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International audience; BACKGROUND:Fibroblast growth factor receptor 3 (FGFR3) is an actionable target in bladder cancer. Preclinical studies show that anti-FGFR3 treatment slows down tumor growth, suggesting that this tyrosine kinase receptor is a candidate for personalized bladder cancer treatment, particularly in patients with mutated FGFR3. We addressed tumor heterogeneity in a large multicenter, multi-laboratory study, as this may have significant impact on therapeutic response.PATIENTS AND METHODS:We evaluated possible FGFR3 heterogeneity by the PCR-SNaPshot method in the superficial and deep compartments of tumors obtained by transurethral resection (TUR, n = 61) and in radical cystectomy (RC, n = 614) specimens and corresponding cancer-positive lymph nodes (LN+, n = 201).RESULTS:We found FGFR3 mutations in 13/34 (38%) T1 and 8/27 (30%) ≥T2-TUR samples, with 100% concordance between superficial and deeper parts in T1-TUR samples. Of eight FGFR3 mutant ≥T2-TUR samples, only 4 (50%) displayed the mutation in the deeper part. We found 67/614 (11%) FGFR3 mutations in RC specimens. FGFR3 mutation was associated with pN0 (P < 0.001) at RC. In 10/201 (5%) LN+, an FGFR3 mutation was found, all concordant with the corresponding RC specimen. In the remaining 191 cases, RC and LN+ were both wild type.CONCLUSIONS:FGFR3 mutation status seems promising to guide decision-making on adjuvant anti-FGFR3 therapy as it appeared homogeneous in RC and LN+. Based on the results of TUR, the deep part of the tumor needs to be assessed if neoadjuvant anti-FGFR3 treatment is considered. We conclude that studies on the heterogeneity of actionable molecular targets should precede clinical trials with these drugs in the perioperative setting.

Purpose: Abnormally high levels of epidermal growth factor receptor (EGFR) protein are associated with advanced tumor stage/grade. The objective of this study was to evaluate the effects of the specific EGFR tyrosine kinase inhibitor gefitinib on activation of the Akt and mitogen-activated protein kinase (MAPK) pathways in human urothelial cell carcinoma (UCC) cell lines and to identify potential markers of gefitinib responsiveness in biopsy samples of UCC. Experimental Design: Changes in markers of UCC growth and invasion after exposure to gefitinib were studied in six human UCC cell lines expressing various levels of EGFR. The findings were related to activation of Akt and MAPK. We studied the influence of gefitinib on intraepithelial expansion of the responsive 1207 cell line. EGFR, Akt, and MAPK activation was studied by Western blot analysis of a panel of 57 human UCC. Results: Gefitinib had a growth-inhibitory and anti-invasive effect in two of six UCC cell lines (i.e., 647V and 1207). Gefitinib was also able to block the expansion of 1207 at the expense of normal urothelial cells. These effects did not depend on the level of expression of EGFR but they were associated with the down-regulation of MAPK and Akt activity; in 1207 cells, gefitinib activity was associated with p27 up-regulation and p21 and matrix metalloproteinase-9 down-regulation. Similarly, the Akt and MAPK pathways were found to be strongly phosphorylated in association with EGFR activation in a subset of human UCC specimens. Conclusions: Activation of EGFR, Akt, and MAPK defines a subset of UCC which might provide information for the identification of gefitinib responders.

// Prashant Kumar 1,* , Sayantani Nandi 1,* , Tuan Zea Tan 2,* , Siok Ghee Ler 3 , Kee Seng Chia 4 , Wei-Yen Lim 5 , Zentia Butow 6 , Dimitrios Vordos 6 , Alexandre De laTaille 6 , Muthafar Al-Haddawi 1 , Manfred Raida 7 , Burkhard Beyer 8 , Estelle Ricci 9 , Marc Colombel 9 , Tsung Wen Chong 10 , Edmund Chiong 11 , Ross Soo 12 , Mi Kyoung Park 13 , Hong Koo Ha 14,** , Jayantha Gunaratne 3,4,** and Jean Paul Thiery 1,2,7,** 1 Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore 2 Cancer Science Institute, National University of Singapore, Singapore 3 Quantitative Proteomics Group, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 4 Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 5 Saw Swee Hock School of Public Health, National University of Singapore, Singapore 6 CHU Hopital Henri Mondor, Department of Urology, Creteil, France 7 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 8 Department of Urology, Section for Translational Prostate Cancer Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 9 Service d’Urologie et Chirurgie de la Transplantation, Hopital Edouard Herriot, Lyon, France 10 Department of Urology, Singapore General Hospital, Singapore 11 Department of Urology, University Surgical Cluster, National University Health System (NUHS), Singapore 12 Haematology-Oncology Research Group, Department of Haematology-Oncology, National University Cancer Institute (NCIS), National University Hospital, Singapore 13 Institute of Microelectronics (IME), A*STAR, Singapore 14 Department of Urology, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea * These authors are co-first authors ** These authors are co-senior authors Correspondence to: Jean Paul Thiery, email: // Keywords : transitional bladder carcinoma, urine biomarkers, receiving operating characteristics, combination model Received : December 08, 2014 Accepted : March 19, 2015 Published : April 15, 2015 Abstract Transitional bladder carcinoma (BCa) is prevalent in developed countries, particularly among men. Given that these tumors frequently recur or progress, the early detection and subsequent monitoring of BCa at different stages is critical. Current BCa diagnostic biomarkers are not sufficiently sensitive for substituting or complementing invasive cystoscopy. Here, we sought to identify a robust set of urine biomarkers for BCa detection. Using a high-resolution, mass spectrometry-based, quantitative proteomics approach, we measured, compared and validated protein variations in 451 voided urine samples from healthy subjects, non-bladder cancer patients and patients with non-invasive and invasive BCa. We identified five robust biomarkers: Coronin-1A, Apolipoprotein A4, Semenogelin-2, Gamma synuclein and DJ-1/PARK7. In diagnosing Ta/T1 BCa, these biomarkers achieved an AUC of 0.92 and 0.98, respectively, using ELISA and western blot data (sensitivity, 79.2% and 93.9%; specificity, 100% and 96.7%, respectively). In diagnosing T2/T3 BCa, an AUC of 0.94 and 1.0 was attained (sensitivity, 86.4% and 100%; specificity, 100%) using the same methods. Thus, our multiplex biomarker panel offers unprecedented accuracy for the diagnosis of BCa patients and provides the prospect for a non-invasive way to detect bladder cancer.

Therapeutic strategy remains unclear with no clear consensus for men with high-risk prostate cancer after radical prostatectomy. We aimed to evaluate into a prospective randomized trial the effectiveness and the feasibility of adjuvant weekly paclitaxel combined with androgen deprivation therapy (ADT) in these patients. 47 patients with high risk prostate cancer were randomized 6 weeks after radical prostatectomy: ADT alone versus combination of ADT and weekly paclitaxel. Toxicity, quality-of-life and functional results were compared between the two arms. All 23 patients completed 8 cycles of paclitaxel. Toxicity was predominantly of grade 1–2 severity. There were no differences in EORTC QLQ-C30 scores between the two groups and between baseline and last assessment at 24 months after surgery. Urinary continence was complete at one year after surgery for all patients and no significant differences was noted at each assessment between the two groups. The interim analysis of this trial confirms the feasibility of weekly paclitaxel in combination with androgen deprivation therapy in men at high risk prostate cancer with curative intent. This adjuvant combined therapy does no alter quality-of-life and continence recovery after surgery plus ADT. A larger cohort is awaited to determine the oncological outcomes of this strategy.

The aim of the study was to evaluate factors of progression after radical prostatectomy in patients with bladder neck invasion (BNI). From 1988 to 2006, 1395 patients underwent radical prostatectomy, 120 (8.6%) had microscopic BNI (pT4 N0, TNM 2002). Group 1 was defined as BNI alone, group 2 as BNI plus extracapsular extension and group 3 as BNI plus seminal vesicle invasion (SVI). Postoperative follow-up data were obtained through routine serum prostate-specific antigen (PSA) and digital rectal examination. Biochemical progression was defined as a single detectable PSA level postoperatively (>0.2 ng ml(-1)). Groups 1, 2 and 3 included 38 (31%), 35 (30%) and 47 (39%) patients, respectively. Preoperative PSA (11.1 vs 24.7 and 23.3 ng ml(-1), P=0.01), biopsy Gleason score (5 vs 6 and 6, P=0.003) and specimen Gleason score (6 vs 7 and 7, P=0.02) were statistically different between three groups. None of the patients had a specimen Gleason score >or=8 in group 1. After a mean follow-up of 27 months, 51 (42.5%) patients had biochemical progression. The 5-year progression-free survival was 87, 53 and 17% for groups 1, 2 and 3, respectively (P

The objective of this work was to evaluate the oncological outcomes and complications of prostate cancer patients with prostate specific antigen (PSA)10 ng/ml after radical prostatectomy by retropubic, perineal and laparoscopic approach. From 1988 to 2001, 306 patients with PSA10 ng/ml underwent radical prostatectomy by the retropubic, perineal or laparoscopic approach. Mean operative time, complication rates, length of hospital stay, catheterization time and pathological results were reviewed. Kaplan-Meier analysis was used to evaluate the likelihood of biochemical PSA recurrence. There were no statistical differences between the three groups in terms of preoperative characteristics except for PSA levels (5.5, 6.5 and 6.6 ng/ml for the retropubic, perineal, and laparoscopic approach, respectively, P0.05) and for the T1c stage prevalence (50%, 43.1% and 68.4%, P0.05). Operating time was significatively longer in the laparoscopic approach (266 min), whereas transfusion rate (22.1%), bladder catetherization (12.1 days), and length of hospital stay (12.1 days) were higher in the retropubic group (P0.05). The percentage of medical and surgical complications were 6.9%, 3.1% and 3.4% (P0.05) and 18.6%, 16.9% and 11.6% (P0.05) for the retropubic, perineal, and laparoscopic approach, respectively. Pathological staging revealed pT2 in 76.7%, 78.4% and 81.3% for retropubic, perineal and laparoscopic approach, respectively (P0.05). Positive surgical positive margins were noted in 20.9%, 18.4% and 20.6% (P0.05). The actuarial 3-year recurrence-free survival rate was 89.3%, 89.2% and 86.2% (P0.05) for retropubic, perineal and laparoscopic approach, respectively. It can be concluded that in patients with preoperative PSA10 ng/ml, clinical outcome and complication rates were similar, regardless of the choice of surgical approach.