Mamoru Tsukuda

A Selective Cyclooxygenase‐2 Inhibitor Suppresses Tumor Growth in Nude Mouse Xenografted with Human Head and Neck Squamous Carcinoma Cells

The anti‐tumor effect of a selective cyclooxygenase (COX)‐2 inhibitor, JTE‐522, was examined with the human head and neck squamous cell carcinoma cell line KB. KB cells do not produce prostaglandin (PG)‐E2. In vitro, JTE‐522 induced an increase of G1 phase‐arrested cells, suppression of platelet‐derived growth factor (PDGF) production and inhibition of telomerase activity. No cytotoxic effect was detected. In vivo, the growth of the tumor xenografted into nude mice was significantly suppressed by JTE‐522. Suppression of angiogenesis at the periphery of the tumor, increase of G1‐arrested cells and suppression of telomerase activity were observed, together with an increase of apoptotic cell death in the tumor. Immunological enhancement did not play a role. We concluded that the anti‐tumor effect of JTE‐522 was caused by anti‐angiogenesis action, cell cycle arrest and inhibition of telomerase activity of the tumor cells. These combined effects might induce apoptosis.

Differentiation between schwannoma of the vagus nerve and schwannoma of the cervical sympathetic chain by imaging diagnosis.

Ultrasonography, computed tomography, and magnetic resonance imaging were performed to differentiate preoperatively between schwannomas of the vagus nerve and schwannomas of the cervical sympathetic chain by observing the position of schwannomas in regard to the surrounding blood vessels. Ultrasonography also permitted direct visualization of the vagus nerve, so its position relative to the schwannoma could be examined.

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.

Randomized scheduling feasibility study of S-1 for adjuvant chemotherapy in advanced head and neck cancer

The purpose of this study was to determine the feasible adjuvant therapy administration schedule of S-1 for locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN). Patients receiving definitive treatments were randomly assigned to either arm A (51 cases) receiving oral S-1 of 2-week administration followed by 1-week rest for 6 months, or arm B receiving S-1 of 4-week administration followed by 2-week rest for 6 months. Planned treatment was given in 40% of patients in arm A and 29% in arm B. The cumulative rates of the relative total administration dose of S-1 at 100% were 54.9% (95% CI: 40.1–69.7%) in arm A and 34.3% (95% CI: 21.1–47.4%) in arm B, respectively (P=0.054). Adverse events were recorded in 41 patients (82.0%) in arm A and 48 patients (94.1%) in arm B (P=0.060). The incidences of diarrhoea (10 vs 28%; P<0.05) and skin toxicities (18 vs 37%; P<0.05) were significantly higher in arm B. One-year disease-free survival was similar in both arms: arm A 81.2% (95% CI: 70.0–92.4%); arm B 77.0% (95% CI: 65.0–89.0%). The schedule of 2-week administration followed by 1-week rest seems to be more feasible for oral 6-month administration of S-1 in adjuvant chemotherapy of locoregionally advanced SCCHN.

Acute epiglottitis: analysis of factors associated with airway intervention.

We reviewed acute epiglottitis (AE) and identified factors associated with airway intervention. This report was a retrospective review of patients with AE and compared with factors associated with airway intervention. We reviewed 96 patients who were diagnosed with AE in our hospitals in Japan. Ninety-two (96 per cent) patients were adults, and no seasonal variation in the incidence of AE was encountered. Eight (8 per cent) patients had tracheostomy and endotracheal intubation had not been done. We found that symptoms of stridor and muffled voice, a rapid clinical course, and diabetes mellitus were the factors associated with airway intervention. Extremely severe swelling of the epiglottis such that only less than half of the posterior vocal fold (scope classification (SC): III) could be seen, and extension of the swelling to the arytenoids (SC: B) were the two factors that were strongly associated with airway intervention.

New clinical diagnostic criteria for eosinophilic chronic rhinosinusitis

OBJECTIVE Chronic rhinosinusitis is a heterogeneous disease. Most cases of chronic rhinosinusitis with nasal polyp(s) (CRSwNP) in Western countries show a strong tendency for recurrence after surgery and pronounced eosinophil infiltration in the nasal polyps. The prevalence of CRSwNP with pronounced eosinophilic inflammation is steadily increasing and is classified as eosinophilic chronic rhinosinusitis (ECRS) in Japan. However, less than 50% of CRSwNP patients in Japan and East Asia show such features. Since the treatment strategy of ECRS differs from that of non-ECRS, clinical diagnostic criteria that distinguish ECRS from non-ECRS are needed. METHODS A total of 124 patients with CRSwNP patients who underwent endonasal sinus surgery were classified as ECRS or non-ECRS according to their clinical characteristics and the clinical features of the two groups were compared. Computed tomography (CT) images of the sinuses were graded according to the Lund-Mackay system. We also graded CT images of the olfactory cleft. Blood examination findings, sinus CT images and asthma complications were analyzed by multivariate logistic regression. Clinical findings that were significantly different between ECRS and non-ECRS were analyzed by receiver operating characteristic curves to determine optimal predictors of ECRS. RESULTS Blood eosinophilia, asthma complications and CT image scores were significantly different between ECRS and non-ECRS. In particular, increased blood eosinophil percentage and CT image scores for the posterior ethmoid and the olfactory cleft showed good accuracy as predictors of ECRS. A combination of the cut-off values for three predictors (increased blood eosinophil percentage above the normal range, olfactory cleft score ≥1 and posterior ethmoid score ≥1) indicated high accurate diagnostic ability (sensitivity, 84.6%; specificity, 92.3%). CONCLUSION A set of three clinical findings can differentiate ECRS from non-ECRS with high accuracy, even when these findings are assessed in regular outpatient clinics.

Phase I/II trial of weekly docetaxel and concomitant radiotherapy for squamous cell carcinoma of the head and neck

BackgroundA phase I/II trial of concurrent docetaxel and radiation for head and neck cancer was conducted to estimate the recommended dose schedule of docetaxel, and then to evaluate the therapeutic benefit.MethodsPatients received radiation in 2.0-Gy single daily fractions to a total dose of 60 Gy. Docetaxel was administered weekly for 6 consecutive weeks.ResultsDocetaxel 15 mg/m2 was considered the maximum tolerated dose (MTD). The recommended dose was decided as 10 mg/m2. The phase II study was conducted using docetaxel at 10 mg/m2. Thirty-nine patients were enrolled. The overall response rate was 96.9%. The prognosis of the complete response (CR) patients was significantly better than that of the partial response (PR) patients. Grade 3 or 4 adverse events consisted of lymphopenia, stomatitis, and anorexia. Thirty-two of the 35 eligible patients showed high compliance, of over 90%, and their toxicities were manageable.ConclusionEven low-dose docetaxel shows a strong effect in combination with radiation, with a high survival rate in CR patients. The effect on survival will be assessed by further follow-up.

Acidic extracellular pH increases calcium influx‐triggered phospholipase D activity along with acidic sphingomyelinase activation to induce matrix metalloproteinase‐9 expression in mouse metastatic melanoma

Acidic extracellular pH is a common feature of tumor tissues. We have reported that culturing cells at acidic pH (5.4–6.5) induced matrix metalloproteinase‐9 expression through phospholipase D, extracellular signal regulated kinase 1/2 and p38 mitogen‐activated protein kinases and nuclear factor‐κB. Here, we show that acidic extracellular pH signaling involves both pathways of phospholipase D triggered by Ca2+ influx and acidic sphingomyelinase in mouse B16 melanoma cells. We found that BAPTA‐AM [1,2‐bis(2‐aminophenoxy)‐ethane‐N,N,N′,N′‐tetraacetic acid tetrakis (acetoxymethyl) ester], a chelator of intracellular free calcium, and the voltage dependent Ca2+ channel blockers, mibefradil (for T‐type) and nimodipine (for L‐type), dose‐dependently inhibited acidic extracellular pH‐induced matrix metalloproteinase‐9 expression. Intracellular free calcium concentration ([Ca2+]i) was transiently elevated by acidic extracellular pH, and this [Ca2+]i elevation was repressed by EGTA and the voltage dependent Ca2+ channel blockers but not by phospholipase C inhibitor, suggesting that acidic extracellular pH increased [Ca2+]i through voltage dependent Ca2+ channel. In contrast, SR33557, an L‐type voltage dependent Ca2+ channel blocker and acidic sphingomyelinase inhibitor, attenuated matrix metalloproteinase‐9 induction but did not affect calcium influx. We found that acidic sphingomyelinase activity was induced by acidic extracellular pH and that the specific acidic sphingomyelinase inhibitors (perhexiline and desipramine) and siRNA targeting aSMase/smpd1 could inhibit acidic extracellular pH‐induced matrix metalloproteinase‐9 expression. BAPTA‐AM reduced acidic extracellular pH‐induced phospholipase D but not acidic sphingomyelinase acitivity. The acidic sphingomyelinase inhibitors did not affect the phosphorylation of extracellular signal regulated kinase 1/2 and p38, but they suppressed nuclear factor‐κB activity. These data suggest that the calcium influx‐triggered phospholipase D and acidic sphingomyelinase pathways of acidic extracellular pH induced matrix metalloproteinase‐9 expression, at least in part, through nuclear factor‐κB activation.

Phase I trial of concurrent chemoradiotherapy with docetaxel, cisplatin and 5-fluorouracil (TPF) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).

The aim of this study was to evaluate the efficacy and toxicity of a concurrent chemoradiotherapy using docetaxel, cisplatin and 5-fluorouracil (5-FU) (TPF) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). In total, 19 patients with previously untreated stage III–IV SCCHN were entered onto this trial. Patients received two cycles of chemotherapy. Cycles were repeated every 4 weeks. The starting doses (dose level 1) were docetaxel 60 mg m−2, cisplatin 70 mg m−2, and 5-day continuous infusion of 5-FU 600 mg m−2 day−1. Radiation was targeted to begin on the first day of chemotherapy, day 1. The total radiation dose to the primary tumour site and neck lymph nodes was between 63.0 and 74.0 Gy. At least three patients were examined at each dose level before advancing to the next level. The maximum-tolerated dose (MTD) of this regimen was docetaxel 60 mg m−2, cisplatin 60 mg m−2 and 5-FU 600 mg m−2 day−1. The main toxicities were mucositis (grade 3 and 4, 79%), leukocytopenia (grade 3 and 4, 53%), neutropenia (grade 3 and 4, 42%), anaemia (grade 3, 16%), liver dysfunction (grade 3, 11%) and renal dysfunction (grade 2, 11%). The overall response rate was 100%, including 84% complete responses (CRs). This concurrent chemoradiotherapy with TPF was safe and well tolerated. The high CR rate justifies further evaluation of this chemoradiotherapy modality in advanced SCCHN patients.

Inhibition of head and neck metastatic and/or recurrent cancer by local administration of multi-cytokine inducer OK-432.

The multi-cytokine inducer OK-432 is a pulverized preparation of the low-virulence SU strain of Streptococcus pyogenes of human origin. A reduction of the tumour mass in the OK-432-injected areas was observed in 11 out of 13 patients with metastatic and/or recurrent head and neck cancer. Complete response (CR), partial response (PR) and minor response (MR) were noted in six, three and two cases respectively. OK-432 local administration therapy could create a new strategy for cancer therapy.