RESUMO
KRAS mutations occur in 30-40% of all cases of human colorectal cancer (CRC). However, to date, specific therapeutic agents against KRAS-mutated CRC have not been developed. We previously described the generation of mouse models of colon cancer with and without Kras mutations (CDX2P-G22Cre;Apc(flox/flox); LSL-Kras(G12D) and CDX2P-G22Cre;Apc(flox/flox) mice, respectively). Here, the two mouse models were compared to identify candidate genes, which may represent novel therapeutic targets or predictive biomarkers. Differentially expressed genes in tumors from the two mouse models were identified using microarray analysis, and their expression was compared by quantitative reverse transcription-PCR (qRT-PCR) and immunohistochemical analyses in mouse tumors and surgical specimens of human CRC, with or without KRAS mutations, respectively. Furthermore, the functions of candidate genes were studied using human CRC cell lines. Microarray analysis of 34 000 transcripts resulted in the identification of 19 candidate genes. qRT-PCR analysis data showed that four of these candidate genes (Clps, Irx5, Bex1 and Rcan2) exhibited decreased expression in the Kras-mutated mouse model. The expression of the regulator of calcineurin 2 (RCAN2) was also observed to be lower in KRAS-mutated human CRC. Moreover, inhibitory function for cancer cell proliferation dependent on calcineurin was indicated with overexpression and short hairpin RNA knockdown of RCAN2 in human CRC cell lines. KRAS mutations in CRC lead to a decrease in RCAN2 expression, resulting in tumor proliferation due to derepression of calcineurin-nuclear factor of activated T cells (NFAT) signaling. Our findings suggest that calcineurin-NFAT signal may represent a novel molecular target for the treatment of KRAS-mutated CRC.
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BACKGROUND: In Japan, S-1 plus cisplatin has been used as first-line therapy for advanced gastric cancer (AGC). Patients with no response to first-line treatment with S-1 often receive a taxane-alone or irinotecan-alone as second-line treatment. However, second-line treatment with S-1 plus irinotecan is widely used in patients with AGC resistant to first-line S-1-based chemotherapy. The goal of this trial was to determine whether the consecutive use of S-1 plus irinotecan improves survival when compared with irinotecan-alone as second-line treatment for AGC. PATIENTS AND METHODS: Patients who had disease progression during first-line S-1-based chemotherapy were randomly assigned to receive S-1 plus irinotecan or irinotecan-alone. The S-1 plus irinotecan group received oral S-1 (40-60 mg/m(2)) on days 1-14 and intravenous irinotecan (150 mg/m(2)) on day 1 of a 21-day cycle. The irinotecan-alone group received the same dose of irinotecan intravenously on day 1 of a 14-day cycle. The primary end point was overall survival (OS). RESULTS: From February 2008 to May 2011, a total of 304 patients were enrolled. The median OS was 8.8 months in the S-1 plus irinotecan group and 9.5 months in the irinotecan-alone group. This difference was not significant (hazard ratio for death, 0.99; 95% confidence interval 0.78-1.25; P = 0.92). Grade 3 or higher toxicities were more common in the S-1 plus irinotecan group than in the irinotecan-alone group. CONCLUSION: The consecutive use of S-1 plus irinotecan is not recommended as second-line treatment in patients who are refractory to S-1-based first-line chemotherapy. ClinicalTrials.gov ID: NCT00639327.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/análogos & derivados , Ácido Oxônico/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Tegafur/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/efeitos adversos , Camptotecina/uso terapêutico , Intervalo Livre de Doença , Esquema de Medicação , Combinação de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Ácido Oxônico/efeitos adversos , Neoplasias Gástricas/mortalidade , Tegafur/efeitos adversos , Resultado do Tratamento , Adulto JovemRESUMO
The pharmacokinetics of oxaliplatin in plasma and ascitic fluid was investigated in 5 gastrointestinal cancer patients with malignant ascites. Oxaliplatin was administered at 85 mg/m² by 2-hour infusion in the FOLFOX4 regimen, and the concentrations of total and free platinum were measured. There was a trend of lower plasma C(max) values of total platinum in patients with a larger volume of ascitic fluid. The AUC(0-t) values of mean concentration curves of total plasma platinum, total ascites platinum, free plasma platinum, and free ascites platinum were 31.15, 7.96, 4.93 and 2.93 mgâ¢h/ml, respectively. The concentrations of free ascites platinum were similar to those of free plasma platinum at the last sampling time of 26 h in each patient. The decrease or disappearance of ascitic fluid was observed in 4 patients. These results suggest that oxaliplatin exerted a beneficial effect in gastrointestinal cancer patients with malignant ascites, even when administered intravenously.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias Gastrointestinais/metabolismo , Compostos Organoplatínicos/farmacocinética , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/sangue , Área Sob a Curva , Ascite/sangue , Ascite/metabolismo , Ascite/patologia , Líquido Ascítico/metabolismo , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/sangue , Fluoruracila/farmacocinética , Neoplasias Gastrointestinais/sangue , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/patologia , Humanos , Infusões Intravenosas , Leucovorina/administração & dosagem , Leucovorina/sangue , Leucovorina/farmacocinética , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/sangue , Compostos Organoplatínicos/uso terapêutico , Oxaliplatina , Platina/sangue , Platina/farmacocinéticaRESUMO
Our previous studies have demonstrated the oxidative stress properties of sodium ascorbate (SAA) and its benzaldehyde derivative (SBA) on cancer cell lines, but the molecular mechanisms mediating their cytotoxicity remain unclear. In this study, we treated human colon cancer HT-29 cells with SAA and SBA, and found a significant exposure time-dependent increase of cytotoxicity in both treatments, with a higher cytotoxicity for 24 h with SAA (IC(50) = 5 mM) than SBA (IC(50) = 10 mM). A short-term treatment of cells with 10 mM SAA for 2 h revealed a destabilization of the lysosomes and subsequent induction of cell death, whereas 10 mM SBA triggered a remarkable production of reactive oxidative species, phosphorylation of survival kinase AKT, expression of cyclin kinase-dependent inhibitor p21, and induction of transient growth arrest. The crucial role of p21 mediating this cytotoxicity was confirmed by isogenic derivatives of the human colon carcinoma HCT116 cell lines (p21(+/+) and p21(-/-)), and immunoprecipitation studies with p21 antibody. The SAA cytotoxicity was blocked by co-incubation with catalase, whereas the SBA cytotoxicity and its subsequent growth arrest were abolished by N-acetyl-L-cysteine (NAC), but was not affected by PI3K phosphorylation inhibitor LY294002, or catalase, suggesting two separated oxidative stress pathways were mediated by these two ascorbates. In addition, neither active caspase 3 nor apoptotic bodies but autophagic vacuoles associated with increased LC3-II were found in SBA-treated HT-29 cells; implicating that SBA induced AKT phosphorylation-autophagy and p21-growth arrest in colon cancer HT-29 cells through an NAC-inhibitable oxidative stress pathway.
Assuntos
Ácido Ascórbico/análogos & derivados , Autofagia/efeitos dos fármacos , Compostos de Benzilideno/farmacologia , Ciclo Celular/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Antineoplásicos , Antioxidantes , Ácido Ascórbico/farmacologia , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de TempoRESUMO
BACKGROUND AND PURPOSE: On diffusion-weighted imaging (DWI), metastatic tumors of the brain may exhibit different signal intensities (SI) depending on their histology and cellularity. The purpose of our study was to verify the hypotheses (1) that SI on DWI predict the histology of metastases and (2) that apparent diffusion coefficient (ADC) values reflect tumor cellularity. MATERIALS AND METHODS: We assessed conventional MR images, DWI, and ADC maps of 26 metastatic brain lesions from 26 patients, 13 of whom underwent surgery after the MR examination. Two radiologists performed qualitative assessment by consensus of the SI on DWI in areas corresponding to their enhancing portions. We measured the contrast-to-noise ratio (CNR) on T2-weighted images and normalized ADC (nADC) values, and compared them with tumor cellularity. RESULTS: The mean SI on DWI and the CNR on T2-weighted images were significantly lower in well differentiated than in poorly differentiated adenocarcinomas and lesions other than adenocarcinoma. The mean nADC value was significantly higher in well differentiated than poorly differentiated adenocarcinomas and lesions other than adenocarcinoma. All 3 small-cell carcinomas and 1 large-cell neuroendocrine carcinoma exhibited high SI on DWI. The nADC value showed a significant inverse correlation with tumor cellularity. There was no significant correlation between the CNR and tumor cellularity. CONCLUSION: The SI on DWI may predict the histology of metastases; well differentiated adenocarcinomas tended to be hypointense, and small- and large-cell neuroendocrine carcinomas showed hyperintensity. Their ADC values reflect tumor cellularity.
Assuntos
Neoplasias Encefálicas/secundário , Imagem de Difusão por Ressonância Magnética , Adenocarcinoma/patologia , Adenocarcinoma/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/patologia , Carcinoma de Células Grandes/patologia , Carcinoma de Células Grandes/secundário , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/secundário , Carcinoma de Células Pequenas/patologia , Carcinoma de Células Pequenas/secundário , Núcleo Celular/patologia , Meios de Contraste , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/secundário , Feminino , Previsões , Humanos , Aumento da Imagem/métodos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-IdadeRESUMO
Lymphocytes are frequently observed in human malignant glioma, the mechanism(s) underlying their appearance is not fully understood. To clarify tumor immunity in malignant gliomas, we analyzed the expression of 8 novel lymphocyte-specific chemokines in human glioma cell lines and glioma tissues by RT-PCR, Northern blot, immunoblot and immunohistochemistry, and examined the correlation with the infiltration of various subsets of lymphocytes. For the 8 chemokines examined (LARC, TARC, ELC, SLC, PARC, LEC, HCC-2, and SCM-1alpha), expression of LARC was clearly detectable in all 12 glioma cell lines by RT-PCR. Additionally, expression of TARC and SCM-1alpha was detectable in the majority of glioma cell lines. However, the expression level of most chemokines was low, so that Northern blot analysis could not demonstrate their expression with the exception of LARC in 2 cell lines. Expression of LARC mRNA and LARC protein was strongly induced by phorbol myristate ester in U87 MG cells. The production of LARC protein was demonstrated in 4 of 8 glioblastoma tissues by immunoblotting, and 9 of 33 samples (27.3%) by immunohistochemistry. Interestingly, the positivity of LARC staining was significantly correlated with the infiltration of CD8-, CD4-, and CD45R0-positive cells (p<0.001). Although the constitutive expression level of LARC is low, certain stimulations could strongly induce its expression, and play a crucial role in the tumor immunity of human malignant glioma.
Assuntos
Quimiocinas CC/fisiologia , Quimiocinas/biossíntese , Glioma/imunologia , Glioma/metabolismo , Linfócitos/metabolismo , Proteínas Inflamatórias de Macrófagos , Receptores de Quimiocinas , Northern Blotting , Linfócitos T CD4-Positivos/metabolismo , Quimiocina CCL20 , Quimiocinas CC/biossíntese , DNA Complementar/metabolismo , Humanos , Immunoblotting , Imuno-Histoquímica , Antígenos Comuns de Leucócito/biossíntese , Receptores CCR6 , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais CultivadasRESUMO
Our aim was to review the MRI appearances of primary intracranial germ-cell tumours (GCT). We reviewed the MRI studies of 32 patients: 19 with germinomas, five with teratomas, one with an embryonal carcinoma, five with mixed and two with malignant nongerminomatous GCT. Eleven were in the pineal region, 12 suprasellar, five in the both sites, two in the basal ganglia and two in the corpus callosum. Contrast-enhanced images were available for 27 patients. The solid parts of GCT were nearly isointense with grey matter on both T1- and T2-weighted images. In seven patients with nongerminomatous GCT high-signal components were found on T1-weighted images, representing haemorrhage, high-protein fluid or fat. Cystic components were detected in 17 of 27 patients; eight germinomas and all nine nongerminomatous GCT had cysts. The solid components of germinomas enhanced homogeneously in eight cases and heterogeneously in 10, while all nongerminomatous GCT showed heterogeneous enhancement. MRI features tumours can facilitate correct diagnosis of GCT, including histological subtypes.
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Neoplasias Encefálicas/diagnóstico , Germinoma/diagnóstico , Imageamento por Ressonância Magnética , Adolescente , Adulto , Encéfalo/patologia , Criança , Pré-Escolar , Feminino , Humanos , MasculinoRESUMO
The FLEP regimen (5-FU, LV, ETP and CDDP) is a combination chemotherapy administered regionally and systemically for the control of both local and disseminated disease in intra- and extra-abdominal regions in patients with advanced and recurrent gastric cancer. Sixty-one patients with advanced and recurrent gastric cancer were entered into this study. The treatment regimen consisted of 5-FU at 370 mg/m2 (days 1 to 5, i.v. 24 h); LV at a dose of 30 mg (days 1 to 5, i.v. bolus); and ETP and CDDP each at 70 mg/m2 (days 7 and 21, ia 2 h). This regimen was repeated every four weeks. The overall response rate was 36.1% (22/61) and the 50% and median survival times were 10.23 and 11.80 months, respectively. The adverse events were Grade 3/4 leukocytopenia (18.0%), Grade 3/4 thrombocytopenia (4.9%), Grade 3 nausea and/or vomiting (3.3%) and Grade 3 stomatitis (1.6%). Of the 17 NAC patients, the six curability B patients showed a statistically higher survival rate than the curability C and unresected patients. Based on the encouraging response rate and the improvement in prognosis, we recommend the FLEP regimen for patients with primary gastric cancer. Neoadjuvant chemotherapy using the FLEP regimen should be performed with curative resection as an objective.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cisplatino/administração & dosagem , Esquema de Medicação , Etoposídeo/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Neoplasias Gástricas/mortalidade , Taxa de SobrevidaRESUMO
OBJECT: The most frequent genetic abnormality in human malignant gliomas is loss of heterozygosity (LOH) on chromosome 10. Candidate genes on chromosome 10 that are associated with the prognosis of patients with anaplastic astrocytoma (AA) and glioblastoma (GBM) were evaluated. METHODS: The authors used 12 fluorescent microsatellite markers on both arms of chromosome 10 to study LOH in 108 primary astrocytic tumors. The LOH on chromosome 10 was observed in 11 (32%) of 34 AAs and 34 (56%) of 61 GBMs. No LOH was detected in 13 low-grade gliomas. Loss of heterozygosity was not detected in any AA in the seven patients younger than 35 years, but it was discovered in 41% of the patients older than 35 years. The prognostic significance of LOH at each locus was evaluated in 89 patients older than 15 years; 33 (37%) had supratentorial AAs and 56 (63%) had supratentorial GBMs. The Cox proportional hazards model, adjusted for patient age at surgery, the preoperative Karnofsky Performance Scale score, and the extent of surgical resection revealed that LOH on marker D10S209 near the FGFR2 and DMBT1 genes was significantly associated with shorter survival in patients with AA. The LOH on markers D10S215 and D10S541, which contain the PTEN/MMAC1 gene between them, was significantly associated with shorter survival in patients with GBM. CONCLUSIONS: In the present study it is found that LOH on chromosome 10 is an age-dependent event for patients with AAs and that LOH on marker D10S209 near the FGFR2 and DMBT1 loci is a significantly unfavorable prognostic factor. It is also reported that LOH on the PTEN/MMAC1 gene is a significantly unfavorable prognostic factor in patients with GBM.
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Astrocitoma/genética , Neoplasias Encefálicas/genética , Cromossomos Humanos Par 10 , Glioblastoma/genética , Perda de Heterozigosidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/fisiologia , Mapeamento Cromossômico , Feminino , Humanos , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Análise de SobrevidaRESUMO
BACKGROUND: Hemangioblastoma (HBL) in the suprasellar region is extremely rare. CASE DESCRIPTION: A suprasellar mass was found in a 33-year-old woman with retinal HBL and bilateral adrenal pheochromocytomas. The diagnosis of von Hippel-Lindau (VHL) disease was confirmed preoperatively not only by these clinical manifestations but also by germline mutation study. The existence of VHL disease indicated a diagnosis of HBL for the suprasellar mass. The results of our mutation study indicated that this patient had type II VHL disease, suggesting that careful follow-up is essential for the early detection of renal cell carcinoma, which is often associated with type II VHL disease. Here, we summarize the previously reported features of sellar and suprasellar HBLs. CONCLUSIONS: HBLs in this region may be one manifestation of VHL disease. Genetic testing of the VHL gene of our patient could provide useful information to determine appropriate medical care and management.
Assuntos
Mutação em Linhagem Germinativa/genética , Hemangioblastoma/genética , Neoplasias Hipofisárias/genética , Proteínas Supressoras de Tumor , Ubiquitina-Proteína Ligases , Doença de von Hippel-Lindau/genética , Adulto , Sequência de Bases/genética , Análise Mutacional de DNA , Feminino , Hemangioblastoma/patologia , Hemangioblastoma/cirurgia , Humanos , Ligases/genética , Imageamento por Ressonância Magnética , Mutação de Sentido Incorreto/genética , Neoplasias Hipofisárias/patologia , Neoplasias Hipofisárias/cirurgia , Proteína Supressora de Tumor Von Hippel-Lindau , Doença de von Hippel-Lindau/patologia , Doença de von Hippel-Lindau/cirurgiaRESUMO
BACKGROUND AND PURPOSE: The different sensitivities to vessel size of gradient-echo echo-planar imaging (GE-EPI) and spin-echo EPI (SE-EPI) might indicate the relative cerebral blood volumes (rCBVs) of different tumor sizes. The techniques of GE-EPI and SE-EPI were compared for detecting low- versus high-grade gliomas. METHODS: Six patients with low-grade gliomas and 19 patients with high-grade gliomas underwent two perfusion-sensitive MR procedures, one produced by a GE- and the other by an SE-EPI technique. Maximum rCBV ratios normalized with rCBV of contralateral white matter were calculated for evaluation. P <.05 was considered statistically significant. RESULTS: Maximum rCBV ratios of high-grade gliomas obtained with the GE-EPI technique (mean, 5.0 +/- 2.9) were significantly higher than those obtained with the SE-EPI technique (mean, 2.9 +/- 2.3) (P =.02). Maximum rCBV ratios of low-grade gliomas obtained with the GE-EPI technique (mean, 1.2 +/- 0.7) were almost equal to those obtained with the SE-EPI technique (mean, 1.2 +/- 0.6), and there was no significant difference (P =.66). The difference in the maximum rCBV ratios between the low- and high-grade gliomas reached significance when obtained with the GE-EPI technique (P =.01). CONCLUSION: The GE-EPI technique seems more useful for detecting low- versus high-grade gliomas than the SE-EPI technique.
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Volume Sanguíneo/fisiologia , Neoplasias Encefálicas/irrigação sanguínea , Imagem Ecoplanar , Glioma/irrigação sanguínea , Aumento da Imagem , Imageamento por Ressonância Magnética , Adolescente , Adulto , Idoso , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Neoplasias Encefálicas/diagnóstico , Neoplasias do Tronco Encefálico/irrigação sanguínea , Neoplasias do Tronco Encefálico/diagnóstico , Feminino , Glioma/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Ponte/irrigação sanguínea , Ponte/patologia , Estudos Prospectivos , Fluxo Sanguíneo Regional/fisiologia , Sensibilidade e EspecificidadeRESUMO
Simvastatin is one of the competitive inhibitors of HMG-CoA reductase. During clinical trials, it has shown the ability to lower serum cholesterol. We investigated the effect of simvastatin on the growth of malignant gliomas in vitro, semi-in vivo, and in vivo. An in-vitro MTT assay revealed that human malignant glioma cell lines: U-251MG, U-373MG, and U-87MG, and rat malignant glioma cell line C6 were well inhibited in growth in a dose-dependent fashion. An anchorage-independent growth assay showed that the number of colonies (more than 100 microM in size) of human (U-373MG) and rat malignant gliomas (C6) was markedly reduced in a dose-dependent fashion. A flow cytometry analysis revealed that simvastatin treatment led U-251MG cells to accumulate in sub G0-G1. Immunostaining by TUNEL method showed that most glioma cells treated by 10 microM simvastatin had nuclear immunostaining, suggesting apoptotic changes of the treated cells. The human umbilical vein endothelial cells and human lung fibroblasts were inhibited in growth by no more than 20% of controls even with a high dose (10 microM) of simvastatin. In the semi-in vivo model, using newborn rat brain slice cultures, the rhodamine-labeled glioma cells were abolished after 7 days of local simvastatin treatment with fibrin glue probably suggesting that simvastatin led the cells to apoptosis. In rat models using subcutaneously inoculated C6, the local application of simvastatin combined with fibrin glue (spray method) was quite effective in inhibiting the growth of the tumor. These data suggest that simvastatin may be a novel anti-glioma drug, and the local application of simvastatin combined with fibrin glue (by spray method) may be a crucial new clinical strategy against glioma growth.
Assuntos
Inibidores Enzimáticos/uso terapêutico , Adesivo Tecidual de Fibrina/uso terapêutico , Glioma/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Sinvastatina/farmacologia , Adesivos Teciduais/uso terapêutico , Células Tumorais Cultivadas/efeitos dos fármacos , Animais , Adesão Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Inibidores Enzimáticos/farmacologia , Adesivo Tecidual de Fibrina/administração & dosagem , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Citometria de Fluxo , Glioma/enzimologia , Glioma/patologia , Humanos , Hidroximetilglutaril-CoA Redutases/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Marcação In Situ das Extremidades Cortadas , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Ratos , Ratos Wistar , Rodaminas , Adesivos Teciduais/administração & dosagem , Células Tumorais Cultivadas/enzimologiaRESUMO
BACKGROUND: Vertebral arteriovenous fistulas are relatively rare. Although the common treatment is transarterial embolization, it may be impossible to pass through the fistula (e.g. a microfistula created by a needle puncture). We report two patients with vertebral arteriovenous fistulas due to penetrating trauma who were successfully treated by transvenous embolization. METHOD: We present 2 patients with vertebral arteriovenous fistulas. One patient is presented to demonstrate complications following attempted internal jugular cannulation and the other is presented to demonstrate complications after surgery for a jugular foramen neurinoma. Both patients manifested the sign of a severe bruit. FINDINGS: To identify the fistula point, simultaneous transarterial and transvenous angiography was performed. Using the transvenous approach, microcoils were applied to the fistula and the bruit completely disappeared. Interpretation. Transvenous embolization is a useful technique and a first-choice strategy to treat patients with the vertebral arteriovenous fistula due to penetrating trauma.
Assuntos
Fístula Arteriovenosa/cirurgia , Embolização Terapêutica/métodos , Artéria Vertebral/patologia , Ferimentos Penetrantes/complicações , Adulto , Idoso , Angiografia , Feminino , Humanos , Complicações Pós-Operatórias , Stents , Resultado do Tratamento , Artéria Vertebral/cirurgiaRESUMO
BACKGROUND: Although mutational inactivation and allelic loss in the NF2 gene appear to be causal events in the majority of vestibular schwannomas, involvement of another potentially important mechanism, transcriptional inactivation, has not been investigated. RESULTS: We cloned and functionally characterized the 5'-flanking region of the human NF2 gene and identified the molecular mechanisms that regulate NF2 expression. Luciferase assay and site-directed mutagenesis demonstrated that a 70-base pair (bp) region (-591 to -522 bp from the translation start site) was essential for the basic expression of the NF2 gene. A gel mobility shift assay indicated recognition by nuclear protein of the unusually long ( approximately 66 bp) sequences in this region. Recognition was inhibited by either mutation of the binding core sequence or by methylation of three CpG sites. Point mutations at these CpG sites significantly decreased promoter activity, suggesting the importance of these sites. In 14 of 23 vestibular schwannomas, these three CpG sites were methylated in a site-specific manner and the methylation status was consistent with the expression of NF2 mRNA. CONCLUSIONS: Suppressed expression by aberrant methylation or mutation of the promoter elements could be an alternative mechanism for inactivation of the NF2 gene.
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Neoplasias Encefálicas/genética , Ilhas de CpG/fisiologia , Inativação Gênica , Genes da Neurofibromatose 2 , Mutação , Neurilemoma/genética , Regiões Promotoras Genéticas , Animais , Sequência de Bases , Northern Blotting , Clonagem Molecular , Ilhas de CpG/genética , Metilação de DNA , Genes Reporter , Humanos , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Ratos , TransfecçãoRESUMO
A 56-year-old male was admitted for treatment of advanced gastric cancer. The patient was diagnosed as having an unresectable advanced gastric cancer because cancer cells had invaded the pancreas head and there were metastatic lymph nodes. The patient underwent preoperative chemotherapy (FLEP: intra-arterial infusion of CDDP, ETP and intravenous infusion of 5-FU, LV). The primary tumor and metastatic lymph nodes were reduced by three course of chemotherapy. The patient underwent curative resection and survived without recurrence for 14 months after operation. Preoperative chemotherapy using FLEP was performed in 15 patients with unresectable primary advanced gastric cancer. This therapy resulted in significantly higher survival times. In conclusion, FLEP has been shown to be effective for unresectable advanced gastric cancer.
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Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bombas de Infusão Implantáveis , Terapia Neoadjuvante , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cisplatino/administração & dosagem , Terapia Combinada , Esquema de Medicação , Etoposídeo/administração & dosagem , Fluoruracila/administração & dosagem , Gastrectomia , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Cuidados Pré-Operatórios , Neoplasias Gástricas/cirurgiaRESUMO
In order to elucidate the mechanisms of antitumor action of sodium 5,6-benzylidene-L-ascorbate (SBA), we established a mouse hepatocellular carcinoma model by oral administration of N-nitrosodiethylamine (NDA) and examined the ascorbate radical intensity and putrescine content in the liver. The oral intake of NDA induced precancerous lesion and a significant increase in putrescine content among three major polyamines. When the oral intake of NDA was stopped, morphological changes were reversed. ESR spectroscopy showed that the homogenate of precancerous tissues produced greater amounts of ascorbate radical than that of normal liver tissue. Intravenous administration of SBA 30 minutes before removal of the liver prolonged the higher level of ascorbate radical generation in the homogenate of precancerous tissue. The antitumor activity of SBA might be due to the long-term production of radicals in tumor tissues by its prooxidant action.
Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Ácido Ascórbico/análogos & derivados , Ácido Ascórbico/farmacologia , Compostos de Benzilideno/farmacologia , Neoplasias Hepáticas Experimentais/metabolismo , Animais , Dietilnitrosamina , Espectroscopia de Ressonância de Spin Eletrônica , Cinética , Fígado/patologia , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Poliaminas/metabolismo , Superóxidos/metabolismoRESUMO
Neoadjuvant chemotherapy for high-risk patients with advanced gastric cancer is important to increase the chance for curative resection and make unresectable gastric cancer tumors resectable by down-staging of the tumor. Tumors with H0, P0, T3, T4, or N3 are the best candidates for this therapy. Randomized controlled phase III studies are needed in conjunction with accurate staging of the disease by laparoscopy. The results of histopathologic evaluation of resected materials following preoperative chemotherapy using oral fluoropyrimidine are thought to be useful as an indicator of chemosensitivity for postoperative adjuvant setting.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Administração Oral , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cisplatino/administração & dosagem , Esquema de Medicação , Etoposídeo/administração & dosagem , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Terapia Neoadjuvante , Cuidados Pré-Operatórios , Neoplasias Gástricas/mortalidade , Taxa de SobrevidaRESUMO
Combination chemotherapy with 5-FU, LV, ETP and CDDP (FLEP) for advanced gastric cancer uses a combination of regional and systemic delivery for the control of both local and disseminated disease in the intra- and extra-abdominal regions. We performed this regimen as neoadjuvant chemotherapy (NAC). Fifteen patients with unresectable primary advanced gastric cancer underwent FLEP. The treatment regimen was 5-FU at 370 mg/m2, LV at 30 mg/body (days 1 to 5, i.v. 24 h) and ETP and CDDP each at 70 mg/m2 (days 7 and 21, ia 2 h). This regimen was repeated every four weeks. The overall response rate was 46.7% (7/15), and the 50% and median survival times were 11.43 and 12.35 months, respectively. The adverse events were Grade 3 leukocytopenia, Grade 3 thrombocytopenia, and Grade 3 stomatitis in 20.0%, 13.3%, and 6.7% of the patients, respectively. The 50% and median survival time overall were 11.43 and 12.35 months, respectively. Of the 15 NAC patients, curability B patients showed a statistically higher survival rate than curability C and unresected patients. In conclusion, FLEP was effective for unresectable advanced gastric cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cisplatino/administração & dosagem , Esquema de Medicação , Epirubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Terapia NeoadjuvanteRESUMO
The effect of CoCl2 on the cytotoxic activity of various antioxidants against human oral tumor cell lines (HSC-2, HSG) and normal human gingival fibroblasts (HGF) was investigated. Noncytotoxic concentrations of CoCl2 significantly reduced the cytotoxic activity of sodium ascorbate, gallic acid, epigallocatechin gallate (EGCG), curcumin and dopamine, but not that of sodium 5,6-benzylidene-L-ascorbate (SBA) and benzaldehyde. Among these compounds, benzaldehyde showed the most prominent tumor-specific cytotoxic action. ESR spectroscopy showed that these antioxidants produced radicals under alkaline condition and that their radical intensity was transiently enhanced and finally disappeared by addition of CoCl2. Antioxidants which are sensitive to CoCl2 generally had higher cytotoxic activity and oxidation potential (measured by NO monitor) and addition of CoCl2 significantly reduced their oxidation potential. The present study suggests that cobalt ion stimulates the oxidation of antioxidants to their inactive products.