Christopher J Sweeney

Harvard Medical School, Boston, Massachusetts, United States

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Publications (140)840.24 Total impact

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    ABSTRACT: To determine whether patients with Gleason score 5+3=8 prostate cancer have outcomes more similar to other patients with Gleason 8 disease or to patients with Gleason 9 disease. The SEER database was used to study 40,533 men diagnosed with N0M0 Gleason 8 or 9 prostate cancer from 2004 - 2011. Using Gleason 4+4=8 as the referent, Fine and Gray competing risks regression analyses modeled the association between Gleason score and prostate cancer-specific mortality (PCSM). Five-year PCSM rates for patients with Gleason 4+4=8, Gleason 3+5=8, Gleason 5+3=8, and Gleason 9 disease were 6.3%, 6.6%, 13.5%, and 13.9%, respectively (P<0.001). Patients with Gleason 5+3=8 or Gleason 9 disease had up to a two-fold increased risk for PCSM ([Adjusted Hazard Ratio (AHR) 1.89; 95% CI 1.50 - 2.38; P<0.001] and [AHR 2.17; 95% CI 1.99 - 2.36; P<0.001], respectively) compared to the referent group of patients (Gleason 4+4=8). There was no difference in PCSM between patients with Gleason 5+3=8 versus 9 disease (P=0.25). Gleason 8 disease represents a heterogeneous entity with PCSM outcomes distinguishable by the primary Gleason pattern. The PCSM of Gleason 3+5=8 and Gleason 4+4=8 disease are similar, but patients with Gleason 5+3=8 have a risk of PCSM that is twice as high as other patients with Gleason 8 disease and should be considered to have similar poor prognosis as patients with Gleason 9 disease. Such patients should be allowed onto trials seeking the highest-risk patients in which to test novel aggressive treatment strategies. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    BJU International 07/2015; DOI:10.1111/bju.13239 · 3.13 Impact Factor
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    ABSTRACT: Preclinical xenograft models have contributed to advancing our understanding of the molecular basis of prostate cancer and to the development of targeted therapy. However, traditional preclinical in vivo techniques using caliper measurements and survival analysis evaluate the macroscopic tumor behavior, whereas tissue sampling disrupts the microenvironment and cannot be used for longitudinal studies in the same animal. Herein, we present an in vivo study of [(18)F]-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) designed to evaluate the metabolism within the microenvironment of LAPC4-CR, a unique murine model of castration-resistant prostate cancer. Mice bearing LAPC4-CR subcutaneous tumors were administered [(18)F]-FDG via intravenous injection. After a 60-minute distribution phase, the mice were imaged on a PET/CT scanner with submillimeter resolution; and the fused PET/CT images were analyzed to evaluate tumor size, location, and metabolism across the cohort of mice. The xenograft tumors showed [(18)F]-FDG uptake that was independent of tumor size and was significantly greater than uptake in skeletal muscle and liver in mice (Wilcoxon signed-rank P values of .0002 and .0002, respectively). [(18)F]-FDG metabolism of the LAPC4-CR tumors was 2.1 ± 0.8 ID/cm(3)*wt, with tumor to muscle ratio of 7.4 ± 4.7 and tumor to liver background ratio of 6.7 ± 2.3. Noninvasive molecular imaging techniques such as PET/CT can be used to probe the microenvironment of tumors in vivo. This study showed that [(18)F]-FDG-PET/CT could be used to image and assess glucose metabolism of LAPC4-CR xenografts in vivo. Further work can investigate the use of PET/CT to quantify the metabolic response of LAPC4-CR to novel agents and combination therapies using soft tissue and possibly bone compartment xenograft models. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Translational oncology 06/2015; 63(3). DOI:10.1016/j.tranon.2015.03.004 · 3.40 Impact Factor
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    ABSTRACT: In order to help inform the discussion about the risks versus benefits of prostate cancer screening among older men, we determined whether advanced age is associated with a higher probability of harboring high-grade or high-risk disease. The Surveillance, Epidemiology, and End Results (SEER) database was used to identify 383,039 men diagnosed with prostate cancer in 2004-2011. The percentage of patients diagnosed with low-, intermediate-, or high-risk disease or a Gleason score of 6, 7, or 8 to 10 was calculated by age range. As a secondary analysis, we examined whether this relationship was different in 2010-2011 versus 2007-2008 (before and after the 2009 publication of screening trials). The probability of Gleason score 8 to 10 or high-risk disease increased significantly with increasing age. The percentage of Gleason score 8 to 10 disease among men ages 50 to 54, 70 to 74, and 80 to 84 years was 8.9%, 16.2%, and 28.5%, respectively, and the percentage of high-risk disease was 14.3%, 22.4%, and 38.7% (P < .001). There were similar relationships among men with stage T1c disease. In addition, older men experienced a significant increase in the relative probability of high-risk or high-grade disease from 2007-2008 to 2010-2011. In this large US-based cohort, older men had a much higher probability of high-grade or high-risk prostate cancer. Physicians and patients should take into account the higher risk of more aggressive or advanced disease in older men when discussing the risks and benefits of prostate-specific antigen screening with healthy older men with a substantial life expectancy. Copyright © 2015 Elsevier Inc. All rights reserved.
    Clinical Genitourinary Cancer 06/2015; DOI:10.1016/j.clgc.2015.05.007 · 1.69 Impact Factor
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    ABSTRACT: The first St.Gallen Advanced Prostate Cancer Consensus Conference (APCCC) Expert Panel identified and reviewed the available evidence for the ten most important areas of controversy in advanced prostate cancer management. The successful registration of several drugs for castration-resistant prostate cancer and the recent studies of chemo-hormonal therapy in men with castration-naïve prostate cancer have led to considerable uncertainty as to the best treatment choices, sequence of treatment options and appropriate patient selection.Management recommendations based on expert opinion, and not based on a critical review of the available evidence, are presented. The various recommendations carried differing degrees of support, as reflected in the wording of the article text and in the detailed voting results recorded in supplementary material, available at Annals of Oncology online. Detailed decisions on treatment as always will involve consideration of disease extent and location, prior treatments, host factors, patient preferences as well as logistical and economic constraints. Inclusion of men with advanced prostate cancer in clinical trials should be encouraged. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email:
    Annals of Oncology 06/2015; DOI:10.1093/annonc/mdv257 · 6.58 Impact Factor
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    ABSTRACT: Long-term androgen deprivation therapy (ADT) was proven in randomized trials to be superior to short-term ADT for radiation-managed patients who have clinical T3 (cT3) disease, but it is unknown whether patients with T3 disease seen only on magnetic resonance imaging require similarly aggressive treatment. We attempted to study this issue by analogy by comparing the long-term post-prostatectomy survival of patients with cT3 disease versus cT1/T2 disease upstaged to pathologic T3 disease. The Surveillance, Epidemiology, and End Results (SEER) database was used to identify 60,165 men diagnosed with prostate adenocarcinoma between 1995 and 2002 who underwent prostatectomy. Prostate cancer-specific mortality (PCSM) was evaluated by stage after adjusting for grade, marital status, race, sex, year of diagnosis, and age. The median follow-up was 10.5 years. Patients with cT1/T2 but pathologic T3a disease had significantly better 10-year PCSM than men with cT3 disease had (3.0% vs. 9.9%, adjusted hazard ratio [AHR] = 0.420, P<0.001), but they had worse PCSM than men with pathologic T2 disease had (3.0% vs. 0.91%, AHR = 2.53, P<0.001). Of patients with occult T3a disease, those with low-grade/intermediate-grade disease (Gleason score 7 or less) had a slightly higher 10-year PCSM when compared with those with pathologic T2 disease (1.34% vs. 0.91%, AHR = 1.69, P<0.001). Patients with cT1/T2 and pathologic T3b disease had similar PCSM as men presenting with cT3 disease (11.0% vs. 9.86%, AHR = 1.14 [0.862, 1.52], P = 0.353). Patients with occult T3a disease had less than half the risk of PCSM as those with cT3 disease, and a subset of those men had similar risk as patients with pathologic T2 disease. Therefore, it is possible that radiation-managed patients with low-grade/intermediate-grade T3a disease by magnetic resonance imaging only might not require long-term ADT. However, patients with occult T3b or high-grade occult T3a disease have similar PCSM as that of those presenting with cT3 disease, so they should be treated as aggressively, including long-course ADT when managed by radiation. Copyright © 2015 Elsevier Inc. All rights reserved.
    Urologic Oncology 05/2015; 33(7). DOI:10.1016/j.urolonc.2015.03.010 · 3.36 Impact Factor
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    ABSTRACT: Importance Statin use has been associated with improved prostate cancer outcomes. Dehydroepiandrosterone sulfate (DHEAS) is a precursor of testosterone and a substrate for SLCO2B1, an organic anionic transporter. We previously demonstrated that genetic variants of SLCO2B1 correlated with time to progression (TTP) during receipt of androgen deprivation therapy (ADT). Statins also use SLCO2B1 to enter cells, and thus we hypothesized that they may compete with DHEAS uptake by the tumor cells.Objective To evaluate whether statin use prolongs TTP during ADT for hormone-sensitive prostate cancer.Design, Setting, and Participants In vitro studies were performed using prostate cancer cell lines at an academic, comprehensive cancer center. Statin use was retrospectively analyzed in 926 patients who had received ADT for biochemical or metastatic recurrence or de novo metastatic prostate cancer between January 1996 and November 2013. Main Outcomes and Measures To determine whether statins interfere with DHEAS uptake, we performed in vitro studies using prostate cancer cell lines. Next, we queried our institutional clinical database to assess for an association between statin use and TTP during ADT using multivariable Cox regression analysis and adjusted for known prognostic factors.Results In vitro, we demonstrated that statins block DHEAS uptake by competitively binding to SLCO2B1. In our ADT cohort of 926 patients, 283 (31%) were taking a statin at ADT initiation. After a median follow-up of 5.8 years, 644 patients (70%) had experienced disease progression while receiving ADT. Median TTP during ADT was 20.3 months (95% CI, 18-24 months). Men taking statins had a longer median TTP during ADT compared with nonusers (27.5 [95% CI, 21.1-37.7] vs 17.4 [95% CI, 14.9-21.1] months; P < .001). The association remained statistically significant after adjusting for predefined prognostic factors (adjusted hazard ratio, 0.83 [95% CI, 0.69-0.99]; P = .04). The positive statin effect was observed for both patients with and without metastases (adjusted hazard ratio, 0.79 [95% CI, 0.58-1.07] for M0 disease and 0.84 [95% CI, 0.67-1.06] for M1 disease; P for interaction = .72).Conclusions and Relevance Statin use at the time of ADT initiation was associated with a significantly longer TTP during ADT even after adjustment for known prognostic factors. Our in vitro finding that statins competitively reduce DHEAS uptake, thus effectively decreasing the available intratumoral androgen pool, affords a plausible mechanism to support the clinical observation of prolonged TTP in statin users.
    05/2015; 1(4). DOI:10.1001/jamaoncol.2015.0829
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    ABSTRACT: Active surveillance is an increasingly accepted approach for managing patients with germ cell tumors after an orchiectomy. Here we investigate a time-to-relapse stratification scheme for clinical stage 1 non-seminoma (NS) germ cell tumor (GCT) patients according to factors associated with relapse and identify a group of patients with a lower frequency and longer time to relapse who may require an alternative surveillance strategy. We analyzed 266 CS1 GCT patients from the IRB-approved DFCI GCT database that exclusively underwent surveillance following orchiectomy from 1997-2013. We stratified NSGCT patients according to predominance of embryonal carcinoma (EmbP) and lymphovascular invasion (LVI), using a 0,1,2 scoring system. Cox regression and conditional risk analysis were used to compare each NSGCT group to patients in the seminoma (SGCT) category. Median time-to-relapse values were then calculated among those patients who underwent relapse. Relapse-free survival curves were generated using the Kaplan-Meier method. Fifty (37%) NSGCT and 20 (15%) SGCT patients relapsed. The median time-to-relapse was 11.5 vs. 6.3 months for the SGCT and NSGCT groups respectively. For NSGCT patients, relapse rates were higher and median time-to-relapse faster with increasing number of risk factors. Relapse rates (%) and median time to relapse (months) were 25%/8.5 months, 41%/6.8 months & 78%/3.8months for RF0, RF1 and RF2, respectively. We found a statistically significant difference between SGCT and patients with 1 or 2 risk factors (p<0.001) but not between SGCT and NSGCT RF0 (p=0.108). NSGCT patients grouped by a risk score system based on embryonal predominance and lymphovascular invasion yielded three groups with distinct relapse patterns -and patients with neither EmbP nor LVI appear to behave similar to SGCT. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email:
    Annals of Oncology 04/2015; DOI:10.1093/annonc/mdv180 · 6.58 Impact Factor
  • The Journal of Urology 04/2015; 193(4):e1088-e1089. DOI:10.1016/j.juro.2015.02.1957 · 3.75 Impact Factor
  • European Urology Supplements 04/2015; 14(2):e672-e672a. DOI:10.1016/S1569-9056(15)60665-0 · 3.37 Impact Factor
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    ABSTRACT: Objectives To describe outcomes of patients with prostate cancer (PCa) diagnosed after another malignancy and identify factors associated with PCa death in this population, as little is known about the clinical significance of PCa as a subsequent malignancy.Patients and methodsWe studied 18,225 men diagnosed with PCa after another malignancy from 1973 to 2006. We compared demographic and clinical variables and proportion of death from PCa versus prior malignancy with T-test and chi-squared analyses. Fine and Gray's regression was used to consider the effect of treatment on PCa death. We then studied a second cohort of 88,013 men with PCa as a first or second malignancy to describe current diagnostic and treatment patterns.ResultsOne in seven men died from PCa in our first cohort. More died from PCa following colorectal cancer (16.8 vs. 13.7%), melanoma (13.4 vs. 7.56%), and oral cancer (19.1 vs. 4.04%), but fewer following bladder, kidney, lung, leukemia and non-Hodgkin's lymphoma (all p<0.001). PCa treatment was associated with a nearly 50% lower-risk of death when high-grade or high-stage PCa (AHR 0.55; 0.47-0.64). Patients who died from PCa had higher-grade and stage disease and received less treatment than patients who died of prior malignancy. The second cohort showed subsequent PCa had more high-risk disease (36.3 vs. 22.2%,p<0.001) and less PCa treatment (AOR 0.872, 0.818-0.930) than primary PCa.ConclusionsPCa remains a significant cause of mortality when diagnosed as a subsequent cancer. These results suggest PCa treatment should be seriously considered in patients with prior malignancies, especially those with high-grade or locally-advanced PCa.This article is protected by copyright. All rights reserved.
    BJU International 04/2015; DOI:10.1111/bju.13144 · 3.13 Impact Factor
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    ABSTRACT: Whole exome sequencing of metastatic castration-resistant prostate cancer (mCRPC) reveal that 5~7% of tumors harbor promyelocytic zinc finger protein (PLZF) homozygous deletions. PLZF is a canonical androgen-regulated putative tumor suppressor gene whose expression is inhibited by androgen deprivation therapy (ADT). Here, we demonstrate that knockdown of PLZF expression promotes a CRPC and enzalutamide resistant phenotype in prostate cancer cells. Reintroduction of PLZF expression is sufficient to reverse androgen-independent growth mediated by PLZF depletion. PLZF loss enhances CRPC tumor growth in a xenograft model. Bioinformatic analysis of the PLZF cistrome shows that PLZF negatively regulates multiple pathways including the MAPK pathway. Accordingly, our data support an oncogenic program activated by ADT and this acquired mechanism together with the finding of genetic loss in CRPC implicate PLZF inactivation as a mechanism promoting ADT resistance and the CRPC phenotype. Copyright © 2015, American Association for Cancer Research.
    Cancer Research 03/2015; 75(10). DOI:10.1158/0008-5472.CAN-14-3602 · 9.28 Impact Factor
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    ABSTRACT: BNC105P inhibits tubulin polymerization, and preclinical studies suggest possible synergy with everolimus. In this phase I/II study, efficacy and safety of the combination were explored in patients with metastatic renal cell carcinoma (mRCC). A phase I study in patients with clear cell mRCC and any prior number of therapies was conducted using a classical 3+3 design to evaluate standard doses of everolimus with increasing doses of BNC105P. At the recommended phase II dose (RP2D), patients with clear cell mRCC and 1-2 prior therapies (including ≥1 VEGF-TKI) were randomized to BNC105P with everolimus (Arm A) or everolimus alone (Arm B). The primary endpoint of the study was 6-month progression-free survival (6MPFS). Secondary endpoints included response rate, PFS, overall survival (OS) and exploratory biomarker analyses. In the phase I study (n=15), a dose of BNC105P at 16 mg/m2 with everolimus at 10 mg daily was identified as the RP2D. In the phase II study, 139 patients were randomized, with 69 and 67 evaluable patients in Arms A and B, respectively. 6MPFS was similar in the treatment arms (Arm A: 33.82% v Arm B: 30.30%, P=0.66) and no difference in median PFS was observed (Arm A: 4.7 mos v Arm B: 4.1 mos; P=0.49). Changes in matrix metalloproteinase-9, stem cell factor, sex hormone binding globulin and serum amyloid A protein were associated with clinical outcome with BNC105P. Although the primary endpoint was not met in an unselected population, correlative studies suggest several biomarkers that warrant further prospective evaluation. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 03/2015; DOI:10.1158/1078-0432.CCR-14-3370 · 8.19 Impact Factor
  • Loana B Valenca, Christopher J Sweeney, Mark M Pomerantz
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    ABSTRACT: The standard treatment for metastatic prostate cancer is androgen deprivation therapy. However, progressive, metastatic disease usually develops, giving rise to metastatic castration-resistant prostate cancer (mCRPC). Great improvements have been made recently in the management of mCRPC, with current approved treatments including chemotherapy, androgen receptor-targeted agents, immunotherapies and radiopharmaceuticals. While the emergence of multiple effective therapies is encouraging, devising a treatment strategy can be difficult and it is becoming increasingly important, and challenging, to identify factors that influence the ideal timing of specific therapies. Considering where to place these agents in the treatment schedule of mCRPC, or whether these agents should be sequenced or combined to derive the optimal benefit for the patient, is not yet clear. Furthermore, cross-resistance may exist between these agents, which may ultimately influence treatment decisions and sequence choices. Preliminary data are emerging regarding the safety and activity for sequential treatment regimens, but there are currently no prospective studies. As prostate cancer is highly heterogeneous clinically, it is likely that no single treatment sequence will be optimal for all patients. However, at present, there are no validated biomarkers to guide individualized treatment for mCRPC. Here we review available data for the different mCRPC treatments, discussing potential sequencing of agents and possible cross-resistance or synergy among the recently approved and emerging therapies. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Cancer Treatment Reviews 03/2015; 41(4). DOI:10.1016/j.ctrv.2015.02.010 · 6.47 Impact Factor
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    ABSTRACT: In the United States, half of men with prostate cancer harbor the androgen-regulated gene fusion TMPRSS2:ERG. We hypothesized that men with TMPRSS2:ERG positive tumors are more responsive to androgen deprivation therapy (ADT). We studied a cohort of 239 men with prostate cancer from the Physicians' Health Study and Health Professionals Follow-up Study who received ADT during their disease course. Fusion status was assessed on available tumor tissue by immunohistochemistry for ERG protein expression. We used Cox models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for assessment of prostate cancer-specific mortality after ADT initiation. Roughly half of the men had stage T3 or higher tumors at diagnosis and 39% had Gleason 8-10 tumors. During an average follow up of 10.2 years, 42 men died from prostate cancer. There was a non-significant inverse association between positive fusion status and time to death from prostate cancer after ADT (multivariable HR: 0.76; 95% CI: 0.40-1.45). Harboring the TMPRSS2:ERG fusion was associated with a statistically significant lower risk of prostate cancer mortality among men who were treated with orchiectomy (multivariable HR: 0.13; 95% CI: 0.03-0.62), based on 15 events. Our results, combined with those from earlier studies, provide suggestive evidence that men with TMPRSS2:ERG positive tumors may have longer prostate cancer survival after ADT. Larger cohorts are needed for more robust results and to assess whether men with tumors harboring the fusion benefit from treatment with ADT in the (neo) adjuvant or metastatic setting specifically. Prostate © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    The Prostate 03/2015; 75(9). DOI:10.1002/pros.22973 · 3.57 Impact Factor
  • Brandon Bernard, Christopher J Sweeney
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    ABSTRACT: In 2014, prostate cancer will affect roughly 15 % of American men during their lifetimes with about 230,000 new cases and 29,000 deaths per year. If required, most can be treated with curative surgery or radiotherapy. Upon relapse, androgen deprivation therapy (intermittent or continuous) is the cornerstone of treatment for hormone-sensitive disease. Response is variable and treatment is associated with a significant risk of toxicity. Recently, significant advances in survival have been demonstrated with chemohormonal therapy in men with high-volume disease. In addition, new findings have informed the approach to preventing bone complications in patients on therapy for metastatic hormone-sensitive prostate cancer. Devising clinical prediction tools and biomarkers is needed to select patients most likely to benefit from certain therapies and allow for a personalized approach.
    Current Urology Reports 03/2015; 16(3):488. DOI:10.1007/s11934-015-0488-8 · 1.51 Impact Factor
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    ABSTRACT: To determine the incidence of pathologic upgrading and upstaging for contemporary, clinically low-risk patients and identify predictors of having occult, advanced disease to inform selection of patients for active surveillance. We studied 10,273 patients in the Surveillance, Epidemiology, and End Results database diagnosed with clinically low-risk disease (cT1c/T2a, Prostate specific antigen(PSA)<10ng/mL, Gleason 3+3=6) in 2010-2011 and treated with prostatectomy. The primary outcome was the incidence of upgrading to pathologic Gleason score 7-10 or upstaging to pathologic T3-T4/N1 disease. Multivariable logistic regression of men with complete biopsy data (n=5,581) identified significant predictors of upgrading or upstaging, which were then used to create a risk-stratification table. At prostatectomy, 44% of patients were upgraded and 9.7% were upstaged. Multivariable analysis of 5,581 patients showed age, PSA, and percent positive cores (all p<0.001), but not race, were associated with occult, advanced disease. With these variables dichotomized at the median, age >60 (Adjusted Odds Ratio[AOR]1.39), PSA>5.0 (AOR1.28), and >25% positive cores (AOR1.76) were significantly associated with upgrading (all p<0.001). Similarly, age>60 (AOR1.42), PSA>5.0 (AOR1.44), and >25% positive cores (AOR2.26) were associated with upstaging (all p<0.001). Sixty percent of 5,581 low-risk patients with PSA 7.5-9.9 and >25% positive cores were upgraded. This study is limited by possible bias introduced by only using patients selected for prostatectomy. Nearly half of clinically low-risk patients harbor Gleason ≥7 or ≥pT3 disease and should be risk-stratified by PSA and percent positive cores for consideration of further testing before deciding on active surveillance. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
    The Journal of Urology 02/2015; DOI:10.1016/j.juro.2015.02.015 · 3.75 Impact Factor
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    ABSTRACT: The long-term prostate cancer-specific survival for patients initially managed with active surveillance for low-risk prostate cancer ranges from 97-100%. We characterized factors that are associated with aggressive treatment with either radical prostatectomy or radiation for indolent prostate cancer (defined as screening-detected, low-risk disease). The Surveillance, Epidemiology and End Results Program was used to extract a cohort of 39,803 men diagnosed with PSA-detected, low-risk prostate cancer (clinical category T1c, Gleason score<6, and PSA<10) from 2004 - 2010. After socioeconomic profiles were generated from county-linked education and income data, multivariable logistic regression was used to determine whether there were any factors associated with high rates of aggressive treatment. The rate of aggressive treatment among all men with indolent prostate cancer was 64.3%. Greater rates of aggressive treatment were experienced by high socioeconomic status, Caucasian, and married men (P<0.001 for all cases). The increased adjusted odds for receipt of aggressive therapy was 1.25 (95% CI 1.17-1.32; P<0.001), 1.26 (95% CI 1.21-1.32; P<0.001), and 1.88 (95% CI 1.80-1.97; P<0.001) for high socioeconomic status, Caucasian, and married men, respectively, compared to low socioeconomic status, non-Caucasian, and unmarried men, respectively. While high socioeconomic status, Caucasian, and married men often receive the highest quality health care and have the best outcomes for many cancers, it appears that they are most at risk for the avoidable potential harms of aggressive treatment of indolent prostate cancer. Future policy should encourage more stringent guidelines for deferred treatment and culturally and sociodemographically competent counseling of active surveillance. Copyright © 2015 Elsevier Inc. All rights reserved.
    The American Journal of Medicine 01/2015; 128(6). DOI:10.1016/j.amjmed.2014.12.030 · 5.30 Impact Factor
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    ABSTRACT: The transcription factor nuclear factor-kappaB (NF-κB) is constitutively active in several cancers and is a target of therapeutic development. We recently developed dimethylaminoparthenolide (DMAPT), a clinical grade water-soluble analog of parthenolide, as a potent inhibitor of NF-κB and demonstrated in vitro and in vivo anti-tumor activities in multiple cancers. In this study, we show DMAPT is an epigenetic modulator functioning in an NF-κB-dependent and -independent manner. DMAPT-mediated NF-κB inhibition resulted in elevated histone H3K36 trimethylation (H3K36me3), which could be recapitulated through genetic ablation of the p65 subunit of NF-κB or inhibitor-of-kappaB alpha super-repressor overexpression. DMAPT treatment and p65 ablation increased the levels of H3K36 trimethylases NSD1 (KMT3B) and SETD2 (KMT3A), suggesting that NF-κB directly represses their expression and that lower H3K36me3 is an epigenetic marker of constitutive NF-κB activity. Overexpression of a constitutively active p65 subunit of NF-κB reduced NSD1 and H3K36me3 levels. NSD1 is essential for DMAPT-induced expression of pro-apoptotic BIM, indicating a functional link between epigenetic modification and gene expression. Interestingly, we observed enhanced H4K20 trimethylation and induction of H4K20 trimethylase KMT5C in DMAPT-treated cells independent of NF-κB inhibition. These results add KMT5C to the list NF-κB-independent epigenetic targets of parthenolide, which include previously described histone deacetylase 1 (HDAC-1) and DNA methyltransferase 1. As NSD1 and SETD2 are known tumor suppressors and loss of H4K20 trimethylation is an early event in cancer progression, which contributes to genomic instability, we propose DMAPT as a potent pharmacologic agent that can reverse NF-κB-dependent and -independent cancer-specific epigenetic abnormalities.
    Cell Death & Disease 01/2015; 6(1):e1608. DOI:10.1038/cddis.2014.569 · 5.18 Impact Factor
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    ABSTRACT: To evaluate (18)F-labeled-fluorodeoxyglucose ((18)F-FDG-) and (18)F-labeled-sodium fluoride ((18)F-NaF-) positron emission tomography/computed tomography (PET/CT) as biomarkers in metastatic castrate-resistant prostate cancer (mCRPC). Nine men (53-75 years) in a phase 1 trial of abiraterone and cabozantinib had (18)F-FDG-PET/CT, (18)F-NaF-PET/CT and standard imaging ((99m)Tc-labeled-methylene-diphosphonate ((99m)Tc-MDP) bone scan and abdominal/pelvic CT) at baseline and after 8 weeks of therapy. Baseline disease was classified as widespread (18)F-FDG-avid, oligometastatic (18)F-FDG-avid (1 site), or non-(18)F-FDG-avid. Metabolic response was classified using European Organisation for Research and Treatment of Cancer (EORTC) criteria. Treatment response using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, Prostate Cancer Working Group 2 (PCWG2) guidelines and days on trial (DOT) were recorded. All men were followed for 1 year or until progression. Four men had (18)F-FDG-avid disease: two with widespread (DOT 53 and 76) and two with oligometastatic disease (DOT 231 and still on trial after 742+ days). Five men had non-(18)F-FDG-avid disease; three remained stable or improved (2 still on trial while one discontinued for non-oncologic reasons; DOT 225-563+), and 2 progressed (DOT 285 and 532). Despite the small sample size, Kaplan-Meier analysis showed a significant difference in progression free survival (PFS) between men with widespread (18)F-FDG-avid, oligometastatic (18)F-FDG-avid and non-(18)F-FDG-avid disease (p < 0.01). All men had (18)F-NaF-avid disease. Neither (18)F-NaF-avid disease extent nor intensity was predictive of treatment response. (18)F-FDG-PET/CT may be superior to (18)F-NaF-PET/CT and standard imaging in men with mCRPC on abiraterone and cabozantinib. (18)F-FDG-PET/CT may have potential to stratify men into 3 groups (widespread vs. oligometastatic (18)F-FDG-avid vs. non-(18)F-FDG-avid mCRPC) to tailor therapy. Further evaluation is warranted.
    American Journal of Nuclear Medicine and Molecular Imaging 01/2015; 5(1):72-82. · 3.25 Impact Factor
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    ABSTRACT: Objectives: Treating high-risk prostate cancer (CaP) with definitive therapy improves survival. We evaluated whether having health insurance reduces racial disparities in the use of definitive therapy for high-risk CaP. Materials and methods: The Surveillance, Epidemiology, and End Results Program was used to identify 70,006 men with localized high-risk CaP (prostate-specific antigen level 4 20 ng/ml or Gleason score 8–10 or stage 4 cT3a) diagnosed from 2007 to 2010. We used multivariable logistic regression to analyze the 64,277 patients with complete data to determine the factors associated with receipt of definitive therapy. Results: Compared with white men, African American (AA) men were significantly less likely to receive definitive treatment (adjusted odds ratio [AOR] ¼ 0.60; 95% CI: 0.56–0.64; P o 0.001) after adjusting for sociodemographics and known CaP prognostic factors. There was a significant interaction between race and insurance status (P interaction ¼ 0.01) such that insurance coverage was associated with a reduction in racial disparity between AA and white patients regarding receipt of definitive therapy. Specifically, the AOR for definitive treatment for AA vs. white was 0.38 (95% CI: 0.27–0.54, P o 0.001) among uninsured men, whereas the AOR was 0.62 (95% CI: 0.57–0.66, P o 0.001) among insured men. Conclusions: AA men with high-risk CaP were significantly less likely to receive potentially life-saving definitive treatment when compared with white men. Having health insurance was associated with a reduction in this racial treatment disparity, suggesting that expansion of health insurance coverage may help reduce racial disparities in the management of aggressive cancers. r
    Urologic Oncology 12/2014; 32(8):1285-1291. DOI:10.1016/j.urolonc.2014.04.014 · 3.36 Impact Factor

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  • 2013–2015
    • Harvard Medical School
      • Department of Radiation Oncology
      Boston, Massachusetts, United States
  • 2010–2015
    • Dana-Farber Cancer Institute
      • • Lank Center for Genitourinary Oncology
      • • Department of Medical Oncology
      Boston, Massachusetts, United States
  • 2014
    • Massachusetts General Hospital
      Boston, Massachusetts, United States
  • 2013–2014
    • Brigham and Women's Hospital
      Boston, Massachusetts, United States
  • 2010–2014
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1999–2011
    • Indiana University-Purdue University Indianapolis
      • • Department of Medicine
      • • Department of Surgery
      • • Division of Hematology/Oncology
      Indianapolis, Indiana, United States
  • 2009–2010
    • University of Adelaide
      • Faculty of Health Sciences
      Tarndarnya, South Australia, Australia