Utilization of genetic testing in men with advanced prostate cancer.

BACKGROUND: Genetic evaluation of men with advanced prostate cancer is recognized as imperative both to guide treatment decisions and to trigger cascade genetic testing of family members. Here we investigate utilization patterns of genetic testing among a contemporary cohort of men with advanced prostate cancer at our institution. METHODS: We queried the Northwestern Electronic Data Warehouse from January 2021 to present for all men diagnosed with National Comprehensive Cancer Network high-risk/very high-risk, regional, or metastatic prostate cancer. Patients were excluded from analyses if treated at an outside institution and/or presented for a second opinion evaluation. Statistics were performed using t-test, Chi-squared test, and univariable and multivariable logistic regression with significance defined as p < 0.05. RESULTS: Atotal of 320 men (52.5%) had local/regional disease and 290 (47.5%) had metastatic disease, 53 (18.3%) of whom had castrate resistant prostate cancer. Rates of germline genetic testing rate were low in patients with localized disease (9.4%) and metastatic disease (34.1%). Only 19 (35.8%) men diagnosed with metastatic castrate resistant prostate cancer underwent germline genetic evaluation. Germline testing was most frequently discussed or ordered by medical oncologists (52%) followed by urologists (20%). Men who underwent germline testing were younger (p < 0.001), more likely to have Medicaid or private insurance (p = 0.002), and more likely to have metastatic disease (p < 0.001). There were no statistically significant differences in baseline PSA, ethnicity, race, or castration sensitivity status. Age (odds ratio [OR]: 0.94, 95% confidence interval [CI]: 0.91-0.97, p < 0.001) and metastatic disease (OR: 5.71, 95% CI: 3.63-9.22, p < 0.001) were significant independent predictors of genetic testing on multivariable logistic regression. CONCLUSIONS: Here we report that utilization of genetic testing is associated with metastatic disease and inversely associated with age. Overall, utilization rates of genetic testing remain low in all patient groups, including in the metastatic castrate resistant setting, where genetic testing can identify patients with homologous recombination repair deficiency who may benefit from use of targeted therapeutics such as PARP inhibitors. Genetic testing in men with aggressive prostate cancer is critical and barriers to routine implementation of testing require further study to develop strategies to improve utilization rates.

Disparities in access to robotic technology and perioperative outcomes among patients treated with radical prostatectomy.

BACKGROUND: Most radical prostatectomies are completed with robotic assistance. While studies have previously evaluated perioperative outcomes of robot-assisted radical prostatectomy (RARP), this study investigates disparities in access and clinical outcomes of RARP. STUDY DESIGN: The National Cancer Database (NCDB) was used to identify patients who received radical prostatectomy for cancer between 2010 and 2017 with outcomes through 2018. RARP was compared to open radical prostatectomy (ORP). Odds of receiving RARP were evaluated while adjusting for covariates. Overall survival was evaluated using a propensity-score matched cohort. RESULTS: Overall, 354 752 patients were included with 297 676 (83.9%) receiving RARP. Patients who were non-Hispanic Black (82.8%) or Hispanic (81.3%) had lower rates of RARP than non-Hispanic White (84.0%) or Asian patients (87.7%, p < 0.001). Medicaid or uninsured patients were less likely to receive RARP (75.5%) compared to patients with Medicare or private insurance (84.4%, p < 0.001). Medicaid or uninsured status was associated with decreased odds of RARP in adjusted multivariable analysis (OR 0.61, 95% CI 0.49-0.76). RARP was associated with decreased perioperative mortality and improved overall survival compared to ORP. CONCLUSION: Patients who were underinsured were less likely to receive RARP. Improved access to RARP may lead to decreased disparities in perioperative outcomes for prostate cancer.

Detection of clinically significant prostate cancer following initial omission of biopsy in multiparametric MRI era.

BACKGROUND: Multiparametric prostate MRI (mpMRI) is being increasingly adopted for work-up of prostate cancer. For patients selected to omit biopsy, we identified factors associated with repeat MRI, eventual prostate biopsy, and subsequent detection of clinically significant prostate cancer (csPCa, Grade Group ≥2). METHODS: We identified biopsy-naïve men presenting with PSA 2-20 ng/mL (March 2018-June 2021) undergoing initial mpMRI with PIRADS 1-3 lesions who were not selected for biopsy with ≥6 months follow-up. We examined factors associated with repeat mpMRI, progression to biopsy, and subsequent detection of csPCa with univariable and multivariable logistic regression. RESULTS: Of 1494 men, 31% (463/1494) did not pursue biopsy. PSA density (PSAD) ≤ 0.1, prostate health index (PHI) < 55, and PIRADS 1-2 were associated with omission of prostate biopsy. csPCa diagnosis-free survival was 97.6% (326/334) with median follow up of 23.1 months (IQR 15.1-34.6 months). Black race, PSA, PHI, PSA density, and PSA and PHI velocity were significant predictors of undergoing repeat mpMRI (15.6%, 52/334) and subsequent biopsy (8.4%, 28/334). 8 men were subsequently diagnosed with csPCa (N = 7 on prostate biopsy; N = 1 incidentally on holmium enucleation of prostate). All patients diagnosed with csPCa had PIRADS 4-5 on repeat mpMRI. CONCLUSIONS: The subsequent detection rate of csPCa among patients not initially biopsied after mpMRI was low at 2.4%. Decisions to omit biopsy after initial reassuring PHI, PSAD, and mpMRI appear safe with subsequent reassuring serum biomarkers and for cause mpMRI during follow-up.

Relationships between holmium laser enucleation of the prostate and prostate cancer.

Holmium laser enucleation of the prostate (HoLEP) is a size-independent surgical option for treating benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS) with excellent, durable functional outcomes. The prevalence of LUTS secondary to BPH and prostate cancer both increase with age, although the two diseases develop independently. Urologists often face a diagnostic dilemma, as men with LUTS secondary to BPH might also present with an elevated PSA and, therefore, need a diagnostic work-up to exclude prostate cancer. Nevertheless, ~15% of men with a negative elevated PSA work-up will undergo HoLEP and will be diagnosed with incidental prostate cancer at the time of HoLEP. Indeed, prostate cancer is often found in men undergoing HoLEP, and this situation can be challenging to manage. Variables associated with the detection of incidental prostate cancer, strategies to reduce incidental prostate cancer, as well as the natural history and management of this condition have been extensively studied, but further work in this area is still needed.

Real-world use of MRI for risk stratification prior to prostate biopsy.

BACKGROUND: The utilization of MRI to risk stratify elevated PSA prior to prostate biopsy has been inconsistently adopted and varies considerably by practice setting. This study aims to evaluate the usage and performance of MRI as an advanced risk stratification tool of elevated PSA prior to biopsy and identify factors associated with differential utilization of MRI at a large academic setting with ready access to 3T multiparametric MRI of the prostate. METHODS: A retrospective single-center study of 2900 men presenting with elevated PSA 2-20 ng/mL from 2018 through 2021 was conducted. We analyzed trends in MRI utilization and outcomes of prostate biopsy by MRI usage. Univariate and multivariate logistic regressions were performed to calculate odds ratios to identify patient- and provider-level predictors of MRI usage. RESULTS: Rates of prebiopsy MRI utilization increased from 56% in 2018 to 89% in 2021 (p < 0.001). Prebiopsy MRI led to biopsy avoidance in 31% of men. MRI usage enhanced detection of clinically significant prostate cancer by 13% and reduced identification of Gleason Grade Group 1 disease by 3% and negative biopsies by 10% (p < 0.001). Men who received MRI were more likely to be younger than 75 years in age and have private or Medicare insurance, PSA >4 ng/mL, and PHI >27. In both univariate and multivariate analysis, black race and Medicaid insurance were associated with reduced MRI utilization (all p < 0.001). Urologic provider was an independent predictor of MRI usage (p < 0.001). CONCLUSIONS: Use of MRI as a risk stratification tool for elevated PSA rose during this 4-year study period. Men who self-identify as black or men with Medicaid coverage have diminished rates of MRI usage. Considerable provider-level variability in MRI use was observed. Future research aimed at identifying factors affecting implementation of MRI as a routine risk assessment tool is warranted.

Optimizing detection of clinically significant prostate cancer through nomograms incorporating mri, clinical features, and advanced serum biomarkers in biopsy naïve men.

PURPOSE: To develop nomograms that predict the detection of clinically significant prostate cancer (csPCa, defined as ≥GG2 [Grade Group 2]) at diagnostic biopsy based on multiparametric prostate MRI (mpMRI), serum biomarkers, and patient clinicodemographic features. MATERIALS AND METHODS: Nomograms were developed from a cohort of biopsy-naïve men presenting to our 11-hospital system with prostate specific antigen (PSA) of 2-20 ng/mL who underwent pre-biopsy mpMRI from March 2018-June 2021 (n = 1494). The outcomes were the presence of csPCa and high-grade prostate cancer (defined as ≥GG3 prostate cancer). Using significant variables on multivariable logistic regression, individual nomograms were developed for men with total PSA, % free PSA, or prostate health index (PHI) when available. The nomograms were both internally validated and evaluated in an independent cohort of 366 men presenting to our hospital system from July 2021-February 2022. RESULTS: 1031 of 1494 men (69%) underwent biopsy after initial evaluation with mpMRI, 493 (47.8%) of whom were found to have ≥GG2 PCa, and 271 (26.3%) were found to have ≥GG3 PCa. Age, race, highest PIRADS score, prostate health index when available, % free PSA when available, and PSA density were significant predictors of ≥GG2 and ≥GG3 PCa on multivariable analysis and were used for nomogram generation. Accuracy of nomograms in both the training cohort and independent cohort were high, with areas under the curves (AUC) of ≥0.885 in the training cohort and ≥0.896 in the independent validation cohort. In our independent validation cohort, our model for ≥GG2 prostate cancer with PHI saved 39.1% of biopsies (143/366) while only missing 0.8% of csPCa (1/124) with a biopsy threshold of 20% probability of csPCa. CONCLUSIONS: Here we developed nomograms combining serum testing and mpMRI to help clinicians risk stratify patients with elevated PSA of 2-20 ng/mL who are being considered for biopsy. Our nomograms are available at https://rossnm1.shinyapps.io/MynMRIskCalculator/ to aid with biopsy decisions.

Delayed administration of a small molecule tropomyosin-related kinase B ligand promotes recovery after hypoxic-ischemic stroke.

BACKGROUND AND PURPOSE: Stroke is the leading cause of long-term disability in the United States, yet no drugs are available that are proven to improve recovery. Brain-derived neurotrophic factor stimulates neurogenesis and plasticity, processes that are implicated in stroke recovery. It binds to both the tropomyosin-related kinase B and p75 neurotrophin receptors. However, brain-derived neurotrophic factor is not a feasible therapeutic agent, and no small molecule exists that can reproduce its binding to both receptors. We tested the hypothesis that a small molecule (LM22A-4) that selectively targets tropomyosin-related kinase B would promote neurogenesis and functional recovery after stroke. METHODS: Four-month-old mice were trained on motor tasks before stroke. After stroke, functional test results were used to randomize mice into 2 equally, and severely, impaired groups. Beginning 3 days after stroke, mice received LM22A-4 or saline vehicle daily for 10 weeks. RESULTS: LM22A-4 treatment significantly improved limb swing speed and accelerated the return to normal gait accuracy after stroke. LM22A-4 treatment also doubled both the number of new mature neurons and immature neurons adjacent to the stroke. Drug-induced differences were not observed in angiogenesis, dendritic arborization, axonal sprouting, glial scar formation, or neuroinflammation. CONCLUSIONS: A small molecule agonist of tropomyosin-related kinase B improves functional recovery from stroke and increases neurogenesis when administered beginning 3 days after stroke. These findings provide proof-of-concept that targeting of tropomyosin-related kinase B alone is capable of promoting one or more mechanisms relevant to stroke recovery. LM22A-4 or its derivatives might therefore serve as "pro-recovery" therapeutic agents for stroke.

Efficacy and Adverse Events of Docetaxel for Metastatic, Hormone-sensitive Prostate Cancer Among Elderly Men: A Post Hoc Analysis of the CHAARTED Trial.

BACKGROUND: Combination therapy with docetaxel and androgen deprivation therapy (ADT) prolongs overall survival (OS) in men with metastatic hormone-sensitive prostate cancer. We assessed the benefits and adverse effects of docetaxel and ADT in relation to advancing age. METHODS: We performed a post hoc analysis of the CHAARTED trial comparing docetaxel and ADT vs. ADT alone (n = 773). Patients were stratified in age groups <60, 60-70, and >70 years old. Multivariable-adjusted progression-free survival (PFS) and OS were assessed using Kaplan-Meier curves and compared using multivariable Cox regressions with calculated interaction terms between age group and treatment arm. In the combination arm, the incidence of ≥1 adverse event (grade ≥3) and the number of adverse events per patient were compared for each age group using multivariable logistic and linear regressions, respectively. RESULTS: After adjusting for clinical variables, docetaxel's effect did not vary by age group for PFS and OS. There was no significant difference in the odds ratio of ≥1 adverse event (P > .1 for age groups 60-70 and >70 years old compared with <60 years old). However, men age >70 years old experienced +0.37 more adverse events per patient compared with men age <60 years old (95% CI, 0.11-0.64; P = .006). CONCLUSIONS: PFS and OS were similar across age groups for the combination of docetaxel and ADT compared with ADT. Older men experienced a modest increase in adverse events per patient, highlighting the importance of balancing treatment benefits and adverse effects in this age group.

Medicaid Expansion Did not Improve Time to Treatment for Young Patients With Metastatic Renal Cell Carcinoma.

INTRODUCTION: The absence of health insurance coverage has been associated with worse outcomes for patients with metastatic renal cell carcinoma (mRCC). Medicaid expansion in the United States was an important provision of the Affordable Care Act, which increased the number of low-income individuals eligible for Medicaid starting in January 2014 in several states. The effect of Medicaid expansion on access to healthcare for patients with mRCC is unknown. MATERIALS AND METHODS: We performed a retrospective cohort study of 6844 patients aged < 65 years with mRCC at diagnosis within the National Cancer Database. We compared the time to treatment and the rates of no insurance before (2012-2013) and after (2015-2016) expansion between patients living in states that had and had not expanded Medicaid using difference-in-difference (DID) analyses. DIDs were calculated using linear regression analysis with adjustment for sociodemographic covariates. RESULTS: The rate of no insurance did not change in the expansion states compared with the nonexpansion states (DID, -0.55%; 95% confidence interval, -3.32% to 2.21%; P = .7). The percentage of patients receiving treatment within 60 days of diagnosis had increased in the expansion states from 43% to 49% and in the nonexpansion states from 42% to 46% after expansion. No change was found in treatment within 60 days of diagnosis among all patients (DID, 2.81%; 95% confidence interval, -2.61% to 8.22%; P = .3). CONCLUSIONS: Medicaid expansion was not associated with improved healthcare access for patients with mRCC as reflected by timely treatment. Future work should assess the association between Medicaid expansion and oncologic outcomes.

Targeting Epidermal Growth Factor Receptor (EGFR) and Human Epidermal Growth Factor Receptor 2 (HER2) Expressing Bladder Cancer Using Combination Photoimmunotherapy (PIT).

Bladder cancer (BC) is heterogeneous and expresses various cell surface targets. Photoimmunotherapy (PIT) involves monoclonal antibodies (MAbs) conjugated to a photoabsorber (PA), IR Dye 700Dx, and then activated by near infra-red light (NIR) to specifically target tumors. We have demonstrated that tumors expressing EGFR can be targeted with PIT. However, PIT may be less effective when a tumor lacks "overwhelming" expression of a single target such as EGFR. We present a combinatorial PIT approach for targeting BC expressing EGFR and HER2, using PA- labeled panitumumab (pan) and trastuzumab (tra), respectively. Human BC tissues and cell lines were analyzed for EGFR and HER2 expression. Efficacy of PA-labeled MAbs singly and in combination was analyzed. About 45% of BC tissues stain for both EGFR and HER2. In vitro, the combination of pan IR700 and tra IR700 with NIR was more efficacious than either agent alone. Tumor xenografts treated with combination PIT showed significant tumor growth retardation. Combination PIT is a promising approach for treating BC with low/moderate expression of surface receptors. In addition, given the molecular heterogeneity of bladder cancer, targeting more than one surface receptor may allow for more effective cell death across different bladder tumors.

Case Presentation: Lung Consolidation as Sequelae of BCG Sepsis After Combined Intravesical and Intraurethral BCG.

BCG sepsis is rarely seen with modern intravesical therapy and therefore its presentation may not be apparent to recently trained urologists. We describe BCG sepsis occurring in a patient treated with combined intravesical and intraurethral BCG which resulted in lung consolidation with acid-fast bacilli requiring cessation of BCG and initiation of systemic antibiotic therapy.

Distal hypoxic stroke: a new mouse model of stroke with high throughput, low variability and a quantifiable functional deficit.

C57BL/6J are the most commonly used strain of mouse for stroke experiments but vascular anatomy of the Circle of Willis within this strain is extremely variable and the cortex has extensive collateralization. This causes large variability in stroke models that target the middle cerebral artery proximally and confers resistance to ischemia in those that target it distally. We tested the hypothesis that by combining distal middle cerebral artery occlusion with 1h of hypoxia, we could generate a large lesion that causes a behavioral deficit with low variability. We found that this new distal hypoxic (DH) model of stroke generates a lesion with a volume of 25% of the ipsilateral hemisphere, extends to the motor cortex and causes a behavioral deficit. It also has a very clear border, exceptionally low variability, and can be performed by a single surgeon on up to 30 animals a day. Moreover, survivability is 100% in young adult animals, the model can be performed on old animals, and therapeutic intervention can reduce infarct volume. Therefore DH stroke is an excellent complement to existing stroke models and could be used for preclinical studies in C57BL/6J mice.

Improvement of cardiac function in mouse myocardial infarction after transplantation of epigenetically-modified bone marrow progenitor cells.

OBJECTIVE: To study usefulness of bone marrow progenitor cells (BPCs) epigenetically altered by chromatin modifying agents in mediating heart repair after myocardial infarction in mice. METHODS AND RESULTS: We tested the therapeutic efficacy of bone marrow progenitor cells treated with the clinically-used chromatin modifying agents Trichostatin A (TSA, histone deacetylase inhibitor) and 5Aza-2-deoxycytidine (Aza, DNA methylation inhibitor) in a mouse model of acute myocardial infarction (AMI). Treatment of BPCs with Aza and TSA induced expression of pluripotent genes Oct4, Nanog, Sox2, and thereafter culturing these cells in defined cardiac myocyte-conditioned medium resulted in their differentiation into cardiomyocyte progenitors and subsequently into cardiac myocytes. Their transition was deduced by expression of repertoire of markers: Nkx2.5, GATA4, cardiotroponin T, cardiotroponin I, α-sarcomeric actinin, Mef2c and MHC-α. We observed that the modified BPCs had greater AceH3K9 expression and reduced histone deacetylase1 (HDAC1) and lysine-specific demethylase1 (LSD1) expression compared to untreated BPCs, characteristic of epigenetic changes. Intra-myocardial injection of modified BPCs after AMI in mice significantly improved left ventricular function. These changes were ascribed to differentiation of the injected cells into cardiomyocytes and endothelial cells. CONCLUSION: Treatment of BPCs with Aza and TSA converts BPCs into multipotent cells, which can then be differentiated into myocyte progenitors. Transplantation of these modified progenitor cells into infarcted mouse hearts improved left ventricular function secondary to differentiation of cells in the niche into myocytes and endothelial cells.