Clinicopathological and Molecular Features of Penile Melanoma With a Proposed Staging System.

Penile melanomas (PM) are an exceedingly rare subtype of mucosal melanoma (MM), and we reviewed the clinicopathologic features and molecular profile in 8 PMs. The patient ages ranged from 46 to 78 (mean: 62.8) years with involvement on the glans (n=5; 62.5%), penile urethra (n=2; 25%), and foreskin (n=1, 12.5%). Tumor depth ranged from 1.6 to 10.0 (mean: 5.25) mm. Most of the patients underwent partial penectomy (n=6; 75%) and sentinel lymph node (LN) biopsy N=7; 87.5%). Seven patients had metastatic disease at diagnosis, 6 involving LNs and 1 the adrenal gland, and 4 died of disease with a mean follow-up period of 40.5 (2 to 95) months. Five of 7 (71%) cases identified 15 molecular alterations within KIT , CDKN2A , NF1 , PTEN , and APC (n=2 each), and NRAS , MAP3K1 , CDH1 , MSH6 , and TERT (n=1 each). Two cases were not found to harbor genetic aberrations, and 1 case failed testing. In addition, we reviewed the English literature and included 93 cases with a reported depth of invasion and follow-up. A total of 101 PMs were analyzed for prognostic parameters, and the overall survival was significantly worse in patients with LN metastasis (P=0.0008), distant metastasis (P=0.0016), and greater depth of invasion (P=0.0222) based upon T-stage. While T4 conferred substantially worse survival, the delineation of the survival curves between T2 and T3 was less clear, and combining T2+T3 disease had a strong prognostic impact ( P =0.0024). Prognostic parameters used in the staging of cutaneous melanomas may also be used in PMs. An alternative staging system expanding the inclusion criteria for T2 might provide a more accurate prognostic stratification.

A contemporary comparison of laparoscopic versus open partial nephrectomy for renal cell carcinoma.

PURPOSE: To analyze surgical and oncologic outcomes of patients undergoing open partial nephrectomy (OPN) versus laparoscopic partial nephrectomy (LPN) for treatment of renal cell carcinoma (RCC). METHODS: We retrospectively investigated our institutional RCC database for patients who underwent PN for RCC from 1997 to 2018. Decision for technique was at the discretion of the operating urologist, following practice patterns and training history. Outcomes analyzed included pre/peri/post-operative parameters, pathologic outcomes, and disease recurrence rates. RESULTS: 1088 patients underwent PN from 1997 to 2018. After exclusionary criteria, 631 patients who underwent 647 unique PNs for a total of 162 OPN and 485 LPN remained. Baseline, pre-op, and pathologic characteristics were not statistically different. Surgical time was lower in laparoscopic cases [185 vs. 205 min] (p = 0.013). Margin involvement was not statistically different; LPN had lower estimated blood loss (EBL) [150 vs. 250 mL] (p < 0.001) and longer ischemia time [21 vs. 19 min] (p = 0.005). LPN had shorter length of stay [2 vs. 4 days] (p < 0.001), fewer overall complications (p < 0.001), and no significant difference in high-grade complications [2.89 vs. 4.32%] (p = 0.379). Fewer LPN patients developed metastases [1.65 vs. 4.94%] (p = 0.0499). Local recurrence rates were not statistically different [1.24 vs. 3.09%] (p = 0.193). Renal function was equivalent between cohorts post-operatively. CONCLUSION: Long-term oncologic outcomes were not significantly different between LPN versus OPN, with no statistical difference in patient and tumor characteristics. LPN was associated with lower EBL, shorter length of stay, and lower overall complication risk. Renal function was not significantly different between cohorts.

Urinary volatile organic compounds in prostate cancer biopsy pathologic risk stratification using logistic regression and multivariate analysis models.

Prostate cancer (PCa) is the second leading cause of cancer-related death in American men after lung cancer. The current PCa diagnostic method, the serum prostate-specific antigen (PSA) test, is not specific, thus, alternatives are needed to avoid unnecessary biopsies and over-diagnosis of clinically insignificant PCa. To explore the application of metabolomics in such effort, urine samples were collected from 386 male adults aged 44-93 years, including 247 patients with biopsy-proven PCa and 139 with biopsy-proven negative results. The PCa-positive group was further subdivided into two groups: low-grade (ISUP Grade Group = 1; n = 139) and intermediate/high-grade (ISUP Grade Group ≥ 2; n = 108). Volatile organic compounds (VOCs) in urine were extracted by stir bar sorptive extraction (SBSE) and analyzed using thermal desorption with gas chromatography and mass spectrometry (GC-MS). We used machine learning tools to develop and evaluate models for PCa diagnosis and prognosis. In total, 22,538 VOCs were identified in the urine samples. With regularized logistic regression, our model for PCa diagnosis yielded an area under the curve (AUC) of 0.99 and 0.88 for the training and testing sets respectively. Furthermore, the model for differentiating between low-grade and intermediate/high-grade PCa yielded an average AUC of 0.78 based on a repeated test-sample approach for cross-validation. These novel methods using urinary VOCs and logistic regression were developed to fill gaps in PCa screening and assessment of PCa grades prior to biopsy. Our study findings provide a promising alternative or adjunct to current PCa screening and diagnostic methods to better target patients for biopsy and mitigate the challenges associated with over-diagnosis and over-treatment of PCa.

The effect of limited english proficiency on prostate-specific antigen screening in American men.

PURPOSE: To evaluate how limited English proficiency (LEP) impacts the prevalence of prostate-specific antigen (PSA) screening in a contemporary, nationally representative cohort of men in the USA. METHODS: The Medical Expenditure Panel Survey was utilized to identify the prevalence of PSA screening between 2013 and 2016 among men ≥ 55. Men who speak a language other than English at home were stratified by self-reported levels of English proficiency (men who speak English very well, well, not well, or not at all). Survey weights were applied, and groups were compared using the adjusted Wald test. A multivariable logistic regression model was used to identify predictors of PSA screening adjusting for patient-level covariates. RESULTS: The cohort included 2,889 men, corresponding to a weighted estimate of 4,765,682 men. 79.6% of men who speak English very well reported receiving at least one lifetime PSA test versus 58.4% of men who do not speak English at all (p < 0.001). Men who reported not speaking English at all had significantly lower prevalence of PSA screening (aOR 0.56; 95% CI 0.35-0.91; p = 0.019). Other significant predictors of PSA screening included older age, income > 400% of the federal poverty level, insurance coverage, and healthcare utilization. CONCLUSIONS: Limited English proficiency is associated with significantly lower prevalence of PSA screening among men in the USA. Interventions to mitigate disparities in prostate cancer outcomes should account for limited English proficiency among the barriers to guideline-concordant care.

Clinical significance of prostate cancer identified by transperineal standard template biopsy in men with nonsuspicious multiparametric magnetic resonance imaging.

OBJECTIVE: Multiparametric magnetic resonance imaging (mpMRI) of the prostate has excellent sensitivity in detecting clinically significant prostate cancer (csCaP). However, whether a negative mpMRI in patients with a clinical suspicion of CaP can omit a confirmatory biopsy remains less understood and without consensus. Transperineal (TP) standard template biopsy (SBx) provides an effective approach to CaP detection. Our aim is to provide a comprehensive understanding of the CaP characteristics detected through TP SBx that are systematically overlooked by mpMRI. METHODS: We conducted a retrospective analysis of all men who underwent prebiopsy mpMRI and subsequent a 20-core TP SBx at our hospital from September 2019 to February 2021. Patients with suspicious mpMRI received a combined TP SBx and targeted biopsy (TBx) (suspicious group), while those without suspicious (negative) mpMRI and who proceeded to biopsy, received TP SBx only (nonsuspicious group). A negative mpMRI was defined as the absence of suspicious findings and/or the presence of low-risk areas with a PI-RADS score of ≤2. Subsequently, we compared and evaluated the clinical and biopsy characteristics between these 2 groups. RESULTS: We identified 301 men in suspicious group and 215 men in nonsuspicious group. The overall CaP detection rate and csCaP detection rate by TP SBx were 74.1%, 38.9% for suspicious group and 43.3%, 14.9% for nonsuspicious group, respectively. csCaP NPV of mpMRI was 85.1% with a csCaP prevalence 28.9%. The greatest percentage of cancer involvement (GPC) in biopsy core from nonsuspicious group was significantly lower than those of suspicious group (40% vs. 50%, p = 0.005), In multivariate logistic analysis, only PSAD > 0.15 ng/ml/cc was identified as an independent and significant predictor of csCaP in nonsuspicious group. CONCLUSION: Within our cohort, false-negative rates of mpMRI for csCaP are substantial, reaching 15%. Nonsuspicious cases may contain a large volume tumor since the high GPC of SBx. For cases with nonsuspicious imaging and higher PSAD, a confirmatory biopsy may be necessary due to the increased risk of missed csCaP by mpMRI.

First analysis of the safety and efficacy of UGN-101 in the treatment of ureteral tumors.

OBJECTIVE: UGN-101 has been approved for the chemoablation of low-grade upper tract urothelial cancer (UTUC) involving the renal pelvis and calyces. Herein is the first reported cohort of patients with ureteral tumors treated with UGN-101. PATIENTS AND METHODS: We performed a retrospective review of patients treated with UGN-101 for UTUC at 15 high-volume academic and community centers focusing on outcomes of patients treated for ureteral disease. Patients received UGN-101 with either adjuvant or chemo-ablative intent. Response rates are reported for patients receiving chemo-ablative intent. Adverse outcomes were characterized with a focus on the rate of ureteral stenosis. RESULTS: In a cohort of 132 patients and 136 renal units, 47 cases had tumor involvement of the ureter, with 12 cases of ureteral tumor only (8.8%) and 35 cases of ureteral plus renal pelvic tumors (25.7%). Of the 23 patients with ureteral involvement who received UGN-101 induction with chemo-ablative intent, the complete response was 47.8%, which did not differ significantly from outcomes in patients without ureteral involvement. Fourteen patients (37.8%) with ureteral tumors had significant ureteral stenosis at first post-treatment evaluation, however, when excluding those with pre-existing hydronephrosis or ureteral stenosis, only 5.4% of patients developed new clinically significant stenosis. CONCLUSIONS: UGN-101 appears to be safe and may have similar efficacy in treating low-grade urothelial carcinoma of the ureter as compared to renal pelvic tumors.

Estimated Prostate Volume by Semiautomatic Segmentation of MRI Is More Accurately Correlated with Radical Prostatectomy Specimen Weight than the Volume Calculated by Ellipsoid Formula.

INTRODUCTION: Accurate in vivo prostate volume (PV) estimation is important for obtaining prostate-specific antigen density (PSAD) and further predicting clinically significant prostate cancer (csPCa). We aimed to evaluate the accuracy of multiparametric magnetic resonance imaging (mpMRI)-estimated PV compared to both volume and weight of radical prostatectomy (RP). METHODS: We identified 310 PCa patients who underwent RP following combined targeted and systematic biopsy in our institution from September 2019 to February 2021. The MRI PV was determined using a semiautomated segmentation algorithm. RP PV was calculated using the prolate ellipsoid formula (length × width × height × π/6). Formula (prostate weight = [actual weight-3.8 g]/1.05 g/mL) was applied, and the resulting volume was used in further analysis. RESULTS: The median PV from MRI, RP, and RP weight were 39 mL, 38 mL, and 44 mL, respectively. Spearman's rank correlation coefficients (ρ) were 0.841 (MRI PV vs. RP weight), 0.758 (RP PV vs. RP weight), and 0.707 (MRI PV vs. RP PV) (all p < 0.001). Decreased correlation between the MRI PV and RP PV was observed in the larger (more than 55 mL) prostate. The PSAD derived from MRI PV showed most efficient to detect csPCa in RP specimen (57.9% vs. 57.6% vs. 45.4%). CONCLUSION: MRI PV is correlated better with RP weight than calculated RP PV, especially in larger prostate. The high csPCa detection rate in final pathology suggested that PSAD derived from MRI PV can be confidently used in clinical practice.

Genomic Tumor Correlates of Clinical Outcomes Following Organ-Sparing Chemoradiation Therapy for Bladder Cancer.

PURPOSE: There is an urgent need for biomarkers of radiation response in organ-sparing therapies. Bladder preservation with trimodality therapy (TMT), consisting of transurethral tumor resection followed by chemoradiation, is an alternative to radical cystectomy for muscle-invasive bladder cancer (MIBC), but molecular determinants of response are poorly understood. EXPERIMENTAL DESIGN: We characterized genomic and transcriptomic features correlated with long-term response in a single institution cohort of patients with MIBC homogeneously treated with TMT. Pretreatment tumors from 76 patients with MIBC underwent whole-exome sequencing; 67 underwent matched transcriptomic profiling. Molecular features were correlated with clinical outcomes including modified bladder-intact event-free survival (mBI-EFS), a composite endpoint that reflects long-term cancer control with bladder preservation. RESULTS: With a median follow-up of 74.6 months in alive patients, 37 patients had favorable long-term response to TMT while 39 had unfavorable long-term response. Tumor mutational burden was not associated with outcomes after TMT. DNA damage response gene alterations were associated with improved locoregional control and mBI-EFS. Of these alterations, somatic ERCC2 mutations stood out as significantly associated with favorable long-term outcomes; patients with ERCC2 mutations had significantly improved mBI-EFS [HR, 0.15; 95% confidence interval (CI), 0.06-0.37; P = 0.030] and improved BI-EFS, an endpoint that includes all-cause mortality (HR, 0.33; 95% CI, 0.15-0.68; P = 0.044). ERCC2 mutant bladder cancer cell lines were significantly more sensitive to concurrent cisplatin and radiation treatment in vitro than isogenic ERCC2 wild-type cells. CONCLUSIONS: Our data identify ERCC2 mutation as a candidate biomarker associated with sensitivity and long-term response to chemoradiation in MIBC. These findings warrant validation in independent cohorts.

Characterization of the metabolomic profile of renal cell carcinoma by high resolution magic angle spinning proton magnetic resonance spectroscopy.

BACKGROUND: Renal cell carcinoma (RCC) is a metabolic disease, with subtypes exhibiting aberrations in different metabolic pathways. Metabolomics may offer greater sensitivity for revealing disease biology. We investigated the metabolomic profile of RCC using high-resolution magic angle spinning (HRMAS) proton magnetic resonance spectroscopy (1HMRS). METHODS: Surgical tissue samples were obtained from our frozen tissue bank, collected from radical or partial nephrectomy. Specimens were fresh-frozen, then stored at -80 °C until analysis. Tissue HRMAS-1HMRS was performed. A MatLab-based curve fitting program was used to process the spectra to produce relative intensities for 59 spectral regions of interest (ROIs). Comparisons of the metabolomic profiles of various RCC histologies and benign tumors, angiomyolipoma, and oncocytoma, were performed. False discovery rates (FDR) were used from the response screening to account for multiple testing; ROIs with FDR p < 0.05 were considered potential predictors of RCC. Wilcoxon rank sum test was used to compare median 1HMRS relative intensities for those metabolites that may differentiate between RCC and benign tumor. Logistic regression determined odds ratios for risk of malignancy based on the abundance of each metabolite. RESULTS: Thirty-eight RCC (16 clear cell, 11 papillary, 11 chromophobe), 10 oncocytomas, 7 angiomyolipomas, and 13 adjacent normal tissue specimens (matched pairs) were analyzed. Candidate metabolites for predictors of malignancy based on FDR p-values include histidine, phenylalanine, phosphocholine, serine, phosphocreatine, creatine, glycerophosphocholine, valine, glycine, myo-inositol, scyllo-inositol, taurine, glutamine, spermine, acetoacetate, and lactate. Higher levels of spermine, histidine, and phenylalanine at 3.15 to 3.13 parts per million (ppm) were associated with decreased risk of RCC (OR 4 × 10-5, 95% CI 7.42 × 10-8, 0.02), while 2.84 to 2.82 ppm increased the risk of malignant pathology (OR 7158.67, 95% CI 6.3, 8.3 × 106). The specific metabolites characterizing this region remain to be identified. Tumor stage did not affect metabolomic profile of malignant tumors, suggesting that metabolites are dependent on histologic subtype. CONCLUSIONS: HRMAS-1HMRS identified metabolites that may predict RCC. We demonstrated that those in the 3.14 to 3.13 ppm ROI were present in lower levels in RCC, while higher levels of metabolites in the 2.84 to 2.82 ppm ROI were associated with substantially increased risk of RCC. Further research in a larger population is required to validate these findings.

Differentiation of patients with and without prostate cancer using urine 1 H NMR metabolomics.

Prostate cancer (PCa) is one of the most prevalent cancers in men worldwide. For its detection, serum prostate-specific antigen (PSA) screening is commonly used, despite its lack of specificity, high false positive rate, and inability to discriminate indolent from aggressive PCa. Following increases in serum PSA levels, clinicians often conduct prostate biopsies with or without advanced imaging. Nuclear magnetic resonance (NMR)-based metabolomics has proven to be promising for advancing early-detection and elucidation of disease progression, through the discovery and characterization of novel biomarkers. This retrospective study of urine-NMR samples, from prostate biopsy patients with and without PCa, identified several metabolites involved in energy metabolism, amino acid metabolism, and the hippuric acid pathway. Of note, lactate and hippurate-key metabolites involved in cellular proliferation and microbiome effects, respectively-were significantly altered, unveiling widespread metabolomic modifications associated with PCa development. These findings support urine metabolomics profiling as a promising strategy to identify new clinical biomarkers for PCa detection and diagnosis.

Detection of extraprostatic extension by transperineal multiparametric magnetic resonance imaging-ultrasound fusion targeted combined with systemic template prostate biopsy.

BACKGROUND: Extraprostatic extension (EPE) of prostate cancer (PCa) on transrectal (TR) needle core biopsy (Bx) is a rare histopathological finding that can help in clinical decision-making. The detection efficiency of the transperineal (TP) approach is yet to be explored. METHODS: We retrospectively reviewed 2848 PCa cases using concomitant systemic template biopsy (SBx) and multiparametric magnetic resonance imaging (MRI)-ultrasound fusion-targeted biopsy (TBx) using the TR (n = 1917) or TP (n = 931) approach at our institution between January 2015 and July 2022. We assessed and compared clinical, MRI, and biopsy characteristics using different approaches (TP and TR) and methods (SBx and TBx). RESULTS: In total, 40 EPE cases were identified (40/2848, 1.4%). TP showed a significantly higher EPE detection rate compared to TR in SBx (TR:0.7% vs. TP:1.6%; p = 0.028) and TBx (TR:0.5% vs. TP:1.2%; p = 0.033), as well as the combined methods (2.1% vs. 1.1%, p = 0.019). A significantly higher incidence of EPEs was found at non-base sites in TP than in TR (76.7% vs. 50%, p = 0.038). SBx showed a higher EPE detection rate than TBx; however, the difference was not statistically significant. TP showed higher prostate-specific antigen density (0.35 vs. 0.17, p = 0.005), higher frequency of GG4-5 in the cores with EPE (65.0% vs. 50.0%, p = 0.020), and more PCa-positive SBx cores (10 vs. 8, p = 0.023) compared to the TR. CONCLUSIONS: TP may improve EPE detection compared with TR and should be applied to patients with adverse pre-biopsy features.

Development and Multicenter Case-Control Validation of Urinary Comprehensive Genomic Profiling for Urothelial Carcinoma Diagnosis, Surveillance, and Risk-Prediction.

PURPOSE: Urinary comprehensive genomic profiling (uCGP) uses next-generation sequencing to identify mutations associated with urothelial carcinoma and has the potential to improve patient outcomes by noninvasively diagnosing disease, predicting grade and stage, and estimating recurrence risk. EXPERIMENTAL DESIGN: This is a multicenter case-control study using banked urine specimens collected from patients undergoing initial diagnosis/hematuria workup or urothelial carcinoma surveillance. A total of 581 samples were analyzed by uCGP: 333 for disease classification and grading algorithm development, and 248 for blinded validation. uCGP testing was done using the UroAmp platform, which identifies five classes of mutation: single-nucleotide variants, copy-number variants, small insertion-deletions, copy-neutral loss of heterozygosity, and aneuploidy. UroAmp algorithms predicting urothelial carcinoma tumor presence, grade, and recurrence risk were compared with cytology, cystoscopy, and pathology. RESULTS: uCGP algorithms had a validation sensitivity/specificity of 95%/90% for initial cancer diagnosis in patients with hematuria and demonstrated a negative predictive value (NPV) of 99%. A positive diagnostic likelihood ratio (DLR) of 9.2 and a negative DLR of 0.05 demonstrate the ability to risk-stratify patients presenting with hematuria. In surveillance patients, binary urothelial carcinoma classification demonstrated an NPV of 91%. uCGP recurrence-risk prediction significantly prognosticated future recurrence (hazard ratio, 6.2), whereas clinical risk factors did not. uCGP demonstrated positive predictive value (PPV) comparable with cytology (45% vs. 42%) with much higher sensitivity (79% vs. 25%). Finally, molecular grade predictions had a PPV of 88% and a specificity of 95%. CONCLUSIONS: uCGP enables noninvasive, accurate urothelial carcinoma diagnosis and risk stratification in both hematuria and urothelial carcinoma surveillance patients.

Route of Administration for UGN-101 and Impact on Oncological and Safety Outcomes.

BACKGROUND: UGN-101 can be used for chemoablation of low-grade upper tract urothelial carcinoma (UTUC). The gel can be administered via a retrograde route through a ureteral catheter or an antegrade route via a nephrostomy tube. OBJECTIVE: To report outcomes of UGN-101 by route of administration. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective review of 132 patients from 15 institutions who were treated with UGN-101 for low-grade UTUC via retrograde versus antegrade administration. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Survival outcomes are reported per patient. Treatment, complications, and recurrence outcomes are reported per renal unit. Statistical analysis was performed for primary endpoints of oncological response and ureteral stricture occurrence. RESULTS AND LIMITATIONS: A total of 136 renal units were evaluated, comprising 78 retrograde and 58 antegrade instillations. Median follow-up was 7.4 mo. There were 120 cases (91%) of biopsy-proven low-grade UTUC. Tumors were in the renal pelvis alone in 89 cases (65%), in the ureter alone in 12 cases (9%), and in both in 35 cases (26%). Seventy-six patients (56%) had residual disease before UGN-101 treatment. Chemoablation with UGN-101 was used in 50/78 (64%) retrograde cases and 26/58 (45%) antegrade cases. A complete response according to inspection and cytology was achieved in 31 (48%) retrograde and 30 (60%) antegrade renal units (p = 0.1). Clavien grade 3 ureteral stricture occurred in 21 retrograde cases (32%) and only six (12%) antegrade cases (p < 0.01). Limitations include treatment bias, as patients in the antegrade group were more likely to undergo endoscopic mechanical ablation before UGN-101 instillation. CONCLUSIONS: These preliminary results show a significantly lower rate of stricture occurrence with antegrade administration of UGN-101, with no apparent impact on oncological efficacy. PATIENT SUMMARY: We compared results for two different delivery routes for the drug UGN-101 for treatment of cancer in the upper urinary tract. For the antegrade route, a tube is inserted through the skin into the kidney. For the retrograde route, a catheter is inserted past the bladder into the upper urinary tract. Our results show a lower rate of narrowing of the ureter (the tube draining urine from the kidney into the bladder) using the antegrade route, with no difference in cancer control.

The Risk of Catastrophic Healthcare Expenditures Among Prostate and Bladder Cancer Survivors in the United States.

INTRODUCTION: Little is known about the rates of catastrophic health care expenditures among survivors of prostate and bladder cancer or the factors that place patients at highest risk for undue cost. MATERIALS AND METHODS: The Medical Expenditure Panel Survey was utilized to identify prostate and bladder cancer survivors from 2011 to 2019. Rates of catastrophic health care expenditures (out-of-pocket health care spending >10% household income) were compared between cancer survivors and adults without cancer. A multivariable regression model was used to identify risk factors for catastrophic expenditures. RESULTS: Among 2620 urologic cancer survivors, representative of 3,251,500 (95% CI 3,062,305-3,449,547) patients annually after application of survey weights, there were no significant differences in catastrophic expenditures among respondents with prostate cancer compared to adults without cancer. Respondents with bladder cancer had significantly greater rates of catastrophic expenditures (12.75%, 95% CI 9.36%-17.14% vs. 8.33%, 95% CI 7.66%-9.05%, P = .027). Significant predictors of catastrophic expenditures in bladder cancer survivors included older age, comorbidities, lower income, retirement, poor health status, and private insurance. Though White respondents with bladder cancer had no significantly increased risk of catastrophic expenditures, among Black respondents the risk of catastrophic expenditures increased from 5.14% (95% CI 3.95-6.33) without bladder cancer to 19.49% (95% CI 0.84-38.14) with bladder cancer (OR 6.41, 95% CI 1.28-32.01, P = .024). CONCLUSIONS: Though limited by small sample size, these data suggest that bladder cancer survivorship is associated with catastrophic health care expenditures, particularly among Black cancer survivors. These findings should be taken as hypothesis-generating and warrant further investigation with larger sample sizes and, ideally, prospective investigation.

The ablative effect of mitomycin reverse thermal gel: Expanding the role for nephron preservation therapy in low grade upper tract urothelial carcinoma.

PURPOSE: Assess the real-world ablative effect of mitomycin reverse thermal gel for low-grade upper tract urothelial carcinoma (UTUC) in patients who undergo biopsy only or partial ablation and evaluate utility of complete ablation prior to UGN-101. MATERIAL AND METHODS: We retrospectively reviewed low-grade UTUC patients treated with UGN-101 from 15 high-volume centers. Patients were categorized based on initial endoscopic ablation (biopsy only, partial ablation, or complete ablation) and by size of remaining tumor (complete ablation, <1cm, 1-3cm, or >3cm) prior to UGN-101. The primary outcome was rendered disease free (RDF) rate at first post-UGN-101 ureteroscopy (URS), defined as complete response or partial response with minimal mechanical ablation to endoscopically clear the upper tract of visible disease. RESULTS: One hundred and sixteen patients were included for analysis after excluding those with high-grade disease. At first post-UGN-101 URS, there were no differences in RDF rates between those who at initial URS (pre-UGN-101) had complete ablation (RDF 77.0%), partial ablation (RDF 55.9%) or biopsy only (RDF 66.7%) (P = 0.14). Similarly, a complimentary analysis focusing on tumor size (completely ablated, <1cm, 1-3cm or >3cm) prior to UGN-101 induction did not demonstrate significant differences in RDF rates (P = 0.17). CONCLUSION: The results of the early real-world experience suggest that UGN-101 may play a role in initial chemo-ablative cytoreduction of larger volume low-grade tumors that may not initially appear to be amenable to renal preservation. Further studies will help to better quantify the chemo-ablative effect and to identify clinical factors for patient selection.

Radical cystectomy versus trimodality therapy for muscle-invasive bladder cancer: a multi-institutional propensity score matched and weighted analysis.

BACKGROUND: Previous randomised controlled trials comparing bladder preservation with radical cystectomy for muscle-invasive bladder cancer closed due to insufficient accrual. Given that no further trials are foreseen, we aimed to use propensity scores to compare trimodality therapy (maximal transurethral resection of bladder tumour followed by concurrent chemoradiation) with radical cystectomy. METHODS: This retrospective analysis included 722 patients with clinical stage T2-T4N0M0 muscle-invasive urothelial carcinoma of the bladder (440 underwent radical cystectomy, 282 received trimodality therapy) who would have been eligible for both approaches, treated at three university centres in the USA and Canada between Jan 1, 2005, and Dec 31, 2017. All patients had solitary tumours less than 7 cm, no or unilateral hydronephrosis, and no extensive or multifocal carcinoma in situ. The 440 cases of radical cystectomy represent 29% of all radical cystectomies performed during the study period at the contributing institutions. The primary endpoint was metastasis-free survival. Secondary endpoints included overall survival, cancer-specific survival, and disease-free survival. Differences in survival outcomes by treatment were analysed using propensity scores incorporated in propensity score matching (PSM) using logistic regression and 3:1 matching with replacement and inverse probability treatment weighting (IPTW). FINDINGS: In the PSM analysis, the 3:1 matched cohort comprised 1119 patients (837 radical cystectomy, 282 trimodality therapy). After matching, age (71·4 years [IQR 66·0-77·1] for radical cystectomy vs 71·6 years [64·0-78·9] for trimodality therapy), sex (213 [25%] vs 68 [24%] female; 624 [75%] vs 214 [76%] male), cT2 stage (755 [90%] vs 255 [90%]), presence of hydronephrosis (97 [12%] vs 27 [10%]), and receipt of neoadjuvant or adjuvant chemotherapy (492 [59%] vs 159 [56%]) were similar between groups. Median follow-up was 4·38 years (IQR 1·6-6·7) versus 4·88 years (2·8-7·7), respectively. 5-year metastasis-free survival was 74% (95% CI 70-78) for radical cystectomy and 75% (70-80) for trimodality therapy with IPTW and 74% (70-77) and 74% (68-79) with PSM. There was no difference in metastasis-free survival either with IPTW (subdistribution hazard ratio [SHR] 0·89 [95% CI 0·67-1·20]; p=0·40) or PSM (SHR 0·93 [0·71-1·24]; p=0·64). 5-year cancer-specific survival for radical cystectomy versus trimodality therapy was 81% (95% CI 77-85) versus 84% (79-89) with IPTW and 83% (80-86) versus 85% (80-89) with PSM. 5-year disease-free survival was 73% (95% CI 69-77) versus 74% (69-79) with IPTW and 76% (72-80) versus 76% (71-81) with PSM. There were no differences in cancer-specific survival (IPTW: SHR 0·72 [95% CI 0·50-1·04]; p=0·071; PSM: SHR 0·73 [0·52-1·02]; p=0·057) and disease-free survival (IPTW: SHR 0·87 [0·65-1·16]; p=0·35; PSM: SHR 0·88 [0·67-1·16]; p=0·37) between radical cystectomy and trimodality therapy. Overall survival favoured trimodality therapy (IPTW: 66% [95% CI 61-71] vs 73% [68-78]; hazard ratio [HR] 0·70 [95% CI 0·53-0·92]; p=0·010; PSM: 72% [69-75] vs 77% [72-81]; HR 0·75 [0·58-0·97]; p=0·0078). Outcomes for radical cystectomy and trimodality therapy were not statistically different among centres for cancer-specific survival and metastasis-free survival (p=0·22-0·90). Salvage cystectomy was done in 38 (13%) trimodality therapy patients. Pathological stage in the 440 radical cystectomy patients was pT2 in 124 (28%), pT3-4 in 194 (44%), and 114 (26%) node positive. The median number of nodes removed was 39, the soft tissue positive margin rate was 1% (n=5), and the perioperative mortality rate was 2·5% (n=11). INTERPRETATION: This multi-institutional study provides the best evidence to date showing similar oncological outcomes between radical cystectomy and trimodality therapy for select patients with muscle-invasive bladder cancer. These results support that trimodality therapy, in the setting of multidisciplinary shared decision making, should be offered to all suitable candidates with muscle-invasive bladder cancer and not only to patients with significant comorbidities for whom surgery is not an option. FUNDING: Sinai Health Foundation, Princess Margaret Cancer Foundation, Massachusetts General Hospital.

Association of BCG Vaccine Treatment With Death and Dementia in Patients With Non-Muscle-Invasive Bladder Cancer.

Importance: The BCG vaccine-used worldwide to prevent tuberculosis-confers multiple nonspecific beneficial effects, and intravesical BCG vaccine is currently the recommended treatment for non-muscle-invasive bladder cancer (NMIBC). Moreover, BCG vaccine has been hypothesized to reduce the risk of Alzheimer disease and related dementias (ADRD), but previous studies have been limited by sample size, study design, or analyses. Objective: To evaluate whether intravesical BCG vaccine exposure is associated with a decreased incidence of ADRD in a cohort of patients with NMIBC while accounting for death as a competing event. Design, Setting, and Participants: This cohort study was performed in patients aged 50 years or older initially diagnosed with NMIBC between May 28, 1987, and May 6, 2021, treated within the Mass General Brigham health care system. The study included a 15-year follow-up of individuals (BCG vaccine treated or controls) whose condition did not clinically progress to muscle-invasive cancer within 8 weeks and did not have an ADRD diagnosis within the first year after the NMIBC diagnosis. Data analysis was conducted from April 18, 2021, to March 28, 2023. Main Outcomes and Measures: The main outcome was time to ADRD onset identified using diagnosis codes and medications. Cause-specific hazard ratios (HRs) were estimated using Cox proportional hazards regression after adjusting for confounders (age, sex, and Charlson Comorbidity Index) using inverse probability scores weighting. Results: In this cohort study including 6467 individuals initially diagnosed with NMIBC between 1987 and 2021, 3388 patients underwent BCG vaccine treatment (mean [SD] age, 69.89 [9.28] years; 2605 [76.9%] men) and 3079 served as controls (mean [SD] age, 70.73 [10.00] years; 2176 [70.7%] men). Treatment with BCG vaccine was associated with a lower rate of ADRD (HR, 0.80; 95% CI, 0.69-0.99), with an even lower rate of ADRD in patients aged 70 years or older at the time of BCG vaccine treatment (HR, 0.74; 95% CI, 0.60-0.91). In competing risks analysis, BCG vaccine was associated with a lower risk of ADRD (5-year risk difference, -0.011; 95% CI, -0.019 to -0.003) and a decreased risk of death in patients without an earlier diagnosis of ADRD (5-year risk difference, -0.056; 95% CI, -0.075 to -0.037). Conclusions and Relevance: In this study, BCG vaccine was associated with a significantly lower rate and risk of ADRD in a cohort of patients with bladder cancer when accounting for death as a competing event. However, the risk differences varied with time.

Impact of a negative confirmatory biopsy on risk of disease progression among men on active surveillance for prostate cancer.

OBJECTIVE: Most prostate cancer active surveillance (AS) protocols suggest a confirmatory biopsy within 12 to 18 months of diagnosis to mitigate the risk of unsampled high-grade disease. We investigate whether the results of confirmatory biopsy impact AS outcomes and could be used to tailor surveillance intensity. METHODS: We retrospectively reviewed our institutional database of prostate cancer patients managed by AS from 1997 to 2019 who underwent confirmatory biopsy and ≥3 biopsies overall. Biopsy progression was defined as either an increase in grade group or an increase in the proportion of positive biopsy cores to >34% and was compared between patients with a negative vs positive confirmatory biopsy using the Kaplan-Meier method and Cox proportional hazards regression. RESULTS: We identified 452 patients meeting inclusion criteria for this analysis, of whom 169 (37%) had a negative confirmatory biopsy. With a median follow-up of 6.8 years, 37% of patients progressed to treatment, most commonly due to biopsy progression. A negative confirmatory biopsy was significantly associated with biopsy progression-free survival in multivariable analysis (HR 0.54, 95% CI 0.34-0.88, P = 0.013), adjusting for known clinical and pathologic factors, including use of mpMRI prior to confirmatory biopsy. Negative confirmatory biopsy was also associated with an increased risk of adverse pathologic features at prostatectomy but not with biochemical recurrence among men who ultimately underwent definitive treatment. CONCLUSIONS: A negative confirmatory biopsy is associated with a lower risk of biopsy progression. While the increased risk of adverse pathology at time of definitive treatment sounds a small cautionary note regarding decreasing surveillance intensity, the majority of such patients have a favorable outcome on AS.

Impact of an Expanded Definition of Family History on Outcomes of Active Surveillance for Prostate Cancer.

PURPOSE: Despite family history being an established risk factor for prostate cancer, the role of a broader definition of family history inclusive of not just prostate cancer but other genetically related malignancies has not been investigated in the active surveillance population. Here, we evaluate the impact of an expanded definition of family history on active surveillance outcomes. MATERIALS AND METHODS: Patients undergoing active surveillance for prostate cancer at Massachusetts General Hospital from 1997-2019 with detailed data available on family cancer history were identified. Primary outcome was biopsy progression-free survival, and secondary outcomes were treatment-free survival, adverse pathological features at prostatectomy, and biochemical recurrence after treatment. Statistical analyses were conducted using the Kaplan-Meier method and Cox regression. RESULTS: Among 855 evaluable patients, 300 (35.1%) patients had any family history of prostate cancer, and 95 (11.1%) had a family history of related malignancies suggestive of a hereditary cancer syndrome. Family history of prostate cancer alone was not associated with biopsy progression, whereas family history suggestive of a hereditary cancer syndrome was associated with a significantly increased risk of biopsy progression (HR 1.43, 95%CI 1.01-2.02), independent of other known clinicopathological risk factors in multivariable analysis. Similarly, family history suggestive of a hereditary cancer syndrome was associated with significantly lower treatment-free survival (HR 1.58, 95%CI 1.14-2.18) in multivariable analysis. No significant association was found between family history and adverse features on surgical pathology or biochemical recurrence. CONCLUSIONS: An expanded family history suggestive of a hereditary cancer syndrome is an independent predictor of biopsy progression during active surveillance. Men with such a family history may still be offered active surveillance but should be counseled regarding the higher risk of disease progression.