RESUMO
This paper reports successful measurement of even-related potential (ERP) using candle-like dry microneedle electrodes, which can acquire high-quality electroencephalogram (EEG) from hairy parts without any pretreatment. In our previous work, we successfully measured spontaneous EEG activity and its application to assess the stress state of the subjects. ERPs originate from electrophysiological response to stimulus and are one of the most important indices to capture the cognitive and sensory activities. In this work, using the candle-like dry microelectrodes, we demonstrate successful measurement of ERPs elicited by oddball tasks. Two oddball tasks using pure tone stimuli and speech stimuli were assigned to the subjects, where EEG was acquired from the parietal region (Cz in international 10-20 system). Note that no pretreatment, such as removal of hairs and abrasion of the scalp, was applied. As a result, P300 and mismatch negativity (MMN) were successfully measured in the both oddball tasks from the averaged EEG after the stimuli. Based on these results and given the attractive natures of the candle-like dry microneedle electrodes; they do not need any skin treatment and conductive gels and they can measure EEG from the hairy parts, the developed electrodes will accelerate cognitive neuroscience research using ERPs.
Assuntos
Eletroencefalografia , Potenciais Evocados , Estimulação Acústica , Eletrodos , Cabelo , Microeletrodos , Couro CabeludoRESUMO
BACKGROUND: Inoperable patients with lymph node metastasis from extramammary Paget's disease (EMPD) have limited curative treatment options. OBJECTIVE: The aim of this study was to review the efficacy and toxicity of radiation therapy for lymph node metastasis from EMPD. METHODS: Eight EMPD patients with pelvic and inguinal lymph node metastasis, representing a total of 43 metastatic lymph nodes, underwent radiation therapy. Of these eight patients, two received radiation therapy as an initial treatment for EMPD and six for recurrence only in the lymph nodes after they had undergone surgery. Total doses of 45-61.2 Gy (median, 59.4 Gy) were delivered to metastatic lymph nodes in 25-34 fractions (median, 33 fractions). RESULTS: Of the 43 metastatic lymph nodes in the eight patients, all but one had no progression at the median follow-up time of 22 months. The 2-year local control rates were 86% in all patients and 98% in all metastatic lymph nodes, respectively. No therapy-related toxicities of grade 3 or greater were observed. CONCLUSION: Radiation therapy is effective and safe, and appears to offer a curative treatment option for lymph node metastasis from EMPD.
Assuntos
Metástase Linfática/radioterapia , Doença de Paget Extramamária/complicações , Neoplasias Cutâneas/complicações , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Relação Dose-Resposta à Radiação , Feminino , Seguimentos , Humanos , Linfonodos/efeitos da radiação , Masculino , Doença de Paget Extramamária/terapia , Estudos Retrospectivos , Neoplasias Cutâneas/terapia , Resultado do TratamentoRESUMO
A lot of research has been carried out in the last decade to find a cure for neurodegenerative diseases especially Parkinson's disease but to little avail. In this study we have demonstrated the use of poly(lactic-co-glycolic acid) (PLGA)/collagen biodegradable microparticles formed using water-in-oil-in-water (W/O/W) double emulsion method, as a neurotrophic factor delivery vehicle. The microparticles were encapsulated with glial cell-derived neurotrophic factor (GDNF) fused with collagen binding peptide (CBP) immobilized to the inner collagen phase. The novelty lies in the strict regulation of release of GDNF-CBP from the microparticles as compared to a burst release from standard microparticles. The microparticles were demonstrated to be non-cytotoxic till 300 µg/2 × 105 cells and revealed a maximum release of 250 ng GDNF-CBP/mg microparticles in 0.3% collagenase. Differentiation of neural progenitor cells (NPCs) into mature neurons was demonstrated by co-culturing microparticles with cells in a medium containing collagenase which enabled the release of encapsulated GDNF-CBP, signaling the differentiation of NPCs into microtubule-associated protein 2 (MAP2)-expressing neurons. The successful ability of these microparticles to deliver neurotrophic factors and allow differentiation of NPCs into mature neurons provides some scope in its use for the treatment of Parkinson's disease and other neurodegenerative diseases.
Assuntos
Colágeno/química , Fator Neurotrófico Derivado de Linhagem de Célula Glial/química , Ácido Láctico/química , Fragmentos de Peptídeos/química , Ácido Poliglicólico/química , Sialoglicoproteínas/química , Diferenciação Celular , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Fator Neurotrófico Derivado de Linhagem de Célula Glial/administração & dosagem , Humanos , Células-Tronco Neurais/citologia , Células-Tronco Neurais/efeitos dos fármacos , Neurônios/citologia , Fragmentos de Peptídeos/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/química , Sialoglicoproteínas/administração & dosagemRESUMO
BACKGROUND AND PURPOSE: Primary subglottic cancer is a rare malignancy. We investigated the efficacy and toxicity of radiotherapy for subglottic cancer. PATIENTS AND METHODS: Nineteen patients with primary squamous cell carcinoma of the subglottis received radiotherapy, 14 of whom also underwent chemotherapy. Of the 19 patients, 15 received definitive radiotherapy to the gross tumors with total doses of 70-70.2 Gy in 35-39 fractions, and 4 underwent preoperative radiotherapy with total doses of 37.8-55.8 Gy in 21-31 fractions, followed by total laryngectomy. RESULTS: Of the 19 patients, 5 developed local progression and 2 developed distant metastasis at the median follow-up period of 5 years. The 5-year local control and disease-free rates were 74 and 63%, respectively. Three patients died of tumor progression, and the 5-year overall and disease-free survival rates were 80 and 63%, respectively. Regarding acute toxicities, transient mucositis and dermatitis of grade 3 or lower were observed in all patients, but there were no late toxicities of grade 3 or higher. CONCLUSION: Radiotherapy is a safe and effective treatment for patients with primary squamous cell carcinoma of the subglottis. The use of chemotherapy together with radiotherapy may enhance treatment efficacy and contribute to larynx preservation through good local control.
Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Neoplasias Laríngeas/tratamento farmacológico , Neoplasias Laríngeas/radioterapia , Laringe/efeitos da radiação , Lesões por Radiação/etiologia , Adulto , Idoso , Carcinoma de Células Escamosas/patologia , Quimioterapia Adjuvante , Terapia Combinada , Progressão da Doença , Intervalo Livre de Doença , Fracionamento da Dose de Radiação , Feminino , Seguimentos , Humanos , Neoplasias Laríngeas/patologia , Laringectomia , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Dosagem Radioterapêutica , Resultado do TratamentoRESUMO
BACKGROUND AND PURPOSE: Surgical excision remains the standard and most reliable curative treatment for eyelid carcinoma, but frequently causes functional and cosmetic impairment of the eyelid. We therefore investigated the efficacy and safety of radiation therapy in eyelid carcinoma. PATIENTS AND METHODS: Twenty-three patients with primary carcinoma of the eyelid underwent radiation therapy. Sebaceous carcinoma was histologically confirmed in 16 patients, squamous cell carcinoma in 6, and basal cell carcinoma in 1. A total dose of 50-66.6 Gy (median, 60 Gy) was delivered to tumor sites in 18-37 fractions (median, 30 fractions). RESULTS: All but 3 of the 23 patients had survived at a median follow-up period of 49 months. The overall survival and local progression-free rates were 87% and 93% at 2 years, and 80% and 93% at 5 years, respectively. Although radiation-induced cataracts developed in 3 patients, visual acuity in the other patients was relatively well preserved. There were no other therapy-related toxicities of grade 3 or greater. CONCLUSION: Radiation therapy is safe and effective for patients with primary carcinoma of the eyelid. It appears to contribute to prolonged survival as a result of good tumor control, and it also facilitates functional and cosmetic preservation of the eyelid.
Assuntos
Adenocarcinoma Sebáceo/radioterapia , Carcinoma Basocelular/radioterapia , Carcinoma de Células Escamosas/radioterapia , Neoplasias Palpebrais/radioterapia , Visão Ocular/efeitos da radiação , Adenocarcinoma Sebáceo/mortalidade , Adenocarcinoma Sebáceo/patologia , Adenocarcinoma Sebáceo/cirurgia , Idoso , Idoso de 80 Anos ou mais , Piscadela/efeitos da radiação , Carcinoma Basocelular/mortalidade , Carcinoma Basocelular/patologia , Carcinoma Basocelular/cirurgia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Causas de Morte , Estética , Neoplasias Palpebrais/mortalidade , Neoplasias Palpebrais/patologia , Neoplasias Palpebrais/cirurgia , Pálpebras/efeitos da radiação , Feminino , Seguimentos , Humanos , Técnicas In Vitro , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteção Radiológica/instrumentação , Radioterapia Adjuvante/instrumentação , Taxa de SobrevidaRESUMO
Interleukin-18 (IL-18) has recently been considered a promising marker of stress responses. In this study, to evaluate IL-18 as a noninvasive stress marker in pigs, we investigated the expression of IL-18 in porcine salivary glands and its presence in saliva, and its dynamics during acute immobilization stress in pigs. IL-18 mRNA was detected robustly in the pig salivary glands by RT-PCR. Immunohistochemical staining of IL-18 protein expression revealed that the expression patterns differed among the three types of salivary glands (parotid, submandibular, and sublingual gland). IL-18 was also detected in pig saliva by ELISA, and a diurnal rhythm with a peak in the afternoon was observed. The IL-18 concentration in saliva was significantly increased during a 60-min acute immobilization stress in thirteen 5-month-old pigs. These results are the first evidence of a stress-related change of IL-18 in pig saliva. Salivary IL-18 may thus become a useful noninvasive marker for the evaluation of acute stress in pigs.
Assuntos
Interleucina-18/biossíntese , Saliva/química , Glândulas Salivares/metabolismo , Estresse Psicológico/fisiopatologia , Animais , Biomarcadores/metabolismo , Ritmo Circadiano , Feminino , Imobilização/psicologia , Imunoglobulina A/metabolismo , Imuno-Histoquímica , Interleucina-18/metabolismo , Masculino , Sus scrofaRESUMO
BACKGROUND: Staphylococcus epidermidis is one of the prominent pathogens in ocular infection. The prevalence of mutations in the quinolone resistance determining region (QRDR) area in S epidermidis isolated from the ocular surface and its association with fluoroquinolone resistance has not been fully elucidated. METHODS: Mutations in the QRDR of gyrA, gyrB, parC, and parE genes of 138 isolates of S epidermidis recovered from the human conjunctival flora were analysed. The minimal inhibitory concentrations (MICs) of four fluoroquinolones (levofloxacin, gatifloxacin, moxifloxacin and tosufloxacin) against these isolates were also determined using agar dilution methods. RESULTS: The MIC(90) values of levofloxacin, gatifloxacin, moxifloxacin and tosufloxacin were 3.13, 1.56, 0.78 and 3.13 microg/ml, respectively. The MIC values of all fluoroquinolones showed a bimodal distribution (susceptible strain and less susceptible strain). Mutations with amino acid substitution in the QRDR were present in 70 (50.7%) isolates. 19 different combinations of mutations were detected: 3 isolates (2.2%) had four mutations, 8 (5.8%) had three mutations, 43 (31.2%) had double mutations and 16 (11.6%) had single mutations. Isolates with mutations in the QRDR of both gyrA and parC (n = 53) were less susceptible to fluoroquinolones. CONCLUSIONS: The present findings show that approximately half the S epidermidis isolates from the normal human conjunctiva have mutation(s) in the QRDR. The presence of mutations in both gyrA and parC is strongly associated with reduced susceptibility to fluoroquinolones.
Assuntos
Túnica Conjuntiva/microbiologia , Genes MDR , Mutação , Quinolonas , Staphylococcus epidermidis/genética , Compostos Aza/farmacologia , DNA Girase/genética , DNA Topoisomerase IV/genética , Farmacorresistência Bacteriana Múltipla , Fluoroquinolonas/farmacologia , Gatifloxacina , Humanos , Levofloxacino , Testes de Sensibilidade Microbiana , Moxifloxacina , Naftiridinas/farmacologia , Ofloxacino/farmacologia , Quinolinas/farmacologia , Staphylococcus epidermidis/efeitos dos fármacosRESUMO
We conducted the present study to determine the outcome of patients with early ovarian cancer who underwent three courses of adjuvant chemotherapy after complete surgical staging. One hundred consecutive patients with stage I-II epithelial ovarian cancer who had undergone complete surgical staging and received three courses of platinum-based chemotherapy were entered in this study. Twenty-one patients were low risk, defined as stage IA-B, grade 1 and histologic types except for clear cell adenocarcinoma, and remaining 79 were high risk. All patients with stage IA or IB, whatever histologic type and histopathologic grade, were alive without disease. The 5-year survival rate was 89.4% for patients with stage IC and 76.2% for those with stage II. The 5-year survival rate for low- and high-risk patients was 100% and 89.4%, respectively. The survival rate for grade 1 was significantly better than that for grade 2 or 3. Multivariate analysis revealed that histologic grade was an independent prognostic factor in stage IC-II ovarian cancer. The outcome of patients with early ovarian cancer undergoing three courses of chemotherapy after complete surgical staging was favorable even in high-risk patients.
Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/cirurgia , Adenocarcinoma/patologia , Adulto , Idoso , Carboplatina/administração & dosagem , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Terapia Combinada , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Prognóstico , Análise de SobrevidaRESUMO
We presented a case of locally advanced cervical cancer treated by intraarterial infusion chemotherapy, and evaluated the blood flow of uterine arteries before and after chemotherapy by using a transvaginal ultrasonic color Doppler device. Pulsatility index (PI) of each uterine artery increased after first course of chemotherapy compared to that of before chemotherapy. But PI did not change after second course in spite of a significant reduction in tumor size. Blood flow change assessed by Doppler ultrasound may be a limited but useful parameter for the efficacy of neoadjuvant chemotherapy in patients with cervical cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias do Colo do Útero/tratamento farmacológico , Útero/irrigação sanguínea , Artérias , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Feminino , Humanos , Histerectomia , Infusões Intra-Arteriais , Excisão de Linfonodo , Pessoa de Meia-Idade , Mitomicina/administração & dosagem , Peplomicina/administração & dosagem , Fluxo Pulsátil , Ultrassonografia Doppler em Cores , Neoplasias do Colo do Útero/cirurgiaRESUMO
We discussed the role of DNA topoisomerase I (topo I) inhibitor, which is now widely used in clinical practice, in cisplatin-resistant ovarian cancer. Our study showed the synergistic actions between cisplatin and 7-ethyl-10-hydroxycamptothecin (SN-38), an active metabolite of 7-ethyl-10-[4-(1-pyperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11), in two cisplatin-resistant cancer cell lines, HeLa/CDDP and KFr cells, but not in each parent cell line, HeLa and KF cells. Furthermore, HeLa/CDDP cells had a collateral sensitivity to SN-38. The levels of topo I protein in the cisplatin-resistant cells did not differ from those of their parent cell lines and were unaffected by exposure to cisplatin. In contrast, topo I enzymatic activity was 2-4 fold higher in the cisplatin-resistant cell lines compared with their respective parent cell lines. A significant correlation between the sensitivity for SN-38 and topo I activity human clear cell carcinoma cell lines, which are known as intrinsically ciasplatin-resistant cancer, was observed. Next, we examined the relationship between topo I activity and sensitivity to second-line chemotherapy consisting of cisplatin and CPT-11. A total of 30 patients with ovarian cancer who had initially undergone chemotherapy consisting of cisplatin, doxorubicin, and cyclophosphamide (CAP) and exhibited measurable lesions were entered in the study. Tumor samples were obtained in the period between the initial and the second-line chemotherapy. Of those 30 patients, 18 responded to second-line chemotherapy and 12 did not. Topo I activity in tumor samples of responder was significantly greater than that of in nonresponders. In 8 cases whose samples could be obtained before and after CAP, topo I activity significantly increased after CAP therapy. Consequently, the combination therapy with cisplatin and CPT-11 may be effective for patients with cisplatin-resistant ovarian cancer. In addition, topo I enzymatic activity may be a predictor of the sensitivity for topo I inhibitor.
Assuntos
Camptotecina , Camptotecina/análogos & derivados , Cisplatino , Resistencia a Medicamentos Antineoplásicos , Inibidores Enzimáticos , Neoplasias Ovarianas/tratamento farmacológico , Inibidores da Topoisomerase I , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/administração & dosagem , Camptotecina/farmacologia , Cisplatino/administração & dosagem , Cisplatino/farmacologia , DNA Topoisomerases Tipo I/metabolismo , Sinergismo Farmacológico , Inibidores Enzimáticos/administração & dosagem , Feminino , Células HeLa , Humanos , Irinotecano , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/patologia , Células Tumorais CultivadasRESUMO
OBJECTIVE: The aim of this study was to evaluate the combination effect of paclitaxel (PTX) and cisplatin (CDDP) and to determine the mechanisms of interaction between these agents. METHODS AND RESULTS: We used human ovarian adenocarcinoma cell lines, namely a parent cell line (KF), a CDDP-resistant cell line (KFr) and a PTX-resistant cell line (KFTx).The combination effect of PTX and CDDP was synergistic on KF and KFTx and additive on KFr. The incidence of anaphase or telophase, evaluated by immunofluorescence microscopy, decreased with PTX and significantly decreased with PTX and CDDP in KF and KFTx. The concentration of PTX, which was measured by high-performance liquid chromatography, was higher in KF and KFTx cells treated with a combination of PTX and CDDP than those treated with PTX alone. Multidrug resistance gene mRNA appeared in KFTx and its expression decreased after exposure to PTX and CDDP. After exposure to CDDP, the expression of multidrug resistance-associated protein (MRP) and the concentration of glutathione increased in KF, but not in KFr or KFTx. MRP expression slightly increased in KF and KFTx after exposure to PTX. In contrast, its expression decreased in KFr. CONCLUSION: The present study suggests that CDDP enhances PTX accumulation and that the interaction of these agents is synergistic in CDDP-sensitive cells.
Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Anáfase/efeitos dos fármacos , Antineoplásicos Fitogênicos/metabolismo , Antineoplásicos Fitogênicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cisplatino/metabolismo , Cisplatino/uso terapêutico , Primers do DNA , DNA Complementar/análise , DNA de Neoplasias/análise , Regulação para Baixo/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Mitose/efeitos dos fármacos , Paclitaxel/metabolismo , Paclitaxel/uso terapêutico , Reação em Cadeia da Polimerase , Telófase/efeitos dos fármacos , Células Tumorais CultivadasRESUMO
AIMS: The aim of the present study was to evaluate the outcome of patients with stage lb-IIb cervical adenocarcinoma treated with radical hysterectomy, and to determine the clinicopathological characteristics of those patients. METHODS: A total of 255 patients with cervical carcinoma stage Ib-IIb (57 adenocarcinoma and 198 squamous cell carcinoma) who had undergone radical hysterectomy were included in this study. Patient survival distribution was calculated using the Kaplan-Meier method. RESULTS: The estimated 5-year survival rate for patients with adenocarcinoma was significantly poorer than that for patients with squamous cell carcinoma (77.9% vs 91.7%). The survival rate in stage Ib patients did not differ between two groups (95.8% vs 94.4% respectively). The incidence of lymph node involvement was significantly higher in patients with adenocarcinoma than in those with squamous cell carcinoma (31.6% vs 14.8%). Among patients receiving post-operative radiotherapy, the survival rate for adenocarcinoma (71.1%) was significantly poorer than that for squamous cell carcinoma (90.0%). When patients underwent radical hysterectomy, the survival rate for stage II patients with adenocarcinoma was significantly poorer than that for patients with squamous cell carcinoma. CONCLUSIONS: The higher incidence of lymph node involvement and lower response to post-operative radiotherapy are considered to be factors of poorer prognosis in cervical adenocarcinoma.
Assuntos
Adenocarcinoma/patologia , Carcinoma de Células Escamosas/patologia , Histerectomia , Neoplasias do Colo do Útero/patologia , Adenocarcinoma/mortalidade , Adenocarcinoma/cirurgia , Adulto , Idoso , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/cirurgia , Feminino , Humanos , Histerectomia/métodos , Metástase Linfática , Prontuários Médicos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Análise de Sobrevida , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/cirurgiaRESUMO
We conducted this study to determine whether the sensitivity of ovarian cancer cells to paclitaxel (PTX) relates to cells undergoing p53-dependent apoptosis. Human ovarian adenocarcinoma cell lines (SK-OV-3, KF and KP cells) were used in this study. In SK-OV-3 and KP cells, which have a homozygous deletion of the TP53 gene, wild-type TP53 gene-transduction markedly enhanced the sensitivity to cisplatin (CDDP), but did not enhance the sensitivity to PTX. In all cells, the apoptotic index was increased by CDDP or PTX. After exposure to CDDP, p53 and Bax protein expression increased and Bcl-xL expression decreased in the KF cells and TP53 gene-transducted SK-OV-3 cells. However, these proteins did not change in KP cells. Therefore, the role of p53 in CDDP-induced apoptosis depends upon the cell type. In contrast, TP53 gene status did not correlate with PTX-induced cytotoxicity in any of the cell lines with differing apoptotic pathways. In conclusion, the sensitivity to PTX may not be related to p53-dependent apoptosis in ovarian cancer cells.
Assuntos
Antineoplásicos/uso terapêutico , Apoptose/genética , Genes p53/genética , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2 , Antineoplásicos Fitogênicos/uso terapêutico , Cisplatino/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Humanos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Proteínas Proto-Oncogênicas/genética , Células Tumorais Cultivadas , Proteína X Associada a bcl-2RESUMO
The aim of this longitudinal study was to examine whether and how the p53 gene is altered in patients with recurrent ovarian cancer and to determine the significance of p53 mutation in recurrent tumors. The primary and recurrent tumors were examined in 15 patients who had recurrent epithelial ovarian cancer, and whose primary tumor contained a wild-type p53 gene. The interval between cytoreductive surgery and the appearance of recurrence ranged from 5. 2 to 63.6 months (mean 23.4 months). Mutations in the p53 gene were screened by polymerase chain reaction single strand conformation polymorphism analysis and determined by cycle sequencing. Mutation of the p53 gene in the recurrent tumor was found in 7 of the 15 patients (46.7%). Estimated 3- and 5-year survival rates were 57.1 and 0%, respectively, for patients with p53 gene mutation detected in the recurrence tumor, and 75.0% and 37.5% for patients without the mutation (p = 0.0155). The interval between cytoreductive surgery and the appearance of recurrence did not differ between those groups (549.7 +/- 102.2 vs. 832.9 +/- 283.8 days). Mean survival time after recurrence was significantly better in the patients without mutation (438.6 +/- 56.4 vs. 873.0 +/- 157.5 days, p = 0.0125). The present study suggests that p53 gene mutation frequently occurs in recurrent ovarian cancer and that alteration of p53 gene status affects salvage chemotherapy. This phenomenon affects the prognosis of recurrent disease and may predict outcome.
Assuntos
Genes p53/genética , Mutação , Neoplasias Ovarianas/genética , Idoso , Aminoácidos/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Estadiamento de Neoplasias , Nucleotídeos/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Terapia de Salvação , Análise de SobrevidaRESUMO
BACKGROUND: Although p53 gene mutation frequently is observed in ovarian carcinoma, the function of the p53 gene in chemosensitivity has not been defined conclusively. The objective of the current study was to elucidate the relation between chemotherapy-induced apoptosis through the p53 pathway and chemosensitivity to ovarian carcinoma. METHODS: Tumor samples were obtained from 24 patients with epithelial ovarian carcinoma before and after chemotherapy with cisplatin, doxorubicin, and cyclophosphamide. Mutations in the p53 gene were screened by polymerase chain reaction-single-strand conformation polymorphism analysis and determined by cycle sequencing. Expression of the p53, Bax, and bcl-2 proteins and proliferating cell nuclear antigen (PCNA) were determined by immunohistochemical staining. Apoptotic cells were detected by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick-end labeling method. RESULTS: Of the 24 patients, 12 responded to chemotherapy and 12 did not. p53 gene mutation was observed in ten nonresponders and two responders. The incidence of p53 protein expression in tumors with the gene mutation was 58% (7 of 12) and was 17% (2 of 12) in tumors without the gene mutation. A significant reverse correlation between apoptotic index (AI) and labeling index (LI), determined by the percentage of PCNA positive cells, was observed in tumors after chemotherapy. AI was found to increase significantly after chemotherapy in tumors with the wild-type p53 gene (3.84 +/- 1.64 vs. 7.13 +/- 5.23) but LI did not change in either tumor type. The expression of Bax protein was significantly greater in tumors with the wild-type p53 gene after chemotherapy. bcl-2 protein expression did not relate to p53 gene status before or after chemotherapy. CONCLUSIONS: The current study suggests that p53-dependent apoptosis in tumors is strongly related to the chemosensitivity in epithelial ovarian carcinoma.
Assuntos
Apoptose , Carcinoma/tratamento farmacológico , Genes p53 , Neoplasias Ovarianas/tratamento farmacológico , Carcinoma/genética , Cisplatino/administração & dosagem , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Ovarianas/genética , Antígeno Nuclear de Célula em Proliferação/análise , Proteínas Proto-Oncogênicas c-bcl-2/análiseRESUMO
The aim of this study was to determine the significance of bowel resection in advanced ovarian cancer. A total of 64 women with stage IIIc or IV epithelial ovarian cancer, who consecutively received primary treatment between 1991 and 1995, were entered in this prospective study. The outcome of the patients undergoing bowel resection was evaluated. Thirty-nine patients underwent cytoreductive surgery at initial surgery. Of them, 16 patients could undergo optimal operation without bowel resection. Twenty-three patients received bowel resection at initial surgery. Of these 23 patients, 16 underwent optimal operation and 7 did not. Among 25 patients judged as inoperable cases at initial surgery, 21 responded to chemotherapy and underwent second surgery. Of 21 patients receiving second surgery, 15 underwent optimal operation (7 without bowel resection and 8 with bowel resection). The 3-year survival rate for 24 patients undergoing optimal operation with bowel resection (46.8%) was not significantly different from that for 23 patients without bowel resection (59.1%). Postoperative complications were seen in 8 patients (21.6%) of the patients receiving bowel resection and 3 (13.0%) of those without bowel resection. Cytoreductive surgery including bowel resection is effective for an improvement of the survival in patients with advanced ovarian cancer, if an optimal operation can be performed.
Assuntos
Intestinos/cirurgia , Neoplasias Ovarianas/cirurgia , Adulto , Idoso , Feminino , Humanos , Japão/epidemiologia , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Complicações Pós-Operatórias , Prognóstico , Análise de Regressão , Taxa de Sobrevida , Resultado do TratamentoRESUMO
The aim of the present study was to clarify the relationship between topoisomerase-I (topo-I) activity and sensitivity to second-line chemotherapy consisting of cisplatin and camptothecin-11 (CPT-11) in patients with ovarian cancer. Thirty Japanese women with relapsed epithelial ovarian cancer who received treatment at Tottori University Hospital or Kurume University Hospital between 1992 and 1997 were included in this study. All patients had initially undergone chemotherapy consisting of cisplatin, doxorubicin and cyclophosphamide (CAP). All subjects exhibited measurable lesions and received second-line chemotherapy consisting of 50 to 60 mg/m(2) CPT-11 on days 1, 8 and 15 and 60 mg/m(2) cisplatin on day 1. Tumor samples were obtained in the period between initial and second-line chemotherapy. Topo-I activity was assayed by relaxation of supercoiled plasmid substrate DNA. Of the 30 patients, 18 responded to second-line chemotherapy and 12 did not. We found no significant difference in patient characteristics in responders and non-responders. The interval from the end of the initial course of chemotherapy to the beginning of the second-line chemotherapy did not significantly differ in the 2 groups. The minimum amount of extraction showing complete DNA relaxation in non-responders was significantly greater than that in responders (201.7 +/- 92.5 vs. 124.1 +/- 59.4 ng; p = 0.0164). In 8 cases whose samples could be obtained before and after CAP, the amount of protein significantly decreased after CAP therapy (286.4 +/- 142.1 vs. 138.5 +/- 97.8 ng; p = 0.0294). Topo-I activity, which is enhanced by CAP therapy, can play an important role in sensitivity to CPT-11.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/análogos & derivados , Cisplatino/administração & dosagem , DNA Topoisomerases Tipo I/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Camptotecina/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Irinotecano , Pessoa de Meia-Idade , Neoplasias Ovarianas/enzimologiaRESUMO
Since HeLa cells possess very little functional p53 activity, they could be originally resistant to genotoxic stress-induced apoptosis. Therefore, it is likely that the drug-resistant cells derived from HeLa cells are more resistant to apoptosis. The aim of this study was to determine whether cisplatin-resistant cells derived from HeLa cells have an apoptosis-resistant phenotype. A cisplatin-resistant cell subline, HeLa/CDDP cells, showed a 19-fold resistance to cisplatin compared with the parent cells. The subline showed a collateral sensitivity to paclitaxel. An equitoxic dose (IC50) of cisplatin produced DNA fragmentation in HeLa cells but not in HeLa/CDDP cells. Transfection of wild-type p53 gene enhanced the cytotoxicity of cisplatin and cisplatin-induced apoptosis in HeLa cells but not in HeLa/CDDP cells, although it caused p53 overexpression in both cell lines. The expression of caspase 1 (interleukin-1beta-converting enzyme, ICE) mRNA and the overexpression of bax protein were observed only in HeLa cells. Paclitaxel-induced DNA fragmentation appeared less in HeLa/CDDP cells than in HeLa cells. p53 gene transfection did not affect the extent of DNA fragmentation in either cell line, suggesting that paclitaxel may induce p53-independent apoptosis. These findings suggest that HeLa/CDDP cells may have an acquired phenotype that is resistant to p53-dependent and -independent apoptosis.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Cisplatino/farmacologia , Células HeLa/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/fisiologia , Antineoplásicos Fitogênicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Paclitaxel/farmacologia , Fenótipo , Proteína Supressora de Tumor p53/genéticaRESUMO
BACKGROUND: We conducted a phase II trial of radical surgery following neoadjuvant chemotherapy in patients with stage IIIB cervical cancer. METHODS: A total of 26 patients with stage IIIB cervical cancer were entered in this study. Patients were treated with a chemotherapeutic regimen consisting of intraarterial infusion of cisplatin and intravenous infusion of other anticancer agents, to a maximum of 3 courses. If the results of the evaluation indicated that surgery was feasible, radical surgery, including complete removal of pelvic vessels, partial resection of adjacent organs, and pelvic and paraaortic lymphadenectomy, was performed. Patients whose tumors showed no response received radiotherapy. We evaluated operability, survival rate, toxicities, and complications. Additionally, we examined prognostic variables by multivariate analysis in the patients treated by radical surgery. RESULTS: Eighteen patients (69.2%) underwent radical surgery. The remaining eight patients received radiation therapy. The 3-year disease-free survival rate was 72.2% in patients who received surgery and 25.0% in those who received radiotherapy. Multivariate analysis did not show any independent prognostic factors in the patients who underwent surgery. CONCLUSION: Radical surgery following neoadjuvant chemotherapy may be feasible in two thirds of patients with stage IIIB cervical cancer; therefore, phase III trials can be recommended.