BACKGROUND AND OBJECTIVE:Management of local prostate cancer (PCa) recurrence after primary radiotherapy (RT) remains challenging in daily practice. Salvage high-intensity focused ultrasound (S-HIFU) represents a valid option, but large prospective data are missing. METHODS:A prospective, nationwide study was conducted in 32 French centers assessing S-HIFU as a local treatment after RT failure in patients with biopsy-confirmed intraprostatic recurrence without regional or distant metastases. The primary endpoint was androgen deprivation therapy-free survival (ADT-FS). Secondary endpoints were PCa-specific survival and overall survival, and functional outcomes. KEY FINDINGS AND LIMITATIONS:From 2015 to 2019, 531 patients were included. Median age and prostate-specific antigen (PSA) at S-HIFU were 75 yr and 4.5 ng/ml, respectively. Median PSA was 0.7 and 1.02 ng/ml at 12 and 30 mo after HIFU, respectively. The 30-mo ADT-FS was 71% in the overall cohort (95% CI, 67-76). A pre-S-HIFU PSA level ≤ 4.5 ng/ml and Gleason score 6-7 had the most favorable ADT- FS rates at 30-mo: 84% (95% CI, 78-91). High-grade (>IIIa) complications graded with the Dindo-Clavien classification were reported in 19/531 patients. The number of cases with severe incontinence increased from 7% to 12% after S-HIFU. The quality-of-life study showed no deterioration in the EORTC QLQC-30 median score at 12 mo. CONCLUSION AND CLINICAL IMPLICATIONS:This large prospective trial demonstrates good oncologic and functional outcomes after S-HIFU for treating local PCa recurrence after RT. The importance of pre-S-HIFU PSA for efficacy prediction highlights the need for earlier detection of recurrence in patients eligible for local salvage treatment. Further studies should focus on comparisons between different salvage local treatment options within high-level evidence trials. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT04307056.

Background and objective: High-intensity focused ultrasound (HIFU) has emerged as an interesting ablative alternative to radical prostatectomy (RP) and radiation therapy (RT) for localized prostate cancer (PC). However, no prospective comparative data have been published for HIFU. Methods: We performed a prospective nonrandomized nationwide trial in 46 centers in France comparing RP versus HIFU. The main inclusion criterion was low-to intermediate-risk PC. The primary endpoint was salvage therapy-free survival (STFS). Secondary endpoints were metastasis-free survival, PC-specific survival, overall survival, and functional outcomes. Key findings and limitations: From 2015 to 2019, 3328 patients were included (1967 HIFU and 1361 RP). Median age was 74.7 versus 65.1 yr (p < 0.001) and median PSA was 7.1 versus 6.9 ng/ml (p = 0.5) in the HIFU and RP groups, respectively. Intermediate-risk PC was diagnosed in 61% of patients in the HIFU group and 64% in the RP group (p = 0.10). The 30-mo STFS was not inferior in the HIFU group (hazard ratio 0.71, 95% confidence interval 0.52-0.97; p = 0.008). Some 10% of patients experienced urinary retention after HIFU. Grade >IIIa complications occurred in 54/1967 cases in the HIFU group and 29/1361 cases in the RP group (p = 0.3). In the HIFU group, fewer patients experienced a deterioration in 12-mo urinary continence (29% vs 44%) and the decrease in median International Index of Erectile Function-5 score was lower (difference 7 vs 13) in comparison to RP. Internal Prostate Symptom Scores and quality-of-life scores were comparable in the two groups. The main limitations are the lack of randomization and the age difference between the groups. Conclusions and clinical implications: This large prospective trial demonstrates that whole-gland or subtotal HIFU provides comparable medium-term STFS outcomes to RP. Urinary continence and erectile function were less impaired after HIFU. These results should be interpreted with caution owing to the lack of randomization and the age difference between the groups. Future research should consider longer follow-up and evaluate focal treatments. (c) 2024 European Association of Urology. Published by Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Abstract In patients with bladder cancer (BC) immune therapies have recently demonstrated an improvement for overall survival rates compared to chemotherapy alone. However, several challenges persist and it remains an unmet need to develop novel therapeutic strategies. Organoids have emerged as a promising animal-free tool revealing patients’ heterogeneity and allowing large preclinical therapeutic screening. Urosphere developed a BC organoids biobank with phenotypic, pharmacological and molecular characterization. The aim of this study was to demonstrate the relevance of our organoids models and their use for validation of therapeutic approaches such as targeted or CAR-T cell therapies using EGFR as target. Molecular characterization of the organoids was performed by exome and whole transcriptome sequencing. Cell architecture and differentiation were assessed by labeling cytokeratins (CK) 5, 17 and 20, and uroplakin 3 (UPK3). Proliferation and tumor status were validated with Ki67 and GATA3, respectively. To evaluate targeted-therapy, organoids were treated with erlotinib for 5 days and cell viability was measured with CellTiter-Glo3D® (CTG) assay. To validate CAR-T cell approach, organoids were co-cultured with anti-EGFR or control anti-CD19 CAR-T cells at 4 effector:target ratios. Cell viability was measured with CTG and Caspase-Glo® 3/7 3D assays. Pro-inflammatory and granzyme B release were analyzed by Luminex® assay. Phenotypically, organoids showed proliferating structures whose tumor status was confirmed by GATA3 expression. Cellular heterogeneity present in original tumors was also found, with differential expression of CKs showing the presence of basal (CK5/CD17) and/or differentiated superficial (CK20/UPK3) cells. Organoids from 2 models with high transcriptomic EGFR expression were selected and protein expression was confirmed by immunofluorescence. For targeted therapy, erlotinib presented significant efficacy in both models with a better activity in the model presenting the highest EGFR expression. After 48h of co-culture with anti-EGFR CAR-T cells, a decrease of cell viability associated with an increase of apoptosis was observed. After 72h of co-culture, an increase in the secretion of pro-inflammatory cytokines (IFN-γ and TNF-α) and granzyme B by anti-EGFR CAR-T cells was also observed. In co-cultures with organoids higher expressing EGFR, CAR-T cells activation appeared higher compared to those co-cultured with organoids lower expressing EGFR. Organoids reproduce characteristics of the tumor from which they are derived, making them a predictive preclinical model. In an EGFR targeting approach, the use of organoids to evaluate both targeted- and CAR-T cell therapies was validated with concordant results. This robust translational model is fully transposable to other therapeutic approaches, whether in a traditional culture model or in a co-culture system. Citation Format: Emilie Decaup, Claire Béraud, Anne Sophie Bajeot, Xavier Gamé, Nicolas Monjotin, Pascal Rischmann, Philippe Lluel, Mathieu Roumiguié. A biobank of bladder cancer organoids as a platform for screening new therapeutic approaches [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4231.

BackgroundMuscle-invasive bladder cancer (MIBC) and upper urinary tract urothelial carcinoma (UTUC) are molecularly heterogeneous. Despite chemotherapies, immunotherapies, or anti-fibroblast growth factor receptor (FGFR) treatments, these tumors are still of a poor outcome. Our objective was to develop a bank of patient-derived xenografts (PDXs) recapitulating the molecular heterogeneity of MIBC and UTUC, to facilitate the preclinical identification of therapies. MethodsFresh tumors were obtained from patients and subcutaneously engrafted into immune-compromised mice. Patient tumors and matched PDXs were compared regarding histopathology, transcriptomic (microarrays), and genomic profiles [targeted Next-Generation Sequencing (NGS)]. Several PDXs were treated with chemotherapy (cisplatin/gemcitabine) or targeted therapies [FGFR and epidermal growth factor (EGFR) inhibitors]. ResultsA total of 31 PDXs were established from 1 non-MIBC, 25 MIBC, and 5 upper urinary tract tumors, including 28 urothelial (UC) and 3 squamous cell carcinomas (SCCs). Integrated genomic and transcriptomic profiling identified the PDXs of three different consensus molecular subtypes [basal/squamous (Ba/Sq), luminal papillary, and luminal unstable] and included FGFR3-mutated PDXs. High histological and genomic concordance was found between matched patient tumor/PDX. Discordance in molecular subtypes, such as a Ba/Sq patient tumor giving rise to a luminal papillary PDX, was observed (n=5) at molecular and histological levels. Ten models were treated with cisplatin-based chemotherapy, and we did not observe any association between subtypes and the response. Of the three Ba/Sq models treated with anti-EGFR therapy, two models were sensitive, and one model, of the sarcomatoid variant, was resistant. The treatment of three FGFR3-mutant PDXs with combined FGFR/EGFR inhibitors was more efficient than anti-FGFR3 treatment alone. ConclusionsWe developed preclinical PDX models that recapitulate the molecular heterogeneity of MIBCs and UTUC, including actionable mutations, which will represent an essential tool in therapy development. The pharmacological characterization of the PDXs suggested that the upper urinary tract and MIBCs, not only UC but also SCC, with similar molecular characteristics could benefit from the same treatments including anti-FGFR for FGFR3-mutated tumors and anti-EGFR for basal ones and showed a benefit for combined FGFR/EGFR inhibition in FGFR3-mutant PDXs, compared to FGFR inhibition alone.

Purpose: Prostate cancer (PCa) is the second most common oncologic disease among men. Radical treatment with curative intent provides good oncological results for PCa survivors, although definitive therapy is associated with significant number of serious side-effects. In modern-era of medicine tissue-sparing techniques, such as focal HIFU, have been proposed for PCa patients in order to provide cancer control equivalent to the standard-of-care procedures while reducing morbidities and complications. The aim of this systematic review was to summarise the available evidence about focal HIFU therapy as a primary treatment for localized PCa. Material and methods: We conducted a comprehensive literature review of focal HIFU therapy in the MEDLINE database (PROSPERO: CRD42021235581). Articles published in the English language between 2010 and 2020 with more than 50 patients were included. Results: Clinically significant in-field recurrence and out-of-field progression were detected to 22% and 29% PCa patients, respectively. Higher ISUP grade group, more positive cores at biopsy and bilateral disease were identified as the main risk factors for disease recurrence. The most common strategy for recurrence management was definitive therapy. Six months after focal HIFU therapy 98% of patients were totally continent and 80% of patients retained sufficient erections for sexual intercourse. The majority of complications presented in the early postoperative period and were classified as low-grade. Conclusions: This review highlights that focal HIFU therapy appears to be a safe procedure, while short-term cancer control rate is encouraging. Though, second line treatment or active surveillance seems to be necessary in a significant number of patients.

INTRODUCTION AND OBJECTIVE:Although HIFU treatment showed promising oncological results in several retrospective studies, large and comparative prospective studies are yet missing. The HiFi study (...

Cellular senescence is a state of cell cycle arrest induced by repetitive cell mitoses or different stresses, which is implicated in various physiological or pathological processes. The beneficial or adverse effects of senescent cells depend on their transitory or persistent state. Transient senescence has major beneficial roles promoting successful post-injury repair and inhibiting malignant transformation. On the other hand, persistent accumulation of senescent cells has been associated with chronic diseases and age-related illnesses like renal/urinary tract disorders. The deleterious effects of persistent senescent cells have been related, in part, to their senescence-associated secretory phenotype (SASP) characterized by the release of a variety of factors responsible for chronic inflammation, extracellular matrix adverse remodeling, and fibrosis. Recently, an increase in senescent cell burden has been reported in renal, prostate, and bladder disorders. In this review, we will summarize the molecular mechanisms of senescence and their implication in renal and urinary tract diseases. We will also discuss the differential impacts of transient versus persistent status of cellular senescence, as well as the therapeutic potential of senescent cell targeting in these diseases.

Abstract Background: Muscle-invasive bladder cancers (MIBCs) constitute a heterogeneous group of tumors with poor outcome. Recently, MIBC molecular subtyping efforts from an international consortium led to the identification of six subtypes, improving prediction of clinical outcomes and treatment responses. FGFR3 alterations (mutations and translocations), observed in 20% of MIBCs, are found mainly in the luminal papillary subtype that respond poorly to chemo- and immunotherapy. Basal tumors represent 35% of MIBCs and were shown to be better responders to chemotherapy. Here, we describe the development and characterization of patient-derived primary MIBC xenografts (PDX) belonging to these main subtypes. Methods: Bladder tumors were obtained from patients at surgery. Tumor fragments were subcutaneously engrafted into immune-compromised mice. Primary tumors and matched PDX tumors at multiple passages were analyzed regarding growth characteristics, histopathology (H&E staining, CK5/6, FOXA1, and GATA3 immunohistochemistry), gene expression (Affymetrix U133 plus 2.0 microarray), and genetic stability (STR profiling). Hotspot oncogenic mutations for FGFR3, PIK3CA, HRAS, KRAS, NRAS, PPARG, and RXRA were also assessed. Additionally, pharmacologic responses to standard-of-care and targeted therapies were characterized. Findings: From 152 MIBC tumors at all stages and grades, 32 PDX models were successfully established (21.1% success rate). This take rate did not seem correlated to any classical tumor characteristics. Importantly, transcriptomic analysis allowed us to identify PDX models belonging to different molecular subtypes, notably the basal-like and luminal papillary subtypes, including PDXs with FGFR3 mutations. All histologic, genetic, and molecular features validated the stability of the PDX models compared to the parental tumors. Histologic analyses correlated with the molecular classification. These models reproduced the response to cisplatin-based therapies observed in the clinic. Basal models, except one harboring a FGFR3 mutation, were sensitive to anti-EGFR therapies but to a lesser extent than to chemotherapy. FGFR3-mutated PDX models, including a basal model, were highly responsive to FGFR3 inhibitors and less responsive to chemotherapy. Conclusion: We have developed and characterized highly relevant preclinical models for MIBCs, including basal and FGFR3-mutated tumors, recapitulating molecular heterogeneity and drug responses as observed in patients with MIBCs. They represent essential tools for developing new, efficient therapies against this deadly disease. Citation Format: Claire Béraud, Hervé Lang, Myriam Lassalle, Véronique Lindner, Aurélie Kamoun, Michel Soulié, Elodie Guillon, Clémentine Krucker, Xavier Gamé, Pascal Rischmann, Aurélien De Reynies, Yves Allory, François Radvanyi, Philippe Lluel, Thierry Massfelder, Isabelle Bernard-Pierrot. Establishment of a panel of patient-derived tumor xenograft models recapitulating molecular heterogeneity and drug response of muscle-invasive bladder tumors [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr A24.

You have accessJournal of UrologyTransplantation & Vascular Surgery: Renal Transplantation & Vascular Surgery II (MP52)1 Apr 2020MP52-14 ROBOT-ASSISTED KIDNEY TRANSPLANTATION IN THE OBESE: UPDATE OF A MONOCENTRIC STUDY WITH 28 PATIENTS Lesourd Marine*, Mathieu Roumiguié, Federico Sallusto, Pascal Rischmann, Michel Soulié, Xavier Gamé, Jean Baptiste Beauval, Nassim Kamar, and Nicolas Doumerc Lesourd Marine*Lesourd Marine* More articles by this author , Mathieu RoumiguiéMathieu Roumiguié More articles by this author , Federico SallustoFederico Sallusto More articles by this author , Pascal RischmannPascal Rischmann More articles by this author , Michel SouliéMichel Soulié More articles by this author , Xavier GaméXavier Gamé More articles by this author , Jean Baptiste BeauvalJean Baptiste Beauval More articles by this author , Nassim KamarNassim Kamar More articles by this author , and Nicolas DoumercNicolas Doumerc More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000914.014AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Kidney transplantation (KT) is the gold standard treatment for patients with end-stage renal disease. The last decade we observed an achievement of Robot-assisted kidney transplantation (RAKT) that allowed available KT to obese patients.We present the updated results of RAKT in obese conditions at 2 years follow-up. METHODS: A prospective, monocentric study started in December 2015 evaluating peri-operative and post-operative results of robot-assisted RT in obese patients. At the beginning of the study, all the patients were concerned by this technique. Since September 2016, only obese and patients with abdominal perimeter > 105cm contraindicated to laparotomy TR have been concerned by this technique. RESULTS: 28 patients were included, 8 women and 20 men with a mean age of 54.05 years (32-75), mean BMI of 32.08 kg/m2 (30-40), an average creatinine pre-transplantation at 533 micromol/L (269 -919), eGFR 10.96 ml/min/1.73m2 (4-24), an average ASA score of 2. The mean operating time was 158 min (110-300) with a mean duration for vascular anastomoses of 31 min (17-43) and average blood loss <150 ml. The warm ischemia time was 44 min (28-55). 1 patient had 2 renal arteries. 3 patients had a vaginal approach. 1 patient had conversion to laparotomy for poor graft position. 7 days after the graft, the creatinemia was 149 micromol/l (105-850). The average length of stay was 6 days (4-8). CONCLUSIONS: Main advantages of this technique seem to be the quality of vascular anastomotis and the fast post-operative recovery. It opens up new opportunities for morbidly obese patients usually contraindicated in renal transplantation. Source of Funding: none © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e777-e778 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Lesourd Marine* More articles by this author Mathieu Roumiguié More articles by this author Federico Sallusto More articles by this author Pascal Rischmann More articles by this author Michel Soulié More articles by this author Xavier Gamé More articles by this author Jean Baptiste Beauval More articles by this author Nassim Kamar More articles by this author Nicolas Doumerc More articles by this author Expand All Advertisement PDF downloadLoading ...

You have accessJournal of UrologyTransplantation & Vascular Surgery: Renal Transplantation & Vascular Surgery III (MP76)1 Apr 2019MP76-12 ROBOT-ASSISTED KIDNEY TRANSPLANTATION IN THE OBESE: RESULT AT 2 YEARS OF THE FIRST FRENCH SERIES Marine Lesourd*, Jean-Baptiste Beauval, Federico Sallusto, Nassim Kamar, Michel Soulié, Xavier Gamé, Pascal Rischmann, Mathieu Roumiguié, and Nicolas Doumerc Marine Lesourd*Marine Lesourd* More articles by this author , Jean-Baptiste BeauvalJean-Baptiste Beauval More articles by this author , Federico SallustoFederico Sallusto More articles by this author , Nassim KamarNassim Kamar More articles by this author , Michel SouliéMichel Soulié More articles by this author , Xavier GaméXavier Gamé More articles by this author , Pascal RischmannPascal Rischmann More articles by this author , Mathieu RoumiguiéMathieu Roumiguié More articles by this author , and Nicolas DoumercNicolas Doumerc More articles by this author View All Author Informationhttps://doi.org/10.1097/01.JU.0000557304.55266.7dAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVES: Kidney transplantation (KT) is the gold standard treatment for patients with end-stage renal disease. Robot-assisted kidney transplantation (RAKT) makes the transplant accessible to patients with a body mass index (BMI) greater than 30. Obese patients are mostly contraindicated for laparotomy. We present the results at 2 years of a prospective, monocentric study in patients with a BMI> 30. METHODS: A prospective, monocentric study started in December 2015 evaluating peri-operative and post-operative results of robot-assisted RT in obese patients. RESULTS: 16 patients were included, 4 women and 12 men with a mean age of 49 years (32-75), mean BMI of 31 kg/m2 (30-40), an average creatinine pre-transplantation at 535 micromol/L (269 -919), eGFR 11 ml/min/1.73m2 (4-24), an average ASA score of 2. The mean operating time was 168 min (110-300) with a mean duration for vascular anastomoses of 33 min (17-43) and average blood loss <150 ml. The warm ischemia time was 44 min (28-55). 1 patient had 2 renal arteries. During the surgery, a doppler and an arteriography were performed due to poor graft staining. 1 patient had conversion to laparotomy for poor graft position. 7 days after the graft, the creatinemia was 264 micromol/l (105-850). The average length of stay was 6 days (4-8). CONCLUSIONS: This is the first French series on RAKT in obese patients. This assisted robotic approach is reproductible and safe and opens up new opportunities for morbidly obese patients usually contraindicated in renal transplantation. Source of Funding: none Toulouse, France© 2019 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 201Issue Supplement 4April 2019Page: e1127-e1127 Advertisement Copyright & Permissions© 2019 by American Urological Association Education and Research, Inc.MetricsAuthor Information Marine Lesourd* More articles by this author Jean-Baptiste Beauval More articles by this author Federico Sallusto More articles by this author Nassim Kamar More articles by this author Michel Soulié More articles by this author Xavier Gamé More articles by this author Pascal Rischmann More articles by this author Mathieu Roumiguié More articles by this author Nicolas Doumerc More articles by this author Expand All Advertisement PDF downloadLoading ...

Purpose: The main objective of this multicentric retrospective pilot study was to evaluate the 1-year follow-up safety (i.e., minor [Clavien-Dindo I-II] and major [Clavien-Dindo >= III] complications) of holmium laser enucleation of the prostate (HoLEP), GreenLight photoselective vaporization of the prostate (GL PVP), and transurethral resection of the prostate (TURP) performed after kidney transplantation (KT). The secondary objectives were to evaluate the efficacy and to assess the impact of these procedures on graft function. Materials and Methods: We retrospectively included all KT recipients who underwent a HoLEP or GL PVP or TURP for benign prostatic hyperplasia (BPH) in three French university centers. Results: From January 2013 to April 2018, 60 BPH endoscopic surgical procedures in KT recipients were performed: 17 HoLEP (HoLEP group), 9 GL PVP (GL PVP group), and 34 TURP (TURP group). Age, body mass index, preoperative serum creatinine, preoperative International Prostatic Symptom Score, preoperative Q(max), preoperative prostate-specific antigen, medical history of acute urinary retention (AUR), urinary tract infection (UTI), and indwelling urethral catheter were similar in all study groups. Mean preoperative prostate volume was higher in HoLEP group. The rate of overall postoperative complications was statistically higher in the HoLEP group (11/17 [64.7%] vs 1/9 [11.1%] vs 12/34 [35.3%] in HoLEP group, GL PVP group, and TURP group, respectively, p = 0.02), with higher rate of long-term UTI and AUR. Q(max) improved in all groups after operation. Delta postoperative month 12-preoperative serum creatinine was similar in the all groups. Conclusions: Although our study is underpowered, the rate of postoperative complications is higher with HoLEP procedure, in comparison with GL PVP, for the treatment of BPH after KT. One-year efficacy is similar in HoLEP, GL PVP, and TURP groups. Further prospective randomized controlled trials are needed to confirm our results.

Abstract Muscle-invasive bladder cancers (MIBCs) constitute a heterogeneous group of tumors with a poor outcome. Recently, MIBC molecular subtyping efforts from an international consortium led to the identification of six subtypes to improve prediction of clinical outcomes and treatment responses. These subtypes can be schematically divided into luminal (differentiated) and non-luminal subtypes. FGFR3 alterations (mutations and translocations) are among the most frequent genetic events in bladder carcinoma and are found mainly in one subtype, the luminal papillary that respond poorly to chemo- and immuno-therapy. Here we describe the development and characterization of patient-derived primary MIBC xenografts (PDX) belonging to these different subtypes. Bladder primary tumors and normal corresponding tissues were directly obtained from patients at surgery. Tumor fragments were subcutaneously xenografted into immune-compromised mice. After the first growth in mice, they were serially passaged. PDXs tumors at multiple passages and patients’ primary tumors from which they are derived were processed for analyses including growth characteristics, histopathology (H&E, CK5/6, FOXA1 and GATA3), gene expression (Affymetrix U133 plus 2.0 microarray), genetic stability (STR profiling). Specifically, hotspot oncogenic mutations including FGFR3, PIK3CA, HRAS, KRAS, NRAS, and PPARG were also explored. Additionally, pharmacological responses to standards of care and targeted therapies were characterized. Since 10 years, we have collected 152 MIBC tumors at all stages and grades. Up to now, 32 PDX models have been successfully established (> P3 in mice), i.e. 21.1 % success rate. This take rate seems not to be correlated to any classical tumor characteristics. Importantly, transcriptomic analysis allowed us to identify PDX models belonging to the different molecular subtypes including the basal-like and the luminal papillary subtypes (which include several PDX with FGFR3 mutations). All histological, genetic and molecular features validated the stability of the PDX models compared to the parental tumors. Histological analyses were correlated with the molecular classification. These models reproduced the response to cisplatin-based therapies observed in the clinic and FGFR3-mutated PDX models were shown to be highly responder to FGFR3 inhibitors. We have developed highly relevant preclinical models for MIBCs corresponding to the main subtypes which have been described. They represent essential tools for developing adapted and efficient therapies against this deadly disease. Citation Format: Hervé Lang, Claire Beraud, Myriam Lassalle, Véronique Lindner, Michel Soulié, Xavier Gamé, Pascal Rischmann, Yves Allory, François Radvanyi, Isabelle Bernard-Pierrot, Philippe Lluel, Thierry Massfelder. High specific characterization of patient-derived tumor xenograft models for accelerating drug development in muscle-invasive bladder cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1930.

Background With growing interest in focal therapy (FT) of prostate cancer (PCa) there is an increasing armamentarium of treatment modalities including high-intensity focused ultrasound (HIFU), cryotherapy, focal laser ablation (FLA), irreversible electroporation (IRE), vascular targeted photodynamic therapy (VTP), focal brachytherapy (FBT) and stereotactic ablative radiotherapy (SABR). Currently there are no clear recommendations as to which of these technologies are appropriate for individual patient characteristics. Our intention was to review the literature for special aspects of the different technologies that might be of advantage depending on individual patient and tumour characteristics. Methods The current literature on FT was screened for the following factors: morbidity, repeatability, tumour risk category, tumour location, tumour size and prostate volume and anatomical issues. The ESUT expert panel arrived at consensus regarding a position statement on a structured pathway for available FT technologies based on a combination of the literature and expert opinion. Results Side effects were low across different studies and FT modalities with urinary continence rates of 90-100% and erectile dysfunction between 5 and 52%. Short to medium cancer control based on post-treatment biopsies were variable between ablative modalities. Expert consensus suggested that posterior lesions are better amenable to FT using HIFU. Cryotherapy provides best possible outcomes for anterior tumours. Apical lesions, when treated with FBT, may yield the least urethral morbidity. Conclusions Further prospective trials are required to assess medium to long term disease control of different ablative modalities for FT. Amongst different available FT modalities our ESUT expert consensus suggests that some may be better for diffe`rent tumour locations. Tumour risk, tumour size, tumour location, and prostate volume are all important factors to consider and might aid in designing future FT trials.

BACKGROUND:Focal therapy for prostate cancer (PCa) remains experimental. Aim of the current study is to review available evidence and perform a pooled analysis exploring oncologic and functional results of high intensity focus ultrasound (HIFU) focal therapy for the treatment of unilateral PCa.METHODS:The National Library of Medicine Database was searched for relevant articles. A wide search was performed, including the combination of following words: "HIFU," "prostate," "cancer," and "focal." Overall, 167 articles were reviewed. Of these, seven articles were identified and eligible for the pooled analysis. Data on HIFU hemiablation or focal prostate ablation, oncologic and functional results were pooled from these seven studies that included 366 men with unilateral PCa.RESULTS:In the 366 analyzed cases, mean age was 67 years (95% confidence interval 66-69), and mean preoperative prostate-specific antigen was 6.4 ng/cc (5.5-7.4). Three studies included PCa up to Gleason 7 (3 + 4), three studies did include also Gleason 7 (4 + 3), whereas one study had no limitation in terms of Gleason score. Regarding early complications, low-grade Clavien-Dindo I-II were reported in 26% (16-37), whereas high-grade Clavien-Dindo ≥III were found in 3.8% (0-8.6). Analyzing oncologic outcomes mean follow-up was 26 months (23-31): at one year after HIFU, negative biopsy rate for clinically significant PCa was 87% (79-96), whereas salvage treatment-free survival rate was 92% (85-98). Regarding functional outcomes, reported potency rates were 74% (64-84), and continence 96% (91-100), although definitions of potency and continence were not homogenous across studies.CONCLUSIONS:This pooled analysis of the results of focal HIFU treatment of PCa shows promising oncologic and functional outcomes. Well-selected patients may be candidates for such a conservative partial treatment of the gland. Well-designed trials are awaited to compare HIFU focal treatment with current standard of care.

Abstract Kidney, prostate and bladder cancers (KCa, PCa and BCa, respectively) represent 1 700 000 cases and 450 000 deaths worldwide per year, with an incidence rising yearly by 1-10%. Surgery is usually curative at early and localized stages but there are no efficient therapies at advanced and metastatic stages for any of them. Although genetically-modified and/or chemically-induced avatar models do exist for these cancers and may help to identify new therapeutic targets, they suffer from a lack of an extended biological concordance with the natural history and heterogeneity of the diseases. Patient-derived tumor xenograft models are now well recognized as reliably reproducing tumor heterogeneity and have become over the past few years the preclinical tools of choice to test drugs and identify biomarkers. Since 10 years, we are continuously developing a unique panel of PDX models for these major urological cancers. Tumor tissues along with normal corresponding tissues were obtained from patients at surgery. Patient informed consent and clinical history are available for all patients. Tumor tissues pieces were xenografted subcutaneously in the interscapular space of nude mice, and serially passaged into mice after the first engraftment, up to passage 10. To ensure model stability between primary tumors and tumors growing in mice but also from passage to passage, we performed various analyses at histopathological, genetic (short tandem repeat fingerprinting) and molecular (cDNA profiling) levels. In addition, growth characteristics and responses to standards of care (SOCs) were examined. Finally, specific molecular characteristics were also explored including expression of the androgen receptor, PSA and pan-cytokeratin for PCa models and hotspot mutations of FGFR3, PIK3CA, K/N/H-RAS for BCa models. Up to now, we have xenografted 336 (on 569 samples), 247 and 152 KCa, PCa and BCa tumor tissues, and developed 30 (8.9% success rate), 6 (2.1%) and 30 (19.7%) PDX models, respectively. We recently published part of the KCa PDX models collection (Lang et al., Oncotarget, 2016). Characterization studies showed that PDX models are stable at all levels analyzed considering concordance to primary tumors and from passage to passage; and less than 5% of genes were differentially expressed between the primary tumors and PDX tumors at various passages. Responses to SOCs recapitulated the clinical state. Only for KCa PDX models, the take rate was correlated to tumor stage and grade, and sarcomatoid components. Importantly, several molecular subtypes were defined in our collection of BCa PDX models including PDXs with FGFR3 mutations and PDXs of basal subtype, the most aggressive one. Overall, this panel of PDX models for urological cancers should definitely help to find molecularly guided targeted therapies for these still incurable cancers at metastatic stages. Citation Format: Hervé Lang, Claire Béraud, Myriam Lassalle, Isabelle Bernard-Pierrot, Véronique Lindner, Yves Allory, Michel Soulié, Xavier Gamé, Pascal Rischmann, Eric Potiron, François Radvanyi, Philippe Lluel, Thierry Massfelder. A comprehensive patient-derived tumor xenograft (PDX) collection representing the heterogeneity of kidney, prostate and bladder cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1035.

Varicocele is a condition characterized by dilated, tortuous veins within the pampiniform venous plexus of the scrotal sac. Presence of varicocele is associated with an increased risk of alteration of semen parameters. The objective of this study was to compare the current standard in varicocele treatment procedures: sub-inguinal microscopic ligation to percutaneous embolization in terms of semen parameters improvement, fertility, and morbidity at the university hospital of Toulouse (France). Seventy six patients with clinical varicocele, alteration of semen parameters and infertility, underwent either procedure (microsurgery in 49 case performed by a single surgeon and embolization in 27 cases) and were prospectively analyzed. Outcome measures were: semen parameters, spontaneous pregnancies, pain, side effects, recovery time and overall satisfaction. All patients were contacted in January 2015 in order to determine reproductive events.