Richard J Lee

Massachusetts General Hospital, Boston, Massachusetts, United States

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Publications (20)176.36 Total impact

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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; · 15.03 Impact Factor
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  • New England Journal of Medicine 01/2014; 370(3):263-71. · 51.66 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 01/2014; · 1.43 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; · 3.65 Impact Factor
  • 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; · 7.84 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. · 10.76 Impact Factor
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    ABSTRACT: Background Cabozantinib is an oral MET/VEGFR2 inhibitor. A recent phase II study of cabozantinib (100mg daily) demonstrated improved bone scans in subjects with metastatic castration-resistant prostate cancer (mCRPC), but adverse events (AEs) caused frequent dose reductions. This study was designed to determine the efficacy and tolerability of cabozantinib at lower starting doses. Patients and Methods An adaptive design was used to determine the lowest active daily dose among 60mg, 40mg, and 20mg. 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 (CTCs). Results Among 11 evaluable subjects enrolled at 40mg, there were 9 partial responses (PRs), 1 complete response, and 1 stable disease (SD). Of 10 subjects subsequently enrolled at 20mg, there were 1 PR, 5 SDs, and 4 with progressive disease. Among 13 subjects enrolled on the 40mg 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 40mg, median treatment duration was 27 weeks. 58% of subjects with ≥5 CTCs/7.5mL at baseline converted to <5. Conclusions Cabozantinib 40mg daily was associated with a high rate of bone scan response. Cabozantinib 40mg daily was associated with better tolerability than previously reported for cabozantinib 100mg daily. These observations informed the design of phase III studies of cabozantinib in mCRPC.
    Clinical Cancer Research 04/2013; · 7.84 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;
  • 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. · 3.66 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.© RSNA, 2012Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12121015/-/DC1.
    Radiology 12/2012; · 6.34 Impact Factor
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    ABSTRACT: Androgen deprivation therapy (ADT) is initially effective in treating metastatic prostate
    Cancer Discovery 11/2012; · 10.14 Impact Factor
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    ABSTRACT: 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.
    Cancer Discovery 10/2012; · 10.14 Impact Factor
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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. · 18.04 Impact Factor
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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. · 3.82 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. 01/2011; 1(2):115-25.
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    ABSTRACT: Skeletal complications are major causes of morbidity in patients with prostate cancer. Despite the osteoblastic appearance of prostate cancer bone metastases, elevated serum and urinary markers of bone resorption are indicative of high osteoclast activity. Increased osteoclast activity is independently associated with subsequent skeletal complications, disease progression, and death. Osteoclast-targeted therapies aim to reduce the risk for disease-related skeletal complications, bone metastases, and treatment-related fractures. This review focuses on recent advances in osteoclast-targeted therapies in the treatment and prevention of bone complications in prostate cancer. Osteoclast-targeted therapies have been extensively studied in men with prostate cancer. The potent bisphosphonate zoledronic acid significantly decreased the risk of skeletal complications in men with castration-resistant prostate cancer and bone metastases, and is Federal Drug Administration approved for this indication. Denosumab is a human monoclonal antibody that inhibits receptor activator of nuclear factor-κB (RANK) ligand, a critical mediator of osteoclast differentiation, activation, and survival. Data from recent phase III clinic trials demonstrate the emerging role for denosumab in the treatment of prostate cancer bone metastases and prevention of fractures associated with androgen deprivation therapy.
    Clinical Genitourinary Cancer 12/2010; 8(1):29-36. · 1.43 Impact Factor
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    ABSTRACT: Rare circulating tumor cells (CTCs) present in the bloodstream of patients with cancer provide a potentially accessible source for detection, characterization, and monitoring of nonhematological cancers. We previously demonstrated the effectiveness of a microfluidic device, the CTC-Chip, in capturing these epithelial cell adhesion molecule (EpCAM)-expressing cells using antibody-coated microposts. Here, we describe a high-throughput microfluidic mixing device, the herringbone-chip, or "HB-Chip," which provides an enhanced platform for CTC isolation. The HB-Chip design applies passive mixing of blood cells through the generation of microvortices to significantly increase the number of interactions between target CTCs and the antibody-coated chip surface. Efficient cell capture was validated using defined numbers of cancer cells spiked into control blood, and clinical utility was demonstrated in specimens from patients with prostate cancer. CTCs were detected in 14 of 15 (93%) patients with metastatic disease (median = 63 CTCs/mL, mean = 386 ± 238 CTCs/mL), and the tumor-specific TMPRSS2-ERG translocation was readily identified following RNA isolation and RT-PCR analysis. The use of transparent materials allowed for imaging of the captured CTCs using standard clinical histopathological stains, in addition to immunofluorescence-conjugated antibodies. In a subset of patient samples, the low shear design of the HB-Chip revealed microclusters of CTCs, previously unappreciated tumor cell aggregates that may contribute to the hematogenous dissemination of cancer.
    Proceedings of the National Academy of Sciences 10/2010; 107(43):18392-7. · 9.81 Impact Factor
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    ABSTRACT: Osteoporosis causes morbidity and mortality in men. The National Osteoporosis Foundation recommends fracture risk assessment with the online WHO/FRAX tool. Although androgen deprivation therapy for prostate cancer increases fracture risk, there is limited information about which men require preventative drug therapy. We applied the WHO/FRAX tool to men treated with androgen deprivation therapy for prostate cancer. Information was collected from a practice cohort of men treated with gonadotropin-releasing hormone agonists, and included age, height, weight, history of gonadotropin-releasing hormone agonist treatment, dual energy x-ray absorptiometry results, prior bone targeted therapy and clinical risk factors for fracture. Subjects were evaluated with the WHO/FRAX algorithm (http://www.shef.ac.uk/FRAX/). A total of 363 men treated with androgen deprivation therapy (median age 72 years) were evaluated. By the FRAX algorithm with clinical information (no dual energy x-ray absorptiometry data) the 3% hip fracture risk threshold for treatment was exceeded by 51.2% of the men (median risk 3.1%). When subjects were grouped by age the treatment threshold was reached by 3.3% of those younger than 70 years, 76.6% of those 70 to 79 years old and by 98.8% of those 80 years old or older. Using FRAX with bone mineral density data in the 93 patients who underwent bone mineral density testing the median 10-year hip fracture risk was 0.9% and the treatment threshold was exceeded by 15% of these subjects. In this cohort of men receiving androgen deprivation therapy the prevalence of risk sufficient to necessitate drug therapy was high and was strongly influenced by age. The WHO/FRAX algorithm identifies a greater proportion of men for treatment than the traditional threshold of T score -2.5 or less.
    The Journal of urology 06/2010; 183(6):2200-5. · 4.02 Impact Factor
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    ABSTRACT: Rare circulating tumor cells (CTCs) are present in the blood of patients with metastatic epithelial cancers but have been difficult to measure routinely. We report a quantitative automated imaging system for analysis of prostate CTCs, taking advantage of prostate-specific antigen (PSA), a unique prostate tumor-associated marker. The specificity of PSA staining enabled optimization of criteria for baseline image intensity, morphometric measurements, and integration of multiple signals in a three-dimensional microfluidic device. In a pilot analysis, we detected CTCs in prostate cancer patients with localized disease, before surgical tumor removal in 8 of 19 (42%) patients (range, 38 to 222 CTCs per milliliter). For 6 of the 8 patients with preoperative CTCs, a precipitous postoperative decline (<24 hours) suggests a short half-life for CTCs in the blood circulation. Other patients had persistent CTCs for up to 3 months after prostate removal, suggesting early but transient disseminated tumor deposits. In patients with metastatic prostate cancer, CTCs were detected in 23 of 36 (64%) cases (range, 14 to 5000 CTCs per milliliter). In previously untreated patients followed longitudinally, the numbers of CTCs declined after the initiation of effective therapy. The prostate cancer-specific TMPRSS2-ERG fusion was detectable in RNA extracted from CTCs from 9 of 20 (45%) patients with metastatic disease, and dual staining of captured CTCs for PSA and the cell division marker Ki67 indicated a broad range for the proportion of proliferating cells among CTCs. This method for analysis of CTCs will facilitate the application of noninvasive tumor sampling to direct targeted therapies in advanced prostate cancer and warrants the initiation of long-term clinical studies to test the importance of CTCs in invasive localized disease.
    Science translational medicine 03/2010; 2(25):25ra23. · 10.76 Impact Factor

Publication Stats

506 Citations
176.36 Total Impact Points

Institutions

  • 2010–2014
    • Massachusetts General Hospital
      • Department of Radiation Oncology
      Boston, Massachusetts, United States
  • 2013
    • Beverly Hospital, Boston MA
      Beverly, Massachusetts, United States
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 2011
    • University of Massachusetts Boston
      Boston, Massachusetts, United States