Development and Optimization of a Subtraction-Normalized Immunocyte Profiling Signature for Prostate Cancer Active Surveillance Risk Stratification.

PURPOSE: Less invasive decision support tools are desperately needed to identify occult high-risk disease in men with prostate cancer (PCa) on active surveillance (AS). For a variety of reasons, many men on AS with low- or intermediate-risk disease forgo the necessary repeat surveillance biopsies needed to identify potentially higher-risk PCa. Here, we describe the development of a blood-based immunocyte transcriptomic signature to identify men harboring occult aggressive PCa. We then validate it on a biopsy-positive population with the goal of identifying men who should not be on AS and confirm those men with indolent disease who can safely remain on AS. This model uses subtraction-normalized immunocyte transcriptomic profiles to risk-stratify men with PCa who could be candidates for AS. MATERIALS AND METHODS: Men were eligible for enrollment in the study if they were determined by their physician to have a risk profile that warranted prostate biopsy. Both training (n = 1017) and validation cohort (n = 1198) populations had blood samples drawn coincident to their prostate biopsy. Purified CD2+ and CD14+ immune cells were obtained from peripheral blood mononuclear cells, and RNA was extracted and sequenced. To avoid overfitting and unnecessary complexity, a regularized regression model was built on the training cohort to predict PCa aggressiveness based on the National Comprehensive Cancer Network PCa guidelines. This model was then validated on an independent cohort of biopsy-positive men only, using National Comprehensive Cancer Network unfavorable intermediate risk and worse as an aggressiveness outcome, identifying patients who were not appropriate for AS. RESULTS: The best final model for the AS setting was obtained by combining an immunocyte transcriptomic profile based on 2 cell types with PSA density and age, reaching an AUC of 0.73 (95% CI: 0.69-0.77). The model significantly outperforms (P < .001) PSA density as a biomarker, which has an AUC of 0.69 (95% CI: 0.65-0.73). This model yields an individualized patient risk score with 90% negative predictive value and 50% positive predictive value. CONCLUSIONS: While further validation in an intended-use cohort is needed, the immunocyte transcriptomic model offers a promising tool for risk stratification of individual patients who are being considered for AS.

A Diagnostic Test Combining Molecular Testing with Phenotypic Pooled Antibiotic Susceptibility Improved the Clinical Outcomes of Patients with Non-E. coli or Polymicrobial Complicated Urinary Tract Infections.

Purpose: Complicated UTIs (cUTIs) cause significant morbidity and healthcare resource utilization and cost. Standard urine culture has limitations in detecting polymicrobial and non-E. coli infections, resulting in the under-diagnosis and under-treatment of cUTIs. In this study, patient-reported outcomes were compared between treated and untreated patients when an advanced diagnostic test combining multiplex-polymerase chain reaction (M-PCR) with a pooled antibiotic susceptibility method (P-AST) was incorporated into the patients' clinical management. Methods: Patients who had symptoms typical of cUTI and positive M-PCR/P-AST test results were recruited from urology clinics. Symptom reduction and clinical cure rates were measured from day 0 through day 14 using the American English Acute Cystitis Symptom Score (ACSS) Questionnaire. Clinical cure was defined based on the sum of the scores of four US Food and Drug Administration (FDA) symptoms and the absence of visible blood in the urine. Results: Of 264 patients with suspected cUTI, 146 (55.4%) had exclusively non-E. coli infections (115 treated and 31 untreated) and 190 (72%) had polymicrobial infections (162 treated and 28 untreated). Treated patients exhibited greater symptom reduction compared to untreated ones on day 14 for those with exclusively non-E. coli organisms (3.18 vs 1.64, p = 0.006) and polymicrobial infections (3.52 vs 1.41, p = 0.002), respectively. A higher percentage of treated patients than of untreated patients achieved clinical cure for polymicrobial infections on day 14 (58.7% vs 36.4%, p = 0.049). Conclusion: Patients with cUTIs treated based on the M-PCR/P-AST diagnostic test had significantly improved symptom reduction and clinical cure rates compared to untreated patients among those with non-E. coli or polymicrobial infections.

Positive Impact of Implementing a Comprehensive Genetic Testing Protocol for Prostate Cancer Patients in a Multi-disciplinary Uro-oncology Practice.

INTRODUCTION: Prior to the 2017 Philadelphia Consensus Conference guidelines, genetic testing for prostate cancer was conducted based on personal and family history of malignancy pursuant to National Comprehensive Cancer Network recommendations. The updated 2019 guidelines addressed the subject of genetic testing by endorsing point-of-care genetic testing and referral to genetic counseling. However, limited literature is available regarding successful implementation of a streamlined method for genetic testing. This paper explores the benefits of implementing an on-site guideline-based genetic testing process for prostate cancer patients. METHODS: Data were retrospectively reviewed for 552 prostate cancer patients seen in a uro-oncology clinic since January 2017. Prior to September 2018 genetic testing was recommended based on National Comprehensive Cancer Network guidelines, and swabs for testing were procured off-site 1 mile from the clinic (n = 78). After September 2018 genetic testing was recommended based on the Philadelphia Consensus Conference guidelines, and swabs for testing were procured at the clinic itself (n = 474). RESULTS: A statistically significant increase in testing compliance was observed after the implementation of on-site, guideline-based testing. Genetic testing compliance increased from 33.3% to 98.7%. The time to receive the genetic test results was also reduced from 38 days to 21 days. CONCLUSIONS: The implementation of an on-site, guideline-based genetic testing model for prostate cancer patients significantly improved compliance with genetic testing to 98.7% and decreased the time to receive genetic test results by 17 days. Adopting a guideline-based model with on-site genetic testing can significantly improve the detection rate for pathogenic and actionable mutations and increase the utilization of targeted therapies.

Variation and Correlation in Postoperative Imaging After Shockwave Lithotripsy and Ureteroscopy by Treatment Modality: Results of a Statewide Clinical Registry.

OBJECTIVE: To understand how patient, practice/urologist-level factors impact imaging after ureteroscopy (URS) and shockwave lithotripsy (SWL). METHODS: Using the Reducing Operative Complications from Kidney Stones (ROCKS) clinical registry from the Michigan Urological Surgery Improvement Collaborative (MUSIC), we identified patients undergoing URS and SWL between 2016-2019. Frequency and modality of 60-day postoperative imaging was assessed. We made bivariate comparisons across demographic/clinical data and assessed provider/practice-level imaging rate variation. We assessed correlation between imaging use within practices by treatment modality. Multivariable logistic regression controlling for practice/urologist variation was used to adjust for group differences. RESULTS: 14,894 cases were identified (9621 URS, 5273 SWL) from 33 practices and 205 urologists. Overall postoperative imaging rate was 49.1% and was significantly different following URS and SWL (36.3% vs 72.4%, P<0.01). Substantial practice variation was seen in rates following URS (range 0-93.1%) and SWL (range 36-95.2%). Odds of postoperative imaging by practice varied significantly (range 0.02-1.96). Moderate postoperative imaging correlation for URS and SWL (0.7, P<0.001) was seen. No practice had significantly higher odds of post-URS imaging. There was increased odds of postoperative imaging for SWL modality, larger stones and renal stones. CONCLUSION: Imaging rates after URS are almost half the rate for SWL with wide variation, underscoring uncertainty with how postoperative imaging is approached. However, practices who have higher post-URS imaging rates also image highly after SWL. Increased patient complexity and renal stone location drive imaging following URS.

Hereditary cancer risk assessment and genetic testing in the community urology practice setting.

OBJECTIVES: To evaluate the feasibility of integrating a hereditary cancer risk assessment (HCRA) process in the community urology practice setting for patients with prostate cancer (PCa). METHODS: In this prospective intervention, an HCRA process was implemented across six different community urology clinics between May 2019 and April 2020. The intervention included a process integration during which the workflow at each site was refined, a post-integration period during which HCRA was conducted in all patients with PCa, and a follow-up period during which healthcare providers and patients reported their satisfaction with the HCRA and genetic testing process. RESULTS: Among patients who completed a family history assessment during the post-integration period, 23.6% met guideline criteria for genetic testing. Of all patients seen at the clinic during the post-integration period, 8.7% completed genetic testing; this was a twofold increase over the period immediately preceding process integration (4.2%), and a sevenfold increase over the same period 1 year prior (1.2%). The majority of providers reported that the HCRA was as important as other regularly performed assessments (61.0%) and planned to continue using the process in their practice (68.3%). Most patients believed that the genetic test results were important for their future cancer care (84.7%) and had already shared their test results with at least one family member (63.2%). CONCLUSIONS: This study demonstrated that implementing an HCRA process in the community urology practice setting was feasible, generally favored by providers and patients, and resulted in an increase in the number of patients with PCa who completed genetic testing.

Evaluation of an RNAseq-Based Immunogenomic Liquid Biopsy Approach in Early-Stage Prostate Cancer.

The primary objective of this study is to detect biomarkers and develop models that enable the identification of clinically significant prostate cancer and to understand the biologic implications of the genes involved. Peripheral blood samples (1018 patients) were split chronologically into independent training (n = 713) and validation (n = 305) sets. Whole transcriptome RNA sequencing was performed on isolated phagocytic CD14+ and non-phagocytic CD2+ cells and their gene expression levels were used to develop predictive models that correlate to adverse pathologic features. The immune-transcriptomic model with the highest performance for predicting adverse pathology, based on a subtraction of the log-transformed expression signals of the two cell types, displayed an area under the curve (AUC) of the receiver operating characteristic of 0.70. The addition of biomarkers in combination with traditional clinical risk factors (age, serum prostate-specific antigen (PSA), PSA density, race, digital rectal examination (DRE), and family history) enhanced the AUC to 0.91 and 0.83 for the training and validation sets, respectively. The markers identified by this approach uncovered specific pathway associations relevant to (prostate) cancer biology. Increased phagocytic activity in conjunction with cancer-associated (mis-)regulation is also represented by these markers. Differential gene expression of circulating immune cells gives insight into the cellular immune response to early tumor development and immune surveillance.

A 17-gene Panel for Prediction of Adverse Prostate Cancer Pathologic Features: Prospective Clinical Validation and Utility.

OBJECTIVE: To validate the 17-gene Oncotype DX Genomic Prostate Score (GPS) biopsy-based gene expression assay as a predictor of adverse pathology (AP, Gleason score [pGS] ≥4+3and/or ≥pT3) in a prospectively enrolled cohort. METHODS: Between July 2014 and September 2015, 1200 men with very low-, low-, and favorable intermediate-risk prostate cancer enrolled in a multi-institutional prospective study of the GPS assay (NCT03502213). The subset who proceeded to immediate radical prostatectomy (RP) after GPS testing was included in a prespecified subanalysis of GPS on biopsy and its association with surgical AP on RP using logistic regression and receiver operating characteristic curves. The effect of GPS testing on physicians' and patients' attitudes about decision making was assessed with the Decisional Conflict Scale. RESULTS: One hundred fourteen patients (treated by 59 physicians from 19 sites) elected RP and 40 (35%) had AP. GPS result was a significant predictor of AP (odds ratio per 20 GPS units [OR/20 units]: 2.2; 95% CI 1.2-4.1; P = .008) in univariable analysis and remained significant after adjustment for biopsy Gleason score, clinical T-stage, and logPSA (OR/20 units: 1.9; 95% CI 1.0-3.8; P = .04), or NCCN risk group (OR/20 units: 2.0; 95% CI 1.1-3.7; P = .02). Mean pre-GPS Decisional Conflict Scale score was 27 (95% CI 24-31), which improved significantly after GPS testing to 14 (95% CI 11-17) (P < .001). CONCLUSION: In this real-world multi-institutional study, the GPS assay was prospectively confirmed as an independent predictor of AP at surgery. GPS testing was associated with reduced patient decisional conflict.

Percutaneous Cryoablation vs Partial Nephrectomy: Cost Comparison of T1a Tumors.

PURPOSE: To compare cost of percutaneous cryoablation vs open and robot-assisted partial nephrectomy of T1a renal masses from the hospital perspective. MATERIALS AND METHODS: We retrospectively compared cost, clinical and tumor data of 37 percutaneous cryoablations to 26 open and 102 robot-assisted partial nephrectomies. Total cost was the sum of direct and indirect cost of procedural and periprocedural variables. Clinical data included demographics, Charlson Comorbidity Index (CCI), hospitalization time, complication rate, ICU admission rate, and 30-day readmission rates. Tumor data included size, RENAL nephrometry score, and malignancy rate. Student's t-test was used for continuous variables and Fisher's exact or chi-square tests for categorical data. RESULTS: Mean total cost was lower for percutaneous cryoablation than open or robot-assisted partial nephrectomy: $6067 vs $11392 or $11830 (p<0.0001) with lower cost of procedure room: $1516 vs $3272 or $3254 (p<0.0001), room and board: $95 vs $1907 or $1106 (p<0.0001), anesthesia: $684 vs $1223 or $1468 (p<0.0001), and laboratory/pathology fees: $205 vs $804 or $720 (p<0.0001). Supply and device cost was higher than open: $2596 vs $1352 (p<0.0001), but lower than robot-assisted partial nephrectomy: $3207 (p=0.002). Mean hospitalization times were lower for percutaneous cryoablation (p<0.0001), while age and CCI were higher (p<0.0001). No differences in tumor size, nephrometry score, malignancy rate complication, ICU, or 30-day readmission rates were observed. CONCLUSION: Percutaneous cryoablation can be performed at significantly lower cost than open and robotic partial nephrectomies for similar masses.

Impact of a prostate multidisciplinary clinic program on patient treatment decisions and on adherence to NCCN guidelines: the William Beaumont Hospital experience.

OBJECTIVES: In order to demonstrate the impact of multidisciplinary care in the community oncology setting, we evaluated treatment decisions after the initiation of a dedicated prostate and genitourinary (GU) multidisciplinary clinic (MDC). METHODS: In March 2010, a GU MDC was created at William Beaumont Hospital with the goal of providing patients with a comprehensive multidisciplinary evaluation and consensus treatment recommendations in a single visit. Urologists, radiation, and medical oncologists along with ancillary support staff participated in this comprehensive initial evaluation. The impact of this experience on patient treatment decisions was analyzed. RESULTS: During the first year, a total of 182 patients were seen. Compared with previous years, low-risk MDC patients more frequently chose external beam radiation therapy (41.1% vs. 26.6%, P=0.02), and active surveillance (14.3% vs. 6.1%, P=0.02) and less frequently prostatectomy (30.4% vs. 44.0%, P=0.03). Similar increases in external beam were seen in intermediate and high-risk patients. Increased use of hormonal therapy was found in high-risk patients compared with the years before the initiation of the MDC (76.2% vs. 51.1%, P=0.03). Increased adherence to National Comprehensive Cancer Network (NCCN) guidelines was seen with intermediate-risk patients (89.8% vs. 75.9%, P=0.01), whereas nonsignificant increases were seen in low-risk (100% vs. 98.9%, P=0.43) and high-risk patients (100% vs. 94.2%, P=0.26). CONCLUSIONS: The establishment of a GU MDC improved the quality of care for cancer patients as demonstrated by improved adherence to National Comprehensive Cancer Network guidelines, and a broadening of treatment choices made available.

Clinicopathologic analysis of extracapsular extension in prostate cancer: should the clinical target volume be expanded posterolaterally to account for microscopic extension?

PURPOSE: We performed a complete pathologic analysis examining extracapsular extension (ECE) and microscopic spread of malignant cells beyond the prostate capsule to determine whether and when clinical target volume (CTV) expansion should be performed. METHODS AND MATERIALS: A detailed pathologic analysis was performed for 371 prostatectomy specimens. All slides from each case were reviewed by a single pathologist (N.S.G.). The ECE status and ECE distance, defined as the maximal linear radial distance of malignant cells beyond the capsule, were recorded. RESULTS: A total of 121 patients (33%) were found to have ECE (68 unilateral, 53 bilateral). Median ECE distance=2.4 mm [range: 0.05-7.0 mm]. The 90th-percentile distance = 5.0 mm. Of the 121 cases with ECE, 55% had ECE distance>or=2 mm, 19%>or=4 mm, and 6%>or=6 mm. ECE occurred primarily posterolaterally along the neurovascular bundle in all cases. Pretreatment prostrate-specific antigen (PSA), biopsy Gleason, pathologic Gleason, clinical stage, bilateral involvement, positive margins, percentage of gland involved, and maximal tumor dimension were associated with presence of ECE. Both PSA and Gleason score were associated with ECE distance. In all 371 patients, for those with either pretreatment PSA>or=10 or biopsy Gleason score>or=7, 21% had ECE>or=2 mm and 5%>or=4 mm beyond the capsule. For patients with both of these risk factors, 49% had ECE>or=2 mm and 21%>or=4 mm. CONCLUSIONS: For prostate cancer with ECE, the median linear distance of ECE was 2.4 mm and occurred primarily posterolaterally. Although only 5% of patients demonstrate ECE>4 to 5 mm beyond the capsule, this risk may exceed 20% in patients with PSA>or=10 ng/ml and biopsy Gleason score>or=7. As imaging techniques improve for prostate capsule delineation and as radiotherapy delivery techniques increase in accuracy, a posterolateral CTV expansion should be considered for patients at high risk.

Performance of urine test in patients monitored for recurrence of bladder cancer: a multicenter study in the United States.

PURPOSE: We assessed the performance of the ImmunoCyt immunocytochemical test for detecting bladder cancer recurrence in patients with prior superficial bladder cancers compared with cystoscopic and histological findings. MATERIALS AND METHODS: A total of 341 patients with a history of bladder cancer undergoing monitoring were evaluated at 4 sites. The results of cytology and/or ImmunoCyt were analyzed for sensitivity and specificity compared with biopsy confirmed cancer. RESULTS: The overall sensitivity of cytology alone, ImmunoCyt alone and the 2 methods combined was 23%, 81% and 81%, respectively. The specificity of cytology alone, ImmunoCyt alone and of the 2 methods combined was 93%, 75% and 73%, respectively. The immunocytochemical test was more sensitive than cytology for detecting grades 1 and 2, and stages Ta, T1, and T2 urothelial carcinoma, and it was equally sensitive for detecting grade 3 cancers and carcinoma in situ (CIS). The sensitivity of the combined tests for grades 1 to 3/CIS was 79%, 90% and 82%, while for stages Ta, T1, T2+ and CIS it was 83%, 75%, 100% and 100%, respectively. The overall positive and negative predictive values of the combined tests were 37% and 95%, respectively. Importantly the immunocytochemical test could detect 71% of small (less than 1 cm) tumors. CONCLUSIONS: ImmunoCyt is a sensitive test for detecting bladder cancer. Because of its high sensitivity for detecting small tumors, even those of low histological grade, and its high negative predictive value, this test may have a role in decreasing the frequency of cystoscopic examinations for monitoring patients with low risk bladder cancer.

A new model using number of needles and androgen deprivation to predict chronic urinary toxicity for high or low dose rate prostate brachytherapy.

PURPOSE: Prostate brachytherapy is an established treatment modality in early stage prostate cancer. We retrospectively reviewed our experience with low dose rate (LDR) and high dose rate (HDR) brachytherapy as a single treatment modality for early prostate cancer with emphasis on chronic toxicity. MATERIALS AND METHODS: From June 1996 to August 2003, 253 patients with stage II prostate cancer, prostate specific antigen less than 12 and Gleason score less than 7 were treated with brachytherapy alone at our institution. A total of 92 patients underwent HDR brachytherapy with 192Ir, while 161 underwent LDR brachytherapy with 103Pd. HDR minimum prostate dose was 38 Gy, delivered in 4 fractions with a single implant during 36 hours. For HDR we used real-time dynamic 3-dimensional ultrasound base dosimetry. For 103Pd seed implants the dose was 120 Gy using selective peripheral weighted dose distribution. Treatment was given based on patient preference after pretreatment transrectal ultrasound. Toxicity was scored using the National Cancer Institute Common Toxicity Criteria 2.0. Median followup in all 253 cases was 2.9 years. RESULTS: In all patients the rate of 3-year urinary toxicity grade 2 or greater and grade 3 or greater was 26% and 6.9%, which was not significantly different between HDR and LDR (p = 0.3 and 0.4, respectively). However, grade 1 urogenital toxicity was lower for HDR (p = 0.002). The 3-year grade 2 rectal toxicity rate was 0.8% with no grade 3 or greater events, which was and similar in the HDR and LDR groups (1% and 0.6%, respectively). No cancer related deaths occurred and 4-year overall survival was 99% for HDR and 96.4% for LDR (p = 0.4). The 3-year American Society for Therapeutic Radiology and Oncology biochemical control rate was 90% for LDR and 93% for HDR. Cox multivariate analysis for grade 2 or greater urinary toxicity was significant for the use of 14 or greater needles (HR 6.1, p = 0.02) and hormonal therapy (HR 2.2, p = 0.02). In the absence of risk factors the 4-year grade 2 or greater urinary toxicity rate was 7% vs 65% if the 2 risk factors were present (p <0.001). Impotence crude rates were 18.3% for HDR and 41.3% for LDR (p = 0.002). CONCLUSIONS: HDR and LDR chronic urinary toxicity grade 2 or greater rates were equivalent. However, grade 1 was lower for HDR. The impotence rate was decrease by half with HDR. Neoadjuvant hormonal therapy and 14 or greater needles were significantly associated with increased chronic urinary toxicity on multivariate analysis.

Treatment of prostate cancer with radiotherapy: should the entire seminal vesicles be included in the clinical target volume?

PURPOSE: When treating high-risk prostate cancer with radiation therapy, inclusion of the seminal vesicles (SVs) within the clinical target volume (CTV) can dramatically increase the volume of radiated normal tissues and hinder dose escalation. Because cancer may involve only the proximal portion of the frequently lengthy SVs, we performed a complete pathology review of prostatectomy specimens to determine the appropriate length of SV to include within the CTV when SV treatment is indicated. METHODS AND MATERIALS: A detailed pathologic analysis was performed for 344 radical prostatectomy specimens (1987-2000). All slides from each case were reviewed by a single pathologist (N.S.G.). Factors recorded for each case included length of each SV (cm), length of cancer involvement in each SV (cm) measured from the prostate-SV junction, and percentage of SV length involved. RESULTS: Fifty-one patients (15%) demonstrated SV involvement in 81 SVs (21 unilateral, 30 bilateral SV involvement). The median SV length was 3.5 cm (range: 0.7-8.5 cm). Factors associated with SV involvement included the pretreatment PSA level, biopsy Gleason score, and clinical T classification. The commonly used risk group stratification was very effective at predicting SV positivity. Only 1% of low-risk patients (PSA <10 ng/mL, Gleason or=10 ng/mL, biopsy Gleason >or=7, or clinical T stage >or=T2b). When treating the SV for prostate cancer, only the proximal 2.0-2.5 cm (approximately 60%) of the SV should be included within the CTV.

A centralized comparison of radical perineal and retropubic prostatectomy specimens: is there a difference according to the surgical approach?

PURPOSE: We performed a central review of pathology specimens from radical perineal and radical retropubic prostatectomies performed by a single surgeon. We determined whether differences exist in the 2 approaches in regard to the ability to obtain adequate surgical margins around the tumor and adequate extracapsular tissue around the prostate, and avoid inadvertent capsular incision. MATERIALS AND METHODS: The review included whole mount prostates from 60 patients who underwent radical retropubic prostatectomy and 40 who underwent radical perineal prostatectomy. The pathologist (N. S. G.) was blinded to the surgical approach. All prostatectomies were consecutive and performed by the same surgeon (H. J. K.). To ensure consistency of the pathological measurements patients were excluded from analysis if they had undergone preoperative androgen ablation or a nerve sparing procedure, leaving 45 retropubic and 27 perineal prostatectomy specimens for further evaluation. Pertinent clinical parameters were assessed and a detailed pathological analysis of each specimen was performed. RESULTS: In the retropubic and perineal groups 78% of the tumors were organ confined (stage pT2) with extracapsular extension (stage pT3) in the majority of the remaining patients. There was no significant difference in the positive margin rate for the retropubic and perineal procedures (16% and 22%, p = 0.53) or for Gleason 6 and 7 tumors only in the 2 groups (10% and 17%, respectively, p = 0.47). The capsular incision rate was 4% in each group. The distance of the tumor from the posterolateral margins and the amount of extracapsular tissue excised were equivalent in each group. Subgroups of patients with a prostate of less than 50 gm. and containing only low grade, low stage neoplasms were also analyzed. Subgroup analysis showed no difference in any variable. CONCLUSIONS: Radical perineal prostatectomy is comparable to radical retropubic prostatectomy for obtaining adequate surgical margins, avoiding inadvertent capsular incisions and excising adequate extracapsular tissue around tumor foci. Additional patient accrual and prostate specific antigen followup would further help validate the similar efficacy of the 2 surgical approaches as treatment for prostate cancer.