RESUMO
Chemopreventive and potential therapeutic effects of soy isoflavones have been shown to be effective in numerous preclinical studies as well as clinical studies in prostate cancer. Although the inhibition of androgen receptor signaling has been supposed as one mechanism underlying their effects, the precise mechanism of androgen receptor inhibition remains unclear. Thus, this study aimed to clarify their mechanism. Among soy isoflavones, equol suppressed androgen receptor as well as prostate-specific antigen expression most potently in androgen-dependent LNCaP cells. However, the inhibitory effect on androgen receptor expression and activity was less prominent in castration-resistant CxR and 22Rv1 cells. Consistently, cell proliferation was suppressed and cellular apoptosis was induced by equol in LNCaP cells, but less so in CxR and 22Rv1 cells. We revealed that the proteasome pathway through S-phase kinase-associated protein 2 (Skp2) was responsible for androgen receptor suppression. Taken together, soy isoflavones, especially equol, appear to be promising as chemopreventive and therapeutic agents for prostate cancer based on the fact that equol augments Skp2-mediated androgen receptor degradation. Moreover, because Skp2 expression was indicated to be crucial for the effect of soy isoflavones, soy isoflavones may be applicable for precancerous and cancerous prostates.
Assuntos
Equol/farmacologia , Fitoestrógenos/farmacologia , Neoplasias da Próstata/patologia , Receptores Androgênicos/metabolismo , Proteínas Quinases Associadas a Fase S/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Di-Hidrotestosterona/farmacologia , Humanos , Masculino , Antígeno Prostático Específico/metabolismo , Ligação Proteica/efeitos dos fármacosRESUMO
BACKGROUND: To improve antitumor effects against metastatic renal cell carcinoma (mRCC), use of molecular target-based drugs in sequential or combination therapy has been advocated. In combination therapy, interferon (IFN)-α amplified the effect of sorafenib in our murine model (J Urol 184:2549, 2010), and cytokine-treated mRCC patients in Japan had good prognoses (Eur Urol 57:317, 2010). We thus conducted a phase II clinical trial of sorafenib plus IFN-α for untreated mRCC patients in Japan. METHODS: In this multicenter, prospective study, provisionally registered patients with histologically confirmed metastatic clear cell RCC received natural IFN-α (3 dosages of 3 million U per week) for 2 weeks. Only IFN-α-tolerant patients were registered to this trial, and treated additionally with oral sorafenib (400 mg, bid). The primary end point of the study was rate of response (CR + PR) to sorafenib plus IFN-α treatment assessed using RECIST v1.0. The secondary end points were disease control rate (CR + PR + SD), progression free survival (PFS), overall survival (OS), and safety of the combined treatment. PFS and OS curves were plotted using the Kaplan-Meier method. RESULTS: From July 2009 to July 2012, a total of 53 untreated patients were provisionally registered, and 51 patients were finally registered. Rate of Response to the combined therapy of sorafenib plus IFN-α was 26.2 % (11/42) (CR 1, PR 10). The median PFS was 10.1 months (95 % CI, 6.4 to 18.5 months), and the median OS has not been reached yet. The combined therapy increased neither the incidence of adverse effects (AE) nor the incidence of unexpected AE. A limitation was that a relatively high number of patients (9 patients) were excluded for eligibility criteria violations. CONCLUSION: Our data have demonstrated that sorafenib plus IFN-α treatment is safe and effective for untreated mRCC patients. TRIAL REGISTRATION: UMIN000002466 , 9(th) September, 2009.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Renais/mortalidade , Feminino , Humanos , Interferon-alfa/administração & dosagem , Japão , Estimativa de Kaplan-Meier , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Niacinamida/administração & dosagem , Niacinamida/análogos & derivados , Compostos de Fenilureia/administração & dosagem , Sorafenibe , Resultado do TratamentoRESUMO
OBJECTIVE: Axitinib is a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3. The efficacy and safety of axitinib in Japanese patients with metastatic renal cell carcinoma were evaluated. METHODS: A subgroup analysis was conducted in Japanese patients enrolled in the randomized Phase III trial of axitinib versus sorafenib after failure of one prior systemic therapy for metastatic renal cell carcinoma. RESULTS: Twenty-five (of 361) and 29 (of 362) patients randomized to the axitinib and sorafenib arms, respectively, were Japanese and included in this analysis. Median progression-free survival in Japanese patients was 12.1 months (95% confidence interval 8.6 to not estimable) for axitinib and 4.9 months (95% confidence interval 2.8-6.6) for sorafenib (hazard ratio 0.390; 95% confidence interval 0.130-1.173; stratified one-sided P = 0.0401). The objective response rate was 52.0% for axitinib and 3.4% for sorafenib (P = 0.0001). The common all-causality adverse events (all grades) in Japanese patients were dysphonia (68%), hypertension (64%), hand-foot syndrome (64%) and diarrhea (56%) for axitinib, and hand-foot syndrome (86%), hypertension (62%) and diarrhea (52%) for sorafenib. The safety profiles of axitinib and sorafenib in Japanese patients were generally similar to those observed in the overall population, with the exceptions of higher incidences of hypertension, dysphonia, hand-foot syndrome, hypothyroidism and stomatitis. CONCLUSIONS: Axitinib is efficacious and well tolerated in Japanese patients with previously treated metastatic renal cell carcinoma, consistent with the results in the overall population, providing a new targeted therapy for these Japanese patients.
Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Imidazóis/uso terapêutico , Indazóis/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Axitinibe , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Diarreia/induzido quimicamente , Intervalo Livre de Doença , Feminino , Síndrome Mão-Pé/etiologia , Humanos , Hipertensão/induzido quimicamente , Hipotireoidismo/induzido quimicamente , Imidazóis/efeitos adversos , Indazóis/efeitos adversos , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Niacinamida/efeitos adversos , Niacinamida/uso terapêutico , Compostos de Fenilureia/efeitos adversos , Proteinúria/induzido quimicamente , Sorafenibe , Resultado do Tratamento , Adulto JovemRESUMO
Mechanisms linked to actin filaments have long been thought to cooperate in smooth muscle contraction, although key molecules were unclear. We show evidence that cardiac troponin T (cTnT) substantially contributes to Ca(2+)-mediated contraction in a physiological range of cytosolic Ca(2+) concentration ([Ca(2+)](i)). cTnT was detected in various smooth muscles of the aorta, trachea, gut and urinary bladder, including in humans. Also, cTnT was distributed along with tropomyosin in smooth muscle cells, suggesting that these proteins are ready to cause smooth muscle contraction. In chemically permeabilised smooth muscle of cTnT(+/-) mice in which cTnT reduced to ~50%, the Ca(2+)-force relationship was shifted toward greater [Ca(2+)](i), indicating a sizeable contribution of cTnT to smooth muscle contraction at [Ca(2+)](i) < 1â µM. Furthermore, addition of supplemental TnI and TnC reconstructed a troponin system to enhance contraction. The results indicated that a Tn/Tn-like system on actin-filaments cooperates together with the thick-filament pathway.
Assuntos
Sinalização do Cálcio/fisiologia , Cálcio/metabolismo , Coração/fisiologia , Contração Muscular/fisiologia , Músculo Liso/fisiologia , Troponina T/metabolismo , Animais , Humanos , Técnicas In Vitro , Camundongos , Distribuição TecidualRESUMO
OBJECTIVE: Sorafenib is an oral multi-kinase inhibitor of Raf-1, VEGF and PDGF receptors and others, resulting in tumor regression and anti-angiogenesis. We studied serum pancreatic enzyme increase associated with sorafenib treatment. PATIENTS AND METHODS: In a phase II study of Japanese patients with metastatic renal cell carcinoma, a total of 131 patients received sorafenib 400 mg twice per day. Serum levels of lipase and amylase were measured on day 7 and every 3-4 weeks thereafter during treatment period. When grade 3 or 4 enzyme abnormalities were observed, ultrasound or computed tomography scan was performed to detect pancreatitis. RESULTS: The incidence of all-grades lipase and amylase increases were 55. 7% and 38. 2%, respectively, while those of grade 3 or 4 were 30. 5% and 5. 3%, respectively. The majority of these events were observed in the first 3 weeks of sorafenib treatment. Grade 3 or 4 lipase increase was detected in 32 patients (24. 4%)on day 7 measurement. These abnormal elevations spontaneously resolved in all patients. Regarding grade 3 lipase increase, the median time to recovery to grade 2 and 1 were 7 and 14 days, respectively. Three patients required interruption of the treatment. No patient showed any clinical manifestation or abnormal imaging finding suggesting pancreatitis. CONCLUSION: Pancreatic enzyme increases observed frequently under sorafenib treatment were transient and asymptomatic. They were not related to symptomatic pancreatitis.
Assuntos
Amilases/sangue , Benzenossulfonatos/efeitos adversos , Lipase/sangue , Pâncreas/efeitos dos fármacos , Pâncreas/enzimologia , Inibidores de Proteínas Quinases/efeitos adversos , Piridinas/efeitos adversos , Adulto , Idoso de 80 Anos ou mais , Benzenossulfonatos/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Compostos de Fenilureia , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , SorafenibeRESUMO
UNLABELLED: What's known on the subject? and What does the study add? Interim result of this study had shown promising efficacy, with response rate of 14.7% and median PFS of 7.4 months, and good tolerability of sorafenib in previously-treated Japanese patients with metastatic RCC. Final result of the study adds: (1) the median overall survival of 25.3 months, which is longer than that in the global phase III study TARGET; (2) the response rate which elevated to 19.4% because of 6 late responders achieved after 9.2 months or longer of SD period; (3) lack of either unknown adverse events nor cumulative toxicity in the long-term use of sorafenib. OBJECTIVE: ⢠To explore the long-term efficacy and safety of sorafenib in Japanese patients with metastatic renal cell carcinoma (RCC) in a phase II trial. PATIENTS AND METHODS: ⢠In all, 131 Japanese patients with metastatic RCC who had received nephrectomy and failed at least one cytokine-containing systemic therapy received continuous sorafenib 400 mg twice daily, and the efficacy and safety parameters were evaluated in these patients, including objective response rate, progression-free survival and overall survival. RESULTS: ⢠Of the total, 129 patients were valid for intention-to-treat analyses and 131 patients were valid for safety analyses. ⢠Twenty-five patients (19.4%) had confirmed partial response and 87 patients (67.4%) had stable disease as best overall response. The 25 patients included six late-responders who achieved response after 9.2 months or longer of stable disease. The objective response rate and disease control rate were 19.4% and 73.6%, respectively. ⢠The median overall survival and median progression-free survival were 25.3 and 7.9 months, respectively. ⢠Safety profile was consistent with those previously reported, with hand-foot skin reaction (58.0%), lipase elevation (57.3%) and diarrhoea (42.7%) as the most frequently observed drug-related adverse events. Neither unknown adverse event nor cumulative toxicity was observed over the long-term use of sorafenib. ⢠Despite the dose discontinuation/interruption/reduction, the mean and median relative dose intensities were 86.4% and 97.4%, respectively. CONCLUSION: ⢠The final results of this trial showed that long-term use of sorafenib after cytokine treatment was well tolerated and provided new efficacy data, including late-response events and favourable overall survival in Japanese patients with metastatic RCC.
Assuntos
Antineoplásicos/uso terapêutico , Benzenossulfonatos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Piridinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/secundário , Citocinas/uso terapêutico , Intervalo Livre de Doença , Humanos , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Compostos de Fenilureia , Sorafenibe , Resultado do TratamentoRESUMO
OBJECTIVES: Various types of minimally invasive surgical treatments, including transurethral resection of prostate (TURP), are being carried out in Japan for patients with benign prostatic hyperplasia (BPH). The aim of the present study was to elucidate the current status of perioperative care for these treatments by carrying out a nationwide survey. METHODS: Assisted by the Japanese Endourology and ESWL Association, perioperative data from 157 institutions participating in this survey were collected and analyzed. RESULTS: This survey included 3918 patients undergoing TURP, 242 TUR in saline (TURis), 638 holmium laser enucleation of the prostate (HoLEP), 90 holmium laser ablation (HoLAP) and 241 photoselective vaporization (PVP). Mean operative time was shorter in TURP (71 min) and longer in HoLEP (127). Although no transfusions were required in cases undergoing HoLAP or PVP, blood was frequently transfused in those undergoing TURis (25.6%), TURP (10.2%) and HoLEP (7.8%), and the difference was significant. During the hospital stay, the incidence of TUR-syndrome, postoperative bleeding requiring bladder irrigation, acute urinary retention/difficulty on micturition and pad use at discharge was highest in TURP (2.3%), TURis (7.9%), HoLAP (16.7%) and HoLEP (15.1%), respectively. Two patients undergoing TURP died (0.05%). The shortest mean postoperative hospital stay was for PVP (1.6 days, even if the readmission rate within 90 days was the highest in this same group; 6.2%). Perioperative care during hospital stay varied among the five types of procedures. CONCLUSIONS: This survey provides useful documentation on the current status of minimally invasive treatments for BPH in Japan. Complication rates for TURP are not significantly higher as compared with other procedures. Thus, TURP can still be considered as the gold standard for BPH treatment.
Assuntos
Assistência Perioperatória , Hiperplasia Prostática/cirurgia , Ressecção Transuretral da Próstata , Idoso , Estudos Transversais , Inquéritos Epidemiológicos , Humanos , Japão , MasculinoRESUMO
PURPOSE: The multikinase and tyrosine kinase inhibitor sorafenib has antitumor activity in patients with advanced renal cell carcinoma. Recent reports show the ability of sorafenib to synergize with interferon-α, leading to greater antitumor activity. We examined the underlying mechanism of sorafenib and interferon-α synergism for renal cell carcinoma treatment in vitro and in tumor bearing murine models. MATERIALS AND METHODS: We used murine and human renal cell carcinoma cell lines for in vitro cell proliferation assay. ACHN (ATCC®) and RENCA tumors were subcutaneously transplanted into NCr-nu/nu and syngeneic BALB/c mice (Charles River Laboratories, Yokohama, Japan), respectively. Mice were treated with sorafenib and/or interferon-α, and tumor growth was monitored. Immunological assays were done in the RENCA model. RESULTS: In the ACHN and RENCA cell lines combination index analysis clearly revealed the synergistic antiproliferative effects of interferon-α and sorafenib in vitro. In the ACHN NCr-nu/nu model we clearly noted the synergistic antitumor effects of interferon-α and sorafenib, indicating the synergistic direct effects of each drug on tumor growth. In the RENCA BALB/c model flow cytometry showed no change in the proportion of lymphocytes. However, while sorafenib alone did not induce natural killer or cytotoxic T-lymphocyte activity against RENCA in that model, interferon-α alone or combined with sorafenib induced natural killer and cytotoxic T-lymphocyte activity. CONCLUSIONS: Our results show the synergistic activity of interferon-α and sorafenib. These findings provided the rationale for combination therapy with interferon-α and sorafenib in patients with advanced renal cell carcinoma.
Assuntos
Antineoplásicos/uso terapêutico , Benzenossulfonatos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Interferon-alfa/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Piridinas/uso terapêutico , Animais , Linhagem Celular Tumoral , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Niacinamida/análogos & derivados , Compostos de Fenilureia , SorafenibeRESUMO
UNLABELLED: Kidney cancer accounts for approximately 2% of all cancers worldwide, with renal cell carcinoma being the most common form and this report is focused on renal cell carcinoma. Globally, the incidence and mortality rates are increasing by 2-3% per decade. Kidney cancer is less common in Asia compared with the West. Cigarette smoking, obesity, acquired cystic kidney disease and inherited susceptibility are known risk factors for kidney cancer. The National Comprehensive Cancer Network Guidelines recommend surgical excision as first line of treatment for Stage I, II or III kidney cancer patients and Stage IV patients with resectable tumours. Immunotherapy has a 20-year history in treatment of metastatic kidney cancer. High-dose interleukin-2 (IL-2) is administered in some countries, whereas low-dose IL-2 and interferon-alpha (IFN-α) are popular in Japan. Molecular-targeted drugs, including sunitinib, bevacizumab and sorafenib, are being used for previously untreated and refractory patients. Asian and non-Asian populations have shown large differences in the incidences of adverse events with sorafenib and sunitinib. CONSENSUS STATEMENT: Kidney cancer is relatively uncommon in Asia compared with the West, but its incidence is increasing in more developed Asian nations. Guidelines from the National Comprehensive Cancer Network , etc., for treating metastatic renal cell carcinoma are based on Phase III clinical trials conducted primarily in Western patients. Targeted therapies are now becoming primary recommendations, but efficacy/toxicity data from Asian patients are lacking. Some drugs cause adverse effects in Asians because their recommended dosages are optimal for Caucasians but may be too high for Asians. Further research is necessary to develop optimal treatment strategies for Asians.
Assuntos
Carcinoma de Células Renais/terapia , Neoplasias Renais/terapia , Ásia/epidemiologia , Carcinoma de Células Renais/epidemiologia , Humanos , Neoplasias Renais/epidemiologiaRESUMO
PURPOSE: We evaluated the use of narrow-band imaging (NBI) cystoscopy for the detection of bladder cancer and analyzed its diagnostic efficacy in cases of carcinoma in situ (CIS) and in cases with known urine cytology results. PATIENTS AND METHODS: A prospective controlled study of NBI was conducted in 104 consecutive patients with definite or suspected bladder cancer. Transurethral targeted biopsies were performed after white light imaging (WLI) and NBI cystoscopy, and the histologic outcomes were compared. RESULTS: A total of 313 biopsies were taken, including 161 from sites identified as potentially abnormal by NBI and/or WLI cystoscopy, and 152 from apparently normal sites. The percentage of malignancies in the sites identified only by NBI was 55.7% (39/70 places). In 26.9% of patients (28/104), bladder tumors were detected only by NBI. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and likelihood ratio of a negative test (NLR) for the detection of bladder tumors using NBI in all patients were 92.7%, 70.9%, 63.4%, 94.7%, and 0.10, respectively. The sensitivity, specificity, PPV, NPV, and NLR for the detection of CIS using NBI were 89.7%, 74.5%, 78.8%, 87.2%, and 0.14, respectively. The sensitivity, specificity, PPV, NPV, and NLR for the detection of bladder tumors using NBI in patients with positive vs negative urine cytology were 85.4% vs 98.4%, 75.7% vs 66.3%, 61.2% vs 64.5%, 92.0% vs 98.5%, and 0.19 vs 0.02, respectively. CONCLUSIONS: NBI is a simple and effective method for identifying bladder tumors including CIS without the need for dyes because of its high sensitivity, high NPV, and low NLR.
Assuntos
Terapias Complementares/métodos , Diagnóstico por Imagem/métodos , Neoplasias da Bexiga Urinária/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma in Situ/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Bexiga Urinária/patologiaRESUMO
Patients with advanced cancer including breast cancer, hepatocellular cancer and urothelial cancer frequently receive a chemotherapy regimen containing doxorubicin. However, doxorubicin-resistance is a major obstacle for cancer chemotherapy. Recently, several molecular-targeted agents have become available. Sorafenib (BAY 43-9006) is known to target multiple kinases and has demonstrated activity in renal cell and hepatocellular cancer. In this study, sorafenib was found to inhibit phosphorylation of the eukaryotic initiation factor-2alpha (eIF2alpha), induce cell cycle arrest at G2 phase and increase cellular apoptosis in doxorubicin-resistant human urothelial cell lines. An eIF2alpha kinase, PERK was responsible for eIF2alpha phosphorylation and PERK knockdown induced cellular apoptosis similar to sorafenib treatment in doxorubicin-resistant cancer cells. Furthermore, sorafenib sensitized doxorubicin-resistant cancer cells, but not their parental cells to oxidative stress exerted by both hydrogen peroxide and doxorubicin. In addition, PERK knockdown sensitized doxorubicin-resistant cancer cells to oxidative stress. In conclusion, PERK inhibition using sorafenib with or without doxorubicin might be a promising therapeutic approach for doxorubicin-resistant cancers retaining high phosphorylation levels of eIF2alpha.
Assuntos
Benzenossulfonatos/farmacologia , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fator de Iniciação 2 em Eucariotos/metabolismo , Neoplasias/patologia , Piridinas/farmacologia , eIF-2 Quinase/antagonistas & inibidores , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Benzenossulfonatos/administração & dosagem , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Fator de Iniciação 2 em Eucariotos/antagonistas & inibidores , Fator de Iniciação 2 em Eucariotos/fisiologia , Humanos , Peróxido de Hidrogênio/administração & dosagem , Peróxido de Hidrogênio/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Niacinamida/análogos & derivados , Compostos de Fenilureia , Fosforilação/efeitos dos fármacos , Piridinas/administração & dosagem , Sorafenibe , Células Tumorais Cultivadas , eIF-2 Quinase/metabolismoRESUMO
OBJECTIVES: To compare photoselective vaporization of the prostate (PVP) and transurethral resection of the prostate (TURP) in patients with benign prostatic hyperplasia. METHODS: Patients were enrolled in a prospective non-randomized trial and underwent PVP (n = 78) and TURP (n = 51). Primary outcome variables included: International Prostate Symptom Score, quality-of-life score, urinary peak flow and post-void residual urine volume at 3, 6 and 12 months postoperatively. Secondary outcomes were urodynamic variables, including the index of bladder outlet obstruction (BOO) and detrusor contractility. RESULTS: Improvement in all outcome variables after PVP was comparable to that after TURP within 12 months. Outcome based on urodynamic parameters was also similar. Pre/post median value of the BOO index was 63/2 in the PVP group and 61/5 in the TURP group. Pre/post rate of detrusor overactivity was 49%/27% in the PVP and 53%/29% in the TURP group. There was minimal change in detrusor contractility. Overall, morbidity was comparable in the two groups. CONCLUSIONS: The 12-month outcome after PVP is similar to that of TURP with an effective relief from BOO and detrusor overactivity and minimal change in detrusor contractility.
Assuntos
Hiperplasia Prostática/fisiopatologia , Hiperplasia Prostática/cirurgia , Ressecção Transuretral da Próstata , Urodinâmica , Idoso , Humanos , Masculino , Estudos ProspectivosRESUMO
AIMS: To identify the prognostic variables concerning the improvement of overactive bladder syndrome (OAB) related symptoms following a transurethral resection of the prostate (TURP) in patients with benign prostatic obstruction (BPO). METHODS: A retrospective review was conducted in 298 patients with BPO who had undergone TURP. All patients had completed the preoperative evaluations including OAB related symptoms and full urodynamics, as well as symptomatic assessment postoperatively. OAB related symptoms were defined by the International Prostate Symptom Score questionnaires (questions 2, 4 and 7 stand for frequency, urgency and nocturia). They were divided into three categories based on an individual score >or=3 for on urgency, frequency and nocturia in the preoperative state. The association between the baseline variables and the improvement in each symptom score was analyzed. RESULTS: A multivariate analysis suggested that the baseline degree of detrusor contractility was consistently associated with the improvement in each OAB symptom (The odds ratio in normal/weak detrusor: 9.5, 3.4, 3.0 for score on urgency, frequency and nocturia, respectively). Both the patient's age (Odds ratio: 0.93) and the maximum flow rate (Odds ratio: 0.20) influenced the improvement in the score on nocturia. CONCLUSION: The observation of a positive and consistent correlation between the baseline degree of detrusor contractility and the improvement in OAB related symptoms, suggests that good detrusor contractility is essential for the symptomatic benefits after the surgical relief of bladder outlet obstruction. Aging males with good urinary flow rates appear to experience a reduced improvement of nocturia symptoms after undergoing TURP.
Assuntos
Complicações Pós-Operatórias/fisiopatologia , Hiperplasia Prostática/cirurgia , Ressecção Transuretral da Próstata/efeitos adversos , Bexiga Urinária Hiperativa/etiologia , Fatores Etários , Idoso , Seguimentos , Humanos , Modelos Logísticos , Masculino , Análise Multivariada , Noctúria/epidemiologia , Razão de Chances , Valor Preditivo dos Testes , Prognóstico , Inquéritos e Questionários , Resultado do Tratamento , Urodinâmica/fisiologiaRESUMO
AIMS: To investigate the associations of symptoms and the quality of life (QOL) with objective variables in a strictly selected large cohort of subjects with symptomatic benign prostatic obstruction (BPO). METHODS: A retrospective study was conducted in 557 males with BPO in whom a symptomatic improvement had been achieved by transurethral resection of the prostate (TURP), thus suggesting that their lower urinary tract symptoms were primarily due to BPO. The association between the preoperative International Prostate Symptom Score (IPSS) and QOL score with objective variables including the residual volumes, prostate size and urodynamic parameters was statistically analyzed. RESULTS: Maximum flow rate (Q(max)) positively and a residual urine volume (PVR) negatively correlated with symptoms and QOL score. Detrusor overactivity (DO) also was weakly, but broadly associated with the symptoms. Degree of detrusor contractility and bladder capacity had a weak association with only some storage symptoms. The degree of bladder outlet obstruction (BOO) positively related to the scores on urgency, straining and total IPSS. Patients' age had positive correlation with the score on nocturia. The prostate volume was only negligibly correlated with either any symptoms or the QOL score. CONCLUSIONS: Parameters, such as Q(max) or PVR, obtained from the noninvasive urodynamics were most widely correlated with symptoms and QOL. Despite a large group with strict selection of men with LUTS possibly relating to BPO being studied, only weak association between the symptoms or QOL and objective parameters including urodynamics was confirmed.
Assuntos
Hiperplasia Prostática/cirurgia , Qualidade de Vida , Ressecção Transuretral da Próstata , Obstrução do Colo da Bexiga Urinária/etiologia , Bexiga Urinária Hiperativa/etiologia , Transtornos Urinários/etiologia , Urodinâmica , Idoso , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Hiperplasia Prostática/complicações , Hiperplasia Prostática/fisiopatologia , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Resultado do Tratamento , Obstrução do Colo da Bexiga Urinária/fisiopatologia , Obstrução do Colo da Bexiga Urinária/cirurgia , Bexiga Urinária Hiperativa/fisiopatologia , Bexiga Urinária Hiperativa/cirurgia , Transtornos Urinários/fisiopatologia , Transtornos Urinários/cirurgiaRESUMO
OBJECTIVE: Sorafenib (Nexavar) is an oral multi-kinase inhibitor that targets tumor growth and angiogenesis. This phase II study investigated efficacy, safety, and pharmacokinetics of sorafenib in Japanese patients with advanced renal cell carcinoma (RCC). METHODS: Nonrandomized, open-label study in Japanese patients with metastatic renal cell carcinoma who had received nephrectomy and failed >/=1 cytokine-containing therapy. The primary endpoint was response rate. Patients received sorafenib 400 mg twice daily (b.i.d.) on a continuous dosing schedule. RESULTS: A total of 129 patients (median age 63 years) were valid for intention-to-treat analyses. Confirmed partial responses were observed in 16 (12.4%) patients, and investigators assessed that 19 (14.7%) of the patients achieved a partial response. Stable disease was reported in 93 (72.1%) patients, and 103 (80.5%) patients had tumor shrinkage. Median progression-free survival was 224 days and the 25th percentile of overall survival was estimated at 288 days. The most frequently occurring drug-related adverse events (any grade) were elevated lipase (56%), hand-foot skin reaction (55%), alopecia (39%), increased amylase (38%), rash/desquamation (37%), and diarrhea (34%). A total of 14 (10.7%) patients had serious sorafenib-related adverse events, including one adverse event of worst grade 5 (dyspnea occurred 35 days after the last dose of study medication). The C(trough,steady state) values in RCC patients (n = 63) receiving sorafenib 400 mg b.i.d. were similar to those obtained from a Japanese phase I study involving patients with mixed solid tumors. CONCLUSION: Sorafenib showed encouraging efficacy and was well tolerated in Japanese patients with metastatic RCC.
Assuntos
Benzenossulfonatos/farmacocinética , Benzenossulfonatos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/farmacocinética , Piridinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzenossulfonatos/efeitos adversos , Carcinoma de Células Renais/secundário , Quimioterapia Adjuvante , Intervalo Livre de Doença , Toxidermias/etiologia , Feminino , Humanos , Lipase/efeitos dos fármacos , Lipase/metabolismo , Masculino , Pessoa de Meia-Idade , Nefrectomia , Niacinamida/análogos & derivados , Compostos de Fenilureia , Inibidores de Proteínas Quinases/efeitos adversos , Piridinas/efeitos adversos , SorafenibeRESUMO
The Conference on Asian Trends in Prostate Cancer Hormone Therapy is an annual forum for Asian urologists now in its 5th year. The 2006 conference, held in Bali, Indonesia, was attended by 27 leading urologic oncologists from China, Indonesia, Japan, Korea, Singapore, and Taiwan and featured a packed program of presentations and discussions on a wide range of topics such as relationships among clinicians and the newly opened Asia Regional Office for Cancer Control of the International Union Against Cancer (UICC), detection rates of prostate cancer by biopsy in each of the 6 Asian countries, and favored treatment modalities for hormone-refractory prostate cancer (HRPC) in each country. The first session of the conference kicked off with a keynote lecture entitled "Activities of the UICC ARO". UICC's new office will be the nerve center for its activities in the Asia region. Along with the Asian Pacific Organization for Cancer Prevention (APOCP), UICC aims to shift the focus of attention to cancer control. As such APOCP's long-running publication the APJCP is to be re-launched as the Asian Pacific Journal of Cancer Control. Although UICC is primarily concerned with cancer, several risk factors for cancer are common also to other non-communicable diseases such as diabetes and heart disease, and an important strategy is to implement measures to control these various pathologic conditions as a whole. Apart from contributing to an Asian prostate cancer registry the UICC-ARO will provide training courses, working groups, and assistance in collecting and processing data. The keynote lecture was followed by a roundtable discussion on possible ways in which clinicians from each Asian country can work with UICC. A number of suggestions were put forth including better registration, epidemiology research, possible implementation of UICC prostate cancer guidelines, early detection and screening, and roles of diet and phytotherapy. The underlying reasons for the large but dwindling difference in incidence rates of prostate cancer in various regions of Asia should be studied while the opportunity lasts. Session 2 was devoted to 6 presentations on detection rates by biopsy in each country. Although biopsy is the gold standard for detecting prostate cancer in most areas, indications for conducting biopsy are different in each country. For example, in Indonesia doctors may use PSAD 0.15 as the cutoff level. TRUS-guided biopsy is most widely used in Asian countries. Traditional sextant biopsy is often performed, although multiple-core biopsy is commonly available and associated with better detection rates, especially in men with large prostate volume. Positive DRE, high PSA, and older age were identified as factors associated with high biopsy detection rate, although elevated PSA has limited specificity. First biopsy in men with elevated PSA had a positive detection rate of approximately 30% in all countries. Community-based screening in some countries has an overall detection rate of approximately 1%. The favorable treatment modality for HRPC was the subject of the final session. First priority for doctors in all 6 countries is to maintain serum testosterone at castration level. Many therapeutic options are available, from cytotoxic drugs to traditional herbal medicines Chemotherapeutic agents such as estramustine, docetaxel, cyclophosphamide, and mitoxantrone are often given to patients with HRPC although not all are available in every country. Prednisone and dexamethasone are used for secondary hormonal therapy. External beam radiotherapy, radioisotopic drugs such as strontium 89, and bisphosphonates are common choices to control bone pain.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Oncologia/tendências , Neoplasias da Próstata/tratamento farmacológico , Ásia , Humanos , MasculinoRESUMO
PURPOSE OF REVIEW: The need to treat increasing numbers of patients with symptomatic benign prostatic obstruction has led to the continuous development of various novel or modified instrumental procedures with minimal invasiveness. The aim of the following review is to provide an overview of the current research focused on the complications and morbidity of instrumental treatment options for symptomatic benign prostatic obstruction. RECENT FINDINGS: A systematic Medline database search, over the past 12 months of the literature with a focus on articles about surgical treatment for benign prostatic obstruction or benign prostatic hyperplasia, provided some interesting new data concerning laser prostatectomy (holmium laser enucleation of the prostate and photoselective vaporization of the prostate) and transurethral resection of the prostate using bipolar electrocautery systems available for the review. SUMMARY: The data of this review period confirmed a favorable safety profile of holmium laser enucleation of the prostate for treating patients with comorbidities. Photoselective vaporization of the prostate seems to be an efficient technique with a favorable safety profile. Its long-term potential, however, has to be confirmed by randomized controlled studies. Transurethral resection of the prostate using bipolar electrocautery systems appears to offer the advantages of improved hemostasis and the ability to avoid transurethral resection syndrome. More randomized comparisons, however, need to be undertaken before an accurate general picture is available.
Assuntos
Próstata/cirurgia , Hiperplasia Prostática/cirurgia , Humanos , Terapia a Laser , Masculino , Ressecção Transuretral da PróstataRESUMO
BACKGROUND: We surveyed urologists in the Kyushu and Okinawa regions of Japan regarding their standard approach to patient preparation and their prostate biopsy technique. METHODS: A total of 155 survey questionnaires were prepared and mailed to community and academic urologists in the Kyushu and Okinawa regions. Incidences were derived from the total numbers of responses, by item, divided by the total number of responses per practice type. RESULTS: There were 27 responses from clinics (17.4%), 115 from general hospitals (74.2%), and 13 from university hospitals or cancer centers (8.4%). Most urologists performed biopsy in patients with prostate-specific antigen (PSA) levels greater than 4 ng/ml when digital rectal examination (DRE) and/or transrectal ultrasound (TRUS) results were normal. Of the urologists, 83% reported performing the procedure with hospitalization; 51% of urologists do not advocate enema use, 69% performed the procedure under spinal anesthesia or a sacral block, 53% reported the combined administration of antibiotics orally and intramuscularly or intravenously, 70% used only the transrectal route for prostate biopsy, and 86.5% performed six or more biopsy cores at the initial prostate biopsy session. CONCLUSION: This survey shows substantial variation in the prostate biopsy protocols among urologists in the Kyushu and Okinawa regions in Japan, and suggests that national, evidence-based, guidelines are required, particularly as to antibiotic prophylaxis and the number of biopsy cores.
Assuntos
Biópsia/métodos , Padrões de Prática Médica , Próstata/patologia , Neoplasias da Próstata/diagnóstico , Inquéritos e Questionários , Urologia , Anestesia Local , Antibioticoprofilaxia , Biomarcadores Tumorais/sangue , Exame Retal Digital , Enema , Inquéritos Epidemiológicos , Humanos , Japão , Masculino , Estadiamento de Neoplasias , Padrões de Prática Médica/estatística & dados numéricos , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangueRESUMO
Activation of the superoxide-producing NADPH oxidase Nox1 requires both the organizer protein Noxo1 and the activator protein Noxa1. Here we describe an alternative splicing form of Noxo1, Noxo1gamma, which is expressed in the testis and fetal brain. The Noxo1gamma protein contains an additional five amino acids in the N-terminal PX domain, a phosphoinositide-binding module; the domain plays an essential role in supporting superoxide production by NADPH oxidase (Nox) family oxidases including Nox1, gp91(phox)/Nox2, and Nox3, as shown in this study. The PX domain isolated from Noxo1gamma shows a lower affinity for phosphoinositides than that from the classical splicing form Noxo1beta. Consistent with this, in resting cells, Noxo1gamma is poorly localized to the membrane, and thus less effective in activating Nox1 than Noxo1beta, which is constitutively present at the membrane. On the other hand, cell stimulation with phorbol 12-myristate 13-acetate (PMA), an activator of Nox1-3, facilitates membrane translocation of Noxo1gamma; as a result, Noxo1gamma is equivalent to Noxo1beta in Nox1 activation in PMA-stimulated cells. The effect of the five-amino-acid insertion in the Noxo1 PX domain appears to depend on the type of Nox; in activation of gp91(phox)/Nox2, Noxo1gamma is less active than Noxo1beta even in the presence of PMA, whereas Noxo1gamma and Noxo1beta support the superoxide-producing activity of Nox3 to the same extent in a manner independent of cell stimulation.
Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Processamento Alternativo , NADH NADPH Oxirredutases/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Proteínas Adaptadoras de Transporte Vesicular/efeitos dos fármacos , Sequência de Aminoácidos , Células Cultivadas , DNA Complementar/genética , Humanos , Glicoproteínas de Membrana/efeitos dos fármacos , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Dados de Sequência Molecular , NADPH Oxidase 2 , NADPH Oxidases/efeitos dos fármacos , NADPH Oxidases/metabolismo , Fosfatidilinositóis/metabolismo , Estrutura Terciária de Proteína , Superóxidos/metabolismoRESUMO
Metastatic renal cell carcinoma (RCC) is currently one of the most treatment-resistant malignancies. However, significant advances in understanding the molecular mechanisms underlying RCC have led to the development of rationally designed therapies, which are now being tested clinically. To date, the vascular endothelial growth factor receptor (VEGFR) pathway has been the most promising target, and two agents (BAY 43-9006 and SU 11248) that inhibit not only VEGFR but also other receptors, including platelet-derived growth factor receptor (PDGFR), FMS-like tyrosine kinase 3 (FLT3), KIT, and Raf kinase, were recently approved by the FDA for advanced RCC. In addition, a phase III trial investigating the addition of VEGF inhibition to interferon alpha (IFN-alpha) in RCC is also now going on. Although the clinical activity of existing agents is to be further defined in ongoing trials, the exciting clinical response data with VEGF inhibition in RCC have demonstrated a key role in the treatment of this historically resistant malignancy.