The Use of Donation After Cardiac Death Allografts Does Not Increase Recurrence of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) recurrence in patients undergoing liver transplantation (LT) with donation after brain death (DBD) and donation after cardiac death (DCD) allografts has not previously been investigated. Rates and patterns of HCC recurrences were investigated in patients undergoing DBD (N = 1633) and DCD (N = 243) LT between 2003 and 2012. LT for HCC was identified in 397 patients (340 DBD and 57 DCD). No difference in tumor number (p = 0.26), tumor volume (p = 0.34) and serum alphafetoprotein (AFP) (p = 0.47) was seen between the groups. HCC recurrence was identified in 41 (12.1%) patients in the DBD group and 7 (12.3%) patients in the DCD group. There was no difference in recurrence-free survival (p = 0.29) or cumulative incidence of HCC recurrence (p = 0.91) between the groups. Liver allograft was the first site of recurrence in 22 (65%) patients in the DBD group and two (37%) patients in the DCD group (p = 0.39). LT for HCC with DBD and DCD allografts demonstrate no difference in the rate of HCC recurrence. Previously published differences in survival demonstrated between recipients with HCC receiving DBD and DCD allografts despite statistical adjustment can likely be explained by practice patterns not captured by variables contained in the SRTR database.

The diagnostic conundrum and liver transplantation outcome for combined hepatocellular-cholangiocarcinoma.

Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare primary liver malignancy with mixed hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) histological features. It is almost impossible to obtain an accurate, preoperative noninvasive diagnosis of cHCC-CC with tumor markers or cross-sectional abdominal imaging due to the mixed histological features. Despite these difficulties, accurate cHCC-CC diagnosis remains an important goal with prognostic significance. In our study, we retrospectively reviewed the tumor markers: AFP and CA 19-9, and cross-sectional liver imaging, in light of liver explant findings, to identify and characterize cHCC-CC features followed by liver transplantation (LT) outcome analysis. The results from this 12 patient cohort failed to identify characteristic features for cHCC-CC. None of the imaging features helped to identify the cHCC-CC tumor and they mimicked either HCC or CC, depending on the degree of glandular differentiation expressed histologically. In our cHCC-CC LT recipients, the 1-, 3- and 5-year cumulative survival probabilities were 79%, 66% and 16%, respectively with a 5-year survival comparable to or better than LT for intrahepatic CC but poorer than LT for HCC following the Milan criteria. Conceivably explained by its cholangiocarcinoma component the LT outcome for this rare and hard to diagnose tumor appears poor.

Colorectal and anal neoplasms following liver transplantation.

OBJECTIVE: Liver transplantation (LT) is the treatment of choice for end-stage liver disease. The required immunosuppression increases the risk for developing malignancies. Some viruses play a crucial role. Data on neoplasms of the colon, rectum and anus in LT are limited. METHOD: A retrospective evaluation of the incidence and clinical course of colorectal and anal malignancies and colonic polyps in a series of 467 consecutive LTs in 402 individuals between 1998 and 2001 was performed. Standard immunosuppression included Tacrolimus, Mycophenolic acid and steroids. RESULTS: During a median follow up of 5.2 years, three colon adenocarcinomas, one EBV associated cecal posttransplant lymphoproliferative tumour and two HPV associated anal tumours were identified. Pre-LT colonoscopy was performed in 161 patients (40%), and of 153 evaluable individuals, 53 (34.9%) had polyps. Colonoscopy was performed in 186 patients (46.3%) median 14.8 (range 0.2-77.8) months post-LT and 55 (29.3%) had polyps. Post-LT adenomatous polyps were detected in 47.3% of patients with pre-LT polyps vs 6.7% of patients without pre-LT polyps (P < 0.001). Patients with alcoholic liver disease had a significantly higher rate of adenoma formation (50.0% vs 11.1%, P < 0.001). No patient died from colorectal/anal malignancy. CONCLUSION: The incidence of metachronous and new polyp formation in our study is similar to people who are not immunocompromised, but subgroups are at increased risk. Viral-associated malignancies, including post-transplant lymphoproliferative disorders and anal cancer, are important entities in the LT population suggesting that complete screening of the colon, rectum and anus including pre-LT and post-LT colonoscopy should be utilized.

Incidence and Outcome of Small-for-Size Liver Grafts Transplanted in Adult Recipients.

Small-for-size liver transplantation (SFS-LT) carries high morbidity and mortality after transplantation. SFS-LT is usually associated with living-donor or deceased-donor split LT; however its incidence and outcome are poorly defined in adult LT recipients who receive whole grafts (WLT). In this study, we retrospectively reviewed our cohort of 3,106 deceased-donor LT in adult recipients. We found that among the 31 split LTs, 11 (35.5%) were SFS. In contrast, there only 1.08% of the whole-graft transplants (31 out of 2,868) were SFS. Although less common, SFS-WLT is associated with poorer long-term outcome of both graft and patient survivals.

Allograft Portacaval Shunt in Small-for-Size Liver in Deceased Donor Liver Transplant.

Portal hyperperfusion is detrimental to small-for-size livers (SFSLs) in liver transplantation. Surgical techniques modulating portal inflow provide the most effective approach to protect the SFSL. In this report, we describe a technique creating an allograft portacaval shunt that effectively attenuates portal inflow without a requirement of extensive surgical dissection in the recipient during the transplantation.

Accuracy and interobserver agreement of small-caliber vs. conventional esophagogastroduodenoscopy for evaluating esophageal varices.

BACKGROUND AND STUDY AIMS: Advances in endoscope design have allowed high-quality imaging using small-caliber endoscopes (< 6 mm), and these have been proposed as providing an accurate modality for evaluating esophageal varices in several small studies. We aimed to evaluate the accuracy and interobserver agreement of small-caliber esophagogastroduodenoscopy (EGD) compared with conventional EGD for evaluating esophageal varices in a large prospective cohort. PATIENTS AND METHODS: A total of 115 patients with end-stage liver disease and/or portal hypertension were prospectively enrolled into the study. EGD procedures were performed using conventional (8.6-mm) and small-caliber (4.9-mm) endoscopes, back to back and under standard sedation, by two different endoscopists. Esophageal varices were graded at the time of EGD (the "real-time" grade); and by retrospective review of photographs by three endoscopists, when a "consensus" grade (i. e. a grading agreed by two out of the three endoscopists) was used as the final result. RESULTS: Of the 115 patients, 33 patients (29 %) were classified as Child's class A, 47 patients (41 %) as Child's class B, and 35 patients (30 %) as Child's class C. The mean model for end-stage liver disease (MELD) score was 13.6. Thirty-six patients (31 %) had undergone previous ligation of esophageal varices. Compared with conventional EGD, the accuracy of small-caliber EGD for esophageal varices grading was 94 % (consensus grade) and 95 % (real-time grade). Excellent concordance was demonstrated between real-time grade and consensus grade, with a kappa of 0.95 for both types of EGD. There was excellent interobserver agreement between endoscopists, regardless of the type of EGD. The severity of hepatic dysfunction and the presence or absence of a history of previous esophageal varices ligation did not have any impact on the accuracy or interobserver agreement. CONCLUSIONS: Small-caliber EGD performed under sedation via oral intubation is a highly accurate and reliable modality for evaluating esophageal varices in patients with end-stage liver disease and/or portal hypertension, regardless of the degree of hepatic dysfunction or history of previous esophageal varices ligation.

Choice of Partial Splenic Embolization Technique in Liver Transplant Recipients Correlates With Risk of Infectious Complications.

BACKGROUND: Complications of cirrhosis may persist after liver transplantation. When indicated, partial splenic embolization (PSE) is an alternative to splenectomy but can cause severe infection. The identification of modifiable risk factors when performing PSE in immunocompromised liver transplant recipients may help reduce the risk of severe infection. METHODS: Data were collected retrospectively for all PSE performed after liver transplantation at a single institution and included demographics, etiology of liver disease, indication for PSE, vaccination status, laboratory findings, procedural details, extent and pattern of splenic infarction, hospital length-of-stay, readmissions, procedural complications, and mortality. Statistical analysis included 2-tailed t test, Fisher exact test, and Kaplan-Meier survival curves, with significance defined as P < .05. RESULTS: Sixteen patients received 22 embolizations, with 11 patients undergoing a single session and 5 patients undergoing multiple sessions. Indications included hypersplenism, gastrointestinal hemorrhage, ascites, and autoimmune hemolytic anemia. PSE produced significant and sustained cell count increases, improved ascites, and controlled hemorrhage. Splenic abscess, septic shock, need for splenectomy, and PSE-related mortality were seen in the group with large confluent splenic infarction but not in peripheral/wedge-shaped infarction. Multiple-session PSE exclusively using particles for embolization correlated with the pattern of peripheral/wedge-shaped infarction and avoided severe infection and PSE-related mortality. CONCLUSIONS: PSE in the immunosuppressed liver transplant recipient is an effective alternative to splenectomy, but carries substantial infectious risk. The risk is decreased when PSE performed with polyvinyl alcohol particles results in a pattern of peripheral/wedge-shaped infarction, which correlates with smaller infarction volumes, favorable length-of-stay, and minimal risk of abscess, sepsis, and mortality.

Levetiracetam monotherapy for liver transplant patients with seizures.

Selecting an appropriate anticonvulsant for treatment of recipients of orthostatic liver transplants who have new-onset epileptic seizures can be challenging because first-line agents may contribute to worsening encephalopathy, alter the plasma concentration of immunosuppressive agents, and result in hepatotoxicity. We describe the case of a 55-year-old man who underwent orthotopic liver transplantation because of end-stage liver disease due to alcoholic cirrhosis and hepatitis C. He required two repeat transplantation procedures. After the last procedure, epileptic seizures developed, which were initially managed with phenytoin. However, the patient remained stuporous and mental status fluctuated. Breakthrough seizures later developed in the setting of rejection. Levetiracetam (500 mg orally, twice a day) was chosen for its favorable pharmacokinetic properties as an alternative to phenytoin. By the third day of levetiracetam therapy, the patient became more responsive. At most recent follow-up, 3 months after the start of levetiracetam therapy, the patient was still treated with levetiracetam monotherapy, and seizure control was judged to be excellent.

Abatacept use in graft-versus-host disease after orthotopic liver transplantation: a case report.

BACKGROUND: Graft-versus-host disease (GVHD) is a rare, serious, fatal disease that occurs after orthotopic liver transplantation (OLT). CASE REPORT: We treated a 60-year-old man who underwent OLT owing to familial amyloidosis. The patient developed fever on postoperative day 16. The fever was persistent and did not respond to antibiotic therapy. Cultures and radiologic studies were done and excluded infection as a potential cause. On postoperative day 26, a skin rash appeared on his chest, accompanied by diarrhea and persistent fever. The rash spread all over the trunk, neck, and arms, but spared the palms of his hands and soles of his feet. In the meantime, his blood cell count revealed pancytopenia. Skin biopsy was done and showed interface lymphocytic infiltrate that are largely centered on the dermal-epidermal junction, is consistent with GVHD (this pattern of rash distribution is unique and different from the rash of GVHD after hematopoietic stem cell transplant, which is confined to palms of the hands and soles of the feet; Fig 1). The diagnosis was confirmed by colonoscopy and multiple forceps biopsies, which revealed extensive crypt loss. After hematology consultation, the patient was treated by withdrawal of all immunosuppressive therapy coupled with abatacept infusion. Abatacept is a chimeric protein that inhibits T-lymphocytes and is approved by the US Food and Drug Administration for the treatment of rheumatoid arthritis. Interestingly, after second dose of abatacept the patient showed marked clinical and laboratory improvement. The patient was discharged after 47 days in a stable condition. CONCLUSION: Because of the lack of a consensus for treatment of these patients, we report our experience with a male patient who had post-OLT GVHD and showed a marked improvement in response to abatacept.

High-dose ursodeoxycholic acid increases risk of adverse outcomes in patients with early stage primary sclerosing cholangitis.

BACKGROUND: Ursodeoxycholic acid (UDCA) in a dose of 28-30 mg/kg/day increases the likelihood of clinical deterioration of primary sclerosing cholangitis (PSC) patients. AIM: To compare the risk of adverse clinical endpoints in patients with varying disease status. METHODS: We reviewed records from patients previously enrolled in a study evaluating the effects of high dose (28-30 mg/kg/day) UDCA in PSC. Patients were grouped according to treatment (UDCA vs. placebo) and baseline disease status (histological stage of PSC, total serum bilirubin). Development of clinical endpoints including death, liver transplantation, cirrhosis, oesophageal varices and cholangiocarcinoma was sought. RESULTS: A total of 150 patients were included of whom 49 patients developed endpoints. There was an increased development of endpoints among patients using UDCA vs. placebo (14 vs. 4, P=0.0151) with early histological disease (stage 1-2, n=88) but not with late stage (stage 3-4, n=62) disease (17 vs. 14, P=0.2031). Occurrence of clinical endpoints was also higher in patients receiving UDCA vs. placebo (16 vs. 2, P=0.0008) with normal bilirubin levels (total bilirubin ≤1.0 mg/dL) but not in patients with elevated bilirubin levels (15 vs. 16, P=0.6018). Among patients not reaching endpoints 31.7% had normalisation of their alkaline phosphatase levels when compared to 14.3% in patients who reached endpoints (P=0.073). CONCLUSION: The increased risk of adverse events with UDCA treatment when compared with placebo is only apparent in patients with early histological stage disease or normal total bilirubin.

Primary sclerosing cholangitis: evolving concepts in diagnosis and treatment.

Primary sclerosing cholangitis is an increasingly recognized cause of chronic cholestatic liver disease. The etiology is unknown, although a number of immunologic and nonimmunologic factors have been considered. The most important diagnostic findings are diffuse irregularity and narrowing of extrahepatic and intrahepatic bile ducts. The prognosis varies, and a number of relatively unique complications may develop. No adequate treatment exists, although a number of potential treatments have been evaluated. Liver transplantation still remains the most appropriate treatment for end-stage disease. These various topics related to primary sclerosing cholangitis are reviewed.

Bcl-2 is overexpressed and alters the threshold for apoptosis in a cholangiocarcinoma cell line.

Cholangiocarcinoma is a malignant neoplasm originating from cholangiocytes. The mechanisms responsible for oncogenesis of cholangiocytes are unknown. Resistance to apoptosis, especially by altered expression of B-cell lymphoma/leukemia 2 (Bcl-2) family members, has been implicated as a mechanism contributing to malignant transformation. Thus, our aim was to test the hypothesis that altered expression of Bcl-2 family members by cholangiocarcinoma cells renders them resistant to apoptosis. We compared the apoptotic threshold and expression of the Bcl-2 protein family members, Bcl-2, Bcl-XL, and Bax, in two human cell lines: 1) nonmalignant human cholangiocytes immortalized by transfection with the simian virus 40 (SV 40) large T antigen; and 2) a malignant human cholangiocarcinoma cell line. Apoptosis was induced pharmacologically using beauvericin. Bcl-2, Bcl-x long, and Bax protein expression were evaluated by immunoblot analysis, and Bcl-2 expression was modulated using antisense technology. The cholangiocyte and malignant/nonmaligant phenotype of both cell lines was verified using both in vitro and in vivo approaches. Beauvericin induced apoptosis of nonmalignant cholangiocytes in a concentration- (0 to 25 micromol/L) and time- (0 to 6 hours) dependent manner. In contrast, malignant cholangiocytes were resistant to apoptosis. Although expression of Bcl-x long and Bax protein were similiar in the two cell lines, Bcl-2 protein expression was 15-fold greater in malignant than in nonmalignant cholangiocytes. An 18 mer bcl-2 antisense oligonucleotide reduced expression of Bcl-2 protein by 50% and increased the rate of beauvericin-induced apoptosis more than threefold in the malignant cells. Our results support the hypothesis that resistance to apoptosis by overexpression of Bcl-2 may be a feature of cholangiocarcinoma.

High-dose ursodeoxycholic acid as a therapy for patients with primary sclerosing cholangitis.

OBJECTIVES: To assess the tolerability and efficacy of high-dose (25-30 mg/kg per day) ursodeoxycholic acid (UDCA) in patients with primary sclerosing cholangitis (PSC). METHODS: Thirty patients with PSC were enrolled in this pilot study and treated for 1 yr. Changes in the Mayo risk score at 1 yr of treatment and projected survival at 4 yr were compared with that observed in patients randomized to placebo (n = 52) or UDCA (n = 53) at a dose of 13-15 mg/kg per day. RESULTS: A marked improvement in serum alkaline phosphatase activity (1265+/-172 vs 693+/-110 U/L, p < 0.001), AST (161+/-037 vs 77+/-13 U/L, p = 0.001), albumin (4.0+/-0.1 vs 4.2+/-0.1 g/dl, p = 0.03), and total bilirubin (1.6+/-0.3 vs 1.3+/-0.2 mg/dl, p = 0.1) occurred at 1 yr of therapy with high-dose UDCA. Changes in the Mayo risk score after 1 yr of treatment were significantly different among the three groups (p < 0.001), and these changes would be translated into a significantly different expected survival at 4 yr (p = 0.05). This expected survival at 4 yr was significantly different between placebo and the dose of 25-30 mg/kg per day (p = 0.04), but not between placebo and the dose of 13-15 mg/kg per day (p = 0.4). High-dose UDCA was well tolerated. CONCLUSIONS: UDCA at a dose of 25-30 mg/kg per day may be of benefit for patients with PSC, and this regimen deserves further evaluation in a long-term, randomized, placebo-controlled trial.

Are patients with cirrhotic stage primary sclerosing cholangitis at risk for the development of hepatocellular cancer?

BACKGROUND/AIMS: The risk of cholangiocarcinoma in primary sclerosing cholangitis is widely recognized to be 8-30%, whereas the risk of acquiring hepatocellular carcinoma in primary sclerosing cholangitis is unknown. As in other chronic liver diseases, the presence of hepatocellular carcinoma in a patient with primary sclerosing cholangitis undergoing evaluation for orthotopic liver transplantation would clearly impact on the candidacy, diagnostic evaluation, and alternative treatment options. Thus, the aim of our study was to determine the prevalence of hepatocellular carcinoma in patients undergoing liver transplantation for primary sclerosing cholangitis. METHODS: The records of the 520 patients undergoing orthotopic liver transplantation at our institution between 1985 and May 1995 were reviewed. Of the 134 patients with primary sclerosing cholangitis, three (2%) had hepatocellular carcinoma. In the 386 patients without primary sclerosing cholangitis undergoing orthotopic liver transplantation, 22 (6%) had hepatocellular carcinoma. RESULTS: Neither the duration of primary sclerosing cholangitis (range 7-23 years) nor the presence of ulcerative colitis (two of three patients) distinguished those patients with primary sclerosing cholangitis plus hepatocellular carcinoma from those with primary sclerosing cholangitis alone. None of the three patients with primary sclerosing cholangitis plus hepatocellular carcinoma had evidence for hepatitis B or C, alpha-1-antitrypsin deficiency, or hemochromatosis. None of the tumors was of the fibrolamellar variety of hepatocellular carcinoma. CONCLUSIONS: The prevalence of hepatocellular carcinoma in patients with primary sclerosing cholangitis undergoing orthotopic liver transplantation is 2%. These data suggest that patients with advanced cirrhotic-stage primary sclerosing cholangitis are at increased risk for developing hepatocellular carcinoma and should be screened for hepatocellular carcinoma as well as for cholangiocarcinoma prior to orthotopic liver transplantation.

The utility of CA 19-9 in the diagnoses of cholangiocarcinoma in patients without primary sclerosing cholangitis.

OBJECTIVES: The diagnosis of cholangiocarcinoma is often difficult, making management approaches problematic. A reliable serum tumor marker for cholangiocarcinoma would be a useful additional diagnostic test. Previous studies have demonstrated that elevated serum concentrations of CA 19-9, a tumor-associated antigen, have good sensitivity and specificity for cholangiocarcinoma in patients with primary sclerosing cholangitis. However, the value of this tumor marker for cholangiocarcinoma unassociated with primary sclerosing cholangitis is unclear. Thus, the aims of this study were to determine the usefulness of a serum CA 19-9 determination in the diagnosis of de novo cholangiocarcinoma. METHODS: We prospectively measured serum CA 19-9 concentrations in patients with cholangiocarcinoma (n = 36), nonmalignant liver disease (n = 41), and benign bile duct strictures (n = 26). Serum CA 19-9 concentrations were measured by an immunoradiometric assay (CIS Bio International) without knowledge of the clinical diagnosis. RESULTS: The sensitivity of a CA 19-9 value >100 U/ml in diagnosing cholangiocarcinoma was 53%. When compared with the nonmalignant liver disease and the benign bile duct stricture groups, the true negative rates were 76% and 92%, respectively. Patients with unresectable cholangiocarcinoma had significantly greater mean CA 19-9 concentrations compared to patients with resectable cholangiocarcinoma. CONCLUSIONS: These data suggest that the serum CA 19-9 determination is a useful addition to the available tests for the differential diagnosis of cholangiocarcinoma.

Preoperative hepatic artery chemoembolization followed by orthotopic liver transplantation for hepatocellular carcinoma.

In our experience, the primary obstacle precluding the widespread use of orthotopic liver transplantation (OLT) for definitive therapy of hepatocellular carcinoma (HCC), even for early-stage disease, is preventing tumor recurrence. Chemoembolization is an attractive strategy to minimize tumor progression before OLT because of its shown antitumor effect, ability to be repeated, and minimal systemic toxicity. Thus, this pilot study was undertaken to determine the tolerability and treatment outcomes of pretransplantation chemoembolization of HCC followed by OLT. Between 1992 and 1997, 27 patients with HCC who had cirrhosis, no extrahepatic metastasis, less than three tumor nodules of less than 5 cm each, and no evidence of vascular invasion on preoperative imaging studies were enrolled onto the protocol. Chemoembolization was performed using Ivalon particles with mitomycin, doxorubicin, and cisplatin. Twenty-four patients completed the protocol with chemoembolization and a liver transplant. The mean United Network of Organ Sharing waiting time was 167 days. Chemoembolization was well tolerated. On examination of the explanted liver, the majority of patients had a single lesion, mean tumor size was 3.66 cm (range, 1.5 to 6 cm), and the majority of patients had stage II disease. None of the transplant recipients has developed recurrent HCC (mean follow-up, 29.2 months; range, 9 to 55 months). The 1- and 2-year disease-free survival rates are 91% and 84%, respectively. In conclusion, chemoembolization followed by OLT is well tolerated and associated with excellent outcomes in selected patients with HCC.