Racial disparities in stage at bladder cancer diagnosis in the US Veterans Affairs healthcare system.

OBJECTIVE: To describe patient characteristics and pathological stage at bladder cancer (BCa) diagnosis in a diverse population within a national, equal-access healthcare system. METHODS: This retrospective cohort study identified 15 966 men diagnosed with BCa in the Veterans Affairs (VA) healthcare system from 2000 to 2020. The primary outcome was pathological stage at diagnosis, determined by index transurethral resection of bladder tumour. Logistic regression was used to assess the relationship between race and stage. Competing risk models tested the association between race and BCa-specific mortality with cumulative incidence estimates. RESULTS: Of 15 966 BCa patients, 12 868 (81%), 1726 (11%), 493 (3%) and 879 (6%) were White, Black, Hispanic and Other race, respectively. Black patients had significantly higher muscle-invasive bladder cancer (MIBC) rates than White patients (35% vs 32%; P = 0.009). In multivariable analysis, the odds of presenting with MIBC did not differ significantly between Black and White patients (odds ratio [OR] 1.10, 95% confidence interval [CI] 0.98-1.22) or between Hispanic patients (OR 0.82, 95% CI 0.67-1.01) and White patients. Compared to White patients, Black patients had a similar risk of BCa-specific mortality (hazard ratio [HR] 0.89, 95% CI 0.75-1.06), whereas Hispanic patients had a lower risk (HR 0.56, 95% CI 0.38-0.82). CONCLUSIONS: Black patients presented with the highest rates of de novo MIBC. However, in a large, equal-access healthcare system, this did not result in a difference in BCa-specific mortality. In contrast, Hispanic patients had lower risks of MIBC and BCa-specific mortality.

Contemporary risk of biochemical recurrence after radical prostatectomy in the active surveillance era.

OBJECTIVES: To assess whether contemporary risks of biochemical recurrence (BCR) after radical prostatectomy (RP) in the AS era differ from historical estimates due to changes in tumor risk case mix and improvements in risk stratification. MATERIALS AND METHODS: We sampled 6,682 men who underwent RP for clinically localized disease between 2000 and 2017 from the VA SEARCH database. Kaplan Meier analysis was used to calculate incidence of BCR before and after 2010 overall and within tumor risk subgroups. Multivariable Cox proportional hazard regression analysis including an interaction term between era and tumor risk was used to compare risk of BCR before and after 2010 overall and across tumor risk subgroups. RESULTS: About 3,492 (52%) and 3,190 (48%) men underwent RP before and after 2010, respectively. In a limited multivariable model excluding tumor risk, overall BCR risk was higher post-2010 vs. pre-2010 (HR: 1.15, 95%CI: 1.05-1.25; 40% vs 36% at 8 years post-RP). However, this effect was eliminated after correcting for tumor risk (HR: 0.95, 95%CI: 0.87-1.04), suggesting that differences in tumor risk between eras mediated the change. Yet, within tumor-risk subgroups, BCR risk was significantly lower for favorable intermediate-risk (HR: 0.76, 95%CI:0.60-0.96) and unfavorable intermediate-risk PC (HR: 0.78, 95%CI: 0.67-0.90), but significantly higher for high-risk PC (HR: 1.22, 95%CI: 1.07-1.38) in the post-2010 era. 8-year risks of BCR in the post-2010 era were 21% (95%CI: 16%-25%), 25% (95%CI: 20%-30%), 41% (95%CI: 37%-46%), and 60% (95%CI: 56%-64%) for low-, FIR-, UIR-, and high-risk disease, respectively. Limitations include limited long-term follow-up in the post-2010 subgroup. CONCLUSIONS: Overall BCR risk has increased in the AS era, driven by a higher risk case mix and increased BCR risk among high-risk patients. Physicians should quote contemporary estimates of BCR when counseling patients.

Investigating trends in interest for benign prostatic hyperplasia surgery options using Google Trends.

Understanding patient interest among surgical options is challenging. We used Google Trends to analyze interest in benign prostatic hyperplasia (BPH) surgeries recommended for prostate volumes <80 cc. Google Trends was queried with five BPH surgeries. Final rank of search terms was TURP, UroLift, Rezum, Aquablation, and Greenlight. Google Trends can be an effective tool for evaluating public interest trends in BPH surgery.

Relative search popularity of five advanced prostate cancer medications using Google Trends.

BACKGROUND: There are many FDA-approved drugs for advanced prostate cancer (PC), yet public interest in these drugs is not well understood. We compared public interest and state-level predictors of interest in five common oral adjunctive hormonal therapies. METHODS: Google Trends™ was queried for: "Enzalutamide", "Abiraterone Acetate", "Bicalutamide", "Apalutamide", and "Darolutamide" in the United States from January 2004 to November 2022. Data are presented as relative search index (RSI) by month. RSI ranges from 0 to 100 with 100 being peak popularity, 50 being half of the peak popularity, and 0 representing insufficient data to be determined. RESULTS: Several drugs abruptly increased in popularity following FDA approval including abiraterone, enzalutamide, and apalutamide. All drugs decreased in popularity from January 2020 to July 2020, corresponding with the COVID-19 pandemic. In the most recent 5 years, enzalutamide and abiraterone were the most common searched drugs, with bicalutamide a close 3rd place. States that did not expand Medicaid were significantly more likely to have bicalutamide as the top search drug vs. states that expanded Medicaid (p = 0.012). Across all states with data (n = 39), higher bicalutamide RSIs were significantly associated with lower household income (r = 0.385, p = 0.02) and greater percent of uninsured adults (r = 0.426, p = 0.007). This is the first study using Google Trends to compare advanced PC drugs by search popularity. CONCLUSIONS: Despite the emergence of more effective medications, bicalutamide remains relatively popular, particularly in states with lower household income, more uninsured adults, or those that did not expand Medicaid, possibly due to its lower cost.

A 2-Anilidomethylpyridine Ligand Framework Showcasing Hydride Storage and Transfer Abilities in Its Aluminum Chemistry.

Dearomatized 1,4-dihydropyridyl motifs are significant in both chemistry and biology for their potential abilities to deliver the stored hydride, driven by rearomatization. Biological cofactors like nicotinamide adenine dinucleotide (NADH) and organic 'hydride sources' like Hantzsch esters are prime examples. An organoaluminum chemistry on a 2-anilidomethylpyridine framework is reported, where such hydride storage and transfer abilities are displayed by the ligand's pyridyl unit. The pyridylmethylaniline proligand (NN LH) is simultaneously deprotonated and 1,4-hydroaluminated by AlH3 (NMe2 Et) to [(NN Lde )AlH(NMe2 Et)] (1; NN Lde =hydride-inserted dearomatized version of NN L). A hydride abstraction by B(C6 F5 )3 rearomatizes the pyridyl moiety to give the cationic aluminum hydride [(NN L)AlH(NMe2 Et)][HB(C6 F5 )3 ] (6). Notably, such chemical non-innocence is priorly unseen in this established ligand class. The hydroalumination mechanism is investigated by isolating the intermediate [(NN L)AlH2 ] (2) and by control experiments, and is also analyzed by DFT calculation. The results advocate an intriguing 'self-promoting' pathway, which underlines alane's Lewis acid/Brønsted base duality. NMe2 Et carrying the alane also plays a crucial role. In contrast, the chemistry between NN LH and AlMe3 is much different, giving only [(NN L)AlMe2 ] (4) from the adduct [(NN LH)AlMe3 ] (3) by deprotonation but not a subsequent pyridyl dearomatization in the presence or absence of NMe2 Et. This divergence is also justified by DFT analyses.

The Impact of Blue Light Cystoscopy Use Among Nonmuscle Invasive Bladder Cancer Patients in an Equal Access Setting: Implications on Recurrence and Time to Recurrence.

INTRODUCTION: Prior studies suggest that white light cystoscopy (WLC) alone can fail to detect cases of non-muscle invasive bladder cancer (NMIBC) vs. blue light cystoscopy (BLC). We describe bladder cancer outcomes and the impact of BLC among NMIBC patients in an equal access setting. MATERIALS AND METHODS: We assessed 378 NMIBC patients within the Veterans Affairs system that had a CPT code for BLC from December 1, 2014 to December 31, 2020. We determined recurrence rates and time to recurrence prior to BLC (ie, after previous WLC if available) and following BLC. We used the Kaplan-Meier method to estimate event-free survival and Cox regression to determine association between BLC and recurrence, progression, and overall survival; and further, whether these outcomes differed by race. RESULTS: Of 378 patients with complete data, 43 (11%) were Black and 300 (79%) White. Median follow-up was 40.7 months from bladder cancer diagnosis. Median time to first recurrence following BLC was longer vs. WLC alone (40 [33-NE] vs. 26 [17-39] months). Recurrence risk was significantly lower following BLC (Hazard Ratio [HR] 0.70; 95% Confidence Interval [CI], 0.54-0.90). There was no significant difference in recurrence (HR 0.69; 95% CI, 0.39-1.20), progression (HR 1.13; 95% CI, 0.32-3.96), and overall survival (HR 0.74; 95% CI, 0.31-1.77) following BLC by Black vs. White race. CONCLUSION: In this study from an equal access setting in the VA, we observed significantly decreased recurrence risk and prolonged time interval to recurrence following BLC vs. WLC alone. There was no difference in bladder cancer outcomes by race.

Statins and Cancer Prevention-Association Does Not Mean Causation.

Statins are widely prescribed medications that inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG CoA) reductase and therefore reduce cholesterol synthesis. Given the key role of cholesterol in cancer, statins may therefore have anticancer activities. However, clinical studies investigating the association between statin usage and cancer development have been few and inconsistent. A recent study from Maeda-Minami and colleagues found a significant, though modest, decrease in cancer risk among statin users. However, does this finding mean statin usage directly reduces cancer risk or is merely associated with reduced cancer risk? This editorial analyzes Maeda-Minami and colleagues' study to provide commentary on statin's proposed role in preventing cancer. See related article, p. 37.

27-hydroxycholesterol and DNA damage repair: implication in prostate cancer.

Introduction: We previously reported that cholesterol homeostasis in prostate cancer (PC) is regulated by 27-hydroxycholesterol (27HC) and that CYP27A1, the enzyme that converts cholesterol to 27HC, is frequently lost in PCs. We observed that restoring the CYP27A1/27HC axis inhibited PC growth. In this study, we investigated the mechanism of 27HC-mediated anti-PC effects. Methods: We employed in vitro models and human transcriptomics data to investigate 27HC mechanism of action in PC. LNCaP (AR+) and DU145 (AR-) cells were treated with 27HC or vehicle. Transcriptome profiling was performed using the Affymetrix GeneChip™ microarray system. Differential expression was determined, and gene set enrichment analysis was done using the GSEA software with hallmark gene sets from MSigDB. Key changes were validated at mRNA and protein levels. Human PC transcriptomes from six datasets were analyzed to determine the correlation between CYP27A1 and DNA repair gene expression signatures. DNA damage was assessed via comet assays. Results: Transcriptome analysis revealed 27HC treatment downregulated Hallmark pathways related to DNA damage repair, decreased expression of FEN1 and RAD51, and induced "BRCAness" by downregulating genes involved in homologous recombination regulation in LNCaP cells. Consistently, we found a correlation between higher CYP27A1 expression (i.e., higher intracellular 27HC) and decreased expression of DNA repair gene signatures in castration-sensitive PC (CSPC) in human PC datasets. However, such correlation was less clear in metastatic castration-resistant PC (mCRPC). 27HC increased expression of DNA damage repair markers in PC cells, notably in AR+ cells, but no consistent effects in AR- cells and decreased expression in non-neoplastic prostate epithelial cells. While testing the clinical implications of this, we noted that 27HC treatment increased DNA damage in LNCaP cells via comet assays. Effects were reversible by adding back cholesterol, but not androgens. Finally, in combination with olaparib, a PARP inhibitor, we showed additive DNA damage effects. Discussion: These results suggest 27HC induces "BRCAness", a functional state thought to increase sensitivity to PARP inhibitors, and leads to increased DNA damage, especially in CSPC. Given the emerging appreciation that defective DNA damage repair can drive PC growth, future studies are needed to test whether 27HC creates a synthetic lethality to PARP inhibitors and DNA damaging agents in CSPC.

Satisfaction With Clinician-Led Germline Genetic Counseling in Patients With Prostate Cancer.

PURPOSE: Indications for germline testing in prostate cancer patients have expanded substantially over the past decade. With a near-universal shortage of genetic counselors and increasing demand, increased access to genetic counseling is crucial. We sought to prospectively implement and assess a clinician-led approach to genetic counseling and testing. MATERIALS AND METHODS: Patients with metastatic or localized prostate cancer meeting National Comprehensive Cancer Network® criteria for consideration of genetic testing were offered pre-test genetic counseling by their urologist or medical oncologist as part of their routine clinical care and concurrently approached for enrollment in the Germline Genetics in Prostate Cancer Study. Consented patients filled out a post-counseling survey using validated instruments to assess the quality of counseling. For patients who elected to undergo genetic testing, an additional validated questionnaire was completed following disclosure of results. The primary outcome was the proportion of patients undergoing testing, with a target >60% of patients. The secondary outcome was overall satisfaction with counseling, with a target >85% of patients. RESULTS: A total of 275 patients enrolled, and 203 patients elected to undergo genetic testing. Post-counseling surveys were obtained from 265 patients, and post-genetic testing surveys were obtained from 132 patients. Patient satisfaction was high, with 98% of patients reporting being satisfied with the overall quality of pre-test counseling, and 74% of patients elected to undergo genetic testing. CONCLUSIONS: These results support the effectiveness of clinician-led genetic counseling in prostate cancer. With clinician training, this approach can be utilized to expand access to appropriate germline genetic testing.

Initial Findings from a High Genetic Risk Prostate Cancer Clinic.

OBJECTIVE: To improve prostate cancer screening for high-risk men, we developed an early detection clinic for patients at high genetic risk of developing prostate cancer. Despite the rapidly growing understanding of germline variants in driving aggressive prostate cancer and the increased availability of genetic testing, there is little evidence surrounding how best to screen these men. METHODS: We are reporting on the first 45 patients enrolled, men between the ages of 35-75, primarily with known pathogenic germline variants in prostate cancer susceptibility genes. Screening consists of an intake lifestyle survey, PSA, DRE, and SelectMDx urine assay. A biopsy was recommended for any of the following indications: 1) abnormal DRE, 2) PSA above threshold, or 3) SelectMDx above threshold. The primary outcomes were number needed to screen, and number needed to biopsy to diagnose a patient with prostate cancer. RESULTS: Patients enrolled in the clinic included those with BRCA1 (n=7), BRCA2 (n=16), Lynch Syndrome (n=6), and CHEK2 (n = 4) known pathogenic germline variants. The median age and PSA were 58 (range 35-71) and 1.4 ng/ml (range 0.1-11.4 ng/ml), respectively. 12 patients underwent a prostate needle biopsy and there were 4positive biopsies for prostate cancer. CONCLUSION: These early data support the feasibility of opening a dedicated clinic for men at high genetic risk of prostate cancer. This early report on the initial enrollment of our long-term study will help optimize early detection protocols and provide evidence for personalized prostate cancer screening in men with key pathogenic germline variants.

Bringing Prostate Cancer Germline Genetics into Clinical Practice.

PURPOSE: Until recently the role of germline genetics in prostate cancer care was not well defined. While important questions remain, we reviewed the current understanding of germline genetic alterations related to prostate cancer. We discuss the clinical implications for genetic counseling, genetic testing, early detection and treatment in men with these mutations. MATERIALS AND METHODS: We searched PubMed® for English language articles published since 2001 with the key words "germline mutations," "BRCA," "family history" or "prostate cancer genetics." We also used relevant data from websites, including the Centers for Medicare and Medicaid Services, National Comprehensive Cancer Network®, Bureau of Labor Statistics and National Society of Genetic Counselors websites. RESULTS: A number of germline mutations in DNA damage repair genes ( BRCA1, BRCA2, CHEK2, ATM and PALB2) and in DNA mismatch repair genes ( MLH1, MSH2, MSH6 and PMS2) can drive the development of prostate cancer. Careful genetic counseling coupled with multipanel gene testing can help identify men with these mutations and provide enhanced understanding of the disease risk. Cascade testing of family members can then have an impact extending well beyond the index patient. In men with a pathogenic germline mutation the optimal early detection paradigm is not well defined. Data from the IMPACT study ( ClinicalTrials.gov NCT00261456) that the cancer detection rate is substantially elevated in BRCA1 and BRCA2 carriers at prostate specific antigen greater than 3 ng/ml has helped establish the importance of close prostate specific antigen screening in these men. Additionally, BRCA2 and likely other DNA damage repair mutations are associated with aggressive disease, although it is not yet clear how this impacts localized disease management. However, there is strong evidence that patients with metastatic, castration resistant prostate cancer who have DNA damage repair defects respond positively to targeting PARP enzymes. In many cancers there is also evidence that patients with an increased tumor mutational burden, such as in Lynch syndrome, are particularly sensitive to immune checkpoint inhibitors. CONCLUSIONS: Emerging evidence supports the implementation of germline genetic counseling and testing as a key component of prostate cancer management. Further research is needed to elucidate the clinical significance of lesser known germline mutations and develop optimal screening, early detection and treatment paradigms in this patient population.

Effects of craniopharyngioma cyst fluid on neurons and glial cells cultured from rat brain hypothalamus.

Craniopharyngiomas (CPs) are rare, epithelial tumors of the central nervous system (CNS) that could lead to manifestation of multiple post-operative symptoms, ranging from hormonal imbalance to obesity, diabetes, visual, neurological and neurocognitive impairments. CP is more frequent in children, and has been reported in middle aged adults as well. In fact, arterial laceration and/or brain stroke which may occur following the removal of some CPs is mainly due to calcification of that CPs along with strong attachments to the blood vessels. The dense oily fluid content of CPs is reported to cause brain tissue damage, demyelination and axonal loss in the hypothalamus; however, its exact effect on different cell types of CNS is still unexplored. In this study, we have collected CP cyst fluid (CCF) from mostly young patients during surgical removal and exposed it 9-10 days in vitro to the primary cultures derived from rat brain hypothalamus for 48 h. A gradual decline in cell viability was noted with increasing concentration of CCF. Moreover, a distinct degenerative morphological transformation was observed in neurons and glial cells, including appearance of blebbing and overall reduction of the cell volume. Further, enhanced expression of Caspase-3 in neurons and glial cells exposed to CCF by immunofluorescence imaging, supported by Western blot experiment suggest CCF induced apoptosis of hypothalamic cells in culture. In this study, we have demonstrated the deleterious effects of the cyst fluid on various cell types within the tumors originating region of the brain and its surroundings for the first time. Taken together, this finding could be beneficial towards identifying the region specific toxic effects of the cyst fluid and its underlying mechanism.

Is magnetic resonance imaging helpful in detecting significant prostate cancer in patients with haematospermia, normal prostate specific antigen level and digital rectal examination. A single institution, observational, and retrospective study in a United Kingdom hospital.

INTRODUCTION: Haematospermia is an uncommon clinical condition that may be associated with prostate cancer. The optimal investigation of haematospermia is unknown. The aim of this study was to investigate haematospermia as a presenting symptom of significant pathology and to assess the diagnostic value of magnetic resonance imaging (MRI). MATERIAL AND METHODS: Patient and treatment parameters were collected from a practice cohort of men referred to a urology center presenting with haematospermia. We used a multivariate logistic regression model to test the independent significance of MRI in detecting prostate cancer (PCa) after adjusting for other known predictors of PCa detection. RESULTS: A total of 125 men (median age 58 years) were evaluated between 2012-2015. In the univariate and multivariate logistic regression model MRI was a significant predictor of PCa diagnosis after adjusting for age, prostate specific antigen (PSA) and digital rectal examination (DRE) results (Odds Ratio (OR) 14.15, p = 0.001). Of 107 patients who underwent MRI prostate imaging, 31 (28.9%) had reports suspicious of PCa. In 26 patients, other benign conditions were detected on MRI. PCa was detected in 12 (25.5%) of the 47 men (median age 61 years; range 43 to 85) who underwent prostate biopsies. Eight (17%) of these patients had Gleason ≥7 grade cancer. The persistence of haematospermia was not an independent predictor of cancer diagnosis (OR 0.20, p = 0.15). CONCLUSIONS: PCa is not commonly associated with haematospermia. MRI seems to be improving detection rate of a significant PCa, particularly in patients presenting with haematospermia and normal PSA levels and DRE examination. Duration of haematospermia does not predict the presence of PCa.

Inspection of Ureteral Orifices: The Pearl of Flexible Cystoscopy.

Cystoscopy is most common diagnostic investigation. The examination technique and the findings, both normal and pathological, were well described described a hundred years ago. With technological advances, there has been over-emphasis on imaging modalities for diagnostic purposes. A basic maneuver of examining the ureteral orifices is sometimes rushed through when in fact careful examination can clinch the diagnosis. The importance is exemplified by two cases, one of which is a rare case of Xanthoma of the ureter.

An unusual case of chronic urinary retention and bladder diverticulum presenting with unilateral lower limb swelling.

A 64-year-old man presented with 1 month of gradual-onset left leg swelling and lower urinary tract symptoms including enuresis, frequency and poor stream. He was initially treated for suspected cellulitis, however, he returned 2 weeks later with persistence of his symptoms. Routine biochemical investigation revealed renal failure (Cr 623, Ur 29.9) and hyperkalaemia (K 7.2). Abdominal examination revealed a distended urinary bladder and an ultrasound scan revealed hydronephrosis, confirming the diagnosis of chronic high-pressure urinary retention. A urinary catheter was passed that initially drained 1.5 litre of clear urine. Shortly after insertion, this became heavily blood stained. A CT kidney ureter bladder (CTKUB) revealed a large mass behind the bladder thought to represent either an abscess or tumour. Cystoscopic correlation showed this to be a large, narrow-necked bladder diverticulum tensely distended with clot. Following successful clot evacuation and decompression of the bladder the leg swelling resolved and renal function improved.

Metacarpal lengthening by distraction histiogenesis in adults.

BACKGROUND: Metacarpal lengthening in the hand is a new application for distraction neo-histiogenesis. Metacarpal lengthening with distraction helps in improvement in pinch function. Thumb lengthening is technically easy in comparison to other metacarpals. We present the operative treatment and post-operative outcome in nine patients with amputations and congenital anomalies. MATERIALS AND METHODS: Nine patients underwent distraction osteogenesis for the treatment of amputations of the hand and other congenital anomalies. The dominant right hand was operated in eight cases and the left hand in one case. There were six males and three females. Improvement of function was always the aim of surgery. Age range was between 18 and 23 years. Thumb lengthening was performed in five patients and that of the index finger in four patients. Distraction started on the fifth post-operative day at the rate of 0.25 mm/day. Sensory function and bone consolidation was assessed before fixator removal. RESULTS: The mean duration of distraction was 51 days (range, 42-60 days) and the distractor was removed at a mean of 150 days (range, 140 and 160 days) and the bones were lengthened by a mean of 24 mm (range, 20-28 mm) There was improvement of function in all cases. CONCLUSION: The metacarpal lengthening by distraction histiogenesis in congenital and traumatic amputations is safe and simple method to improve pinch function of hand.

Localized traumatic infarction of the testicle.

Ultrasonically it is extremely difficult to accurately distinguish testicular infarct from neoplasm. We describe a case which highlights this, together with the previously unreported phenomenon of a localized infarct secondary to trauma.