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Paoluzzi L.,Columbia University | Scotto L.,NYU Langone Medical Center | Marchi E.,NYU Langone Medical Center | Zain J.,NYU Langone Medical Center | And 2 more authors.
Clinical Cancer Research

Purpose: Romidepsin and belinostat are inhibitors of histone deacetylases (HDACI). HDACIs are known to induce cell death in malignant cells through multiple mechanisms, including upregulation of death receptors and induction of cell cycle arrest. They are also known to be prodifferentiating. Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin lymphoma characterized by the t(11;14) (q13;q32) translocation leading to the overexpression of cyclin D1. Experimental Design: Assays for cytotoxicty including mathematical analysis for synergism, flow-cytometry, immunoblottings, and a xenograft severe combined immunodeficient beige mouse model were used to explore the in vitro and in vivo activity of romidepsin and/or belinostat alone or in combination with the proteasome inhibitor bortezomib in MCL. Results: In vitro, romidepsin and belinostat exhibited concentration-dependent cytotoxicity against a panel of MCL cell lines. Both HDACI showed strong synergism when combined with the proteasome inhibitor bortezomib in MCL. An HDACI plus bortezomib also induced potent mitochondrial membrane depolarization and apoptosis, whereas no significant apoptosis was observed in peripheral blood mononuclear cells from healthy donors with the combination. These events were associated with a decrease in cyclin D1 and Bcl-XL, and an increase in accumulation of acetylated histone H3, acetylated α-tubulin, and Noxa in cell lines. In a severe combined immunodeficient beige mouse model of MCL, the addition of belinostat to bortezomib enhanced efficacy compared with either drug alone. Conclusions: Collectively, these data strongly suggest that HDACI such as romidepsin or belinostat in combination with a proteasome inhibitor could represent a novel and rationale platform for the treatment of MCL. ©2010 AACR. Source

Acharyya S.,Columbia University | Acharyya S.,Herbert Irving Comprehensive Cancer Center | Massague J.,Sloan Kettering Cancer Center
Cell Research

It is becoming increasingly clear that leukocytes dynamically regulate cancer progression and metastasis, and among leukocytes, granulocytic cells abundantly accumulate in metastatic organs; however, their function in metastasis remains controversial. In a recent report in Nature, Wculek and Malanchi clarify the role of mature neutrophils as mediators of metastatic initiation and provide a targeted approach to prevent the pro-metastatic activity of neutrophils in breast cancer models. Source

Grover S.,Brigham and Womens Hospital | Grover S.,Harvard University | Grover S.,Dana-Farber Cancer Institute | Grover S.,Massachusetts General Hospital | And 10 more authors.
JAMA - Journal of the American Medical Association

Context: Patients with multiple colorectal adenomas may carry germline mutations in the APC or MUTYH genes. Objectives: To determine the prevalence of pathogenic APC and MUTYH mutations in patients with multiple colorectal adenomas who had undergone genetic testing and to compare the prevalence and clinical characteristics of APC and MUTYH mutation carriers. Design, Setting, and Participants: Cross-sectional study conducted among 8676 individuals who had undergone full gene sequencing and large rearrangement analysis of the APC gene and targeted sequence analysis for the 2 most common MUTYH mutations (Y179C and G396D) between 2004 and 2011. Individuals with either mutation underwent full MUTYH gene sequencing. APC and MUTYH mutation prevalence was evaluated by polyp burden; the clinical characteristics associated with a pathogenic mutation were evaluated using logistic regression analyses. Main Outcome Measure: Prevalence of pathogenic mutations in APC and MUTYH genes. Results: Colorectal adenomas were reported in 7225 individuals; 1457 with classic polyposis (≥100 adenomas) and 3253 with attenuated polyposis (20-99 adenomas). The prevalence of pathogenic APC and biallelic MUTYH mutations was 95 of 119 (80% [95% CI, 71%-87%]) and 2 of 119 (2% [95% CI, 0.2%-6%]), respectively, among individuals with 1000 or more adenomas, 756 of 1338 (56% [95% CI, 54%-59%]) and 94 of 1338 (7% [95% CI, 6%-8%]) among those with 100 to 999 adenomas, 326 of 3253 (10% [95% CI, 9%-11%]) and 233 of 3253 (7% [95% CI, 6%-8%]) among those with 20 to 99 adenomas, and 50 of 970 (5% [95% CI, 4%-7%]) and 37 of 970 (4% [95% CI, 3%-5%]) among those with 10 to 19 adenomas. Adenoma count was strongly associated with a pathogenic mutation in multivariable analyses. Conclusions: Among patients with multiple colorectal adenomas, pathogenic APC and MUTYH mutation prevalence varied considerably by adenoma count, including within those with a classic polyposis phenotype. APC mutations predominated in patients with classic polyposis, whereas prevalence of APC and MUTYH mutations was similar in attenuated polyposis. These findings require external validation. ©2012 American Medical Association. All rights reserved. Source

Quante A.S.,Columbia University | Quante A.S.,Ludwig Maximilians University of Munich | Quante A.S.,Helmholtz Center for Environmental Research | Whittemore A.S.,Stanford University | And 7 more authors.
Journal of the National Cancer Institute

Background: Clinical guidelines for breast cancer chemoprevention and MRI screening involve estimates of remaining lifetime risk (RLR); in the United States, women with an RLR of 20% or higher meet "high-risk" criteria for MRI screening. Methods: We prospectively followed 1764 women without breast cancer to compare the RLRs and 10-year risks assigned by the risk models International Breast Cancer Intervention Study (IBIS) and Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) and to compare both sets of model-assigned 10-year risks to subsequent incidence of breast cancer in the cohort. We used chi-square statistics to assess calibration and the area under the receiver operating characteristic curve (AUC) to assess discrimination. All statistical tests are two-sided. Results: The models classified different proportions of women as high-risk (IBIS = 59.3% vs BOADICEA = 20.1%) using the RLR threshold of 20%. The difference was smaller (IBIS = 52.9% vs BOADICEA = 43.2%) using a 10-year risk threshold of 3.34%. IBIS risks (mean = 4.9%) were better calibrated to observed breast cancer incidence (5.2%, 95% confidence interval (CI) = 4.2% to 6.4%) than were those of BOADICEA (mean = 3.7%) overall and within quartiles of model risk (P =. 20 by IBIS and P =. 07 by BOADICEA). Both models gave similar discrimination, with AUCs of 0.67 (95% CI = 0.61 to 0.73) using IBIS and 0.68 (95% CI = 0.62 to 0.74) using BOADICEA. Model sensitivities at thresholds for a 20% false-positive rate were also similar, with 41.8% using IBIS and 38.0% using BOADICEA. Conclusion: RLR-based guidelines for high-risk women are limited by discordance between commonly used risk models. Guidelines based on short-term risks would be more useful, as models are generally developed and validated under a short fixed time horizon (≤10 years). © 2015 The Author 2015. Published by Oxford University Press. Source

Perkins R.B.,Boston University | Zisblatt L.,Boston University | Trucks E.,Boston University | Hanchate A.,Boston University | And 2 more authors.

HPV vaccination is universally recommended for boys and girls, yet vaccination rates remain low nationwide. Methods: We conducted a provider-focused intervention that included repeated contacts, education, individualized feedback, and strong quality improvement incentives to raise HPV vaccination rates at two federally qualified community health centers. To estimate the effectiveness of the intervention, rates of initiation of vaccination, and completion of the next needed HPV vaccination (dose 1, 2 or 3) among boys and girls ages 11-21 were compared at baseline and two follow-up periods in two intervention health centers (. n4093 patients) and six control health centers (. n9025 patients). We conducted multivariable logistic regression accounting for clustering by practice. Results: Girls and boys in intervention practices significantly increased HPV vaccine initiation during the active intervention period relative to control practices (girls OR 1.6, boys OR 11; p<. 0.001 for both). Boys at intervention practices were also more likely to continue to initiate vaccination during the post-intervention/maintenance period (OR 8.5; p<. 0.01). Girls and boys at intervention practices were more also likely to complete their next needed HPV vaccination (dose 1, 2 or 3) than those at control practices (girls OR 1.4, boys OR 23; p<. 0.05 for both). These improvements were sustained for both boys and girls in the post-intervention/maintenance period (girls OR 1.6, boys OR 25; p<. 0.05 for both). Conclusions: Provider-focused interventions including repeated contacts, education, individualized feedback, and strong quality improvement incentives have the potential to produce sustained improvements in HPV vaccination rates. © 2014 Elsevier Ltd. Source

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