A. David Mayer

Colorectal cancer in patients with inflammatory Bowel disease after liver transplantation for primary sclerosing cholangitis

Background. Patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) may have an increased risk of developing colorectal cancer (CRC) after liver transplantation (LT). We evaluated our patients with PSC after LT to identify risk factors for CRC and its impact on survival. Patients and Methods. A total of 152 patients (108 men, 100 with IBD) with PSC who underwent 173 LTs between 1986 and May 2000 were analyzed in three groups: (1) PSC without IBD (n=52); (2) PSC with colectomy (pre-LT and at LT) (n=17, colectomy pre-LT in 13 and simultaneous colectomy at LT in four); and (3) PSC with IBD and an intact colon (n=83). The following factors were studied: age, gender, liver, and renal biochemistry, international normalized ratio, Child-Pugh stage, operative time, blood use, hospital stay, immunosuppression, risk of CRC, retransplantation rate, and mortality. Results. The incidence of CRC after LT was 5.3% (8/152) compared with 0.6% (7/1,184) in non-PSC cases (P <0.001). All CRCs in the PSC group were in patients with IBD and an intact colon. The cumulative risk of developing CRC in the 83 patients with an intact colon and IBD was 14% and 17% after 5 and 10 years, respectively (PSC non-IBD group 0% risk after 10 years, P <0.06). The multivariate analysis showed three significant variables related to the risk of developing CRC: colonic dysplasia after LT (P <0.0003), duration of colitis more than 10 years (P <0.002), and pancolitis (P <0.004). The cause of death in patients with CRC was cancer related in 75% of cases with a reduced 5-year survival of 55% versus 75% without CRC (not significant). Conclusion. Patients with PSC undergoing LT with a long history of ulcerative colitis and pancolitis have an increased risk of developing CRC with reduced survival. We advocate long-term aggressive colonic surveillance and colectomy in selected high-risk patients with longstanding severe colitis.

Recurrence of primary biliary cirrhosis in the liver allograft: the effect of immunosuppression

BACKGROUND Recurrence of primary biliary cirrhosis in the liver allograft remains controversial. METHODS We have examined the liver allograft biopsies taken at 1 and 2 years after transplantation from patients receiving either FK506 or cyclosporin as part of a multi-centre trial. RESULTS Histological features characteristic for primary biliary cirrhosis, including bile duct damage, ductopenia, bile duct proliferation and portal granulomas, were found more commonly and earlier after transplantation in patients receiving FK506 than cyclosporin. During the 2-year period, seven of 16 patients receiving FK506 and only one of 11 on cyclosporin had a graft biopsy suggestive of recurrent primary biliary cirrhosis. CONCLUSIONS These findings confirm earlier reports that features of primary biliary cirrhosis recur in the liver allograft in some patients and suggest that the rate of recurrence may be affected by the immunosuppression regimen used.

The use of liver grafts from donors with bacterial meningitis.

BACKGROUND The shortage of suitable donors for transplantation is a worldwide problem. The use of cadaveric donors with bacterial meningitis may be associated with an increased risk of sepsis. We report the results of orthotopic liver transplantation (OLT) from 33 such donors between 1989 and 1999. METHODS The hospital records of recipients from cadaveric donors with meningitis (study group) were retrospectively reviewed and compared with matched recipients from cadaveric donors dying from causes other than meningitis (recipient-matched control group). RESULTS A total of 34 recipients underwent 21 whole, 10 reduced, and 3 split liver transplants from 33 cadaveric donor livers with bacterial meningitis. The donor meningitis pathogens were Neisseria meningitidis (n=14), Streptococcus pneumoniae (n=4), Haemophilus influenzae (n=1), Streptococcus species (n=2), and unknown (n=12). Twenty-seven patients had an elective OLT and seven patients had an emergency OLT. Adequate antimicrobial therapy before organ procurement and after transplant was administrated. The mean posttransplant follow-up was 37 months (range: 1 day-106 months). There was no difference in recipient and graft survival rates between the study and the recipient-matched groups. In the study group, there were no infectious complications caused by the meningeal pathogens. Overall patient survival rates were 79%, 76%, 72%, and 72% at 1, 6, 12, and 60 months, respectively. Graft survival was 77%, 70%, 65%, and 65% at 1, 6, 12, and 60 months, respectively. The survival rate in elective cases was significantly better than emergency cases (P<0.05). CONCLUSION Liver transplantation from donors with bacterial meningitis is a safe procedure provided both donors and recipients receive adequate antimicrobial therapy.

Reduced acute rejection after liver transplantation with Neoral-based triple immunosuppression

Vol 349 • March 8, 1997 701 risk, whereas factors preventing ovulation, such as pregnancy and use of oral contraceptives, are protective. The rate of increase for the incidence of ovarian cancer diminishes after menopause. We speculate that initiating mutations accumulate during the repeated cycles of cell divisions that epithelial ovarian cells undergo with ovulation, thereby forming the basis for malignant transformation upon loss of chromosome 17. Our data show that this event increases with age. On the assumption that epithelial tumours have a common cellular origin and that specific mutational events contribute to tumour histology and grade, our hypothesis explains the non-random distribution with age of ovarian tumours of different histology.

Specialist Early and Immediate Repair of Post-laparoscopic Cholecystectomy Bile Duct Injuries Is Associated With an Improved Long-term Outcome

Introduction:A majority of bile duct injuries (BDI) sustained during laparoscopic cholecystectomy require formal surgical reconstruction, and traditionally this repair is performed late. We aimed to assess long-term outcomes after repair, focusing on our preferred early approach. Methods:A total of 200 BDI patients [age 54(20–83); 64 male], followed up for median 60 (5–212) months were assessed for morbidity. Factors contributing to this were analyzed with a univariate and multivariate analysis. Results:A total of 112 (56%) patients were repaired by specialist hepatobiliary surgeons [timing of repair: immediate, n = 28; early (<21 days), n = 43; and late (>21 days) n = 41], whereas 45 (22%) underwent repair by nonspecialist surgeons before specialist referral [immediate, n = 16; early, n = 26 and late, n = 03]. Outcomes after immediate and early repairs were comparable to late repairs when performed by specialists [recurrent cholangitis:11%, 12%, and 10%; P = 0.96, NS; re-stricture:18%,5%, and 29%; P = 0.01; nonsurgical intervention: 14%, 5%, and 24%; P<0.03; redo surgery: 4%, 2%, and 5%; P = 0.81, NS; overall morbidity: 21%, 14%, and 39%; P<0.02]. On multivariate analysis, immediate and early repairs done by nonspecialist surgeons were independent risk factors (P < 0.05) for recurrent cholangitis [50% and 27%], re-stricturing (75% and 61%), redo reconstructions (31% and 61%), and overall morbidity (75% and 84%). Conclusion:Immediate and early repair after BDI results in comparable, if not better long-term outcomes compared to late repair when performed by specialists.

RANDOMIZED TRIAL OF CYCLOSPORINE MICROEMULSION (NEORAL) VERSUS CONVENTIONAL CYCLOSPORINE IN LIVER TRANSPLANTATION: MILTON Study1,2

BACKGROUND The new microemulsion formulation of cyclosporine (Neoral) has been developed in an effort to improve the reliability of drug absorption. The objectives of this study were to assess the efficacy, safety, and tolerability of Neoral compared to the original formulation (Sandimmun) in liver transplant recipients. METHODS In a double-blind, parallel group study conducted in 28 centers across Europe and the United States, patients receiving primary orthotopic liver allografts were randomized within 24 hr of transplantation, 198 to Neoral and 192 to Sandimmun. Patients with and without T-tube biliary drainage were included. Postoperatively, all patients also received intravenous (i.v.) cyclosporine, together with prednisolone and azathioprine. Antibody induction was excluded. Efficacy measures were rejections, graft failure, patient survival, and the efficacy of the study medication in achieving the desired cyclosporine blood levels. Safety was assessed by reported adverse events, blood pressure, serum creatinine, and other routine laboratory measurements. RESULTS Kaplan-Meier analyses showed that the Neoral group performed better than the Sandimmun group, with the estimates for patients free of treated rejection and histologically confirmed rejection either showing or approaching statistical significance at the 5% level. By 52 weeks, 5.8% (95% confidence limits: -4.4-15.9%) fewer patients required treatment of acute rejection in the Neoral group. The proportion of patients experiencing at least one treated rejection episode by 2 weeks was 29.8% for Neoral and 43.2% for Sandimmun. For histologically confirmed rejection, these proportions were 32.8% and 44.3%, respectively. The proportion of patients experiencing at least one steroid-resistant rejection was 2.0% for Neoral and 6.3% for Sandimmun at week 2, and 3.0% and 9.9%, respectively, at week 3. All these differences were significant at P<0.05. By 52 weeks, graft failure was 6.3% on Neoral and 11.4% on Sandimmun, with respective patient survival figures of 85.4% and 85.8%. The median duration of the initial episode of i.v. cyclosporine was 4.0 days for Neoral, compared to 6.5 days for Sandimmun (P<0.001). Within the first 2 weeks, a larger percentage of patients in the Neoral group reached the lower target level of cyclosporine (P< or =0.01). The weight-adjusted daily doses of study medication were lower in the Neoral group (median dose: 4.86 vs. 5.42 mg/kg/day, P=0.001), but the blood levels of cyclosporine showed no difference. For those with a T-tube, more of the patients on Neoral remained free of treated rejection throughout the study period (P=0.042, Wilcoxon). By week 2, 44.9% of these patients in the Sandimmun group required treatment for rejection compared to 30.2% in the Neoral group (P=0.007). There was no significant difference between the groups for serum creatinine, blood pressure, other biochemical and hematological variables, or reported adverse events. CONCLUSIONS In liver transplantation in the normal clinical setting, the pharmacokinetic advantages of Neoral translate into clinical superiority over Sandimmun without a negative impact on safety. Recent data indicate that it is not optimal to use i.v. cyclosporine initially in this type of study, but the benefit was seen despite this. In keeping with the previous pharmacokinetic studies, patients managed by T-tube biliary drainage, and hence with no or limited bile available in the gastrointestinal tract, did particularly well with Neoral.

Reduction in bile leaks following adult split liver transplant using a fibrin-collagen sponge: A pilot study

INTRODUCTION Bile leaks are a frequent complication of adult split liver transplantation. We compared surgical complications in patients who had the cut surface of the donor liver treated with a patch to those in whom the cut surface of the liver was treated with fibrin glue. MATERIAL AND METHODS Two consecutive cohorts of 16 patients undergoing adult right lobe split liver transplant were compared. In the first cohort, the liver surface was treated with fibrin glue and in the second the liver surface was treated with TachoSil fibrinogen-thrombin-collagen patches. Post-operative complications were analyzed. RESULTS Bile leaks were significantly fewer among patients in whom the cut surface of the liver was treated with fibrin-collagen sponge compared to those where fibrin glue was used on the cut surface: 1/16 (6.25%) vs. 7/16 (43.75%), respectively; p=0.03. There were some differences in biliary anastomotic techniques used in the two groups but 7/8 leaks (87.5%) arose from the cut surface, and only one was from the anastomosis. CONCLUSION Using a fibrinogen-thrombin-collagen sponge patch may reduce bile leaks from the cut surface of the liver during adult right lobe split liver transplants.

Treatment of microvillus inclusion disease by intestinal transplantation

Microvillus inclusion disease (microvillus) is an uncommon form of congenital protracted diarrhea usually starting in the early neonatal period. It was first reported in 1978 (1) and is probably of autosomal recessive inheritance. Clinical presentation with secretory diarrhea in the first week of life is typical, with massive stools and electrolyte loss even when no enteral nutrition is provided. The diagnosis is based on the ultrastructural finding of intracytoplasmic inclusions that are lined by intact microvilli (2), which are present in the absorptive surface epithelial cells of the small and large intestine, associated with poorly developed surface brush border microvilli. It is thought to be due to a defect in brush border assembly and cellular differentiation, which may be secondary to defective meiosis (3). Recently, defects in small intestine apical but not basolateral membrane transport systems have been demonstrated in this condition (4). There is no effective nutritional or drug therapy, and these children are dependent on parenteral nutrition and intravenous replacement of fluid and electrolytes. Intestinal transplantation has been described in three children (5–7), two of whom were alive at follow-up. In all three cases the native ileocecal valve and at least part of the native colon were removed at the time of transplantation because of concern that, because the colonic enterocytes also expressed microvillus, the native colon would be a source of postoperative secretory diarrhea. The patient described in this report is a 2-year-old girl with MVID who underwent liver and small bowel transplantation with the preservation of 15 cm of the native ileum, the ileocecal valve, and the entire colon, with no deleterious effects. CASE REPORT

Pre-operative stenting is associated with a higher prevalence of post-operative complications following pancreatoduodenectomy

OBJECTIVES Whilst there are theoretical benefits from pre-operatively draining the biliary tree prior to pancreatoduodenectomy (PD), the current literature does not support this intervention. The aim of this study was to explore the relationship between pre-operative stenting, bactibilia and outcome in a large United Kingdom tertiary referral practice. METHODS Patients undergoing PD were identified from a prospectively maintained database. The presence or absence of a stent prior to PD, and the results of bile cultures taken at PD were related to the subsequent post-operative course and the development of complications. RESULTS 280 patients underwent PD for periampullary malignancies, all of whom presented with jaundice. 118 patients were stented prior to referral (98 ERCP, 20 PTC). Bile cultures were positive more frequently in the stent group (83% vs. 55%; p = 0.000002) and bactibilia was more common after ERCP than PTC (83% vs. 56%; p = 0.006). The overall prevalence of complications was 54% in the stented and 41% in the non-stented group (p = 0.03) with statistical significance achieved for pancreatic leak (p = 0.013) and haemorrhagic complications (p = 0.03). Comparing stent with no stent, there as no difference in the 30-day mortalities (8.5% vs. 6.8%; p = 0.6) or the 1-year mortality rates (35% vs. 28%; p = 0.21). Mortality rates in the infection versus no infection groups were comparable at 30 days (8.5% vs. 5.5%; p = 0.21), and at 1 year (30.7% vs. 26.4%; p = 0.25). CONCLUSIONS Pre-operative stent insertion prior to PD is associated with increased morbidity but not mortality and this is greatest for stents placed at ERCP.

Conventional versus piggyback technique of caval implantation; without extra-corporeal veno-venous bypass. A comparative study.

Conventional orthotopic liver transplantation (CON‐LT) involves resection of recipient cava, usually with extra‐corporeal circulation (veno‐venous bypass, VVB), while in the piggyback technique (PC‐LT) the cava is preserved. Along with a temporary portacaval shunt (TPCS), better haemodynamic maintenance is purported with PC‐LT. A prospective, consecutive series of 384 primary transplants (2000–2003) were analysed, 138 CON‐LT (with VVB) and 246 PC‐LT (54 without TPCS). Patient/donor characteristics were similar in the two groups. PC‐LT required less usage of fresh‐frozen plasma and platelets, intensive care stay, number of patients requiring ventilation after day 1 and total days spent on ventilator. The results were not different when comparing, total operating and warm ischaemia time (WIT), red cell usage, requirement for renal support, day 3 serum creatinine and total hospital stay. TPCS had no impact on outcome other than WIT (P = 0.02). Three patients in PC‐LT group (three of 246;1.2%) developed caval outflow obstruction (P = 0.02). There was no difference in short‐ or long‐term graft or patient survival. PC‐LT has an advantage over CON‐LT unsing VVB with respect to intraoperative blood product usage, postoperative ventilation requirement and ITU stay. VVB is no longer required and TPCS may be used selectively in adult transplantation.