Marqibo® (vincristine sulfate liposome injection) improves the pharmacokinetics and pharmacodynamics of vincristine

Vincristine (VCR) is a mainstay of treatment of hematologic malignancies and solid tumors due to its well-defined mechanism of action, demonstrated anticancer activity and its ability to be combined with other agents. VCR is an M-phase cell cycle-specific anticancer drug with activity that is concentration and exposure duration dependent. The pharmacokinetic profile of standard VCR is described by a bi-exponential elimination pattern with a very fast initial distribution half-life followed by a longer elimination half-life. VCR also has a large volume of distribution, suggesting diffuse distribution and tissue binding. These properties may limit optimal drug exposure and delivery to target tissues as well as clinical utility as a single agent or as an effective component of multi-agent regimens. Vincristine sulfate liposome injection (VSLI), Marqibo^®, is a sphingomyelin and cholesterol-based nanoparticle formulation of VCR that was designed to overcome the dosing and pharmacokinetic limitations of standard VCR. VSLI was developed to increase the circulation time, optimize delivery to target tissues and facilitate dose intensification without increasing toxicity. In xenograft studies in mice, VSLI had a higher maximum tolerated dose, superior antitumor activity and delivered higher amounts of active drug to target tissues compared to standard VCR. VSLI recently received accelerated FDA approval for use in adults with advanced, relapsed and refractory Philadelphia chromosome-negative ALL and is in development for untreated adult ALL, pediatric ALL and untreated aggressive NHL. Here, we summarize the nonclinical data for VSLI that support its continued clinical development and recent approval for use in adult ALL.     

Eight-year (2002-2009) summary of the linezolid (Zyvox® Annual Appraisal of Potency and Spectrum; ZAAPS) program in European countries

The linezolid surveillance network (ZAAPS program) has been monitoring linezolid activity and susceptibility rates for eight years (2002-2009) in european medical centers. Samples from 12-24 sites annually in 11 countries were monitored by a central laboratory design using reference MIC methods with international and regional interpretations (EUCAST). A total of 13,404 gram-positive pathogens were tested from 6 pathogen groups. Linezolid remained without documented resistance from 2002 through 2005, but beginning in 2006 resistant strains emerged at very low rates among Staphylococcus aureus (G2576T mutant in ireland, 2007), coagulase-negative staphylococci (CoNS; usually Staphylococcus epidermidis, France and Italy in 2006-2009) and enterococci (Enterococcus faecium in Germany [2006, 2008, 2009] and E. faecalis in Sweden [2008], United Kingdom [2008] and Germany [2009]); all but one strain having a target mutation. A mobile cfr was detected in an italian CoNS strain (2008 and 2009), and clonal spread was noted for linezolid-resistant strains (PFGE results). Overall the linezolid susceptibility rates were >99.9, 99.7 and 99.6% for S. aureus, CoNS and enterococci, respectively; and all streptococcal strains were susceptible (MIC(90), 1 mg/l). In conclusion, the ZAAPS program surveillance confirmed high, sustained levels of linezolid activity from 2002-2009 and without evidence of MIC creep or escalating resistance in gram-positive pathogens across monitored european nations.     

Eight-year (2002-2009) Summary of the Linezolid (Zyvox® Annual Appraisal of potency and Spectrum; ZAAPS) Program in European Countries

Abstract

The linezolid surveillance network (ZAAPS program) has been monitoring linezolid activity and susceptibility rates for eight years (2002-2009) in European medical centers. Samples from 12-24 sites annually in 11 countries were monitored by a central laboratory design using reference MIC methods with international and regional interpretations (EUCAST). A total of 13,404 Gram-positive pathogens were tested from 6 pathogen groups. Linezolid remained without documented resistance from 2002 through 2005, but beginning in 2006 resistant strains emerged at very low rates among Staphylococcus aureus (G2576T mutant in ireland, 2007), coagulase-negative staphylococci (CoNS; usually Staphylococcus epidermidis, France and italy in 2006-2009) and enterococci (Enterococcus faecium in Germany [2006, 2008, 2009] and E. faecalis in Sweden [2008], United Kingdom [2008] and Germany [2009]); all but one strain having a target mutation. A mobile cfr was detected in an italian CoNS strain (2008 and 2009), and clonal spread was noted for linezolid-resistant strains (pfGe results). Overall the linezolid susceptibility rates were >99.9, 99.7 and 99.6% for S. aureus, CoNS and enterococci, respectively; and all streptococcal strains were susceptible (MIC₉₀, 1 mg/L). In conclusion, the ZAAPS program surveillance confirmed high, sustained levels of linezolid activity from 2002-2009 and without evidence of MIC creep or escalating resistance in Gram-positive pathogens across monitored European nations.     

Galenus-von-Pergamon-Preis 2011 Nplate® (Romiplostim)

best practice onkologie -     

Essiac® and Flor-Essence® herbal tonics stimulate the in vitro growth of human breast cancer cells

SummaryBackground People diagnosed with cancer often self-administer complementary and alternative medicines (CAMs) to supplement their conventional treatments, improve health, or prevent recurrence. Flor-Essence^? and Essiac^? Herbal Tonics are commercially available complex mixtures of herbal extracts sold as dietary supplements and used by cancer patients based on anecdotal evidence that they can treat or prevent disease. In this study, we evaluated Flor-Essence^? and Essiac^? for their effects on the growth of human tumor cells in culture.Methods The effect of Flor-Essence^? and Essiac^? herbal tonics on cell proliferation was tested in MCF-7, MDA-MB-436, MDA-MB-231, and T47D cancer cells isolated from human breast tumors. Estrogen receptor (ER) dependent activation of a luciferase reporter construct was tested in MCF-7 cells. Specific binding to the ER was tested using an ICI 182,780 competition assay.Results Flor-Essence^? and Essiac^? herbal tonics at 1%, 2%, 4% and 8% stimulated cell proliferation relative to untreated controls in both estrogen receptor positive (MCF-7 and T47D) and estrogen receptor negative (MDA-MB-231 and MDA-MB-436) cell lines. Exposure to the tonics also produced a dose-dependent increase in ER dependent luciferase activity in MCF-7 cells. A 10⁻⁷ M concentration of ICI 182,780 inhibited the induction of ER dependent luciferase activity by Flor-Essence^? and Essiac^?, but did not affect cell proliferation.Conclusion Flor-Essence^? and Essiac^? Herbal Tonics can stimulate the growth of human breast cancer cells through ER mediated as well as ER independent mechanisms of action.     

Safety and Efficacy of Daptomycin in the Treatment of Osteomyelitis: Results from the CORE® Registry

Abstract

Antibiotic safety is a major determinant in osteomyelitis therapy. Limited data is available describing the long-term safety and efficacy of daptomycin. The safety population was drawn from CORE 2005 and 2006, a retrospective, observational, multicenter study. Clinically evaluable patients received >3 days of daptomycin appropriately adjusted for renal function. Three hundred twenty-seven patients were evaluated for safety; 188 (57%) ≥6 mg/kg, 139 (43%) <6 mg/kg. thirty-one (10%) patients experienced adverse events possibly related to daptomycin and the incidence was similar regardless of dose. No difference was observed in the rate of creatine phosphokinase elevations by dose. A trend toward higher improved rates was noted in patients receiving a final dose of ≥ 6 mg/kg (96% vs. 90% P=0.08). Daptomycin appeared well-tolerated at doses of 6 mg per kg or greater which were associated with greater clinical improvement. These results require verification via a prospective clinical trial.     

Phase 1/2 Study of the Safety and Tolerability of Nivolumab Plus Crizotinib for the First-Line Treatment of Anaplastic Lymphoma Kinase Translocation — Positive Advanced Non–Small Cell Lung Cancer (CheckMate 370)

Introduction

Crizotinib, an anaplastic lymphoma kinase (ALK) inhibitor, is a first-line treatment for ALK translocation–positive advanced non–small cell lung cancer (NSCLC); however, patients eventually progress. Immunotherapies, including the programmed death-1 inhibitor nivolumab, have resulted in durable responses and long-term overall survival in patients with NSCLC. We hypothesized that combining targeted therapy with immunotherapy could result in more patients with responses and/or more durable responses. Herein we report data from a study assessing nivolumab plus crizotinib in patients with previously untreated advanced ALK translocation–positive NSCLC.

Correction to: Tolerability and toxicity of trastuzumab or trastuzumab + lapatinib in older patients: a sub‑analysis of the ALTTO trial (BIG 2‑06; NCCTG (Alliance) N063D)

Breast Cancer Research and Treatment -     

Application of the concept synthetic lethality toward anticancer therapy: A promise fulfilled?

Back in 1997, a suggestion to apply the concept of synthetic lethality towards the development of selective, less toxic, cancer drugs and anticancer targets, was brought forward. The availability of large scale synthetic, low-molecular-weight chemical libraries seemed to lend itself to the concept. Human/mouse genome-wide siRNAs and shRNA-expressing libraries allowing high throughput screening for target genes synergistic lethal with defined human cancer aberrations, also raised high hopes of a soon to be established selective therapy. Sixteen years later, the major experimental aspects relating to the implementation of this more focused approach to cancer drug discovery, is briefly and critically reviewed.     

The associations between the polymorphisms of the ER-α gene and the risk of uterine leiomyoma (ULM)

The ER-α gene polymorphisms have been reported to be associated with uterine leiomyoma (ULM) risk. The purpose of the present study was to perform a meta-analysis to explore the polymorphisms in the ER-α gene and the risk of ULM. A comprehensive search for relevant articles was conducted in MEDLINE (Ovid), PubMed, Embase, Springer, EBSCO, Web of Science, CNKI, Wanfang, Weipu, and Google Scholar. A total of nine articles were identified. Among the nine articles, 11 cohorts reported the PvuII polymorphism and six reported the XbaI polymorphism. The strength of the relationships between the polymorphisms in ER-α (PvuII and XbaI) and the risk of ULM was assessed by odds ratios (ORs). The studies provided overall OR estimates for PvuII and XbaI, leading to a pooled OR of 1.41 (PP+Pp vs. pp: OR?=?1.41, 95 % confidence interval (95 %CI)?=?1.02–1.96, P?=?0.04), 1.13 (XX+Xx vs. xx: OR?=?1.13, 95 %CI?=?0.91–1.41, P?=?0.25), respectively. The PvuII polymorphism in the ER-α gene may be a risk factor for ULM. Future studies are needed to validate our conclusions.     

Discrimination between the enzymatic activities of Candida albicans pleomorphic forms determined using the api® ZYM test

Enzymatic activity profiles for two morphotypes of 37 Candida albicans clinical isolates were compared. Yeast and hyphal forms were grown using yeast extract‐peptone‐glucose broth or undiluted human serum, respectively. Both morphotypes were documented under scanning electron microscopy. The api^® ZYM (BioMérieux, France) test was used to evaluate the enzymatic activity profiles for particular pleomorphic forms. None of the examined enzymatic activities showed good agreement (kappa, κ > 0.80) for the two morphotypes of the tested strains. Only leucine arylamidase activity in blastoconidia and hyphae of 35 out of 37 strains appeared to be in significant agreement (κ = 0.770). This phenomenon should be explored further for clinical benefits. For morphotypes of all tested strains, activity profiles of 11 hydrolytic enzymes demonstrated weak agreement (κ = 0.044–0.197). Moreover, satisfactory (κ = 0.218–0.348) and moderate agreement (κ = 0.413–0.479) were noted for enzymatic activity values of five and two enzymes, respectively. The distinct differences in activity profiles of hydrolytic enzymes between hyphae and blastoconidia is suggested to be related to the specific roles of these two morphotypes in particular steps of pathogenesis. Moreover, both morphotypes should be examined by strain biotyping methods. Beta‐N‐hexosaminidase (HexNAcase) activity assessed by the api^® ZYM test and on CHROMagar Candida^® medium (Becton Dickinson, USA) is also discussed.     

A biological or a synthetic mesh in immediate breast reconstruction? A cohort-study of long-term Health related Quality of Life (HrQoL)

ObjectivesMeshes/matrices are commonly used in immediate breast reconstruction. There are few studies comparing biological and synthetic meshes and it is unknown what type of mesh gives the best long-term results. The aim of this study was to compare long-term health-related quality of life (HrQoL) and patient satisfaction in implant-based immediate breast reconstruction with a biological mesh (Surgisis®) with that of patients reconstructed with a synthetic mesh (TIGR ® Matrix Surgical Mesh).Material and methodsBoth cohorts were prospectively included and consecutively operated. Clinical data was collected. HrQoL was evaluated with EuroQoL-5 dimension – 3 levels questionnaire (EQ-5D-3L) and the Hospital Anxiety and Depression Scale (HADS) and the Breast-Q.Results and conclusionSeventy-one patients were operated on in the biological group and 49 in the synthetic group. The response rates were 75 and 84 per cent, respectively. Mean follow-up time was 74 months and 23 months, respectively. There were no statistical differences in satisfaction and quality of life between the two groups. Complications and radiation seem to lead to a lower satisfaction. Our findings could indicate that biological and synthetic meshes give an equal long-term result as regards patients’ perceived quality of life.     

Comparison between the HyperArc™ technique and the CyberKnife® technique for stereotactic treatment of brain metastases

PurposeThe purpose of this study was to compare the planimetric capacities between HyperArc™-based stereotactic radiosurgery and robotic radiosurgery system-based planning using CyberKnife® M6 for single and multiple cranial metastases.Materials and methodsWe evaluated 51 treatment plans for cranial metastases, including 30 patients with a single lesion and 21 patients with multiple lesions, treated with the CyberKnife® M6. These treatment plans were optimized using the HyperArc™ (HA) system with the TrueBeam. The comparison of the quality of the treatment plans between the two treatment techniques (CyberKnife and HyperArc) was performed using the Eclipse treatment planning system. Dosimetric parameters were compared for target volumes and organs at risk.ResultsCoverage of the target volumes was equivalent between the two techniques, whereas median Paddick conformity index and median gradient index for all target volumes were 0.9 and 3.4, respectively for HyperArc plans, and 0.8 and 4.5 for CyberKnife plans (P < 0.001). The median dose of gross tumor volume (GTV) for HyperArc and CyberKnife plans were 28.4 and 28.8, respectively. Total brain V18 Gy and V12Gy-GTVs were 11 cm³ and 20.2cm³ for HyperArc plans versus 18 cm³ and 34.1 cm³ for CyberKnife plans (P < 0.001).ConclusionThe HyperArc provided better brain sparing, with a significant reduction in V12 Gy and V18 Gy, associated with a lower gradient index, whereas the CyberKnife gave a higher median GTV dose. The HyperArc technique seems to be more appropriate for multiple cranial metastases and for large single metastatic lesions.