Novartis

About: Novartis is a company organization based out in Basel, Switzerland. It is known for research contribution in the topics: Alkyl & Population. The organization has 41930 authors who have published 50566 publications receiving 1978996 citations. The organization is also known as: Novartis International AG.

Pathologic fractures correlate with reduced survival in patients with malignant bone disease.

Abstract: BACKGROUND. Data from randomized, controlled trials of zoledronic acid were retrospectively analyzed to assess the effect of pathologic fractures on survival in patients with malignant bone disease. METHODS. A Cox regression model was used to estimate the effect of fractures (time-dependent variable) on survival in patients with stage III multiple myeloma or bone metastases from solid tumors enrolled in 3 large trials. Patients were randomized to receive zoledronic acid, pamidronate, or placebo every 3–4 weeks for up to 24 months (prostate cancer, breast cancer, and multiple myeloma) or up to 21 months (lung and other solid tumors). RESULTS. A total of 3049 patients with multiple myeloma (n = 513), breast (n = 1130), prostate (n = 640), or lung cancer or other solid tumors (n = 766) were included in this analysis. Patients with multiple myeloma had the highest fracture incidence (43%), followed by breast (35%), prostate (19%), and lung cancer (17%). In all tumor types except lung, pathologic fracture was associated with a significant increase in risk of death, and breast cancer patients had the greatest increased risk. After adjustment for baseline characteristics, including performance status and prior skeletal complications, breast cancer patients who developed a pathologic fracture on study had a significant 32% increased risk of death relative to patients without a fracture (hazard ratio = 1.32; P 20% increased risk of death. CONCLUSIONS. These results suggest that fractures are associated with increased risk of death in patients with malignant bone disease. Therefore, preventing fractures is an important goal of therapy. Cancer 2007. © 2007 American Cancer Society.

Use of the UK General Practice Research Database for pharmacoepidemiology

Abstract: The last decade has seen a surge in the use of computerized health care data for pharmacoepidemiology. Of all European databases, the General Practice Research Database (GPRD) in the UK, has been the most widely used for pharmacoepidemiological research. Since 1994, this database has belonged to the UK Department of Health, and is maintained by the Office of National Statistics (ONS). Currently, around 1500 general practitioners with a population coverage in excess of 3 million, systematically provide their computerized medical data anonymously to ONS. Validation studies of the GPRD have documented the recording of medical data into general practitioners’ computers to be near to complete. The GPRD collects truly population-based data, has a size that makes it possible to follow-up large cohorts of users of specific drugs, and includes both outpatient and inpatient clinical information. The access to original medical records is excellent. Desirable improvements to the GPRD would be additional computerized information on certain variables and linkage to other health care databases. Most published studies to date have been in the area of drug safety. The General Practice Research Database has proved that valuable data can be collected in a general practice setting. The full potential of this rich computerized database has yet to come. This experience should serve to encourage others to develop similar population-based data in other countries.

Interfering with Resistance to Smoothened Antagonists by Inhibition of the PI3K Pathway in Medulloblastoma

Abstract: The malignant brain cancer medulloblastoma is characterized by mutations in Hedgehog (Hh) signaling pathway genes, which lead to constitutive activation of the G protein (heterotrimeric guanosine triphosphate-binding protein)-coupled receptor Smoothened (Smo). The Smo antagonist NVP-LDE225 inhibits Hh signaling and induces tumor regression in animal models of medulloblastoma. However, evidence of resistance was observed during the course of treatment. Molecular analysis of resistant tumors revealed several resistance mechanisms. We noted chromosomal amplification of Gli2, a downstream effector of Hh signaling, and, more rarely, point mutations in Smo that led to reactivated Hh signaling and restored tumor growth. Analysis of pathway gene expression signatures also, unexpectedly, identified up-regulation of phosphatidylinositol 3-kinase (PI3K) signaling in resistant tumors as another potential mechanism of resistance. Probing the relevance of increased PI3K signaling, we demonstrated that addition of the PI3K inhibitor NVP-BKM120 or the dual PI3K-mTOR (mammalian target of rapamycin) inhibitor NVP-BEZ235 to the initial treatment with the Smo antagonist markedly delayed the development of resistance. Our findings may be useful in informing treatment strategies for medulloblastoma.

Management of malignant gastrointestinal stromal tumours.

Abstract: Gastrointestinal stromal tumours (GISTs) are the most common form of mesenchymal tumour of the gastrointestinal tract Clinically, they range from small indolent tumours curable with surgery alone to aggressive cancers Making a distinction between an indolent and a malignant GIST is unreliable with conventional histopathological techniques The presence of metastases at the time of diagnosis confirms malignancy, but all GISTs should be regarded as having malignant potential GISTs characteristically express the KIT protein, a transmembrane tyrosine kinase receptor for stem-cell factor Most GISTs have a mutation in the KIT proto-oncogene that translates into a gain-of-function constitutive activation of the KIT kinase KIT activation seems to be an early tumour-promoting event in pathogenesis Commonly, malignant GISTs show high-level primary resistance to conventional chemotherapy Imatinib mesylate is an orally administered selective inhibitor of certain tyrosine kinases including KIT Most patients with advanced malignant GISTs achieve clinical benefit and significant antitumour responses with imatinib mesylate Responses have been durable, and most patients tolerate the drug well at clinically effective doses Imatinib mesylate is the first effective systemic therapy for advanced GIST