Richard J Lee

Massachusetts General Hospital, Boston, Massachusetts, United States

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Publications (47)405.38 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Prostate cancer is initially responsive to androgen deprivation, but the effectiveness of androgen receptor (AR) inhibitors in recurrent disease is variable. Biopsy of bone metastases is challenging; hence, sampling circulating tumor cells (CTCs) may reveal drug-resistance mechanisms. We established single-cell RNA-sequencing (RNA-Seq) profiles of 77 intact CTCs isolated from 13 patients (mean six CTCs per patient), by using microfluidic enrichment. Single CTCs from each individual display considerable heterogeneity, including expression of AR gene mutations and splicing variants. Retrospective analysis of CTCs from patients progressing under treatment with an AR inhibitor, compared with untreated cases, indicates activation of noncanonical Wnt signaling (P = 0.0064). Ectopic expression of Wnt5a in prostate cancer cells attenuates the antiproliferative effect of AR inhibition, whereas its suppression in drug-resistant cells restores partial sensitivity, a correlation also evident in an established mouse model. Thus, single-cell analysis of prostate CTCs reveals heterogeneity in signaling pathways that could contribute to treatment failure.
    Science 09/2015; 349(6254):1351-6. DOI:10.1126/science.aab0917 · 33.61 Impact Factor
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    ABSTRACT: Background Outcomes with concurrent chemoradiation for penile squamous cell carcinoma (PSCC) are unclear and only anecdotal reports have been published. We performed a retrospective analysis of patients who received concurrent chemotherapy and radiotherapy for PSCC. Patients and methods Individual patient level data were obtained from 5 institutions for outcomes with concurrent chemoradiation for PSCC. Descriptive statistics were calculated and univariable Cox proportional hazards regression analysis was conducted to examine the prognostic impact of candidate factors on progression-free survival (PFS) and overall survival (OS). Results A total of 26 men were evaluable. The mean age was 60.3 years. The clinical stage was ≤3 in 9 patients (36%) and stage 4 in the rest. Soft tissue and visceral metastasis were present in 35% and 20% of patients, respectively. The chemotherapy was cisplatin-based in 92.3% of patients and the median (range) of external beam radiotherapy administered was 4900 cGy (1800-7000). The median OS was 6.9 months (95% CI: 5, 14) and the median PFS was 5.1 months (95% CI: 2.5, 7.0). When excluding patients with M1 disease, the remaining patients (N=21) had a median OS and PFS of 10.0 months (95% CI: 5, 14) and 6.0 months (95% CI: 2.0, 7.0), respectively. Baseline neutrophil by lymphocyte ratio (NLR) was significantly associated with survival and visceral metastasis showed a trend for association with OS. Conclusions Concurrent chemoradiation demonstrated poor outcomes for locally advanced PSCC. Better understanding of tumor biology and study of novel combinations of biologic agents with radiation are warranted.
    Clinical Genitourinary Cancer 12/2014; 12(6). DOI:10.1016/j.clgc.2014.03.009 · 2.32 Impact Factor
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    ABSTRACT: The p53 tumor suppressor protein plays a crucial role in influencing cell fate decisions in response to cellular stress. As p53 elicits cell cycle arrest, senescence or apoptosis, the integrity of the p53 pathway is considered a key determinant of anti-tumor responses. p53 can also promote autophagy, however the role of p53-dependent autophagy in chemosensitivity is poorly understood. VMY-1-103 (VMY), a dansylated analog of purvalanol B, displays rapid and potent anti-tumor activities, however the pathways by which VMY works are not fully defined. Using established prostate cancer cell lines and novel conditionally reprogrammed cells (CRCs) derived from prostate cancer patients; we have defined the mechanisms of VMY-induced prostate cancer cell death. Herein, we show that the cytotoxic effects of VMY required a p53-dependent induction of autophagy, and that inhibition of autophagy abrogated VMY-induced cell death. Cancer cell lines harboring p53 missense mutations evaded VMY toxicity and treatment with a small molecule compound that restores p53 activity re-established VMY-induced cell death. The elucidation of the molecular mechanisms governing VMY-dependent cell death in cell lines, and importantly in CRCs, provides the rationale for clinical studies of VMY, alone or in combination with p53 reactivating compounds, in human prostate cancer.
    Oncotarget 09/2014; 5(21). DOI:10.18632/oncotarget.2528 · 6.36 Impact Factor
  • David T Miyamoto · Lecia V Sequist · Richard J Lee ·
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    ABSTRACT: The availability of new therapeutic options for the treatment of metastatic castration-resistant prostate cancer (mCRPC) has heightened the importance of monitoring and assessing treatment response. Accordingly, there is an unmet clinical need for reliable biomarkers that can be used to guide therapy. Circulating tumour cells (CTCs) are rare cells that are shed from primary and metastatic tumour deposits into the peripheral circulation, and represent a means of performing noninvasive tumour sampling. Indeed, enumeration of CTCs before and after therapy has shown that CTC burden correlates with prognosis in patients with mCRPC. Moreover, studies have demonstrated the potential of molecular analysis of CTCs in monitoring and predicting response to therapy in patients. This Review describes the challenges associated with monitoring treatment response in mCRPC, and the advancements in CTC-analysis technologies applied to such assessments and, ultimately, guiding prostate cancer treatment.
    Nature Reviews Clinical Oncology 05/2014; 11(7). DOI:10.1038/nrclinonc.2014.82 · 14.18 Impact Factor
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    ABSTRACT: Strigolactones are a novel class of plant hormones produced in roots and regulate shoot and root development. We have previously shown that synthetic strigolactone analogues potently inhibit growth of breast cancer cells and breast cancer stem cells. Here we show that strigolactone analogues inhibit the growth and survival of an array of cancer-derived cell lines representing solid and non-solid cancer cells including: prostate, colon, lung, melanoma, osteosarcoma and leukemic cell lines, while normal cells were minimally affected. Treatment of cancer cells with strigolactone analogues was hallmarked by activation of the stress-related MAPKs: p38 and JNK and induction of stress-related genes; cell cycle arrest and apoptosis evident by increased percentages of cells in the sub-G1 fraction and Annexin V staining. In addition, we tested the response of patient-matched conditionally reprogrammed primary prostate normal and cancer cells. The tumor cells exhibited significantly higher sensitivity to the two most potent SL analogues with increased apoptosis confirmed by PARP1 cleavage compared to their normal counterpart cells. Thus, Strigolactone analogues are promising candidates for anticancer therapy by their ability to specifically induce cell cycle arrest, cellular stress and apoptosis in tumor cells with minimal effects on growth and survival of normal cells.
    Oncotarget 04/2014; DOI:10.18632/oncotarget.1849 · 6.36 Impact Factor
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  • New England Journal of Medicine 01/2014; 370(3):263-71. DOI:10.1056/NEJMcpc1310005 · 55.87 Impact Factor
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    ABSTRACT: Prognostic factors in men with penile squamous cell carcinoma (PSCC) receiving systemic therapy are unknown. A prognostic classification system in this disease may facilitate interpretation of outcomes and guide rational drug development. We performed a retrospective analysis to identify prognostic factors in men with PSCC receiving first-line systemic therapy for advanced disease. Individual patient level data were obtained from 13 institutions to study prognostic factors in the context of first-line systemic therapy for advanced PSCC. Cox proportional hazards regression analysis was conducted to examine the prognostic effect of these candidate factors on progression-free survival (PFS) and overall survival (OS): age, stage, hemoglobin, neutrophil count, lymphocyte count, albumin, site of metastasis (visceral or nonvisceral), smoking, circumcision, regimen, ECOG performance status (PS), lymphovascular invasion, precancerous lesion, and surgery following chemotherapy. The effect of different treatments was then evaluated adjusting for factors in the prognostic model. The study included 140 eligible men. Mean age across all men was 57.0 years. Among them, 8.6%, 21.4%, and 70.0% of patients had stage 2, 3, and 4 diseases, respectively; 40.7% had ECOG PS≥1, 47.4% had visceral metastases, and 73.6% received cisplatin-based chemotherapy. The multivariate model of poor prognostic factors included visceral metastases (P<0.001) and ECOG PS≥1 (P<0.001) for both PFS and OS. A risk stratification model constructed with 0, 1, and both poor prognostic factors was internally validated and demonstrated moderate discriminatory ability (c-statistic of 0.657 and 0.677 for OS and PFS, respectively). The median OS for the entire population was 9 months. Median OS was not reached, 8, and 7 months for those with 0, 1, and both risk factors, respectively. Cisplatin-based regimens were associated with better OS (P = 0.017) but not PFS (P = 0.37) compared with noncisplatin-based regimens after adjusting for the 2 prognostic factors. In men with advanced PSCC receiving first-line systemic therapy, visceral metastases and ECOG PS≥1 were poor prognostic factors. A prognostic model including these factors exhibited moderate discriminatory ability for outcomes and warrants external validation. Patients receiving cisplatin-based regimens exhibited better outcomes compared with noncisplatin-based regimens after adjusting for prognostic factors.
    Urologic Oncology 12/2013; 32(4). DOI:10.1016/j.urolonc.2013.10.007 · 2.77 Impact Factor
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    Richard J Lee · Matthew R Smith ·
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    ABSTRACT: Treatment with cabozantinib, an inhibitor of MET and VEGFR2 signaling, has demonstrated clinical benefit in early trials in men with metastatic prostate cancer. Preclinical evidence suggests that cabozantinib can kill cancer cell seeds while disrupting angiogenesis and stromal cells in the metastatic soil.
    Clinical Cancer Research 11/2013; 20(3). DOI:10.1158/1078-0432.CCR-13-2636 · 8.72 Impact Factor
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    ABSTRACT: The objective of this study was to correlate changes in computed tomography perfusion (CTP) parameters in the oropharyngeal mucosa following start of radiotherapy (RT) with acute mucositis in head and neck cancer patients. Fifteen patients were prospectively evaluated with serial CTP imaging. Computed tomography perfusion studies were obtained before RT; at weeks 2, 4, and 6 during RT; and 6 weeks after completion of RT. At week 2 during RT, mean transition time increased to 13.9% and 261.8% in patients with and without mucositis, respectively (P = 0.024). At week 6 of RT, patients with grade 3 mucositis had a 325.4% increase in blood flow compared with a 58.3% increase in patients with grade 0-2 mucositis (P = 0.039). Mean transition time decreased by 29.9% and increased by 187.4% in patients with grade 3 and grade 0-2 mucositis, respectively (P = 0.025). Mean transition time and blood flow changes in the oropharyngeal mucosa correlated with the incidence and severity of RT-related mucositis.
    Journal of computer assisted tomography 07/2013; 37(4):499-504. DOI:10.1097/RCT.0b013e31828aed3f · 1.41 Impact Factor
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    ABSTRACT: Circulating tumor cells (CTCs) are shed into the bloodstream from primary and metastatic tumor deposits. Their isolation and analysis hold great promise for the early detection of invasive cancer and the management of advanced disease, but technological hurdles have limited their broad clinical utility. We describe an inertial focusing-enhanced microfluidic CTC capture platform, termed "CTC-iChip," that is capable of sorting rare CTCs from whole blood at 10(7) cells/s. Most importantly, the iChip is capable of isolating CTCs using strategies that are either dependent or independent of tumor membrane epitopes, and thus applicable to virtually all cancers. We specifically demonstrate the use of the iChip in an expanded set of both epithelial and nonepithelial cancers including lung, prostate, pancreas, breast, and melanoma. The sorting of CTCs as unfixed cells in solution allows for the application of high-quality clinically standardized morphological and immunohistochemical analyses, as well as RNA-based single-cell molecular characterization. The combination of an unbiased, broadly applicable, high-throughput, and automatable rare cell sorting technology with generally accepted molecular assays and cytology standards will enable the integration of CTC-based diagnostics into the clinical management of cancer.
    Science translational medicine 04/2013; 5(179):179ra47. DOI:10.1126/scitranslmed.3005616 · 15.84 Impact Factor
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    ABSTRACT: Background: Cabozantinib is an oral MET/VEGFR2 inhibitor. A recent phase II study of cabozantinib (100 mg daily) showed improved bone scans in subjects with metastatic castration-resistant prostate cancer (mCRPC), but adverse events (AE) caused frequent dose reductions. This study was designed to determine the efficacy and tolerability of cabozantinib at lower starting doses. Experimental design: An adaptive design was used to determine the lowest active daily dose among 60, 40, and 20 mg. The primary endpoint was week 6 bone scan response, defined as ≥30% decrease in bone scan lesion area. The secondary endpoint was change in circulating tumor cells (CTC). Results: Among 11 evaluable subjects enrolled at 40 mg, there were 9 partial responses (PR), 1 complete response, and 1 stable disease (SD). Of 10 subjects subsequently enrolled at 20 mg, there were 1 PR, 5 SDs, and 4 with progressive disease. Among 13 subjects enrolled on the 40 mg expansion cohort, there were 6 PRs and 7 SDs. No subjects required dose reduction or treatment interruption at 6 or 12 weeks; 3 subjects at dose level 0 discontinued due to AEs by 12 weeks. At 40 mg, median treatment duration was 27 weeks. 58% of subjects with ≥5 CTCs/7.5 mL at baseline converted to <5. Conclusions: Cabozantinib 40 mg daily was associated with a high rate of bone scan response. Cabozantinib 40 mg daily was associated with better tolerability than previously reported for cabozantinib 100 mg daily. These observations informed the design of phase III studies of cabozantinib in mCRPC.
    Clinical Cancer Research 04/2013; 19(11). DOI:10.1158/1078-0432.CCR-13-0319 · 8.72 Impact Factor
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    ABSTRACT: During the past 25 years, prospective clinical trials have established that bladder preservation therapy for select patients with muscle-invasive bladder cancer is a safe and effective alternative to an immediate cystectomy. Cisplatin-based chemoradiation is the most well-studied and accepted component of trimodality therapy; however, other systemic agents have recently been shown effective in combination with radiation therapy, increasing the range of options to allow for better personalization of care. In this review, the most recent advances in the field of bladder-preserving trimodality therapy are presented, and future directions for improving the outcomes are outlined.
    Current Urology Reports 01/2013; 14(2). DOI:10.1007/s11934-012-0301-x · 1.51 Impact Factor
  • Richard J Lee · Matthew R Smith ·
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    ABSTRACT: Effective management of bone metastases in men with castration-resistant prostate cancer (CRPC) remains an important unmet medical need. MET and vascular endothelial growth factor receptor (VEGFR) are rational targets for intervention in CRPC. Clinical trials involving agents that inhibit one but not both pathways have reported modest activity and no improvement in overall survival. Cabozantinib is an oral multitargeted tyrosine kinase inhibitor that inhibits both MET and VEGFR-2. A phase II randomized discontinuation study involving subjects with CRPC demonstrated that cabozantinib therapy is associated with improvement in bone scans, bone turnover markers, and pain response, but with significant adverse events leading to dose reduction and treatment discontinuation. Lower doses of cabozantinib retain high levels of activity with less toxicity. Ongoing phase III clinical trials will define the role of cabozantinib in CRPC. We summarize the rationale for targeting MET and VEGFR pathways in CRPC and the clinical data available to date.
    The Cancer Journal 01/2013; 19(1):90-8. DOI:10.1097/PPO.0b013e318281e280 · 4.24 Impact Factor
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    ABSTRACT: Purpose: To demonstrate a limitation of lifetime radiation-induced cancer risk metrics in the setting of testicular cancer surveillance-in particular, their failure to capture the delayed timing of radiation-induced cancers over the course of a patient's lifetime. Materials and methods: Institutional review board approval was obtained for the use of computed tomographic (CT) dosimetry data in this study. Informed consent was waived. This study was HIPAA compliant. A Markov model was developed to project outcomes in patients with testicular cancer who were undergoing CT surveillance in the decade after orchiectomy. To quantify effects of early versus delayed risks, life expectancy losses and lifetime mortality risks due to testicular cancer were compared with life expectancy losses and lifetime mortality risks due to radiation-induced cancers from CT. Projections of life expectancy loss, unlike lifetime risk estimates, account for the timing of risks over the course of a lifetime, which enabled evaluation of the described limitation of lifetime risk estimates. Markov chain Monte Carlo methods were used to estimate the uncertainty of the results. Results: As an example of evidence yielded, 33-year-old men with stage I seminoma who were undergoing CT surveillance were projected to incur a slightly higher lifetime mortality risk from testicular cancer (598 per 100 000; 95% uncertainty interval [UI]: 302, 894) than from radiation-induced cancers (505 per 100 000; 95% UI: 280, 730). However, life expectancy loss attributable to testicular cancer (83 days; 95% UI: 42, 124) was more than three times greater than life expectancy loss attributable to radiation-induced cancers (24 days; 95% UI: 13, 35). Trends were consistent across modeled scenarios. Conclusion: Lifetime radiation risk estimates, when used for decision making, may overemphasize radiation-induced cancer risks relative to short-term health risks.
    Radiology 12/2012; 266(3). DOI:10.1148/radiol.12121015 · 6.87 Impact Factor
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    ABSTRACT: Androgen deprivation therapy (ADT) is initially effective in treating metastatic prostate
    Cancer Discovery 11/2012; · 19.45 Impact Factor
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    ABSTRACT: Unlabelled: Androgen deprivation therapy (ADT) is initially effective in treating metastatic prostate cancer, and secondary hormonal therapies are being tested to suppress androgen receptor (AR) reactivation in castration-resistant prostate cancer (CRPC). Despite variable responses to AR pathway inhibitors in CRPC, there are no reliable biomarkers to guide their application. Here, we used microfluidic capture of circulating tumor cells (CTC) to measure AR signaling readouts before and after therapeutic interventions. Single-cell immunofluorescence analysis revealed predominantly "AR-on" CTC signatures in untreated patients, compared with heterogeneous ("AR-on, AR-off, and AR-mixed") CTC populations in patients with CRPC. Initiation of first-line ADT induced a profound switch from "AR-on" to "AR-off" CTCs, whereas secondary hormonal therapy in CRPC resulted in variable responses. Presence of "AR-mixed" CTCs and increasing "AR-on" cells despite treatment with abiraterone acetate were associated with an adverse treatment outcome. Measuring treatment-induced signaling responses within CTCs may help guide therapy in prostate cancer. Significance: Acquired resistance to first-line hormonal therapy in prostate cancer is heterogeneous in the extent of AR pathway reactivation. Measurement of pre- and posttreatment AR signaling within CTCs may help target such treatments to patients most likely to respond to second-line therapies.
    Cancer Discovery 10/2012; 2(11). DOI:10.1158/2159-8290.CD-12-0222 · 19.45 Impact Factor
  • Philip J Saylor · Richard J Lee · Matthew R Smith ·
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    ABSTRACT: Skeletal morbidity is a prominent burden to men with advanced prostate cancer throughout the natural history of the disease. Bone metastases can cause pain and greatly elevate the risk for fractures and other structural complications. Distinct from the problem of metastases, treatment-related osteoporosis and associated fragility fractures are potential complications of androgen-deprivation therapy. Bone-targeted therapies for prostate cancer have therefore been the focus of considerable research and drug development efforts. The osteoclast is a validated therapeutic target in the management of prostate cancer. Osteoclast inhibition with zoledronic acid (a bisphosphonate) or with denosumab (a monoclonal antibody to RANK ligand) reduces risk for skeletal events in men with castration-resistant prostate cancer metastatic to bone. Osteoclast inhibition with any of several bisphosphonates improves bone mineral density, a surrogate for osteoporotic fracture risk. Denosumab and toremifene (a selective estrogen receptor modulator) have each been shown to reduce osteoporotic fracture risk among men receiving androgen-deprivation therapy. Beta-emitting radiopharmaceuticals reduce pain due to metastatic disease. Investigations involving alpha-emitting radium-223, endothelin-A receptor antagonists atrasentan and zibotentan, proto-oncogene tyrosine-protein kinase (SRC) inhibitor dasatinib, and tyrosine kinase inhibitor cabozantinib (XL184) are ongoing in clinical trials and are also discussed.
    Journal of Clinical Oncology 08/2011; 29(27):3705-14. DOI:10.1200/JCO.2010.34.4994 · 18.43 Impact Factor
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    ABSTRACT: To investigate the anatomy of the pelvis following robotic-assisted radical prostatectomy (RARP) compared to the anatomy of the pelvis following open prostatectomy (OP), and to determine if postoperative radiation field design should take surgical approach into consideration. This report is a retrospective review of the postoperative pelvic magnetic resonance imaging (MRI) scans for all OP patients (10) and all RARP patients (15) who presented consecutively to the radiation oncology clinic and subsequently underwent MRI scanning between January 2007 and December 2008. All patients who presented are included in the study. We measured 13 distinct anatomic distances, and we used t tests to examine mean differences in each of the parameters between RARP and OP and analysis of variance to examine mean differences controlling for length of follow-up MRI postsurgery (in days) and body mass index as covariates. Of the measurements, we found that the superior levator separation is statistically significantly greater in the post-RARP group than in the post-OP group (P < .01). Similarly, the post-RARP group had a greater mean resection defect measurement (P = .01) as measured by a larger width of the bladder infundibulum. This suggests that the size of trigonal musculature defect is more pronounced after RARP. The total urethral length was statistically significantly longer in the RARP group (P = .03). The vesicorectal distance was variable depending on the location along the rectal wall but trended toward larger separation in the post-RARP group (P = .05). The pelvic anatomy after RARP is considerably different from that after OP. The current standard field design for post-prostatectomy radiation is defined by the post-OP pelvis. Our data support that the clinical target volume borders be expanded posteriorly and laterally in men who have undergone RARP. As RARP continues to become a more widespread surgical option for the management of localized prostate cancer, radiation field design may need to be adjusted.
    Practical Radiation Oncology 04/2011; 1(2):115-25. DOI:10.1016/j.prro.2010.11.007
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    Richard J Lee · Philip J Saylor · Matthew R Smith ·
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    ABSTRACT: Bone metastases and skeletal complications are major causes of morbidity in prostate cancer patients. Despite the osteoblastic appearance of bone metastases on imaging studies, patients have elevated serum and urinary markers of bone resorption, indicative of high osteoclast activity. Increased osteoclast activity is independently associated with higher risk of subsequent skeletal complications, disease progression, and death. Osteoclast-targeted therapies are therefore a rational approach to reduction of risk for disease-related skeletal complications, bone metastases, and treatment-related fractures. This review focuses on recent advances in osteoclast-targeted therapy in prostate cancer. Bisphosphonates have been extensively studied in men with prostate cancer. Zoledronic acid significantly decreased the risk of skeletal complications in men with castration-resistant prostate cancer and bone metastases, and it is FDA-approved for this indication. Denosumab is a human monoclonal antibody that binds and inactivates RANKL, a critical mediator of osteoclast differentiation, activation, and survival. Recent global phase 3 clinic trials demonstrated an emerging role for denosumab in the treatment of prostate cancer bone metastases and prevention of fractures associated with androgen deprivation therapy.
    Bone 01/2011; 48(1):88-95. DOI:10.1016/j.bone.2010.05.038 · 3.97 Impact Factor

Publication Stats

3k Citations
405.38 Total Impact Points


  • 2010-2014
    • Massachusetts General Hospital
      • Department of Radiation Oncology
      Boston, Massachusetts, United States
  • 2013
    • Beverly Hospital, Boston MA
      BVY, Massachusetts, United States
    • Boston Medical Center
      Boston, Massachusetts, United States
  • 1999-2013
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
    • Harvard University
      • Department of Molecular and Cell Biology
      Cambridge, Massachusetts, United States
  • 2011
    • University of Massachusetts Boston
      Boston, Massachusetts, United States
  • 2008
    • Thomas Jefferson University
      • Department of Medical Oncology
      Philadelphia, PA, United States
  • 2000
    • McMaster University
      Hamilton, Ontario, Canada
  • 1998-1999
    • Albert Einstein College of Medicine
      • • Department of Cell Biology
      • • Department of Medicine
      New York, New York, United States