Prostate cancer risk stratification using magnetic resonance imaging-ultrasound fusion vs systematic prostate biopsy.

BACKGROUND: Image-guided approaches improve the diagnostic yield of prostate biopsy and frequently modify estimates of clinical risk. To better understand the impact of magnetic resonance imaging-ultrasound fusion targeted biopsy (MRF-TB) on risk assessment, we compared the distribution of National Comprehensive Cancer Network (NCCN) risk groupings, as calculated from MRF-TB vs systematic biopsy alone. METHODS: We performed a retrospective analysis of 713 patients who underwent MRF-TB from January 2017 to July 2021. The primary study objective was to compare the distribution of National Comprehensive Cancer Network risk groupings obtained using MRF-TB (systematic + targeted) vs systematic biopsy. RESULTS: Systematic biopsy alone classified 10% of samples as very low risk and 18.7% of samples as low risk, while MRF-TB classified 10.5% of samples as very low risk and 16.1% of samples as low risk. Among patients with benign findings, low-risk disease, and favorable/intermediate-risk disease on systematic biopsy alone, 4.6% of biopsies were reclassified as high risk or very high risk on MRF-TB. Of 207 patients choosing active surveillance, 64 (31%), 91 (44%), 42 (20.2%), and 10 (4.8%) patients were classified as having very low-risk, low-risk, and favorable/intermediate-risk and unfavorable/intermediate-risk criteria, respectively. When using systematic biopsy alone, 204 patients (28.7%) were classified as having either very low-risk and low-risk disease per NCCN guidelines, while 190 men (26.6%) received this classification when using MRF-TB. CONCLUSION: The addition of MRF-TB to systematic biopsy may change eligibility for active surveillance in only a small proportion of patients with prostate cancer. Our findings support the need for routine use of quantitative risk assessment over risk groupings to promote more nuanced decision making for localized cancer.

Percutaneous Chemical and Mechanical Necrosectomy for Walled-Off Pancreatic Necrosis.

PURPOSE: To test the hypothesis that percutaneous combined chemical and mechanical necrosectomy using a Malecot anchor drain and an Arrow-Trerotola percutaneous thrombolytic device (PTD) in patients with walled-off pancreatic necrosis (WOPN) is feasible, safe, and effective compared with a control group undergoing mechanical necrosectomy alone. MATERIALS AND METHODS: In a retrospective analysis, patients with WOPN not amenable to endoscopic-guided cystogastrostomy placement were studied as case and control groups. The patients in the case group underwent percutaneous combined chemical (hydrogen peroxide 3%) and mechanical necrosectomy using a Malecot anchor drain and/or Arrow-Trerotola PTD from December 2020 to April 2022. The controls underwent mechanical necrosectomy alone without chemical necrosectomy. Clinical success was defined as complete resolution of the cavity on follow-up noncontrast computed tomography scans with subsequent drain removal. RESULTS: Thirteen patients in the case group and 11 patients in the control group underwent percutaneous drain placement followed by percutaneous combined chemical and mechanical necrosectomy (case group) or mechanical necrosectomy only (control group) for WOPN. Drain placement and necrosectomy were technically successful in all patients studied. One patient in the case group developed postprocedural sepsis because of communication between the cavity and the splenic vein. Another patient in the case group developed bleeding from a branch of the pancreaticoduodenal artery on postnecrosectomy day 9, which was successfully embolized by interventional radiology. No pancreaticocutaneous fistula was reported at the 3-month follow-up. The clinical success rates in the case and control groups were 100% and 38.4%, respectively (P = .003). CONCLUSIONS: Percutaneous combined chemical and mechanical necrosectomy is a feasible, safe, and effective treatment of WOPN.

Clinical utility of MR/ultrasound fusion-guided biopsy in patients with lower suspicion lesions on active surveillance for low-risk prostate cancer.

BACKGROUND: The utility of Multiparametric magnetic resonance imaging (mpMRI) guided prostate biopsy among patients with prostate cancer (CaP) managed with active surveillance (AS) with low-suspicion lesions remains unsettled. METHODS: We performed a retrospective analysis of 415 men with low-risk CaP managed with active surveillance. We selected men with mpMRI visible index lesions scored as 2 or 3 according to Prostate Imaging Reporting and Data System (PI-RADS) version 2. The primary outcome was detection of clinically significant prostate cancer (csCaP) was defined as Gleason grade group ≥ 2. We assessed the diagnostic accuracy of biopsy approaches using area under the receiver operator characteristic (ROC) curve and evaluated factors associated with csCaP in these patients using multivariate logistic regression. RESULTS: CsCaP was identified in 22 of 125 patients (17.6%) with PI-RADS 2 or 3 index lesions during surveillance prostate biopsies. These included 10 (45.5%) diagnosed by systematic biopsy alone, 9 (40.9%) by targeted alone, and 3 (13.6%) by both approaches. On multivariable analysis, the only significant variable predicting the detection of csCaP in men with low-risk imaging mpMRI characteristics was higher PSAD (OR per 0.1 unit=2.26, 95% CI 1.25-4.06, P = 0.007. A PSAD cutoff of 0.1, 0.12 and 0.15 resulted in a negative predictive value (NPV) of 90.9%, 87.1% and 86.2%, respectively. When stratified by PI-RADS score, a PSAD cutoff of 0.1, 0.12 and 0.15 resulted in NPV of 96.2%, 90.6% and 89.7% and 86.2%, 84.2% and 83.3% for detection of csCaP in PI-RADS 2 and 3 lesions, respectively. In patients with PIRDAS 2 lesions, using a PSAD of 0.1 would potentially allow 51% of patients to avoid biopsy with only a 3.8% chance of missing csCaP. CONCLUSION: In men with clinical low-risk prostate cancer on active surveillance with PI-RADS 2 and 3 lesions, there is an almost 18% risk of upgrade to csCaP. Integration of PSAD may be a useful adjunctive tool in identifying patients at highest risk for upgrade despite favorable imaging findings. In men with PIRADS 2 lesions with PSAD ≤0.12 biopsy can be avoided. For men with PIRADS 2 lesions with PSAD ≤0.15 informed decision making regarding the AS intensity should include that these patients have a low risk (>10%) of developing csCaP. In men with PIRADS 3 lesions with PSAD >0.1, shared decision making should include discussion of a >10% miss rate of csCaP.

The stanford prostate cancer calculator: Development and external validation of online nomograms incorporating PIRADS scores to predict clinically significant prostate cancer.

BACKGROUND: While multiparametric MRI (mpMRI) has high sensitivity for detection of clinically significant prostate cancer (CSC), false positives and negatives remain common. Calculators that combine mpMRI with clinical variables can improve cancer risk assessment, while providing more accurate predictions for individual patients. We sought to create and externally validate nomograms incorporating Prostate Imaging Reporting and Data System (PIRADS) scores and clinical data to predict the presence of CSC in men of all biopsy backgrounds. METHODS: Data from 2125 men undergoing mpMRI and MR fusion biopsy from 2014 to 2018 at Stanford, Yale, and UAB were prospectively collected. Clinical data included age, race, PSA, biopsy status, PIRADS scores, and prostate volume. A nomogram predicting detection of CSC on targeted or systematic biopsy was created. RESULTS: Biopsy history, Prostate Specific Antigen (PSA) density, PIRADS score of 4 or 5, Caucasian race, and age were significant independent predictors. Our nomogram-the Stanford Prostate Cancer Calculator (SPCC)-combined these factors in a logistic regression to provide stronger predictive accuracy than PSA density or PIRADS alone. Validation of the SPCC using data from Yale and UAB yielded robust AUC values. CONCLUSIONS: The SPCC combines pre-biopsy mpMRI with clinical data to more accurately predict the probability of CSC in men of all biopsy backgrounds. The SPCC demonstrates strong external generalizability with successful validation in two separate institutions. The calculator is available as a free web-based tool that can direct real-time clinical decision-making.

International Multi-Site Initiative to Develop an MRI-Inclusive Nomogram for Side-Specific Prediction of Extraprostatic Extension of Prostate Cancer.

BACKGROUND: To develop an international, multi-site nomogram for side-specific prediction of extraprostatic extension (EPE) of prostate cancer based on clinical, biopsy, and magnetic resonance imaging- (MRI) derived data. METHODS: Ten institutions from the USA and Europe contributed clinical and side-specific biopsy and MRI variables of consecutive patients who underwent prostatectomy. A logistic regression model was used to develop a nomogram for predicting side-specific EPE on prostatectomy specimens. The performance of the statistical model was evaluated by bootstrap resampling and cross validation and compared with the performance of benchmark models that do not incorporate MRI findings. RESULTS: Data from 840 patients were analyzed; pathologic EPE was found in 320/840 (31.8%). The nomogram model included patient age, prostate-specific antigen density, side-specific biopsy data (i.e., Gleason grade group, percent positive cores, tumor extent), and side-specific MRI features (i.e., presence of a PI-RADSv2 4 or 5 lesion, level of suspicion for EPE, length of capsular contact). The area under the receiver operating characteristic curve of the new, MRI-inclusive model (0.828, 95% confidence limits: 0.805, 0.852) was significantly higher than that of any of the benchmark models (p < 0.001 for all). CONCLUSIONS: In an international, multi-site study, we developed an MRI-inclusive nomogram for the side-specific prediction of EPE of prostate cancer that demonstrated significantly greater accuracy than clinical benchmark models.

Utility of PSA Density in Predicting Upgraded Gleason Score in Men on Active Surveillance With Negative MRI.

OBJECTIVES: To determine whether PSA density (PSAD), can sub-stratify risk of biopsy upgrade among men on active surveillance (AS) with normal baseline MRI. METHODS: We identified a cohort of patients with low and favorable intermediate-risk prostate cancer on AS at two large academic centers from February 2013 - December 2017. Analysis was restricted to patients with GG1 cancer on initial biopsy and a negative baseline or surveillance mpMRI, defined by the absence of PI-RADS 2 or greater lesions. We assessed ability of PSA, prostate volume and PSAD to predict upgrading on confirmatory biopsy. RESULTS: We identified 98 patients on AS with negative baseline or surveillance mpMRI. Median PSA at diagnosis was 5.8 ng/mL and median PSAD was 0.08 ng/mL/mL. Fourteen men (14.3%) experienced Gleason upgrade at confirmatory biopsy. Patients who were upgraded had higher PSA (7.9 vs 5.4 ng/mL, P = .04), PSAD (0.20 vs 0.07 ng/mL/mL, P < .001), and lower prostate volumes (42.5 vs 65.8 mL, P = .01). On multivariate analysis, PSAD was associated with pathologic upgrade (OR 2.23 per 0.1-increase, P = .007). A PSAD cutoff at 0.08 generated a NPV of 98% for detection of pathologic upgrade. CONCLUSION: PSAD reliably discriminated the risk of Gleason upgrade at confirmatory biopsy among men with low-grade prostate cancer with negative MRI. PSAD could be clinically implemented to reduce the intensity of surveillance for a subset of patients.

Doubling of Decipher Biopsy Genomic Score Is Related to Disease Reclassification on Subsequent Surveillance Biopsy but Not Adverse Features on Radical Prostatectomy.

The utility of serial Decipher biopsy scores in a true active surveillance population is still unknown. In a man on active surveillance for low-risk prostate cancer, a doubling of the Decipher biopsy score within genomic low-risk category from first to the second biopsy related to biopsy reclassification to Gleason grade group 4 on the third biopsy. However, the final pathology at radical prostatectomy showed Gleason grade group 2 with an organ-confined disease. This case suggests that the genomic risk category of Decipher biopsy scores during active surveillance may be more informative than either the interval genomic score change or the biopsy Gleason grade group.

Outcomes of Serial Multiparametric Magnetic Resonance Imaging and Subsequent Biopsy in Men with Low-risk Prostate Cancer Managed with Active Surveillance.

BACKGROUND: Outcomes of serial multiparametric magnetic resonance imaging (mpMRI) and subsequent biopsy in monitoring prostate cancer (PCa) in men on active surveillance (AS) have not been defined clearly. OBJECTIVE: To determine whether changes in serial mpMRI can predict pathological upgrade among men with grade group (GG) 1 PCa managed with AS. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of men with GG1 on AS with at least two consecutive mpMRI examinations during 2012-2018 who underwent mpMRI/ultrasound fusion or systematic biopsies. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Progression on serial mpMRI was evaluated as a predictor of pathological upgrading to GG≥2 on a follow-up biopsy using clinical, pathological, and imaging factors in binary logistic regression. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were determined. RESULTS AND LIMITATIONS: Of 122 patients, 29 men (23.8%) experienced pathological upgrade on the follow-up biopsy. Progression on mpMRI was not associated with pathological upgrade. The sensitivity, specificity, PPV, and NPV of mpMRI progression for predicting pathological upgrade were 41.3%, 54.8%, 22.2%, and 75%, respectively. Age (odds ratio [OR] 1.17, p=0.006), Prostate Imaging Reporting and Data System (PI-RADS) score on initial mpMRI (4-5 vs ≤3, OR 7.48, p=0.01), number of positive systematic cores (OR 1.84, p=0.03), number of positive targeted cores (OR 0.44, p=0.04), and maximum percent of targeted core tumor involvement (OR 1.04, p=0.01) were significantly associated with pathological upgrade. CONCLUSIONS: We did not observe an association between mpMRI progression and pathological upgrade; however, a PI-RADS score of 4-5 on initial mpMRI was predictive of subsequent pathological progression. The continued use of systematic and fusion biopsies appears necessary due to risks of reclassification over time. PATIENT SUMMARY: Progression on serial multiparametric magnetic resonance imaging during active surveillance (AS) is not associated with progression on the follow-up biopsy. Both systematic and fusion biopsies are necessary to sufficiently capture progression during AS.

National trends in the management of patients with positive surgical margins at radical prostatectomy.

PURPOSE: To evaluate practice patterns of planned post-operative radiation therapy (RT) among men with positive surgical margins (PSM) at radical prostatectomy. METHODS: We identified 43,806 men within the National Cancer Database with pathologic node-negative prostate cancer diagnosed in 2010 through 2014 with PSM. The primary endpoint was receipt of planned (RT) within a patient's initial course of treatment. We examined post-RP androgen deprivation therapy (ADT) with RT as a secondary endpoint. We evaluated patterns of post-operative management and characteristics associated with planned post-prostatectomy RT. RESULTS: Within 12 months of RP, 87.0% received no planned RT, 8.5% RT alone, 1.3% ADT alone, and 3.1% RT with ADT. In a multivariable logistic regression model, planned RT use was associated with clinical and pathologic characteristics as estimated by surgical Cancer of the Prostate Risk Assessment (CAPRA-S) category (intermediate versus low, OR = 2.87, 95% CI 2.19-3.75, P < 0.001; high versus low, OR = 10.23, 95% CI 7.79-13.43, P < 0.001), treatment at community versus academic centers (OR = 1.24, 95% CI 1.15-1.34, P < 0.001), shorter distance to a treatment facility (OR = 0.97 for each 10-mile, 95% CI 0.96-0.98, P < 0.001), and uninsured status (OR = 1.39, 95% CI 1.10-1.77, P = 0.005). The odds of receiving planned RT were lower in 2014 versus 2010 (OR = 0.76, 95% CI 0.68-0.85, P < 0.001). There was no significant change in the use of ADT with RT. High versus low CAPRA-S category was associated with the use of ADT in addition to RT (OR = 5.13, 95% CI 1.57-16.80, P = 0.007). CONCLUSION: The use of planned post-prostatectomy RT remained stable among patients with PSM and appears driven primarily by the presence of other adverse pathologic features.

A mouse model of prostate cancer bone metastasis in a syngeneic immunocompetent host.

We report the establishment of B6CaP, an allograft tumor line from a Hi-Myc transgenic mouse that had been backcrossed onto C57BL/6J background. This tumor line grows subcutaneously in wildtype C57BL/6J immunocompetent mice, expresses AR, and has a luminal cytokeratin profile. When digested into single cells and injected via intracardiac injection, B6CaP produces metastatic widespread metastases including frequent bone lesions. Metastatic lesions occur most often in the femur, spine, and skull, and have a mixed osteolytic/osteoblastic phenotype. B6CaP allografts are androgen dependent, and regress after castration. However, castration resistant tumors regrow after 4-6 months and can be maintained as androgen-independent clones. This is the first example of a prostate-derived tumor line that shows frequent metastasis to bone and grows in an immunocompetent host, making this model useful for studying mechanisms of bone metastasis and tumor immune response.

Brain Metastasis From Renal-Cell Carcinoma: An Institutional Study.

BACKGROUND: Brain metastases (BM) are frequently observed in advanced renal-cell carcinoma (RCC). Historically these individuals have been excluded from clinical trials, but recently, with better local control, many can receive aggressive therapy after treatment. We evaluate our single-institution experience over various treatment eras. PATIENTS AND METHODS: Patients undergoing evaluation for RCC BM from 2001 to 2018 were identified from our institutional database. Clinical notes, demographics, comorbidities, histology, central nervous system (CNS) treatments, systemic therapy, and outcomes were reviewed. Overall survival (OS) and CNS recurrence-free survival (RFS) were evaluated by the Kaplan-Meier method. Cumulative incidence was evaluated using a competing risk model. RESULTS: We identified 158 patients with RCC BM, of whom 94.4% had clear-cell RCC, and 90.6% had extracranial metastases at diagnosis. Of these patients, 94 (60%) developed RCC BM over time, while 46 (29.1%) had RCC BM at initial presentation. Clinical symptoms were noted in 81.9% of patients. The median OS after diagnosis of RCC BM was 8.4 months, with a 3-year OS of 28.2%. The median CNS RFS was 8.5 months overall; however, those with one and more than one lesion had median CNS RFS of 12.4 and 6 months, respectively (P < .001). CONCLUSION: The majority of RCC patients with BM are symptomatic and had prior metastatic disease that progressed to the brain. Those with a solitary RCC BM are less likely to develop CNS recurrence after local therapy and are ideal candidates for enrollment onto clinical trials.

Association Between Tumor Multifocality on Multi-parametric MRI and Detection of Clinically-Significant Prostate Cancer in Lesions with Prostate Imaging Reporting and Data System (PI-RADS) Score 4.

OBJECTIVE: To investigate whether presence of multifocality on multi-parametric magnetic resonance imaging would increase the likelihood of detecting clinically-significant prostate cancer in a PI-RADS 4 lesion. METHODS: We identified patients with at least 1 PI-RADS 4 lesion who underwent multi-parametric magnetic resonance imaging-ultrasound fusion prostate biopsy. Patients were grouped into 1 of 4 cohorts-cohort 1 (a PI-RADS 4 index lesion and an additional PI-RADS 2 or 3 lesion), cohort 2 (single lesion with PI-RADS 4), cohort 3 (2 or more PI-RADS 4 lesions), or cohort 4 (a PI-RADS 4 lesion and an index lesion with PI-RADS 5). We compared the rate of grade group (GG) ≥ 2 pathology on targeted biopsy of PI-RADS 4 lesions between cohorts and evaluated clinical and radiological factors associated with cancer detection. RESULTS: The overall rate of GG ≥ 2 pathology in the PI-RADS 4 lesions was 35.2%. The rate of GG ≥ 2 pathology in the cohorts 1, 2, 3, and 4 was 21.7%, 36.3%, 49.1%, and 42.7%, respectively (P< .001). On multivariable analysis, age (OR1.06, P < .001), clinical stage T2 (OR1.59, P= .03), prostate-specific antigen density (OR1.43, P < .001), peripheral zone lesion (OR1.62, P = .04), and study cohort (cohort 2 vs 1, OR1.93, P = .006; and cohort 3 vs 1, OR3.28, P < .001) were significantly associated with the risk of GG ≥ 2 in the PI-RADS 4 lesion. CONCLUSION: On targeted biopsy of the PI-RADS 4 lesions, the proportion of GG ≥ 2 pathology is approximately 35%. Rate of GG ≥ 2 detection in PI-RADS 4 lesions might differ based on their location, multifocality, and PI-RADS classifications of other lesions identified.

Role of Core Number and Location in Targeted Magnetic Resonance Imaging-Ultrasound Fusion Prostate Biopsy.

The optimal method of magnetic resonance imaging (MRI)-ultrasound (US) fusion biopsy to adequately sample regions of interest (ROIs) remains unknown. We sought to determine the number and location of cores needed to adequately detect clinically significant prostate cancer (PCa). We identified patients undergoing MRI-US fusion prostate biopsy at our institution for known history or clinical suspicion of PCa. Multiparametric MRI studies were reviewed using Likert and Prostate Imaging Reporting and Data System (PI-RADS) v2 schema. Multiple targeted cores were taken from each ROI followed by 12-core systematic biopsy. In a distinct cohort of patients, lesions were targeted using a predetermined five-core template. We estimated cancers detected through sampling of five or fewer cores, assessed by core number and core location. We identified 744 patients with 581 lesions with PCa. Seventy-seven percent (279/361) of Gleason (G) ≥3+4 tumors and 72% (137/189) of G >3+4 tumors were detected on two-core sampling. Relative to all targeted cores, a two-core approach missed 16% of clinically significant cancers at first biopsy, 27% in prior negative, and 32% in active surveillance patients. Detection of G ≥3+4 cancers did not differ by core location. Sampling of two cores of ROIs misses nearly one-quarter of clinically significant PCa detected on additional sampling. PATIENT SUMMARY: We aimed to understand how the number of cores obtained from a suspicious area during prostate magnetic resonance imaging-ultrasound fusion biopsy affects cancer detection. We found that sampling of five cores missed substantially fewer cancers compared to two cores.

Determinants of Active Surveillance in Patients With Small Renal Masses.

OBJECTIVE: To evaluate trends in the utilization of active surveillance (AS) in a nationally representative cancer database. AS has been increasingly recognized as an effective strategy for patients with small renal masses but little is known about national usage patterns. METHODS: We identified patients with clinical T1a renal masses within the National Cancer Database in 2010 through 2014. Patients were classified according to initial management strategy received including AS, surgery, ablation, or other treatment. We characterized time trends in the use of AS vs definitive therapy and examined clinical and socio-demographic determinants of AS among patients with small renal masses using multivariable logistic regression models. RESULTS: We identified 59,189 patients who satisfied the inclusion criteria. Of the total cohort, 1733 (2.9%) individuals received initial management with AS, while 57,456 (97.1%) received definitive treatment. Surveillance rates remained below 5% in all years. On multivariate analysis, patient age (OR: 1.08, 95% CI 1.08-1.09), smaller tumor size of <2 cm vs ≥2 cm (OR: 2.43, 95% CI: 2.20-2.7, P < .0001), management at an academic center vs community center (OR: 2.05, 95% CI: 1.83-2.29), and African American vs Caucasian race (OR: 1.56, 95% CI:1.35-1.80) were independently associated with use of AS as initial management. CONCLUSION: In a representative national cohort of patients with small renal masses, we observed clinical and facility-level differences in the utilization of active surveillance in patients with T1a renal masses. Further investigation is warranted to better understand the forces underlying initial management decisions for patients with small renal masses.

Prostate Cancer Genomic Classifier Relates More Strongly to Gleason Grade Group Than Prostate Imaging Reporting and Data System Score in Multiparametric Prostate Magnetic Resonance Imaging-ultrasound Fusion Targeted Biopsies.

OBJECTIVE: To assess the association between Prostate Imaging Reporting and Data System version 2 (PI-RADSv2) score, the Decipher score, and histologic grade of carcinoma in biopsy tissue among low- to intermediate-risk prostate cancer patients. METHODS: MRI-ultrasound targeted biopsy of regions of interest and concurrent 12-core systematic biopsy was performed on men with Gleason grade group (GG) 1 and 2. We compared Decipher score with PI-RADS scores and biopsy Gleason GG. Subgroup analyses were performed to evaluate patients who underwent radical prostatectomy (RP), and men with Decipher testing from a targeted biopsy core. RESULTS: One hundred two patients with GG1 and GG2 had biopsy Decipher testing. There was no significant difference in the median Decipher scores among the 3 multiparametric magnetic resonance imaging categories. Patients with GG2 vs GG1 in the setting of PI-RADS 4-5 had higher genomic scores (P = .01), but no significant difference was noted in patients with PI-RADS ≤3. The rate of genomic higher-risk disease on a targeted biopsy from PI-RADS5 was higher in GG2 (75%) vs GG1 (11.1%; P = .01). On multivariable logistic regression analysis, the Decipher score ≥0.45, (odds ratio (OR) 2.71; P = .02), and age (OR 1.11; P = .004) remained significant factors associated with Gleason GG2 on biopsy. CONCLUSION: High-risk genomic classification can be seen across all combinations of PI-RADS categories and Gleason GG1 and GG2, confirming a potential utility for Decipher testing in men with low- to favorable intermediate-risk prostate cancer. The Decipher biopsy genomic test related to Gleason GG independent of PI-RADSv2 score. Confirmatory genomic testing for patients undergoing active surveillance appears more valuable than PI-RADSv2 score.

Combining immune check-point blockade and cryoablation in an immunocompetent hormone sensitive murine model of prostate cancer.

BACKGROUND: Prostate cancer remains the second leading cause of cancer related death in men. Immune check point blocking antibodies have revolutionized treatment of multiple solid tumors, but results in prostate cancer remain marginal. Previous reports have suggested that local therapies, in particular cryoablation might increase tumor immunogenicity. In this work, we examine potential synergism between tumor cryoabalation and check point blocking antibodies. METHODS: FVB/NJ mice were injected subcutaneously into each flank with either 1 × 106 or 0.2 × 106 isogenic hormone sensitive Myc-Cap cells to establish synchronous grafts. Mice were treated with four intraperitoneal injections of anti-PD-1 (10 mg/kg), anti-CTLA-4 (1 mg/kg), or isotype control antibody with or without adjuvant cryoablation of the larger tumor graft and with or without neo-adjuvant androgen deprivation with degarelix (ADT). Mouse survival and growth rates of tumor grafts were measured. The immune dependency of observed oncological effects was evaluated by T cell depletion experiments. RESULTS: Treatment with anti-CTLA-4 antibody and cryoablation delayed the growth of the distant tumor by 14.8 days (p = 0.0006) and decreased the mortality rate by factor of 4 (p = 0.0003) when compared to cryoablation alone. This synergy was found to be dependent on CD3+ and CD8+ cells. Combining PD-1 blockade with cryoablation did not show a benefit over use of either treatment alone. Addition of ADT to anti-PD1 therapy and cryoablation doubled the time to accelerated growth in the untreated tumors (p = 0.0021) and extended survival when compared to cryoablation combined with ADT in 25% of the mice. Effects of combining anti-PD1 with ADT and cryoablation on mouse survival were obviated by T cell depletion. CONCLUSION: Trimodal therapy consisting of androgen deprivation, cryoablation and PD-1 blockade, as well as the combination of cryoablation and low dose anti-CTLA-4 blockade showed that local therapies with cryoablation could be considered to augment the effects of checkpoint blockade in prostate cancer.

The Relationship between Carotid and Femoral Artery Intima-Media Thickness and Histopathologic Grade of Atherosclerosis in Patients with Chronic Kidney Disease.

BACKGROUND/AIMS: Variability in the grade of atherosclerosis among patients with chronic kidney disease (CKD) could affect the ultrasound measurements of intima media thickness (IMT). We sought to investigate IMTs of carotid (cIMT) and femoral (fIMT) arteries in CKD patients and assess the degree of their correlation with histopathological atherosclerosis. METHODS: Eighty-nine out of 99 enrolled subjects completed this study. The subjects were divided into 3 groups: 34 patients with CKD (Case group), 31 with coronary artery disease undergoing coronary artery bypass graft (CABG, positive control group), and 24 healthy kidney donors (negative control group). For histopathological assessment of atherosclerosis, arterial tissue samples were obtained from the patients in each study group. The cIMT and fIMTs were measured by ultrasonography. RESULTS: Histopathological atherosclerosis was present in 82.3, 100, and 20.8% of CKD, CABG, and donor groups respectively (p < 0.001). CKD patients had higher values of cIMT and fIMT than the donor group (p = 0.01 and 0.004, respectively). cIMT was positively correlated with the grade of atherosclerosis in the CKD group only (p < 0.001), while fIMT was correlated with the grade of atherosclerosis in both CKD and donor groups (p < 0.001 and p = 0.009 respectively). In CKD patients, cIMT >0.65 mm and femoral values >0.57 mm predicted the presence of histopathological atherosclerosis with sensitivities of 96 and 92% respectively. CONCLUSION: Higher values of cIMT and fIMT in CKD patients are associated with higher rates and degrees of histopathological atherosclerosis. Additionally, when compared to fIMT, cIMT has a higher sensitivity for detecting atherosclerosis in CKD patients.

Combining Prostate Health Index density, magnetic resonance imaging and prior negative biopsy status to improve the detection of clinically significant prostate cancer.

OBJECTIVES: To determine the performance of Prostate Health Index (PHI) density (PHID) combined with MRI and prior negative biopsy (PNB) status for the diagnosis of clinically significant prostate cancer (PCa). PATIENTS AND METHODS: Patients without a prior diagnosis of PCa, with elevated prostate-specific antigen and a normal digital rectal examination who underwent PHI testing prospectively prior to prostate biopsy were included in this study. PHID was calculated retrospectively using prostate volume derived from transrectal ultrasonography at biopsy. Univariable and multivariable logistic regression modelling, along with receiver-operating characteristic (ROC) curve analysis, was used to determine the ability of serum biomarkers to predict clinically significant PCa (defined as either grade group [GG] ≥2 disease or GG1 PCa detected in >2 cores or >50% of any one core) on biopsy. Age, PNB status and Prostate Imaging Reporting and Data System (PI-RADS) score were incorporated into the regression models. RESULTS: Of the 241 men who qualified for the study, 91 (37.8%) had clinically significant PCa on biopsy. The median (interquartile range) PHID was 0.74 (0.44-1.24); it was 1.18 (0.77-1.83) and 0.55 (0.38-0.89) in those with and without clinically significant PCa on biopsy, respectively (P < 0.001). On univariable logistic regression, age and PNB status were associated with clinically significant cancer. Of the tested biomarkers, PHID demonstrated the highest discriminative ability for clinically significant disease (area under the ROC curve [AUC] 0.78 for the univariable model). That continued to be the case in multivariable logistic regression models incorporating age and PNB status (AUC 0.82). At a threshold of 0.44, representing the 25th percentile of PHID in the cohort, PHID was 92.3% sensitive and 35.3% specific for clinically significant PCa; the sensitivity and specificity were 93.0% and 32.4% and 97.4% and 29.1% for GG ≥2 and GG ≥3 disease, respectively. In the 104 men who underwent MRI, PI-RADS score was complementary to PHID, with a PI-RADS score ≥3 or, if PI-RADS score ≤2, a PHID ≥0.44, detecting 100% of clinically significant disease. For that subgroup, of the biomarkers tested, PHID (AUC 0.90) demonstrated the highest discriminative ability for clinically significant disease on multivariable logistic regression incorporating age, PNB status and PI-RADS score. CONCLUSIONS: In this contemporary cohort of men undergoing prostate biopsy for the diagnosis of PCa, PHID outperformed PHI and other PSA derivatives in the diagnosis of clinically significant cancer. Incorporating age, PNB status and PI-RADS score led to even further gains in the diagnostic performance of PHID. Furthermore, PI-RADS score was found to be complementary to PHID. Using 0.44 as a threshold for PHID, 35.3% of unnecessary biopsies could have been avoided at the cost of missing 7.7% of clinically significant cancers. Despite these encouraging results, prospective validation is needed.

Pharmacodynamic and pharmacokinetic neoadjuvant study of hedgehog pathway inhibitor Sonidegib (LDE-225) in men with high-risk localized prostate cancer undergoing prostatectomy.

PURPOSE: To determine the pharmacodynamic effects of Sonidegib (LDE-225) in prostate tumor tissue from men with high-risk localized prostate cancer, by comparing pre-surgical core-biopsy specimens to tumor tissue harvested post-treatment at prostatectomy. METHODS: We conducted a prospective randomized (Sonidegib vs. observation) open-label translational clinical trial in men with high-risk localized prostate cancer undergoing radical prostatectomy. The primary endpoint was the proportion of patients in each arm who achieved at least a two-fold reduction in GLI1 mRNA expression in post-treatment versus pre-treatment tumor tissue. Secondary endpoints included the effect of pre-surgical treatment with Sonidegib on disease progression following radical prostatectomy, and safety. RESULTS: Fourteen men were equally randomized (7 per arm) to either neoadjuvant Sonidegib or observation for 4 weeks prior to prostatectomy. Six of seven men (86%) in the Sonidegib arm (and none in the control group) achieved a GLI1 suppression of at least two-fold. In the Sonidegib arm, drug was detectable in plasma and in prostatic tissue; and median intra-patient GLI1 expression decreased by 63-fold, indicating potent suppression of Hedgehog signaling. Sonidegib was well tolerated, without any Grade 3-4 adverse events observed. Disease-free survival was comparable among the two arms (HR = 1.50, 95% CI 0.26-8.69, P = 0.65). CONCLUSIONS: Hedgehog pathway activity (as measured by GLI1 expression) was detectable at baseline in men with localized high-risk prostate cancer. Sonidegib penetrated into prostatic tissue and induced a >60-fold suppression of the Hedgehog pathway. The oncological benefit of Hedgehog pathway inhibition in prostate cancer remains unclear.

Dynamic Contrast Enhanced Magnetic Resonance Imaging Improves Classification of Prostate Lesions: A Study of Pathological Outcomes on Targeted Prostate Biopsy.

PURPOSE: PI-RADS™, version 2 stipulates that dynamic contrast enhanced imaging should be used to classify diffusion-weighted imaging score 3 peripheral zone lesions as PI-RADS score 3 (dynamic contrast enhanced imaging negative or nonenhancing) or 4 (dynamic contrast enhanced imaging positive or enhancing). However, to our knowledge it is unknown whether dynamic contrast enhanced imaging separates lesions into clinically meaningful pathological groups. We examined whether dynamic contrast enhanced imaging would improve the detection of clinically significant cancer. MATERIALS AND METHODS: We identified patients without a prior diagnosis of prostate cancer who underwent multiparametric magnetic resonance imaging-transrectal ultrasound fusion targeted biopsy of peripheral zone lesions with a diffusion-weighted imaging score of 3 or 4. Each lesion was grouped into 1 of 3 classifications, including group 1-diffusion-weighted imaging score 3/nonenhancing/PI-RADS score 3, group 2-diffusion-weighted imaging score 3/enhancing/PI-RADS score 4 or group 3-diffusion-weighted imaging score 4/PI-RADS score 4. We measured the rate of grade group 2 or greater pathology detected for each lesion group with subgroup analyses in patients with vs without prior negative systematic biopsy. RESULTS: We identified a total of 389 peripheral zone diffusion-weighted imaging score 3 or 4 lesions in 290 patients. The rate of grade group 2 or greater cancer on biopsy for group 1, 2 and 3 lesions was 8.9%, 21% and 36.5%, respectively (p <0.03). The rate of grade group 2 or greater pathology was higher in group 2 than group 1 lesions in patients with prior negative systematic prostate biopsy (28% vs 5.0%, p <0.001) but not in those without such a biopsy (16% vs 12%, p = 0.5). Group 3 lesions had a higher rate of grade group 2 or greater cancer than group 2 lesions in the biopsy naïve subgroup (46% vs 16%, p = 0.001). However, the rates were similar in patients with prior negative systematic prostate biopsy (27% vs 28%, p = 0.9). CONCLUSIONS: Diffusion-weighted imaging score 3 peripheral zone lesions were more likely to be clinically significant cancer (grade group 2 or greater) if they were dynamic contrast enhanced T1-weighted imaging positive. That was most apparent in patients with a prior negative systematic prostate biopsy. In such patients including a dynamic contrast enhanced sequence in multiparametric magnetic resonance imaging allowed for optimal lesion risk stratification.