In the setting of moderate to severe pulmonary artery hypertension, orthotopic liver transplantation (OLT) may be complicated by pulmonary hemodynamic instability and cardiopulmonary mortality. We retrospectively studied the relationship between cardiopulmonary-related mortality and initial (untreated) pre-OLT pulmonary hemodynamics in 43 patients with portopulmonary hypertension who underwent attempted OLT. Thirty-six patients were reported in 18 peer-reviewed studies, and 7 patients underwent OLT at our institution since 1996. Transplantation procedure outcome, mean pulmonary artery pressure (MPAP), pulmonary vascular resistance (PVR), cardiac output, pulmonary capillary wedge pressure, and transpulmonary gradient (TPG) are summarized. Overall mortality was reported in 15 of 43 patients (35%). Fourteen of the 15 deaths (93%) were primarily related to cardiopulmonary dysfunction. Two deaths were intraoperative, 8 deaths occurred during the transplantation hospitalization, and 4 patients died of cardiopulmonary deterioration posthospitalization. In 4 patients, the transplantation procedure could not be successfully completed. Cardiopulmonary mortality was associated with greater pre-OLT MPAP (49 ؎ 14 v 36 ؎ 7 mm Hg; P F .005), PVR (441 ؎ 173 v 261 ؎ 156 dynes·s·cm Ϫ5 ; P F .005), and TPG (37 ؎ 13 v 22 ؎ 10 mm Hg; P F .005). MPAP of 50 mm Hg or greater was associated with 100% cardiopulmonary mortality. In patients with an MPAP of 35 to less than 50 mm Hg and PVR of 250 dynes·s·cm Ϫ5 or greater, the mortality rate was 50%. No mortality was reported in patients with a pre-OLT MPAP less than 35 mm Hg or TPG less than 15 mm Hg. Cardiopulmonaryrelated mortality in OLT patients with portopulmonary hypertension was frequent and associated with significantly increased pre-OLT MPAP, PVR, and TPG compared with survivors. Treated or untreated, we recommend intraoperative cancellation or advise against proceeding to OLT for an MPAP of 50 mm Hg or greater. Patients with an MPAP of 35 to less than 50 mm Hg and PVR of 250 dynes·s·cm Ϫ5 or greater appear to be at high risk for cardiopulmonary-related mortality after OLT. A prospective study is needed to define optimal pretransplantation treatments and pulmonary hemodynamic criteria that minimize OLT mortality associated with portopulmonary hypertension. (Liver Transpl 2000;6:443-450.) P ortopulmonary hypertension is defined as pulmonary artery hypertension (mean pulmonary artery pressure [MPAP], Ͼ25 mm Hg and pulmonary capillary wedge pressure [PCWP] less than 15 mm Hg) in association with portal hypertension. 1-3 Several investigators adhere to the additional criteria of increased pulmonary vascular resistance ([PVR] Ͼ120 dynes·s·cm Ϫ5 ). [4][5][6] A unifying hypothesis explaining the cause of this liver-lung relationship has yet to be proven. 2 Patients with portopulmonary hypertension have a high mortality rate. Within 15 months from the time pulmonary hypertension was diagnosed, death was reported in 38% (10 of 26 patients) to 41% (32 of 78 patients) of the patients describ...

Liver transplantation with neoadjuvant chemoradiation achieved better survival with less recurrence than conventional resection and should be considered as an alternative to resection for patients with localized, node-negative hilar CCA.

BACKGROUND & AIMS Excellent single-center outcomes of neoadjuvant chemoradiation and liver transplantation (LT) for unresectable perihilar cholangiocarcinoma caused the United Network of Organ Sharing (UNOS) 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 US who met the inclusion criteria of treating three or more patients with perihilar cholangiocarcinoma using neoadjuvant therapy followed by liver transplantation from 1993–2010 (n=287 total patients). Center-specific protocols and medical charts were reviewed on-site. RESULTS The patients completed external radiation (99%), brachytherapy (75%), radio-sensitizing (98%), and/or maintenance chemotherapy (65%). Seventy-one patients dropped out before liver transplantation (rate of 11.5% in 3 months). Intent-to-treat survival was 68% and 53%, 2 and 5 years after therapy, respectively; post-transplantation, recurrence-free survival rates were 78% and 65%, respectively. Patients outside the UNOS criteria (those with tumor mass >3 cm, trans-peritoneal 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 operative staging or brachytherapy. Although most patients came from 1 center (n=193), the other 11 centers had similar survival times after therapy. CONCLUSION Patients with perihilar cholangiocarcinoma who were treated with neoadjuvant therapy followed by liver transplantation at 12 US centers had a 65% rate of recurrence-free survival after 5 years, demonstrating this therapy to be highly effective. An 11.5% dropout 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.

To determine the natural history of portopulmonary hypertension (POPH), a retrospective screening-right heart catheterization-survival analysis of patients was performed. We categorized patients by three treatment subgroups: (1) no therapy for pulmonary hypertension (PH) or liver transplantation (LT), (2) therapy for PH alone and (3) therapy for PH followed by LT. Seventyfour patients were identified between 1994 and 2007. Nineteen patients received no therapy for PH and no LT representing the natural history of POPH. Five-year survival was 14%, and 54% had died within 1 year of diagnosis. Five-year survival in 43 patients receiving therapy for PH but no LT was 45%, and 12% had died within 1 year of diagnosis. Twelve patients underwent LT and 5-year survival for the nine receiving therapy for PH was 67% versus 25% in the three who were not pretreated with prostacyclin therapy. The survival of untreated patients with POPH was poor. Subgroups of patients selected to medical treatment with or without LT had better long-term survival. Mortality did not correlate with baseline hemodynamic variables, type of liver disease or severity of hepatic dysfunction. Medical therapy for POPH should be considered in all patients with POPH, but the treatment effects and impact on those considered for LT still requires well-designed, prospective study before practice guidelines can be suggested.

Liver transplantation is the only effective therapeutic option for patients with end-stage liver disease due to primary sclerosing cholangitis (PSC). In this study, we analyzed a single center's experience with 150 consecutive PSC patients who received 174 liver allografts. Mean follow-up was 55 months. Actuarial patient survival at 1, 2, 5, and 10 years was 93.7%, 92.2%, 86.4%, and 69.8%, respectively, whereas graft survival was 83.4%, 83.4%, 79.0%, and 60. 5%, respectively. The main indication for retransplantation was hepatic artery thrombosis, and the major cause of death was severe infection. Patients with PSC had a higher incidence of acute cellular and chronic ductopenic rejection compared to a non-PSC control group. Chronic ductopenic rejection adversely affected patient and graft survival. Biliary strictures, both anastomotic and nonanastomotic, were frequent and occurred in 16.2% and 27.2% of patients, respectively. The incidence of recurrent PSC was 20%. A negative impact on patient survival was not seen in patients with either postoperative biliary strictures or recurrence of PSC. Six patients (4%) had cholangiocarcinoma and 1 patient died related to recurrence of malignant disease. Seventy-eight percent of PSC patients had associated inflammatory bowel disease, most commonly chronic ulcerative colitis, which did not adversely impact patient outcome posttransplantation. Nine patients required proctocolectomy after liver transplantation; 5 because of intractable symptoms related to inflammatory bowel disease and 4 due to the development of colorectal carcinoma/high-grade dysplasia. Our data show that liver transplantation provides excellent long-term patient and graft survival for patients with end-stage PSC.

The authors reviewed their institutional experience with liver resection for metastatic colorectal carcinoma to (1) determine whether perioperative blood transfusion affects survival; (2) identify prognostic determinants; and (3) estimate the patient requirement for a prospective randomized trial designed to demonstrate efficacy of liver resection. Two hundred eighty consecutive patients treated by potentially curative liver resection between 1960 and 1987 were included. Data were obtained for all but 10 patients for at least 5 years after operation or through 1990. Actuarial survival curves related to potential prognostic determinants were analyzed with the log-rank test. Overall, survival was 47 +/- 3% at 3 years and 25 +/- 3% at 5 years, including 4% 60-day operative mortality rate. Eighty-one patients who did not receive blood 7 days before to 14 days after operation had 60 +/- 6% 3-year and 32 +/- 6% 5-year survival compared with 40 +/- 4% and 21 +/- 3% survival rates for 183 patients who received at least one unit (p = 0.03, operative deaths excluded). Extrahepatic disease (p = 0.015), extrahepatic lymph node involvement (p = 0.002), satellite configuration of multiple metastases (p = 0.0052), and initial detection by abnormal liver enzymes (p = 0.0005) were associated with poor survival rates. Synchronous presentation of metastatic and stage B primary disease was associated with a favorable prognosis (p = 0.003). The requirement for a prospective randomized trial estimated by an exponential survival model would be 36, 74, 168, or 428 patients if 5-year survival without resection were 1, 5, 10, or 15%. We conclude that (1) perioperative blood transfusion may be adversely associated with survival; (2) extrahepatic disease, extrahepatic lymph node involvement, satellite configuration, and initial detection by clinical examination or a liver enzyme abnormality portend a poor prognosis; and (3) a prospective randomized trial of liver resection is impractical because of the large patient requirement, at least by a single institution.

Perihilar cholangiocarcinoma is one of the most challenging diseases with poor overall survival. The major problem for anyone trying to convincingly compare studies among centers or over time is the lack of a reliable staging system. The most commonly used system is the Bismuth-Corlette classification of bile duct involvement, which, however, does not include crucial information such as vascular encasement and distant metastases. Other systems are rarely used because they do not provide several key pieces of information guiding therapy. Therefore, we have designed a new system reporting the size of the tumor, the extent of the disease in the biliary system, the involvement of the hepatic artery and portal vein, the involvement of lymph nodes, distant metastases, and the volume of the putative remnant liver after resection. The aim of this system is the standardization of the reporting of perihilar cholangiocarcinoma so that relevant information regarding resectability, indications for liver transplantation, and prognosis can be provided. With this tool, we have created a new registry enabling every center to prospectively enter data on their patients with hilar cholangiocarcinoma (www.cholangioca.org). The availability of such standardized and multicenter data will enable us to identify the critical criteria guiding therapy. (HEPATOLOGY 2011;53:1363-1371 C holangiocarcinoma (CCA) arises from the malignant transformation of the bile duct epithelium; it represents approximately 10% of all primary hepatobiliary cancers and accounts for approximately 2% of all malignancies.1,2 Several lines of evidence indicate that the incidence of CCA has increased over the past 3 decades.3,4 These tumors can develop anywhere along the biliary tree and represent a quite heterogeneous group with distinct patterns, epidemiologies, clinical presentations, and prognoses. The most commonly used classification of CCA has three groups based on the location along the biliary tree: intrahepatic cholangiocarcinoma (IHC); perihilar cholangiocarcinoma (PHC), which is also called a Klatskin tumor 5 ; and distal CCA. The IHC type accounts for less than 10% of the total cases, whereas the PHC type represents about two-thirds of the cases, and distal CCA represents about a quarter of the cases.6 PHC can be defined as tumors that involve or are in close vicinity to the bile duct confluence. We suggest a definition of PHC, which includes tumors above the junction of the cystic duct up to and including the second biliary branches of the right and left bile ducts.The only chance of a cure for this type of cancer is complete surgical resection of the tumor and perhaps liver transplantation in highly select cases. Most of these cancers have a dismal prognosis, and the current 5-year

Orthotopic liver transplantation (OLT) alone for unresectable cholangiocarcinoma is often associated with early disease relapse and limited survival. Because of these discouraging results, most programs have abandoned OLT for cholangiocarcinoma. However, a small percentage of patients have achieved prolonged survival after OLT, suggesting that adjuvant approaches could perhaps improve the survival outcome. Based on these concepts, a protocol was developed at the Mayo Clinic using preoperative irradiation and chemotherapy for patients with cholangiocarcinoma. We report our initial results with this pilot experience. Patients with unresectable cholangiocarcinoma above the cystic duct without intrahepatic or extrahepatic metastases were eligible. Patients initially received external-beam irradiation plus bolus fluorouracil (5-FU), followed by brachytherapy with iridium and concomitant protracted venous infusion of 5-FU. 5-FU was then administered continuously through an ambulatory infusion pump until OLT. After irradiation, patients underwent an exploratory laparotomy to exclude metastatic disease. To date, 19 patients have been enrolled onto the study and have been treated with irradiation. Eight patients did not go on to OLT because of the presence of metastasis at the time of exploratory laparotomy (n ‫؍‬ 6), subsequent development of malignant ascites (n ‫؍‬ 1), or death from intrahepatic biliary sepsis (n ‫؍‬ 1). Eleven patients completed the protocol with successful OLT. Except for 1 patient, all had early-stage disease (stages I and II) in the explanted liver. All patients who underwent OLT are alive, 3 patients are at risk at 12 months or less, and the remaining 8 patients have a median follow-up of 44 months (range, 17 to 83 months; 7 of 9 patients G 36 months). Only 1 patient developed tumor relapse. OLT in combination with preoperative irradiation and chemotherapy is associated with prolonged disease-free and overall survival in highly selected patients with early-stage cholangiocarcinoma. (Liver Transpl 2000;6:309-316.)