A comparison of sirolimus vs. calcineurin inhibitor-based immunosuppressive therapies in liver transplantation.

BACKGROUND: Sirolimus is a potent immunosuppressive agent whose role in liver transplantation has not been well-described. AIM: To evaluate the efficacy and side-effects of sirolimus-based immunosuppression in liver transplant patients. METHODS: Retrospective analysis of 185 patients who underwent orthotopic liver transplantation. Patients were divided into three groups: group SA, sirolimus alone (n = 28); group SC, sirolimus with calcineurin inhibitors (n =56) and group CNI, calcineurin inhibitors without sirolimus (n = 101). RESULTS: One-year patient and graft survival rates were 86.5% and 82.1% in group SA, 94.6% and 92.9% in group SC, and 83.2% and 75.2% in group CNI (P = N.S.). The rates of acute cellular rejection at 12 months were comparable among the three groups. At the time of transplantation, serum creatinine levels were significantly higher in group SA, but mean creatinine among the three groups at 1 month was similar. More patients in group SA required dialysis before orthotopic liver transplantation (group SA, 25%; group SC, 9%; group CNI, 5%; P = 0.008), but at 1 year, post-orthotopic liver transplantation dialysis rates were similar. CONCLUSIONS: Sirolimus given alone or in conjunction with calcineurin inhibitors appears to be an effective primary immunosuppressant regimen for orthotopic liver transplantation patients. Further studies to evaluate the efficacy and side-effect profile of sirolimus in liver transplant patients are warranted.

The liver transplant waiting list--a single-center analysis.

At this transplant center 1340 patients were entered on the liver transplant waiting list during the first 25 months (October 1987 to November 1989) after the initiation of the UNOS allocation system for liver grafts. Of these 972 (72.5%) of the patients received a graft, 120 (9.0%) died waiting for a graft, 109 (8.1%) remained on the active list as of the study endpoint of December 15, 1989, 123 (9.2%) were withdrawn from candidacy, and 16 (1.2%) received a transplant at another center. A total of 1201 patients were candidates for a first graft. Of the 812 primary candidates who received a graft, 64.8% received their graft within one month of entry on the waiting list. Of the 109 primary candidates who died before a graft could be found, 79.0% died within a month of entry onto the waiting list. At time of transplantation, 135 (16.6%) primary recipients of a graft were UNOS class 1, 326 (40.1%) were UNOS class 2, 190 (23.4%) were UNOS class 3, and 161 (19.8%) were UNOS class 4. Actuarial survival rates (percentage) at 6 months for recipients in UNOS class 1, class 2, class 3, and class 4 were 88.7 +/- 2.9, 82.6 +/- 2.1, 78.4 +/- 3.2, and 68.4 +/- 3.9, respectively (P less than 0.001). At the time of death of recipients who failed to get a graft, 6 (5.5%) were UNOS class 1, 14 (12.8%) were UNOS class 2, 23 (21.1%) were UNOS class 3, and 66 (60.6%) were UNOS class 4. These results indicate that a high proportion of liver transplant candidates are in urgent need of a graft and that the UNOS system succeeds in giving these patients high priority. However patient mortality on the waiting list and after transplantation would lessen significantly if more patients with end-stage liver disease were referred to the transplant center in a timely manner before their condition reaches the point where the probability of survival is diminished.

Spontaneous resolution of intestinal obstruction while receiving home parenteral nutrition.

Six patients with intestinal obstruction secondary to benign adhesions so dense and vascular that the operating surgeon could not free them, were placed on a home total parenteral nutrition program. Four patients had enterocutaneous fistulas, and two had their bowels divided and stomas created to divert intestinal contents from distal enterotomies made during the attempt to free the intestine. The enterocutaneous fistulas closed in four patients within 2 weeks to 5 months and the obstructions spontaneously resolved in 2 to 3.5 months. At reoperation on the two patients whose intestinal tracts were purposely divided, the previously matted bowels with dense adhesions were easily freed. We believe complete gastrointestinal rest allows adhesions to mature into long avascular collagen fibers in the absence of a persistent inflammatory reaction that accompanies partial or total small bowel obstruction. We recommend that patients receive 3 months of home total parenteral nutrition before a second operation for persistent obstruction after recent enterolysis should be considered. Spontaneous resolution should occur, but if not, reoperation can be performed safely after the 3 month interval.

Surgical management of biliary gallstone disease during pregnancy.

BACKGROUND: Biliopancreatic gallstone disorders (BPD) manifesting during pregnancy are relatively rare. The management of these conditions remains controversial. Although perioperative problems and fetal loss have been reported, recent publications have advocated an early surgical approach. PATIENTS AND METHODS: Thirty-two pregnant women underwent operation for BPD between January 1993 and December 1997. The mean age was 29 years and ranged from 18 to 41 years. RESULTS: Twelve patients underwent a laparoscopic cholecystectomy (LC), and 20 open cholecystectomies (OC), including two conversions from laparoscopic. Seven of the OC patients required additional open CBD exploration and intraoperative choledochoscopy for CBD stones. No maternal mortality was observed. A single fetal demise (3%) occurred for a patient with gallstone pancreatitis who underwent open cholecystectomy during her 14th week of gestation. CONCLUSIONS: Early involvement of the obstetric team, with preoperative and postoperative fetal monitoring, and adequate management of anesthetic and tocolytic agents make cholecystectomy a safe procedure at any stage of pregnancy.

Current management of recurrent pyogenic cholangitis.

Recurrent pyogenic cholangitis (RPC) is a chronic disease with multiple exacerbations requiring repeated biliary dilatation and stone removal. Even after adequate biliary drainage, most patients will have progression of intrahepatic disease. Management of patients with RPC is a multidisciplinary challenge for endoscopists, interventional radiologists, and surgeons because of the frequency and inaccessibility of strictures and stones. Complete stone clearance at any one operation is difficult. Hepaticojejunostomy with a subcutaneous afferent limb is a safe and effective way to provide access to the biliary tree for the management of patients with RPC. In our experience, trans-stomal cholangioscopic stricture dilatation followed by stone removal remains the basis of therapy in patients with RPC. By diligent surveillance, we should be able to eliminate or decrease the number of stones and prevent cholangitis and its sequelae.

A modified technique of orthotopic transplant of the kidney in rabbits.

In this study kidneys were harvested from bred-for-research cats weighing 4 to 5 kg. General principles of donor bilateral nephrectomy en bloc with aorta, vena cava, renal vessels, and ureters were followed. After the harvest the grafts were placed in lactated Ringer slush. A cuff was prepared on the renal vein over a 10 French plastic tube. The aorta was divided and left in connection with the renal artery at each side. Twenty female checkered Flemish giant rabbits weighing 4.0-6.0 kg served as recipients. After premedication with 40 mg/kg of ketamine, anesthesia was maintained with repeated doses (every 10-15 min) of a 0.1-mL mixture of 5 parts ketamine and 1 part acepromazine diluted 50% in a normal saline. Arterial pressure, CVP, blood gases, and temperature were monitored. Through a limited midline incision a native left nephrectomy was performed. The venous anastomosis was performed with a cuff technique without clamping the vena cava (which causes severe hemodynamic instability); the anastomotic time was 2-3 min. The arterial anastomosis was performed with an end-to-side aorta-to-aorta anastomosis; the anastomotic time was 5 to 7 min. There were no episodes of venous or arterial thrombosis. The donor procedure took approximately 40 min, and the backtable preparation of the graft an additional 45 to 60 min. Preparation of the recipient for the anastomosis took 15 min and the anastomotic time (warm ischemia) was 13 +/- 5 min. In this model suitable for xenograft research the duration of the surgery in the recipient has been greatly reduced because of (1) the previous backtable preparation of the graft, and (2) the cuff technique used for venous anastomosis. The present anesthesia regimen and careful hemodynamic monitoring were also important in the success of this model.

Live-donor liver transplantation: the USC experience.

BACKGROUND: Liver transplantation is currently the standard of care for patients with end stage liver disease. However due to the cadaveric organ shortage, live donor liver transplantation (LDLT), has been recently introduced as a potential solution. We analyzed and support our initial experience with this procedure at USC. MATERIAL AND METHODS: From September 1998 until July 2000, a total of 27 patients underwent LDLT at USC University Hospital and Los Angeles Children's Hospital. There were 12 children with the median age of 10 months (4-114) and 15 adults with the median age of 56 years (35-65). The most common indication for transplantation was biliary atresia for children and hepatitis C for adults. RESULTS: All donors did well postoperatively; the median postoperative stay was five days (5-7) for left lateral segmentectomy and seven days (4-12) for lobar donation. None of the donors required blood transfusion, re-operation or postoperative invasive procedure. However, five of them (18%) experienced minor complications. The survival rate in pediatric patients was 100% and only one graft was lost at nine months due to rejection. Two adult recipients died in the postoperative period, one from graft non-function and one from necrotizing fascitis. 37% of adult recipients experienced postoperative complications, mainly related to biliary reconstruction. Also 26% of the recipients underwent reoperation for some of these complications. CONCLUSION: LDLT is an excellent alternative to cadaveric transplantation with excellent results in the pediatric population. However, in adult patients it still carries a significant complication rate and it should be used with caution.

Risk factors for graft survival after liver transplantation from donation after cardiac death donors: an analysis of OPTN/UNOS data.

Due to increasing use of allografts from donation after cardiac death (DCD) donors, we evaluated DCD liver transplants and impact of recipient and donor factors on graft survival. Liver transplants from DCD donors reported to UNOS were analyzed against donation after brain death (DBD) donor liver transplants performed between 1996 and 2003. We defined a recipient cumulative relative risk (RCRR) using significant risk factors identified from a Cox regression analysis: age; medical condition at transplantation; regraft status; dialysis received and serum creatinine. Graft survival from DCD donors (71% at 1 year and 60% at 3 years) were significantly inferior to DBD donors (80% at 1 year and 72% at 3 years, p < 0.001). Low-risk recipients (RCRR < or = 1.5) with low-risk DCD livers (DWIT < 30 min and CIT < 10 h, n = 226) achieved graft survival rates (81% and 67% at 1 and 3 years, respectively) not significantly different from recipients with DBD allografts (80% and 72% at 1 and 3 years, respectively, log-rank p = 0.23). Liver allografts from DCD donors may be used to increase the cadaveric donor pool, with favorable graft survival rates achieved when low-risk grafts are transplanted in a low-risk setting. Whether transplantation of these organs in low-risk recipients provides a survival benefit compared to the waiting list is unknown.

Alternative procedure for failed reconstruction of a right replaced hepatic artery in liver transplantation.

A right replaced hepatic artery (RRHA) arising from the superior mesenteric artery (SMA) is the most frequent variation of the hepatic arterial supply requiring backtable reconstruction. There are several widely used techniques for backtable reconstruction of the RRHA to a single conduit. If these reconstructions fail, due to technical reasons or size discrepancies, an alternative method of rearterialization is needed. We describe six cases in which an RRHA was anastomosed to the donor's gastroduodenal artery (GDA) stump utilizing a loupe magnification technique. In four cases the reconstruction was performed at the time of the backtable procedure and in two after reperfusion and failure of the original RRHA to splenic artery (SA) reconstruction. In all cases, the anastomoses remained patent. All patients had Doppler sonography and two had subsequent arteriograms that verified anastomotic patency. This method of reconstruction is more demanding technically but obviates the awkward 90-degree twist of the hepatic artery when an RRHA is anastomosed to the SA stump.

Does transjugular intrahepatic portosystemic shunt (TIPS) resolve thrombocytopenia associated with cirrhosis?

Thrombocytopenia is frequently present in patients with cirrhosis. The effect of portal decompression on thrombocytopenia using a variety of shunt procedures has been contradictory. Transjugular intrahepatic portosystemic shunt (TIPS) has been proposed as a less invasive procedure for portal decompression, mainly for control of variceal bleeding or intractable ascites. Its effect on thrombocytopenia has not been defined yet. The aim of this review is to define the effect of TIPS on patients with cirrhosis and thrombocytopenia. Sixty-two patients who underwent TIPS at the University of Pittsburgh and survived without transplant for more than two months were included. Platelet count was determined prior to TIPS as well as at one-week, one-month, and three-month intervals after TIPS. The prevalence of thrombocytopenia prior to TIPS was 49%. TIPS had no effect on thrombocytopenia even when the portosystemic gradient was reduced to less than 12 mm Hg. In conclusion, portal decompression after TIPS did not affect the degree of thrombocytopenia.

Liver transplantation in cystic fibrosis.

Liver disease is the second most common cause of death in patients with cystic fibrosis (CF). Improvement in surgical techniques, medical management, and imaging modalities has broadened the range of options for treatment of these patients. Medical management with ursodeoxycholic acid and nutritional support may help decelerate the progression of liver disease. A timely evaluation of CF patients with liver involvement for transplantation is important. Such evaluation should not be delayed until signs of hepatic decompensation occur. Combined lung-liver transplant can be considered for patients with advanced pulmonary disease. Pretransplant management of portal hypertension with a portosystemic shunt procedure is an option for patients with well-preserved synthetic liver function. Improvement in lung function after liver transplantation and no significant risk of pulmonary infection with immunosuppressive therapy have been reported. Review of individual center experiences have shown satisfactory survival and improved quality of life for CF patients undergoing liver transplant.

Total nutritional support through the peritoneal cavity.

We prepared ten dogs with intraperitoneal catheters to allow total nutritional support for 30 days by constant infusion of a solution containing 1.5% amino acid, 10% glucose, and 1% lipids at a rate of 4 ml/kg/hr. Seven dogs survived in apparent good health but with a 13.9 +/- 1.3% weight loss. There was no correlation between actual caloric input and percentage of weight loss. Serum albumin concentration fell to 2.6 +/- 0.3 gm/dl but other chemistries remained near normal. The peritoneum showed significant inflammatory reaction but this resolved by 30 days. Three dogs died in the first week from what appeared to be circulatory collapse from rapid fluid shifts. We conclude that a significant amount of nutrients can be delivered through the peritoneal cavity but whether total nutritional support is feasible remains to be proven.

Role of promoter methylation in increased methionine adenosyltransferase 2A expression in human liver cancer.

Methionine adenosyltransferase (MAT), an essential enzyme that catalyzes the formation of S-adenosylmethionine (SAM), is encoded by two genes, MAT1A (liver-specific) and MAT2A (non-liver-specific). We showed a switch from MAT1A to MAT2A expression in human liver cancer, which facilitates cancer cell growth. The present work examined the role of methylation in MAT2A transcriptional regulation. We found that the human MAT2A promoter is hypomethylated in hepatocellular carcinoma, in which the gene is upregulated transcriptionally, but hypermethylated in normal liver, in which the gene is minimally expressed. Luciferase activities driven by in vitro methylated MAT2A promoter constructs were 75-95% lower than activities driven by unmethylated constructs. SAM treatment of Hep G2 cells reduced MAT2A endogenous expression by 75%, hypermethylated the MAT2A promoter, and reduced luciferase activities driven by MAT2A promoter constructs by 65-75% while not affecting MAT1A's promoter activity. Treatment of adult rat and human hepatocytes with trichostatin A, an inhibitor of histone deacetylase, upregulated MAT2A expression by more than fourfold. Collectively, these results suggest that MAT2A expression is regulated by promoter methylation and histone acetylation.

The 11-year Pittsburgh experience with liver transplantation for hepatocellular carcinoma: 1981-1991.

Experience with liver transplantation over a period of 11 years at the University of Pittsburgh is presented. The application of liver transplantation to cases of hepatocellular carcinoma has changed considerably over this 11-year period with the sequential introduction of adjuvant and, more recently, neoadjuvant chemotherapy. Results with the combination of chemotherapy plus surgery appear to be better than results with either agent alone. Moreover, the early results with neoadjuvant therapy appear to be better than those achieved with adjuvant therapy. As a result of this experience, conceptual changes in the approach to the problem of hepatic cancer and the role of both chemotherapy and liver transplantation in its management have changed at the University of Pittsburgh. These changes are identified and discussed.

Hepatic artery angioplasty after liver transplantation: experience in 21 allografts.

PURPOSE: To assess whether percutaneous transluminal angioplasty (PTA) can help prolong allograft survival and improve allograft function in patients with hepatic artery stenosis after liver transplantation. PATIENTS AND METHODS: Hepatic artery PTA was attempted in 19 patients with 21 allografts over 12 years. The postangioplasty clinical course was retrospectively analyzed. Liver enzyme levels were measured before and after PTA to determine if changes in liver function occurred after successful PTA. RESULTS: Technical success was achieved in 17 allografts (81%). Retransplantation was required for four of 17 allografts (24%) in which PTA was successful and four of four allografts in which PTA was unsuccessful; this difference was significant (P = .03). Two major procedure-related complications occurred: an arterial leak that required surgical repair and an extensive dissection that necessitated retransplantation 14 months after PTA. Hepatic failure necessitated repeat transplantation in seven cases from 2 weeks to 27 months (mean, 8.4 months) after PTA. Six patients died during follow-up, three of whom had undergone repeat transplantation. Markedly elevated liver enzyme levels at presentation were associated with an increased risk of retransplantation or death regardless of the outcome of PTA. CONCLUSION: PTA of hepatic artery stenosis after liver transplantation is relatively safe and may help decrease allograft loss due to thrombosis. Marked allograft dysfunction at presentation is a poor prognostic sign; thus, timely intervention is important.

Management of duodenal perforation after endoscopic retrograde cholangiopancreatography and sphincterotomy.

OBJECTIVE: To evaluate the authors' experience with periduodenal perforations to define a systematic management approach. SUMMARY BACKGROUND DATA: Traditionally, traumatic and atraumatic duodenal perforations have been managed surgically; however, in the last decade, management has shifted toward a more selective approach. Some authors advocate routine nonsurgical management, but the reported death rate of medical treatment failures is almost 50%. Others advocate mandatory surgical exploration. Those who favor a selective approach have not elaborated distinct management guidelines. METHODS: A retrospective chart review at the authors' medical center from June 1993 to June 1998 identified 14 instances of periduodenal perforation related to endoscopic retrograde cholangiopancreatography (ERCP), a rate of 1.0%. Charts were reviewed for the following parameters: ERCP findings, clinical presentation of perforation, diagnostic methods, time to diagnosis, radiographic extent and location of duodenal leak, methods of management, surgical procedures, complications, length of stay, and outcome. RESULTS: Fourteen patients had a periduodenal perforation. Eight patients were initially managed conservatively. Five of the eight patients recovered without incident. Three patients failed nonsurgical management and required extensive procedures with long hospital stays and one death. Six patients were managed initially by surgery, with one death. Each injury was evaluated for location and radiographic extent of leak and classified into types I through IV. CONCLUSIONS: Clinical and radiographic features of ERCP-related periduodenal perforations can be used to stratify patients into surgical or nonsurgical cohorts. A selective management scheme is proposed based on the features of each type.

Needle-localized thoracoscopic resections of small indeterminate pulmonary nodules in transplant patients.

Indeterminate pulmonary nodules (IPN) in transplant patients create a diagnostic and therapeutic challenge. Patients who are transplant candidates or have already undergone organ transplantation require diagnostic clarification of IPN which may represent oncologic and/or infectious disease processes. Between December 1991 and January 1993, we performed 43 needle-localized thoracoscopic resections (NLTR) on 40 patients for IPN considered too small for less invasive diagnostic techniques. Four of these patients were candidates for orthotopic liver transplantation (OLT) and required exclusion of either extrahepatic malignancy or pulmonary infection before proceeding with transplantation. The 5th patient had undergone OLT for an unresectable hepatocellular carcinoma, and NLTR confirmed the presence of pulmonary metastatic disease. Of the 4 OLT candidates, 2 had pathologically confirmed metastases from their primary hepatic malignancy and did not undergo transplantation. The remaining 2 OLT candidates had benign pulmonary processes (hamartoma, hyaline plaque) and underwent successful OLT. In all patients, the IPN was successfully identified with NLTR. There were no complications. NLTR is a reliable and well-tolerated method to diagnose IPN in transplant patients.