Szabolcs Tóth

Biological and clinical significance of the JAK-STAT pathway; lessons from knockout mice.

Abstract. Originally described as the signal-transducing pathway of interferons, the JAK-STAT pathway soon turned out to participate in the signalling of numerous other immune and even non-immune mediators. Several murine knockout models have been described that underline the biological significance of this signalling system. Some human diseases (mainly neoplastic) are also known where malfunctioning of the JAK-STAT pathway is considered to participate in the pathogenesis. In this brief review article we will try to make a synopsis of its biological and clinical significance.

The Significance of the Circumaortic Left Renal Vein and Other Venous Variations in Laparoscopic Living Donor Nephrectomies

Among the several vascular variation those concerning the venous system of the kidneys show the most significant variability. They often play an important role when it comes to choosing the kidney to be removed for transplantation. Based on our prior studies, we have surveyed these variations. When performing a laparoscopic living donor nephrectomy owing to the limited field of vision and the restricted possibilities for preparation, preoperative radiologic planning is of utmost importance. We evaluated 55 donors who underwent laparoscopic nephrectomies using the 16-section multidetector-row computed tomography angiography. Among the donors who underwent surgeries we observed circumaortic veins (CAV) in three cases, retroaortic veins in 6 cases, multiple renal veins in 10 cases, and a lumbar vein draining into the left renal vein (RV) in 30 cases. In the 2 cases wherein CAVs were discovered, the team decided to use the other kidney. In 1 case, due to a short right RV, we chose the left kidney. The complex development of the CAV that is sometimes difficult to reconstruct in 3D poses a challenge for both the radiologist and the surgeon.

Biliary complications following orthotopic liver transplantation. The Hungarian experience

INTRODUCTION The authors summarize the characteristics of biliary complications following liver transplantation in the Hungarian liver transplant program. Aims were to analyze the frequency and the types of biliary complications as well as their effect on the patient and graft survival. The authors observed the known risk factors in the Hungarian practice, and they also try to find unknown risk factors for biliary complications. They review the therapy of biliary complications. METHOD In the retrospective study, patients were divided into two groups, with and without biliary complication after liver transplantation. These two groups were compared with many factors, and with the survivals. The biliary complication group was divided into two parts: those who had an early and those with a late biliary complication. These two new groups were also compared with the controls. The results are summarized in tables and statistical figures. Categorical variables are evaluated by chi 2 -test, continuous ones are with Levine Test (for homogenicity of means), Student T test and Mann-Whitney U-test. Cumulative survivals are computed with Kaplan-Meier log rank analysis. RESULTS Biliary complication appeared in 25% of the patients. The most frequent complications were stenosis (18%), biliary leakage (9%), biliary necrosis (6%), and ischaemic type of biliary lesions (3%). The 5-year survival is worse when biliary complications were diagnosed (55%) than without such a complication (66%). In the biliary complication group the retransplantation rate was higher (15%). The most frequent treatments were interventional radiologic methods (69%), surgical methods (17%), and the ERCP. CONCLUSIONS The rate of biliary complications met the international reviews. Risk factors for biliary complications were cholangitis, hepatic artery thrombosis and stenosis, high rate of intraoperative blood transfusions, and acute rejection. Biliary complications frequently associated with the initial poor function of the transplanted graft. Early biliary complications have a negative impact on patient survival, while late complications influence a decreased quality of life. Biliary complications were treated mostly by interventional radiologic procedures.

Surgical aspects of pediatric liver transplantation. Living donor liver transplant program in Hungary

Because of the long waiting time for pediatric liver transplantation, new techniques of liver transplantation were invented. Split and living-donor related liver transplantation are common today and the Kaplan-Meier (3 years) overall survival is over 80%. By splitting the liver, two recipients can be transplanted. In general, the left lobe is used for the pediatric, the right lobe for the adult recipient. There are a lot of combinations depending on the donor and recipient weight. The accepted liver volume is approx. 1% of the recipient body weight. The results of the Hungarian pediatric program improve, 27 transplantations were done using 14 partial liver grafts and living donor program was started. Using strict protocols and improving surgical skills, the overall pediatric survival was over 80% in the last 5 years.

Volumetric Hemodynamic Changes and Postoperative Complications in Hypothermic Liver Transplanted Patients

INTRODUCTION Hepatic diseases decrease the livers involvement in thermoregulation. Removal of the liver during transplantation increases the incidence of hypothermia during the surgery. The aims of the present study were to analyze the hemodynamic changes among hypothermic liver transplantations and to determine its relationship to postoperative complications. METHODS Conventional and volumetric hemodynamic monitoring and intramucosal pH measurements were performed during 54 liver transplantations. According to the core temperature until graft reperfusion, patients were classified into group A, hypothermic patients (temperature < 35 °C; n=25) versus group B, normothermic patients (temperature > 36 °C; n=29). We examined the relationships between central venous pressure (CVP), intrathoracic blood volume index, cardiac index (CI), and oxygen delivery index, oxygen consumption index, as well as the fluctuation of the mean arterial pressure (MAP) and gastric intramucosal pH and activated clotting time. We recorded prolonged ventilation time, vasopressor and hemodialysis requirements, occurrence of infections, and intensive care days. RESULTS There were no significant differences in the MELD scores. More Child-Pugh class C patients (P<.01) showed significantly higher APACHE II scores (P<.02) among group A. During hepatectomy and at the same intrathoracic blood volumes, the hypothermic group showed significantly higher CVP levels (P<.02). During the anhepatic and postreperfusion phases, the decreased CI levels (P<.05) were associated with increased MAP values (P<.05). Without differences in oxygen delivery, the oxygen consumption was lower in group A (P<.05). The intramucosal pH levels were the same in the both groups during the whole examination period. More instances of infection, intensive care, and hemodialysis treatment days, were observed as well as significantly longer vasopressor requirements and coagulopathy among the hypothermic group (P<.007).

Elevated CREB activity in embryonic fibroblasts of gene-targeted histamine deficient mice

Abstract.Objectives:Histamine is a known inducer of cAMP-responsive element binding protein (CREB), which plays a key role in initiation of adipogenesis. Our present goal was to study how histamine deficiency impacts CREB signalling and adipogenesis.Methods:We used a histidine-decarboxylase gene-targeted (HDC KO) mice model lacking endogenous histamine. We measured CREB activity and expression by EMSA, Western blot and real-time RT-PCR, as well as cAMP levels by ELISA in primary embryonic fibroblasts derived from WT and HDC KO mice. The ability of these cells to form adipocytes was also tested in preliminary experiments.Results:We found that in the absence of the histamine, cells show higher constitutive CREB activity and greatly increased intracellular cAMP levels, as well as that in contrast to WT cells, HDC KO fibroblasts are more prone to differentiate into adipocytes.Conclusion:These data suggest a newly recognised inhibitory role for histamine in CREB activity and draws attention to the potential role of histamine in adipocyte differentiation.

MARS therapy, the bridging to liver retransplantation — Three cases from the Hungarian liver transplant program

Besides orthotopic liver transplantation (OLT) there is no long-term and effective replacement therapy for severe liver failure. Artificial extracorporeal liver supply devices are able to reduce blood toxin levels, but do not replace any synthetic function of the liver. Molecular adsorbent recirculating system (MARS) is one of the methods that can be used to treat fulminant acute liver failure (ALF) or acute on chronic liver failure (AoCLF). The primary non-function (PNF) of the newly transplanted liver manifests in the clinical settings exactly like acute liver failure. MARS treatment can reduce the severity of complications by eliminating blood toxins, so that it can help hepatic encephalopathy (HE), hepatorenal syndrome (HRS), and the high rate mortality of cerebral herniation. This might serve as a bridging therapy before orthotopic liver retransplantation (reOLT). Three patients after a first liver transplantation became candidate for urgent MARS treatment as a bridging solution prior to reOLT in our center. Authors report these three cases, fo-cusing on indications, MARS sessions, clinical courses, and final outcomes.

Evaluation of liver function before living donor liver transplantation and liver resection

UNLABELLED Liver resection is the curative therapeutic option for hepatocellular carcinoma, biliary tumors, metastases of colorectal and other extrahepatic tumors, living donor liver transplantation and other benign liver diseases. AIM OF STUDY To summarize the evaluation methods of liver function before living donor liver transplantation and liver resection. METHOD We summarize the literature about the evaluation of liver function. RESULTS Perioperative mortality is determined mostly by the extent of preoperative evaluation focused on the liver. After resection the remnant liver parenchyma must cope with the challenge caused by increased metabolism, portal overflow, decreased vascular bed and biliary tract and oxidative stress following the operation. If the remnant liver is unable to grow up to this challenge, acute liver failure occurs. This maintains the necessity of determining the hepatic functional reserve and the hepatic remnant volume. Child-Pugh classification is widely spread to predict outcome. Dynamic functional tests such as indocyanine green retention test, galactosyl human serum albumin scintigraphy and aminopyrine breath tests can be used to evaluate hepatic reserve. To determine remnant liver volume modern imaging processes such as CT volumetry and hepatobiliary scintigraphy are available. CONCLUSION After the detailed evaluation resection can be limited to an extent which is oncologically radical enough (1% remnant liver tissue/kg) and spares parenchyma which can ensure survival yet. With careful preoperative examination mortality can be reduced even to reach zero.

Percutaneous transhepatic metallic stent placement for the treatment of post-transplantation portal vein stenosis

UNLABELLED Liver transplantation is a routinely used therapeutic choice in the treatment of end stage liver disease. Portal vein stenosis is a rare vascular complication after liver transplantation. We report the interventional radiological management of three cases of portal vein stenosis. AIM The surgical management of portal vein stenosis can be hazardous for the patient and the transplanted liver in the early post-transplantation period. In general, interventional radiological methods are tolerable for patients and can be safely performed with high success rate. The aim of this report is to analyze the feasibility, the risks and the efficacy of the percutaneous transhepatic self expanding metallic stent placement into the portal vein. METHOD Three of the 396 liver transplantations cases in Budapest developed significant portal vein stenosis. In these cases, ultrasound guided percutaneous transhepatic portal vein puncture with fine needle was performed. The tract was dilated with a coaxial dilator set, and an adequately sized sheath introducer was inserted into the liver parenchyma. Two nitinol and one stainless steel self expanding metallic stent were implanted at the stenotic portal vein anastomoses. The tract was embolized with gelfoam particles (1 case), or coils (1 case). In the third patient no tract embolization was performed. RESULT All treatments were technically successful, without minor or major complications. In two cases the amount of free abdominal fluid decreased significantly, and in the third case the esophageal varicosity regressed. The morphological success was documented with ultrasound and computed tomography examination. Two patients are alive and well after 10 and 39 months of follow up, while the third patient died after one month in multi organ failure. CONCLUSION Percutaneous transhepatic metallic stent placement for the treatment of post-transplantation portal vein stenosis is a safe and effective method.

Percutan transhepaticus fémstent behelyezésével kezelt májkapuvéna-szu″kületek májátü ltetés után

UNLABELLED Liver transplantation is a routinely used therapeutic choice in the treatment of end stage liver disease. Portal vein stenosis is a rare vascular complication after liver transplantation. We report the interventional radiological management of three cases of portal vein stenosis. AIM The surgical management of portal vein stenosis can be hazardous for the patient and the transplanted liver in the early post-transplantation period. In general, interventional radiological methods are tolerable for patients and can be safely performed with high success rate. The aim of this report is to analyze the feasibility, the risks and the efficacy of the percutaneous transhepatic self expanding metallic stent placement into the portal vein. METHOD Three of the 396 liver transplantations cases in Budapest developed significant portal vein stenosis. In these cases, ultrasound guided percutaneous transhepatic portal vein puncture with fine needle was performed. The tract was dilated with a coaxial dilator set, and an adequately sized sheath introducer was inserted into the liver parenchyma. Two nitinol and one stainless steel self expanding metallic stent were implanted at the stenotic portal vein anastomoses. The tract was embolized with gelfoam particles (1 case), or coils (1 case). In the third patient no tract embolization was performed. RESULT All treatments were technically successful, without minor or major complications. In two cases the amount of free abdominal fluid decreased significantly, and in the third case the esophageal varicosity regressed. The morphological success was documented with ultrasound and computed tomography examination. Two patients are alive and well after 10 and 39 months of follow up, while the third patient died after one month in multi organ failure. CONCLUSION Percutaneous transhepatic metallic stent placement for the treatment of post-transplantation portal vein stenosis is a safe and effective method.