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PURPOSE - N(1),N(11)-diethylnorspermine (DENSPM), a synthetic analog of the naturally occurring polyamine spermine, can induce polyamine depletion and inhibit tumor cell growth. The objectives of this phase I study were to assess the safety, maximum-tolerated dose (MTD), pharmacokinetics, and preliminary antitumor activity of DENSPM in advanced HCC.
METHODS - Patients with measurable advanced HCC, Child-Pugh A or B cirrhosis, CLIP score ≤3, and Karnofsky score ≥60 % were eligible. DENSPM was given as a short intravenous infusion on days 1, 3, 5, 8, 10, and 12 of each 28-day cycle. The starting dose of 30 mg/m(2) was escalated at a fixed increment of 15 mg/m(2) until the MTD was identified. The plasma pharmacokinetics of DENSPM for the first and last doses given in cycle 1 was characterized.
RESULTS - Thirty-eight patients (male 79 %; median age 61 years; Child-Pugh A 84 %; ≥1 prior systemic therapy 45 %) were enrolled and treated. The most common adverse events (AEs) ≥grade 1 were fatigue (53 %), nausea (34 %), diarrhea (32 %), vomiting (32 %), anemia (29 %), and elevated AST (29 %). The most common grade 3-4 AEs were fatigue/asthenia (13 %), elevated AST (13 %), hyperbilirubinemia (11 %), renal failure (8 %), and hyperglycemia (8 %). The MTD was 75 mg/m(2). There were no objective responses, although 7/38 (18 %) patients achieved stable disease for ≥16 weeks. The overall mean (±SD) total body clearance for the initial dose, 66.3 ± 35.9 L/h/m(2) (n = 16), was comparable to the clearance in patients with normal to near normal hepatic function. Drug levels in plasma decayed rapidly immediately after the infusion but remained above 10 nM for several days after dosing at the MTD.
CONCLUSIONS - N(1),N(11)-diethylnorspermine treatment at the MTD of 75 mg/m(2), given intravenously every other weekday for two consecutive weeks of each 28-day cycle, was relatively well tolerated in patients with advanced HCC including those with mild-to-moderate liver dysfunction. This administration schedule provided prolonged systemic exposure to potentially effective concentrations of the drug. Stable disease was seen in 18 % of patients receiving DENSPM treatment. Further evaluation of DENSPM monotherapy for advanced HCC does not appear to be justified because of insufficient evidence of clinical benefit in the patients evaluated in this study.
The aim of this study was to re-evaluate the indications and timing of LT for WD. From 2000 to 2009, eight patients with WD who had been referred to our institution for LT were enrolled in this study. The mean patient age was 15.9 yr (range, 7-37 yr). Four patients could not receive LT, because there were no available donors. All four patients were treated with chelating agent medication. Three of them (two of two patients with fulminant WD and one of two with cirrhotic WD) who did not undergo LT are still alive and doing well with stable liver functional tests. Only one of the patients with cirrhotic WD who did not undergo LT died of hepatic failure. Even among the four patients who underwent LT, one with fulminant WD recovered from hepatic encephalopathy with apheresis therapy and chelating agent. He later required LT because of severe neutropenia from d-penicillamine. The other three patients who underwent LT recovered and have been doing well. Some of the patients with WD can recover and avoid LT with medical treatment. Even when WD has progressed liver cirrhosis and/or fulminant hepatic failure at the time of diagnosis, medical treatment should be tried before considering LT.
© 2013 John Wiley & Sons A/S.
Voriconazole pharmacokinetics are not well characterized in children despite prior studies. To assess the appropriate pediatric dosing, a study was conducted in 40 immunocompromised children aged 2 to <12 years to evaluate the pharmacokinetics and safety of voriconazole following intravenous (IV)-to-oral (PO) switch regimens based on a previous population pharmacokinetic modeling: 7 mg/kg IV every 12 h (q12h) and 200 mg PO q12h. Area under the curve over the 12-h dosing interval (AUC(0-12)) was calculated using the noncompartmental method and compared to that for adults receiving approved dosing regimens (6 → 4 mg/kg IV q12h, 200 mg PO q12h). On average, the AUC(0-12) in children receiving 7 mg/kg IV q12h on day 1 and at IV steady state were 7.85 and 21.4 μg · h/ml, respectively, and approximately 44% and 40% lower, respectively, than those for adults at 6 → 4 mg/kg IV q12h. Large intersubject variability was observed. At steady state during oral treatment (200 mg q12h), children had higher average exposure than adults, with much larger intersubject variability. The exposure achieved with oral dosing in children tended to decrease as weight and age increased. The most common treatment-related adverse events were transient elevated liver function tests. No clear threshold of voriconazole exposure was identified that would predict the occurrence of treatment-related hepatic events. Overall, voriconazole IV doses higher than 7 mg/kg are needed in children to closely match adult exposures, and a weight-based oral dose may be more appropriate for children than a fixed dose. Safety of voriconazole in children was consistent with the known safety profile of voriconazole.
The current voriconazole dosing recommendation in adolescents is based on limited efficacy and pharmacokinetic data. To confirm the appropriateness of dosing adolescents like adults, a pharmacokinetic study was conducted in 26 immunocompromised adolescents aged 12 to <17 years following intravenous (IV) voriconazole to oral switch regimens: 6 mg/kg IV every 12 h (q12h) on day 1 followed by 4 mg/kg IV q12h, then switched to 300 mg orally q12h. Area under the curve over a 12-hour dosing interval (AUC(0-12)) was calculated using a noncompartmental method and compared to the value for adults receiving the same dosing regimens. On average, the AUC(0-12) in adolescents after the first loading dose on day 1 and at steady state during IV treatment were 9.14 and 22.4 μg·h/ml, respectively (approximately 34% and 36% lower, respectively, than values for adults). At steady state during oral treatment, adolescents also had lower average exposure than adults (16.7 versus 34.0 μg·h/ml). Larger intersubject variability was observed in adolescents than in adults. There was a slight trend for some young adolescents with low body weight to have lower voriconazole exposure. It is likely that these young adolescents may metabolize voriconazole more similarly to children than to adults. Overall, with the same dosing regimens, voriconazole exposures in the majority of adolescents were comparable to those in adults. The young adolescents with low body weight during the transitioning period from childhood to adolescence (e.g., 12 to 14 years old) may need to receive higher doses to match the adult exposures. Safety of voriconazole in adolescents was consistent with the known safety profile of voriconazole.
PURPOSE - To report the incidence of liver function test (LFT) toxicities after radioembolization with yttrium-90 ((90)Y) SIR-Spheres and review potential risk factors.
MATERIALS AND METHODS - Patients receiving (90)Y for radioembolization of primary or metastatic liver tumors had follow-up LFTs 29-571 days after treatment. The incidence and duration of bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) toxicities were documented using common terminology criteria. Factors that were assessed included previous intra-arterial (IA) therapy, systemic chemotherapy, low tumor-to-normal liver tissue ratio at mapping angiography, vascular stasis, and higher prescribed (90)Y doses.
RESULTS - There were 81 patients who underwent 122 infusions and had follow-up LFTs. Of 122 infusions, 71 (58%) were associated with toxicity. One patient died with radiation-induced liver disease. Grade 3 or greater toxicities occurred in seven (7%) patients after nine procedures. The median durations of laboratory elevations for bilirubin, AST, and ALT were 29 days, 29 days, and 20 days. Toxicity developed after 51 (71%) of 72 infusions with previous IA therapy versus 20 (40%) of 50 infusions in treatment-naïve areas (P = .0006). Absence of previous systemic therapy was associated with greater risk of toxicity versus previous chemotherapy (47% vs 66%, P = .03). Other factors were not associated with increased toxicity.
CONCLUSIONS - Mild hepatotoxicity developed frequently after infusion of SIR-Spheres using the body surface area method, with normalization of LFTs in most patients. Grade 3 or greater toxicities were seen in < 10% of infusions. Toxicity was strongly associated with previous IA therapy.
Copyright © 2011 SIR. Published by Elsevier Inc. All rights reserved.
BACKGROUND - Liver stiffness measurement (LSM) by transient elastography has recently been validated for the evaluation of liver fibrosis in chronic liver diseases. The present study focused on cases in which liver biopsy and LSM were discordant.
METHODS - Three hundred eighty-six patients with chronic hepatitis C who underwent a liver biopsy between December 2004 and April 2007 were studied. First, the optimal cut-off value of LSM was selected for the determination of cirrhosis based on the receiver operating characteristic curve. Then, the cases in which liver histology and evaluation by LSM were discordant were selected. Laboratory test results such as serum total bilirubin concentration, prothrombin activity, albumin concentration, platelet count and the aspartate aminotransferase to platelet ratio index, together with the presence of esophageal varices, were analyzed.
RESULTS - The optimal cut-off value was chosen to be 15.9 kPa for cirrhosis (fibrosis stage [F] 4) determination to maximize the sum of sensitivity (78.9%) and specificity (81.0%). There were 78 discordant cases: 51 patients showed an LSM of 15.9 kPa or higher and a fibrosis stage of F1 to F3 (high LSM group), and 27 patients had an LSM lower than 15.9 kPa and a fibrosis stage of F4 (low LSM group). Esophageal varices were seen in 11 patients in the high LSM group (n=51) and in no patients in the low LSM group (n=27) (P=0.0012). The aspartate aminotransferase to platelet ratio index was significantly higher in the high LSM group (1.49 versus 0.89, P=0.019). Other parameters did not differ significantly. However, platelet count, prothrombin activity and albumin concentration tended to be lower in the high LSM group.
CONCLUSIONS - Patients with a high LSM need proper attention for cirrhosis, even if liver biopsy does not reveal cirrhosis.
Treatment of primary and secondary hepatic malignancies with transarterial chemoembolization represents an essential component of interventional oncology. This article discusses patient selection, procedure technique, results, and complications associated with transarterial chemoembolization.
BACKGROUND - Abnormal liver enzymes and endstage liver disease are reported to occur in 25%-100% and 15%-40% of adult patients receiving long-term parenteral nutrition (PN), respectively. The purpose of this historic cohort study was to investigate the incidence of and possible factors leading to the development of liver disease in our large home PN population.
METHODS - All patients on home PN for at least 6 months from July 1991 through June 2002 were eligible. Patients were excluded if they had active malignancy, underlying liver disease, or exposure to a hepatotoxin. The presence of PN-associated liver disease was only considered if test results were elevated on more than 1 occasion over at least 6 or more months. The severity of liver-associated enzymes was based on the degree of elevation and was stratified as mild (<2 times normal), moderate (2-5 times normal), and severe (>5 times normal). Severe liver dysfunction was defined as having all of the following criteria: total bilirubin >3 mg/dL; albumin <3.2 g/dL; and prothrombin time >3 seconds prolonged. A cumulative logit model was used to compare age, gender, underlying disease, PN indication, and PN formulas in patients with normal vs abnormal laboratory test results.
RESULTS - Two hundred eight patients received PN for more than 6 months, 36 had exclusion criteria, and 10 could not be analyzed, because of incomplete laboratory test results, leaving 162 in the study group. The average PN duration was 2.14 +/- 2.19 years (maximum, 10.28 years). Abnormal liver tests occurred in 154 patients, with most having a moderate elevation of alkaline phosphatase or aspartate aminotransferase; severe liver dysfunction occurred in 7 patients; 1 patient had completely normal liver enzymes. On average, patients received a PN formula that was high in amino acids (1.45 +/- 0.65 g/kg/d), modest in energy (24.7 +/- 13.4 kcal/kg/d), and in most cases with enough lipid emulsion to meet essential fatty acid requirements (0.28 +/- 0.25 g/kg/d). Only female gender was found to be associated with a greater likelihood of liver failure (p = .02). There was a trend toward a greater amount of total calories, dextrose calories, and duration of PN exposure leading to the development of severe liver dysfunction.
CONCLUSIONS - When long-term PN is given with a modest amount of total energy and a minimal amount of lipid emulsion, abnormal liver enzymes are common, but severe liver dysfunction is unusual.
Previous studies have demonstrated the ability of the dithiocarbamate, disulfiram, to produce a peripheral neuropathy in humans and experimental animals and have also provided evidence that N,N-diethyldithiocarbamate (DEDC) is a proximate toxic species of disulfiram. The ability of DEDC to elevate copper levels in the brain suggests that it may also elevate levels of copper in peripheral nerve, possibly leading to oxidative stress and lipid peroxidation from redox cycling of copper. The study presented here investigates the potential of DEDC to promote copper accumulation and lipid peroxidation in peripheral nerve. Rats were administered either DEDC or deionized water by ip osmotic pumps and fed a normal diet or diet containing elevated copper, and the levels of metals, isoprostanes, and the severity of lesions in peripheral nerve and brain were assessed by ICP-AES/AAS, GC/MS, and light microscopy, respectively. Copper was the only metal that demonstrated any significant compound-related elevations relative to controls, and total copper was increased in both brain and peripheral nerve in animals administered DEDC on both diets. In contrast, lesions and elevated F2-isoprostanes were significantly increased only in peripheral nerve for the rats administered DEDC on both diets. Autometallography staining of peripheral nerve was consistent with increased metal content along the myelin sheath, but in brain, focal densities were observed, and a periportal distribution occurred in liver. These data are consistent with the peripheral nervous system being more sensitive to DEDC-mediated demyelination and demonstrate the ability of DEDC to elevate copper levels in peripheral nerve. Additionally lipid peroxidation appears to either be a contributing event in the development of demyelination, possibly through an increase of redox active copper, or a consequence of the myelin injury.
We analyzed plasma pharmacokinetics of busulfan in 64 children and young adults (age 2.8-26; median 11 years) with homozygous beta-thalassemia transplanted with bone marrow from HLA-identical sibling donors. A uniform conditioning regimen was employed, using busulfan 14 or 16 mg/kg in 12 divided doses, and cyclophosphamide 120 or 200 mg/kg. Three sets of parameters were examined in this homogenous patient population: (1) factors that affect the plasma kinetics of busulfan, such as age and pre-transplant liver status defined by liver function tests, ferritin levels and liver biopsy; (2) busulfan-related toxicity: occurrence of veno-occlusive disease, seizures and idiopathic interstitial pneumonitis; and (3) the relationship between busulfan exposure and transplant outcome: engraftment delay or rejection, aplasia, occurrence of mixed chimeras and mortality. Kinetic analysis of first and 10th dose (using area under the curve (AUC), maximum and minimum concentration) as comparable, showing no sign of accumulation or decline in busulfan plasma levels over time. Age and liver status did not influence busulfan metabolism. No relationship was found between busulfan exposure and toxicities or transplant outcome. We conclude that busulfan monitoring is not predictive in children and young adults with homozygous beta-thalassemia receiving busulfan and high-dose cyclophosphamide along with histocompatable sibling donor marrow.