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1.
Anticancer Res ; 40(1): 335-339, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892584

RESUMO

BACKGROUND/AIM: The novel taxane cabazitaxel has been shown to exert excellent anticancer effects after androgen receptor axis-targeting (ARAT) agents in clinical data, but not in in vitro data. We investigated the clinical outcome of cabazitaxel chemotherapy after docetaxel according to use of ARAT agents. PATIENTS AND METHODS: Prostate specific antigen (PSA) response, progression-free survival, and overall survival were compared between cases with and without prior use of ARAT agents in 74 Japanese patients with metastatic castration-resistant prostate cancer treated with cabazitaxel chemotherapy. RESULTS: Background characteristics were comparable between patients with and without prior use of ARAT agents. PSA response, progression-free survival, and overall survival in cabazitaxel chemotherapy were comparable between patients with and without prior use of ARAT agents. CONCLUSION: No detrimental effects of prior ARAT agents on clinical outcome were observed for cabazitaxel chemotherapy in the post-docetaxel setting, suggesting that cabazitaxel can be expected to remain active even after ARAT agent therapy.


Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Docetaxel/farmacologia , Terapia de Alvo Molecular , Receptores Androgênicos/metabolismo , Taxoides/farmacologia , Idoso , Antagonistas de Receptores de Andrógenos/uso terapêutico , Docetaxel/uso terapêutico , Humanos , Masculino , Prognóstico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Taxoides/uso terapêutico , Resultado do Tratamento
2.
Anticancer Drugs ; 31(3): 298-303, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31913197

RESUMO

This multi-institutional study aimed to identify prognostic factors for cabazitaxel treatment of castration-resistant prostate cancer (CRPC). This study included 74 Japanese patients with CRPC who were treated with cabazitaxel between 2014 and 2017. Associations between clinicopathological factors including serum markers and progression-free survival (PFS) and overall survival (OS) were investigated. On multivariate analysis, high Gleason score [≥9 vs. ≤7; hazard ratio (HR), 95% confidence interval (CI): 2.00 (1.01-4.34); P = 0.047], presence of pain [HR, 95% CI: 2.02 (1.14-3.58); P = 0.016], and lactate dehydrogenase (LDH) level [HR, 95% CI: 47.31 (3.79-577.49); P = 0.0019] were significantly associated with PFS. Similarly, number of docetaxel cycles [HR, 95% CI: 0.050 (0.0037-0.45); P = 0.0057], performance status [≥2 vs. 0; HR, 95% CI: 5.07 (1.57-16.24); P < 0.0001], and LDH level [HR, 95% CI: 2946 (50-420994); P = 0.0001] were significantly associated with OS. This study showed that LDH level is robustly prognostic for both PFS and OS in cabazitaxel chemotherapy for CRPC.

3.
Anticancer Res ; 39(8): 4411-4414, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366538

RESUMO

BACKGROUND/AIM: Cabazitaxel use has usually been limited to up to 10 cycles in most countries according to the protocol in the TROPIC trial. Therefore, clinical data on cabazitaxel use beyond 10 cycles is limited. The aim of this study was to report the therapeutic outcome of cabazitaxel chemotherapy administered for >10 cycles. PATIENTS AND METHODS: This study included 74 Japanese patients with prostate cancer between 2014 and 2017. Patients background, and treatment outcomes including PSA decline, progression-free survival, treatment-failure-free survival, overall survival, and adverse events were investigated, comparing patients treated with ≤10 and >10 cycles. RESULTS: Patients characteristics were favorable as indicated by the higher number of cycles of prior docetaxel chemotherapy, absence of pain, and absence of bony and visceral metastases among men who received >10 cycles of cabazitaxel. PSA response, progression-free survival, treatment-failure-free survival and overall survival were better among patients treated with >10 cycles of cabazitaxel compared to those treated with ≤10 cycles. The incidence of severe adverse events was similar between the two groups. CONCLUSION: Taken together, this study suggested that continuous chemotherapy with cabazitaxel beyond 10 cycles may be beneficial.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Docetaxel/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Taxoides/administração & dosagem , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Docetaxel/efeitos adversos , Esquema de Medicação , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/patologia , Taxoides/efeitos adversos , Resultado do Tratamento
4.
J Urol ; 202(6): 1127-1135, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31251717

RESUMO

PURPOSE: We investigated the impact of previous, simultaneous or subsequent bladder cancer on the clinical outcomes of upper urinary tract urothelial carcinoma. MATERIALS AND METHODS: We retrospectively collected data on 2,668 patients who underwent radical nephroureterectomy of nonmetastatic upper urinary tract urothelial carcinoma in 1995 to 2009. We evaluated the impact of bladder cancer on overall mortality and the factors predictive of subsequent bladder cancer. RESULTS: A total of 631 patients (23.7%) had previous or simultaneous bladder cancer. Patients with previous or simultaneous bladder cancer had significantly shorter overall survival than patients without previous or simultaneous bladder cancer (HR 1.29, 95% CI 1.09-1.53, p=0.0026). Of the 2,037 patients without previous or simultaneous bladder cancer 683 (33.5%) subsequently had bladder cancer after radical nephroureterectomy. Of patients with pT0-2 disease those with subsequent bladder cancer had significantly shorter overall survival than patients without subsequent bladder cancer (HR 1.81, 95% CI 1.23-2.67, p=0.0025). In patients with pT3-4 disease subsequent bladder cancer was not associated with worse overall survival. On multivariable analyses independent predictors of subsequent bladder cancer were gender, preoperative urine cytology and clinical node status in the preoperative setting, and gender, adjuvant chemotherapy and pathological node status in the postoperative setting. CONCLUSIONS: Bladder cancer was significantly associated with worse clinical outcomes after radical nephroureterectomy of upper urinary tract urothelial carcinoma. Preventing subsequent bladder cancer in patients with pT0-2 upper urinary tract urothelial carcinoma may lead to better prognosis in those who undergo radical nephroureterectomy.


Assuntos
Carcinoma de Células de Transição/cirurgia , Nefroureterectomia , Neoplasias Ureterais/cirurgia , Neoplasias da Bexiga Urinária/cirurgia , Idoso , Carcinoma de Células de Transição/mortalidade , Carcinoma de Células de Transição/patologia , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Primárias Múltiplas/mortalidade , Neoplasias Primárias Múltiplas/patologia , Neoplasias Primárias Múltiplas/cirurgia , Estudos Retrospectivos , Neoplasias Ureterais/mortalidade , Neoplasias Ureterais/patologia , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologia
5.
Cancer Chemother Pharmacol ; 84(3): 561-566, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31115605

RESUMO

OBJECTIVE: This study aimed to reveal the efficacy and safety profiles of 4-weekly cabazitaxel in patients with castration-resistant prostate cancer (CRPC). METHODS: The study included 62 Japanese patients who were treated for CRPC with ≥ 2 courses of cabazitaxel between 2014 and 2017. The oncological outcomes and adverse events were compared between 16 (25.8%) and 46 (74.2%) men who were treated with standard 3-weekly and alternative 4-weekly regimens, respectively. RESULTS: The prostate-specific antigen (PSA) response was comparable between the 3-weekly and 4-weekly regimens (median [interquartile range]: - 9.9% [- 64.5 to 13.0%] and - 30.7% [- 52.8 to 10.9%], P = 0.89), respectively. For patients on the 4-weekly regimen, the risks of progression (hazard ratio [HR], 95% confidence interval [CI] 1.27, 0.71-2.43, P = 0.44), treatment failure (HR, 95% CI 0.84, 0.48-1.55, P = 0.57) and any-cause mortality (HR, 95% CI 1.09, 0.58-2.17, P = 0.79) were comparable to those for patients on the 3-weekly regimen. The incidences of severe adverse events were also similar between the 3-weekly and 4-weekly regimens. CONCLUSIONS: 3-weekly and 4-weekly regimens of cabazitaxel showed similar efficacy and safety profiles in a real-world clinical setting. These data suggest that a 4-weekly regimen may be acceptable for selected patients.

6.
Med Oncol ; 36(4): 32, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30815799

RESUMO

This multi-institutional study aimed to investigate the efficacy and safety profiles of cabazitaxel after prior docetaxel chemotherapy in patients with castration-resistant prostate cancer (CRPC). This study included 63 Japanese patients with CRPC who were treated with cabazitaxel from 2014 to 2017. The oncological outcomes and adverse events (AEs) were documented, and prognostic factors for oncological outcomes and predictive factors for AEs were analysed. PSA decline was observed in 68.3% of patients, including 25.4% who achieved a ≥ 50% decline. The median progression-free survival, treatment failure-free survival, and overall survival were 4.3, 4.1, and 9.0 months, respectively. More cycles of prior docetaxel therapy was identified as common favourable prognostic factors for progression-free survival, treatment failure-free survival, and overall survival. Severe neutropenia, febrile neutropenia, and severe non-haematological AEs were observed in 73.0%, 33.3%, and 23.8% of patients, respectively. However, > 10 cycles of docetaxel was not associated with increased incidence of AEs. In conclusion, cabazitaxel chemotherapy was still active in Japanese CRPC patients treated with > 10 cycles of docetaxel chemotherapy, with an acceptable risk of AE burden. Treatment with cabazitaxel after > 10 cycles of docetaxel may be an appropriate option when it can be administered.


Assuntos
Docetaxel/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Esquema de Medicação , Humanos , Masculino , Resultado do Tratamento
7.
World J Urol ; 35(11): 1737-1744, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28508102

RESUMO

PURPOSE: To evaluate the impact of lymph node dissection (LND) on clinical outcome during radical nephroureterectomy (RNU) for patients with upper urinary tract urothelial cancer (UTUC). METHODS: We, the Urologic Oncology Study Group of the Japan Clinical Oncology Group (JCOG), retrospectively collected data from patients with non-metastatic UTUC who underwent RNU in 30 centers in 1995-2009. Ineligible patients and patients with previous and/or synchronous bladder cancer were excluded, and the remaining 2037 patients were analyzed. We compared overall and cancer-specific mortality between patients who underwent LND (LND group) and those without LND (no-LND group). RESULTS: Among 2037 patients, LND was performed in 1046 (51.4%) patients, and 223 (10.9%) patients had pathological node-positive (pN+) disease. All-cause mortality was observed in 503 patients (24.7%) during follow-up (median 45.8 months), including 363 patients (17.8%) who died of UTUC. Patients with pN+ disease showed significantly shorter overall survival (OS) compared with pN0 patients, and the estimated 5-year OS for pN+ patients was 30%. Older age, ≥cT3, and clinical node-positive disease were found as preoperative predictors for pN+ disease by multivariate analysis. In the comparison of OS and cancer-specific mortality between LND and no-LND groups, there was no significant improvement by LND in multivariate analysis. The median number of lymph nodes removed was six (IQR 3-11). There was no significant association between the number of lymph nodes removed and OS. CONCLUSIONS: The present study indicates that there is no therapeutic benefit of LND during RNU for UTUC, although pathologically positive LN status can predict poor prognosis.


Assuntos
Carcinoma de Células de Transição/cirurgia , Neoplasias Renais/cirurgia , Excisão de Linfonodo/estatística & dados numéricos , Linfonodos/patologia , Nefroureterectomia/métodos , Neoplasias Ureterais/cirurgia , Idoso , Carcinoma de Células de Transição/mortalidade , Carcinoma de Células de Transição/patologia , Causas de Morte , Feminino , Humanos , Japão , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Pelve Renal/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias Ureterais/mortalidade , Neoplasias Ureterais/patologia
8.
Prostate ; 77(2): 145-153, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27699813

RESUMO

BACKGROUND: FOXO3a is a member of the forkhead O transcription factors. FOXO3a induces the factors that contribute to cell cycle arrest and is considered a tumor suppressor in several malignant tumors. Y-box binding protein-1 (YB-1) is a multifunctional protein whose high expression is correlated with poor prognoses in various malignant tumors. In the current study, we investigated the relationship between FOXO3a and YB-1 to validate their functional roles in prostate cancer. METHODS: Western blotting and cytotoxicity assays were conducted in prostate cancer cells, LNCaP, and 22Rv1 cells. We also evaluated the protein expressions of FOXO3a and YB-1 in human prostate cancer tissues, using radical prostatectomy specimens. Then, we investigated the correlations between protein expressions and clinicopathologic parameters. RESULTS: We found that both FOXO3a and YB-1 proteins were phosphorylated by ERK signaling, resulting in FOXO3a inactivation and YB-1 activation in LNCaP and 22Rv1 cells. Inversely, inhibition of MEK or treatment with metformin activated FOXO3a through inactivation of ERK signaling and suppressed the viability of LNCaP and 22Rv1 cells in a dose-dependent manner. In immunohistochemical analysis, FOXO3a nuclear expression was inversely correlated with YB-1 nuclear expression (P < 0.0001). Furthermore, high FOXO3a nuclear expression was inversely correlated with a higher Gleason grade (P < 0.0001) and higher preoperative PSA (P = 0.0437). CONCLUSIONS: These results showed that in prostate cancer, FOXO3a, and YB-1 play inverse reciprocal roles as a tumor-suppressor gene and oncogene, respectively, through their master regulator ERK. Prostate 77:145-153, 2017. © 2016 Wiley Periodicals, Inc.


Assuntos
Proteína Forkhead Box O3/biossíntese , Regulação Neoplásica da Expressão Gênica , Sistema de Sinalização das MAP Quinases/fisiologia , Neoplasias da Próstata/metabolismo , Proteína 1 de Ligação a Y-Box/biossíntese , Idoso , Linhagem Celular Tumoral , Proteína Forkhead Box O3/genética , Humanos , Masculino , Pessoa de Meia-Idade , Fosforilação/fisiologia , Neoplasias da Próstata/genética , Proteína 1 de Ligação a Y-Box/genética
9.
J Infect Chemother ; 22(9): 581-6, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27452428

RESUMO

Genital chlamydial infection is a principal sexually transmitted infection worldwide. Chlamydia trachomatis can cause male urethritis, acute epididymitis, cervicitis, and pelvic inflammatory disease as sexually transmitted infections. Fortunately, homotypic resistant C. trachomatis strains have not been isolated to date; however, several studies have reported the isolation of heterotypic resistant strains from patients. In this surveillance study, clinical urethral discharge specimens were collected from patients with urethritis in 51 hospitals and clinics in 2009 and 38 in 2012. Based on serial cultures, the minimum inhibitory concentration (MIC) could be determined for 19 isolates in 2009 and 39 in 2012. In 2009 and 2012, the MICs (MIC90) of ciprofloxacin, levofloxacin, tosufloxacin, sitafloxacin, doxycycline, minocycline, erythromycin, clarithromycin, and azithromycin were 2 µg/ml and 1 µg/ml, 0.5 µg/ml and 0.5 µg/ml, 0.125 µg/ml and 0.125 µg/ml, 0.063 µg/ml and 0.063 µg/ml, 0.125 µg/ml and 0.125 µg/ml, 0.125 µg/ml and 0.125 µg/ml, 0.016 µg/ml and 0.016 µg/ml, and 0.063 µg/ml and 0.063 µg/ml, respectively. In summary, this surveillance project did not identify any resistant strain against fluoroquinolone, tetracycline, or macrolide agents in Japan.


Assuntos
Antibacterianos/farmacologia , Infecções por Chlamydia/epidemiologia , Chlamydia trachomatis/efeitos dos fármacos , Farmacorresistência Bacteriana , Fluoroquinolonas/farmacologia , Adolescente , Adulto , Técnicas de Cultura de Células , Infecções por Chlamydia/transmissão , Chlamydia trachomatis/isolamento & purificação , Humanos , Japão/epidemiologia , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Vigilância em Saúde Pública , Uretrite/microbiologia , Adulto Jovem
11.
Pathobiology ; 83(6): 277-86, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27225469

RESUMO

AIMS: The aims of this study were to investigate the association of renal cell carcinoma (RCC) displaying rhabdoid features and morphologically mesenchymal characteristics with epithelial to mesenchymal transition (EMT), and to clarify the expression of EMT markers. METHODS: We investigated the expression of EMT markers (E-cadherin, vimentin, Snail, Slug, ZEB1, ZEB2 and Twist1) using immunohistochemistry, Western blotting and real-time polymerase chain reaction in 18 cases of clear cell RCC (ccRCC) with rhabdoid features and 74 ccRCC cases with Fuhrman grade 1-3 (G1 to G3). RESULTS: In ccRCCs with rhabdoid features, low E-cadherin and high vimentin expression were found. In G1 to G3 ccRCCs, low E-cadherin expression and high expression of vimentin, ZEB1 and ZEB2 were found. There was no significant difference in the immunoexpression of E-cadherin and vimentin between the two ccRCC groups. CONCLUSIONS: The rhabdoid features may histologically and biologically be associated with EMT in ccRCC. There is a possibility that in G1 to G3 ccRCCs showing epithelial structures, other cell-cell adhesion mechanisms apart from E-cadherin adhesion may continue to work, and that ccRCC with rhabdoid features may be caused by an inactivation or loss of these mechanisms.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/metabolismo , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/metabolismo , Tumor Rabdoide/metabolismo , Antígenos CD , Biomarcadores Tumorais/genética , Caderinas/genética , Caderinas/metabolismo , Carcinoma de Células Renais/cirurgia , Humanos , Imuno-Histoquímica , Japão , Rim/patologia , Neoplasias Renais/cirurgia , Nefrectomia , Inclusão em Parafina , Estudos Retrospectivos , Tumor Rabdoide/cirurgia , Vimentina/genética , Vimentina/metabolismo
12.
Virchows Arch ; 468(3): 357-67, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26649732

RESUMO

In renal cell carcinoma (RCC), tumor cells with rhabdoid features are characterized by eccentric nuclei, prominent nucleoli, and eosinophilic cytoplasm with intracytoplasmic inclusion bodies. In RCC, tumor cells have also been observed resembling rhabdomyoblasts or rhabdoid but without intracytoplasmic inclusion bodies, and here, we defined these rhabdoid-like features of these cells. To this end, we studied a series of clear cell RCC (ccRCC) with rhabdoid features and compared them with a series of ccRCC with rhabdoid-like features to clarify the differences in the immunohistochemical profile and biological behavior. From 695 cases of ccRCC (80.8 % of all RCCs), 18 cases with rhabdoid features (2.1 % of all RCCs) and 25 cases with rhabdoid-like features (2.9 % of all RCCs) were investigated. The 5-year survival rate for ccRCC with rhabdoid features was 44.7 % and for ccRCC with rhabdoid-like features 30.3 %. Although ccRCC with rhabdoid features showed immunohistochemical co-expression of epithelial markers and vimentin as seen in malignant rhabdoid tumors, ccRCC with rhabdoid-like features showed no such co-expression. Multivariate analyses of cancer-specific survival revealed that perinephric tissues invasion was an independent prognostic factor in ccRCC with rhabdoid features (p = 0.0253) but not in ccRCC with rhabdoid-like features. In summary, although their prognosis is similar, the marker profile and pattern of extension of ccRCC with rhabdoid-like is different from that of ccRCC with rhabdoid features. Therefore, ccRCC with rhabdoid-like features should be distinguished from ccRCC with rhabdoid features.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma de Células Renais/diagnóstico , Corpos de Inclusão/patologia , Neoplasias Renais/diagnóstico , Tumor Rabdoide/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/patologia , Diagnóstico Diferencial , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica/métodos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Tumor Rabdoide/patologia
13.
J Infect Chemother ; 21(5): 340-5, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25727286

RESUMO

Worldwide, the most important concern in the treatment of sexually transmitted infections is the increase in antimicrobial resistant Neisseria gonorrhoeae strains including resistance to cephalosporins, penicillins, fluoroquinolones or macrolides. To investigate the trends of antimicrobial susceptibility among N. gonorrhoeae strains isolated from male patients with urethritis, a Japanese surveillance committee conducted the second nationwide surveillance study. Urethral discharge was collected from male patients with urethritis at 26 medical facilities from March 2012 to January 2013. Of the 151 specimens, 103 N. gonorrhoeae strains were tested for susceptibility to 20 antimicrobial agents. None of the strains was resistant to ceftriaxone, but the minimum inhibitory concentration (MIC) 90% of ceftriaxone increased to 0.125 µg/ml, and 11 (10.7%) strains were considered less susceptible with an MIC of 0.125 µg/ml. There were 11 strains resistant to cefixime, and the MICs of these strains were 0.5 µg/ml. The distributions of the MICs of fluoroquinolones, such as ciprofloxacin, levofloxacin and tosufloxacin, were bimodal. Sitafloxacin, a fluoroquinolone, showed strong activity against all strains, including strains resistant to other three fluoroquinolones, such as ciprofloxacin, levofloxacin and tosufloxacin. The azithromycin MICs in 2 strains were 1 µg/ml.


Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana , Neisseria gonorrhoeae/efeitos dos fármacos , Vigilância da População , Uretrite/microbiologia , Adolescente , Adulto , Idoso , Azitromicina/farmacologia , Cefixima/farmacologia , Ceftriaxona/farmacologia , Fluoroquinolonas/farmacologia , Humanos , Japão , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Penicilinas/farmacologia , Adulto Jovem
14.
Urol Oncol ; 32(1): 31.e1-7, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23395237

RESUMO

OBJECTIVE: To investigate the expression and possible roles of Twist1 and Y-box-binding protein-1 (YB-1) in bladder cancer tissue. Twist1 belongs to the family of basic helix-loop-helix transcription factors. A functional link between Twist1 and YB-1 has recently been determined to play an important role in bladder cancer cell lines. MATERIALS AND METHODS: Frozen samples from 75 patients with bladder cancer were analyzed by quantitative real-time polymerase chain reaction (PCR). Formalin-fixed and paraffin-embedded tissues from 53 patients with bladder cancer were examined by immunohistochemistry. RESULTS: Twist1 transcript levels were positively correlated with YB-1 transcript levels (coefficient of correlation = 0.42, P<0.001), tumor grade (low grade vs. high grade; P<0.001), invasiveness (non-muscle-invasive bladder cancer vs. muscle invasive bladder cancer; P = 0.0018), and metastasis (meta- vs. meta+; P<0.001). YB-1 transcript level was also correlated with grade (P = 0.029) and invasiveness (P = 0.006). By immunohistochemistry, Twist1 expression was also correlated with YB-1 expression (P<0.001). Further, both Twist1 and YB-1 expression were positively correlated with invasiveness (P = 0.007 and P = 0.002, respectively). Patients with high Twist1 expression and high YB-1 expression had lower overall survival rates, compared with patients with low expression (log-rank test, P = 0.040 and P<0.001, respectively). CONCLUSIONS: These results suggest a functional link between Twist1 and YB-1, and they indicate that Twist1 and YB-1 promote bladder cancer progression.


Assuntos
Regulação Neoplásica da Expressão Gênica , Proteínas Nucleares/metabolismo , Proteína 1 Relacionada a Twist/metabolismo , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/metabolismo , Proteína 1 de Ligação a Y-Box/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Resultado do Tratamento , Neoplasias da Bexiga Urinária/mortalidade
15.
Clin Cancer Res ; 19(17): 4638-50, 2013 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-23838318

RESUMO

PURPOSE: Y-box-binding protein-1 (YB-1) is known to conduct various functions related to cell proliferation, anti-apoptosis, epithelial-mesenchymal transition, and castration resistance in prostate cancer. However, it is still unknown how YB-1 affects cancer biology, especially its correlations with the mitogen-activated protein kinase (MAPK) signaling pathway. Therefore, we aimed to examine the interaction between YB-1 and the MAPK pathway in prostate cancer. EXPERIMENTAL DESIGN: Quantitative real-time PCR, Western blotting, and co-immunoprecipitation assay were conducted in prostate cancer cells. YB-1, phosphorylated YB-1 (p-YB-1), and ERK2 protein expressions in 165 clinical specimens of prostate cancer were investigated by immunohistochemistry. YB-1, p-YB-1, and ERK2 nuclear expressions were compared with clinicopathologic characteristics and patient prognoses. RESULTS: EGF upregulated p-YB-1, whereas MEK inhibitor (U0126, PD98059) decreased p-YB-1. Inversely, silencing of YB-1 using siRNA decreased the expression of ERK2 and phosphorylated MEK, ERK1/2, and RSK. Furthermore, YB-1 interacted with ERK2 and Raf-1 and regulated their expressions, through the proteasomal pathway. Immunohistochemical staining showed a significant correlation among the nuclear expressions of YB-1, p-YB-1, and ERK2. The Cox proportional hazards model revealed that high ERK2 expression was an independent prognostic factor [HR, 7.947; 95% confidence interval (CI), 3.527-20.508; P<0.0001]. CONCLUSION: We revealed the functional relationship between YB-1 and MAPK signaling and its biochemical relevance to the progression of prostate cancer. In addition, ERK2 expression was an independent prognostic factor. These findings suggest that both the ERK pathway and YB-1 may be promising molecular targets for prostate cancer diagnosis and therapeutics.


Assuntos
Sistema de Sinalização das MAP Quinases/genética , Neoplasias da Próstata/genética , Proteína 1 de Ligação a Y-Box/genética , Quinases raf/genética , Carcinogênese , Proliferação de Células , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Fosforilação , Neoplasias da Próstata/patologia , Transdução de Sinais , Proteína 1 de Ligação a Y-Box/metabolismo
16.
Cancer Immunol Immunother ; 62(3): 517-27, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23052245

RESUMO

Renal cell carcinoma (RCC) accounts for 80-95 % of kidney tumors, and approximately 30 % of RCC patients have metastatic disease at diagnosis. Conventional chemotherapy is not effective in patients with metastatic RCC (MRCC); therefore, immunotherapy with interferon-α (IFN-α) has been employed to improve survival. However, the response rate of MRCC to IFN-α therapy is low. We previously reported that a signal transducer and activator 3 (STAT3) polymorphism was a useful diagnostic marker to predict the response to IFN-α therapy in patients with MRCC. Therefore, we hypothesized the inhibition of STAT3 in the addition of IFN-α therapy might be useful. Moreover, the blockage of STAT3 itself has been reported to enhance the antitumor effects. However, because IFN-α is thought to elicit its therapeutic effect via enhancement of an antitumor immune response mediated by lymphocytes that can be activated by IFN-α administrations, it is probable that the suppression of STAT3 in vivo relates to autoimmune disorders. In the present study, we found Y-box binding protein-1 (YB-1) was poorly expressed in T lymphocytes, as compared with cancer tissues. YB-1 was reported to have an important effect on the STAT3 pathway. Suppression of STAT3 by YB-1 inhibition did not seem to enhance the potential risk for autoimmune disorders. Moreover, we found sensitivity to IFN-α was increased by YB-1 suppression, and this suppression did not down-regulate IFN-α activation of T lymphocytes.


Assuntos
Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/terapia , Interferon-alfa/uso terapêutico , Neoplasias Renais/metabolismo , Neoplasias Renais/terapia , Fator de Transcrição STAT3/metabolismo , Proteína 1 de Ligação a Y-Box/antagonistas & inibidores , Animais , Carcinoma de Células Renais/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Técnicas de Silenciamento de Genes , Humanos , Interferon-alfa/farmacologia , Neoplasias Renais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteólise , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Transplante Heterólogo , Células Tumorais Cultivadas , Proteína 1 de Ligação a Y-Box/farmacologia
17.
Jpn J Clin Oncol ; 42(11): 1094-8, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22952293

RESUMO

A Phase III clinical trial has been started in Japan to determine the optimal treatment strategy for patients with high-grade pT1 bladder cancer who have pT0 histology after second transurethral resection. The aim of this trial is to demonstrate the non-inferiority of relapse-free survival (excluding Tis or Ta intravesical recurrence) for watchful waiting compared with intravesical bacillus Calmette-Guérin therapy for pT0 after second transurethral resection. Patients with high-grade pT1 bladder cancer at the first registration and pT0 after second transurethral resection at the second registration are randomized to either a watchful waiting arm or an intravesical bacillus Calmette-Guérin therapy arm. A total of 575 patients at the first registration and 260 patients at the second registration will be accrued for this study from 38 institutions over 5 years. The primary endpoint is relapse-free survival (excluding Tis or Ta intravesical recurrence), and the secondary endpoints are overall survival, metastasis-free survival with bladder preserved, annual proportion of intravesical relapse-free survival, annual proportion of T2 or deeper relapse-free survival, adverse events and serious adverse events.


Assuntos
Vacina BCG/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Bexiga Urinária/efeitos dos fármacos , Conduta Expectante , Administração Intravesical , Grupo com Ancestrais do Continente Asiático , Vacina BCG/administração & dosagem , Seguimentos , Humanos , Japão , Oncologia , Gradação de Tumores , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Análise de Sobrevida , Resultado do Tratamento , Bexiga Urinária/patologia , Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/etnologia , Neoplasias da Bexiga Urinária/cirurgia
18.
J Urol ; 188(1): 276-86, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22608749

RESUMO

PURPOSE: There are several reports of androgen receptor in bladder cancer cases but androgen receptor expression and the function of androgen/androgen receptor signaling in bladder cancer remain unclear. We investigated androgen receptor expression and the role of androgen/androgen receptor signaling in bladder cancer. MATERIALS AND METHODS: We evaluated AR mRNA expression in bladder cancer tissue by quantitative real-time polymerase chain reaction. The role of androgen receptor in cell growth and drug sensitivity was also evaluated in vitro and in vivo in several bladder cancer cell lines. RESULTS: AR mRNA expression inversely correlated with bladder cancer grade, stage and spread. Of several bladder cancer cell lines UMUC3 and MBT-2 markedly expressed androgen receptor transcript and protein. In each cell line androgen/androgen receptor signaling blockade using androgen deprivation, blockade knockdown and antiandrogen agents decreased cell growth, colony formation and cell viability. Androgen receptor expression was implicated in doxorubicin resistance. Inversely androgen receptor deprivation and knockdown made UMUC3 cells sensitive to doxorubicin. Finally, castration slightly suppressed UMUC3 tumor growth in vivo, although this did not attain statistical significance. CONCLUSIONS: AR transcript expression inversely correlates with bladder cancer clinicopathological characteristics. Androgen/androgen receptor signaling has an important role in the growth and vulnerability to doxorubicin of bladder cancer cells that express androgen receptor. Androgen/androgen receptor signaling might be a possible prophylactic and therapeutic target for bladder cancer that shows androgen receptor expression.


Assuntos
Proliferação de Células/efeitos dos fármacos , Doxorrubicina/uso terapêutico , Regulação Neoplásica da Expressão Gênica , RNA Neoplásico/genética , Receptores Androgênicos/genética , Neoplasias da Bexiga Urinária/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antibióticos Antineoplásicos/uso terapêutico , Ciclo Celular , Linhagem Celular Tumoral , Cistectomia , Feminino , Citometria de Fluxo , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Neoplasias Experimentais , Reação em Cadeia da Polimerase em Tempo Real , Receptores Androgênicos/biossíntese , Estudos Retrospectivos , Transdução de Sinais , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/terapia
19.
BJU Int ; 110(8 Pt B): E357-61, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22416962

RESUMO

OBJECTIVE: To determine the cause of diminished renal function in the affected kidney after partial nephrectomy (PN) for renal tumour, we analyzed the relationship between operative data and postoperative recovery with respect to renal function. PATIENTS AND METHODS: From May 2005 to December 2010, pre- and postoperative (1 week and 3 months after the procedure) renal function was evaluated by 99mTc- mercaptoacetyltriglycine clearance in 51 patients treated with open partial nephrectomy (OPN; n = 24) and laparoscopic partial nephrectomy (LPN; n = 27). LPN was performed via retroperitoneal (RPLPN; n = 14) or transperitoneal (TPLPN; n = 13) routes. Renal cooling was performed after renal hilar clamping in OPN and RPLPN, although not in TPLPN. RESULTS: There were 10 patients (two in OPN, six in TPLPN, two in RPLPN) who had diminished renal function in the affected kidney from 1 week to 3 months after PN. Warm ischaemia (versus cold ischaemia; P = 0.017) during renal hilar clamping resulted in diminished renal function. Using multivariate analysis, renal cooling influenced postoperative diminished renal function (P = 0.008). CONCLUSIONS: Successful preservation of renal function after PN depends on renal cooling during renal hilar clamping. Cold ischaemia for avoiding renal damage is recommended if renal hilar clamping is necessary for tumour extraction.


Assuntos
Neoplasias Renais/cirurgia , Rim/fisiopatologia , Nefrectomia/efeitos adversos , Nefrectomia/métodos , Adulto , Idoso , Feminino , Humanos , Rim/diagnóstico por imagem , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Cintilografia , Compostos Radiofarmacêuticos , Tecnécio Tc 99m Mertiatida
20.
Int J Oncol ; 40(5): 1691-6, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22344606

RESUMO

Bladder cancer patients who are refractory to chemotherapy have a poor prognosis. Furthermore, additional chemotherapies provide little benefit to patients who have relapsed after an initial response. Recently, it was reported that several molecular pathways are implicated in bladder carcinogenesis, including the epidermal growth factor receptor (EGFR) pathway, the vascular endothelial growth factor (VEGF) pathway and the Ras-MAPK pathway. We hypothesized that sunitinib would be effective in bladder cancer as it is an oral inhibitor of multiple receptor tyrosine kinases, including VEGF receptors, platelet derived growth factor (PDGF) receptors and stem cell factor receptor (c-KIT), and is a standard first-line treatment of advanced clear cell renal carcinoma. In the present study, the antiproliferative effects of sunitinib were clearly demonstrated in KK47, KK47/DDP20 and KK47/ADR cell lines in vitro due to the suppression of ERK1/2 phosphorylation. In a mouse model, the antitumor effects of sunitinib were again clearly seen. Also, treatment with sunitinib decreased the abundance of regulatory T cells (Tregs). However, cytotoxic T lymphocyte (CTL) activity was not induced sufficiently as compared with an IFN-α-treated group. Our results suggested that sunitinib was effective in chemotherapy-resistant bladder cancer patients. On the other hand, these findings provided the rationale for combination therapy with sunitinib and immune-based cancer therapy for advanced malignancies to prevent the occurrence of rebound phenomena.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Indóis/farmacologia , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirróis/farmacologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação para Baixo , Feminino , Humanos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Nus , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Sunitinibe , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Fatores de Tempo , Carga Tumoral/efeitos dos fármacos , Neoplasias da Bexiga Urinária/enzimologia , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
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