Elisabeth I Heath

Karmanos Cancer Institute, Detroit, Michigan, United States

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Publications (104)601.85 Total impact

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    ABSTRACT: Purpose PF-00337210 is an oral, highly selective vascular endothelial growth factor receptor (VEGFR) inhibitor. We evaluated a composite of biomarkers in real time to identify the recommended phase 2 dose (RP2D) and preliminary anticancer activity of PF-00337210. Patients and methods Patients (Pts) with advanced cancers were treated once (QD) or twice daily (BID) with escalating doses. Acute effects on tumor perfusion and vascularity were assessed using DCE-MRI, weekly BP readings, soluble VEGFR-2, and hemoglobin levels. Results Forty-six pts were treated with 0.67–9 mg QD and 4–6 mg BID of PF-00337210. Nineteen pts (41 %) previously received VEGF/VEGFR inhibitors. Two pts had dose-limiting toxicity (DLT) at 9 mg QD (troponin I increase and hypertension). The MTD at QD dose was 8 mg. Common drug-related adverse events were hypertension, fatigue, proteinuria, and nausea. Hypertension incidence and intensity corresponded with dose, but was well controlled with medication. Two confirmed partial responses and minor regressions (>10 to <30 % reduction in target lesions) were noted. Complete DCE-MRI was acquired in 21 pts (20 evaluable for vascular response). Ten pts were vascular responders, including 5/6 pts at BID doses. Greatest modulation of soluble VEGFR-2 was at 6 mg BID. The maximum change from baseline in diastolic BP was higher at BID doses. There were no significant differences for systolic BP and hemoglobin levels. Conclusions PF-00337210 has profound VEGFR inhibition effects at well-tolerated doses. Antitumor activity and VEGF inhibition effects were observed across BID doses. The RP2D was 6 mg BID.
    No preview · Article · Jan 2016 · Cancer Chemotherapy and Pharmacology
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    ABSTRACT: Introduction Heat shock protein 90 (Hsp90) has been studied as a therapeutic target in many cancers. In preclinical trials, the Hsp90 ATPase inhibitor ganetespib demonstrated potent inhibition of solid tumor growth, with superior potency than prior Hsp90 inhibitors. Given the promising preclinical outcome and favorable pharmacologic properties of ganetespib, we conducted a phase II trial of single-agent ganetespib in patients with metastatic, castrate-resistant prostate cancer (mCRPC). The primary objective of the study was to determine the 6-month progression-free survival (PFS) rate. Methods Patients with mCRPC who had been previously treated with docetaxel were enrolled after meeting eligibility criteria. All patients received ganetespib at 200 mg/m(2) on days 1, 8, and 15 of every 28 days (one cycle). Subjects who tolerated therapy were continued on ganetespib until disease progression. Considering that Hsp90 acetylation may confer insensitivity to Hsp90 inhibitors and maspin inhibits protein deacetylation, maspin-associated molecular markers were evaluated. Results Eighteen patients were recruited into the trial; most were Caucasian, had performance status 1, had received prior docetaxel, and were heavily pretreated. Of the 17 patients who were treated, none attained 6-month PFS. Only 2 patients achieved PFS > 4 months. The median PFS was 1.9 months. As per the study design, the trial was terminated after the interim analysis. The most frequent types of Grade 3 toxicity were dehydration, diarrhea, and fatigue. Molecular markers provided little additional insight regarding drug activity. Conclusions Ganetespib demonstrated minimal clinical activity in men with mCRPC. The true 6-month PFS rate was, at most, 0.20. Possible reasons for this include selection of a heavily pretreated patient population and lack of agent potency in patients with mCRPC.
    No preview · Article · Nov 2015 · Investigational New Drugs
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    ABSTRACT: Objective: To conduct a phase II trial of the combination of carboplatin, prednisone and everolimus in metastatic castrate resistant prostate cancer (mCRPC) as mTOR inhibition can overcome resistance to chemotherapy in prostate cancer. Methods: Patients with progressive mCRPC pretreated with docetaxel based regimen were eligible. Performance status of 0-1 and adequate bone marrow, renal and liver function were required. Primary endpoint was time to progression. Treatment consisted of carboplatin (starting dose equal to area under the curve (AUC of 5) intravenously every 21 days along with oral everolimus 5 mg once daily and prednisone 5 mg twice daily. Results: 26 patients were enrolled with median age of 69 years with 8 patients of African American origin. Grade 3 or 4 thrombocytopenia or neutropenia in 4 of 6 initial patients, required dose adjustment of carboplatin to AUC of 4 for subsequent patients. There were no PK interactions between carboplatin and everolimus. The median time to progression was 2.5 months (90% confidence interval [CI] 1.8-4.3 months) and median overall survival was 12.5 months (90% CI 7.7-18.7 months). 8 of 10 patients that demonstrated positive nuclear pAKT staining on immunohistochemistry progressed within 9 weeks, whereas two patients with negative staining continued without progression for prolonged durations of 30 and 48 weeks. TSC1 gene mutations did not correlate with clinical outcome. Conclusions: The addition of the MTOR inhibitor everolimus, to carboplatin demonstrated minimal clinical efficacy in metastatic prostate cancer. pAKT testing warrants further evaluation as a predictive marker of response to everolimus therapy.
    No preview · Article · Sep 2015 · Urology
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    ABSTRACT: Future curative cancer chemotherapies have to overcome tumor cell heterogeneity and plasticity. To test the hypothesis that the tumor suppressor maspin may reduce microenvironment-dependent prostate tumor cell plasticity and thereby modulate drug sensitivity, we established a new schematic combination of 2D, 3D and suspension cultures to enrich prostate cancer cell subpopulations with distinct differentiation potentials. We report here that, depending on the level of maspin expression, tumor cells in suspension and 3D collagen I manifest the phenotypes of stem-like and dormant tumor cell populations, respectively. In suspension, the surviving maspin-expressing tumor cells lost the self-renewal capacity, underwent senescence, lost the ability to dedifferentiate in vitro and failed to generate tumors in vivo. Maspin-nonexpressing tumor cells that survived the suspension culture in compact tumorspheres, displayed a higher level of stem cell marker expression, maintained the self-renewal capacity, formed tumorspheres in 3D matrices in vitro and were tumorigenic in vivo. The drug sensitivities of the distinct cell subpopulations depend on the drug target and the differentiation state of the cells. In 2D, Docetaxel, MS275 and Salinomycin were all cytotoxic. In suspension, while MS275 and Salinomycin were toxic, Docetaxel showed no effect. Interestingly, cells adapted to 3D collagen I were only responsive to Salinomycin. Maspin expression correlated with higher sensitivity to MS275 in both 2D and suspension, and to Salinomycin in 2D and 3D collagen I. Our data suggest that maspin reduces prostate tumor cell plasticity, and enhances tumor sensitivity to Salinomycin which may hold promise in overcoming tumor cell heterogeneity and plasticity. Copyright © 2015, American Association for Cancer Research.
    Preview · Article · Jul 2015 · Cancer Research
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    ABSTRACT: Toward development of a precision medicine framework for metastatic, castration-resistant prostate cancer (mCRPC), we established a multi-institutional clinical sequencing infrastructure to conduct prospective whole-exome and transcriptome sequencing of bone or soft tissue tumor biopsies from a cohort of 150 mCRPC affected individuals. Aberrations of AR, ETS genes, TP53, and PTEN were frequent (40%-60% of cases), with TP53 and AR alterations enriched in mCRPC compared to primary prostate cancer. We identified new genomic alterations in PIK3CA/B, R-spondin, BRAF/RAF1, APC, β-catenin, and ZBTB16/PLZF. Moreover, aberrations of BRCA2, BRCA1, and ATM were observed at substantially higher frequencies (19.3% overall) compared to those in primary prostate cancers. 89% of affected individuals harbored a clinically actionable aberration, including 62.7% with aberrations in AR, 65% in other cancer-related genes, and 8% with actionable pathogenic germline alterations. This cohort study provides clinically actionable information that could impact treatment decisions for these affected individuals. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · May 2015 · Cell
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    ABSTRACT: Cixutumumab, formerly IMC-A12, is a recombinant human monoclonal immunoglobulin G1 antibody that targets insulin-like growth factor I receptor (IGF-IR). Cixutumumab was synergistic with castration in a hormone-sensitive prostate cancer xenograft model. Patients with new metastatic prostate cancer were randomly assigned within 30 days of initiating androgen deprivation (AD) to cixutumumab added to a luteinizing hormone-releasing hormone agonist with bicalutamide versus AD alone. With 180 patients and one-sided alpha of 0.10, there would be 90% power to detect an absolute 20% difference in undetectable prostate-specific antigen (PSA; ≤ 0.2 ng/mL) rate at 28 weeks (relative risk, 1.44); this end point was previously strongly correlated with survival. Secondary end points included the proportion of patients with PSA > 4.0 ng/mL, safety and tolerability, circulating tumor cell (CTC) levels, and seven plasma IGF-IR biomarkers. Fisher's exact test was used for the primary end point, and extended Mantel-Haenszel χ(2) test was used for three PSA response categories. The trial accrued 210 eligible patients (105 randomly assigned to each arm). Patient characteristics were similar in both arms. Undetectable PSA rate was 42 (40.0%) of 105 for cixutumumab plus AD and 34 (32.3%) of 105 for AD alone (relative risk, 1.24; one-sided P = .16). Lower baseline CTCs (0 v 1 to 4 v ≥ 5/7.5 mL whole blood) were associated with higher rate of PSA response (three categories; P = .036) in 39 evaluable patients. IGF-IR biomarkers were not correlated with PSA outcome, and cixutumumab did not significantly change these biomarker levels. Cixutumumab plus AD did not significantly increase the undetectable PSA rate in men with new metastatic hormone-sensitive prostate cancer. CTCs at baseline may carry prognostic value. © 2015 by American Society of Clinical Oncology.
    No preview · Article · Apr 2015 · Journal of Clinical Oncology
  • Seongho Kim · Elisabeth Heath · Lance Heilbrun
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    ABSTRACT: Although the sample size for simple logistic regression can be readily determined using currently available methods, the sample size calculation for multiple logistic regression requires some additional information, such as the coefficient of determination ([Formula: see text]) of a covariate of interest with other covariates, which is often unavailable in practice. The response variable of logistic regression follows a logit-normal distribution which can be generated from a logistic transformation of a normal distribution. Using this property of logistic regression, we propose new methods of determining the sample size for simple and multiple logistic regressions using a normal transformation of outcome measures. Simulation studies and a motivating example show several advantages of the proposed methods over the existing methods: (i) no need for [Formula: see text] for multiple logistic regression, (ii) available interim or group-sequential designs, and (iii) much smaller required sample size. © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.
    No preview · Article · Mar 2015 · Statistical Methods in Medical Research

  • No preview · Conference Paper · Mar 2015
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    ABSTRACT: BACKGROUND The mechanism(s) by which androgen receptor (AR) splice variants contribute to castration-resistant prostate cancer (CRPC) is still lacking.METHODS Expressions of epithelial-to-mesenchymal transition (EMT) and stem cell markers were molecularly tested using prostate cancer (PCa) cells transfected with AR and AR3 (also known as AR-V7) plasmids or siRNA, and also cultured cells under androgen deprivation therapy (ADT) condition. Cell migration, clonogenicity, sphere-forming capacity was assessed using PCa cells under all experimental conditions and 3,3′-diindolylmethane (DIM; BR-DIM) treatment. Human PCa samples from BR-DIM untreated or treated patients were also used for assessing the expression of AR3 and stem cell markers.RESULTSOverexpression of AR led to the induction of EMT phenotype, while overexpression of AR3 not only induced EMT but also led to the expression of stem cell signature genes. More importantly, ADT enhanced the expression of AR and AR3 concomitant with up-regulated expression of EMT and stem cell marker genes. Dihydrotestosterone (DHT) treatment decreased the expression of AR and AR3, and reversed the expression of these EMT and stem cell marker genes. BR-DIM administered to PCa patients prior to radical prostatectomy inhibited the expression of cancer stem cell markers consistent with inhibition of self-renewal of PCa cells after BR-DIM treatment.CONCLUSIONAR variants could contribute to PCa progression through induction of EMT and acquisition of stem cell characteristics, which could be attenuated by BR-DIM, suggesting that BR-DIM could become a promising agent for the prevention of CRPC and/or for the treatment of PCa. Prostate © 2014 Wiley Periodicals, Inc.
    No preview · Article · Feb 2015 · The Prostate
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    ABSTRACT: Background: Enzalutamide and abiraterone are new androgen-axis disrupting treatments for metastatic castration-resistant prostate cancer (mCRPC). We examined the response and outcomes of enzalutamide-treated mCRPC patients in the real-world context of prior treatments of abiraterone and/or docetaxel. Methods: We conducted a seven-institution retrospective study of mCRPC patients treated with enzalutamide between January 2009 and February 2014. We compared the baseline characteristics, PSA declines, PSA progression-free survival (PSA-PFS), duration on enzalutamide and overall survival (OS) across subgroups defined by prior abiraterone and/or docetaxel. Results: Of 310 patients who received enzalutamide, 36 (12%) received neither prior abiraterone nor prior docetaxel, 79 (25%) received prior abiraterone, 30 (10%) received prior docetaxel and 165 (53%) received both prior abiraterone and prior docetaxel. Within these groups, respectively, ⩾30% PSA decline was achieved among 67, 28, 43 and 24% of patients; PSA-PFS was 5.5 (95% CI 4.2-9.1), 4.0 (3.2-4.8), 4.1 (2.9-5.4) and 2.8 (2.5-3.2) months; median duration of enzalutamide was 9.1 (7.3-not reached), 4.7 (3.7-7.7), 5.4 (3.8-8.4) and 3.9 (3.0-4.6) months. Median OS was reached only for the patients who received both prior abiraterone and docetaxel and was 12.2 months (95% CI 10.7-16.5). 12-month OS was 78% (59-100%), 64% (45-90%), 77% (61-97%) and 51% (41-62%). Of 70 patients who failed to achieve any PSA decline on prior abiraterone, 19 (27%) achieved ⩾30% PSA decline with subsequent enzalutamide. Conclusions: The activity of enzalutamide is blunted after abiraterone, after docetaxel, and still more after both, suggesting subsets of overlapping and distinct mechanisms of resistance.
    Full-text · Article · Jan 2015 · Prostate Cancer and Prostatic Diseases
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    ABSTRACT: Background: Docetaxel-prednisone (DP) is an approved therapy for metastatic castration-resistant prostate cancer (mCRPC). Orteronel (TAK-700) is an investigational, selective, non-steroidal inhibitor of 17,20-lyase, a key enzyme in androgenic hormone production. This phase 1/2 study evaluated orteronel plus DP in mCRPC patients. Methods: Adult men with chemotherapy-naïve mCRPC, serum prostate-specific antigen (PSA) ≥5 ng/mL, and serum testosterone <50 ng/dL received oral orteronel 200 or 400 mg twice-daily (BID) in phase 1 to determine the recommended dose for phase 2, plus intravenous docetaxel 75 mg/m(2) every 3 weeks, and oral prednisone 5 mg BID. Phase 2 objectives included safety, pharmacokinetics, and efficacy. Results: In phase 1 (n = 6, orteronel 200 mg; n = 8, orteronel 400 mg), there was one dose-limiting toxicity of grade 3 febrile neutropenia at 400 mg BID. This dose was evaluated further in phase 2 (n = 23). After 4 cycles, 68, 59, and 23% of patients achieved ≥30, ≥50, and ≥90% PSA reductions, respectively; median best PSA response was -77%. Seven of 10 (70%) RECIST-evaluable patients achieved objective partial responses. Median time to PSA progression and radiographic disease progression was 6.7 and 12.9 months, respectively. Dehydroepiandrosterone-sulfate (DHEA-S) and testosterone levels were rapidly and durably reduced. Common adverse events were fatigue (78%), alopecia (61%), diarrhea (48%), nausea (43%), dysgeusia (39%), and neutropenia (39%). Orteronel and docetaxel pharmacokinetics were similar alone and in combination. Conclusions: Orteronel plus DP was tolerable, with substantial reductions in PSA, DHEA-S, and testosterone levels, and evidence for measurable disease responses.
    No preview · Article · Jan 2015 · Investigational New Drugs
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    ABSTRACT: Loss of BRCA2 function stimulates prostate cancer (PCa) cell invasion and is associated with more aggressive and metastatic tumors in PCa patients. Concurrently, the receptor tyrosine kinase c-kit is highly expressed in skeletal metastases of PCa patients and induced in PCa cells placed into the bone microenvironment in experimental models. However, the precise requirement of c-kit for intraosseous growth of PCa and its relation to BRCA2 expression remain unexplored. Here, we show that c-kit expression promotes migration and invasion of PCa cells. Alongside, we found that c-kit expression in PCa cells parallels BRCA2 downregulation. Gene rescue experiments with human BRCA2 transgene in c-kit-transfected PCa cells resulted in reduction of c-kit protein expression and migration and invasion, suggesting a functional significance of BRCA2 downregulation by c-kit. The inverse association between c-kit and BRCA2 gene expressions in PCa cells was confirmed using laser capture microdissection in experimental intraosseous tumors and bone metastases of PCa patients. Inhibition of bone-induced c-kit expression in PCa cells transduced with lentiviral short hairpin RNA reduced intraosseous tumor incidence and growth. Overall, our results provide evidence of a novel pathway that links bone-induced c-kit expression in PCa cells to BRCA2 downregulation and supports bone metastasis. © 2014 Wiley Periodicals, Inc.
    No preview · Article · Jan 2015 · International Journal of Cancer

  • No preview · Article · Nov 2014 · European Journal of Cancer
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    ABSTRACT: The goal of the current study is to examine the biological effects of epithelial-specific tumor suppressor maspin on tumor host immune response. Accumulated evidence demonstrates an anti-tumor effect of maspin on tumor growth, invasion and metastasis. The molecular mechanism underlying these biological functions of maspin is thought to be through histone deacetylase inhibition, key to the maintenance of differentiated epithelial phenotype. Since tumor-driven stromal reactivities co-evolve in tumor progression and metastasis, it is not surprising that maspin expression in tumor cells inhibits extracellular matrix degradation, increases fibrosis and blocks hypoxia-induced angiogenesis. Using the athymic nude mouse model capable of supporting the growth and progression of xenogeneic human prostate cancer cells, we further demonstrate that maspin expression in tumor cells elicits neutrophil- and B cells-dependent host tumor immunogenicity. Specifically, mice bearing maspin-expressing tumors exhibited increased systemic and intratumoral neutrophil maturation, activation and antibody-dependent cytotoxicity, and decreased peritumoral lymphangiogenesis. These results reveal a novel biological function of maspin in directing host immunity towards tumor elimination that helps explain the significant reduction of xenograft tumor incidence in vivo and the clinical correlation of maspin with better prognosis of several types of cancer. Taken together, our data raised the possibility for novel maspin-based cancer immunotherapies.
    Full-text · Article · Oct 2014 · Oncotarget

  • No preview · Article · Sep 2014 · International journal of radiation oncology, biology, physics
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    Clara Hwang · Elisabeth I Heath

    Preview · Article · Jul 2014 · Journal of Clinical Oncology
  • Clara Hwang · Elisabeth I Heath
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    ABSTRACT: A 56-year-old man with no significant medical history was referred for management of metastatic renal cell carcinoma (RCC). Eighteen months ago, he underwent radical nephrectomy for a large renal mass. Pathology revealed a 13-cm clear cell RCC, Fuhrman nuclear grade 3 (Fig 1). The tumor invaded the perirenal and renal sinus fat but did not invade Gerota's fascia. Eight lymph nodes were examined and were negative for metastatic involvement. Surgical margins were negative. The final stage was T3aN1M0, stage III with no evidence of distant metastatic disease. The patient was offered a clinical trial evaluating adjuvant therapy, but he declined, citing his busy work and travel schedule. Unfortunately, on his most recent surveillance imaging, he was found to have multiple small pulmonary nodules (Fig 2). One of the nodules was biopsied and confirmed to be metastatic RCC, clear cell type. Currently, he is entirely asymptomatic (Karnofsky performance status, 100%), and examination is remarkable only for a well-healed nephrectomy scar. Laboratory evaluation reveals WBC of 9.4 K/uL, absolute neutrophil count of 7.5 K/uL, hemoglobin of 11.0 gm/dL, platelet count of 254 K/uL, creatinine of 1.7 mg/dL, calcium of 9.7 mg/dL, albumin of 3.7 g/dL, and lactate dehydrogenase of 161 IU/L. He would like to discuss first-line treatment options but is not interested in high-dose interleukin-2 because of the associated toxicity.
    No preview · Article · Feb 2014 · Journal of Clinical Oncology

  • No preview · Conference Paper · Feb 2014
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    Article: Preface.
    Elisabeth I Heath

    Preview · Article · Jan 2014 · CANCER AND METASTASIS REVIEW
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    ABSTRACT: Despite the positive impact of targeted therapies on metastatic renal cell carcinoma (mRCC), durable responses are infrequent and an unmet need exists for novel therapies with distinct mechanisms of action. We investigated the combination of recombinant Interleukin 21 (IL-21), a cytokine with unique immunostimulatory properties, plus sorafenib, a VEGFR tyrosine kinase inhibitor. In this phase 1/2 study, 52 mRCC patients received outpatient treatment with oral sorafenib 400 mg twice daily plus intravenous IL-21 (10-50 mcg/kg) on days 1-5 and 15-19 of each 7-week treatment course. The safety, antitumor activity, pharmacokinetic and pharmacodynamic effects of the combination were evaluated. In phase 1 (n = 19), the maximum tolerated dose for IL-21 with the standard dose of sorafenib was determined to be 30 mcg/kg/day; grade 3 skin rash was the only dose-limiting toxicity. In phase 2, 33 previously-treated patients tolerated the combination therapy well with appropriate dose reductions; toxicities were mostly grade 1 or 2. The objective response rate was 21% and disease control rate was 82%. Two patients have durable responses that are ongoing, despite cessation of both IL-21 and sorafenib, at 41+ and 30+ months, respectively. The median progression-free survival in phase 2 was 5.6 months. The pharmacokinetic and pharmacodynamic properties of IL-21 appeared to be preserved in the presence of sorafenib. IL-21 plus sorafenib has antitumor activity and acceptable safety in previously treated mRCC patients. IL-21 may represent a suitable immunotherapy in further exploration of combination strategies in mRCC. ClinicalTrials.gov Identifier: NCT00389285.
    Full-text · Article · Jan 2014

Publication Stats

2k Citations
601.85 Total Impact Points

Institutions

  • 2005-2016
    • Karmanos Cancer Institute
      Detroit, Michigan, United States
  • 2007-2015
    • Wayne State University
      • Division of Hematology and Oncology
      Detroit, Michigan, United States
    • Cornell University
      Итак, New York, United States
  • 2000-2011
    • Johns Hopkins Medicine
      • Department of Medical Oncology
      Baltimore, Maryland, United States
  • 2002-2008
    • Johns Hopkins University
      • Department of Medicine
      Baltimore, Maryland, United States
  • 2001
    • University of Pennsylvania
      • Division of Hematology/Oncology
      Filadelfia, Pennsylvania, United States
  • 1999
    • Johns Hopkins Bloomberg School of Public Health
      Baltimore, Maryland, United States