RESUMEN
We have developed a novel bladder preservation therapy, balloon-occluded arterial infusion (BOAI) of cisplatin/gemcitabine, concomitantly with hemodialysis, along with concurrent irradiation [the so-called 'OMC (Osaka Medical College) regimen']. The OMC regimen delivers an extremely high concentration of anticancer agent to the site of a tumor without systemic adverse effects, since more than 95% of free Pt was efficiently eliminated by hemodialysis, which enables short hospital stay. In this study, we investigated the efficiency of OMC regimen in patients aged over 70 years with muscle-invasive bladder cancer without metastasis. A total of 134 such patients were assigned to receive either the OMC regimen (n=89) or cystectomy (n=45). OMC regimen patients who failed to achieve CR underwent cystectomy, or secondary BOAI with gemcitabine (1,600 mg). The OMC regimen, which delivers an extremely high concentration of anticancer agent to the tumor site without systemic adverse effects, yielded CR in >91% (81/89) of patients. More than 96% (78/81) of the CR patients survived without recurrence with intact bladder after a mean follow-up of 164 (range 16-818) weeks. The 5- and 10-year bladder intact survival rates were 87.2 and 69.8%, and overall survival rates were 88.4 and 70.7% (vs. 59.9 and 33.3% for cystectomy, p=0.0002), respectively, although the median age in the OMC regimen group was significantly greater than in the cystectomy group (median, range = 77, 70-98 vs. 74, 70-89; p=0.0003). No patients suffered grade II or more severe toxicities; the oldest patient, aged 91 years, successfully completed this therapy. In conclusion, the OMC regimen is a useful bladder preservation strategy for elderly patients with locally invasive bladder cancer, not only in those for whom cystectomy is indicated, but also in patients whose condition is not amenable to curative treatment and for whom palliation would otherwise seem the only option.
Asunto(s)
Cisplatino/administración & dosificación , Desoxicitidina/análogos & derivados , Recurrencia Local de Neoplasia/radioterapia , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Factores de Edad , Anciano , Anciano de 80 o más Años , Oclusión con Balón , Terapia Combinada , Desoxicitidina/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Dosificación Radioterapéutica , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/radioterapia , GemcitabinaRESUMEN
We have developed a novel form of bladder preservation therapy [OMC (Osaka Medical College)-regimen] involving balloon-occluded-arterial-infusion (BOAI) of an anticancer agent (cisplatin/gemcitabine), used concomitantly with hemodialysis, which delivers an extremely high concentration of anticancer agent to the site of a tumor without systemic adverse effects, along with concurrent radiation. We previously reported that the OMC-regimen elicited a complete response (CR) in >90% of patients with organ confined tumors, while LN(+), T4 tumors and a non-UC histological type were statistically significant risk factors for treatment failure and patient survival. In this study, we investigated the effects of the OMC-regimen in patients with organ confined urothelial cancer tumors and the outcomes were compared to those with total cystectomy. Three hundred and one patients were assigned to receive either the OMC-regimen (n=162) or total cystectomy (n=139). Patients in the OMC-regimen group who failed to achieve CR underwent cystectomy, or secondary BOAI with an increased amount of CDDP or gemcitabine (1600 mg). The OMC-regimen yielded 98.1% of clinical response; CR in 93.8% (152/162) of patients; PR in 4.3% (7/162). More than 96% of the CR patients (146/152) were alive with no evidence of recurrence after a mean follow-up of 166 (range 23-960) weeks. No patients suffered grade III toxicity; all patients successfully completed this therapy. The patient survival was significantly better compared to the cystectomy group; the overall 5-, 10- and 15-year survival rates were 87.3, 79.6 and 59.7%, respectively. Moreover, the 5-, 10- and 15-year bladder intact survival rates, the most important issue for bladder preservation therapy, were 85.7, 78.4 and 58.8%, respectively. In conclusion, the OMC-regimen is a useful bladder-preservation strategy, not only in those for whom cystectomy is indicated, but also in patients whose condition is not amenable to curative treatment and for whom palliation would otherwise seem the only option.
Asunto(s)
Oclusión con Balón , Infusiones Intraarteriales , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Cisplatino/administración & dosificación , Terapia Combinada , Cistectomía , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/radioterapia , Recurrencia Local de Neoplasia/cirugía , Estadificación de Neoplasias , Vejiga Urinaria/efectos de los fármacos , Vejiga Urinaria/patología , Vejiga Urinaria/cirugía , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/radioterapia , Neoplasias de la Vejiga Urinaria/cirugía , GemcitabinaRESUMEN
A 31-year-old man visited another hospital with a chief complaint of a solid mass in the left scrotum. The diagnosis was a skin cancer of the scrotum, and he was referred to our hospital. We performed surgical resection of the mass, left testis, and bilateral superfical inguinal nodes. Histopathological findings revealed leiomyosarcoma of the scrotum. He is free of disease at 16 months after the operation.
Asunto(s)
Neoplasias de los Genitales Masculinos/patología , Leiomiosarcoma/patología , Escroto , Adulto , Neoplasias de los Genitales Masculinos/cirugía , Humanos , Leiomiosarcoma/cirugía , MasculinoRESUMEN
In this study, we investigated the novel bladder preservation therapy, the balloon-occluded arterial infusion (BOAI) of cisplatin/gemcitabine, concomitantly with hemodialysis, along with concurrent irradiation [the 'Osaka Medical College (OMC)-regimen'] in patients >70 years of age with muscle-invasive bladder cancer. Eighty-three such patients were assigned to receive either the OMC-regimen (n=56) or cystectomy (n=27). The OMC-regimen patients who failed to achieve complete response (CR) underwent cystectomy, or secondary BOAI with gemcitabine (1600 mg). The OMC-regimen, which delivers an extremely high concentration of anti-cancer agent to the tumor site without systemic adverse effects, yielded CR in >90% (39/43) of patients with locally invasive tumors [70% (39/56) of all patients including those with T4 and N+ disease]. None of the CR patients showed recurrence after a mean follow-up of 162 (range, 35-683) weeks, and 2 patients died of unrelated causes. The 5- and 12-year overall survival rates were 92.7 and 69.5% (vs. 59.6 and 20.9% for cystectomy; P<0.0092), respectively, although the median age in the OMC-regimen group was significantly greater than that in the cystectomy group (median, 77; range, 70-98; vs. 74; 70-79; p<0.0001). No patients suffered grade III or more severe toxicities. The oldest patient, aged 98 years, successfully completed this therapy. The OMC-regimen is a useful bladder preservation strategy for elderly patients with locally invasive bladder cancer, not only for those for whom cystectomy has been indicated, but also for patients whose condition is not amenable to curative treatment and for whom palliation would otherwise seem the only option.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Vejiga Urinaria/terapia , Anciano , Anciano de 80 o más Años , Cateterismo/métodos , Cisplatino/administración & dosificación , Terapia Combinada , Cistectomía , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Femenino , Humanos , Infusiones Intraarteriales , Masculino , Estadificación de Neoplasias , Factores de Riesgo , Análisis de Supervivencia , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/patología , GemcitabinaRESUMEN
We investigated the effect of balloon-occluded arterial infusion (BOAI) of anticancer agent (cisplatin/gemcitabine), used concomitantly with hemodialysis, which delivers an extremely high concentration of anticancer agent to the site of a tumor without systemic adverse effects, along with concurrent radiation (referred to as the OMC-regimen) in patients with advanced bladder cancer. One hundred and ninety-two patients were assigned to receive either the OMC-regimen (n=96) or total cystectomy (n=96). Patients in the OMC-regimen group who failed to achieve CR underwent cystectomy, or secondary BOAI with an increased amount of CDDP or gemcitabine (1600 mg). The OMC-regimen allowed >89% (69/77) of patients with locally invasive tumors to achieve CR [>70% (70/96) of all patients including those with T4 and N(+) disease]. Most (68/69) of the CR patients were still alive with no evidence of recurrence after a mean follow-up of 161 (range 12-805) weeks. The 5- and 15-year overall survival rates were 91.5 and 81.3% (vs. 59.8% and 40.1% for cystectomy, P<0.0001), respectively. No patients suffered Grade III or more severe toxicities. In contrast, at 5 and 15 years after surgery in the total cystectomy group, about 50 and 60% of patients had suffered disease progression or had died, respectively. The OMC-regimen, a new bladder-preservation strategy for patients with locally invasive bladder cancer, can be curative not only in patients for whom cystectomy is indicated, but also in patients whose condition is not amenable to curative treatment and for whom merely palliative therapy would otherwise seem the only option.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Oclusión con Balón , Cistectomía , Diálisis Renal , Neoplasias de la Vejiga Urinaria/terapia , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cisplatino/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Femenino , Humanos , Infusiones Intraarteriales , Japón , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , Oportunidad Relativa , Modelos de Riesgos Proporcionales , Radioterapia Adyuvante , Medición de Riesgo , Factores de Riesgo , Tasa de Supervivencia , Factores de Tiempo , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/mortalidad , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/radioterapia , Neoplasias de la Vejiga Urinaria/cirugía , GemcitabinaRESUMEN
OBJECTIVES: We tested the usefulness of balloon-occluded arterial infusion (BOAI) of anticancer agent (cisplatin/gemcitabine), concomitant with hemodialysis, which delivers an extremely high concentration of anticancer agent to the site of a tumor without systemic adverse effects, along with concurrent radiation [Osaka-Medical College (OMC)-regimen] in patients with locally advanced bladder cancer. The results were compared with those of cystectomy. METHODS: One hundred twenty-four patients were assigned to receive cystectomy (Gp1, n = 62) or OMC-regimen (Gp2, n = 62). In Gp2, patients besides undergoing complete response subsequently received secondary-BOAI with gemcitabine (1600 mg). RESULTS: In Gp1, 27 of 62 patients (43.5%) suffered disease recurrence, and more than half died within 1 year; the remainder died thereafter. The overall 5-, 10-, and 15-year survival rates were 53.8%, 46.0%, and 40.0%, respectively. In contrast, in Gp2, >70% of patients (44 of 62), especially >95% of patients with locally invasive tumors achieved complete response with no evidence of recurrent disease or metastasis after a mean follow-up of 163 (range, 32-736) weeks. At 14 years, overall survival was significantly improved at 79.7% (P = 0.015 vs. Gp1). Moreover, salvage therapy for secondary-BOAI with gemcitabine was effective in all 3 patients with T4 tumors or lymph node involvement, who showed stable disease (SD) after primary therapy with CDDP. No patients suffered Grade III or more severe toxicities. CONCLUSION: OMC-regimen, a new strategy for patients with locally-invasive bladder cancer, can be curative not only in patients for whom cystectomy is indicated, but also in patients whose condition is not amenable to curative treatment and for whom merely palliative treatment would otherwise seem the only option.
Asunto(s)
Antineoplásicos/administración & dosificación , Oclusión con Balón , Cisplatino/administración & dosificación , Cistectomía , Diálisis Renal , Neoplasias de la Vejiga Urinaria/terapia , Adenocarcinoma/patología , Adenocarcinoma/terapia , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/secundario , Carcinoma de Células Escamosas/terapia , Coriocarcinoma/secundario , Coriocarcinoma/terapia , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Infusiones Intraarteriales , Persona de Mediana Edad , Neoplasias de los Músculos/secundario , Neoplasias de los Músculos/terapia , Invasividad Neoplásica , Estadificación de Neoplasias , Pronóstico , Dosificación Radioterapéutica , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
OBJECTIVES: We conducted the present study to evaluate the safety profile and therapeutic value of a combination of etoposide and fosfestrol for treatment of hormone-refractory prostate cancer (HRPC). METHODS: Forty patients with HRPC were included in the study. The median age was 71 years (range, 50-86 years), the Gleason's score ranged from 5 to 10, and the median prostate-specific antigen level was 62.6 ng/mL (range, 4.738-30789 ng/mL). The patients received oral etoposide 25 mg/d and fosfestrol 300 mg/d. RESULTS: The response rate in terms of measurable disease, serum prostate-specific antigen level, and overall evaluation was 36.8% (CR: 18.4%; PR: 18.4%), 80% (CR: 55%; PR: 25%), and 40% (CR: 20%; PR: 20%) with a median duration of response of 13.6, 13.5, and 13.5 months, respectively. An objective clinical response for overall evaluation was shown by 90% (CR: 20%; PR: 20%; SD: 50%) of the patients, with a median response duration of 15.7 months; 16 patients (40%) are currently alive without recurrence after a median follow-up period of 21.2 months. The overall survival and progression-free survival was 30.5% and 28.8% at 40 months, respectively. No grade III toxicities occurred in any of the patients. Serial measurements in 34 patients using the Functional Assessment of Cancer Therapy-Prostate showed a significant improvement in quality of life as a result of the therapy. CONCLUSIONS: The combination of oral etoposide and fosfestrol is active in patients with HRPC. The regimen is tolerable and has a significant impact on quality of life as measured by the Functional Assessment of Cancer Therapy-Prostate in a limited sample of patients.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Adenocarcinoma/patología , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Dietilestilbestrol/administración & dosificación , Dietilestilbestrol/efectos adversos , Dietilestilbestrol/análogos & derivados , Resistencia a Antineoplásicos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Etopósido/administración & dosificación , Etopósido/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Antígeno Prostático Específico/sangre , Antígeno Prostático Específico/efectos de los fármacos , Neoplasias de la Próstata/patología , Calidad de Vida , Terapia Recuperativa , Análisis de SupervivenciaRESUMEN
OBJECTIVE: We tested the usefulness of combined therapy using balloon-occluded arterial infusion (BOAI) of cisplatin and hemodialysis, which delivers an extremely high concentration of cisplatin to the site of a tumor without systemic adverse effects, with concurrent radiation in patients with locally advanced bladder cancer. METHODS: Patients underwent transurethral resection of the bladder tumor followed by BOAI of cisplatin (100, 200, or 300 mg) concurrent with hemodialysis, via both common iliac veins, for 2 hours after initiation of BOAI. A total of 60.4 Gy of radiation was delivered, starting from the day of BOAI. RESULTS: Forty-one patients (30 males and 11 females, aged 55-98 years) were enrolled and assessable for toxicity and response. None of the patients suffered grade II or more severe toxicities; some experienced grade I blood/bone marrow toxicity, gastrointestinal toxicity, or neuropathy. All patients with histologically confirmed transitional cell carcinoma stage T2 or T3 (29 patients) achieved a complete response and were able to retain their bladder with no evidence of recurrent disease or distant metastasis at a mean follow-up of 132 weeks (range 8-648 weeks) after therapy. Patients with stage T4 tumors, besides transitional cell carcinoma, or lymph node involvement had stable or progressive disease. CONCLUSION: This therapy is a new strategy for patients with locally advanced bladder cancer. It can be a curative treatment not only in patients for whom total cystectomy is indicated, but also in patients whose condition is not amenable to curative treatment and for whom merely palliative treatment would otherwise seem the only option.
Asunto(s)
Antineoplásicos/administración & dosificación , Oclusión con Balón , Cisplatino/administración & dosificación , Infusiones Intraarteriales , Diálisis Renal/métodos , Neoplasias de la Vejiga Urinaria/terapia , Adenocarcinoma/patología , Adenocarcinoma/terapia , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Transicionales/patología , Carcinoma de Células Transicionales/terapia , Coriocarcinoma/patología , Coriocarcinoma/terapia , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Inducción de Remisión , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/radioterapiaRESUMEN
We report a case of port-site metastasis of bladder cancer after left retroperitoneoscopy-assisted nephroureterectomy and cystectomy. The patient was a 73-year-old man with a chief complaint of gross hematuria. The diagnosis was invasive bladder cancer with bone metastasis. He received two courses of chemotherapy (methotrexate, vinblastine, adriamycin, cisplatin), and this resulted in resolution of the bone metastases. Two months later, abdominal and pelvic computed tomography showed a bladder tumor invading the left lower ureter with hydronephrosis. Left retroperitoneoscopy-assisted nephroureterectomy and cystectomy were performed. The patient was unable to undergo systemic chemotherapy because of renal dysfunction. Four months later, a lateral abdominal wall tumor was found at a port-site, and needle biopsy confirmed this to be metastatic urothelial carcinoma. Clinicians need to be aware of port-site metastasis, particularly in patients with UC, and take steps to prevent it during laparoscopic procedures.
Asunto(s)
Neoplasias Abdominales/secundario , Carcinoma/cirugía , Cistectomía , Endoscopía , Invasividad Neoplásica , Siembra Neoplásica , Nefrectomía , Uréter/cirugía , Neoplasias Ureterales/cirugía , Neoplasias de la Vejiga Urinaria/cirugía , Anciano , Carcinoma/patología , Endoscopía/efectos adversos , Humanos , Masculino , Neoplasias Ureterales/patología , Neoplasias de la Vejiga Urinaria/patología , UrotelioRESUMEN
ComA of Streptococcus is a member of the bacteriocin-associated ABC transporters, which is responsible for both the processing of the propeptide ComC and secretion of the mature quorum-sensing signal. The quorum-sensing system is a bacterial intercellular communication system implicated in various functions including biofilm formation. In this study, the peptidase domains (PEPs) of the ComAs from six species of Streptococcus and ComCs from four species were expressed, purified, and characterized to address the mechanism of the substrate recognition of PEP. PEPs specifically cleaved ComCs after the Gly-Gly site in all the PEP-ComC combinations examined. The N-terminal leader region of ComC was found to form an amphiphilic alpha-helix structure upon binding to the PEP. Furthermore, mutagenesis studies revealed that four conserved hydrophobic residues in this leader region of ComC extending from -15 to -4 positions are critical in the interaction with PEP. Together with the double glycine motif, these structural features of ComC would explain the strict substrate specificity of the PEP.
Asunto(s)
Proteínas Bacterianas/química , Proteínas Bacterianas/metabolismo , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/metabolismo , Percepción de Quorum , Streptococcus , Transportadoras de Casetes de Unión a ATP/química , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Secuencia de Aminoácidos , Proteínas Bacterianas/genética , Proteínas Bacterianas/aislamiento & purificación , Dicroismo Circular , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/aislamiento & purificación , Expresión Génica , Datos de Secuencia Molecular , Péptido Hidrolasas/química , Péptido Hidrolasas/metabolismo , Desnaturalización Proteica , Procesamiento Proteico-Postraduccional , Estructura Terciaria de Proteína/fisiología , Homología de Secuencia de Aminoácido , Transducción de Señal , Streptococcus/genética , Streptococcus/metabolismo , Especificidad por SustratoRESUMEN
Nuclear factor-kappaB (NF kappaB) plays a pivotal role in cancer progression. In this study, we developed a decoy cis-element oligo-deoxyribonucleic acid against NF kappaB-binding site (NF kappaB-decoy), which effectively inhibits NF kappaB activity, and tested the effect of combined therapy comprising local transfection of NF kappaB-decoy into the liver and transportal injection of paclitaxel on cancer growth and metastasis using an orthotopic murine model of colon cancer liver metastasis. For NF kappaB-decoy transfection, we employed a novel approach using ultrasound exposure with an echocardiographic contrast agent, Optison. We examined the influence of NF kappaB-decoy transfer on susceptibility to paclitaxel in cancer cells and the mechanism involved using several in vitro analysis systems. We then studied the in vivo effect of combined NF kappaB-decoy transfer and paclitaxel in preventing cancer progression using a murine model of liver metastasis created by splenic injection of a human colon cancer cell line, HT29. In vitro experiments, including MTT-assay, fluorescence-activated cell sorter and cDNA array analysis, revealed that NF kappaB-decoy transfer significantly increased the susceptibility of cancer cells to paclitaxel, and that decreased expression of anti-apoptotic genes along with increased expression of genes relevant to the apoptosis-promotor may be involved. In vivo experiments showed that local transfection of NF kappaB-decoy into the liver followed by portal injection of paclitaxel effectively induced cancer cell apoptosis in the liver metastasis, and significantly prolonged animal survival compared to controls, without notable side effects. In conclusion, a combination of local NF kappaB-decoy transfer into the liver and transportal injection of paclitaxel may be a safe and effective new therapy for liver metastasis.
Asunto(s)
Antineoplásicos Fitogénicos/administración & dosificación , Neoplasias del Colon/patología , Terapia Genética/métodos , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/terapia , FN-kappa B/antagonistas & inhibidores , Paclitaxel/administración & dosificación , Transfección , Ultrasonido , Animales , Antineoplásicos Fitogénicos/farmacología , Apoptosis , Línea Celular Tumoral , Quimioterapia Adyuvante , Colorimetría , Regulación hacia Abajo , Citometría de Flujo , Regulación Neoplásica de la Expresión Génica , Humanos , Immunoblotting , Inyecciones Intravenosas , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/tratamiento farmacológico , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Microscopía Fluorescente , FN-kappa B/metabolismo , Oligodesoxirribonucleótidos/administración & dosificación , Análisis de Secuencia por Matrices de Oligonucleótidos , Paclitaxel/farmacología , Vena Porta , Distribución Aleatoria , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transfección/métodos , UltrasonografíaRESUMEN
Gamma-aminobutyric acid (GABA) was first discovered as an inhibitory neurotransmitter in the central nervous system (CNS) and has been reported to have a variety of functions, including regulation of cell division, cell differentiation and maturation, and to be involved in the development of certain cancers outside the CNS. In the present study, using the human renal cell carcinoma cell line Caki-2, we demonstrated that GABA stimulation significantly increased the expression of MMP-2 and -9 and subsequently increased the invasive activity of the cancer cells. Because MAPK signaling is one of the key regulators of MMP expression, we further evaluated MAPK signaling after stimulation with GABA. It was found that GABA stimulation promoted the phosphorylation of MAPKs, including ERK1/2, JNK, and p38. ERK1/2 phosphorylation was sustained for up to 12 h, while phosphorylation of JNK and p38 returned to the endogenous level by 30 min. It was noteworthy that the ras/raf/MEK/ERK pathway inhibitor PD98059 attenuated GABA-induced MMP-9 expression and that both PD98059 and MMP inhibitors attenuated the GABA-induced invasive activity of Caki-2 cells. Moreover, data obtained by depletion of the MEK/ERK pathway using interfering RNA transfection of Caki-2 cells clearly corroborated the above results, as both MMP-9 expression and GABA-induced invasive ability were decreased significantly. We also demonstrated that the GABA-induced increase in invasive ability via ERK1/2 up-regulation was mediated mainly through the GABA-B receptor. These results indicate that GABA stimulation promotes cancer cell invasion and that the effect is partly due to ERK1/2-dependent up-regulation of MMPs.
Asunto(s)
Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Metaloproteinasas de la Matriz/biosíntesis , Proteína Quinasa 1 Activada por Mitógenos/fisiología , Proteína Quinasa 3 Activada por Mitógenos/fisiología , Ácido gamma-Aminobutírico/farmacología , Carcinoma de Células Renales/enzimología , Línea Celular Tumoral , Activación Enzimática , Humanos , Neoplasias Renales/enzimología , Invasividad Neoplásica , Receptores de GABA/análisis , Receptores de GABA/fisiología , Transducción de SeñalRESUMEN
BACKGROUND: A unique immunosuppressant, FTY720, selectively induces apoptosis in activated lymphocytes, but not in other hematopoietic cells. The potential that this unique mechanism could provide anticancer potential by inducing apoptosis in the human renal cancer cell line, ACHN, which is resistant to cisplatin, and its molecular pathway was investigated. MATERIALS AND METHODS: The difference in drug susceptibility to FTY720 between cancer cells and non-cancer cells was examined by MTT assay and flow cytometry. Apoptosis assay, including TUNEL staining, electron microscopy and DNA electrophoresis, was performed and the molecular pathway of FTY720 was evaluated by real time RT-PCR and Western blot. The in vivo effect of FTY720 was evaluated using a murine zenograft model. RESULTS: The susceptibility to FTY720 was significantly higher in ACHN cancer cells than in normal renal tubular cells (HK-2) at a concentration of less than 30 microM, while the susceptibility to cisplatin was even higher in HK-2 than in ACHN. Cancer cells treated with FTY720 showed findings typical of apoptosis with highly condensed nuclear chromatin and fragmented nuclei. The molecular analysis revealed that FTY720-induced apoptosis was mediated by a Fas-independent, Bcl-associated signal transduction pathway, and that inhibition of extracellular signal-regulated kinase (ERK) activity was involved in its underlying mechanism of action. FTY720 treatment significantly prevented in vivo tumor growth without any severe adverse reactions, while cisplatin treatment did not inhibit tumor growth despite exhibiting severe side-effects. CONCLUSION: FTY720 may be a promising candidate for a new anticancer therapy of renal cancer.
Asunto(s)
Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Glicoles de Propileno/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Esfingosina/análogos & derivados , Receptor fas/metabolismo , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/cirugía , Caspasa 3/metabolismo , Caspasa 8/metabolismo , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Cisplatino/farmacología , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Sinergismo Farmacológico , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Clorhidrato de Fingolimod , Humanos , Inmunosupresores/farmacología , Inmunosupresores/toxicidad , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Neoplasias Renales/cirugía , Túbulos Renales/citología , Túbulos Renales/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Nefrectomía , Glicoles de Propileno/toxicidad , Esfingosina/farmacología , Esfingosina/toxicidad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We report a case of adrenal metastasis from renal cell carcinoma. A 52-year-old man was referred to our hospital for a left renal mass. A computed tomography revealed a left renal tumor. Liver cirrhosis and splenomegaly were observed. Blood tests revealed pancytopenia; platelet count was 2.5 x 10(4)/mm3. The patient was treated by partial splenic embolization (PSE) in an attempt to ensure a safe nephrectomy. After the embolization, his platelet count increased to 6.1 x 10(4)/mm3, and left nephrectomy was performed successfully. Histopathological finding was renal cell carcinoma (RCC). We concluded that PSE before surgery was useful for the patients with thrombocytopenia due to hypersplenism. Four years after surgery, computed tomography revealed the presence of a mass on the right adrenal gland. He was suspected of having a non-functioning adrenal tumor. Metastasis of the RCC was suspected and right adrenalectomy was performed by a laparoscopic procedure. Histologically, the mass was identified as a RCC metastasis. It is clinically rare for an RCC metastasis to the contralateral adrenal gland to occur.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/secundario , Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Cirrosis Hepática/complicaciones , Adrenalectomía , Carcinoma de Células Renales/diagnóstico por imagen , Carcinoma de Células Renales/terapia , Humanos , Neoplasias Renales/diagnóstico por imagen , Neoplasias Renales/terapia , Masculino , Persona de Mediana Edad , Esplenomegalia/complicaciones , Tomografía Computarizada por Rayos XRESUMEN
Bladder carcinoma with skin metastasis is extremely rare. We herein report a case of a bladder tumor with skin metastasis. A 68-year-old man was referred to our hospital with macroscopic hematuria. Cystoscopy revealed a trigone papillary tumor. Transurethral resection of bladder tumor (TURBT) was performed and the pathological diagnosis was transitional cell carcinoma (TCC), pT1, G3. Thereafter, he received several courses of TURBT, intravesical chemotherapy (pirarubicin, bacillus Calmette-Guerin and mitomycin C) and intra-arterial chemotherapy because of recurrence. Thirteen years later, he underwent total cystoprostatectomy with neobladder formation. Histological examination revealed muscle-invasive bladder cancer with a staging of T3bNOM0. Two years and three months later, multiple firm nodules with eruptions appeared on the skin in several regions; they were resected and the histological findings revealed TCC. This indicated metastatic spread from the primary bladder TCC. He received only supportive treatment during this period due to renal dysfunction. He died four months after the manifestation of the skin metastasis due to multiple metastases.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Transicionales/secundario , Neoplasias Cutáneas/secundario , Neoplasias de la Vejiga Urinaria/patología , Administración Intravesical , Anciano , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/radioterapia , Carcinoma de Células Transicionales/cirugía , Cisplatino/administración & dosificación , Terapia Combinada , Cistectomía , Doxorrubicina/administración & dosificación , Doxorrubicina/análogos & derivados , Humanos , Infusiones Intraarteriales , Masculino , Metotrexato/administración & dosificación , Mitomicina/administración & dosificación , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/radioterapia , Neoplasias de la Vejiga Urinaria/cirugíaRESUMEN
Primary tumor originated from ureteral stump following nephrectomy for benign disease is extremely rare. A 79-year-old male was referred to our department for asymptomatic macroscopic hematuria. He had undergone left simple nephrectomy for renal tuberculosis 52 years ago. Cystoscopic examination revealed a ureteral tumor on the residual ureteral orifice. Under the diagnosis of left ureteral stump tumor, which was subsequently enhanced on computer tomographic scan and magnetic resonance imaging, he received partial cystectomy and excision of the left ureteral stump. The histological examination revealed grade 2 to 3 urothelial carcinoma with muscle invasion (pT2). He received no adjuvant chemotherapy. He is now alive and free from recurrence 2 months post-operatively. This is the 21st case reported in the Japanese literature.
Asunto(s)
Carcinoma de Células Transicionales/diagnóstico , Nefrectomía , Complicaciones Posoperatorias , Uréter/patología , Neoplasias Ureterales/diagnóstico , Anciano , Carcinoma de Células Transicionales/etiología , Carcinoma de Células Transicionales/cirugía , Cistectomía , Humanos , Masculino , Tuberculosis Renal/cirugía , Neoplasias Ureterales/etiología , Neoplasias Ureterales/cirugíaRESUMEN
A 25-year-old man was admitted to our hospital because of left lumbago. An abdominal X-ray film demonstrated multiple calculi in the medullary positions of both kidneys and an impacted calculus in the left ureter. He was diagnosed with bilateral nephrocalcinosis and nerve deafness due to distal renal tubular acidosis (RTA) in childhood and was treated with alkali agents for several years. Extracorporeal shock wave lithotripsy was performed successfully against the left ureteral calculus. His older brother had also been diagnosed with RTA and nephrocalcinosis at the age of 2 years and 6 months. Nephrocalcinosis due to RTA associated with nerve deafness in brothers is rarely reported.
Asunto(s)
Acidosis Tubular Renal/complicaciones , Acidosis Tubular Renal/genética , Nefrocalcinosis/etiología , Nefrocalcinosis/genética , Adulto , Sordera/complicaciones , Sordera/genética , Humanos , Cálculos Renales/terapia , Litotricia , Hermanos , Cálculos Ureterales/terapiaRESUMEN
A 21-year-old woman who had been injured in a traffic accident appeared with abdominal pain and macroscopic hematuria. Computed tomography (CT) performed 6 hours after the injury showed extravasation of contrast medium in the right retroperitoneal space. Retrograde pyelography (RP) showed the interruption of right ureter at the site of ureteropelvic junction. We performed an abdominal operation 15 hours after the injury under the diagnosis of right ureteral avulsion. We observed a completely separated right ureter at the ureteropelvic junction, and performed an end to end anastomosis. The patient was discharged three weeks after surgery, and has not had any problems for three years.