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D'Amico L.,University of Basel | Belisario D.,University of Basel | Migliardi G.,Institute for Cancer Research and Treatment | Grange C.,University of Turin | And 10 more authors.
Oncotarget | Year: 2016

Cancer stem cells (CSCs) are key players in bone metastasis. In some renal tumors CSCs overexpress the HGF receptor c-MET, speculating that c-MET targeting could lead to bone metastasis inhibition. To address this hypothesis we isolated renal CD105+/CD24-CSCs, expressing c-MET receptor from a primary renal carcinoma. Then, to study their ability to metastasize to bone, we injected renal CSCs in NOD/ SCID mice implanted with a human bone and we tested the effect of a c-MET inhibitor (JNJ-38877605) on bone metastasis development. JNJ-38877605 inhibited the formation of metastases at bone implant site. We showed that JNJ-38877605 inhibited the activation of osteoclasts induced by RCC stem cells and it stimulated osteoblast activity, finally resulting in a reduction of bone turnover consistent with the inhibition of bone metastases. We measured the circulating levels of osteotropic factors induced by RCC stem cells in the sera of mice treated with c-Met inhibitor, showing that IL-11 and CCL20 were reduced in mice treated with JNJ-38877605, strongly supporting the involvement of c-MET in the regulation of this process. To address the clinical relevance of c-MET upregulation during tumor progression, we analysed c-MET in renal cancer patients detecting an increased expression in the bone metastatic lesions by IHC. Then, we dosed CCL20 serum levels resulting significantly increased in patients with bone metastases compared to non-metastatic ones. Collectively, our data highlight the importance of the c-MET pathway in the pathogenesis of bone metastases induced by RCC stem cells in mice and humans.


PubMed | CeRMS, CTO Hospital, Institute for Cancer Research and Treatment, Clinic of Internal Medicine and 5 more.
Type: Journal Article | Journal: Oncotarget | Year: 2016

Cancer stem cells (CSCs) are key players in bone metastasis. In some renal tumors CSCs overexpress the HGF receptor c-MET, speculating that c-MET targeting could lead to bone metastasis inhibition. To address this hypothesis we isolated renal CD105+/CD24-CSCs, expressing c-MET receptor from a primary renal carcinoma. Then, to study their ability to metastasize to bone, we injected renal CSCs in NOD/SCID mice implanted with a human bone and we tested the effect of a c-MET inhibitor (JNJ-38877605) on bone metastasis development. JNJ-38877605 inhibited the formation of metastases at bone implant site. We showed that JNJ-38877605 inhibited the activation of osteoclasts induced by RCC stem cells and it stimulated osteoblast activity, finally resulting in a reduction of bone turnover consistent with the inhibition of bone metastases. We measured the circulating levels of osteotropic factors induced by RCC stem cells in the sera of mice treated with c-Met inhibitor, showing that IL-11 and CCL20 were reduced in mice treated with JNJ-38877605, strongly supporting the involvement of c-MET in the regulation of this process. To address the clinical relevance of c-MET upregulation during tumor progression, we analysed c-MET in renal cancer patients detecting an increased expression in the bone metastatic lesions by IHC. Then, we dosed CCL20 serum levels resulting significantly increased in patients with bone metastases compared to non-metastatic ones. Collectively, our data highlight the importance of the c-MET pathway in the pathogenesis of bone metastases induced by RCC stem cells in mice and humans.


Moreira D.M.,Urologic | Moreira D.M.,Veterans Affairs Medical Center | Presti Jr. J.C.,Stanford University | Aronson W.J.,Urology Section | And 7 more authors.
BJU International | Year: 2010

Study Type - Prognosis (inception cohort) Level of Evidence 1b Objectives To define a level of persistently elevated prostate-specific antigen (PSA) after radical prostatectomy (RP) that equates with high-risk for disease progression, and to identify preoperative predictors of PSA persistence among men from the Shared Equal Access Regional Cancer Hospital (SEARCH) database. Patients and Methods A total of 901 men treated with RP between 2001 and 2008 were separated into groups based upon PSA nadir within 6 months after RP. We explored the association between nadir groups and time to biochemical recurrence (BCR) using multivariate Cox proportional hazards and determined the preoperative predictors of PSA persistence using logistic regression. Results Relative to men with undetectable PSA levels, those with a PSA nadir of 0.03 (hazard ratio [HR] 3.88, P < 0.001), 0.04 (HR 4.87, P < 0.001), 0.05-0.09 (HR 12.69, P < 0.001), 0.1-0.19 (HR 13.17, P < 0.001), and 0.2 ng/mL (HR 13.23, P < 0.001) were at increased risk of BCR while men with a nadir of 0.01 (HR 1.36, P = 0.400) and 0.02 (HR 1.64, P = 0.180) were not. Using the PSA persistence definition of a PSA nadir ≥0.03 ng/mL, 230 men (26%) had persistence. The independent preoperative predictors of PSA persistence were higher body mass index (BMI, P = 0.002), pathological Gleason score (relative to 2-6: 4 + 3-10, P = 0.001) and preoperative PSA level (P < 0.001). Conclusions Men with a PSA nadir ≥0.03 ng/mL after RP were at higher risk for BCR. Using a PSA persistence definition of a PSA nadir ≥0.03 ng/mL, persistence was predicted by known factors associated with aggressive disease (tumour grade, PSA level and BMI). Validation of the present definition in different populations using later end-points remains necessary to assess its prognostic usefulness. © 2009 BJU INTERNATIONAL.


Abern M.R.,University of Illinois at Chicago | Terris M.K.,Veterans Affairs Medical Center | Terris M.K.,Georgia Regents University | Aronson W.J.,Urology Section | And 7 more authors.
Cancer | Year: 2014

BACKGROUND In the prostate-specific antigen (PSA) screening era, approximately 15% of US men still present with clinically high-risk prostate cancer (PC). However, high-risk PC may be downgraded/downstaged at radical prostatectomy (RP), making additional therapy unnecessary. The authors tested the oncologic outcomes in men with clinically high-risk disease stratified on RP pathology. METHODS A total of 611 men with high-risk PC (PSA level > 20 ng/mL, biopsy Gleason sum [bGS] ≥ 8, or clinical classification of ≥ T3) underwent RP and pelvic lymphadenectomy between 1998 and 2011. Outcomes included biochemical disease recurrence (BCR), receipt of androgen deprivation therapy (ADT), metastases, and PC-specific and overall survival. RP pathology was classified as unfavorable (pathologic Gleason sum ≥ 8, pathologic classification of ≥ T3, or lymph node-positive disease), or favorable (no unfavorable features). Multivariable analyses tested oncologic outcomes stratified by pathologic classification. RESULTS Overall, 527 men had complete pathologic data and were included in the current analysis. Of the cohort, 206 of 527 men (39%) had favorable pathology. This finding was more common in men with only 1 clinical high-risk feature, and a lower body mass index, PSA level, bGS, and percentage positive biopsy cores. Favorable pathology was associated with decreased BCR (hazards ratio [HR], 0.34), metastases (HR, 0.17), and PC death (HR, 0.17). After a median follow-up of 82 months (range, 49 months-131 months), 193 of the 527 men (37%) received ADT, including only 35 of the 206 men with favorable pathology (17%). Unfavorable pathology was associated with early (≤ 5 years) but not late treatment with ADT. CONCLUSIONS In a large cohort of men with high-risk PC who were managed with RP, 39% had favorable pathology and superior oncologic outcomes.© 2014 American Cancer Society.


Moreira D.M.,Duke University | Moreira D.M.,Medical Center Durham | Banez L.L.,Duke University | Banez L.L.,Medical Center Durham | And 9 more authors.
BJU International | Year: 2010

OBJECTIVE To investigate the predictors of secondary treatment for recurrent prostate cancer after radical prostatectomy (RP) among subjects from the Shared Equal Access Regional Cancer Hospital (SEARCH) database. PATIENTS AND METHODS We used Kaplan-Meier curves and Cox proportional hazard models to identify factors associated with time to secondary treatment and type of secondary treatment received among 697 men who developed biochemical recurrence (BCR) after RP. RESULTS During a median follow-up of 45 months after BCR, 357 men received salvage treatment. The 1-, 3-, and 5-year risk of receiving any salvage treatment was 29% (95% confidence interval (CI) 26-33%), 48% (95%CI 44-52%), and 53% (95%CI 49-57%), respectively. In multivariate analysis, more recent year of recurrence, centre, shorter disease-free interval, and pathological high-grade disease (Gleason 8-10) predicted increased risk of salvage treatment (all P < 0.01). Predictors of specifically receiving radiotherapy were shorter disease-free interval, centre, and more recent year of BCR (all P < 0.001). Predictors of specifically receiving hormonal therapy were shorter disease-free interval, more recent year of BCR, centre, high Gleason score, and higher tumour stage (all P < 0.05). In a subset analysis of men with available prostate-specific antigen doubling time (PSADT) data, shorter PSADT predicted receipt of any salvage treatment as well as radiation and hormonal therapy separately. CONCLUSIONS Among men who recur after RP, salvage treatment was associated with disease severity, centre and year of BCR; patient-specific factors (race, body mass index and age) were not predictive of secondary treatment. Although patients are being treated more aggressively in contemporary years, the affect on long-term survival is unknown. © 2009 BJU International.


Ferraz Arruda P.F.,Urology Section | Spessoto L.C.F.,Urology Section | Godoy M.,Medicine School | Pereira De Godoy J.,Medicine School
Urology Annals | Year: 2011

The case of a rare complication is reported of a 53-year-old patient with giant polycystic kidney (4250 g) that evolved with acute small bowel occlusion. The patient was submitted to surgery which identified that the intestinal occlusion was due to external compression of the intestinal loops. Excision of the mass solved the case.


Secin F.P.,Urology Section | Secin F.P.,Columbia University | Bianco F.J.,Urology Section | Bianco F.J.,Columbia University
Archivos Espanoles de Urologia | Year: 2010

Advances in the understanding of prostate and pelvic anatomy in recent years made a substantial contribution to improve the surgical technique for the treatment of prostate cancer (PC) with the potential preservation of anatomic structures responsible for erectile and urinary function postoperatively. Knowledge of these anatomic structures is key to achieve a complete removal of the prostate and seminal vesicles while preserving the best possible quality of life. The literature on prostate and pelvic anatomy has been reviewed and an updated notion of the surgical anatomy is herein provided.


PubMed | Urology Section
Type: Journal Article | Journal: Urology annals | Year: 2011

The case of a rare complication is reported of a 53-year-old patient with giant polycystic kidney (4250 g) that evolved with acute small bowel occlusion. The patient was submitted to surgery which identified that the intestinal occlusion was due to external compression of the intestinal loops. Excision of the mass solved the case.

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