treating 3 or more patients with perihilar cholangiocarcinoma using neoadjuvant therapy, followed by liver transplantation, from 1993 to 2010 (n = 287 total patients). Center-specific protocols and medical charts were reviewed on-site. RESULTS The patients completed external radiation (99%), brachytherapy (75%), radiosensitizing therapy (98%), and/or maintenance chemotherapy (65%). Seventy-one patients dropped out before liver transplantation (rate, 11.5% in 3 months). Intent-to-treat survival rates were 68% and 53%, 2 and 5 years after therapy, respectively; post-transplant, recurrence-free survival rates were 78% and 65%, respectively. Patients outside the United Network of Organ Sharing criteria (those with tumor mass >3 cm, transperitoneal tumor biopsy, or metastatic disease) or with a prior malignancy had significantly shorter survival times (P < .001). There were no differences in outcomes among patients based on differences in surgical staging or brachytherapy. Although most patients came from 1 center (n = 193), the other 11 centers had similar survival times after therapy. CONCLUSIONS Patients with perihilar cholangiocarcinoma who were treated with neoadjuvant therapy followed up by liver transplantation at 12 US centers had a 65% rate of recurrence-free survival after 5 years, showing this therapy to be highly effective. An 11.5% drop-out rate after 3.5 months of therapy indicates the appropriateness of the MELD exception. Rigorous selection is important for the continued success of this treatment.

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.

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.

Role of an Intestinal Rehabilitation Program in the Treatment of Advanced Intestinal Failure

Objective: To analyze outcomes in children with intestinal failure treated by our Intestinal Rehabilitation Program (IRP) in a 4-year period. Patients and Methods: A total of 51 parenteral nutrition (PN)–dependent patients (20 male) were enrolled in the IRP. Median age was 1.7 years, with the primary diagnoses being gastroschisis, necrotizing enterocolitis, volvulus, and congenital atresia. Median small bowel intestinal length was 35 cm, with the majority of patients having only jejunum as remaining bowel anatomy. Thirty-six of the 51 patients had liver disease characterized by cirrhosis, advance bridging fibrosis, and portal and periportal fibrosis. Height, weight z score, platelet count, albumin, and bilirubin levels were measured at the beginning and end of the study. Results: Of the 51 patients, 29 had 46 different surgical intestinal repairs. Twenty-nine of the 36 patients with hyperbilirubinemia had normalized serum bilirubin with treatment. Ten patients required transplantation. Five patients died of sepsis, influenza, or complications after intestinal transplantation. Of the remaining 37 patients in the IRP, 31 were weaned from parenteral nutrition (5 with cirrhosis); 6 patients are in the process of weaning. Survival rate of the patients in the IRP was 90%. Growth has continued along the same curve, and some patients have exhibited significant catch-up. Conclusions: With an aggressive medical/surgical approach, even patients with intestinal failure and advanced liver disease can avoid transplantation. Patients in the IRP showed improved liver function and nutritional parameters with the ability to discontinue PN while maintaining growth. Early referral of these patients to specialized centers before the development of advanced liver disease is recommended.

Left lobe adult-to-adult living donor liver transplantation: Small grafts and hemiportocaval shunts in the prevention of small-for-size syndrome

Adult‐to‐adult living donor liver transplantation (AA‐LDLT) has better outcomes when a graft weight to recipient weight ratio (GW/RW) > 0.8 is selected. A smaller GW/RW may result in small‐for‐size syndrome (SFSS). Portal inflow modulation seems to effectively prevent SFSS. Donor right hepatectomy is associated with greater morbidity and mortality than left hepatectomy. In an attempt to shift the risk away from the donor, we postulated that left lobe grafts with a GW/RW < 0.8 could be safely used with the construction of a hemiportocaval shunt (HPCS). We combined data from 2 centers and selected suitable left lobe living donor/recipient pairs. Since January 2005, 21 patients underwent AA‐LDLT with left lobe grafts. Sixteen patients underwent the creation of an HPCS between the right portal vein and the inferior vena cava. The portocaval gradient (portal pressure − central venous pressure) was measured before the unclamping of the shunt and 10 minutes after unclamping. The median actual graft weight was 413 g (range = 350‐670 g), and the median GW/RW was 0.67 (range = 0.5‐1.0). The portocaval gradient was reduced from a median of 18 to 5 mmHg. Patient survival and graft survival at 1 year were 87% and 81%, respectively. SFSS developed in 1 patient, who required retransplantation. Two patients died at 3 and 10 months from a bile leak and fungal sepsis, respectively. The median recipient bilirubin level and INR were 1.7 mg/dL and 1.1, respectively, at 4 weeks post‐transplant. One donor had a bile leak (cut surface). This is the first US series of small left lobe AA‐LDLT demonstrating that the transplantation of small grafts with modulation of the portal inflow by the creation of an HPCS may prevent the development of SFSS while at the same time providing adequate liver volume. As it matures, this technique has the potential for widespread application and could positively effect donor safety, the donor pool, and waiting list times. Liver Transpl 16:649‐657, 2010.

West Nile Virus—Associated Encephalitis in Recipients of Renal and Pancreas Transplants: Case Series and Literature Review

Although West Nile fever is mild in the vast majority of infected persons, there is growing evidence that the disease may be more severe in the immunocompromised population. We describe 3 recipients of kidney or pancreas transplants who developed West Nile fever, 2 of whom had meningoencephalitis. As is the norm when treating serious infections in transplant recipients, a reduction of immunosuppression was pursued for these patients. Despite the severe nature of the disease in 2 patients, all recovered from the disease. The time course of neurologic recovery in the 2 patients with meningoencephalitis is highlighted. We also review the literature on West Nile fever in organ transplant recipients. In areas where West Nile virus is endemic, one must have a high index of suspicion for the illness when dealing with fever in transplant recipients.

Quality of Life after Pediatric Intestinal Transplantation: The Perception of Pediatric Recipients and Their Parents

The objective was to examine the perception of physical and psychosocial functioning of pediatric intestinal transplant recipients who are beyond the perioperative period and compare these with normal and chronically ill children.

Repeat surgical bowel lengthening with the STEP procedure.

Background. Feasibility of repeat lengthening has been demonstrated in animals, but in humans, none of the three clinical case reports have achieved enteral autonomy after secondary lengthening with serial transverse enteroplasty (STEP). Patients and Methods. Institutional Review Board approved retrospective review of a single center series of repeat intestinal lengthening after prior Bianchi lengthening or STEP. Outcome measures examined include patient survival, weaning from parenteral nutrition, and need for intestinal transplantation. Results. Repeat lengthening with STEP was performed 16 times in 14 patients including 2 adults and 7 male patients after prior Bianchi (n=7) and prior STEP (n=7). Median time after initial lengthening to reSTEP was 12 months (2 months–15 years). Median remnant bowel length before initial lengthening was 35 cm (15–110), before reSTEP was 56.5 cm (27–100) and final length after reSTEP was 90 cm (39–120). Survival is 100% with a median follow-up of 14.5 months (1–65 months). Discontinuation of parenteral nutrition (PN) after reSTEP was achieved in 6 of 14 (43%) patients at a median of 3 months (0.5–13 months) after reSTEP. Intestinal transplant salvage was performed in four patients at 7, 9, 13 months, and 4.6 years, respectively, after reSTEP. All four of those undergoing intestinal transplantation have also subsequently discontinued PN. Conclusions. Repeat lengthening is technically feasible after either of the available surgical lengthening procedures (Bianchi and STEP). In the stable patient, who is unable to wean from PN, repeat lengthening led to discontinuation of TPN in almost half of these carefully selected patients and does not preclude intestinal transplantation.

Isolated liver transplantation in infants with end‐stage liver disease due to short bowel syndrome

Infants with short bowel syndrome (SBS) and associated liver failure are often referred for combined liver/intestinal transplantation. We speculated that in some young children, nutritional autonomy would be possible with restoration of normal liver function. Features we believed to predict nutritional autonomy include history of at least 50% enteral tolerance, age less than 2 yr, and no underlying intestinal disease. This report documents our experience with liver transplantation alone in children with liver failure associated with SBS. Twenty‐three children with SBS and end‐stage liver disease, considered to have good prognostic features for eventual full enteral adaptation, underwent isolated liver transplantation. Median age was 11 months (range, 6.5 to 48 months). Median pretransplant weight was 7.4 kg (range, 5.2 to 15 kg). All had growth retardation and advanced liver disease. Bowel length ranged from 25 to 100 cm. Twenty‐three children underwent 28 isolated liver transplants. There were 14 whole livers and 14 partial grafts (five living donors). Seventeen patients are alive at a median follow‐up of 57 months (range, 6 to 121 months). Actuarial patient and graft survival rates at 1 yr are 82% and 75% and at 5 yr are 72% and 60%, respectively. Four deaths resulted from sepsis, all within 4 months of transplantation, and 1 death resulted from progressive liver failure. Two allografts developed chronic rejection; both children were successfully retransplanted with isolated livers. Of 17 surviving patients, three require supplemental intravenous support; the remaining 14 have achieved enteral autonomy, at a median of 3 months (range, 1 to 72 months) after transplantation. Linear growth is maintained and, in many, catch‐up growth is evident. Median change in z score for height is 0.57 (range, −4.47 to 2.68), and median change in z score for weight is 0.42 (range, −1.65 to 3.05). In conclusion, Isolated liver transplantation in children with liver failure as a result of SBS, who have favorable prognostic features for full enteral adaptation, is feasible with satisfactory long‐term survival. Liver Transpl 12:1062–1066, 2006.

Hepatic fibrosis persists and progresses despite biochemical improvement in children treated with intravenous fish oil emulsion.

Objectives: Intestinal failure–associated liver disease (IFALD) is a multifactorial process, which can culminate in cirrhosis and need for transplantation. Fish oil–based lipid emulsions (FOE) reportedly reverse hyperbilirubinemia, but there are little data on their effect on the histopathology of IFALD. Methods: We blindly examined sequential liver biopsy data on 6 children receiving FOE, with scoring of cholestasis, inflammation, fibrosis, and ductal proliferation based on standardized systems. This information was correlated with biochemical and clinical data to determine any possible relations between biologic and histologic improvement. Results: The median gestational age was 35 weeks, median birth weight 2064 g, and common most reason for intestinal loss was gastroschisis (5/6 children). Median intestinal length was 26 cm beyond the ligament of Treitz and most children had roughly 2 of 3 of their colonic length. It was observed that although hyperbilirubinemia reversed and hepatic synthetic function was preserved across timepoints, fibrosis was persistent in 2 cases, progressive in 3 cases, and regressed in only 1. It remained severe (grade 2 or higher) in 5 of 6 children at last biopsy. Histologic findings of cholestasis improved in all patients and inflammation improved in 5 of 6 children. There were mixed effects on ductal proliferation and steatosis. Conclusions: In children treated with FOE, reversal of hyperbilirubinemia is not reflected by a similar histologic regression of fibrosis at the timepoints studied. Children with IFALD should have active ongoing treatment and be considered for early referral to an Intestinal Failure Program even with a normalized bilirubin.