[Pathology findings after radical prostatectomy for prostate cancer in patients eligible for active surveillance: Contribution of multiparametric MRI to treatment decision]. / Résultats anatomopathologiques après prostatectomie totale pour cancer chez des patients éligibles à une surveillance active : apport de l'IRM multiparamétrique dans la décision de traitement.

OBJECTIVES: To analyze, in patients with prostate cancer (PC) potentially eligible for active surveillance (AS), whether multiparametric-MRI (mp-MRI) predicts presence of clinically significant cancer on radical prostatectomy (RP) specimen. METHODS: We identified 77 men with PC eligible for AS (PSA≤15ng/mL, stage≤T2a, Gleason score≤6, up to 3 positive cores, maximal cancer core length≤5mm) who underwent RP between 01/2008 and 08/2015. All patients had prebiopsy mp-MRI followed by systematic±targeted biopsies. For each patient, the likelihood of the presence of cancer on mp-MRI was assigned using Likert scale (1 to 5). The predictive factors for the presence of significant cancer on RP specimen (Gleason score≥7 and/or tumoral maximal diameter>10mm) were evaluated using logistic regression. RESULTS: Median age was 61 and median PSA was 6.7ng/mL. Overall, 49 (64%) patients had a positive mp-MRI (score≥3). Clinically significant cancer on RP specimen was found in 45 (58%) patients (69% in MRI-positive patients vs 39% in MRI-negative patients). In multivariate analysis, a positive MRI was a predictive factor for the presence of significant cancer on the surgical specimen (OR=3.0; CI95% [1.01-8.88]; P=0.04), as was age (OR=1.17; CI95% [1.05-1.31]; P=0.004) and PSAD (OR=1.10; CI95% [1.01-1.20]; P=0.02). CONCLUSION: Mp-MRI is a useful exam for selecting patients eligible for AS even if the situation remains unclear after prostate biopsies including targeted biopsies. Upon confirmation by further studies, mp-MRI should be considered as an independent criterion before entering an AS program. LEVEL OF EVIDENCE: 4.

Overall survival and oncological outcomes after partial nephrectomy and radical nephrectomy for cT2a renal tumors: A collaborative international study from the French kidney cancer research network UroCCR.

BACKGROUND: Partial nephrectomy (PN) is recommended as first-line treatment for cT1 stage kidney tumors because of a better renal function and probably a better overall survival than radical nephrectomy (RN). For larger tumors, PN has a controversial position due to lack of evidence showing good cancer control. The aim of this study was to compare the results of PN and RN in cT2a stage on overall survival and oncological results. METHOD: A retrospective international multicenter study was conducted in the frame of the French kidney cancer research network (UroCCR). We considered all patients aged≥18 years who underwent surgical treatment for localized renal cell carcinoma (RCC) stage cT2a (7.1-10cm) between 2000 and 2014. Cox and Fine-Gray models were performed to analyze overall survival (OS), cancer specific survival (CSS) and cancer-free survival (CFS). Comparison between PN and RN was realized after an adjustment by propensity score considering predefined confounding factors: age, sex, tumor size, pT stage of the TNM classification, histological type, ISUP grade, ASA score. RESULTS: A total of 267 patients were included. OS at 3 and 5 years was 93.6% and 78.7% after PN and 88.0% and 76.2% after RN, respectively. CSS at 3 and 5 years was 95.4% and 80.2% after PN and 91.0% and 85.0% after RN. No significant difference between groups was found after propensity score adjustment for OS (HR 0.87, 95% CI: 0.37-2.05, P=0.75), CSS (HR 0.52, 95% CI: 0.18-1.54, P=0.24) and CFS (HR 1.02, 95% CI: 0.50-2.09, P=0.96). CONCLUSION: PN seems equivalent to RN for OS, CSS and CFS in cT2a stage kidney tumors. The risk of recurrence is probably more related to prognostic factors than the surgical technique. The decision to perform a PN should depend on technical feasibility rather than tumor size, both to imperative and elective situation. LEVEL OF EVIDENCE: 4.

[Salvage radical prostatectomy for recurrent prostate cancer. Morbidity, oncological and functional results]. / Prostatectomie totale de rattrapage après échec de traitement local pour cancer de prostate : morbidité, résultats oncologiques et fonctionnels.

INTRODUCTION: Salvage radical prostatectomy (sRP) for radiorecurrent prostate cancer (PCa) is a challenging procedure. To report our experience with sRP for selected patients with local recurrence after primary treatment for localised PCa. METHODS: From 2005 to 2015, 24 patients underwent sRP for recurrent PCa in our center and were included in this retrospective study. Local recurrence was suspected by PSA increase>nadir+2ng/mL and was confirmed by biopsy. Perioperative complications according to Clavien-Dindo classification, oncological and functional results were analysed. RESULTS: Overall, 24 patients with a median age of 59 years (IQR: 55-60) were included. Median follow-up was 25 months (IQR: 9-26). Procedures were performed with open-retropubic approach in 50 % and robot-assisted laparoscopic approach in 50 %. Overall, 5 (21 %) and 2 (8 %) patients experienced grade≤IIIa and grade≥IIIb postoperative complication, respectively. Surgical margins were positive in 46 % of cases. Three out of 4 patients with postoperatively detectable PSA (>0.2ng/mL) had positive surgical margins. Seven patients experienced biochemical recurrence in a median delay of 19 months (9-62). Seventy-one percent (5) of these patients experienced clinical recurrence in a median delay of 24 months (10-113). Severe urinary incontinence (≥3 pads/day) and erectile dysfunction were reported in 25 % and 63 %, respectively. CONCLUSION: sRP for patients is a feasible procedure with encouraging local control rate and acceptable morbidity. This technique should be discussed as a treatment option for locally recurrent PCa in well-selected patients. LEVEL OF EVIDENCE: 4.

Guidelines for the definition of time-to-event end points in renal cell cancer clinical trials: results of the DATECAN project†.

BACKGROUND: In clinical trials, the use of intermediate time-to-event end points (TEEs) is increasingly common, yet their choice and definitions are not standardized. This limits the usefulness for comparing treatment effects between studies. The aim of the DATECAN Kidney project is to clarify and recommend definitions of TEE in renal cell cancer (RCC) through a formal consensus method for end point definitions. MATERIALS AND METHODS: A formal modified Delphi method was used for establishing consensus. From a 2006-2009 literature review, the Steering Committee (SC) selected 9 TEE and 15 events in the nonmetastatic (NM) and metastatic/advanced (MA) RCC disease settings. Events were scored on the range of 1 (totally disagree to include) to 9 (totally agree to include) in the definition of each end point. Rating Committee (RC) experts were contacted for the scoring rounds. From these results, final recommendations were established for selecting pertinent end points and the associated events. RESULTS: Thirty-four experts scored 121 events for 9 end points. Consensus was reached for 31%, 43% and 85% events during the first, second and third rounds, respectively. The expert recommend the use of three and two endpoints in NM and MA setting, respectively. In the NM setting: disease-free survival (contralateral RCC, appearance of metastases, local or regional recurrence, death from RCC or protocol treatment), metastasis-free survival (appearance of metastases, regional recurrence, death from RCC); and local-regional-free survival (local or regional recurrence, death from RCC). In the MA setting: kidney cancer-specific survival (death from RCC or protocol treatment) and progression-free survival (death from RCC, local, regional, or metastatic progression). CONCLUSIONS: The consensus method revealed that intermediate end points have not been well defined, because all of the selected end points had at least one event definition for which no consensus was obtained. These clarified definitions of TEE should become standard practice in all RCC clinical trials, thus facilitating reporting and increasing precision in between trial comparisons.

[Long term biochemical recurrence free survival after radical prostatectomy for cancer: comparative analysis according to surgical approach and clinicopathological stage]. / Survie sans récidive biologique à long terme après prostatectomie totale pour cancer: analyse comparative selon la voie d'abord et le stade clinico-pathologique.

OBJECTIVE: To assess long term biochemical recurrence free survival after radical prostatectomy according to open, laparoscopic and robot-assisted surgical approach and clinicopathological stage. MATERIAL AND METHODS: A cohort study of 1313 consecutive patients treated by radical prostatectomy for localized or locally advanced prostate cancer between 2000 and 2013. Open surgery (63.7%), laparoscopy (10%) and robot-assisted laparoscopy (26.4%) were performed. Biochemical recurrence was defined by PSA>0,1ng/mL. The biochemical recurrence free survival was described by Kaplan Meier method and prognostic factors were analysed by multivariable Cox regression. RESULTS: Median follow-up was 57 months (IQR: 31-90). Ten years biochemical recurrence free survival was 88.5%, 71.6% and 53.5% respectively for low, intermediate and high-risk D'Amico groups. On multivariable analysis, the worse prognostic factor was Gleason score (P<0.001). Positive surgical margins rate was 53% in pT3 tumours and 24% in pT2 tumours (P<0.001). Biochemical recurrence free survival (P=0.06) and positive surgical margins rate (P=0.87) were not statistically different between the three surgical approaches. CONCLUSION: Biochemical recurrence free survival in our study does not differ according to surgical approach and is similar to published series. Ten years biochemical recurrence free survival for high-risk tumours without hormone therapy is 54% justifying the role of surgery in the therapeutic conversations in this group of tumours. LEVEL OF EVIDENCE: 3.

[Family refusal of organ donation: a retrospective study in a French organ procurement center]. / Opposition des familles aux dons d'organes: analyse rétrospective des causes de refus dans un centre régional de prélèvement.

OBJECTIVES: In France, organ donation refusal rates approach 32% of eligible brain deaths. Outright family refusal represents the primary barrier reason for declining organ donation. This retrospective study evaluated factors influencing this decision. MATERIAL AND METHODS: A retrospective chart review at Lille Hospital, France, was conducted on brain-death patients eligible for organ donation between 2010 and 2011. Data were collected regarding patient characteristics, death conditions and reasons for refusal based upon family interview. Descriptive statistic analyses were conducted to identify circumstances associated with family refusal. RESULTS: Of 227 eligible organ donors identified, 70 families (30.8%) refused organ donation. The most frequent reason for refusal was desire to keep the body's wholeness (46.3%), followed by religion (16.4%), mistrust of the medical community (13.4%), and revolt against society (6%). The most common causes of death associated with refusal were brutality and suddenness of death (44.8%), early age (23.9%), denial of death (17.9%), and the family culpability (11.9%). In 30% of cases, the family followed the deceased's wishes before his death. CONCLUSION: Family refusal remains a significant factor associated with the approximately one third of declined eligible organ donations. This retrospective analysis suggested that the most important cause for refusal was a desire to keep the body's wholeness, and the brutality and suddenness of the potential donor's death. Additional research addressing these factors, and their underlying causes, paired with measures to improve professional training and public awareness are warranted to improve organ donation rates.

[Choice of new drugs in castration-resistant prostate cancer: predictive factors and effectiveness assessment]. / Choix des nouveaux traitements médicaux dans le cancer de la prostate résistant à la castration: marqueurs prédictifs et évaluation de l'efficacité.

INTRODUCTION: Docetaxel has been the cornerstone in the treatment of castration- resistant prostate cancer (CRPC) since 2004. The recent and almost simultaneous arrival of new and effective molecules - several of which are already available on the market - has added to the CRPC treatment arsenal. Several studies have explored the optimal order in which these new treatments should be administered. The aim of this review was to present their respective predictive and evaluative factors and suggest potential administration sequences. METHODS: The PubMed medical literature citations database was searched using the following key words: prostate cancer, castration resistant, metastatic, targeted therapy, treatment sequence, immunotherapy and clinical trials. The reports of the most recent European and North American congresses were also included. RESULTS: While no predictive factors have been clearly identified for these new therapies to date, a Gleason score of not less than 8 and one or more chemotherapy sessions seemed to be predictive of lower efficacy for abiraterone. Promising elements for further investigation include the circulating tumour cell count and variation in this count per treatment, ERG mutation status or the intratumoural androgen status. Substitution criteria have not yet been reported but, as is the case with all hormone therapies, changes in PSA levels emerge as a valuable indicator of the efficacy of abiraterone. The best treatment sequence for patients who develop castration-resistance remains to be defined. CONCLUSION: Although new molecules have recently become available, the experience with their use is limited. Thus, no predictive markers of response rates and treatment outcomes or data concerning the best treatment sequence to use in patients with CRPC are as yet available.

[Prostate cancer and new hormonal treatments: mechanism of action and main clinical results]. / Cancer de la prostate et nouveaux traitements hormonaux: mécanismes d'action et principaux résultats cliniques.

INTRODUCTION: New drugs have recently been developed, through a better understanding of the mechanisms involved in the progression of prostate cancer, including castration-resistant ones (CRPC). This article aims to describe the mechanisms of action of these new hormonal treatments and their major clinical outcomes and development programs. MATERIALS AND METHODS: A bibliographic research in French and English using Medline(®) and Embase(®) using the keywords "castration-resistant prostate cancer", "abiraterone acetate", "orteronel", "enzalutamide", and "clinical trials" was performed. RESULTS: the androgen signaling pathway remains the cornerstone of advanced cancers management. Hence, some molecules target the androgen biosynthesis, as abiraterone acetate and orteronel, which are selective inhibitors of the enzyme CYP17. Others act as antagonists of the androgen receptor: the enzalutamide, RNA-509 and ODM201. Finally, galeterone combines the two effects. CONCLUSION: Progress conferred by these molecules in terms of overall survival and quality of life in patients with metastatic CRPC, suggest that their use at earlier stages of the disease could reduce morbidity and mortality from prostate cancer. Determining the best strategy for sequence or combination therapy to optimize the use of these new molecules should be investigated.

Psychometric properties of the psychosocial impact of assistive devices scale (PIADS): A systematic review.

The Psychosocial Impact of Assistive Devices Scale (PIADS) is commonly used to assess the psychosocial effects of an assistive device. Given its growing use, an appraisal of the evidence regarding its psychometric properties is required. We conduct a systematic review using validated critical appraisal scales to analyze both the quality and content of the evidence on the psychometric properties of the PIADS. PubMed/Medline, Embase, and CINAHL were systematically searched for identification of studies. Two independent reviewers appraised the retrieved studies using MacDermid and COSMIN-RoB checklists, and extracted data regarding the psychometric measurements reported. MacDermid scores showed that 8 out of 11 studies were, at least, of good methodological quality. COSMIN-RoB scores ranged from inadequate to very good. Except criterion and construct validity, which have presented a moderate level of evidence, the other psychometric properties assessed have demonstrated a high level of evidence. Cross-cultural validity, measurement error, and responsiveness have not been studied. Few studies have yet evaluated the psychometric properties of the PIADS. However, the quality of the evidence that they provide is mostly adequate. Therefore, this review supports the use of the PIADS, which has overall good psychometric properties.

Th17 alloimmunity prevents neonatal establishment of lymphoid chimerism in IL-4-deprived mice.

Immune responses in newborn mice are known to be biased toward the helper type 2 phenotype. This may account for their propensity to develop tolerance. Herein, we evaluated the effects of IL-4 deprivation on CD4(+) T-cell activities elicited by neonatal exposure to allogeneic spleen cells. We showed that chimerism, Th2-type polarization and pathology, as well as skin allograft acceptance were inhibited in BALB/c mice immunized at birth with (A/J x BALB/c) F(1) spleen cells upon in vivo IL-4 neutralization. While IL-4 neutralization inhibited the development of Th2 cells in this model, it led to the accumulation of IL-17A, IL-17F, IL-22, IL-6 and RORγt mRNA in the spleen or graft tissues. Moreover, IL-4 deprivation led to the differentiation of donor-specific Th17 cells with a concomitant Th1 response characterized by IFN-γ production. The Th17-type response emerging in IL-4-deprived mice was found to mediate both intragraft neutrophil infiltration and the abrogation of B-cell chimerism. Neutralization of this Th17 response failed however to restore functional skin graft acceptance. Collectively, our observations indicate that the neonatal Th2 response opposes the development of Th17 cells, and that Th17 cells are responsible for controlling lymphoid chimerism in mice neonatally injected with semiallogeneic cells.

Expansion of regulatory CD8+ CD25+ T cells after neonatal alloimmunization.

Transplantation tolerance induced by neonatal injection of semi-allogeneic spleen cells is associated with a pathological syndrome caused by T helper type 2 (Th2) differentiation of donor-specific CD4(+) T lymphocytes. We have shown previously that this Th2-biased response is inhibited by host CD8(+) T cells. Herein, we demonstrate that upon neonatal immunization with (A/J × BALB/c)F(1) spleen cells, BALB/c mice expand a population of CD8(+) T cells expressing both CD25 and forkhead box P3 (FoxP3) markers. In this setting, CD8(+) CD25(+) T cells predominantly produce interferon (IFN)-γ and interleukin (IL)-10 and are efficient in controlling IL-4, IL-5 and IL-13 production by donor-specific CD4(+) T cells in vitro. CD8(+) FoxP3(-) T cells are single producers of IFN-γ or IL-10, whereas CD8(+) FoxP3(+) T cells are double producers of IFN-γ and IL-10. We further demonstrate that IFN-γ and IL-10 are two major cytokines produced by CD8(+) T cells involved in the in vivo regulation of Th2-type pathology. In this setting, we conclude that neonatal alloimmunization induces the expansion of several regulatory CD8(+) T cells which may control Th2 activities via IFN-γ and IL-10.

Delayed maturation of CD4- CD8- Fc gamma RII/III+ T and natural killer cell precursors in Fc epsilon RI gamma transgenic mice.

Fc epsilon RI gamma (gamma) is a member of a group of related proteins (the zeta-family dimers) that function as signal-transducing components of both Fc receptors and the T cell antigen receptor (TCR). Analysis of gamma expression during fetal thymus ontogeny revealed that it is expressed in early thymocytes, before the initiation of clonotypic TCR-alpha and TCR-beta gene rearrangement but is down-regulated in most adult thymocytes. To explore a possible role for gamma in thymocyte development, we generated transgenic mice in which this protein was overexpressed at all stages of ontogeny. Overexpression of gamma inhibited the maturation of T cells as well as natural killer (NK) cells. The developmental effects were transgene dose related and correlated with markedly delayed maturation of fetal CD4-CD8- FcRII/III+ thymocytes, cells thought to include the progenitors of both T and NK cells. These results suggest that the zeta and gamma chains serve distinctive functions in thymocyte development and indicate that Fc receptor(s) may play an important role in regulating the differentiation of early progenitor cells within the thymus.

Antigen-pulsed dendritic cells can efficiently induce an antibody response in vivo.

The aim of this study was to develop an immunization procedure avoiding external adjuvant. Data are presented showing that syngeneic dendritic cells (DC), which have been pulsed in vitro with antigen, induce a strong antibody response in mice. By contrast, antigen (Ag)-pulsed low-density B cells, although equally able to induce interleukin 2 secretion by an Ag-specific T cell hybridoma in vitro, only weakly prime the mice in vivo. Moreover, we show that the injection of Ag-pulsed DC induces the synthesis of isotypes similar to the immunoglobulin classes detected after immunization with the same Ag in complete Freund's adjuvant. Importantly, high amounts of IgG2a antibodies are produced, suggesting that T helper type 1 cells are activated. Collectively, these data indicate that DC can initiate a primary humoral response and that they may be used as physiological adjuvant in vivo.