BACKGROUND & AIMS:Recurrence of primary biliary cholangitis (PBC) after liver transplantation (LT) is frequent and can impair graft and patient survival. Ursodeoxycholic acid (UDCA) is the current standard therapy for PBC. We investigated the effect of preventive exposure to UDCA on the incidence and long-term consequences of PBC recurrence after LT. METHODS:We performed a retrospective cohort study in 780 patients transplanted for PBC, between 1983-2017 in 16 centers (9 countries), and followed-up for a median of 11 years. Among them, 190 received preventive UDCA (10-15 mg/kg/day). The primary outcome was histological evidence of PBC recurrence. The secondary outcomes were graft loss, liver-related death, and all-cause death. The association between preventive UDCA and outcomes was quantified using multivariable-adjusted Cox and restricted mean survival time (RMST) models. RESULTS:While recurrence of PBC significantly shortened graft and patient survival, preventive exposure to UDCA was associated with reduced risk of PBC recurrence (adjusted hazard ratio [aHR] 0.41; 95% CI 0.28-0.61; p <0.0001), graft loss (aHR 0.33; 95% CI 0.13-0.82; p <0.05), liver-related death (aHR 0.46; 95% CI 0.22-0.98; p <0.05), and all-cause death (aHR 0.69; 95% CI 0.49-0.96; p <0.05). On RMST analysis, preventive UDCA led to a survival gain of 2.26 years (95% CI 1.28-3.25) over a period of 20 years. Exposure to cyclosporine rather than tacrolimus had a complementary protective effect alongside preventive UDCA, reducing the cumulative incidence of PBC recurrence and all-cause death. CONCLUSIONS:Preventive UDCA after LT for PBC is associated with a reduced risk of disease recurrence, graft loss, and death. A regimen combining cyclosporine and preventive UDCA is associated with the lowest risk of PBC recurrence and mortality. LAY SUMMARY:Recurrence of primary biliary cholangitis after liver transplantation is frequent and can impair graft and patient survival. We performed the largest international study of transplanted patients with primary biliary cholangitis to date. Preventive administration of ursodeoxycholic acid after liver transplantation was associated with reduced risk of disease recurrence, graft loss, liver-related and all-cause mortality. A regimen combining cyclosporine and preventive ursodeoxycholic acid was associated with the best outcomes.

Introduction. Although ampullary carcinoma has the best prognosis among all periampullary carcinomas, its long-term survival remains low. Prognostic factors are only available for a period of 10 years after pancreaticoduodenectomy. The aim of this retrospective study was to identify factors that influence the long-term patient survival over a 15-year observation period. Methods. From 1992 to 2007, 143 patients with ampullary carcinoma underwent pancreatic resection. 86 patients underwent pylorus-preserving pancreaticoduodenectomy (60%) and 57 patients underwent standard Kausch-Whipple pancreaticoduodenectomy (40%). Results. The overall 1-, 5-, 10-, and 15-year survival rates were 79%, 40%, 24%, and 10%, respectively. Within a mean observation period of 30 (0–205) months, 100 (69%) patients died. Survival analysis showed that positive lymph node involvement P=0.001, lymphatic vessel invasion P=0.0001, intraoperative administration of packed red blood cells P=0.03, an elevated CA 19-9 P=0.03, jaundice P=0.04, and an impaired patient condition P=0.01 are strong negative predictors for a reduced patient survival. Conclusions. Patients with ampullary carcinoma have distinctly better long-term survival than patients with pancreatic adenocarcinoma. Long-term survival depends strongly on lymphatic nodal and vessel involvement. Moreover, a preoperative elevated CA 19-9 proved to be a significant prognostic factor. Adjuvant therapy may be essential in patients with this risk constellation.

BACKGROUND: After pancreaticoduodenectomy, the incidence of postoperative pancreatic fistula remains high, especially in patients with "soft" pancreatic tissue remnants. No "gold standard" surgical technique for pancreaticoenteric anastomosis has been established. This study aimed to compare the postoperative morbidity and mortality of pancreaticogastrostomy and pancreaticojejunostomy for "soft" pancreatic tissue remnants using modified mattress sutures.METHODS: Seventy-five patients who had undergone pancreaticogastrostomy and 75 who had undergone pancreaticojejunostomy after pancreaticoduodenectomy between 2002 and 2008 were retrospectively compared using matched-pair analysis. A modified mattress suture technique was used for the pancreaticoenteric anastomosis. Patients with an underlying "hard" pancreatic tissue remnant, as in chronic pancreatitis, were excluded. Both groups were homogeneous for age, gender, and underlying disease. Postoperative morbidity, mortality, and preoperative and operative data were analyzed.RESULTS: There were no significant differences between the groups for the incidence of postoperative pancreatic fistula (10.7% in both). Postoperative morbidity and mortality, median operation time, median length of hospital stay, intraoperative blood loss, and the amount of intraoperatively transfused erythrocyte concentrates also did not significantly differ between the groups. Patient age > 65 years (P=0.017), operation time > 350 minutes (P=0.001), and intraoperative transfusion of erythrocyte concentrates (P=0.038) were identified as risk factors for postoperative morbidity.CONCLUSIONS: Our results showed no significant differences between the groups in the pancreaticogastrostomy and pancreaticojejunostomy anastomosis techniques using mattress sutures for "soft" pancreatic tissue remnants. In our experience, the mattress sutures are safe and simple to use, and pancreaticogastrostomy in particular is feasible and easy to learn, with good endoscopic accessibility to the anastomosis region. However, the location of the anastomosis and the surgical technique need to be individually evaluated to further reduce the incidence of postoperative pancreatic fistula. (Hepatobiliary Pancrent Dis Int 2012;11:89-95)

We further characterize the heterogeneous carcinomas of the papilla of Vater (CPVs) in relation to various clinicopathologic patient characteristics and patient survival. Of the 71 reevaluated CPVs, 32 were intestinal, 26 were pancreatobiliary, 6 were mixed, 4 were mucinous, and 3 were poorly differentiated carcinomas. The prevalence of cytokeratin 20 and cytokeratin 7 correlated with the intestinal (25/32 [78%] vs 13/32 [41%]) and pancreatobiliary (6/26 [23%] vs 24/26 [92%]) phenotypes. CDX2 was found in mucinous (3/4 [75%]), intestinal (7/32 [22%]), and some mixed (1/6 [1%]) CPVs. A KRAS mutation was detected in all poorly differentiated CPVs and in about 20% of each of the other types. In multivariate analyses, tumor type, local tumor spread, and lymph node metastases were independent prognostic factors of patient survival. We provide further evidence of the prognostic relevance of the phenotypic and genotypic diversity of CPVs. Besides the poorly differentiated CPV, the most common KRAS wild type makes them a putative target for an anti-epidermal growth factor receptor therapy.

Conservative Management of Intrahepatic Abscesses due to Arterial Thrombosis after Liver Transplantation Objective: Thrombosis of the hepatic artery (HAT) after liver transplantation (OLT) is a severe complication. From the clinical and therapeutic view, HAT is classified into an early and a late event. Early HAT occurs within the first 2 months after OLT and finally leads to retransplantation for acute liver failure. Late HAT is frequently associated with intrahepatic abscesses and cholangitis, with subsequent liver resection or retransplantation. Case Report: A female patient with late HAT after OLT presented with intrahepatic abscesses. Treatment was managed with drainage and specific antibiotics. 3 months later, the patient was discharged free of symptoms. Conclusion: Our experience demonstrates that conservative management for liver abscesses due to late HAT after OLT may be taken into consideration as a treatment option.

BACKGROUND:Trans-umbilical single-port laparoscopic cholecystectomy for chronic gallbladder disease is becoming increasingly accepted worldwide. But so far, no reports exist about the challenging single-port surgery for acute cholecystitis. The objective of this study was to describe our experience with single-port cholecystectomy in comparison to the conventional laparoscopic technique.METHODS:Between August 2008 and March 2010, 73 patients with symptomatic gallbladder disease and histopathological signs of acute cholecystitis underwent laparoscopic cholecystectomy at our institution. Thirty-six patients were operated on with the single-port technique (SP group) and the data were compared with a control group of 37 patients who were treated with the multi-port technique (MP group).RESULTS:The mean age in the SP group was 61.5 (range 21-81) years and in the MP group was 60 (range 21-94) (P=0.712). Gender, ASA status and BMI were not significantly different. The number of white blood cells was different before [SP: 9.2 (range 2.8-78.4); MP: 13.2 (range 4.4-28.6); P=0.001] and after the operation [SP: 7.8 (range 3.5-184.8); MP: 11.1 (range 5-20.8); P=0.002]. Mean operating time was 88 (range 34-174) minutes in the SP group vs 94 (range 39-209) minutes in the MP group (P=0.147). Four patients (5%) required conversion to an open procedure (SP: 1; MP: 3; P=0.320). During the follow-up period of 332 (range 29-570) days in the SP group and 428 (range 111-619) days in the MP group (P=0.044), eleven (15%) patients developed postoperative complications (P=0.745) and two patients in the SP group required reoperation (P=0.154).CONCLUSIONS:Trans-umbilical single-port cholecystectomy for beginning acute cholecystitis is feasible and the complication rate is comparable with the standard multi-port operation. In spite of our good results, these operations are difficult to perform and should only be done in high-volume centers for laparoscopic surgery with experience in single-port surgery.

OBJECTIVES:Risk factors for survival after liver transplant owing to primary biliary cirrhosis have been extensively investigated, whereas the donor-specific influence and particularly, the histologic data, have not been sufficiently analyzed. PATIENTS AND METHODS:Donor data of 121 patients who underwent liver transplant for primary biliary cirrhosis and histologic findings of 69 donor liver grafts were assessed according to preoperative status and histologic criteria. Findings were correlated with the histologic and clinical course up to 20 years after orthotopic liver transplant. RESULTS:Risk factors for death were a longer stay in intensive care units (> 7 days) (P < .02), a hypotensive period > 60 minutes (P < .03), and the administration of red blood cells (P < .04). Grafts from donors with liver fibrosis (P < .03), fatty degeneration (P < .04), and liver cell hydrops (P < .04) resulted in a significantly higher risk of primary biliary cirrhosis recurrence. Log rank analysis revealed a significant decreased survival for patients if donors had a prolonged hypotensive period (P < .02) and administration of epinephrine (P < .03) and red blood cells (P < .05). CONCLUSIONS:Our results show that donor histology can affect disease recurrence, especially the grade of inflammation, fibrosis, and fatty degeneration. In addition, prolonged intensive care hospitalization for donors should be avoided.

Introduction: Activation of the hedgehog signal transduction pathway, triggered by hedgehog binding to the transmembrane receptor PTCH or by mutations in the PTCH gene, plays an important role in the development of various tumors including cutaneous basal cell carcinomas and cerebellar medulloblastomas. Recent findings indicate that digestive tract tumors including pancreatic adenocarcinomas also display increased hedgehog signaling activity due to an abnormal expression of the secreted hedgehog ligand sonic hedgehog (Shh). Material: To investigate if alterations of PTCH may also be involved in the pathogenesis of pancreatic adenocarcinoma we screened human pancreatic carcinomas and 3 cell lines for mutations using single-strand conformation polymorphism analysis (SSCP) of all coding exons and direct sequencing. Furthermore, the expression levels of known hedgehog target genes were determined using the competitive RT-PCR method. For Inhibition of the pathway in vitro we used the small — molecule inhibitor Hh-Antag. In vivo experiments were performed using a standardized heterotopic tumor model (nu/nu nude mouse) for treatment with the steroidal alkaloid cyclopamine and cyclopamine in combination with gemcitabine. Results: In the majority of pancreatic cancers we found significant overexpression of the target genes GLI-1 and PTCH compared to the corresponding normal pancreatic tissue. Additionally the effects of the small molecule inhibitor of the Hedgehog-Patched pathway Hh-Antag were investigated. Hh-Antag inhibits the function of Smoothened in pancreatic cancer cells; this results in inhibition of cell proliferation. Combination of cyclopamine+gemcitabine showed a significant reduction of tumor growth in vivo. Expression of target gens after treatment with cyclopamine showed a reduced expression of PTCH indicating an inactivation of the pathway in vivo as well. Conclusion: Overexpression of the taget genes GLI-1 and PTCH indicate an activation of hedgehog signaling in human pancreatic carcinoma. Inhibition of the pathway reduces tumor growth in vitro and in vivo. Therefore, inhibition of hedgehog signaling is a promising approach for treatment of pancreatic carcinoma.

BACKGROUND:Survival after orthotopic liver transplantation (OLT) for primary biliary cirrhosis (PBC) is excellent. In order to define the optimal time point for OLT, the Mayo risk score (MRS) was developed and a score of 7.8 was identified for transplantation. However, in reality most recipients are in a bad condition with a MRS above 7.8. So far it is still unknown if a higher score is associated with more complications after OLT perioperatively and in a long-term follow-up. Therefore, this study was designed to investigate the association of the MRS score with postoperative survival and complications. MATERIAL/METHODS:Between 1989 and 2006, 115 patients were transplanted for histologically proven PBC at the Charité Campus Virchow Clinic. In 98 of these patients, MRS data was available and retrospectively analyzed. Median age of 87 women and 11 men was 54 years (25 to 66 years). RESULTS:The median follow-up after liver transplantation was 109 months (0.5-205 months). Actuarial patient survival after 5, 10 and 15 years was 90%, 88%, and 83%. Calculated survival by MRS without transplantation after 1, 5 and 7 years was 20%, 2% and 1% for these patients. Twelve patients (12%) died and histological recurrence of PBC was detected in 14 patients (14%). Seven patients underwent retransplantation (7%) and 58 patients developed an acute rejection episode (59%). Mean MRS was in all patients 9.54+/-1.35 and did not differ between patients with lethal course, retransplantations, PBC recurrence, rejection episodes and duration of hospital stay. Classification of all patients into a low (<8.5), middle (8.5-10) and high MRS score (>10) did not show a significant difference in long-term survival. Univariate analysis for identifying the level of MRS as risk for death, PBC-recurrence, retransplantation, acute rejection episodes and hospital stay only showed a significant increased risk for acute rejection episodes (1 episode = 0.04; 2 episodes = 0.01) for patients with a MRS above 8.5. CONCLUSIONS:The Mayo risk score is an approved mathematical model predicting survival in non-transplanted patients suffering from PBC. However, the score did not predict the course of our liver transplanted patients in a long-term follow-up. We could not demonstrate a reduced patient survival at a median MRS of 9.4 and about 10.0. Therefore, it is, from our point of view, questionable if the optimal time point for OLT is still 7.8.

Tumor related pancreatic surgery has progressed significantly during recent years. Pancreatoduodenectomy (PD) with lymphadenectomy, including vascular resection, still presents the optimal surgical procedure for carcinomas in the head of pancreas. For patients with small or low-grade malignant neoplasms, as well as small pancreatic metastases located in the mid-portion of pancreas, central pancreatectomy (CP) is emerging as a safe and effective option with a low risk of developing de-novo exocrine and/or endocrine insufficiency. Total pancreatectomy (TP) is not as risky as it was years ago and can nowadays safely be performed, but its indication is limited to locally extended tumors that cannot be removed by PD or distal pancreatectomy (DP) with tumor free surgical margins. Consequently, TP has not been adopted as a routine procedure by most surgeons. On the other hand, an aggressive attitude is required in case of advanced distal pancreatic tumors, provided that safe and experienced surgery is available. Due to the development of modern instruments, laparoscopic operations became more and more successful, even in malignant pancreatic diseases. This review summarizes the recent literature on the above mentioned topics.

Background/Purpose. Carcinoma of the distal bile duct is associated with poor prognosis. Surgical resection remains the only potentially curative treatment. We conducted a retrospective study to identify prognostic factors determining longterm survival.Methods. From 1990 to 2006, 95 patients with distal and/or middle bile duct carcinoma had resections. Fifty-four patients underwent pylorus-preserving pancreaticoduodenectomy (57%) and 41 patients underwent standard Kausch-Whipple pancreaticoduodenectomy (43%). Nine patients underwent pancreaticoduodenectomy including portal vein resection (9%).Results. Overall 1-, 3-, and 5-year survival rates were 60%, 36%, and 29%, respectively. Five-year survival after R0 resection was 34%, and after R1 resection it was 0%. Four patients died during their hospital stay (4%). Multivariate analysis showed negative resection margins (P = 0.040), lymphatic vessel invasion (P = 0.036), and portal vein infiltration (P = 0.027) as strong predictors for survival, whereas the location of the tumor (distal bile duct vs middle bile duct) and lymph node status were not identified as independent prognostic factors.Conclusions. Five-year survival depends strongly on negative resection margins, independent of nodal status. Portal vein resections in patients with portal vein involvement fail to ameliorate long-term survival. Primary tumor site - middle bile duct or distal bile duct - did not determine prognosis.

Background and Aim:  Chemoresistance often leads to loss of the last treatment option for cancer. 2‐Methoxyestradiol (2‐ME2) has been shown to inhibit tumor growth. The aim was to examine the efficacy of 2‐ME2 on multidrug‐resistant human cells from pancreatic and gastric cancer.

BACKGROUND AND AIM:Neuroendocrine pancreatic carcinomas are rare and little information on factors influencing the clinical course and prognosis is presently available. The aim of this study was to retrospectively review all patients who underwent pancreatic resection for malignant neuroendocrine tumor of the pancreas at the one department from 1989 to 2003.METHODS:Eleven male and eight female patients with a mean age of 51 years (range 13-76 years) underwent surgery for malignant neuroendocrine tumor of the pancreas. The prognostic relevance for long-term survival was investigated for intrapancreatic localization of the primary, histological classification including proliferation index (Ki67), lymph node involvement, surgical treatment and long-term survival after resection. The clinical course after resection was also evaluated. Statistical analysis was performed using multivariate analysis and Kaplan-Meier method.RESULTS:Functional or non-functional tumors occurred in six (32%) and 13 (68%) patients, respectively. The tumors were located in the pancreatic head in 10 patients (53%), body in three (15%) and tail in two (11%). Multilocular tumors were found in five (26%). Surgical procedures performed were six pylorus preserving pancreaticoduodenectomies (32%), four standard pancreaticoduodenectomies (21%), four distal pancreatectomies (21%), three total pancreatectomies (15%) and two segmental resections (11%). Multivariate analysis showed sex (P = 0.018), Ki67 proliferation index (P = 0.023), tumor diameter (P = 0.02) and tumor site (P = 0.011) as significant predictors of outcome.CONCLUSION:Malignant neuroendocrine tumors of the pancreas are associated with poor prognosis. Surgical resection is an appropriate and safe procedure with low morbidity rates. The prognosis seems to be determined by various biological factors. However, with regard to the principles of surgical oncology, tumor-free resection margins are important and radical surgical procedures are justified in selected patients.