Giant-cell tumor of bone (GCTB) is a locally aggressive histologically benign neoplasm with a less common malignant counterpart. Longitudinal data sources on GCTB are sparse, limited to single institution case series or surgical outcomes studies. The Swedish Cancer Registry is one of the few national population-based databases recording GCTB, representing a unique source to study GCTB epidemiology. We estimated incidence rate (IR) and overall mortality rates based on registry data.
We identified patients with a GCTB diagnosis in the Swedish Cancer Registry from 1983 to 2011: benign (ICD-7 196.0-196.9; PAD 741) and malignant (PAD 746). Results were stratified by age at diagnosis, gender, and anatomical lesion location.
The cohort included 337 GCTB cases (IR of 1.3 per million persons per year). The majority (n=310) had primary benign GCTB (IR of 1.2 per million per year). Median age at diagnosis was 34 years (range 10-88) with 54% (n=183) females. Malignant to benign ratio for women was 0.095 (16/167) and for men 0.077 (11/143). Incidence was highest in the 20-39 years age group (IR of 2.1 per million per year). The most common lesion sites were distal femur and proximal tibia. Mortality at 20 years from diagnosis was 14% (n=48) and was slightly higher for axial (17%; n=6) and pelvic (17%; n=4) lesions. Recurrence occurred in 39% of primary benign cases and 75% of primary malignant cases.
In our modern population-based series primary malignant cases were uncommon (8%), peak incidence 20-39 years with slight predominance in women. Recurrence rates remain significant with overall 39% occurring in benign GCTB, and 75% in malignant form. The linkage between databases allowed the first population based estimates of the proportion of patients who received surgery at initial GCTB diagnosis, and those who also received subsequent surgeries.
Copyright © 2016 Elsevier Ltd. All rights reserved.

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Clinical response to methotrexate in cancer is variable and depends on several factors including serum drug exposure. This study aimed to develop a population pharmacokinetic model describing methotrexate disposition in cancer patients using retrospective chart review data available from routine clinical practice.
A retrospective review of medical records was conducted for cancer patients in Qatar. Relevant data (methotrexate dosing/concentrations from multiple occasions, patient history, and laboratory values) were extracted and analyzed using NONMEM VII(). A population pharmacokinetic model was developed and used to estimate inter-individual and inter-occasion variability terms on methotrexate pharmacokinetic parameters, as well as patient factors affecting methotrexate pharmacokinetics.
Methotrexate disposition was described by a two-compartment model with clearance (CL) of 15.7 L/h and central volume of distribution (V c) of 79.2 L. Patient weight and hematocrit levels were significant covariates on methotrexate V c and CL, respectively. Methotrexate CL changed by 50 % with changes in hematocrit levels from 23 to 50 %. Inter-occasion variability in methotrexate CL was estimated for patients administered the drug on multiple occasions (48 and 31 % for 2nd and 3rd visits, respectively).
Therapeutic drug monitoring data collected during routine clinical practice can provide a useful tool for understanding factors affecting methotrexate pharmacokinetics. Patient weight and hematocrit levels may play a clinically important role in determining methotrexate serum exposure and dosing requirements. Future prospective studies are needed to validate results of the developed model and evaluate its usefulness to predict methotrexate exposure and optimize dosing regimens.

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Androgenetic alopecia (AGA) is a common heritable and androgen-dependent hair loss condition in men. Twelve genetic risk loci are known to date but it is unclear which genes at these loci are relevant for AGA. Dermal papilla cells (DPC) located in the hair bulb are the main site of androgen activity in the hair follicle. Widely used monolayer-cultured primary DPC in hair-related studies often lack dermal papilla (DP) characteristics. In contrast, immortalised DPC have high resemblance to intact DP. We derived immortalised human DPC lines from balding (BAB) and non-balding (BAN) scalp. Both BAB and BAN retain high proportions of DP signature gene and versican protein expression. We performed expression analysis of BAB and BAN and annotated AGA risk loci with differentially-expressed genes. We found evidence for AR but not EDA2R as the candidate gene at the AGA risk locus on chromosome X. Further, our data suggest TWIST1 and SSPN to be the functionally relevant AGA genes at the 7p21.1 and 12p12.1 risk loci, respectively. Down-regulated genes in BAB compared to BAN were highly enriched for vasculature-related genes, suggesting that deficiency of DPC from balding scalps in fostering vascularisation around the hair follicle may contribute to the development of AGA.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

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On April 11, 2016 Curis, Inc. (NASDAQ:CRIS), a biotechnology company focused on the development and commercialization of innovative and effective drug candidates for the treatment of human cancers, reported that Curis scientists and its collaborator, Aurigene will present data from multiple programs at the Annual Meeting of American Association of Cancer Research (AACR) (Free AACR Whitepaper) to be held from April 16 – 20, 2016 in New Orleans, LA (Press release, Curis, APR 11, 2016, View Source [SID:1234510647]).

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Curis researchers will present data for its proprietary targeted cancer drug candidate, CUDC-907, an oral inhibitor of histone deacetylase (HDAC) and phosphoinositide 3-kinase (PI3K). Curis’ collaborator, Aurigene will present data from the immuno-oncology programs, including CA-170 (previously AUPM-170), a first-in-class oral, small molecule immune checkpoint antagonist targeting programmed death ligand-1 (PD-L1) and V-domain Ig suppressor of T cell activation (VISTA), as well as the PD-L1/ T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) antagonist program. In addition, Aurigene will present data from the interleukin-1 receptor associated kinase 4 (IRAK4) inhibitor program, including the lead compound CA-4948. Curis has exclusive licenses to CA-170 and CA-4948 under a collaboration agreement with Aurigene established in 2015.

Additional information on the presentations can be found below and abstracts can be accessed at www.aacr.org.

Poster Presentations

Date/Time: Wednesday, Apr 20, 2016, 8:00 AM – 12:00 PM
Session Title: Cellular Responses to Anticancer Drugs
Presentation Title: Novel dual HDAC & PI3K inhibitor, CUDC-907, for MYC-driven malignancies
Abstract Number: 4634

Date/Time: Wednesday, Apr 20, 2016, 8:00 AM – 12:00 PM
Session Title: Immune Modulating Agents 2
Presentation Title: Oral immune checkpoint antagonists targeting PD-L1/VISTA or PD-L1/Tim3 for cancer therapy
Abstract Number: 4861

Date/Time: Wednesday, Apr 20, 2016, 8:00 AM – 12:00 PM
Session Title: Novel Chemotherapies
Presentation Title: Efficacy and safety of highly selective novel IRAK4 inhibitors for treatment of ABC-DLBCL
Abstract Number: 4798

On April 11, 2016 Aduro Biotech, Inc. (Nasdaq:ADRO), reported that the company’s chief scientific officer, Thomas W. Dubensky, Jr., Ph.D., will be a featured speaker at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2016 Annual Meeting being held April 16-20 in New Orleans, Louisiana (Press release, Aduro BioTech, APR 11, 2016, View Source;p=RssLanding&cat=news&id=2155861 [SID:1234510645]). Dr. Dubensky’s presentation is part of a Major Symposium, "Cancer Immunotherapy: Small Molecule Approaches," taking place on April 20, 2016, during which he will highlight Aduro’s landmark first-in-human immunotherapeutic approach in cancer to target the Stimulator of Interferon Genes (STING) pathway.

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The presentation will focus on ADU-S100, a novel synthetic cyclic dinucleotide (CDN) that is one of a family of proprietary small molecules being developed by Aduro that broadly activates the human STING receptor. STING is expressed in immune cells that are present in the tumor microenvironment (TME) and is a central and potent mediator of the innate immune response, a necessary step in the development of effective tumor-specific immunity. Activation of the STING pathway has been shown to correlate with infiltration of lymphocytes and a "T-cell inflamed TME" in patients with melanoma. Stimulation of STING induces signaling through several innate immune response pathways, resulting in the expression of various interferons, cytokines and T cell recruitment factors that amplify and strengthen immune activity. Dr. Dubensky will discuss preclinical data demonstrating that the direct engagement of STING through the intratumoral injection of ADU-S100 resulted in effective, durable and systemic anti-tumor activity. The data suggest that the resulting tumor regression is due to an acute pro-inflammatory cytokine response and induction of tumor-specific CD8+ T cell immunity. Preclinical data will be presented which also demonstrate the potential synergistic effects of combining ADU-S100 and immune checkpoint inhibitors, including anti-PD1. In addition, Dr. Dubensky will present an overview of the Phase 1 clinical trial to evaluate the safety, tolerability and possible anti-tumor activity of ADU-S100 given by intratumoral injection to patients with advanced cutaneously accessible solid tumors or lymphomas.

"We are excited to share this new research and planned Phase 1 clinical trial, which highlights ADU-S100, Aduro’s lead STING activator candidate, and its translational potential for treating patients with metastatic solid tumors and lymphomas," said Dr. Dubensky. "Our data suggest that the stimulation of a local immune response in the TME can result in a sustained and effective tumor-specific immune response against metastases throughout the body. This observation reinforces the importance of the STING signaling pathway in cancer immunotherapy and the potential of ADU-S100 to be used alone or in combination treatment approaches for advanced cancer patients."

Based on these promising preclinical results, Aduro and Novartis, as part of a collaboration focused on STING pathway activator compounds in the field of oncology, will initiate a Phase 1 dose escalation trial with ADU-S100 in patients with cutaneously accessible metastatic solid tumors or lymphomas who have no other treatment options.

Aduro will also be presenting a poster at AACR (Free AACR Whitepaper) on Monday, April 18, 2016 titled "STING Activation in the Tumor Microenvironment with a Synthetic Human Cyclic Dinucleotide Leads to Potent Anti-Tumor Immunity." This will provide additional details on preclinical research showing the effectiveness of ADU-S100 in activating the STING receptor and inducing an immune response across diverse tumor models.

Details of the presentations:

Oral Presentation "SY39-02: Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity," Wednesday, April 20, 2016 10:55 AM – 11:20 AM, New Orleans Theater C. Morial Convention Center
Poster Presentation "STING Activation in the Tumor Microenvironment with a Synthetic Human Cyclic Dinucleotide Leads to Potent Anti-Tumor Immunity," Monday, April 18, 2016 8:00 AM – 12:00 PM, Section 24