David D. Douglas

Report of a national conference on liver allocation in patients with hepatocellular carcinoma in the United States.

A national conference was held to better characterize the long‐term outcomes of liver transplantation (LT) for patients with hepatocellular carcinoma (HCC) and to assess whether it is justified to continue the policy of assigning increased priority for candidates with early‐stage HCC on the transplant waiting list in the United States. The objectives of the conference were to address specific HCC issues as they relate to liver allocation, develop a standardized pathology report form for the assessment of the explanted liver, develop more specific imaging criteria for HCC designed to qualify LT candidates for automatic Model for End‐Stage Liver Disease (MELD) exception points without the need for biopsy, and develop a standardized pretransplant imaging report form for the assessment of patients with liver lesions. At the completion of the meeting, there was agreement that the allocation policy should result in similar risks of removal from the waiting list and similar transplant rates for HCC and non‐HCC candidates. In addition, the allocation policy should select HCC candidates so that there are similar posttransplant outcomes for HCC and non‐HCC recipients. There was a general consensus for the development of a calculated continuous HCC priority score for ranking HCC candidates on the list that would incorporate the calculated MELD score, alpha‐fetoprotein, tumor size, and rate of tumor growth. Only candidates with at least stage T2 tumors would receive additional HCC priority points. Liver Transpl 16:262–278, 2010.

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.

Treatment of recurrent hepatitis C infection after liver transplantation with combination of pegylated interferon α2b and ribavirin: An open-label series

Background. Hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (OLT) is universal. We aimed to evaluate the efficacy and safety of pegylated interferon (PEG-IFN) and ribavirin (RIB) in the treatment of post-OLT HCV recurrence. Methods. Thirty-seven patients with recurrent HCV after OLT were screened and began treatment. Nineteen patients have completed therapy. PEG-IFN was started at a dose of 0.5 &mgr;g/kg per week and titrated toward a maximum dose of 1.5 &mgr;g/kg per week. RIB was started at a dose of 400 mg per day and titrated toward a maximum of 1000 mg per day, as tolerated. Therapy continued for 1 year after HCV replication was undetectable by reverse transcriptase-polymerase chain reaction and was discontinued if there was no virologic clearance at 48 weeks. Results. Twelve patients (63%) completed the combination regimen. Therapy was discontinued in seven (37%) patients. Seven patients (37%) had undetectable viral load at the end of treatment. Of those, five patients (26%) had sustained viral response 6 months after discontinuation of therapy. Five patients (26%) had no virologic response. Necro-inflammatory score declined from 5.22 to 2.89 (P =0.05) in nonresponders versus 6.8 to 2.6 (P <0.01) in responders. Fibrosis stage did not change in either group. Genotype 1-infected patients had a lower likelihood of attaining end of treatment or sustained viral response (P <0.05 for both). Conclusions. Post-OLT HCV recurrence can be safely treated with PEG-IFN and RIB. Bone marrow toxicity, depression, and rejection are limiting factors that require aggressive management. There was short-term histologic benefit to the use of this regimen, even in those patients without viral clearance.

Endoscopic treatment of anastomotic biliary strictures after living donor liver transplantation: outcomes after maximal stent therapy

BACKGROUND The optimal endoscopic treatment for anastomotic biliary strictures after deceased donor liver transplantation is undefined. Endoscopic therapy with conventional methods of biliary dilation and stent placement has been successful but often requires prolonged therapy. OBJECTIVE To determine the outcomes of an aggressive endoscopic approach that uses endoscopic dilation followed by maximal stent placement. SETTING Tertiary-care academic medical center. PATIENTS Of 176 patients who underwent deceased donor liver transplantation between June 1999 and July 2004, 25 were diagnosed with anastomotic biliary strictures. INTERVENTIONS Patients were treated endoscopically with a combined technique of balloon dilation and maximal stent placement. MAIN OUTCOME MEASUREMENTS Treatment outcomes, including bile-duct patency, a need for surgical intervention, morbidity, and mortality, were evaluated retrospectively. RESULTS Endoscopic dilation followed by maximal stent placement was performed until resolution of strictures in 22 of 25 patients (88% immediate success on intent-to-treat analysis). Persistent resolution of strictures was achieved in 18 of these 22 patients. Re-treatment was successful in 2 of 4 patients with recurrent strictures. Overall, 20 of 22 patients who completed endoscopic therapy (91%) avoided surgical intervention. Median duration of endoscopic treatment was 4.6 months. Patients with early onset strictures required a significantly shorter duration of endoscopic therapy (3 vs 9 months; P<.01). Multiple stent placement was not technically difficult, and no major complications were encountered. CONCLUSIONS Aggressive endoscopic therapy with combined biliary dilation and maximal stent placement allows resolution of anastomotic biliary strictures after deceased donor liver transplantation in a relatively short period, with sustained success and minimal complications.

Six‐minute walk distance predicts mortality in liver transplant candidates

The 6‐minute walk distance (6MWD) is a simple test measuring global physical function. It is commonly used to predict mortality in patients with cardiac and pulmonary diseases, but it is also useful in assessing the functional status of patients with a variety of other medical conditions. We sought to determine (1) the characteristics of the 6MWD in patients listed for liver transplantation (LT), (2) the existence of a relationship between the 6MWD and the quality of life, and (3) the relationship between the 6MWD and survival in LT candidates. The 6MWD was prospectively measured in all patients listed for LT. The 6MWD was determined when the listed Model for End‐Stage Liver Disease (MELD) score was ≥15. Patients were followed until LT, death, removal from the wait list, or the end of the study period. Quality of life was assessed with the Short Form 36 (SF‐36). In 121 patients, the mean 6MWD was 369 ± 122 m; it was not related to age, height, weight, body mass index, albumin level, or etiology of liver disease and showed a moderate correlation with the physical component score (PCS) on the SF‐36 (r = 0.4) and a moderate inverse correlation with the native MELD score (r = −0.61). In an unadjusted analysis, a high native MELD score, a low 6MWD, and a low PCS were associated with mortality, with only the 6MWD retaining significance after adjustment for covariates. Each 100‐m increase in the 6MWD was significantly associated with increased survival (hazard ratio = 0.48, P = 0.0001), with 6MWD < 250 m being associated with an increased risk of death (P = 0.0001). In conclusion, the 6MWD is significantly reduced in patients awaiting LT and is inversely correlated with the native MELD score. A pretransplant 6MWD < 250 m is a risk for death on the wait list. Liver Transpl 16:1373–1378, 2010.

A randomized, prospective, double-blinded evaluation of selective bowel decontamination in liver transplantation.

Background. Bacterial infection is a frequent, morbid, and mortal complication of liver transplantation. Selective bowel decontamination (SBD) has been reported to reduce the rate of bacterial infection after liver transplantation in uncontrolled trials, but benefits of this intervention have been less clear in controlled studies. Methods. Eighty candidates for liver transplantation were randomly assigned in a double-blinded fashion to an SBD regimen consisting of gentamicin 80 mg+polymyxin E 100 mg+nystatin 2 million units (37 patients) or to nystatin alone (43 patients). Both treatments were administered orally in 10 ml (increasing to 20 ml, according to predefined criteria), four times daily, through day 21 after transplantation. Anal fecal swab cultures were performed on days 0, 4, 7, and 21. Rates of infection, death, and charges for medical care were assessed from day 0 through day 60. Results. More than 85% of patients in both treatment groups began study treatment more than 3 days before transplantation. Rates of infection (32.4 vs. 27.9%), death (5.4 vs. 4.7%), or charges for medical care (median

A randomized, multicenter study comparing steroid-free immunosuppression and standard immunosuppression for liver transplant recipients with chronic hepatitis C

194,000 vs.

Natural History of Post-Liver Transplantation Hepatitis C: A Review of Factors That May Influence Its Course

163,000) were not reduced in patients assigned to SBD. On days 0, 4, 7, and 21, growth of aerobic gram-negative flora in fecal cultures of patients assigned to SBD was significantly less than that of patients taking nystatin alone; growth of aerobic gram-positive flora, anaerobes, and yeast was not significantly different. Conclusion. Routine use of SBD in patients undergoing liver transplantation is not associated with significant benefit.

Hepatic steatosis in hepatitis C virus genotype 3 infection: Does it correlate with body mass index, fibrosis, and HCV risk factors?

This randomized, prospective, multicenter trial compared the safety and efficacy of steroid‐free immunosuppression (IS) to the safety and efficacy of 2 standard IS regimens in patients undergoing transplantation for hepatitis C virus (HCV) infection. The outcome measures were acute cellular rejection (ACR), severe HCV recurrence, and survival. The patients were randomized (1:1:2) to tacrolimus (TAC) and corticosteroids (arm 1; n = 77), mycophenolate mofetil (MMF), TAC, and corticosteroids (arm 2; n = 72), or MMF, TAC, and daclizumab induction with no corticosteroids (arm 3; n = 146). In all, 295 HCV RNA–positive subjects were enrolled. At 2 years, there were no differences in ACR, HCV recurrence (biochemical evidence), patient survival, or graft survival rates. The side effects of IS did not differ, although there was a trend toward less diabetes in the steroid‐free group. Liver biopsy samples revealed no significant differences in the proportions of patients in arms 1, 2, and 3 with advanced HCV recurrence (ie, an inflammation grade ≥ 3 and/or a fibrosis stage ≥ 2) in years 1 (48.2%, 50.4%, and 43.0%, respectively) and 2 (69.5%, 75.9%, and 68.1%, respectively). Although we have found that steroid‐free IS is safe and effective for liver transplant recipients with chronic HCV, steroid sparing has no clear advantage in comparison with traditional IS. Liver Transpl, 2011.

Early results of targeted prophylaxis for coccidioidomycosis in patients undergoing orthotopic liver transplantation within an endemic area

Our aim was to assess long‐term survival in patients transplanted for HCV‐related end‐stage liver disease (ESLD) and evaluate potentially modifiable predictors of survival. We performed a retrospective analysis of adult liver transplants (LT) at our institution for HCV‐related ESLD since the programs inception. Pertinent demographic, clinical, and biochemical information was retrieved from electronic medical records and histological data from 990 per‐protocol liver biopsies were collected. Three hundred eighty LT were performed at our institution during the study period, 206 patients were transplanted for HCV‐related ESLD; 6 died within 30 days of transplantation and were not included. The remaining 200 recipients (DDLT 168 LDLT 32) constituted the evaluable population. The demographics were as follows: 150 males, median age 53 years; median donor age 39 years; hepatocellular carcinoma (HCC) in 26%. Overall 1‐, 5‐, and 7‐year survival: 95%, 81%, and 79%; median survival 43 months, mortality 15%. Significant HCV recurrence (HAI ≥6 and/or fibrosis ≥2) was present in 49%, “early recurrence” (within 1 year of LT) in 30.5% and biopsy‐proven acute rejection was present in 27%. Factors with a significant negative impact on patient survival included: fibrosis stage ≥2 at 12‐month biopsy, advanced donor age, history of HCC and early acute rejection. Survival was similar regardless of the donor type (DDLT vs. LDLT). Early and aggressive HCV recurrence has a very heavy toll on patient survival. Prompt recognition and treatment of “rapid fibrosers” may impart benefit. As has been described before, avoidance of rejection and selection of young donors for HCV‐positive recipients will also improve survival in this population. On the basis of our findings, LDLT is a good option for HCV‐positive recipients. Liver Transpl 15:1872–1881, 2009.