Localized Prostate Cancer Cases Research Articles

Robot-assisted radical prostatectomy with the Hugo™ robot-assisted surgery system: A single-center initial experience in Japan.

Recently, various novel robotic systems have been put into clinical use. The aim of the present study was to assess the perioperative outcomes of robot-assisted radical prostatectomy (RARP) using the Hugo™ RAS system, one of brand-new robot-assisted surgical platforms. We performed RARP with the Hugo™ RAS system in 13 cases of localized prostate cancer (PCa) between August 2023 and February 2024 at our hospital. The perioperative outcomes of these 13 patients were assessed. The median operative and console times were 197 (interquartile range [IQR], 187-228) and 134 min (IQR, 125-157), respectively. The median docking time was 7 min (IQR, 6-10), and the median estimated blood loss was 150 mL (IQR, 80-250). The vesical catheter was removed on postoperative day 6 in all cases. A positive surgical margin was observed in one patient (7.7%), and none experienced major perioperative complications, defined as Clavien-Dindo classification ≥3. The median postoperative length of stay was 8 days (IQR, 8-8.5). This was the first study to focus on RARP using the Hugo™ RAS system in Japan. Although further investigations should be conducted to assess the long-term oncological and functional outcomes, the Hugo™ RAS system could provide safe and favorable perioperative outcomes for patients with localized PCa undergoing RARP.

Precision low-dose brachytherapy of prostate cancer under PSMA-receptor molecular visualization

Brachytherapy with implantation of micro sources based on isotope 125I is a preferred treatment for localized prostate cancer without signs of germination of the gland capsule and in the absence of signs of metastases (stage cT1-T23aN0M0). Structural imaging methods (ultrasound, computed tomography, and magnetic resonance imaging) do not have high specificity in the differential diagnosis of prostate cancer. Hybrid technologies of radiation imaging (single-photon emission computed tomography/computed tomography, positron emission tomography/computed tomography, and positron emission tomography/magnetic resonance imaging) combine the advantages of high sensitivity of cross-sectional structural imaging methods (computed tomography and magnetic resonance imaging) and high specificity of molecular imaging methods (single-photon emission computed tomography and positron emission tomography) with tumorotropic radiopharmaceuticals. In this original clinical study, based on seven observations of localized prostate cancer (Gleason 67), it was shown that the precision of low-dose brachytherapy using 125I micro sources of localized prostate carcinomas, along with targeted biopsy, can be increased using hybrid methods of PSMA-receptor molecular imaging (single-photon emission computed tomography/ computed tomography, positron emission tomography/ computed tomography). The single-photon emission computed tomography/ computed tomography method is more accessible than positron emission tomography/ computed tomography. Moreover, when coupled with cold kits (HYNIC-PSMA), it allows research within any radioisotope diagnostics laboratory equipped with single-photon emission computed tomography/ computed tomography. The innovative technology of PSMA-navigation biopsy and brachytherapy, under the control of hybrid molecular imaging, can be used in primary and recurrent cases of localized prostate cancer, increases the accuracy and reduces the traumatic nature of procedures, and increases the medical and economic efficiency of low-dose brachytherapy with 125I micro sources. Further research is needed to improve the technology and evaluate its long-term results.

Development and external validation of multivariate prediction models for erectile dysfunction in men with localized prostate cancer.

While the 10-year survival rate for localized prostate cancer patients is very good (>98%), side effects of treatment may limit quality of life significantly. Erectile dysfunction (ED) is a common burden associated with increasing age as well as prostate cancer treatment. Although many studies have investigated the factors affecting erectile dysfunction (ED) after prostate cancer treatment, only limited studies have investigated whether ED can be predicted before the start of treatment. The advent of machine learning (ML) based prediction tools in oncology offers a promising approach to improve the accuracy of prediction and quality of care. Predicting ED may help aid shared decision-making by making the advantages and disadvantages of certain treatments clear, so that a tailored treatment for an individual patient can be chosen. This study aimed to predict ED at 1-year and 2-year post-diagnosis based on patient demographics, clinical data and patient-reported outcomes (PROMs) measured at diagnosis. We used a subset of the ProZIB dataset collected by the Netherlands Comprehensive Cancer Organization (Integraal Kankercentrum Nederland; IKNL) that contained information on 964 localized prostate cancer cases from 69 Dutch hospitals for model training and external validation. Two models were generated using a logistic regression algorithm coupled with Recursive Feature Elimination (RFE). The first predicted ED 1 year post-diagnosis and required 10 pre-treatment variables; the second predicted ED 2 years post-diagnosis with 9 pre-treatment variables. The validation AUCs were 0.84 and 0.81 for 1 year and 2 years post-diagnosis respectively. To immediately allow patients and clinicians to use these models in the clinical decision-making process, nomograms were generated. In conclusion, we successfully developed and validated two models that predicted ED in patients with localized prostate cancer. These models will allow physicians and patients alike to make informed evidence-based decisions about the most suitable treatment with quality of life in mind.

Localized prostate cancer: An analysis of the Centers for Disease Control and Prevention Breast and Prostate Cancer Data Quality and Patterns of Care study (CDC PoC-BP).

Limited evidence exists on the comparative effectiveness of local treatments for prostate cancer (PCa) due to the lack of generalizability. Using granular national data, we sought to examine the association between radical prostatectomy (RP) and intensity-modulated radiation therapy (IMRT) treatment and survival. Records were abstracted for localized PCa cases diagnosed in 2004 across seven state registries to identify patients undergoing RP (n=3019) or IMRT (n=667). Comorbidity was assessed by the Adult Comorbidity Evaluation-27 (ACE-27). Propensity score matching (PSM) was used to balance covariates between treatment groups. All-cause and PCa-specific mortality were primary endpoints. A subgroup analysis of patients with high-risk PCa (RP, n=89; IMRT, n=95) was conducted. Following PSM, matched patients (n=502 pairs) treated with either RP or IMRT were well-balanced with respect to covariates. With a median followup of 10.5 years (interquartile range [IQR] 9.9-11.0), the 11-year overall survival (OS) was 71.2% (95% confidence interval [CI] 66.9-75.8) for RP and 62.3% (95% CI 57.4-67.6) for IMRT. IMRT was associated with a 41% increased risk of all-cause mortality (hazard ratio [HR] 1.41, 95% CI 1.13-1.76) but not PCa-specific mortality (HR 1.75, 95% CI 0.84-3.64), as compared to RP. In patients with high-risk PCa, IMRT, as compared to RP, was not associated with a statistically significant difference in all-cause (HR 1.53, 95% CI 0.97-2.42) or PCa-specific mortality (HR 1.92, 95% CI 0.69-5.36). Despite a low mortality rate at 10 years and possible residual confounding, we found a significantly increased risk of all-cause mortality but no PCa-specific mortality associated with IMRT as compared to RP in this population-based study.

HOXB5 Overexpression Is Associated with Neuroendocrine Differentiation and Poor Prognosis in Prostate Cancer.

Homeobox genes function as master regulatory transcription factors during embryogenesis. HOXB5 is known to play an important role in several cancers. However, the biological role of HOXB5 in prostate cancer (PCa) is not fully elucidated. This study aimed to analyze the expression and function of HOXB5 and involvement of HOXB5 in neuroendocrine differentiation in PCa. Immunohistochemistry showed that 56 (43.8%) of 128 cases of localized PCa were positive for HOXB5. HOXB5-positive cases were associated with poor prostate-specific antigen recurrence-free survival after prostatectomy. Among 74 cases of metastatic PCa, 43 (58.1%) were positive for HOXB5. HOXB5 expression was higher in metastatic PCa than that in localized PCa. HOXB5 knockdown suppressed cell growth and invasion, but HOXB5 overexpression increased cell growth and invasion in PCa cell lines. Furthermore, HOXB5 regulated RET expression. Gene set enrichment analysis revealed that Nelson androgen response gene set was enriched in low HOXB5 expression group. RB1 knockout increased HOXB5 expression. Of note, additional p53 knockdown further increased HOXB5 expression in RB1 knockout cells. In silico analysis showed that HOXB5 expression was increased in neuroendocrine PCa (NEPC). These results suggest that HOXB5 may be a promising prognostic marker after prostatectomy and is involved in progression to NEPC.

A Subset of Localized Prostate Cancer Displays an Immunogenic Phenotype Associated with Losses of Key Tumor Suppressor Genes.

A subset of primary prostate cancer expresses programmed death-ligand 1 (PD-L1), but whether they have a unique tumor immune microenvironment or genomic features is unclear. We selected PD-L1-positive high-grade and/or high-risk primary prostate cancer, characterized tumor-infiltrating lymphocytes with multiplex immunofluorescence, and identified genomic alterations in immunogenic and nonimmunogenic tumor foci. One quarter of aggressive localized prostate cancer cases (29/115) had tumor PD-L1 expression more than 5%. This correlated with increased density of CD8+ T cells, a large fraction coexpressing PD-1, versus absent PD-1 expression on sparse CD8 T cells in unselected cases. Most CD8+PD-1+ cells did not express terminal exhaustion markers (TIM3 or LAG3), while a subset expressed TCF1. Consistent with these CD8+PD-1+TCF1+ cells being progenitors, they were found in antigen-presenting cell niches in close proximity to MHC-II+ cells. CD8 T-cell density in immunogenic prostate cancer and renal cell carcinoma (RCC) was nearly identical. Shallow RB1 and BRCA2 losses, and deep deletions of CHD1, were prevalent, the latter being strongly associated with a dendritic cell gene set in The Cancer Genome Atlas. Tumor mutation burden was variable; neither high microsatellite instability nor CDK12 alterations were present. A subset of localized prostate cancer is immunogenic, manifested by PD-L1 expression and CD8+ T-cell content comparable with RCC. The CD8+ T cells include effector cells and exhausted progenitor cells, which may be expanded by immune checkpoint inhibitors (ICI). Genomic losses of RB1, BRCA2, and CHD1 may be drivers of this phenotype. These findings indicate that immunotherapies may be effective in biomarker-selected subpopulations of patients with localized prostate cancer.

A multi-level spatio-temporal analysis on prostate cancer outcomes

BackgroundGeographic and temporal variation in positive surgical margins (PSM) for prostate cancer after radical prostatectomy (RP) has been observed. However, it is unclear how much of this variation could be attributed to patient, surgeon, institution, or socioeconomic-related factors and the impact of PSM on death among localized prostate cancer patients. MethodsThis study aimed to assess the independent and relative contribution of the patient, surgeon, institution and area-level risk factors on geographic and temporal variation of PSM and evaluate the impact of PSM on five-year all-cause and prostate cancer-specific mortality among localized prostate cancer patients. Within the hierarchical-related regression approach, we utilised Bayesian spatial-temporal multi-level models to study individual and area-level predictors with the outcomes, while accounting for geographically structured and unstructured correlation and non-linear trends. ResultsIndividual-level data included 10,075 localized prostate cancer cases with RP reported to the Prostate Cancer Outcomes Registry Victoria between 2009 and 2018. Area-level data comprised socio-economic disadvantage and remoteness data at the local government area level in Victoria, Australia. 26 % of patients had PSM, and the rates varied across areas by years. This variation was mainly associated with NCCN risk, followed by RP techniques, surgical institution type, surgeon volume and socio-economic disadvantage. Intermediate (Odds ratio/OR = 1.21,95 % credible interval/Crl = 1.05−1.41), high/very-high risk groups (OR = 2.24,95 % Crl = 1.91−2.64) and public surgical institution (OR = 1.64, 95 % Crl = 1.46−1.84) were independently associated with a higher likelihood of PSM. Robot-assisted (OR = 0.61, 95 % Crl = 0.55−0.68), laparoscopic RP (OR = 0.76, 95 % Crl = 0.62−0.93), high-volume surgeon (OR = 0.84, 95 % Crl = 0.76−0.93) and socio-economically least disadvantaged status (OR = 0.78, 95 % Crl = 0.64−0.94) showed a lower likelihood of PSM. PSM was also independently associated with a higher five-year all-cause and prostate cancer-specific mortality. ConclusionAggressive tumour characteristics and RP techniques were the main contributors to the likelihood of PSM following RP. Reducing the prevalence of PSM will generally improve prostate cancer-specific and all-cause mortality.

Radiation dose homogeneity and critical organs in radiotherapy treatment of prostate cancer

Present study compares two different 3D radiotherapy techniques: three-dimensional conformal radiotherapy (3D-CRT) and 3D external-beam radiation dose fields from computerized treatment plans, produced for 30 prostate cancer patients. All of the patients were the subject of treatment at the National Cancer Institute in Egypt. Evaluation was made of dose homogeneity within the target volume and the dose to critical organs (organs at risk, OAR). The plans were based on CT scans, all for cases of localized prostate cancer (all stage T2N0M0), with the CT scans transferred to the treatment planning systems. Comparison of the two different 3D radiation techniques was made in terms of isodose distributions and dose-volume histograms. The percentage of the planning target volume receiving 95% (V95) and 107% (V107) of the prescribed dose were obtained. For the 3D-CRT technique, the mean values for these were respectively 90.6% and 5.7% while for the other 3D technique they were 94.9% and 3.8%. In examining the dose received by the OAR, use of the 3D-CRT technique was found to provide the preferred dose distribution, with much greater sparing of the bladder, rectum and head of both femora. For the rectum the mean V70, V75 and D95 values (the latter referring to doses to 95% of the treatment volume) for the 3D-CRT technique were 35.5%, 32.2% and 34% while for the other 3D technique these were 8.4%, 0.2% and 12% respectively. For the bladder, the mean V40 and V65 values obtained using the 3D-CRT technique were 80.8% and 74.9% while for the alternative 3D technique they were 20.4% and 17% respectively. Thus for the particular cohort, the 3D-CRT technique provided superior target coverage and reduction of dose to the OAR.

MP19-18 ROBOT-ASSISTED LAPAROSCOPIC RADICAL PROSTATECTOMY (RARP) PERFORMED VIA TRANSPERITONEAL AND EXTRAPERITONEAL APPROACHES: PERIOPERATIVE AND EARLY ONCOLOGIC OUTCOMES FROM A SINGLE SURGEON EXPERIENCE

You have accessJournal of UrologyProstate Cancer: Localized: Surgical Therapy I (MP19)1 Apr 2020MP19-18 ROBOT-ASSISTED LAPAROSCOPIC RADICAL PROSTATECTOMY (RARP) PERFORMED VIA TRANSPERITONEAL AND EXTRAPERITONEAL APPROACHES: PERIOPERATIVE AND EARLY ONCOLOGIC OUTCOMES FROM A SINGLE SURGEON EXPERIENCE Yu Xia*, Shuai Jiang, and Jianming Guo Yu Xia*Yu Xia* More articles by this author , Shuai JiangShuai Jiang More articles by this author , and Jianming GuoJianming Guo More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000852.018AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: To compare the perioperative and early oncologic outcomes after transperitoneal (Tp-RARP) and extraperitoneal (Ep-RARP) robot-assisted laparoscopic radical prostatectomy for localized prostate cancer. METHODS: We retrospectively collected the clinical data of 337 localized prostate cancer cases done by a single surgeon, in which 182 patients were treated by Tp-RARP, and 155 underwent Ep-RARP. Tp-RARP were mostly done from May 2015 to Nov 2017, and Ep-RARP from Dec 2017 to Mar 2019. RESULTS: There was no significant difference for age, body mass index (BMI), preoperative prostate-specific antigen, pathological stage and Gleason score, tumor volume, positive surgical margin, lymph node status, blood loss, bladder catheterization time and complication rates between these two different approaches. Ep-RARP had shorter operative time (102.6 mins for Ep-RARP and 125.6 for Tp-RARP, P<0.001) and faster patient oral diet intake (9.3 vs and 23.6 hours, respectively, P<0.001). The average hospitalization time were 6.6 and 8.5 days after Ep-RARP and Tp-RARP (P<0.05). For patients with prior abdominal surgical history, the operative time difference between Ep and Tp-RARP was even greater (114.5 vs 154.1 mins, P<0.001). For those patients with BMI>32, the Ep-RARP approach also has advantages in shorter operative time and less blood loss. CONCLUSIONS: Ep-RARP is a well-developed technique which has the advantages of shorter operation time and less bowel disturbance rate compared with traditional Tp-RARP, especially in patients with prior abdominal surgical history or obesity. However, further multi-centered randomized controlled trials are need for evaluating its safety and efficacy. Source of Funding: The authors declare no conflict of interest © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e304-e305 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yu Xia* More articles by this author Shuai Jiang More articles by this author Jianming Guo More articles by this author Expand All Advertisement PDF downloadLoading ...

Detection of Molecular Signatures of Homologous Recombination Deficiency in Prostate Cancer with or without BRCA1/2 Mutations

Prostate cancers with mutations in genes involved in homologous recombination (HR), most commonly BRCA2, respond favorably to PARP inhibition and platinum-based chemotherapy. We investigated whether other prostate tumors that do not harbor deleterious mutations in these particular genes can similarly be deficient in HR, likely rendering those sensitive to HR-directed therapies. Homologous recombination deficiency (HRD) levels can be estimated using various mutational signatures derived from next-generation sequencing data. We used this approach on whole-genome sequencing (WGS; n = 311) and whole-exome sequencing (WES) data (n = 498) of both primary and metastatic prostate adenocarcinomas to determine whether prostate cancer cases display clear signs of HRD in somatic tumor biopsies. Known BRCA-deficient samples showed all previously described HRD-associated mutational signatures in the WGS data. HRD-associated mutational signatures were also detected in a subset of patients who did not harbor germline or somatic mutations in BRCA1/2 or other HR-related genes. Similar results, albeit with lower sensitivity and accuracy, were also obtained from WES data. These findings may expand the number of cases likely to respond to PARP inhibitor treatment. On the basis of the HR-associated mutational signatures, 5% to 8% of localized prostate cancer cases may be good candidates for PARP-inhibitor treatment (including those with BRCA1/2 mutations).

Low Abundance of Circulating Tumor DNA in Localized Prostate Cancer.

PURPOSEDespite decreased screening-based detection of clinically insignificant tumors, most diagnosed prostate cancers are still indolent, indicating a need for better strategies for detection of clinically significant disease before treatment. We hypothesized that patients with detectable circulating tumor DNA (ctDNA) were more likely to harbor aggressive disease.METHODSWe applied ultra-low-pass whole-genome sequencing to profile cell-free DNA from 112 patients diagnosed with localized prostate cancer and performed targeted resequencing of plasma DNA for somatic mutations previously identified in matched solid tumor in nine cases. We also performed similar analyses of data from patients with metastatic prostate cancer.RESULTSIn all cases of localized prostate cancer, even in clinically high-risk patients who subsequently had recurrent disease, ultra-low-pass whole-genome sequencing and targeted resequencing did not detect ctDNA in plasma acquired before surgery or before recurrence. In contrast, using both approaches, ctDNA was detected in patients with metastatic prostate cancer.CONCLUSIONOur findings demonstrate clear differences between localized and advanced prostate cancer with respect to the dissemination and detectability of ctDNA. Because allele-specific alterations in ctDNA are below the threshold for detection in localized prostate cancer, other approaches to identify cell-free nucleic acids of tumor origin may demonstrate better specificity for aggressive disease.

Management Strategies and Patient Selection After a Hospital Funding Reform for Prostate Cancer Surgery in Canada

Hospital funding reforms for prostate cancer surgery may have altered management of localized prostate cancer in the province of Ontario, Canada. To determine whether changes in hospital funding policy aimed at improving health care quality and value were associated with changes in the management of localized prostate cancer or the characteristics of patients receiving radical prostatectomy (RP) for localized prostate cancer. This population-based, interrupted time series study used linked population-based administrative data regarding adults in Ontario with incidental localized prostate cancer and those who underwent RP for localized prostate cancer. Patients who underwent RP were compared with patients who underwent surgical procedures for localized renal cell carcinoma, which was not included in the policy change but was subjected to similar secular trends and potential confounders. Monthly outcomes were analyzed using interventional autoregressive integrated moving average models. Data were collected from January 2011 to November 2017 and analyzed in January 2019. Funding policy change in April 2015 from flexible block funding for all hospital-based care to prespecified payment amounts per procedure for treatment of localized prostate cancer, coupled with the dissemination of a diagnosis-specific handbook outlining best practices. Initial management (RP vs radiation therapy vs active surveillance) and tumor risk profiles per management strategy among incident cases of localized prostate cancer. Additional outcomes were case volume, mean length of stay, proportion of patients returning to hospital or emergency department within 30 days, proportion of patients older than 65 years, mean Charlson Comorbidity Index, and proportion of minimally invasive surgical procedures among patients undergoing RP for localized prostate cancer. A total of 33 128 patients with incident localized prostate cancer (median [interquartile range (IQR)] age, 67 [61-73] years; median [IQR] cases per monthly observation interval, 466 [420-516]), 17 159 patients who received radical prostatectomy (median [IQR] age, 63 [58-68] years; median [IQR] cases per monthly observation interval, 209 [183-225]), and 5762 individuals who underwent surgery for renal cell carcinoma (median [IQR] age, 62 [53-70] years; median [IQR] cases per monthly observation interval, 71 [61-77]) were identified. By the end of the observation period, radical prostatectomy and radiation therapy were used in comparable proportions (30.3% and 28.9%, respectively) and included only a small fraction of low-risk patients (6.4% and 2.9%, respectively). No statistically significant association of the funding policy change with most outcomes was found. The implementation of funding reform for hospitals offering RP was not associated with changes in the management of localized prostate cancer, although it may have encouraged more appropriate selection of patients for RP. Mostly preexisting trends toward guideline-conforming practice were observed. Co-occurring policy changes and/or guideline revisions may have weakened signals from the policy change.

Shifting patterns of care in localized prostate cancer: Impact on patient reported outcome measures (PROMs).

e16603 Background: In localized prostate cancer (LPC), evolving therapeutic techniques and patterns of care including the use of active surveillance (AS) are expected to have had a positive effect on quality of life. A longitudinal assessment of changes in disease presentations and patterns of care in LPC correlated to PROMs is required. Methods: All cases of LPC (T1-T4, N0-N1) at a tertiary care institution were identified between 2005 and 2015. Two cohorts (C1: 2005-10, C2: 2010-15) with a minimum of 2-years follow-up, were identified. Demographics, disease characteristics and management strategies were compared across cohorts. To assess PROMs, a one-time questionnaire including EPIC-26 and Clark’s Quality of Life was administered. Domain summary scores were compared across cohorts. Results: 873 patients met criteria [C1: 422, C2: 535]. Demographics were well balanced (p = 0.10): overall 64.1% white, 12.7% AA, 12.7% Asian. D’Amico risk scores increased over time (p = 0.001): fewer low-risk cases [C1: 49.2%, C2: 43.7%], higher intermediate-risk disease [C1: 34.6%, C2: 40.3%], and stable high-risk proportions [C1: 15.7%, C2: 14.9%]. Patterns of care shifted significantly (p = 0.005) with a marked decrease in radiation therapy [C1: 25.7%, C2: 15.4%], unchanged radical prostatectomy rates [C1: 47.9%, C2: 51.0%], a shift to robotic surgery [C1: 23.8%, C2: 90.3%], and an increase in AS [C1: 21.8%, C2: 30.8%], particularly in low-risk disease [C1: 32.4%, C2: 53.5%]. Questionnaire response rate was 45.1%. Using multivariate regression, C2 demonstrated an improvement in bowel function (p = 0.031) but not in urinary, sexual, or psychometric scores. Conclusions: Notwithstanding an increase in AS utilization for low-risk disease, an improvement in bowel function and lack of improvement in urinary/sexual PROMs in LPC across time-cohorts was noted. This may be accounted for by increased presentations of higher-risk disease managed with robotic surgeries at the expense of radiation therapy. Although time-length bias can influence comparisons, given national trends with a similar shift in presentation and care patterns, these PROM correlations are likely generalizable to the U.S. population.

PCN213 RACIAL-ETHNIC DISPARITIES IN ADDITIONAL SURGICAL PROCEDURES UP TO FIVE YEARS AFTER INITIAL TREATMENT FOR LOCALIZED PROSTATE CANCER, SEER-MEDICARE, 2004-2013

We sought to describe disparities in additional surgical procedures up to 5 years after initial treatment for localized prostate cancer. We analyzed localized prostate cancer cases reported in 2004–2013 to Surveillance, Epidemiology and End Results (SEER) cancer registries, and linked with Medicare claims. We used a Cox regression model to calculate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for receipt of additional surgical procedures up to 5 years after initial treatment, adjusting for: the type of initial treatment; SEER race/ethnicity; age group; Gleason score; Charlson comorbidity score; and procedures prior to initial treatment. Our final study cohort included a total of 111,069 men with localized prostate cancer, with 86,798 non-Hispanic white, 11,032 non-Hispanic black, 3,955 non-Hispanic Asian or Pacific Islanders (APIs), and 6,454 Hispanic any race. During follow-up after initial treatment, after adjustment, non-Hispanic blacks were less likely than non-Hispanic whites to receive cystoscopy (HR, 0.939; 95% CI, 0.893-0.987) and more likely to receive urethral dilation (HR, 1.130; 95% CI, 1.049-1.217) or bladder irrigation/cystotomy (HR 1.094; 95% CI, 1.002-1.194). Non-Hispanic APIs were less likely than non-Hispanic whites to receive artificial urinary sphincter (HR, 0.607; 95% CI, 0.411-0.897), cystoscopy (HR, 0.805; 95% CI, 0.740-0.875), urethral dilation (HR, 0.751; 95% CI, 0.653-0.863), TURP/bladder neck procedures (HR, 0.698; 95% CI, 0.561-0.869), or bladder irrigation/cystotomy (HR, 0.636; 95% CI, 0.531-0.760). Hispanics of any race were more likely than non-Hispanic whites to receive urethral dilation (HR, 1.125; 95% CI, 1.026-1.233). Racial-ethnic disparities were present in additional surgical procedures up to 5 years after initial treatment for localized prostate cancer during 2004-2013.

Protocadherin B9 promotes resistance to bicalutamide and is associated with the survival of prostate cancer patients.

Background Prostate cancer (PCa) is a common malignancy worldwide and is the second leading cause of cancer death in men. The standard therapy for advanced PCa is androgen deprivation therapy (ADT). Although ADT, including bicalutamide treatment, is initially effective, resistance to bicalutamide frequently occurs and leads to the development of castration-resistant PCa. Thus, clarifying the mechanisms of bicalutamide resistance is urgently needed. We designed this study to assess the expression and function of PCDHB9, which encodes the protocadherin B9 protein. Methods The expression of PCDHB9 was determined using immunohistochemistry and a qRT-PCR. The effects of the overexpression or knockdown of PCDHB9 on cell growth, migration, adhesion were evaluated. To evaluate the PCDHB9-mediated effects in PCa, we performed a gene expression analysis using DU145 transfected with PCDHB9. We examined the effects of PCDHB9 inhibition on bicalutamide resistance. Results The qRT-PCR revealed that the expression of PCDHB9 was much higher in PCa than that in non-neoplastic prostate tissues. In 152 clinically localized PCa cases immunohistochemistry showed that 59% of PCa cases were positive for protocadherin B9. A Kaplan-Meier analysis showed that the high expression of protocadherin B9 was associated with PSA recurrence after radical prostatectomy. A functional analysis showed that PCDHB9 modulated cell migration and adhesion. We also found that PCDHB9 induced the expression of ITGB6 based on a gene expression analysis. The effect of PCDHB9 inhibition on bicalutamide sensitivity was examined using MTT assays. The IC50 value of PCDHB9 siRNA-transfected PCa cells was significantly lower than that of negative control siRNA-transfected cells. Furthermore, immunohistochemical staining of protocadherin B9 in 74 PCa patients who were treated with androgen depletion therapy, including bicalutamide treatment, demonstrated that the high expression of protocadherin B9 was significantly associated with poor overall survival. Conclusions PCDHB9 plays an important role in the progression of PCa and bicalutamide resistance. Collectively, our results suggest that PCDHB9 targeted therapy may be more effective than bicalutamide alone.

Association of ERG/PTEN status with biochemical recurrence after radical prostatectomy for clinically localized prostate cancer.

We have previously demonstrated a significant correlative relationship between PTEN deletion and ERG rearrangement, both in the development of clinically localized prostate cancers and metastases. Herein, we evaluate the cooperative role of ERG and PTEN in oncological outcomes after radical prostatectomy for clinically localized prostate cancer. We evaluated ERG and PTEN status using three previously described cohorts. The first cohort included 235 clinically localized prostate cancer cases represented on tissue microarrays (TMA), evaluated using previously validated FISH assays for ERG and PTEN. The second cohort included 167 cases of clinically localized prostate cancer on TMAs evaluated for PTEN by FISH, and for PTEN and ERG by dual IHC. The third cohort comprised 59 clinically localized prostate cancer cases assessed by array comparative genomic hybridization (aCGH). Kaplan-Meir plots and long rank tests were used to assess the association of ERG and PTEN status with biochemical recurrence after radical prostatectomy for clinically localized prostate cancer. Of the 317 cases eligible for analyses with evaluable ERG and PTEN status, 88 (27.8%) patients developed biochemical recurrence over a median follow-up of 5.7years. Overall, 45% (142/317) of cases demonstrated ERG rearrangement and 20% (62/317) of cases demonstrated PTEN loss. Hemizygous and homozygous deletion of PTEN was seen in 10% (18/175) and 3% (5/175) of ERG-negative cases, respectively. In contrast, hemizygous and homozygous deletion of PTEN was seen in 11% (15/142) and 17% (24/123) of ERG-positive cases, respectively. PTEN loss (heterozygous or homozygous) was significantly associated with shorter time to biochemical recurrence compared to no PTEN loss (p < 0.001). However, ERG rearrangement versus no rearrangement was not associated with time to PSA recurrence (p = 0.15). Patients who exhibited ERG rearrangement and loss of PTEN had no significant difference in time to recurrence compared to patients with wild-type ERG and loss of PTEN (p = 0.30). Our findings confirm a mutual cooperative role of ERG and PTEN in the pathogenesis of prostate cancer, particularly for homozygous PTEN deletion. ERG did not stratify outcome either alone or in combination with PTEN in this cohort.

Relationships between Circulating and Intraprostatic Sex Steroid Hormone Concentrations.

Background: Sex hormones have been implicated in prostate carcinogenesis, yet epidemiologic studies have not provided substantiating evidence. We tested the hypothesis that circulating concentrations of sex steroid hormones reflect intraprostatic concentrations using serum and adjacent microscopically verified benign prostate tissue from prostate cancer cases.Methods: Incident localized prostate cancer cases scheduled for surgery were invited to participate. Consented participants completed surveys, and provided resected tissues and blood. Histologic assessment of the ends of fresh frozen tissue confirmed adjacent microscopically verified benign pathology. Sex steroid hormones in sera and tissues were extracted, chromatographically separated, and then quantitated by radioimmunoassays. Linear regression was used to account for variations in intraprostatic hormone concentrations by age, body mass index, race, and study site, and subsequently to assess relationships with serum hormone concentrations. Gleason score (from adjacent tumor tissue), race, and age were assessed as potential effect modifiers.Results: Circulating sex steroid hormone concentrations had low-to-moderate correlations with, and explained small proportions of variations in, intraprostatic sex steroid hormone concentrations. Androstane-3α,17β-diol glucuronide (3α-diol G) explained the highest variance of tissue concentrations of 3α-diol G (linear regression r2 = 0.21), followed by serum testosterone and tissue dihydrotestosterone (r2 = 0.10), and then serum estrone and tissue estrone (r2 = 0.09). There was no effect modification by Gleason score, race, or age.Conclusions: Circulating concentrations of sex steroid hormones are poor surrogate measures of the intraprostatic hormonal milieu.Impact: The high exposure misclassification provided by circulating sex steroid hormone concentrations for intraprostatic levels may partly explain the lack of any consistent association of circulating hormones with prostate cancer risk. Cancer Epidemiol Biomarkers Prev; 26(11); 1660-6. ©2017 AACR.

The outcome of prostate cancer patients treated with curative intent strongly depends on survival after metastatic progression

BackgroundFive-year survival in patients with localized prostate cancer (PCa) is nearly 100%, but metastatic disease still remains incurable. Clinical management of metastatic patients has become increasingly complex as novel therapeutic strategies have emerged. This study aims at evaluating the impact of the first metastatic progression on the outcome of PCa patients treated with curative intent.MethodsThe analysis was conducted using data of 913 cases of localized PCa diagnosed between 2000 and 2014. All patients were treated with curative surgery (N = 382) or radiotherapy (N = 531) with or without adjuvant therapy. All metastases were radiologically documented. The prognostic impact of the first site of metastasis on metastasis-free survival (MFS) and PCa-specific survival (PCaSS) was investigated by univariate and multivariate analyses.ResultsOne hundred and thirty-six (14.9%) patients developed a metastatic hormone-sensitive PCa and had a median PCaSS of 50.4 months after first metastatic progression. Bone (N = 50, 36.8%) and LN or locoregional (N = 52, 38.2%) metastases occurred more frequently with a median PCaSS of 39.7 and 137 months respectively (p < 0.0001). Seven patients developed visceral metastasis only (5.1%; liver, lung, brain) and 27 (19.9%) concurrent metastases; this last group was associated with the worst survival with a median value of only 17 months. Thus, each subgroup exhibited a survival after metastasis significantly different from each other. In multivariate analysis the site of the first metastasis was an independent prognostic factor for PCaSS along with Gleason score at diagnosis. The correlation between survival and first site of metastasis was confirmed separately for each therapy subgroup. Median metastasis-free survival from primary diagnosis to first metastasis was not correlated with the first site of metastasis.ConclusionsIn non-metastatic PCa patients treated with curative intent, the PCa-specific survival time depends on the time after metastatic progression rather than the time from diagnosis to metastasis. Moreover, the site of first metastasis is an independent prognostic factor for PCaSS. Our data confirm that the first metastatic event may confer a differential prognostic impact and may help in identifying patient at high risk of death supporting the treatment-decision making process following metastatic progression.

Abstract 751: Characterization of STAT3 activation in human prostate cancer

Abstract Signal transducers and activators of transcription (STATs) were initially associated with cytokine signal transduction pathways but are now also recognized as key modulators of key survival processes in in various cancers. Activation of STAT3 occurs by the binding of various cytokines to its receptors leading to the activation of the JAK/ STAT3 signaling pathway. Interleukin-6 (IL-6) has been implicated in regulating growth of various malignant tumors. Activated IL-6 has also been shown to be elevated in the sera from patients with metastatic prostate cancer, and persistent activation of STAT3 is a common feature. To better characterize the potential role of JAK/STAT3 as a therapeutic target for advanced prostate cancer, we examined expression patterns of activated STAT3 in 111 cases of localized prostate cancer from patients who underwent radical prostatectomy. Association studies were conducted with clinicopathological characteristics and biochemical recurrence. We also analyzed the expression of IL-6/KAK/STAT3 genes from RNA-sequencing data form the Cancer Genome Atlas Prostate Adenocarcinoma (TCGA-PRAD) data set and its association to long-term outcomes. Immunohistochemical analysis revealed that 11.7%, 42.3% and 45.9% of patients had high, moderate or low/negative expression of phosphorylated-STAT3 (Tyr705). Cancerous glands tended to have higher STAT3 expression compared to paired normal adjacent tissue, P=0.088. No correlations were observed between STAT3 expression and clinicopathological parameters. Patients with moderate-high p-STAT3 expression tended to experience shorter times to biochemical recurrence (median time, 15 months) compared to patients with low/negative STAT3 activity, (median time to recurrence not reached, P=0.064). Cluster analysis suggested a trend for decreased disease-free survival for patients with high IL-6/KAK/STAT3 gene expression signature. Our data suggests an association between STAT3 signaling and prostate cancer recurrence and provides clinical evidence to support JAK/STAT3 as a potential therapeutic target for patients with advanced prostate cancer. Citation Format: Marco A. De Velasco, Yuji Hatanaka, Yurie Kura, Naomi Ando, Kazuko Sakai, Koichi Sugimoto, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Characterization of STAT3 activation in human prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 751. doi:10.1158/1538-7445.AM2017-751

Dosimetric and radiobiological comparison of Cyberknife and Tomotherapy in stereotactic body radiotherapy for localized prostate cancer.

As recent studies have suggested relatively low α/β for prostate cancer, the interest in hypofractionated stereotactic body radiotherapy (SBRT) for prostate cancer is rising. The aim of this study is to compare dosimetric results of Cyberknife (CK) with Tomotherapy (HT) in SBRT for localized prostate cancer. Furthermore, the radiobiologic consequences of heterogeneous dose distribution are also analyzed. A total of 12 cases of localized prostate cancer previously treated with SBRT were collected. Treatments had been planned and delivered using CK. Then HT plans were generated for comparison afterwards. The prescribed dose was 37.5Gy in 5 fractions. Dosimetric indices for target volumes and organs at risk (OAR) were compared. For radiobiological evaluation, generalized equivalent uniform dose (gEUD) and normal tissue complication probability (NTCP) were calculated and compared. Both CK and HT achieved target coverage while meeting OAR constraints adequately. HT plans resulted in better dose homogeneity (Homogeneity index: 1.04±0.01 vs. 1.21±0.01; p = 0.0022), target coverage (97.74±0.86% vs. 96.56±1.17%; p = 0.0076) and conformity (new vonformity index: 1.16±0.05 vs. 1.21±0.04; p = 0.0096). HT was shown to predict lower late rectal toxicity as compared to CK. Integral dose to body was also significantly lower in HT plans (46.59±6.44 Gy'L vs 57.05±11.68 Gy'L; p = 0.0029). Based on physical dosimetry and radiobiologic considerations, HT may have advantages over CK, specifically in rectal sparing which could translate into clinical benefit of decreased late toxicities.