Kuno Lehmann

A multicenter randomized clinical trial of primary anastomosis or Hartmann's procedure for perforated left colonic diverticulitis with purulent or fecal peritonitis.

Objectives:To evaluate the outcome after Hartmanns procedure (HP) versus primary anastomosis (PA) with diverting ileostomy for perforated left-sided diverticulitis. Background:The surgical management of left-sided colonic perforation with purulent or fecal peritonitis remains controversial. PA with ileostomy seems to be superior to HP; however, results in the literature are affected by a significant selection bias. No randomized clinical trial has yet compared the 2 procedures. Methods:Sixty-two patients with acute left-sided colonic perforation (Hinchey III and IV) from 4 centers were randomized to HP (n = 30) and to PA (with diverting ileostomy, n = 32), with a planned stoma reversal operation after 3 months in both groups. Data were analyzed on an intention-to-treat basis. The primary end point was the overall complication rate. The study was discontinued following an interim analysis that found significant differences of relevant secondary end points as well as a decreasing accrual rate (NCT01233713). Results:Patient demographics were equally distributed in both groups (Hinchey III: 76% vs 75% and Hinchey IV: 24% vs 25%, for HP vs PA, respectively). The overall complication rate for both resection and stoma reversal operations was comparable (80% vs 84%, P = 0.813). Although the outcome after the initial colon resection did not show any significant differences (mortality 13% vs 9% and morbidity 67% vs 75% in HP vs PA), the stoma reversal rate after PA with diverting ileostomy was higher (90% vs 57%, P = 0.005) and serious complications (Grades IIIb-IV: 0% vs 20%, P = 0.046), operating time (73 minutes vs 183 minutes, P < 0.001), hospital stay (6 days vs 9 days, P = 0.016), and lower in-hospital costs (US

Preconditioning, organ preservation, and postconditioning to prevent ischemia‐reperfusion injury to the liver

16,717 vs US

Chemotherapy before liver resection of colorectal metastases: friend or foe?

24,014) were significantly reduced in the PA group. Conclusions:This is the first randomized clinical trial favoring PA with diverting ileostomy over HP in patients with perforated diverticulitis.

γ-Radiation Promotes Immunological Recognition of Cancer Cells through Increased Expression of Cancer-Testis Antigens In Vitro and In Vivo

Ischemia and reperfusion lead to injury of the liver. Ischemia‐reperfusion injury is inevitable in liver transplantation and trauma and, to a great extent, in liver resection. This article gives an overview of the mechanisms involved in this type of injury and summarizes protective and treatment strategies in clinical use today. Intervention is possible at different time points: during harvesting, during the period of preservation, and during implantation. Liver preconditioning and postconditioning can be applied in the transplant setting and for liver resection. Graft optimization is merely possible in the period between the harvest and the implantation. Given that there are 3 stages in which a surgeon can intervene against ischemia‐reperfusion injury, we have structured the review as follows. The first section reviews the approaches using surgical interventions, such as ischemic preconditioning, as well as pharmacological applications. In the second section, static organ preservation and machine perfusion are addressed. Finally, the possibility of treating the recipient or postconditioning is discussed. Liver Transpl 15:1172–1182, 2009.

What is critical for liver surgery and partial liver transplantation: size or quality?

Objective: We conducted a systematic review of the published literature to critically assess benefits and risks of the use of preoperative chemotherapy in patients presenting with colorectal liver metastases. Background: In many centers, chemotherapy is used before hepatic resection of colorectal metastases, even in the presence of a single lesion. Application of chemotherapy requires clear conceptual distinction between patients presenting with resectable lesions (neoadjuvant) versus patients presenting with unresectable lesions, for which chemotherapy is used to reach a resectable situation (downsizing). Methods: The literature (PubMed) was systematically reviewed for publications related to liver surgery and chemotherapy according to the methodology recommended by the Cochrane Collaboration. Results: For unresectable liver metastases, combination regimens result in enhanced tumor response and resectability rates up to 30%, although the additional benefit from targeted agents such as bevacizumab or cetuximab is marginal. For resectable lesions, studies on neoadjuvant chemotherapy failed to convincingly demonstrate a survival benefit. Most reports described increased postoperative complications in a subset of patients due to parenchymal alterations such as chemotherapy-associated steatohepatitis or sinusoidal obstruction syndrome. Conclusion: Preoperative standard chemotherapy can be recommended for downsizing unresectable liver metastases, but not for resectable lesions, for which adjuvant chemotherapy is preferred.

Liver Failure After Extended Hepatectomy in Mice Is Mediated by a p21-Dependent Barrier to Liver Regeneration

Background γ-radiation is an effective treatment for cancer. There is evidence that radiotherapy supports tumor-specific immunity. It was described that irradiation induces de novo protein synthesis and enhances antigen presentation, we therefore investigated whether γ-radiation results in increased expression of cancer-testis (CT) antigens and MHC-I, thus allowing efficient immunological control. This is relevant because the expression of CT-antigens and MHC-I on tumor cells is often heterogeneous. We found that the changes induced by γ-radiation promote the immunological recognition of the tumor, which is illustrated by the increased infiltration by lymphocytes after radiotherapy. Methods/Findings We compared the expression of CT-antigens and MHC-I in various cancer cell lines and fresh biopsies before and after in vitro irradiation (20 Gy). Furthermore, we compared paired biopsies that were taken before and after radiotherapy from sarcoma patients. To investigate whether the changed expression of CT-antigens and MHC-I is specific for γ-radiation or is part of a generalized stress response, we analyzed the effect of hypoxia, hyperthermia and genotoxic stress on the expression of CT-antigens and MHC-I. In vitro irradiation of cancer cell lines and of fresh tumor biopsies induced a higher or de novo expression of different CT-antigens and a higher expression of MHC-I in a time- and dose-dependent fashion. Importantly, we show that irradiation of cancer cells enhances their recognition by tumor-specific CD8+ T cells. The analysis of paired biopsies taken from a cohort of sarcoma patients before and after radiotherapy confirmed our findings and, in addition showed that irradiation resulted in higher infiltration by lymphocytes. Other forms of stress did not have an impact on the expression of CT-antigens or MHC-I. Conclusions Our findings suggest that γ-radiation promotes the immunological recognition of the tumor. We therefore propose that combining radiotherapy with treatments that support tumor specific immunity may result in increased therapeutic efficacy.

Fasting protects liver from ischemic injury through Sirt1-mediated downregulation of circulating HMGB1 in mice

M ajor liver resections and partial orthotopic liver transplantation (OLT) have become established procedures in liver surgery; for many patients, these techniques offer the only curative option. Yet, many patients develop postoperative complications because the remnant livers or grafts are too small or of poor quality to sustain sufficient organ function. This somewhat new and poorly defined phenomenon has been termed ‘‘small-for-size syndrome’’ (SFSS) to describe this scenario. The concept is, in fact, not a new one, because as early as the 1970s, Thomas E. Starzl described the complicated postoperative course of a young woman subjected to an almost 90% hepatectomy and who was subsequently characterized by prolonged hyperbilirubinemia, encephalopathy, and coagulopathy. In an unconventional way for a review, we will start with three case reports to illustrate the scope and clinical relevance of SFSS after liver surgery and transplantation. Case 1: A 47-year-old healthy man, whose wife was listed for OLT due to a symptomatic nonresectable hemangioendothelioma of the liver, offered to be considered for living donor liver transplantation (LDLT). Following the standard work-up for this procedure, he underwent a right hemi-hepatectomy including the middle hepatic vein to serve as allograft for his wife. The remnant left hemi-liver was estimated by computed tomographic (CT) volumetry to weigh 450 g, i.e., around 32% of the whole liver. The ratio of the remnant liver weight to body weight (RLBW) was 0.65%. The donor had a difficult postoperative course developing mild encephalopathy and hyperbilirubinemia lasting 20 days peaking at 178 lmol/L (10.4 mg/ dL) by day five, and severe coagulopathy (prothrombin time <30%) that normalized by day 7. The donor eventually recovered fully, and was discharged in good general condition 22 days after surgery. Case 2: A 42-year-old male was listed for OLT because of Child B cirrhosis (Model for End-Stage Liver Disease [MELD] score: 21) and a small (3 cm) hepatocellular carcinoma (HCC) related to hepatitis B virus infection. He received the right hemi-liver containing the middle hepatic vein from his wife (graft weighing 620 g), who had an uneventful postoperative course. The ratio of graft size in grams to her husband’s body weight (80 kg) (graft-to-recipient weight ratio [GRWR]) was 0.7%. The postoperative period was complicated by encephalopathy, hyperbilirubinemia (up to 262 lmol/L, 15.3 mg/dL) for 2 weeks, and prolonged coagulopathy with a factor V level below 20% at day 4. As a result of the delayed graft function, the patient required intensive care unit treatment for 1 week before the liver graft function improved. He was able to be discharged in good general condition on postoperative day 21. Case 3: A 58-year-old male presented with multiple colorectal liver metastases in the right hemi-liver as well as in segment II, III, and 10 months after resection of the primary rectal tumor followed by 5 cycles of chemotherapy containing Folfox and Avastin. A Abbreviations: CALI, chemotherapy-associated liver injury; CT, computed tomography; DOI, 2,5-dimethoxy-4-iodoamphetamine; EHPBA, European Hepato-Pancreatico-Biliary Association; GRWR, graft-to-recipient weight ratio; HCC, hepatocellular carcinoma; IHPBA, International Hepato-PancreaticoBiliary Association; IL-6, interleukin-6; LDLT, living donor liver transplantation; MELD, Model for End-Stage Liver Disease; OLT, orthotopic liver transplantation; PTX, pentoxifylline; RLBW, remnant liver to body weight; SFSS, small-for-size syndrome; TNF, tumor necrosis factor. From the Swiss Hepato-Pancreatico-Biliary and Transplantation Center, Department of Surgery, University of Zurich, Zurich, Switzerland Funded in part by Grants from the Swiss National Foundation to P.A.C. (SNF 3200B0-109906), Krebsliga Zurich, Switzerland and Sassella Stiftung Zurich, Switzerland, also to P.A.C. Presented as a Thomas E. Starzl Transplant Surgery State-of-the-Art Lecture at the 60th Annual Meeting of the American Association for the Study of Liver Diseases; October 30-November 3, 2009; Boston, MA. This article is dedicated to Thomas E. Starzl for his lifelong contribution to liver surgery and transplantation. Address reprint requests to: Pierre-Alain Clavien, M.D., Ph.D., Department of Surgery, University Hospital of Zurich, Raemistrasse 100, 8091 Zurich, Switzerland. E-mail: clavien@access.uzh.ch; fax: þ41 44 255 44 49. CopyrightVC 2010 by the American Association for the Study of Liver Diseases. Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hep.23713 Potential conflict of interest: Nothing to report.

Serotonin protects mouse liver from cholestatic injury by decreasing bile salt pool after bile duct ligation

BACKGROUND & AIMS Extended liver resection leads to hepatic failure because of a small remnant liver volume. Excessive parenchymal damage has been proposed as the principal cause of this failure, but little is known about the contribution of a primary deficiency in liver regeneration. We developed a mouse model to assess the regenerative capacity of a critically small liver remnant. METHODS Extended (86%) hepatectomy (eHx) was modified to minimize collateral damage; effects were compared with those of standard (68%) partial hepatectomy (pHx) in mice. Markers of liver integrity and survival were evaluated after resection. Liver regeneration was assessed by weight gain, proliferative activity (analyses of Ki67, proliferating cell nuclear antigen, phosphorylated histone 3, mitosis, and ploidy), and regeneration-associated molecules. Knockout mice were used to study the role of p21. RESULTS Compared with pHx, survival of mice was reduced after eHx, and associated with cholestasis and impaired liver function. However, no significant differences in hepatocyte death, sinusoidal injury, oxidative stress, or energy depletion were observed between mice after eHx or pHx. No defect in the initiation of hepatocyte proliferation was apparent. However, restoration of liver mass was delayed after eHx and associated with inadequate induction of Foxm1b and a p21-dependent delay in cell-cycle progression. In p21(-/-) mice, the cell cycle was restored, the gain in liver weight was accelerated, and survival improved after eHx. CONCLUSIONS Significant parenchymal injury is not required for liver failure to develop after extended hepatectomy. Rather, liver dysfunction after eHx results from a transient, p21-dependent block before hepatocyte division. Therefore, a deficiency in cell-cycle progression causes liver failure after extended hepatectomy and can be overcome by inhibition of p21.

Systematic review of pressurized intraperitoneal aerosol chemotherapy for the treatment of advanced peritoneal carcinomatosis

BACKGROUND & AIMS Fasting and calorie restriction are associated with a prolonged life span and an increased resistance to stress. The protective effects of fasting have been exploited for the mitigation of ischemic organ injury, yet the underlying mechanisms remain incompletely understood. Here, we investigated whether fasting protects liver against ischemia reperfusion (IR) through energy-preserving or anti-inflammatory mechanisms. METHODS Fasted C57BL6 mice were subjected to partial hepatic IR. Injury was assessed by liver enzymes and histology. Raw264-7 macrophage-like cells were investigated in vitro. Sirt1 and HMGB1 were inhibited using Ex527 and neutralizing antibodies, respectively. RESULTS Fasting for one, but not two or three days, protected from hepatic IR injury. None of the investigated energy parameters correlated with the protective effects. Instead, inflammatory responses were dampened in one-day-fasted mice and in starved macrophages. Fasting alone led to a reduction in circulating HMGB1 associated with cytoplasmic HMGB1 translocation, aggregate formation, and autophagy. Inhibition of autophagy re-elevated circulating HMGB1 and abolished protection in fasted mice, as did supplementation with HMGB1. In vitro, Sirt1 inhibition prevented HMGB1 translocation, leading to elevated HMGB1 in the supernatant. In vivo, Sirt1 inhibition abrogated the fasting-induced protection, but had no effect in the presence of neutralizing HMGB1 antibody. CONCLUSIONS Fasting for one day protects from hepatic IR injury via Sirt1-dependent downregulation of circulating HMGB1. The reduction in serum HMGB1 appears to be mediated by its engagement in the autophagic response. These findings integrate Sirt1, HMGB1, and autophagy into a common framework that underlies the anti-inflammatory properties of short-term fasting.

Clamping techniques and protecting strategies in liver surgery.

Obstructive cholestasis induces liver injury, postoperative complications, and mortality after surgery. Adaptive control of cholestasis, including bile salt homeostasis, is necessary for recovery and survival. Peripheral serotonin is a cytoprotective neurotransmitter also associated with liver regeneration. The effect of serotonin on cholestatic liver injury is not known. Therefore, we tested whether serotonin affects the severity of cholestatic liver injury. We induced cholestasis by ligation of the bile duct (BDL) in either wild‐type (WT) mice or mice lacking peripheral serotonin (Tph1−/− and immune thrombocytopenic [ITP] mice). Liver injury was assessed by the levels of plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT) and tissue necrosis. Bile salt–regulating genes were measured by quantitative polymerase chain reaction and confirmed by western blotting and immunohistochemistry. Tph1−/− mice displayed higher levels of plasma AST, ALT, bile salts, and hepatic necrosis after 3 days of BDL than WT mice. Likewise, liver injury was disproportional in ITP mice. Moreover, severe cholestatic complications and mortality after prolonged BDL were increased in Tph1−/− mice. Despite the elevation in toxic bile salts, expression of genes involved in bile salt homeostasis and detoxification were not affected in Tph1−/− livers. In contrast, the bile salt reabsorption transporters Ostα and Ostβ were up‐regulated in the kidneys of Tph1−/− mice, along with a decrease in urinary bile salt excretion. Serotonin reloading of Tph1−/− mice reversed this phenotype, resulting in a reduction of circulating bile salts and liver injury. Conclusion: We propose a physiological function of serotonin is to ameliorate liver injury and stabilize the bile salt pool through adaptation of renal transporters in cholestasis. (HEPATOLOGY 2012;56:209–218)