Izumi Mochimatsu

A study of the early stage of Dysphagia in amyotrophic lateral sclerosis.

In amyotrophic lateral sclerosis (ALS) patients, dysphagia eventually occurs independent of time of onset. We studied dysphagia conditions in the early stage of ALS, principally at the oral phase. Videofluoroscopic and manometric studies were conducted on 11 patients (5 males and 6 females, age range = 47–82 years) who were diagnosed at our Neurology Clinic as having ALS. All patients were able to ingest orally. Swallowing scores on the ALS severity scale were from 10 to 5. In the oral phase of swallowing, abnormal movements of the anterior and/or posterior tongue were recognized in 8 cases. Dysphagia severity tended to be particularly influenced by dysfunction of the posterior tongue. Manometric studies were almost normal in all cases except one. These results suggested that the early stage of dysphagia in ALS was mainly caused by oral dysfunction, and the oral phase disorders began in some cases with a decreased function of bolus transport at the anterior part of the tongue, and in other cases with a deteriorated function of holding the bolus at the posterior part of the tongue. In conclusion, the tongue function of holding the bolus in the oral cavity mainly affects the severity of the early stage of dysphagia in ALS.

Induction chemotherapy in advanced head and neck cancer.

Induction chemotherapy, followed by definitive treatment, was performed in patients with advanced squamous-cell carcinoma of the head and neck. In this study, carried out between 1984 and 1991, testing the effectiveness of multimodality therapy in patients with previously untreated advanced (stage III and IV) squamous-cell carcinoma of the pharynx, patients received two different induction chemotherapy regimens: cisplatin, vincristine (Oncovin) plus peplomycin (COP), and cisplatin plus continuous 120-hr 5-fluorouracil (5-FU) infusion (CF) for two courses. Overall response rates (complete response plus partial response) to each of the two induction chemotherapy regimens were high: 76 and 82%, respectively. Superior complete response rate in the group receiving CF therapy was 16% versus 10% for COP therapy. Responders to induction chemotherapy had significantly better survival compared with non-responders. The toxicity of these two regimens was tolerable and manageable. It is indispensable to develop the more efficacious chemotherapy regimen with the potential to induce complete disappearance of tumors in patients with advanced head and neck carcinomas.

Tumours metastasizing to the head and neck--a report of seven cases.

Metastatic tumours involving the head and neck region are rare. Over the past 18 years, seven such cases were treated at our clinic. Of those, four were in one of the paranasal sinuses, three had arisen from a primary hepatocellular carcinoma and one from an osteogenic fibrosarcoma of the leg. In the remaining three cases, metastases to the larynx, the tonsil, and the parotid gland arose from a primary renal cell carcinoma, a thyroid carcinoma, and a breast carcinoma, respectively. In metastatic tumours, the primary site can often be identified by the histopathological features. Accordingly, when malignant head and neck tumours are suspected of being metastatic in character, it is important to search carefully for the primary site.

Chemotherapy for recurrent adeno- and adenoidcystic carcinomas in the head and neck

We have investigated the effectiveness of chemotherapy for patients with recurrent adeno- and adenoidcystic carcinomas in the head and neck. Fourteen cases received a monthly combination chemotherapy regimen of cyclophosphamide, pirarubicin and cisplatin (CAP therapy). A response rate of 36% (5/14) was achieved. There was one complete response and four partial responses. The median duration of response was 37 months in the complete response case and 16 months (range, 6 to 20) in the partial response cases. The toxicity of this chemotherapy was acceptable. The result demonstrates that CAP therapy is an effective regimen for adeno- and adenoidcystic carcinomas. It may also be available as induction or adjuvant chemotherapy for patients with advanced tumors of these cancers.

Inostamycin, an inhibitor of cytidine 5′-diphosphate 1,2-diacyl-sn-glycerol (CDP-DG): Inositol transferase, suppresses invasion ability by reducing productions of matrix metalloproteinase-2 and -9 and cell motility in HSC-4 tongue carcinoma cell line

Inostamycin is an inhibitor of cytidine 5′-diphosphate 1,2-diacyl-sn-glycerol (CDP-DG): inositol transferase. It significantly reduced epidermal growth factor (EGF)-induced in vitro invasion of the tongue carcinoma cell line, HSC-4, through reconstituted basement membrane Matrigel®. Since phosphatidylinositol (PI) 4,5-biphosphate is important for signal transduction through protein kinase C and actin reorganisation, we further examined the effect of inostamycin on production of two matrix metalloproteinases (MMPs), MMP-2 and -9, and on cell motility. Zymographic analysis showed that inostamycin suppressed pro-MMP-2 and pro-MMP-9 levels at a dose-dependent fashion, while MMP-2 activity was not significantly affected. By reverse transcription-polymerase chain reaction, it was found that inostamycin diminished steady state levels of MMP-2 and -9 but not membrane type 1-MMP mRNA expressions. Inostamycin partially blocked both EGF- and phorbol 12-myristate 13-acetate-stimulated pro-MMP- 9 production. A cytoplasmic calcium chelator (BAPTA-AM) dramatically elevated pro- MMP-9 and slightly elevated pro-MMP-2 secretions. EGF-stimulated motility of HSC-4 cells was suppressed by inostamycin treatment along with reduction of actin cytoskeletal reorganisation, filopodia formation and cdc42 expression. These results suggested that inostamycin would be useful for an anti-invasive agent in tongue cancer.

Clinical application of recombinant human erythropoietin for treatments in patients with head and neck cancer

SummaryThe therapeutic effects of intravenous recombinant human erythropoietin (r-hEPO) administration on anemia induced by radiation therapy (3 cases), chemotherapy (18 cases) and combined therapies (5 cases) in patients with head and neck malignancies were examined. The effectiveness was evaluated by the changes in the hemoglobin concentration examined before and after the r-hEPO administration. The r-hEPO administration combined with anticancer therapies improved anemia induced by all three treatments. The therapeutic effectiveness of r-hEPO injection was also noted on anemia induced by all of four different chemotherapeutic regimens that have been ordinarily used for head and neck malignancies. Furthermore, the efficacy of the different dose schedules, 3000 IU (12 cases) or 6000 IU (14 cases), three times a week, was compared. Both of the r-hEPO dose schedules were effective for anemia, but the efficacy of 6000 IU was superior to that of 3000 IU. No significant changes were observed in the number of white blood cells and platelets and the results of biochemical examinations after the r-hEPO injection. There were no objective side-effects related to the r-hEPO administration. These results suggest that anemia induced by chemotherapy and/or radiotherapy could be prevented by r-hEPO administration. The addition of r-hEPO to anticancer therapies would make it possible to pursue the planned therapeutic schedules, prevent the decrease of immunity after allogeneic blood transfusion and bring about an improvement in the prognosis of patients with malignancies.

Cytostatic effect of inostamycin, an inhibitor of cytidine 5'-diphosphate 1,2-diacyl-sn-glycerol (CDP-DG): inositol transferase, on oral squamous cell carcinoma cell lines.

Inostamycin, which was recently isolated from Streptomyces sp. MH816‐AF15 as an inhibitor of cytidine 5′‐diphosphate 1,2‐diacyl‐sn‐glycerol (CDP‐DG): inositol transferase, caused a G1‐phase accumulation in the cell cycle of small cell lung carcinomas. To investigate whether the cytostatic effect of inostamycin is restricted to lung carcinoma cell lines or applicable to other type of cells, we tested five oral squamous cell carcinoma (SCC) cell lines. Cell growth was suppressed in 62.5–125ng/ml inostamycin in the culture medium in all oral cancer cell lines tested, with non‐viable cells being <1%, indicating inostamycin is cytostatic on SCC cell lines. Decrease in cyclin D1 mRNA and protein expression due to the inostamycin treatment was accompanied by suppression of phosphorylated retinoblastoma susceptibility gene product (pRB‐P) levels. Moreover, flow cytometric analysis showed that inostamycin induced an increase in G1/G0 cells (1.2–3.2 fold) over 24h. These results suggest that inostamycin is a useful agent for tumour dormant cytostatic therapy for oral SCC.

Inostamycin suppresses vascular endothelial growth factor-stimulated growth and migration of human umbilical vein endothelial cells

Angiogenesis involves multiple steps including proliferation and migration of endothelial cells. In the present study, we determined the effect of inostamycin (an inhibitor of phosphatidylinositol synthesis) on vascular endothelial growth factor (VEGF)-induced proliferation and migration of human umbilical vein endothelial cells (HUVECs). Inostamycin significantly attenuated both VEGF-induced proliferation and migration of HUVECs. Inostamycin inhibited activation of mitogen-activated kinases (ERK and p38) and elevation of cyclin D1 induced by VEGF. These data suggest that inostamycin reduced both proliferation and migration of HUVECs by targeting ERK-cyclin D1 and p38, respectively.

Modified Combination Chemotherapy of Cisplatin and 5-Fluorouracil in Squamous Cell Carcinomas of the Head and Neck

Randomized studies on the efficacy of two courses of different types of chemotherapy, including cisplatin and 5-fluorouracil (5-FU), were performed on 130 previously untreated cases with advanced squamous cell carcinomas of the head and neck. Cisplatin, followed by 120-hr continuous 5-FU infusion given in the conventional way, was administered to 60 patients (Group A), while cisplatin was administered 72 hr after the initiation of continuous 5-FU infusion in 70 other patients (Group B). The overall response rates (complete response plus partial response) were 58% in group A and 69% in group B, respectively. A superior complete response rate was obtained in cases receiving modified chemotherapy (10% in group A vs 20% in group B). There was no significant difference in the incidence of side effects between the two groups. These findings indicate that the modified cisplatin plus 5-FU combination chemotherapy tested here is more efficacious regimen than that of the conventional one to achieve high complete response rate and subsequently, to improve the survival of advanced carcinoma cases of the head and neck.

Extramedullary plasmacytoma of the larynx

A case of IgD myeloma in a 54-year-old male with a long-standing history of extramedullary plasmacytoma involving the larynx is reported. The patient was treated with radiation therapy and laryngectomy. Twelve years later, he complained of nasal bleeding. On examination he was found to have large masses in the left nasal cavity and in the left supraclavicular region. Histological examination of both lesions showed plasmacytoma. Serum immunoglobulin studies revealed an IgD monoclonal spike of the lambda type. Bence-Jones protein was present. Using the immunoperoxidase staining technique, cytoplasmic monoclonal IgD was detected.