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Biomedical subjects

Masato Nakamura

Publications and source records attributed to Masato Nakamura.

At least 37 records · Page 2Linked to original sources
PubMed2006

Angiogenesis in cholangiocellular carcinoma: expression of vascular endothelial growth factor, angiopoietin-1/2, thrombospondin-1 and clinicopathological significance.

Angiogenesis in cholangiocellular carcinoma (CCC) has rarely been investigated. The aim of this study was to determine the angiogenesis status of CCC and assess its relationship with angiogenic factors and clinicopathological characteristics. We examined 33 surgically resected CCC specimens. Tumor angiogenesis was assessed by microvessel density (MVD) using the anti-CD34 antibody, and the expression of VEGF, Ang-1, Ang-2, and TSP-1 was determined by immunohistochemistry. The mean (+/- SD) MVD was 87.2+/-52.6/mm2 (range, 0-229/mm2). A total of 75.6% cases were positive for VEGF expression, 36% for Ang-1, 57.6% for Ang-2 and 45.5% for TSP-1. VEGF and Ang-2 expression was associated with a significantly higher level of MVD (p=0.004 and 0.015, respectively). TSP-1 expression was associated with a significantly lower level of MVD (p=0.005) and a higher level of intrahepatic metastasis (46.7% vs. 5.6%, p=0.012). There was no significant correlation between VEGF, Ang-1, Ang-2, and TSP-1 expression and tumor size, capsule formation, infiltration of capsule, portal vein invasion, intrahepatic metastasis or CCC differentiation. There was no significant correlation between MVD levels, VEGF, Ang-1, Ang-2, and TSP-1 expression and postoperative survival. A considerable degree of angiogenesis, comparable to that of other solid tumors, was observed in CCC. VEGF and Ang-2 might play a proangiogenic role, and TSP-1 may play an inhibitory role in CCC. Although TSP-1 may increase intrahepatic CCC metastases, neither MVD levels nor the expression of VEGF, Ang-1, or Ang-2 was associated with clinicopathological factors and prognosis.

Adult↗
PubMed2006

A novel method for deploying a stent into a highly angulated position through use of a stent strut: application of a five-in-seven system.

Provisional stenting of the side branch seems to be an attractive strategy even in the DES era. One of the technical problems in provisional side branch stenting is how to deliver the stent through a stent strut. In this case presentation, we suggest a novel method for deploying a stent through the use of a 5 Fr guiding catheter. A 5 Fr guiding catheter within a 7 Fr guiding catheter was advanced to the lesion, through a stent strut, facilitating the deployment of the stent. This system permits negotiation of the stent strut that otherwise obstructs stent passage.

Aged↗
PubMed2006

Poor outcome of patients with pulmonary adenocarcinoma showing decreased E-cadherin combined with increased S100A4 expression.

A loss or reduced expression of E-cadherin, the main cell-to-cell adhesion molecule, correlates with distant metastasis in various cancers. Recent studies have reported a close correlation between the expression of E-cadherin and that of S100A4, calcium-binding protein. In this study, we investigated the expression of E-cadherin and S100A4 status in relation to the clinicopathological parameters of pulmonary adenocarcinoma. We finely and quantitatively examined the expression of E-cadherin and S100A4 using real-time polymerase chain reaction (PCR) in a total of 92 pulmonary adenocarcinomas obtained by surgical resection. All of the pulmonary adenocarcinomas showed significant expression of E-cadherin and S100A4. Real-time PCR showed lower E-cadherin expression in 21 adenocarcinomas, while 71 adenocarcinomas expressed a higher expression of E-cadherin. Of 21 adenocarcinomas with lower-expressing E-cadherin, 12 showed a higher expression of S100A4. These 12 cases significantly showed a poorer prognosis than others (p=0.047, Kaplan-Meier, log-rank test) and significantly showed more frequent venous involvement than others (p=0.042, chi2 test). These results suggested that reduced E-cadherin expression combined with higher S100A4 expression is related to a poor prognosis through hematogenous metastasis in pulmonary adenocarcinoma.

Adenocarcinoma↗
PubMed2006

Expression of type I interferon receptor as a predictor of clinical response to interferon-alpha therapy of gastrointestinal cancers.

Interferon (IFN) is used in the treatment of many malignancies and viral disorders. We recently reported a significant correlation between the efficacy of IFN-alpha combined with chemotherapy in the treatment of advanced hepatocellular carcinoma (HCC) and IFN-alpha/type I IFN receptor (IFNAR2) expression. It is possible that the expression of IFNAR2 in gastrointestinal cancerous tissue, apart from HCC, may predict the efficacy of IFN-alpha combination therapy. We investigated the expression of IFNAR2 in 100 gastrointestinal cancerous tissues. IFNAR2 expression was examined using immunohistochemistry, in surgically resected tissue samples (20 esophageal, 20 gastric, 20 colorectal, 20 cholangiocarcinoma, and 20 pancreatic samples). The expression rate of IFNAR2 was 35.0% (7/20), 25.0% (5/20), 20.0% (4/20), 45.0% (9/20), and 25.0% (5/20) in esophageal, gastric cancer, colorectal, cholangiocarcinoma and pancreatic cancer samples, respectively. In our previous report, the expression rate of IFNAR2 in HCC samples was 64.8% (59/91). Thus, the expression rates of IFNAR2 in the five types of gastrointestinal cancers tested here were low, compared with HCC. The clinical efficacy of IFN-alpha mono- or combination therapies in patients with gastrointestinal neoplasms is expected to be lower than in patients with HCC based on the expression level of IFNAR2.

Gastrointestinal Neoplasms↗
PubMed2006

Increased S100A4 expression combined with decreased E-cadherin expression predicts a poor outcome of patients with pancreatic cancer.

The calcium-binding protein, S100A4, with an inverse association of E-cadherin, is known to correlate with prognosis in various cancers. In this study, we investigated the expression of the S100A4 and E-cadherin status in relation to the clinicopathological parameters of pancreatic cancer. The expression status of these two proteins was examined in 72 specimens of primary pancreatic carcinoma with immunohistochemistry. Fifty-six of 72 (78%) surgical specimens of primary pancreatic cancer were positive for S100A4 according to immunohistochemistry. Thirty-one (43%) specimens of pancreatic cancer showed positive expression of E-cadherin. The inverse association of S100A4 and E-cadherin expression was significant in the cancers (p < 0.0001). The S100A4 expression correlated significantly with the pathological T stage and poorer prognosis (p = 0.024). The 41 E-cadherin-negative cases showed poorer prognoses and a higher incidence of liver metastasis (p = 0.0344, p = 0.027). The 10 cases with S100A4-negative/E-cadherin-positive cancers showed a significantly better prognosis than the others (p < 0.05). The histological grade (p = 0.004), nodal status (p < 0.0001) and S100A4-positive status (p = 0.048) were highly significant independent prognostic predictors (p < 0.05). These results suggest that S100A4 overexpression combined with reduced E-cadherin expression play important roles in tumor progression and metastasis in pancreatic cancer. The combined examination of these two molecules is useful in evaluating the outcome of pancreatic cancer patient.

Aged↗
PubMed2006

[S-1 treatment against advanced HCC].

We have reported a remarkably high anti-tumor efficacy using intra arterial 5-FU infusion chemotherapy combined with subcutaneous interferon-alpha injection to treat advanced hepatocellular carcinoma (HCC) with portal vein thrombus. However, we have been confirming distant metastases along with a prognosis extension as hepatic lesions could possibly be controlled to a certain extent. Even though there has been no effective chemotherapy against hepatocellular carcinoma with distant metastases, we performed S-1 and interferon-alpha combination chemotherapy for the cases where good results were exhibited from interferon-alpha combined with arterial 5-FU infusion. As a result, we confirmed CR in the anti-tumor effect against distant metastases with no severe adverse effects. It was suggested that a combination therapy of S-1 and interferon-alpha may be one of the most effective treatment modalities against advanced HCC with distant metastases.

Administration, Oral↗
PubMed2006

Alternating hepatic arterial infusion and systemic chemotherapy for stage IV colorectal cancer with synchronous liver metastasis.

Among 41 patients with synchronous liver metastases of colorectal cancer, 15 patients underwent synchronous resection of their liver metastases and achieved a median survival time (MST) of 1,441 days (versus 748 days for the 26 patients without resection, p=0.038), a median relapse-free survival time of 652 days (MST not reached), and a recurrence rate in the residual liver of 20% (3/15 patients). The alternating hepatic arterial infusion and systemic chemotherapy showed partial response (PR) in 6 cases, stable disease (SD) in 8 cases, and progressive disease (PD) in 1 case (n=15/26). They had an objective response rate of 40% (6/15), tumor control rate (>/= SD) of 93.3% (14/15), one-year progression-free survival rate of 35.7%, 50% time to progression of 270 days, one-year survival rate of 76.2%, and two-year survival rate of 50.8% (MST not reached). Grade 3 leucopenia was observed in 2/15 patients (13.3%). These results suggest that the present alternating therapy may become a standard regimen for patients in whom synchronous resection of liver metastases is impossible and patients who have stage IV colorectal cancer with a risk of recurrence in the remnant liver and/or at extrahepatic sites such as the lungs.

Antineoplastic Agents↗
PubMed2006

[Intra arterial infusion chemotherapy combined with interferon-alpha following palliative hepatic resection against advanced hepatoma with portal venous tumor thrombus in the major trunk and multiple nodules--a preliminary study].

Recently, we reported the beneficial effects of intra arterial 5-FU infusion chemotherapy combined with interferon-alpha (IFN-alpha/5-FU combined chemotherapy) for advanced hepatocellular carcinoma (HCC). This report describes the preliminary results of treatment of IFN-alpha/5-FU combined chemotherapy following palliative hepatic resection for advanced hepatocellular carcinoma with tumor thrombus in the main trunk of the portal vein with multiple nodules in the whole liver. The 15 patients of HCC with portal venous tumour thrombi (PVTT) and multiple intra-hepatic multiple nodules (IM3) were treated with IFN-alpha/5-FU combined chemotherapy following palliative surgery in this study. No leukopenia, thrombocytopenia, or myelosuppression was observed in any of the 15 patients. Other adverse effects were, in general, clinically manageable. Concerning the anti-tumor effect, 6 showed an objective response and 9 showed a progressive disease; the response rate was 40.0% (6/15). The 1-year and 3-year survival rates were 48% and 21% in all 15 cases, respectively. In conclusion, IFN-alpha/5-FU combined therapy may be a promising modality for advanced HCC with tumor thrombi in the major trunk with multiple nodules after following palliative surgery.

Antimetabolites, Antineoplastic↗
PubMed2005

In vitro and in vivo evaluation of the metabolism and bioavailability of ester prodrugs of mgs0039 (3-(3,4-dichlorobenzyloxy)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic Acid), a potent metabotropic glutamate receptor antagonist.

MGS0039 (3-(3,4-dichlorobenzyloxy)-2-amino-6-fluorobicyclo-[3.1.0]hexane-2,6-dicarboxylic acid) has been identified as a potent and selective antagonist for metabotropic glutamate receptors. However, the oral bioavailability of MGS0039 is 10.9% in rats, due to low absorption. Several prodrugs, synthesized to improve absorption, exhibited 40 to 70% bioavailability in rats. This study investigated in vitro metabolism using liver S9 fractions from both cynomolgus monkeys and humans and oral bioavailability in cynomolgus monkeys to select the prodrug most likely to exhibit optimal pharmacokinetic profiles in humans. In monkeys, transformation to active substance was observed (5.9-72.8%) in liver S9 fractions, and n-butyl, n-pentyl, 3-methylbutyl, and 4-methylpentyl ester prodrugs exhibited high transformation ratios (>64%). Cmax levels and F values after oral dosing increased to 4.1- to 6.3-fold and 2.4- to 6.3-fold, respectively, and a close relationship between transformation ratios and Cmax and F values was observed, indicating that the hydrolysis rate in liver S9 fractions is the key factor in determining oral bioavailability in monkeys. In humans, n-hexyl, n-heptyl, n-octyl, 5-methylbutyl, and 6-methylpentyl ester prodrugs exhibited high transformation ratios (>65%) in liver S9 fractions. With these prodrugs, n-hexyl, n-heptyl, and 5-methylpentyl ester, almost complete recovery (96-99%) was obtained. Given the transformation ratio, we anticipated that the n-heptyl alkyl ester prodrug would exhibit the highest oral bioavailability of active substances in humans, if the hydrolysis rate in liver S9 fractions is indeed the key factor in determining oral bioavailability in humans. On this basis, MGS0210 (3-(3,4-dichlorobenzyloxy)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid n-heptyl ester) seems to be a promising candidate among MGS0039 prodrugs.

Animals↗
PubMed2005

Comparison of coronary arterial finding by intravascular ultrasound in patients with "transient no-reflow" versus "reflow" during percutaneous coronary intervention in acute coronary syndrome.

Previous studies have shown that transient no-reflow during coronary intervention but with Thrombosis in Myocardial Infarction (TIMI) grade 3 flow at the completion of the procedure is associated with increased in-hospital and 6-month mortality. We hypothesized that the use of intravascular ultrasound before intervention could identify morphologic features that were predictive of transient no-reflow in patients who had acute coronary syndrome (ACS). We analyzed 220 patients with ACS who had suitable intravascular ultrasound images that were acquired before intervention. We defined "transient no-reflow" as TIMI grade 0, 1, or 2 flow during the procedure and TIMI grade 3 flow at the completion of the procedure. We defined "reflow" as good coronary flow (TIMI grade 3 flow) during and after the procedure. Patients were categorized to a transient no-reflow group (n = 20) or a reflow group (n = 200). In the transient no-reflow group, vessel area and amount of plaque burden in the culprit lesion were significantly greater than in the reflow group (vessel 20.8 +/- 5.4 vs 16.4 +/- 6.2 mm(2), p < 0.01; plaque burden 0.90 +/- 0.03 vs 0.83 +/- 0.08, p < 0.001). The presence of ruptured plaque, lipid pool-like images, and thrombus formation were significantly higher in the transient no-reflow group than in the reflow group. Multivariate analysis identified the presence of thrombus formation (odds ratio 4.53, 95% confidence interval 1.03 to 20.0, p = 0.04) and larger plaque burden (odds ratio 1.79, 95% confidence interval 1.01 to 3.23, p = 0.05) as independent predictors of transient no-reflow. In conclusion, lesion morphologies are different for transient no-reflow and reflow. These findings suggest that the presence of thrombus formation and large plaque burden increase the risk for developing transient no-reflow during coronary intervention for ACS.

Aged↗
PubMed2005

Patent foramen ovale: current pathology, pathophysiology, and clinical status.

Patent foramen ovale (PFO) is experiencing increased clinical interest as a congenital cardiac lesion persisting into adulthood. It is implicated in several serious clinical syndromes, including stroke, myocardial infarction, and systemic embolism. The PFO is now amenable to percutaneous interventional therapies, and multiple novel technologies are either available or under development for lesion closure. The PFO should be better understood to take advantage of emerging percutaneous treatment options. This paper reviews PFO anatomy, pathology, pathophysiology, and clinical impact and discusses current therapeutic options.

Heart Septal Defects, Atrial↗
PubMed2005

Metabolism and disposition of a potent group II metabotropic glutamate receptor agonist, in rats, dogs, and monkeys.

Metabolism and disposition of MGS0028 [(1R,2S,5S,6S)-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid monohydrate], a potent group II metabotropic glutamate receptor agonist, were examined in three preclinical species (Sprague-Dawley rats, beagle dogs, and rhesus monkeys). In rats, MGS0028 was widely distributed and primarily excreted in urine as parent and as a single reductive metabolite, identified as the 4R-isomer MGS0034 [(1R,2S,4R,5S,6S)-2-amino-6-fluoro-4-hydroxybicyclo[3.1.0]-hexane-2,6-dicarboxylic acid]. MGS0028 had a low brain to plasma ratio at efficacious doses in rats and was eliminated more slowly in rat brain than in plasma. Exposure increased proportionally (1--10 mg/kg p.o.) in rats, with bioavailability>60% at all doses. However, bioavailability was only approximately 20% in monkeys, and MGS0034 was found in relatively high abundance in plasma. In dogs, oral bioavailability was >60%, and the metabolite was not detected. In vitro metabolism was examined in liver subcellular fractions (microsomes and cytosol) from rat, dog, monkey, and human. Reductive metabolism was observed in rat, monkey, and human liver cytosol incubations, but not in dog liver cytosol incubations. No metabolism of MGS0028 was detected in incubations with liver microsomes from any species. Similar to in vivo results, MGS0028 was reduced in cytosol stereospecifically to MGS0034. The rank order of in vitro metabolite formation (monkey >> rat approximately human >> dog) was in agreement with in vivo observations in rats, dogs, and monkeys. Based on the observation of species difference in reductive metabolism, rat and monkey were recommended to be the preclinical species for further characterization prior to testing in humans. Finally, allometric scaling predicts that human pharmacokinetic parameters would be acceptable for further development.

Animals↗
PubMed2005

Fate of unprotected side branches as related to embolic complications during stent implantation for acute coronary syndromes using a distal protection procedure.

Coronary lesion stenting with aspiration and distal balloon occlusion is more often associated with embolic occlusion of interposed side branches when the branch arises at an angle of </=45 degrees and the artery containing the lesion is large. However, this event is infrequent, often resolving during the procedure and uniformly resolving by 6 months.

Aged↗
PubMed2005

Combination of IFN-alpha and 5-fluorouracil induces apoptosis through IFN-alpha/beta receptor in human hepatocellular carcinoma cells.

PURPOSE: Several studies showed the effectiveness of combination therapy with IFN-alpha and 5-fluorouracil (5-FU) for advanced hepatocellular carcinoma. However, only little is known about the underlying mechanism of combination therapy. In the present study, we examined whether apoptosis through IFN-alpha/beta receptor (IFN-alpha/betaR) was associated with the effects of combination therapy. EXPERIMENTAL DESIGN: HuH7, PLC/PRF/5, HLE, and HLF were treated with IFN- (500 units/mL), 5-FU (0.5 microg/mL), or their combination for 10 days. In addition, IFN-alpha/betaR gene transfer with combination therapy was done. RESULTS: Ten-day treatment by combination therapy resulted in >80% cell growth inhibition. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling analysis showed synergistic effects for combination therapy on PLC/PRF/5, HLE, and HLF. Concordant results were obtained with DNA fragmentation. Moreover, there was an evidence showing that changes in the expression of Bcl-2 family lead to apoptosis. On the other hand, the expression of IFN-alpha/betaR and up-regulation of alpha-phospho-signal transducer and activator of transcription 1, IFN regulatory factor-1 by combination therapy were observed in all cell lines. Furthermore, IFN-alpha/type 2 IFN receptor long form-transfected HuH7 cells treated with combination therapy showed strong DNA fragmentation compared with nontransfected or transfected with IFN-alpha- and 5-FU-treated HuH7. CONCLUSIONS: Our results showed that combination of IFN-alpha plus 5-FU strongly induced cell growth inhibition of human hepatocellular carcinoma cells and indicated that one of the direct mechanisms of combination therapy may in part be attributable to alterations in induction of apoptosis through IFN-alpha/betaR.

Apoptosis↗
PubMed2005

Hippocampal complexin proteins and cognitive dysfunction in schizophrenia.

BACKGROUND: Converging neuroimaging and postmortem evidence indicates synaptic terminals are abnormal in schizophrenia. A putative molecular mechanism implicates abnormalities of proteins involved in the presynaptic secretory machinery, including the modulator proteins complexin I and complexin II. OBJECTIVES: To determine the amount and distribution of complexin proteins in the hippocampus of subjects with schizophrenia, in parallel with markers for excitatory and inhibitory nerve terminals. The functional implications were also investigated. DESIGN: We used immunocytochemistry to study complexin I and complexin II proteins in hippocampus, as well as the vesicular transporters for gamma-aminobutyric acid (GABA) and for glutamate. Immunocytochemical findings were correlated with cognitive function assessed through medical record review. To further explore the implications of the human findings, we studied rats exposed to haloperidol, amphetamine, and ketamine as well as rats trained in memory tasks. SUBJECTS: We studied hippocampal sections from 12 subjects with schizophrenia and 12 subjects with no known neuropsychiatric disorder. RESULTS: The absolute values and ratio of the hippocampal presynaptic proteins complexin II-complexin I were lower in subjects with schizophrenia. Disturbances in the complexin proteins in subjects with schizophrenia were greater than those observed for vesicular gamma-aminobutyric acid or vesicular glutamate transporters. The lower complexin II-complexin I ratio in several hippocampal subfields in subjects with schizophrenia was inversely correlated with the severity of antemortem cognitive impairment. In contrast, the hippocampal complexin II-complexin I ratio was higher in rats trained in a memory task compared with untrained rats. Treatment of rats with antipsychotic drugs or with the psychotomimetic drugs amphetamine or ketamine did not alter the complexin II-complexin I ratio. CONCLUSIONS: The pathology of hippocampal complexin proteins might play an important role in schizophrenia, especially concerning cognitive disturbances.

Adaptor Proteins, Vesicular Transport↗
PubMed2005

Coronary artery fistula with an associated aneurysm detected by 16-slice multidetector row computed tomographic angiography.

We describe a case of a 60-year-old man with effort-induced angina pectoris. Coronary angiography showed an aneurysm in the proximal left anterior descending coronary artery. It was unclear whether it was a coronary artery aneurysm or a coronary fistula with an associated aneurysm. Three-dimensional reconstruction images from 16-slice multidetector row computed tomographic (MDCT) angiography showed an aneurysm that drained into the pulmonary artery. Images from 16-slice MDCT coronary angiography can be helpful in understanding complex coronary artery anatomy.

Coronary Aneurysm↗
PubMed2005

Association between recurrence of hepatocellular carcinoma and alpha-fetoprotein messenger RNA levels in peripheral blood.

PURPOSE: Intra- and extrahepatic recurrence is common, even after curative resection for hepatocellular carcinoma (HCC), suggesting preoperative or intraoperative tumor cell dissemination. Reverse transcription - polymerase chain reaction (RT-PCR) for alpha-fetoprotein (AFP) is used to detect circulating liver cancer cells. We previously developed a quantitative method that allows estimation of the AFP mRNA level by real-time PCR. In the present study, we used this method to measure the AFP mRNA level before and after resection of HCC, then correlated the findings with various clinicopathological characteristics and prognosis. METHODS: We prospectively examined peripheral blood samples from 38 patients with HCC, and bone marrow aspirate from 25 of these patients. As a control, we examined bone marrow from 20 patients with benign diseases. The follow-up period ranged from 32 to 66 months. Real-time RT-PCR was used to detect AFP mRNA levels in the samples. RESULTS: AFP was expressed in 9 (23.7%) of the 38 peripheral blood samples. The detection of AFP mRNA was significantly correlated with extrahepatic metastasis after primary surgery, and a shorter disease-free survival time (P = 0.0245 each). Bone marrow samples were defined as positive if they expressed AFP mRNA at levels higher than the maximum expressed level in the controls, because only 1 (5%) of the 20 control bone marrow samples had low AFP mRNA expression. Using this cutoff level, 12 (48%) of the 25 patients with HCC had positivity for AFP mRNA. The results of bone marrow RT-PCR did not correlate with the clinocopathological characteristics of prognosis. CONCLUSIONS: Using real-time PCR to measure the AFP mRNA level in blood, but not bone marrow, could be useful for predicting postoperative tumor recurrence.

Adult↗