Takumi Endo

Implications of Serum Bone Turnover Markers in Prostate Cancer Patients With Bone Metastasis

OBJECTIVES To assess the diagnostic accuracy of serum bone turnover markers for detection of bone metastasis in patients with prostate cancer (PCa) and to assess the usefulness of these markers as predictors of mortality from PCa. METHODS Serum total alkaline phosphatase, bone-specific alkaline phosphatase, carboxy-terminal pyridinoline cross-linked telopeptide parts of type-I collagen (1CTP), tartrate-resistant acid phosphatase type 5 b, and prostate-specific antigen (PSA) levels were measured in 222 patients (58 with bone metastasis, 57 with T2M0 PCa, 55 with T3M0 PCa, and 52 without PCa). Multivariate stepwise logistic regression analysis was used to identify independent predictors of bone metastasis. Correlation of serum marker levels with bone metastasis was assessed using receiver operating characteristics analysis. Multivariate Cox proportional hazards analysis was used to predict cause-specific survival in PCa patients with bone metastasis. RESULTS Serum total alkaline phosphatase, bone-specific alkaline phosphatase, 1CTP, tartrate-resistant acid phosphatase type 5 b, and PSA levels were significantly elevated in patients with bone metastasis, and correlated significantly with the extent of disease on bone scintigraphy. Multivariate stepwise logistic regression analysis demonstrated that serum PSA and 1CTP were significant predictors of bone metastasis. Receiver operating characteristics analyses showed that serum 1CTP level was the most reliable predictor of bone metastasis (area under the curve = 0.85). Multivariate Cox proportional hazards analysis revealed that only serum 1CTP was an independent prognostic factor for PCa-related death. CONCLUSIONS Serum 1CTP level was a more reliable marker than the others to detect bone metastatic spread and to predict survival probability in PCa patients with bone metastasis.

FOXA1 promotes tumor progression in prostate cancer via the insulin-like growth factor binding protein 3 pathway.

Fork-head box protein A1 (FOXA1) is a “pioneer factor” that is known to bind to the androgen receptor (AR) and regulate the transcription of AR-specific genes. However, the precise role of FOXA1 in prostate cancer (PC) remains unknown. In this study, we report that FOXA1 plays a critical role in PC cell proliferation. The expression of FOXA1 was higher in PC than in normal prostate tissues (P = 0.0002), and, using immunohistochemical analysis, we found that FOXA1 was localized in the nucleus. FOXA1 expression levels were significantly correlated with both PSA and Gleason scores (P = 0.016 and P = 0.031, respectively). Moreover, FOXA1 up-regulation was a significant factor in PSA failure (P = 0.011). Depletion of FOXA1 in a prostate cancer cell line (LNCaP) using small interfering RNA (siRNA) significantly inhibited AR activity, led to cell-growth suppression, and induced G0/G1 arrest. The anti-proliferative effect of FOXA1 siRNA was mediated through insulin-like growth factor binding protein 3 (IGFBP-3). An increase in IGFBP-3, mediated by depletion of FOXA1, inhibited phosphorylation of MAPK and Akt, and increased expression of the cell cycle regulators p21 and p27. We also found that the anti-proliferative effect of FOXA1 depletion was significantly reversed by simultaneous siRNA depletion of IGFBP-3. These findings provide direct physiological and molecular evidence for a role of FOXA1 in controlling cell proliferation through the regulation of IGFBP-3 expression in PC.

Additive effect of zoledronic acid on serum prostate-specific antigen changes for hormone-sensitive prostate cancer patients with bone metastasis treated by combined androgen blockade

Combined androgen blockade is widely used to treat patients with advanced prostate cancer. Recently, zoledronic acid was proven to be effective in preventing skeletal‐related events for prostate cancer patients with bone metastases. Aim of the present study was to assess the effect of adding zoledronic acid to combined androgen blockade in the treatment of hormone‐naïve metastatic prostate cancer patients by analyzing the changes of biomarker levels. Patients were treated with either a combination of combined androgen blockade and zoledronic acid (n = 23) or combined androgen blockade alone (historical control combined androgen blockade group, n = 42). Zoledronic acid was injected intravenously at 4 mg every 4 weeks for 2 years. Prostate‐specific antigen and bone turnover markers (alkaline phosphatase and pyridinoline cross‐linked carboxyterminal telopeptide of type 1 collagen) were examined before treatment and at 3, 6, and 12 months after treatment. Sequential changes of prostate‐specific antigen, alkaline phosphatase and pyridinoline cross‐linked carboxyterminal telopeptide of type 1 collagen for the two groups versus pretreatment levels were compared. Prostate‐specific antigen values in both groups significantly declined at 3, 6 and 12 months compared with pretreatment levels. However, the decline of the prostate‐specific antigen was lower in the combined androgen blockade group. Alkaline phosphatase significantly declined at 6 and 12 months in the combination of combined androgen blockade and zoledronic acid group, with no significant changes seen in the combined androgen blockade group. The addition of zoledronic acid to combined androgen blockade showed prostate‐specific antigen and bone turnover markers response compared with combined androgen blockade therapy only, suggesting a potential antitumor effect of zoledronic acid in the management of metastatic prostate cancer patients.

Implications of Body Mass Index in Japanese Patients with Prostate Cancer Who Had Undergone Radical Prostatectomy

OBJECTIVE To determine the association between obesity and prostate cancer in Japanese recurrence after primary treatment with radical prostatectomy. METHODS The subjects were 173 Japanese patients with prostate cancer who had been treated with radical prostatectomy at Chiba University Hospital between April 1997 and March 2007. Clinicopathological characteristics and biochemical recurrence outcomes after radical prostatectomy were compared between the three body mass index cohorts. RESULTS Mean body mass index was 23.4 kg/m(2) with a standard deviation of 2.4, and mean follow-up period was 37.4 months. Operative time was longer and estimated blood loss was much more in obese patients. Patients with pT3>or= had significantly higher serum prostate-specific antigen, total cholesterol levels, Gleasons sum and positive of surgical margin than pT2 patients. Recurrence rate was significantly higher in the 26.5 kg/m(2) and hyperlipidemia groups in pT3>or= patients. CONCLUSIONS Obesity is an independent predictor of disease recurrence in Japanese patients with pT3>or= prostate cancer who underwent radical prostatectomy. Obese patients who underwent radical prostatectomy require vigilant follow-up care.

Association between serum sex hormone levels and prostate cancer: effect of prostate cancer on serum testosterone levels

Androgens are essential for prostatic growth and development, but also play a significant role in the pathogenesis of prostate disease. The traditional view that higher testosterone levels represent a risk factor for prostate cancer (PCa) appears to have little evidentiary support. Some studies have described a relationship between lower testosterone levels and more advanced disease. Serum androgen levels, within a broad range, are thus suggested to show no association with PCa risk, whereas low rather than high serum testosterone levels have been found to be associated with advanced or high-grade disease at the time of PCa diagnosis. Dihydrotestosterone, the principal prostatic androgen, is transformed from testosterone by type 1 and type 2 5alpha-reductase, and therapeutic benefits may thus be potentially achieved through the inhibition of 5alpha-reductase.

Oral analgesia by non-steroidal anti-inflammatory drug zaltoprofen to manage cystoscopy-related pain: A prospective study

Objectives:  To examine the pre‐emptive analgesic effect of the non‐steroidal anti‐inflammatory drug zaltoprofen against rigid cystoscopy‐associated pain, and compare it with the effect of an anesthetic gel.

External validation and comparison of two nomograms predicting the probability of Gleason sum upgrading between biopsy and radical prostatectomy pathology in two patient populations: a retrospective cohort study

The aim of this study is to validate and compare the predictive accuracy of two nomograms predicting the probability of Gleason sum upgrading between biopsy and radical prostatectomy pathology among representative patients with prostate cancer. We previously developed a nomogram, as did Chun et al. In this validation study, patients originated from two centers: Toho University Sakura Medical Center (n = 214) and Chibaken Saiseikai Narashino Hospital (n = 216). We assessed predictive accuracy using area under the curve values and constructed calibration plots to grasp the tendency for each institution. Both nomograms showed a high predictive accuracy in each institution, although the constructed calibration plots of the two nomograms underestimated the actual probability in Toho University Sakura Medical Center. Clinicians need to use calibration plots for each institution to correctly understand the tendency of each nomogram for their patients, even if each nomogram has a good predictive accuracy.

MP52-06 SERUM LIPID PROFILE CANNOT IMPROVE AFTER WITHDRAWAL OF ANDROGEN DEPRIVATION THERAPY IN PATIENTS WITH PROSTATE CANCER DESPITE THE RECOVERY OF SERUM TESTOSTERONE: IS THE CARDIOVASCULAR RISK STILL REMAINING?

METHODS: Patients with CRPC and bone metastases who completed 6 initial Ra-223 inj with no disease progression in bone and later progressed were eligible for Ra-223 re-tx (up to 6 additional Ra223 inj), provided that hematologic parameters were adequate. No concomitant cytotoxic agents were allowed; other concomitant agents (eg, abiraterone and enzalutamide) were allowed at investigator discretion. The primary objective was safety. Exploratory objectives included time to radiographic bone progression, radiographic progression-free survival (rPFS), time to total alkaline phosphatase (tALP) and prostate-specific antigen (PSA) progression, overall survival (OS), and time to first symptomatic skeletal event (SSE), all calculated from start of re-tx. The evaluation of safety and exploratory objectives included an active 2-year follow-up. Safety results from the active follow-up period and updated efficacy are reported. RESULTS: 44 patients were re-treated with Ra-223; 29 (66%) completed all 6 inj (median number inj 1⁄4 6). 34 (77%) of 44 patients entered active follow-up, during which no new safety concerns were noted. One new primary malignancy was reported (basal cell carcinoma; not considered related to study drug). There were no serious drug-related adverse events. 19 (43%) of 44 patients had an rPFS event (radiographic progression or death); median rPFS was 9.9 months. Only 5 (11%) of 44 patients had radiographic bone progression; median time to radiographic bone progression was not reached. Median time to tALP progression was not reached, median time to PSA progression was 2.2 months. Median OS was 24.4 months. Median time to first SSE was 16.7 months. CONCLUSIONS: Re-treating patients with Ra-223 was well tolerated in this select population, led to minimal hematologic toxicity, and provided continued disease control in bone at the 2-year follow-up.

Alternative Antiandrogen Therapy for CRPC

Androgen deprivation therapy continues to be a mainstream treatment for prostate cancer. Failure after initial hormonal treatment including combined androgen blockade (CAB)/maximum androgen blockade (MAB) does not necessarily imply treatment-refractory disease progression. Antiandrogen withdrawal syndrome (AWS) is a manifestation of a prostate-specific antigen (PSA) decrease with or without subjective or objective symptomatic improvement on discontinuation of the antiandrogen. In general, the incidence of this effect has been reported to be 10–30%, and it lasts for 3–5 months. Some patients with progressive disease who have undergone initial CAB/MAB therapy respond to second- and third-line hormonal therapy after AWS is recognized. Mutations in the androgen receptor (AR) gene are thought to account for this phenomenon by enabling the previous antiandrogens to act as receptor agonists. Alternative antiandrogens probably have different functional interactions with the AR. Alternative antiandrogen therapy has been shown to improve symptoms and decrease pain in patients with prior antiandrogen therapy. A 50% PSA decrease has been reported after second-line treatment with nonsteroidal antiandrogens in 35–50% of cases. Responders to second-line hormonal treatment are expected to survive significantly longer than nonresponders. Responsiveness to second-line regimens is the most important prognostic factor for increased cause-specific and overall survival.

External validation of two web-based postoperative nomograms predicting the probability of early biochemical recurrence after radical prostatectomy: a retrospective cohort study

The present study aimed to validate and compare the predictive accuracies of the Memorial Sloan Kettering Cancer Center (MSKCC) and Johns Hopkins University (JHU) web-based postoperative nomograms for predicting early biochemical recurrence (BCR) after radical prostatectomy (RP) and to analyze clinicopathological factors to predict early BCR after RP using our dataset. The c-index was 0.72 (95% confidence (CI): 0.61-0.83) for the MSKCC nomogram and 0.71 (95% CI: 0.61-0.81) for the and JHU nomogram, demonstrating fair performance in the Japanese population. Furthermore, we statistically analyzed our 174 patients to elucidate prognostic factors for early BCR within 2 years. Lymphovascular invasion (LVI) including lymphatic vessel invasion (ly) was a significant predictor of early BCR in addition to common variables (pT stage, extraprostatic extension, positive surgical margin and seminal vesicle invasion). LVI, particularly ly, may provide a good predictor of early BCR after RP and improve the accuracy of the nomograms.