PubMed Health⌕ Search

Biomedical subjects

Keiichi Fujiwara

Publications and source records attributed to Keiichi Fujiwara.

At least 19 recordsLinked to original sources
PubMed2007

Gefitinib induces premature senescence in non-small cell lung cancer cells with or without EGFR gene mutation.

Despite its tremendous antitumor effect in a subset of patients with non-small cell lung cancer (NSCLC), the exact mechanism of gefitinib-induced cell death has not been fully determined. In this study, forms of cell death in various NSCLC cell lines after gefitinib exposure was analyzed to elucidate the cell death mechanism of gefitinib. Though higher concentration of gefitinib (10 microM) induced extensive apoptosis in two cell lines (EGFR-mutated PC-9 cells and EGFR wild- type EBC-2/R cells), clinically relevant concentrations of gefitinib (1 microM) induced prominent premature senescence instead of apoptosis in these cells. This induction of senescence was preceded by immediate increase of p16INK4A, p21WAF1/Cip1 and p27Kip1 levels and subsequent G1 cell cycle arrest. These phenomena were not observed in gefitinib-resistant (RERF-LC-MS) cells. Additionally, ex vivo exposure to gefitinib induced senescence in short-term cultured tumor cells that were obtained from malignant pleural effusion of a patient with NSCLC, whose tumor was later revealed to be clinically sensitive to gefitinib. Our results indicate that senescence might be a major anti-tumor mechanism of gefitinib in these NSCLC cells regardless of the EGFR gene mutation status.

Antineoplastic Agents↗
PubMed2006

Randomized phase II study of immunomodulator Z-100 in patients with stage IIIB cervical cancer with radiation therapy.

OBJECTIVE: To find the optimal dose of immunomodulator Z-100 in patients with stage IIIB squamous cell carcinoma of the cervix in combination with radiation therapy. METHODS: The patients were randomly assigned to the dosage levels of 2, 20 or 40 mug of Z-100. Z-100 was subcutaneously injected twice a week during radiotherapy and once in two weeks during the maintenance period. The response rate after radiotherapy was evaluated, and the optimal clinical dosage was then determined. Safety of Z-100 was evaluated during the radiation therapy and maintenance therapy. Survival was also evaluated. RESULTS: A total of 116 patients were entered. The adverse reactions were not dose-dependent and no serious toxicities were observed. The response rates were 72.2% (26/36) in the 2 microg group, 84.6% (33/39) in the 20 microg group and 94.3% (33/35) in the 40 microg group (P = 0.006). However, the survival was not significantly different. CONCLUSIONS: The optimal dose of Z-100 was determined to be 40 mug in combination with radiation therapy for stage IIIB cervical cancer. However, impact of Z-100 on survival must be determined by the placebo controlled randomized trial, because survival benefit was not observed in this small population study.

Adolescent↗
PubMed2006

Feasibility of extraperitoneal laparoscopic para-aortic and common iliac lymphadenectomy.

OBJECTIVE: The aim of this study is to evaluate the feasibility of extraperitoneal laparoscopic para-aortic and common iliac lymphadenectomy for cervical and endometrial carcinoma. METHODS: Seventy-six patients underwent extraperitoneal laparoscopic para-aortic and common iliac lymphadenectomy between February 1999 and September 2005. The lymph nodes dissected with the laparoscopic procedure included the inframesenteric para-aortic lymph nodes, the sacral lymph nodes, and the bilateral common iliac lymph nodes. The extraperitoneal laparoscopic operation was performed with pelvic open surgery using Lap Disc to ensure the safety of patients. RESULTS: The number of patients with cervical and endometrial carcinoma was 36 and 40, respectively. The median age of patients was 51 years (range 24-75 years). Conversion to open surgery was necessary in 8 patients. These include 3 patients who encountered blood loss of 400, 136 and 128 ml; 2 extremely obese women; and 3 patients who had peritoneal tears causing CO2 gas leakage. Among the remaining 68 patients, the median operating time for extraperitoneal laparoscopic para-aortic and common iliac lymphadenectomy was 75 min (range 45-145 min), and the median estimated blood loss was 5 ml (range 5-138 ml). The median total number of resected nodes was 14 (range 2-31), and 4 patients had lymph node metastasis. No patient encountered postoperative complications attributable to extraperitoneal laparoscopic para-aortic and common iliac lymphadenectomy. CONCLUSIONS: Extraperitoneal laparoscopic para-aortic and common iliac lymphadenectomy with pelvic open surgery using Lap Disc is a feasible procedure, particularly in the surgeons learning phase.

Adult↗
PubMed2006

Twenty-four weeks of interferon alpha-2b in combination with ribavirin for Japanese hepatitis C patients: sufficient treatment period for patients with genotype 2 but not for patients with genotype 1.

BACKGROUND: Hepatitis C virus (HCV) RNA titer and HCV genotype are two major determinants of the outcome of interferon (IFN) monotherapy. To clarify the usefulness of combination therapy with IFN and ribavirin in Japanese hepatitis C patients, we treated patients with a relatively high dose of IFN in combination with ribavirin for 24 weeks and examined the effects in relation to the viral parameters. METHODS: Two hundred and ninety-five patients were enrolled in the study. The patients received either 6 or 10 million units (MU) of interferon alpha-2b every day for 2 weeks and then three times a week for 22 weeks with a daily dose of either 600 or 800 mg of ribavirin. The treatment response and safety of this treatment were examined. RESULTS: The sustained virologic response (SVR) rates were 26.8% in genotype 1 and 76.5% in genotype 2 (P < 0.001), and 36.1% with the 6 MU group and 45.8% with the 10 MU group (P = 0.09). Multivariate analysis indicated that SVR was associated with genotype 2, HCV RNA <500 kilointernational unit/ml (kIU/ml), and HCV RNA undetectability at week 8 of treatment. CONCLUSION: Our current study showed that a 24-week course of IFN plus ribavirin combination therapy was effective with respect to virologic response in Japanese hepatitis C patients, particularly in patients with HCV genotype 2.

Adolescent↗
PubMed2005

Phase III double-blind randomized trial of radiation therapy for stage IIIb cervical cancer in combination with low- or high-dose Z-100: treatment with immunomodulator, more is not better.

BACKGROUND: To evaluate the efficacy of low or high-dose immunomodulator, Z-100, in combination with radiotherapy for cervical cancer. METHODS: Between 1995 and 1999, 221 patients with stage IIIb squamous cell carcinoma of the cervix were randomly assigned to treatment with Z-100 either at 0.2 microg or 40 microg in a double-blind manner in combination with radiotherapy. RESULTS: The 5-year survival of patients with high-dose and low-dose Z-100 was 41.5% (95% CI: 31.7-51.3%) and 58.2% (95% CI: 48.7-67.7%), respectively, showing a 30% reduction in the death rate (hazard ratio: 0.670 [95% CI: 0.458-0.980], P = 0.039). Survival of high-dose group was equivalent to the 4-year survival of the radiotherapy plus hydroxyurea arm (49.7%) of GOG120 study, and that of low-dose group was similar to the survival of the cisplatin-based chemoradiation arm. The progression-free survival was also significantly improved in favor of low-dose group (hazard ratio: 0.667 [95% CI: 0.447-0.997], P = 0.048). The survival of low-dose group was similar to the survival of the cisplatin-based chemoradiation arms of the GOG120 study. CONCLUSIONS: Unexpectedly, the survival of patients with advanced cervical cancer treated by lower dose of Z-100 in combination with radiotherapy was significantly better than those treated with higher dose Z-100, which was equivalent to the survival with radiotherapy alone. The hypothesis that lower dose of Z-100 enhances the efficacy of radiation therapy is now being tested by placebo-controlled randomized trial.

Adjuvants, Immunologic↗
PubMed2005

A phase I study of 3-day topotecan and cisplatin in elderly patients with small-cell lung cancer.

PURPOSE: The aim of this phase I study was to determine the maximum-tolerated dose (MTD) in elderly patients with small-cell lung cancer (SCLC). PATIENTS AND METHODS: Patients aged over 75 years with previously untreated SCLC were enrolled in this study. Both topotecan and cisplatin were administered on days 1-3 and repeated every 3 weeks. The starting dose of topotecan was 0.5 mg/m2/day, while cisplatin was fixed at the dose of 20 mg/m2/day. Patients with limited disease (LD) SCLC received thoracic irradiation after the completion of chemotherapy. RESULTS: Twenty-one elderly patients were enrolled in this study and received a total of 59 cycles. The major hematological toxicity was neutropenia and non-hematological toxicities including diarrhea were generally mild and reversible. The MTD of topotecan was determined as 1.2 mg/m2/day. The recommended phase II study dose of topotecan was determined as 1.0 mg/m2/day with cisplatin 20 mg/m2/day daily for 3 days. An objective response was observed in 6 of 10 patients (60%) with LD-SCLC and 6 of 11 (55%) with extensive disease (ED) SCLC. The median survival time in patients with LD-SCLC and those with ED-SCLC were 16.0 and 11.0 months, respectively. CONCLUSION: The combination chemotherapy of 3-day topotecan and cisplatin appears to be tolerable and effective in elderly patients with SCLC.

Aged↗
PubMed2005

Intraperitoneal carboplatin infusion may be a pharmacologically more reasonable route than intravenous administration as a systemic chemotherapy. A comparative pharmacokinetic analysis of platinum using a new mathematical model after intraperitoneal vs. intravenous infusion of carboplatin--a Sankai Gynecology Study Group (SGSG) study.

OBJECTIVE: To clarify the pharmacological advantage of carboplatin-based intraperitoneal chemotherapy using the three-compartment mathematical model. METHODS: Eleven consecutive patients in one institution underwent intraperitoneal administration of carboplatin, and 11 consecutive patients in another institution received intravenous administration. Carboplatin (AUC=6 mg x min/ml) was diluted in 500 ml 5% glucose and administered either as an intraperitoneal bolus infusion or intravenous drip infusion during 1 h. Patients undergoing intravenous injection also received an infusion of 500 ml 5% glucose to obtain intraperitoneal samples. Intraperitoneal fluid and blood samples were obtained, immediately and 1, 2, 4, 8, 12, and 24 h after administration. The mathematical model consisting of a three-compartment model was applied to analyze the pharmacokinetics. The model was created with simultaneous differential equations and was solved by the Runge-Kutta method. RESULTS: The rate constants of platinum diffusion from the peritoneal cavity to serum, serum to peritoneal cavity, serum to peripheral space, peripheral space to serum, and elimination were 0.94+/-0.79 (mean+/-SD), 1.28+/-2.50, 16.50+/-9.26, 0.99+/-0.62, and 4.14+/-1.45 (h-1), respectively. When the theoretical pharmacological concentration of platinum was calculated using this mathematical model, 24-h platinum AUC in the serum was exactly the same regardless of intraperitoneal or intravenous administration of carboplatin. However, the 24-h platinum AUC in the peritoneal cavity was approximately 17 times higher when carboplatin was administered by the intraperitoneal route. CONCLUSION: The present pharmacological analysis suggests that intraperitoneal infusion of carboplatin is feasible not only as an intraperitoneal regional therapy but also as a more reasonable route for systemic chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Difference of carboplatin clearance estimated by the Cockroft-Gault, Jelliffe, Modified-Jelliffe, Wright or Chatelut formula.

OBJECTIVE: Although the Calvert formula is the standard method to calculate the dose of carboplatin, there is no consensus how to determine the glomerular filtration rate (GFR) without using [51Cr]-ethylenediamine tetraacetic acid (51Cr-EDTA). Creatinine clearance (Ccr), calculated using the Cockroft-Gault, Jelliffe, Modified-Jelliffe or Wright formulae, has been used as a substitute for the GFR. In addition to these four formulae, the Chatelut formula has been proposed as a way to calculate carboplatin clearance. Among these formulae, Jelliffe formula does not include body surface area (BSA) or body weight to adjust the body size and thus may have greater bias than the other four formulae in estimating carboplatin clearance. The purpose of this study is to evaluate if these five formulae could equally estimate the carboplatin clearance. METHODS: : Carboplatin clearance was estimated in 253 patients with gynecologic cancer who received carboplatin-based chemotherapy between January 1996 and August 2004. Ccr was estimated using the Cockroft-Gault, Jelliffe, Modified-Jelliffe or Wright formulae. Carboplatin clearance was also calculated directly by using the Chatelut formula. The five estimations of carboplatin clearance were compared with each other using the post-hoc Wilcoxon signed rank test. The median percent error (MPE) and the median absolute percent error (MAPE) were evaluated by comparing carboplatin clearance. The relationships between BSA and ratios of estimated carboplatin clearance (Jelliffe/Cockroft-Gault, Jelliffe/Modified-Jelliffe, Jelliffe/Wright, Jelliffe/Chatelut) were evaluated by using simple regression. RESULTS: : The estimated carboplatin clearances were: Cockroft-Gault formula, 109.8 +/- 28.4; Jelliffe formula, 128.5 +/- 28.2; Modified-Jelliffe formula, 110.8 +/- 25.7; Wright formula, 112.2 +/- 24.3; Chatelut formula, 114.1 +/- 33.0. A statistically significant difference was observed between carboplatin clearance calculated using Jelliffe formula and that given by each of the other four formulae. Comparing the results of the Cockroft-Gault formula with the Jellife, Modified-Jelliffe, Wright and Chatelut formulae yielded MPEs of +19%, +2%, +3% and +3% and MAPEs of 27%, 5%, 6% and 6%, respectively. There was a significant correlation between BSA and ratio of estimated carboplatin clearance (Jelliffe/Cockroft-Gault, Jelliffe/Modified-Jelliffe, Jelliffe/Wright, Jelliffe/Chatelut), with Pearson correlation coefficients of 0.928, 0.847, 0.965 and 0.839 respectively. As the BSA of patient became smaller, the differences between the carboplatin clearance calculated by the Jelliffe formula from other four formulas became larger. CONCLUSIONS: : Estimates of carboplatin clearance calculated by the Jelliffe formula tend to have greater positive bias compared to the other four formulae, particularly when the BSA of the patient is small. In order to conduct collaborative international studies, it may be necessary to standardize the formula used to estimate carboplatin clearance to perform international collaboration studies.

Adolescent↗
PubMed2005

Amantadine inhibits hepatitis A virus internal ribosomal entry site-mediated translation in human hepatoma cells.

The effect of six drugs (amantadine, glycyrrhizin, ribavirin, ursodeoxycholic acid, alcohol, and IFN) on HAV RNA translation from the HAV internal ribosomal entry site (IRES) was investigated using a bicistronic reporter construct containing HAV IRES as intragenic spacer. Huh-7 cells and derivatives were transfected with in vitro transcripts, and the reporter gene activity was determined. IFN suppressed both cap-dependent and HAV IRES-dependent translation, while amantadine specifically inhibited HAV IRES-dependent translation. In contrast to IFN, by reporter assay, amantadine did not activate the interferon-stimulated response element (ISRE) or interferon gamma-activated sequence (GAS)-associated pathways. Immunoblot analysis revealed that amantadine had no effect on PKR and on IFN-regulatory factor-1 (IRF-1) expression. These findings demonstrated a novel antiviral effect of amantadine against HAV with or without HCV infection.

Amantadine↗
PubMed2005

Importance of adequate immunosuppressive therapy for the recovery of patients with "life-threatening" severe exacerbation of chronic hepatitis B.

AIM: Hepatitis B virus (HBV) re-activation often occurs spontaneously or after withdrawal of immunosuppressive therapy in patients with chronic hepatitis B. Severe exacerbation, sometimes developing into fulminant hepatic failure, is at high risk of mortality. The efficacy of corticosteroid therapy in "clinically severe" exacerbation of chronic hepatitis B has not been well demonstrated. In this study we evaluated the efficacy of early introduction of high-dose corticosteroid therapy in patients with life-threatening severe exacerbation of chronic hepatitis B. METHODS: Twenty-two patients, 14 men and 8 women, were defined as "severe" exacerbation of chronic hepatitis B using uniform criteria and enrolled in this study. Eleven patients were treated with corticosteroids at 60 mg or more daily with or without anti-viral drugs within 10 d after the diagnosis of severe disease ("early high-dose" group) and 11 patients were either treated more than 10 d or untreated with corticosteroids ("non-early high-dose" group). RESULTS: Mean age, male-to-female ratio, mean prothrombin time (PT) activity, alanine transaminase (ALT) level, total bilirubin level, positivity of HBeAg, mean IgM-HBc titer, and mean HBV DNA polymerase activity did not differ between the two groups. Ten of 11 patients of the "early high-dose" group survived, while only 2 of 11 patients of the "non-early high-dose" group survived (P<0.001). During the first 2 wk after the introduction of corticosteroids, improvements in PT activities and total bilirubin levels were observed in the "early high-dose" group. Both ALT levels and HBV DNA polymerase levels fell in both groups. CONCLUSION: The introduction of high-dose corticosteroid can reverse deterioration in patients with "clinically life-threatening" severe exacerbation of chronic hepatitis B, when used in the early stage of illness.

Acute Disease↗
PubMed2005

Identification of epigenetic aberrant promoter methylation in serum DNA is useful for early detection of lung cancer.

PURPOSE: The purpose of this study is to evaluate the usefulness of serum DNA methylation of five tumor suppressor genes for early detection of lung cancer. EXPERIMENTAL DESIGN: Methylation status in serum DNA from 200 patients undergoing bronchofiberscopic examination for abnormal findings on chest radiograph detected by lung cancer screening or surveillance was examined using methylation-specific PCR. RESULTS: Ninety-one patients were given a pathologic diagnosis of lung cancer, 9 other malignant diseases, and 100 nonmalignant pulmonary diseases. In patients with lung cancer, methylation was detected in 18.7% for MGMT, 15.4% for p16(INK4a), 12.1% for RASSF1A, 11.0% for DAPK, and 6.6% for RAR-beta, which was higher compared with that in patients with nonmalignant diseases. Age and smoking status seemed to associate with methylation status. Sensitivity, specificity, and predictive value of methylation in at least one gene for diagnosis of lung cancer were 49.5%, 85.0%, and 75.0%, respectively. Adjusted odds ratio (95% confidence interval) for having lung cancer was 5.28 (2.39-11.7) for patients with methylation in one gene and 5.89 (1.53-22.7) for those with methylation in two or more genes. It is of note that methylation was identified in 50.9% of stage I lung cancer patients, whereas serum protein tumor markers were positive in 11.3% of them. CONCLUSIONS: These results suggest that identification of promoter methylation of tumor suppressor genes in serum DNA could be useful for early detection of lung cancer.

Adult↗
PubMed2005

Ultrasonographic measurement of intima-media thickness of the carotid artery before coronary artery bypass grafting.

PURPOSE: We evaluated the usefulness of measuring intima-media thickness (IMT) of the carotid artery by ultrasonography before coronary artery bypass grafting (CABG). METHODS: Seventy-three patients who underwent carotid ultrasonography before CABG were selected for this study. The maximum IMT (max IMT) in the bilateral common carotid artery was used as the index of carotid ultrasonography. As a quantitative measure of coronary atherosclerosis, we calculated Gensini's coronary score (GCS) from the preoperative coronary angiography. RESULTS: There was a positive correlation between the max IMT and the GCS. Furthermore, the max IMT of the patients with myocardial infarction was significantly greater than that of the patients with angina pectoris. CONCLUSIONS: Carotid ultrasonography before CABG is useful, not only for the morphological evaluation of the stenotic lesions of the neck vessels, but also for the quantitative prediction of atherosclerosis in the native coronary artery. The max IMT may predict the progression of atherosclerotic change of the native coronary artery from angina pectoris to myocardial infarction.

Aged↗
PubMed2005

Successful repair of traumatic tricuspid valve regurgitation.

Isolated traumatic tricuspid valve regurgitation is an uncommon complication of blunt chest trauma. Tricuspid valve replacement has been ordinarily managed for this lesion. Herein, we report two cases of successful repair for traumatic tricuspid valve regurgitation, 11 and 40 years following blunt chest trauma, respectively. Tricuspid valve repairs were performed using an artificial chordae implantation with expanded polytetrafluoroethylene (CV-5) sutures and ring annuloplasty. Postoperative echocardiography revealed that the tricuspid valve regurgitation improved to mild and trivial respectively in two patients. They are presently doing well, 4 and 2 years after the repair, respectively.

Adult↗
PubMed2005

Combination chemotherapy of docetaxel and carboplatin in advanced or recurrent cervix cancer. A pilot study.

OBJECTIVES: This is a pilot study for a future trial to assess the efficacy and safety of combination chemotherapy with docetaxel and carboplatin in advanced or recurrent uterine cervix cancer. METHODS: The patients eligible for this study had histologically confirmed, advanced (stage IB2-IV) or recurrent uterine cervix cancer. Eligible patients had measurable lesions and must have sufficient bone marrow, renal, and liver functions. Docetaxel was administered intravenously (IV) at 60 mg/m2 followed by IV carboplatin administration based on AUC = 6. Chemotherapy was repeated in 1-6 courses depending on the purpose of the therapy. The response was evaluated based on RECIST criteria. The toxicity grade was determined by NCI-CTC version 2. RESULTS: During January 2001 and April 2004, 17 patients were entered in this study. The distribution of stage was IB2, 3; IIB, 8; IIIB, 3; IVB, 1; recurrent, 2. There were 9 squamous cell carcinomas, 6 adenocarcinomas, 1 adenosquamous cell carcinoma, and 1 small cell carcinoma. The overall response rate was 76% (2 CR, 11 PR, and 4 SD). No progression of disease was observed. All 5 adenocarcinoma patients in the neoadjuvant chemotherapy group responded including 1 pathological CR. The incidences of grade 3/4 toxicities were 76% for neutrocytopenia, 12% for thrombocytopenia, and 6% for anemia. No grade 3/4 neurotoxicity was observed. CONCLUSIONS: The combination of docetaxel and carboplatin is an effective and safe treatment for uterine cervix cancer. Further evaluation particularly targeted on cervical adenocarcinoma is warranted.

Adult↗
PubMed2005

Intraperitoneal carboplatin-based chemotherapy for epithelial ovarian cancer.

OBJECTIVE: Intraperitoneal (IP) chemotherapy is an attractive approach to the treatment of ovarian cancer because the disease remains confined to the peritoneal cavity for a large part of its natural history. In this review article, we discuss the current status and future perspectives of IP chemotherapy for ovarian cancer. METHODS: A systematic review of IP carboplatin-based chemotherapy for ovarian cancer treatment was conducted through evaluation of published manuscripts as well as abstracts from the proceedings of the American Society of Clinical Oncology and the Society of Gynecologic Oncologists. RESULTS: Despite the fact that survival or progression-free survival benefit has been demonstrated by three large randomized trials (Survival Hazard Ratio for GOG104/SWOG 0.76, Relative Risk Reduction of Progression: 0.78 for GOG114, and 0.73 for GOG172), IP chemotherapy has not been accepted as a standard treatment. This appears to be mainly due to the cisplatin-related toxicity and IP catheter failure. Substituting cisplatin with carboplatin may make this approach more tolerable. Recent pharmacological data suggest that carboplatin-based IP chemotherapy not only exposes the peritoneal cavity to higher doses of the agent, but also attains levels of systemic platinum comparable to intravenous (IV) administration. A large retrospective study has demonstrated excellent survival for patients with advanced ovarian cancer who underwent carboplatin-based IP chemotherapy. Low observed toxicity as well as infrequent catheter-related complications was significant findings in this report. CONCLUSION: A large scale phase III randomized trial is now urgently needed to clarify the role of carboplatin-based IP chemotherapy in ovarian cancer.

Antineoplastic Agents↗
PubMed2005

Serum hemoglobin level determined at the first presentation is a poor prognostic indicator in patients with lung cancer.

OBJECTIVES: Anemia is observed in various malignancies including lung cancer and is recently considered to be a poor prognostic indicator. We investigated whether there is a correlation between anemia, other clinicopathologic factors, and survival. METHODS: We retrospectively examined the clinical records of 611 patients with lung cancer. RESULTS: Of those, 298 (48.8%) patients had anemia at the time of their first visit to our hospital. There was a significant correlation between anemia and age (p=0.0006) or ECOG performance status (p=0.0002), however, there was no correlation of anemia with gender, histological type, clinical stage, or serum level of lactate dehydrogenase. Survival was significantly shorter in 298 patients with anemia (median survival time (MST): 7.5 months) compared with 313 patients without anemia (MST: 11.8 months, p<0.0001). Multivariate analysis of prognostic factors using the Cox proportional hazards model revealed that anemia appeared to be an independent prognostic indicator. CONCLUSION: Anemia observed at the first presentation is an independent poor prognostic indicator in patients with lung cancer.

Adult↗