A Pilot Study on Patient-specific Computational Forecasting of Prostate Cancer Growth during Active Surveillance Using an Imaging-informed Biomechanistic Model.

Active surveillance (AS) is a suitable management option for newly diagnosed prostate cancer, which usually presents low to intermediate clinical risk. Patients enrolled in AS have their tumor monitored via longitudinal multiparametric MRI (mpMRI), PSA tests, and biopsies. Hence, treatment is prescribed when these tests identify progression to higher-risk prostate cancer. However, current AS protocols rely on detecting tumor progression through direct observation according to population-based monitoring strategies. This approach limits the design of patient-specific AS plans and may delay the detection of tumor progression. Here, we present a pilot study to address these issues by leveraging personalized computational predictions of prostate cancer growth. Our forecasts are obtained with a spatiotemporal biomechanistic model informed by patient-specific longitudinal mpMRI data (T2-weighted MRI and apparent diffusion coefficient maps from diffusion-weighted MRI). Our results show that our technology can represent and forecast the global tumor burden for individual patients, achieving concordance correlation coefficients from 0.93 to 0.99 across our cohort (n = 7). In addition, we identify a model-based biomarker of higher-risk prostate cancer: the mean proliferation activity of the tumor (P = 0.041). Using logistic regression, we construct a prostate cancer risk classifier based on this biomarker that achieves an area under the ROC curve of 0.83. We further show that coupling our tumor forecasts with this prostate cancer risk classifier enables the early identification of prostate cancer progression to higher-risk disease by more than 1 year. Thus, we posit that our predictive technology constitutes a promising clinical decision-making tool to design personalized AS plans for patients with prostate cancer. SIGNIFICANCE: Personalization of a biomechanistic model of prostate cancer with mpMRI data enables the prediction of tumor progression, thereby showing promise to guide clinical decision-making during AS for each individual patient.

High expression of Trop2 is associated with aggressive localized prostate cancer and is a candidate urinary biomarker.

Distinguishing indolent from clinically significant localized prostate cancer is a major clinical challenge and influences clinical decision-making between treatment and active surveillance. The development of novel predictive biomarkers will help with risk stratification, and clinical decision-making, leading to a decrease in over or under-treatment of patients with prostate cancer. Here, we report that Trop2 is a prognostic tissue biomarker for clinically significant prostate cancer by utilizing the Canary Prostate Cancer Tissue Microarray (CPCTA) cohort composed of over 1100 patients from a multi-institutional study. We demonstrate that elevated Trop2 expression is correlated with worse clinical features including Gleason score, age, and pre-operative PSA levels. More importantly, we demonstrate that elevated Trop2 expression at radical prostatectomy predicts worse overall survival in men undergoing radical prostatectomy. Additionally, we detect shed Trop2 in urine from men with clinically significant prostate cancer. Our study identifies Trop2 as a novel tissue prognostic biomarker and a candidate non-invasive marker for prostate cancer.

UCHL1 is a potential molecular indicator and therapeutic target for neuroendocrine carcinomas.

Neuroendocrine carcinomas, such as neuroendocrine prostate cancer and small-cell lung cancer, commonly have a poor prognosis and limited therapeutic options. We report that ubiquitin carboxy-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme, is elevated in tissues and plasma from patients with neuroendocrine carcinomas. Loss of UCHL1 decreases tumor growth and inhibits metastasis of these malignancies. UCHL1 maintains neuroendocrine differentiation and promotes cancer progression by regulating nucleoporin, POM121, and p53. UCHL1 binds, deubiquitinates, and stabilizes POM121 to regulate POM121-associated nuclear transport of E2F1 and c-MYC. Treatment with the UCHL1 inhibitor LDN-57444 slows tumor growth and metastasis across neuroendocrine carcinomas. The combination of UCHL1 inhibitors with cisplatin, the standard of care used for neuroendocrine carcinomas, significantly delays tumor growth in pre-clinical settings. Our study reveals mechanisms of UCHL1 function in regulating the progression of neuroendocrine carcinomas and identifies UCHL1 as a therapeutic target and potential molecular indicator for diagnosing and monitoring treatment responses in these malignancies.

Effects of curcumin and ursolic acid in prostate cancer: A systematic review.

The major barriers to phytonutrients in prostate cancer therapy are non-specific mechanisms and bioavailability issues. Studies have pointed to a synergistic combination of curcumin (CURC) and ursolic acid (UA). We investigate this combination using a systematic review process to assess the most likely mechanistic pathway and human testing in prostate cancer. We used the PRISMA statement to screen titles, abstracts, and the full texts of relevant articles and performed a descriptive analysis of the literature reviewed for study inclusion and consensus of the manuscript. The most common molecular and cellular pathway from articles reporting on the pathways and effects of CURC (n = 173) in prostate cancer was NF-κB (n = 25, 14.5%). The most common molecular and cellular pathway from articles reporting on the pathways and effects of UA (n = 24) in prostate cancer was caspase 3/caspase 9 (n = 10, 41.6%). The three most common molecular and cellular pathway from articles reporting on the pathways and effects of both CURC and UA (n = 193) in prostate cancer was NF-κB (n = 28, 14.2%), Akt (n = 22, 11.2%), and androgen (n = 19, 9.6%). Therefore, we have identified the potential synergistic target pathways of curcumin and ursolic acid to involve NF-κB, Akt, androgen receptors, and apoptosis pathways. Our review highlights the limited human studies and specific effects in prostate cancer.

Comparative Effectiveness Randomized Clinical Trial Using Next-generation Microbial Sequencing to Direct Prophylactic Antibiotic Choice Before Urologic Stone Lithotripsy Using an Interprofessional Model.

Background: Next-generation sequencing (NGS) methods for microbial profiling have increased sensitivity to detect urinary pathogens. Objective: To determine whether NGS microbial profiling can be used to guide antibiotic prophylaxis and reduce infection compared with the standard of care. Design setting and participants: A prospective randomized controlled clinical trial of patients undergoing urologic stone interventions at an academic health center from December 2019 to January 2022 was conducted. Urine was collected at the preoperative visit for standard culture and intervention NGS diagnostics. Evaluable patients were culture negative, met 2-wk follow-up, and did not cancel surgery. Of 240 individuals (control = 121, intervention = 119), 83 control and 74 intervention patients were evaluable. Intervention: Microbial findings (paired quantitative polymerase chain reaction and NGS) were sent to an infectious disease pharmacist to recommend prophylactic antimicrobial regimen. Outcome measurements and statistical analysis: The primary outcome was postoperative urinary infection within the follow-up period (Fisher's exact test). The primary outcome was analyzed by modified intent-to-treat (mITT) and per-protocol analyses. Secondary endpoints considered included positive culture concordance, antibiotic use, and adverse events. Additional post hoc analyses investigated factors contributing to infection (univariate logistic regression). Results and limitations: The intervention significantly reduced postsurgical urinary infection risk by 7.1% (-0.73%, 15%) compared with the standard of care in the mITT analysis (1.4% vs 8.4%, p = 0.045) or by 8.5% (0.88%, 16%) compared with the per-protocol analysis (0% vs 8.5%, p = 0.032). NGS-guided treatment altered the distribution of antibiotics used (p = 0.025), and antibiotics poorly matched with NGS findings were associated with increased infection odds (odds ratio [OR] = 5.9, p = 0.046). Women were at greater odds to develop infection (OR = 10, p = 0.03) and possessed differentiated microbial profiles (p < 0.001). Conclusions: Urinary microbial NGS-guided antibiotic prophylaxis before endoscopic urologic stone lithotripsy improves antibiotic selection to reduce healthcare-associated urinary infections; however, treatment efficacy may be limited by the ability to adhere to the recommended protocol. Patient summary: We investigated whether microbial DNA sequencing could improve the selection of antibiotics before kidney stone surgery in patients not known to have any bacteria in the urine on standard culture. We found that using microbe DNA to guide antibiotic choices decreased postoperative infection rate and may encourage individualized use of available antibiotics.

Impact of rural residence on the presentation, management and survival of patients with non-metastatic muscle-invasive bladder carcinoma.

PURPOSE: To assess the impact of rural and remote residence on the receipt of guidelines-recommended treatment, quality of treatment and overall survival (OS) in patients with non-metastatic muscle-invasive bladder cancer (MIBC). MATERIALS AND METHODS: Patients with MIBC were identified using National Cancer Database. Patients were classified into three residential areas. Logistic regression models were used to assess associations between geographic residence and receipt of radical cystectomy (RC) or chemoradiation therapy (CRT). Models were fitted to assess quality benchmarks of RC and CRT. RESULTS: We identified 71,395 patients. Of those 58,874 (82.5%) were living in Metro areas, 8,534 (11.9%) in urban-rural adjacent (URA), and 3,987 (5.6%) in urban-rural remote to metro area (URR). URR residence was significantly associated with poor OS compared to URA and Metro residence (HR 0.87, 95% CI 0.81-0.94 and HR 0.90, 95% CI 0.87-0.93, p<0.001). There was no difference in the likelihood of receiving RC and CRT among different residential areas. Among patients who underwent RC; individuals living in URR were less likely to receive neoadjuvant chemotherapy and adequate lymph node dissection, and had a higher probability of positive surgical margin than those living in metro areas. For those who received CRT; individuals living in Metro areas were more likely to receive concomitant systemic therapy compared to URR. CONCLUSIONS: Rural residence is associated with lower OS for MIBC patients and less likelihood of meeting quality benchmarks for RC and CRT. This data should be used to guide further health policy and allocation of resources for rural population.

Phagocytosis-initiated tumor hybrid cells acquire a c-Myc-mediated quasi-polarization state for immunoevasion and distant dissemination.

While macrophage phagocytosis is an immune defense mechanism against invading cellular organisms, cancer cells expressing the CD47 ligand send forward signals to repel this engulfment. Here we report that the reverse signaling using CD47 as a receptor additionally enhances a pro-survival function of prostate cancer cells under phagocytic attack. Although low CD47-expressing cancer cells still allow phagocytosis, the reverse signaling delays the process, leading to incomplete digestion of the entrapped cells and subsequent tumor hybrid cell (THC) formation. Viable THCs acquire c-Myc from parental cancer cells to upregulate both M1- and M2-like macrophage polarization genes. Consequently, THCs imitating dual macrophage features can confound immunosurveillance, gaining survival advantage in the host. Furthermore, these cells intrinsically express low levels of androgen receptor and its targets, resembling an adenocarcinoma-immune subtype of metastatic castration-resistant prostate cancer. Therefore, phagocytosis-generated THCs may represent a potential target for treating the disease.

Diabetes, Obesity, and Pathological Upstaging in Renal Cell Carcinoma: Results From a Large Multi-institutional Consortium.

PURPOSE: We sought to determine whether clinical risk factors and morphometric features on preoperative imaging can be utilized to identify those patients with cT1 tumors who are at higher risk of upstaging (pT3a). MATERIALS AND METHODS: We performed a retrospective international case-control study of consecutive patients treated surgically with radical or partial nephrectomy for nonmetastatic renal cell carcinoma (cT1 N0) conducted between January 2010 and December 2018. Multivariable logistic regression models were used to study associations of preoperative risk factors on pT3a pathological upstaging among all patients, as well as subsets with those with preoperative tumors ≤4 cm, renal nephrometry scores, tumors ≤4 cm with nephrometry scores, and clear cell histology. We also examined association with pT3a subsets (renal vein, sinus fat, perinephric fat). RESULTS: Among the 4,092 partial nephrectomy and 2,056 radical nephrectomy patients, pathological upstaging occurred in 4.9% and 23.3%, respectively. Among each group independent factors associated with pT3a upstaging were increasing preoperative tumor size, increasing age, and the presence of diabetes. Specifically, among partial nephrectomy subjects diabetes (OR=1.65; 95% CI 1.17, 2.29), male sex (OR=1.62; 95% CI 1.14, 2.33), and increasing BMI (OR=1.03; 95% CI 1.00, 1.05 per 1 unit BMI) were statistically associated with upstaging. Subset analyses identified hilar tumors as more likely to be upstaged (partial nephrectomy OR=1.91; 95% CI 1.12, 3.16; radical nephrectomy OR=2.16; 95% CI 1.44, 3.25). CONCLUSIONS: Diabetes and higher BMI were associated with pathological upstaging, as were preoperative tumor size, increased age, and male sex. Similarly, hilar tumors were frequently upstaged.

Volumetric Analysis of Renal Masses as Predictors of Partial Nephrectomy Outcomes.

Objective: To examine the role of endophytic tumor volume (TV) assessment (endophycity) on perioperative partial nephrectomy (PN) outcomes. Patients and Methods: Retrospective review of 212 consecutive laparoscopic and open partial nephrectomies from single institution using preoperative imaging and 1-year follow-up. Demographics, comorbidities, RENAL nephrometry scores, and all peri- and postoperative outcomes were recorded. Volumetric analysis performed using imaging software, independently assessed by two blinded radiologists. Univariate and multivariate statistical analysis were completed to assess predictive value of endophycity for all clinically meaningful outcomes. Results: Among those undergoing minimally invasive surgery (MIS), lower tumor endophycity was associated with higher likelihood of trifecta outcome (negative surgical margin, <10% decline in estimated glomerular filtration rate, the absence of complications) irrespective of max tumor size. For MIS, estimated blood loss increased with greater tumor endophycity regardless of tumor size. Among those who underwent open partial nephrectomy, lower tumor endophycity was associated with trifecta outcomes for tumors >4 cm only. On multivariate analysis with log-scaled odds ratios (OR), tumor endophycity and total kidney volume had the strongest correlation with tumor-related complications (OR = 3.23, 2.66). The analysis identified that tumor endophycity and TV on imaging were inversely correlated with of trifecta outcomes (OR = 0.53 for both covariates). Conclusions: Volumetric assessment of tumor endophycity performed well in identifying PN outcomes. As automated imaging software improves, volumetric analysis may prove to be a useful adjunct in preoperative planning and patient counseling.

Patency outcomes of primary inferior vena cava repair in radical nephrectomy and tumor thrombectomy.

OBJECTIVE: The reconstruction of inferior vena cava (IVC) during radical nephrectomy and venous tumor thrombectomy (RN-VTT) is mostly performed with primary repair or with a patch/graft. We sought to systematically evaluate the outcomes of IVC patency over short- to intermediate-term follow-up for patients undergoing primary repair of IVC and to assess the association with survival. METHODS: A retrospective review of patients undergoing RN-VTT between January 2013 and August 2018 was conducted. Patients were followed until death, last available follow-up, or March 2022. The patency outcomes and IVC diameters were studied using follow-up cross-sectional imaging. The χ2 test, Student t test, and Kaplan-Meier survival analysis were used. RESULTS: Seventy-seven patients were included. The mean age was 59.2 ± 12.2 years and 45.4% had Mayo classification level III thrombus or higher. At a median follow-up of 36.5 months (13.3-60.7 months), the 3-year overall survival (OS) was 64%. Sixty patients underwent primary repair of the IVC and 48 of these patients were assessed for IVC patency. Ten patients (20.8%) developed caval occlusion, either from recurrent tumor (8.3%), new-onset bland thrombus (8.3%), or stenosis (4.2). The IVC patency seemed to be a significant predictor of OS (hazard ratio, 2.85; P = .021). Although the IVC diameters decreased significantly at the 3-month postoperative scan at the infrarenal (P = .019), renal (P < .001), and suprarenal (P < .001) levels, they did not decrease further on long-term follow-up imaging. CONCLUSIONS: IVC reconstruction with primary repair results in an overall patency rate of 80.2% with only a 4.0% rate of stenosis. Recurrence of tumor thrombus (8.3%) or bland thrombus (8.3%) are the predominant reasons for IVC occlusion after RN-VTT, and this outcome is associated with poor OS.

Prevalence of genotoxic bacteria in men undergoing biopsy for prostate cancer.

BACKGROUND: New evidence suggests that bacteria-produced DNA toxins may have a role in the development or progression of prostate cancer. To determine the prevalence of these genes in a noninfection (i.e., colonized) state, we screened urine specimens in men before undergoing a biopsy for prostate cancer detection. METHODS: We developed a multiplex polymerase chain reaction using three of the most described bacterial genotoxin gene primers: Colibactin (polyketone synthase [pks] gene island: clbN and clbB), cytotoxic necrotizing factor (cnf1) toxin, and cytolethal distending toxin B (cdtB) represented gene islands. After calibration on Escherichia coli samples of known genotypes, we used a training and validation cohort. We performed multiplex testing on a training cohort of previously collected urine from 45 men undergoing prostate biopsy. For the validation cohort, we utilized baseline urine samples from a previous randomized clinical trial (n = 263) with known prostate cancer outcomes. RESULTS: The prevalence of four common bacterial genotoxin genes detected in the urine before prostate biopsy for prostate cancer is 8% (25/311). The prevalence of pks island (clbN and clbB), cnf1, and cdt toxin genes are 6.1%, 2.4%, and 1.7%, respectively. We found no association between urinary genotoxins and prostate cancer (p = 0.83). We did identify a higher proportion of low-grade cancer (92% vs. 44%) in those men positive for urinary genotoxin and higher-grade cancer in those genotoxin negative (8% vs. 56%, p = 0.001). CONCLUSIONS: The prevalence of urinary genotoxins is low and does not correspond to a prostate cancer diagnosis. The urine was taken at one point in time and does not rule out the possibility of previous exposure.

Revisiting current National Comprehensive Cancer Network (NCCN) high-risk prostate cancer stratification: a National Cancer Database analysis.

BACKGROUND: High-risk prostate cancer includes heterogenous populations with variable outcomes. This study aimed to compare the prognostic ability of individual high-risk factors, as defined by National Comprehensive Cancer Network (NCCN) risk stratification, in prostate cancer patients undergoing radical prostatectomy. METHODS: We queried the National Cancer Database from 2004 to 2018 for patients with non-metastatic high-risk prostate cancer who underwent radical prostatectomy and stratified them as Group H1: Prostate specific antigen (PSA) > 20 ng/ml alone, Group H2: cT3a stage alone and Group H3: Gleason Grade (GG) group 4/5 as per NCCN guidelines. The histopathological characteristics and rate of adjuvant therapy were compared between different groups. Inverse probability weighting (IPW)-adjusted Kaplan-Meier curves were utilized to compare overall survival (OS) in group H1 and H2 with H3. RESULTS: Overall, 61,491 high-risk prostate cancer patients were identified, and they were classified into Group H1 (n = 14,139), Group H2 (n = 2855) and Group H3 (n = 44,497). Compared to group H1 or H2, pathological GG group > 3 (p < 0.001), pathological stage pT3b or higher (p < 0.001), lymph nodal positive disease (pN1) (p < 0.001) and rate of adjuvant therapy (p < 0.001) were significantly in Group H3. IPW-adjusted Kaplan-Meier curves showed significantly better 5-year OS in group H1 compared to group H3 [95.1% vs 93.3%, p < 0.001] and group H2 compared to group H3 [94.4% vs 92.9%, p < 0.001]. CONCLUSION: PSA > 20 ng/ml or cT3a stage in isolation have better oncologic and survival outcomes compared to GG > 3 disease and sub-stratification of 'High-risk' category might lead to better patient prognostication.

Impact of Finasteride on Survival in Bladder Cancer: A Retrospective Multi-institutional Database Analysis.

INTRODUCTION: Androgen suppression therapy has been associated with a lower incidence of bladder cancer (BCa) or improved overall/cancer-specific survival. Results are ofent conflicting; therefore, we aim to assess the impact of use of finasteride on overall survival (OS) for BCa using multi-institutional database. METHODS: The South Texas Veterans Healthcare System from 5 medical centers was queried for patients with BCa with or without use of finasteride after diagnosis of BCa. The primary outcome was the impact of finasteride use after diagnosis on the OS in BCa and in the high-risk Non-muscle invasive BCa (NMIBC) cohort. RESULTS: A total of 1890 patients were included, amongst which 619 (32.8%) men were classified as finasteride users and 1271 (67.2%) men as controls. At a median (IQR) follow up of 53.8 (27.4, 90.9) months, death due to any cause was noted in 272 (43.9%) finasteride-treated, and 672 (49.3%) control groups (P = .028). The patients in the finasteride group had significantly better OS in overall cohort (112.1 months vs. 84.8 months, P < .001) as well as in the NMIBC cohort (129.3months vs. 103.2 months, P = .0046). The use of finasteride was independently associated with improved OS in both, overall cohort (HR 0.74, 95% CI 0.63-0.86; P < .001) and in the NMIBC cohort (HR = 0.71, 95% CI 0.55-0.93; P = .011). CONCLUSION: Finasteride use is associated with the improved overall survival in patients with BCa, specifically in patients with NMIBC. We, further, propose a randomized clinical trial to investigate the use of finasteride in BCa patients.

A comparative analysis of radical cystectomy with perioperative chemotherapy, chemoradiation therapy, or systemic therapy in patients with clinically advanced node-positive bladder cancer (cN2/N3).

Introduction: The management of non-metastatic clinically advanced lymph nodal (cN2/N3) bladder cancer (Stage IIIB) could involve radical cystectomy, chemoradiation, or systemic therapy alone. However, a definitive comparison between these approaches is lacking. This study aims to compare the outcomes of patients undergoing radical cystectomy with pelvic lymph node dissection (RC-PLND), chemoradiation therapy (CRT) or systemic therapy (including immunotherapy) (ST) only in patients with stage IIIB bladder cancer. Materials and methods: A retrospective analysis of the National Cancer Database for patients with stage IIIB urothelial bladder cancer was done from 2004-2019. Patients were classified as Group A: Those who received RC-PLND with perioperative chemotherapy, Group B: Those who received CRT, and Group C: Those who received only ST alone. The primary outcome was overall survival (OS). Inverse probability weighting (IPW)-adjusted Kaplan Meier curves were utilized to compare overall survival (OS) and cox multivariate regression analysis was used to identify predictors for OS. Results: Overall, 2,575 patients were identified. They were classified into Group A (n=1,278), Group B (n=317) and Group C (n=980). Compared to Group B, patients in Group A were younger (SMD=19.6%), had lower comorbidities (SMD=18.2%), had higher income (SMD=31.5%), had private insurance (SMD= 26.7%), were treated at academic centres (SMD=29.3%) and had higher percentage of N2 disease (SMD=31.1%). Using IPW-adjusted survival analysis, compared to Group C, the median OS was significantly higher in Group A (20.7 vs 14.2 months, p<0.001) and Group B (19.7 vs 14.2 months, p<0.001) but similar between Group A and Group B (20.9 vs 19.7 months, p=0.74). Both surgery (HR=0.72 (0.65-0.80), p<0.001) and CRT (0.70 (0.59-0.82), p<0.001) appeared to be independent predictors for OS on cox-regression analysis. The major limitations include bias due to retrospective analysis and non-assessment of cancer-specific survival. Conclusion: In stage IIIB bladder cancer with advanced lymph nodal disease, both RC and CRT offer equivalent survival benefits and are superior to systemic therapy alone.

Molecular genetic testing does not improve the detection of fluoroquinolone resistance before transrectal prostate biopsy.

Background: Fluoroquinolone-resistant (FQR) Escherichia coli (E. coli) causes transrectal prostate biopsy infections. We seek to further identify fluoroquinolones resistance by the incorporation of genetic profiling to influence antibiotic selection for transrectal prostate biopsy and whether the addition of this genetic testing could improve the prediction of FQR detection at the time of biopsy. Materials and methods: In this prospective observational cohort study, rectal swabs were collected within 30 days of an upcoming prostate biopsy. These swabs were sent for phenotypic and genotypic assessment to predict FQR on the day of the biopsy. Phenotype: Specimens were inoculated onto MacConkey agar containing ciprofloxacin using standard culture techniques to determine FQR status. Genotype: We compared cultures to polymerase chain reaction (PCR) sequence typing (E.coli- ST131/H30/ST69) and bacterial plasmids (gyrA, qnrQ, and qnrS). The presence of FQR on this testing was compared to the second rectal swab collected just before biopsy (2 hours after ciprofloxacin prophylaxis), which served as the gold standard for FQR. Results: Overall, the FQR rate was 23.6%. The bacterial plasmids (qnr) were present in 54.1% of samples, and multidrug-resistant E. coli ST131 was present in 12.5% of samples. In comparison, phenotypic assessment using rectal culture had a better prediction for the presence of FQR as compared to genotypic testing [area under the curve (AUC) = 0.85 in phenotype arm vs. AUC = 0.45 in genotype arm]. Conclusion: We detected a high prevalence of FQR genes in the rectum, but the addition of PCR-based genotyping did not improve the prediction of culture-based FQR at the time of biopsy.

Predictors of participants' retention-socioeconomic factors or nonadherence: insights from a urological clinical prospective study.

BACKGROUND: To investigate various patient-level variables, specifically socioeconomic status, as risk factors for withdrawal in a recently completed clinical study. We specifically investigated a non-interventional prospective study assessing the role of novel imaging as a biomarker for cancer upgradation in prostate cancer for this objective. METHODS: In this retrospective analysis, we assessed the association between various patient-level factors including clinic-demographic factors, socioeconomic status, and the number of non-adherences with the participants' retention or withdrawal from the study. For socioeconomic status (SES), we used the zip code-based Economic Innovation Group Distressed Community Index (DCI) which classifies into five even distress tiers: prosperous, comfortable, mid-tier, at-risk, or distressed. Low SES was defined as those with a DCI Distress tier of at-risk or distressed. We compared values between the two retention and withdrawal groups using t-test, chi-square test, and logistic regression analysis. RESULTS: Of 273 men screened, 123 men were enrolled. Among them, 86.2% (106/123) retained through the study whereas 13.8% (17/123) withdrew from the study. The mean (SD) age was 64 (6.4) years. Overall, 31.7% (39/123) were Hispanics and 24.3% (30/123) were African Americans. The median (IQR) DCI score was 34 (10.3, 68.1) and 30.8% (38/123) of patients belonged to low SES. The median DCI score in participants who retained in the study was statistically similar to those who withdrew from the study (p=0.4). Neither the DCI tiers (p=0.7) nor the low SES (p=0.9) were associated with participants' retention or withdrawal of the study. In terms of non-adherence, all participants in the withdrawn group had at least one non-adherent event compared to 48.1% in the retained group (p<0.001). Repetitive non-adherence was significantly higher in participants who withdrew from the study vs those who retained in the study [88.2% vs 16.9%, p <0.001]. On multivariate logistic regression analysis, the number of non-adherences (OR=12.5, p<0.001) and not DCI (OR=0.99, p=0.7) appeared to be an independent predictor for participants' retention or withdrawal from the study. CONCLUSIONS: Expanding diverse inclusion and limiting withdrawal with real-time non-adherence monitoring will lead to more efficient clinical research and greater generalizability of results.

Prospective comparison of restriction spectrum imaging and non-invasive biomarkers to predict upgrading on active surveillance prostate biopsy.

BACKGROUND: Protocol-based active surveillance (AS) biopsies have led to poor compliance. To move to risk-based protocols, more accurate imaging biomarkers are needed to predict upgrading on AS prostate biopsy. We compared restriction spectrum imaging (RSI-MRI) generated signal maps as a biomarker to other available non-invasive biomarkers to predict upgrading or reclassification on an AS biopsy. METHODS: We prospectively enrolled men on prostate cancer AS undergoing repeat biopsy from January 2016 to June 2019 to obtain an MRI and biomarkers to predict upgrading. Subjects underwent a prostate multiparametric MRI and a short duration, diffusion-weighted enhanced MRI called RSI to generate a restricted signal map along with evaluation of 30 biomarkers (14 clinico-epidemiologic features, 9 molecular biomarkers, and 7 radiologic-associated features). Our primary outcome was upgrading or reclassification on subsequent AS prostate biopsy. Statistical analysis included operating characteristic improvement using AUROC and AUPRC. RESULTS: The individual biomarker with the highest area under the receiver operator characteristic curve (AUC) was RSI-MRI (AUC = 0.84; 95% CI: 0.71-0.96). The best non-imaging biomarker was prostate volume-corrected Prostate Health Index density (PHI, AUC = 0.68; 95% CI: 0.53-0.82). Non-imaging biomarkers had a negligible effect on predicting upgrading at the next biopsy but did improve predictions of overall time to progression in AS. CONCLUSIONS: RSI-MRI, PIRADS, and PHI could improve the predictive ability to detect upgrading in AS. The strongest predictor of clinically significant prostate cancer on AS biopsy was RSI-MRI signal output.