Long short-term memory artificial neural network model for prediction of prostate cancer survival outcomes according to initial treatment strategy: development of an online decision-making support system.

PURPOSE: The delivery of precision medicine is a primary objective for both clinical and translational investigators. Patients with newly diagnosed prostate cancer (PCa) face the challenge of deciding among multiple initial treatment modalities. The purpose of this study is to utilize artificial neural network (ANN) modeling to predict survival outcomes according to initial treatment modality and to develop an online decision-making support system. METHODS: Data were collected retrospectively from 7267 patients diagnosed with PCa between January 1988 and December 2017. The analyses included 19 pretreatment clinicopathological covariates. Multilayer perceptron (MLP), MLP for N-year survival prediction (MLP-N), and long short-term memory (LSTM) ANN models were used to analyze progression to castration-resistant PCa (CRPC)-free survival, cancer-specific survival (CSS), and overall survival (OS), according to initial treatment modality. The performances of the ANN and the Cox-proportional hazards regression models were compared using Harrell's C-index. RESULTS: The ANN models provided higher predictive power for 5- and 10-year progression to CRPC-free survival, CSS, and OS compared to the Cox-proportional hazards regression model. The LSTM model achieved the highest predictive power, followed by the MLP-N, and MLP models. We developed an online decision-making support system based on the LSTM model to provide individualized survival outcomes at 5 and 10 years, according to the initial treatment strategy. CONCLUSION: The LSTM ANN model may provide individualized survival outcomes of PCa according to initial treatment strategy. Our online decision-making support system can be utilized by patients and health-care providers to determine the optimal initial treatment modality and to guide survival predictions.

Optimal sequencing strategy using docetaxel and androgen receptor axis-targeted agents in patients with castration-resistant prostate cancer: utilization of neutrophil-to-lymphocyte ratio.

PURPOSE: To investigate the prognostic value of neutrophil-to-lymphocyte ratio (NLR) for the selection of the optimal sequencing strategy using docetaxel and androgen receptor axis-targeted (ARAT) agents in patients with M0 or M1 castration-resistant prostate cancer (CRPC). Currently, there is a need to identify biomarkers to guide optimal sequential treatment in CRPC. METHODS: This multicenter, retrospective analysis included 303 consecutive patients initially diagnosed with M0 or M1 CRPC between September 2009 and March 2017. Of these, 52 (17.2%) patients received pre-docetaxel ARAT agents and 189 (62.4%) patients received post-docetaxel ARAT agents. The prognostic ability of NLR at CRPC diagnosis regarding radiographic progression-free survival (rPFS) and cancer-specific survival (CSS) were investigated. For the analysis, the NLR level was dichotomized at 2.5, and evaluated according to sequencing strategy. RESULTS: Multivariate analysis revealed NLR ≥ 2.5 as an independent predictor of a lower risk for CSS. During the median follow-up of 18.5 months, patients with NLR ≥ 2.5 exhibited significantly lower 1-year rPFS (p = 0.011) and 2-year CSS rates (p = 0.005) compared to patients with NLR < 2.5. Among patients with NLR < 2.5, the post-docetaxel ARAT agent sequencing group exhibited higher 1-year rPFS (p = 0.031) and 2-year CSS (p = 0.026) rates compared to the pre-docetaxel ARAT agent sequencing group. Among patients with NLR ≥ 2.5, rPFS and CSS rates were comparable regardless of ARAT agent sequencing. CONCLUSION: NLR ≥ 2.5 at CRPC diagnosis is associated with a lower risk for CSS. Patients with NLR < 2.5 should primarily be offered docetaxel considering the survival benefit of docetaxel-to-ARAT agent sequencing.

Pathological Characteristics of Prostate Cancer in Men Aged < 50 Years Treated with Radical Prostatectomy: a Multi-Centre Study in Korea.

BACKGROUND: Recently, younger prostate cancer (PCa) patients have been reported to harbour more favourable disease characteristics after radical prostatectomy (RP) than older men. We analysed young men (<50 years) with PCa among the Korean population, paying attention to pathological characteristics on RP specimen and biochemical recurrence (BCR). METHODS: The multi-centre, Severance Urological Oncology Group registry was utilized to identify 622 patients with clinically localized or locally advanced PCa, who were treated with RP between 2001 and 2017. Patients were dichotomized into two groups according to age (< 50-year-old [n = 75] and ≥ 50-year-old [n = 547]), and clinicopathological characteristics were analysed. Propensity score matching was used when assessing BCR between the two groups. RESULTS: Although biopsy Gleason score (GS) was lower in younger patients (P = 0.033), distribution of pathologic GS was similar between the two groups (13.3% vs. 13.9% for GS ≥ 8, P = 0.191). There was no significant difference in pathologic T stage between the < 50- and ≥ 50-year-old groups (69.3% vs. 68.0% in T2 and 30.7% vs. 32.0% in ≥ T3, P = 0.203). The positive surgical margin rates were similar between the two groups (20.0% vs. 27.6%, P = 0.178). BCR-free survival rates were also similar (P = 0.644) between the two groups, after propensity matching. CONCLUSION: Contrary to prior reports, younger PCa patients did not have more favourable pathologic features on RP specimen and showed similar BCR rates compared to older men. These findings should be considered when making treatment decisions for young Korean patients with PCa.

Subcutaneous Fat Distribution is a Prognostic Biomarker for Men with Castration Resistant Prostate Cancer.

PURPOSE: The relationship between body fat distribution and survival remains unclear in patients with castration resistant prostate cancer treated with docetaxel and androgen receptor axis targeted agents. We investigated whether body composition parameters could predict radiographic progression-free and cancer specific survival in patients with castration resistant prostate cancer. MATERIALS AND METHODS: In this multicenter retrospective study we evaluated data on 282 consecutive patients diagnosed with castration resistant prostate cancer between September 2009 and March 2017. The subcutaneous fat index, the visceral fat index and the skeletal muscle index at the diagnosis of castration resistant prostate cancer were determined by computerized tomography data. Survival analyses were performed using the subcutaneous fat, visceral fat and skeletal muscle indexes dichotomized at 39.9, 58 and 52.4 cm2/m2, respectively. RESULTS: At the diagnosis of castration resistant prostate cancer, cancer specific survival was independently predicted using prostate specific antigen levels, Gleason score 8 or greater, performance status, a shorter interval from androgen deprivation therapy to castration resistant prostate cancer and a subcutaneous fat index of less than 39.9 cm2/m2. During the median followup of 16.0 months patients with a subcutaneous fat index of 39.9 cm2/m2 or greater received more docetaxel cycles than patients with a subcutaneous fat index of less than 39.9 cm2/m2. Compared to patients with a subcutaneous fat index of less than 39.9 cm2/m2 those with an index of 39.9 cm2/m2 or greater had better 1-year progression-free and 2-year cancer specific survival (p = 0.009 and 0.021, respectively). CONCLUSIONS: Patients with a subcutaneous fat index of 39.9 cm2/m2 or greater at the diagnosis of castration resistant prostate cancer showed higher progression-free and cancer specific survival rates than those with a subcutaneous fat index of less 39.9 cm2/m2 at diagnosis. The subcutaneous fat index determined by computerized tomography data could serve as a useful objective prognostic factor to discuss patient therapeutic options. Further studies are needed to define the roles of each body composition parameter in relation to pharmacokinetics and oncologic outcome.

Predictors of adverse pathologic features after radical prostatectomy in low-risk prostate cancer.

BACKGROUND: Prostate-specific antigen (PSA) screening more frequently detects early stage prostate cancer (PC). However, adverse pathologic features (APFs) after radical prostatectomy (RP) in low-risk PC occur. Previous related studies had utilized outdated staging criteria or small sample cohorts. In this study, we analyzed predictors of APFs after RP in low-risk PC using classification under the current criteria. MATERIALS AND METHODS: We retrospectively reviewed medical records of 546 low-risk PC patients who had undergone RP. Low-risk PC was defined as PC with clinical T1-T2a, Gleason score ≤ 6, and PSA levels < 10 ng/mL. Clinical and pathological parameters were analyzed to predict APFs. APFs were defined as extracapsular extension (ECE), seminal vesicle invasion (SVI), or positive surgical margins (PSM). We analyzed our data using univariable and multivariable logistic regression analyses, as well as receiver operator characteristics to predict APFs. RESULTS: Among 546 patients, ECE, SVI, and PSM were present in 199 (36.4%), 8 (1.5%), and 179 cases (32.8%), respectively. PSM had a significant correlation with preoperative high PSA levels and number of positive cores obtained. ECE/SVI was also significantly correlated with PSA levels and number of positive cores. As a result, presence of APFs after RP was associated with high PSA levels and large number of positive cores. PSA > 4.5 ng/mL and number of positive cores > 2 in low-risk PC were significantly associated with APFs, and suggested as cut-off values for predicting APFs. CONCLUSIONS: PSA > 4.5 ng/mL and number of positive cores > 2 in low-risk PC were associated with presence of APFs and patients with such records should be considered carefully to provide active surveillance.

Impact of clinical trial participation on survival in patients with castration-resistant prostate cancer: a multi-center analysis.

BACKGROUND: Clinical trial (CT) participation may confer access to new, potentially active agents before their general availability. This study aimed to investigate the potential survival benefit of participation in investigational CTs of novel hormonal, chemotherapeutic, and radiopharmaceutical agents in patients with castration-resistant prostate cancer (CRPC). METHODS: This multi-center, retrospective analysis included 299 consecutive patients with newly diagnosed, non-metastatic or metastatic CRPC between September 2009 and March 2017. Of these, 65 (21.7%) patients participated in CTs pertaining to systemic treatment targeting CRPC and 234 (78.3%) patients received pre-established, standard systemic treatment outside of a CT setting. The survival advantage of CT participation regarding cancer-specific survival (CSS) was investigated. RESULTS: An Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2 at CRPC diagnosis was found in a lower proportion CT participants than in non-participants (4.6% vs. 14.9%; p = 0.033). During the median follow-up period of 16.0 months, CT participants exhibited significantly higher 2-year CSS survival rates (61.3% vs. 42.4%; p = 0.003) than did non-participants. Multivariate analysis identified prostate-specific antigen and alkaline phosphatase levels at CRPC onset, Gleason score ≥ 8, ECOG PS ≥2, less number of docetaxel cycles administered, and non-participation in CTs as independent predictors for a lower risk of CSS. CONCLUSIONS: Patients diagnosed with CRPC who participated in CTs exhibited longer CSS durations than non-participants who received pre-established, standard systemic therapy outside of a CT setting. Our findings imply that CT participation is associated with CSS, and that CT participation should be offered to patients with CRPC whenever indicated.

Does robot-assisted radical prostatectomy benefit patients with prostate cancer and bone oligometastases?

OBJECTIVE: To investigate the peri-operative and oncological outcomes of robot-assisted radical prostatectomy (RARP) in patients with oligometastatic prostate cancer (PCa). PATIENTS AND METHODS: We retrospectively reviewed the records of 79 patients with oligometastatic PCa treated with RARP or androgen deprivation therapy (ADT) between 2005 and 2015 at our institution. Of these 79 patients, 38 were treated with RARP and 41 were treated with ADT without local therapy. Oligometastatic disease was defined as the presence of five or fewer hot spots detected by preoperative bone scan. We evaluated peri-operative outcomes, progression-free survival (PFS), and cancer-specific survival (CSS). We analysed data using Kaplan-Meier methods, with log-rank tests and multivariate Cox regression models. RESULTS: Patients treated with RARP experienced similar postoperative complications to those previously reported in RP-treated patients, and fewer urinary complications than ADT-treated patients. PFS and CSS were longer in RARP-treated compared with ADT-treated patients (median PFS: 75 vs 28 months, P = 0.008; median CSS: not reached vs 40 months, P = 0.002). Multivariate analysis further identified RARP as a significant predictor of PFS and CSS (PFS: hazard ratio [HR] 0.388, P = 0.003; CSS: HR 0.264, P = 0.004). CONCLUSIONS: We showed that RARP in the setting of oligometastatic PCa is a safe and feasible procedure which improves oncological outcomes in terms of PFS and CSS. In addition, our data suggest that RARP effectively prevents urinary tract complications from PCa. The study highlights results from expert surgeons and highly selected patients that cannot be extrapolated to all patients with oligometastatic PCa; to confirm our findings, large, prospective, multicentre studies are required.

Time to Disease Recurrence Is a Predictor of Metastasis and Mortality in Patients with High-risk Prostate Cancer Who Achieved Undetectable Prostate-specific Antigen Following Robot-assisted Radical Prostatectomy.

BACKGROUND: Robot-assisted radical prostatectomy (RARP) is a feasible treatment option for high-risk prostate cancer (PCa). While patients may achieve undetectable prostate-specific antigen (PSA) levels after RARP, the risk of disease progression is relatively high. We investigated metastasis-free survival, cancer-specific survival (CSS), and overall survival (OS) outcomes and prognosticators in such patients. METHODS: In a single-center cohort of 342 patients with high-risk PCa (clinical stage ≥ T3, biopsy Gleason score ≥ 8, and/or PSA levels ≥ 20 ng/mL) treated with RARP and pelvic lymph node dissection between August 2005 and June 2011, we identified 251 (73.4%) patients (median age, 66.5 years; interquartile range [IQR], 63.0-71.0 years) who achieved undetectable PSA levels (< 0.01 ng/mL) postoperatively. Survival outcomes were evaluated for the entire study sample and in groups stratified according to the time to biochemical recurrence dichotomized at 60 months. RESULTS: During the median follow-up of 75.9 months (IQR, 59.4-85.8 months), metastasis occurred in 38 (15.1%) patients, most often to the bones, followed by the lymph nodes, lungs, and liver. The 5-year metastasis-free, cancer-specific, and OS rates were 87.1%, 94.8%, and 94.3%, respectively. Multivariate Cox-regression analysis revealed time to recurrence as an independent predictor of metastasis (P < 0.001). Time to metastasis was an independent predictor of OS (P = 0.003). Metastasis-free and CSS rates were significantly lower among patients with recurrence within 60 months of RARP (log-rank P < 0.001). CONCLUSION: RARP confers acceptable oncological outcomes for high-risk PCa. Close monitoring beyond 5 years is warranted for early detection of disease progression and for timely adjuvant therapy.

Prognostic Factors of Penile Cancer and the Efficacy of Adjuvant Treatment after Penectomy: Results from a Multi-institution Study.

BACKGROUND: Penile cancer is a rare malignancy associated with high rates of mortality and morbidity. Currently, the efficacy of adjuvant treatment (AT), including radiotherapy and chemotherapy, for penile cancer remains unclear. Therefore, we investigated the prognostic factors for treatment outcomes and the efficacy of AT in consecutive patients who underwent penectomy for penile cancer at multiple Korean institutions between 1999 and 2013. METHODS: AT was defined as the administration of chemotherapy, radiotherapy, or both within 12 months after initial treatment. All patients were divided into two groups according to the AT status. RESULTS: Forty-three patients (median age 67.0 years) with a median follow-up after penectomy of 26.4 (interquartile range: 12.0-62.8) months were enrolled. Patients with AT had a significantly higher pathologic stage. However, no differences in age, histologic grade, or type of surgery were identified according to the presence of AT. The 3- and 5-year cancer-specific survival (CSS) rates were 79.0% and 33.0%, respectively. In a multivariate analysis, American Joint Committee on Cancer (AJCC) stage ≥ III disease was an independent predictor of CSS and recurrence-free survival (RFS). However, AT was not associated with CSS and RFS. The type of primary surgical treatment and inguinal lymph node dissection at diagnosis were also not significantly associated with overall survival, CSS, or RFS. CONCLUSION: AJCC stage ≥ III disease, which mainly reflects lymph node positivity, is a significant prognosticator in patients with penile cancer. By contrast, AT does not seem to affect CSS and RFS.

Prognostic Significance of Vas Deferens Invasion After Radical Prostatectomy in Patients with Pathological Stage T3b Prostate Cancer.

BACKGROUND: Seminal vesicle invasion (SVI) is associated with adverse clinical outcomes in prostate cancer (PCa) patients. Despite its anatomical similarity and close proximity to the seminal vesicle, the prognostic significance of vas deferens invasion (VDI) by PCa has not been elucidated. For these reasons, we investigated the impact of VDI on the oncological outcome of pT3b PCa in association with SVI. METHODS: We retrospectively reviewed the medical records of 3359 patients who had undergone a radical prostatectomy at our institution between January 2000 and December 2014 for PCa. Patients who received neoadjuvant or adjuvant treatment (radiation, androgen deprivation therapy, or both) and those without adequate medical records were excluded. A Kaplan-Meier analysis was performed to analyze biochemical recurrence-free survival (BCRFS), and a Cox regression model was used to test the influence of VDI on biochemical recurrence (BCR). RESULTS: Of 350 patients with pathologically confirmed SVI (pT3b), 87 (24.9%) had VDI, while the remaining 263 patients (75.1%) had isolated SVI. Compared with SVI patients without VDI, SVI patients with VDI were noted to have a significantly worse 5-year BCRFS (25.1 vs. 17.1%, respectively). VDI was a significant predictor of BCR in multivariate Cox regression analysis (hazard ratio 1.39, 95% confidence interval 1.02-1.90; p = 0.039). CONCLUSIONS: Our results shows that the prognosis of PCa with SVI might be further stratified by VDI status, thus suggesting the role of VDI either as a surrogate for poor prognosis or as a determinant for adjuvant therapy.

Diffusion-weighted imaging predicts upgrading of Gleason score in biopsy-proven low grade prostate cancers.

OBJECTIVE: To analyse whether diffusion-weighted imaging (DWI) predicts Gleason score (GS) upgrading in biopsy-proven low grade prostate cancer (PCa). PATIENTS AND METHODS: A total of 132 patients who had biopsy-proven low grade (GS < 7) PCa, 3T DWI results, and surgical confirmation were retrospectively included in the study. Clinical variables (prostate-specific antigen, greatest percentage of cancer in a biopsy core and percentage of positive cores) and DWI variables (minimum apparent diffusion coefficient [ADCmin ] and mean ADC [ADCmean ]) were evaluated. ADCmin was measured, by two independent, blinded readers, using a region of interest (ROI) of 5-10 mm2 at the area of lowest ADC value within a cancer, while ADCmean was measured using an ROI covering more than half of a cancer. Logistic regression and receiver-operating characteristic curve analyses were performed. RESULTS: The rate of GS upgrading was 46.1% (61/132). In both univariate and multivariate analyses, ADCmin and ADCmean were persistently significant for predicting GS upgrading (P < 0.05), whereas clinical variables were not (P > 0.05). In both readers' results, the area under the curve (AUC) of ADCmin was significantly greater than that of ADCmean (reader 1: AUC 0.760 vs 0.711; P < 0.001; reader 2: AUC 0.752 vs 0.714; P = 0.003). CONCLUSION: Our results showed that DWI may predict GS upgrading of biopsy-proven low grade PCa. The variable ADCmin in PCa may perform better than ADCmean .

PI-RADS version 2: quantitative analysis aids reliable interpretation of diffusion-weighted imaging for prostate cancer.

OBJECTIVES: To determine whether apparent diffusion coefficient (ADC) ratio aids reliable interpretation of diffusion-weighted imaging (DWI) for prostate cancer (PCa). METHODS: Seventy-six consecutive patients with PCa who underwent DWI and surgery were included. Based on pathologic tumour location, two readers independently performed DWI scoring according to the revised Prostate Imaging Reporting and Data System (PI-RADSv2). ADC ratios of benign to cancerous prostatic tissue were then measured independently and compared between cases showing concordant and discordant DWI scores ≥4. Area under the curve (AUC) and threshold of ADC ratio were analyzed for DWI scores ≥4. RESULTS: The rate of inter-reader disagreement for DWI score ≥4 was 11.8% (9/76). ADC ratios were higher in concordant vs. discordant DWI scores ≥4 (median, 1.7 vs. 1.1-1.2; p < 0.001). For DWI scores ≥4, the AUCs of ADC ratios were 0.970 for reader 1 and 0.959 for reader 2. In patients with an ADC ratio >1.3, the rate of inter-reader disagreement for DWI score ≥4 decreased to 5.9-6.0%. An ADC ratio >1.3 yielded 100% (reader 1, 54/54; reader 2, 51/51) positive predictive value for clinically significant cancer. CONCLUSION: ADC ratios may be useful for reliable interpretation of DWI score ≥4 in PI-RADSv2. KEY POINTS: • The ADC ratio correlated positively with DWI score of PI-RADSv2. • ADC ratio >1.3 was associated with concordant interpretation of DWI score ≥4. • ADC ratio >1.3 was associated with high PPV for clinically significant cancer. • ADC ratio is useful for reliable interpretation of DWI scoring in PI-RADSv2.

Prostate Cancer: PI-RADS Version 2 Helps Preoperatively Predict Clinically Significant Cancers.

Purpose To retrospectively analyze whether Prostate Imaging Reporting and Data System (PI-RADS) version 2 is helpful for the detection of clinically significant prostate cancer. Materials and Methods Institutional review board approved this retrospective study. A total of 425 patients with prostate cancer who had undergone magnetic resonance (MR) imaging and radical prostatectomy were included. Preoperative parameters such as prostate-specific antigen, biopsy Gleason score, greatest percentage of the core, percentage of the positive core number, and score at PI-RADS version 2 with MR imaging were investigated. Two independent readers performed PI-RADS scoring. Clinically significant prostate cancer was defined as follows: (a) Gleason score of 7 or greater, (b) tumor volume of 0.5 cm(3) or greater, or a (c) positive extracapsular extension or seminal vesicle invasion. The reference standard was based on review of surgical specimen. Logistic regression was conducted to determine which parameters are associated with the presence of clinically significant cancer. Interreader agreement (ie, score ≥4 or not) was investigated by using κ statistics. Results At univariate analysis, all of the preoperative parameters were significant for clinically significant prostate cancer (P < .05). However, multivariate analysis revealed that PI-RADS score was the only significant parameter for both readers (reader 1: odds ratio = 28.170, P = .002; reader 2: odds ratio = 5.474, P = .007). The interreader agreement was excellent for PI-RADS score of 4 or greater (weighted κ = 0.801; 95% confidence interval: 0.737, 0.865). Conclusion The use of PI-RADS version 2 may help preoperatively diagnose clinically significant prostate cancer. (©) RSNA, 2016.

Oncological outcomes after partial vs radical nephrectomy in renal cell carcinomas of ≤7 cm with presumed renal sinus fat invasion on preoperative imaging.

OBJECTIVES: To compare oncological outcomes of partial nephrectomy (PN) and radical nephrectomy (RN) for renal tumours of ≤7 cm in which preoperative imaging reveals potential renal sinus fat invasion (cT3a), as RN is preferred for these tumours due to concerns about high tumour stage. PATIENTS AND METHODS: Among 1137 nephrectomies performed for renal tumours of ≤7 cm from January 2005 to August 2012, 401 solitary cT3a renal cell carcinomas (RCCs) without metastases were analysed. Classification as cT3a included only renal sinus fat invasion, as there were no tumours with suspected perinephric fat invasion. Multivariate models were used to evaluate predictors of recurrence-free survival (RFS) and cancer-specific survival (CSS). RESULTS: There were 34 RCCs (8.5%) with unexpected perinephric fat invasion, but only 77 RCCs (19.2%) were staged as pT3a. During the median follow-up of 43.0 months, recurrence occurred in seven (6.7%) PN cases and 25 (8.4%) RN cases. Six recurred PN cases had positive surgical margins (PSMs). The two cohorts showed equal oncological outcomes for 5-year RFS and CSS. Multivariate analyses showed PSM, pathological T stage, sarcomatoid dedifferentiation, and type of surgery as significant predictors of recurrence. Older age, pathological T stage, and sarcomatoid dedifferentiation were significant predictors of cancer-specific mortality. CONCLUSIONS: Renal tumours of ≤7 cm with presumed renal sinus fat invasion were mostly pT1. PN conferred equivalent oncological outcomes to RN. If clear surgical margins can be obtained, PN should be considered for these tumours, as patients may benefit from renal function preservation.

Prediction of biochemical recurrence after radical prostatectomy with PI-RADS version 2 in prostate cancers: initial results.

OBJECTIVES: To determine whether the Prostate Imaging Reporting and Data System version 2 (PI-RADSv2) helps predict biochemical recurrence (BCR) after radical prostatectomy for prostate cancer (PCa). METHODS: We included 158 patients with PCa who underwent magnetic resonance imaging (MRI) and radical prostatectomy (RP). Clinical (prostate-specific antigen, greatest percentage of core, and percentage of positive core number), PI-RADSv2 score on MRI, and surgical parameters (Gleason score, extracapsular extension, seminal vesicle invasion, and tumour volume) were investigated. Univariate and multivariate analyses using Cox's proportional hazards model were performed to assess parameters predictive of BCR (two consecutive prostate specific antigens ≥0.2 ng/ml). Kaplan-Meier survival curves were analyzed. RESULTS: The rate of BCR was 13.3 % (21/158) after surgery (median follow-up, 25 months; range, 12-36). No subject with a PI-RADS score <4 had BCR. In univariate analysis, all parameters were significant for BCR (p < 0.05), except seminal vesicle invasion (p = 0.254). Meanwhile, PI-RADS score was the only independent parameter for BCR in multivariate analysis (p < 0.05). Two-year, BCR-free survival post-RP was significantly lower for PI-RADS ≥4 (84.7-85.5 %) than for PI-RADS <4 (100 %; p < 0.05). CONCLUSION: As a preoperative imaging tool, PI-RADSv2 may be useful to predict BCR after radical prostatectomy for PCa. KEY POINTS: • No subject with PI-RADS <4 had BCR after RP • PI-RADSv2 was the only predictor of BCR in multivariate analysis • Two-year, BCR-free survival following RP was lower for PI-RADS≥4 than for PI-RADS<4 • Inter-rater agreement was good for PI-RADS ≥4 or not.

Prognostic impact of synchronous second primary malignancies on the overall survival of patients with metastatic prostate cancer.

PURPOSE: We determined the prognostic impact of a synchronous second primary malignancy on overall survival in patients with metastatic prostate cancer. Identifying features that stratify the risk of overall survival is critical for judiciously applying definitive therapy. MATERIALS AND METHODS: We retrospectively analyzed the records of 582 consecutive patients with prostate cancer diagnosed with metastasis between May 7, 1998 and August 27, 2011. Patient age, body mass index, ECOG performance status, Charlson comorbidity index, prostate specific antigen, T and N stages, Gleason and ASA® scores, progression to castration resistant prostate cancer, prior local treatments and synchronous second primary malignancies at metastasis were assessed. A synchronous second primary malignancy was defined as a cytologically or histologically proven solid malignancy. Cox proportional hazards regression analysis was done to estimate overall survival by second primary type and evaluate predictive variables. RESULTS: A total of 164 patients (28.1%) had a synchronous second primary malignancy, of which colorectal (9.1%), stomach (7.3%) and lung (7.1%) cancers were the most prevalent types. During a median followup of 34.1 months patients without a synchronous second primary malignancy had a significantly higher overall survival rate than those with lung or stomach cancer. However, men without a second malignancy had outcomes comparable to those in men with colorectal cancer. Clinical stage T4 or greater, ASA score 1 or greater and lung or stomach cancer were independent predictors of overall mortality. CONCLUSIONS: A substantial proportion of patients with metastatic prostate cancer present with a synchronous second primary malignancy. Definitive therapy targeting prostate cancer may confer a limited survival benefit in patients with synchronous lung or stomach cancer.

Prognostic impact of time to undetectable prostate-specific antigen in patients with positive surgical margins following radical prostatectomy.

BACKGROUND: The purpose of this article was to determine the impact of time to undetectable prostate-specific antigen (PSA) for predicting biochemical recurrence (BCR) in patients with a positive surgical margin (PSM) following radical prostatectomy (RP). A PSM is an independent predictor of BCR; however, not all patients develop BCR later on. METHODS: A retrospective analysis was conducted on 1,117 consecutive prostate cancer patients who underwent RP without neoadjuvant or adjuvant therapy from July 2005 to December 2009. Of these, 516 (46.2 %) patients without PSMs, and 214 (19.2 %) patients with PSMs who later achieved undetectable PSA, defined as <0.01 ng/ml, were identified. Patients with PSMs were stratified according to time to undetectable PSA dichotomized at 6 weeks and compared with patients without PSMs. Patients with PSMs who did not achieve undetectable PSA were excluded. BCR was defined as two consecutive increases of post-undetectable PSA ≥0.2 ng/ml. RESULTS: During the median follow-up of 58.2 months, patients with PSMs who achieved undetectable PSA in <6 weeks had comparable 5-year BCR-free survival rates to those without PSMs; however, patients with PSMs who achieved undetectable PSA in ≥6 weeks showed significantly lower rates compared with both patients without PSMs (59.2 vs 74.3 %; p < 0.001) and patients with PSMs who achieved undetectable PSA in <6 weeks (59.2 vs 78.8 %; p = 0.004). Among patients with PSMs, multivariate analysis revealed time to undetectable PSA at ≥6 weeks and seminal vesicle invasion to be independent predictors of BCR. No perioperative factors were associated with undetectable PSA at ≥6 weeks. CONCLUSIONS: Patients with PSMs who achieve undetectable PSA in <6 weeks show comparable risks of BCR to patients with negative surgical margins.

Predicting the response of patients with advanced urothelial cancer to methotrexate, vinblastine, Adriamycin, and cisplatin (MVAC) after the failure of gemcitabine and platinum (GP).

BACKGROUND: Platinum-based systemic chemotherapy is the treatment of choice for patients with advanced urothelial carcinoma (UC). Although no chemotherapeutic regimen is established as a second-line therapy, recent studies reported that methotrexate, vinblastine, Adriamycin and cisplatin (MVAC) elicited a significant response in patients who failed gemcitabine and platinum (GP) chemotherapy. We investigated the clinical factors useful for predicting a favourable response to MVAC in UC patients who failed GP. METHODS: Forty-five patients with advanced UC who received second-line MVAC chemotherapy after failure with first-line GP chemotherapy were enrolled in this study. Univariate and multivariate analyses based on Cox's regression were performed to identify independent prognostic factors for progression-free survival (PFS) after second-line MVAC chemotherapy. RESULTS: The median follow-up period after the first MVAC administration was 10.0 months. The median PFS and overall survival (OS) were 6.5 months (95% confidence interval [CI]: 5.1-7.9) and 14.5 months (95% CI, 7.4-21.4), respectively. The overall response rate was 57.8%. The response to first-line GP chemotherapy (hazard ratio [HR], 2.500; p = 0.012) and patient age (HR, 1.047; p = 0.033) were predictors of PFS after MVAC chemotherapy. CONCLUSIONS: The response to first-line GP chemotherapy and age were independent predictors of PFS in patients who received second-line MVAC chemotherapy. This report is the first to describe independent predictors of PFS after MVAC chemotherapy.

The novel histone deacetylase inhibitor, N-hydroxy-7-(2-naphthylthio) hepatonomide, exhibits potent antitumor activity due to cytochrome-c-release-mediated apoptosis in renal cell carcinoma cells.

BACKGROUND: Epigenetic modifications play a critical role in the regulation of all DNA-based processes, such as transcription, repair, and replication. Inappropriate histone modifications can result in dysregulation of cell growth, leading to neoplastic transformation and cell death. Renal tumors have been shown to have a higher global methylation percentage and reduced histone acetylation. Preclinical models have revealed that histone gene modifiers and epigenetic alterations play important roles in renal cell carcinoma (RCC) tumorigenesis. Recently, a novel HDAC inhibitor, N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA), has been introduced as an example of a new class of anti-cancer agents. The anti-cancer activity of HNHA and the underlying mechanisms of action remain to be clarified. METHODS: The MTS assay using a panel of RCC cells was used to evaluate the anti-proliferative effects of HNHA. The established HDAC inhibitors, SAHA and TSA, were used for comparison. Western blotting analysis was performed to investigate the acetylation of histone H3 and the expression of apoptotic markers in vitro and in vivo. Subcellular fractionation was performed to evaluate expression of Bax and cytochrome c in the cytosol and mitochondria, and also translocation of cytochrome c from the cytoplasm to the nucleus. A confocal microscopic evaluation was performed to confirm inhibition of cell proliferation, induction of apoptosis, and the nuclear translocation of cytochrome c in RCC cells. RESULTS: In this study, we investigated the apoptosis-inducing activity of HNHA in cultured kidney cancer cells. Apoptosis in the HNHA-treated group was induced significantly, with marked caspase activation and Bcl-2 suppression in RCC cells in vitro and in vivo. HNHA treatment caused cytochrome c release from mitochondria, which was mediated by increased Bax expression and caspase activation. HNHA also induced nuclear translocation of cytochrome c, suggesting that HNHA can induce caspase-independent nuclear apoptosis in RCC cells. An in vivo study showed that HNHA had greater anti-tumor and pro-apoptotic effects on RCC xenografts than the established HDAC inhibitors. CONCLUSIONS: HNHA has more potent anti-tumor activity than established HDAC inhibitors. Its activities are mediated by caspase-dependent and cytochrome-c-mediated apoptosis in RCC cells. These results suggest that HNHA may offer a new therapeutic approach to RCC.

Transurethral resection of the prostate for patients with Gleason score 6 prostate cancer and symptomatic prostatic enlargement: a risk-adaptive strategy for the era of active surveillance.

OBJECTIVE: To investigate whether transurethral resection of the prostate can be used as both (i) treatment for symptomatic prostatic enlargement in patients with prostate cancer and (ii) a risk-adaptive strategy for reducing prostate-specific antigen levels and broadening the indications of active surveillance. METHODS: We retrospectively reviewed data of 3680 patients who underwent prostate biopsies at a single institution (March 2006 to January 2012). Of 529 men who had Gleason score 6 prostate cancer and were ineligible for active surveillance, 86 (16.3%) underwent transurethral resection of the prostate for symptomatic prostatic enlargement. We assessed how changes in prostate-specific antigen and prostate-specific antigen density influenced the eligibility for active surveillance and the outcome of subsequent therapy. The following active surveillance criteria were used: prostate-specific antigen ≤ 10 ng/ml, prostate-specific antigen density ≤ 0.15, positive cores ≤ 3 and single core involvement ≤ 50%. RESULTS: The median age, pre-operative prostate-specific antigen and prostate volume were 71 years, 6.95 ng/ml, and 45.8 g, respectively. In 82.6% (71/86) of analyzed cases, ineligibility for active surveillance had resulted from elevated prostate-specific antigen level or prostate-specific antigen density. With a median resection of 16.5 g, transurethral resection of the prostate reduced the percentage of prostate-specific antigen and the percentage of prostate-specific antigen density by 34.5 and 50.0%, respectively, making 81.7% (58/71) of the patients eligible for active surveillance. Prostate-specific antigen level remained stabilized in all (21/21) patients maintained on active surveillance without disease progression during the median follow-up of 50.6 months. Among patients who underwent radical prostatectomy, 96.7% (29/30) exhibited localized disease. CONCLUSIONS: Risk-adaptive transurethral resection of the prostate may prevent overtreatment and allay prostate-specific antigen-associated anxiety in patients with biopsy-proven low-grade prostate cancer and elevated prostate-specific antigen. Additional benefits include voiding symptom improvement and the avoidance of curative therapy's immediate side effects.