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The use of minimally invasive liver surgery, such as laparoscopic and robotic surgery, is increasing worldwide. Robot-assisted laparoscopy is a new surgical technique that improves surgical handling. The advantage of this technique is improved dexterity, which leads to increased surgical precision and no tremor or fatigue. Comparable oncological results were documented for laparoscopic and open surgery. Currently, "conventional" laparoscopic liver surgery has limitations with respect to the treatment of lesions in the posterior-superior segments, and there are limited technical features for the reconstruction steps. These limitations might be overcome with the use of robotic surgery. The use of robotic surgery for hepatic procedures originated because of the technical potential to overcome several of the major technical limitations known from conventional laparoscopy and the possibility of performing more extended liver resections. Additionally, there is increasing evidence indicating that robotic hepatic surgery is feasible and safe in resections of the posterior segments. Studies showed that using the robotic technique is associated with a decreased or at least equal amount of intraoperative blood loss compared to that of the conventional laparoscopic or open technique. There is increasing evidence that robotic liver surgery might be as safe as conventional laparoscopic procedures in cancer cases in terms of resection margins, disease-free and overall survival. Furthermore, robotic surgery might be more favorable with respect to postoperative patient recovery. Despite promising results, still large, multicenter, randomized and prospective studies are needed to analyze the exact value of robotic liver surgery in patients with malignant liver tumors.

Obesity has become a global health problem that contributes to numerous life-threatening and disabling diseases, such as type 2 diabetes mellitus and coronary artery disease. The long-term results of traditional weight loss therapies, including diet, exercise, and medications, are relatively poor. Bariatric surgery is the most effective treatment of morbidly obese patients to allow substantial, sustained weight loss and to improve or resolve obesity-associated comorbidities, thereby reducing mortality. According to US practice guidelines, patients qualify for bariatric surgery with a body mass index of 35 kg/m(2) and associated comorbidities, or a body mass index of 40 kg/m(2), after failure of conservative weight loss measures. Currently, the established procedures in the United States are the laparoscopic Roux-en-Y gastric bypass, adjustable gastric banding, sleeve gastrectomy, and biliopancreatic diversion with duodenal switch. The surgeries vary substantially in their postoperative amount of weight loss, resolution of comorbidities, nutritional requirements, and nature and severity of complications. There is no perfect bariatric surgery, an informed risk and benefit assessment should be made by each patient. The procedures are safe, with a mortality rate of 0.3%. Sustained weight loss depends finally on patient re-education in terms of diet, need for regular exercise, and careful bariatric follow-up evaluation.

A number of studies have reported a lower atherogenic lipid profile in liver transplant recipients under tacrolimus (FK506) than in those under cyclosporine A (CyA) immunosuppression. This has mainly been attributed to the steroid-saving effect of FK506. However, the effects of converting CyA to FK506 monotherapy on lipid metabolism have not been specifically investigated. In 20 patients with stable graft function, immunosuppressive monotherapy was switched from CyA to FK506 because of CyA-related side-effects (hypertension, nephrotoxicity, hypercholesterolaemia). Serum lipid levels were measured before and 3, 6 and 12 months after conversion. In 5 patients, a modification of immunosuppression became necessary during the study period (4 were reconverted to CyA, 1 to glucocorticoids). In the remaining 15 patients on FK506 monotherapy, 12 months after conversion, a slight decrease in mean serum cholesterol, a slight increase in LDL, but a significant decrease in mean serum HDL were observed, resulting in a significant increase in Chol/HDL and LDL/HDL ratios. Conversion of immunosuppressive monotherapy from CyA to FK506 had no beneficial effect on the atherogenic lipid profile in this selected study population of long-term liver transplant survivors.

Calcifications in arterial media are clinically well documented, but the role played by magnesium in pathophysiology and therapy is uncertain. To clarify this, an animal model in which the juxtacardial aorta was grafted to the infrarenal aorta, and the subsequent calcifications in the media of the graft and their response to oral supplementation with three magnesium-containing and alkalinizing preparations was investigated. Groups of highly inbred rats were formed as follows: sham-operation (Sham, n = 12), aorta transplantation (ATx, n = 12), ATx + magnesium citrate (MgC, n = 12), ATx + MgC + potassium citrate (MgCPC, n = 12), ATx + MgC + MgCPC (MgCPCSB, n = 12). At 84 (+/-2) days after ATx with or without treatment the following observations were made: (1) weight gain and general status were normal; (2) ATx rats developed massive media calcification, mineral accumulation in the graft, decreased erythrocyte magnesium and plasma parathyroid hormone, and increased plasma ionized magnesium and calcium, and uric acid; (3) Mg-treated rats developed variable degrees of metabolic alkalosis, but only MgCPCSB supplementation prevented calcifications. Additional findings after ATx alone were: imbalance in endothelin and nitric oxide production, the mineral deposited in media was poorly crystallized calcium phosphate, calcium exchange between plasma and graft, and bone resorption were unchanged. The superior anti-calcification effect of MgCPCSB was characterized by complete restoration of normal extracellular mineral homeostasis and uric acid, but sub-optimal normalization of erythrocyte magnesium. It was concluded that in the rat: (1) ATx causes loss of cellular magnesium, excess of extracellular magnesium and calcium in the presence of apparently unchanged bone resorption, and increased uricemia; (2) ATx facilitates enhanced influx of calcium into vascular tissue, leading to calcium phosphate deposition in the media; (3) ATx-induced calcification is prevented by dietary supplementation with a combination of magnesium, alkali citrate and bases. Although the described circulatory model of media calcification in the rat requires further investigation, the data allow ascribing a fundamental role to magnesium and acid-base metabolism.

Pancreatic islet mass, represented by islet equivalent (IEQ), is the most important parameter in decision making for clinical islet transplantation. To obtain IEQ, the sample of islets is routinely counted under a microscope and discarded thereafter. Islet purity, another parameter in islet processing, is routinely assessed by estimation only. In this study, we validated our digital image analysis (DIA) system by using the software of Image Pro Plus and a custom-designed Excel template to assess islet mass and purity to better comply with current good manufacturing practice (cGMP) standards. Human islet samples (60 collected from a single isolation and 24 collected from 12 isolations) were captured as calibrated digital images for the permanent record. Seven trained technicians participated in determination of IEQ and purity by the manual counting method (manual image counting, Manual I) and DIA. IEQ count showed statistically significant correlations between the Manual I and DIA in all sample comparisons ( r > 0.819 and p < 0.0001). A statistically significant difference in IEQ between Manual I and DIA was not found in all sample groups ( p > 0.05). In terms of purity determination, statistically significant differences between assessment and DIA measurement were found in high-purity 100-μl samples ( p < 0.005) and low-purity 100-μl samples ( p < 0.001) of the single isolation. In addition, islet particle number (IPN) and the IEQ/IPN ratio did not differ statistically between Manual I and DIA. In conclusion, the DIA used in this study is a reliable technique to determine IEQ and purity. Islet sample preserved as a digital image and results produced by DIA can be permanently stored for verification, technical training, and information exchange among islet centers. Therefore, DIA complies better with cGMP requirements than the manual counting method. We propose DIA as a quality control tool to supplement the established standard manual method for islet counting and purity estimation.

Background. Several case reports suggested the use of pancreaticoduodenal allotransplantation alone or in combination with multivisceral transplants to treat exocrine and endocrine deficiency after pancreatectomy for chronic pancreatitis, upper abdominal malignancies, and cystic fibrosis. Our objective was to establish the metabolic consequences of this technique. Methods. Inbred rats, which either underwent pancreaticoduodenectomy before receiving an orthotopic duodenopancreas transplant (Tx, n518) or laparotomy (sham, n518), were subjected 3 months postoperatively to oral and “isoglycemic” i.v. glucose tolerance tests with arterial blood sampling (n512) or oral glucose tolerance test with additional portal blood sampling (n56). Fecal fat and chymotrypsin were evaluated in the 11th postoperative week as indicators of pancreatic exocrine function in eight animals of each group. Results. The incremental arterial plasma glucose integrated over a 90-min period was similar after oral and i.v. glucose in the respective groups, but was significantly lower in Tx versus sham rats after oral glucose. Incremental portal glucose was also lower after oral glucose, while hepatic glucose extraction remained unchanged. The incremental response of arterial glucose-dependent insulinotropic peptide, and of arterial and portal insulin, was comparable in Tx and sham rats; also in both groups the arterial response was significantly greater with oral versus i.v. glucose, and the incretin effect for insulin was intact after transplantation. Fecal fat and chymotrypsin levels did not differ between the two groups. Conclusions. 1) In the Tx rat lower incremental plasma glucose after oral glucose intake likely results from decreased intestinal glucose uptake; 2) preservation of a normal entero-insular axis of insulin together with the absence of intestinal malabsorption of lipids suggest that orthotopic transplantation of a duodenopancreas preserved endocrine and exocrine pancreatic function and therefore qualifies as treatment modality for the above named indications. Pancreas transplantation is now well established as endocrine replacement therapy for insulin-dependent diabetes mellitus with advanced secondary complications (1). It is routinely done in uremic diabetic recipients of kidney grafts which thereby become consistently insulin-independent and dialysis-free. Less commonly the pancreas is transplanted alone in patients with very labile diabetes and unawareness of hypoglycemia. These patients benefit from complete obviation of insulin reactions (2), and remission of secondary diabetic complications (3).

Primary disturbances in mineral metabolism and deficiencies in insulin and insulin-like growth factor-I (IGF-I) have been implicated in the pathogenesis of diabetic osteopenia. This prompted us to investigate whether normal bone minerals and bone morphology are preserved after pancreas transplantation. To this end, 8 inbred rats (transplants) were compared with 9 sham-operated rats (controls) 20 months after orthotopic pancreas transplantation. While basal levels of insulin remained unaffected by transplantation, an oral glucose load elicited hyperinsulinemia (integrated incremental response: mean +/- SEM, 62+/-8 nmol l(-1) 60 min in transplants vs. 32+/-6 nmol l(-1) 60 min in controls; p

Heterotopic pancreas transplantation in type I diabetic patients does not correct hyperglucagonemia, which is thought to be due to insufficiently suppressed glucagon release by the host pancreas. The diabetogenic effects of glucagon then have to be corrected by higher than normal insulin secretion from the transplant, with the attendant risk of earlier loss of islet cell function, and development of atherosclerosis. To establish whether this situation can be prevented, we investigated glucose homeostasis and blood lipids, as well as fecal fat and chymotrypsin as indicators for pancreatic exocrine function 14 weeks after orthotopic pancreas transplantation in inbred rats. The pancreas was resected before orthotopic transplantation of the donor pancreas with portal venous drainage (n=8). Laparotomized animals served as controls (n=8). Basal plasma glucagon, basal plasma insulin to glucagon molar ratio, and basal and integrated incremental responses of plasma glucose, insulin, and C-peptide after an oral glucose load (2 g/kg body weight) were similar in both groups. However, hepatic insulin clearance was slightly but significantly lower in the transplanted group (1.1± 0.1 vs 1.6±0.2; P

The effects of converting cyclosporine A to tacrolimus on bone mineral density (BMD) have not yet been evaluated thoroughly in liver transplant patients. Interfering factors in this patient population often are concomitant glucocorticoid treatment or exposure to estrogens. Here, we investigated in a homogeneous population of 10 male liver transplant recipients the impact of converting low-dose cyclosporine A monotherapy to low-dose tacrolimus monotherapy on BMD by using dual-energy x-ray absorptiometry. During the 12-month study period, an increase in BMD at the lumbar spine was observed in 9 out of 10 men (P

Die Technik der permanenten PVA stellt eine einfache Methode dar, um den portalen Blutfluss im Transplantat sicherzustellen. Nach PVA ohne Reduktion des Blutflusses konnte ein signifikanter Anstieg der Kollagensynthese und Gehaltes im Gewebe gefunden werden. Die Regenerationsfahigkeit und Funktion der resezierten Leber bleibt nach PVA erhalten, ist jedoch nicht gesteigert. Anhand der im Rahmen dieser Studie erhobenen Befunde konnen die negativen Effekte der «Uberarterialisierung» durch eine Reduktion des Blutflusses weitgehend vermieden werden, daher sollte die permanente PVA bei der temporaren auxiliaren und der orthotopen Lebertransplantation nur in Verbindung mit einer portalen Regulierung des Blutflusses durchgefuhrt werden.

The liver plays a central role in glucose and lipid homeostasis. Because liver transplantation severs the hepatic nerves which influence this function, we hypothesized that insulin resistance and hyperlipidemia develop after liver transplantation, thus increasing the atherosclerotic risk. Therefore, we studied inbred rats 8 months after orthotopic liver transplantation (Tx, n = 39) or laparotomy (sham, n = 37) by either oral glucose tolerance test (Tx, n = 13; sham, n = 8), meal tolerance test (Tx, n = 9; sham, n = 13), or euglycemic hyperinsulinemic clamp with tritiated glucose infusion (Tx, n = 17; sham, n = 16). We found that liver transplantation significantly increased basal hepatic glucose production (HGP) in the clamp study by 20% (37.3 +/- 2.2 vs 31.0 +/- 2.1 micromol kg -1 .min -1 , P < .05) and fasting plasma low-density lipoprotein (LDL) cholesterol by 36% (0.79 +/- 0.06 vs 0.58 +/- 0.05 mmol/L, P < .05). However, it did not affect HGP, total glucose uptake, metabolic clearance rate of insulin, and suppression of plasma nonesterified fatty acids, which were all normal in response to rising plasma insulin concentrations in the dose-response clamp studies. The oral glucose tolerance test and meal tolerance test also showed normal glucose and nonesterified fatty acids homeostasis with adequate pancreatic insulin secretion and hepatic insulin clearance after liver transplantation. The only consequences of liver transplantation are increased basal HGP and plasma LDL cholesterol, which may be caused by persistent vagal denervation of the liver. Although insulin resistance is absent, elevated plasma LDL cholesterol increases the atherosclerotic risk.

Background Portal vein arterialization (PVA) has been proposed as a technical variant in liver transplantation in the case of non-recanalizable thrombosis. The present study investigates the effects of the arterialized portal vein on the function, morphology, and regenerative behavior of the liver. Methods Different PVA techniques, including orthotopic liver transplantation, were used in a rat model. Portal blood flow was measured using a ultrasonic flowmeter. The regeneration capacity was determined on the basis of the increase of liver weight and the proliferating cell nuclear antigen index. The amount of hydroxyproline and the transcript levels of procollagen I were measured to determine the degree of fibrosis. The extracellular matrix was visualized with Picro-Sirius staining. Results The measurements obtained with an ultrasonic probe revealed a significant increase in portal blood flow after PVA. The regeneration capacity in the groups after PVA with no flow reduction was comparable to that of the control. Liver transplantation and PVA with no flow reduction was followed by a significant increase (four- to sixfold) in the amount of hydroxyproline and the level of the mRNA for procollagen I. In the Picro-Sirius staining, periportal and perivascular fibrosis with incipient formation of septa was seen. After reduction of the portal blood flow, these effects were significantly less pronounced. Conclusions These operative techniques represent an excellent small animal model for studying the mechanism of liver regeneration and the genesis of fibrosis in liver and vessel tissue. The presenting findings indicate that the negative effects of "overarterialization" may be largely avoided by reducing portal blood flow. This implies that permanent PVA in clinical liver transplantation should be performed only in conjunction with a down-regulation of portal flow.

Bone loss and long-term persistence of osteoporosis with increased fracture risk are common after liver transplantation. It is unknown whether transplantation-induced disruption of hepatic nerves, serving numerous regulatory metabolic and sensory functions, is herein involved. To test this possibility, we measured bone mineral density (BMD) by peripheral quantitative computed tomography (pQCT) and studied dynamic histomorphometry, radiocalcium kinetics, and biochemical parameters in 7 liver-transplanted and 7 shamoperated inbred rats. Although liver function was normal in TX rats, trabecular BMD of the first lumbar vertebra and total BMD of the femoral diaphysis were decreased by 13% and 6%, respectively, 9 months postsurgery. The breaking force of the femur was significantly lower by 21%. However, bone mass in the femoral and tibial metaphysis was preserved as evidenced by pQCT measurements and histomorphometry. Trabecular width and wall thickness were significantly decreased in vertebral cancellous bone, whereas indices of bone formation and resorption were normal or slightly reduced. Serum minerals, mineral balance, fractional and net absorption of Ca and Mg, serum calciotropic hormones, IGF-I, leptin, specific activity of 4 5 Ca in bone, 4 5 Ca excretion, and biochemical indices of bone formation and bone resorption remained unchanged. We conclude that liver transplantation-related denervation causes cancellous and cortical bone loss in well-innervated bone sites such as the lumbar spine and the long bone diaphysis. Cancellous bone loss in TX rats is due to an impairment of osteoblast team performance and subsequent trabecular thinning. The mechanism uncovered by our study may contribute to long-term bone loss after liver transplantation.

The aim of the present study was to determine the influence of the venous drainage site on insulin homeostasis and the possible risk for atherosclerosis development after pancreas transplantation. We studied inbred rats that received pancreas transplants with either systemic (STX) or portal (PTX) venous drainage after prior induction of diabetes with streptozotocin and sham-operated controls. The observation period was 6 months. Fasting plasma glucose and insulin levels were similar in all 3 groups, but fasting plasma glucagon levels were elevated in STX (mean +/- SEM, 282+/-35 ng/L) in comparison to PTX rats (119+/-9 ng/L, P.05), although the difference versus the control group (191+/-31 ng/L) was insignificant. Glucose utilization and hepatic glucose production (HGP), assessed by a dose-response euglycemic-hyperinsulinemic clamp in combination with tritiated glucose infusion, were similar in all 3 groups. The groups were also similar with respect to the molar ratio of plasma C-peptide and insulin during basal steady state and the metabolic clearance rate (MCR) of insulin during the clamp studies, suggesting an unchanged hepatic insulin extraction (HIE) after transplantation with either technique. Factors known to be related to atherosclerosis, ie, blood pressure, intracellular magnesium, and fasting levels of plasma cholesterol, triglycerides, and high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, were similar in all 3 groups. Light microscopy of the aorta showed a slightly thicker intima in STX rats (24.3+/-0.5 microm, P.05) versus PTX rats (21.4+/-0.7 microm) and control (21.4+/-0.6 microm); however, atherosclerosis-like lesions were absent in all 3 groups. In conclusion, in a rat model with streptozotocin-diabetes and pancreas transplantation but no need for immunosuppression, both systemic and portal venous drainage avoid peripheral and hepatic insulin resistance; also, there is no increased risk for atherosclerosis.

To establish whether the incretin effect is under neural control, insulin, C-peptide, and glucose-dependent insulinotropic peptide (GIP) responses and hepatic insulin clearance were investigated after oral and "isoglycemic" intravenous glucose in 12 inbred rats after denervation of the pancreas by orthotopic transplantation with portal venous drainage (Tx group) and in 12 laparotomized controls (sham group). Effective pancreas denervation was documented by a decreased pancreatic polypeptide (PP) response to insulin-induced hypoglycemia and by decreased levels of norepinephrine and calcitonin gene-related peptide (CGRP) in pancreatic tissue. Basal and incremental arterial plasma glucose integrated over 180 minutes did not differ between oral and intravenous glucose, but the integrated insulin response (mean +/- SEM) was significantly greater with oral versus intravenous glucose (Tx group, 104.9 +/- 22.0 v 31.0 +/- 4.9 nmol x L(-1) x min, P.01; sham group, 79.5 +/- 10.6 v 36.6 +/- 5.8 nmol x L(-1) x min, P.01). The integrated response of C-peptide was similar during both tests (Tx group, 105 +/- 14 v 79 +/- 8 pmol x mL(-1) x min; sham group, 112 +/- 10 v 121 +/- 12 pmol x mL(-1) x min). Hepatic insulin clearance was significantly decreased in both groups by oral compared with intravenous glucose administration (Tx group, 1.3 +/- 0.2 v 3.3 +/- 0.6 mmol/mmol, P.01; sham group, 1.6 +/- 0.1 v 3.9 +/- 0.6 mmol/mmol, P.02). The incretin effects for insulin (Tx group, 5.6 +/- 2.7; sham group, 3.0 +/- 0.8) and C-peptide (Tx group, 1.4 +/- 0.2; sham group, 1.1 +/- 0.2), calculated as the ratio of the integrated oral response and integrated intravenous response, and GIP responses to oral and intravenous glucose were not significantly different between the two groups. We conclude that there is preservation of the incretin effect in rats with orthotopically transplanted and hence extrinsically denervated pancreas, thus ruling out the possibility that the autonomic nervous system substantially contributes. Hepatic insulin clearance and insulinotropic hormones such as GIP appear to be more important.