Publications by authors named "Richard J Lee"

77 Publications

Disparities in Cancer Care and the Asian American Population.

Oncologist 2021 Mar 8. Epub 2021 Mar 8.

University of Washington and Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

Asian Americans are the only racial/ethnic group in the U.S. for whom cancer is the leading cause of death in men and women, unlike heart disease for all other groups. Asian Americans face a confluence of cancer risks, with high rates of cancers endemic to their countries of origin due to infectious and cultural reasons, as well as increasing rates of "Western" cancers that are due in part to assimilation to the American diet and lifestyle. Despite the clear mortality risk, Asian Americans are screened for cancers at lower rates than the majority of Americans. Solutions to eliminate the disparity in cancer care are complicated by language and cultural concerns of this very heterogeneous group. This review addresses the disparities in cancer screening, the historical causes, the potential contribution of racism, the importance of cultural perceptions of health care, and potential strategies to address a very complicated problem. Noting that the health care disparities faced by Asian Americans may be less conspicuous than the structural racism that has inflicted significant damage to the health of Black Americans over more than four centuries, this review is meant to raise awareness and to compel the medical establishment to recognize the urgent need to eliminate health disparities for all. IMPLICATIONS FOR PRACTICE: Cancer is the leading cause of death in Asian Americans, who face cancers endemic to their native countries, perhaps because of infectious and cultural factors, as well as those faced by all Americans, perhaps because of "Westernization" in terms of diet and lifestyle. Despite the mortality rates, Asian Americans have less cancer screening than other Americans. This review highlights the need to educate Asian Americans to improve cancer literacy and health care providers to understand the important cancer risks of the fastest-growing racial/ethnic group in the U.S. Eliminating disparities is critical to achieving an equitable society for all Americans.
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http://dx.doi.org/10.1002/onco.13748DOI Listing
March 2021

Genome-wide profiling of BK polyomavirus integration in bladder cancer of kidney transplant recipients reveals mechanisms of the integration at the nucleotide level.

Oncogene 2021 01 13;40(1):46-54. Epub 2020 Oct 13.

Division of Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Chronic BK polyomavirus (BKPyV) infection is recognized as a potential oncogenic factor of urothelial carcinoma (UC) in renal transplant recipients. Recent studies have reported a positive correlation among BKPyV integration, persistent overexpression of viral large T antigen (TAg), and malignancy, yet little is known about the specific integration mechanisms and the impacts of viral integration. Here, we performed whole-genome sequencing (WGS) and viral capture-based sequencing on high-grade immunohistochemically TAg-positive UCs in two renal transplant recipients. A total of 181 integration sites, including the three found by WGS, were identified by viral capture-based sequencing, indicating its enhanced sensitivity and ability in identifying low-read integration sites in subpopulations of the tumor cells. The microhomologies between human and BKPyV genomes were significantly enriched in the flanking regions of 84.5% the integration sites, with a median length of 7 bp. Notably, 75 human genes formed fusion sequences due to viral insertional integration. Among them, the expression of 15 genes were statistically associated with UC based on GEO2R expression analysis. Our results indicated a multisite and multifragment linear integration pattern and a potential microhomology or nonhomologous end joining integration mechanism at the single-nucleotide level. We put forward a potential selection mechanism driven by immunity and centered on viral integration in the carcinogenesis of BKPyV.
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http://dx.doi.org/10.1038/s41388-020-01502-wDOI Listing
January 2021

PIK Carefully, AKT Accordingly: Towards Precision Medicine in Prostate Cancer.

Eur Urol 2020 12 6;78(6):845-846. Epub 2020 Sep 6.

Massachusetts General Hospital Cancer Center, Boston, MA, USA.

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http://dx.doi.org/10.1016/j.eururo.2020.08.034DOI Listing
December 2020

Predicting new drug indications for prostate cancer: The integration of an in silico proteochemometric network pharmacology platform with patient-derived primary prostate cells.

Prostate 2020 10 6;80(14):1233-1243. Epub 2020 Aug 6.

Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC.

Background: Drug repurposing enables the discovery of potential cancer treatments using publically available data from over 4000 published Food and Drug Administration approved and experimental drugs. However, the ability to effectively evaluate the drug's efficacy remains a challenge. Impediments to broad applicability include inaccuracies in many of the computational drug-target algorithms and a lack of clinically relevant biologic modeling systems to validate the computational data for subsequent translation.

Methods: We have integrated our computational proteochemometric systems network pharmacology platform, DrugGenEx-Net, with primary, continuous cultures of conditionally reprogrammed (CR) normal and prostate cancer (PCa) cells derived from treatment-naive patients with primary PCa.

Results: Using the transcriptomic data from two matched pairs of benign and tumor-derived CR cells, we constructed drug networks to describe the biological perturbation associated with each prostate cell subtype at multiple levels of biological action. We prioritized the drugs by analyzing these networks for statistical coincidence with the drug action networks originating from known and predicted drug-protein targets. Prioritized drugs shared between the two patients' PCa cells included carfilzomib (CFZ), bortezomib (BTZ), sulforaphane, and phenethyl isothiocyanate. The effects of these compounds were then tested in the CR cells, in vitro. We observed that the IC values of the normal PCa CR cells for CFZ and BTZ were higher than their matched tumor CR cells. Transcriptomic analysis of CFZ-treated CR cells revealed that genes involved in cell proliferation, proteases, and downstream targets of serine proteases were inhibited while KLK7 and KLK8 were induced in the tumor-derived CR cells.

Conclusions: Given that the drugs in the database are extremely well-characterized and that the patient-derived cells are easily scalable for high throughput drug screening, this combined in vitro and in silico approach may significantly advance personalized PCa treatment and for other cancer applications.
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http://dx.doi.org/10.1002/pros.24050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540414PMC
October 2020

Resolution of a High Grade and Metastatic BK Polyomavirus-Associated Urothelial Cell Carcinoma Following Radical Allograft Nephroureterectomy and Immune Checkpoint Treatment: A Case Report.

Transplant Proc 2020 Nov 30;52(9):2720-2725. Epub 2020 Jul 30.

Department of Surgery/Division of Transplant Surgery, Massachusetts General Hospital, Boston, MA.

Background: BK viral infection in the posttransplant setting continues to cause serious morbidity with effects ranging from allograft nephropathy and dysfunction to urothelial malignancy.

Results: In this report, we present a patient that developed BK-associated nephropathy and, 6 years later, locally advanced urothelial malignancy in the renal allograft with nodal, muscle, and extremity involvement. Following radical allograft nephroureterectomy, he was treated with palliative radiation and the immune checkpoint inhibitor atezolizumab. Follow-up imaging at 1 year demonstrated radiographic complete response.

Conclusions: This report supports the growing body of evidence supporting the association of urothelial malignancy and BK virus infection in renal transplant recipients. Further, it highlights the novel application of immune checkpoint inhibitors in the treatment of advanced posttransplant malignancy, in particular when the allograft is removed and the tumor is possibly of donor origin.
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http://dx.doi.org/10.1016/j.transproceed.2020.06.012DOI Listing
November 2020

Viral integration in BK polyomavirus-associated urothelial carcinoma in renal transplant recipients: multistage carcinogenesis revealed by next-generation virome capture sequencing.

Oncogene 2020 08 28;39(35):5734-5742. Epub 2020 Jul 28.

Department of Organ Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou, China.

BK polyomavirus (BKPyV)-associated cancer after transplantation has gained increasing attention. However, the role of BKPyV integration on oncogenesis is still unclear. In this study, next-generation virome capture sequencing of primary and metastatic tumors were performed in three patients with BKPyV-associated urothelial carcinoma after renal transplantation. As a result, a total of 332 viral integration sites were identified in the six tumors. Integration of BKPyV in both primary and metastatic tumors followed the mechanism of microhomology-mediated end joining mostly, since microhomologies between human and BKPyV genomes were significantly enriched in flanking regions of 84% of the integration sites. Viral DNA breakpoints were nonrandom and tended to assemble in large T gene, small T gene and viral protein 2 gene. There were three, one and one consensus integration sites between the primary and metastatic tumors, which affected LINC01924, eIF3c, and NEIL2 genes in the three cases respectively. Thus, we concluded that integration of BKPyV was a continuous process occurring in both primary and metastatic tumors, generating heterogenous tumor cell populations. Through this ongoing process, certain cell populations might have gained growth advantage or metastatic potential, as a result of viral integration either affecting the cellular genes where the viral DNA integrated to or altering the expression or function of the viral genes.
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http://dx.doi.org/10.1038/s41388-020-01398-6DOI Listing
August 2020

The Art of Oncology: COVID-19 Era.

Oncologist 2020 11 10;25(11):997-1000g. Epub 2020 Sep 10.

Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

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http://dx.doi.org/10.1634/theoncologist.2020-0512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405267PMC
November 2020

Prospective Comprehensive Genomic Profiling of Primary and Metastatic Prostate Tumors.

JCO Precis Oncol 2019 10;3. Epub 2019 May 10.

University of Utah, Salt Lake City, UT.

Purpose: Comprehensive genomic profiling (CGP) is increasingly used for routine clinical management of prostate cancer. To inform targeted treatment strategies, 3,476 clinically advanced prostate tumors were analyzed by CGP for genomic alterations (GAs) and signatures of genomic instability.

Methods: Prostate cancer samples (1,660 primary site and 1,816 metastatic site tumors from unmatched patients) were prospectively analyzed by CGP (FoundationOne Assay; Foundation Medicine, Cambridge, MA) for GAs and genomic signatures (genome-wide loss of heterozygosity [gLOH], microsatellite instability [MSI] status, tumor mutational burden [TMB]).

Results: Frequently altered genes were (44%), (32%), (31%), and (23%). Potentially targetable GAs were frequently identified in DNA repair, phosphatidylinositol 3-kinase, and RAS/RAF/MEK pathways. DNA repair pathway GAs included homologous recombination repair (23%), Fanconi anemia (5%), (6%), and mismatch repair (4%) GAs. and GAs were associated with high gLOH, whereas altered tumors were infrequently gLOH high. Median TMB was low (2.6 mutations/Mb). A subset of cases (3%) had high TMB, of which 71% also had high MSI. Metastatic site tumors were enriched for the 11q13 amplicon ( and GAs in and compared with primary tumors.

Conclusion: Routine clinical CGP in the real-world setting identified GAs that are investigational biomarkers for targeted therapies in 57% of cases. gLOH and MSI/TMB signatures could further inform selection of poly (ADP-ribose) polymerase inhibitors and immunotherapies, respectively. Correlation of DNA repair GAs with gLOH identified genes associated with homologous recombination repair deficiency. GAs enriched in metastatic site tumors suggest therapeutic strategies for metastatic prostate cancer. Lack of clinical outcome correlation was a limitation of this study.
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http://dx.doi.org/10.1200/PO.18.00283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583915PMC
May 2019

Current Status of MRI and PET in the NCCN Guidelines for Prostate Cancer.

J Natl Compr Canc Netw 2019 05;17(5):506-513

Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri.

Prostate cancer (PCa) represents a significant source of morbidity and mortality for men in the United States, with approximately 1 in 9 being diagnosed with PCa in their lifetime. The role of imaging in the evaluation of men with PCa has evolved and currently plays a central role in diagnosis, treatment planning, and evaluation of recurrence. Appropriate use of multiparametric MRI (mpMRI) and MRI-guided transrectal ultrasound (MR-TRUS) biopsy increases the detection of clinically significant PCa while decreasing the detection of clinically insignificant PCa. This process may help patients with clinically insignificant PCa avoid the adverse effects of unnecessary therapy. In the setting of a known PCa, patients with low-grade disease can be observed using active surveillance, which often includes a combination of prostate-specific antigen (PSA) testing, serial mpMRI, and, if indicated, follow-up systematic and targeted TRUS-guided tissue sampling. mpMRI can provide important information in the posttreatment setting, but PET/CT is creating a paradigm shift in imaging standards for patients with locally recurrent and metastatic PCa. This article examines the strengths and limitations of mpMRI for initial PCa diagnosis, active surveillance, recurrent disease evaluation, and image-guided biopsies, and the use of PET/CT imaging in men with recurrent PCa. The goal of this review is to provide a rational basis for current NCCN Clinical Practice Guidelines in Oncology for PCa as they pertain to the use of these advanced imaging modalities.
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http://dx.doi.org/10.6004/jnccn.2019.7306DOI Listing
May 2019

Effect of PD-L1 testing on the cost-effectiveness and budget impact of pembrolizumab for advanced urothelial carcinoma of the bladder in the United States.

Urol Oncol 2019 03 6;37(3):180.e11-180.e18. Epub 2018 Dec 6.

Institute for Technology Assessment, Massachusetts General Hospital, Boston, MA; Harvard Medical School, Boston, MA. Electronic address:

Purpose: Our purpose was to evaluate the effect of PD-L1 testing on the cost-effectiveness of pembrolizumab for second-line treatment of advanced urothelial carcinoma in the bladder from the U.S. societal perspective.

Materials And Methods: We developed a microsimulation model to compare 3 treatment strategies: (1) treat all patients with standard-of-care chemotherapy, (2) treat all patients with pembrolizumab, and (3) treat patients with PD-L1-positive tumors at a ≥1% expression threshold with pembrolizumab, and all others with standard-of-care chemotherapy. Additionally, we performed a budget impact analysis based on the projected number of urothelial carcinoma patients eligible for second-line pembrolizumab treatment.

Results: Treating all patients with chemotherapy resulted in a mean cost of $17,232 and mean effect of 0.43 quality-adjusted life-years. The PD-L1 test strategy was the most efficient strategy, with an incremental cost-effectiveness ratio of $122,933/quality-adjusted life-year. Treating all patients with pembrolizumab resulted in an incremental cost-effectiveness ratio of $197,383/quality-adjusted life-year compared to the PD-L1 test strategy. The PD-L1 test strategy would produce an incremental budget impact of $14.9 million in the first year of use compared to chemotherapy, increasing to $16.5 million in the fifth year of use. Treating all patients with pembrolizumab would produce an incremental budget impact of $19.6 million compared to the PD-L1 test strategy in its first year of use, increasing to $20.9 million by year 5.

Conclusions: Pembrolizumab was not cost-effective in either strategy based on a $100,000/quality-adjusted life-year willingness-to-pay threshold. Using PD-L1 testing to select for patients who may have better associated outcomes may improve the affordability of pembrolizumab.
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http://dx.doi.org/10.1016/j.urolonc.2018.11.016DOI Listing
March 2019

Prostate cancer in transgender women.

Urol Oncol 2018 12 12;36(12):518-525. Epub 2018 Oct 12.

Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. Electronic address:

Introduction: As the transgender patient population continues to increase, urologists and other providers who treat genitourinary malignancies will increasingly encounter cases of prostate cancer in transgender women. Little exists in the current literature to help summarize the challenges and opportunities which face this unique patient population. Similarly, little exists to provide guidance on how we may best diagnose, manage, and follow transgender women diagnosed with prostate cancer. We sought to review the available literature in hopes of providing a resource for providers moving forward.

Materials And Methods: We collaboratively reviewed the currently available literature, guidelines, and statements of best practice to compile a comprehensive review of this emerging and important topic.

Results: Transgender persons face numerous systemic barriers to care with well documented increased risks of suicide and poor health outcomes. Though uncommon, the diagnosis of prostate cancer in transgender women is often associated with significant disease. While many options for management remain in line with standard guidelines, the unique aspects of care in this population-prior/current hormone usage, gender-affirming surgical procedures etc.-must be considered. Surgical, radiation, and hormonal treatments all play a potential role in appropriate treatment. Longitudinal studies are currently lacking and clinical trials are often structured with exclusive language which may lead to further marginalization of this patient population.

Conclusion: Transgender persons will almost certainly continue to grow as a population encountered and treated by healthcare professionals. Better training and understanding are needed to ensure all healthcare needs are met as best possible. Prostate cancer represents an area in which great strides may be made to improve both diagnosis and treatment. Urologists, and others who manage urologic cancers, must take the lead to improve the care of transgender persons with genitourinary malignancies.
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http://dx.doi.org/10.1016/j.urolonc.2018.09.011DOI Listing
December 2018

Characterization of the effects of defined, multidimensional culture conditions on conditionally reprogrammed primary human prostate cells.

Oncotarget 2018 Jan 18;9(2):2193-2207. Epub 2017 Dec 18.

Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.

The inability to propagate human prostate epithelial cells indefinitely has historically presented a serious impediment to prostate cancer research. The conditionally reprogrammed cell (CRC) approach uses the combination of irradiated J2 mouse fibroblasts and a Rho kinase inhibitor such as Y27632 to support the continuous culture of cells derived from most epithelial tissues, including the prostate. Due to their rapid establishment and overall ease of use, CRCs are now widely used in a variety of basic and preclinical settings. In addition, CRCs were successfully used to clinically treat respiratory papillomatosis. Although both normal and tumor-derived prostate CRCs have been used to study the basic biology of prostate cancer and to test new therapies, certain limitations exist. We have previously reported that prostate CRCs form functional prostate glands when implanted under the mouse renal capsule. However in conventional culture, the prostate CRCs exist in an adult stem-like, transient amplifying state and consequently do not adequately recapitulate several important features of a differentiated prostate epithelium. To address these limitations, we previously described a transwell dish-based model that supported the culturing of prostate CRCs and the collection of cells and cell extracts for molecular and genetic analyses. Using normal and tumor-derived prostate CRCs, we describe the combined effects of the multi-dimensional transwell platform and defined culture media on prostate cellular proliferation, differentiation and signaling.
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http://dx.doi.org/10.18632/oncotarget.23363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788632PMC
January 2018

Evaluation of take-home exposure to asbestos from handling asbestos-contaminated worker clothing following the abrasive sawing of cement pipe.

Inhal Toxicol 2017 Oct - Dec;29(12-14):555-566. Epub 2018 Jan 16.

f Cardno ChemRisk , Jackson , WY , USA.

Although industrial uses of asbestos have declined since the 1970s, in recent years there has been a renewed interest in para-occupational ("take-home") exposure to these fibers. The aim of this study was to quantify the release of asbestos fibers, if any, during the shaking out of crocidolite- and chrysotile-contaminated clothing in a simulated at-home setting. An exposure study was conducted in which personal and area air samples were collected during the handling (i.e. shake-out) of work clothing (shirt and pants) previously worn by an operator who had cut asbestos-containing cement pipe. During eight "loading" events, the operator cut a historically representative asbestos-containing cement pipe (10% crocidolite and 25% chrysotile) using a powered abrasive saw. Subsequently, 30-minute air samples were collected during four "shake-out" events, each of which consisted of the handling of two complete sets of contaminated work clothes. Samples were analyzed in accordance with NIOSH methods 7400 and 7402. The mean phase contrast microscopy equivalent (PCME) airborne concentrations were 0.52 f/cc (SD = 0.34 f/cc) for total asbestos fibers, 0.36 f/cc (SD = 0.26 f/cc) for chrysotile and 0.17 f/cc (SD = 0.096 f/cc) for crocidolite. Based on likely estimates of the frequency of laundering activities, and assuming that the dusty clothing (1) is not blown off in the occupational setting using compressed air and (2) is not shaken out before entering the home, a family member handling the clothing could potentially have a lifetime cumulative exposure to chrysotile and crocidolite of approximately 0.20 f/cc-year and 0.096 f/cc-year, respectively.
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http://dx.doi.org/10.1080/08958378.2017.1418940DOI Listing
January 2019

An RNA-Based Digital Circulating Tumor Cell Signature Is Predictive of Drug Response and Early Dissemination in Prostate Cancer.

Cancer Discov 2018 03 4;8(3):288-303. Epub 2018 Jan 4.

Massachusetts General Hospital Cancer Center, Boston, Massachusetts.

Blood-based biomarkers are critical in metastatic prostate cancer, where characteristic bone metastases are not readily sampled, and they may enable risk stratification in localized disease. We established a sensitive and high-throughput strategy for analyzing prostate circulating tumor cells (CTC) using microfluidic cell enrichment followed by digital quantitation of prostate-derived transcripts. In a prospective study of 27 patients with metastatic castration-resistant prostate cancer treated with first-line abiraterone, pretreatment elevation of the digital CTC score identifies a high-risk population with poor overall survival (HR = 6.0; = 0.01) and short radiographic progression-free survival (HR = 3.2; = 0.046). Expression of in CTCs identifies 6 of 6 patients with ≤12-month survival, with a subset also expressing the splice variant. In a second cohort of 34 men with localized prostate cancer, an elevated preoperative CTC score predicts microscopic dissemination to seminal vesicles and/or lymph nodes ( < 0.001). Thus, digital quantitation of CTC-specific transcripts enables noninvasive monitoring that may guide treatment selection in both metastatic and localized prostate cancer. There is an unmet need for biomarkers to guide prostate cancer therapies, for curative treatment of localized cancer and for application of molecularly targeted agents in metastatic disease. Digital quantitation of prostate CTC-derived transcripts in blood specimens is predictive of abiraterone response in metastatic cancer and of early dissemination in localized cancer. .
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http://dx.doi.org/10.1158/2159-8290.CD-16-1406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342192PMC
March 2018

Role of Androgen Receptor Variants in Prostate Cancer: Report from the 2017 Mission Androgen Receptor Variants Meeting.

Eur Urol 2018 05 16;73(5):715-723. Epub 2017 Dec 16.

Department of Urology, UT Southwestern Medical Center at Dallas, Dallas, TX, USA; Department of Urology and Pharmacology, UT Southwestern Medical Center at Dallas, Dallas, TX, USA. Electronic address:

Context: Although a number of studies have demonstrated the importance of constitutively active androgen receptor variants (AR-Vs) in prostate cancer, questions still remain about the precise role of AR-Vs in the progression of castration-resistant prostate cancer (CRPC).

Objective: Key stakeholders and opinion leaders in prostate cancer convened on May 11, 2017 in Boston to establish the current state of the field of AR-Vs.

Evidence Acquisition: The meeting "Mission Androgen Receptor Variants" was the second of its kind sponsored by the Prostate Cancer Foundation (PCF). This invitation-only event was attended by international leaders in the field and representatives from sponsoring organizations (PCF and industry sponsors). Eighteen faculty members gave short presentations, which were followed by in-depth discussions. Discussions focused on three thematic topics: (1) potential of AR-Vs as biomarkers of therapeutic resistance; (2) role of AR-Vs as functionally active CRPC progression drivers; and (3) utility of AR-Vs as therapeutic targets in CRPC.

Evidence Synthesis: The three meeting organizers synthesized this meeting report, which is intended to summarize major data discussed at the meeting and identify key questions as well as strategies for addressing these questions. There was a critical consensus that further study of the AR-Vs is an important research focus in CRPC. Contrasting views and emphasis, each supported by data, were presented at the meeting, discussed among the participants, and synthesized in this report.

Conclusions: This article highlights the state of knowledge and outlines the most pressing questions that need to be addressed to advance the AR-V field.

Patient Summary: Although further investigation is needed to delineate the role of androgen receptor (AR) variants in metastatic castration-resistant prostate cancer, advances in measurement science have enabled development of blood-based tests for treatment selection. Detection of AR variants (eg, AR-V7) identified a patient population with poor outcomes to existing AR-targeting therapies, highlighting the need for novel therapeutic agents currently under development.
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http://dx.doi.org/10.1016/j.eururo.2017.11.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5929166PMC
May 2018

Neutron vibrational spectroscopic studies of novel tire-derived carbon materials.

Phys Chem Chem Phys 2017 Aug;19(33):22256-22262

Chemical Sciences Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA.

Sulfonated tire-derived carbons have been demonstrated to be high value-added carbon products of tire recycling in several energy storage system applications including lithium, sodium, potassium ion batteries and supercapacitors. In this communication, we compared different temperature pyrolyzed sulfonated tire-derived carbons with commercial graphite and unmodified/non-functionalized tire-derived carbon by studying the surface chemistry and properties, vibrational spectroscopy of the molecular structure, chemical bonding such as C-H bonding, and intermolecular interactions of the carbon materials. The nitrogen adsorption-desorption studies revealed the tailored micro and meso pore size distribution of the carbon during the sulfonation process. XPS and neutron vibrational spectra showed that the sulfonation of the initial raw tire powders could remove the aliphatic hydrogen containing groups ([double bond splayed left]CH and -CH groups) and reduce the number of heteroatoms that connect to carbon. The absence of these functional groups could effectively improve the first cycle efficiency of the material in rechargeable batteries. Meanwhile, the introduced -SOH functional group helped in producing terminal H at the edge of the sp bonded graphite-like layers. This study reveals the influence of the sulfonation process on the recovered hard carbon from used tires and provides a pathway to develop and improve advanced energy storage materials.
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http://dx.doi.org/10.1039/c7cp03750cDOI Listing
August 2017

Active Travel Behavior in a Border Region of Texas and New Mexico: Motivators, Deterrents, and Characteristics.

J Phys Act Health 2017 08 19;14(8):636-645. Epub 2017 Apr 19.

Background: Active travel has been linked with improved transportation and health outcomes, such as reduced traffic congestion and air pollution, improved mobility, accessibility, and equity, and increased physical and mental health. The purpose of this study was to better understand active travel characteristics, motivators, and deterrents in the El Paso, TX, region.

Methods: A multimodal transportation survey brought together elements of transportation and health, with a focus on attitudinal characteristics. The analysis consisted of an initial descriptive analysis, spatial analysis, and multivariate binary and ordered-response models of walking and bicycling behavior.

Results: The motivators and deterrents of active travel differed for walkers, bicyclists, and noncyclists interested in bicycling. The link between active travel and life satisfaction was moderated by age, with a negative association for older travelers. This effect was stronger for bicycling than it was for walking.

Conclusions: Based on the findings, several interventions to encourage walking and bicycling were suggested. These included infrastructure and built environment enhancements, workplace programs, and interventions targeting specific subpopulations.
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http://dx.doi.org/10.1123/jpah.2016-0503DOI Listing
August 2017

Expression of β-globin by cancer cells promotes cell survival during blood-borne dissemination.

Nat Commun 2017 02 9;8:14344. Epub 2017 Feb 9.

Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.

Metastasis-competent circulating tumour cells (CTCs) experience oxidative stress in the bloodstream, but their survival mechanisms are not well defined. Here, comparing single-cell RNA-Seq profiles of CTCs from breast, prostate and lung cancers, we observe consistent induction of β-globin (HBB), but not its partner α-globin (HBA). The tumour-specific origin of HBB is confirmed by sequence polymorphisms within human xenograft-derived CTCs in mouse models. Increased intracellular reactive oxygen species (ROS) in cultured breast CTCs triggers HBB induction, mediated through the transcriptional regulator KLF4. Depletion of HBB in CTC-derived cultures has minimal effects on primary tumour growth, but it greatly increases apoptosis following ROS exposure, and dramatically reduces CTC-derived lung metastases. These effects are reversed by the anti-oxidant N-Acetyl Cysteine. Conversely, overexpression of HBB is sufficient to suppress intracellular ROS within CTCs. Altogether, these observations suggest that β-globin is selectively deregulated in cancer cells, mediating a cytoprotective effect during blood-borne metastasis.
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http://dx.doi.org/10.1038/ncomms14344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321792PMC
February 2017

Long-term Outcomes After Bladder-preserving Tri-modality Therapy for Patients with Muscle-invasive Bladder Cancer: An Updated Analysis of the Massachusetts General Hospital Experience.

Eur Urol 2017 06 9;71(6):952-960. Epub 2017 Jan 9.

Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA. Electronic address:

Background: Tri-modality therapy (TMT) is a recognized treatment strategy for selected patients with muscle-invasive bladder cancer (MIBC).

Objective: Report long-term outcomes of patients with MIBC treated by TMT.

Design, Setting, And Participants: Four hundred and seventy-five patients with cT2-T4a MIBC were enrolled on protocols or treated as per protocol at the Massachusetts General Hospital between 1986 and 2013.

Intervention: Patients underwent transurethral resection of bladder tumor followed by concurrent radiation and chemotherapy. Patients with less than a complete response (CR) to chemoradiation or with an invasive recurrence were recommended to undergo salvage radical cystectomy.

Outcome Measurements And Statistical Analysis: Disease-specific survival (DSS) and overall survival (OS) were calculated using the Kaplan-Meier method.

Results And Limitations: Median follow-up for surviving patients was 7.21 yr. Five- and 10-yr DSS rates were 66% and 59%, respectively. Five- and 10-yr OS rates were 57% and 39%, respectively. The risk of salvage cystectomy at 5 yr was 29%. In multivariate analyses, T2 disease (OS hazard ratio [HR]: 0.57, 95% confidence interval [CI]: 0.44-0.75, DSS HR: 0.51, 95% CI: 0.36-0.73), CR to chemoradiation (OS HR: 0.61, 95% CI: 0.46-0.81, DSS HR: 0.49, 95% CI: 0.34-0.71), and presence of tumor-associated carcinoma in situ (OS HR: 1.56, 95% CI: 1.17-2.08, DSS HR: 1.50, 95% CI: 1.03-2.17) were significant predictors for OS and DSS. When evaluating our cohort over treatment eras, rates of CR improved from 66% to 88% and 5-yr DSS improved from 60% to 84% during the eras of 1986-1995 to 2005-2013, while the 5-yr risk of salvage radical cystectomy rate decreased from 42% to 16%.

Conclusions: These data demonstrate high rates of CR and bladder preservation in patients receiving TMT, and confirm DSS rates similar to modern cystectomy series. Contemporary results are particularly encouraging, and therefore TMT should be discussed and offered as a treatment option for selected patients.

Patient Summary: Tri-modality therapy is an alternative to radical cystectomy for patients with muscle-invasive bladder cancer, and is associated with comparable long-term survival and high rates of bladder preservation.
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http://dx.doi.org/10.1016/j.eururo.2016.12.020DOI Listing
June 2017

Clinical Outcomes of Patients with Histologic Variants of Urothelial Cancer Treated with Trimodality Bladder-sparing Therapy.

Eur Urol 2017 07 28;72(1):54-60. Epub 2016 Dec 28.

Department of Radiation Oncology, Massachusetts General Hospital. Harvard Medical School, Boston, MA, USA. Electronic address:

Background: Trimodality bladder-sparing therapy (TMT) is an acceptable treatment for selected patients with muscle-invasive urothelial cancer. Outcomes of TMT in histologic variants remains largely unknown.

Objective: To compare outcomes of pure urothelial carcinoma (PUC) to variant urothelial carcinoma (VUC) after TMT.

Design, Setting, And Participants: Retrospective study of patients treated with TMT at a single cancer center from 1993 until 2013.

Outcome Measurements And Statistical Analysis: Kaplan-Meier survival probabilities, and univariate and multivariable Cox regression analysis.

Results And Limitations: Of 303 patients treated with TMT, 66 (22%) had VUC. Fifty (76%) had VUC with squamous and/or glandular differentiation and 16 (24%) had other forms. Complete response rate after induction TMT was 83% in PUC and 82% in VUC (p=0.9). The 5-yr and 10-yr disease-specific survival (DSS) was 75% and 67% in PUC versus 64% and 64% in VUC. The 5-yr and 10-yr overall survival (OS) was 61% and 42% in PUC versus 52% and 42% in VUC. On multivariable analysis VUC was not associated with DSS (hazard ratio: 1.3, 95% confidence interval: 0.8-2.2, p=0.3) or OS (hazard ratio: 1.2, 95% confidence interval: 0.8-1.7, p=0.4). Salvage cystectomy rates were similar (log-rank p=0.3). Limitations include retrospective design and restriction to variants of urothelial cancer.

Conclusions: VUC responded to TMT, and there was no significant difference in complete response, OS, DSS, or salvage cystectomy rates compared with PUC. The presence of VUC should not exclude patients from TMT.

Patient Summary: The response of histologic variants of bladder cancer to bladder-sparing chemoradiation is largely unknown. We compared the outcomes of histologic variants of urothelial cancer to pure urothelial cancer in a large series of patients from a single institution. We found that variant histology does not significantly influence outcomes.
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http://dx.doi.org/10.1016/j.eururo.2016.12.002DOI Listing
July 2017

Cell-free and circulating tumor cell-based biomarkers in men with metastatic prostate cancer: Tools for real-time precision medicine?

Urol Oncol 2016 11 19;34(11):490-501. Epub 2016 Oct 19.

Massachusetts General Hospital Cancer Center, Boston, MA; Department of Medicine, Massachusetts General Hospital, Boston, MA; Harvard Medical School, Boston, MA.

The recent expansion of therapeutic options for the treatment of metastatic prostate cancer highlights the need for precision medicine approaches to enable the rational selection of appropriate therapies for individual patients. In this context, circulating biomarkers in the peripheral blood are attractive as readily accessible tools for predicting and monitoring therapeutic response. In the case of circulating tumor cells and circulating tumor DNA, they may also serve as a noninvasive means of assessing molecular aberrations in tumors at multiple time points before and during therapy. These so-called "liquid biopsies" can provide a snapshot view of tumor molecular architecture and may enable clinicians to monitor the molecular status of tumors as they evolve during treatment, thus allowing for individualized precision therapeutic decisions for patients over time. In this review, we outline recent progress in the field of circulating biomarkers in metastatic prostate cancer and evaluate their potential for enabling this vision of real-time precision medicine.
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http://dx.doi.org/10.1016/j.urolonc.2016.09.001DOI Listing
November 2016

Quality of Life in Long-term Survivors of Muscle-Invasive Bladder Cancer.

Int J Radiat Oncol Biol Phys 2016 12 24;96(5):1028-1036. Epub 2016 Aug 24.

Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address:

Purpose: Health-related quality of life (QOL) has not been well-studied in survivors of muscle-invasive bladder cancer (MIBC). The present study compared long-term QOL in MIBC patients treated with radical cystectomy (RC) versus bladder-sparing trimodality therapy (TMT).

Methods And Materials: This cross-sectional bi-institutional study identified 226 patients with nonmetastatic cT2-cT4 MIBC, diagnosed in 1990 to 2011, who were eligible for RC and were disease free for ≥2 years. Six validated QOL instruments were administered: EuroQOL EQ-5D, European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire and EORTC MIBC module, Expanded Prostate Cancer Index Composite bowel scale, Cancer Treatment and Perception Scale, and Impact of Cancer, version 2. Multivariable analyses of the mean QOL scores were conducted using propensity score matching.

Results: The response rate was 77% (n=173). The median follow-up period was 5.6 years. Of the 173 patients, 64 received TMT and 109, RC. The median interval from diagnosis to questionnaire completion was 9 years after TMT and 7 years after RC (P=.009). No significant differences were found in age, gender, comorbidities, tobacco history, performance status, or tumor stage. On multivariable analysis, patients who received TMT had better general QOL by 9.7 points of 100 compared with those who had received RC (P=.001) and higher physical, role, social, emotional, and cognitive functioning by 6.6 to 9.9 points (P≤.04). TMT was associated with better bowel function by 4.5 points (P=.02) and fewer bowel symptoms by 2.7 to 7.1 points (P≤.05). The urinary symptom scores were similar. TMT was associated with better sexual function by 8.7 to 32.1 points (P≤.02) and body image by 14.8 points (P<.001). The patients who underwent TMT reported greater informed decision-making scores by 13.6 points (P=.01) and less concern about the negative effect of cancer by 6.8 points (P=.006). The study limitations included missing baseline QOL data and different follow-up times.

Conclusions: Both TMT and RC result in good long-term QOL outcomes in MIBC survivors, supporting TMT as a good alternative to RC for selected patients. Whether TMT leads to superior QOL requires prospective validation.
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http://dx.doi.org/10.1016/j.ijrobp.2016.08.023DOI Listing
December 2016

Transportation Planning and Quality of Life: Where Do They Intersect?

Transp Policy (Oxf) 2016 May 16;48:146-155. Epub 2016 Mar 16.

Texas A&M Transportation Institute, 505 E. Huntland Dr., Suite 455, Austin, TX 78752, Tel 512.407.1119 | Fax 512.467.8971,

Policy makers and researchers are increasingly recognizing the connections between public health and transportation, but health improvements are typically framed from a physical health perspective rather than considering broader quality of life (QOL) impacts. Currently, there is a limited understanding of the ways in which transportation and QOL intersect, and little is known about how metropolitan planning organizations (MPOs) in the United States are addressing QOL outcomes. This study addressed these gaps by developing a conceptual framework holistically linking transportation to QOL. The proposed framework identified four transportation-related QOL dimensions-physical, mental, social, and economic well-being-which are predominantly influenced by three components of the transportation system: mobility/accessibility, the built environment, and vehicle traffic. This framework then formed the basis for a content analysis of 148 long-range transportation plans in the United States to evaluate the extent to which QOL is being considered in the planning process. The results of the analysis and a follow-up examination of 13 plans revealed that MPOs are inconsistently addressing QOL. Plans primarily targeted QOL enhancement from the perspective of physical well-being, while mental and social well-being were rarely considered. Policy recommendations were provided to more comprehensively integrate QOL into the transportation planning process.
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http://dx.doi.org/10.1016/j.tranpol.2016.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988690PMC
May 2016

Branched Chain RNA In Situ Hybridization for Androgen Receptor Splice Variant AR-V7 as a Prognostic Biomarker for Metastatic Castration-Sensitive Prostate Cancer.

Clin Cancer Res 2017 Jan 20;23(2):363-369. Epub 2016 Jul 20.

Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Purpose: The androgen receptor (AR) mRNA splice variant AR-V7 has emerged as a predictive biomarker for response to AR-targeted therapies. There are currently no commercially available assays to detect AR splice variants. The branched chain RNA in situ hybridization (ISH) platform enables the highly sensitive detection of RNA transcripts in formalin-fixed, paraffin-embedded (FFPE) tissues.

Experimental Design: We designed a branched chain RNA ISH probe to target the unique cryptic exon CE3 of AR-V7 using multiple tiling probes. This automated ISH assay was applied to tumor tissue from two distinct clinical cohorts that we hypothesized would differ in AR-V7 status.

Results: We detected AR-V7 in all tumor samples from men with metastatic castration-resistant prostate cancer with tissue obtained after disease progression despite at least one subsequent line of hormonal therapy (abiraterone, enzalutamide, or bicalutamide; n = 12). We detected AR-V7 in just one tumor from men who had undergone prostatectomy for localized adenocarcinoma (n = 30; Gleason 4 + 5 = 9 in the AR-V7-positive sample). Given the apparent distinction between the above groups by AR-V7 signal, we analyzed pretreatment AR-V7 status as a predictive and prognostic biomarker in men with treatment-naïve metastatic disease. Patients with metastases but without detectable AR-V7 RNA at baseline had significantly longer overall survival (log-rank P = 0.044) and a trend toward superior progression-free survival (log-rank P = 0.055).

Conclusions: Within an institutional cohort, the RNA ISH assay identified AR-V7 within FFPE tissue and may have prognostic value in metastatic castration-sensitive prostate cancer. These preliminary findings warrant further study in larger cohorts. Clin Cancer Res; 23(2); 363-9. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-16-0237DOI Listing
January 2017

Potential Health Implications and Health Cost Reductions of Transit-Induced Physical Activity.

J Transp Health 2016 Jun;3(2):133-140

Texas A&M Transportation Institute, 701 North Post Oak Rd., Suite 430, Houston, TX 77024, USA.

Transit has the potential to increase an individual's level of physical activity due to the need to walk or bike at the beginning and end of each trip. Consideration of these health benefits would allow transit proponents to better demonstrate its true costs and benefits. In light of transit's potential health-related impacts, this study contributes to the growing discussion in the emerging field of health and transportation by providing a review of the current level of understanding and evidence related to the physical activity implications of transit use and its associated health cost benefits. Findings from the review revealed that transit use is associated with increased levels of physical activity and improved health outcomes, but the magnitude of these effects is uncertain. There were few studies that estimated the health care cost savings of transit systems, and those that did tended to be imprecise and simplistic. Objective physical activity measures and frequency-based transit measures would allow for greater consistency across studies and help more directly attribute physical activity gains to transit ridership. Additionally, research in this area would benefit from disaggregate estimation techniques and more robust health datasets that can be better linked with existing transit data.
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http://dx.doi.org/10.1016/j.jth.2016.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917017PMC
June 2016

Prostate Cancer, Version 1.2016.

J Natl Compr Canc Netw 2016 01;14(1):19-30

National Comprehensive Cancer Network

The NCCN Guidelines for Prostate Cancer address staging and risk assessment after an initial diagnosis of prostate cancer and management options for localized, regional, and metastatic disease. Recommendations for disease monitoring, treatment of recurrent disease, and systemic therapy for metastatic castration-recurrent prostate cancer also are included. This article summarizes the NCCN Prostate Cancer Panel's most significant discussions for the 2016 update of the guidelines, which include refinement of risk stratification methods and new options for the treatment of men with high-risk and very-high-risk disease and progressive castration-naïve disease.
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http://dx.doi.org/10.6004/jnccn.2016.0004DOI Listing
January 2016

Managing juvenile idiopathic arthritis-associated uveitis.

Surv Ophthalmol 2016 Mar-Apr;61(2):197-210. Epub 2015 Oct 24.

Retinal Treatment and Research Unit, Bristol Eye Hospital, Bristol, UK. Electronic address:

Bilateral chronic anterior uveitis is an extra-articular feature of juvenile idiopathic arthritis. Although figures vary, uveitis occurs in approximately 11%-13% of patients with this disease and is most commonly associated with the female gender, oligoarthritis, and presence of antinuclear antibodies. The disease has an insidious onset and is often asymptomatic. Managing patients with juvenile idiopathic arthritis-associated uveitis remains challenging as the disease may prove to be refractory to traditional treatment regimens. Stepwise immunomodulatory therapy is indicated, with new biologic drugs being used last in cases of refractory uveitis. Small scale studies and practice have provided the evidence to undertake randomized control trials to evaluate the efficacy, safety, and cost-effectiveness of anti-tumor necrosis factor-α therapies, such as infliximab and adalimumab. These have demonstrated promising results, with further data awaited from ongoing trials for adalimumab (as SYCAMORE and ADJUVITE trials). Lower grade evidence is supporting the use of newer biologics such as rituximab, daclizumab, tocilizumab, and abatacept in those cases refractory to anti-tumor necrosis factor-α therapy.
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http://dx.doi.org/10.1016/j.survophthal.2015.10.005DOI Listing
September 2016

RNA-Seq of single prostate CTCs implicates noncanonical Wnt signaling in antiandrogen resistance.

Science 2015 Sep;349(6254):1351-6

Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.

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.
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http://dx.doi.org/10.1126/science.aab0917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872391PMC
September 2015

Proposed prognostic scoring system evaluating risk factors for biochemical recurrence of prostate cancer after salvage radiation therapy.

BJU Int 2016 08 22;118(2):236-42. Epub 2015 Aug 22.

Department of Radiation Oncology, Mayo Clinic, Jacksonville, FL, USA.

Objective: To update a previously proposed prognostic scoring system that predicts risk of biochemical recurrence (BCR) after salvage radiation therapy (SRT) for recurrent prostate cancer when using additional patients and a PSA value of 0.2 ng/mL and rising as the definition of BCR.

Patients And Methods: We included 577 patients who received SRT for a rising PSA after radical prostatectomy in this retrospective cohort study. Clinical, pathological, and SRT characteristics were evaluated for association with BCR using relative risks (RRs) from multivariable Cox regression models.

Results: With a median follow-up of 5.5 years after SRT, 354 patients (61%) experienced BCR. At 5 years after SRT, 40% of patients were free of BCR. Independent associations with BCR were identified for the PSA level before SRT (RR [doubling]: 1.25, P < 0.001), pathological tumour stage (RR [T3a vs T2] 1.21, P = 0.19; RR [T3b/T4 vs T2] 2.09, P < 0.001; overall P < 0.001), Gleason score (RR [7 vs <7] 1.63, P < 0.001; RR [8-10 vs <7] 2.28, P < 0.001; overall P < 0.001), and surgical margin status (RR [positive vs negative] 0.71, P = 0.003). We combined these four variables to create a prognostic scoring system that predicted BCR risk with a c-index of 0.66. Scores ranged from 0 to 7, and 5-year freedom from BCR for different levels of the score was as follows: Score = 0-1: 66%, Score = 2: 46%, Score = 3: 28%, Score = 4: 19%, and Score = 5-7: 15%.

Conclusion: We developed a scoring system that provides an estimation of the risk of BCR after SRT. These findings will be useful for patients and physicians in decision making for radiation therapy in the salvage setting.
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http://dx.doi.org/10.1111/bju.13229DOI Listing
August 2016

Molecular Determinants of Metastasis in Renal Cell Cancer: Tracking Down the Real Killer.

Authors:
Richard J Lee

J Urol 2015 Aug 15;194(2):278-9. Epub 2015 May 15.

Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1016/j.juro.2015.05.032DOI Listing
August 2015