O. Celhay

Expression of estrogen related proteins in hormone refractory prostate cancer: association with tumor progression.

PURPOSE Despite increasing evidence that estrogen signaling has a key role in prostate cancer development and progression, few studies have focused on the estrogen pathway in the transition from hormone sensitive to hormone refractory tumors. We investigated the expression of proteins related to androgen and estrogen metabolism in paired prostate cancer samples collected before androgen deprivation therapy and after hormonal relapse. MATERIALS AND METHODS The study included 55 patients treated for prostate cancer only with androgen deprivation therapy and in whom tissue was available before treatment induction and after recurrence. Immunohistochemistry was performed using tissue microarray with antibodies directed against androgen receptor, phosphorylated androgen receptor, estrogen receptor α, estrogen receptor β, 5α-reductase 1 and 2, aromatase, BCAR1 and the proliferation marker Ki67. RESULTS Compared to hormone sensitive samples, tissues collected after hormonal relapse were characterized by increased expression of Ki67, androgen receptor, phosphorylated androgen receptor (p <0.001) and BCAR (p = 0.03), and by lower staining for 5α-reductase 2 (p = 0.002), estrogen receptor β (p = 0.016) and aromatase (p <0.001). Shorter time to hormonal relapse was associated with high expression of aromatase and BCAR1 on diagnostic biopsy, together with low staining for estrogen receptor α in stromal cells. Overall survival was significantly shorter when tissues collected after relapse showed a high proliferation index and low estrogen receptor α expression. CONCLUSIONS Results revealed dysregulation of proteins involved in androgen pathways, and in estrogen synthesis and signaling during the development of hormone refractory prostate cancer.

Prognostic Interest in Discriminating Muscularis Mucosa Invasion (T1a vs T1b) in Nonmuscle Invasive Bladder Carcinoma: French National Multicenter Study with Central Pathology Review

PURPOSE Predictive factors of T1 nonmuscle invasive bladder cancer evolution that could guide treatment decision making are lacking. We assessed the prognostic value of muscularis mucosa invasion in nonmuscle invasive bladder cancer. MATERIALS AND METHODS In a national multicenter study patients with primary T1 nonmuscle invasive bladder cancer were recruited from 6 French hospitals. All patients had undergone transurethral resection of bladder tumor. All T1 tumors were substaged according to muscularis mucosa invasion as T1a-no invasion beyond the muscularis mucosa or T1b-invasion beyond the muscularis mucosa with muscle preservation. Subsequent central pathology review was then done by a single referent uropathologist. Muscularis mucosa invasion was tested as a prognostic factor for survival on univariate and multivariate analysis. RESULTS A total of 587 patients were enrolled in the study, including 388 (66%) with T1a and 199 (34%) with T1b tumors. Median followup after transurethral resection of bladder tumor was 35 months (IQR 14-54). There was no significant difference between groups T1a and T1b except high tumor grade in T1b cases (p <0.0001). After central review, initial pathological substaging was confirmed in 84% of cases. On multivariate analysis muscularis mucosa invasion (T1b substage) was significantly associated with recurrence-free (p = 0.03), progression-free (p = 0.0002) and cancer specific (p = 0.02) survival. The main study limitation was absent systematic subsequent transurethral resection of bladder tumor. CONCLUSIONS Muscularis mucosa invasion appears to be highly predictive of T1 nonmuscle invasive bladder cancer behavior. Consequently, systematic T1a vs T1b discrimination should be highly advocated by urologists and pathologists. We believe that it could aid in crucial decision making when choosing between conservative management and radical cystectomy remains a moot point.

Continuous versus six months a year maximal androgen blockade in the management of prostate cancer: a randomised study.

OBJECTIVE To evaluate systematically interrupted androgen suppression (SIAS) 6 mo a year compared with continuous androgen suppression (CAS) in prostate cancer treatment. PATIENTS AND METHODS All patients underwent maximal androgen blockade for 6 mo. Then, depending on the randomisation arm, they continued (CAS) or stopped their treatment for 6 mo before they resumed it a year later and so on (SIAS). Primary end points were patients health-related quality of life (HQOL) and time to progression. Secondary end points were cancer-specific and overall survival. Progression was defined by a clinical event or PSA value exceeding double the value obtained at the end of the first 6 mo of therapy. RESULTS Sixty-two patients were randomised to CAS and 67 to SIAS. There were no significant differences between groups at baseline. Androgen suppression was associated with HQOL deterioration except for an improvement in urinary symptoms. The 6-mo off-therapy period was not long enough to regain normal testosterone values. There was no difference in HQOL scores between CAS and SIAS except that men in the latter group reported a greater need for painkillers but a better ability to have an erection. Progression occurred in 62 patients (48.1%) with no significant difference between CAS and SIAS with a mean follow-up of 44.8 mo. Death occurred in 41 patients and specific death in 19 patients (10% and 19% of the CAS and SIAS groups, respectively). CONCLUSIONS Although patients in the SIAS group were maintained off-therapy 50% of the time, insufficient testosterone recovery in this group likely explains why differences between the two groups were moderate or absent with regards to HQOL and survival, respectively.

Differential expression of the semaphorin 3A pathway in prostatic cancer

Aims:  To analyse the expression pattern of the semaphorin 3A (Sema3A) pathway, including the receptor neuropilin 1 (NRP1) and its ligands the ‘antitumoral’ Sema3A and the ‘protumoral’ vascular endothelial growth factor (VEGF)in prostatic cancer.

Fluctuating prostate-specific antigen levels in patients with initial negative biopsy: should we be reassured?

To evaluate whether the risk of having a positive repeat prostate biopsy is lower in patients with fluctuating prostate‐specific antigen (PSA) levels than in patients with a steady or steadily increasing PSA level.

Percentage of Positive Biopsy Cores at the Onset of Hormone Therapy for Prostate Cancer: Prognostic Significance

Introduction: The percentage of positive prostate biopsy cores (%PBC) has been shown to be a prognostic factor in localized prostate cancer. We hypothesized that it would predict time to hormonal independence and survival in prostate cancer patients treated with androgen deprivation therapy (ADT). Patients and Methods: We used clinical data from 403 men treated with ADT between 1980 and 1999 and focused on a subgroup of 220 patients treated with GnRH analogue. %PBC was defined as the number of positive biopsy cores multiplied by 100 and divided by the total number of biopsy cores. Results: Median %PBC was 83.3% (16.7–100%). Mean follow-up was 57.4 months. Survival at 5 years in men with 83.3% PBC or less was 62.3, 89.1 and 82.6% for recurrence-free, specific and overall survival, respectively, significantly better than that of men with a %PBC of more than 83.3% (32.2, 74.7 and 67.7%, respectively; p < 0.004). Among the factors available in the pretreatment setting, namely age, clinical stage, PSA, Gleason score, bone scan and %PBC, the latter was independently associated with survival in multivariate analysis. Conclusions: %PBC may improve the ability to predict time to hormonal resistance and survival in patients treated with ADT for prostate cancer. This finding warrants further investigation.

Variation du PCA3 urinaire après biopsie de prostate transrectale échoguidée

INTRODUCTION Serum PSA is known to rise slightly following an attentive digital rectal examination (DRE) and dramatically following prostatic biopsy. The aim of this study was to evaluate the PCA3 response in these situations. PATIENTS AND METHODS In 15 consecutive men undergoing transrectal ultrasound-guided needle biopsy of the prostate and who gave their informed consent, urinary PCA3 was determined twice: at a first consultation, urine being sampled immediately after an attentive DRE and second within 2 hours after the biopsy. The mean interval between the two samplings was 14 days (median 15). PCA3 measurements were centralized and performed by the same biologist. At least twelve cores were taken using a biopsy gun with an 18-gauge needle. Changes in PCA3 levels were studied. RESULTS Mean age of the 15 men was 67.3 years (range 50.9-79.1). Mean (median) pre-biopsy total and %free PSA were respectively 6.6 ng/ml (5.7) and 15.8% (15.5). Mean prostate volume was 43.6 cm(3). Seven patients complained of mild LUTS. DRE was suspicious in eight patients. Of the 15 men, 6 (40%) had adenocarcinoma on biopsy (all clinically confined to the prostate). Median (range) Gleason score was 6 (6-7). Median PCA3 score (range) before and after prostatic biopsy were respectively 36 (9-287) and 27 (5-287) with no significant difference between the two groups (sign test for matched series p > 0.05). The median variation between pre- and post-biopsy PCA3 was -18%. When considering a PCA3 cut-off of 35, two patients changed group: one patient had 51 before and 31 after (PSA 4.6; no cancer on prostate biopsy) and the second had 36 before and 27 after (PSA 5.6; low-risk PCa). The figure represents the PCA3 values for each case (squares for the pre-biopsy and diamonds for the post-biopsy). When considering only the six patients with PCA, median (mean) PCA3 score before and after prostatic biopsy were respectively 51.5 (60.8) and 44.5 (54.8) with no significant difference between the two groups (sign test for matched series p > 0.5) and a median variation between pre- and post-biopsy PCA3 of 1.5%. CONCLUSIONS Prostate biopsy did not alter significantly urinary PCA3 value. This confirms what was theoretically expected.

PSA "en dents de scie" et PSA "en escalier" : quelles implications pronostiques ?

Resume But Evaluer le risque de diagnostiquer un cancer de la prostate sur des biopsies iteratives chez des patients ayant des valeurs de PSA fluctuantes, compare a des patients ayant des valeurs de PSA stables ou en augmentation reguliere. Materiel Etude retrospective menee sur les bases de donnees 2000 - 2003 de 2 CHU. Les patients selectionnes avaient eu une premiere biopsie prostatique negative, puis au minimum une nouvelle serie de biopsies prostatiques. Le PSA “en dents de scie” (DdS) etait definie par une valeur de PSA inferieure a la valeur du dosage precedent. Dans les autres cas, il s’agissait d’un PSA “en escalier” (ESC). Resultats Parmi les 191 patients inclus, 79 etaient dans le groupe DdS et 112 dans le groupe ESC. Un cancer de prostate a ete diagnostique chez 53 patients (27.7%), dont 39 lors de la deuxieme biopsie prostatique. Parmi les 79 patients du groupe DdS, un cancer a ete retrouve chez 17 (21.5%). Cette proportion n’etait pas significativement differente (p=0.14) de celle retrouvee chez les patients du groupe ESC, soit 36/112 (32.1%). Il n’y avait pas de difference significative quant a l’âge, le stade, le score de Gleason et le PSA initial entre les patients ayant eu le diagnostic de cancer dans les groupes DdS et ESC. Conclusion Dans notre etude, le risque de decouverte d’un cancer sur des biopsies prostatiques iteratives n’etait pas plus important chez les patients ayant un PSA en escalier par rapport aux patients ayant un PSA en dents de scie.