Current Concepts in Curative Surgery for Cystic Echinococcosis of Liver

Cystic echinococcosis (CE) may cause unspecific symptoms like abdominal discomfort in the right upper quadrant of the abdomen due to capsule tension pain of the liver related to an increased expansion of the cyst. Further, a growing cyst may put pressure on intrahepatic bile ducts or can get direct access to the biliary system with complications like obstruction, cholangitis and fistulas. Large or rapid growing cysts may cause compression of blood vessels with thrombosis or Budd-Chiari syndrome. However, the vast majority of patients with CE of the liver is asymptomatic. CE of the liver can be cured surgically in many cases. In the past, cystectomy with resection of the pericyst components was performed as a standard. The today’s parenchymal sparing state-of-the-art surgery is endocystectomy combined with partial cystectomy. This procedure includes (i) evacuation of paracyte-derived cyst content, (ii) sterilization of the cyst wall (host) and (iii) deroofing of the cyst (partial cystectomy). Here the advantages, risks and outcomes of the surgical approaches are discussed, and the need for an interdisciplinary treatment of these patients is outlined

Evaluating the efficacy, safety and evolution of renal function with early initiation of everolimus-facilitated tacrolimus reduction in de novo liver transplant recipients: Study protocol for a randomized controlled trial

Background: Introduction of calcineurin inhibitors had led to improved survival rates in liver transplant recipients. However, long-term use of calcineurin inhibitors is associated with a higher risk of chronic renal failure, neurotoxicity, de novo malignancies, recurrence of hepatitis C viral (HCV) infection and hepatocellular carcinoma. Several studies have shown that everolimus has the potential to provide protection against viral replication, malignancy, and progression of fibrosis, as well as preventing nephrotoxicity by facilitating calcineurin inhibitor reduction without compromising efficacy. The Hephaistos study evaluates the beneficial effects of early initiation of everolimus in de novo liver transplant recipients. Methods/Design: Hephaistos is an ongoing 12-month, multi-center, open-label, controlled study aiming to enroll 330 de novo liver transplant recipients from 15 centers across Germany. Patients are randomized in a 1:1 ratio (7–21 days post-transplantation) to receive everolimus (trough levels 3–8 ng/mL) with reduced tacrolimus (trough levels <5 ng/mL), or standard tacrolimus (trough levels 6–10 ng/mL) after entering a run-in period (3–5 days post-transplantation). In the run-in period, patients are treated with induction therapy, mycophenolate mofetil, tacrolimus, and corticosteroids according to local practice. Randomization is stratified by HCV status and model of end-stage liver disease scores at transplantation. The primary objective of the study is to exhibit superior renal function (estimated glomerular filtration rate assessed by the Modification of Diet in Renal Disease (MDRD)-4 formula) with everolimus plus reduced tacrolimus compared to standard tacrolimus at Month 12. Other objectives are: to assess the incidence of treated biopsy-proven acute rejection, graft loss, or death; the incidences of components of the composite efficacy endpoint; renal function via estimated glomerular filtration rate using various formulae (MDRD-4, Nankivell, Cockcroft-Gault, chronic kidney disease epidemiology collaboration and Hoek formulae); the incidence of proteinuria; the incidence of adverse events and serious adverse events; the incidence and severity of cytomegalovirus and HCV infections and HCV-related fibrosis. Discussion: This study aims to demonstrate superior renal function, comparable efficacy, and safety in de novo liver transplant recipients receiving everolimus with reduced tacrolimus compared with standard tacrolimus. This study also evaluates the antiviral benefit by early initiation of everolimus. Trial registration: NCT0155121

Outcomes and risk factors for cancer patients undergoing endoscopic intervention of malignant biliary obstruction

Background: Malignant bile duct obstruction is a common problem among cancer patients with hepatic or lymphatic metastases. Endoscopic retrograde cholangiography (ERC) with the placement of a stent is the method of choice to improve biliary flow. Only little data exist concerning the outcome of patients with malignant biliary obstruction in relationship to microbial isolates from bile. Methods: Bile samples were taken during the ERC procedure in tumor patients with biliary obstruction. Clinical data including laboratory values, tumor-specific treatment and outcome data were prospectively collected. Results: 206 ERC interventions in 163 patients were recorded. In 43 % of the patients, systemic treatment was (re-) initiated after successful biliary drainage. A variety of bacteria and fungi was detected in the bile samples. One-year survival was significantly worse in patients from whom multiresistant pathogens were isolated than in patients, in whom other species were detected. Increased levels of inflammatory markers were associated with a poor one-year survival. The negative impact of these two factors was confirmed in multivariate analysis. In patients with pancreatic cancer, univariate analysis showed a negative impact on one-year survival in case of detection of Candida species in the bile. Multivariate analysis confirmed the negative prognostic impact of Candida in the bile in pancreatic cancer patients. Conclusion: Outcome in tumor patients with malignant bile obstruction is associated with the type of microbial biliary colonization. The proof of multiresistant pathogens or Candida, as well as the level of inflammation markers, have an impact on the prognosis of the underlying tumor disease

Ischemia/Reperfusion Injury in Liver Surgery and Transplantation: Pathophysiology

Liver ischemia/reperfusion (IR) injury is caused by a heavily toothed network of interactions of cells of the immune system, cytokine production, and reduced microcirculatory blood flow in the liver. These complex networks are further elaborated by multiple intracellular pathways activated by cytokines, chemokines, and danger-associated molecular patterns. Furthermore, intracellular ionic disturbances and especially mitochondrial disorders play an important role leading to apoptosis and necrosis of hepatocytes in IR injury. Overall, enhanced production of reactive oxygen species, found very early in IR injury, plays an important role in liver tissue damage at several points within these complex networks. Many contributors to IR injury are only incompletely understood so far. This paper tempts to give an overview of the different mechanisms involved in the formation of IR injury. Only by further elucidation of these complex mechanisms IR injury can be understood and possible therapeutic strategies can be improved or be developed

PROUD: Effects of preoperative long-term immunonutrition in patients listed for liver transplantation

<p>Abstract</p> <p>Background</p> <p>Patients with end stage liver disease are characteristically malnourished which is associated with poor outcome. Formulas enriched with arginine, ω-3 fatty acids, and nucleotides, "immunonutrients", potentially improve their nutritional status. This study is designed to evaluate the clinical outcome of long-term "immunonutrition" of patients with end-stage liver disease while on the waiting list for liver transplantation.</p> <p>Methods/design</p> <p>A randomized controlled double blind multi-center clinical trial with two parallel groups comprising a total of 142 newly registered patients for primary liver transplantation has been designed to assess the safety and efficacy of the long-term administration of ORAL IMPACT^®, an "immunonutrient" formula, while waiting for a graft. Patients will be enrolled the day of registration on the waiting list for liver transplantation. Study ends on the day of transplantation. Primary endpoints include improved patients' nutritional and physiological status, as measured by mid-arm muscle area, triceps skin fold thickness, grip strength, and fatigue score, as well as patients' health related quality of life. Furthermore, patients will be followed for 12 postoperative weeks to evaluate anabolic recovery after transplantation as shown by reduced post-transplant mechanical ventilation, hospital stay, wound healing, infectious morbidities (pneumonia, intraabdominal abscess, sepsis, line sepsis, wound infection, and urinary tract infection), acute and chronic rejection, and mortality.</p> <p>Discussion</p> <p>Formulas enriched with arginine, ω-3 fatty acids, and nucleotides have been proven to be beneficial in reducing postoperative infectious complications and length of hospital stay among the patients undergoing elective gastrointestinal surgery. Possible mechanisms include downregulation of the inflammatory responses to surgery and immune modulation rather than a sole nutritional effect.</p> <p>Trial registration</p> <p>ClinicalTrials.gov NCT00495859</p

HEGPOL: Randomized, placebo controlled, multicenter, double-blind clinical trial to investigate hepatoprotective effects of glycine in the postoperative phase of liver transplantation [ISRCTN69350312]

BACKGROUND: Kupffer cell-dependent ischemia / reperfusion (I/R) injury after liver transplantation is still of high clinical relevance, as it is strongly associated with primary dysfunction and primary nonfunction of the graft. Glycine, a non-toxic, non-essential amino acid has been conclusively shown in various experiments to prevent both activation of Kupffer cells and reperfusion injury. Based on both experimental and preliminary clinical data this study protocol was designed to further evaluate the early effect of glycine after liver transplantation. METHODS / DESIGN: A prospective double-blinded randomized placebo-controlled multicenter study with two parallel groups in a total of 130 liver transplant recipients was designed to assess the effect of multiple intravenous doses of glycine after transplantation. Primary endpoints in hierarchical order are: peak levels of both aspartat-amino-transaminase (AST) and alanine-amino-transaminase (ALT) as surrogates for the progression of liver related injury, as well as both graft and patient survival up to 2 years after transplantation. Furthermore, the effect of glycine on cyclosporine A-induced nephrotoxicity is evaluated. DISCUSSION: The ongoing clinical trial represents an advanced element of the research chain, along which a scientific hypothesis has to go by, in order to reach the highest level of evidence; a randomized, prospective, controlled double-blinded clinical trial. If the data of this ongoing research project confirm prior findings, glycine would improve the general outcome after liver transplantation

Portal vein embolization using a Histoacryl/Lipiodol mixture before right liver resection

Purpose: The purpose of this retrospective study was to evaluate the efficacy and safety of percutaneous transhepatic portal vein embolization (PVE) of the right liver lobe using Histoacryl/Lipiodol mixture to induce contralateral liver hypertrophy before right-sided (or extended right-sided) hepatectomy in patients with primarily unresectable liver tumors. Methods: Twenty-one patients (9 females and 12 males) underwent PVE due to an insufficient future liver remnant; 17 showed liver metastases and 4 suffered from biliary cancer. Imaging was performed prior to and 4 weeks after PVE. Surgery was scheduled for 1 week after a CT or MRI control. The primary study end point was technical success, defined as complete angiographical occlusion of the portal vein. The secondary study end point was evaluation of liver hypertrophy by CT and MRI volumetry and transfer to operability. Results: In all the patients, PVE could be performed with a with a Histoacryl/Lipiodol mixture (n = 20) or a Histoacryl/ Lipiodol mixture with microcoils (n = 1). No procedure-related complications occurred. The volume of the left liver lobe increased significantly (p < 0.0001) by 28% from a mean of 549 ml to 709 ml. Eighteen of twenty-one patients (85.7%) could be transferred to surgery, and the intended resection could be performed as planned in 13/18 (72.3%) patients. Conclusion: Preoperative right-sided PVE using a Histoacryl/Lipiodol mixture is a safe technique and achieves a sufficient hypertrophy of the future liver remnant in the left liver lobe

Protocol TOP-Study (tacrolimus organ perfusion): a prospective randomized multicenter trial to reduce ischemia reperfusion injury in transplantation of marginal liver grafts with an "ex vivo" tacrolimus perfusion

Background: Critical organ shortage results in the utilization of extended donor criteria (EDC) liver grafts. These marginal liver grafts are prone to increased ischemia reperfusion injury (IRI) which may contribute to deteriorated graft function and survival. Experimental data have shown that the calcineurin inhibitor tacrolimus exerts protective effects on hepatic IRI when applied intravenously or directly as a hepatic rinse. Therefore, the aim of the present study is to examine the effects of an ex vivo tacrolimus perfusion on IRI in transplantation of EDC liver grafts. Methods/Design: The TOP-Study (tacrolimus organ perfusion) is a randomized multicenter trial comparing the ex vivo tacrolimus perfusion of marginal liver grafts with placebo. We hypothesize that a tacrolimus rinse reduces IRI, potentially improving organ survival following transplantation of EDC livers. The study includes livers with two or more EDC, according to Eurotransplant International Foundation’s definition of EDC livers. Prior to implantation, livers randomized to the treatment group are rinsed with tacrolimus at a concentration of 20 ng/ml in 1000 ml Custodiol solution and in the placebo group with Custodiol alone. The primary endpoint is the maximum serum alanine transamninase (ALT) level within the first 48 hours after surgery; however, the study design also includes a 1-year observation period following transplantation. The TOP-Study is an investigator-initiated trial sponsored by the University of Munich Hospital. Seven other German transplant centers are participating (Berlin, Frankfurt, Heidelberg, Mainz, Münster, Regensburg, Tübingen) and aim to include a total of 86 patients. Discussion: Tacrolimus organ perfusion represents a promising strategy to reduce hepatic IRI following the transplantation of marginal liver grafts. This treatment may help to improve the function of EDC grafts and therefore safely expand the donor pool in light of critical organ shortage. Trial register: EudraCT number: 2010-021333-31, ClinicalTrials.gov identifier: NCT0156409

Involvement of the epidermal growth factor receptor in the modulation of multidrug resistance in human hepatocellular carcinoma cells in vitro

<p>Abstract</p> <p>Background</p> <p>Hepatocellular carcinoma (HCC) is a molecular complex tumor with high intrinsic drug resistance. Recent evidence suggests an involvement of the tyrosine kinase pathway in the regulation of ATP-binding cassette protein (ABC-transport protein) mediated multidrug resistance in cancer cells. The aim of this study was to examine whether EGFR inhibition sensitizes HCCs to chemotherapy and to elucidate its mechanism.</p> <p>Results</p> <p>Chemotherapeutic treatment induces multidrug resistance and significantly increases ABC-transport protein expression and function in a time- and dose-dependent manner in HCC cells. Furthermore, cytostatic treatment increases the mRNA expression of tyrosine kinases and induces the phosphorylation of ERK. EGF activation of the tyrosine kinase pathway up-regulated the ABC-transport protein mRNA expression and enhanced the survival of resistant HCC cells. Consistent with these effects, inhibition of the EGFR using siRNA decreased the ABC-transport protein mRNA expression and inhibited the proliferation of resistant cells. Additional treatment with Gefitinib, a clinically approved EGFR inhibitor, caused a dose-dependent reversal of resistance to conventional chemotherapy.</p> <p>Conclusion</p> <p>The present study demonstrates that the multidrug resistance of HCC is modulated through the EGF-activated tyrosine kinase cascade. Consequentially, the restoration of chemosensitivity by EGFR inhibition may lead towards new tailored therapies in patients with highly resistant tumors.</p

همانژیواندوتلیومای اپیتلیویید کبدی بدخیم اولیه، یک مرور جامع از متون تحقیقی با تأکید بر درمان جراحی

زمینه و هدف: همانژیواندوتلیـومای اپیتلیویید کبدی (HEH) بدخیم، یک تومـور عروقی بدخیـم نادر با علت ناشناخته و سیر طبیعی متغیر است. نویسندگان این مقاله، مـرور جامعی از متـون تحقیقی در مـورد HEH را با تمـرکز بر پیامدهای بالینی پس از راهبـردهای درمانی متفاوت، ارائه می‌دهند. مواد و روش‌ها: در این مـرور، تمامی مجمـوعه‌های منتشر شده در مورد بیماران مبتلا به HEH (تعداد 434 بیمـار) از نخستین توصیف این بیمـاران در سال 1984 تا مقالة حاضر مـورد تحلیل قـرار گرفت. پارامتـرهای مرور شده شامل: داده‌های جمعیت ـ شناختی، تظاهـرات بالینی، روش‌های درمانی و پیامـدهای بالینی بود. یافته‌ها: میانگین سنی بیماران مبتلا به HEH، 7/41 سال و نسبت مرد به زن، 2 به 3 بود. شایعترین تظاهـرات بالینی: درد ربع فـوقانی راست شکم، هپاتومگالی و کاهش وزن بود. اغلـب بیماران با تومور چند کانونی که هر دو لـوب را درگیـر کرده، مـراجعه کردند. شایعترین مناطق درگیری خارج کبدی در زمان تشخیص: ریه، صفاق، گـره‌های لنفـاوی و استخوان بود. شایعتـرین تدابیـر درمانی: پیـوند کبد (LTx)‌ (8/44% از بیمـاران)، پیگیـری بدون درمان (8/24% از بیماران)، شیمی درمانی یا پرتو درمانی (21% از بیماران)، و رزکسیـون کبد (LRx) (4/9% از بیمـاران) بود. میـزان بقـای یک و پنـج سالة پس از LTx به ترتیب 96% و 5/54%، پس از عـدم درمان به ترتیب 3/39% و 5/4% پس از شیمـی درمانی یا پرتودرمانی به ترتیب 3/73% و 30% و پس از LRx به ترتیب 100% و 75% بود. نتیجه‌گیـری: LRx درمان انتخـابی برای بیمـاران مبتلا به HEH قابل رزکسیـون است، با این وجـود، به دلیل چند مـرکزی بودن HEH کبـدی، LTx به عنوان درمـان انتخـابی پیشنهـاد شده است. علاوه بر این، LTx گزینة قابل قبـولی برای بیمارانی است که HEH با تظاهـرات خارج کبدی دارند. شاید بتوان بیماران کاملاً گزینش شده را تحت LTx از اهـداء کنندة زنده (با حفـظ منبع اهـداء) قـرار داد. نقش درمان‌های کمکی مختلف برای بیمارن مبتلا به HEH همچنان نامعلـوم است