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HER2, encoded by the ERBB2 gene, is an important druggable driver of human cancer gaining increasing importance as a therapeutic target in urothelial carcinoma (UC). The genomic underpinnings of HER2 overexpression in ERBB2 nonamplified UC are poorly defined. To address this knowledge gap, we investigated 172 UC tumors from patients treated at the University of California San Francisco, using immunohistochemistry and next-generation sequencing. We found that GATA3 and PPARG copy number gains individually predicted HER2 protein expression independently of ERBB2 amplification. To validate these findings, we interrogated the Memorial Sloan Kettering/The Cancer Genome Atlas (MSK/TCGA) dataset and found that GATA3 and PPARG copy number gains individually predicted ERBB2 mRNA expression independently of ERBB2 amplification. Our findings reveal a potential link between the luminal marker HER2 and the key transcription factors GATA3 and PPARG in UC and highlight the utility of examining GATA3 and PPARG copy number states to identify UC tumors that overexpress HER2 in the absence of ERBB2 amplification. In summary, we found that an increase in copy number of GATA3 and PPARG was independently associated with higher ERBB2 expression in patient samples of UC. This finding provides a potential explanation for HER2 overexpression in UC tumors without ERBB2 amplification and a way to identify these tumors for HER2-targeted therapies.
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Variações do Número de Cópias de DNA , Fator de Transcrição GATA3 , PPAR gama , Receptor ErbB-2 , Humanos , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Feminino , PPAR gama/genética , PPAR gama/metabolismo , Masculino , Neoplasias Urológicas/genética , Neoplasias Urológicas/patologia , Idoso , Pessoa de Meia-Idade , Amplificação de Genes , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Regulação Neoplásica da Expressão GênicaRESUMO
BACKGROUND: Women's sexual health after radical cystectomy is an important but poorly understood aspect of bladder cancer survivorship. Dedicated investigation is needed to elucidate patient perceptions on sexual function and dysfunction in this setting. AIMS: In this study we sought to qualitatively examine women's perceptions and experiences of sexual health following radical cystectomy for bladder cancer. METHODS: We conducted one-on-one qualitative telephone interviews with 40 women who underwent radical cystectomy in the past 6 months to 5 years and signed a research consent form to be contacted for future studies. We examined women's experiences of engaging in sexual activity after surgery and their attitudes toward sex and body image. We audio recorded, transcribed, and coded the interviews using ATLAS.ti software and applied grounded theory methods for analysis. OUTCOMES: For data that emerged during the qualitative interviews that was related to lack of knowledge about how physical and psychological sexual health would be affected after surgery, we reviewed and discussed transcripts that enabled coding of the data into emerging topic areas. RESULTS: Our analysis yielded 4 main themes. (1) Women reported receiving little to no information from providers about female sexual dysfunction prior to or after radical cystectomy. Women wished they had been provided more information about female sexual dysfunction from their clinicians, including strategies for postoperative self-pleasure and nonintercourse methods of sexual pleasure with partners. (2) Women shared that they were not sexually active following surgery due to physical and mental barriers. (3) When women did try to engage in sex, they described feeling disappointed that it did not feel the same as prior to surgery. (4) Some women found that physical therapy helped them to physically and mentally recover their strength to engage in sexual activity again. CLINICAL IMPLICATIONS: Clinicians must directly address sexual health concerns with patients who undergo radical cystectomy. STRENGTHS AND LIMITATIONS: This study has several key strengths. Investigation into women's sexual function and dysfunction addresses a gap in understanding of this component of women's health-related quality of life after radical cystectomy, which represents an unmet need. The large number of interviews conducted as well as the in-depth information obtained through one-on-one interviews are additional strengths. This study also has limitations, including possible shortcomings of telephone interviews compared with in-person interviews. However, telephone interviews were beneficial because the interviews took place during the COVID-19 pandemic and spared patients from extra visits or from having to travel long distances to the respective medical centers. Other possible limitations were that patients may have been reluctant to share all of their experiences and that patients who underwent urostomies, also termed ileal conduits, were overrepresented in this study compared with women who underwent continent urine diversions, which allow greater control over urine output. CONCLUSION: Broadening the understanding of sexual health beyond sexual intercourse to encompass sexuality and self-pleasure can provide clinicians, patients, and their families with more effective preparation and strategies to care for an essential aspect of their wellbeing.
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Cistectomia , Pesquisa Qualitativa , Comportamento Sexual , Disfunções Sexuais Fisiológicas , Neoplasias da Bexiga Urinária , Humanos , Feminino , Neoplasias da Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/psicologia , Disfunções Sexuais Fisiológicas/etiologia , Disfunções Sexuais Fisiológicas/psicologia , Pessoa de Meia-Idade , Idoso , Comportamento Sexual/psicologia , Imagem Corporal/psicologia , Saúde Sexual , Vagina/cirurgia , Entrevistas como Assunto , AdultoRESUMO
BACKGROUND: Financial toxicity of bladder cancer care may influence how patients utilize healthcare resources, from emergency department (ED) encounters to office visits. We aim to examine whether greater household net worth (HHNW) confers differential access to healthcare resources after radical cystectomy (RC). METHODS: This population-based cohort study examined the association between HHNW and healthcare utilization costs in the 90 days post-RC in commercially insured patients with bladder cancer. Costs accrued from the index hospitalization to 90 days after including health plan costs (HPC) and out-of-pocket costs (OPC). Multivariable logistic regression models were generated by encounter (acute inpatient, ED, outpatient, and office visit). RESULTS: A total of 141,903 patients were identified with HHNW categories near evenly distributed. Acute inpatient encounters incurred the greatest HPC and OPC. Office visits conferred the lowest HPC while ED visits had the lowest OPC. Black patients harbored increased odds of an acute inpatient encounter (OR 1.22, 95% CI 1.16-1.29) and ED encounter (OR 1.20, 95% CI 1.14-1.27) while Asian (OR 0.76, 95% CI 0.69-0.85) and Hispanic (OR 0.74, 95% CI 0.69-0.78, p < 0.001) patients had lower odds of an outpatient encounter, compared to White counterpart. Increasing HHNW was associated with decreasing odds of acute inpatient or ED encounters and greater odds of office visits. CONCLUSIONS: Lower HHNW conferred greater risk of costly inpatient encounters while greater HHNW had greater odds of less costly office visits, illustrating how financial flexibility fosters differences in healthcare utilization and lower costs. HHNW may serve as a proxy for financial flexibility and risk of financial hardship than income alone.
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Cistectomia , Neoplasias da Bexiga Urinária , Humanos , Estados Unidos , Estudos de Coortes , Declarações Financeiras , Custos de Cuidados de Saúde , Neoplasias da Bexiga Urinária/cirurgia , Estudos Retrospectivos , Serviço Hospitalar de EmergênciaRESUMO
BACKGROUND: The gold standard for detecting bladder cancer is cystoscopy with biopsy or transurethral resection confirming histologic diagnosis. URO17® employs a chromogenically labeled monoclonal antibody to keratin 17 (k17), an intermediate filament cytoskeleton molecule associated with bladder, pancreatic, and cervical cancers. Preliminary studies evaluating k17 demonstrated a high sensitivity and specificity for the detection of bladder cancer, supporting the need for further study. OBJECTIVE: To evaluate the sensitivity and specificity of URO17. METHODS: This is a cross-sectional study of participants undergoing urologic procedures between July 6, 2018 and July 17, 2019 at a single institution. Patients undergoing cystectomy, endoscopic bladder and/or upper tract procedure for probable urothelial carcinoma comprised cases; patients undergoing urologic procedures for other reasons comprised the control group (i.e. prostatectomy, nephrectomy, etc.). Voided urine samples were at the time of procedure; a minority of participants underwent multiple resections in the study period, thus, as many as three urine samples were taken from any given participant. Samples were distributed for blinded testing with URO17. Sensitivity and specificity were calculated. RESULTS: In 152 participants and 167 samples, URO17 demonstrated an overall sensitivity of 90% and 92% and a specificity of 88% and 87%, respectively. In 76 participants and 91 samples from patients with suspected urothelial carcinoma, the sensitivity was 90% and 92%, and the specificity was 50% and 54%, respectively. No controls demonstrated a positive URO17 result, and URO17 superseded urine cytology detection of low-grade and high-grade Ta. False positive results were associated with inflamed tissue or urothelial atypia on histology; the large majority had a history of intravesical therapy. CONCLUSION: Limitations include cross-sectional design and convenience sampling. URO17 may improve sensitivity of urine cytology in the detection of urothelial cancer, though further study is required to refine the application of this biomarker in clinical practice.
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Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/urina , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/patologia , Masculino , Estudos Transversais , Feminino , Idoso , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Biomarcadores Tumorais/urina , Biomarcadores Tumorais/análise , Idoso de 80 Anos ou maisRESUMO
Improved imaging modalities are needed to accurately stage patients with muscle-invasive bladder cancer (MIBC) and metastatic urothelial carcinoma. Imaging with small-molecule ligands or inhibitors of fibroblast activation protein (FAP) is a promising modality that has demonstrated initial efficacy across a broad range of tumors. We present our experience with the novel FAP-peptide binder 68Ga-FAP-2286 in patients with MIBC. Methods: Patients with histopathologically confirmed bladder cancer who had either localized disease at diagnosis (localized cohort, n = 13) or known metastatic disease (metastatic cohort, n = 8) were imaged with 68Ga-FAP-2286 PET as part of a clinical trial (NCT04621435). The SUVmax of 68Ga-FAP-2286 PET-positive lesions and lesion size were documented. In patients who had available 18F-FDG PET performed within 45 d of 68Ga-FAP-2286 PET (n = 5), uptake on the 2 scans was compared. When there was a discrepancy between imaging modalities on retrospective review, biopsy of suggestive lesions was performed as the standard of care. Results: In the metastatic and localized cohorts, 36 and 18 68Ga-FAP-2286-avid lesions, respectively, were identified across multiple anatomic locations, including lymph nodes, visceral metastases, and bones. Fourteen of 36 lesions in the metastatic cohort and 14 of 18 lesions in the localized cohort were lymph nodes measuring less than 1 cm. Among lesions measuring less than 0.5 cm, 0.5-1 cm, and more than 1 cm, average SUVmax was 5.2 ± 2.6, 9.6 ± 3.7, and 13.0 ± 4.3, respectively, in the metastatic cohort and 10.5 ± 5.1, 10.8 ± 5.7, and 9.9 ± 5.4, respectively, in the localized cohort. Five patients had 18F-FDG PET available for comparison. The average SUVmax for lesions avid on 68Ga-FAP-2286 PET and 18F-FDG PET was 9.9 ± 3.4 versus 4.2 ± 1.9, respectively (n = 16 lesions). For 3 patients in the localized cohort, 68Ga-FAP-2286 PET informed clinical management, including identification of both false-positive findings on 18F-FDG PET and false-negative findings on conventional CT. Conclusion: 68Ga-FAP-2286 imaging is highly sensitive in patients with urothelial cancer and is effective in identifying metastatic lesions across a variety of anatomic sites, including subcentimeter lymph nodes that would not have raised suspicion on conventional scans. This novel imaging modality may inform clinical decision-making in patients with MIBC both by refining local nodal staging and by defining metastatic disease that would otherwise be undetectable on conventional imaging.
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Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Humanos , Radioisótopos de Gálio , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Neoplasias da Bexiga Urinária/diagnóstico por imagem , Tomografia por Emissão de PósitronsRESUMO
OBJECTIVE: To explore factors associated with productivity in urologic practice. Work-relative value units (wRVUs), the basis for Center for Medicare & Medicaid Services (CMS) and private payer reimbursements, commonly serve to estimate physician productivity. Limited data describes which practice factors predict increased wRVU productivity. METHODS: The 2017 and 2018 CMS databases were retrospectively queried for urologic Medicare provider demographics and procedural/service details. Medical school graduation year was used to estimate years in practice and generation (Millennial, Gen X, Baby Boomer, or Post-War). Treated patients' demographics were obtained. Adjusted and unadjusted linear mixed models were performed to predict wRVU production. RESULTS: Included were 6773 Medicare-participating urologists across the United States. Millennials produced 1115 wRVUs per year, while Gen X and Baby Boomers produced significantly more (1997 and 2104, respectively, P <.01). Post-War urologists produced numerically more (1287, P = .88). In adjusted analyses, predictors of Medicare wRVU productivity included female and pelvic medicine and reconstructive surgery (exponentiated beta estimate (ß) 1.46, 95% CI 1.32-1.60), men's health (ß 1.22, 95% CI 1.13-1.32), and oncologic subspecialization (ß 1.08, 95% CI 1.02-1.14), female gender (ß 0.87, 95% CI 0.82-0.92), wRVUs generated from inpatient procedures (ß 1.08, 95% CI 1.06-1.09) and office visits (ß 0.88, 95% CI 0.87-0.89), and the level of education (ß 1.10, 95% CI 1.07-1.14) and percent impoverished patients (ß 0.85, 95% CI 0.83-0.88) in provider's practice zip code. CONCLUSION: Urologic experience, specialization, demographics, practice patterns, and patient demographics are significantly associated with wRVU productivity in Medicare settings. Further work should incorporate quality metrics into wRVUs and ensure patient demographics do not affect reimbursement.
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There are multiple ongoing and planned clinical trials that are evaluating novel therapies to treat patients with BCG-unresponsive high grade nonmuscle invasive bladder cancer (NMIBC). Importantly, there is considerable variation in surveillance strategies between these clinical trials, specifically with regards to the use of advanced imaging, enhanced cystoscopy, and mandatory biopsies, which could impact landmark efficacy assessments of investigational agents. To present guideline recommendations for the standardization of cystoscopic evaluation, surveillance, and efficacy assessments for patients with BCG-unresponsive NMIBC participating in clinical trials. On September 29, 2023 at the annual meeting of the International Bladder Cancer Network, a breakout session was convened, during which representatives from various disciplines discussed potential guidance statements with opportunity for discussion and comment. A set of statements regarding use of white light and enhanced cystoscopy were developed to help guide a pragmatic approach to surveillance and efficacy assessments of patients in clinical trials. The use of "for cause" and "mandatory" biopsies was also addressed. A standard approach to evaluation of patients within the context of clinical trials is necessary to accurately assess the efficacy of novel agents, especially within single arm trials that lack an appropriate comparator. Additionally, the utilization and timing of mandatory biopsies is critical, as these biopsies may impact both disease evaluations and the determination of duration of response.
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Vacina BCG , Ensaios Clínicos como Assunto , Neoplasias da Bexiga Urinária , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/terapia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Humanos , Vacina BCG/uso terapêutico , Invasividade Neoplásica , Gradação de Tumores , Cistoscopia/métodos , Neoplasias não Músculo Invasivas da BexigaRESUMO
The use of blue light cystoscopy (BLC) has been shown to improve bladder tumor detection. However, data demonstrating the efficacy of BLC across different races are limited. Herein, we aim to evaluate heterogeneity in the characteristics of BLC for the detection of malignant lesions among various races. Clinicopathologic information was collected from patients enrolled in the multi-institutional Cysview® registry (2014-2021) who underwent transurethral resection or biopsy of bladder tumors. Outcome variables included sensitivity and negative and positive predictive values of BLC and white light cystoscopy (WLC) for the detection of malignant lesions among various races. Overall, 2379 separate lesions/tumors were identified from 1292 patients, of whom 1095 (85%) were Caucasian, 96 (7%) were African American, 51 (4%) were Asian, and 50 (4%) were Hispanic. The sensitivity of BLC was higher than that of WLC in the total cohort, as well as in the Caucasian and Asian subgroups. The addition of BLC to WLC increased the detection rate by 10% for any malignant lesion in the total cohort, with the greatest increase in Asian patients (18%). Additionally, the positive predictive value of BLC was highest in Asian patients (94%), while Hispanic patients had the highest negative predictive value (86%). Our study showed that regardless of race, BLC increases the detection of bladder cancer when combined with WLC.
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PURPOSE: There is significant interest in identifying complete responders to neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) to potentially avoid removal of a pathologically benign bladder. However, clinical restaging after NAC is highly inaccurate. The objective of this study was to develop a next-generation sequencing-based molecular assay using urine to enhance clinical staging of patients with bladder cancer. METHODS: Urine samples from 20 and 44 patients with bladder cancer undergoing RC were prospectively collected for retrospective analysis for molecular correlate analysis from two clinical trials, respectively. The first cohort was used to benchmark the assay, and the second was used to determine the performance characteristics of the test as it correlates to responder status as measured by pathologic examination. RESULTS: First, to benchmark the assay, known mutations identified in the tissue (MT) of patients from the Accelerated Methotrexate, Vinblastine, Doxorubicin, Cisplatin trial (ClinicalTrials.gov identifier: NCT01611662, n = 16) and a cohort from University of California-San Francisco (n = 4) were cross referenced against mutation profiles from urine (MU). We then determined the correlation between MU persistence and residual disease in pre-RC urine samples from a second prospective clinical trial (The pT0 trial; ClinicalTrials.gov identifier: NCT02968732). Residual MU status correlated strongly with residual disease status (pT0 trial; n = 44; P = .0092) when MU from urine supernatant and urine pellet were assessed separately and analyzed in tandem. The sensitivity, specificity, PPV, and NPV were 91%, 50%, 86%, and 63% respectively, with an overall accuracy of 82% for this second cohort. CONCLUSION: MU are representative of MT and thus can be used to enhance clinical staging of urothelial carcinoma. Urine biopsy may be used as a reliable tool that can be further developed to identify complete response to NAC in anticipation of safe RC avoidance.
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Biomarcadores Tumorais , Cistectomia , Estadiamento de Neoplasias , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/urina , Neoplasias da Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Biomarcadores Tumorais/urina , Biópsia , Estudos Retrospectivos , Terapia NeoadjuvanteRESUMO
BACKGROUND: Few studies have specifically examined sleep health in patients with non-muscle invasive bladder cancer (NMIBC). Further study is warranted to inform future strategies in patients with NMIBC. OBJECTIVE: We aim to describe sleep health in a cohort of patients with NMIBC, and its relationship with quality of life (QOL). METHODS: We conducted an observational cross-sectional study in patients undergoing surveillance for NMIBC. The validated Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep health (scores from 0-21) in the overall study population as well as stratified. We assessed QOL among participants with and without poor sleep quality using the SF-12 and QLQ-NMIBC-24. RESULTS: In a cohort of 94 NMIBC patients, median age was 67 years (IQR: 58, 72) and median time since initial diagnosis was 27 months (IQR: 9, 41). The mean PSQI score was 6.3 (SD: 3.8) and 64% percent of participants met or exceeded the PSQI cut-off score of 5, with a score of 5 or more indicating overall poor sleep quality. In those with poor sleep quality, there were statistically significant detriments in multiple QOL domains. CONCLUSIONS: In patients undergoing surveillance for NMIBC, there is a substantial burden of sleep disturbances and resulting decrements in QOL. These data support the need for future interventions to support sleep quality and highlight the importance of addressing sleep health as part of NMIBC survivorship care to improve QOL in patients with NMIBC.
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BACKGROUND: Despite recent drug development for non-muscle invasive bladder cancer (NMIBC), few therapies have been approved by the US Food and Drug Administration (FDA), and there remains an unmet clinical need. Bacillus Calmette-Guerin (BCG) supply issues underscore the importance of developing safe and effective drugs for NMIBC. OBJECTIVE: On November 18-19, 2021, the FDA held a public virtual workshop to discuss NMIBC research needs and potential trial designs for future development of effective therapies. METHODS: Representatives from various disciplines including urologists, oncologists, pathologists, statisticians, basic and translational scientists, and the patient advocacy community participated. The workshop format included invited lectures, panel discussions, and opportunity for audience discussion and comment. RESULTS: In a pre-workshop survey, 92% of urologists surveyed considered the development of alternatives to BCG as a high drug development priority for BCG-naïve high-risk patients. Key topics discussed included definitions of disease states; trial design for BCG-naïve NMIBC, BCG-unresponsive carcinoma in situ, and BCG-unresponsive papillary carcinoma; strengths and limitations of single-arm trial designs; assessing patient-reported outcomes; and considerations for assessing avoidance of cystectomy as an efficacy measure. CONCLUSIONS: The workshop discussed several important opportunities for trial design refinement in NMIBC. FDA encourages sponsors to meet with the appropriate review division to discuss trial design proposals for NMIBC early in drug development.