RESUMO
BACKGROUND: The length of tumour-vein contact between the portal-superior mesenteric vein (PV/SMV) and pancreatic head cancer, and its relationship to prognosis in patients undergoing pancreatic surgery, remains controversial. METHODS: Patients diagnosed with pancreatic head cancer who were eligible for pancreatoduodenectomy between October 2002 and December 2016 were analysed. The PV/SMV contact was assessed retrospectively on CT. Using the minimum P value approach based on overall survival after surgery, the optimal cut-off value for tumour-vein contact length was identified. RESULTS: Among 491 patients included, 462 underwent pancreatoduodenectomy for pancreatic head cancer. PV/SMV contact with the tumour was detected on preoperative CT in 248 patients (53·7 per cent). Overall survival of patients with PV/SMV contact exceeding 20 mm was significantly worse than that of patients with a contact length of 20 mm or less (median survival time (MST) 23·3 versus 39·3 months; P = 0·012). Multivariable analysis identified PV/SMV contact longer than 20 mm as an independent predictor of poor survival, whereas PV/SMV contact greater than 180° was not a predictive factor. Among patients with a PV/SMV contact length exceeding 20 mm on pretreatment CT, those receiving neoadjuvant therapy had significantly better overall survival than patients who had upfront surgery (MST not reached versus 21·6 months; P = 0·002). CONCLUSION: The length of PV/SMV contact predicts survival, and may be used to suggest a role for neoadjuvant therapy to improve prognosis.
ANTECEDENTES: El valor pronóstico de la longitud del contacto del tumor de la cabeza pancreática con las venas porta y mesentérica superior (portal-superior mesenteric vein, PV/SMV) en los pacientes sometidos a cirugía pancreática sigue siendo un tema controvertido. MÉTODOS: Se analizaron los pacientes diagnosticados de un cáncer de la cabeza pancreática a los que se realizó una duodenopancreatectomía cefálica entre octubre de 2002 y diciembre de 2016. El contacto tumoral con la PV/SMV se evaluó de forma retrospectiva mediante tomografía computarizada (TC). Se identificó el valor de corte óptimo para la longitud del contacto tumoral con la PV/SMV, utilizando el valor mínimo de la P basado en la supervivencia global (overall survival, OS) después de la cirugía. RESULTADOS: De 491 pacientes incluidos, en 462 pacientes se realizó una duodenopancreatectomía cefálica por cáncer de la cabeza de páncreas. En la TC preoperatoria, se detectó contacto tumoral con la PV/SMV en 248 (53,7%) pacientes. La OS de los pacientes en los que el contacto del tumor con la PV/SMV fue > 20 mm fue significativamente peor que en aquellos cuyo contacto fue ≤ 20 mm (mediana de supervivencia (median survival time, MST) 23,3 versus 39,3 meses; P = 0,012). En un análisis multivariado se identificó el contacto tumoral-PV/SMV > 20 mm como un factor independiente predictor de mala supervivencia, pero el contacto tumor-PV/SMV > 180° no fue un factor pronóstico. En los pacientes en los que el contacto tumor-PV/SMV fue > 20 mm en el TC preoperatorio, la OS en aquellos que recibieron tratamiento neoadyuvante fue significativamente mejor en comparación con los pacientes tratados directamente con cirugía (MST, no alcanzada versus 21,6 meses, P = 0,002). Conclusión La longitud del contacto tumoral con la PV/SMV predice la supervivencia, por lo cual dicha longitud podría jugar un papel en la indicación de tratamiento neoadyuvante para mejorar el pronóstico.
Assuntos
Veias Mesentéricas/patologia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Veia Porta/patologia , Idoso , Feminino , Humanos , Masculino , Veias Mesentéricas/diagnóstico por imagem , Pessoa de Meia-Idade , Terapia Neoadjuvante , Invasividade Neoplásica , Neoplasias Pancreáticas/diagnóstico por imagem , Pancreaticoduodenectomia , Veia Porta/diagnóstico por imagem , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Gemcitabine plus cisplatin (GC) is the standard treatment of advanced biliary tract cancer (BTC); however, it causes nausea, vomiting, and anorexia, and requires hydration. Gemcitabine plus S-1 (GS) reportedly has equal to, or better, efficacy and an acceptable toxicity profile. We aimed to confirm the non-inferiority of GS to GC for patients with advanced/recurrent BTC in terms of overall survival (OS). PATIENTS AND METHODS: We undertook a phase III randomized trial in 33 institutions in Japan. Eligibility criteria included chemotherapy-naïve patients with recurrent or unresectable BTC, an Eastern Cooperative Oncology Group Performance Status of 0 - 1, and adequate organ function. The calculated sample size was 350 with a one-sided α of 5%, a power of 80%, and non-inferiority margin hazard ratio (HR) of 1.155. The primary end point was OS, while the secondary end points included progression-free survival (PFS), response rate (RR), adverse events (AEs), and clinically significant AEs defined as grade ≥2 fatigue, anorexia, nausea, vomiting, oral mucositis, or diarrhea. RESULTS: Between May 2013 and March 2016, 354 patients were enrolled. GS was found to be non-inferior to GC [median OS: 13.4 months with GC and 15.1 months with GS, HR, 0.945; 90% confidence interval (CI), 0.78-1.15; P = 0.046 for non-inferiority]. The median PFS was 5.8 months with GC and 6.8 months with GS (HR 0.86; 95% CI 0.70-1.07). The RR was 32.4% with GC and 29.8% with GS. Both treatments were generally well-tolerated. Clinically significant AEs were observed in 35.1% of patients in the GC arm and 29.9% in the GS arm. CONCLUSIONS: GS, which does not require hydration, should be considered a new, convenient standard of care option for patients with advanced/recurrent BTC. CLINICAL TRIAL NUMBER: This trial has been registered with the UMIN Clinical Trials Registry (http://www.umin.ac.jp/ctr/index.htm), number UMIN000010667.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias do Sistema Biliar/tratamento farmacológico , Cisplatino/administração & dosagem , Desoxicitidina/análogos & derivados , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias do Sistema Biliar/epidemiologia , Neoplasias do Sistema Biliar/patologia , Cisplatino/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Intervalo Livre de Doença , Combinação de Medicamentos , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Náusea/patologia , Ácido Oxônico/administração & dosagem , Ácido Oxônico/efeitos adversos , Tegafur/administração & dosagem , Tegafur/efeitos adversos , Vômito/induzido quimicamente , Vômito/patologia , GencitabinaRESUMO
BACKGROUND: Although some retrospective studies have suggested the value of adjuvant therapy, no recommended standard exists in bile duct cancer. The aim of this study was to test the hypothesis that adjuvant gemcitabine chemotherapy would improve survival probability in resected bile duct cancer. METHODS: This was a randomized phase III trial. Patients with resected bile duct cancer were assigned randomly to gemcitabine and observation groups, which were balanced with respect to lymph node status, residual tumour status and tumour location. Gemcitabine was given intravenously at a dose of 1000 mg/m2 , administered on days 1, 8 and 15 every 4 weeks for six cycles. The primary endpoint was overall survival, and secondary endpoints were relapse-free survival, subgroup analysis and toxicity. RESULTS: Some 225 patients were included (117 gemcitabine, 108 observation). Baseline characteristics were well balanced between the gemcitabine and observation groups. There were no significant differences in overall survival (median 62·3 versus 63·8 months respectively; hazard ratio 1·01, 95 per cent c.i. 0·70 to 1·45; P = 0·964) and relapse-free survival (median 36·0 versus 39·9 months; hazard ratio 0·93, 0·66 to 1·32; P = 0·693). There were no survival differences between the two groups in subsets stratified by lymph node status and margin status. Although haematological toxicity occurred frequently in the gemcitabine group, most toxicities were transient, and grade 3/4 non-haematological toxicity was rare. CONCLUSION: The survival probability in patients with resected bile duct cancer was not significantly different between the gemcitabine adjuvant chemotherapy group and the observation group. Registration number: UMIN 000000820 (http://www.umin.ac.jp/).
Assuntos
Adenocarcinoma/tratamento farmacológico , Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias dos Ductos Biliares/tratamento farmacológico , Procedimentos Cirúrgicos do Sistema Biliar , Carcinoma Adenoescamoso/tratamento farmacológico , Desoxicitidina/análogos & derivados , Adenocarcinoma/mortalidade , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/cirurgia , Carcinoma Adenoescamoso/mortalidade , Carcinoma Adenoescamoso/cirurgia , Quimioterapia Adjuvante , Desoxicitidina/uso terapêutico , Esquema de Medicação , Feminino , Seguimentos , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Resultado do Tratamento , GencitabinaRESUMO
BACKGROUND: We evaluated the efficacy and toxicity of adding oral leucovorin (LV) to S-1 when compared with S-1 monotherapy in patients with gemcitabine-refractory pancreatic cancer (PC). PATIENTS AND METHODS: Gemcitabine-refractory PC patients were randomly assigned in a 1:1 ratio to receive S-1 at 40, 50, or 60 mg according to body surface area plus LV 25 mg, both given orally twice daily for 1 week, repeated every 2 weeks (SL group), or S-1 monotherapy at the same dose as the SL group for 4 weeks, repeated every 6 weeks (S-1 group). The primary end point was progression-free survival (PFS). RESULTS: Among 142 patients enrolled, 140 were eligible for efficacy assessment (SL: n = 69 and S-1: n = 71). PFS was significantly longer in the SL group than in the S-1 group [median PFS, 3.8 versus 2.7 months; hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.37-0.85; P = 0.003]). The disease control rate was significantly higher in the SL group than in the S-1 group (91% versus 72%; P = 0.004). Overall survival (OS) was similar in both groups (median OS, 6.3 versus 6.1 months; HR, 0.82; 95% CI, 0.54-1.22; P = 0.463). After adjusting for patient background factors in a multivariate analysis, OS tended to be better in the SL group (HR, 0.71; 95% CI, 0.47-1.07; P = 0.099). Both treatments were well tolerated, although gastrointestinal toxicities were slightly more severe in the SL group. CONCLUSION: The addition of LV to S-1 significantly improved PFS in patients with gemcitabine-refractory advanced PC, and a phase III trial has been initiated in a similar setting. CLINICAL TRIALS NUMBER: Japan Pharmaceutical Information Center: JapicCTI-111554.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucovorina/uso terapêutico , Ácido Oxônico/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Tegafur/uso terapêutico , Idoso , Antimetabólitos Antineoplásicos/efeitos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Progressão da Doença , Intervalo Livre de Doença , Combinação de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Japão , Leucovorina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Ácido Oxônico/efeitos adversos , Pâncreas/patologia , Tegafur/efeitos adversos , Resultado do Tratamento , GencitabinaRESUMO
This study was conducted to evaluate changes in milk profiles of oxidative stress (OS) biomarkers in dairy cows with ovulatory and an-ovulatory oestrous cycles. Thirty healthy, cycling Holstein cows averaging 60±17 days in milk, and producing 33±6kg of milk per day (the week before commencing the study) were enrolled in this study. Composite milk samples were collected thrice weekly and assayed for the following OS biomarkers: lipoperoxides (LPO), biological advanced potential, superoxide dismutase (SOD), advanced oxidation protein products (AOPP), ceruloplasmin, glutathione (GSH), ß-carotene and glutathione peroxidase (GSH-Px). Milk samples were also tested for fat and protein composition and the fat:protein ratio (FPR) was categorized as low (≤1.31), medium (1.32-1.56) and high (>1.57) to evaluate their main effect and the interaction effect of FPR and the week of study on OS using linear mixed models with cow identification being a random factor. Cows with ovulatory oestrous cycles (n=20) presented significantly greater SOD levels than cows that did not ovulate ((n=10; P<0.05). On the other hand, LPO, GSH-Px and GSH concentrations were lower in ovulated cows compared to the an-ovulated cows (P<0.05). The highest level of LPO and AOPP were noted at prooestrus phase while ß-carotene presented the lowest value at that phase of oestrous cycle. It could be postulated that the elevated level of milk SOD and the observed lower level of LPO, GSH-Px and GSH in ovulating cows may be an essential event preceding the ovulatory response.
Assuntos
Bovinos/fisiologia , Ciclo Estral/fisiologia , Lactação/fisiologia , Leite/química , Ovulação/fisiologia , Estresse Oxidativo/fisiologia , Animais , Biomarcadores , Feminino , Progesterona/química , Progesterona/metabolismoRESUMO
BACKGROUND: This randomised, open-label, multicenter phase II study compared progression-free survival (PFS) of S-1 plus oxaliplatin (SOX) with that of S-1 alone in patients with gemcitabine-refractory pancreatic cancer. METHODS: Patients with confirmed progressive disease following the first-line treatment with a gemcitabine-based regimen were randomised to receive either S-1 (80/100/120 mg day(-1) based on body surface area (BSA), orally, days 1-28, every 6 weeks) or SOX (S-1 80/100/120 mg day(-1) based on BSA, orally, days 1-14, plus oxaliplatin 100 mg m(-2), intravenously, day 1, every 3 weeks). The primary end point was PFS. RESULTS: Between January 2009 and July 2010, 271 patients were randomly allocated to either S-1 (n=135) or SOX (n=136). Median PFS for S-1 and SOX were 2.8 and 3.0 months, respectively (hazard ratio (HR)=0.84; 95% confidence interval (CI), 0.65-1.08; stratified log-rank test P=0.18). Median overall survival (OS) was 6.9 vs 7.4 months (HR=1.03; 95% CI, 0.79-1.34; stratified log-rank test P=0.82). The response rate (RR) was 11.5% vs 20.9% (P=0.04). The major grade 3/4 toxicities (S-1 and SOX) were neutropenia (11.4% and 8.1%), thrombocytopenia (4.5% and 10.3%) and anorexia (12.9% and 14.7%). CONCLUSIONS: Although SOX showed an advantage in RR, it provided no significant improvement in PFS or OS compared with S-1 alone.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Adenoescamoso/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Adenoescamoso/mortalidade , Carcinoma Adenoescamoso/secundário , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Combinação de Medicamentos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Ácido Oxônico/administração & dosagem , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Prognóstico , Taxa de Sobrevida , Tegafur/administração & dosagem , GencitabinaRESUMO
BACKGROUND: TAS-102 consists of α, α, α-trifluorothymidine (TFT) and an inhibitor of thymidine phosphorylase (TPI). We conducted a dose-escalation phase I study in Japanese patients with advanced solid tumours. METHODS: TAS-102 was administered twice daily on days 1-5 and days 8-12 in a 28-day cycle to patients with solid tumours refractory to standard chemotherapy, to determine its maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics (PKs). MTD was evaluated in cycle 1. RESULTS: Safety and PKs were evaluated in 21 patients treated with TAS-102 at 30, 40, 50, 60, or 70 mg m(-2) per day. DLTs, such as grade 4 leucopenia, grade 4 neutropenia, and grade 4 thrombocytopenia, were observed in two patients at doses of 30 and 70 mg m(-2). α, α, α-trifluorothymidine and TPI exposures increased dose dependently, and the percentage of decrease in neutrophil count and TFT exposure were significantly correlated. The disease control rate was 50.0% with a median progression-free survival of 2.4 months in 18 colorectal cancer patients. The dose of TAS-102 was not increased above 70 mg m(-2) per day because of the increased tendency for grade 3 and 4 neutropenia, and 70 mg m(-2) per day was the recommended dose for phase II studies. CONCLUSIONS: TAS-102 at 70 mg m(-2) per day was tolerated in Japanese patients with advanced solid tumours. Phase II studies are ongoing in patients with colorectal cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias/tratamento farmacológico , Timidina Fosforilase/antagonistas & inibidores , Trifluridina/administração & dosagem , Uracila/análogos & derivados , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Povo Asiático , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Combinação de Medicamentos , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/metabolismo , Pirrolidinas , Timina , Trifluridina/efeitos adversos , Trifluridina/farmacocinética , Uracila/administração & dosagem , Uracila/efeitos adversos , Uracila/farmacocinéticaRESUMO
BACKGROUND: A British randomised study of gemcitabine plus cisplatin (GC) combination showed promising results in biliary tract cancer (BTC) patients. In our study, we evaluated the efficacy and safety of this combination compared with gemcitabine alone (G) in Japanese BTC patients. METHODS: Overall, 84 advanced BTC patients were randomised to either cisplatin 25 mg m(-2) plus gemcitabine 1000 mg m(-2) on days 1, 8 of a 21-day cycle (GC-arm), or single-agent gemcitabine 1000 mg m(-2) on days 1, 8 and 15 of a 28-day cycle (G-arm). Treatments were repeated for at least 12 weeks until disease progression or unacceptable toxicity occurred, up to a maximum of 48 weeks. RESULTS: A total of 83 patients were included in the analysis. For the GC and G-arms, respectively, the 1-year survival rate was 39.0 vs 31.0%, median survival time 11.2 vs 7.7 months, median progression-free survival time 5.8 vs 3.7 months and overall response rate 19.5 vs 11.9%. The most common grade 3 or 4 toxicities (GC-arm/G-arm) were neutropenia (56.1%/38.1%), thrombocytopenia (39.0%/7.1%), leukopenia (29.3%/19.0%), haemoglobin decrease (36.6%/16.7%) and gamma-GTP increase (29.3%/35.7%). CONCLUSIONS: Gemcitabine plus cisplatin combination therapy was found to be effective and well tolerated, suggesting that it could also be a standard regimen for Japanese patients.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Cisplatino/uso terapêutico , Desoxicitidina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Biliar/mortalidade , Desoxicitidina/uso terapêutico , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , GencitabinaRESUMO
We retrospectively investigated the impact of the pre-chemoradiotherapy hemoglobin level (pre-CRT Hb level) for T4 and/or M1 lymph node (LYM) squamous cell carcinoma of the esophagus. Chemotherapy consisted of protracted infusion with 5-fluorouracil (5-FU) at 400 mg/m(2)/day on days 1-5 and 8-12, combined with cisplatin at 40 mg/m(2)/day on days 1 and 8, repeated twice at a 5-week interval. Concurrent radiation therapy was started on day 1 and delivered at 2 Gy/day for five days a week for a total radiation dose of 60 Gy, with a two-week break after a cumulative dose of 30 Gy. Several factors considered to be related with treatment outcome were evaluated by univariate and multivariate analysis. A total of 48 patients with T4/M1 LYM (lymphocyte) esophageal cancer treated with chemoradiotherapy (CRT) between September 2002 and April 2005 were enrolled. The complete response rate to this regimen was 44% and median survival time was 13.6 months, with a median follow-up period of 26.8 months. Median pre-CRT Hb level was 13.5 (10.4-15.3) g/dL. The CR rate in patients with a pre-CRT Hb level of 13 g/dL or less was only 24% but it was 60% in those with a level that was more than 13 g/dL (P=0.01). As for survival, anovarevealed that a pre-CRT Hb of 13 g/dL or less was a significant prognostic factor with a hazard ratio of 0.45 (95% confidence interval [CI]); 0.21-0.97, P=0.04), while on manova, including performance status, tumor size, TNM stage and pre-CRT Hb level, a pre-CRT Hb level of 13 g/dL or less was the only significant prognostic factor, with a hazard ratio of 0.35 (95% CI; 0.13-0.90, P=0.03). In conclusion, the pre-CRT Hb level may be an important determinant of outcome in patients with T4/M1 LYM squamous cell carcinoma of the esophagus.
Assuntos
Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/mortalidade , Neoplasias Esofágicas/sangue , Neoplasias Esofágicas/mortalidade , Hemoglobinas/análise , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/secundário , Terapia Combinada , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/radioterapia , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
A 79-year-old woman was admitted on January 18, 2000, with a lumbar compression fracture. Two days after admission, a chest X-ray film showed reticular infiltrates in the right lung field. She was diagnosed as having pneumonia and was treated with antibiotics. Despite this therapy, her symptoms did not improve and the infiltrates diffusely extended to involve both lungs on chest X-ray films. She was placed on noninvasive positive pressure ventilation (NIPPV) for progressive respiratory failure at 5 days after admission in order to avoid endotracheal intubation. Her hypoxemia was immediately improved by oronasal bilevel positive airway pressure ventilation (BiPAP) and chest X-ray films revealed improvement of the reticular infiltrates. Measurement of viral antibody titers showed that the cause of acute respiratory failure was influenza A virus pneumonia. In conclusion, NIPPV may reduce the need for intubation of elderly patients with acute respiratory failure, as well as chronic obstructive pulmonary disease (COPD) patients.
Assuntos
Vírus da Influenza A , Influenza Humana/complicações , Pneumonia Viral/complicações , Respiração com Pressão Positiva , Insuficiência Respiratória/terapia , Doença Aguda , Idoso , Feminino , Humanos , Insuficiência Respiratória/etiologiaRESUMO
BACKGROUND: The causes and pathologic and prognostic phenotypes of late-onsetfamilial breast cancers are still unknown. The purpose of this study was to document the clinicopathological features of late-onset familial breast cancers using genetic testing of BRCA1 and BRCA2. METHODS: We analyzed 11 breast cancers from 10 patients from 8 Japanese late-onset Breast cancer families. RESULTS: The average age of the patients was 55 years (range 43 to 89). Bilateral occurrence was noted in 2 patients (8%). All the tumors were invasive ductal carcinomas, except for 1 case of invasive lobular carcinoma. Tumor size rangedfrom 0.8 cm to 7.8 cm (median 2.3 cm) and lymph node metastasis occurred in 6 of the 11 patients (55%). Six (55%) of the 11 tumors were histologically grade 2 and 5 (45%) were histologically grade 3. Estrogen receptor (ER) positivity was 80% (8/10). Overexpression of c-erbB-2 and p53 protein was detected in 18% (2/11)and 9% (1/11) of the tumors, respectively. Five patients from 4 families received genetic testing but all were negative for BRCA1 and BRCA2 germline mutations.All the patients were alive after a median follow-up period of 32 months, except for 1 patient. CONCLUSION: In this study, no germline mutations of BRCA1 or BRCA2 were detected. However, there was a tendency towards ER-positive tumors, but the positivity of p53 protein was considered to be lower then that of sporadic tumors.
RESUMO
X protein of hepatitis B virus (HBV) transactivates transcription of various viral and cellular genes. It has been suggested that X protein plays a major role in hepatocarcinogenesis by HBV. The protein possesses amino acid sequence homology to the functionally essential domain of Kunitz-type serine protease inhibitors. This Kunitz domain-like sequence in X protein is indispensable for the transactivation function. To clarify whether X protein has a serine protease inhibitor activity, a search was made for serine proteases which interact with, but not degrade X protein. Tryptase TL2, one of serine proteases in hepatic cells, was found to directly interact with X protein without degradation. Moreover, the activities of tryptase TL2 and an analogous protease were substantially inhibited by X protein. These results suggest that transactivation function of X protein is exerted by modulation of the hepatic serine protease activity, giving rise to quantitative or qualitative change of cellular transcription factor(s) through protection from proteolytic degradation and/or suppression of processing.
Assuntos
Serina Endopeptidases/metabolismo , Transativadores/metabolismo , Sequência de Aminoácidos , Animais , Ligação Competitiva , Proteína gp120 do Envelope de HIV/metabolismo , Humanos , Dados de Sequência Molecular , Testes de Precipitina , Ligação Proteica , Homologia de Sequência de Aminoácidos , Inibidores de Serina Proteinase/metabolismo , Inibidores de Serina Proteinase/fisiologia , Transativadores/fisiologia , Triptases , Proteínas Virais Reguladoras e AcessóriasAssuntos
Colágeno/genética , DNA Complementar/genética , Genes , Sequência de Aminoácidos , Clonagem Molecular , Colágeno/química , Colágeno/classificação , Humanos , Dados de Sequência Molecular , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Alinhamento de Sequência , Homologia de Sequência de AminoácidosRESUMO
A processing protease for the human immunodeficiency virus type I (HIV-I) envelope glycoprotein gp160 precursor has been purified to homogeneity from the post-nuclear membrane fraction of a human T4+ lymphocyte clone. Most of the processing activity was found to be present in the fractions of endoplasmic reticulum and Golgi apparatus of the cells. The purified enzyme has a monomeric structure with a molecular mass of 26 +/- 3 kDa, as judged by gel-permeation liquid chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing and nonreducing conditions. The purified enzyme converted gp160 to gp120 and gp41, showing a pH optimum of 6.5-7.0. Direct amino acid sequencing of the amino terminus of the product gp41 revealed that the cleavage site of gp160 was between Arg511 and Ala512. The enzyme activity was inhibited by trypsin-type protease inhibitors, but was not affected by CaCl2, MgCl2 or chelating agents. The properties of the purified enzyme are clearly distinct from those of processing proteases reported previously. Although the significance of the enzyme in vivo is not currently certain, judging from its cleavage specificity and subcellular localization, this endopeptidase appears to be a processing enzyme for the human immunodeficiency virus type I gp160 precursor protein in human T cells.
Assuntos
Linfócitos T CD4-Positivos/enzimologia , Endopeptidases/metabolismo , Produtos do Gene env/metabolismo , HIV-1/metabolismo , Precursores de Proteínas/metabolismo , Sequência de Aminoácidos , Linhagem Celular , Membrana Celular/enzimologia , Cromatografia Líquida , Eletroforese em Gel de Poliacrilamida , Endopeptidases/isolamento & purificação , Proteína gp160 do Envelope de HIV , HIV-1/fisiologia , Humanos , Dados de Sequência Molecular , Inibidores de Proteases/metabolismo , Processamento de Proteína Pós-Traducional , Especificidade por Substrato , Replicação ViralRESUMO
A novel trypsin-like protease associated with rat bronchiolar epithelial Clara cells, named Tryptase Clara, was purified to homogeneity from rat lung by a series of standard chromatographic procedures. The enzyme has apparent molecular masses of 180 +/- 16 kDa on gel filtration and 30 +/- 1.5 kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions. Its isoelectric point is pH 4.75. Studies with model peptide substrates showed that the enzyme preferentially recognizes a single arginine cleavage site, cleaving Boc-Gln-Ala-Arg-4-methylcoumaryl-7-amide most efficiently and having a pH optimum of 7.5 with this substrate. The enzyme is strongly inhibited by aprotinin, diisopropylfluorophosphate, antipain, leupeptin, and Kunitz-type soybean trypsin inhibitor, but inhibited only slightly by Bowman-Birk soybean trypsin inhibitor, benzamidine, and alpha 1-antitrypsin. Immunohistochemical studies indicated that the enzyme is located exclusively in the bronchiolar epithelial Clara cells and colocalized with surfactant. An immunoreactive protein with a molecular mass of 28.5 kDa was also detected in airway secretions by Western blotting analyses, suggesting that the 30-kDa protease in Clara cells is processed before or after its secretion. Proteolytic cleavage of the hemagglutinin of influenza virus is a prerequisite for the virus to become infectious. Tryptase Clara was shown to cleave the hemagglutinin and activate infectivity of influenza A virus in a dose-dependent way. These results suggest that the enzyme is a possible activator of inactive viral fusion glycoprotein in the respiratory tract and thus responsible for pneumopathogenicity of the virus.
Assuntos
Brônquios/enzimologia , Serina Endopeptidases/metabolismo , Proteínas Virais de Fusão/metabolismo , Sequência de Aminoácidos , Animais , Especificidade de Anticorpos , Western Blotting , Brônquios/citologia , Células Cultivadas , Cromatografia Líquida , Eletroforese em Gel de Poliacrilamida , Células Epiteliais , Epitélio/enzimologia , Hidrólise , Imuno-Histoquímica , Vírus da Influenza A/imunologia , Masculino , Dados de Sequência Molecular , Ratos , Serina Endopeptidases/imunologia , Serina Endopeptidases/isolamento & purificação , Especificidade por Substrato , TriptasesRESUMO
A novel membrane-bound serine esterase in cultured human T4+ lymphocytes, recently purified and named tryptase TL2, binds specifically to the external envelope protein gp 120 of HIV-1, interacting with its V3 domain. This binding was selectively blocked by inhibitors of tryptase TL2 with a GPCR sequence in their reactive site, synthetic peptides corresponding with the sequences of the V3 domains of various HIV-1 strains with the GPGR sequence, and antibody against tryptase TL2, or neutralizing antibody against the V3 domain of HTLV-IIIB. These findings suggest that tryptase TL2 is a binding protein of the V3 domain of HIV-1 envelope glycoprotein.
Assuntos
Linfócitos T CD4-Positivos/enzimologia , Membrana Celular/enzimologia , Proteína gp120 do Envelope de HIV/metabolismo , HIV-1 , Fragmentos de Peptídeos/metabolismo , Serina Endopeptidases/metabolismo , Sequência de Aminoácidos , Linfócitos T CD4-Positivos/ultraestrutura , Humanos , Dados de Sequência Molecular , Especificidade por Substrato , TriptasesRESUMO
A novel membrane-bound serine esterase, named tryptase TL2, which is immunologically reactive with the antibody inhibiting induction of syncytia by human immunodeficiency virus-1 (HIV-1) (HATTORI, T., KOITO, A., TAKATSUKI, K., KIDO, H., and KATUNUMA, N., 1989, FEBS Lett., 248, 48-52), has been purified from a human T4+ lymphocyte clone. The enzyme has a molecular mass of 198 +/- 15 kDa, and is composed of two subunits of 32 kDa and four subunits of 28 kDa. The enzyme was strongly inhibited by the envelope glycoprotein gp120 of HIV-1, by synthetic peptides of V3 domains of gp120 s with the sequence GPGR in their center, which correspond to the principal neutralizing epitopes of the gp120s of various HIV-1 strains, by Kunitz-type inhibitors with the sequence GPCR in their active site, such as trypstatin, H130, and [Arg15, Glu52] aprotinin and by the microbial inhibitors leupeptin and antipain. This enzyme was specifically bound to the inhibitor V3 domain of gp120 of HIV-1, and this binding was blocked by the inhibitors of tryptase TL2, with a central motif GPCR or GPGR sequence in their center, but not by leupeptin and antipain without the motif. These findings suggest that tryptase TL2 is important in target site recognition and binding of HIV-1 in co-operation with CD4 receptor in the initial process of HIV-1 infection.
Assuntos
Linfócitos T CD4-Positivos/enzimologia , Esterases/metabolismo , Proteína gp120 do Envelope de HIV/metabolismo , Proteínas , alfa-Globulinas , Sequência de Aminoácidos , Linfócitos T CD4-Positivos/microbiologia , Proteínas de Transporte/metabolismo , Proteína gp120 do Envelope de HIV/química , HIV-1/efeitos dos fármacos , HIV-1/metabolismo , Humanos , Dados de Sequência Molecular , Oligopeptídeos/química , Peptídeo Hidrolases/metabolismo , Inibidores de Serina Proteinase/farmacologiaRESUMO
A novel membrane-bound serine esterase, named tryptase TL2, which is immunologically reactive with the antibody inhibiting induction of syncytia by human immunodeficiency virus-1 (HIV-1) (Hattori, T., Koito, A., Takatsuki, K., Kido, H., and Kutunuma, N. (1989) FEBS Lett., 248, 48-52), has been purified from a human T4+ lymphocyte clone. The enzyme has a molecular mass of 198 +/- 15 kDa, as judged by gel-permeation liquid chromatography, and is composed of two subunits of 32 kDa and four subunits of 28 kDa, as shown by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Studies with model peptide substrates showed that the enzyme preferentially recognized L-arginine and cleaved Boc-Gln-Gly-Arg-4-methyl-coumaryl-7-amide and Boc-Gln-Ala-Arg-4-methyl-coumaryl-7-amide with high efficiency at a pH optimum of 8.5. The enzyme was strongly inhibited by the envelope glycoprotein gp 120 of HIV-1, by synthetic peptides with the sequence GPGR in their center, which corresponds to the principal neutralizing epitope of the gp 120s of various HIV-1 strains, by Kunitz-type inhibitors with the sequence GPCR in their active site, such as trypstatin, HI30, and [Arg15, Glu52]aprotinin and by the microbial inhibitors leupeptin and antipain. Studies on the subcellular distribution of tryptase TL2, immunohistochemical analysis, and cell surface radioiodination indicated that the enzyme is mainly localized in the plasma membrane.
Assuntos
Linfócitos T CD4-Positivos/enzimologia , Peptídeo Hidrolases/isolamento & purificação , Serina Endopeptidases/isolamento & purificação , Western Blotting , Fusão Celular , Membrana Celular/enzimologia , Reações Cruzadas , Esterases , Proteína gp120 do Envelope de HIV/farmacologia , Infecções por HIV/patologia , Humanos , Concentração de Íons de Hidrogênio , Peso Molecular , Peptídeo Hidrolases/imunologia , Peptídeo Hidrolases/metabolismo , Testes de Precipitina , Serina Endopeptidases/imunologia , Serina Endopeptidases/metabolismo , Frações Subcelulares/enzimologia , Especificidade por Substrato , Triptases , Células Tumorais CultivadasRESUMO
The putative inhibitor domain of Alzheimer's disease amyloid protein precursor was purified from E. coli containing a synthetic gene encoding the Kunitz domain. The purified protein (A4 inhibitor) inhibited the activity of trypsin, forming a 1:1 molar complex with the enzyme. It also strongly inhibited plasmin (Ki = 7.5 x 10(-11) M) from human serum and tryptase (Ki = 2.2 x 10(-10) M) from rat mast cells (tryptase M). In addition, it inhibited rat pancreatic trypsin, alpha-chymotrypsin and kallikrein and human serum kallikrein, but did not inhibit rat chymase, pancreatic elastase, alpha-thrombin, urokinase, papain or cathepsin B.