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2.
Praxis (Bern 1994) ; 109(13): 1070-1073, 2020.
Artigo em Alemão | MEDLINE | ID: mdl-33050809

RESUMO

Unusual Cause of Acute Kidney Failure in a Patient with Metastatic Bladder Carcinoma Undergoing Palliative Chemotherapy Abstract. Tumour lysis syndrome is a potentially life-threatening complication of cancer and its treatment. It mostly occurs in highly proliferative haematological neoplasms under cytotoxic therapy but can also be seen spontaneously and in solid neoplasms, particularly with high tumour burden and/or high chemosensitivity. The present case report describes a tumour lysis syndrome in a patient with metastatic bladder cancer with an elevated lactate dehydrogenase as only potential correlate of a high tumour burden.


Assuntos
Lesão Renal Aguda , Síndrome de Lise Tumoral , Neoplasias da Bexiga Urinária , Lesão Renal Aguda/etnologia , Antineoplásicos/uso terapêutico , Humanos , Cuidados Paliativos , Neoplasias da Bexiga Urinária/complicações , Neoplasias da Bexiga Urinária/tratamento farmacológico
3.
Medicine (Baltimore) ; 99(35): e21930, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871933

RESUMO

BACKGROUND: This study will systematically assess the efficacy and safety of Bacillus Calmette-Guerin (BCG) for patients with bladder cancer (BC). METHODS: Literature searches will be performed in multiple electronic databases from inception to present: MEDLINE, EMBASE, CINAHL, Science Direct, Cochrane Library, Web of Science, and China National Knowledge Infrastructure. We will also examine grey literature through identifying conference proceedings, thesis, dissertations, and website of clinical trials registry. Two investigators will independently scan all citation titles, abstracts, and full-text studies. The study quality will be assessed by Cochrane Risk of Bias Tool. If possible, we will perform meta-analysis. Additional analyses will be carried out to test the potential sources of heterogeneity among included trials. RESULTS: The present study will summarize high quality trials on investigating the efficacy and safety of BCG for patients with BC. CONCLUSION: The results of this study will supply helpful evidence to determine whether BCG is effective or not for BC. STUDY REGISTRATION NUMBER: INPLASY202070042.


Assuntos
Vacina BCG/efeitos adversos , Vacina BCG/uso terapêutico , Revisões Sistemáticas como Assunto , Neoplasias da Bexiga Urinária/tratamento farmacológico , Administração Intravesical , Humanos , Metanálise como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto
4.
BMC Infect Dis ; 20(1): 708, 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32993546

RESUMO

BACKGROUND: Intravesical administration of Bacillus Calmette-Guérin (BCG) has proven useful for treatment and prevention of recurrence of superficial bladder cancer and in situ carcinoma. However, fatal side effects such as disseminated infections may occur. Early diagnosis and accurate therapy for interstitial pneumonitis (IP) are important because exacerbation of IP triggered by infections is the major cause of death. Although some fatality reports have suggested newly appeared IP after intravesical BCG treatment, to our knowledge, there are no reports which have demonstrated acute exacerbation of existing IP. Moreover, autopsy is lacking in previous reports. We report the case of a patient with fatal IP exacerbation after BCG instillation and the pathological findings of the autopsy. CASE PRESENTATION: A 77-year-old man with a medical history of IP was referred to our hospital because of fever and malaise. He had received an intravesical injection of BCG 1 day before the admission. His fever reduced after the use of antituberculosis drugs, so he was discharged home. He was referred to our hospital again because of a high fever 7 days after discharge. On hospitalisation, he showed high fever and systemic exanthema. Hepatosplenomegaly and myelosuppression were also observed. Biopsies revealed multiple epithelioid cell granulomas with Langhans giant cells of the liver and bone marrow. Biopsy DNA analyses of Mycobacterium bovis in the bone marrow, sputum, and blood were negative. His oxygen demand worsened drastically, and the ground-glass shadow expanded on the computed tomography scan. He was diagnosed with acute exacerbation of existing IP. We recommenced the antituberculosis drugs with steroid pulse therapy, but he died on day 35 because of respiratory failure. The autopsy revealed a diffuse appearance of multiple epithelioid cell granulomas with Langhans giant cells in multiple organs, although BCG was not evident. CONCLUSIONS: We report the first case of acute exacerbation of chronic IP by BCG infection. This is also the first case of autopsy of a patient with acute exacerbation of existing IP induced by intravesical BCG treatment. Whether the trigger of acute IP exacerbation is infection or hypersensitivity to BCG is still controversial, because pathological evidence confirming BCG infection is lacking. Physicians who administer BCG against bladder cancer should be vigilant for acute exacerbation of IP.


Assuntos
Antituberculosos/uso terapêutico , Vacina BCG/efeitos adversos , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/etiologia , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/etiologia , Esteroides/uso terapêutico , Exacerbação dos Sintomas , Administração Intravesical , Idoso , Autopsia , Vacina BCG/administração & dosagem , Vacina BCG/uso terapêutico , Carcinoma in Situ/tratamento farmacológico , Carcinoma in Situ/prevenção & controle , Evolução Fatal , Humanos , Doenças Pulmonares Intersticiais/microbiologia , Masculino , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Mycobacterium bovis/genética , Resultados Negativos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/prevenção & controle , Pulsoterapia , Resultado do Tratamento , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/prevenção & controle
5.
Hinyokika Kiyo ; 66(9): 313-317, 2020 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-32988169

RESUMO

A 74-year-old man presented with further treatment for muscle invasive small cell carcinoma of the bladder. After three courses of neoadjuvant chemotherapy with cisplatine + etoposide (EP), total cystectomy was performed. The pathological findings revealed small cell carcinoma of the bladder (ypT2N0M0). Eleven months after the operation, thoracoabdominal computed tomography (CT) showed right pelvic lymph node metastasis. He underwent 9 courses of EP chemotherapy, and everolimus, finally, Amrubicin was administered. Amrubicin might be useful for small cell carcinoma of the bladder.


Assuntos
Carcinoma de Células Pequenas/diagnóstico por imagem , Carcinoma de Células Pequenas/tratamento farmacológico , Neoplasias da Bexiga Urinária/diagnóstico por imagem , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/cirurgia , Idoso , Cistectomia , Etoposídeo , Humanos , Masculino
6.
Anticancer Res ; 40(9): 5295-5299, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878820

RESUMO

BACKGROUND: To assess the prophylactic efficacy of postoperative single intravesical instillation with pirarubicin (THP) and mitomycin C (MMC) for low-risk non-muscle-invasive bladder cancer (NMBC). PATIENTS AND METHODS: A total of 103 clinically low-risk NMBC patients were preoperatively randomized into either THP (n=49) or MMC (n=54) groups. The primary endpoint was recurrence-free survival. RESULTS: The median follow-up periods of the THP and MMC groups were 955 and 1008 days, respectively (p=0.76). Twelve patients (24.5%) in the THP group and 7 (13%) in the MMC group had bladder cancer recurrences. The two-year recurrence-free survival of the THP group and the MMC group was 77.8% and 86.4%, respectively (p=0.20). Neither groups had severe toxicity. CONCLUSION: In low-risk NMBC, the prophylactic effect against postoperative single intravesical instillation with THP was not superior to that with MMC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cuidados Pós-Operatórios , Neoplasias da Bexiga Urinária/tratamento farmacológico , Administração Intravesical , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Terapia Combinada , Cistoscópios , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mitomicina/administração & dosagem , Gradação de Tumores , Estadiamento de Neoplasias , Recidiva , Resultado do Tratamento , Carga Tumoral , Neoplasias da Bexiga Urinária/diagnóstico
7.
Nat Commun ; 11(1): 4858, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978382

RESUMO

Overtreatment with cisplatin-based chemotherapy is a major issue in the management of muscle-invasive bladder cancer (MIBC), and currently none of the reported biomarkers for predicting response have been implemented in the clinic. Here we perform a comprehensive multi-omics analysis (genomics, transcriptomics, epigenomics and proteomics) of 300 MIBC patients treated with chemotherapy (neoadjuvant or first-line) to identify molecular changes associated with treatment response. DNA-based associations with response converge on genomic instability driven by a high number of chromosomal alterations, indels, signature 5 mutations and/or BRCA2 mutations. Expression data identifies the basal/squamous gene expression subtype to be associated with poor response. Immune cell infiltration and high PD-1 protein expression are associated with treatment response. Through integration of genomic and transcriptomic data, we demonstrate patient stratification to groups of low and high likelihood of cisplatin-based response. This could pave the way for future patient selection following validation in prospective clinical trials.


Assuntos
Cisplatino/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Biomarcadores Tumorais , Quimioterapia Adjuvante , Cisplatino/uso terapêutico , Metilação de DNA , Tratamento Farmacológico , Instabilidade Genômica , Humanos , Mutação , Terapia Neoadjuvante , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Transcriptoma , Neoplasias da Bexiga Urinária/patologia
8.
Anticancer Res ; 40(10): 5861-5868, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988916

RESUMO

AIM: To evaluate our experience with radical radiotherapy and chemotherapy in patients with muscle-invasive bladder cancer. PATIENTS AND METHODS: The study consisted of 27 patients treated with cisplatin-based chemoradiation (CCRT), 48 treated with radiation alone (RT), and 42 with locally advanced disease treated with neoadjuvant chemotherapy and radiation (neoCRT). RESULTS: The incidence of acute grade 3 or more genitourinary (GU) toxicity in the RT, CCRT and neoCRT groups was: 25%, 11% and 19%, respectively (p=0.029). The 3-year freedom from grade 2 or more GU toxicity was: 81%, 89%, 54%, respectively (p=0.36). The long-term outcomes of 3-year local control, overall survival, and disease-free survival were as follows: RT group: 74%, 61% and 55%; CCRT group: 76%, 76% and 56%; neoCRT group: 31%, 43% and 18%, respectively. CONCLUSION: The preferable bladder-conserving approach is CRT, however RT alone might also be an option for appropriately selected patients. NeoCRT for those with locally advanced tumors remain unsatisfactory; adequate selection of patients for radical treatment is of importance.


Assuntos
Cisplatino/uso terapêutico , Músculo Esquelético/patologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/radioterapia , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia/efeitos adversos , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Invasividade Neoplásica/patologia , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/cirurgia
9.
Cancer Treat Rev ; 89: 102072, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32769039

RESUMO

BACKGROUND: Patients with advanced urothelial carcinoma (UC) have poor outcomes, with 5-year survival rates of <5% for those with metastatic, stage IV disease. We have reviewed current treatment paradigms and emerging treatment options for these patients. METHODS: The websites of seven national or international organizations were searched for metastatic UC treatment guidelines. Systematic literature reviews were conducted to identify evidence from randomized controlled trials (RCTs) of chemotherapy for patients with previously untreated, unresectable, stage IV UC. Searches included congress databases and articles published between 1990 and 2018. In order to align with the latest treatment paradigms in first-line advanced UC, a focused literature search was conducted to identify evidence supporting immuno-oncology (IO) agents. RESULTS: For advanced UC, guidelines universally recommend cisplatin-based chemotherapy as first-line treatment for eligible patients and carboplatin-based regimens for those unfit to receive cisplatin. Despite the evaluation of a number of different cytotoxic regimens over the years, including triplet combinations, survival outcomes have not improved markedly with chemotherapy. Median overall survival with standard of care chemotherapy is ~13 months. Based on the results of single-arm, phase II studies, recent treatment guidelines have included atezolizumab (anti-PD-L1) and pembrolizumab (anti-PD-1) as first-line options for cisplatin-ineligible patients whose tumors express high levels of PD-L1. However, emerging evidence from RCTs of IO agents, including both cisplatin-eligible and cisplatin-ineligible patients, suggest that survival times exceeding 20 months are possible. CONCLUSIONS: After having reached a plateau with chemotherapy, the treatment landscape for advanced UC is evolving. Survival outcomes for patients with advanced UC are improving with treatment modalities involving IO agents.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Carcinoma de Células de Transição/patologia , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Metástase Neoplásica , Estadiamento de Neoplasias , Guias de Prática Clínica como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias da Bexiga Urinária/patologia
10.
Asia Pac J Clin Oncol ; 16 Suppl 3: 18-23, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32852900

RESUMO

For advanced and metastatic urothelial carcinomas (UCs), platinum (preferably cisplatin)-based chemotherapy has been the standard treatment for many years. However, many patients are ineligible for cisplatin-based chemotherapy because of poor performance status and/or other age-related conditions. At the other end of the spectrum, patients with localized non-muscle-invasive bladder cancer who are unresponsive to intravesical Bacillus Calmette-Guérin (BCG) treatment often face radical cystectomy as the only option. In recent years, the application of immunotherapy in the form of immune-checkpoint inhibitors has provided viable alternatives in the second-line postplatinum and first-line cisplatin-ineligible settings. Recent and ongoing clinical trials are also assessing the safety and efficacy of immunotherapy for neoadjuvant and adjuvant uses before/after cystectomy, for BCG-unresponsive cases, and for combination treatments that include the newer indoleamine 2,3-dioxygenase-1 inhibitors and/or BCG. This review summarizes recent developments in immunotherapy for UCs.


Assuntos
Imunoterapia/métodos , Neoplasias da Bexiga Urinária/complicações , Neoplasias da Bexiga Urinária/tratamento farmacológico , Feminino , Humanos , Masculino , Metástase Neoplásica , Neoplasias da Bexiga Urinária/patologia
11.
Rev Med Liege ; 75(7-8): 518-520, 2020 Jul.
Artigo em Francês | MEDLINE | ID: mdl-32779902

RESUMO

Bladder cancer (urothelial carcinoma in 90 % of cases) is the most common neoplasia of the urinary tract. Superficial carcinoma represents 70-80 % of bladder cancers. The treatment of these tumours includes, after transuretral resection, intravesical Bacillus Calmette-Guerin (BCG) instillation therapy. This treatment constitutes, by its immune-mediated anti-tumoral action, the first step of immunotherapy in cancer. Severe complications (granulomatosis, hypersensitivity pneumonitis or orchitis) are rare (0.5-2 %). Here we report a complex case of pulmonary granulomatosis secondary to BCG therapy. This is a 74-year-old male, treated for superficial bladder carcinoma by transuretral resection (pT1G3) and then endovesical instillations of BCG therapy for two months. Two years later, a new transuretral resection shows an infiltrating urothelial carcinoma pT2G3. The extension balance finds a persistent micro-nodular pulmonary infiltrate. A broncho-alveolar lavage is then realised but no mycobacteria was found. A surgical biopsy of a nodule is performed and revealed a histiocytic reaction without any neoplastic element. Detection of Mycobacterium tuberculosis by Polymerase Chain Reaction (PCR) was finally positive. In the absence of a secondary lesion, the patient had a cysto-prostatectomy and began a tritherapy against tuberculosis. Post-BCG therapy granulomatosis is a rare complication but should remain a differential diagnosis in front of the appearance of pulmonary nodes in patients who have received posttransuretral resection BCG instillations. Mycobacterial DNA PCR research remains the most sensitive examination.


Assuntos
Mycobacterium bovis , Tuberculose Miliar , Tuberculose Pulmonar , Neoplasias da Bexiga Urinária/tratamento farmacológico , Administração Intravesical , Idoso , Humanos , Masculino
12.
Bull Cancer ; 107(5S): S6-S16, 2020 Jun.
Artigo em Francês | MEDLINE | ID: mdl-32620209

RESUMO

Until 2014, no new therapeutic agent have been approved by authorities in more than 2 decades for bladder cancer. But the panel of treatments has expended in recent years with the emergence of at least 3 different therapeutic classes. First, the immune checkpoint inhibitors that have demonstrated an overall survival benefit in metastatic patients after failure of platinum based chemotherapy. They are therefore currently evaluated alone or in combination with chemotherapy in multiple studies at earlier stages (localized and meta-static). The second and third therapeutic classes are the targeted therapies (especially FGFR inhibitor) and the antibody-drug conjugates with promising results in early clinical trials. In this article, we review all the current and future studies conducted in urothelial carcinoma of the bladder.


Assuntos
Carcinoma de Células de Transição/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Carcinoma de Células de Transição/secundário , Humanos , Imunoconjugados/uso terapêutico , Imunoterapia , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Terapias em Estudo
13.
Bull Cancer ; 107(5S): eS1-eS7, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32620210

RESUMO

BACKGROUND: The standard treatment in first line of advanced or metastatic urothelial bladder cancer (MBC) is the association of Gemcitabine and Cisplatin (GC). Avelumab, an anti-PD-L1 agent, has recently demonstrated efficacy. The objective is to evaluate the combination of these 3 agents. METHODS: This phase II randomized open-label study, evaluated if GC-avelumab increases response rate and duration of response of patients in 1st line treatment for MBC compared to GC. Severe toxicities should not overlap and be acceptable. The two co-primary end points are the objective response rate and the incidence of severe toxicity after six cycles of treatment. The study will recruit 90 participants, randomized in two arms (1:2), GC (gemcitabine 1 000 mg/m2/j, J1,J8, Cisplatine 70 mg/m2, J1 = J21), and GC-avelumab (10 mg/Kg/3 semaines). Randomization will be stratified on Karnofsky status (≥ 80 % vs. < 80 %) and visceral vs non visceral metastases. The duration of the inclusion period is 24 months, with a duration of participation of each patient of 18 months and a total study duration of 42 months. DISCUSSION: If both efficacy and safety of the association of GC+avelumab are in the range of acceptable through this specific study design, this will support a subsequent randomized phase III study comparing both arms with an overall survival end-point. In addition, the evaluation of predictive parameters to be confirmed (e.g. the impact of tumor PD-L1 expression) or other immunological parameters, may support a selection of the population. NCT number : NCT03324282.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma de Células de Transição/tratamento farmacológico , Cisplatino/administração & dosagem , Ensaios Clínicos Fase II como Assunto/métodos , Desoxicitidina/análogos & derivados , Estudos Multicêntricos como Assunto/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Carcinoma de Células de Transição/patologia , Desoxicitidina/administração & dosagem , Humanos , Invasividade Neoplásica , Estudos Prospectivos , Neoplasias da Bexiga Urinária/patologia
14.
Bull Cancer ; 107(5S): eS8-eS15, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32620213

RESUMO

BACKGROUND: Neoadjuvant cisplatin-based chemotherapy (NAC) is the standard of care in localized muscle-invasive bladder cancer (MIBC). However, 60-70% of patients have residual tumor after NAC. Based on the overall response rate observed in the metastatic setting, ddMVAC is the most commonly used NAC regimen in Europe. The emergence of immune checkpoint inhibitor (ICI) in the metastatic setting raises the question if the combination of chemo plus ICI could increase the pCR rate. METHODS/DESIGN: NEMIO is a French open-label randomized phase I/II trial assessing in the neoadjuvant setting the combination of ddMVAC plus durvalumab alone or with tremelimumab: 4 cycles of ddMVAC/2 weeks + 2 cycles of Durvalumab +/- Tremelimumab/4 weeks. Cystectomy is performed 4-8 weeks after the last dose of ddMVAC. Six pts will be included in each arm in a safety run-in cohort to evaluate the toxicity rate. Each arm will be expanded to a maximum of 60 pts. The primary endpoint of the safety run-in phase will be the rate of grade 3/4 treatment-related adverse events G3/4 TRAE. The primary endpoint of the phase II will be the pathological response rate and G 3/4 TRAE. Exploratory endpoints will include biomarkers of response and resistance to the combo. A total of 120 patients will be included in 15 French centers and we expect the recruitment to be completed in 2021. DISCUSSION: NEMIO trial will assess for the first time the tolerance and the efficacy of ddMVAC regimen associated with checkpoints inhibitors as neoadjuvant treatment in localized MIBC. NCT number: NCT03549715. Registered on June 8, 2018.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma de Células de Transição/tratamento farmacológico , Ensaios Clínicos Fase II como Assunto/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células de Transição/patologia , Cisplatino/uso terapêutico , Doxorrubicina/uso terapêutico , Humanos , Metotrexato/uso terapêutico , Terapia Neoadjuvante , Invasividade Neoplásica , Resultado do Tratamento , Neoplasias da Bexiga Urinária/patologia , Vimblastina/uso terapêutico
15.
Yonsei Med J ; 61(7): 587-596, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32608202

RESUMO

PURPOSE: The current study aimed to investigate the synergistic antitumor effect of combined treatment with 17-DMAG (HSP90 inhibitor) and NVP-BEZ235 (PI3K/mTOR dual inhibitor) on cisplatin-resistant human bladder cancer cells. MATERIALS AND METHODS: Human bladder cancer cells exhibiting cisplatin resistance (T24R2) were exposed to escalating doses of 17-DMAG (2.5-20 nM) with or without NVP-BEZ236 (0.5-4 µM) in combination with cisplatin. Antitumor effects were assessed by CCK-8 analysis. Based on the dose-response study, synergistic interactions between the two regimens were evaluated using clonogenic assay and combination index values. Flow cytometry and Western blot were conducted to analyze mechanisms of synergism. RESULTS: Dose- and time-dependent antitumor effects for 17-DMAG were observed in both cisplatin-sensitive (T24) and cisplatin-resistant cells (T24R2). The antitumor effect of NVP-BEZ235, however, was found to be self-limiting. The combination of 17-DMAG and NVP-BEZ235 in a 1:200 fixed ratio showed a significant antitumor effect in cisplatin-resistant bladder cancer cells over a wide dose range, and clonogenic assay showed compatible results with synergy tests. Three-dimensional analysis revealed strong synergy between the two drugs with a synergy volume of 201.84 µM/mL²%. The combination therapy resulted in G1-phase cell cycle arrest and caspase-dependent apoptosis confirmed by the Western blot. CONCLUSION: HSP90 inhibitor monotherapy and in combination with the PI3K/mTOR survival pathway inhibitor NVP-BEZ235 shows a synergistic antitumor effect in cisplatin-resistant bladder cancers, eliciting cell cycle arrest at the G1 phase and induction of caspase-dependent apoptotic pathway.


Assuntos
Antineoplásicos/uso terapêutico , Benzoquinonas/uso terapêutico , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Lactamas Macrocíclicas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Neoplasias da Bexiga Urinária/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica , Apoptose/efeitos dos fármacos , Benzoquinonas/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cisplatino/farmacologia , Dano ao DNA/efeitos dos fármacos , Humanos , Imidazóis , Lactamas Macrocíclicas/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Quinolinas , Serina-Treonina Quinases TOR/metabolismo
16.
Cancer Sci ; 111(9): 3397-3400, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32678492

RESUMO

We found that FOXO1-shRNA sublines or FOXO1-positive cells co-treated with a FOXO1 inhibitor were significantly more resistant to cisplatin treatment at pharmacological concentrations, compared with respective control sublines or those with mock treatment. Western blot demonstrated considerable increases in the expression levels of a phosphorylated inactive form of FOXO1 (p-FOXO1) in cisplatin-resistant sublines established by long-term culture with low/increasing doses of cisplatin, compared with respective controls. Immunohistochemistry in surgical specimens from patients with muscle-invasive bladder cancer undergoing cisplatin-based neoadjuvant therapy further showed a strong trend to associate between p-FOXO1 positivity and unfavorable response to chemotherapy.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Proteína Forkhead Box O1/genética , Inativação Gênica , Neoplasias da Bexiga Urinária/genética , Proteína Forkhead Box O1/metabolismo , Expressão Gênica , Humanos , Imuno-Histoquímica , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/metabolismo
17.
PLoS One ; 15(7): e0229193, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32614890

RESUMO

BACKGROUND: Urine-based diagnostics indicated involvement of oncoprotein 18 (OP18) in bladder cancer. In cell culture models we investigated the role of OP18 for malignant cell growth. METHODS: We analyzed 113 urine samples and investigated two human BCa cell lines as a dual model: RT-4 and ECV-304, which represented differentiated (G1) and poorly differentiated (G3) BCa. We designed specific siRNA for down-regulation of OP18 in both cell lines. Phenotypes were characterized by cell viability, proliferation, and expression of apoptosis-related genes. Besides, sensitivity to cisplatin treatment was evaluated. RESULTS: Analysis of urine samples from patients with urothelial BCa revealed a significant correlation of the RNA-ratio OP18:uroplakin 1A with bladder cancer. High urinary ratios were mainly found in moderately to poorly differentiated tumors (grade G2-3) that were muscle invasive (stage T2-3), whereas samples from patients with more differentiated non-invasive BCa (G1) showed low OP18:UPK1A RNA ratios. Down-regulation of OP18 expression in ECV-304 shifted its phenotype towards G1 state. Further, OP18-directed siRNA induced apoptosis and increased chemo-sensitivity to cisplatin. CONCLUSIONS: This study provides conclusive experimental evidence for the link between OP18-derived RNA as a diagnostic marker for molecular staging of BCa in non-invasive urine-based diagnostics and the patho-mechanistic role of OP18 suggesting this gene as a therapeutic target.


Assuntos
Biomarcadores Tumorais/urina , RNA/urina , Estatmina/genética , Neoplasias da Bexiga Urinária/diagnóstico , Idoso , Antineoplásicos/uso terapêutico , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Cisplatino/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Musculares/secundário , Gradação de Tumores , Fenótipo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Estatmina/antagonistas & inibidores , Estatmina/metabolismo , Estatmina/urina , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Uroplaquina Ia/genética
19.
Toxicol Appl Pharmacol ; 401: 115109, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32544403

RESUMO

Bladder cancer (BCa) is the fourth leading cause of cancer deaths worldwide due to its aggressiveness and resistance against therapies. Intricate interactions between cancer cells and the tumor microenvironment (TME) are essential for both disease progression and regression. Thus, interrupting molecular communications within the TME could potentially provide improved therapeutic efficacies. M2-polarized tumor-associated macrophages (M2 TAMs) were shown to contribute to BCa progression and drug resistance. We attempted to provide evidence for ovatodiolide (OV) as a potential therapeutic agent that targets both TME and BCa cells. First, tumor-suppressing functions of OV were determined by cell viability, colony, and tumor-sphere formation assays using a coculture system composed of M2 TAMs/BCa cells. Subsequently, we demonstrated that extracellular vesicles (EVs) isolated from M2 TAMs containing oncomiR-21 and mRNAs, including Akt, STAT3, mTOR, and ß-catenin, promoted cisplatin (CDDP) resistance, migration, and tumor-sphere generation in BCa cells, through increasing CDK6, mTOR, STAT3, and ß-catenin expression. OV treatment also prevented M2 polarization and reduced EV cargos from M2 TAMs. Finally, in vivo data demonstrated that OV treatment overcame CDDP resistance. OV only and the OV + CDDP combination both resulted in significant reductions in mTOR, ß-catenin, CDK6, and miR-21 expression in tumor samples and EVs isolated from serum. Collectively, we demonstrated that M2 TAMs induced malignant properties in BCa cells, in part via oncogenic EVs. OV treatment prevented M2 TAM polarization, reduced EV cargos derived from M2 TAMs, and suppressed ß-catenin/mTOR/CDK6 signaling. These findings provide preclinical evidence for OV as a single or adjuvant agent for treating drug-resistant BCa.


Assuntos
Quinase 6 Dependente de Ciclina/metabolismo , Diterpenos/uso terapêutico , MicroRNAs/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , beta Catenina/metabolismo , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Técnicas de Cocultura , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Relação Dose-Resposta a Droga , Exossomos/efeitos dos fármacos , Exossomos/metabolismo , Exossomos/patologia , Feminino , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , MicroRNAs/antagonistas & inibidores , Plantas Medicinais , Serina-Treonina Quinases TOR/antagonistas & inibidores , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , beta Catenina/antagonistas & inibidores
20.
Urologe A ; 59(7): 797-803, 2020 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-32500171

RESUMO

The first-line therapy of metastatic bladder cancer (urothelial carcinoma, UC) depends on whether a patient is cisplatin-fit or not. Cisplatin-fit patients should be treated with the standard chemotherapy protocol GC (gemcitabine/cisplatin) or alternatively MVAC (methotrexate/vinblastine/doxorubicin/cisplatin). The optimal first-line therapy for cisplatin-unfit patients remains unclear due to the lack of high level of evidence. One criterion for selecting therapy can be the PD-L1 (programmed cell death ligand 1) status of the tumor. The PD-L1-negative patients (PD-L1 <5% for atezolizumab and combined positivity score [CPS] <10 for pembrolizumab) seem to have a greater benefit from the combination chemotherapy GCa (carboplatin/gemcitabine). The PD-L1-positive patients (PD-L1 ≥5% or CPS ≥10) on the other hand may have a greater benefit from and a longer response to the two immune checkpoint inhibitors that are currently approved for this indication, namely atezolizumab and pembrolizumab. Two phase 3 trials that compare head-to-head immunotherapy alone or in combination with chemotherapy vs. chemotherapy alone may help to define the optimal first-line therapy for metastatic UC. Preliminary data from one of these studies indicate an advantage for the combination of immunotherapy with chemotherapy in all subgroups.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Imunoterapia/métodos , Imunoterapia/tendências , Neoplasias Ureterais/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias Urológicas/tratamento farmacológico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/imunologia , Carcinoma de Células de Transição/imunologia , Carcinoma de Células de Transição/patologia , Cisplatino/administração & dosagem , Humanos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Resultado do Tratamento , Neoplasias Ureterais/patologia , Neoplasias da Bexiga Urinária/patologia , Neoplasias Urológicas/patologia
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