Plasma Disappearance Research Articles

Indocyanine green clearance as an outcome prediction tool in cardiac surgery: A prospective study

PurposeTo evaluate the role of plasma disappearance rate of indocyanine green (PDR-ICG) as an outcome prediction tool in cardiac surgery. Patients and MethodsOne hundred ninety patients undergoing coronary artery bypass grafting, valve surgery or combined procedures were enrolled. PDR-ICG measurements along with standard lab values were performed preoperative and on postoperative days 1, 2, and on discharge from the intensive care unit. Adverse outcomes were defined as prolonged length of stay in the intensive care unit and/or mortality. Two groups were defined according to length of stay in the intensive care unit (≤3 days vs >3 days). ResultsPDR-ICG values differed significantly for all time points between the groups. In a multivariate model, in patients over 65 years with a EuroSCORE below 8.5, a preoperative PDR-ICG value below 12.85%/min was the strongest independent predictor for prolonged intensive care unit stay (>3 days). A preoperative PDR-ICG value below 8.2%/min was the strongest independent predictor for mortality in a multivariate analysis including age, cardiac function, and EuroSCORE. ConclusionsIn addition to the established scores, PDR-ICG may provide valuable information for the assessment of perioperative morbidity and mortality in cardiac surgery. Pre- and early postoperative measurements may help to identify patients at risk for developing perioperative complications.

The influence of continuous venovenous renal replacement therapy on the plasma disappearance rate of indocyanine green

The influence of continuous venovenous renal replacement therapy on the plasma disappearance rate of indocyanine green

Indocyanine green plasma disappearance rate: a new tool for the classification of paediatric patients with acute liver failure

Pediatric acute liver failure is a rare disorder which results in death or the need for liver transplantation in 25-50% of cases. The adults scores are unable to predict survival without liver transplantation of pediatric patients. The present study assessed the use the of indocyanine green plasma disappearance rate as a tool to predict the evolution of pediatric patients with acute liver failure. All patients met the criteria of acute liver failure according to the Pediatric Acute Liver Failure Study Group. King's College, Clichy's criteria and ICG-PDR were obtained on admission or when acute liver failure was diagnosed and repeated every 12-24 hours, respectively. Thirteen out of 48 patients suffered an irreversible liver damage. Seven of them underwent a liver transplantation and 6 died on the waiting. A total of 154 ICG-PDR measurements were taken during the study (Median 12.4 %/min, r:6.2 - 26.3). The ICG-PDR was significantly lower in patients who suffered irreversible liver damage compared with those who survived without liver transplantation (median ICG-PDR 4.1 %/min; r:4.0 - 5.7 vs median ICG-PDR 20.3 %/min; r: 9.1 - 30.1; respectively. P < 0.001). Using a ROC curve the cutoff of ICG-PDR for assessing the need for liver transplantation was set at 5.9 %/min (sensitivity 92.3%, specificity 97.1%). Sensitivity, specificity, PPV, NPV and DA for ICG-PDR were higher than the King's College and Clichy's criteria. ICG-PDR is a powerful tool that would improve the categorization of patients with pediatric acute liver failure.

Dobutamine Pretreatment Improves Survival, Liver Function, and Hepatic Microcirculation After Polymicrobial Sepsis in Rat

Dobutamine is recommended for the treatment of sepsis-related circulatory failure in international guidelines. Furthermore, dobutamine has been demonstrated to improve liver function and hepatic perfusion after experimental hemorrhagic shock. Yet, it is unknown whether dobutamine may also induce hepatoprotective effects in sepsis. This study was designed to investigate the effect of dobutamine on survival, hepatic function, and microcirculation after polymicrobial sepsis in rat. Under general anesthesia, male Sprague-Dawley rats (n = 25/group) underwent pretreatment with dobutamine (10 μg/kg per minute) in the presence or absence of β1-receptor antagonist esmolol (500 μg/kg per minute), esmolol alone, or vehicle for 6 h, before induction of sepsis (cecal ligation and incision [CLI]). Sham-operated animals were treated likewise but underwent no CLI. Five hours after CLI, either liver function was assessed by plasma disappearance rate of indocyanine green (n = 5/group), or intravital microscopy was performed (n = 5/group) for evaluation of hepatic perfusion index and hepatic integrity (as propidium iodide-stained cells per field). Alternatively, survival time after induction of CLI was monitored under general anesthesia (n = 15/group). Compared with controls, dobutamine pretreatment significantly improved plasma disappearance rate of indocyanine green (13.8% ± 4.1% vs. 20.6% ± 4.6%; P = 0.029), hepatic perfusion index (275.0 ± 126.1 vs. 703.5 ± 177.4 pL/s per mm; P < 0.001), hepatocellular injury (22.2 ± 6.7 vs. 6.4 ± 3.1 cells per field; P < 0.001), and survival time (326 ± 20 vs. 603 ± 41 min; P < 0.001). Coadministration of esmolol abolished the protective effect of dobutamine completely. Our results indicate that pretreatment with dobutamine may improve survival, liver function, and hepatic microcirculation after polymicrobial sepsis in rat via β1-adrenoceptor activation. Dobutamine could therefore play a relevant role for hepatoprotection under septic conditions.

Semi-mechanistic physiologically-based pharmacokinetic modeling of clinical glibenclamide pharmacokinetics and drug–drug-interactions

We studied if the clinical pharmacokinetics and drug–drug interactions (DDIs) of the sulfonylurea-derivative glibenclamide can be simulated via a physiologically-based pharmacokinetic modeling approach. To this end, a glibenclamide PBPK-model was build in Simcyp using in vitro physicochemical and biotransformation data of the drug, and was subsequently optimized using plasma disappearance data observed after i.v. administration. The model was validated against data observed after glibenclamide oral dosing, including DDIs. We found that glibenclamide pharmacokinetics could be adequately modeled if next to CYP metabolism an active hepatic uptake process was assumed. This hepatic uptake process was subsequently included in the model in a non-mechanistic manner. After an oral dose of 0.875mg predicted Cmax and AUC were 39.7 (95% CI:37.0–42.7)ng/mL and 108 (95% CI: 96.9–120)ng/mLh, respectively, which is in line with observed values of 43.6 (95% CI: 37.7–49.5)ng/mL and 133 (95% CI: 107–159)ng/mLh. For a 1.75mg oral dose, the predicted and observed values were 82.5 (95% CI:76.6–88.9)ng/mL vs 91.1 (95% CI: 67.9–115.9) for Cmax and 224 (95% CI: 202–248) vs 324 (95% CI: 197–451)ng/mLh for AUC, respectively. The model correctly predicted a decrease in exposure after rifampicin pre-treatment. An increase in glibenclamide exposure after clarithromycin co-treatment was predicted, but the magnitude of the effect was underestimated because part of this DDI is the result of an interaction at the transporter level. Finally, the effects of glibenclamide and fluconazol co-administration were simulated. Our simulations indicated that co-administration of this potent CYP450 inhibitor will profoundly increase glibenclamide exposure, which is in line with clinical observations linking the glibenclamide-fluconazol combination to an increased risk of hypoglycemia. In conclusion, glibenclamide pharmacokinetics and its CYP-mediated DDIs can be simulated via PBPK-modeling. In addition, our data underline the relevance of modeling transporters on a full mechanistic level to further improve pharmacokinetic and DDI predictions of this sulfonylurea-derivative.

Effects of dobutamine on systemic, regional and microcirculatory perfusion parameters in septic shock: a randomized, placebo-controlled, double-blind, crossover study

The role of dobutamine during septic shock resuscitation is still controversial since most clinical studies have been uncontrolled and no physiological study has unequivocally demonstrated a beneficial effect on tissue perfusion. Our objective was to determine the potential benefits of dobutamine on hemodynamic, metabolic, peripheral, hepatosplanchnic and microcirculatory perfusion parameters during early septic shock resuscitation. We designed a randomized, controlled, double-blind, crossover study comparing the effects of 2.5-h infusion of dobutamine (5mcg/kg/min fixed-dose) or placebo in 20 septic shock patients with cardiac index≥2.5l/min/m(2) and hyperlactatemia. Primary outcome was sublingual perfused microvascular density. Despite an increasing cardiac index, heart rate and left ventricular ejection fraction, dobutamine had no effect on sublingual perfused vessel density [9.0 (7.9-10.1) vs. 9.1n/mm (7.9-9.9); p=0.24] or microvascular flow index [2.1 (1.8-2.5) vs. 2.1 (1.9-2.5); p=0.73] compared to placebo. No differences between dobutamine and placebo were found for the lactate levels, mixed venous-arterial pCO2 gradient, thenar muscle oxygen saturation, capillary refill time or gastric-to-arterial pCO2 gradient. The indocyanine green plasma disappearance rate [14.4 (9.5-25.6) vs. 18.8%/min (11.7-24.6); p=0.03] and the recovery slope of thenar muscle oxygen saturation after a vascular occlusion test [2.1 (1.1-3.1) vs. 2.5%/s (1.2-3.4); p=0.01] were worse with dobutamine compared to placebo. Dobutamine failed to improve sublingual microcirculatory, metabolic, hepatosplanchnic or peripheral perfusion parameters despite inducing a significant increase in systemic hemodynamic variables in septic shock patients without low cardiac output but with persistent hypoperfusion.

Blood Lead Level and Measured Glomerular Filtration Rate in Children with Chronic Kidney Disease

Background: The role of environmental exposure to lead as a risk factor for chronic kidney disease (CKD) and its progression remains controversial, and most studies have been limited by a lack of direct glomerular filtration rate (GFR) measurement.Objective: We evaluated the association between lead exposure and GFR in children with CKD.Methods: In this cross-sectional study, we examined the association between blood lead levels (BLLs) and GFR measured by the plasma disappearance of iohexol among 391 participants in the Chronic Kidney Disease in Children (CKiD) prospective cohort study.Results: Median BLL and GFR were 1.2 µg/dL and 44.4 mL/min per 1.73 m2, respectively. The average percent change in GFR for each 1-µg/dL increase in BLL was –2.1 (95% CI: –6.0, 1.8). In analyses stratified by CKD diagnosis, the association between BLL and GFR was stronger among children with glomerular disease underlying CKD; in this group, each 1-µg/dL increase in BLL was associated with a –12.1 (95% CI: –22.2, –1.9) percent change in GFR. In analyses stratified by anemia status, each 1-µg/dL increase in BLL among those with and without anemia was associated with a –0.3 (95% CI: –7.2, 6.6) and –4.6 (95% CI: –8.9, –0.3) percent change in GFR, respectively.Conclusions: There was no significant association between BLL and directly measured GFR in this relatively large cohort of children with CKD, although associations were observed in some subgroups. Longitudinal analyses are needed to examine the temporal relationship between lead and GFR decline, and to further examine the impact of underlying cause of CKD and anemia/hemoglobin status among patients with CKD.

Intraoperative ICG plasma disappearance rate helps to predict absence of early postoperative complications after orthotopic liver transplantation

Early postoperative complications after orthotopic liver transplantation (OLT) are a common problem in intensive care medicine. Adequate assessment of initial graft function remains difficult, however, plasma disaperance rate of indocyanine green (PDRICG) may have an additional diagnostic and prognostic value in this setting. We retrospectively evaluated the ability of intraoperative PDRICG values to predict absence of early postoperative complications in 62 subjects. PDRICG was measured non-invasively by pulse dye densitometry during surgery and was correlated with initial graft function. At the end of surgery, PDRICG was higher in patients without complications: 24.9%min(-1) (n=40) versus 21.0%min(-1), (n=22; p=0.034). An area under the ROC curve (AUROC) for PDRICG was 0.70, while the AUROC for pH, lactate and PT at ICU admission were 0.53, 0.50 and 0.46, respectively. The AUROC of serum bilirubin and PT at postoperative day 5 were 0.68 and 0.49, respectively. The optimal cut-off PDRICG value for predicting absence of development early postoperative complications was determined to be 23.5%min(-1) with 72.4% sensitivity and 71.0% specificity. Intraoperative point-of-care PDRICG measurement during OLT already predicts absence of early postoperative complications, better and earlier than clinically used laboratory parameters.

Indocyanine green plasma disappearance rate for assessment of liver function: re-evaluation of normal ranges and impact of biometric data

The indocyanine green plasma disappearance rate (ICG-PDR) is a dynamic liver function test that can be non-invasively measured by pulse densitometry. ICG-PDR is associated with mortality and other markers of outcome. Due to predominant use of ICG-PDR in the ICU setting, the normal range is based on scarce data available outside the ICU and given with 18 to 25%/minute.

Prediction of 28-day mortality by indocyanine green disappearance rate, other markers of hepatic function and transpulmonary thermodilution parameters: a prospective study in 154 patients

Hepatic dysfunction has been associated with outcome of ICU patients. However, most scoring systems including APACHE II only marginally reflect acute liver dysfunction on admission. Indocyanine green (ICG) is eliminated by hepatobiliary excretion. Therefore, the ICG plasma disappearance rate (ICG-PDR) is used as a dynamic liver function test. ICG-PDR has been associated with mortality in several studies.

Rapid assessment of renal reserve in young adults by cystatin C

Background. The kidney can increase glomerular filtration rate (GFR) in response to a protein load (renal reserve). In a pilot study of healthy young adults we examined renal reserve using changes in serum cystatin C (cysC). Methods. Glomerular filtration rate was obtained using iohexol single slope plasma disappearance. To stimulate GFR, subjects ingested a beefburger containing 60 grams of protein. CysC was measured by immunonephelometry before and 125–141 minutes after protein loading. Results. All subjects were found to have a normal iohexol plasma disappearance GFR with a mean of 104.6 ± 9.9 mL/min per 1.73 m2. CysC decreased in each subject after the meat meal. Baseline cysC-based estimated GFR was 98.1 ± 9.1 mL/min per 1.73 m2 with a mean increase of 12.0 ± 5.2 (p = 0.0003). Conclusions. Our study showed a consistent decrease in serum cysC and increase in cysC-based estimated GFR following a protein load in young adults. Further studies are needed using renal clearance methods to confirm that cysC accurately determines renal reserve in patients with and without chronic kidney disease.

Methods of assessing renal function

Accurate assessment of renal function is critical for appropriate drug dosing of renally excreted compounds. Glomerular filtration rate (GFR) is considered the best marker of kidney function. Inulin clearance forms the gold standard for measuring GFR, both in adults and in children. The method is invasive, cumbersome, and smaller children require urinary catheterization for accurate timed urine collections. Nuclear medicine methods replaced inulin clearance in the 1970s after (51)Cr EDTA clearance was introduced. Inulin has no plasma protein binding, whereas all commonly used radioisotopes have a small amount of plasma protein binding that leads to lower values. Only iohexol does not have significant plasma protein binding. The underestimation due to plasma protein binding is partially offset by overestimation due to the use of non-compartmental pharmacokinetic modeling of the plasma disappearance of the radioisotope. The problem could be overcome with a urinary nuclear medicine clearance method, but these have not been validated in children. Endogenous markers of GFR include serum creatinine and low molecular weight proteins such as cystatin C and beta-trace protein. Of these, estimation of GFR using cystatin C appears to be the most promising, although its accuracy in pregnancy and in the neonatal period may be limited.

Postoperative Bile Leakage Inhibits Liver Regeneration after 70% Hepatectomy in Rats

ABSTRACTBackground: Postoperative bile leakage is a typical complication in liver surgery. The influence of small bile leakage and concomitant bile peritonitis on the regenerative capacity of the liver remnant has not yet been investigated thoroughly. Material and Methods: Fifty-four rats were randomized in the following groups: Sham operation (Sh), 70% liver resection (LR), and 70% LR with simultaneous induction of a small bile leakage. Animals were euthanized 6, 24, 48, and 96 hr after surgery. Liver regeneration was measured by relative liver weight, mitotic index, Ki-67 immunohistochemistry, and BrdU labeling index. Liver function was evaluated by thromboplastin time, serum bilirubin, and albumin levels as well as indocyanine green plasma disappearance rate (ICG-PDR). The inflammatory response was characterized by assessment of the hepatic transcription of TNF-α, IL-6, and TGF-β and the serum concentration of IL-1β. In addition, myeloperoxidase (MPO) activity in liver tissue was measured. Transaminases and histological sections of the liver were used as markers for hepatocellular damage, and the bacterial concentration in different organs was quantified. Results: With a small bile leakage, mitotic index was reduced by 89% ( p < .05) and the number of Ki-67 positive hepatocytes was reduced by 92% ( p < .05) 24 hr after LR. Likewise, the ICG-PDR dropped by 57% ( p < .05). No differences in liver histology were observed between the groups. With bile leakage, the postoperative transcription of cytokines was markedly higher. A bacterial superinfection could be excluded. Conclusion: Small intraabdominal bile leakage can suppress liver function and impair the regenerative capacity of the liver.

Toxicological, toxicokinetic and gastroprotective evaluation of the benzaldehyde semicarbazone

Benzaldehyde semicarbazone (BS) has presented positive results in several pharmacological models, including anticonvulsivant and anti-inflammatory models. The present study evaluated the preclinical toxicity (acute and subchronic), as well as the toxicokinetic and gastroprotective effects of BS against ethanol lesions. Oral doses of 300 and 2000mg/kg were used in the preclinical acute toxicity study; 100, 200, and 300mg/kg were used in both the subchronic toxicity evaluation and the gastric study; and 300mg/kg was used in the toxicokinetic study. No impact from the dose of 300mg/kg could be identified; while, one animal died at 2000mg/kg in the acute toxicity test. In the subchronic toxicity test, changes in the biochemical parameters of the liver, as well as in the histopatological evaluation, demonstrated that BS is a hepatotoxic drug. BS proved to be effective for moderate and severe gastric lesions. In the toxicokinetics study, BS presented a low concentration and rapid plasma disappearance. Several results also indicate that BS is likely to be mostly eliminated from the liver and may well undergo a first-pass effect after oral absorption. It was impossible to estimate the noobserved-adverse-effect-levels (NOAEL) and lowest-observed-adverse-effect-levels (LOAEL) due to the presence of hepatotoxicity in all tested doses.

Simultaneous determination of renal plasma flow and glomerular filtration rate in conscious mice using dual bolus injection

IntroductionThe present report describes and evaluates a simple protocol for serial measurements of glomerular filtration rate (GFR) and renal plasma flow (RPF) in conscious mice. MethodsIn conscious mice, a bolus of [3H]methoxy-inulin and [14C]para-amino-hippuric (PAH) was injected in the tail vein whereupon eight blood samples were taken during the following 75min. Plasma concentrations were determined by liquid scintillation and clearances of the injected markers were calculated by non-compartmental pharmacokinetic data analysis of the plasma disappearance curves. In anaesthetized mice, the renal extraction ratio of PAH was determined by infusion of PAH and subsequent analysis of blood taken from the carotid artery and the renal vein. The acquired value (0.70±0.02) was used for all subsequent calculations of RPF. To evaluate the protocol, a crossover study was performed where either the vehicle or the angiotensin II AT1 receptor antagonist candesartan was given prior to the clearance measurements. ResultsBaseline values of GFR and RPF were in line with those earlier reported in mice. Administration of candesartan increased RPF and reduced the filtration fraction, whereas GFR was unaltered. These changes are supported by earlier findings and demonstrate that GFR and RPF can be determined independently. Furthermore, modelling experiments demonstrated that acceptable results are obtained even if the number of blood samples is reduced to four which is a way to further simplify the procedure. DiscussionThe method provides an effective way for repeated measurements of GFR and RPF in mice without potentially confounding effects of anaesthesia.

ICG clearance is a relevant outcome prediction tool in cardiac surgery

Objective: Predicting outcome is a significant challenge in cardiac surgery. The plasma disappearance rate of indocyanine green (PDR-ICG) has been shown to predict outcome in subsets of critically ill patients, and derangements of PDR-ICG seem to be associated with adverse outcome in patients undergoing coronary artery bypass grafting. This prospective observational trial was designed to evaluate the potential role of PDR-ICG as an outcome prediction tool in a mixed set of cardiac surgery patients.

Aktuelle Aspekte zur Diagnostik der hepatischen Dysfunktion beim kritisch Kranken

Hepatic dysfunction may develop in critically ill patients in the course of extrahepatic diseases such as sepsis and is frequently limiting prognosis. Conventional "static" laboratory parameters assess hepatocellular damage, synthetic function or cholestasis, providing informations about (differential) diagnostic aspects, while their significance to assess rapid changes in flow and function in the critical care setting is limited. In contrast, quantitative (or "dynamic") liver function tests, such as measurement of plasma disappearance rate of indocyanine green (PDRICG) or 13C-methacetin metabolism, assess specific metabolic and/or excretory function of the liver together with sinusoidal perfusion at the time of measurement and can detect liver dysfunction early in the course of critical illness. In addition, PDRICG demonstrated prognostic significance, albeit, severity of canalicular excretory dysfunction might be underestimated. For chronic liver disease, scoring systems, such as the Child-Turcotte-Pugh-score or the MELD, were developed to assess severity of disease and probability of survival. Scoring systems are also used for graft allocation. Combining scoring systems with dynamic tests holds the potential to improve predictive value, e.g. in the transplant setting.

O1-080 - Phase I and Dose Finding Study of U3-1287, a Human Monoclonal Antibody Targeting HER3, in Japanese Patients with Advanced Solid Tumors

ABSTRACT Background HER3 is a key dimerization partner for HER-family members that activates oncogenic signaling pathways lead to cell survival and proliferation. U3-1287 is a fully human anti-HER3 monoclonal antibody that has demonstrated anticancer activity in preclinical models. In a preceding US phase I study, the tolerability of U3-1287 was evaluated up to the dose of 20 mg/kg without dose-limiting toxic effects (DLTs). In this study, we evaluated the tolerability, pharmacokinetics (PK) and potential antitumor activities of U3-1287 in Japanese patients with solid tumors up to the dose of 18 mg/kg. Methods Patients with advanced solid tumors that were well known to express HER3 were eligible (e.g. lung, breast, colorectal, cervical, esophageal, and sarcoma). Patients received U3-1287 9 or 18 mg/kg intravenously every 3 weeks (q3w). The incidence of anti-U3-1287 antibodies (HAHA), tumor response and U3-1287 related biomarkers were also evaluated. Results Nine patients, three at 9 mg/kg and six at 18 mg/kg, were enrolled. Five patients were male, all patients had ECOG PS ≤ 1 and median (range) age was 67 (50–69) years. Primary tumor types were lung (2), colorectal (2), esophageal (2), breast (1), cervical (1) and sarcoma (1). U3-1287-related AEs reported in ≥2 patients were ALT increase (3 patients), platelet count decrease, diarrhea, stomatitis, cheilitis, rash maculo-papular and AST increase (2 each). No DLTs were observed. Plasma disappearance of U3-1287 was bi-phasic and terminal half-life at the dose of 18 mg/kg was approximately 9 days. The PK profile was similar to the US phase I study. Four patients had a best response of stable disease. All patients tested negative for HAHA formation. Conclusions U3-1287 was well tolerated up to 18 mg/kg in Japanese patients with solid tumors. These data support a dosing regimen of 18 mg/kg q3w in future studies.

467P - Phase I Study of U3-1287, A Human Monoclonal Antibody Targeting Her3, in Japanese Patients with Advanced Solid Tumors

ABSTRACT Background HER3 is a key dimerization partner for HER-family members that activates oncogenic signaling pathways lead to cell survival and proliferation. Acquired-resistance to EGFR inhibitors may result from the activation of HER3 and/or HER2, which share overlapping the signaling pathways. U3-1287 is a fully human anti-HER3 monoclonal antibody that has demonstrated anticancer activity in preclinical models. In a preceding US phase I study, the tolerability of U3-1287 was evaluated up to the dose of 20 mg/kg without dose-limiting toxicities (DLTs). In this study, we evaluated the tolerability, pharmacokinetics (PK) and potential antitumor activities of U3-1287 in Japanese patients with solid tumors up to the dose of 18 mg/kg. Methods Patients received U3-1287 at a dose of 9 mg/kg or 18 mg/kg intravenously every 3 weeks (q3w). Tumor response, incidence of anti-U3-1287 antibodies (HAHA), and level of soluble HER3 (sHER3) were also evaluated. Results Nine patients, 3 at 9 mg/kg and 6 at 18 mg/kg, were enrolled. Five patients were male and median (range) age of 67 (50-69) years. Tumor types were lung (2), colorectal (2), esophageal (2), breast (1), cervical (1), and sarcoma (1). No DLTs were reported. U3-1287-related AEs were ALT increase (3 patients), thrombocytopenia, diarrhea, stomatitis, cheilitis, rash, and AST increase (2 each). Plasma disappearance was bi-phasic and terminal half-life at the dose of 18 mg/kg was approximately 9 days. PK profiles were similar to those in the US phase I study. Four patients had best responses of stable disease. All patients tested were negative for HAHA formation. Level of sHER3 unexpectedly increased about four times in all patients. Mean sHER3 concentrations at baseline and day 15 were 3.8 ng/mL and 16.5 ng/mL, respectively. These changes did not correlate with clinical response (at day15 in SD and PD patients; 16.7 ng/mL and 16.9 ng/ml, respectively). Conclusions U3-1287 was well tolerated up to 18 mg/kg in Japanese patients with solid tumors. These data support a dosing regimen of 18 mg/kg q3w in future studies. Disclosure All authors have declared no conflicts of interest.

Effect of pre- and probiotics on liver regeneration after resection: a randomised, double-blind pilot study

Liver regeneration is a prerequisite for extended liver surgery. Several studies have shown that the bacterial gut flora is able to modulate liver function. Previously we observed that synbiotics could partly reverse the impaired mitosis rate of hepatocytes in a rat model of synchronous liver resection and colon anastomosis. The effect of synbiotics on liver function after hepatic resection has not been analysed yet. A prospective randomised double-blind pilot trial was undertaken in 19 patients scheduled for right hepatectomy. All patients received enteral nutrition immediately post-operatively. Comparison was made between a group receiving a combination of four probiotics and four fibres and a placebo group receiving the fibres only starting the day before surgery and continuing for 10 days. Primary study endpoint was the liver function capacity measured by 13C-methacetin breath test and indocyanine green plasma disappearance rate. Portal vein flow, liver volumetry, laboratory parameters for liver function, length of hospital stay, post-operative complications and side effects of synbiotic therapy were recorded. Liver function capacity was comparable in both groups. Complications had a negative impact on liver function. Because complications were more severe in the verum group, a sub-analysis was performed. In case of an uncomplicated course, liver function capacity was better in the patients with synbiotics. No severe side effects occurred. Synbiotics might be able to increase liver function capacity in patients after liver resection, but patient numbers were too small and the clinical courses too heterogeneous to draw any definite conclusions.