Prognostic model for second progression-free survival and overall survival in patients with high-risk metastatic hormone-sensitive prostate cancer treated with abiraterone acetate and androgen deprivation therapy.

BACKGROUND: To develop and validate a prognostic risk model for high-risk metastatic hormone-sensitive prostate cancer (mHSPC) patients treated with upfront abiraterone acetate (ABI). METHODS: This retrospective multicenter study involved 233 high-risk mHSPC patients who received upfront ABI, developed by three academic centers. The model was externally validated with an independent cohort of 282 patients. To identify independent prognostic factors for second progression-free survival (PFS2) and develop the best-fitted model, Cox proportional hazards regression, followed by the Akaike information criterion, was used. Patients were categorized into three groups based on their risk scores. PFS2 and overall survival (OS) were evaluated according to the risk groups in the discovery and validation cohorts. RESULTS: The median age was 72 (range 51-89) years, with a median follow-up duration of 27 months. Independent factors linked to PFS2 included an Eastern Cooperative Oncology Group performance status ≥2, a primary Gleason score of 5, an extent of disease score of ≥3 or liver metastasis, and lactate dehydrogenase >220 U/L. Median PFS2 for favorable-, intermediate-, and poor-risk groups were not reached, 43 months, and 16 months, respectively. The median OS was 29 months in the poor-risk group, whereas it was not reached in the favorable- and intermediate-risk groups. The 2-year OS rates in the favorable-, intermediate- and poor-risk groups were 94.5%, 80.1%, and 60.3%, respectively. The validation cohort confirmed the risk model's relationship with PFS2 and OS. The median PFS2 and OS in the high-risk group were 21 months and 32 months, respectively. CONCLUSIONS: Our prognostic model, including five clinical factors, is useful for patient care and treatment selection in high-risk mHSPC patients treated with ADT plus ABI. The developed model could provide more accurate information, guide treatment decisions, or classify patients in future clinical trials.

Efficacy of robot-assisted partial nephrectomy compared to conventional laparoscopic partial nephrectomy for completely endophytic renal tumor: a multicenter, prospective study.

BACKGROUND: This study aimed to compare the efficacy of robot-assisted partial nephrectomy for completely endophytic renal tumors with the reported outcomes of conventional laparoscopic partial nephrectomy and investigate the transition of renal function after robot-assisted partial nephrectomy. METHODS: We conducted a prospective, multicenter, single-arm, open-label trial across 17 academic centers in Japan. Patients with endophytic renal tumors classified as cT1, cN0, cM0 were included and underwent robot-assisted partial nephrectomy. We defined two primary outcomes to assess functional and oncological aspects of the procedure, which were represented by the warm ischemic time and positive surgical margin, respectively. Comparisons were made using control values previously reported in laparoscopic partial nephrectomy studies. In the historical control group, the warm ischemia time was 25.2, and the positive surgical margin was 13%. RESULTS: Our per-protocol analysis included 98 participants. The mean warm ischemic time was 20.3 min (99% confidence interval 18.3-22.3; p < 0.0001 vs. 25.2). None of the 98 participants had a positive surgical margin (99% confidence interval 0-5.3%; p < 0.0001 vs. 13.0%). The renal function ratio of eGFR before and after protocol treatment multiplied by splits was 0.70 (95% confidence interval: 0.66-0.75). Factors such as preoperative eGFR, resected weight, and warm ischemic time influenced the functional loss of the partially nephrectomized kidney after robot-assisted partial nephrectomy. CONCLUSIONS: Robot-assisted partial nephrectomy for completely endophytic renal tumors offers a shorter warm ischemia time and comparable positive surgical margin rate compared with conventional laparoscopic partial nephrectomy.

Novel image-guided marker aimed at organ-preserving therapies for prostate cancer.

OBJECTIVE: We developed fiducial imaging-guidance markers for the prostate with less imaging artifacts than currently commercially available markers. The aim of this study was to evaluate the imaging artifacts and potential usefulness and safety of these novel fiducial imaging markers in preclinical experiments. METHODS: We selected specific metal materials and a shape that can minimize artifacts in line with a license we obtained for a metal with a gold-platinum (Au-Pt) alloy composition that maximized artifact-free MRI images. Both phantom and canine prostate tests were conducted in order to evaluate the imaging artifacts for three imaging modalities, MRI, CT and ultrasound, and the risk of migration of the markers from the site of insertion to elsewhere, as well as crushing. RESULTS: The newly developed Au-Pt material had less imaging artifacts in the MRI, CT and ultrasound imaging modalities in comparison with current commercially available fiducial markers made from gold materials only. The Au-Pt markers had sufficient strength and durability and were considered to be potentially clinically useful and safe markers. CONCLUSION: The developed Au-Pt markers could be potential tools for accurate lesion-targeted, organ-preserving therapies such as lesion-targeted focal therapy and active surveillance in addition to conventional radiation therapies.

Comorbidities in Japanese testicular cancer survivors: A multi-institutional, cross-sectional study.

OBJECTIVE: To evaluate comorbidities in Japanese testicular cancer (TC) survivors in a multi-institutional, cross-sectional study. METHODS: This study enrolled TC survivors who visited any of the eight high-volume institutions in Japan from 2018 to 2019. After obtaining informed consent, participants answered questionnaires about their comorbidities. We analyzed the impact of treatment on comorbidities rate in TC survivors. RESULTS: A total of 509 TC survivors responded to the comorbidity questionnaires. Median age at the time of response was 43 years (IQR 35-51 years) and median follow-up period after treatment was 5.1 years (IQR 2.1-9.2 years). TC survivors were divided according to the number of cycles of chemotherapy into the following groups: None (n = 153); 1-2 cycles (n = 34); 3-4 cycles (n = 234); or ≥5 cycles (n = 88). The prevalence of kidney disease increased significantly with increasing number of cycles of chemotherapy (p < 0.05). The relative risk of cardiovascular disease in the groups with three or more cycles was 2.6 compared to the group without chemotherapy. CONCLUSION: The present study showed that the prevalence of kidney disease in TC survivors was increased with increasing number of cycles of chemotherapy.

Japanese clinical practice guidelines for prostate cancer 2023.

This fourth edition of the Japanese Clinical Practice Guidelines for Prostate Cancer 2023 is compiled. It was revised under the leadership of the Japanese Urological Association, with members selected from multiple academic societies and related organizations (Japan Radiological Society, Japanese Society for Radiation Oncology, the Department of EBM and guidelines, Japan Council for Quality Health Care (Minds), Japanese Society of Pathology, and the patient group (NPO Prostate Cancer Patients Association)), in accordance with the Minds Manual for Guideline Development (2020 ver. 3.0). The most important feature of this revision is the adoption of systematic reviews (SRs) in determining recommendations for 14 clinical questions (CQs). Qualitative SRs for these questions were conducted, and the final recommendations were made based on the results through the votes of 24 members of the guideline development group. Five algorithms based on these results were also created. Contents not covered by the SRs, which are considered textbook material, have been described in the general statement. In the general statement, a literature search for 14 areas was conducted; then, based on the general statement and CQs of the Japanese Clinical Practice Guidelines for Prostate Cancer 2016, the findings revealed after the 2016 guidelines were mainly described. This article provides an overview of these guidelines.

A nomogram to predict the absence of clinically significant prostate cancer in males with negative MRI

PURPOSE: To create a nomogram to predict the absence of clinically significant prostate cancer (CSPCa) in males with non-suspicion multiparametric magnetic resonance imaging (mpMRI) undergoing prostate biopsy (PBx). MATERIALS AND METHODS: We identified consecutive patients who underwent 3T mpMRI followed by PBx for suspicion of PCa or surveillance follow-up. All patients had Prostate Imaging Reporting and Data System score 1-2 (negative mpMRI). CSPCa was defined as Grade Group ≥2. Multivariate logistic regression analysis was performed via backward elimination. Discrimination was evaluated with area under the receiver operating characteristic (AUROC). Internal validation with 1,000x bootstrapping for estimating the optimism corrected AUROC. RESULTS: Total 327 patients met inclusion criteria. The median (IQR) age and PSA density (PSAD) were 64 years (58-70) and 0.10 ng/mL2 (0.07-0.15), respectively. Biopsy history was as follows: 117 (36%) males were PBx-naive, 130 (40%) had previous negative PBx and 80 (24%) had previous positive PBx. The majority were White (65%); 6% of males self-reported Black. Overall, 44 (13%) patients were diagnosed with CSPCa on PBx. Black race, history of previous negative PBx and PSAD ≥0.15ng/mL2 were independent predictors for CSPCa on PBx and were included in the nomogram. The AUROC of the nomogram was 0.78 and the optimism corrected AUROC was 0.75. CONCLUSIONS: Our nomogram facilitates evaluating individual probability of CSPCa on PBx in males with PIRADS 1-2 mpMRI and may be used to identify those in whom PBx may be safely avoided. Black males have increased risk of CSPCa on PBx, even in the setting of PIRADS 1-2 mpMRI.

Phase I/II study of multipeptide cancer vaccine IMA901 after single-dose cyclophosphamide in Japanese patients with advanced renal cell cancer with long-term follow up.

BACKGROUND: IMA901 is the first therapeutic vaccine for renal cell cancer (RCC). It contains multiple tumor-associated peptides (TUMAPs) that are naturally present in human cancers. METHODS: In a phase I/II study, we treated a total of 10 Japanese patients with advanced RCC who were human leukocyte antigen A (HLA-A)*02 +. Vaccination involved i.d. injection of GM-CSF (75 µg), followed within 15-30 min by i.d. injection of IMA901 (containing 413 µg of each peptide). No treatment with either anticancer agents or immunosuppressants was allowed within 4 weeks before entering the trial. Patients were scheduled to receive 7 vaccinations during the first 5 weeks of treatment (induction period), followed by 10 further vaccinations at 3-week intervals for up to 30 weeks (maintenance period). The primary endpoints were safety and tolerability, while the secondary endpoints were PFS, OS, and immunogenicity. RESULTS: There were no treatment-related serious adverse events or deaths during the study period. When the response was assessed after 4 months, 10% of patients showed a partial response, 80% had stable disease, and 10% had progressive disease. Among patients in whom the T-cell response was analyzed, five patients showed a vaccine-induced T-cell response against at least one HLA class I-restricted TUMAP and two patients had T-cell responses to multiple TUMAPs. PFS was 5.5 months and OS was 18 months. CONCLUSIONS: This study demonstrated the safety and tolerability of IMA901 vaccine in Japanese RCC patients, and also showed that vaccination elicited an immune response.

Plasma circulating tumor DNA profiling in patients with chemo-refractory germ cell tumors.

OBJECTIVES: Molecular analysis of tumor tissues has been extensively analyzed in germ cell tumors. However, genetic analysis of plasma circulating tumor DNA has been limited. Our objective was to analyze genetic alterations in circulating tumor DNA as well as its impact on prognosis in patients with chemo-refractory germ cell tumors. METHODS: We included 13 patients with chemo-refractory germ cell tumors who relapsed after second-line or higher previous chemotherapy and performed targeted sequencing of plasma cell-free DNA using an AVENIO Expanded kit. RESULTS: Tumor-specific genetic alterations were identified in all patients. The most frequently mutated gene was TP53 (53.4%), followed by PTEN (23.1%), GNAS (15.4%) and MTOR (15.4%). Moreover, EGFR amplification (38.5%) and MET amplification (15.4%) were also identified. We defined two or more single nucleotide variants detected in plasma cell-free DNA as circulating tumor DNA-positive. Kaplan-Meier analysis revealed that overall survival was significantly shorter in circulating tumor DNA-positive patients than circulating tumor DNA negative-patients (median overall survival 3.13 vs. 8.73 months; p = 0.042). CONCLUSION: Analysis of plasma circulating tumor DNA could detect genetic alterations in patients with chemo-refractory GCT. Moreover, detectable circulating tumor DNA in plasma was associated with poor prognosis in those patients. These results suggest that liquid biopsy using analysis of plasma circulating tumor DNA may be clinically useful for germ cell tumor patients.

Sexual function using the EORTC QLQ-TC26 in testicular cancer survivors: A multi-institutional, cross-sectional study.

OBJECTIVE: To evaluate sexual function after treatment using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Testicular Cancer 26 (EORTC QLQ-TC26) questionnaire in Japanese testicular cancer (TC) survivors in a multi-institutional, cross-sectional study. METHODS: This study enrolled TC survivors who visited any of eight high-volume institutions in Japan from 2018 to 2019. After obtaining informed consent, participants completed the EORTC QLQ-TC26 questionnaires. We evaluated sexual function after treatment for TC using the EORTC QLQ-TC26 and analyzed the impact of treatment on sexual function in TC survivors. RESULTS: A total of 567 TC survivors responded to the EORTC QLQ-TC26. Median age at the time of response was 43 years (interquartile range [IQR] 35-51 years), and median follow-up period after treatment was 5.2 years (IQR 2.2-10.0 years). Sexual function, particularly ejaculatory function, was significantly lower after post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) than after Surveillance or Chemotherapy groups (p < 0.05). In the PC-RPLND group, nerve-sparing procedure preserved postoperative ejaculatory function after RPLND compared with the non-nerve-sparing and offered improved ejaculatory function with time. On multivariate analysis, RPLND was a significant predictor of post-treatment ejaculatory dysfunction, particularly without nerve-sparing (odds ratio 3.0, 95% CI 1.2-7.7, p < 0.05). In addition, TC survivors with nerve-sparing RPLND had higher sexual activity than those without. CONCLUSION: This survey of the EORTC QLQ-TC26 showed that sexual function and activity in TC survivors after RPLND was reduced in the absence of nerve-sparing techniques.

Artificial intelligence trained with integration of multiparametric MR-US imaging data and fusion biopsy trajectory-proven pathology data for 3D prediction of prostate cancer: A proof-of-concept study.

BACKGROUND: We aimed to develop an artificial intelligence (AI) algorithm that predicts the volume and location of clinically significant cancer (CSCa) using convolutional neural network (CNN) trained with integration of multiparametric MR-US image data and MRI-US fusion prostate biopsy (MRI-US PBx) trajectory-proven pathology data. METHODS: Twenty consecutive patients prospectively underwent MRI-US PBx, followed by robot-assisted radical prostatectomy (RARP). The AI algorithm was trained with the integration of MR-US image data with a MRI-US PBx trajectory-proven pathology. The relationship with the 3D-cancer-mapping of RARP specimens was compared between AI system-suggested 3D-CSCa mapping and an experienced radiologist's suggested 3D-CSCa mapping on MRI alone according to the Prostate Imaging Reporting and Data System (PI-RADS) version 2. The characteristics of detected and undetected tumors at AI were compared in 22,968 image data. The relationships between CSCa volumes and volumes predicted by AI as well as the radiologist's reading based on PI-RADS were analyzed. RESULTS: The concordance of the CSCa center with that in RARP specimens was significantly higher in the AI prediction than the radiologist' reading (83% vs. 54%, p = 0.036). CSCa volumes predicted with AI were more accurate (r = 0.90, p < 0.001) than the radiologist's reading. The limitations include that the elastic fusion technology has its own registration error. CONCLUSIONS: We presented a novel pilot AI algorithm for 3D prediction of PCa. AI was trained by integration of multiparametric MR-US image data and fusion biopsy trajectory-proven pathology data. This deep learning AI model may more precisely predict the 3D mapping of CSCa in its volume and center location than a radiologist's reading based on PI-RADS version 2, and has potential in the planning of focal therapy.

Urine cell image recognition using a deep-learning model for an automated slide evaluation system.

OBJECTIVES: To develop a classification system for urine cytology with artificial intelligence (AI) using a convolutional neural network algorithm that classifies urine cell images as negative (benign) or positive (atypical or malignant). PATIENTS AND METHODS: We collected 195 urine cytology slides from consecutive patients with a histologically confirmed diagnosis of urothelial cancer (between January 2016 and December 2017). Two certified cytotechnologists independently evaluated and labelled each slide; 4637 cell images with concordant diagnoses were selected, including 3128 benign cells (negative), 398 atypical cells, and 1111 cells that were malignant or suspicious for malignancy (positive). This pathologically confirmed labelled dataset was used to represent the ground truth for AI training/validation/testing. Customized CutMix (CircleCut) and Refined Data Augmentation were used for image processing. The model architecture included EfficientNet B6 and Arcface. We used 80% of the data for training and validation (4:1 ratio) and 20% for testing. Model performance was evaluated with fivefold cross-validation. A receiver-operating characteristic (ROC) analysis was used to evaluate the binary classification model. Bayesian posterior probabilities for the AI performance measure (Y) and cytotechnologist performance measure (X) were compared. RESULTS: The area under the ROC curve was 0.99 (95% confidence interval [CI] 0.98-0.99), the highest accuracy was 95% (95% CI 94-97), sensitivity was 97% (95% CI 95-99), and specificity was 95% (95% CI 93-97). The accuracy of AI surpassed the highest level of cytotechnologists for the binary classification [Pr(Y > X) = 0.95]. AI achieved >90% accuracy for all cell subtypes. In the subgroup analysis based on the clinicopathological characteristics of patients who provided the test cells, the accuracy of AI ranged between 89% and 97%. CONCLUSION: Our novel AI classification system for urine cytology successfully classified all cell subtypes with an accuracy of higher than 90%, and achieved diagnostic accuracy of malignancy superior to the highest level achieved by cytotechnologists.

Microwave focal therapy of prostate cancer: a non-clinical study and exploratory clinical trial.

OBJECTIVE: To examine the safety and efficacy of microwave tissue coagulation (MTC) for prostate cancer and assess its use in lesion-targeted focal therapy in a non-clinical study and a clinical phase II trial. METHODS: In the non-clinical study using Microtaze® -AFM-712 (Alfresa Pharma Corporation, Osaka, Japan) with an MTC needle, MTC was performed using a transperineal approach to targeted canine prostatic tissue under real-time ultrasonography guidance. Using various MTC output and irradiation time combinations, the targeted and surrounding tissues (rectum, bladder and fat) were examined to confirm the extent of coagulative necrosis or potential cell death, and to compare intra-operative ultrasonography and pathology findings. The exploratory clinical trial was conducted to examine the safety and efficacy of MTC. Five selected patients underwent transperineal MTC to clinically single lesion magnetic resonance imaging (MRI)-visible lesions with Gleason score 3 + 4 or 4 + 4. Prostate-specific antigen (PSA), MRI and Expanded Prostate Cancer Index Composite questionnaire findings were compared before and 6 months after surgery. RESULTS: The region of coagulative necrosis was predictable by monitoring of ultrasonically visible vaporization; thus, by placing the MTC needle at a certain distance, we were able to perform a safe procedure without adverse events affecting the surrounding organs. Based on the non-clinical study, which used various combinations of output and irradiation time, MTC with 30-W output for 60-s irradiation was selected for the prostate. Based on the predictable necrosis, the therapeutic plan (where to place the MTC needle to achieve complete ablation of the target and how many sessions) was strictly determined per patient. There were no serious adverse events in any patient and only temporary urinary symptoms related to MTC therapy were observed. Furthermore, post-treatment satisfaction was very high. All preoperative MRI-visible lesions disappeared, and PSA decreased by 55% 6 months after surgery. CONCLUSION: Microwave tissue coagulation may be an option for lesion-targeted focal therapy for prostate cancer.

Virtual reality of three-dimensional surgical field for surgical planning and intraoperative management.

PURPOSE: To investigate the impact of virtual reality (VR) technologies on urological surgeries, specifically in the management of prostate cancer and renal cancer. METHODS: A non-systematic review of the literature was performed. Medline, Pubmed, and the Cochrane Database were screened for studies regarding the use of VR technologies in the management of prostate and renal cancer. RESULTS: In the management of prostate cancer, VR technologies have been increasingly applied for diagnosis with magnetic resonance imaging/ultrasound fusion biopsy, surgical training using a simulator, surgical navigation in robot-assisted radical prostatectomy, and targeted focal therapy. In partial nephrectomy, surgical simulation and intra-surgical guidance with three-dimensional VR have been used for better understanding of the hilar vascular information, tumor location, and positional relationships of the tumor-feeding vessel and pyelocaliceal system. CONCLUSIONS: VR contributes to the education, training, and simulation of surgical procedures as well as helping the surgeons to tailor surgical planning on each patient. Further prospective studies are needed to assess the beneficial impacts of this technology for both the physician and patient by objective parameters.

Predictive factors for the efficacy of abiraterone acetate therapy in high-risk metastatic hormone-sensitive prostate cancer patients.

PURPOSE: There is a discrepancy in the efficacy of abiraterone acetate for overall survival (OS) in patients with high-risk metastatic hormone-sensitive prostate cancer (mHSPC). This study aimed to identify predictive factors for the efficacy of abiraterone acetate for OS in high-risk mHSPC patients by analyzing them over a longer observation period. METHODS: Five hundred high-risk mHSPC patients were retrospectively identified at our hospital and affiliated hospitals in the Kindai Oncology Study Group and Kyoto Prefectural University of Medicine Oncology Study Group between December 2013 and March 2022. Two hundred patients were treated with abiraterone acetate (1000 mg/day) plus prednisolone (5 mg/day) combined with androgen deprivation therapy (ADT). A total of 300 patients were treated with bicalutamide (80 mg/day) in combination with ADT. RESULTS: OS was not significantly different between the two treatments in the overall cohort (p = 0.1643). In the subgroup without Gleason pattern 5 at the primary lesion, OS was significantly better in patients treated with abiraterone acetate than in those treated with bicalutamide (p = 0.0192). In the subgroup with Gleason pattern 5 at the primary lesion, no significant difference was found between the two treatments (p = 0.1799). Univariate and multivariate analyses in the subgroup without Gleason pattern 5 at the primary lesion suggested that abiraterone therapy may be an important and independent predictor of OS in high-risk mHSPC patients. CONCLUSION: The presence of Gleason pattern 5 at the primary lesion may be a predictor for high-risk mHSPC patients who could benefit from abiraterone acetate treatment.

Focal therapy of localized prostate cancer.

In the treatment of localized prostate cancer, controlling the cancer and maintaining quality of life are important. Focal therapy of localized prostate cancer aims to treat the lesion/part of the prostate that includes the index lesion, which determines the prognosis. We performed a non-systematic review of novel studies on focal therapy of localized prostate cancer as primary treatment published between 2016 and 2021. For mainly intermediate-risk patients, therapeutic technology, such as cryoablation, brachytherapy, high-intensity focused ultrasound, photodynamic therapy, microwave-coagulation, electroporation, and laser ablation, etc., were performed. These procedures are minimally invasive and safe, and provide good functional outcome: a 94-100% pad-free rate against urinary incontinence and 47-86% erectile function, which is sufficient for sexual intercourse. Accurate three-dimensional mapping of the targeted lesion could be an essential navigation technique for therapeutic success. Intermediate- to short-term oncological outcomes were good, resulting in downstaging of the patient's status to no clinically significant cancer; however, transition to conventional whole-gland treatment was necessary in about 10-30% of patients. It is important to select appropriate patients by both multiparametric magnetic resonance imaging and targeted biopsy, and to follow-up postoperatively with methods such as active surveillance. Clinically significant prostate-specific antigen reduction, image response using preoperative and postoperative multiparametric magnetic resonance imaging, and histological analysis should be combined for follow-up.

Association of financial toxicity with quality of life in testicular cancer survivors.

OBJECTIVES: Most testicular cancer (TC) survivors have long-term survival. However, the association between financial toxicity (FT), which is an economic side effect of cancer treatment, and the quality of life (QOL) of TC survivors is still unclear. Thus, the impact of FT on the QOL of TC survivors was examined in a multi-institutional cross-sectional study. METHODS: We recruited TC survivors from eight high-volume institutions in Japan between January 2018 and March 2019. A total of 562 participants completed the EORTC QLQ-C30, EORTC QLQ-TC26 and the questionnaires on demographics, including annual income. Financial difficulty in the EORTC QLQ-C30 and low income were used to assess financial distress (FD) and financial burden (FB), respectively. FT was defined as FD and FB. The QOL scores were compared, and a multivariate logistic regression analysis for FT was performed. RESULTS: With severe FD, TC survivors had more treatment side effects, physical limitations, and anxiety concerning employment and future. The TC survivors who reported low income were worried about their jobs and the future. The QOL of the survivors with FT exhibited high impairment, except for sexual activity. In particular, the TC survivors with FT were physically limited and anxious concerning the future. The multivariate logistic regression analysis revealed that four or more chemotherapy cycles were substantial risk factors for FT (4 cycles, odds ratio (OR) = 4.17; ≥5 cycles, OR = 6.96). CONCLUSIONS: TC survivors who received multi-cycle chemotherapy were prone to experience FT, resulting in a decline in their health-related QOL.

Phase II trial of nivolumab monotherapy and biomarker screening in patients with chemo-refractory germ cell tumors.

OBJECTIVES: Germ cell tumors are highly susceptible to chemotherapy; however, there is a lack of established treatments for consistently relapsing germ cell tumor. Therefore, in this phase II study, we evaluated the efficacy and safety of nivolumab for relapsed germ cell tumor. METHODS: Seventeen adult patients (median age 34 years) with refractory primary germ cell tumor after second-line or higher chemotherapy were enrolled. Nivolumab was administered over 30 min at 240 mg/body every 2 weeks until disease progression or intolerable adverse event occurrence. The primary endpoint was the overall response rate. RESULT: We performed a biomarker analysis of programmed death ligand-1 expression and genomic sequencing. Tumor histology revealed nonseminoma and seminoma in 14 and three patients, respectively. Patients were pretreated with a median of three chemotherapy lines, and three patients received high-dose chemotherapy. The median number of nivolumab doses was 3 (range 2-46). One patient showed a partial response and three showed stable disease. Responses were durable in one patient with a partial response and one patient with stable disease (median 90 and 68 weeks, respectively). Nivolumab was well-tolerated, with only two Grade 3 adverse events observed. Programmed death ligand-1 expression was not associated with objective responses. Genomic sequencing revealed a high tumor mutation burden in a patient with a durable partial response. While a small subset of chemorefractory germ cell tumors may respond to nivolumab, programmed death ligand-1 is unreliable to measure response. CONCLUSIONS: Tumor mutation burden is a potential biomarker for future testing of germ cell tumor response.

Systematic Biopsy of the Prostate can Be Omitted in Men with PI-RADS™ 5 and Prostate Specific Antigen Density Greater than 15.

PURPOSE: We evaluated the prostate cancer and clinically significant prostate cancer detection on systematic biopsy (SB), target biopsy (TB) alone and combined SB and TB in men with Prostate Imaging Reporting and Data System™ (PI-RADS™) 5 lesion. MATERIALS AND METHODS: From a prospectively maintained prostate biopsy database, we identified consecutive patients with PI-RADS 5 lesion on multiparametric magnetic resonance imaging. The patients underwent multiparametric magnetic resonance imaging followed by transrectal TB of PI-RADS 5 lesion and 12-core SB. The prostate cancer and clinically significant prostate cancer (Grade Group, GG ≥2) detection on SB, TB and SB+TB were determined for all men and accordingly to prostate specific antigen density. Statistic significant was set a p <0.05. RESULTS: Overall, 112 patients met inclusion criteria. The detection rate of prostate cancer for SB, TB and SB+TB was 89%, 93% and 95%, respectively, and for clinically significant prostate cancer it was 72%, 81% and 85%, respectively. SB added 2% prostate cancer and 4% clinically significant prostate cancer detection to TB. A total of 78 patients had prostate specific antigen density >0.15 ng/ml2, and the detection rate of PCa for SB, TB and SB+TB was 92%, 97% and 97%, respectively, and for clinically significant prostate cancer it was 79%, 91% and 95%, respectively. In this population, if SB was omitted, 0 prostate cancer and only 4% (3) of clinically significant prostate cancer would be missed. The clinically significant prostate cancer detection rate improved with increased prostate specific antigen density for SB (p=0.01), TB (p <0.0001) and combined SB+TB (p=0.002). CONCLUSIONS: In patients with PI-RADS 5 on multiparametric magnetic resonance imaging and prostate specific antigen density >0.15 ng/ml2, SB marginally increases clinically significant prostate cancer detection, but not overall prostate cancer detection in comparison to TB alone. Systematic biopsy did not affect patients' management and can be omitted on this population.

Multiparametric magnetic resonance imaging facilitates reclassification during active surveillance for prostate cancer.

OBJECTIVE: To investigate the utility of multiparametric magnetic resonance imaging (mpMRI) in the reassessment and monitoring of patients on active surveillance (AS) for Grade Group (GG) 1 prostate cancer (PCa). PATIENTS AND METHODS: We identified, from our prospectively maintained institutional review board-approved database, 181 consecutive men enrolled on AS for GG 1 PCa who underwent at least one surveillance mpMRI followed by MRI/prostate biopsy (PBx). A subset analysis was performed among 68 patients who underwent serial (at least two) mpMRI/PBx during AS. Pathological progression (PP) was defined as upgrade to GG ≥2 on follow up biopsy. RESULTS: Baseline MRI was performed in 34 patients (19%). At a median follow-up of 2.2 years for the overall cohort, the PP was 12% (6/49) for Prostate Imaging Reporting and Data System (PI-RADS) 1-2 lesions and 37% (48/129) for the PI-RADS ≥3 lesions. The 2-year PP-free survival rate was 84%. Surveillance prostate-specific antigen density (P < 0.001) and surveillance PI-RADS ≥3 (P = 0.002) were independent predictors of PP on reassessment MRI/PBx. In the serial MRI cohort, the 2-year PP-free survival was 95% for the No-MRI-progression group vs 85% for the MRI-progression group (P = 0.02). MRI progression was significantly higher in the PP (62%) than in the No-PP (31%) group (P = 0.04). If serial MRI were used for PCa surveillance and biopsy were triggered based only on MRI progression, 63% of PBx might be postponed at the cost of missing 12% of GG ≥2 PCa in those with stable MRI. Conversely, this strategy would miss 38% of those with upgrading to GG ≥2 PCa on biopsy. Stable serial mpMRI correlates with no reclassification to GG ≥3 PCa during AS. CONCLUSION: On surveillance mpMRI, PI-RADS ≥3 was associated with increased risk of PCa reclassification. Surveillance biopsy based only on MRI progression may avoid a large number of biopsies at the cost of missing many PCa reclassifications.

Five-alpha reductase inhibitors in men undergoing active surveillance for prostate cancer: impact on treatment and reclassification after 6 years follow-up.

OBJECTIVES: To evaluate the impact of 5-alpha reductase inhibitors (5-ARIs) on definitive treatment (DT) and pathological progression (PP) in patients on active surveillance (AS) for prostate cancer. METHODS: We identified 361 consecutive patients, from an IRB-approved database, on AS for prostate cancer with minimum 2 years follow-up. Patients were grouped into two cohorts, those using 5-ARIs (5-ARI; n = 119) or not using 5-ARIs (no 5-ARI; n = 242). Primary and secondary endpoints were treatment-free survival (TFS) and PP-free survival (PPFS), which were evaluated by Kaplan-Meier analysis. Univariate and multivariable cox regression analysis were used to identify predictors for PP and DT. A p value < 0.05 was considered statistically significant. RESULTS: Baseline characteristics and the prostate biopsy rate were similar between the two groups. Median (range) follow-up was 5.7 (2.0-17.2) years. Five-year and 10-year TFS was 92% and 59% for the 5-ARI group versus 80% and 51% for the no 5-ARI group (p = 0.005), respectively. Five-year and 10-year PPFS was 77% and 41% for the 5-ARI group versus 70% and 32% for the no 5-ARI group (p = 0.04), respectively. Independent predictors for treatment and PP were not taking 5-ARIs (p = 0.005; p = 0.02), entry PSA > 2.5 ng/mL (p = 0.03; p = 0.01) and Gleason pattern 4 on initial biopsy (p < 0.001; p < 0.001), respectively. The main limitation is the retrospective study design. CONCLUSIONS: 5-ARIs reduces reclassification and cross-over to treatment in men on active surveillance for prostate cancer. Further, taking 5-ARIs was an independent predictor for prostate cancer progression and definitive treatment.