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BACKGROUND: The recurrence rate of non-muscle invasive bladder cancer (NMIBC) is high, despite intravesical treatments. Importantly, patients are frequently unfit or unwilling to undergo a recommended radical cystectomy when standard intravesical treatments fail, due to the substantial risk of morbidity and mortality. For these patients, radiofrequency-induced hyperthermia combined with intravesical chemotherapy (RF-CHT) has shown promising results. We aim to determine treatment outcomes and assess the effect of (ablative) dose. METHODS: 299 intensively pretreated patients treated with RF-CHT were included in safety analysis. Of these, 274 patients who fulfilled induction treatments were included in efficacy analysis. Six-month complete response (CR) and durable response were reported for (concomitant) carcinoma in situ (CIS) patients and recurrence-free survival (RFS) for papillary patients. RESULTS: For CIS, six-month CR-rate was 56.0%; and durable response rates were 79.7%, 66.5%, and 40.3% at one-, two- and five-year, respectively. RFS rates for papillary patients were 77.9%, 57.5%, and 37.2%, respectively. Patients treated with ablative dose are less likely to develop recurrence (adjusted Hazard Ratio 0.54, p = 0.01), compared to adjuvant dose. CONCLUSIONS: RF-CHT is effective in NMIBC patients in whom standard intravesical treatments have failed and should be considered in patients who are unwilling or unfit to undergo radical cystectomy. Patients with CIS or residual papillary tumor at baseline benefit from ablative dose.
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BACKGROUND: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial. OBJECTIVE: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management. DESIGN: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts prior to voting during a consensus conference. SETTING: Online Delphi survey and consensus conference. PARTICIPANTS: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Statements were ranked by experts according to their level of agreement: 1-3 (disagree), 4-6 (equivocal), and 7-9 (agree). A priori (level 1) consensus was defined as ≥70% agreement and ≤15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus). RESULTS AND LIMITATIONS: Overall, 116 statements were included in the Delphi survey. Of these statements, 33 (28%) achieved level 1 consensus and 49 (42%) achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease, and the evolving role of checkpoint inhibitor therapy in metastatic disease. CONCLUSIONS: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time when further evidence is available to guide our approach. PATIENT SUMMARY: This report summarises findings from an international, multistakeholder project organised by the EAU and ESMO. In this project, a steering committee identified areas of bladder cancer management where there is currently no good-quality evidence to guide treatment decisions. From this, they developed a series of proposed statements, 71 of which achieved consensus by a large group of experts in the field of bladder cancer. It is anticipated that these statements will provide further guidance to health care professionals and could help improve patient outcomes until a time when good-quality evidence is available.
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Neoplasias da Bexiga Urinária/terapia , Humanos , Cooperação Internacional , Estadiamento de Neoplasias , Neoplasias da Bexiga Urinária/patologiaRESUMO
Apaziquone is an interesting drug for intravesical use in patients with nonmuscle invasive bladder cancer; however, more research is needed to prove its actual benefit. Although the apaziquone trials demonstrate the potential of this new drug, the singular phase 3 trials did not reach their primary endpoint. To date, no new trials are recruiting, so the development of apaziquone seems to have stopped.
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Aziridinas/administração & dosagem , Carcinoma de Células de Transição/tratamento farmacológico , Indolquinonas/administração & dosagem , Neoplasias da Bexiga Urinária/tratamento farmacológico , Administração Intravesical , Antineoplásicos/administração & dosagem , Carcinoma de Células de Transição/patologia , Humanos , Invasividade Neoplásica , Resultado do Tratamento , Neoplasias da Bexiga Urinária/patologiaRESUMO
In an effort to decrease recurrence and progression rates in non-muscle-invasive bladder cancer (NMIBC), transurethral resection of a bladder tumor is followed by intravesical instillations using Mitomycin-C (MMC) and Bacillus Calmette-Guérin (BCG). In spite of these adjuvant treatment modalities, recurrence and progression rates remain high. Because of these limitations of current standard therapy and the shortage of BCG, there is a search for alternative forms of treatment in NMIBC. Intravesical MMC combined with hyperthermia, especially RF-induced QHT being most extensively investigated in the past 20 years, is one of these alternatives for intermediate- and high-risk NMIBC. There are several different techniques and devices to create hyperthermia of the bladder wall raising temperatures up to 40.5-44.0 â´ C. Hyperthermia can be the result of ultrasound waves, direct thermal conduction, or electromagnetic fields. An overview of hyperthermia systems concerning their technical aspects, treatment outcomes and adverse events (AE's) will be described in this review. In patients failing standard treatment who are not fit or unwilling to undergo surgery, RF-induced QHT should be considered. Besides QHT, there are more forms of treatment currently being investigated in NMIBC like EMDA and neoadjuvant intravesical chemotherapy, these require more clinical trials to determine patient selection and efficiency.
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Antibióticos Antineoplásicos/administração & dosagem , Hipertermia Induzida , Mitomicina/administração & dosagem , Neoplasias da Bexiga Urinária/terapia , Administração Intravesical , Terapia Combinada , Previsões , Humanos , Invasividade Neoplásica , Neoplasias da Bexiga Urinária/patologiaRESUMO
INTRODUCTION: Non-muscle invasive bladder cancer (NMIBC) is a highly recurrent disease with potential progression to muscle invasive disease despite the standard bladder instillations with mitomycin C (MMC) or Bacille Calmette-Guérin immunotherapy. Therefore, alternatives such as radiofrequency-induced chemohyperthermia (RF-CHT) with MMC are being investigated. The mechanism explaining the efficacy of RF-CHT is only partly understood. We examined whether RF-CHT results in higher MMC tissue concentrations as compared to cold MMC instillation. PATIENTS AND METHODS: Prior to a planned transurethral resection of bladder tumour (TURBT), patients with stage Ta NMIBC were allocated to either (1) cold MMC instillation or (2) RF-CHT. After MMC instillation, three biopsies were taken of both normal and tumour tissue. Biopsies were snap-frozen and MMC tissue concentrations were analysed using ultra-performance liquid chromatography. RESULTS: Eleven patients were included of which six received RF-CHT. Ten patients had TaG2-LG/HG papillary tumours at pathology. One patient in the RF-CHT group appeared to be free of malignancy and was excluded from the analysis as no tumour biopsies were available. The median MMC concentration in tumour tissue was higher in the RF-CHT group (median 665.00 ng/g vs. 63.75 ng/g, U = 51.0, p = 0.018). Moreover, in both techniques the MMC concentration was lower in normal tissue compared to tumour tissue. Tissue MMC concentration measurements varied substantially within, and between, different patients from the same group. CONCLUSION: Intravesical RF-CHT results in higher tumour MMC concentrations vs. cold MMC instillation which contributes to its superior efficacy.
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Hipertermia Induzida/métodos , Mitomicina/uso terapêutico , Neoplasias da Bexiga Urinária/terapia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mitomicina/farmacologia , Neoplasias da Bexiga Urinária/patologiaRESUMO
BACKGROUND: Despite adjuvant intravesical therapy, recurrences in non-muscle-invasive bladder cancer (NMIBC) are still high; therefore, new treatment options are needed. The use of chemohyperthermia (CHT) as an alternative treatment is expanding in Europe. To date, however, there has been a lack of prospective randomised data. OBJECTIVE: To compare CHT using mitomycin C (MMC) with bacillus Calmette-Guérin (BCG) as adjuvant treatment for intermediate- and high-risk NMIBC. DESIGN, SETTING, AND PARTICIPANTS: Between 2002 and 2012, 190 NMIBC patients were randomised in this controlled, open-label, multicentre trial for 1-yr CHT (six weekly treatments and six maintenance treatments) and 1-yr BCG immunotherapy (six weekly treatments and three weekly maintenance treatments at months 3, 6, and 12). Patients and physicians giving the interventions were aware of assignment. This study is registered with ClinicalTrials.gov (NCT00384891). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary end point was 24-mo recurrence-free survival (RFS) in the intention-to-treat (ITT) and per-protocol (PP) analyses in all papillary NMIBC patients (n=147). Analyses were done with the log-rank test and Fisher exact test. All tests were two-sided. RESULTS AND LIMITATIONS: The 24-mo ITT RFS was 78.1% in the CHT group compared with 64.8% in the BCG group (p=0.08). The 24-mo RFS in the PP analysis was 81.8% in the CHT group compared with 64.8% in the BCG group (p=0.02). Progression rates were <2% in both groups. Regarding the side-effects, no new safety concerns were identified. A concern is that this study closed prematurely and thus is underpowered. Furthermore, blinding of treatment for patients and physicians was impossible; this may have resulted in unavoidable bias. CONCLUSIONS: CHT is a safe and effective treatment option in patients with intermediate- and high-risk papillary NMIBC. A significantly higher 24-mo RFS in the CHT group was seen in the PP analysis. Based on the results above, CHT is an option for BCG therapy as adjuvant treatment for intermediate- and high-risk papillary NMIBC. PATIENT SUMMARY: Recurrences in non-muscle-invasive bladder cancer are common, despite adjuvant therapies. We compared 24-mo recurrence-free survival (RFS) with chemohyperthermia (CHT) versus bacillus Calmette-Guérin (BCG) therapy. According to these data, CHT therapy appears to be safe and has higher 24-mo RFS than BCG therapy.
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Adjuvantes Imunológicos/uso terapêutico , Antibióticos Antineoplásicos/uso terapêutico , Vacina BCG/uso terapêutico , Carcinoma in Situ/terapia , Carcinoma Papilar/terapia , Hipertermia Induzida , Mitomicina/uso terapêutico , Neoplasias da Bexiga Urinária/terapia , Administração Intravesical , Idoso , Carcinoma in Situ/patologia , Carcinoma Papilar/patologia , Terapia Combinada , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Liso/patologia , Invasividade Neoplásica , Estudos Prospectivos , Fatores de Risco , Neoplasias da Bexiga Urinária/patologiaRESUMO
INTRODUCTION: Data from single-center series suggest that a delay in time to radical cystectomy (RC) more than 3 months after diagnosis of muscle-invasive bladder cancer (MIBC) is associated with pathological upstaging and decreased survival. However, limited data is available from population-based studies. In this study, the effect of delayed RC was assessed in a nationwide cohort. MATERIALS AND METHODS: Patients who underwent RC between 2006 and 2010 with primary clinical T2-T4N0M0 urothelial bladder cancer were selected using the Netherlands Cancer Registry database. Data from the Netherlands Cancer Registry was supplemented with data from the Nationwide Network and Registry of Histo- and Cytopathology database in case of incomplete information. The cohort was divided in patients who underwent RC ≤3 months (group I) vs. patients who underwent RC >3 months (group II). Median time from MIBC diagnosis to RC, variables associated with delayed RC >3 and the effect of delayed RC on staging and overall survival (OS) were evaluated in patients who underwent neoadjuvant therapy and patients who did not. RESULTS: A total of 1,782 patients were included. Median follow-up time was 5.1 years for living patients and 1.3 years for deceased patients. Median time from MIBC diagnosis to RC was 50 days (interquartile range: 27 days) and 93% of patients underwent RC≤3 months. Patients older than 75 years (odds ratio [OR] = 0.50; 95% CI: 0.32-0.77), referred for RC (OR = 0.41; 95% CI: 0.26-0.69), and treated in a university hospital (OR = 0.34; 95% CI: 0.21-0.56) were less likely to undergo RC≤3 months. Pathologic upstaging rate (43.9% vs. 42.1%) and node-positive disease rate (20.2% vs. 21.7%) did not differ for group I and II. Delayed RC>3 months was not associated with decreased OS adjusting for confounding variables (hazard ratio = 1.16; 95% CI: 0.91-1.48; P = 0.25). Median time from MIBC diagnosis to RC in patients that received neoadjuvant therapy (n = 105) was 133 days (interquartile range: 62 days). Adjusting for confounding variables, delayed RC>3 months was not associated with OS (hazard ratio = 0.90; 95% CI: 0.45-1.82). CONCLUSIONS: The vast majority of patient underwent RC within 3 months after diagnosis of MIBC, as recommended in the European Association of Urology MIBC guideline. Delayed RC for more than 3 months had no adverse effect on staging and survival.
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Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/cirurgia , Idoso , Cistectomia/métodos , Cistectomia/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Países Baixos/epidemiologia , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologiaRESUMO
Non-muscle-invasive bladder cancer is a highly recurrent disease. The health care costs for non-muscle-invasive bladder cancer are a major burden for society. Bladder cancer treatment starts with a presumed complete transurethral resection of a bladder tumor. Despite international guidelines for perioperative and/or adjuvant intravesical instillation therapy in non-muscle-invasive bladder cancer, adequate worldwide application is lacking. In patients who do get adjuvant intravesical instillations, recurrences are still frequent. New therapies in non-muscle-invasive bladder cancer are unsatisfactory and still experimental.
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Gerenciamento Clínico , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/terapia , Progressão da Doença , Gradação de Tumores , Invasividade Neoplásica , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Neoplasias da Bexiga Urinária/mortalidadeRESUMO
INTRODUCTION/BACKGROUND: Non-muscle-invasive bladder cancer (NMIBC) has a strong tendency to recur despite adjuvant instillations. TMX-101 is a new liquid form of imiquimod for intravesical instillation and has activity in vitro against urothelial carcinoma. The purpose was to analyze the activity of TMX-101 in low-grade NMIBC. Furthermore, pharmacokinetic and pharmacodynamic characteristics and adverse events were evaluated. PATIENTS AND METHODS: A multicenter, prospective phase 1 trial in 7 patients with low-grade NMIBC was conducted. All patients underwent a marker lesion transurethral resection of the bladder tumor and 6 weekly instillations with TMX-101 0.2% or 0.4%. Cystoscopy 2 to 4 weeks after the last instillation evaluated the effect of TMX-101. RESULTS: The effective biologic dose (EBD = complete response [CR] in > 2 patients) could not be defined because none of the patients experienced CR. Maximum plasma concentration was 75.1 ng/mL in the 0.4% dose group. No drug accumulation was observed. In the pharmacodynamic analysis, urinary interleukin 1 receptor agonist (IL-1ra) represents the most sensitive and uniform response after TMX-101 instillation. A total of 87.0% reported at least 1 adverse event. All events were of grade 2 severity or less (Common Terminology Criteria of Adverse Events version 4.02). No clinically significant changes in laboratory parameters or vital signs were observed during or after treatment. CONCLUSION: Toll-like receptor 7 (TLR-7) agonists are effective in urothelial carcinoma in preclinical research. The EBD in this phase 1 study could not be determined because no patient experienced CR. IL-1ra could be valuable as a urinary biomarker in future developments. The safety of TMX-101 has been reconfirmed. New doses, other schedules, and NMIBC subgroups should be tested to define the EBD. A pilot study in carcinoma-in-situ patients is currently ongoing and results are expected shortly.
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Aminoquinolinas/administração & dosagem , Antineoplásicos/administração & dosagem , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Administração Intravesical , Aminoquinolinas/efeitos adversos , Aminoquinolinas/farmacocinética , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/cirurgia , Cistoscopia , Relação Dose-Resposta a Droga , Feminino , Humanos , Imiquimode , Proteína Antagonista do Receptor de Interleucina 1/urina , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do TratamentoRESUMO
OBJECTIVES: To explore whether urinary cytokine and chemokine (CK) levels differed between cold mitomycin-C (cold-MMC)-treated patients and chemohyperthermia (C-HT)-treated patients, to shed light on the possible molecular mechanisms that might explain the superior outcome of C-HT. Furthermore, CK-differences were explored between C-HT responders and C-HT non-responders. METHODS: Twelve NMIBC patients were included. Nine received six-weekly C-HT, and three received four-weekly cold-MMC instillations. Urine was collected on 8-12 time points before and after every treatment. MDC, IL-2, IL-6, IL-8, IP-10, MCP-1 and RANTES were determined by Luminex(®)-analysis. RESULTS: Elevated urinary CK levels were observed in both groups after treatment. In general, CK-peaks were lower in the cold-MMC group in comparison with levels in the C-HT group. Significant higher MCP-1 and IL-6 levels were observed in C-HT-treated patients. Additionally, significant cumulative effects were observed for IP-10 and IL-2. However, IP-10 and IL-2 levels did not significantly differ between treatments. MDC levels after the first week of treatment were significantly higher in the C-HT responders compared with the non-responders. CONCLUSION: MMC treatment leads to elevated urinary CK levels with significantly higher MCP-1 and IL-6 levels in C-HT-treated patients. Increased MDC levels after the first C-HT instillation appear to be related to good clinical outcome and might be of additional value to personalize treatment. Studies involving more patients and longer follow-up are needed to substantiate this observation.
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Carcinoma de Células de Transição/terapia , Citocinas/urina , Hipertermia Induzida/métodos , Mitomicina/administração & dosagem , Neoplasias da Bexiga Urinária/terapia , Administração Intravesical , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/administração & dosagem , Biomarcadores Tumorais/urina , Carcinoma de Células de Transição/patologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Instilação de Medicamentos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Neoplasias da Bexiga Urinária/patologiaRESUMO
PURPOSE: Nonmuscle invasive bladder cancer is characterized by a high recurrence rate. New adjuvant treatments are needed to decrease this high number of recurrences. We present the results of more than 10 years of experience with chemohyperthermia in patients with nonmuscle invasive bladder cancer. MATERIALS AND METHODS: Using standardized medical record forms we prospectively collected patient and tumor characteristics of patients treated with chemohyperthermia between 2002 and 2013. Median followup was 75.6 months. Recurrence-free survival was the primary objective. The secondary objective was to observe recurrence-free survival differences in 1) the epirubicin group vs the mitomycin group and 2) the highly recurrent (greater than 2 recurrences in 24 months) nonmuscle invasive bladder cancer group vs the other groups. RESULTS: A total of 160 patients with nonmuscle invasive bladder cancer were included in study, including 20 (13%) treated with epirubicin and 129 (81%) previously treated with bacillus Calmette-Guérin. One and 2-year recurrence-free survival was 60% and 47%, respectively. Muscle invasive progression was seen in 4% of cases. Two-year recurrence-free survival in the epirubicin and mitomycin groups was 55% and 46%, respectively (p = 0.30). The highly recurrent nonmuscle invasive bladder cancer group had significant decreased recurrence-free survival compared to other groups (p <0.01). Patients treated with 2 or fewer vs greater than 2 transurethral bladder tumor resections before chemohyperthermia had higher recurrence-free survival (p = 0.01). On multivariable analysis the highly recurrent cancer criteria remained independently associated with decreased recurrence-free survival (HR 2.40, 95% CI 1.30-4.43, p = 0.01). CONCLUSIONS: Chemohyperthermia is an effective approach to nonmuscle invasive bladder cancer for which standard intravesical treatments fail. Patients with highly recurrent disease before chemohyperthermia have lower recurrence-free survival. Furthermore, recurrence-free survival appears to improve with earlier chemohyperthermia. No significant differences were observed between the 2 chemotherapy agents.
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Antibióticos Antineoplásicos/uso terapêutico , Epirubicina/uso terapêutico , Hipertermia Induzida , Mitomicina/uso terapêutico , Neoplasias da Bexiga Urinária/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/prevenção & controle , Estudos Prospectivos , Fatores de Tempo , Neoplasias da Bexiga Urinária/tratamento farmacológicoRESUMO
BACKGROUND: The aim of this study was to present survival outcomes and identify prognostic factors in patients undergoing radical cystectomy (RC) for urothelial bladder cancer (UBC) in a homogeneous surgery-only series. PATIENTS AND METHODS: Patients who underwent RC for UBC with intent-to-cure between January 1998 and December 2010 without neoadjuvant or adjuvant treatment were included in this retrospective study. Clinical and histopathologic data were collected and institutional review board approval was obtained. Outcomes of interest were 30-day mortality (30dM), RFS, and OS. Univariable and multivariable analysis were performed. Median follow-up was 9.1 years. RESULTS: Two hundred forty-five patients were included with a median age of 65 years (range, 34-92 years). 30dM rate was in 5 out of 245 patients (2.0%) and 5-year RFS and OS rates were 67% and 58%, respectively. A total of 223 patients (91%) underwent lymph node (LN) dissection. Median number of removed and positive LNs were 9 and 1.5, respectively. Variables independently associated with decreased OS and RFS were tumor stage and LN status. In addition, positive soft tissue surgical margin (STSM) status was independently associated with decreased OS. In LN-positive patients, presence of extranodal extension (ENE) was associated with decreased RFS (39.7% vs. 7.3%; P = .005). CONCLUSION: Radical cystectomy for UBC was associated with low perioperative mortality rate and provided 5-year disease control in approximately two-thirds of patients. Independent prognostic factors included tumor stage, LN status (RFS and OS), and STSM status (OS). Presence of ENE in LN-positive patients was univariably associated with decreased RFS and OS.
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Carcinoma de Células de Transição/secundário , Carcinoma de Células de Transição/cirurgia , Neoplasias da Bexiga Urinária/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células de Transição/mortalidade , Cistectomia , Intervalo Livre de Doença , Feminino , Hospitais Universitários , Humanos , Estimativa de Kaplan-Meier , Excisão de Linfonodo , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Países Baixos , Prognóstico , Modelos de Riscos Proporcionais , Resultado do Tratamento , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologiaRESUMO
Non-muscle-invasive bladder cancer is a highly prevalent disease and recurrences, after initial therapy, are common. Consequently, the healthcare costs for non-muscle-invasive bladder cancer are high. Despite a primary adequate response to adjuvant intravesical treatment, many patients suffer from recurrences, and some even from progression. To date, cystectomy remains the only option for those non-responding patients with high risk of recurrence and progression. Mainly because outcome after progression, in this group, is poor. Therefore, new intravesical therapies are needed. Moreover, new accurate and individual parameters, to distinguish responder from non-responders, will provide additional benefit in clinical decision-making. In this review, current diagnostics and therapies will be discussed. In addition, we will elucidate developing therapies in non-muscle-invasive bladder cancer.
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Antineoplásicos/administração & dosagem , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Administração Intravesical , Humanos , Invasividade NeoplásicaRESUMO
Regulated exocytosis of Weibel-Palade bodies (WPBs) is a pivotal mechanism via which vascular endothelial cells initiate repair in response to injury and inflammation. Several pathways have been proposed to enable differential release of bioactive molecules from WPBs under different pathophysiologic conditions. Due to the complexity, many aspects of WPB biogenesis and exocytosis are still poorly understood. Herein, we have investigated the regulated exocytosis of the major WPB constituent, von Willebrand Factor (VWF), which upon its release forms strings of up to several millimeters long that capture circulating platelets and thereby initiate the formation of a haemostatic plug. Using correlative, fluorescence, and electron microscopic imaging techniques, we provide evidence that multigranular exocytosis is an important pathway for VWF release in secretagogue-challenged human umbilical vein endothelial cells. A novel membrane-delimited structure (secretory pod) was identified as the site of WPB coalescence and VWF exocytosis. Clathrin-coated profiles present on the secretory pods suggested remodeling via compensatory membrane retrieval. Small, 30- to 40-nm cytoplasmic vesicles (nanovesicles) mediated the fusion of WPBs with secretory pods. Multigranular exocytosis may facilitate VWF string formation by pooling the content of multiple WPBs. In addition, it may provide a novel mechanism for the differential release of WPB cargo.