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1.
Br J Cancer ; 108(10): 1957-63, 2013 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-23640393

RESUMO

BACKGROUND: A phase III trial was conducted to determine whether neoadjuvant chemotherapy (NACT) before radical surgery (RS) improves overall survival. METHODS: Patients with stage IB2, IIA2, or IIB squamous cell carcinoma of the uterine cervix were randomly assigned to receive either BOMP (bleomycin 7 mg days 1-5, vincristine 0.7 mg m(-2) day 5, mitomycin 7 mg m(-2) day 5, cisplatin 14 mg m(-2) days 1-5, every 3 weeks for 2 to 4 cycles) plus RS (NACT group) or RS alone (RS group). Patients with pathological high-risk factors received postoperative radiotherapy (RT). The primary end point was overall survival. RESULTS: A total of 134 patients were randomly assigned to treatment. This study was prematurely terminated at the first planned interim analysis because overall survival in the NACT group was inferior to that in the RS group. Patients who received postoperative RT were significantly lower in the NACT group (58%) than in the RS group (80%; P=0.015). The 5-year overall survival was 70.0% in the NACT group and 74.4% in the RS group (P=0.85). CONCLUSION: Neoadjuvant chemotherapy with BOMP regimen before RS did not improve overall survival, but reduced the number of patients who received postoperative RT.


Assuntos
Carcinoma de Células Escamosas/terapia , Neoplasias do Colo do Útero/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bleomicina/administração & dosagem , Bleomicina/uso terapêutico , Braquiterapia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Terapia Combinada , Feminino , Humanos , Histerectomia/métodos , Japão , Oncologia/organização & administração , Pessoa de Meia-Idade , Mitomicina/administração & dosagem , Mitomicina/uso terapêutico , Terapia Neoadjuvante , Estadiamento de Neoplasias , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/cirurgia , Vincristina/administração & dosagem , Vincristina/uso terapêutico , Adulto Jovem
2.
Int Angiol ; 29(2 Suppl): 2-13, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20357743

RESUMO

AIM: To investigate the current status of peripheral arterial disease (PAD) drug treatment in Japan, and the effects of drug treatment, risk factors, and complications on disease progress and onset of cardiovascular events in PAD patients. METHODS: In this prospective observational cohort study, 557 PAD patients were followed up for 3 years, and the current status of PAD treatment, risk factors, and cardiovascular events were monitored. RESULTS: Three drugs, i.e., beraprost sodium, cilostazol, and aspirin, were most frequently used. The patients who had undergone vascular reconstruction of the lower limbs before enrollment showed significant improvement in ABI. Among the patients who had not undergone vascular reconstruction before enrollment, there was a significant improvement in ABI after treatment with beraprost. During the observation period, cardiovascular deaths occurred in 35 patients (6.3%), heart diseases in 63 (11.3%), brain diseases in 39 (7.0%), and events in the lower limbs in 94 (16.9%). The factors affecting the increase of the cardiovascular events were explored by multivariate analysis (Cox regression analysis). As a result, age (75 years or older), ischemic heart disease and increase in severity on the Fontaine classification were identified as significant factors for cardiovascular deaths, whereas kidney disorders and increase in severity on the Fontaine classification were identified for heart diseases, the number of oral drugs for treating PAD was identified for brain diseases, and age (younger than 75 years), dialysis, ABI (less than 0.7) and aspirin were identified for the events in the lower limbs. CONCLUSION: As a result of the three-year follow-up on the Japanese PAD cohort, the current status of PAD treatment, risk factors, and cardiovascular events could be identified.


Assuntos
Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Doenças Vasculares Periféricas/complicações , Doenças Vasculares Periféricas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice Tornozelo-Braço , Aspirina/uso terapêutico , Doenças Cardiovasculares/mortalidade , Cilostazol , Progressão da Doença , Epoprostenol/análogos & derivados , Epoprostenol/uso terapêutico , Feminino , Seguimentos , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Doenças Vasculares Periféricas/diagnóstico , Doenças Vasculares Periféricas/mortalidade , Doenças Vasculares Periféricas/cirurgia , Inibidores da Agregação Plaquetária/uso terapêutico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Qualidade de Vida , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Sociedades Médicas , Tetrazóis/uso terapêutico , Fatores de Tempo , Resultado do Tratamento , Procedimentos Cirúrgicos Vasculares , Vasodilatadores/uso terapêutico
3.
Eur J Gynaecol Oncol ; 27(6): 561-5, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17290583

RESUMO

PURPOSE: A fractal is a shape made of parts similar to the whole. Our objective was to determine whether surface growth patterns in malignant epithelial ovarian tumors are 3-D fractal, and if the mean fractal dimension differs according to histologic types. METHODS: After the images of photographs of 139 resected malignant epithelial ovarian tumors were digitized, the fractal dimensions of surface of solid portions were measured using 3-D fractal analysis software. RESULTS: The mean fractal dimensions of the surface of a solid area of tumor in serous, mucinous, endometrioid, and clear cell adenocarcinoma were 2.320, 2.224, 2.229, and 2.298, respectively. Those of serous and mucinous cystadenoma of low malignant potential (LMP) were 2.398 and 2.282, respectively. These values were significantly greater than the topological dimension of a surface (= 2). The mean fractal dimensions of a solid area of tumor inside the cyst for serous, mucinous, endometrioid, and clear cell carcinoma were 2.347, 2.223, 2.228, and 2.310, respectively. The values for serous and mucinous cystadenoma of LMP were 2.398 and 2.282, respectively. CONCLUSION: This study shows that the surface of a solid area of malignant epithelial ovarian tumors has a 3-D fractal structure, and the mean fractal dimension may differ according to histologic types.


Assuntos
Adenocarcinoma/patologia , Cistadenoma Seroso/patologia , Fractais , Imageamento Tridimensional/métodos , Neoplasias Ovarianas/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pessoa de Meia-Idade , Fotografação , Estudos Retrospectivos
4.
Br J Cancer ; 92(12): 2286-91, 2005 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-15886699

RESUMO

The DNA mismatch repair gene is a key regulator in the elimination of base-base mismatches and insertion/deletion loops (IDLs). Human MutS homologue 2 (hMSH2), originally identified as a human homologue of the bacterial MutS, is a tumour suppressor gene frequently mutated in hereditary non-polyposis colorectal cancer. Hereditary non-polyposis colorectal cancer is characterised by the early onset of colorectal cancer and the development of extracolonic cancers such as endometrial, ovarian, and urological cancers. Oestrogen receptor (ER) alpha and beta are members of a nuclear receptor (NR) superfamily. Ligand-dependent transcription of ER is regulated by the p160 steroid receptor coactivator family, the thyroid hormone receptor-associated proteins/the vitamin D receptor-interacting proteins (TRAP/DRIP) mediator complex, and the TATA box-binding protein (TBP)-free TBP associated factor complex (TFTC) type histone acetyltransferase complex. Here, we report the interaction between ER alpha/beta and hMSH2. Immunoprecipitation and glutathione-S-transferase pull-down assay revealed that ER alpha and hMSH2 interacted in a ligand-dependent manner, whereas ER beta and hMSH2 interacted in a ligand-independent manner. Oestrogen receptor alpha/beta bound to hMSH2 through the hMSH3/hMSH6 interaction domain of hMSH2. In a transient expression assay, hMSH2 potentiated the transactivation function of liganded ER alpha, but not that of ER beta. These results suggest that hMSH2 may play an important role as a putative coactivator in ER alpha dependent gene expression.


Assuntos
Pareamento Incorreto de Bases/genética , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , Receptor alfa de Estrogênio/genética , Proteínas Proto-Oncogênicas/genética , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Mapeamento Cromossômico , Neoplasias do Endométrio/genética , Receptor beta de Estrogênio/genética , Feminino , Expressão Gênica , Genes Supressores de Tumor , Humanos , Proteína 2 Homóloga a MutS , Ativação Transcricional
5.
Br J Cancer ; 92(6): 1026-32, 2005 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-15770211

RESUMO

The value of secondary cytoreductive surgery (SCS) for recurrent ovarian cancer is still controversial. The aim of this study was to clarify candidates for SCS. Between January 1987 and September 2000, we performed SCS in 44 patients with recurrent ovarian cancer, according to our selection criteria, disease-free interval (DFI) >6 months, performance status <3, no apparent multiple diseases, age <75 years and no progressive disease during preoperative chemotherapy, if undertaken. The variables were investigated by univariate and multivariate analyses. Of 44 patients, 26 (59.1%) achieved complete removal of all visible tumours at SCS. Secondary cytoreductive surgery outcome, complete or incomplete resection, was significantly related to overall survival (P=0.0019). As for variables determined before SCS, DFI >12 months, no liver metastasis, solitary tumour and tumour size <6 cm were independently associated with favourable overall survival after recurrence in the multivariate analysis. Patients with three or all four variables (n=31) had significantly better survival compared with the other patients (n=13) (47 vs 20 months in median survival, P<0.0001). In these patients, fairly good median survival (40 months) was obtained even in patients with incomplete resection. Secondary cytoreductive surgery had a large impact on survival of patients with recurrent ovarian cancer when they had three or all of the above-mentioned four factors at recurrence. These patients should be considered as ideal candidates for SCS.


Assuntos
Recidiva Local de Neoplasia/cirurgia , Neoplasias Epiteliais e Glandulares/cirurgia , Neoplasias Ovarianas/cirurgia , Seleção de Pacientes , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias Epiteliais e Glandulares/mortalidade , Neoplasias Ovarianas/mortalidade , Prognóstico
6.
Br J Cancer ; 90(1): 194-9, 2004 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-14710229

RESUMO

Recently, a LAP protein, scribble, was identified in Drosophila epithelia as a basolateral protein that controls the apical-basolateral polarity. Loss of scribble causes disorganisation and overgrowth of the epithelia. Scribble has a human homologue, human scribble (hScrib), which is a substrate of ubiquitin-mediated degradation by human papillomavirus E6 and the E6AP ubiquitin-protein ligase. In the present study, we revealed that hScrib localised to the basolateral regions of the epithelial cell line MDCK and human uterine cervical epithelial tissues by immunofluorescence. Human scribble colocalised rather with the adherens junction protein E-cadherin, but not with the tight junction protein ZO-1. Histochemical analysis showed a dramatic decrease in the expression of hScrib with the progression of disease from normal uterine cervical tissues to invasive cervical cancers through the precursor lesions. In contrast, the expression of hScrib was retained in the throughout epithelial layer of the HPV-negative cervical high-grade squamous intraepithelial lesions (H-SIL). Although quantitative RT-PCR revealed no significant downregulation of hScrib mRNA expression in the H-SIL, it revealed a clear downregulation in the invasive cancers. These results suggest the possibility that degradation by HPV E6 is one of the causal roles for the progressive decrease of hScrib expression during the disease progression from low-grade squamous intraepithelial lesions to H-SIL, and a cooperative role of downregulation of hScrib mRNA expression and ubiquitin-mediated degradation of hScrib by E6 and E6AP led to the complete decrease of hScrib expression during the process of carcinogenesis from H-SIL to invasive cancer. These data underscore the importance of hScrib in the construction of tissue architecture and prevention of cancer development.


Assuntos
Transformação Celular Neoplásica , Colo do Útero/patologia , Regulação da Expressão Gênica , Proteínas de Membrana/biossíntese , Displasia do Colo do Útero/genética , Displasia do Colo do Útero/patologia , Neoplasias do Colo do Útero/genética , Western Blotting , Linhagem Celular , Colo do Útero/citologia , Progressão da Doença , Regulação para Baixo , Células Epiteliais , Feminino , Imunofluorescência , Humanos , Proteínas de Membrana/análise , Invasividade Neoplásica , Infecções por Papillomavirus/complicações , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas Supressoras de Tumor , Neoplasias do Colo do Útero/patologia
7.
Ultrasound Obstet Gynecol ; 22(6): 622-6, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14689536

RESUMO

OBJECTIVE: To investigate the usefulness of intraoperative sonography for the assessment of para-aortic lymph nodes in gynecological malignancies. METHODS: The assessment of para-aortic lymph node swelling by computed tomography (CT), palpation during surgery and intraoperative sonography was performed in 43 women with a gynecological malignancy. The sensitivity, specificity and predictive values of each technique for assessment of node metastasis were examined in the 33 women who underwent para-aortic lymphadenectomy. For each of the three assessment techniques, the number of para-aortic lymphadenectomies that would have been performed and the number of women who would have had missed metastasis were evaluated assuming a para-aortic lymphadenectomy would be performed only when swollen nodes were detected. RESULTS: Para-aortic nodes were assessed to be swollen by CT, palpation, and intraoperative sonography, respectively, in one, six and 10 of 43 women in total, and in one, six and nine of the 33 women who underwent para-aortic lymphadenectomy. The sensitivity and negative predictive value of intraoperative sonography were 100%, while the specificity and positive predictive value of CT were 100%. If para-aortic lymphadenectomy had been performed only when swollen nodes were detected by intraoperative sonography, the number performed would have decreased from 33 to nine without missing lymph-node metastasis. CONCLUSION: Intraoperative sonography has potential for the assessment of para-aortic lymph nodes in gynecological malignancies.


Assuntos
Endossonografia/métodos , Neoplasias dos Genitais Femininos/cirurgia , Cuidados Intraoperatórios/métodos , Metástase Linfática/diagnóstico por imagem , Aorta , Feminino , Neoplasias dos Genitais Femininos/patologia , Humanos , Excisão de Linfonodo , Estadiamento de Neoplasias , Palpação , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Tomografia Computadorizada por Raios X
9.
Br J Cancer ; 88(8): 1213-6, 2003 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-12698186

RESUMO

We analysed the expression of the fragile histidine triad (FHIT) gene in cervical cancer to evaluate its clinical relevance in relation to human papillomavirus (HPV) infection. A total of 73 women with cervical cancer of stage Ib or more advanced (67 squamous cell carcionomas, four adenocarcinomas, two adenosquamous carcinomas) were examined for Fhit expression by immunohistochemistry. They were further analysed for the presence of HPV and its subtype. Abnormal expression of Fhit (absent or reduced Fhit expression) was observed in 52 cases (71.2%). The high-risk HPV DNAs for cervical cancer, including type 16, 18, 31, 33, 51, 52, 58, 68, were identified in 63 cases (86%). The abnormal Fhit expression was not related to the clinicopathological factors including histology, tumour stage, and HPV type. Notably, the 5-year survival of patients showing the abnormal Fhit expression was significantly poorer than those showing normal Fhit expression (64 versus 87%, P=0.035). Interestingly, the mean age of the patients with the abnormal Fhit expression was significantly less than those with the normal Fhit expression (51.6 versus 58.7 years of age, P=0.027, student's t-test). These data imply that the aberrant Fhit expression could be a poor prognostic factor independent of HPV. In the light of a high incidence of abnormal Fhit expression in younger patients and HPV as a key player in cervical carcinogenesis, abnormal Fhit expression may accelerate carcinogenesis in concert with HPV.


Assuntos
Hidrolases Anidrido Ácido/genética , Proteínas de Neoplasias/genética , Neoplasias do Colo do Útero/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Papillomaviridae/classificação , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/complicações , Prognóstico , Análise de Sobrevida , Fatores de Tempo , Infecções Tumorais por Vírus/complicações , Neoplasias do Colo do Útero/mortalidade
10.
Clin Cancer Res ; 7(9): 2636-42, 2001 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11555573

RESUMO

Although the prognostic impact of PTEN mutation in endometrial carcinoma is beginning to be analyzed, the prognostic significance of mutated PTEN exons has not ever been described. Sixty-seven endometrial carcinomas were analyzed for PTEN mutations using single-strand conformation polymorphism analysis and DNA sequencing. First, survival rates were compared according to PTEN status and mutated PTEN exons. Subsequently, univariate and multivariate analyses of various favorable prognostic factors for survival were conducted. The associations between PTEN mutation and clinicopathological features were also statistically evaluated. PTEN mutations were detected in 37 of 67 (55%) specimens. Among 47 mutations, frameshifts (57%) and mutations in exon 8 (38%) were most frequent. In univariate analysis, a factor of PTEN mutation only outside exons 5-7 was associated with significantly better survival (P = 0.02), although mutation in any exon of PTEN was not (P = 0.33). Subsequent multivariate analysis revealed that factors of mutation only outside exons 5-7 of PTEN, stage I/II, and G1 were significant and independent prognostic indicators for favorable survival (P = 0.004, 0.004, and 0.0006, respectively). In the subset of advanced-stage disease, mutation only outside exons 5-7 was associated with a trend toward better survival (P = 0.13). No significant correlation was observed between PTEN mutation and estrogen-related clinicopathological features. In conclusion, we find that PTEN mutation located only outside exons 5-7 is a significant and independent positive prognostic indicator for survival. The current observation has prognostic and therapeutic implications for the management of patients with endometrial carcinoma.


Assuntos
Neoplasias do Endométrio/patologia , Éxons/genética , Monoéster Fosfórico Hidrolases/genética , Proteínas Supressoras de Tumor , Adulto , Idoso , Análise Mutacional de DNA , DNA de Neoplasias/química , DNA de Neoplasias/genética , Neoplasias do Endométrio/genética , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , PTEN Fosfo-Hidrolase , Polimorfismo Conformacional de Fita Simples , Valor Preditivo dos Testes , Prognóstico , Análise de Sobrevida
11.
Cancer Lett ; 170(1): 19-24, 2001 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-11448530

RESUMO

The variation of the E6 region of human papillomavirus type 16 (HPV16) is associated with a high risk for cervical carcinogenesis. To see whether the same is the case with HPV33, 52 and 58, known to have high homology with HPV16, we analyzed the E6 sequence variation of these HPVs in 107 Japanese women with cervical intraepithelial neoplasia (CIN) or invasive cervical cancer (ICC): 20 HPV33-positive, 46 HPV52-positive and 41 HPV58-positive cases. HPV33 variants were more frequently observed in CINs I/II than in CIN III/ICCs (71% (5/7) versus 15% (2/13), P=0.02). In HPV52-positive cases, a single E6 variant was detected in 98% of the cases, whereas the prototype accounted for 98% of HPV58-positive cases. In summary, the distribution of E6 variants is different among HPV types tested, suggesting a link between E6 variation and oncogenic potential being type-specific.


Assuntos
Proteínas Oncogênicas Virais/análise , Papillomaviridae/isolamento & purificação , Displasia do Colo do Útero/virologia , Neoplasias do Colo do Útero/virologia , Feminino , Humanos , Japão/epidemiologia , Proteínas Oncogênicas Virais/genética , Papillomaviridae/genética , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/etiologia , Displasia do Colo do Útero/epidemiologia , Displasia do Colo do Útero/etiologia
12.
J Surg Oncol ; 77(1): 61-4, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-11344485

RESUMO

BACKGROUND: Because of a relative rarity of the cases with an artificial vagina, the incidence of a case with malignant disease arising in the neovagina is extremely rare. A case of adenocarcinoma arising from a neovagina is presented with a review of the literature. CASE: A neovagina was constructed using the sigmoid colon at the age of 23 for congenital agenesis of the vagina, Rokitansky-Küster-Hauser syndrome. Subsequently, the patient had regular sexual intercourse for about 20 years. At the age of 53, she came to our outpatient clinic with a complaint of vaginal bleeding, and adenocarcinoma was found at the anterior wall of the neovagina adjoining the introitus. Total resection of the neovagina and adjuvant radiotherapy was performed. The pathological diagnosis was mucinous adenocarcinoma. CONCLUSIONS: In view of relatively low incidence of mucinous carcinoma arising in the sigmoid colon along with the ectopic localization, this case may have implications for the understanding of pathogenesis of sigmoid colon cancer.


Assuntos
Adenocarcinoma Mucinoso/patologia , Colo Sigmoide/transplante , Procedimentos de Cirurgia Plástica/métodos , Vagina/anormalidades , Vagina/cirurgia , Adenocarcinoma Mucinoso/etiologia , Feminino , Humanos , Pessoa de Meia-Idade , Fatores de Tempo
13.
Gynecol Obstet Invest ; 50 Suppl 1: 11-7, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-11093056

RESUMO

Endometriosis may be the precursor of clear cell or endometrioid ovarian cancer. In this review, we focus on the prevalence of endometriosis in ovarian cancer and related clinical and epidemiological issues. According to 15 published reports, the rank order of the prevalence of endometriosis in each histologic type was clear cell (39.2%) > endometrioid (21.2%) > serous (3.3%) > mucinous type (3.0%). The high prevalence of endometriosis in clear cell and endometrioid types is a consistent finding in Japan and western countries. However, the incidence of the clear cell type is much higher (15-20% vs. 7-8%), and that of the endometrioid type is lower (7-16% vs. 18-26%), in Japan compared with western countries. This review is also concerned with the relationship between the presence of ovarian endometriosis and clinical features such as age, parity, menopausal status, clinical stage, and survival in ovarian cancer patients.


Assuntos
Transformação Celular Neoplásica/patologia , Endometriose/epidemiologia , Endometriose/patologia , Neoplasias Ovarianas/patologia , Adenocarcinoma de Células Claras/epidemiologia , Adenocarcinoma de Células Claras/patologia , Adenocarcinoma Mucinoso/epidemiologia , Adenocarcinoma Mucinoso/patologia , Adolescente , Adulto , Distribuição por Idade , Idoso , Carcinoma Endometrioide/epidemiologia , Carcinoma Endometrioide/patologia , Comorbidade , Feminino , Humanos , Japão/epidemiologia , Pessoa de Meia-Idade , Neoplasias Ovarianas/epidemiologia , Prevalência , Medição de Risco
14.
J Med Virol ; 62(2): 251-8, 2000 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11002256

RESUMO

The presence of human papillomavirus (HPV) DNA in almost all of the cervical carcinomas is one of the most compelling evidence for the viral carcinogenesis. HPVs are thought to induce cervical carcinoma most likely through the expression of E6 and E7 genes presumably by inactivating the tumor suppressor proteins, p53 and pRb, respectively. Thus far, the presence of HPV E6 and E7 transcripts have been identified only in cervical carcinoma-derived cell lines harboring type 16 or 18, and in a limited number of cervical neoplasia specimens positive for type 16, 18, 33 or 51. To see whether the expression of E6 and E7 genes is an essential finding in HPV-positive cervical carcinoma and cervical intraepithelial neoplasia (CIN), we constructed a reverse transcription-polymerase chain reaction (RT-PCR) assay using a pair of consensus primers in the E6 and E7 regions. Using the assay, E6 transcripts (full-length E6/E7 transcripts) and E7 transcripts (spliced E6/E7 transcripts, E6* mRNA) were identified in 97% (30/31) and 100% (all 31) of cervical carcinomas and in 100% (all 23) and 74% (17/23) of CINs, respectively. This assay also revealed unknown splice donor and acceptor sites of E6* mRNA of less frequent HPV types 31, 35, 52, 56, 58 and 59 based on sequence analyses of the PCR products. Thus, the present study demonstrates that E6 and E7 transcripts of HPV exist in virtually all HPV-positive cervical neoplasia specimens except for the absence of E7 transcripts in some of CINs.


Assuntos
Proteínas Oncogênicas Virais/genética , Papillomaviridae/metabolismo , Displasia do Colo do Útero/virologia , Neoplasias do Colo do Útero/virologia , Sequência de Bases , DNA Viral , Feminino , Humanos , Dados de Sequência Molecular , Papillomaviridae/genética , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/virologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Viral/genética , RNA Viral/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição Gênica , Infecções Tumorais por Vírus/virologia
15.
Cancer Lett ; 156(2): 159-65, 2000 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-10880765

RESUMO

To investigate whether HPV16 E6 variants carry an elevated risk for cervical cancer in Japanese population, we investigated the E6 sequence variation in 40 cervical intraepithelial neoplasias (CINs) I-III and 43 invasive cervical cancers (ICCs), all positive for HPV16. HPV16 E6 variants were frequently found in ICCs than in CINs (88 vs. 65%, P=0.01). The E6 D25E, a rare variant in Western countries, was most frequently observed in ICC (44%). CIN I/II lesions with HPV16 variants were less likely to regress than those with HPV16 prototype (P=0.048). The finding that HPV16 E6 variants represent a significant risk factor is common between Western and Japanese women despite the different distribution of each variant.


Assuntos
Proteínas Oncogênicas Virais/genética , Papillomaviridae/genética , Proteínas Repressoras , Displasia do Colo do Útero/virologia , Neoplasias do Colo do Útero/virologia , Sequência de Bases , DNA Viral/genética , Feminino , Humanos , Invasividade Neoplásica , Papillomaviridae/classificação , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Fatores de Risco , Homologia de Sequência do Ácido Nucleico , Infecções Tumorais por Vírus/complicações , Infecções Tumorais por Vírus/virologia , Neoplasias do Colo do Útero/patologia
17.
Biochem Biophys Res Commun ; 258(1): 128-31, 1999 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-10222247

RESUMO

Human papillomavirus type 16 (HPV16) is known to be a major causative agent of cervical cancer. To test the hypothesis that an enhanced Th1 response favors the natural course of cervical intraepithelial neoplasia (CIN), we measured IgG subclasses toward HPV16 L1-capsids because IgG1/IgG2 balance reflects Th2 and Th1 responses, respectively. We examined IgG2/IgG1 ratios in sera from 67 anti-HPV16 L1-positive women; 18 were cytologically normal women, 29 were CIN patients, and 20 were cervical cancer patients. The IgG2 dominance (IgG2/IgG1 ratio >1) was observed in 94, 48, and 5%, respectively (p < 0.001). The regression rate of CIN lesions was significantly different between patients with and without IgG2 dominance: 83.3% (5/6) versus 16.7% (1/6), respectively (p < 0.05). These findings raise the possibility that IgG2 dominance toward HPV16 L1-capsids, i.e., Th1 dominance, may be a useful marker to predict viral clearance or the regression of HPV16-positive CIN.


Assuntos
Proteínas do Capsídeo , Capsídeo/imunologia , Imunoglobulina G/classificação , Proteínas Oncogênicas Virais/imunologia , Displasia do Colo do Útero/imunologia , Feminino , Humanos , Imunoglobulina G/imunologia , Regressão Neoplásica Espontânea , Proteínas Virais
18.
Br J Cancer ; 79(7-8): 1139-44, 1999 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-10098748

RESUMO

The p53 mutation has been found only in 0-6% of cervical carcinomas. In light of recent studies demonstrating that mutation of p53 gene was found in over 20% of the patients with vulvar carcinoma, a disease of elderly women and a known human papillomavirus (HPV)-related malignancy, we analysed mutation of the p53 gene in 46 women with cervical carcinomas at the age of 60 or more (mean; 71 years, range; 60-96 years). The presence of HPV and its type were analysed by polymerase chain reaction (PCR)-based assay using the consensus primers for L1 region. Mutation of the p53 gene was analysed by PCR-based single-strand conformation polymorphism and DNA sequencing technique. Point mutation of the p53 gene was detected in 5 out of 46 (11%) cervical carcinomas: 1 of 17 (6%) samples associated with high-risk HPVs (HPV 16 and HPV 18) and 4 of 27 samples (15%) with intermediate-risk HPVs (P= 0.36) whereas no mutation was found in 2 HPV negative cases. The mutated residues resided in the selective sequence known as a DNA-binding domain. The immunohistochemistry revealed the overexpression in cancer tissues positive for p53 mutation. All of the observed mutations of the p53 gene were transition type, suggesting that the mutation may be caused by endogenous mutagenesis. Although falling short of statistical significance reduces the strength of the conclusion, data presented here imply that p53 gene mutation, particularly along with intermediate-risk HPV types, may constitute one pathogenetic factor in cervical carcinoma affecting elderly women.


Assuntos
Adenocarcinoma/genética , Adenocarcinoma/virologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/virologia , Genes p53/genética , Papillomaviridae/isolamento & purificação , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/virologia , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Mutação , Papillomaviridae/classificação , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples
19.
Br J Cancer ; 79(3-4): 589-94, 1999 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-10027335

RESUMO

To investigate involvement of an aberrant expression of the FHIT (fragile histidine triad) gene in the process of carcinogenesis and progression in cervical carcinoma, we examined its expression by the reverse transcriptase polymerase chain reaction (RT-PCR) and cDNA sequence method in 32 cervical invasive carcinomas (25 squamous cell carcinomas and seven adeno- or adenosquamous carcinomas) and 18 of its precursor lesions [four low-grade and 14 high-grade cervical intraepithelial neoplasias (CINs)]. We also examined a link between the occurrence of the aberrant expression and human papillomavirus (HPV). We detected the aberrant FHIT transcripts in 11 of 25 (44%) cervical invasive squamous cell carcinomas and in 5 of 14 (36%) high-grade CINs (CIN 2 or 3), whereas they were not found in seven non-squamous type and four low-grade CINs (CIN 1). The alteration patterns of the FHIT gene expression in high-grade CINs were virtually similar to those found in invasive carcinomas, such that the exons 5-7 were consistently deleted associated or unassociated with loss of the exon 4 and/or 8. The incidence of the aberrant expression was not related to the presence of HPV and its type. These data indicate that the aberrant expression of the FHIT gene is observed in precursor lesions of cervical carcinoma as well as invasive carcinomas, with its incidence not increasing with advance of clinical stage. Given the squamous cell type dominant expression, the aberrant expression may play a critical role in the generation of squamous cell carcinoma of the uterine cervix, but not the consequence of the progression of the cancer.


Assuntos
Carcinoma de Células Escamosas/genética , Transformação Celular Neoplásica/genética , Fragilidade Cromossômica/genética , Regulação Neoplásica da Expressão Gênica , Histidina/genética , Neoplasias do Colo do Útero/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/patologia , Progressão da Doença , Feminino , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Papillomaviridae/patogenicidade , Neoplasias do Colo do Útero/patologia
20.
Jpn J Cancer Res ; 89(10): 1041-6, 1998 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9849583

RESUMO

Direct activation of human cytotoxic T lymphocytes (CTL) by interleukin (IL)-18 was observed in a system in which CTL effective against autologous tumor cells were generated. Peripheral blood mononuclear cells (PBMC) from tumor-bearing patients, after removal of natural killer (NK) cells, were cultured in a medium containing IL-1, -2, -4, and -6, with or without IL-18, and stimulated with autologous tumor cells. IL-18 increased the activity of the CTL and the proportion of autologous CD8+ T cells present after 28 days in the induction culture. When purified CD8+ T cells were cultured in the presence of IL-18 and IL-2 for 7 days, the CTL showed enhanced cytotoxic activity against autologous tumor cells. Moreover, a purified CD8+ T cell population, which did not exhibit any apparent cytotoxic activity against autologous tumor cells, displayed cytotoxic activity after 7-day incubation with IL-18. These results suggest that IL-18 may be useful to generate autologous CTL in humans and may thereby contribute to adoptive immunotherapy for tumors.


Assuntos
Citotoxicidade Imunológica , Interleucina-18/farmacologia , Interleucinas/farmacologia , Ativação Linfocitária , Neoplasias/imunologia , Linfócitos T Citotóxicos/imunologia , Adenocarcinoma , Carcinoma de Células Renais , Células Cultivadas , Técnicas de Cocultura , Glioblastoma , Humanos , Interleucina-1/farmacologia , Interleucina-2/farmacologia , Interleucina-4/farmacologia , Interleucina-6/farmacologia , Neoplasias Renais , Ativação Linfocitária/efeitos dos fármacos , Proteínas Recombinantes/farmacologia , Neoplasias Gástricas , Linfócitos T Citotóxicos/efeitos dos fármacos , Células Tumorais Cultivadas
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