Jeffrey Campsen

Sirolimus-based immunosuppression following liver transplantation for hepatocellular carcinoma.

Experience with sirolimus (SRL)‐based immunosuppression following orthotopic liver transplantation (OLT) is rapidly accumulating. In combination with calcineurin inhibitors (CNIs), SRL may reduce the incidence of acute rejection and lower overall required drug levels. This study sought to quantify long‐term outcome following OLT in patients with cirrhosis and concomitant hepatocellular carcinoma (HCC) who were treated with an SRL‐based regimen as a primary therapy. From January 2000 to June 2007, 97 patients underwent OLT for end‐stage liver disease and HCC at the University of Colorado Health Sciences Center. Of those, 45 patients received SRL, in addition to CNIs, as a component of their primary immunosuppression regimen post‐OLT. Conversely, 52 patients received the standard immunosuppression regimen including CNIs, mycophenolate mofetil, and corticosteroids. The 2 treatment groups were compared with respect to the following variables: age, gender, tumor stage by explant, grade, size, presence of vascular invasion, focality, Childs class, baseline creatinine, and warm and cold ischemic times. The 2 groups were comparable by all factors save for cold ischemic time, which was significantly longer in the CNI‐treated group. Overall survival at 1 and 5 years post‐OLT for patients treated with SRL was 95.5% and 78.8%, respectively. Conversely, survival in patients treated with CNIs exclusively at the same time intervals was 83% and 62%. Although there was no difference in the incidence of major complications, the SRL group experienced a modest improvement in renal function. Cumulatively, these data suggest a potential survival benefit with SRL‐based therapy in patients undergoing OLT for end‐stage liver disease and concomitant malignancy. Liver Transpl 2008.

Liver transplantation for autoimmune hepatitis and the success of aggressive corticosteroid withdrawal.

Our center has attempted to minimize corticosteroid (CS) use in all of our orthotopic liver transplantation (OLT) recipients. Because patients with autoimmune hepatitis (AIH) typically require CSs after transplantation, we reviewed our experience in this cohort of patients to determine (1) patient outcomes including recurrent disease and (2) long‐term requirements for CS use in AIH patients. From 1988 to 2006, 1102 OLTs were performed in 1032 adult patients at the University of Colorado, of whom 66 (6%) with AIH received 68 allografts. Recurrence was defined by a clinically worsening examination and histological evidence from biopsy. Bivariate and multivariate analyses were used to evaluate predictors of CS withdrawal. Twelve potential predictors of CS discontinuation were considered: age, gender, presence of inflammatory bowel disease (IBD), type of graft (cadaver or living donor), recurrence of AIH, warm ischemia time, follow‐up time (time since transplant), and immunosuppressants (cyclosporine, tacrolimus, sirolimus, azathioprine, and mycophenolate mofetil). Overall survival at 5 years was 91%. The 1‐ and 5‐year recurrence‐free survival was 88% and 59%, respectively. Risk (incidence) of recurrent AIH at 1, 3, and 5 years was 12%, 26%, and 36%, respectively. Disease recurred in 23 of 66 patients or 34.8%. Of the 23 patients who developed recurrent disease, none received a second transplant because of recurrent disease. CSs were withdrawn in 50% of patients at the time of review. Only 2 factors on multivariate analysis were strongly associated negatively with CS withdrawal: (1) an increasing dose of the immunosuppressant and (2) the presence of IBD. Controlling for these other factors, we found that recurrent disease did not strongly influence CS withdrawal. In conclusion, outcomes in AIH patients were quite favorable, and none of the patients required retransplantation for recurrent AIH. With a CS minimization approach, one‐half of the patients were able to remain CS‐free. Liver Transpl 14:1281–1286, 2008.

Predictors of long‐term outcome following liver transplantation for hepatocellular carcinoma: a single‐center experience

Orthotopic liver transplantation (OLT) is increasingly being applied for cure in patients with cirrhosis and concomitant hepatocellular carcinoma (HCC). In recipients with limited tumor burden, OLT achieves reasonable long‐term outcome. This study sought to identify clinical and pathologic variables predictive of long‐term disease‐free survival and the presence of vascular invasion. From 1992 to 2006, 130 patients underwent OLT for cirrhosis and HCC. Malignancy was diagnosed in 107 patients prior to OLT and in 23 patients on pathologic examination of the explant. Nine clinical and pathologic variables were considered including: TNM stage, nodularity, vascular invasion, Milan criteria, incidental lesion, differentiation, tumor size, preOLT transarterial chemoembolization (TACE), and administration of sirolimus‐based immunosuppression. The overall incidence of HCC recurrence was 17% with the majority (82%) being stage III. Cumulatively, tumor recurrence‐free survival (RFS) is 84, 74, and 67% at 1, 3, and 5 years respectively. Independent predictors of RFS included stage III and poorly differentiated lesions (P < 0.05). Furthermore, stage III tumors and those >3.5 cm in size were predictive of vascular invasion. Importantly, preOLT, TACE and postOLT sirolimus had no influence on survival. Pathologic variables including tumor stage and grade have a significant impact on outcome. Importantly, it seems that TACE and sirolimus had no beneficial effect.

Outcomes of Donor Evaluations for Adult-to-Adult Right Hepatic Lobe Living Donor Liver Transplantation

The purpose of this study is to determine the role of liver biopsy and outcome of patients undergoing donor evaluation for adult‐to‐adult right hepatic lobe living donor liver transplantation (LDLT). Records of patients presenting for a comprehensive donor evaluation between 1997 and February 2005 were reviewed. Liver biopsy was performed only in patients with risk factors for abnormal histology. Two hundred and sixty patients underwent a comprehensive donor evaluation and 116 of 260 (45%) were suitable for donation, 14 of 260 (5.4%) did not complete evaluation and 130 of 260 (50%) were rejected. Four patients underwent unsuccessful hepatectomy surgery due to discovery of intraoperative abnormalities. Between 1997 and 2001, the acceptance rate of donor candidates (63%) was higher than 2002–2005 (36%), p < 0.0001. Sixty‐six of the 150 eligible patients (44%) fulfilled criteria for liver biopsy and 28 of 66 (42%) had an abnormal finding. Less than half of the patients undergoing donor evaluation were suitable donors and the donor acceptance rate has declined over time. A large proportion of the patients undergoing liver biopsy have abnormal findings. Our evaluation process failed to identify 4 of 103 who had aborted donor surgeries.

Implications of a positive crossmatch in liver transplantation: A 20-year review

Whether a positive crossmatch result has any relevance to liver transplantation (LT) outcomes remains controversial. We assessed the impact of a positive crossmatch result on patient and graft survival and posttransplant complications. During a 20‐year period, 2723 LT procedures with crossmatch results were identified: 2479 primary transplants and 244 retransplants. The rates of positive B cell and T cell crossmatches were 10.1% and 7.4%, respectively, for primary transplants and 14.6% and 6.4%, respectively, for retransplants (P = 0.049 for a B cell crossmatch). Across all primary transplants, females (P < 0.001) and patients with autoimmune hepatitis (P < 0.001) had greater frequencies of positive crossmatches. There was no effect from race or age. For both primary transplants and retransplants, patient survival and graft survival were not affected by the presence of a positive crossmatch. With respect to posttransplant complications, there were no differences in rejection episodes (hyperacute, acute, or chronic) or technical complications (biliary and vascular) between negative and positive crossmatch groups. However, there were significant differences in the pathological findings of preservation injury (PI) on liver biopsy samples taken at the time of transplantation and within the first week of transplantation (P = 0.003 for B cells and P = 0.03 for T cells). In summary, a positive crossmatch had no significant impact on patient survival or graft outcomes. However, there was a significantly higher incidence of PI in primary LT recipients with a positive crossmatch. This finding is important for a broader understanding of PI, which may include a significant immunological component. Liver Transpl 18:455–460, 2012.

Choledochoduodenostomy is a Safe Alternative to Roux-en-Y Choledochojejunostomy for Biliary Reconstruction in Liver Transplantation

IntroductionBile duct reconstruction during liver transplantation is usually performed by a duct-to-duct anastomosis or a Roux-en-Y choledochojejunostomy (CDJ). Direct anastomosis of the bile duct to the duodenum (choledochoduodenostomy—CDD) is another option for biliary reconstruction. This technique has been used with good outcome for the treatment of choledochal cysts, ampullary stenosis, and major bile duct injuries; however, there is little published experience with CDD in liver transplantation. We provide preliminary evidence that CDD is a safe technique for biliary anastomosis in liver transplant recipients.MethodsFrom September 2000 to August 2007 a total of 619 adult first-time cadaveric or living donor liver transplants were performed at the University of Colorado Health and Science Center. Bile duct repair was performed by direct end-to-end anastomosis in 466 patients and by choledocoenterostomy in the remaining 153 patients, 82 of whom were cadaveric recipients. The cadaveric choledocoenterostomy patients were divided into two groups: CDD in 25 and CDJ in 57 recipients.ResultsThere were no significant differences in the 1-year patient or graft survival between the cadaveric groups. The 1-year patient survival was 100% in the CDD group and 97.1% in the CDJ group. The CDD group did not experience more surgical complications compared to the CDJ group.ConclusionsCholedochoduodenostomy is a safe alternative to CDJ biliary anastomosis when a duct-to-duct anastomosis cannot be performed. There is no significant difference in mortality, graft survival, or biliary complications. In addition, CDD offers the advantage of postoperative access to the billiary system by endoscopy and avoids complications associated with the CDJ bowel anastomosis.

Donor Complications Following Laparoscopic Compared to Hand-Assisted Living Donor Nephrectomy: An Analysis of the Literature

There are two approaches to laparoscopic donor nephrectomy: standard laparoscopic donor nephrectomy (LDN) and hand-assisted laparoscopic donor nephrectomy (HALDN). In this study we report the operative statistics and donor complications associated with LDN and HALDN from large-center peer-reviewed publications. Methods. We conducted PubMed and Ovid searches to identify LDN and HALDN outcome studies that were published after 2004. Results. There were 37 peer-reviewed studies, each with more than 150 patients. Cumulatively, over 9000 patients were included in this study. LDN donors experienced a higher rate of intraoperative complications than HALDN donors (5.2% versus. 2.0%, P < .001). Investigators did not report a significant difference in the rate of major postoperative complications between the two groups (LDN 0.5% versus HALDN 0.7%, P = .111). However, conversion to open procedures from vascular injury was reported more frequently in LDN procedures (0.8% versus 0.4%, P = .047). Conclusion. At present there is no evidence to support the use of one laparoscopic approach in preference to the other. There are trends in the data suggesting that intraoperative injuries are more common in LDN while minor postoperative complications are more common in HALDN.

A Decade of Experience Using mTor Inhibitors in Liver Transplantation

Some studies suggest that Sirolimus (SRL) is associated with an increased risk of death in liver transplant recipients compared to treatment with calcineurin inhibitors (CNIs). We compared patients who received SRL or CNI in the first year after liver transplant. Our database included 688 patients who received a liver transplant. The patients were divided into groups. (1) CNI + MPS (mycophenolate sodium) at time of discharge. (2) CNI + MPS at time of discharge; SRL was added within the first 6 months and continued through the first year. (3) CNI + MPS at time of discharge; SRL was added within the first 6 months and discontinued before the first year. (4) SRL as primary immunosuppression. (5) SRL as primary immunosuppression and discontinued before the first year. We used mortality and graft loss as the primary measures of outcome. We also quantified renal function using the change in glomerular filtration rate (GFR), the presence of biopsy proven acute cellular reject (ACR), and steroid-resistant rejection (SRR). There were no significant differences in mortality or graft loss. There was no difference in patient or graft survival. Patients that received SRL as primary immunosuppression had 50% less rejection compared to controls.

Liver transplantation for hepatitis B liver disease and concomitant hepatocellular carcinoma in the United States With hepatitis B immunoglobulin and nucleoside/nucleotide analogues

Reinfection with hepatitis B virus (HBV) after liver transplantation (LT) may favor the recurrence of hepatocellular carcinoma (HCC), and combination therapy with hepatitis B immunoglobulin (HBIG) and nucleoside/nucleotide analogues may reduce HBV recurrence after LT. To test associations between HBV, HCC, and survival, we performed a retrospective chart review of patients undergoing LT for HBV between January 1985 and December 2010 at 7 US transplant centers. After we divided the patients into 3 eras based on evolving strategies in antiviral therapy (1985‐1994, 1995‐2004, and 2005‐2010), we reviewed 16 variables to determine whether there were associations between survival and HCC recurrence. Seven hundred thirty‐eight patients underwent transplantation for HBV, and 354 (48.0%) had concomitant HCC, which recurred in 58 patients (16.4%). Three‐year survival was much better in era 3 versus era 1 (87% versus 40%, P = 0.001), and the incidence of HCC recurrence was lower (12% versus 29%, P = 0.009). The lungs were the most frequent first site of HCC recurrence, and they were followed by the liver. A multivariate analysis showed that HBV reinfection, HCC recurrence, and HBIG use were associated with worse survival (P < 0.001, P < 0.001, and P = 0.002, respectively); HCC recurrence and stage 3 HCC, among other factors, were associated with HBV reinfection (P < 0.001 and P = 0.004); and stage 3 HCC, vascular invasion of the explanted tumor, and post‐LT chemotherapy were associated with HCC recurrence (P = 0.008, P < 0.001, and P < 0.001, respectively). Patients with HBV reinfection were 3.6 times more likely than patients without HBV to have HCC recurrence. These data suggest further study of attempts at LT for patients with HBV and HCC beyond the Milan criteria if their HBV is aggressively and successfully treated. Liver Transpl 19:1020‐1029, 2013.

Hepaticoduodenostomy Is an Alternative to Roux-en-Y Hepaticojejunostomy for Biliary Reconstruction in Live Donor Liver Transplantation

Introduction. A Roux-en-Y hepaticojejunostomy (HJ) is usually performed during live donor liver transplantation (LDLT) when a duct-to-duct reconstruction is not possible. However, direct anastomosis of the bile duct to the duodenum (hepaticoduodenostomy [HD]) is an alternative technique for biliary repair that has been previously used for conventional biliary surgery and at our center for cadaveric liver transplant. We provide the first evidence that HD is an alternative technique for biliary reconstruction in LDLT. Methods. We performed a total of 71 LDLT between 2002 and 2008. An end-to-end anastomosis was used in 30 patients. Forty-one patients had a biliary enteric anastomosis in which seven were reconstructed with an HD. Accessory ducts were fashioned into a common duct or implanted into the duodenum separately. Results. There were no patient deaths or retransplants in a follow-up period that ranged from 90 to 771 days after surgery. One patient was diagnosed with cholangitis that responded to intravenous antibiotics and removal of the stent by endoscopy. Conclusions. This preliminary case series suggests that that HD is a feasible alternative to HJ biliary anastomosis when a duct-to-duct anastomosis cannot be performed. HD offers the possible advantage of simple postoperative access to the biliary system by endoscopy and avoids complications caused by HJ bowel anastomosis.