Clin Cancer Res
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Giant-cell tumor of bone (GCTB) is a locally aggressive, benign osteolytic tumor in which bone destruction is mediated by RANK ligand (RANKL). The RANKL inhibitor denosumab is being investigated for treatment of GCTB. We describe histologic analyses of GCTB tumor samples from a phase II study of denosumab in GCTB. ⋯ Denosumab treatment of patients with GCTB significantly reduced or eliminated RANK-positive tumor giant cells. Denosumab also reduced the relative content of proliferative, densely cellular tumor stromal cells, replacing them with nonproliferative, differentiated, densely woven new bone. Denosumab continues to be studied as a potential treatment for GCTB.
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This retrospective study was undertaken to investigate the impact of initial gefitinib or erlotinib (EGFR tyrosine kinase inhibitor, EGFR-TKI) versus chemotherapy on the risk of central nervous system (CNS) progression in advanced non-small cell lung cancer (NSCLC) with EGFR mutations. ⋯ Our data show lower rates of CNS progression in EGFR-mutant advanced NSCLC patients initially treated with an EGFR-TKI compared with upfront chemotherapy. If validated, our results suggest that gefitinib and erlotinib may have a role in the chemoprevention of CNS metastases from NSCLC.
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Characterizing the earliest chromosomal alterations of pancreatic precursor neoplasms from individuals with a familial aggregation of pancreatic cancer may provide clues as to the loci of pancreatic cancer susceptibility genes. ⋯ Low- and intermediate-grade PanINs and IPMNs from patients with a family history of pancreatic cancer harbor few if any somatic chromosomal alterations. The absence of a locus of recurrent chromosomal loss in most low-grade pancreatic cancer precursor lesions supports the hypothesis that there is no one tumor suppressor gene locus consistently involved in initiating familial pancreatic neoplasia.
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Review
Molecular pathways: targeting phosphoinositide 3-kinase p110-delta in chronic lymphocytic leukemia.
The advent of targeted therapy, specifically to the B-cell receptor (BCR), has changed the convention for the treatment of chronic lymphocytic leukemia (CLL). The phosphoinositide 3-kinase (PI3K) pathway, activated upstream by the BCR, receptor tyrosine kinases, and cytokine receptors, has been a potential target for a multitude of cancers, but until the recent introduction of isoform-specific inhibitors has not been widely used. ⋯ In addition, the clinical advances from targeting p110δ are described, with a focus on clinical outcome, toxicities, and rational combination therapies. The experiences with p110δ in CLL have led to a more fundamental understanding of CLL signaling defects and may be predictive of other BCR-directed therapeutics.
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Cancer cell microenvironments, including host cells, can critically affect cancer cell behaviors, including drug sensitivity. Although crizotinib, a dual tyrosine kinase inhibitor (TKI) of ALK and Met, shows dramatic effect against EML4-ALK lung cancer cells, these cells can acquire resistance to crizotinib by several mechanisms, including ALK amplification and gatekeeper mutation. We determined whether microenvironmental factors trigger ALK inhibitor resistance in EML4-ALK lung cancer cells. ⋯ Paracrine receptor activation by ligands from the microenvironment may trigger resistance to ALK inhibitors in EML4-ALK lung cancer cells, suggesting that receptor ligands from microenvironment may be additional targets during treatment with ALK inhibitors.