Liver Partitioning Research Articles

Modification of ALPPS to avoid ischemia and congestion after stage 1: a case report

BackgroundAssociating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has been advocated for treating advanced liver tumors, but the devascularized ischemic area resulting from liver parenchymal division can become a nidus for sepsis. We present a patient who underwent ALPPS modified to avoid ischemia and congestion after liver partitioning during stage 1.Case presentationALPPS was carried out for a patient with multiple bilobar liver metastases from rectosigmoid colon cancer. The 2-stage treatment included 3 partial resections within the left lateral section and parenchymal division at the umbilical fissure with right portal vein ligation as stage 1, followed by right trisectionectomy as stage 2. During parenchymal division at the umbilical fissure, Segment 4 portal pedicles and the middle hepatic vein had to be resected at their roots. To safely accomplish this, combined resection of Segment 4 and the drainage area of the middle hepatic vein was performed after parenchymal partition, aiming to avoid ischemia and congestion within the remnant liver. Successful stage 2 hepatectomy followed later. No ischemia or congestion occurred during stage 1 or 2.ConclusionsDuring ALPPS, ischemia and congestion after stage 1 must be avoided to reduce morbidity and mortality. The modification described here should reduce likelihood of severe postoperative complications.

Individualized Selection Criteria Based on Tumor Burden in Future Remnant Liver for Staged Hepatectomy of Advanced CRLM: Conventional TSH or ALPPS.

Simple SummaryCurrently, two established staged hepatectomy techniques are used for curative resection of advanced colorectal liver metastasis (CRLM) as well as preventing inadequate future remnant liver (FRL). However, the selection of staged hepatectomy between the conventional two-stage hepatectomy (cTSH) and the associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) remains under debate. Therefore, the present study proposed a selection criterion based on tumor burden related to the size and number of metastases within the FRL for decision making when utilizing staged hepatectomy for advanced CRLM. Accordingly, metastatic tumors within the FRL should not exceed three nodules and none of the nodules should measure larger than 3 cm for ALPPS. By contrast, cTSH would be considered in patients whose tumor burdens within the FRL beyond the aforementioned criteria. The individualized selection criteria appear to be promising and can be used to select a more effective staged hepatectomy approach for patients with advanced CRLM.Staged hepatectomy is a promising strategy for curative resection of advanced colorectal liver metastasis (CRLM) to prevent inadequate future remnant liver (FRL). However, the selection criteria for conventional two-stage hepatectomy (cTSH) and associating liver partitioning and portal vein ligation for staged hepatectomy (ALPPS) remain unclear. This study aimed to propose a selection criterion for determining the optimal staged hepatectomy for patients with advanced CRLM. A selection criterion based on the degree of metastatic tumors within the FRL was established to determine staged hepatectomy approaches. Generally, ALPPS is recommended for patients with ≤3 metastatic nodules and whose nodules do not measure >3 cm in the FRL. cTSH is performed for patients whose tumor burden in FRL beyond the selection criteria. Data of 37 patients who underwent staged hepatectomy and curative intent of CRLM were analyzed. The clinical characteristics and outcomes of the two approaches were compared. Overall, cTSH and ALPPS were performed for 27 (73.0%) and 10 (27.0%) patients, respectively. Of those, 20 patients in the cTSH group and all patients in the ALPPS group had completed staged hepatectomy. The 1-, 3-, and 5-year survival rates were 91.6%, 62.4%, and 45.4% for all patients, respectively. The outcomes of patients who had successfully completed the staged hepatectomy were significantly better than those of other patients who failed to achieve staged hepatectomy. However, no significant difference was observed in the overall survival of patients who underwent staged hepatectomy between the two groups, but those in the ALPPS group had 100% survival at the end of this study. The individualized selection criteria based on tumor burden in the FRL that could balance the operative risk and oncologic outcome appear to be a promising strategy for achieving complete staged hepatectomy in patients with advanced CRLM.

The LiTOS-Approach: Liver Partitioning and Total Venous Occlusion for Staged Hepatectomy

The LiTOS-Approach: Liver Partitioning and Total Venous Occlusion for Staged Hepatectomy

Combining Laparoscopic Liver Partitioning and Simultaneous Portohepatic Venous Deprivation for Rapid Liver Hypertrophy

Future liver remnant (FLR) volume is an important indicator of the risk of posthepatectomy liver failure (PHLF) and limits the feasibility of major hepatectomies. A case series of 5 patients treated with a novel approach is presented. Laparoscopic liver partitioning was combined with subsequent liver venous deprivation (embolization of both the portal and the hepatic veins). Baseline average FLR was 28.8%. All procedures were successfully performed without major complications. Mean 1-, 2- and 4-week hypertrophy of the FLR were 35%, 40.3%, and 46.4%, respectively. Four patients underwent planned surgery after a mean interval of 28 days. Of these, 2 patients achieved sufficient FLR volume and function after 2 weeks and underwent surgery before the 4-week volumetric analysis. One patient did not undergo surgery because of intraoperative diagnosis of peritoneal metastases. No cases of PHLF were observed at 5-day follow-up.

Intraoperative Indocyanine Green Retention Test of Left Hemiliver in Decision-Making for Patients With Hepatocellular Carcinoma Undergoing Right Hepatectomy

Introduction: The aim of this study was to select qualified patients with hepatocellular carcinoma (HCC) who underwent right hepatectomy (RH) via intraoperative indocyanine green retention test at 15 min (ICG-R15) of the left hemiliver, which prevents severe posthepatectomy liver failure (PHLF).Methods: Twenty HCC patients who were preoperatively planned to undergo RH were enrolled. Intraoperative ICG-R15 of left hemiliver was measured after the right Glissonean pedicle was completely blocked. Patients then underwent RH if intraoperative ICG-R15 was ≤ 10%. Otherwise, patients underwent staged RH (SRH), either associating liver partitioning and portal vein ligation for staged hepatectomy (ALPPS) or portal vein ligation (PVL), followed by stage-2 RH. The comparison group consisted of patients with a ratio of standard left liver volume (SLLV) of > 40% and preoperative ICG-R15 ≤ 10% who underwent RH. The clinical outcomes of these two groups were compared.Results: Of the 20 patients, six underwent stage-1 RH, six underwent ALPPS, five underwent PVL followed by stage-2 RH, and three failed to proceed to stage-2 RH after PVL. No significant differences were found among the 17 patients who underwent stage-1 or stage-2 RH in the study group, the 19 patients in the comparison group, the 11 patients in the stage-2 RH group, and the six patients in the stage-1 RH group in incidences of PHLF, postoperative complications, hospital stay, and HCC recurrence within 1 year after RH. Compared with the stage-1 ALPPS group, the mean operative time and blood loss of the stage-1 PVL group were significantly less (p <0.001 and p = 0.022, respectively). The stage-1 PVL group had a significantly longer waiting-time (43.4 vs. 14.0 days, p = 0.016) than the stage-1 ALPPS group to proceed to stage-2 RH. After stage-2 RH, tumor recurrence within 1 year was 20% (1/5) in patients after PVL and 50% (3/6) after stage-1 ALPPS.Conclusions: Intraoperative ICG-R15 ≤ 10% of left hemiliver was valuable in intraoperative decision-making for patients who were planned to undergo RH. There is a possibility that stage-1 PVL might help to select patients with more favorable biological behavior to undergo stage-2 RH.

First two-stage robotic ALPPS in HCC patients with hepatic vein invasion: a step-by-step procedure from a clinical case

BackgroundThe associating liver partitioning and portal vein occlusion for staged hepatectomy (ALPPS) procedure is gaining interest because it brings hope to patients who cannot undergo radical surgical resection due to insufficient remnant liver volume. However, the indications and technical aspects of this procedure are still under debate. This report demonstrates the technical aspects of the first two-stage robotic ALPPS for HCC.Case presentationA 55-year-old man with type II portal vein variation was diagnosed with hepatocellular carcinoma. Preoperative 3D reconstruction of the liver based on CT showed a future liver remnant/standard liver volume (FLR/SLV) of 24.45%. The ALPPS procedure was performed using the da Vinci Si system. At the first stage of the operation, we removed the gallbladder and ligated the right anterior branch of the portal vein and the right posterior branch. Following blocking of the hepatic hilum, the liver parenchyma was removed 1 cm away from the right side of the falciform ligament in an incision manner from the top to the bottom and from shallow to deep. The second-stage operation was performed on the 12th postoperative day with a FLR/SLV of 45.13%. During this step, the right hemiliver plus left medial section was separated and removed. Postoperative pathology showed a negative margin. The operative times were 195 and 217 min, respectively. Estimated blood loss was 250 and 500 ml, respectively. There was no need for transfusion or hospitalization in intensive care. The patient was discharged on the 6th postoperative day. Recovery was uneventful after both stages, and the patient did not present any sign of liver failure. Elevation of liver enzymes was minimal. The patient had no evidence of the disease 14 months after the procedure.ConclusionsThe two-stage robotic ALPPS procedure is a safe and feasible technique for select patients with HCC.

Expansion of Knowledge on OCT1 Variant Activity In Vitro and In Vivo Using Oct1/2-/- Mice.

The role of organic cation transporter 1 (OCT1) in humans is gaining attention as data emerges regarding its role in physiology, drug exposure, and drug response. OCT1 variants with decreased in vitro function correlate well with altered exposure of multiple OCT1 substrates in variant carriers. In the current research, we investigate mechanisms behind activity of OCT1 variants in vitro by generating cell lines expressing known OCT1 variants and quantifying membrane OCT1 protein expression with corresponding OCT1 activity and kinetics. Oct knockout mice have provided additional insight into the role of Oct1 in the liver and have reproduced effects of altered OCT1 activity observed in the clinic. To assess the complex effect of Oct1 depletion on pharmacokinetics of prodrug proguanil and its active moiety cycloguanil, both of which are OCT1 substrates, Oct1/2−/− mice were used. Decreased membrane expression of OCT1 was demonstrated for all variant cell lines, although activity was substrate-dependent, as reported previously. Lack of change in activity for OCT1*2 resulted in increased intrinsic activity per pmol of OCT1 protein, particularly for sumatriptan but also for proguanil and cycloguanil. Similar to that reported in humans with decreased OCT1 function, systemic exposure of proguanil was minimally affected in Oct1/2−/− mice. However, proguanil liver partitioning and exposure decreased. Cycloguanil exposure decreased following proguanil administration in Oct1/2−/− mice, as did the systemic metabolite:parent ratio. When administered directly, systemic exposure of cycloguanil decreased slightly; however liver partitioning and exposure were decreased in Oct1/2−/− mice. Unexpectedly, following proguanil administration, the metabolite ratio in the liver changed only minimally, and liver partitioning of cycloguanil was affected in Oct1/2−/− mice to a lesser extent following proguanil administration than direct administration of cycloguanil. In conclusion, these in vitro and in vivo data offer additional complexity in understanding mechanisms of OCT1 variant activity as well as the effects of these variants in vivo. From cell lines, it is apparent that intrinsic activity is not directly related to OCT1 membrane expression. Additionally, in situations with a more complicated role of OCT1 in drug pharmacokinetics there is difficulty translating in vivo impact simply from intrinsic activity from cellular data.

The LiTOS hepatectomy: liver partitioning and total venous occlusion for staged hepatectomy

The LiTOS hepatectomy: liver partitioning and total venous occlusion for staged hepatectomy

Pharmacokinetics of Organic Cation Transporter 1 (OCT1) Substrates in Oct1/2 Knockout Mice and Species Difference in Hepatic OCT1-Mediated Uptake

Organic cation transporter 1 (OCT1) plays a role in hepatic uptake of drugs, affecting in vivo exposure, distinguished primarily through pharmacogenetics of the SLC22A1 gene. The role of OCT1 in vivo has not been confirmed, however, via drug-drug interactions that similarly affect exposure. In the current research, we used Oct1/2 knockout mice to assess the role of Oct1 in hepatic clearance and liver partitioning of clinical substrates and assess the model for predicting an effect of OCT1 function on pharmacokinetics in humans. Four OCT1 substrates (sumatriptan, fenoterol, ondansetron, and tropisetron) were administered to wild-type and knockout mice, and plasma, tissue, and urine were collected. Tissue transporter expression was evaluated using liquid chromatography-mass spectrometry. In vitro, uptake of all compounds in human and mouse hepatocytes and human OCT1- and OCT2-expressing cells was evaluated. The largest effect of knockout was on hepatic clearance and liver partitioning of sumatriptan (2- to 5-fold change), followed by fenoterol, whereas minimal changes in the pharmacokinetics of ondansetron and tropisetron were observed. This aligned with uptake in mouse hepatocytes, in which inhibition of uptake of sumatriptan and fenoterol into mouse hepatocytes by an OCT1 inhibitor was much greater compared with ondansetron and tropisetron. Conversely, inhibition of all four substrates was evident in human hepatocytes, in line with reported clinical pharmacogenetic data. These data confirm the role of Oct1 in the hepatic uptake of the four OCT1 substrates and elucidate species differences in OCT1-mediated hepatocyte uptake that should be considered when utilizing the model to predict effects in humans. SIGNIFICANCE STATEMENT: Studies in carriers of SLC22A1 null variants indicate a role of organic cation transporter 1 (OCT1) in the hepatic uptake of therapeutic agents, although OCT1-mediated drug-drug interactions have not been reported. This work used Oct1/2 knockout mice to confirm the role of Oct1 in the hepatic clearance and liver partitioning in mice for OCT1 substrates with reported pharmacogenetic effects. Species differences observed in mouse and human hepatocyte uptake clarify limitations of the knockout model for predicting exposure changes in humans for some OCT1 substrates.

Physiologically Based Pharmacokinetic Modeling of Transporter-Mediated Hepatic Clearance and Liver Partitioning of OATP and OCT Substrates in Cynomolgus Monkeys.

In the present investigations, we evaluate in vitro hepatocyte uptake and partitioning for the prediction of in vivo clearance and liver partitioning. Monkeys were intravenously co-dosed with rosuvastatin and bosentan, substrates of the organic anion transporting polypeptides (OATPs), and metformin, a substrate of organic cation transporter 1 (OCT1). Serial plasma and liver samples were collected over time. Liver and plasma unbound fraction was determined using equilibrium dialysis. In vivo unbound partitioning (Kpu,u) for rosuvastatin, bosentan, and metformin, calculated from total concentrations in the liver and plasma, were 243, 553, and 15, respectively. A physiologically based pharmacokinetic monkey model that incorporates active and passive hepatic uptake was developed to fit plasma and liver concentrations. In addition, a two-compartment model was used to fit in vitro hepatic uptake curves in suspended monkey hepatocyte to determine active uptake, passive diffusion, and intracellular unbound fraction parameters. At steady-state in the model, in vitro Kpu,u was determined. The results demonstrated that in vitro values under-predicted in vivo active uptake for rosuvastatin, bosentan, and metformin by 6.7-, 28-, and 1.5-fold, respectively, while passive diffusion was over-predicted. In vivo Kpu,u values were under-predicted from in vitro data by 30-, 79-, and 3-fold. In conclusion, active uptake and liver partitioning in monkeys for OATP substrates were greatly under-predicted from in vitro hepatocyte uptake, while OCT-mediated uptake and partitioning scaled reasonably well from in vitro, demonstrating substrate- and transporter-dependent scaling factors. The combination of in vitro experimental and modeling approaches proved useful for assessing prediction of in vivo intracellular partitioning.

Improving the safety of associating liver partition and portal vein ligation for staged hepatectomy

Liver resection is the only potential curative treatment option in patients with colorectal liver metastases (CRLM). Between 15–25% of the patients are primarily resectable, whereas in the majority of patients, the extent of and biological behavior of the disease, anatomical proximity to vital hepatic structures and insufficient future liver remnant (FLR) precludes resection. Modern chemotherapy has provided vast improvement by providing downsizing of tumors and various methods like portal vein embolization (PVE) and two stage hepatectomy have been established as standard practice in order to increase the number of patients that can be offered resection (1,2). Association liver partitioning and portal vein ligation for staged hepatectomy was first reported in a small case series from Germany in 2010, and was more formally published and described in 2012 as a novel technique to induce rapid volume growth of FLR (3). The method has, however, been regarded as controversial and evoked debates due to high procedure related morbidity and mortality rates, that does not seem to be merely related to lack of experience, since it has also been reported from experienced referral HPB centers (4,5). The mortality risk associated with associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) by far exceeds the standards commonly associated with liver resection for metastatic disease. Cause of perioperative death has in particular been attributed to liver failure and infectious complications.

Hypothalamic Regulation of Liver and Muscle Nutrient Partitioning by Brain-Specific Carnitine Palmitoyltransferase 1C in Male Mice.

Carnitine palmitoyltransferase (CPT) 1C, a brain-specific protein localized in the endoplasmic reticulum of neurons, is expressed in almost all brain regions. Based on global knockout (KO) models, CPT1C has demonstrated relevance in hippocampus-dependent spatial learning and in hypothalamic regulation of energy balance. Specifically, it has been shown that CPT1C is protective against high-fat diet-induced obesity (DIO), and that CPT1C KO mice show reduced peripheral fatty acid oxidation (FAO) during both fasting and DIO. However, the mechanisms mediating CPT1C-dependent regulation of energy homeostasis remain unclear. Here, we focus on the mechanistic understanding of hypothalamic CPT1C on the regulation of fuel selection in liver and muscle of male mice during energy deprivation situations, such as fasting. In CPT1C-deficient mice, modulation of the main hypothalamic energy sensors (5' adenosine monophosphate-activated protein kinase, Sirtuin 1, and mammalian target of rapamycin) was impaired and plasma catecholamine levels were decreased. Consequently, CPT1C-deficient mice presented defective fasting-induced FAO in liver, leading to higher triacylglycerol accumulation and lower glycogen levels. Moreover, muscle pyruvate dehydrogenase activity was increased, which was indicative of glycolysis enhancement. The respiratory quotient did not decrease in CPT1C KO mice after 48 hours of fasting, confirming a defective switch on fuel substrate selection under hypoglycemia. Phenotype reversion studies identified the mediobasal hypothalamus (MBH) as the main area mediating CPT1C effects on fuel selection. Overall, our data demonstrate that CPT1C in the MBH is necessary for proper hypothalamic sensing of a negative energy balance and fuel partitioning in liver and muscle.

A novel rat model of liver regeneration: possible role of cytokine induced neutrophil chemoattractant-1 in augmented liver regeneration.

BackgroundLiver resection is the mainstay of treatment for most of the liver tumors. Liver has a unique capability to restore the lost volume following resection, however, most of the primary tumors grow in a liver with preexisting parenchymal diseases and secondary tumors often present in multiple liver lobes precluding a safe curative resection. Two-stage hepatectomy and portal vein ligation (PVL) are used to achieve a safer future remnant liver volume (FRLV), however, these procedures take several weeks to achieve adequate FRLV. A recently introduced faster alternative two-stage hepatectomy, also know as associated liver partitioning and portal vein ligation for staged hepatectomy (ALPPS), produces a desirable FRLV in days.MethodsTo have an insight into the mechanism of ALPPS associated liver regeneration, we reproduced a rat model of ALPPS and compared the results with the PVL group.ResultsOur results convincingly showed an advantage of the ALPPS procedure over PVL group in terms of early regeneration, however, in 1-week time the amount of regeneration was comparable. An early regeneration in the ALPPS group coincided with an early entry of hepatocytes into the cell proliferation phase, a significant increase in portal pressure and increase in hepatic enzymes in the ALPPS group compared with the PVL group. According to the protein array evaluation of 29 cytokines/chemokines, cytokine induced neutrophil chemoattractant-1 had the highest expression whereas IL-6 had the highest fold (>6 vs PVL group) expression at the early phase of regeneration in the ALPPS group.ConclusionsThis unique rat model of ALPPS would help to improve our understanding about the liver generation process and also will help in further refinement of the ALPPS procedure for the clinical benefit.Electronic supplementary materialThe online version of this article (doi:10.1186/s13022-015-0020-3) contains supplementary material, which is available to authorized users.

Rosuvastatin Liver Partitioning in Cynomolgus Monkeys: Measurement In Vivo and Prediction Using In Vitro Monkey Hepatocyte Uptake

Unbound plasma concentrations may not reflect those in target tissues, and there is a need for methods to predict tissue partitioning. Here, we investigate the unbound liver partitioning (Kpu,u) of rosuvastatin, a substrate of hepatic organic anion transporting peptides, in cynomolgus monkeys and compare it with that determined using hepatocytes in vitro. Rosuvastatin (3 mg/kg) was administered orally to monkeys and plasma and liver (by ultrasound-guided biopsy) collected over time. Uptake into monkey hepatocytes was evaluated up to steady state. Binding in monkey plasma, liver, and hepatocytes was determined using equilibrium dialysis. Mean in vivo Kpu,u was 118 after correcting total liver partitioning by plasma and liver binding. In vitro uptake data were analyzed by compartmental modeling to determine active uptake clearance, passive diffusion, the intracellular unbound fraction, and Kpu,u. In vitro Kpu,u underpredicted that in vivo, resulting in the need for an empirical in vitro to in vivo scaling factor of 10. Adjusting model parameters using hypothetical scaling factors for transporter expression and surface area or assuming no effect of protein binding on active transport increased partitioning values by 1.1-, 6-, and 9-fold, respectively. In conclusion, in vivo rosuvastatin unbound liver partitioning in monkeys was underpredicted using hepatocytes in vitro. Modeling approaches that allow integrating corrections from passive diffusion or protein binding on active uptake could improve the estimation of in vivo intracellular partitioning of this organic anion transporting peptide substrate. A similar assessment of other active hepatic transport mechanisms could confirm and determine the extent to which limited accumulation in isolated hepatocytes needs to be considered in drug development.

Impact of Neoadjuvant Chemotherapy on Hypertrophy of the Future Liver Remnant after Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has been demonstrated as a feasible procedure in extended liver resections as a means of successfully increasing the volume of the future liver remnant (FLR). Neoadjuvant chemotherapy (CTx) is toxic to the organ and may impair hepatic regeneration. This study was performed to assess the procedure's effect on hypertrophy of the FLR, including the short-term survival. We analyzed 19 consecutive ALPPS patients, of whom 58% (n = 11) received neoadjuvant CTx because of colorectal liver metastasis (CRM). Patients presented with multifocal CRM (n = 11, 58%); cholangiocarcinoma (n = 7, 37%), of which 5 were in the Klatskin position; and gallbladder carcinoma (n = 1, 5%). Hepatectomy was performed within 6 to 13 days after hepatic partition. Volumetry was performed before both liver partitioning and hepatectomy. A survival analysis was performed. Liver partition and portal vein ligation induced sufficient hypertrophy of the FLR, with an increased volume of 74% ± 35%. Patients underwent hepatectomy after a median of 8 days; in all cases R0 resection was achieved. Neoadjuvant CTx was shown to significantly impair hypertrophy. The volume of the FLR in non-CTx patients increased by 98% ± 35%; an increase of 59% ± 22% was observed in patients who underwent CTx (p = 0.027). Chemotherapy did not have an impact on either morbidity or in-hospital mortality, which were 68% and 16%, respectively. One-year overall survival was 53%, with a 1-year survival of 67% in CRM patients and 38% in non-CRM patients (p > 0.05). Data presented here demonstrate for the first time that neoadjuvant CTx significantly impairs hypertrophy of the FLR after ALPPS.

Multi-parameter optimization of aza-follow-ups to BI 207524, a thumb pocket 1 HCV NS5B polymerase inhibitor. Part 2: Impact of lipophilicity on promiscuity and in vivo toxicity

We describe our efforts to identify analogs of thumb pocket 1 HCV NS5B inhibitor 1 (aza-analog of BI 207524) with improved plasma to liver partitioning and a predicted human half-life consistent with achieving a strong antiviral effect at a reasonable dose in HCV-infected patients. Compounds 3 and 7 were identified that met these criteria but exhibited off-target promiscuity in an in vitro pharmacology screen and in vivo toxicity in rats. High lipophilicity in this class was found to correlate with increased probability for promiscuous behavior and toxicity. The synthesis of an 8×11 matrix of analogs allowed the identification of C3, an inhibitor that displayed comparable potency to 1, improved partitioning to the liver and reduced lipophilicity. Although C3 displayed reduced propensity for in vitro off-target inhibition and the toxicity profile in rats was improved, the predicted human half-life of this compound was short, resulting in unacceptable dosing requirements to maintain a strong antiviral effect in patients.

Defining indications to ALPPS procedure: technical aspects and open issues

The limit to surgical treatment of patients with hepatic tumors is represented by the proportion of residual hepatic parenchyma at the end of surgery (FLR, future liver remnant) that provides an estimation of the risk of postoperative liver failure. Recently, a new two-stage technique has been developed with the acronym (ALPPS) associating liver partitioning and portal vein ligation for staged hepatectomy with the aim of obtaining a more rapid and effective increase in FLR, even though indications are not clear yet. Between January and December 2012, eight patients were candidates to ALPPS at the Hepatobiliary Surgery Unit of San Raffaele Hospital, Milan. The first three patients (Series 1) underwent right trisectionectomy and were affected by tumors infiltrating biliary confluence, while the others (Series 2) were candidates to right hepatectomy for colorectal liver metastases. Two patients were then excluded from Series 2 because intraoperative finding of irresectable disease. Intra- and postoperative outcome was evaluated with the aim of defining indications to ALPPS. All patients reached an adequate FLR after a median of 7.5days from the first procedure (rate of program completion 100%). In Series 1 two patients developed complications related to bile leakage from the raw surface of the liver to be resected and septic events secondary to ischemic necrosis of the liver segment IV. One patient died following multi-organ failure secondary to sepsis. In Series 2 postoperative course was uneventful in all the patients, and in particular no patient showed disease progression between the two procedures or signs of postoperative liver failure. ALPPS approach was initially considered suitable for patients affected by Klatskin tumors who require, despite a small tumor volume, extended hepatectomies associated with surgery of the biliary tract: the analysis of this first series of patients has led to a re-evaluation of the indication to this strategy, as a consequence of encountered criticisms. Actually only a subset of patients affected by colorectal liver metastases are candidates to ALPPS.

Discovery of Hepatitis C Virus NS3-4A Protease Inhibitors with Improved Barrier to Resistance and Favorable Liver Distribution

Given the emergence of resistance observed for the current clinical-stage hepatitis C virus (HCV) NS3 protease inhibitors, there is a need for new inhibitors with a higher barrier to resistance. We recently reported our rational approach to the discovery of macrocyclic acylsulfonamides as HCV protease inhibitors addressing potency against clinically relevant resistant variants. Using X-ray crystallography of HCV protease variant/inhibitor complexes, we shed light on the complex structural mechanisms by which the D168V and R155K residue mutations confer resistance to NS3 protease inhibitors. Here, we disclose SAR investigation and ADME/PK optimization leading to the identification of inhibitors with significantly improved potency against the key resistant variants and with increased liver partitioning.

The “carving” liver partitioning technique for graft hepatectomy in live donor liver transplantation: A single-center experience

In adult live donor liver transplantation, postoperative venous congestion of graft and remnant livers can lead to life-threatening complications. The purpose of this study was to evaluate the safety and benefits of our 3-dimensional, computed tomographic, computer-assisted donor hepatectomy using the "carving" partitioning technique. Eighty-three consecutive adult live donor liver transplantations were performed based on data obtained from individualized preoperative 3-dimensional, computed tomographic reconstructions and virtual graft hepatectomies. There were 71 right and 12 left grafts. Small grafts (graft volume body weight ratio, <1.0) were used in 20 cases. We observed no clinically important differences in postoperative function between right and left grafts. Four recipients developed lethal small-for-size syndrome. Reversible small-for-size syndrome was observed in a right graft recipient and in 2 right graft donors. Preoperative 3-dimensional, computed tomographic, computer-assisted planning using virtual liver partitioning allowed for: (1) an individualized carving technique based on specific donor anatomic characteristics, (2) donor safety based on individualized patterns of venous outflow, and (3) optimized drainage of the medial area of the graft based on the preferential inclusion of the middle hepatic vein.

Effects of Exercise Training on Molecular Markers of Lipogenesis and Lipid Partitioning in Fructose-Induced Liver Fat Accumulation

The present study was designed to investigate the impact of exercise training on lipogenic gene expression in liver and lipid partitioning following the ingestion of a high fructose load. Female rats were exercise-trained for 8 wk or kept sedentary before being submitted to a fasting/refeeding protocol. Rats were further subdivided as follow: rats were fasted for 24 h, refed a standard diet for 24 h, starved for another 24 h, and refed with a standard or a high-fructose diet 24 h before sacrifice. Fructose refeeding was associated with an increase in hepatic lipid content, endocannabinoid receptor 1, sterol regulatory element-binding protein1c, and stearoyl-CoA desaturase1 gene expression in both Sed and TR rats. However, desaturation indexes measured in liver (C16 : 1/C16 : 0 and C18 : 1/C18 : 0) and plasma (C18 : 1/C18 : 0) were higher (P < 0.01) in TR than in Sed rats following fructose refeeding. It is concluded that exercise training does not significantly affect fat accumulation and the molecular expression of genes involved in lipogenesis after fasting and fructose refeeding but does modify the partitioning of lipids so as to provide more unsaturated fatty acids in liver without affecting liver fat content.