Susan F Slovin

Memorial Sloan-Kettering Cancer Center, New York, New York, United States

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Publications (113)742.1 Total impact

  • Susan F Slovin

    No preview · Article · Dec 2015 · Urologic Oncology
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    ABSTRACT: The effects of mammalian target of rapamycin (mTOR) inhibition are limited by feedback reactivation of receptor tyrosine kinase signaling in phosphatase and tensin homolog-null tumors. Thus, this study tested the combination of mTOR inhibition (everolimus) and epidermal growth factor receptor inhibition (gefitinib) in castration-resistant prostate cancer (CRPC). In phase 1, 12 patients (10 with CRPC and 2 with glioblastoma) received daily gefitinib (250 mg) with weekly everolimus (30, 50, or 70 mg). In phase 2, 27 CRPC patients received gefitinib with everolimus (70 mg). Phase 1 revealed no pharmacokinetic interactions and no dose-limiting toxicities. In phase 2, 18 of 27 patients (67%) discontinued treatment before the 12-week evaluation because of progression as evidenced by prostate-specific antigen (PSA) levels (n = 6) or imaging (n = 5) or because of a grade 2 or higher toxicity (n = 7). Thirteen of the 37 CRPC patients (35%) exhibited a rapidly rising PSA level after they had begun treatment, and this declined upon discontinuation. Fluorodeoxyglucose positron emission tomography 24 to 72 hours after the initiation of treatment showed a decrease in the standardized uptake value consistent with mTOR inhibition in 27 of the 33 evaluable patients (82%); there was a corresponding rise in PSA in 20 of these 27 patients (74%). The combination of gefitinib and everolimus did not result in significant antitumor activity. The induction of PSA in tumors treated with mTOR inhibitors was consistent with preclinical data showing that phosphoinositide 3-kinase (PI3K) pathway signaling feedback inhibits the androgen receptor (AR). This clinical evidence of relief of feedback inhibition promoting enhanced AR activity supports future studies combining PI3K pathway inhibitors and second-generation AR inhibitors in CRPC. Cancer 2015 © 2015 American Cancer Society. © 2015 American Cancer Society.
    No preview · Article · Jul 2015 · Cancer
  • Susan F Slovin
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    ABSTRACT: Despite multiple immunologic approaches with peptide, protein, and DNA vaccines, no single therapy has induced complete remission or maintained durability of response in patients with castration-resistant prostate cancer (CRPC). Historically, immunotherapy has had limited effect on solid tumors with the exception of melanoma and renal cell carcinomas, which have been deemed as immunologic cancers given their potential for remissions either spontaneously or after removal of the primary lesion. There is considerable excitement about using an immunotherapy in combination with biologic agents such as checkpoint inhibitors, cytokines, other vaccines, or chemotherapy. Sipuleucel-T represents one of several novel immunologic therapeutic approaches to treat prostate cancer in addition to other solid tumors. It is the first in its class of autologous cellular therapies to demonstrate safety and an overall survival benefit in patients with asymptomatic or minimally symptomatic CRPC and represents a unique treatment method that may be further enhanced with other agents. Although sipuleucel-T can be used as a foundation on which to build and enhance future immunologic clinical trials, other exciting strategies are in development that may be easily integrated into the algorithm of current care.
    No preview · Article · May 2015
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    Preview · Article · Apr 2015 · The Journal of Urology
  • Susan Slovin
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    ABSTRACT: Immunotherapy for genitourinary malignancies such as prostate, renal, and bladder cancers has experienced a resurgence since the development of 3 novel strategies: the autologous cellular product therapy, Sipuleucel-T for prostate cancer, the checkpoint inhibitors, anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4), anti-programmed cell death ligand 1 (anti-PD1), and anti-programmed cell death ligand 1), respectively. These agents have led to strikingly durable responses in several of these solid tumors, but their efficacy has been inconsistent. Why all solid tumors are not equal in their response to these therapies is unclear. More importantly, changes in humoral or cellular responses which may reflect changes in a tumor's biology have been limited due to differences in immune monitoring and lack of consistency in established reliable immunologic endpoints. How to design immunologic end points that reflect a meaningful effect on the cancer remains a challenge for clinical trial development. The issues faced by clinical investigators and the current state of immune monitoring are discussed. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Mar 2015 · Urologic Oncology
  • Oladapo Yeku · Susan F Slovin
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    ABSTRACT: Introduction: Prostate cancer metastatic to bone is a cause of significant morbidity and mortality. Bone pain and other skeletal events negatively impact the quality of life in patients who might otherwise be functioning well. As such, there has been intense interest in the development of strategies and pharmaceuticals to address this problem. Areas covered: The authors reviewed the current literature for articles relevant to metastatic prostate cancer, clinical radiopharmaceuticals, castrate-resistant prostate cancer and development of Radium-223 . The authors have referenced primary literature, clinical trials and relevant review articles that summarize the history, development and current utilization of radiopharmaceuticals for management of bone metastases from prostate cancer. Expert opinion: Radium-223 is the first radiopharmaceutical with an overall survival benefit approved for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastasis and no known visceral metastatic disease. The additional benefit of clinically significant improved overall survival should lead to exploration of whether this agent can be used earlier in the treatment algorithm or combined with chemotherapy or androgen deprivation therapy. An individualized approach needs to be tailored to each patient based on their overall symptoms, disease burden, hematologic profile and goals of care.
    No preview · Article · Mar 2015 · Expert Opinion on Drug Metabolism & Toxicology
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    ABSTRACT: Cancer immunotherapy induces a variety of auto-inflammatory responses, including those against the thyroid gland, which can be exploited to predict clinical outcomes. Considering the paucity of information about thyroid autoimmunity in patients receiving cancer vaccines, we designed the present study to assess the development of thyroglobulin antibodies (TgAbs) in patients treated with GVAX and/or ipilimumab and correlated seroconversion with survival. Using both in house and commercial ELISA assays, we measured TgAbs in patients with pancreatic (No. = 53), prostate (No.= 35), or colon (No.= 8) cancer, before and after treatment with GVAX only (No= 34), GVAX plus ipilimumab (No = 42), or ipilimumab (No =20), and correlated their levels with patient's survival, disease status, and T cell surface markers. Antibodies to thyroperoxidase, myeloperoxidase, proteinase 3, insulin and actin were also measured. TgAbs specifically developed after GVAX, independent of the underlying cancer (81% in prostate, 75% colon cancer, and 76% pancreatic cancer) and co-administration of ipilimumab (75% in GVAX only and 78% in GVAX plus ipilimumab). This TgAbs seroconversion could be detected mainly by the in house assay, suggesting that the thyroglobulin epitopes recognized by the antibodies induced by GVAX are different from the epitopes seen in the classic form of Hashimoto thyroiditis. Notably, TgAbs seroconversion was associated with significantly prolonged survival (p=0.01 for pancreas and p= 0.005 for prostate cancer). In conclusion, GVAX immunotherapy induces the appearance of TgAbs that recognize a unique antigenic repertoire and associate with prolonged survival. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · Jan 2015 · International Journal of Cancer

  • No preview · Article · Nov 2014 · Clinical Genitourinary Cancer
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    ABSTRACT: Background: Prostate cancer survivors with a rising prostate-specific antigen (PSA) level have few treatment options, experience a heightened state of uncertainty about their disease trajectory that might include the possibility of cancer metastasis and death, and often experience elevated levels of distress as they have to deal with a disease they thought they had conquered. Guided by self-regulation theory, the present study examined the cognitive and affective processes involved in shared decision making between physicians and patients who experience a rising PSA after definitive treatment for prostate cancer. Methods: In-depth interviews were conducted with 34 prostate cancer survivors who had been diagnosed with a rising PSA (i.e., biochemical failure) within the past 12 months. Survivors were asked about their experiences and affective responses after being diagnosed with a rising PSA and while weighing potential treatment options. In addition, patients were asked about their decision-making process for the initial prostate cancer treatment. Results: Compared with the initial diagnosis, survivors with a rising PSA reported increased negative affect following their diagnosis, concern about the treatability of their disease, increased planning and health behavior change, heightened levels of worry preceding doctor appointments (especially prior to the discussion of PSA testing results), and a strong reliance on physicians' treatment recommendations. Conclusions: Prostate cancer survivors' decision-making processes for the treatment of a rising PSA are markedly different from those of the initial diagnosis of prostate cancer. Because patients experience heightened distress and rely more heavily on their physicians' recommendations with a rising PSA, interactions with the health care provider provide an excellent opportunity to address and assist patients with managing the uncertainty and distress inherent with rising PSA levels.
    No preview · Article · Nov 2014 · Medical Decision Making
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    ABSTRACT: Purpose: To endorse the American Urological Association (AUA)/American Society for Radiation Oncology (ASTRO) guideline on adjuvant and salvage radiotherapy after prostatectomy. The American Society of Clinical Oncology (ASCO) has a policy and set of procedures for endorsing clinical practice guidelines developed by other professional organizations. Methods: The guideline on adjuvant and salvage radiotherapy after prostatectomy was reviewed for developmental rigor by methodologists. An ASCO endorsement panel then reviewed the content and recommendations. Results: The panel determined that the guideline recommendations on adjuvant and salvage radiotherapy after prostatectomy, published in August 2013, are clear, thorough, and based on the most relevant scientific evidence. ASCO endorsed the guideline on adjuvant and salvage radiotherapy after prostatectomy, adding one qualifying statement that not all candidates for adjuvant or salvage radiotherapy have the same risk of recurrence or disease progression, and thus, risk-benefit ratios are not the same for all men. Those at the highest risk for recurrence after radical prostatectomy include men with seminal vesicle invasion, Gleason score 8 to 10, extensive positive margins, and detectable postoperative prostate-specific antigen (PSA). Recommendations: Physicians should discuss adjuvant radiotherapy with patients with adverse pathologic findings at prostatectomy (ie, seminal vesicle invasion, positive surgical margins, extraprostatic extension) and salvage radiotherapy with patients with PSA or local recurrence after prostatectomy. The discussion of radiotherapy should include possible short- and long-term adverse effects and potential benefits. The decision to administer radiotherapy should be made by the patient and multidisciplinary treatment team, keeping in mind that not all men are at equal risk of recurrence or clinically meaningful disease progression. Thus, the risk-benefit ratio will differ for each patient.
    Preview · Article · Nov 2014 · Journal of Clinical Oncology
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    ABSTRACT: The lack of in vitro prostate cancer models that recapitulate the diversity of human prostate cancer has hampered progress in understanding disease pathogenesis and therapy response. Using a 3D organoid system, we report success in long-term culture of prostate cancer from biopsy specimens and circulating tumor cells. The first seven fully characterized organoid lines recapitulate the molecular diversity of prostate cancer subtypes, including TMPRSS2-ERG fusion, SPOP mutation, SPINK1 overexpression, and CHD1 loss. Whole-exome sequencing shows a low mutational burden, consistent with genomics studies, but with mutations in FOXA1 and PIK3R1, as well as in DNA repair and chromatin modifier pathways that have been reported in advanced disease. Loss of p53 and RB tumor suppressor pathway function are the most common feature shared across the organoid lines. The methodology described here should enable the generation of a large repertoire of patient-derived prostate cancer lines amenable to genetic and pharmacologic studies.
    Full-text · Article · Sep 2014 · Cell
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    ABSTRACT: Answer questions and earn CME/CNE Prostate cancer survivors approach 2.8 million in number and represent 1 in 5 of all cancer survivors in the United States. While guidelines exist for timely treatment and surveillance for recurrent disease, there is limited availability of guidelines that facilitate the provision of posttreatment clinical follow-up care to address the myriad of long-term and late effects that survivors may face. Based on recommendations set forth by a National Cancer Survivorship Resource Center expert panel, the American Cancer Society developed clinical follow-up care guidelines to facilitate the provision of posttreatment care by primary care clinicians. These guidelines were developed using a combined approach of evidence synthesis and expert consensus. Existing guidelines for health promotion, surveillance, and screening for second primary cancers were referenced when available. To promote comprehensive follow-up care and optimal health and quality of life for the posttreatment survivor, the guidelines address health promotion, surveillance for prostate cancer recurrence, screening for second primary cancers, long-term and late effects assessment and management, psychosocial issues, and care coordination among the oncology team, primary care clinicians, and nononcology specialists. A key challenge to the development of these guidelines was the limited availability of published evidence for management of prostate cancer survivors after treatment. Much of the evidence relies on studies with small sample sizes and retrospective analyses of facility-specific and population databases. CA Cancer J Clin 2014. © 2014 American Cancer Society.
    Full-text · Article · Jun 2014 · CA A Cancer Journal for Clinicians
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    ABSTRACT: Androgen receptor-mediated transcription is directly coupled with the induction of DNA damage, and castration-resistant tumor cells exhibit increased activity of poly (ADP-ribose) polymerase (PARP)-1, a DNA repair enzyme. This study assessed the efficacy and safety of low dose oral PARP inhibitor veliparib (ABT-888) and temozolomide (TMZ) in docetaxel-pretreated patients with metastatic castration-resistant prostate cancer (mCRPC) in a single-arm, open-label, pilot study. Patients with mCRPC progressing on at least one docetaxel-based therapy and prostate specific antigen (PSA) ≥ 2 ng/mL were treated with veliparib 40 mg twice daily on days 1-7 and TMZ once daily (150 mg/m(2)/day cycle 1; if well tolerated then 200 mg/m(2)/day cycle 2 onwards) on days 1-5 q28 days. Patients received 2 (median) treatment cycles (range, 1-9). The primary endpoint was confirmed PSA response rate (decline ≥ 30 %). Twenty-six eligible patients were enrolled, 25 evaluable for PSA response. Median baseline PSA was 170 ng/mL. Two patients had a confirmed PSA response (8.0 %; 95 % CI: 1.0-26.0), 13 stable PSA, and 10 PSA progression. The median progression-free survival was 9 weeks (95 % CI: 7.9-17) and median overall survival 39.6 weeks (95 % CI: 26.6-not estimable). The most frequent treatment-emergent adverse events (AEs) were thrombocytopenia (77 %), anemia (69 %), fatigue (50 %), neutropenia (42 %), nausea (38 %), and constipation (23 %). Grade 3/4 AEs occurring in > 10 % of patients were thrombocytopenia (23 %) and anemia (15 %). Veliparib and TMZ combination was well tolerated but with modest activity. Biomarker analysis supported the proof of concept that this combination has some antitumor activity in mCRPC.
    No preview · Article · Apr 2014 · Investigational New Drugs
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    ABSTRACT: Hypophysitis is a chronic inflammation of the pituitary gland of unknown (primary forms) or recognizable (secondary forms) etiology, such as the use of ipilimumab in cancer immunotherapy. Ipilimumab, which blocks the T cell inhibitory molecule CTLA-4 (cytotoxic T lymphocyte antigen-4), induces hypophysitis in about 4% of patients through unknown mechanisms. We first established a model of secondary hypophysitis by repeated injections of a CTLA-4 blocking antibody into SJL/J or C57BL/6J mice, and showed that they developed lymphocytic infiltration of the pituitary gland and circulating pituitary antibodies. We next assessed the prevalence of pituitary antibodies in a cohort of 20 patients with advanced melanoma or prostate cancer, 7 with a clinical diagnosis of hypophysitis, before and after ipilimumab administration. Pituitary antibodies, negative at baseline, developed in the 7 patients with hypophysitis but not in the 13 without it; these antibodies predominantly recognized thyrotropin-, follicle-stimulating hormone-, and corticotropin-secreting cells. We then hypothesized that the injected CTLA-4 antibody could cause pituitary toxicity if bound to CTLA-4 antigen expressed "ectopically" on pituitary endocrine cells. Pituitary glands indeed expressed CTLA-4 at both RNA and protein levels, particularly in a subset of prolactin- and thyrotropin-secreting cells. Notably, these cells became the site of complement activation, featuring deposition of C3d and C4d components and an inflammatory cascade akin to that seen in type II hypersensitivity. In summary, the study offers a mechanism to explain the pituitary toxicity observed in patients receiving ipilimumab, and highlights the utility of measuring pituitary antibodies in this form of secondary hypophysitis.
    No preview · Article · Apr 2014 · Science translational medicine
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    ABSTRACT: Prostate cancer is often associated with metastases to bone and/or soft tissue. The progression to metastatic castrate-resistant prostate cancer is a seminal event in disease progression affecting treatment decisions. A multidisciplinary group was convened to review the currently available imaging guidelines for metastatic disease in prostate cancer and found no consensus on eligibility criteria, type of imaging modality, and the frequency of scanning for detecting metastatic disease. The aim of this review was to present the recommendations from the group to identify optimal strategies for early identification of metastases in patients with prostate cancer.
    No preview · Article · Mar 2014 · Urology
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    Susan Slovin

    Preview · Article · Dec 2013
  • Susan F Slovin
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    ABSTRACT: Antibodies administered either alone or in a unique construct that can enhance targeting, immunologic recognition and cell killing, remain an area of active interest for a variety of solid tumors. Prostate cancer has unique characteristics as a target for immune-mediated therapies, particularly since it has not only a wide array of antigens expressed on its cell surface, but also has an associated biomarker, which not only can monitor the disease status but also its response to therapy. A number of unique cell surface antigens, as well as internally mediated cell molecules, have shown their clinical activity and efficacy as prostate cancer treatments. The continued evolution of novel antibody-drug and antibody-imaging constructs will probably offer more efficient ways to deliver a therapeutic to the tumor and enhance imaging of active or treated sites of disease.
    No preview · Article · Dec 2013 · Immunotherapy
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    ABSTRACT: Human endogenous retroviruses (HERV) encode 8% of the human genome. While HERVs may play a role in autoimmune and neoplastic disease, no mechanistic association has yet been established. We studied the expression and immunogenicity of a HERV-K GAG protein encoded on chromosome 22q11.23 in relation to the clinical course of prostate cancer. Experimental design: In vitro expression of GAG-HERV-K was analyzed in panels of normal and malignant tissues, microarrays, and cell lines, and effects of demethylation and androgen stimulation were evaluated. Patient sera were analyzed for seroreactivity to GAG-HERV-K and other self-antigens by ELISA and seromics (protein array profiling). GAG-HERV-K expression was most frequent in prostate tissues, and regulated both by demethylation of the promoter region and by androgen stimulation. Serum screening revealed that antibodies to GAG-HERV-K are found in a subset of prostate cancer patients (33/483, 6.8%), but rarely in male healthy donors (1/55, 1.8%). Autoantibodies to GAG-HERV-K occurred more frequently in advanced prostate cancer patients (29/191 in stage III-IV, 21.0%) than in early prostate cancer (4/292 in stage I-II, 1.4%). Presence of GAG-HERV-K serum antibody was correlated with worse survival of prostate cancer patients, with a trend for faster biochemical recurrence in patients with antibodies to GAG-HERV-K. Preferential expression of GAG-HERV-K ch22q11.23 in prostate cancer tissue and increased frequency of autoantibodies observed in advanced prostate cancer patients make this protein one of the first bona fide retroviral cancer antigens in humans, with potential as a biomarker for progression and biochemical recurrence rate of prostate cancer.
    Full-text · Article · Sep 2013 · Clinical Cancer Research
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    ABSTRACT: ARN-509 is a novel androgen receptor (AR) antagonist for the treatment of castration-resistant prostate cancer (CRPC). ARN-509 inhibits AR nuclear translocation and AR binding to androgen response elements and, unlike bicalutamide, does not exhibit agonist properties in the context of AR overexpression. This first-in-human phase I study assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of ARN-509 in men with metastatic CRPC. Thirty patients with progressive CRPC received continuous daily oral ARN-509 at doses between 30 and 480 mg, preceded by administration of a single dose followed by a 1-week observation period with pharmacokinetic sampling. Positron emission tomography/computed tomography imaging was conducted to monitor [(18)F]fluoro-α-dihydrotestosterone (FDHT) binding to AR in tumors before and during treatment. Primary objective was to determine pharmacokinetics, safety, and recommended phase II dose. Pharmacokinetics were linear and dose proportional. Prostate-specific antigen declines at 12 weeks (≥ 50% reduction from baseline) were observed in 46.7% of patients. Reduction in FDHT uptake was observed at all doses, with a plateau in response at ≥ 120-mg dose, consistent with saturation of AR binding. The most frequently reported adverse event was grade 1/2 fatigue (47%). One dose-limiting toxicity event (grade 3 abdominal pain) occurred at the 300-mg dose. Dose escalation to 480 mg did not identify a maximum-tolerated dose. ARN-509 was safe and well tolerated, displayed dose-proportional pharmacokinetics, and demonstrated pharmacodynamic and antitumor activity across all dose levels tested. A maximum efficacious dose of 240 mg daily was selected for phase II exploration based on integration of preclinical and clinical data.
    Preview · Article · Sep 2013 · Journal of Clinical Oncology
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    ABSTRACT: CRPC). In combination, these agents simultaneously target the bone stroma and cancer cell to optimize antitumor effects. The toxicity and efficacy when each agent is combined at full, recommended doses, in a repetitive fashion is not well established. Patients with progressive mCRPC and ≥3 bone lesions received 153Sm-EDTMP (samarium-153 ethylene diamine tetramethylene phosphonate) at a dose of 1.0 mCi/kg every 9 weeks and docetaxel at a dose of 75 mg/m2 every 3 weeks. In the absence of unacceptable toxicity, patients were allowed to continue additional cycles, defined by 9 weeks of treatment, until intolerance or biochemical/radiographic disease progression. Of the 30 patients treated, approximately 50% were considered to be taxane-naive, 36.7% were taxane-refractory, and 13.3% had previously been exposed to taxanes but were not considered refractory. Patients received on average 2.5 cycles of treatment (6.5 doses of docetaxel and 2.5 doses of 153Sm-EDTMP). Twelve patients (40%) demonstrated a decline in their prostate-specific antigen level of ≥50%. The median progression-free survival (biochemical or radiographic) was 7.0 months and the overall survival was 14.3 months. Nine patients (30%) did not recover platelet counts >100 K/mm3 after a median of 3 cycles to allow for additional treatment, with 4 patients experiencing prolonged thrombocytopenia. The most common reasons for trial discontinuation were progressive disease and hematologic toxicity. The results of the current study indicate that 153Sm-EDTMP can be safely combined with docetaxel at full doses on an ongoing basis in patients with mCRPC. Although thrombocytopenia limited therapy for some patients, preliminary efficacy supports the strategy of combining a radiopharmaceutical with chemotherapy, which is an appealing strategy given the anticipated availability of α emitters that can prolong survival. Cancer 2013;119:3186–3194.
    No preview · Article · Sep 2013 · Cancer

Publication Stats

4k Citations
742.10 Total Impact Points

Institutions

  • 1997-2015
    • Memorial Sloan-Kettering Cancer Center
      • • Department of Medicine
      • • Genitourinary Oncology Service
      New York, New York, United States
  • 2002-2009
    • Cornell University
      • Department of Medicine
      Итак, New York, United States
  • 2005
    • Merck
      Whitehouse Station, New Jersey, United States