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1.
J Urol ; 211(2): 241-255, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37922370

RESUMO

PURPOSE: The treated natural history of nonmetastatic plasmacytoid variant of bladder cancer (PV-BCa) is poorly understood owing to its rarity. We sought to examine the disease recurrence and metastasis patterns in this select group of patients in order to identify opportunities for intervention. MATERIALS AND METHODS: We conducted a natural language processing algorithm-augmented retrospective chart review of 56 consecutive patients who were treated with curative intent for nonmetastatic PV-BCa at our institution between 1998 and 2018. Kaplan-Meier and multivariable Cox regression methods were used for survival analyses. RESULTS: The stage at presentation was: ≤ cT2N0 in 22 (39.3%), cT3N0 in 15 (26.8%), cT4N0 in 13 (23.2%), and ≥ cN1 in 6 patients (10.7%). Forty-nine patients (87.5%) received chemotherapy, and 42 (75%) were able to undergo the planned surgery. Notably, only 4 patients (7.2%) had pT0 stage, while 22 (52.4%) had pN+ disease at the time of surgery. At 36-month follow-up, 28.4% of patients (95% CI: 22.1%-34.5%) were alive and 22.2% (95% CI: 16.1%-28.5%) were free of metastatic disease. The benefit of surgical extirpation was stage specific: successful completion of surgery was associated with improved metastasis-free survival (at 36 months 32.4% vs 0%, log-rank P < .001) in patients with localized or locally advanced disease (≤cT2N0/cT3N0); however, in patients with regionally advanced disease (cT4N0/≥cN1), consolidative surgery following chemotherapy was not associated with improved metastasis-free survival (12.5% vs 10% at 36 months, log-rank P = .49). The median time to metastasis from primary treatment end was 6.5 months (IQR: 2.9-14.7). The predominant site of recurrence/metastasis was the peritoneum (76.1%), either in isolation or along with extraperitoneal lesions. Salvage immunotherapy in these patients significantly reduced the risk of death (HR = 0.11, P = .001). CONCLUSIONS: PV-BCa is a disease with high lethality. Despite multimodal treatment, a vast majority of patients develop atypical intraperitoneal metastasis soon after therapy and rapidly succumb to it. Clinical trials evaluating utility of hyperthermic intraperitoneal chemotherapy and/or immunotherapy may be warranted in this high-risk population.


Assuntos
Recidiva Local de Neoplasia , Neoplasias da Bexiga Urinária , Humanos , Estudos Retrospectivos , Recidiva Local de Neoplasia/epidemiologia , Neoplasias da Bexiga Urinária/terapia , Neoplasias da Bexiga Urinária/patologia , Terapia Combinada , Resultado do Tratamento
2.
J Urol ; 212(1): 74-86, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38704840

RESUMO

PURPOSE: Nadofaragene firadenovec-vncg is a nonreplicating adenoviral vector-based gene therapy for bacillus Calmette-Guérin (BCG)-unresponsive carcinoma in situ (CIS) with/without high-grade Ta/T1. We report outcomes following 5 years of planned follow-up. MATERIALS AND METHODS: This open-label phase 3 trial (NCT02773849) enrolled patients with BCG-unresponsive nonmuscle-invasive bladder cancer in 2 cohorts: CIS ± Ta/T1 (CIS; n = 107) and Ta/T1 without CIS (Ta/T1 cohort; n = 50). Patients received 75 mL (3 × 1011 vp/mL) nadofaragene firadenovec intravesically once every 3 months with cystoscopy and cytology assessments, with continued treatment offered to those remaining high grade recurrence-free (HGRF). RESULTS: One hundred fifty-seven patients were enrolled from 33 US sites (n = 151 included in efficacy analyses). Median follow-up was 50.8 months (interquartile range 39.1-60.0), with 27% receiving ≥ 5 instillations and 7.6% receiving treatment for ≥ 57 months. Of patients with CIS 5.8% (95% CI 2.2-12.2) were HGRF at month 57, and 15% (95% CI 6.1-27.8) of patients with high-grade Ta/T1 were HGRF at month 57. Kaplan-Meier-estimated HGRF survival at 57 months was 13% (95% CI 6.9-21.5) and 33% (95% CI 19.5-46.6) in the CIS and Ta/T1 cohorts, respectively. Cystectomy-free survival at month 60 was 49% (95% CI 40.0-57.1): 43% (95% CI 32.2-53.7) in the CIS cohort and 59% (95% CI 43.1-71.4) in the Ta/T1 cohort. Overall survival at 60 months was 80% (71.0, 86.0): 76% (64.6-84.5) and 86% (70.9-93.5) in the CIS and Ta/T1 cohorts, respectively. Only 5 patients (4 with CIS and 1 with Ta/T1) experienced clinical progression to muscle-invasive disease. CONCLUSIONS: At 60 months, nadofaragene firadenovec-vncg allowed bladder preservation in nearly half of the patients and proved to be a safe option for BCG-unresponsive nonmuscle-invasive bladder cancer.


Assuntos
Vacina BCG , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/terapia , Neoplasias da Bexiga Urinária/mortalidade , Masculino , Feminino , Vacina BCG/administração & dosagem , Vacina BCG/uso terapêutico , Administração Intravesical , Seguimentos , Idoso , Pessoa de Meia-Idade , Carcinoma in Situ/patologia , Carcinoma in Situ/terapia , Carcinoma in Situ/tratamento farmacológico , Invasividade Neoplásica , Resultado do Tratamento , Adenoviridae/genética , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/uso terapêutico , Idoso de 80 Anos ou mais
3.
Lancet Oncol ; 22(1): 107-117, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33253641

RESUMO

BACKGROUND: BCG is the most effective therapy for high-risk non-muscle-invasive bladder cancer. Nadofaragene firadenovec (also known as rAd-IFNa/Syn3) is a replication-deficient recombinant adenovirus that delivers human interferon alfa-2b cDNA into the bladder epithelium, and a novel intravesical therapy for BCG-unresponsive non-muscle-invasive bladder cancer. We aimed to evaluate its efficacy in patients with BCG-unresponsive non-muscle-invasive bladder cancer. METHODS: In this phase 3, multicentre, open-label, repeat-dose study done in 33 centres (hospitals and clinics) in the USA, we recruited patients aged 18 years or older, with BCG-unresponsive non-muscle-invasive bladder cancer and an Eastern Cooperative Oncology Group status of 2 or less. Patients were excluded if they had upper urinary tract disease, urothelial carcinoma within the prostatic urethra, lymphovascular invasion, micropapillary disease, or hydronephrosis. Eligible patients received a single intravesical 75 mL dose of nadofaragene firadenovec (3 × 1011 viral particles per mL). Repeat dosing at months 3, 6, and 9 was done in the absence of high-grade recurrence. The primary endpoint was complete response at any time in patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour). The null hypothesis specified a complete response rate of less than 27% in this cohort. Efficacy analyses were done on the per-protocol population, to include only patients strictly meeting the BCG-unresponsive definition. Safety analyses were done in all patients who received at least one dose of treatment. The study is ongoing, with a planned 4-year treatment and monitoring phase. This study is registered with ClinicalTrials.gov, NCT02773849. FINDINGS: Between Sept 19, 2016, and May 24, 2019, 198 patients were assessed for eligibility. 41 patients were excluded, and 157 were enrolled and received at least one dose of the study drug. Six patients did not meet the definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore excluded from efficacy analyses; the remaining 151 patients were included in the per-protocol efficacy analyses. 55 (53·4%) of 103 patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour) had a complete response within 3 months of the first dose and this response was maintained in 25 (45·5%) of 55 patients at 12 months. Micturition urgency was the most common grade 3-4 study drug-related adverse event (two [1%] of 157 patients, both grade 3), and there were no treatment-related deaths. INTERPRETATION: Intravesical nadofaragene firadenovec was efficacious, with a favourable benefit:risk ratio, in patients with BCG-unresponsive non-muscle-invasive bladder cancer. This represents a novel treatment option in a therapeutically challenging disease state. FUNDING: FKD Therapies Oy.


Assuntos
Adenoviridae/genética , Vacina BCG/administração & dosagem , Carcinoma in Situ/terapia , Resistencia a Medicamentos Antineoplásicos , Terapia Genética , Vetores Genéticos , Interferon alfa-2/genética , Neoplasias da Bexiga Urinária/terapia , Administração Intravesical , Idoso , Vacina BCG/efeitos adversos , Carcinoma in Situ/genética , Carcinoma in Situ/mortalidade , Carcinoma in Situ/patologia , Progressão da Doença , Feminino , Terapia Genética/efeitos adversos , Terapia Genética/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Recidiva Local de Neoplasia , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologia
4.
J Urol ; 205(6): 1612-1621, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33502236

RESUMO

PURPOSE: Recurrent disease after bacillus Calmette-Guérin treatment presents a therapeutic challenge. To aid trial development, the U.S. Food and Drug Administration defined "adequate bacillus Calmette-Guérin" therapy and adopted the "bacillus Calmette-Guérin unresponsive" disease state. Available data for efficacy benchmark comparison are outdated, leading to concerns about appropriate control arms and sample size calculations. We describe a contemporary cohort of patients with nonmuscle-invasive bladder cancer treated with intravesical bacillus Calmette-Guérin, and provide benchmark outcomes data. MATERIALS AND METHODS: We retrospectively reviewed patients receiving adequate bacillus Calmette-Guérin therapy at a tertiary cancer center between January 2004 and August 2018. Unadjusted univariable analysis was conducted using the Pearson chi-square test. Kaplan-Meier estimates for recurrence-free survival-high grade, progression-free survival-muscle-invasive bladder cancer and overall survival were used to create survival curves and compared using the log-rank test. RESULTS: Of the 542 patients who received adequate bacillus Calmette-Guérin, 518 (90%) had European Association Urology high risk disease, with carcinoma in situ present in 175 (32%). With a median followup of 47.8 months, freedom from high grade recurrence at 1, 3 and 5 years was 81%, 76% and 74%, respectively, and progression-free survival was 97%, 93% and 92%. Progression to muscle invasion at 5 years was exclusively seen in patients with high risk disease (progression-free survival 91%; log-rank test, p=0.024). CONCLUSIONS: A contemporary cohort of patients with nonmuscle-invasive bladder cancer treated with adequate bacillus Calmette-Guérin demonstrated markedly better outcomes than seen in prior studies. These data could be used in the design of clinical trials, to guide power calculations, as well as serve as benchmarks for comparison to evaluate nonrandomized studies.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Vacina BCG/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Idoso , Ensaios Clínicos como Assunto/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Projetos de Pesquisa , Estudos Retrospectivos , Resultado do Tratamento , Neoplasias da Bexiga Urinária/patologia
5.
BJU Int ; 128(5): 568-574, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-33484074

RESUMO

OBJECTIVE: To evaluate the impact of upper tract urothelial carcinoma (UTUC) on bacillus Calmette-Guerin (BCG) response and progression in patients with non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: We performed an institutional review board-approved review of patients with NMIBC treated with adequate intravesical BCG, as defined by the US Food and Drug Administration, at our institution between 2000 and 2018. Patients were stratified by presence of any UTUC and time of UTUC diagnosis (preceding vs synchronous to NMIBC diagnosis or metachronous disease after NMIBC diagnosis). Descriptive statistics were used to summarize the data overall and by groups, and t-tests or Wilcoxon's rank sum tests and Pearson's chi-squared or Fisher's exact tests were used to analyse continuous and categorical data, respectively. RESULTS: Of 541 patients with NMIBC treated with adequate BCG, 59 (10.9 %) were diagnosed with UTUC. Of these, 34 had a history of UTUC prior to NMIBC (UTUC-P; median [interquartile range {IQR}] 13.1 [7.4-27.6] months prior), while 25 developed UTUC after diagnosis of NMIBC (six synchronous and 19 metachronous; median [IQR] 12.1 [1.7-28.1] months after). Compared to the non-UTUC group, patients with UTUC-P were more likely to exhibit Tis without papillary tumour in the bladder (20.6% vs 5.0%; P < 0.001), but were less likely to have T1 disease on index transurethral resection (8.8% vs 49.4%; P < 0.001). Patients with UTUC-P developed more recurrences (55.9% vs 34.0%; P = 0.010), any stage/grade progression (23.5% vs 9.8%; P = 0.012) and progression to muscle-invasive or metastatic disease (17.6% vs 6.4%; P = 0.014). The presence of high-grade UTUC-P compared to low-grade UTUC-P was associated with increased NMIBC recurrence (68.2% vs 25.0%; P = 0.049). There was no significant difference in rates of recurrence or progression based on timing of UTUC with respect to the index bladder tumour, although this analysis was limited by small numbers. CONCLUSIONS: Presence of UTUC prior to a diagnosis of NMIBC was associated with an almost twofold increased recurrence and progression rates after adequate BCG therapy. This should be considered when counselling patients and designing cohorts for clinical trials.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Vacina BCG/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/patologia , Neoplasias Renais/patologia , Recidiva Local de Neoplasia/patologia , Segunda Neoplasia Primária/patologia , Neoplasias Ureterais/patologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Idoso , Carcinoma de Células de Transição/secundário , Carcinoma de Células de Transição/cirurgia , Progressão da Doença , Feminino , Humanos , Pelve Renal , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Fatores de Risco , Fatores de Tempo , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/cirurgia
6.
BJU Int ; 128(1): 65-71, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33210440

RESUMO

OBJECTIVES: To evaluate if the obesity paradox, wherein obesity portends worse overall prognosis for a disease but improved outcomes for patients receiving immunotherapy, exists for patients receiving bacillus Calmette-Guérin (BCG) in a contemporary cohort. PATIENTS AND METHODS: We performed an Institutional Review Board-approved database review to identify patients with non-muscle-invasive bladder cancer (NMIBC) completing at least an induction course of BCG. Clinicopathological variables collected included: body mass index (BMI), medications, and diabetes mellitus (DM). Outcomes of interest included: recurrence-free (RFS), progression-free (PFS), cancer-specific (CSS), and overall survival (OS). Univariate and multivariate modelling were used to evaluate the association between outcomes and clinical factors. RESULTS: A total of 579 patients (median follow-up 4.6 years) received BCG induction for NMIBC; 90% had high-grade disease (47.2% clinical stage T1). In all, 75.7% of patients were overweight or obese and 18% had DM. Aspirin, statins, metformin and ß-blockers were used in 34%, 42%, 11%, and 29% of patients, respectively. Overweight and obese patients had improved PFS, CSS and OS. DM was associated with worse RFS. Medications of interest had no association with outcomes. CONCLUSION: Elevated BMI is associated with improved outcomes in patients with NMIBC treated with BCG immunotherapy. Patients with DM are at increased risk of recurrence. These findings support a potential obesity paradox in bladder cancer. Evaluation of the underlying mechanism and the role of global patient assessment, counselling, and risk factor modification are warranted.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Vacina BCG/uso terapêutico , Índice de Massa Corporal , Complicações do Diabetes/complicações , Obesidade/complicações , Neoplasias da Bexiga Urinária/complicações , Neoplasias da Bexiga Urinária/tratamento farmacológico , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estudos Retrospectivos , Resultado do Tratamento , Neoplasias da Bexiga Urinária/patologia
7.
J Sex Med ; 17(10): 1995-2004, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32713807

RESUMO

BACKGROUND: Cancer-related changes in sexual function (SF) negatively impact quality of life and intimate partner relationships. There is a lack of data regarding SF among patients who underwent radical cystectomy (RC). AIM: To comparatively evaluate perioperative SF among patients who underwent RC. METHODS: A prospective cohort of 150 patients undergoing RC for bladder cancer and participating in an internal validation study at a single institution from 2016 to 2019 were eligible for analysis. The European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire-Bladder Cancer Muscle Invasive (EORTC QLQ-BLM 30) and Functional Assessment of Cancer Therapy-Bladder were administered; those completing the SF subscale of the EORTC QLQ-BLM 30 were included in final analysis. Analysis was performed using descriptive statistics and generalized linear modeling. OUTCOMES: The primary outcome was interest or engagement in sexual activity within 4 weeks of survey completion, whereas the secondary outcome was a mean score on the EORTC QLQ-BLM 30 SF subscale. RESULTS: Overall, 132 of 150 (88%) of patients were eligible, of whom 82% were male, and the median age was 68.5 years. 53% reported at least a little interest in sexual activity, and 40% endorsed sexual activity within the last 4 weeks. The mean SF subscale score was 61.5 ± 25.2. Women had significantly worse mean scores of 72.9 ± 27.1 versus 59.1 ± 24.2 for men (P = .02). On multivariate analysis, both age and female gender were independently associated with higher SF domain scores. CLINICAL IMPLICATIONS: A substantial portion of patients who underwent RC endorse being sexually active or express interest in sexually activity in the perioperative period. Given the recent increase in attention given to SF outcomes and quality of life, this work supports further efforts to explore this area and develop novel interventions to improve outcomes. STRENGTHS AND LIMITATIONS: Strengths include rigorously collected, cross-sectional data using standardized methodology. Limitations include a relatively small sample size of female patients and unknown meaningful clinical difference. CONCLUSIONS: A substantial portion of patients report sexual interest and activity in the perioperative period; however, female gender is associated with worse SF domain scores. These findings support further inquiry into this topic. Westerman ME, Kokorovic A, Wang XS, et al. Radical Cystectomy and Perioperative Sexual Function: A Cross-Sectional Analysis. J Sex Med 2020;17:1995-2004.


Assuntos
Cistectomia , Disfunções Sexuais Fisiológicas , Neoplasias da Bexiga Urinária , Idoso , Estudos Transversais , Cistectomia/efeitos adversos , Feminino , Humanos , Masculino , Período Perioperatório , Estudos Prospectivos , Qualidade de Vida , Disfunções Sexuais Fisiológicas/etiologia , Neoplasias da Bexiga Urinária/cirurgia
9.
BJU Int ; 119(5): 684-691, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-27753185

RESUMO

OBJECTIVE: To analyse survival in patients with clinically localised, surgically resectable micropapillary bladder cancer (MPBC) undergoing radical cystectomy (RC) with and without neoadjuvant chemotherapy (NAC) and develop risk strata based on outcome data. PATIENTS AND METHODS: A review of our database identified 103 patients with surgically resectable (≤cT4acN0 cM0) MPBC who underwent RC. Survival estimates were calculated using Kaplan-Meier method and compared using log-rank tests. Classification and regression tree (CART) analysis was performed to identify risk groups for survival. RESULTS: For the entire cohort, estimated 5-year overall survival and disease-specific survival (DSS) rates were 52% and 58%, respectively. CART analysis identified three risk subgroups: low-risk: cT1, no hydronephrosis; high-risk: ≥cT2, no hydronephrosis; and highest-risk: cTany with tumour-associated hydronephrosis. The 5-year DSS for the low-, high-, and highest-risk groups were 92%, 51%, and 17%, respectively (P < 0.001). Patients down-staged at RC

Assuntos
Carcinoma Papilar/cirurgia , Cistectomia , Neoplasias da Bexiga Urinária/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Papilar/tratamento farmacológico , Carcinoma Papilar/mortalidade , Quimioterapia Adjuvante , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estudos Retrospectivos , Medição de Risco , Taxa de Sobrevida , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/mortalidade
11.
Ann Surg Oncol ; 23(12): 4110-4114, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27387678

RESUMO

BACKGROUND: A phase 1b trial was conducted to evaluate the duration of interferon-alpha (IFNα) production after intravesical administration of recombinant adenovirus-mediated interferon α2b (Ad-IFN) formulated with the excipient Syn3. The primary aim was to determine whether a second instillation 3 days after initial treatment produced prolonged urinary IFN production. METHODS: The study enrolled seven patients who experienced recurrent non-muscle invasive bladder cancer after bacillus Calmette-Guerin therapy. Each treatment consisted of intravesical instillation of SCH721015 (Syn3) and Ad-IFN at a concentration of 3 × 1011 particles/mL to a total volume of 75 mL given on days 1 and 4. The patients were followed for 12 weeks, during which the magnitude and duration of gene transfer were determined by urine INFα levels. Drug efficacy was determined by cystoscopy and biopsy, and patients who had no recurrence at 12 weeks were eligible for a second course of treatment. RESULTS: Seven patients were treated with an initial course (instillation on days 1 and 4). Two of the patients had a complete response at 12 weeks and received a second course of treatment. One patient remained without evidence of recurrence after a second course (total 24 weeks). One patient experienced a non-treatment-associated adverse event. Despite a transient rise in IFNα levels, sustained production was not demonstrated. CONCLUSION: Previously, Ad-IFNα intravesical therapy has shown promising drug efficacy. A prior phase 1 trial with a single instillation compared similarly with the current study, suggesting that a second instillation is not necessary to achieve sufficient urinary IFNα levels.


Assuntos
Terapia Genética/métodos , Interferon-alfa/administração & dosagem , Recidiva Local de Neoplasia/cirurgia , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/terapia , Adenoviridae/genética , Administração Intravesical , Idoso , Idoso de 80 Anos ou mais , Vacina BCG/uso terapêutico , Ácidos Cólicos , Dissacarídeos , Relação Dose-Resposta a Droga , Esquema de Medicação , Excipientes , Vetores Genéticos , Humanos , Interferon alfa-2 , Interferon-alfa/genética , Interferon-alfa/urina , Masculino , Invasividade Neoplásica , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/genética , Falha de Tratamento
12.
J Urol ; 194(6): 1771-6, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26173102

RESUMO

PURPOSE: Genetic factors that influence bladder cancer risk remain largely unknown. Previous research has suggested that there is a strong genetic component underlying the risk of bladder cancer. The Wnt/ß-catenin signaling pathway is a key modulator of cellular proliferation through its regulation of stem cell homeostasis. Furthermore, variants in the Wnt/ß-catenin signaling pathway have been implicated in the development of other cancers, leading us to believe that this pathway may have a vital role in bladder cancer development. MATERIALS AND METHODS: A total of 230 single nucleotide polymorphisms in 40 genes in the Wnt/ß-catenin signaling pathway were genotyped in 803 bladder cancer cases and 803 healthy controls. RESULTS: A total of 20 single nucleotide polymorphisms were nominally significant for risk. Individuals with 2 variants of LRP6: rs10743980 were associated with a decreased risk of bladder cancer in the recessive model in the initial analysis (OR 0.76, 95% CI 0.58-0.99, p=0.039). This was validated using the bladder genome-wide association study chip (OR 0.51, 95% CI 0.27-1.00, p=0.049 and for combined analysis p=0.007). CONCLUSIONS: Together these findings implicate variants in the Wnt/ß-catenin stem cell pathway as having a role in bladder cancer etiology.


Assuntos
Predisposição Genética para Doença/genética , Variação Genética/genética , Neoplasias da Bexiga Urinária/genética , Via de Sinalização Wnt/genética , beta Catenina/genética , Idoso , Idoso de 80 Anos ou mais , Transformação Celular Neoplásica/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Valores de Referência , Bexiga Urinária/metabolismo
13.
Curr Opin Urol ; 25(5): 449-58, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26218634

RESUMO

PURPOSE OF REVIEW: Recently completed cancer genomics projects identified intrinsic subtypes in muscle-invasive bladder cancers. Here we will describe the studies that led to their discovery and review their biological and clinical properties. RECENT FINDINGS: Whole genome mRNA expression profiling and unsupervised hierarchical cluster analyses identified intrinsic basal and luminal subtypes in muscle-invasive bladder cancers that are similar to the ones found in breast cancer. Tumors within each subtype have distinct responses to conventional cisplatin-based combination chemotherapy, and they contain gene expression signatures and DNA alterations that may render them vulnerable to clinically available targeted therapies. SUMMARY: Like their breast cancer counterparts, basal bladder cancers are characterized by poor clinical outcomes in the absence of effective systemic therapy, but a large fraction of them do respond to neoadjuvant chemotherapy, suggesting that the tumors should be managed aggressively. On the contrary, tumors that belong to the 'p53-like' subtype tend to be chemoresistant, so patients with these tumors should probably be managed differently. It seems likely that prospective identification of tumor intrinsic subtype membership could complement the use of DNA-based biomarkers to identify the groups of patients who will benefit the most from chemotherapy and targeted agents.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Bexiga Urinária/genética , Antineoplásicos/uso terapêutico , Análise por Conglomerados , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Humanos , Técnicas de Diagnóstico Molecular , Terapia de Alvo Molecular , Invasividade Neoplásica , Fenótipo , Medicina de Precisão , Valor Preditivo dos Testes , RNA Mensageiro/genética , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia
14.
Cancer ; 120(12): 1794-9, 2014 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-24633966

RESUMO

BACKGROUND: High-grade upper tract urothelial carcinoma (UTUC) is frequently upstaged after surgery and is associated with uniformly poor survival. Neoadjuvant chemotherapy may offer a way to improve clinical outcomes. The authors compared the survival rates of patients with UTUC who received neoadjuvant chemotherapy before surgery with the rates among patients who did not. METHODS: A retrospective review was conducted of patients with high-risk UTUC who received neoadjuvant chemotherapy followed by surgery from 2004 to 2008 (study group) compared with a matched cohort who underwent initial surgery from 1993 to 2003 (control group). Fisher exact tests, Wilcoxon rank-sum tests, and Kaplan-Meier methods were used. The log-rank test and Cox proportional-hazards models were used to evaluate the association of the 2 outcomes with patient, treatment, and tumor characteristics in univariate and multivariate models. RESULTS: Of 112 patients, there were 31 in the study group and 81 in the control group. Patients who received neoadjuvant chemotherapy had improved overall survival (OS) and disease-specific survival (DSS) with a 5-year DSS rate of 90.1% and a 5-year OS rate of 80.2% versus DSS and OS rates of 57.6% for those who underwent initial surgery (P = .0204 and P = .0015, respectively). In multivariate analyses, the neoadjuvant group had a lower risk of mortality (OS: hazard ratio, 0.42 [P = .035]; DSS: hazard ratio, 0.19 [P = .006]). CONCLUSIONS: Neoadjuvant chemotherapy improved the survival of patients with UTUC compared with a matched historic cohort of patients who underwent initial surgery. Patients with high-risk UTUC should be considered for neoadjuvant chemotherapy in view of the limited opportunity to administer effective cisplatin-based chemotherapy after nephroureterectomy.


Assuntos
Carcinoma de Células de Transição/tratamento farmacológico , Neoplasias Urológicas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células de Transição/patologia , Carcinoma de Células de Transição/cirurgia , Quimioterapia Adjuvante , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Pelve Renal/patologia , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Neoplasias Ureterais , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/cirurgia , Neoplasias Urológicas/patologia , Neoplasias Urológicas/cirurgia
15.
J Urol ; 191(1): 40-7, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23911605

RESUMO

PURPOSE: We evaluated the survival of patients with muscle invasive bladder cancer undergoing radical cystectomy without neoadjuvant chemotherapy to confirm the utility of existing clinical tools to identify low risk patients who could be treated with radical cystectomy alone and a high risk group most likely to benefit from neoadjuvant chemotherapy. MATERIALS AND METHODS: We identified patients with muscle invasive bladder cancer who underwent radical cystectomy without neoadjuvant chemotherapy at our institution between 2000 and 2010. Patients were considered high risk based on the clinical presence of hydroureteronephrosis, cT3b-T4a disease, and/or histological evidence of lymphovascular invasion, micropapillary or neuroendocrine features on transurethral resection. We evaluated survival (disease specific, progression-free and overall) and rate of pathological up staging. An independent cohort of patients from another institution was used to confirm our findings. RESULTS: We identified 98 high risk and 199 low risk patients eligible for analysis. High risk patients exhibited decreased 5-year overall survival (47.0% vs 64.8%) and decreased disease specific (64.3% vs 83.5%) and progression-free (62.0% vs 84.1%) survival probabilities compared to low risk patients (p <0.001). Survival outcomes were confirmed in the validation subset. On final pathology 49.2% of low risk patients had disease up staged. CONCLUSIONS: The 5-year disease specific survival of low risk patients was greater than 80%, supporting the distinction of high risk and low risk muscle invasive bladder cancer. The presence of high risk features identifies patients with a poor prognosis who are most likely to benefit from neoadjuvant chemotherapy, while many of those with low risk disease can undergo surgery up front with good expectations and avoid chemotherapy associated toxicity.


Assuntos
Carcinoma de Células de Transição/mortalidade , Seleção de Pacientes , Neoplasias da Bexiga Urinária/mortalidade , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/patologia , Carcinoma de Células de Transição/cirurgia , Cistectomia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Análise de Sobrevida , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/cirurgia
16.
BJU Int ; 113(5b): E28-33, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24053608

RESUMO

OBJECTIVE: To assess the incidence and clinical significance of 'skip lesions' that are present in proximal but not in distal ureteric sections, which are occasionally found during the pathological examination of ureteric margins during radical cystectomy (RC). PATIENTS AND METHODS: We identified 660 patients who underwent a RC and had at least two permanent margins for a given ureter. In all, 1173 ureters were analysed and classified as follows: 'normal' (no tumour, reactive atypia, mild or moderate dysplasia) or 'abnormal' (severe dysplasia, carcinoma in situ (CIS), or tumour). Transitions from 'normal' distal pathology to 'abnormal' on proximal section(s) determined frequency of skip lesions. Fisher's exact test and the log-rank test were used to study correlations. RESULTS: Ureteric skip lesions were found in 4.8% patients (2.9% ureters). Pathology of skip lesions was CIS in 55.9%, transitional cell carcinoma in 23.5% and severe dysplasia in 20.6%. Skip lesions were associated with lymphovascular invasion (34.4% vs 13.7%, P = 0.004) and advanced pT stage (P = 0.007). On multivariate analysis, skip lesions correlated with lower median overall survival (OS) (inestimable vs 8.2 years, P = 0.014) in patients with pT0 or pTa disease and a trend towards lower OS (2.7 vs 8.8 years, P = 0.066) in pTis disease. Concordance between frozen distal margin and permanent proximal margin varied; sensitivity was 80% in those without and 20% in those with skip lesions. CONCLUSIONS: The presence of a ureteric skip lesion may be associated with lower survival in patients with pT0, pTa or pTis urothelial carcinoma. Thus, while uncommon, ureteric skip lesions should be reported in pathological findings.


Assuntos
Cistectomia , Neoplasias Ureterais/epidemiologia , Neoplasias Ureterais/patologia , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/cirurgia , Idoso , Cistectomia/métodos , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estudos Retrospectivos , Análise de Sobrevida
17.
Eur Urol Oncol ; 2024 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-39406613

RESUMO

BACKGROUND AND OBJECTIVE: Urinary tumor DNA (utDNA) profiling identifies mutations associated with urothelial carcinoma and can be used to detect minimal residual disease (MRD). We evaluate the utility of utDNA profiling to predict treatment failure in bacillus Calmette-Guérin-unresponsive high-grade (HG) non-muscle-invasive bladder cancer (NMIBC) treated with nadofaragene firadenovec. METHODS: Urine was collected from participants prior to induction (n = 32) and at their 3-mo evaluation (n = 18) in the parallel-arm, phase 2 study (NCT01687244) of nadofaragene firadenovec. The UroAmp MRD assay (Convergent Genomics, South San Francisco, CA, USA) was used to perform utDNA testing. Risk of HG NMIBC recurrence was determined using two algorithm versions, and recurrence-free survival (RFS) was assessed using a Kaplan-Meier analysis. KEY FINDINGS AND LIMITATIONS: TP53, TERT, PIK3CA, ARID1A, PLEKHS1, ELF3, and ERBB2 were the most prevalently mutated genes. With pretreatment urine, the validated MRD algorithm resulted in 12-mo RFS of 56% for negative and 22% for positive patients (p = 0.097). The experimental, enhanced algorithm classified two additional patients as positive, giving RFS of 71% for negative and 20% for positive patients (p = 0.012). With 3-mo urine, both algorithms gave RFS of 100% for negative and 38% for positive patients (p = 0.038). Longitudinal utDNA testing classified patients as negative (7%), complete responders (13%), partial responders (27%), unresponsive (20%), and expanding (33%). CONCLUSIONS AND CLINICAL IMPLICATIONS: Urinary MRD testing after nadofaragene firadenovec induction provided statistically significant prognostication of recurrence among phase 2 trial participants. PATIENT SUMMARY: By analyzing urine-borne tumor DNA, we can help determine which patients with high-grade non-muscle-invasive bladder cancer are at the greatest risk of recurrence when receiving second-line therapy.

18.
Eur Urol ; 86(4): 297-300, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39003201

RESUMO

We previously reported that tumors harboring any one of four gene mutations (ATM, RB1, FANCC, or ERCC2) were likely to respond to neoadjuvant cisplatin-based chemotherapy (NAC), resulting in cancer-free surgical specimens at the time of cystectomy (pT0). Here, we report our validation of this finding. Using the CARIS 592 Gene Panel (Caris Life Sciences, Phoenix, AZ, USA), we analyzed 105 pre-NAC tumor specimens from a large multicenter trial (S1314) of either neoadjuvant gemcitabine and cisplatin (GC), or dose-dense methotrexate, vinblastine, Adriamycin, and cisplatin (DDMVAC). We found that a mutation in any one of these four genes predicted for pT0 at surgery (odds ratio = 5.36; 95% confidence interval [CI] 2.05, 14.02; two-sided p = 0.0006). The biomarker was better at predicting the presence of disease (negative predictive value for pT0 86%; 95% CI 73%, 94%) than the absence of disease (positive predictive value for pT0 48%; 95% CI 35%, 62%). There was no evidence of an interaction between the treatment arm (DDMVAC vs GC) and the genetic variant in terms of pT0. When combined with clinical assessment, these findings help inform patient selection for bladder preservation after cisplatin-based chemotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Proteínas Mutadas de Ataxia Telangiectasia , Cisplatino , Cistectomia , Proteína do Grupo de Complementação C da Anemia de Fanconi , Mutação , Terapia Neoadjuvante , Proteínas de Ligação a Retinoblastoma , Neoplasias da Bexiga Urinária , Proteína Grupo D do Xeroderma Pigmentoso , Humanos , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/cirurgia , Cisplatino/uso terapêutico , Cisplatino/administração & dosagem , Proteína Grupo D do Xeroderma Pigmentoso/genética , Proteínas de Ligação a Retinoblastoma/genética , Masculino , Proteínas Mutadas de Ataxia Telangiectasia/genética , Feminino , Proteína do Grupo de Complementação C da Anemia de Fanconi/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pessoa de Meia-Idade , Ubiquitina-Proteína Ligases/genética , Idoso , Invasividade Neoplásica , Biomarcadores Tumorais/genética , Resultado do Tratamento , Quimioterapia Adjuvante , Resposta Patológica Completa
19.
Cancer Res Commun ; 4(9): 2444-2453, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-39207194

RESUMO

PURPOSE: We performed a pilot study of daratumumab (an mAb directed against CD38) in muscle-invasive bladder cancer (MIBC) and treatment-refractory metastatic renal cell carcinoma (mRCC). EXPERIMENTAL DESIGN: Patients with MIBC underwent baseline transurethral resection of the bladder tumor followed by four weekly doses of daratumumab prior to cystectomy. Patients with mRCC underwent baseline and sequential biopsies after eight weekly doses. The primary endpoint was safety. The secondary endpoints were pathologic complete response rate for the MIBC cohort and objective response rate and progression-free survival for the mRCC cohort. Exploratory analyses included immune monitoring and overall survival. A Bayesian sequential monitoring design for toxicity was used for excessive toxicity. RESULTS: In both the MIBC (n = 8) and mRCC (n = 8) cohorts, no toxicity events were encountered. In the MIBC cohort, one patient experienced pathologic complete response rate. In the mRCC cohort, no objective responses were reported, and the median progression-free survival was 1.5 months (95% confidence interval, 1.1-1.8 months). Immune monitoring found significant reductions in NK cells in circulation in both cohorts after treatment. In the tissue analysis, IHC found evidence of diminished CD38 presence in mRCC with treatment, whereas the baseline levels in MIBC were low. CONCLUSION: Treatment with daratumumab was safe. No signal of efficacy was detected in mRCC, and conclusions on the activity in MIBC were limited. Evidence of daratumumab targeting CD38 was detected in circulating immune cells and within the tumor microenvironment of mRCC and MIBC. SIGNIFICANCE: In this prospective clinical trial of daratumumab, treatment in patients with MIBC and mRCC was safe. Limited efficacy was observed. Treatment with daratumumab resulted in CD38-expressing immune cell subsets to be targeted both in circulation and within the tumor microenvironment.


Assuntos
ADP-Ribosil Ciclase 1 , Anticorpos Monoclonais , Carcinoma de Células Renais , Neoplasias Renais , Neoplasias da Bexiga Urinária , Humanos , Projetos Piloto , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Masculino , ADP-Ribosil Ciclase 1/antagonistas & inibidores , Idoso , Feminino , Pessoa de Meia-Idade , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/imunologia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/imunologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Neoplasias Renais/imunologia , Invasividade Neoplásica/patologia , Intervalo Livre de Progressão , Idoso de 80 Anos ou mais , Glicoproteínas de Membrana
20.
J Urol ; 190(3): 850-6, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23507396

RESUMO

PURPOSE: A phase I trial of intravesical recombinant adenovirus mediated interferon-α2b gene therapy (rAd-IFNα) formulated with the excipient SCH Syn3 was conducted in patients with nonmuscle invasive bladder cancer who had disease recurrence after treatment with bacillus Calmette-Guérin. The primary objective was to determine the safety of rAd-IFNα/Syn3. Secondary end points were demonstrated effective rAd-IFNα gene expression and preliminary evidence of clinical activity at 3 months. MATERIALS AND METHODS: A total of 17 patients with recurrent nonmuscle invasive bladder cancer after bacillus Calmette-Guérin treatment were enrolled in the study. A single treatment of rAd-IFNα (3 × 10(9) to 3 × 10(11) particles per ml) formulated with the excipient Syn3 was administered. Patient safety was evaluated for 12 or more weeks. Efficacy of gene transfer was determined by urine IFNα protein concentrations. Preliminary drug efficacy was determined at 3 months. RESULTS: Intravesical rAd-IFNα/Syn3 was well tolerated as no dose limiting toxicity was encountered. Urgency was the most common adverse event and all cases were grade 1 or 2. rAd-IFNα DNA was not detected in the blood. However, transient low serum IFNα and Syn3 levels were measured. High and prolonged dose related urine IFNα levels were achieved with the initial treatment. Of the 14 patients treated at doses of 10(10) or more particles per ml with detectable urine IFNα, 6 (43%) experienced a complete response at 3 months and 2 remained disease-free at 29.0 and 39.2 months, respectively. CONCLUSIONS: Intravesical rAd-IFNα/Syn3 was well tolerated with no dose limiting toxicity encountered. Dose dependent urinary IFNα concentrations confirmed efficient gene transfer and expression. Intravesical rAd-IFNα/Syn3 demonstrated clinical activity in nonmuscle invasive bladder cancer recurring after bacillus Calmette-Guérin.


Assuntos
Carcinoma de Células de Transição/terapia , Terapia Genética/métodos , Interferon-alfa/administração & dosagem , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/terapia , Neoplasias da Bexiga Urinária/terapia , Adenoviridae/genética , Administração Intravesical , Adulto , Idoso , Idoso de 80 Anos ou mais , Vacina BCG/administração & dosagem , Carcinoma de Células de Transição/mortalidade , Carcinoma de Células de Transição/patologia , Ácidos Cólicos/administração & dosagem , Dissacarídeos/administração & dosagem , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Vetores Genéticos , Humanos , Interferon alfa-2 , Interferon-alfa/genética , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/patologia , Prognóstico , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/genética , Medição de Risco , Análise de Sobrevida , Falha de Tratamento , Resultado do Tratamento , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologia
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