Treatment Of Organ-confined Prostate Cancer Research Articles

Immune effects of α and β radionuclides in metastatic prostate cancer.

External beam radiotherapy is used for radical treatment of organ-confined prostate cancer and to treat lesions in metastatic disease whereas molecular radiotherapy with labelled prostate-specific membrane antigen ligands and radium-223 (223Ra) is indicated for metastatic prostate cancer and has demonstrated substantial improvements in symptom control and overall survival compared with standard-of-care treatment. Prostate cancer is considered an immunologically cold tumour, so limited studies investigating the treatment-induced effects on the immune response have been completed. However, emerging data support the idea that radiotherapy induces an immune response in prostate cancer, but whether the response is an antitumour or pro-tumour response is dependent on the radiotherapy regime and is also cell-line dependent. In vitro data demonstrate that single-dose radiotherapy regimes induce a greater immune-suppressive profile than fractionated regimes; less is known about the immune response induced by molecular radiotherapy agents, but evidence suggests that these agents might induce an immune-suppressive systemic immune response, indicated by increased expression of inhibitory checkpoint molecules such as programmedcelldeath 1ligand 1 and 2, and that these changes could be associated with clinical response. Different radiotherapy modalities can induce distinct immune profiles, which can either activate or suppress immune-mediated tumour killing and the current preclinical models used for prostate cancer research are not yet optimal for studying the complexity of the radiotherapy-induced immune response.

Testosterone Treatment of Men with Unequivocal Hypogonadism Following Treatment of Organ-Confined Prostate Cancer

ObjectiveTo determine if testosterone treatment of men with unequivocal hypogonadism and organ-confined prostate cancer is associated with recurrence of the cancer. The testosterone dependence of metastatic prostate cancer has made physicians reluctant to treat hypogonadal men with testosterone even after treatment of prostate cancer. Prior studies of testosterone treatment of men with treated prostate cancer have not documented that the men were unequivocally hypogonadal. MethodsA computerized search of electronic medical records from January 1, 2005, to September 20, 2021, identified 269 men aged ≥50 years who were diagnosed with prostate cancer and hypogonadism. We reviewed the individual records of these men and identified those treated by radical prostatectomy and had no evidence of extraprostatic extension. We then identified men who were hypogonadal prior to the diagnosis of prostate cancer based on at least 1 morning serum testosterone concentration of ≤220 ng/dL, discontinued testosterone treatment when the prostate cancer was diagnosed, resumed testosterone treatment within 2 years after treatment of the cancer, and were monitored for cancer recurrence, defined by a prostate-specific antigen level of ≥0.2 ng/mL. ResultsSixteen men met the inclusion criteria. Their baseline serum testosterone concentrations were 9-185 ng/dL. The median duration of testosterone treatment and monitoring was 5 years (range, 1-20 years). None of the 16 men had biochemical recurrence of prostate cancer during this period. ConclusionTestosterone treatment of men with unequivocal hypogonadism whose organ-confined prostate cancer is treated by radical prostatectomy may be safe.

MP73-09 A RETROSPECTIVE CLINICAL SERVICE EVALUATION OF LESION-TARGETED MRI-GUIDED TRANSURETHRAL ULTRASOUND ABLATION (TULSA) FOR THE TREATMENT OF LOCALIZED PROSTATE CANCER

You have accessJournal of UrologyCME1 Apr 2023MP73-09 A RETROSPECTIVE CLINICAL SERVICE EVALUATION OF LESION-TARGETED MRI-GUIDED TRANSURETHRAL ULTRASOUND ABLATION (TULSA) FOR THE TREATMENT OF LOCALIZED PROSTATE CANCER Rolf Muschter, Leonhard Steinmeister, and Agron Lumiani Rolf MuschterRolf Muschter More articles by this author , Leonhard SteinmeisterLeonhard Steinmeister More articles by this author , and Agron LumianiAgron Lumiani More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003341.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: MR-guided transurethral ultrasound ablation (TULSA) is a novel minimally-invasive therapy option for the treatment of organ-confined prostate cancer (PCa) through a whole-gland or lesion-targeted approach. TULSA has shown promising safety and oncological outcomes with minimum side-effect on patients urinary, bowel, and sexual functions. The objective of this retrospective single-center study was to perform a clinical service evaluation of lesion-targeted TULSA for patients with localized PCa. METHODS: Men with organ-confined PCa (proved by MRI and biopsy) received lesion-targeted TULSA with sparing of sphincter, urethra, and rectum. A customized treatment was planned for every patient based on his expectations and PCa characteristics. For a subset of men with concurrent PCa and benign prostate hyperplasia (BPH), TULSA was applied as a combined therapy. Repeat TULSA was allowed and a suprapubic catheter was used. The Clavien-Dindo stratification was used to assess the frequency and severity of all adverse events (AEs). Mid-term oncological outcomes were evaluated using multi-parametric MRI (mpMRI) and prostate-specific antigen (PSA). Surgeon-assessed functional outcomes were recorded. RESULTS: 180 patients (150 primary and 30 salvage) with median [IQR] age, baseline PSA, and follow-up availability of 67 [63-76], 8.0 ng/ml [5.2-13], and 12-mon (max 48), respectively, were treated. 40 patients experienced Grade 1 and 2 AEs, resolving within 4 weeks using antibiotics or relevant medication. Grade 3 AEs (urinary retention requiring surgical intervention) occurred in two patients, resolving within 3 months. No grade 4 or higher events and no bowel-related complications occurred. 98% of men preserved pad-free continence. 94/94 men, who were previously potent, maintained erectile potency. 85% of men with concurrent BPH and PCa experienced symptom relief. The mid-term oncological success rate was 88%. A single repeat TULSA was performed on 13 patients. CONCLUSIONS: Lesion-targeted TULSA is a safe and customizable prostate ablation therapy with promising mid-term oncological outcomes and minimal side-effect profile on patients erectile, bowel, and urinary functions. TULSA offers the flexibility to treat localized prostate cancer in a primary, salvage, or concurrent setting of BPH through a patient-tailored whole-gland or lesion-targeted approach. Source of Funding: No funding was received © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1038 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Rolf Muschter More articles by this author Leonhard Steinmeister More articles by this author Agron Lumiani More articles by this author Expand All Advertisement PDF downloadLoading ...

High-risk, recurrent and oligometastatic prostate cancer: recent developments on the role of radiation.

Although a standard of care in the treatment of organ-confined prostate cancer, use of radiation for treatment in the high-risk, metastatic and salvage settings is evolving rapidly. Recent clinical trials have explored the role of increased treatment for high-risk disease with the addition of adjuvant chemotherapy and expanded the role of radiation in settings previously reserved for systemic therapy. Addition of adjuvant chemotherapy for high-risk prostate cancer is controversial and recent evidence is discussed that continues to refine the patient population for further evaluation. Evidence recently published demonstrates that for patients with low burden metastatic disease and those with oligometastatic disease may have a survival benefit with radiation treatment to all sites of known disease. Finally, reirradiation after prior radiotherapy-based treatment offers a potential salvage option for patients with locally recurrent prostate cancer. As treatment paradigms evolve for prostate cancer, recent evidence continues to demonstrate benefit for the use of local therapy, both in patients with organ-confined disease and, more increasingly, in those with limited metastatic or locally recurrent disease. Further work is needed to identify subgroups of patients who may benefit from available treatment escalation approaches.

New Evolution of Robotic Radical Prostatectomy: A Single Center Experience with PERUSIA Technique

Radical prostatectomy (RP) is the standard surgical treatment of organ-confined prostate cancer in patients with a life expectancy of at least 10 years. In a recent prospective study, we described the PERUSIA (Posterior, Extraperitoneal, Robotic, Under Santorini, Intrafascial, Anterograde) technique, which is an extraperitoneal full nerve sparing robotic RP, showing its feasibility and safety. The aim of this retrospective study was to evaluate the peri-operative, oncologic, and functional outcomes of the PERUSIA technique. We retrospectively analyzed the data of 454 robotic-assisted radical prostatectomies (RARP) performed using the PERUSIA technique from January 2012 to October 2019. We evaluated perioperative outcomes (operative time, estimated blood loss, catheterization time, complication rate, length of stay), oncological (positive surgical margins and biochemical recurrence), and functional outcomes in terms of urinary continence and sexual potency. The overall complication rate was 16%, positive surgical margins were 8.1%, and biochemical recurrence occurred in 8.6% at median follow-up of 47 months. Urinary continence was achieved in 69% of cases the day after the removal of the catheter, in 92% at 3 months, and in 97% at 12 months after surgery. The average rate of sexual potency was 72% and 82% respectively 3 and 12 months after surgery. Our findings show that the PERUSIA technique is a safe extraperitoneal approach to perform a full nerve sparing technique providing exciting functional outcomes.

Should We Reconsider the Necessity of a Refinement of Prostate Cancer Risk Classification and Radiotherapy Treatment Strategy? Experiences from a Retrospective Analysis of Data from a Single Institution.

Background: Radiation therapy has undergone significant technical development in the past decade. However, the complex therapy of intermediate-risk patients with organ-confined prostate carcinoma still poses many questions. Our retrospective study investigated the impact of selected components of the treatment process including radiotherapy, hormone deprivation, risk classification, and patients’ response to therapy. Methods: The impact of delivered dose, planning accuracy, duration of hormone deprivation, risk classification, and the time to reach prostate-specific antigen (PSA) nadir state were analyzed among ninety-nine individuals afflicted with organ-confined disease. Progression was defined as a radiological or biochemical relapse within five years from radiotherapy treatment. Results: We found that 58.3% of the progressive population consisted of intermediate-risk patients. The progression rate in the intermediate group was higher (21.9%) than in the high-risk population (12.1%). Dividing the intermediate group, according to the International Society of Urological Pathology (ISUP) recommendations, resulted in the non-favorable subgroup having the highest rate of progression (33.3%) and depicting the lowest percentage of progression-free survival (66.7%). Conclusion: Extended pelvic irradiation on the regional lymph nodes may be necessary for the ISUP Grade 3 subgroup, similarly to the high-risk treatment. Therapy optimization regarding the intermediate-risk population based on the ISUP subgrouping suggestions is highly recommended in the treatment of organ-confined prostate cancer.

Impact of organ confined prostate cancer treatment on quality of life

IntroductionProstate cancer (PCa) is the second most common male cancer in the world. Its incidence is estimated to grow to 1.7 million new cases and 499,000 new deaths by 2030. Treatment of OCPC can affect patients physically and mentally, as well as their close relationships and their job or career, which conditions health-related quality of life (QoL). ObjectiveEvaluate the impact on QoL attributable to the treatment for Organ Confined Prostate Cancer (OCPC). Materials and methodsProspective multicenter observational study of 406 patients with OCPC treated from January 2015 to June 2018. The sample was divided into four study groups, according to the type of treatment: radical prostatectomy (RP) (GA), external radiotherapy (ERT) (GB), brachytherapy (BT) (GC) and other treatments different from monotherapy with RP, ERT or BT (GD). ResultsThe age in GC was lower, the mean Prostate Specific Antigen (PSA) of all patients was 8.13ng/ml, the group with the highest mean PSA was GB with a mean of 10.43ng/dL, the mean Tumor Stage (TNM) was 3.82, and GD had the lowest post treatment quality of life. ConclusionOCPC treatment affects QoL. Curative monotherapies, specifically RP and BT, have less effect on QoL than external radiotherapy or other therapeutic alternatives. Urinary incontinence and fistulas secondary to OCPC have the highest impact on QOL impairment. The internationally validated SF 36 questionnaire is a useful cross-sectional measure of QOL to compare the impact of OCPC treatment modalities.

Impacto en la calidad de vida del tratamiento del cáncer de próstata organoconfinado

IntroductionProstate cancer (PCa) is the second most common male cancer in the world. Its incidence is estimated to grow to 1.7 million new cases and 499,000 new deaths by 2030. Treatment of OCPC can affect patients physically and mentally, as well as their close relationships and their job or career, which conditions health-related quality of life (QoL). ObjectiveEvaluate the impact on QoL attributable to the treatment for Organ Confined Prostate Cancer (OCPC). Materials and methodsProspective multicenter observational study of 406 patients with OCPC treated from January 2015 to June 2018. The sample was divided into four study groups, according to the type of treatment: radical prostatectomy (RP) (GA), external radiotherapy (ERT) (GB), brachytherapy (BT) (GC) and other treatments different from monotherapy with RP, ERT or BT (GD). ResultsThe age in GC was lower, the mean Prostate Specific Antigen (PSA) of all patients was 8.13 ng/ml, the group with the highest mean PSA was GB with a mean of 10.43 ng/dL, the mean Tumor Stage (TNM) was 3.82, and GD had the lowest post treatment quality of life. ConclusionOCPC treatment affects QoL. Curative monotherapies, specifically RP and BT, have less effect on QoL than external radiotherapy or other therapeutic alternatives. Urinary incontinence and fistulas secondary to OCPC have the highest impact on QOL impairment. The internationally validated SF 36 questionnaire is a useful cross-sectional measure of QOL to compare the impact of OCPC treatment modalities.

Evaluation of a marker-less, intra-operative, augmented reality guidance system for robot-assisted laparoscopic radical prostatectomy.

Robot-assisted laparoscopic radical prostatectomy (RALRP) using the da Vinci surgical robot is a common treatment for organ-confined prostate cancer. Augmented reality (AR) can help during RALRP by showing the surgeon the location of anatomical structures and tumors from preoperative imaging. Previously, we proposed hand-eye and camera intrinsic matrix estimation procedures that can be carried out with conventional instruments within the patient during surgery, take <3min to perform, and fit seamlessly in the existing surgical workflow. In this paper, we describe and evaluate a complete AR guidance system for RALRP and quantify its accuracy. Our AR system requires three transformations: the transrectal ultrasound (TRUS) to da Vinci transformation, the camera intrinsic matrix, and the hand-eye transformation. For evaluation, a 3D-printed cross-wire was visualized in TRUS and stereo endoscope in a water bath. Manually triangulated cross-wire points from stereo images were used as ground truth to evaluate overall TRE between these points and points transformed from TRUS to camera. After transforming the ground-truth points from the TRUS to the camera coordinate frame, the mean target registration error (TRE) (SD) was [Formula: see text]mm. The mean TREs (SD) in the x-, y-, and z-directions are [Formula: see text] mm, [Formula: see text] mm, and [Formula: see text] mm, respectively. We describe and evaluate a complete AR guidance system for RALRP which can augment preoperative data to endoscope camera image, after a deformable magnetic resonance image to TRUS registration step. The streamlined procedures with current surgical workflow and low TRE demonstrate the compatibility and readiness of the system for clinical translation. A detailed sensitivity study remains part of future work.

Noninvasive treatment of organ-confined prostate cancer in elderly patients-results of the HAROW study

Noninvasive treatment options such as active surveillance (AS), watchful waiting (WW), and hormone deprivation therapy (HT) are particularly important in elderly patients with localized prostate cancer (PCa). We examine the use of these noninvasive treatment options in the everyday care in acohort of patients ≥70years old. In the HAROW study, the treatment of localized PCa under everyday conditions is investigated. The only inclusion criterion was newly diagnosed organ-confined PCa (≤cT2c). In AS, WW, and HT patients, we compared initial tumor and patient characteristics, follow-up examinations and changes of therapy. Of 457 patients ≥70years, 210 chose AS, 160 HT, and 87WW. Observation times were 6.3 years (AS), 7.5 years (HT), and 7.0 years (WW). AS patients (73.2 years) were younger than WW (76.0 years) and HT patients (76.9 years) and had ahigher proportion of low-risk tumors (80%) versus WW (31%) and HT (19%). Achange of therapy was observed in 47.1% of AS, 17.2% of WW and 13.1% of HT patients. Metastasis occurred in 1.0% of AS, 4.6% of WW, and 6.9% of HT patients. Overall survival was 94.3% for AS, 90.8% for WW and 81.9% for HT. Within the first 28.4months, the mean number of PSA determinations did not differ between AS and WW (6.1 vs. 5.2; p = 0.09); arebiopsy was performed in 37.6% of AS, 11.4% of WW, and 17% of HT patients. The allocation to curative and palliative strategies should be made according to patient and tumor characteristics by definition. Palliative procedures may represent concepts in older patients who initially chose acurative AS strategy.

Fast prostate retrieval in robot-assisted laparoscopic prostatectomy for next-generation biobanking.

Robotic-assisted laparoscopic radical prostatectomy (RALP) has become the most widespread treatment for organ-confined prostate cancer. Here, we describe a fast specimen retrieval technique for RALP to obtain high-quality tissue specimen with minimal warm ischemia time for next-generation biobanking. Here, we show that using fast retrieval technique, short warm ischemia times can be achieved while not increasing the surgical time. Patients undergoing RALP with written informed consent participated in Helsinki Urological Bank study. Previously operated RALP patients and those, who were not willing to participate in the study, served as a control group. The study consisted of 1685 patients, 684 in fast retrieval and 1001 in control group. We developed a novel fast retrieval technique in which fascia is opened for camera port according to the prostate size and a running suture is placed and tightened against the camera port in the beginning of the operation. Immediately after prostate is freed from attachments, suture is loosened and the prostate is extirpated inside the endoscopic bag through the camera port fascial opening, then the fascial suture is again tightened against the camera port and the RALP procedure is completed. The mean warm ischemia times in fast retrieval group were 20min 18s and 22min 30s, respectively, in patients without and with lymphadenectomy. The mean console and surgery times with and without lymphadenectomy were similar in both groups. There were no technique-related complications associated with Fast Retrieval procedure. Tissue integrity test results for the RNA and DNA quality showed good quality for the specimen. Fast retrieval technique can easily and safely be utilized to maximize usefulness of RALP tissue specimen in downstream biobank applications.

MP60-18 ROBOT-ASSISTED RADICAL PROSTATECTOMY IN THE ELDERLY: A PROPENSITY-MATCHED COMPARISON OF ONCOLOGICAL AND FUNCTIONAL OUTCOMES

INTRODUCTION AND OBJECTIVES:Radical prostatectomy is the recommended definitive surgical treatment for organ-confined prostate cancer in eligible men who meet the criteria for curative radical ther...

On the feasibility of transperineal 3D ultrasound image guidance for robotic radical prostatectomy.

Prostate cancer is the most prevalent form of male-specific cancers. Robot-assisted laparoscopic radical prostatectomy (RALRP) using the da Vinci surgical robot has become the gold-standard treatment for organ-confined prostate cancer. To improve intraoperative visualization of anatomical structures, many groups have developed techniques integrating transrectal ultrasound (TRUS) into the surgical workflow. TRUS, however, is intrusive and does not provide real-time volumetric imaging. We propose a proof-of-concept system offering an alternative noninvasive transperineal view of the prostate and surrounding structures using 3D ultrasound (US), allowing for full-volume imaging in any anatomical plane desired. The system aims to automatically track da Vinci surgical instruments and display a real-time US image registered to preoperative MRI. We evaluate the approach using a custom prostate phantom, an iU22 (Philips Healthcare, Bothell, WA) US machine with an xMATRIX X6-1 transducer, and a custom probe fixture. A novel registration method between the da Vinci kinematic frame and 3D US is presented. To evaluate the entire registration pipeline, we use a previously developed MRI to US deformable registration algorithm. Our US calibration technique yielded a registration error of 0.84mm, compared to 1.76mm with existing methods. We evaluated overall system error with a prostate phantom, achieving a target registration error of 2.55mm. Transperineal imaging using 3D US is a promising approach for image guidance during RALRP. Preliminary results suggest this system is comparable to existing guidance systems using TRUS. With further development and testing, we believe our system has the potential to improve patient outcomes by imaging anatomical structures and prostate cancer in real time.

Abstract B073: Stat5a/b blockade sensitizes prostate cancer to radiation through inhibition of Rad51 and DNA repair

Abstract Purpose: The standard treatment for organ-confined prostate cancer (PC) is surgery or radiation, and locally advanced PC is typically treated with radiotherapy alone or in combination with androgen-deprivation therapy. Here, we investigated whether Stat5a/b participates in regulation of double-strand DNA break repair in PC, and if Stat5 inhibition may provide a novel strategy to sensitize PC to radiation therapy. Experimental Design: Stat5a/b regulation of DNA repair in PC was evaluated by comet assay and clonogenic survival assay, followed by assays specific to homologous recombination (HR) DNA repair and nonhomologous end-joining (NHEJ) DNA repair. For HR DNA repair, Stat5a/b regulation of Rad51 and the mechanisms underlying the regulation were investigated in PC cells, xenograft tumors, and patient-derived PCs ex vivo in 3D explant cultures. Stat5a/b induction of Rad51 and HR DNA repair and responsiveness to radiation were evaluated in vivo in mice bearing PC xenograft tumors. Results: Stat5a/b is critical for Rad51 expression in PC via Jak2-dependent mechanisms by inducing Rad51 mRNA levels. Consistent with this, genetic knockdown of Stat5a/b suppressed HR DNA repair while not affecting NHEJ DNA repair. Pharmacologic Stat5a/b inhibition potently sensitized PC cell lines and PC tumors to radiation, while not affecting radiation sensitivity of the neighboring tissues. Conclusion: This work introduces a novel concept of a pivotal role of Jak2-Stat5a/b signaling for Rad51 expression and HR DNA repair in PC. Inhibition of Jak2-Stat5a/b signaling sensitizes PC to radiation and, therefore, may provide an adjuvant therapy for radiation to reduce radiation-induced damage to the neighboring tissues. Citation Format: Cristina Maranto, Vindhya Udhane, Ayush Dagvadorj, David T. Hoang, Lei Gu, Vitali Alexeev, Kareem Malas, Karmel Cardenas, Mateusz Koptyra, Jonathan R. Brody, Ulrich Rodeck, Carmen Bergom, Ken A. Iczkowski, Ken Jacobsohn, William See, Sara M. Schmitt, Marja T. Nevalainen. Stat5a/b blockade sensitizes prostate cancer to radiation through inhibition of Rad51 and DNA repair [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B073.

Abstract A032: miR-205 reconstitution sensitizes prostate cancer cells and xenografts to radiotherapy, through PKCε suppression

Abstract Radiotherapy is a standard treatment for organ-confined prostate cancer (PCa). Although treatment technical optimization has greatly improved local tumor control, a significant percentage of patients still undergo recurrence. The onset of radioresistance is a complex phenomenon involving several genetic and epigenetic abnormalities, including the deregulation of microRNAs (miRNAs), endogenous small noncoding RNA molecules that negatively regulate gene expression. In this study, we investigated the ability of miR-205 to radiosensitize PCa cells. The possible relevance of the miRNA in PCa radiation response is based on our previous observation that miR-205 reconstitution in PCa cells i) exerts a tumor-suppressive effect in human PCa cells by counteracting epithelial-mesenchymal transition (EMT) and reducing cell migration/invasion, at least in part through the downregulation of its target PKCε, shown to play a role also in the nuclear translocation of EGFR, and ii) counteracts CAF-induced EMT, thus impairing enhancement of tumor cell invasion, acquisition of stem cell traits, tumorigenicity, and metastatic dissemination. The biologic role of miR-205 was elucidated through reconstitution in DU145 PCa cells by using a miRNA mimic. Radiation response in miRNA-reconstituted and control cells was assessed by the clonogenic assay. Transfected cells were exposed to 2-8 Gy delivered as a single dose using the 137Cs γ-irradiator IBL-437. Xenografts generated in mice following s.c. transplantation of DU145 cells stably expressing miR-205 received 5 Gy single-dose irradiation using a micro-CT/microirradiator (225Cx, Precision X-ray). We found that transient or stable reconstitution of miR-205 in DU145 cells consistently increased in vitro radiosensitivity. Among miR-205 direct targets, we were able to attribute a functional role in the radiosensitizing effect to PKCε. Indeed, siRNA-mediated silencing of PKCε in DU145 cells fully reproduced the enhanced radiation response induced by the miRNA. The effect was mediated, at least in part, by a decreased radiation-induced EMT and a reduced Non-Homologous End-Joining-based repair, as a consequence of the inhibited EGFR nuclear translocation. Based on our previous evidence indicating the ability of miR-205 to improve the activity of DNA damaging drugs through the downregulation of the lysosome-associated protein LAMP3 and autophagy impairment, we assessed the effect of LAMP3 knockdown on DU145 cell radiosensitivity and observed an enhanced radiation response, though at a lower extent compared to that induced by miR-205 reconstitution. The miRNA-mediated in vitro radiosensitizing effect was also appreciable in vivo. Indeed, xenografts generated by DU145 cells stably expressing the miRNA showed a significantly enhanced tumor growth inhibition following 5 Gy single-dose irradiation, as compared to control xenografts. Moreover, miR-205 reconstitution significantly increased the time for DU145 xenografts to reach 1,000 mm3 tumor burden. Consistent with in vitro findings, immunohistochemistry data obtained in tumor sections from miR-205-reconstituted xenografts revealed decreased PKCε expression. Overall, our results suggest miR-205 as a possible relevant determinant of ionizing radiation response, supporting the clinical interest in developing a novel therapeutic approach based on miR-205 reconstitution to increase PCa sensitivity to radiotherapy. Citation Format: Paolo Gandellini, Rihan El Bezawy, Marco Folini, Denis Cominetti, Stella Tinelli, Tiziana Rancati, Riccardo Valdagni, Nadia Zaffaroni. miR-205 reconstitution sensitizes prostate cancer cells and xenografts to radiotherapy, through PKCε suppression [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A032.

STAT5A/B Blockade Sensitizes Prostate Cancer to Radiation through Inhibition of RAD51 and DNA Repair.

Purpose: The standard treatment for organ-confined prostate cancer is surgery or radiation, and locally advanced prostate cancer is typically treated with radiotherapy alone or in combination with androgen deprivation therapy. Here, we investigated whether Stat5a/b participates in regulation of double-strand DNA break repair in prostate cancer, and whether Stat5 inhibition may provide a novel strategy to sensitize prostate cancer to radiotherapy.Experimental Design: Stat5a/b regulation of DNA repair in prostate cancer was evaluated by comet and clonogenic survival assays, followed by assays specific to homologous recombination (HR) DNA repair and nonhomologous end joining (NHEJ) DNA repair. For HR DNA repair, Stat5a/b regulation of Rad51 and the mechanisms underlying the regulation were investigated in prostate cancer cells, xenograft tumors, and patient-derived prostate cancers ex vivo in 3D explant cultures. Stat5a/b induction of Rad51 and HR DNA repair and responsiveness to radiation were evaluated in vivo in mice bearing prostate cancer xenograft tumors.Results: Stat5a/b is critical for Rad51 expression in prostate cancer via Jak2-dependent mechanisms by inducing Rad51 mRNA levels. Consistent with this, genetic knockdown of Stat5a/b suppressed HR DNA repair while not affecting NHEJ DNA repair. Pharmacologic Stat5a/b inhibition potently sensitized prostate cancer cell lines and prostate cancer tumors to radiation, while not inducing radiation sensitivity in the neighboring tissues.Conclusions: This work introduces a novel concept of a pivotal role of Jak2-Stat5a/b signaling for Rad51 expression and HR DNA repair in prostate cancer. Inhibition of Jak2-Stat5a/b signaling sensitizes prostate cancer to radiation and, therefore, may provide an adjuvant therapy for radiation to reduce radiation-induced damage to the neighboring tissues. Clin Cancer Res; 24(8); 1917-31. ©2018 AACR.

Laparoscopic radical prostatectomy without ligation of the Santorini's venous plexus

The goal of our work is to demonstrate how, in the approach to laparoscopic radical prostatectomy, the ligation of Santorini?s dorsal venous complex is not necessary. The retrospective evaluation of video-laparoscopich radical prostatectomy performed at UOC of Jesi with this technical device, showed an increased blood loss compared to a technique that provides for the ligation of Santorini's plexus and, overall, reduced blood loss compared with the average radical open prostatectomy. 50 video-laparoscopic extraperitoneal radical prostatectomies were evaluated, which were performed with the same technique and by the same operator. The technique involves the non-ligation of Santorini's venous plexus. Surgical, oncological, functional outcomes were considered and in particular blood loss. The results are consistent with those reported in literature, and without ligation of the Santorini's venous plexus , there has been no increase in blood loss intra-and / or post-operatively, or in the percentage of patients with hemotransfusion. The video-laparoscopic radical prostatectomy, although a not yet codified and standardized technique for the treatment of organ-confined prostate cancer, did show oncological and functional results basically l similar to open-sky technique. But compared to this, it has certainly demonstrated a lower blood loss and a reduction of morbidity. The non ligation of Santorini's venous plexus, always necessary during open prostatectomy, in our experience is not necessary in video-laparoscopy.

Impact of a robotic surgical system on treatment choice for men with clinically organ-confined prostate cancer.

Introducing a new surgical technology may affect behaviors and attitudes of patients and surgeons about clinical practice. Robot-assisted laparoscopic radical prostatectomy (RALP) was approved in 2012 in Japan. We investigated whether the introduction of this system affected the treatment of organ-confined prostate cancer (PCa) and the use of radical prostatectomy (RP). We conducted a retrospective multicenter study on 718 patients with clinically determined organ-confined PCa treated at one of three Japanese academic institutions in 2011 (n=338) or 2013 (n=380). Two patient groups formed according to the treatment year were compared regarding the clinical characteristics of PCa, whether referred or screened at our hospital, comorbidities and surgical risk, and choice of primary treatment. Distribution of PCa risk was not changed by the introduction of RALP. Use of RP increased by 70% (from 127 to 221 cases, p<0.0001), whereas the number of those undergoing radiotherapy or androgen deprivation therapy decreased irrespective of the disease risk of PCa. Increased use of RP (from 34 to 100 cases) for intermediate- or high-risk PCa patients with mild perioperative risk (American Society of Anesthesiologists score 2) accounted for 70% of the total RP increase, whereas the number of low- or very low-risk PCa patients with high comorbidity scores (Charlson Index≥4) increased from 8 to 25 cases, accounting for 18%. Use of expectant management (active surveillance, watchful waiting) in very low-risk PCa patients was 15% in 2011 and 12% in 2013 (p=0.791). Introduction of a robotic surgical system had little effect on the risk distribution of PCa. Use of RP increased, apparently due to increased indications in patients who are candidates for RP but have mild perioperative risk. Although small, there was an increase in the number of RPs performed on patients with severe comorbidities but with low-risk or very low-risk PCa.

Surgical Management of Organ-Confined Prostate Cancer with Review of Literature and Evolving Evidence

Prostate cancer is the most common solid organ malignancy in men in the USA with an annual incidence of 105 and an annual mortality rate of 19 per 100,000 people. With the advent of PSA screening, the majority of prostate cancer diagnosed is organ confined. Recent studies including the SPCG-4 and PIVOT trials have demonstrated a survival benefit for those undergoing active treatment for localized prostate cancer. The foremost surgical option has been radical prostatectomy (RP). The gold standard has been open radical retropubic prostatectomy (RRP); however, minimally invasive approaches including laparoscopic and robotic approaches are commonplace and increasing in popularity. We aim to describe the surgical options for the treatment of localized prostate cancer by reviewing the literature. A review of the literature was undertaken using MEDLINE and PubMed. Articles addressing the topic of radical prostatectomy by open, laparoscopic and robotic approaches were selected. Studies comparing the different modalities were also identified. These articles were reviewed for data pertaining to perioperative, oncological and functional outcomes. There is a paucity of randomized studies comparing the three modalities. The published data has demonstrated a benefit in favour of robotically assisted laparoscopic prostatectomy (RALP) over laparoscopic radical prostatectomy (LRP) and traditional open RRP in perioperative outcomes. When reviewing the best-reported outcomes for RALP compared to LRP and RRP, operative times are lower (105 vs. 138 vs. 138min), estimated blood loss rates are lower (111 vs. 200 vs. 300ml) and blood transfusion rates are lower as in the length of stay (1 vs. 2 vs. 2.3days) and overall complication rates (4.3 vs. 5 vs. 20%). Similarly, when reviewing functional outcomes, RALP compared to LRP was not inferior. At 12months, the reported continence was 97 vs. 94 vs. 89% and potency was 94 vs. 77 vs. 90%. In comparative studies, however, these differences did not always meet statistical significance. With respect to oncological outcomes, there was no clear evidence of superiority of one modality over another. RALP is now the most common modality for surgical treatment of organ-confined prostate cancer. Individual series appear to support better perioperative outcomes and perhaps quicker return to functional outcomes. There does not appear to be a clear advantage to date in oncological parameters; however, RALP does not appear to be inferior to either LRP or RRP. It is anticipated that further high quality randomized studies will shed more light on the clinical and statistical significance in the comparison between these modalities.

Percutaneous image-guided cryoablation: current applications and results in the oncologic field.

Percutaneous imaging-guided cryoablation (PICA) is a recently developed technique, which applies extreme hypothermia to destroy tumours under close imaging surveillance. It is minimally invasive, safe, repeatable, and does not interrupt or compromise other oncologic therapies. It presents several advantages over more established heat-based thermal ablation techniques (e.g. radiofrequency ablation; RFA) including intrinsic analgesic properties, superior monitoring capability on multi-modal imaging, ability to treat larger tumours, and preservation of tissue collagenous architecture. There has been a recent large increase in reports evaluating the utility of PICA in a wide range of patients and tumours, but systematic analysis of the literature is challenging due to the rapid pace of change and predominance of extensively heterogeneous level III studies. The precise onco-therapeutic role of PICA has not been established. This narrative review outlines the available evidence for PICA in a range of tumours. Current indications include curative therapy of small T1a renal tumours; curative/palliative therapy of small primary/secondary lung tumours where RFA is unsuitable; palliation of painful bone metastases; and urologic treatment of organ-confined prostate cancer. There is growing evidence to support its use for small hepatic tumours, and encouraging results have been obtained for breast tumours, extra-abdominal desmoid tumours, and management of higher-stage tumours and oligometastatic disease. However, the overall evidence base is weak, effectively restricting PICA to cases where standard therapy and RFA are unsuitable. As the technique and evidence continue to mature, the benefits of this emerging technique will hopefully become more widely available to cancer patients in the future.