Biomedical subjects

Masanori Fukushima

Publications and source records attributed to Masanori Fukushima.

15 recordsLinked to original sources

PubMed2006

Single-agent gemcitabine for biliary tract cancers. Study outcomes and systematic review of the literature.

OBJECTIVE: The aim of this study was to investigate the outcomes of gemcitabine-treated patients with inoperable biliary tract cancers. METHODS: We conducted a retrospective study of consecutively treated 22 inoperable biliary tract cancer patients with gemcitabine (500-1,000 mg/m(2) on days 1, 8, 15 every 4 weeks) as first-line, and 17 patients as second- or third-line treatment. RESULTS: The response rate of patients treated with gemcitabine as first-line and second- or third-line treatment was 5.3 and 28.5%, respectively. The median overall survival time in the first-, and second- or third-line treatment groups was 8.3 and 17.0 months, and the 1-year survival rate was 44.0 and 50.9%, respectively. The present study also suggests the possibility that the prognosis of patients with high levels of C-reactive protein and total bilirubin, or a low level of albumin might be worse. CONCLUSIONS: Our results indicate that the treatment of inoperable biliary tract cancers with gemcitabine is feasible. There was no difference in the response rate and overall survival between biliary tract cancer patients in the first- and second- or third-line treatment groups. We also present the systematic review of literature of the recent treatment results of biliary tract cancers treated with gemcitabine.

Adult↗

PubMed2006

Efficacy and safety of leptin-replacement therapy and possible mechanisms of leptin actions in patients with generalized lipodystrophy.

BACKGROUND: Lack of leptin is implicated in insulin resistance and other metabolic abnormalities in generalized lipodystrophy; however, the efficacy, safety, and underlying mechanisms of leptin-replacement therapy in patients with generalized lipodystrophy remain unclear. METHODS: Seven Japanese patients with generalized lipodystrophy, two acquired and five congenital type, were treated with the physiological replacement dose of recombinant leptin during an initial 4-month hospitalization followed by outpatient follow-up for up to 36 months. RESULTS: The leptin-replacement therapy with the twice-daily injection dramatically improved fasting glucose (mean +/- SE, 172 +/- 20 to 120 +/- 12 mg/dl, P < 0.05) and triglyceride levels (mean +/- SE, 700 +/- 272 to 260 +/- 98 mg/dl, P < 0.05) within 1 wk. The leptin-replacement therapy reduced insulin resistance evaluated by euglycemic clamp method and augmented insulin secretion at glucose tolerance test with different responses between acquired and congenital types. Improvement of the fatty liver was also observed. The efficacy and safety of the once-daily injection were comparable to those of the twice-daily injection. The leptin-replacement therapy ameliorated macro- and microalbuminuria and showed no deterioration of neuropathy and retinopathy of these patients. The leptin-replacement therapy is beneficial to diabetic complications and lipodystrophic ones. Two patients developed antileptin antibodies but not neutralizing antibodies. The therapy was well tolerated, and its effects were maintained for up to 36 months without any notable adverse effects such as hypoglycemia, high blood pressure, or reduction of bone mineral density. CONCLUSIONS: The present study demonstrates the efficacy and safety of the long-term leptin-replacement therapy and possible mechanisms of leptin actions in patients with generalized lipodystrophy.

Adolescent↗

PubMed2006

Evaluation for surrogacy of end points by using data from observational studies: tumor downstaging for evaluating neoadjuvant chemotherapy in invasive bladder cancer.

PURPOSE: In clinical cancer trials for evaluating neoadjuvant chemotherapy, tumor downstaging is frequently used as a surrogate end point for overall survival. We evaluated the surrogacy of tumor downstaging using data from a follow-up observational study in bladder cancer. EXPERIMENTAL DESIGN: A total of 586 patients (from 32 Japanese hospitals) who underwent radical cystectomy for invasive bladder cancer (clinical T2 to T4) between 1990 and 2000 were analyzed. We considered changes over time in clinical stage at diagnosis and pathologic stage at cystectomy as a surrogate end point, and survival time after cystectomy as a true end point. First, we developed a new criterion for tumor downstaging. Second, we statistically evaluated surrogacy for the criterion using Prentice's criteria. RESULTS: To develop the criterion of end points based on tumor downstaging, we selected the best classification among all possible classifications in an attempt to separate prognosis for patients. The hazard ratios after adjustment for prognostic factors in the intermediate effect patients and the poor effect patients were 1.9 (95% confidence interval, 1.0-3.7) and 5.0 (95% confidence interval, 2.6-9.8), respectively, compared with that in the good effect patients. The conditions for correlation and conditional independency of Prentice's criteria were satisfied approximately. Neoadjuvant chemotherapy has a statistically significant tumor downstaging effect, whereas there was no difference on survival between treatment groups. CONCLUSIONS: The tumor downstaging effect could be an appropriate intermediate end point for screening novel neoadjuvant chemotherapy for invasive bladder cancer. The dataset from follow-up studies were useful for evaluating the surrogacy of end points.

Adult↗

PubMed2006

Classification of human liver transplant recipients by their preoperative CD8+ T cell subpopulation and its relation to outcome.

The primed status of T cells is markedly different among liver transplant recipients, due to a lifetime of antigen exposure and reduced thymopoiesis by aging, and diseases. This study aims to characterize the preoperative immunological status of CD8+ T cell subpopulations and relate it to the outcome for liver transplant recipients. We classified 112 liver transplant recipients into 5 groups, based on hierarchical clustering of the CD8+CD45 isoform proportion of T cells. In Groups I and II (pediatric), the naive T cell proportion was more than 50%. In adult recipients, Group III was characterized by a naive T cell proportion of 50%, Group IV had the greatest effector/memory T cells (EM), and Group V had the greatest proportion of effector T cells. In Groups IV and V, the effector T cell proportion was considerably higher, and was accompanied by marked downregulation of the CD27+CD28+ subsets and upregulation of interferon gamma (IFN)-gamma, tumor necrosis factor-alpha, and perforin expression. Group V recipients tended to be complicated postoperatively, with a significantly reduced survival rate (1 yr, 66.8%) and markedly reduced Eastern Cooperative Oncology Group performance status.

Adolescent↗

PubMed2006

Retrospective analysis of 45 consecutive patients with advanced gastric cancer treated with neoadjuvant chemotherapy using an S-1/CDDP combination.

BACKGROUND: Standard treatment for highly advanced gastric cancer (AGC) has not been established yet. Neoadjuvant chemotherapy (NAC) represents a promising approach, which may improve the prognosis of AGC. In this study, we analyzed the feasibility and efficacy of NAC with S-1 (TS-1)/cisplatin CDDP in order to design appropriate clinical trials for AGC. METHODS: Results for a series of 45 consecutive patients with AGC treated with S-1/CDDP induction chemotherapy since January 2002 were analyzed retrospectively. RESULTS: The primary tumor was resected in 36 of the 45 patients (resectability, 80.0%). Progression of the disease during chemotherapy was observed in 1 patient only (2.2%). No treatment-related deaths occurred, and serious adverse effects (grade 3-4) were noted in only 2.2% of the patients. The overall median survival time was 1.82 years. Especially noteworthy is that, in patients with highly advanced disease (pretreatment [c]-stage IV; n = 27), resectability was 66.7% and curative (R0) resection was possible in 10 patients. The median survival times for c-stage IV patients who had total, curative, and noncurative resections were 20.8, 22.3 and 12.6 months, respectively. R0 resection was possible for all c-stage III patients (n = 17), with a 2-year overall survival of 90.9%. The downstaging rate was 55.6% (20/36), resulting in a significantly improved prognosis for the downstaged patients (P = 0.012). CONCLUSION: Induction chemotherapy using S-1/CDDP for AGC appears to be a safe and promising treatment. We have therefore started two independent multiinstitutional clinical trials to evaluate the efficacy of this treatment.

Aged↗

PubMed2005

The current status of perioperative chemotherapy for invasive bladder cancer: a multiinstitutional retrospective study in Japan.

BACKGROUND: We conducted a multiinstitutional analysis to clarify the clinical significance of perioperative chemotherapy, in invasive bladder cancers in Japan, and to identify the patient subpopulations who could benefit from perioperative chemotherapy. METHODS: A total of 913 consecutive patients aged less than 80 years who underwent radical cystectomy for invasive bladder cancer from 1990 to 2000 at 32 Japanese hospitals were retrospectively analyzed. Median follow-up was 3.8 years (range, 0.1 to 11.8 years). RESULTS: In total, 341 patients (37.3%) were treated with perioperative chemotherapy, including neoadjuvant chemotherapy (n = 174), adjuvant chemotherapy (n = 114), or a combination of both chemotherapies (n = 53). With cisplatin-based combination chemotherapy, the MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) regimen was the one most frequently used for perioperative chemotherapy, but the average number of cycles was distinctly less than that in reported randomized trials. MEC (methotrexate, epirubicin, and cisplatin) chemotherapy had efficacy similar to that of the MVAC regimen. On analysis of patients stratified by stage, the overall survival of patients with adjuvant chemotherapy was significantly better than that of those without adjuvant chemotherapy, in patients with pT2b, pN0 or pT3, pN0 (P = 0.016 or 0.020, respectively), but adjuvant chemotherapy had no, or the opposite, effect on patients with pT2a, pN0, pT4, pN0, or pTany, pN+. On the other hand, neoadjuvant chemotherapy provided a statistically significant survival benefit only for patients with clinical T3N0 (P = 0.015). Of note, in the high-risk subgroup, the overall survival rate for patients with complete response (CR) after neoadjuvant chemotherapy was significantly better than that of patients with partial response (PR) or no change (NC)/progressive disease (PD) (P = 0.043). CONCLUSION: In Japan, cisplatin-based combination chemotherapy has been the main modality adopted perioperatively for high-risk patients with radical cystectomy. This study's clinical results indicated that perioperative chemotherapy may improve survival in patients with T3N0 or pT2b/pT3, pN0 bladder cancer.

Adult↗

PubMed2005

Prognostic factor analysis for plaque psoriasis.

BACKGROUND: Little is known about the long-term prognostic factors which affect clinical outcomes after the diagnosis of psoriasis. OBJECTIVE: To identify the prognostic factors which predict long-term outcomes after diagnosis. METHODS: Patients' clinical characteristics at diagnosis were associated with long-term prognosis using the logistic regression method for 169 psoriasis patients (median follow-up time 11.6 years). RESULTS: The factors age > or =40 [odds ratio 0.27, 95% confidence interval (CI) 0.10-0.72, p = 0.0091], male (odds ratio 2.67, 95% CI 1.02-7.00,p = 0.0459) and BMI > or =25 (odds ratio 2.74, 95% CI 1.01-7.42, p = 0.0480) had significant effects on long-term prognosis after diagnosis. A simple prognostic index based on these factors was proposed. CONCLUSIONS: Three major prognostic factors were identified. The proposed index may be useful in the design of future clinical trials for psoriasis and in the selection of appropriate therapeutic approaches for individual patients.

Adolescent↗

PubMed2004

Creutzfeldt-Jakob disease and cadaveric dura mater grafts in Japan: an updated analysis of incubation time.

The incubation time for 76 patients with cadaveric dura mater-transmitted Creutzfeldt-Jakob disease reported in Japan by November 2001 was analyzed to clarify its distributional feature and the risk factors which affect the earlier onset of the disease. Cluster analysis indicated that cases could be divided into 3 clusters with respect to the incubation time, i.e., short (1.4-6.2 years), medium (7.0-11.9 years) and long (12.9-17.6 years). The incubation time in females was significantly shorter than those in males. Patients who were transplanted dura mater for facial spasms had a significantly shorter incubation time than those who received transplantation for other diseases including meningioma, aneurysm, or acoustic schwannoma. These results suggest that some host factors may have an influence on the incubation time of the disease.

Cadaver↗

PubMed2004

Clinical outcome of a large-scale multi-institutional retrospective study for locally advanced bladder cancer: a survey including 1131 patients treated during 1990-2000 in Japan.

OBJECTIVE: We conducted a multi-institutional analysis to establish the contemporary clinical outcome of invasive bladder cancer treated with radical cystectomy in Japan. METHODS: A total of 1131 consecutive patients who underwent radical cystectomy for invasive bladder cancer between January 1990 and December 2000 at 32 hospitals were retrospectively analyzed. RESULTS: Histopathological analysis demonstrated that 1042 patients (92.1%) harbored transitional cell carcinomas (TCCs), whereas 89 patients (7.9%) presented non-TCCs, including squamous cell carcinoma and adenocarcinoma. Pelvic lymphadenectomy was performed in 1013 patients in total, and pathologically confirmed lymph node metastases were found in 162 (16.0%). The overall survival at 5 years was 68.0% and most deaths (79.0%) occurred within 3 years. Multivariate analysis demonstrated that gender, clinical stage, pathological stage, lymph node involvement and lymph node dissection were the independent predictive factors for survival, whereas histological type, sex and grade had no significant impact on survival. CONCLUSIONS: These clinical results demonstrate that radical cystectomy with lymph node dissection results in good survival for invasive bladder cancer, providing standard data with which other forms of therapy can be compared.

Adult↗

PubMed2004

Structural basis for the specificity, catalysis, and regulation of human uridine-cytidine kinase.

Uridine-cytidine kinase (UCK) catalyzes the phosphorylation of uridine and cytidine and activates pharmacological ribonucleoside analogs. Here we present the crystal structures of human UCK alone and in complexes with a substrate, cytidine, a feedback inhibitor, CTP or UTP, and with phosphorylation products, CMP and ADP, respectively. Free UCK takes an alpha/beta mononucleotide binding fold and exists as a homotetramer with 222 symmetry. Upon inhibitor binding, one loop region was loosened, causing the UCK tetramer to be distorted. Upon cytidine binding, a large induced fit was observed at the uridine/cytidine binding site, which endows UCK with a strict specificity for pyrimidine ribonucleosides. The first UCK structure provided the structural basis for the specificity, catalysis, and regulation of human uridine-cytidine kinase, which give clues for the design of novel antitumor and antiviral ribonucleoside analogs that inhibit RNA synthesis.

Adenosine Triphosphate↗

PubMed2004

Pharmacokinetics, safety, and endocrine and appetite effects of ghrelin administration in young healthy subjects.

OBJECTIVE: It has been demonstrated that ghrelin plays a major role in the regulation of GH secretion and food intake. These actions make ghrelin a strong candidate for the treatment of GH deficiency, anorexia and cachexia. However, only preliminary studies have been performed to assess ghrelin administration in humans. In this study, we have conducted a double-blind, randomized, placebo-controlled trial to investigate the pharmacokinetics, safety, and endocrine and appetite effects of ghrelin in young healthy volunteers. DESIGN: Eighteen male volunteers were randomly assigned into three groups of six subjects: low- and high-dose ghrelin groups, who received intravenous injections of 1 and 5 microg/kg ghrelin (acylated form) respectively, and a placebo group who were injected with mannitol instead of ghrelin. RESULTS: Acylated ghrelin disappeared more rapidly from plasma than total ghrelin, with elimination half life (t(1/2)) of 9-13 and 27-31 min respectively. The number of subjects that experienced adverse effects did not significantly differ among the three groups, and all adverse effects were transient and well tolerated. Both the low and high doses of ghrelin strongly stimulated GH release (peak plasma concentration (C(max,0-90 min)): 124.2+/-63.9 and 153.2+/-52.2 ng/ml for 1 and 5 microg/kg ghrelin respectively). Slight alterations of blood glucose and insulin levels after the injection were observed. Although not statistically significant, ghrelin administration tended to increase hunger sensation in a dose-dependent manner. CONCLUSIONS: These results suggest that ghrelin is safe, and that clinical trials may be started to assess the usefulness of ghrelin for the treatment of disorders related to GH secretion and appetite.

Adult↗

PubMed2003

Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial of cardiovascular events in high-risk hypertensive patients: rationale, design, and methods.

Hypertension continues to be a major public health issue in the world. To combat this problem, many anti-hypertensive drugs have been developed and proven effective at controlling blood pressure in the last half century. In recent decades, antihypertensive drugs have been shown to have cardiovascular benefits beyond the reduction of blood pressure, and the focus has shifted to clarification of these effects. Angiotensin II receptor antagonists and calcium channel blockers are the most widely used antihypertensive drugs in Japan. However, these two classes of drugs have not yet been compared with respect to their efficacy for treating cardiovascular events. The Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial described herein is a prospective, multicenter, randomized, open-label, active-controlled, 2-arm parallel group comparison with a response-dependent dose titration and blinded assessment of endpoints in high-risk hypertensive patients treated with either an angiotensin II receptor antagonist (candesartan cilexetil) or a third-generation calcium channel blocker (amlodipine besilate). The eligibility criteria in this study were 1) age between 20 and 85 years; 2) systolic blood pressure (SBP) > or = 140 mmHg in those below 70 years of age or > or = 160 mmHg in those above 70 years of age or diastolic blood pressure (DBP) > or = 90 mmHg on two consecutive measurements at clinic; and 3) at least one of the following high risk factors for cardiovascular events: a) SBP > or = 2180 mmHg or DBP > or = 110 mmHg on two consecutive visits, b) type 2 diabetes mellitus (fasting blood glucose > or = 126 mg/dl, casual blood glucose > or = 200 mg/dl, HbA1c > or = 6.5%, 2 h blood glucose on 75 g oral glucose tolerance test (OGTT) > or = 200 mg/dl, or current treatment with hypoglycemic therapy), c) history of cerebral hemorrhage, cerebral infarction, or transient ischemic attack until 6 months prior to the screening, d) left ventricular hypertrophy on either echocardiography or ECG, angina pectoris, or history of myocardial infarction until 6 months prior to screening, e) proteinuria or serum creatinine > or = 1.3 mg/dl, and f) symptoms of arteriosclerotic artery obstruction. The therapeutic goals of blood pressure control were set as follows: SBP < 130 mmHg and DBP < 85 mmHg for patients below 60 years of age, SBP < 140 mmHg and DBP < 90 mmHg for those in their 60s, SBP < 150 mmHg and DBP < 90 mmHg for those in their 70s, and SBP < 160 mmHg and DBP < 90 mmHg for those in their 80s. A total of 3,200 patients, equally allocated to each of the two treatment arms, were required based on a two-sided alpha level 0.05 and 90% power. The CASE-J is also the first study to employ the newly developed Automatic Bar Code Data-Capturing/Allocation, Booking & Trial Coding, Data Management (ABCD) system for data collection and management. Enrollment of patients started in September 2001 and ended in December 2002. Follow-up data will be collected every 6 months until December 2005. The CASE-J trial will provide important evidence on the comparative effectiveness of candesartan cilexetil and amlodipine besilate on cardiovascular morbidity and mortality among Japanese. In addition, the use of the ABCD system is expected to contribute to the development of more efficient data management systems for large-scale clinical trials.

Antihypertensive Agents↗

PubMed1981

Increase of beta-endorphin in cerebrospinal fluid after removal of ACTH-secreting pituitary adenoma.

beta-Endorphin and methionine(met)-enkephalin in cerebrospinal fluid (CSF) were measured before and after removal of an adrenocorticotropic hormone-(ACTH)-secreting adenoma in Cushing's disease by a sensitive radioimmunoassay and a radio-receptor assay, respectively. After tumor resection, the level of ACTH in plasma markedly decreased from 82.6 +/- 22.7 pg/ml to 16.7 +/- 4.1 pg/ml (mean +/- S.E., n = 4). It was found that the level of beta-endorphin in CSF significantly increases from 32.0 +/- 4.5 pg/ml to 61.8 +/- 10.7 pg/ml (P less than 0.05) after tumor resection, while the level of metenkephalin in CSF remained unaltered. This result suggests that hypophysectomy induces an increase of beta-endorphin in CSF.

Adenoma↗

PubMed1980

Radioreceptor assay of methionine-enkephalin-like substance in human cerebrospinal fluid.

A sensitive and simple radioreceptor assay system for measuring methionine(met)-enkephalin-like substance in human cerebrospinal fluid (CSF) was developed using a particulate fraction of rat brain as a receptor preparation and [3H]dihydromorphine as a radiolabeled ligand in the presence of 1 mM ethylenediamine tetracetate (EDTA) and 2 mM magnesium acetate. Metenkephalin-like substance was purified from CSF by the combination of Sephadex G-10 and SP-Sephadex (H+) column chromatographies to be free of sodium and large molecular weight substance such as beta-endorphin. The assays were carried out on samples obtained from normal subjects and patients with the disease of the brain or pituitary by lumbar or ventricular puncture. Mean level in samples obtained from normal subjects by lumbar puncture was 2.6 +/- 1.0 pmoles/ml.

Animals↗

PubMedDate not supplied

Projection of creutzfeldt-jakob disease frequency based on cadaveric dura transplantation in Japan.

BACKGROUND: Projections of the size of the Creutzfeldt-Jakob disease (CJD) epidemic are of great importance for future health care and understanding of the natural history of this disease. OBJECTIVE: We have estimated the incubation period and have projected the number of patients with iatrogenic CJD in Japan, using 75 patients who were transplanted with cadaveric dura mater grafts between 1979 and 1991 and developed CJD by the end of 2000. METHODS: Several plausible scenarios, combinations of incubation period distribution forms, competing risks and exposure distributions were evaluated for the projections using data from the Japanese Ministry of Health, Labor and Welfare. RESULTS: The range of median incubation periods from the time of dura mater transplantation to the onset of the disease was 10.8-34.3 years, and the range of the number of new CJD patients between 2001 and 2020 was 21-84. CONCLUSIONS: Since the potential incubation period was estimated to be considerably long, as few as 21 and as many as 84 new patients may develop CJD by 2020.

Adult↗