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.

Do Hispanic Puerto Rican men have worse outcomes after radical prostatectomy? Results from SEARCH.

BACKGROUND: We previously reported that outcomes after radical prostatectomy (RP) were similar among non-Hispanic Black, non-Hispanic White, and Hispanic White Veterans Affairs (VA) patients. However, prostate cancer (PC) mortality in Puerto Rican Hispanics (PRH) may be higher than in other Hispanic groups. Data focused on PRH patients is sparse; thus, we tested the association between PR ethnicity and outcomes after RP. METHODS: Analysis included men in SEARCH cohort who underwent RP (1988-2020, n = 8311). PRH patients (n = 642) were treated at the PR VA, and outcomes were compared to patients treated in the Continental US regardless of race. Logistic regression was used to test the associations between PRH and PC aggressiveness, adjusting for demographic and clinicopathological features. Multivariable Cox models were used to investigate PRH versus Continental differences in biochemical recurrence (BCR), metastases, castration-resistant PC (CRPC), and PC-specific mortality (PCSM). RESULTS: Compared to Continental patients, PRH patients had lower adjusted odds of pathological grade group ≥2 (p < 0.001), lymph node metastasis (p < 0.001), and positive margins (p < 0.001). In contrast, PRH patients had higher odds of extracapsular extension (p < 0.001). In Cox models, PRH patients had a higher risk for BCR (HR = 1.27, p < 0.001), metastases (HR = 1.49, p = 0.014), CRPC (HR = 1.80, p = 0.001), and PCSM (HR = 1.74, p = 0.011). Further adjustment for extracapsular extension and other pathological variables strengthened these findings. CONCLUSIONS: In an equal access setting, PRH RP patients generally had better pathological features, but despite this, they had significantly worse post-treatment outcomes than men from the Continental US, regardless of race. The reasons for the poorer prognosis among PRH men require further research.

Exposure to Agent Orange and Risk of Bladder Cancer Among US Veterans.

Importance: To date, limited data exist regarding the association between Agent Orange and bladder cancer, and the Institute of Medicine concluded that the association between exposure to Agent Orange and bladder cancer outcomes is an area of needed research. Objective: To examine the association between bladder cancer risk and exposure to Agent Orange among male Vietnam veterans. Design, Setting, and Participants: This nationwide Veterans Affairs (VA) retrospective cohort study assesses the association between exposure to Agent Orange and bladder cancer risk among 2 517 926 male Vietnam veterans treated in the VA Health System nationwide from January 1, 2001, to December 31, 2019. Statistical analysis was performed from December 14, 2021, to May 3, 2023. Exposure: Agent Orange. Main Outcomes and Measures: Veterans exposed to Agent Orange were matched in a 1:3 ratio to unexposed veterans on age, race and ethnicity, military branch, and year of service entry. Risk of bladder cancer was measured by incidence. Aggressiveness of bladder cancer was measured by muscle-invasion status using natural language processing. Results: Among the 2 517 926 male veterans (median age at VA entry, 60.0 years [IQR, 56.0-64.0 years]) who met inclusion criteria, there were 629 907 veterans (25.0%) with Agent Orange exposure and 1 888 019 matched veterans (75.0%) without Agent Orange exposure. Agent Orange exposure was associated with a significantly increased risk of bladder cancer, although the association was very slight (hazard ratio [HR], 1.04; 95% CI, 1.02-1.06). When stratified by median age at VA entry, Agent Orange was not associated with bladder cancer risk among veterans older than the median age but was associated with increased bladder cancer risk among veterans younger than the median age (HR, 1.07; 95% CI, 1.04-1.10). Among veterans with a diagnosis of bladder cancer, Agent Orange was associated with lower odds of muscle-invasive bladder cancer (odds ratio [OR], 0.91; 95% CI, 0.85-0.98). Conclusions and Relevance: In this cohort study among male Vietnam veterans, there was a modestly increased risk of bladder cancer-but not aggressiveness of bladder cancer-among those exposed to Agent Orange. These findings suggest an association between Agent Orange exposure and bladder cancer, although the clinical relevance of this was unclear.

The 17-Gene Genomic Prostate Score Test Is Prognostic for Outcomes After Primary External Beam Radiation Therapy in Men With Clinically Localized Prostate Cancer.

PURPOSE: The Oncotype DX Genomic Prostate Score (GPS) assay has been validated as a strong prognostic indicator of adverse pathology, biochemical recurrence, distant metastasis (DM), and prostate cancer (PCa)-related death (PCD) in men with localized PCa after radical prostatectomy. However, it has yet to be tested in men undergoing external beam radiation therapy (EBRT), for whom assessing PCa progression risk could inform decisions on treatment intensity. We analyzed whether GPS results are associated with time to biochemical failure (BCF), DM, and PCD after EBRT in men with localized PCa and whether the association is modified by race. METHODS AND MATERIALS: We conducted a retrospective study of men with localized PCa treated with EBRT at the VA Health Care System in Durham, NC from 2000 to 2016. Study endpoints were time to BCF per the Phoenix criteria, DM, and PCD. The association of GPS results, per 20-unit increase or dichotomous variable (0-40 vs 41-100), was evaluated with each endpoint using univariable and multivariable Cox proportional hazards models. Results were then stratified by race. RESULTS: A total of 238 patients (69% Black) met the eligibility criteria. Median follow-up for patients who did not experience BCF was 7.6 years. GPS results per 20-unit increase were significantly associated with BCF (hazard ratio [HR], 3.62; 95% confidence interval [CI], 2.59-5.02), DM (HR, 4.48; 95% CI, 2.75-7.38), and PCD (HR, 5.36; 95% CI, 3.06-9.76) in univariable analysis. GPS results remained significant in multivariable models adjusted for baseline clinical and pathological factors, with HRs being similar to the univariable analysis. There was no significant interaction between the GPS assay and race (P = .923). HRs for BCF were similar in Black men (HR, 3.88; 95% CI, 2.40-6.24) versus non-Black men (HR, 4.01; 95% CI, 2.42-6.45). CONCLUSIONS: Among men treated with EBRT, the GPS assay is a strong, independent prognostic indicator of time to BCF, DM, and PCD, and performs similarly in Black and non-Black men.

Food Sensitivities in a Diverse Nationwide Cohort of Veterans With Interstitial Cystitis/Bladder Pain Syndrome.

PURPOSE: Prior studies suggest that certain foods exacerbate interstitial cystitis/bladder pain syndrome symptoms. However, these studies were limited in size and demographics. We assessed the presence of diet sensitivities among patients with interstitial cystitis/bladder pain syndrome and compared them with patients with other pelvic pain conditions and healthy controls. MATERIALS AND METHODS: We identified Veterans Affairs patients nationwide by querying ICD-9/10 codes for interstitial cystitis/bladder pain syndrome. Patients were assigned to interstitial cystitis, other pelvic pain, or healthy control cohorts after chart review. We mailed all patients the Shorter-Moldwin Food Sensitivity Questionnaire to evaluate the self-perceived effects of specific foods/beverages on urinary symptoms and/or bladder pain. RESULTS: In the interstitial cystitis/bladder pain syndrome cohort, 70% had ≥1 food sensitivity vs 37% of the other pelvic pain cohort and 32% of healthy controls (P < .001). The average number of sensitivities were similar between other pelvic pain conditions and healthy control cohorts, which were significantly less than in interstitial cystitis/bladder pain syndrome patients. Interstitial cystitis/bladder pain syndrome patients were more sensitive to acidic, spicy foods, and certain beverages vs other cohorts (all P < .001). Within the interstitial cystitis/bladder pain syndrome cohort, Black patients had significantly higher sensitivity to alcoholic and noncaffeinated beverages than Whites. Black patients did report significantly worsened urinary urgency than Whites (P < .05). CONCLUSIONS: In a diverse population of veterans, interstitial cystitis/bladder pain syndrome patients had significantly more food sensitivities than those without interstitial cystitis/bladder pain syndrome. This suggests that food sensitivities could be suggestive of interstitial cystitis/bladder pain syndrome, which could make the Shorter-Moldwin Food Sensitivity Questionnaire a helpful diagnostic tool and aid in distinguishing interstitial cystitis/bladder pain syndrome from conditions often confused with interstitial cystitis/bladder pain syndrome.

Is time to castration resistant prostate cancer a potential intermediate end-point for time to metastasis among men initiating androgen deprivation therapy for non-metastatic prostate cancer with rapid PSA doubling time (<9 months)?

PURPOSE: Metastasis-free survival (MFS) is a surrogate for overall survival (OS) in men with non-metastatic castration-resistant prostate cancer (CRPC), but this endpoint may take years to develop in men with non-metastatic castrate-sensitive disease. The study objective was to examine whether progression to CRPC is a potential intermediate endpoint for developing metastatic disease in patients with biochemical recurrence (BCR) after radical prostatectomy (RP). MATERIALS AND METHODS: Men with BCR following RP who had PSA doubling times (PSADT) < 9 months and no metastasis at the time of initiating androgen deprivation therapy (ADT) (n = 210) were included. The primary objective was to assess the correlation between CRPC-free survival (CRPC-FS) and MFS, and the secondary objective was to assess the correlation between time to metastasis and time to CRPC. Kendall's Tau was used to test the correlation for the primary and secondary outcomes. RESULTS: The median MFS was 104 months (95% CI: 83-114) and median CRPC-FS was 100 months (95% CI: 80-114). Based on the Kaplan-Meier curve, the greatest difference in time to MFS and CRPC-FS was around 70% free survival, which was reached at 61.2 months for MFS and 49.6 months for CRPC-FS. Kendall's Tau for the correlation between CRPC-FS and MFS and between time to CRPC and time to metastasis was 0.867 (95% CI: 0.765-0.968) and 0.764 (95% CI: 0.644-0.884), respectively. CONCLUSIONS: Given the high correlation between CRPC-FS and MFS, after validation, CRPC-FS may serve as a potential intermediate endpoint in trials for men with BCR initiating ADT following local therapy.

Hypoxia-inducible factor pathway genes predict survival in metastatic clear cell renal cell carcinoma.

PURPOSE: Hypoxia inducible factor (HIF) pathway alterations drive progression of clear cell renal cell carcinoma (ccRCC). We aim to evaluate genes within the canonical and non-canonical HIF pathways as predictors of survival in metastatic ccRCC. MATERIALS AND METHODS: Gene expression was determined from 324 archival pretreatment nephrectomy specimens from CALGB90206, a phase III trial of patients treated with interferon alpha (INF-α) vs. INF-α plus bevacizumab. TaqMan RT-qPCR was performed using RNA from tumors macrodissected based on review by genitourinary pathology. RESULTS: A total of 35 HIF-related genes were assessed by Cox regression analysis. After adjusting for sex and Memorial Sloan Kettering Cancer Center risk score (MSKCC-RS), 11 genes predicted OS: HIF2A (HR 1.059, P = 0.012), EGLN3 (HR 1.089, P = 0.012), VEGFC (HR 0.904, P = 0.039), VEGFD (HR 1.085, P = 0.016), FLT4 (HR 1.093, P = 0.038), CCND1 (HR 1.077, P = 0.026), TGFA (HR 1.127, P = 0.003), EGFR (HR 1.151, P = 0.028), VHL (HR 0.764, P = 0.002), HSP90AA1 (HR 0.845, P = 0.002), and PTEN (HR 1.163, P = 0.050); 7 genes predicted PFS: HIF2A (HR 1.060, P = 0.011), CCND1 (HR 1.082, P = 0.016), TGFA (HR 1.096, P = 0.026), EP300 (HR 1.171, P = 0.031), VHL (HR 0.775, P = 0.007), HSP90AA1 (HR 0.871, P = 0.015), and TP53 (HR 1.119, P = 0.050). Most of these genes validated as significant predictors of survival in the external, TCGA dataset. In multivariate analysis of all externally validated genes, VEGFC (HR 0.906, P = 0.043), TGFA (HR 1.122, P = 0.003), CITED2 (HR 1.113, P = 0.035) and EP300 (HR 1.136, P = 0.049) predicted OS; and HIF2A (HR 1.049, P = 0.036) and EP300 (HR 1.199, P = 0.010) predicted PFS. EGLN3 (HR 1.156, P = 0.045) and BNIP3 (HR 1.254, P = 0.049) significantly interacted with treatment status and predicted PFS in patients treated with IFN-α and IFN-α+bevacizumab, respectively. CONCLUSIONS: We identified specific gene isoforms in both the canonical and non-canonical HIF pathways associated with metastatic RCC survival. EGLN3 and BNIP3 showed significant interaction with treatment arm and may be predictive of treatment response. We have identified genes for future prospective investigation as predictive biomarkers and novel drug targets.

Red Blood Cell Distribution Width Is Associated with All-cause Mortality but Not Adverse Cancer-specific Outcomes in Men with Clinically Localized Prostate Cancer Treated with Radical Prostatectomy: Findings Based on a Multicenter Shared Equal Access Regional Cancer Hospital Registry.

BACKGROUND: Recent reports with a small number of patients showed an association of red blood cell distribution width (RDW) with prostate cancer (PCa) progression. OBJECTIVE: To investigate whether preoperative RDW can serve as a prognostic marker in patients with PCa undergoing radical prostatectomy (RP) in a large, equal access, and diverse patient cohort. DESIGN SETTING AND PARTICIPANTS: Data were retrospectively collected on 4756 men treated with RP at eight Veteran Affairs medical centers within the Shared Equal Access Regional Cancer Hospital (SEARCH) database from 1999 through 2017. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Biochemical recurrence (BCR) was the primary outcome, while metastasis, all-cause mortality (ACM), and prostate cancer-specific mortality (PCSM) were secondary outcomes. RESULTS AND LIMITATIONS: The mean (standard deviation) age was 62 yr (6.1), and 1589 (33%) men were black. The median (interquartile range) follow-up was 82 mo (46-127). Preoperative RDW either as a continuous variable or when stratified by quartiles was not associated with BCR. Likewise, preoperative RDW was not associated with metastases or PCSM. However, higher RDW was significantly associated with higher ACM, both as a continuous variable (p < 0.001) and when stratified by quartiles in univariable and multivariable models (p < 0.001). RDW was found to be correlated with D'Amico risk classification of PCa. Study limitations include its retrospective nature and lack of data regarding advanced PCa. CONCLUSIONS: Preoperative RDW was not associated with PCa outcomes in men treated with RP but was associated with ACM. While RDW may be a biomarker of overall health, it is not a biomarker for PCa outcomes. These results emphasize the importance of diverse, larger sized studies in genitourinary cancer research. PATIENT SUMMARY: Prostate cancer includes a wide spectrum of diseases with different genetic, pathological, and oncological behaviors. Red blood cell distribution width is helpful in predicting the overall survival for a localized prostate cancer patient, and hence, it can help inform personalized treatment decisions and operative care.

Prostate weight and prostate cancer outcomes after radical prostatectomy: Results from the SEARCH cohort study.

BACKGROUND: Smaller prostates have been linked to unfavorable clinical characteristics and poor short-term outcomes following radical prostatectomy (RP). We examined the relation between prostate weight at RP and prostate cancer (PC) outcomes post-RP. METHODS: Men in the SEARCH cohort undergoing RP between 1988 and 2017 (N = 6242) were studied for PC-specific mortality (PCSM) as the primary outcome, and for biochemical recurrence (BCR), castration-resistant PC (CRPC) and metastasis as secondary outcomes. Hazard ratios (HR) and 95% confidence intervals (CI) were determined for associations between prostate weight and outcomes using Fine-Gray competing risk regression multivariable analyses. Sensitivity analyses were also carried out following exclusion of: (i) men with extreme prostate weights (<20 g and ≥100 g); and (ii) men with elevated prostate specific antigen (PSA) levels. RESULTS: Median values for age, pre-RP PSA and prostate weight were 63 years, 6.6 ng/ml, and 42.0 g, respectively. During a median follow-up of 7.9 years, 153 (3%) died from PC, 2103 (34%) had BCR, 203 (3%) developed CRPC, and 289 (5%) developed metastases. Prostate weight was not associated with PCSM in the main analyses (multivariable HR = 1.43; 95% CI: 0.87-2.34) or in sensitivity analyses. Prostate weight was inversely associated with BCR in the main analyses (multivariable HR = 0.70; 95%CI: 0.61-0.79) which was unchanged in sensitivity analyses. HRs for prostate weight and CRPC and metastasis were elevated but statistical significance was not attained. Similar results were observed in sensitivity analyses. CONCLUSIONS: Inconsistent results for prostate weight and short-term vs longer-term outcomes highlight the need to better understand the complex biology leading to prostate size and the relevance of prostate size as a predictor of PC outcomes.

Opioid-prescribing patterns among shoulder and elbow surgeons: considerations for future prescription guidelines.

BACKGROUND: Although the achievement of adequate analgesia is critical to patient comfort and recovery following orthopedic procedures, no standard protocol exists to dictate the appropriate duration and quantity of narcotic prescription in the postoperative period. Therefore, the purpose of this survey was to determine patterns of opioid prescribing among orthopedic shoulder and elbow providers. METHODS: In March 2020, a survey was distributed through a LISTSERV to 989 members of the American Shoulder and Elbow Surgeons orthopedic society. Survey recipients were asked to describe their personal and practice characteristics. Additionally, they were asked to list their 3 most commonly performed procedures and, for each operation, to list which narcotic pain medication they most commonly prescribe postoperatively, along with the corresponding number of tablets typically given. Similarly, respondents were asked to record frequently recommended alternative strategies for postoperative pain control, factors influencing the respondents' prescribing practices, and methods of patient counseling regarding opioid use and disposal. RESULTS: A total of 177 providers responded to the survey. Across all selected procedures, Percocet (5 mg of oxycodone hydrochloride and 325 mg of acetaminophen) was the most commonly prescribed drug, with 21-30 tablets being the most commonly prescribed amount. The majority of surgeons (82%) indicated that previous opioid prescriptions influence their decision to prescribe opioids. Respondents most frequently reported patient age (48%) and duration of the patient's symptoms (32%) as additional influential factors. Most surgeons (93%) reported counseling their patients regarding the use of opioid medications. However, only 30% of surgeons reported providing information regarding how to dispose of unused opioids. In lieu of opioids, nearly all investigators reported the use of ice as a pain-relief strategy, with rest and the use of nonsteroidal anti-inflammatory drugs reported as other commonly recommended alternatives. Of 137 respondents who were aware of prescription guidelines, 21% reported using recommendations from the American Academy of Orthopaedic Surgeons, 21% used institutional policies, and 20% used personal guidelines, whereas the remaining respondents used other literature findings in their prescription decisions. Of particular concern, 21% of overall respondents were unaware of any type of guidelines. DISCUSSION: To prevent both misuse and abuse of opioid prescribing, this analysis serves as a starting point for the establishment of more consistent, evidence-based opioid prescription guidelines for surgical procedures on the shoulder and elbow. In addition to recommending safe, procedure-specific opioid dosages and standardizing pain management strategies, these guidelines should include effective methods of educating both providers and patients regarding the use of opioid medication.

Comparative Effectiveness of Targeted Intrathecal Drug Delivery Using a Combination of Bupivacaine with Either Low-Dose Fentanyl or Hydromorphone in Chronic Back Pain Patients with Lumbar Postlaminectomy Syndrome.

OBJECTIVE: Targeted intrathecal drug delivery (TIDD) is an effective interventional pain management modality often used in postlaminectomy patients with refractory chronic low back pain. A combination of intrathecal bupivacaine with an opioid is often used. However, intrathecal catheter tip granulomas have occurred with use of morphine or hydromorphone but generally not with fentanyl. The objective of this study was to compare the efficacy of TIDD using bupivacaine/fentanyl vs bupivacaine/hydromorphone in patients with chronic intractable low back pain postlaminectomy. MATERIALS AND METHODS: A retrospective comparative analysis of consecutive patients with lumbar postlaminectomy syndrome who were trialed and later received TIDD with a combination of bupivacaine/hydromorphone or bupivacaine/fentanyl between June 2009 and May 2016 at a single tertiary medical center. RESULTS: We identified a cohort of 58 lumbar postlaminectomy patients receiving a TIDD admixture of either hydromorphone/bupivacaine (30 patients) or low-dose fentanyl/bupivacaine (28 patients) with at least two years of follow-up. The fentanyl group had significantly lower baseline opioid consumption and a lower rate of intrathecal opioid dose escalation. Both groups had similar and significant reductions in pain scores over the two-year follow-up period. No granulomas were observed. CONCLUSION: TIDD using a low-dose fentanyl admixture with bupivacaine in patients with postlaminectomy syndrome and refractory chronic low back pain results in similar pain relief to TIDD with hydromorphone and bupivacaine. Low-dose intrathecal fentanyl leads to a lower rate of opioid escalation and may be safer than hydromorphone.