Biomedical subjects

M Tsukuda

Publications and source records attributed to M Tsukuda.

At least 55 records · Page 3Linked to original sources

PubMed1999

[Late phase II clinical study of RP56976 (docetaxel) in patients with advanced/recurrent head and neck cancer].

A late phase II clinical study of RP56976 (docetaxel), a new anticancer agent for advanced/recurrent head and neck cancer, was conducted in 29 institutions all over Japan as a multi-institutional cooperative study. Docetaxel was administered by 1 to 2-hour intravenous infusion at a dose of 60 mg/m2 every 3 to 4 weeks. Of 63 patients eligible in this study, 59 were judged as complete cases. Complete response (CR) was observed in 1 patient, partial response (PR) in 13, no change (NC) in 25, and progressive disease (PD) in 20, for an overall response rate of 22.2% (14/63, 95% CI: 12.7-34.5%) in eligible cases, and 23.7% (14/59, 95% CI: 13.6-36.6%) in complete cases. Previously treated patients showed a 17.9% (10/56) response rate, whereas treatment--naive patients showed a 57.1% (4/7) response rate. Among 46 patients who received prior chemotherapy, one CR and 7 PR were observed with a 17.4% response rate. Major hematological toxicities were leucopenia in 95.1% (> or = grade 3, 59.7%) and neutropenia in 90.3% (> or = grade 3, 79.0%). Other severe toxicities (> or = grade 3) included anorexia in 9.7% (6 cases), diarrhea in 3.2% (2 cases), dyspnea in 3.2% (2 cases), and fatigue in 3.2% (2 cases). One patient had a grade 3 interstitial pneumonia; however, symptoms were resolved by the administration of corticosteroids. During this study, one patient died due to multiple organ failure (MOF) caused by disseminated intravascular coagulation (DIC), and this case was reported as a therapy-related death. Based on these results, docetaxel is an active agent for treatment of head and neck cancer.

Adenocarcinoma↗

PubMed1998

IL-12 promotes the adhesion of NK cells to endothelial selectins under flow conditions.

This study examined the adhesive interactions of peripheral blood NK cells with P- and E-selectin and analyzed the effect of IL-12 on the binding of NK cells to these selectins. P-selectin glycoprotein ligand-1 (PSGL-1) is expressed on most resting and IL-12-activated NK cells. However, the percentage of resting NK cells bound to P-selectin-IgG was 15%, and that of activated NK cells bound to P-selectin-IgG was 65%. Furthermore, the number of IL-12-activated NK cells bound to P-selectin-transfected Chinese hamster ovary cells was significantly higher than that of resting NK cells under flow conditions. These interactions were abolished by the incubation of these NK cells with anti-PSGL-1 (PL-1) mAb. Thus, PSGL-1/P-selectin interaction is important in the binding of resting and activated NK cells to P-selectin. NK cells express sialyl-Lewis(x) (sLe(x)) structure recognized by anti-sLe(x) mAb (KM-93), and IL-12 activation of NK cells increased the mean fluorescence intensity of KM-93-reactive NK cells. Adhesion of IL-12-activated NK cells to E-selectin-transfected Chinese hamster ovary cells was stronger than that of resting NK cells under flow conditions. These interactions were reduced markedly by incubation with anti-sLe(x) mAb. Thus, sLe(x) is the major ligand of resting and activated NK cells for E-selectin. These findings indicate that IL-12 stimulation of NK cells promotes their adhesion activity to endothelial selectins.

Animals↗

PubMed1998

Substance P- and calcitonin gene-related peptide-containing nerve fibers in the nasal mucosa of chronically hypoxic rats.

The distribution of substance P-immunoreactive and calcitonin gene-related peptide-immunoreactive nerve fibers in the nasal mucosa was compared between normoxic and chronically hypoxic rats (10% O2 and 3.0-4.0% CO2 for 3 months). In the normoxic nasal mucosa, substance P- and calcitonin gene-related peptide-immunoreactive nerve fibers were found within and under the epithelium and around the glands and blood vessels in the lamina propria. These immunoreactive fibers have many varicosities. In the chronically hypoxic nasal mucosa, the relative density of intra- and subepithelial substance P-immunoreactive and calcitonin gene-related peptide-immunoreactive fibers and those in the lamina propria was higher than in normoxic mucosa. The length of substance P-positive fibers within the chronically hypoxic olfactory and respiratory epithelium was 1.66 and 2.45 times higher than within the normoxic epithelium, respectively. The length of calcitonin gene-related peptide-immunostained fibers within the chronically hypoxic olfactory and respiratory epithelium was 1.56 and 1.84 times higher, respectively. Because substance P and calcitonin gene-related peptide are the predominant signal peptides of primary sensory neurons, the increased number of these fibers may represent enhanced sensory mechanisms in the hypoxic nasal mucosa. In addition, considered together with the findings in chronically hypoxic tracheal mucosa, the increased density of intraepithelial fibers containing substance P and calcitonin gene-related peptide suggests that this is a predominant feature of hypoxic adaptation throughout the upper and lower respiratory tracts.

Animals↗

PubMed1998

Cyclin D1 expression as a prognostic factor in advanced hypopharyngeal carcinoma.

Hypopharyngeal carcinoma (HPC) has a poor prognosis. We investigated the expression of cyclin D1 in 34 advanced HPCs, and the value of cyclin D1 expression was evaluated as a predictive marker in terms of the prognosis of HPC, compared with other clinical factors. Using immunohistochemical staining, 20 of 34 patients showed positive immunoreactivity for cyclin D1. The statistical trend of the survival rate was lower in the cyclin D1-positive patients than in the cyclin D-negative ones (p = 0.0805). The predictive factors for the survival rate were effectiveness of neo-adjuvant chemotherapy (F = 8.698) (p = 0.0066), cyclin D1 expression (F = 6.244) (p = 0.0191) and N classification (F = 5.037) (p = 0.0335). The cyclin D1-positive patients had approximately four-fold higher mortality than the cyclin D1-negative ones. These data indicate that the expression of cyclin D1, in advanced patients with hypopharyngeal carcinoma is a useful marker for prognosis.

Adult↗

PubMed1998

Effectiveness of weekly subcutaneous recombinant human erythropoietin administration for chemotherapy-induced anemia.

The effects of weekly subcutaneous recombinant human erythropoietin (r-hEPO) administration on anemia during chemotherapy including cisplatin and 5-fluorouracil in patients with head and neck carcinomas were examined. Weekly subcutaneous r-hEPO administration in cancer patients has not been investigated previously. Patients were treated with r-hEPO 100 IU/kg (2 patients), 200 IU/kg (6 patients), or 400 IU/kg (5 patients), or placebo, and effectiveness was evaluated by monitoring hemoglobin concentration changes after administration for 8 weeks. Hemoglobin concentrations in all 3 r-hEPO dosage groups were higher than that in the control group during chemotherapy. All r-hEPO doses produced improvements in the anemia induced by chemotherapy; however, the 400 IU/kg dose was most effective. The requirement for blood transfusions decreased in patients receiving r-hEPO therapy, and no significant side-effects were associated with r-hEPO administration. These results suggest that chemotherapy-induced anemia can be prevented by weekly subcutaneous r-hEPO administration.

Aged↗

PubMed1998

Immunohistochemical localisation of regulatory neuropeptides in human circumvallate papillae.

The occurrence and distribution of neuropeptide-containing nerve fibres in the human circumvallate papillae were examined by the peroxidase-antiperoxidase immunolocalisation method using surgical specimens that had not been subjected to radiotherapy, and the abundance of neuropeptide-containing fibres was expressed as the percentage of total nerve fibres demonstrated by protein gene product (PGP) 9.5 immunoreactivity for a quantitative representation of these peptidergic fibres. Substance P (SP) and calcitonin gene-related peptide (CGRP) immunoreactive (IR) nerve fibres were densely distributed in the connective tissue core of the circumvallate papillae, and some SP and CGRP-IR fibres were associated with the taste buds. A moderate number of vasoactive intestinal polypeptide (VIP)-IR fibres and a few galanin (GAL)-IR fibres were also seen in the connective tissue core and subepithelial layer. There were, however, no VIP-IR or GAL-IR fibres associated with the taste buds. Neuropeptide Y (NPY)-IR fibres were few and were associated with the blood vessels. Within the epithelium of the circumvallate papillae, no peptidergic fibres were found, although a number of PGP 9.5-IR fibres were detected. The abundance of SP, CGRP, VIP, and GAL-IR fibres expressed as the percentage of total PGP 9.5 IR fibres was 25.35+/-3.45%, 22.18+/-3.26%, 10.23+/-1.18%, and 4.12+/-1.05%, respectively. The percentage of NPY-IR fibres was below 3%. In a deeper layer of the papillae, a few VIP, GAL, and NPY-IR ganglion cells were found, and VIP immunoreactivity was detected in a few cells of the taste buds. There was no somatostatin, leucine enkephalin, or methionine enkephalin immunoreactivity in the circumvallate papillae. These results suggest that the dense SP and CGRP-IR fibres within the connective tissue core of the human circumvallate papillae may be involved in the deep sensation of the tongue.

Adult↗

PubMed1998

Elevation of cytoplasmic cytochrome c in radiation-induced apoptosis.

The signal transduction pathway involved in radiation-induced apoptosis remains unclear, especially as regards the site at which the primary effect of radiation occurs. In this study, we demonstrate that cytochrome c may be released from mitochondria into the cytosol after irradiation, but that direct irradiation of isolated mitochondria induces no elevation of cytochrome c release. These observations suggest that cytochrome c and mitochondria may be involved in the radiation-induced apoptotic pathway, but mitochondria might not be a target of radiation, and that a signal transduction pathway from an unknown target might exist upstream of mitochondria during radiation-induced apoptosis.

Apoptosis↗

PubMed1998

Distribution of VIP receptors in the human submandibular gland: an immunohistochemical study.

Distribution of vasoactive intestinal polypeptide (VIP)-immunoreactive nerve fibers and VIP-receptor (VIP-R)-immunoreactive sites in the human submandibular gland were examined by the peroxidase-antiperoxidase method using the specimens taken from patients that had not received radiotherapy. VIP-immunoreactive fibers were found around both serous and mucous acini, the duct system, and those around the mucous acini were more numerous than those around the serous acini. VIP-R immunoreactivity was restricted to the mucous acini and the intercalated duct segment. The serous acini, striated duct, and excretory ducts lacked VIP-R immunoreactivity. These findings suggest that the mucous acinar cells contain VIP-R, and that VIP-R-mediated VIP action is involved in regulating synthesis of viscous saliva and its release.

Aged↗

PubMed1998

[Telomerase activity of tumors in the head and neck].

Telomerase is a maintaining enzyme of telomere repeats. Telemorase is expressed in immortal and cancer cells, but not in the normal tissues. We investigated telomerase activity of tumors in the head and neck. Telomerase activity was found in all of the cell lines derived from squamous cell carcinomas of the head and neck. Six of 9 (67%) primary fresh tissues from squamous cell carcinomas of the head and neck contained detectable telomerase activity. There were no apparent relationship between telomerase activity and clinical stage. Telomerase activity differed, depend on the responses to chemotherapy and radiotherapy: complete response, 0 of 3(0%); partial response; 0 of 1(0%); no change; 7 of 7 (100%). Therapy-resistant tumor seemed to have much telomerase activity and much malignant potential. In benign tumors, neither of 2 benign parotid tumors expressed telomerase activity, but one of 2(50%)papillomas had the telomerase activity. Telomerase is considered useful tumor marker for the diagnosis and prognosis.

Biomarkers, Tumor↗

PubMed1998

[Basic studies on IL-2 gene therapy for head and neck carcinoma].

Basic studies on transduction of the interleukin-2 (IL-2) gene into tumor cells were carried out in order to develop a new immunotherapy for head and neck carcinomas. We transduced the IL-2 gene into KB cells using defective herpes simplex viral (HSV) amplicon vector as the gene transfer vehicle. A high level of IL-2 was produced by IL-2 gene transduced KB cells (KB/IL-2). Human peripheral blood mononuclear cells (PBMC) cultured in medium containing the culture supernatant of KB/IL-2 cells showed stronger cytotoxic activity against KB cells than the control. In in vivo studies, high levels of IL-2 and interferon-gamma (IFN-gamma) were detected in the serum of nude mice transplanted with KB/IL-2 cells. The spleen cells of KB/IL-2 cell-transplanted nude mice exhibited high cytotoxic activity. Three of 5 nude mice transplanted with KB/IL-2 cells were completely cured of their tumor, and all 3 mice survived for over 120 days. All 5 nude mice transplanted with KB/lacZ cells, and all 5 nude mice transplanted with KB cells died within 120 days as a result of tumor progression. In conclusion, transduction of IL-2 gene tumor cells was corroborated by the high level of IL-2 produced by KB/IL-2 cells. The mechanisms of tumor rejection on KB/IL-2 transplanted nude mice were thought to be that effector cells stimulated by IL-2 derived from transplanted KB/IL-2 cells killed tumor cells, and IFN-gamma produced by activated NK cells showed a synergistic effect on tumor cells-killing.

Animals↗

PubMed1998

[Treatment for recurrent head and neck carcinomas].

In head and neck carcinomas, over 50% of patients present with advanced local and regional disease. Despite curative treatments of radiotherapy and/or surgery for these advanced cases, locoregional control remains a significant problem with locoregional recurrences in up to 50-60% of cases. The prognosis of cases who relapse in the early period after their primary therapy, is poor, because of the poor response to chemotherapy and/or radiation therapy. Furthermore, metastatic recurrences in distant organs and second primaries are other medical problems. Chemotherapy is a key treatment in the management of locally recurrent patients during the early period after curative radiotherapy in primary therapy. Recently, chemotherapy including CDDP has been applied for locally recurrent patients. The response rate or chemotherapy, however, is low with a short duration time. The recent studies in terms of reirradiation for patients with locoregional recurrences were reviewed. Because of radiation therapy given in the primary therapy, reirradiation combined with chemotherapy (chemoradiation) has been used to improve the efficacy and to reduce the cumulative dose of reirradiation. Chemoradiation consisting of efficacious chemotherapy and a radiation dose of about 60 Gy is important to improve local control and survival of recurrent cases of head and neck carcinomas.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1998

[Thymidylate synthase expression in patients with hypopharyngeal carcinoma].

We analyzed the relationship between clinical response to neo-adjuvant chemotherapy including 5-fluorouracil (5-FU) in patients with hypopharyngeal carcinoma (HPC) and thymidylate synthase (TS) expression in their tumors. TS expression was evaluated with immunohistochemical staining techniques on biopsy specimens from HPC patients. TS immunostaining was divided into four levels (TS0-TS3) according to its level and pattern. The relationship between prognosis, tumor size, nodal status, differentiation of tumor cells and TS expression were also investigated. There was a statistically significant association between the level of TS expression and tumor size (p < 0.01). In terms of the effectiveness of chemotherapy, tumor differentiation, nodal status and prognosis, a statistical difference was not found in TS expression. These results suggest that the level of TS expression may show the degree of tumor proliferation, but may not necessarily be useful to obtain a response to chemotherapy including other drugs, e.g., cisplatin and other derivatives of platinum.

Aged↗

PubMed1998

Evaluation of Epstein-Barr Virus infection in hypopharyngeal carcinomas from 37 Japanese patients.

Thirty-seven biopsy specimens from primary sites, 18 surgically removed metastatic neck nodes, and 18 surgically removed primary sites from 37 patients with hypopharyngeal carcinoma (HPC) were evaluated for the presence of Epstein-Barr Virus (EBV) infection by in situ hybridization (ISH) and polymerase chain reaction (PCR). Although some of normal lymphocytes in 6 of 18 metastatic nodes were positive by ISH, there were no positive results from HPC tumor cells themselves. Our results indicate that EBV-infected non-neoplastic cells such as lymphocytes can be a cause of false positivity, if a study were conducted with PCR alone. Because ISH for EBV-encoded early RNAs was highly sensitive, even more sensitive than PCR from paraffin-embedded samples in our study, this method should be the first choice for identification of EBV infection to avoid false positives.

Adult↗

PubMed1998

[Early phase II study of S-1 in patients with advanced head and neck cancer. S-1 Cooperative Study Group (Head and Neck Working Group)].

In developing new anticancer agents, the most important thing is the balancing of antitumor activity and toxicity. To achieve high activity and low toxicity, S-1 was designed, in which tegafur, prodrug of 5-FU, was combined with two classes of modulators. CDHP, inhibitor of 5-FU degradation in liver and Oxo, inhibitor of 5-FU phosphoribosylation in digestive tract, respectively. This cooperative study with 15 nation-wide institutes was conducted to evaluate the antitumor activity and toxicity of S-1 in patients with advanced head and neck cancer from Jan. 1994 to March 1996 in Japan. Out of 26 patients, CR was achieved in 1 and PR in 11 with a response rate of 46.2%, while adverse events of grade 3 were as follows: hemoglobinemia (7.7%), leukocytopenia, neutropenia, stomatitis and anorexia (3.8%), each. Neither grade 4 adverse event nor treatment-related deaths were observed. Based on these findings, it was concluded that S-1 is a useful anticancer agent with the low grade toxicities for treatment of the patients with advanced head and neck cancer, and the effects of CDHP and Oxo found in preclinical studies might be also reflected in these results.

Administration, Oral↗

PubMed1998

[Recent treatment modality for advanced head and neck carcinomas].

Histopathologically, about 90% of head and neck cancer is squamous cell carcinoma. The curative treatments for head and neck cancer are conventional radiotherapy and/or surgical resection. Multidisciplinary treatment, including combinations of the curative therapy, chemotherapy and immunotherapy, has been applied for advanced head and neck carcinomas with poor outcomes. Nowadays, chemotherapy is under investigation in the neo-adjuvant, adjuvant and concurrent chemoradiotherapy. In this paper, the treatment approach was reviewed in terms of prognostic factors which have been retrospectively estimated, along with recent developments in treatment modalities of advanced cases.

Carcinoma, Squamous Cell↗

PubMed1997

Analysis of initial attachment of B cells to endothelial cells under flow conditions.

This study examined the adhesive interactions of peripheral blood B cells with TNF-alpha-activated endothelial monolayers, and analyzed the roles of E-selectin, P-selectin, or VCAM-1 molecules expressed on activated HUVEC. B cell interaction occurred on activated HUVEC, but not on resting HUVEC under flow conditions. The majority of peripheral blood B cells expressed P-selectin glycoprotein ligand-1 and alpha4 integrin. However, the expression of cutaneous lymphocyte Ag on B cells was low. Under flow conditions, B cells could bind to P-selectin-coated tubes and VCAM-1-transfected Chinese hamster ovary cells. In contrast, B cells could not bind to E-selectin-coated tubes. Adhesion activity of B cells to P-selectin-coated tubes was weaker than that of T cells. Furthermore, adhesion activity of B cells to VCAM-1-transfected Chinese hamster ovary cells was similar to that of T cells. Treatment of activated HUVEC with anti-VCAM-1 mAb reduced interaction of B cells under flow conditions. However, the treatment of activated HUVEC with anti-P-selectin mAb did not reduce interaction. These data indicated that the interaction of VCAM-1 with alpha4 integrin plays a major role in an initial attachment of B cells to endothelial monolayers under flow conditions.

Animals↗

PubMed1997

Distribution of neuropeptide-containing nerve fibers in the human submandibular gland, with special reference to the difference between serous and mucous acini.

Distribution of neuropeptide Y (NPY)-, vasoactive intestinal polypeptide (VIP)-, galanin (GAL)-, substance P (SP)-, and calcitonin gene-related peptide (CGRP)-immunoreactive nerve fibers in the human submandibular gland was examined by the peroxidase-antiperoxidase method with attention to high-quality fixation and the condition of patients. NPY-, VIP-, and GAL-immunoreactive varicose fibers were densely distributed around the acini and ducts. Some of these fibers extended between acinar cells. The density of SP- and CGRP-immunoreactive fibers was relatively low. The number of NPY-, VIP-, and GAL-immunoreactive fibers around the mucous acini was significantly higher than around the serous acini. In the perivasculature, NPY-immunoreactive fibers were more numerous than other immunoreactive fibers. No somatostatin-, leucine-, or methionine-enkephalin-immunoreactive fibers were detected. Our findings suggest that a large number of periacinar VIP-, NPY-, and GAL-immunoreactive fibers may participate in regulating the synthesis of saliva and its secretion. Since the VIP-, NPY-, and GAL-immunoreactive fibers are more numerous around the mucous acini than around the serous ones, these fibers may take part more actively in regulating the secretory mechanisms in the mucous acini than in the serous ones. The relatively low number of CGRP- and SP-immunoreactive fibers suggests that they are less involved in the function of the human submandibular gland. Perivascular peptidergic fibers, especially NPY-immunoreactive fibers, may be involved in controlling local blood flow in this gland.

Aged↗

PubMed1997

Analysis of DNA ploidy using fresh frozen tissues of head and neck squamous cell carcinomas.

The DNA ploidy of fresh frozen tissues of head and neck squamous cell carcinomas was determined by flow cytometry to investigate whether DNA ploidy is correlated with various clinical and pathological parameters. The subjects were 51 patients who had been treated radically by our department. The DNA ploidy pattern was classified into three types, diploid, single aneuploid and multiploid, according to the DNA index and the DNA histogram. This is our original classification. No particular correlation could be detected between the DNA ploidy pattern and sex, age, primary tumour site or disease stage. The degree of tissue differentiation tended to be poorer in aneuploid tissues than in diploid tissues. The efficacy of chemotherapy was higher in aneuploid cases than in diploid cases. The recurrence rate was significantly lower in diploid cases than in multiploid cases. When disease stage, degree of histological differentiation, efficacy of the chemotherapy and the DNA ploidy pattern were subjected to multivariate analysis for correlation with the prognosis, the DNA ploidy pattern showed the highest correlation. The results suggest that the DNA ploidy as analyzed by flow cytometry can be used as an important prognostic factor.

Aged↗