Increased Liver Transaminases Research Articles

PL03.05: BRAIN: A Phase III Trial Comparing WBI and Chemotherapy with Icotinib in NSCLC with Brain Metastases Harboring EGFR Mutations (CTONG 1201)

Non-small cell lung cancer (NSCLC) with brain metastases (M) had a poor prognosis. Whole brain irradiation (WBI) is a standard of care for this critical medical condition. The median survival is only 4-6 months. Small molecule inhibitors of epidermal growth factor receptor (EGFR) including icotinib achieved very successful results in advanced NSCLC with EGFR mutations. There were no prospective randomized clinical trials to explore the efficacy of EGFR tyrosine kinase inhibitors (TKIs) on brain M. Advanced NSCLC with EGFR sensitive mutations and brain M were randomized to WBI plus chemotherapy (chemo) or icotinib. Patients in WBI arm received radiotherapy with 30Gy/3Gy/10 fractions plus concurrent or sequential doublet chemo of 4-6 cycles. Patients in EGFR TKI arm received icotinib 125mg orally tid until disease progression. Icotinib could be continued beyond progression if clinical benefit was observed by the investigator. Crossover to icotinib from WBI could be permitted. Key inclusion criteria were EGFR mutations and radiologically confirmed brain M with at least 3 lesions. The primary endpoint was intracranial progression-free survival (iPFS) by investigator assessments according to RECIST v1.1. The secondary endpoints included objective response rate (ORR), PFS and overall survival (OS). Safety and tolerability were assessed by measuring adverse events (AEs)(CTCAE v4). From Dec. 2012 to June 2015, 176 patients from 17 sites were randomized to WBI+Chemo arm (N=91) or icotinib arm (N=85). The baseline clinicopathologic factors were balanced between the two groups. Median age was 58, PS 1 was 87.2%, non-smoker 70.9%, adenocarcinoma 96.8%, symptomatic brain M were 16.5%. Icotinib significantly improved median iPFS compared with WBI+chemo: hazard ratio [HR] 0.56; 95% CI: 0.36-0.90; p=0.014 (10.0 vs 4.8 months). Median PFS was 6.8 vs 3.4 months, (HR 0.44, 95% CI 0.31-0.63, P<0.001). Median OS had no significant difference between the arms (18.0 vs 20.5 months, HR 0.93, 95%CI 0.60-1.44, P=0.734). Intracranial ORR was significantly improved with icotinib than WBI+Chemo (67.1% vs 40.9%; p<0.001); Overall ORR was 55.0% vs 11.1% (P<0.001). Grade ≥3 AEs assessed by the investigators were reported in 8.2% (N=7) of patients treated with icotinib and 26.2% (N=28) treated with WBI+Chemo. Most common causally related AEs in the icotinib arm were increased liver transaminase & rash; in the WBI+Chemo arm were hematologic toxicity. Icotinib demonstrated superior iPFS, PFS and ORR over WBI+Chemo in EGFR mutant advanced NSCLC with brain M, and well-tolerated safety profile. Icotinib would be a treatment option for EGFR mutant patients with brain M (NCT01724801).

Clinical, Biochemical, and Histopathology Features of Patients With Glycogenic Hepatopathy.

Glycogenic hepatopathy, a syndrome characterized by hepatomegaly and increased liver transaminases in patients with type 1 diabetes, has not been well characterized in adults. We describe the clinical, biochemical, and histopathology profile of a cohort of patients with glycogenic hepatopathy. We also examined differences between patients with type 1 diabetes with versus without glycogenic hepatopathy. We performed a case-control study of patients with type 1 diabetes diagnosed with glycogenic hepatopathy and patients with type 1 diabetes without glycogenic hepatopathy (control subjects). Cases were identified in the database of electronic medical records at Mayo Clinic, Rochester from January 1, 1998, through January 1, 2014. Age- and sex-matched control subjects were identified from a Mayo Clinic registry of patients with type 1 diabetes who had normal levels of liver enzymes. Demographic, clinical, laboratory, and histopathology data were collected and compared between cases and control subjects. The primary outcome was difference in frequency of diabetic ketoacidosis episodes and hemoglobin (Hb) A1c levels between cases and control subjects. Among the 36 patients diagnosed with glycogenic hepatopathy, 20 had undergone liver biopsy analysis. Most cases were female (n= 28; 77.8%). Abdominal pain was the most common symptom (n= 23; 63.9%); 28 patients (77.8%) had hepatomegaly. All patients had poor control of diabetes (mean HbA1c level, 11.2 ± 2.4%). A higher proportion of cases had recurrent episodes of diabetic ketoacidosis (61%) than control subjects (9%) (P= .009), and cases had a higher mean level of HbA1c (11.2 ± 2.4% vs 9.0 ± 2.2% in control subjects; P= .0004). Adult cases had higher levels of aspartate transaminase (312.5 IU/L; range, 245.5-775 IU/L) than pediatric cases (157; range, 104-267 IU/L; P= .02) and lower serum levels of albumin (3.7 ± 0.5 g/dL vs 4.3 ± 0.4 g/dL for pediatric cases; P= .008). Only 16.7% of pediatric patients with glycogenic hepatopathy had growth retardation. Levels of liver transaminases were normalized at follow-up examinations of 18 of 21 adult or pediatric patients with glycogenic hepatopathy. More than half of patients with glycogenic hepatopathy and type 1 diabetes have recurrent episodes of diabetic ketoacidosis, and these patients have higher levels of HbA1c than patients with type 1 diabetes without glycogenic hepatopathy. We observed growth retardation in only about 17% of pediatric patients with glycogenic hepatopathy.

No Increased Risk of Ketoconazole Toxicity in Drug-Drug Interaction Studies.

In July 2013 the U.S. Food and Drug Administration (FDA) released a safety announcement regarding the use of ketoconazole and its adverse drug reactions. The FDA report advised against the use ketoconazole tablets as a first-line treatment for any fungal infections because of the risk of potentially serious drug-drug interactions and liver and adrenal gland complications. The European Medicines Agency (EMA) also proposed to limit the use of oral ketoconazole in fungal infections because of the same risk of harmful effects and interactions. In addition, the FDA also advised against the use of oral ketoconazole in drug interaction studies, in which it has been extensively used as an index inhibitor of drug metabolism. The aim of this investigation was to evaluate the risks of ketoconazole-induced hepatotoxicity described by the FDA and EMA in published drug interaction studies with ketoconazole and compare these data with the toxicity reported for ketoconazole when used as antifungal treatment. In the drug interaction studies (2355 participants; healthy volunteers and patients; median treatment duration, 6 days), only 40 participants were reported to have increased liver transaminase activity (1.7%), and no deaths were reported or associated with ketoconazole. In studies investigating ketoconazole treatment, patients were treated for 276 days (median), and 5.6% of patients had elevated liver enzyme activity. Because of the short treatment period in drug interaction studies the risk of drug-induced hepatic injury is considered very low. As such, we recommend that ketoconazole remain a safe CYP3A index inhibitor for use in drug interaction studies with healthy volunteers.

To compare the efficacy of alternate day versus everyday dosing of atorvastatin in hyperlipidemic rabbits

Background: Muscle pain is often seen with statin therapy. Statins have also been associated with increase in liver transaminases as they lead to hepatic injury. The half - life of atorvastatin is increased due to its active metabolites which suggest the possibility for its alternate day use over everyday use. This would mean reduction in side effects such as hepatotoxicity and myopathy and solving the problem of statin underutilization in patients of lower socio economic class. Methods: Institutional Animal Ethics Committee (IAEC) approval was taken before the start of study. Hyperlipidemia was induced in New Zealand White rabbits by oral administration of high fat diet for 3 weeks. After 3 weeks all the laboratory tests were done to see if animals had developed hyperlipidemia. This day was considered as day 0 for further study. Hyperlipidemic rabbits were divided into two groups, first group receiving atorvastatin orally (5mg/kg) daily for duration of 6 weeks while the other group receiving atorvastatin orally (5mg/kg) at alternate days for same duration. All the laboratory tests were done at week 3 and week 6. Both the treatment groups were compared pairwise and also with day 0 to check for efficacy and safety. Results: At the end of 6 weeks every day and alternate day dosing of atorvastatin, showed a statistical decrease in total cholesterol, triglycerides and LDL-C with respect to day 0. Pairwise comparison did not show any statistical difference in between the two treatment groups. Statistical increase in HDL-C was seen only with everyday dosing of atorvastatin as compared to day 0. Pairwise comparison showed statistical difference in between two treatment groups. At the end of 6 weeks, there was no statistical difference in SGOT, SGPT and CK levels when compared to day 0. Conclusions: Alternate day dosing of atorvastatin was as efficacious and safe as everyday dosing of atorvastatin in hyperlipidemic New Zealand White rabbits, thus being a cost effective alternative.

Individual analysis of patients with HoFH participating in a phase 3 trial with lomitapide: The Italian cohort

Background and aimsThe efficacy and safety of lomitapide as adjunct treatment for adults with homozygous familial hypercholesterolaemia (HoFH) have been confirmed in a phase 3 trial. Given the small number of patients (N = 29), and variations in patient characteristics, examining individual cases provides additional details regarding patient management with lomitapide. Here, we examine the details of the Italian patient cohort in the phase 3 trial. Methods and resultsThe methodology of the multinational, single-arm, open-label, 78-week, dose-escalation, phase 3 trial has been previously reported. The current report details the Italian cohort of six patients (three males, three females) based on individual patient data, individual patient histories and narratives, and by mean data ± SD.Lomitapide was administered according to the dose-escalation protocol. At Week 78, concentrations of low-density lipoprotein-cholesterol were decreased by a mean of 42.6 ± 21.8% compared with baseline. Lomitapide was similarly well tolerated in the Italian cohort as in the entire study population. The most common adverse events were gastrointestinal symptoms. One patient showed an increase in liver transaminases >5× upper limit of normal that resolved after lomitapide treatment was reduced and maintained at a lower dose. ConclusionThe efficacy, safety and tolerability of lomitapide demonstrated in the Italian subgroup of patients are consistent with findings in the entire study population, and illustrate the broad applicability of lomitapide therapy across genotypes and clinical phenotypes. These data also provide an insight into the management of lomitapide use in a cohort of patients within a clinical trial protocol.Clinicaltrials.gov Identifier: NCT00730236.

Eltrombopag: a review of its use in patients with severe aplastic anaemia.

Eltrombopag (Promacta®) is an orally active thrombopoietin receptor agonist recently approved in the US for the treatment of patients with severe aplastic anaemia who have had an insufficient response to immunosuppressive therapy. This article reviews the efficacy and tolerability of eltrombopag in this indication and overviews its pharmacological properties. Eltrombopag does not compete with thrombopoietin and binds to a different site on the receptor, producing additive effects. It stimulates haematopoietic stem cells and promotes haematopoietic recovery in patients with aplastic bone marrow. Eltrombopag increased platelet counts and can also increase red blood cell and neutrophil counts. In patients with severe aplastic anaemia refractory to prior immunosuppressive therapy, oral eltrombopag at dosages ≤150 mg once daily for 12-16 weeks produced a haematological response in at least one cell lineage in 40 % of patients. Trilineage responses were achieved in nearly one-half of the responders during extended treatment. In robust responders, stable haematological counts were maintained after eltrombopag discontinuation. Eltrombopag was generally well tolerated, with increased liver transaminases as the only dose-limiting toxicity. Clonal cytogenetic abnormalities were observed in 19 % of patients and dysplasia in 5 % of patients.

Brentuximab Vedotin Followed By ABVD in Patients with Previously Untreated Hodgkin Lymphoma. a Pilot Phase II Study

active and well tolerated single agent in the treatment of heavily pretreated Hodgkin lymphoma patients. In this pilot phase II study patients with previously untreated HL underwent sequential regimen consisting in 2 cycles of BV before doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) +/- radiotherapy (RT). The primary endpoint of the study was the response to BV assessed by positron emission tomography (PET) after the 2 cycles (PET2), defined as reduction of Deauville score or, in case of no change in Deauville score, as any reduction in standard uptake value (SUV) intensity compared to basal SUV.Between April and October 2013, 12 patients with a median age at diagnosis of 36 years (range, 19-70), 11 stage I-IIA and 1 stage IIIA, were enrolled. BV was administered as scheduled and at the full dose of 1.8 mg/kg in all patients. After the 2 cycles of BV, the overall response rate was 91%, comprising of ten (83%) complete responses and one (8%) partial metabolic response. The non responding patient had stage III and showed a new lesion at PET2. After ABVD +/- RT, the overall response rate was 100% with 11 complete responses and 1 partial response (converting from progression disease). At a median follow up of 8 months, all 11 patients are still in complete response, while the remaining one relapsed.During BV therapy, the only grade 3 adverse events were transient and asymptomatic increase in liver transaminases (n=3, 25%) and gamma glutamyl transpeptidase (n=2, 17%). During ABVD +/- RT grade III-IV neutropenia occurred in 9 (75%) patients. All toxicities were transient and resolved with growth factor support.Two cycles of BV as first line-treatment in limited stage HL induced an outstanding complete response rate with limited toxicity and reducing the need of chemotherapy. Waiting for a longer follow up to assess the duration of response, our data (sequential administration of immunotherapy and chemotherapy) should be considered the starting point for further studies in first line therapy for limited stage HL patients. DisclosuresNo relevant conflicts of interest to declare.

Interrelation of blood lipid spectrum, level of systemic inflammation and mass of body in patients with coronary heart disease in combination with nonalcoholic fatty liver disease and their dynamics in terms of secondary prevention.

The article analyzes the blood lipid spectrum, level of systemic inflammation and their dynamics depending on body mass index in patients with coronary heart disease (CHD) in combination with nonalcoholic fatty liver disease (NAFLD) under the of influence statin therapy. 20 men (mean age 56,4±1,44 years) with CHD and NAFLD were examined. Levels of triglycerides (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), C-reactive protein (CRP) were studied. 2 groups of patients according to BMI were distinguished: group 1 consisted of 9 (45%) patients who are overweight (BMI 25 to 30 kg/m 2 ), group 2-8 (40%) with first degree of obesity (BMI 30 to 35). It was at found that at the initial state BMI increase at the range of 25-35 kg/m 2 was not associated with a significant difference in the lipid spectrum, on the other hand on the background of treatment with pitavastatin in the dose of 2 mg for 8 weeks in patients with BMI of 25-30 kg/m 2 more intensive reduction of TG (56.6%), LDL-C (31,8%), total cholesterol (22%), CRP (29.8%) and increased HDL-C (14,7%) was registered in contrast to the patients with BMI 30-35 kg/m 2 – 33,7%, 22,8%, 8,8%, 10,1%, 11,9% respectively. Thus, in patients with CHD and NAFLD, pitavastatin in the dose of 2 mg has a moderate lipid-lowering effect, causes no significant increase in liver transaminases, which required dose adjustment or discontinuation of the drug.

Phase 3, Double-Blind, Placebo-Controlled Study of Vemurafenib Versus Vemurafenib + Cobimetinib in Previously Untreated Brafv600 Mutation–Positive Patients with Unresectable Locally Advanced or Metastatic Melanoma (Nct01689519)

was 68% in the combination and 45% in the control arm (P<0.0001), including complete response in 10% in the combination and 4% of patients in the control group. Subgroup analyses of PFS based on key demographic and tumor characteristics were consistent with PFS in the intent-to-treat population, including those with normal or elevated baseline lactate dehydrogenase (LDH). PFS assessed by independent review was comparable with investigator-assessed PFS. Interim overall survival (OS) data showed an HR of 0.65 (95% CI, 0.42-1.00) but did not cross the prespecified stopping boundary. Compared with vemurafenib alone, the combination was associated with a higher incidence of grade 3 or 4 adverse events (65% vs 59%), with no difference in the rate of adverse events leading to study drug discontinuation (13% vs 12%). Most grade ≥3 events occurred in the first 28 days and resolved quickly. Known MEK inhibitor–related toxicities such as diarrhea, serous retinopathy, elevated creatine phosphokinase, and increased liver transaminase levels were more commonly observed with the combination. The majority was grade 1 or 2, occurred between 1 and 4 months in the treatment course, and resolved quickly. The occurrence of secondary cutaneous neoplasms decreased with the combination (4% vs 18%). Photosensitivity was more common in patients treated with the combination (all grades 32% vs 18%).

Liver sinusoidal endothelial dysfunction after LPS administration: A role for inducible-nitric oxide synthase

Sepsis is associated with microvascular dysfunction, which contributes to organ failure. Intrahepatic endothelial dysfunction occurs after exposure to lipopolysaccharide (LPS). The upregulation of inducible nitric oxide synthase (iNOS) has been shown to contribute to systemic vascular dysfunction after LPS administration. However, little is known about the effects of iNOS induction on the liver microcirculation. This study aimed at exploring, in the isolated rat liver perfusion model, the role of iNOS induction in liver microvascular dysfunction associated with endotoxemia. All experiments were conducted in male Wistar rats, after 24 h of LPS (5 mg/kg i.p.) or saline administration in the presence or absence of the iNOS inhibitor 1400 W (3 mg/kg i.p.), administered 3 and 23 h after LPS/saline injection. Liver microvascular function was assessed by isolated liver perfusion, followed by molecular studies and liver function tests. At 24 h, LPS induced liver endothelial dysfunction, as shown by a decreased vasodilatory response to acetylcholine and decreased eNOS phosphorylation at Ser(1176). This was associated with liver injury, assessed by an increase in liver transaminases and decreased indocyanin green clearance, and increased nitrooxidative stress. iNOS inhibition prevented liver endothelial dysfunction, blunted the development of liver injury and attenuated LPS-induced nitrooxidative stress. iNOS upregulation contributes to liver microvascular dysfunction in endotoxemia. This suggests that this mechanism deserves further exploration in studies addressing liver protection in the context of severe acute bacterial infection.

Macitentan does not interfere with hepatic bile salt transport.

Treatment of pulmonary arterial hypertension with the endothelin receptor antagonist bosentan has been associated with transient increases in liver transaminases. Mechanistically, bosentan inhibits the bile salt export pump (BSEP) leading to an intrahepatic accumulation of cytotoxic bile salts, which eventually results in hepatocellular damage. BSEP inhibition by bosentan is amplified by its accumulation in the liver as bosentan is a substrate of organic anion-transporting polypeptide (OATP) transport proteins. The novel endothelin receptor antagonist macitentan shows a superior liver safety profile. Introduction of the less acidic sulfamide moiety and increased lipophilicity yield a hepatic disposition profile different from other endothelin receptor antagonists. Passive diffusion rather than OATP-mediated uptake is the driving force for macitentan uptake into the liver. Interaction with the sodium taurocholate cotransporting polypeptide and BSEP transport proteins involved in hepatic bile salt homeostasis is therefore limited due to the low intrahepatic drug concentrations. Evidence for this conclusion is provided by in vitro experiments in drug transporter-expressing cell lines, acute and long-term studies in rats and dogs, absence of plasma bile salt changes in healthy human volunteers after multiple dosing, and finally the liver safety profile of macitentan in the completed phase III morbidity/mortality SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome) trial.

A novel missense SMPD1 gene mutation, T460P, and clinical findings in a patient with Niemann–Pick disease type B presenting to a lipid disorders clinic

Niemann-Pick disease, type B (NPD-B; OMIM 607616) is an inborn error of metabolism where reduced concentrations of the enzyme acid sphingomyelinase (ASM; EC 3.1.4.12) lead to multisystem disease though with survival into adulthood. The natural history of NPD-B is one of progressive hypersplenism and gradual deterioration of pulmonary function. We describe a 46-year-old South African man of French Huguenot descent who presented to a lipid disorders clinic with mixed hyperlipidaemia. Clinical examination and imaging findings revealed the presence of massive hepatosplenomegaly, interstitial lung disease and subclinical atherosclerosis; there were no neurological or cognitive abnormalities. Laboratory testing showed thrombocytopaenia, increased liver transaminases and mild hyperbilirubinaemia. Lysosomal enzyme analysis showed markedly reduced ASM activity, suggestive of NPD. DNA sequence analysis of the SMPD1 gene revealed that he was a compound heterozygote for the previously reported c.1829_1831delGCC (ΔR608) mutation and a novel missense mutation c.1378A > C (p.T460P). In conclusion, we describe the clinical findings of a case of NPD-B with mixed hyperlipidaemia, compound heterozygous for the SMPD1 ΔR608 mutation and a novel mutation, T460P.

Drug information update: agomelatine

SummaryAgomelatine is a new antidepressant, licensed for the treatment of unipolar major depression, with a mode of action that combines activation of melatonin receptors with blockade of 5-HT2C receptors. Agomelatine is notable for its short duration of action in the body and modest side-effect burden; however, a number of theoretical and practical challenges have limited its adoption into mainstream treatment in the UK. Current meta-analyses show marginal clinical benefits of agomelatine relative to placebo and an association with occasional increases in liver transaminases. Theoretically it is not clear whether agomelatine does block brain 5-HT2C receptors in humans at therapeutic doses and the optimum daily timing of administration in depression has not been clearly established. However, agomelatine's novel mode of action justifies further study, perhaps with the eventual aim of matching its use in depression to patients with specific disturbances in circadian rhythm.

Acute metabolic decompensation due to influenza in a mouse model of ornithine transcarbamylase deficiency

ABSTRACTThe urea cycle functions to incorporate ammonia, generated by normal metabolism, into urea. Urea cycle disorders (UCDs) are caused by loss of function in any of the enzymes responsible for ureagenesis, and are characterized by life-threatening episodes of acute metabolic decompensation with hyperammonemia (HA). A prospective analysis of interim HA events in a cohort of individuals with ornithine transcarbamylase (OTC) deficiency, the most common UCD, revealed that intercurrent infection was the most common precipitant of acute HA and was associated with markers of increased morbidity when compared with other precipitants. To further understand these clinical observations, we developed a model system of metabolic decompensation with HA triggered by viral infection (PR8 influenza) using spf-ash mice, a model of OTC deficiency. Both wild-type (WT) and spf-ash mice displayed similar cytokine profiles and lung viral titers in response to PR8 influenza infection. During infection, spf-ash mice displayed an increase in liver transaminases, suggesting a hepatic sensitivity to the inflammatory response and an altered hepatic immune response. Despite having no visible pathological changes by histology, WT and spf-ash mice had reduced CPS1 and OTC enzyme activities, and, unlike WT, spf-ash mice failed to increase ureagenesis. Depression of urea cycle function was seen in liver amino acid analysis, with reductions seen in aspartate, ornithine and arginine during infection. In conclusion, we developed a model system of acute metabolic decompensation due to infection in a mouse model of a UCD. In addition, we have identified metabolic perturbations during infection in the spf-ash mice, including a reduction of urea cycle intermediates. This model of acute metabolic decompensation with HA due to infection in UCD serves as a platform for exploring biochemical perturbations and the efficacy of treatments, and could be adapted to explore acute decompensation in other types of inborn errors of metabolism.

A Novel SMPD1 gene mutation, T460P, in a patient with niemann–pick disease type b presenting to a lipid disorders clinic

Niemann–Pick disease type B (NPD-B; OMIM 607616) is an inborn error of metabolism where reduced levels of the enzyme acid sphingomyelinase (EC 3.1.4.12) lead to multisystem disease though with survival into adulthood. The natural history of NPD-B is one of progressive hypersplenism and gradual deterioration of pulmonary function. We report a 46-year-old South African man of French-Huguenot descent who presented to a lipid disorders clinic with mixed hyperlipidaemia. Clinical examination and imaging findings revealed the presence of massive hepatospleno-megaly, interstitial lung disease and subclinical atherosclerosis, in the absence of neurological abnormalities. Laboratory testing showed thromboctyopenia, increased liver transaminases and mild hyperbilirubinaemia. Lysosomal enzyme analysis showed markedly reduced acid sphingomyelinase activity, suggestive of NPD. DNA sequence analysis of the SMPD1 gene revealed that he was a compound heterozygote for the previously reported c.1829_1831delGCC (delta R608) mutation and a novel missense mutation c.1378A>C (p.T460P). In summary, we describe a case of NPD-B and report a novel missense SMPD1 mutation, T460P.

Toxicity Profile of Small-Molecule IAP Antagonist GDC-0152 Is Linked to TNF-α Pharmacology

Inhibitor-of-apoptosis (IAP) proteins suppress apoptosis and are overexpressed in a variety of cancers. Small-molecule IAP antagonists are currently being tested in clinical trials as novel cancer therapeutics. GDC-0152 is a small-molecule drug that triggers tumor cell apoptosis by selectively antagonizing IAPs. GDC-0152 induces NF-κB transcriptional activity leading to expression of several chemokines and cytokines, of which tumor necrosis factor alpha (TNF-α) is the most important for single-agent tumor activity. TNF-α is a pleiotropic cytokine that drives a variety of cellular responses, comprising inflammation, proliferation, and cell survival or death depending on the cellular context. As malignant and normal cells produce TNF-α upon IAP antagonism, increased TNF-α could drive both efficacy and toxicity. The toxicity profile of GDC-0152 in dogs and rats was characterized after iv dose administration once every 2 weeks for four doses. Findings in both species consisted of a dose-related, acute, systemic inflammatory response, and hepatic injury. Laboratory findings included elevated plasma cytokines, an inflammatory leukogram, and increased liver transaminases with histopathological findings of inflammatory infiltrates and apoptosis/necrosis in multiple tissues; a toxicology profile consistent with TNF-α-mediated toxicity. Dogs exhibited more severe findings than rats, and humans did not exhibit these findings, at comparable exposures across species. Furthermore, elevations in blood neutrophil count, serum monocyte chemoattractant protein-1, and other markers of inflammation corresponded to GDC-0152 exposure and toxicity and thus may have utility as safety biomarkers.

A phase II study of RO4929097 (RO), a gamma-secretase inhibitor, in advanced platinum (Pt)-resistant (R) ovarian cancer (OC): A study of the PMH, Chicago, and California phase II consortia.

5019 Background: Notch signalling pathway plays a critical role in regulating cellular differentiation, proliferation, and apoptosis in preclinical cancer models. The Notch receptor, its ligands, and down-stream effectors are over-expressed in OC. Inhibition of γ-secretase-mediated Notch cleavage is a primary focus for the development of targeted therapeutics. Methods: Women (pts) with progressive, measurable (RECIST), Pt-R OC treated with ≤ 2 chemotherapy regimens for recurrent disease were treated with oral RO at 20mg od, 3 days on/4 days off every week, q3w. The primary objective was to determine the antitumor efficacy of RO in Pt-R OC by the progression-free survival (PFS) rate at the end of 4 cycles. Secondary objectives were to assess the safety of RO and to explore molecular correlates of outcome in archival tumor tissue. A Simon two-stage design was used. The study would open to second stage accrual if &gt; 4 pts of the first 17 accrued remain progression-free at the end of 4 cycles. Results: 39 pts have been enrolled after first-stage criteria were met. Median age was 59 (range 26-81). Median number of cycles was 2 (range 1-18). 30 (83%) pts had high-grade serous OC. 34 pts were evaluable for response. 8 pts (20%) were progression-free after 4 cycles.12 pts (35%) had stable disease, with a median duration of 3.9 months (range 2.5-12.2). Median PFS was 1.3 months (1.2-2.3). The most common drug-related adverse events (AEs) of any grade (% pts) were: nausea (36), fatigue (28), anorexia (15), hypophosphatemia (15), anemia (13), and increased alanine aminotransferase [ALT] (13). There were 5 G3-4 AEs at least possibly related with RO: increased liver transaminases (2), diarrhea (1), headache (1), and hypophosphatemia (1). Intracellular Notch (NIC) and JAG1 protein expression on high-grade serous OC were correlated with response in 17 pts. Median PFS for pts with high NIC (n=6) was 3.3 months (1.0-not reached), compared to 1.3 months (1.1-2.6) for pts with low NIC (n=11), p=0.09. Conclusions: RO has limited clinical activity in unselected Pt-R OC as a single agent. Future studies need to assess potential for cohort enrichment using NIC expression.

Safety of statins: an update.

Statins are widely used and have been proven to be effective in the prevention of atherosclerotic vascular disease events, primarily by reducing plasma low-density lipoprotein cholesterol concentrations. Although statins are generally well tolerated and present an excellent safety profile, adverse effects from muscle toxicity and liver enzyme abnormalities may occur in some patients. Myopathy and rhabdomyolysis are rare with statin monotherapy at the approved dose ranges, but the risk increases with use of higher doses, interacting drugs and genetic predisposition. Asymptomatic increases in liver transaminases with statin treatment do not seem to be associated with an increased risk of liver disease. Therefore, statin treatment can be safely used in patients with mild to moderately abnormal liver tests that are potentially attributable to nonalcoholic fatty liver disease and can improve liver tests and reduce cardiovascular morbidity in this group of patients. The risks of other unfavorable effects such as the slightly increased risk of new-onset diabetes and potentially increased risk of haemorrhagic stroke are much smaller than the cardiovascular benefits with the use of statins.

Acute hepatitis in a woman following excessive ingestion of an energy drink: a case report

IntroductionThe consumption of energy drinks has increased significantly. We report the case of a patient who presented to our hospital with jaundice, abdominal pain, and markedly increased liver transaminases likely due to the increased consumption of an energy drink. To the best of our knowledge, this is the first case report in the literature linking the development of acute hepatitis to the consumption of an energy drink.Case presentationA 22-year-old Caucasian woman presented to our hospital with epigastric pain, nausea, vomiting, and low-grade fever. She had been drinking 10 cans of an energy drink daily for two weeks prior to presentation. Her physical examination revealed mild epigastric tenderness. Her initial blood tests revealed elevated alanine aminotransferase, aspartate aminotransferase, and total bilirubin. A computed tomographic scan of the abdomen and pelvis was normal, and the patient was discharged to home. She returned to the Emergency Department of our hospital with worsening pain and new-onset jaundice. This time her physical examination revealed epigastric tenderness and icteric sclera. Her aspartate aminotransferase, alanine aminotransferase, and international normalized ratio were markedly elevated. Further radiological studies were non-specific, and she was admitted to our hospital with a diagnosis of acute hepatitis. Her viral serology and toxicology screens were negative. The patient was treated supportively and was discharged after resolution of her symptoms and a marked decrease in her liver enzymes.ConclusionThe development of acute hepatitis in this patient was most likely due to the excessive ingestion of an energy drink, and we speculate that niacin was the culprit ingredient.

317 Cytomegalovirus Disease Causing Guillain-Barre' Syndrome in Living Renal Allograft Recipient: A Rare Presentation

CYTOMEGALOVIRUS DISEASE CAUSING GUILLAINBARRE’ SYNDROME IN LIVING RENAL ALLOGRAFT RECIPIENT: A RARE PRESENTATION Deepti D Torri ; Madhu Bhaskaran; Ernesto Molmenti; Mala Sachdeva NSLIJHS-Hofstra NS-LIJ School of Medicine, Great Neck, NY, USA. Guillain–Barre syndrome (GBS) is a rare neurological complication described in renal allograft recipients. To our knowledge; there is only one case report of a patient three months post cadaveric renal transplant who presented with simultaneous Cytomegalovirus (CMV) infection and GBS. We report the first case of GBS presenting after acute CMV infection in a patient who had received a living donor renal transplant. This is 47 year-old man with medical history significant for hypertension, metastatic melanoma of lung in remission and end stage renal disease. He underwent living unrelated renal transplant in 2008. His donor was CMV positive, and he was CMV negative. He was prophylaxed with valganciclovir for CMV for one and a half year. Two years post transplant he first presented with fever, chills, myalgias, and headache for seven days. His workup revealed mild thrombocytopenia, increase in liver transaminases, and a stable creatinine. Diagnosis of acute CMV infection was made based on positive CMV IgM, negative, CMV IgG and CMVPCR with 4800 copies/ml. Lumbar puncture (LP) and other serologic workup were negative. Patient was started on oral valganciclovir. Five days after initial presentation, he developed numbness and tingling in his hands and feet which ascended to his elbows and knees with decreased temperature sensation in his extremities. Two days later, his neurologic exam had changed significantly and involved tetraparesis with absent deep tendon reflexes bilaterally. Based on these findings, a diagnosis for GBS was made. He again underwent an LP, CSF fluid was typical for albuminocytologic dissociation. The patient was promptly started on plasmapheresis and was continued on oral valganciclovir. He received a total of 12 cycles of plasmapheresis and had complete recovery in 14 days. Post-transplant GBS in association with CMV has rarely been described. Early recognition and prompt treatment is critical to both proper management and overall outcomes. Plasmapheresis along with oral valganciclovir had significant impact on our patient’s clinical course, resulting in full recovery.