Michelle L. DeOliveira

Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution.

Objective:To assess long-term survival and prognostic factors in a large series of patients with bile duct cancer. Summary Background Data:The incidence of bile duct cancer is low but increasing. Determinants of survival vary in the literature, due to a lack of sufficient numbers of patients in most series. Methods:We studied 564 consecutive patients with bile duct cancer operated upon between 1973 and 2004. Patients were divided into intrahepatic, perihilar, and distal groups. Principle outcome measures were complications, 30-day mortality, and survival. Results:Of the 564 patients, 44 (8%) had intrahepatic, 281 (50%) had perihilar, and 239 (42%) had distal tumors. Approximately half (294, 52%) were treated before 1995, while 270 (48%) were treated thereafter. The perioperative mortality rate was 4%. In log-rank analyses, survival was higher in the later time period (P = 0.002), in patients with intrahepatic disease (P = 0.001), with negative resection margins (P < 0.001), with well/moderately differentiated tumors (P < 0.001), and those with negative lymph nodal status (P < 0.001). In multivariate analysis, negative margins (P < 0.001), tumor differentiation (P < 0.001), and negative nodal status (P < 0.001), but not tumor diameter, were significant independent prognostic factors. In R0-resected patients, lymph node status (P < 0.001), but not tumor diameter, histology, or differentiation, further predicted survival. The median survivals for R0-resected intrahepatic, perihilar, and distal tumors were 80, 30, and 25 months, respectively, and the 5-year survivals were 63%, 30%, and 27%, respectively. Conclusion:R0 resection remains the best chance for long-term survival, and lymph node status is the most important prognostic factor following R0 resection.

Assessment of Complications After Pancreatic Surgery A Novel Grading System Applied to 633 Patients Undergoing Pancreaticoduodenectomy

Objective:To define a simple and reproducible classification of complications following pancreaticoduodenectomy (PD) based on a therapy-oriented severity grading system. Background:While mortality is rare after PD, morbidity rates remain high. The lack of standardization in evaluating morbidity after PD has severely hampered meaningful comparisons over time and among centers. We adapted a novel classification of complication to stratify morbidity by severity after PD, to test whether the incidence of pancreatic fistula has changed over time, and to identify risk factors in a single North American center. Methods:The classification was applied to a consecutive series of 633 patients undergoing PD between February 2003 and August 2005. Another series of 141 patients treated between 1987 and 1990 was also analyzed to identify changes in the incidence and severity of fistula. Univariate and multivariate analyses were performed to link respective complications with preoperative and intraoperative parameters, length of hospital stay, and long-term survival. Results:A total of 263 (41.5%) patients did not develop any complication, while 370 (58.5%) had at least one complication; 62 (10.0%) patients had only grade I complications (no need for specific intervention), 192 patients (30.0%) had grade II (need for drug therapy such as antibiotics), 85 patients (13.5%) had grade III (need for invasive therapy), and 19 patients (3.0%) had grade IV complications (organ dysfunction with ICU stay). Grade V (death) occurred in 12 patients (2.0%). A total of 57 patients (9.0%) developed pancreatic fistula, of which 33 (58.0%) were classified as grade II, 17 (30.0%) as grade III, 5 (9.0%) as grade IV, and 2 (3.5%) as grade V. Delayed gastric emptying was documented in 80 patients (12.7%); half of them were scored as grade II and the other half as grade III. A significant decrease in the incidence of fistula was observed between the 2 periods analyzed (14.0% vs. 9.0%, P < 0.001), mostly due to a decrease in grade II fistula. Cardiovascular disease was a risk factor for overall morbidity and complication severity, while texture of the gland and cardiovascular disease were risk factors for pancreatic fistula. Conclusion:This study demonstrates the applicability and utility of a new classification in grading complications following pancreatic surgery. This novel approach may provide a standardized, objective, and reproducible assessment of pancreas surgery enabling meaningful comparison among centers and over time.

New staging system and a registry for perihilar cholangiocarcinoma

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;)

Novel and simple preoperative score predicting complications after liver resection in noncirrhotic patients.

Objective:To develop and validate a simple score to predict postoperative complications by severity after liver resection, using readily available preoperative risk factors. Background:Although liver surgery has enjoyed major development with dramatic reduction in mortality rates, the incidence of serious yet nonlethal complications remains high. No scoring system is currently available to identify those patients at higher risk for a complicated course. Methods:Complications were prospectively assessed in 615 consecutive noncirrhotic patients undergoing liver resection at the same institution. In randomly selected 60% of the population, multivariate-logistic-regression analysis was used to develop a score to predict severe complications defined as complications grades III, IV, and mortality (grade V) (Clavien-Dindo classification). The score was validated by calibration within the remaining 40% of the patients. Results:Grades III to V complications occurred in 159 (26%) of the 615 patients after liver resection, 90 (15%) were grade III, 48 (8%) grade IV, and 21 (3%) grade V. Four preoperative parameters were identified as independent predictors including American Society of Anesthesiologists category, transaminases levels (aspartate aminotransferase), extent of liver resection (>3 vs <3 segments), and the need for an additional hepaticojejunostomy or colon resection. A prediction score was calculated on the basis of 60% of the population (369 patients) using the 4 independent predictors ranging from 0 to 10 points. The risk to develop serious postoperative complications was 16% in “low risk” patients (0–2 points), 37% in “intermediate risk” patients (3–5 points) and 60% in “high risk” patients (6–10 points). The predicted mean for absolute risk for grades III to V complications was 27% in the validation population including 40% of the patients (n = 246), whereas the observed risk was 24%. Predicted and observed risks were similar throughout the different risk categories (P = 0.8). The score was significantly associated with hospital and intensive care unit stays. Costs of the entire procedure doubled among the 3 risk groups. Conclusions:This novel and simple score accurately predicts postoperative complications and cost in patients undergoing liver resection. This score allows early identification of patients at risk and may impact not only decision making for surgical intervention but also quality assessment and reimbursement.

Challenges to Liver Transplantation and Strategies to Improve Outcomes

Liver transplantation (LT) is a highly successful treatment for many patients with nonmalignant and malignant liver diseases. However, there is a worldwide shortage of available organs; many patients deteriorate or die while on waiting lists. We review the important clinical challenges to LT and the best use of the scarce organs. We focus on changes in indications for LT and discuss scoring systems to best match donors with recipients and optimize outcomes, particularly for the sickest patients. We also cover controversial guidelines for the use of LT in patients with hepatocellular carcinoma and cholangiocarcinoma. Strategies to increase the number of functional donor organs involve techniques to perfuse the organs before implantation. Partial LT (living donor and split liver transplantation) techniques might help to overcome organ shortages, and we discuss small-for-size syndrome. Many new developments could increase the success of this procedure, which is already one of the major achievements in medicine during the second part of the 20th century.

Improving outcome in patients undergoing liver surgery

Liver surgery is associated with many factors, which may affect outcome. Preoperative assessment of patients general condition, resectability, and liver reserve are paramount for success. The Child–Pugh score and other scoring systems only partially enables to assess the risk associated with liver surgery. The presence of portal hypertension per se is a major risk factor for hepatectomy. Intraoperatively, any attempts should be made to minimize blood loss. Low central venous pressure and inflow occlusion best prevent bleeding. Ischemic preconditioning and intermittent clamping are routinely applied in many centers to protect against long periods of ischemia, although the mechanisms of protection remain unclear. In this review we describe recent advances in activated pathways associated with protection against ischemia. Postoperatively, the best factor impacting on outcome probably resides in experienced medical care particularly in the intensive care setting. Currently, no drug or gene therapy approaches has reached the clinic. The future relies on new insight into mechanisms of ischemia–reperfusion injury.

Expression of Serotonin Receptors in Human Hepatocellular Cancer

Purpose: Serotonin is a well-known neurotransmitter and vasoactive substance. Recent research indicates that serotonin contributes to liver regeneration and promotes tumor growth of human hepatocellular cancer. The aim of this study is to investigate the expression of serotonin receptors in hepatocellular cancer and analyze their potential as a cytotoxic target. Experimental Design: Using a tissue microarray and immunohistochemistry, we analyzed the expression of serotonin receptors in the liver from 176 patients with hepatocellular carcinoma, of which nontumor tissue was available in 109 patients. Relevant clinicopathologic parameters were compared with serotonin receptor expression. Two human hepatocellular cancer cell lines, Huh7 and HepG2, were used to test serotonin antagonists as a possible cytotoxic drug. Results: The serotonin receptors 1B and 2B were expressed, respectively, in 32% and 35% of the patients with hepatocellular cancer. Both receptors were associated with an increased proliferation index, and receptor 1B correlated with the size of the tumor. Serotonin antagonists of receptors 1B and 2B consistently decreased viability and proliferation in Huh7 and HepG2 cell lines. Conclusion: We identified two serotonin receptors that are often overexpressed in human hepatocellular cancer and may serve as a new cytotoxic target. Clin Cancer Res; 18(21); 5902–10. ©2012 AACR.

Ultrasound monitoring of tissue ablation via deformation model and shape priors

A rapid approach to monitor ablative therapy through optimizing shape and elasticity parameters is introduced. Our motivating clinical application is targeting and intraoperative monitoring of hepatic tumor thermal ablation, but the method translates to the generic problem of encapsulated stiff masses (solid organs, tumors, ablated lesions, etc.) in ultrasound imaging. The approach involves the integration of the following components: a biomechanical computational model of the tissue, a correlation approach to estimate/track tissue deformation, and an optimization method to solve the inverse problem and recover the shape parameters in the volume of interest. Successful convergence and reliability studies were conducted on simulated data. Then ex-vivo studies were performed on 18 ex-vivo bovine liver samples previously ablated under ultrasound monitoring in controlled laboratory environment. While B-mode ultrasound does not clearly identify the development of necrotic lesions, the proposed technique can potentially segment the ablation zone. The same framework can also yield both partial and full elasticity reconstruction.

Effects of pentoxifylline on liver regeneration: a double-blinded, randomized, controlled trial in 101 patients undergoing major liver resection.

Objectives:To evaluate the effects of pentoxifylline (PTX) on liver regeneration in patients undergoing major liver resection. Background:Recent experimental data suggest that PTX, a tumor necrosis factor (TNF) &agr; inhibitor, enhances liver regeneration and reduces ischemic injury through activation of the interleukin-6 (IL-6) signaling pathway. However, the clinical impact of PTX in patients undergoing major liver surgery is unknown. Methods:One hundred one consecutive noncirrhotic patients undergoing major liver surgery with inflow occlusion were included in a double-blinded, randomized, controlled trial (RCT) at a single tertiary care center (2006–2009). Fifty-one patients received intravenous administration of PTX starting 12 hours before and ending 72 hours after surgery, whereas 50 control patients received a placebo infusion. Primary endpoint was liver regeneration as assessed by three-dimensional volumetry based on magnetic resonance (MR) tomography at postoperative day 8 compared with preoperative images. Secondary endpoints were transaminases, cytokines, and postoperative complications. Results:Both groups were comparable regarding demographics, risk score, preoperative laboratory tests, and type and extent of liver resection. Treatment with PTX resulted in significantly better volume regeneration for small remnant livers [remnant liver to body weight (RLBW) ratio ⩽ 1.2%], whereas no beneficial effect was observed for RLBW ratio of more than 1.2%. There was a 3.6-fold stronger induction of IL-6 mRNA for the PTX group (P < 0.001). Postoperative alanine aminotransferase (AST) levels were significantly decreased for the PTX group on the second postoperative day (442 vs 585 U/L, P = 0.025). No significant benefit could be identified regarding the number and severity of postoperative complications and median ICU (1 vs 1 day) and hospital stay (10 vs 10 days). However, the PTX group had significantly more drug-related adverse events (23 vs 8, P = 0.007). Conclusions:This is the first RCT evaluating the effects of PTX on liver regeneration after major liver resection. The study demonstrates beneficial effects of PTX on regeneration of small remnant livers (RLBW ratio ⩽ 1.2%) that seems to be mediated by IL-6.

Conditioning With Sevoflurane in Liver Transplantation: Results of a Multicenter Randomized Controlled Trial

Background During times of organ scarcity and extended use of liver grafts, protective strategies in transplantation are gaining importance. We demonstrated in the past that volatile anesthetics such as sevoflurane attenuate ischemia-reperfusion injury during liver resection. In this randomized study, we examined if volatile anesthetics have an effect on acute graft injury and clinical outcomes after liver transplantation. Methods Cadaveric liver transplant recipients were enrolled from January 2009 to September 2012 at 3 University Centers (Zurich/Sao Paulo/Ghent). Recipients were randomly assigned to propofol (control group) or sevoflurane anesthesia. Postoperative peak of aspartate transaminase was defined as primary endpoint, secondary endpoints were early allograft dysfunction, in-hospital complications, intensive care unit, and hospital stay. Results Ninety-eight recipients were randomized to propofol (n = 48) or sevoflurane (n = 50). Median peak aspartate transaminase after transplantation was 925 (interquartile range, 512–3274) in the propofol and 1097 (interquartile range, 540–2633) in the sevoflurane group. In the propofol arm, 11 patients (23%) experienced early allograft dysfunction, 7 (14%) in the sevoflurane one (odds ratio, 0.64 (0.20 to 2.02, P = 0.45). There were 4 mortalities (8.3%) in the propofol and 2 (4.0%) in the sevoflurane group. Overall and major complication rates were not different. An effect on clinical outcomes was observed favoring the sevoflurane group (less severe complications), but without significance. Conclusions This first multicenter trial comparing propofol with sevoflurane anesthesia in liver transplantation shows no difference in biochemical markers of acute organ injury and clinical outcomes between the 2 regimens. Sevoflurane has no significant added beneficial effect on ischemia-reperfusion injury compared to propofol.