Collaborative Research Building

Scottsdale, AZ, United States

Collaborative Research Building

Scottsdale, AZ, United States

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Stewart A.K.,Collaborative Research Building | Jacobus S.,Dana-Farber Cancer Institute | Fonseca R.,Collaborative Research Building | Weiss M.,Marshfield Clinic | And 2 more authors.
Blood | Year: 2015

This phase 3 trial (Eastern Cooperative Oncology Group [ECOG] E1A06) compared melphalan, prednisone, and thalidomide (MPT-T) with melphalan, prednisone, and lenalidomide (mPR-R) in patients with untreated multiple myeloma (MM). A noninferiority design was used, and inferiority was defined as a progression-free survival (PFS) hazard ratio (HR) of MPT-T/mPR-R ≤0.82. A total of 306 patients enrolled, with a median age of 75.7 years. Median follow-up was 40.7 months. Median time on therapy was 12.1 months and 23.1 months for the 46.6% of treated patients who received maintenance, with no differences by arm. Median PFS was 21 months on MPT-T and 18.7 months on mPR-R (HR, 0.84; 95% confidence interval, 0.64-1.09). Overall survival was 52.6 months (MPT-T) vs 47.7 months (mPR-R) (P = .476). Perprotocol response rates were 63.6% (MPT-T) and 59.9% (mPR-R) (P = .557). Grade ≥3 nonhematologic toxicity was 59.5% for MPT-T vs 40.0% for mPR-R (P = .001). Second malignancies were observed in 18 MPT-T patients vs 14 mPR-R patients. Quality-of-life analysis favored mPR-R by induction end (P = .007). Use of MPT-T or mPR-R in elderly patients with untreated MM demonstrates no statistical or clinically relevant differences in response rates, PFS, and OS; however, quality of life at end of induction was improved and lower toxicity reported with mPR-R. This trial was registered at as #NCT00602641. © 2015 by The American Society of Hematology.

Schmidt J.,Collaborative Research Building | Braggio E.,Collaborative Research Building | Kortuem K.M.,Collaborative Research Building | Egan J.B.,Collaborative Research Building | And 11 more authors.
Leukemia | Year: 2013

RNA interference screening identified XPO1 (exportin 1) among the 55 most vulnerable targets in multiple myeloma (MM). XPO1 encodes CRM1, a nuclear export protein. XPO1 expression increases with MM disease progression. Patients with MM have a higher expression of XPO1 compared with normal plasma cells (P<0.04) and to patients with monoclonal gammopathy of undetermined significance/smoldering MM (P<0.0001). The highest XPO1 level was found in human MM cell lines (HMCLs). A selective inhibitor of nuclear export compound KPT-276 specifically and irreversibly inhibits the nuclear export function of XPO1. The viability of 12 HMCLs treated with KTP-276 was significantly reduced. KPT-276 also actively induced apoptosis in primary MM patient samples. In gene expression analyses, two genes of probable relevance were dysregulated by KPT-276: cell division cycle 25 homolog A (CDC25A) and bromodomain-containing protein 4 (BRD4), both of which are associated with c-MYC pathway. Western blotting and reverse transcription-PCR confirm that c-MYC, CDC25A and BRD4 are all downregulated after treatment with KPT-276. KPT-276 reduced monoclonal spikes in the Vk*MYC transgenic MM mouse model, and inhibited tumor growth in a xenograft MM mouse model. A phase I clinical trial of an analog of KPT-276 is ongoing in hematological malignancies including MM. © 2013 Macmillan Publishers Limited.

Geda Y.E.,Collaborative Research Building
Current Psychiatry Reports | Year: 2012

Mild cognitive impairment (MCI) is the intermediate stage between the cognitive changes of normal aging and dementia. MCI is important because it constitutes a high risk group for dementia. Ideally, prevention strategies should target individuals who are not even symptomatic. Indeed, the field is now moving towards identification of asymptomatic individuals who have underlying Alzheimer's disease (AD) pathology that can be detected using biomarkers and neuroimaging technologies. To this effect, the Alzheimer's Association and the National Institute on Aging have developed a new classification scheme that has categorized AD into a preclinical phase (research category), MCI due to AD, and dementia of Alzheimer's type. However, there are also ongoing research studies to understand high-risk groups for non-Alzheimer's dementia. © Springer Science+Business Media, LLC 2012.

Braggio E.,Collaborative Research Building | Fonseca R.,Collaborative Research Building
Clinical Lymphoma, Myeloma and Leukemia | Year: 2013

Waldenström macroglobulinemia (WM) is a lymphoproliferative disease characterized by a heterogeneous lymphoplasmacytic bone marrow infiltrate and monoclonal immunoglobulin M production. WM shows similarities in presentations with related B-cell malignancies, sometimes making it difficult to distinguish them. To better characterize the genetic basis of WM, we performed a comparative genomic analysis with the related entities, lymphoplasmacytic lymphomas without monoclonal immunoglobulin M protein, marginal zone lymphomas, chronic lymphocytic leukemia, and monoclonal gammopathy of undetermined significance. Overall, WM shows a very stable karyotype and shares most of the chromosomal abnormalities with most of the indolent B-cell malignancies. Trisomy 4 is unique to WM; however, no candidate genes have been identified in the chromosome. Abnormalities that affect myeloid differentiation primary response 88 (MYD88) - interleukin-1 receptor-associated kinase 4 (IRAK4) and nuclear factor kappa B (NF-κB) signaling pathways were found in a significant proportion of WM cases, which suggest their relevance in the pathogenesis of the disease and opening new avenues that may be a guide to design novel therapeutic approaches. © 2013 Elsevier Inc.

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