[Correction of cronic liver failure by transplantation of liver cells suspension and cell-engineering designs (experimental investigation)].

On an experimental model of chronic fibrotic liver damage (male rats Wistar (n-60), damage of CCl4, the duration of the experiment 90 days) it was studied the effectiveness of cell therapy for the correction of chronic liver failure. These rats were divided into 3 experimental groups: in the Ist-group (control, n=10) isotonic saline (650 mkl.) was injected; in the IInd-group (n=20) suspension of liver cells was applicated in a dose 8 - l0 x 10(6) cells; in the IIIrd-group (n=30) suspension of liver cells and bone marrow cells (mesenchymal stromal cells) in ratio 5:1 were used as cell associates on microparticles intjectable heterogeneous biopolymer hydrogel "SpheroGEL" (cell-engineering design) in common dose 8 - l0 x 10(6) It was ascertained that in the 2nd and in the 3rd groups the accelerated normalization of disturbed liver functional indices (ALT, AST, ALP) took place - to 30 days, but in the control group only to 90 days. The reliable differences in rats ofnormalization offunctional indices were absent between the IInd and the IIIrd groups. But in 90 days by using special histological dyeing it was found out that defibrotic processes in liver tissue were more expressed in the IIIrd group in comparison with the IIIrd group. Received results were consequence of prolonged vital activity of cells (liver cells and mesenchymal stromal bone marrow cells) into cell-engineering designs, which were transplanted in the IIIrd group. The obtained effect can be explained by that the developed cell-engineering designs provide adequate conditions for prolonged vital activity of the transplanted cells.

[Type 1 diabetes mellitus, diabetic nephropathy: transplantology potential].

The review covers the role of transplantology in treatment of patients with type 1 diabetes and the state of its development in the world and in Russia. The results of major multicenter studies, devoted to the influence of simultaneous kidney and pancreas transplantation and kidney transplantation alone on life expectancy and quality of life of diabetic patients are summarized here. Experience in pancreas-kidney transplantation, gained in Academician VI. Shumakov Federal Research Center of Transplantology and Artificial Organs, is described, including surgical technical and postoperative treatment. Also we perform the results of research work, devoted to the influence of pancreas transplantation on dfferent homeostasis parameters, such as: oxidative stress parameters, homocysteine, receptor for advanced glycation endproduct (RAGE), and markers ofendocrine function of pancreas transplant.

[Prognosis for patients with chronic diseases of the liver in formulating indications to orthotopic liver transplantation].

AIM: To analyse a clinical course of hepatic cirrhosis of various etiology in potential recipients of donor liver; to formulate symptom complex which determines life span prognosis in patients with chronic diffuse diseases of the liver (CDDL). MATERIAL AND METHODS: We studied 74 recipients of the liver (73 adults aged 15-58 years and 1 boy aged 13 years, mean age at liver transplantation 27.04 +/- 1.5 years, 41% males, 59% females). Orthotopic transplantation of the liver (OTL) was made from a live relative donor. All the patients have undergone clinical, biochemical, immunological, virological, ultrasonic, x-ray and other examinations. Severity of the patients' condition was assessed according to the Child-Pugh classification. Indications to transplantation of the liver were formulated basing on the syndromal approach. RESULTS: Asthenic syndrome was diagnosed in 34, pruritus--in 25, articular syndrome--in 11, jaundice--in 43, hepatomegaly--in 40, splenomegaly--in 65, ascitis--in 26, peripheral edema-- in 8, esophageal varicose veins--in 66, encephalopathy--in 5 patients. Main syndrome manifestations of CDDL involved in formulating indications for liver transplantation consisted in the syndrome of liver cell insufficiency (diagnosed in 77% cases), syndrome of portal hypertension (detected in 100% cases), edemo-ascitic syndrome (41% cases), cholestasis syndrome (95% cases), autoimmune cytopenia syndrome (77% cases), hepatorenal syndrome (5.4%). Most of potential recipients who had liver transplantation were classified as having class B and C by Child-Pugh (66.3%), but often indications for OTL were considered in terms of a combination of various syndromes significant for life prognosis in each patient and in terms of urgency of OTL performance. CONCLUSION: In determination of indications for OTL syndromal approach seems most adequate. Main syndromes influencing primarily on OTL decision making are portal hypertension with consideration of esophageal varicose veins, syndrome of hepatic cell deficiency, edemoascytic syndrome, hepatorenal syndrome, syndrome of autoimmune cytopenia and cholestasis.

[Indications and optimal terms of liver transplantation in chronic diffuse hepatic disease].

Patients with chronic diffuse hepatic disease (CDHD) take a great part in structure of morbidity of adult population. Problem of treatment of patients with hepatic cirrhosis (HC) is still very important. Main contingent of these patients who need hepar transplantation consists from HC patients with various ethiology, cholestatic diseases, inborn metabolism disturbances and hepatic tumors. At present in the world there is a tendency to early performing of operation while decompensation of other organs and systems still do not exist. When there is diagnosis of inborn metabolism disturbance indication to ortotopic transplantation of hepar (OTH) are put at the same time with verification of diagnosis. In case of HC urgency of OTH depends on stage of disease (system assessment of severity of hepatic insufficiency by 'hild-Pugh, MELD), response of patients on therapy and frequency of hospitalizing. Performance of OTH makes possible to prolongate of patients' life and significantly improve its quality.

[Transplantation of the liver right lobe from a related donor]. / Transplantatsiia pravoi doli pecheni ot rodstvennogo donora.

From 1997 to 2003 transplantation of liver's right lobe from alive related donor was performed in 64 patients (28 men, 36 women) aged from 6 to 61 years (mean age was 22.6 +/- 3.2 years). Body weight of recipients ranged from 18 to 92 Kg (52.7 +/- 2.8 Kg on average). Indications for surgery were following: cirrhosis of liver due to Wilson's disease (34), primary sclerotic cholangitis (6), viral cirrhosis of liver (6), primary biliary cirrhosis (4), Bayler's disease (3), Caroly's disease (3), Budd-Chiary syndrome (3), secondary biliary cirrhosis (2), cirrhosis of liver due to deficient of alpha(1)-antitrypsin (1), hepatocellular carcinoma (1), total nodular transformation of liver (1). Intensive care before transplantation was needed for 68.75% potential recipients. Donors of liver's right lobe were relatives of patients similar to blood group. Age of donors ranged from 18 to 49 years, mean age was 37.9 +/- 1.4 years. Donors underwent right-sided hemihepatectomy, there were no complications. Lethal outcome in recipients was seen in 2 (3.1%) cases and was not associated with function of transplant. Lethal outcome in long-term period after transplantation was seen in 4 (6.5%) cases. All the others patients survived and followed from 1 to 73 months (23.8 +/- 2.4 months on average). Quality of life was good. Transplantation of liver's right lobe from related donor is the independent line in orthotopic transplantation of liver and ensure reliable results.

[Reparative regeneration of the human liver grafted from a cadaver and a relative donor]. / Reparativnaia regeneratsiia pecheni cheloveka, transplantirovannoi ot trupa i rodstvennogo donora.

The morphological features and dynamics of regeneration of the grafted human liver were studied by using data on 609 needle biopsies obtained for morphological monitoring in 38 recipients during transplantation of the liver from cadavers and relative donors. The biopsy specimens of donor organs taken prior to grafting served as a control. Irrespective of the type of grafting, regenerative processes in the grafted liver were shown to have common regularities and to run by using the mechanisms of both intracellular regeneration and proliferation. Their maximum rate was seen within a month after grafting of a cadaverous organ and within 3 months after grafting a part of the liver from a relative donor. In cadaverous transplantation, regenerative processes depended mainly on the degree of ischemic lesions; in relative donor organ transplantation, that depended on the fitness of graft mass (the index K being close to 0.5), proliferative processes and the time of higher hepatocytic ploidity increased. An adequate evaluation of the status of a cadaverous organ, estimation of the optimum mass of a grafted hepatic part from a relative donor, and effective immunosuppressive therapy ensure required reparation rates and a complete recovery of the structure of a graft.

[Transplantation of the right hepatic lobe from an alive relative donor]. / Transplantatsiia pravoi doli pecheni ot zhivogo rodstvennogo donora.

The use of relative donors in the transplantation of the liver has shown a good performance as an alternative line in its orthotopical grafting. Shortage of donor organs actively stimulates the development of relative transplantation. The main problem of relative hepatic transplantation is the limited capacity of obtaining a required mass of a hepatic graft for obese recipients. To settle this problem, the Russian Surgery Research Center, Russian Academy of Medical Sciences, has developed an original safe procedure for obtaining the right lobe of the liver from an alive relative donor and for implanting it in a recipient. In November 1997 to October 2001, transplantation of the right hepatic lobe from an alive relative donor was made in 23 recipients (10 males and 13 females aged 9 to 55 (mean 22.3 +/- 3.1) years. Their body weight was 24 to 80 (mean 51.4 +/- 3.0) kg. Indications for surgery were as follows: hepatic cirrhosis (HC) at the end stage of the Wilson-Konovalov disease (n = 10), primary sclerotic cholangitis (n = 4), HC of viral etiology (n = 3), Bailer's disease (n = 2), primary biliary HC (n = 2), HC in the presence of alpha 1-antitrypsin deficiency (n = 1), and secondary biliary HC (n = 1). The donors of the right lobe of the liver were recipients' mothers in 9 cases, their fathers in 6 cases, sisters in 2 cases, sons in 1 cases, their daughter, brother, aunt, cousin in 1 case each. The donors' age ranged from 19 to 49 (mean 37.9 +/- 1.4) years. The donors underwent right hemihepatectomy, complications were absent in them. There were early mortality among the recipients. Two patients died in the late postoperative period. The remaining 21 recipients were survivors and followed up for 1 to 48 (mean 14.9 +/- 2.9) months. Their life quality was good. The use of the right lobe of the liver from an alive relative donor is the optimum alternative to transplantation of the cadaverous liver and partially compensates the shortage of donor organs for children, adolescents, and adults.

[Anesthesia during liver transplantation]. / Anesteziologicheskoe obespechenie transplantatsii pecheni.

Different methods and components of anesthesia during operations in donors and recipients were studied by using the experience in maintaining anesthesia during 39 relative and 7 cadaveric hepatic transplantations. The experience in using epidural anesthesia and total intravenous anesthesia at the donor stage of hepatic lobar transplantation was comparatively analyzed. Combined epidural anesthesia (CEA) may be used during long-term and traumatic operations dealing with hepatic lobectomy in a relative donor since it is noted for low hepatotoxicity and no drastic hemodynamic exposures. CEA can substantially reduce pharmacological loading with opioids or myorelaxants, which is particularly important in taking the lobe of the liver. This reduces the recovery period of adequate own respiration, activates a patient more rapidly, substantially reduces the risk for postoperative iatrogenic complications. Balanced general anesthesia whose major component is inhalational anesthesia with isoflurane is the method of choice in performing an operation in the recipient. The use of isoflurane in the minimal-flow mode is cost-effective and safe. When anesthesia is performed in the recipient, it is necessary to take in account drastic hemodynamic pattern changes at the liverless stage during vein-venous bypass surgery, including the liver into systemic circulation, and the likelihood of development of significant reperfusion and concomitant metabolic and coagulative disorders.

[Differential diagnosis of hepatocellular carcinoma using laser DNA-cytofluorometry]. / Differentsial'no-diagnosticheskie kriterii gepatotselliuliarnogo raka, opredelennye metodom lazernoi DNK-protochnoi tsitofliuorometrii.

Because of insufficient amount of material obtained in many cases of puncture biopsy, Differential diagnosis of hepatocellular carcinoma (HCC) with benign tumors and focal cirrhotic lesions of the liver is difficult. The study was aimed at development of additional criteria for HCC differential diagnosis of the basis of a comparison of morphological data (histological and cytological) with DNA content in the cells of focal lesion of the liver and is based on the research of biopsy material from 111 patients with focal liver lesions. Laser DNA flow cytometry (DNA-FCM) was carried out in 59 samples using laser flowing cytometer FACScan (Becton Dickinson, USA). The complex of three HCC histological criteria was established (trabecular histoarchitecture, increased nuclear-cytoplasmatic rate and nuclear crowding) for comparison with puncture biopsy of the liver (diagnostic efficiency 93.7%). Optimal quantitative parameters for HCC diagnosis were the following: reduction of the number of cells in a GO/1 phase of the cell cycle (< 77.5%), appearance of aneuploid clone of cell DNA index > 1.0 and decreased percent of binucleated cells (< 10%). Very high diagnostic specificity of the research was found (98.3%). Usage of quantitative parameters in the complex with histological criteria of HCC increased efficiency of the diagnosis up to 98%.

[liver portion transplantation from living donor: pilot clinical experience]. / Transplantatsiia chasti pecheni ot zhivogo rodstvennogo donora: pervyi klinicheskii opyt.

The unique in Russia experience of 35 liver transplantations since 1990 has revealed benefits of the method and quite encouraging results with 81% survival of the recipients. But the extreme shortage of cadaveric donor organs followed by more than 60 per cent mortality in waiting list and absence of any real facilities to improve the situation dictate the living related donation to become a considerable alternative. Totally 12 living related liver transplant procedures were performed with no morbidity in donors. In 7 donors the routine surgical technique of harvesting were used to get left lateral segment in five and whole left lobe in two cases. The unique twin-to-twin liver left lobe donation with no consequent immunosuppression was observed in this series. New special technique of living donor surgery was successfully developed for liver right lobe harvesting. The living related liver right lobe replacement was used in 5 cases and appeared to become a real compensation of donor organs shortage for elder children with body weight more than 20 kg and adults.

[Clinical experience with low- and minimal-flow isoflurane in extensive resections of the liver and liver transplantation]. / Klinicheskii opyt ispol'zovaniia izofliurana v rezhimakh low- i minimal-flow pri obshirnykh rezektsiiakh i transplantatsii pecheni.

A comparative study was performed of general balanced anesthesia on the basis of neuroleptic analgesia (NLA) and inhalation low- and minimal-flow anesthesia with isoflurane in anesthesiological management of extensive operations on the liver. A total of 75 anesthesias were conducted. Because of low hepatotoxicity, absence of its metabolites' pharmacological activity, fast elimination from the body unchanged, isoflurane is effective in long and traumatic operations on the liver. Low-flow isoflurane significantly lowers pharmacological load with opiates, myorelaxants which is essential in patients with hepatic diseases. This leads to more rapid recovery of adequate spontaneous respiration and activation of the patient in low risk of postoperative iatrogenic complications.

[Perfusion management in liver transplantation]. / Perfuziologicheskoe obespechenie transplantatsii pecheni.

Veno-venous bypass (VVB) with a Biopump centrifugal pump (Biomedicus, USA) was used in 36 patients with liver diseases during orthotopic transplantation of the liver. Volume rate of perfusion (VR), systolic, diastolic, and mean arterial pressure (AP), and central venous pressure (CVP) were monitored. VR during liver-free period was 850-1350 (1064.2 +/- 87.5) ml/min in femoral-axillary bypass and 1700-3500 (2630.5 +/- 112.3) ml/min in femoral-porto-axillary bypass. A trend to a decrease of the mean AP to 65 mm Hg was observed at the end of liver-free period (p < 0.05), while CVP decreased to 2 mm Hg (p < 0.05); there was a trend to a moderate tachycardia. No significant shifts in acid-base balance, oxygen balance, and blood electrolytes were observed during the liver-free period. Maximum blood loss occurred during the liver-free period and reperfusion of the transplant. Blood loss was evaluated by the amount of washed autoerythrocytes obtained after processing of collected blood in the Cell-Saver device. VVB had a favorable impact on the course of orthotopic transplantation of the liver, maintaining stable hemodynamic and biochemical parameters and preventing ischemia of the abdominal organs. Preservation of autoerythrocytes by the Cell-Saver device minimized the need in donor erythrocytes, thus ruling out the complications associated with homologous blood transfusion.

[The anesthesiological support of liver transplantation]. / Anesteziologicheskoe obespechenie transplantatsii pecheni.

The choice of anesthesia for a high risk operation, orthotopic transplantation of the liver (OTL), is discussed. The authors propose a protocol of anesthesia for OTL. For induction anesthesia, intravenous drugs should be preferred; the liver-free stage of the operation is carried out under anesthesia with a closed isoflurane contour, and the initial metabolic disorders of patients are corrected. When the bloodflow is let in the transplanted organ, intravenous drugs (ketamine, phentanyl, and benzodiazepines) should be administered in order to reduce the vasodilating effect of isoflurane and vasopressors for preventing relative hypovolemia. At the final stage of anesthesia, isoflurane is used. Before transporting the patient into intensive care ward, phentanyl in a dose of 1.5-3 micrograms/kg was injected, because of rapid elimination of isoflurane and awakening of the patient. This protocol maintained the hemodynamics and the major metabolic parameters at the optimal level.

[Orthotopic liver transplantation]. / Ortotopicheskaia transplantatsiia pecheni.

Orthotopic liver transplantation is the only method of choice for many severe liver diseases with poor prognosis. The development of liver transplantation programmes is based on medical science achievements and high technology in surgery, anesthesiology and perfusiology. The experience of the Surgery Research Center, Russian Academy of Medical Sciences, made it possible to obtain positive results of liver transplantation and posttransplantation management. This in turn provided longer survival for 80% of recipients. At the same time the mortality of potential recipients was 60.4%, which is due to the greater shortage of donor organs and which is the main problem in the development of organ grafting in Russia. The fact that there is a high proportion of children who are recipients for the donor's liver requires that liver transplantation from living related donors should be developed.

[Surgical hepatology: liver transplantation and extensive resections]. / Khirurgicheskaia gepatologiia: transplantatsiia pecheni, obshirnye rezektsii.

During 7 years (from 1990 until now) the only in Russia program of transplantation of the liver is under way in RCS RAMS. Up to now the experience has been accumulated of 24 transplantations in 23 patients, including 1 retransplantation and 6 transplantations from alive relative donor. Indications for the operation were incurable diseases of the liver with fatal prognosis including unresectable primary focal diseases. Long-term survival of the recipients in the last followed up series was obtained in 80% of cases. The longest survival reached 7 years. The quality of life of the recipients is quite satisfactory, 2 patients gave birth to healthy children. At the same time at the background of extreme deficiency of donor organs mortality rate of potential recipients during "waiting" period made up to 60.4%. Parallel development of resectional surgery of the liver made it possible to perform 49 extensive and maximally spacious resections with good results (early postoperative lethality--4.1%, actuarial 5 year survival rate of these patients--64%). Accumulated experience was a basement for the development of program for transplantation of a fragment of the liver from living relative donor.

[Surgical classification of liver local lesions]. / Khirurgicheskaia klassifikatsiia ochagovykh porazhenii pecheni.

There is a variety of liver focal lesions (LFL) and every clinical case should be considered carefully in deciding the problem of indications to surgical treatment. The existing classifications, including the TNM classification, are limited by the peculiar features of liver anatomy. The authors propose an original surgical classification of LFL that combines TNM principles and segmental characteristics of volume of lesion. The classification takes into account intraorganic and extraorganic location of LFL, and marks it by special letter indices. The indication of nosology of LFL in combination with letter and a B digital indices provides the universality of classification. The authors recommend to use the classification in evaluation of malignant and benign liver lesions, as well as alveococcosis and liver trauma.

[Orthotopic liver transplantation: surgery research center's experience]. / Opyt ortotopicheskoí transplantatsii pecheni v Nauchnom Tsentre Khirurgii RAMN.

From 1990 to 1996, 178 patients with severe diffuse and advanced focal liver diseases with grave prognosis were observed for indications to orthotopic liver transplantation (OLT). According to the revealed indications and contraindications, 95 patients were enrolled for the procedure. Eighteen patients underwent 19 OLTs, including 1 urgent retransplantation and 3 living related graftings. Surgical techniques were conventional; with these, intraoperative mortality and biliary complications could be avoided. Long-term survival (6 to 68 months) was achieved in 8 recipients, including in those after liver retransplantation. Double or triple suppressive regimens were used. These included corticosteroids, cyclosporin A, azathioprine, antithymocytic globulin. The life quality of recipients promoted restoration of their working capacities. Two recipients gave birth to healthy babies.

[Radical resections in advanced hepatic tumors]. / Radikal'nye rezektsii pri obshirnykh ochagovykh porazheniiakh pecheni.

Experience with 32 curative major and extended liver resections performed in 30 patients with different disseminated focal diseases. The scope of resections was 50 to 85% of the liver parenchyma. Owing to the developed criteria for resectability and surgical techniques of operations, there was no hepatic failure due to the small mass of the liver stump. There were no intraoperative deaths. Postoperative complications were observed in 15.6% of cases. Early postoperative mortality was 6.25%, the deaths were caused by fulminant pleuropneumonia and acute cerebrovascular circulatory disorder. Late mortality (at months 2.5 to 28 (mean 17.6 +/- 4.0 months) was 18.75% and it was due to the generalization of cancer diseases. After extensive hepatic resections, survival was observed in 73.3% of cases with the maximum time of 63 months. The authors' own guidelines for extensive and maximum large resections of the liver are presented in the paper.