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Sharma J.,Dana-Farber Cancer Institute | Gray K.P.,Dana-Farber Cancer Institute | Gray K.P.,Harvard University | Harshman L.C.,Dana-Farber Cancer Institute | And 13 more authors.
Prostate | Year: 2014

Background Chemokines and cytokines have been implicated in progression to castration-resistant prostate cancer (CRPC). Methods Retrospective data were accessed from 122 men with serum samples drawn at a median of 0.5 months after starting ADT for metastatic prostate cancer. MCP-1, IL-1-β, IL-2, IL-8, IL-6, and TNF-α levels were measured by multiplex electrochemiluminescence assays. A multivariable Cox model assessed the association of time to CRPC and overall survival by the protein levels and adjusted for clinical variables (age and prostate specific antigen (PSA) levels at start of ADT, race, ECOG status, and extent of metastases). Associations were reported as hazard ratio (HR) with 95% confidence interval (CI). Results Median follow-up and overall survival were 44 and 42.2 months, respectively. ECOG performance status (≥1 vs. 0) was negatively associated with overall survival [HR=2.8 (1.1-7.0), P=0.03], and PSA nadir<0.2 was predictive of longer time to development of CRPC [HR=0.3 (0.2-0.5), P<0.0001]. The HR for time to CRPC by protein above the median was 1.4 (95% CI: 0.9, 2.2, P=0.13) for IL-8; 1.3 (95% CI: 0.8, 2, P=0.18) for TNF-α; 1.0 (95% CI: 0.7, 1.6, P=0.95) for MCP-1. The HR for median overall survival for protein levels above the median was: 1.9 (95% CI: 1.0, 3.5, P=0.04) for IL-8; 2.0 (95% CI: 1.1, 3.5, P=0.02) for TNF-α; 1.7 (95% CI: 1.7, 3.0, P=0.08) for MCP-1. There was no association with IL-1-β, IL-2, or IL-6. Conclusion Higher levels of inflammation-associated cytokines correlate with poorer prostate cancer outcomes and may guide strategies to improve prostate cancer therapy. © 2014 Wiley Periodicals, Inc. Source


Hahn N.M.,Indiana University | Yiannoutsos C.T.,Indiana University | Kirkpatrick K.,Hoosier Oncology Group | Sharma J.,Dana-Farber Cancer Institute | Sweeney C.J.,Dana-Farber Cancer Institute
Clinical Genitourinary Cancer | Year: 2014

Background Elevated markers of bone turnover are prognostic for shorter survival in castration-resistant prostate cancer. We aimed to determine the prognostic value of bone turnover markers in metastatic hormone-sensitive prostate cancer. Patients and Methods Markers of bone turnover (urine deoxypyridinoline [DPD] and N-telopeptide, serum bone alkaline phosphatase (AP), and osteocalcin [OC]) from baseline and after 6 months of study were assessed in men enrolled in a prospective metastatic prostate cancer trial with androgen deprivation therapy (ADT) with or without risedronate (ClinicalTrials.gov, NCT00216060). Results Serum samples were collected from 63 patients with bone involvement and a median follow-up of 39.7 months. A multivariate model using Cox regression - which included prostate-specific antigen (PSA) nadir, bisphosphonate treatment, and extent of metastases - showed that suppression of bone turnover markers after 6 months of therapy compared with baseline was significantly associated with longer skeletal-related event (SRE)-free survival. ADT without bisphosphonate therapy was also associated with a decline in markers of bone turnover, presumably resulting from direct anticancer activity. Elevated baseline bone turnover markers were not prognostic. Conclusion Failure to suppress bone turnover while receiving ADT, even when otherwise responding to therapy, may identify patients with hormone-sensitive metastatic prostate cancer who are destined for a shorter time to SREs and progression. © 2014 Elsevier Inc. All rights reserved. Source


Sharma J.,Dana-Farber Cancer Institute | Gray K.P.,Dana-Farber Cancer Institute | Gray K.P.,Harvard University | Evan C.,Dana-Farber Cancer Institute | And 11 more authors.
Prostate | Year: 2014

Background Insulin-like growth factor (IGF) and adipokines have been implicated in prostate cancer carcinogenesis. METHOD Data from 122 men with serum samples drawn within 3 months of starting ADT for metastatic prostate cancer was accessed retrospectively. IGF-1, IGF binding protein (BP)-1, leptin, and adiponectin levels were measured by multiplex electrochemiluminescence assays. A multivariable Cox model assessed the association of time to castration resistant prostate cancer (CRPC) and overall survival by the protein levels, adjusted for clinical variables, age and prostate specific antigen (PSA) levels at start of ADT, race, ECOG status, extent of metastases and were reported as hazard ratio (HR) with 95% confidence interval (CI). RESULTS Median follow-up and overall survival were 44 and 42.2 months, respectively. ECOG performance status (≥1 vs. 0) was negatively associated with overall survival [HR = 2.8 (1.1-7.0), P = 0.03], and PSA nadir <0.2 was predictive of longer time to CRPC [HR = 0.3 (0.2-0.5), P < 0.0001]. The median time to CRPC by low, middle, and top IGFBP-1 tertile distribution was 20.7, 18.1, and 12.4 months, respectively, with HR for middle versus low tertile levels 3.1 (1.7-5), P = 0.0003, and for top versus low tertile levels was 2.4 (1.3-4.2), P = 0.003. The median overall survival by low, middle and top tertile IGFBP-1 level was 48.5, 46.4, and 32.8 months, respectively, with HR for top versus low tertile 2.5 (1.2-5.1), P = 0.01. There was no association with IGF-1, adiponectin and leptin. CONCLUSION Elevated IGFBP-1 appears to be associated with shorter time to CRPC and lower overall survival in men with metastatic prostate cancer. Prostate 74:225-234, 2014. © 2013 Wiley Periodicals, Inc. © 2013 Wiley Periodicals, Inc. Source


Chiorean E.G.,Indiana University | Sanghani S.,Indiana University | Schiel M.A.,Indiana University | Yu M.,Indiana University | And 11 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2012

Purpose: We designed this study in locally advanced rectal cancer to determine the pathological response, toxicity, and disease-free survival (DFS) with induction capecitabine plus irinotecan followed by capecitabine-based chemoradiotherapy (CRT) and analyze the gene expression of enzymes involved in the metabolism of capecitabine and irinotecan for associations with response and toxicity. Methods: Patients with T3/T4 or node positive rectal cancer were treated with capecitabine 1,000 mg/m 2 twice daily (BID) days 1-14, and irinotecan 200 mg/m 2 on day 1 every 21 days for 2 cycles, followed by capecitabine 825 mg/m 2 BID days 1-5 per week with concurrent radiotherapy 50.4 Gy in 28 fractions. Surgical resection occured a median of 7.4 weeks after CRT. Gene expression levels or sequencing were used to analyze carboxylesterase-converting enzymes (CES1, CES2), thymidylate synthase (TS), thymidine phosphorylase (TP), dehydropyrimidine dehydrogenase (DPD), topoisomerase I (TOPO I), and uridine-diphosphate (UDP) glucuronosyl transferase 1A1 in pre- and post-treatment tumor and normal tissue samples. Results: Twenty-two patients were enrolled, and 18 completed neoadjuvant therapy and underwent R0 resection. Two patients with UGT1A1 7/7 had grade 3 and 4 neutropenic fever and sepsis. Pathological complete response (pCR) occurred in 6 of 18 patients (33 %) and 10 (56 %) had tumor and/or nodal downstaging. The 3-year DFS was 75.5 % (95 % CI, 39.7-91.8 %). Locoregional control rate was 100 %. We observed higher TP gene expression in pCR patients, but no correlations with toxicity. Conclusions: This neoadjuvant regimen was safe and demonstrated significant antitumor activity. High TP tumor gene expression was associated with obtaining pCR. © 2012 Springer-Verlag. Source


Cardenes H.R.,Indiana University | Moore A.M.,Howard Regional Health System | Johnson C.S.,Indiana University | Yu M.,Indiana University | And 7 more authors.
American Journal of Clinical Oncology: Cancer Clinical Trials | Year: 2011

OBJECTIVE: A Phase II study was conducted at Indiana University to evaluate the safety and efficacy of combined weekly Gemcitabine (GEM) with external beam radiotherapy (RT) in unresectable, locally advanced pancreatic cancer (LAPC). METHODS: Eligible patients had biopsy-proven LAPC without evidence of metastatic disease. In part A of the treatment plan, patients received GEM 600 mg/m IV weekly, with concurrent RT (50.4 Gy in 28 fractions, 1.8 Gy/d, 5 days per week). Part B of the treatment plan began approximately 4 weeks after completing part A: patients without disease progression received weekly GEM 1000 mg/m on days 1, 8, and 15 of a 28-day cycle for 6 cycles or until disease progression. RESULTS: From April 2001 to June 2003, of 28 patients evaluated, 24 (86%) completed part A. About 22 patients had grade 3 toxicities, primarily hematologic (43%) and gastrointestinal (36%). Three patients (11%) had grade 4 toxicities (one each for hyperbilirubinemia, infection, and dyspnea). The median follow-up was 10 months (1-63 months) for all enrolled patients. Six patients (21%) had a radiologic partial response, 16 (57%) had stable disease, 5 (18%) had progressive disease, and 1 patient (4%) had an unevaluable response at last follow-up. Four patients (14%) underwent surgical resection (2 with R0 resection). Median time to progression was 6 months (0-36 months). Median survival time was 10.3 months (95% confidence interval, 7.9-14.6 months). The 1- and 2-year actuarial survival rates were 30% and 11%. At last analysis, all but 2 patients died. CONCLUSION: The activity and toxicity profile of combination GEM and RT indicates that this can be safely administered for patients with LAPC. Copyright © 2011 by Lippincott Williams & Wilkins. Source

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