Increased Aminotransferase Levels Research Articles

Chemoembolization Adopting Polyethylene Glycol Drug-Eluting Embolics Loaded With Doxorubicin for the Treatment of Hepatocellular Carcinoma.

The purpose of this study is to determine the efficacy and tolerability of transarterial chemoembolization (TACE) using polyethylene glycol (PEG) drug-elutable microspheres loaded with doxorubicin for treatment of hepatocellular carcinoma (HCC). Forty-two patients with unresectable HCC, as determined by a tumor board, were assigned to undergo TACE and were treated with PEG drug-elutable embolics loaded with doxorubicin. Patients were prospectively enrolled and included 32 (76%) men and 10 (24%) women. Their median age was 65 years (range, 42-83 years). Patients were treated with 50 mg of doxorubicin loaded in 2 mL of PEG embolics (mean [± SD] diameter, 100 ± 25 µm) that were infused via a chemoembolization method. Data collected included previous cancer therapy, tumor size, number of lesions, history of TACE, tumor response (at 1, 3, and 6 months), type and intensity of adverse events, and quality of life (QOL) analysis. One month after TACE, the overall tumor response rate was 79% (50% complete response, 29% partial response, 17% stable disease, and 5% progressive disease). At 3 months, the rates were 48% for complete response, 24% for partial response, 24% for stable disease, and 3% for progressive disease. At 6 months, the rates were 43% for complete response, 19% for partial response, 29% for stable disease, and 10% for progressive disease. TACE was well tolerated by all patients, with no evidence of procedure-related complications or systemic drug-related adverse events. Fever (33%), increase in transaminase level (17%), and pain (33%) were the most frequent adverse events, and their intensity was mostly mild (grades 1 and 2). The QOL scores were 80 at 1 month, 81 at 3 months, and 82 at 6 months after TACE. These data suggest that PEG embolics are efficacious and safe for the treatment of HCC, as indicated by their good tolerability, QOL scores, and high tumor response.

Phase II study of BKM120 in patients with advanced esophageal squamous cell carcinoma (EPOC1303).

4069 Background: BKM120 is an oral pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, which showed promising activity in breast cancer and squamous cell carcinoma of head and neck. We prospectively investigated clinical activity, safety and biomarkers of BKM120 in advanced esophagus squamous cell carcinoma (ESCC). Methods: We conducted a multicenter phase II study of BKM120 monotherapy in patients with pretreated advanced ESCC. All the patients had a treatment history of fluoropyrimidine and platinum. BKM120 of 100 mg/day was orally administered in a 28-day cycle. A primary end-point was a disease control rate (DCR). Using Simon’s minimax two-stage design, total of 41 patients were required for primary analysis (promising DCR of 60%, non-promising one of 40%, one-sided alpha level of 10% and power of 90%). The response rate (RR), progression-free survival (PFS), overall survival (OS), and safety were also evaluated as secondary endpoints. Tumor samples for all the patients were required for gene alternation analysis in comprehensive genomic profiling assay (FoundationOne). Results: A total of 42 patients (median age, 62.5 years; performance status 0/1 = 28/14) were enrolled. One ineligible patient was excluded from primary analysis. Nineteen and two patients had SD and unconfirmed PR. DCR was 51.2% (95% CI, 35.1% to 67.1%), which met the primary endpoint of the study. Median PFS and OS was 2.0 months (95% CI, 1.8 to 3.2 months) and 9.0 months (95% CI, 6.4 to 11.7 months), respectively. Common grade 3 or 4 adverse events were anorexia, rash, hyponatremia, lipase increased, and abnormal hepatic function (including increased transaminase levels), which were profiles similar to previous studies of BKM120 monotherapy. No treatment-related deaths occurred. Further analyses of the gene alternation are ongoing. Conclusions: BKM120 monotherapy showed promising efficacy and mild toxicity profile in patients with pretreated advanced ESCC. BKM120 is worth evaluating in a further confirmatory study. Result of subgroup analyses with respect to gene alternation status will be presented. Clinical trial information: UMIN000011217.

Methotrexate-cytarabine-dexamethasone combination chemotherapy with or without rituximab in patients with primary central nervous system lymphoma.

PurposeHigh-dose methotrexate based chemotherapy is the standard treatment for patients with newly diagnosed primary central nervous system lymphoma (PCNSL). The role of rituximab is controversial because of its large size, which limits its penetration of the blood-brain barrier. In this study, we investigated the efficacy and tolerability of adding rituximab to methotrexate-cytarabine-dexamethasone combination therapy (RMAD regimen).ResultsThe patients treated with RMAD had a complete remission rate of 66.7% after induction chemotherapy; this rate was only 33.3% in patients treated with MAD alone (p = .011). The most common grade 1–3 adverse events were similar and included hematologic toxicity, increased aminotransferase levels, and gastrointestinal reactions. Multivariate analysis revealed that rituximab treatment was associated with longer progression-free survival (PFS, p = .005) but not overall survival (OS). Additionally, we observed that elevated serum lactate dehydrogenase was associated with shorter OS and PFS.Materials and MethodsWe retrospectively analyzed 60 immunocompetent patients with newly diagnosed PCNSL at Beijing Tiantan Hospital, Capital Medical University from January 2010 to June 2016. Twenty-four patients received 3–6 courses of 3.5 g/m2 methotrexate on day 1; 0.5–1 g/m2 cytarabine on day 2; and 5–10 mg dexamethasone on days 1, 2 and 3. Thirty-six patients received the same combination plus rituximab 375 mg/m2 on day 0. All patients repeated the treatment every 3 weeks.ConclusionsHigh-dose methotrexate based chemotherapy with rituximab yields a higher complete remission rate and does not increase serious toxicities. PFS benefits from the addition of rituximab. OS has an increasing trend in patients treated with rituximab without statistical significance.

Asymptomatic persistent non-virus non-alcohol related elevation of aminotransferase levels: a rare case and review of the literature

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are found in the liver in their highest concentrations. Two most common causes of asymptomatic transaminase elevation are viral infections and alcohol intake. Persistent non-viral nonalcohol related elevation of aminotransferases indicates that one or both aminotransferase levels exceed the upper reference limit for a period of at least 4 weeks. Causes are classified as hepatic; such as steatosis, autoimmune hepatitis, Wilson’s disease, hemachromatosis, and nonhepatic; such as celiac disease, myopathy and hyperthyroidism. Drug use and substance abuse may also cause an increase in aminotransferase levels. Here, we report a fifty-eight-year old female patient who had asymptomatic non-viral non-alcohol related aminotransferase elevation for a year incidentally diagnosed with malignant infiltration of the liver. It should be noted that, malignant infiltration of the liver may also be a rare cause of asymptomatic persistent elevation of transaminases. Such cases, especially with suspected malignancy should be evaluated in terms of this condition. Keywords: Aspartate aminotransferase, Alanine aminotransferase, Asymptomatic diseases, Incidental findings

Polyethylene glycol microspheres loaded with irinotecan for arterially directed embolic therapy of metastatic liver cancer.

AIMTo study tumor response, and tolerability of arterially directed embolic therapy (ADET) with polyethylene glycol embolics loaded with irinotecan for the treatment of colorectal cancer liver metastases (CRC-LM). Secondary objectives were to monitor quality of life, time to progression and survival of patients.METHODSPatients were included in the study if they were affected by CRC-LM, refractory to systemic chemotherapy, treated with ADET using polyethylene glycol embolics, and had liver involvement < 50%. Tumor response, performance status (PS), tumor marker antigens, and quality of life (QoL) were monitored at 1, 3 and 6 mo after ADET. QoL was assessed with the Palliative Performance Scale (PPS).RESULTSWe treated 50 consecutive CRC-LM patients with ADET using polyethylene glycol embolics. Their tumor response one month after ADET was: 28% of complete response (CR), 48% of partial response (PR), 8% stable disease (SD), and 16% of progression. Tumor response 3 mo after ADET was CR 24%, PR 38%, SD 19% and progression disease (PD) 19%. Tumor response 6 mo after ADET was CR 18%, PR 44%, SD 21% and PD 18%. QoL was 90% PPS at each time point. Median time to progression for patients who progressed was 2.5 mo (range 0.8-6). Median follow-up was 14 mo (0.8-25 range). ADETs were performed with no complications. Observed side effects (mild or moderate intensity) were: Pain in 32% of patients, increase of transaminase levels in 20% and fever in 14%, whereas 30% of patients did not complain any adverse event.CONCLUSIONThe treatment of unresectable CRC-LM with ADET using polyethylene glycol microspheres loaded with irinotecan was effective in tumor response and resulted in mild toxicity, and good QoL.

Drug-induced cytolytic syndrome in pregnancy: clinical and biochemical diagnostic criteria

The aim of the study was evaluation of clinical and laboratory manifestations of drug-induced cytolytic syndrome in pregnancy. In the research group included 62 pregnant women with drug-induced liver injury (DILI) in the first trimester of pregnancy. These pregnant women received hormone therapy at the planning stage and/or during pregnancy for the prevention and treatment of miscarriage and had clinical and biochemical manifestations of cytolytic syndrome. Pregnancy after IVF and ovulation induction was in 60.8% of cases. Hormone therapy for pregnant patients received long-term, 85% of pregnant women used estrogen and progestin drugs. DILI during pregnancy characterized by low-symptom or asymptomatic clinical manifestations. DILI manifested cytolytic biochemical syndrome, in which there is isolated increase of transaminase levels, in some cases accompanied by increased level of gamma glutamyl transpeptidase, liver glutamate dehydrogenase and decreased total protein levels, in the first place due to the albumin fraction.

Incidence, laboratory detection and prognostic relevance of hypoxic hepatitis in cardiogenic shock.

Despite the improvement of therapeutic options for patients in acute myocardial infarction (AMI), cardiogenic shock (CS) remains a complication with high mortality rates. Organ failure centrally determines the prognosis of these high-risk patients. Aim of the current study was to assess the incidence of hypoxic hepatitis (HH) in CS, its laboratory detection evaluating novel and established biomarkers and to estimate the prognostic relevance of HH in current clinical practice. In 172 patients with CS complicating AMI, blood samples were collected at admission and after 1day as prespecified subanalysis of the intra-aortic balloon pumping IABP-SHOCK II trial. Classic parameters of HH were measured in addition to argininosuccinate synthase 1 and sulfotransferase isoform SULT2A1 was determined as new biomarker using standard enzyme-linked immunosorbent assay kits. All-cause mortality at 30days was used for outcome assessment. The overall mortality rate was 40%. The incidence of HH with an increase of aminotransferase levels to be 20 times above the upper normal level was 18%. Patients with HH had a distinctly higher 30-day mortality rate compared to patients without HH (68 vs. 34%; p<0.001). After multivariable adjustment aspartate-aminotransferase (ASAT) remained an independent predictor of 30-day mortality together with serum lactate and serum creatinine, while the new biomarkers failed to predict outcome. Comparing different liver markers using receiver operating characteristic analysis, ASAT showed the highest area under the curve for the prediction of outcome. HH occurs frequently in CS and is associated with particular poor outcome. As conventional biomarker, ASAT is the strongest laboratory predictor of outcome. ClinicalTrials.gov Identifier: NCT00491036.

Clinicopathological features of choledocholithiasis patients with high aminotransferase levels without cholangitis

Common bile duct (CBD) stones are generally associated with greater elevations of alkaline phosphatase and gamma-glutamyl transpeptidase levels than aspartate aminotransferase and alanine aminotransferase levels. However, some patients with CBD stones show markedly increased aminotransferase levels, sometimes leading to the misdiagnosis of liver disease. Therefore, the aim of this study was to investigate the clinicopathologic features of patients with CBD stones and high aminotransferase levels.This prospective cohort study included 882 patients diagnosed with CBD stones using endoscopic retrograde cholangiopancreatography (ERCP). Among these patients, 38 (4.3%) exhibited aminotransferase levels above 400 IU/L without cholangitis (gallstone hepatitis [GSH] group), and 116 (13.2%) exhibited normal aminotransferase levels (control group). We compared groups in terms of clinical features, laboratory test results, radiologic images, and ERCP findings such as CBD diameter, CBD stone diameter and number, and periampullary diverticulum. Liver biopsy was performed for patients in the GSH group.GSH patients were younger and more likely to have gallbladder stones than control patients, implying a higher incidence of gallbladder stone migration. Also, GSH patients experienced more severe, short-lasting abdominal pain. ERCP showed narrower CBDs in GSH patients than in control patients. Histological analysis of liver tissue from GSH patients showed no abnormalities except for mild inflammation.Compared with control patients, GSH patients were younger and showed more severe, short-lasting abdominal pain, which could be due to a sudden increase of CBD pressure resulting from the migration of gallstones through narrower CBDs. These clinical features could be helpful not only for the differential diagnosis of liver disease but also for investigating the underlying mechanisms of liver damage in obstructive jaundice. Moreover, we propose a new definition of “gallstone hepatitis” based on the specific clinicopathologic characteristics observed in our patients.

Characterisation of Agomelatine-Induced Increase in Liver Enzymes: Frequency and Risk Factors Determined from a Pooled Analysis of 7605 Treated Patients.

Antidepressant-induced liver injury is a major concern and a liver monitoring scheme has been recommended by the European Medicines Agency for agomelatine. The objective of this study was to assess the liver safety and identify the characteristics of patients who developed a significant increase in transaminases whilst taking agomelatine. A retrospective pooled analysis of changes in transaminase levels in 9234 patients treated with agomelatine (25 or 50mg/day; n=7605) or placebo (n=1629) from 49 phaseII and III studies was undertaken. A significant increase in transaminase levels was defined as an increase to >3 times the upper limit of normal (ULN) (>3×ULN). Final causality was determined in a case-by-case review by five academic experts. Serum transaminases increased to >3×ULN in 1.3 and 2.5% of patients treated with 25 and 50mg of agomelatine, respectively, compared with 0.5% for placebo. The onset of increased transaminases occurred before 12weeks in 64% of patients. The median time to recovery (to ≤2×ULN) was 14days following treatment withdrawal. Liver function tests recovered in 36.1% of patients despite continuation of agomelatine, suggesting the presence of a liver adaptive mechanism. No cases of acute liver failure or fatal outcome occurred. Patients with elevated transaminases at baseline, secondary to obesity/fatty liver disease, had an equally increased risk of developing further elevations of transaminases with agomelatine and placebo. Incidence of abnormal transaminases was low and dose dependent. No specific population was identified regarding potential risk factors. Withdrawal of agomelatine led to rapid recovery, and some patients exhibited an adaptive phenomenon. Overall, in clinical trials, the liver profile of agomelatine seems safe when serum transaminases are monitored.

Liver Function Test Abnormalities in Depressed Patients Treated with Antidepressants: A Real-World Systematic Observational Study in Psychiatric Settings

BackgroundConcerning the risk of antidepressant induced liver injury, it is not clear whether psychiatrists perform a liver function test (LFT) and whether an increase in aminotransferase levels should contraindicate antidepressant treatment.AimTo evaluate LFT availability, the prevalence of LFT abnormalities and the probable cause of an altered LFT in patients with a major depressive episode (MDE) requiring an antidepressant drug.MethodsWe studied LFT evaluation in a real world psychiatric setting, in a sample of 321 consecutive patients with a current major depressive episode (MDE) requiring an antidepressant drug treatment, but without current alcohol or drug dependence or unstable medical disease.ResultsAn LFT is performed in 36.1% (116/321) of depressed patients. One fifth of antidepressant-treated patients who had an LFT evaluation had abnormal results. The most frequent causes of LFT abnormalities were: NAFLD (nonalcoholic fatty liver disease) (7/321; 2.1%), acute alcohol consumption (4/321; 1.2%), antidepressant-induced liver injury (3/321; 0.9%), hepatitis C virus infection (2/321; 0.6%) and heart failure (1/321; 0.3%). The cause of LFT abnormalities was unknown in 32% of patients (8/25) due to the absence of etiological investigations.ConclusionThese results demonstrate that an LFT is infrequently performed by psychiatrists in depressed patients requiring an antidepressant drug. Baseline LFT assessment and observations during the first six months of antidepressant treatment may be useful for detection of patients with pre-existing liver disease such as NAFLD, and early identification of cases of antidepressant-induced liver injury. An increase in aminotransferase levels may be related to an underlying liver disease, but does not contraindicate antidepressant treatment.

Viable RNaseH1 knockout mice show RNaseH1 is essential for R loop processing, mitochondrial and liver function.

Viable constitutive and tamoxifen inducible liver-specific RNase H1 knockout mice that expressed no RNase H1 activity in hepatocytes showed increased R-loop levels and reduced mitochondrial encoded DNA and mRNA levels, suggesting impaired mitochondrial R-loop processing, transcription and mitochondrial DNA replication. These changes resulted in mitochondrial dysfunction with marked changes in mitochondrial fusion, fission, morphology and transcriptional changes reflective of mitochondrial damage and stress. Liver degeneration ensued, as indicated by apoptosis, fibrosis and increased transaminase levels. Antisense oligonucleotides (ASOs) designed to serve as substrates for RNase H1 were inactive in the hepatocytes from the RNase H1 knockout mice and in vivo, demonstrating that RNase H1 is necessary for the activity of DNA-like ASOs. During liver regeneration, a clone of hepatocytes that expressed RNase H1 developed and partially restored mitochondrial and liver function.

P450 3A-Catalyzed O-Dealkylation of Lapatinib Induces Mitochondrial Stress and Activates Nrf2.

Lapatinib (LAP), an oral tyrosine kinase inhibitor for the treatment of metastatic breast cancer, has been associated with idiosyncractic hepatotoxicity. Recent investigations have implicated the importance of P450 3A4/5 enzymes in the formation of an electrophilic quinone imine (LAPQI) metabolite generated through further oxidation of O-dealkylated lapatinib (OD-LAP). In the current study, hepatic stress was observed via mitochondrial impairment. OD-LAP caused a time- and concentration-dependent decrease in oxygen consumption in HepG2 cells, whereas LAP did not alter the oxygen consumption rate. Interestingly, however, HepG2 cells transfected with human P450 3A4 did exhibit mitochondrial dysfunction via P450 3A4-mediated metabolism of LAP to OD-LAP. OD-LAP-induced mitochondrial toxicity was enhanced upon depletion of intracellular GSH levels, demonstrating that cellular GSH levels are important in the protection of mitochondrial function against LAPQI. Given the nature of LAPQI and the importance of GSH levels in LAP-induced mitochondrial stress, the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) was evaluated, as this transcription factor induces the expression of NAD(P)H quinone oxidoreductase 1, glutathione S-transferase, UDP-glucuronosyltransferases, and glutathione synthetase, all of which might be expected to decrease the toxicity of LAP. Using a FRET-based target gene assay in HepG2 cells, OD-LAP was indeed found to activate Nrf2. Follow-up assays showed increased mRNA levels of Nrf2 target genes after a 4 h treatment with OD-LAP but not with LAP. LAP activation of Nrf2 was observed only when HepG2 cells were transduced with P450 3A4. The significance of Nrf2 protection was established in vivo in Nrf2-KO mice. Increased transaminase levels were found after a single LAP dose in both Nrf2-KO and control mice, indicating elevated hepatic necrosis, although transaminase levels reverted to baseline levels in the control mice upon repeat dosing. They continued to rise in Nrf2-KO mice, however, indicating the likelihood that Nrf-2 plays a significant role in combatting the hepatotoxicity triggered by LAP.

Spironolactone Effect in Hepatic Ischemia/Reperfusion Injury in Wistar Rats.

Introduction. Ischemia/reperfusion (IR) injury, often associated with liver surgery, is an unresolved problem in the clinical practice. Spironolactone is an antagonist of aldosterone that has shown benefits over IR injury in several tissues, but its effects in hepatic IR are unknown. Objective. To evaluate the effect of spironolactone on IR-induced damage in liver. Materials and Methods. Total hepatic ischemia was induced in rats for 20 min followed by 60 min of reperfusion. Spironolactone was administered and hepatic injury, cytokine production, and oxidative stress were assessed. Results. After IR, increased transaminases levels and widespread acute inflammatory infiltrate, disorganization of hepatic hemorrhage trabeculae, and presence of apoptotic bodies were observed. Administration of SPI reduced biochemical and histological parameters of liver injury. SPI treatment increased IL-6 levels when compared with IR group but did not modify either IL-1β or TNF-α with respect to IR group. Regarding oxidative stress, increased levels of catalase activity were recorded in IR + SPI group in comparison with group without treatment, whereas MDA levels were similar in IR + SPI and IR groups. Conclusions. Spironolactone reduced the liver damage induced by IR, and this was associated with an increase in IL-6 production and catalase activity.

Feasibility study of docetaxel plus bevacizumab as first line therapy for elderly patients with advanced non-small-cell lung cancer: Thoracic Oncology Research Group (TORG) 1014.

BackgroundDocetaxel monotherapy is one of the standard treatments for non-small-cell lung cancer in elderly patients. The addition of bevacizumab to docetaxel seems promising; however, the feasibility of this combination has not been investigated in such patients.MethodsPatients with advanced non-squamous non-small-cell lung cancer aged 70 years or older who had not previously received cytotoxic chemotherapy were enrolled. Patients in the Level 0 cohort received docetaxel 60 mg/m2 and bevacizumab 15 mg/kg, whereas those in the Level-1 cohort received docetaxel 50 mg/m2 and bevacizumab 15 mg/kg. Chemotherapy was repeated 3 weekly for six cycles. The primary endpoint was toxicity and the secondary endpoints were response rate, progression-free survival, overall survival, and proportion of patients who underwent three or more cycles of chemotherapy.ResultsTwenty-one patients were enrolled from December 2010 to September 2012 at six institutes. Of the nine patients enrolled in Level 0, two experienced dose-limiting toxicity (febrile neutropenia and prolonged Grade 4 neutropenia in one patient, and Grade 3 infection in another patient) during the first cycle. Enrollment to the Level 0 cohort was terminated because two patients developed Grade 4 sepsis during later cycles. The remaining 12 patients were enrolled in the Level-1 cohort, in which two dose-limiting toxicities (prolonged Grade 4 neutropenia and Grade 3 increased aminotransferase level) were observed. No patient in the Level-1 cohort experienced Grade 4 nonhematologic toxicity. Grade 4 neutropenia occurred in 89 % of Level 0 patients and 50 % of Level-1 patients. The proportion of patients who experienced Grade 3/4 infection, febrile neutropenia or sepsis was 44 % in the Level 0 cohort, and 8 % in the Level-1 cohort. The overall response rate to chemotherapy and progression-free survival were 29 % (95 % CI, 11–52 %) and 5.9 months (95 % CI, 3.6–9.1 months), respectively. Efficacy outcomes did not differ significantly between the cohorts.ConclusionsToxicities were tolerable in level-1 cohort. The recommended dose of combination chemotherapy with docetaxel and bevacizumab for elderly patients was determined as 50 mg/m2 of docetaxel and 15 mg/kg of bevacizumab and toxicities were tolerable. Further studies are warranted.Trial registrationUMIN Clinical Trial Registry; UMIN000004240.

Evaluation of safety, efficacy and post-cessation efficacy durability of tocilizumab in patients with active rheumatoid arthritis.

To evaluate safety and efficacy of tocilizumab (TCZ) in a post-approval pilot study among selected Iranian patients with moderate to severe rheumatoid arthritis (RA) and inadequate responses to disease-modifying antirheumatic drugs (DMARDs). Twenty-four weeks monitoring of adverse events and efficacy of TCZ plus previously used DMARD(s) and steroids, as well as investigating durability of TCZ effects within a year after the drug cessation. The efficacy end-points included 28-joint Disease Activity Score (DAS28) and an annual change in radiographic Sharp-van der Heijde score (SHS). With no withdrawal from the study due to adverse events (AE) or unsatisfactory responses in the 21 treated patients, the most common drug-related AEs were dermatologic and the most common serious AEs were infectious in origin (all of the latter occurring after the last drug dose). The only case of TCZ dose alteration was due to increased transaminase levels. Changes in lipid and hemoglobin levels were within the expected ranges. At week 24, cumulative frequencies for significant clinical response, low disease activity and remission were 100%, 90.5% and 76.2%, respectively. The mean SHS in both hands showed no significant change a year after the first TCZ dose. Mean DAS28 levels gradually increased through 1year post-cessation follow-up, with a somewhat slower rate compared to the initial mean DAS28 reduction. In our DMARD-resistant RA patients, TCZ plus DMARD provided a predicted rapid clinical improvement and inhibited structural joint damage, but with some unexpected safety concerns and an expected vanishing of post-cessation efficacy.

The Clinical Significance of Azole Antifungals’ Effects on the Liver and Transaminase Levels

Various case reports have been published regarding the incidence of hepatotoxicity and the triazoles. To date, of the more commonly used triazoles, voriconazole has been liked to the highest incidence of transaminase elevations followed by posaconazole, fluconazole, and itraconazole, respectively. Discontinuation of each of the drugs has been shown to resolve the increase of transaminase levels; however, no clear guidance has been suggested on as to when discontinuation of therapy is warranted. Close monitoring particularly patients of Asian decent, underlying liver disease, bone marrow, or lung transplant may be prudent as well as target drug monitoring (TDM) for posaconazole and voriconazole to help assess the necessity of alteration or discontinuation of therapy.

In antisynthetase syndrome, ACPA are associated with severe and erosive arthritis: an overlapping rheumatoid arthritis and antisynthetase syndrome.

Anticitrullinated peptide/protein antibodies (ACPA), which are highly specific for rheumatoid arthritis (RA), may be found in some patients with other systemic autoimmune diseases. The clinical significance of ACPA in patients with antisynthetase syndrome (ASS), a systemic disease characterized by the association of myositis, interstitial lung disease, polyarthralgia, and/or polyarthritis, has not yet been evaluated with regard to phenotype, prognosis, and response to treatment. ACPA-positive ASS patients were first identified among a French multicenter registry of patients with ASS. Additionally, all French rheumatology and internal medicine practitioners registered on the Club Rhumatismes et Inflammation web site were asked to report their observations of ASS patients with ACPA. The 17 collected patients were retrospectively studied using a standardized questionnaire and compared with 34 unselected ACPA-negative ASS patients in a case–control study. All ACPA-positive ASS patients suffered from arthritis versus 41% in the control group (P < 0.0001). The number of swollen joints was significantly higher (7.0 ± 5.0 vs 2.9 ± 3.9, P < 0.005), with a distribution resembling that of RA. Radiographic damages were also more frequent in ACPA-positive ASS patients (87% vs 11%, P < 0.0001). Aside from a significantly higher transfer factor for carbon monoxide in ACPA–ASS patients, lung, muscle, and skin involvements had similar incidences, patterns, and severity in both groups. Although Nonbiologic treatments were similarly used in both groups, ACPA-positive patients received biologics more frequently (59% vs 12%, P < 0.0008), mostly due to refractory arthritis (n = 9). Eight patients received anti-Cluster of differentiation 20 (CD20) monoclonal antibodies (mAbs) with good efficacy and tolerance, whereas 2 of the 5 patients treated with antitumor necrosis factor drugs had worsened myositis and/or interstitial lung disease. After a >7-year mean follow-up, extra-articular outcomes and survival were not different. ACPA-positive ASS patients showed an overlapping RA–ASS syndrome, were at high risk of refractory erosive arthritis, and might experience ASS flare when treated with antitumor necrosis factor drugs. In contrast, other biologics such as anti-CD20 mAb were effective in this context, without worsening systemic involvements.

Assessment of Evidence for Positive Association and Seroprevalence of Hepatitis B and C in Diabetic Patients in a Developing Country

Background and AimThe data related to the association between hepatitis virus infections and diabetes mellitus (DM) are conflicting. The aim of this study was to investigate the seroprevalence of hepatitis...

Clinical and Translational Results from a Phase II Trial of Imprime PGG, Alemtuzumab, and Rituximab in the Early Treatment of Patients with High Risk Chronic Lymphocytic Leukemia

Results from the Phase I portion of this study in high risk chronic lymphocytic leukemia (CLL) patients (pts) (NCT01269385) showed that the combination of Imprime PGG (IPGG) at doses up to 4 mg/kg, with alemtuzumab (ALM) and rituximab (RTX), was well tolerated and associated with a 73% complete response (CR) rate (Blood 120: Abstr 1792, 2013). IPGG is a yeast-derived beta 1,3/1,6 glucan that engages innate immune cells, enhancing anti-tumor activity in combination with complement activating monoclonal antibodies (mAb) via a mechanism involving complement receptor 3 (J Immunol 177:1661, 2006). Endogenous anti-beta glucan antibodies (ABA) are required for IPGG binding to complement receptors and modulation of innate immune cell function. In pts with stage IV non-small cell lung cancer (NSCLC), correlation between serum ABA concentrations and response to an IPGG-containing frontline regimen has been observed (J Clin Oncol 32: 15S; Abstr 3045, 2014). Here we report clinical and translational results at the end of the Phase II portion of this CLL study.Methods: The primary endpoint of the Phase II study was the proportion of pts experiencing CR 3 months after completing 5 weeks of treatment with IPGG 4 mg/kg, ALM and RTX. Eligible pts (n=14) had a diagnosis of CLL by standard criteria (IWCLL-NCI 2008), no prior treatment for CLL, high risk CLL based on molecular markers (17p13-; 11q22-; unmutated [<2%] IGHV and/or use of VH3-21 AND CD38+ [³30%] and/or ZAP70+ [³20%]), no standard indication for initiation of CLL therapy, and adequate performance status and organ function. Planned enrollment was up to 39 pts but the study was terminated early due to slow accrual. Translational studies evaluated baseline serum ABA levels and in vitro binding of IPGG to immune cell subsets in whole blood.Results: The median age was 63.5 (range 47-77); 71% were male; and 6 (43%), 5 (36%) and 3 (21%) pts had Rai Stage 0, 1 and 2, respectively. CLL high-risk parameters were 17p13- in 3 (21%), 11q22- in 5 (36%), and unmutated IGHV or use of VH3-21 together with either expression of ZAP70 and/or CD38 in 6 (43%) pts. Grade 3 AEs were diarrhea (n=3) and increased transaminase levels, dehydration, gastritis, hypertension, hyponatremia, and hypertension (each n=1). Grade 4 AEs were neutropenia (n=2) and febrile neutropenia (n=1). Thirteen (93%) patients responded to therapy, with 7 CR, 2 CR with incomplete marrow recovery, 1 nodular PR and 3 PR (IWCLL-NCI 2008 criteria). Median follow-up was 12.7 mo (range 6.7 - 28.0). The overall median duration of response cannot be determined, as only 5/13 responders have progressed (median of 5.6 mo; range: 2.9 - 8.5) and the other 8 remain progression-free after a median of 8.0 mo (range 5.6 - 21.0). Four progressing pts were retreated after a median of 14.2 mo (range 12.4 - 20.5). There were no deaths during or after treatment. Translational studies demonstrated a correlation between ABA concentrations and binding of IPGG to neutrophils, monocytes and B-cells. However, there was no correlation between ABA concentrations and response to treatment. Potential functional implications of binding of IPGG to leukemic B cells, including direct and indirect enhancement of the antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis mediated by anti-tumor mAbs are under investigation.Discussion: The combination of IPGG with ALM and RTX appeared safe and well tolerated overall with an ORR of 93% and a 64% CR/CRi rate. ABA concentrations did not correlate with clinical response to an IPGG containing regimen in these CLL patients. Data on functional implications of IPGG binding to leukemic B cells will be presented. DisclosuresBose:Biothera: Corporate stock options Other, Employment, Research Funding. Zent:Biothera: Research Funding. Ottoson:Biothera: Corporate stock options Other, Employment. Leonardo:Biothera: Corporate stock options Other, Employment. Ansell:Biothera: Research Funding.

Use of anti-tumor necrosis factor alpha therapy in patients with concurrent rheumatoid arthritis and hepatitis B or hepatitis C: a retrospective analysis of 32 patients.

The safety of tumor necrosis factor-alpha (TNF-α) inhibitors in the setting of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections is controversial. The use of anti-TNF-α in rheumatoid arthritis (RA) is associated with an increased risk of hepatitis re-activation. This paper reports experience of using etanercept and adalimumab in 32 patients with RA and previous HBV or HCV infection. No cases of HBV or HCV reactivation were seen. In just over a fifth of patients, increased transaminases levels were seen, which were associated with concomitant use of disease-modifying antirheumatic drugs, isoniazid prophylaxis, or alcohol abuse. In our experience, anti-TNF-α therapy appears to be safe in RA patients with previous HBV or HCV infection, but monitoring remains necessary in these patients.