Biomedical subjects

Yasuhiro Fujiwara

Publications and source records attributed to Yasuhiro Fujiwara.

At least 37 records · Page 2Linked to original sources

PubMed2006

[Pharmacogenomics in chemotherapy and drug development for breast cancer].

Tumor response and toxicities are different among individual patients. Pharmacogenomics studies aim to elucidate the genetic bases for interindividual differences and to allow individualization of care, using the knowledge of molecular biology, recently developed high-throughput biotechnology and bioinformatics. Transcription profiling of gene expression have been extensively studied in breast cancer. Breast cancer may be re-subclassified into subtypes according to molecular profiles with distinct differences in prognosis and response to therapy. Although there still lay problems in standardization of methodology and statistical validation, genomics studies have the potential to play the key role in the development of novel therapeutical strategies in the management of breast cancer.

Breast Neoplasms↗

PubMed2006

[Rumination syndrome in an adult with normal intelligence].

A 32-year-old woman visited our department because of repeated regurgitation of food, and was diagnosed with rumination syndrome based on possession of symptoms typical for it. Although rumination syndrome is classified as a functional esophageal disorder according to the Rome II criteria, it is not well known in Japan, and there have been no previous reports of it in an adult with normal intelligence. Since patients with rumination syndrome are often misdiagnosed and receive unnecessary treatment, awareness of it by physicians is important.

Adult↗

PubMed2006

[The revision of Guidelines for Clinical Evaluation Methods of Anti-Cancer Drugs in Japan].

It has been ten years since the Ministry of Health and Welfare in Japan issued Guidelines for Clinical Evaluation Methods of anti-cancer Drugs in February, 1991. The circumstance surrounding anti-cancer drugs have now changed dramatically with the development of molecular-targeting drugs, introduction of clinical data in overseas countries for approval of new drugs in Japan, etc. Based on these changes, this guideline was revised in November 2005.

Antineoplastic Agents↗

PubMed2006

[A feasibility study of doxorubicin/cisplatin (AP) for postoperative chemotherapy in patients with advanced endometrial cancer].

OBJECTIVE: We evaluated the feasibility of doxorubicin/cisplatin (AP) for postoperative chemotherapy in patients with advanced endometrial cancer. METHODS: Patients with newly diagnosed advanced endometrial cancer received AP (doxorubicin 60 mg/m(2), cisplatin 50 mg/m(2)) every 3 weeks. Treatment was continued until disease progression or completion of 6 courses. Toxicities were evaluated every cycle according to NCI-CTCAE Ver.3.0. RESULTS: Fifteen patients were enrolled from April 2004 through December 2005. All patients successfully completed therapy. There were two patients who needed dose reduction and nine patients with prolongation of treatment interval. Patients with over Grade 3/4 toxicity were observed to have leucopenia (47%), neutropenia (67%), anemia (26%), and vomiting (13%). No grade 3/4 cardiac and renal failure were observed. CONCLUSIONS: The doxorubicin/cisplatin (AP) regimen is tolerated and can be safely given without severe toxicity.

Adenocarcinoma↗

PubMed2005

Roles of epidermal growth factor and Na+/H+ exchanger-1 in esophageal epithelial defense against acid-induced injury.

Epidermal growth factor (EGF) is predominantly secreted by salivary glands and activates Na(+)/H(+) exchanger-1 (NHE-1), which regulates intracellular pH (pH(i)). We investigated the roles of EGF and NHE-1 in esophageal epithelial defense against acid using human esophageal epithelial cell lines and a rat chronic esophagitis model. Esophageal epithelial cells were incubated with acidified medium in the absence or presence of EGF. Cell viability and changes in pH(i) were measured. Chronic acid reflux esophagitis was induced in rats with and without sialoadenectomy. Esophageal lesion index, epithelial proliferation, and expression of EGF receptors and NHE-1 were examined. EGF protected esophageal epithelial cells against acid in a dose-dependent manner, and the cytoprotective effect of EGF was completely blocked by treatment with NHE-1 inhibitors. Tyrosine kinase, calmodulin, and PKC inhibitors significantly inhibited cytoprotection by EGF, whereas MEK, phosphatidylinositol 3-kinase, and PKA inhibitors had no effect. EGF significantly increased pH(i) recovery after NH(4)Cl pulse acidification, and this increase in pH(i) recovery was significantly blocked by inhibitors of calmodulin and PKC. Sialoadenectomy led to an increase in the severity of chronic esophagitis but affected neither epithelial proliferation nor expression of EGF receptors. Expression of NHE-1 mRNA was increased in esophagitis and upregulated in rats with sialoadenectomy. The increasing severity of esophagitis in rats with sialoadenectomy was prevented by exogenous administration of EGF. In conclusion, EGF protects esophageal epithelial cells against acid through NHE activation via Ca(2+)/calmodulin and the PKC pathway. Deficiency in endogenous EGF is associated with increased severity of esophagitis. EGF and NHE-1 play crucial roles in esophageal epithelial defense against acid.

Animals↗

PubMed2005

The safety and efficacy of the weekly dosing of irinotecan for platinum- and taxanes-resistant epithelial ovarian cancer.

OBJECTIVE: Irinotecan is one of the drugs that might be effective against platinum- and taxanes-resistant epithelial ovarian cancer. We investigated efficacy and safety of the weekly dosing schedule of irinotecan. METHODS: From September 2001 to March 2003, 28 eligible patients who have histologically confirmed epithelial ovarian cancer, which was resistant or refractory to both platinum and taxanes, were consecutively treated at the National Cancer Center Hospital. Irinotecan (100 mg/m(2)) was administered intravenously over 90 min on days 1, 8, and 15. The chemotherapy was repeated every 4 weeks, up to 6 cycles. RESULTS: A total of 107 treatment cycles of irinotecan were administered to 28 patients. The median number of prior chemotherapy regimen was 3. Among 28 patients, 8 (29%) responded to irinotecan (2 complete responses and 6 partial responses). The median time to progression was 17 weeks. Three patients experienced hematological toxicities of Grade 4. Five patients experienced non-hematological toxicities Grade 3 or 4. No treatment-related death occurred. CONCLUSION: The weekly dosing schedule of irinotecan seems to be effective and safe salvage chemotherapy regimen for platinum- and taxanes-resistant or refractory epithelial ovarian cancer. Gastrointestinal toxicities, especially diarrhea, were moderate and manageable in an outpatient setting.

Adult↗

PubMed2005

Carotenoids in three species of Corbicula Clams, Corbicula japonica, Corbicula sandai, and Corbicula sp. (Chinese Freshwater Corbicula Clam).

Carotenoids were investigated in three species of corbicula clams, Corbicula japonica, Corbicula sandai, and Corbicula sp. (Chinese freshwater corbicula clam). Forty-three carotenoids were isolated. Among them, 7,8-didehydro-beta-cryptoxanthin (12), peridininol 5,8-furanoxide (38), pyrrhoxanthin 5,8-furanoxide (40), and pyrrhoxanthinol 5,8-furanoxide (43) are newly reported as naturally occurring carotenoids. Their structures were characterized on the basis of UV-vis, FAB-MS including MS/MS experiments, and 1H NMR spectroscopic data. The total carotenoid contents in C. japonica, C. sandai, and Chinese freshwater corbicula clam were found to be 5.3, 2.6, and 0.3 mg/100 g in the edible part (wet weight), respectively. Peridinin (34) and its derivatives were found to be major carotenoids in C. japonica, which inhabits brackish water. On the other hand, lutein (13) was found to be the major carotenoid in C. sandai and Chinese corbicula clams, which inhabit freshwater. These patterns well reflected the carotenoids in their dietary algae. 7',8'-Didehydrodeepoxyneoxanthin (19), corbiculaxanthin (21), corbiculaxanthin 3'-acetate (22), and 6-epiheteroxanthin (24) were found in all three species of corbicula clams and have not previously been found in other shellfishes. They were assumed to be peculiar carotenoids in corbicula clams.

Animals↗

PubMed2005

A phase I study and pharmacologic evaluation of irinotecan and carboplatin for patients with advanced ovarian carcinoma who previously received platinum-containing chemotherapy.

BACKGROUND: The objectives of the current study were to determine the maximum tolerated dose (MTD) of irinotecan and carboplatin in combination, to evaluate the efficacy and toxicity of the combination in patients with advanced ovarian carcinoma who previously received platinum-containing chemotherapy, and to examine the pharmacokinetics and pharmacodynamics of both drugs by using the Chatelut formula. METHODS: Patients with advanced ovarian carcinoma who previously received platinum-containing chemotherapy were treated with a combination of irinotecan and carboplatin. Carboplatin was administered as a 60-minute intravenous infusion on Day 1 and was followed by irinotecan, which was administered as a 90-minute intravenous infusion on Days 1, 8, and 15. Six dose levels of irinotecan (in mg/m(2))/carboplatin (mg . mL/min) were planned: 50 mg/m(2)/4 mg . mL/minute, 60 mg/m(2)/4 mg . mL/minute, 50 mg/m(2)/5 mg . mL/minute, 60 mg/m(2)/5 mg . mL/minute, 50 mg/m(2)/6 mg . mL/minute, and 60 mg/m(2)/6 mg . mL/minute. The carboplatin dosage was calculated by using the Chatelut formula. Treatment was repeated at 28-day intervals. RESULTS: In total, 19 patients in cohorts of 3 to 5 patients received irinotecan and carboplatin at 5 dose levels. The dose-limiting toxicities were Grade 4 neutropenia and Grade 4 thrombocytopenia. The MTD of the irinotecan/carboplatin combination was 60 mg/m(2)/5 . mg mL/minute. Partial responses were observed at higher dose levels. Pharmacologic studies demonstrated that administration of the dosage estimated with the Chatelut formula instead of the Chatelut formula with adjustment for serum creatinine resulted in a slightly excessive dose of carboplatin. CONCLUSIONS: The recommended dose for the Phase II study was irinotecan 60 mg/m(2) on Days 1, 8, and 15 with carboplatin 5 mg/mL . minute on Day 1 repeated every 4 weeks.

Adult↗

PubMed2005

Translational studies for target-based drugs.

The biological background for the clinical and prognostic heterogeneity among tumors within the same histological subgroup is due to individual variations in the biology of tumors. The number of investigations looking at the application of novel technologies within the setting of clinical trials is increasing. The most promising way to improve cancer treatment is to build clinical research strategies on intricate biological evidence. New genomic technologies have been developed over recent years. These techniques are able to analyze thousands of genes and their expression profiles simultaneously. The purpose of this approach is to discover new cancer biomarkers, to improve diagnosis, predict clinical outcomes of disease and response to treatment, and to select new targets for novel agents with innovative mechanisms of action. Gene expression profiles are also used to assist in selecting biomarkers of pharmacodynamic effects of drugs in the clinical setting. Biomarker monitoring in surrogate tissues may allow researchers to assess "proof of principle" of new treatments. Clinical studies of biomarkers monitoring toxicity profiles have also been done. Such pharmacodynamic markers usually respond to treatment earlier than clinical response, and as such may be useful predictors of efficacy. Epidermal growth factor receptor (EGFR) mutation in lung cancer tissues is a strong predictive biomarker for EGFR-targeted protein tyrosine kinase inhibitors. Monitoring of EGFR mutation has been broadly performed in retrospective and prospective clinical studies. However, global standardization for the assay system is essential for such molecular correlative studies. A more sensitive assay for EGFR mutation is now under evaluation for small biopsy samples. Microdissection for tumor samples is also useful for the sensitive detection of EGFR mutation. Novel approaches for the detection of EGFR mutation in other clinical samples such as cytology, pleural effusion and circulating tumor cells are ongoing.

Biomarkers, Tumor↗

PubMed2005

Weekly paclitaxel in patients with CAP-resistant advanced or recurrent endometrial carcinoma: a series of four patients.

We evaluated the feasibility of weekly paclitaxel in patients with recurrent or advanced endometrial carcinoma who had failed treatment with cyclophosphamide, doxorubicin, and cisplatin (CAP). We treated four patients with CAP-resistant recurrent or advanced endometrial carcinoma with paclitaxel. Paclitaxel (80 mg/m(2); infused over 1 h) was administered weekly for a maximum of 18 weeks, unless disease progression or intractable toxicity developed. A complete response was observed in one patient and a partial response in two patients. Disease progression was found in one patient. Two patients developed grade 3 leukopenia or neutropenia. Neurotoxicity for all patients was within grade 1. Outpatient treatment with weekly paclitaxel was well-tolerated and feasible for patients with CAP-resistant recurrent or advanced endometrial carcinoma. Further trials to confirm the efficacy and toxicity of weekly paclitaxel are warranted.

Adenocarcinoma, Clear Cell↗

PubMed2005

Efficacy of weekly paclitaxel in patients with docetaxel-resistant metastatic breast cancer.

BACKGROUND: Partial cross-resistance to paclitaxel and docetaxel has been demonstrated in pre-clinical studies. PATIENTS AND METHODS: We retrospectively evaluated the efficacy of weekly paclitaxel 80 mg/m(2) in 82 patients with docetaxel-resisitant metastatic breast cancer. Docetaxel resistance was classified into primary resistance, defined as progressive disease while receiving docetaxel, and secondary resistance, defined as progression after achievement of a documented clinical response to docetaxel. Secondary resistance was subclassified according to the interval between the final infusion of docetaxel and the start of weekly paclitaxel into: (1) short interval, < or =120 days, and (2) long interval, >120 days. RESULTS: The response rate of the 82 patients was 19.5% (95% confidence interval, 10.8-27.9%). The response rate according to the docetaxel resistance category was: primary resistance (n = 24), 8.3%; secondary resistance (n = 58), 24.1% (short interval [n = 39], 17.9%, and long interval, [n = 19], 36.8%). The differences in response rates among the three categories were statistically significant (p = 0.0247, Cochran-Mantel-Haenszel test). The interval between from the final docetaxel infusion and disease progression were predictors for response of weekly paclitaxel. CONCLUSION: Weekly paclitaxel is modestly effective and safe in docetaxel-resistant metastatic breast cancer patients. However, weekly paclitaxel should not be recommended for primary resistance patients with docetaxel.

Antineoplastic Agents, Phytogenic↗

PubMed2005

15th anniversary of rebamipide: looking ahead to the new mechanisms and new applications.

Rebamipide, a gastro-protective drug, was developed in Japan for the treatment of peptic ulcer disease. It was proven superior to the former same category drug cetraxate in a randomized, controlled, double-blind, comparative clinical study in 1989. Rebamipide's mechanisms of actions are different from anti-secretory drugs; it accelerates and improves the quality of ulcer healing and reduces ulcer recurrence rate. Numerous studies have been conducted to explain the mechanisms responsible for these actions, 37 papers were published by 1998. Major properties of rebamipide include: stimulation of prostaglandin and mucus glycoprotein synthesis, inhibition of reactive oxygen species, inflammatory cytokines and chemokines, and inhibition of neutrophils activation. Since 1998, 107 papers were published, clarifying further effects of rebamipide on cyclooxygenase-2, prostaglandin E receptors, growth factors (i.e., HGF, EGF, and VEGF), heat-shock proteins, nitric oxide, adhesion molecules, neutrophils, and Helicobacter pylori- and NSAID-related pathology. Moreover, inhibitory action of rebamipide on gastric cancer growth has also been shown. In this issue we reviewed recent advances in understanding of rebamipide's mechanism of action and its newest clinical applications.

Alanine↗

PubMed2005

Rebamipide reduces delay in gastric ulcer healing in cyclooxygenase-2-deficient mice.

Rebamipide is an antiulcer drug capable of various actions including the induction of cyclooxygenase-2 (COX-2). In this study, we investigated the effect of rebamipide on gastric ulcer healing in COX-2-deficient mice. Wild-type (N=34) and COX-2-deficient mice (N=28) with gastric ulcers were administered 30 mg/kg of rebamipide or the vehicle. Ulcerous tissues were subjected to measurements of ulcer size, immunohistochemical staining of CD31 (an endothelial cell marker), and mRNA levels. COX-2 deficiency delayed ulcer healing and inhibited angiogenesis and bFGF mRNA expression in the granulation tissue. In wild-type mice, rebamipide accelerated ulcer healing and increased COX-2 mRNA expression. In COX-2-deficient mice, rebamipide prevented delayed ulcer healing and reversed the inhibition in angiogenesis and bFGF mRNA expression. The effect of rebamipide on the enhancement of ulcer healing, angiogenesis, and induction of bFGF expression was more prominent in wild-type mice than in COX-2-deficient mice. In conclusion, rebamipide may accelerate gastric ulcer healing through both COX-2-dependent and COX-2-independent mechanisms.

Alanine↗

PubMed2005

Structure of new carotenoids from corbicula clam Corbicula japonica.

Six new carotenoids, named corbiculaxanthin (1), corbiculaxanthin 3'-acetate (2), 6-epiheteroxanthin (3), 7',8'-didehydrodeepoxyneoxanthin (4), cyclopyrrhoxanthin (5), and hydratoperidinin (6), were isolated from the corbicula clam (Shijimi in Japanese), Corbicula japonica. Their structures were determined by chemical and spectral data.

Animals↗

PubMed2005

Prevalence of gastroesophageal reflux disease and gastroesophageal reflux disease symptoms in Japan.

BACKGROUND AND AIM: Epidemiological studies have shown that 10-48% of people in developed countries have gastroesophageal reflux disease (GERD) symptoms such as heartburn and acid regurgitation. The present study aimed to examine the prevalence of GERD symptoms and GERD in Japanese subjects. METHODS: A cross-sectional study of Japanese subjects who visited a clinic for a routine health check up was carried out. Subjects were asked to fill out a self-report questionnaire. GERD was defined as the presence of heartburn and/or acid regurgitation at least twice per week. RESULTS: Of the 6035 eligible subjects, 2662 (44.1%) reported having had heartburn and/or acid regurgitation during the past year: 124 (2.1%) daily, 275 (4.6%) twice per week, 773 (12.8%) twice per month and 1490 (24.7%) less than twice per month. Three hundred and ninety-nine (6.6%) subjects were diagnosed as having GERD and there was no relationship between the prevalence of GERD and either sex or age. The prevalence of bothersome GERD symptoms was significantly higher in subjects with GERD than in those without GERD. CONCLUSION: Approximately 6.6% of Japanese have GERD and most persons with GERD described heartburn or acid regurgitation as bothersome.

Adult↗

PubMed2005

Association between dinner-to-bed time and gastro-esophageal reflux disease.

OBJECTIVE: It is generally recommended that patients with gastro-esophageal reflux disease (GERD) refrain from eating within 3 h of going to sleep. In addition to a remarkable lack of supporting clinical evidence, whether GERD patients have shorter dinner-to-bed time is unknown. This study was designed to determine a possible association between dinner-to-bed time and GERD, compared with healthy adults. METHODS: In a matched case-control study, we enrolled 147 GERD patients, and age- and sex-matched 294 controls without GERD symptoms such as heartburn and acid regurgitation during the previous year. Dinner-to-bed time, defined as the time intervals until going to bed after finishing eating dinner, was examined by a self-report questionnaire. Logistic regression was used to calculate odds ratio (OR) and 95% confidence intervals (CI) for GERD. RESULTS: After adjustment for smoking habits, drinking habits, and body mass index, shorter dinner-to-bed time was significantly associated with an increased OR of GERD (p < 0.0001) and the OR for patients whose dinner-to-bed time was less than 3 h was 7.45 (95% CI 3.38-16.4) compared with patients whose dinner-to-bed time was 4 h or more. These observations were consistent in both patients with non-erosive GERD and erosive esophagitis, and there was no significant difference in dinner-to-bed time intervals between non-erosive GERD and erosive esophagitis. CONCLUSION: In this matched case-control study, shorter dinner-to-bed time was significantly associated with an increased OR for GERD.

Adult↗

PubMed2005

Differences in clinical characteristics between patients with endoscopy-negative reflux disease and erosive esophagitis in Japan.

OBJECTIVE: Helicobacter pylori infection and atrophic gastritis are inversely related to erosive esophagitis. Whether these factors affect the pathogenesis of endoscopy-negative reflux disease is not clear. We aimed to elucidate the differences in clinical characteristics between endoscopy-negative erosive disease and erosive esophagitis. METHODS: 253 subjects (89 with endoscopy-negative reflux disease and 164 with erosive esophagitis) were studied. Gastric atrophy was assessed by measurement of serum pepsinogen. Logistic regression was used to calculate the odds ratio (OR) and 95% confidence intervals (CI) of endoscopy-negative reflux disease compared with erosive esophagitis. RESULTS: Among GERD patients, female gender (OR = 2.27, 95% CI, 1.25-4.10), smoking (OR = 0.45, 95% CI, 0.22-0.91), and the presence of hiatal hernia (OR = 0.30, 95% CI, 0.17-0.56) were significantly associated with endoscopy-negative reflux disease compared with male gender, not smoking, and absence of hiatal hernia, respectively. Body mass index (BMI) was also significantly associated with a decreased OR for endoscopy-negative reflux disease. Although H. pylori infection and gastric atrophy were significantly more common in patients with endoscopy-negative reflux disease, these associations did not persist in a multiple-adjustment model. After adjustment for gender, BMI, smoking, and hiatal hernia, a decrease in serum pepsinogen I/II ratio was significantly associated with an increased OR for endoscopy-negative reflux disease (p for trend = 0.018). CONCLUSIONS: Female gender, low BMI, not smoking, absence of hiatal hernia, and severity of gastric atrophy were positively associated with endoscopy-negative reflux disease compared with erosive esophagitis among Japanese patients.

Adult↗

PubMed2005

AP-1 and colorectal cancer.

Activator protein-1 (AP-1) is a transcription factor that consists of either a Jun-Jun homodimer or a Jun-Fos heterodimer. AP-1 regulates the expression of multiple genes essential for cell proliferation, differentiation and apoptosis. Numerous reports suggest that AP-1 plays an important role in various human diseases. Among them, the roles relating to human cancers have been strongly suggested for a long time. In human cancers, colorectal cancer is still a leading cause of morbidity and mortality in the world. Since there are some reports about the role of AP-1 in colorectal cancer response to a number of stimuli, such as cytokines and growth factors, and oncogenictransformation, therapeutic inhibition of AP-1 activity has attracted considerable interest. Here, we demonstrate the biological properties of AP-1 and its role in colorectal cancer, and discuss a possibility of an AP-1 inhibitor, an adenovirus dominant-negative mutant of c-Jun, as a therapeutic agent for gene therapy.

Animals↗