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The maximum number of vertebral bodies with bony bridges between adjacent vertebrae (max VB) helps assess the risk of fracture in diffuse idiopathic skeletal hyperostosis (DISH). In addition to max VB, the maximum thickness of bone cross-bridges (max TB) may be an index of bone mineral density (BMD). Therefore, this study investigated the relationship among max VB, max TB, and BMD. The participants in this cross-sectional study were male patients (n = 123) with various max VB from the thoracic vertebrae to the sacrum without sacroiliac ankylosis. The participants were grouped by max VB. For example, a group with max VB from 4 to 8 would be listed as max VB (4–8). The relation between femur proximal BMD and mean max TB and max VB was assessed. Femur proximal BMD was then compared after adjusting for confounding factors. The results indicated that max VB was correlated with femur proximal BMD in max VB (0–8) and max VB (9–18) groups. The mean max TB was correlated only with femur proximal BMD in max VB (0–8). After adjusting, max VB (4–8) showed a significantly higher femur proximal BMD than max VB (0–3) and max VB (9–18). Femur proximal BMD and mean max TB showed different trends after max VB = 9, which suggests that max VB is an index of BMD, and that DISH has at least two possible populations in terms of BMD and bone cross-link thickness.

STUDY DESIGN Retrospective comparative study. OBJECTIVE To evaluate the changes in global spinal sagittal alignment (GSSA) following selective anterior spinal fusion (ASF) in patients with Lenke type 5 adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA Few studies have assessed the changes in postoperative GSSA, including cervical, thoracic, and lumbosacral sagittal alignment in AIS patients with major thoracolumbar/lumbar (TL/L) curve who underwent selective ASF. METHODS Fifty-two patients with Lenke type 5 AIS (2 males and 50 females, mean age at surgery of 16.4 ± 3.1 years) were included in this study. The average final follow-up was 8.3 ± 3.1 years after surgery. The variations of outcome variables were analyzed in various spinal sagittal profiles using radiographic outcomes (pre-operation, immediate post-operation, and final follow-up). The clinical outcomes at the final follow-up were assessed using Scoliosis Research Society (SRS)-22 and Oswestry Disability Index (ODI) questionnaires. RESULTS The mean Cobb angle of the main TL/L and minor thoracic curve was significantly improved after selective ASF, which was maintained up to the final follow-up. On the other hand, in all cases, the various sagittal parameters examined (sagittal vertical axis (SVA), C2-7 SVA, C2-7 lordosis, T1 slope, thoracic kyphosis, T10-L2 kyphosis, lumbar lordosis, pelvic incidence, pelvic tilt, and sacral slope), did not significantly change in the immediate postoperative period, and all GSSA parameters were maintained up to the final follow-up. Furthermore, the magnitude of coronal curve correction and fused levels did not affect each GSSA parameter postoperatively. During the period up to the final follow-up, no significant clinical symptoms were observed. The final SRS-22 global score was 4.5 ± 0.3, and ODI scored 0.8 ± 2.4. CONCLUSION Selective ASF did not influence various GSSA parameters postoperatively and could maintain excellent correction for coronal deformity with satisfactory final functional and clinical outcomes confirmed by long-term follow-up.Level of Evidence: 4.

Background Ossification of the posterior longitudinal ligament of the spine (OPLL) is characterized by heterotopic bone formation in the posterior longitudinal ligament of the spine. We know that the size and distribution of the ossified lesions in patients with OPLL are different in each case. However, the characteristics of the patients with radiologically severe cervical OPLL remain unknown. Methods The participants of our study were symptomatic patients with cervical OPLL who were diagnosed by standard radiographs of the cervical spine. Whole-spine CT data and demographic data such as age and sex were obtained from 20 institutions belonging to the Japanese Multicenter Research Organization for Ossification of the Spinal Ligament. According to the number of the levels involved by OPLL, we stratified the patients into two subgroups: severe group (S-group) and non-severe group (NS-group) to delineate the characteristics of radiologically severe patients with cervical OPLL. We also evaluated the most compressed level and the degree of occupying ratio of cervical spinal canal by OPLL at the most compressed level. Results A total of 234 patients with a mean age of 65 years were recruited. The S-group consisted of 48 patients (21%, 12 females and 36 males) and the NS-group consisted of 92 patients (79%, 22 females and 70 males). The mean age of males in the S-group (68 years old) was significantly higher than that of males in the NS-group (64 years old); however there was no significant difference in the mean age in females between the S-group (69 years old) and the NS-group (66 years old). No significant difference of body mass index, ossification of the nuchal ligament-positivity and presence of diabetes mellitus were found between the S- and the NS-group. Conclusions It is likely that the manner of extension of cervical OPLL is different between male and female patients.

This was a retrospective multicenter study.To clarify the progression of diffuse idiopathic skeletal hyperostosis (DISH) using whole-spine computed tomography in patients with cervical ossification of the posterior longitudinal ligament (OPLL).DISH and cervical OPLL frequently coexist, and can cause ankylosing spinal fractures due to biomechanical changes and fragility of the affected vertebrae. The epidemiology and pathophysiology of DISH occurring with cervical OPLL are unclear.We used whole-spine computed tomography to determine the prevalence of DISH in 234 patients with a diagnosis of cervical OPLL based on plain cervical radiographs. We established a novel system for grading the progression of DISH based on a cluster analysis of the DISH distribution along the spine. We calculated the correlation coefficient between this grading system and patient age.The prevalence of DISH in patients with cervical OPLL was 48.7%. Patients with DISH were significantly older than those who did not have DISH (67.3 vs. 63.4 y; P=0.005). Cluster analysis classified the DISH distribution into 6 regions, based on the levels affected: C2-C5, C3-T1, C6-T5, T3-10, T8-L2, and T12-S1. DISH was observed most frequently at T3-T10. We defined a system for grading DISH progression based on the number of regions involved, from grade 0 to 6. DISH was distributed at T3-T10 in60% of the grade 1 patients, whereas most patients with DISH at the cervical or lumbar spine were grade 4 or 5. There was a weak but significant correlation between the DISH grade and patient age.DISH was present in nearly half of the patients with cervical OPLL. DISH was more common in older patients. DISH developed at the thoracic level and progressed into the cervical and/or lumbar spine with age.Level III.

Background In patients with ossification of the posterior longitudinal ligament (OPLL) in the cervical spine, it is well known that the thoracic ossified lesions often coexist with the cervical lesions and can cause severe myelopathy. However, the prevalence of OPLL at each level of the thoracic and lumbar spinal segments is unknown. The aims of this study were to investigate how often OPLL occurs at each level in the thoracolumbar spine in patients with a radiological diagnosis of cervical OPLL and to identify the spinal levels most likely to develop ossification. Methods Data were collected from 20 institutions in Japan. Three hundred and twenty-two patients with a diagnosis of cervical OPLL were included. The OPLL index (OP index), defined as the sum of the vertebral body and intervertebral disc levels where OPLL is present, was used to determine disease severity. An OP index ≥20 was defined as severe OPLL. The prevalence of OPLL at each level of the thoracic and lumbar spinal segments was calculated. Results Women were more likely to have ossified lesions in the thoracolumbar spine than men. Severe OPLL was significantly more common in women than in men (20% vs. 4.5%). For thoracic vertebral OPLL, the most frequently affected was the T1 segment in both men and women, followed by the T1/2 and T3/4 intervertebral levels in men and women, respectively. Ossified lesions were frequently seen at the intervertebral and vertebral levels around the cervicothoracic and thoracolumbar junctions in men with severe OPLL, whereas OPLL was more diffusely distributed in the thoracic spine in women with severe OPLL. Conclusion Thoracolumbar OPLL occurred most often at T1 in men and at T3/4 in women. In severe OPLL cases, although ossified lesions were frequently seen at the intervertebral and vertebral levels around the cervicothoracic and thoracolumbar junctions in men, OPLL could be observed more diffusely in the thoracic spine in women.

Background Previous studies have shown that patients with cervical ossification of the posterior longitudinal ligament (OPLL) often have co-existing ossification of the nuchal ligament (ONL). However, no studies have focused on ONL and its relevance to the severity of OPLL or ossification of other spinal ligaments, such as anterior longitudinal ligament (OALL), ligamentum flavum (OLF), and supraspinous/interspinous ligament (OSIL). Methods In this multicenter study, we investigated ossification of the spinal ligaments in the whole spine computed tomography (CT) images of 233 cervical OPLL patients. The severity of ossification was evaluated using ossification index for each spinal ligament, calculated as the sum of the level of ossification. We compared the severity of ossification in each spinal ligament between patients with ONL and those without ONL. Furthermore, we investigated how the number of segments, where ONL exists, affects the severity of ossification in each spinal ligament. Results One hundred thirty patients (55.8%) had co-existing ONL in the cervical OPLL patients included in this study. The ONL (+) group included more male and aged patients. The cervical ossification indexes of OPLL and OALL were higher in ONL (+) patients than in ONL (−) patients. The thoracolumbar ossification indexes of OALL and OSIL were also higher in ONL (+) patients. Logistic regression analysis revealed that age, gender and cervical OA-index were independent factors correlating to the existence of ONL. In the cervical spine, both the ossification indexes of OALL and OPLL increased as the levels of ONL increased. Similarly, in the thoracolumbar spine, both the ossification indexes of OALL and OSIL were increased as the levels of cervical ONL increased. In the multiple regression analysis, cervical OA-index and thoracolumbar OSI-index showed significant correlation with the number of ONL levels. Conclusions Co-existence of ONL in cervical OPLL patients was associated with the severity of spinal hyperostosis especially in cervical OPLL, OALL, thoracolumbar OALL and OSIL.

Study design A retrospective study. Summary of background data Posterior lumbar interbody fusion (PLIF) increases mechanical stress and can cause degenerative changes at the adjacent segment. However, the precise causes of adjacent segment disease (ASD) after PLIF are not known, and it is unclear whether simultaneous decompression surgery for symptomatic ASD is effective. Objective To study, radiographically and symptomatically, the risk factors for adjacent segment disease (ASD) in the lumbar spine after L4/5 PLIF and to examine whether decompression surgery for the adjacent segment (L3/4) reduces the occurrence of symptomatic ASD. Methods Fifty-four patients who underwent L4/5 PLIF for L4 degenerative spondylolisthesis and could be followed up for at least 2 years were included. Of these, 37 were treated simultaneously with decompression surgery at L3/4. We measured radiographic changes and assessed symptoms from the cranial adjacent segment. Results Thirty-one patients (57.4%) met radiologic criteria for ASD. The length of follow-up (P=0.004) and simultaneous decompression surgery at L3/4 (P=0.009) were statistically significant factors for radiologic diagnosis of ASD. Seven patients (13.0%) had symptomatic ASD: 6 in the decompression group (16.2%) and 1 in the PLIF-only group (5.9%). Simultaneous decompression surgery did not reduce the incidence of symptomatic ASD (P=0.256). Local lordosis at the fused segment (P=0.005) and the sagittal angle of the facet joint at L3/4 (P=0.024) were statistically significant predictors of symptomatic ASD, which was accompanied by postoperative anterior listhesis above the fused segment (S group, 8.4%±8.0%; nonsymptomatic group: -0.7%±5.0%, P=0.024). Conclusions Patients whose facet joint at the adjacent segment had a more sagittal orientation had postoperative anterior listhesis, which caused symptomatic ASD. Simultaneous decompression surgery without fusion at the adjacent level was not effective for these patients, but rather, there was a possibility that it induced symptomatic ASD.

Osteoid osteoma is a relatively common benign bone tumor first described by Jaffe [1]. It most frequently arises in the long bones and exhibits a characteristic X-ray appearance, that is, a small radiolucent zone surrounded by reactive circumferential sclerosis (nidus) [2, 3]. Nocturnal pain, which can be alleviated by aspirin, is one of the characteristic clinical manifestations of this bone tumor [4]. Although it is relatively rare, osteoid osteoma can also arise in the intra-articular regions, and we found 14 such cases arising in the knee joint in the literature [5–18]. Patients with intra-articular osteoid osteoma often present with joint pain, intracapsular effusion, restricted motion, and muscle atrophy in the affected limb, which can be mistaken for more common entities, such as traumatic or degenerative pathologies of the joint. Furthermore, X-ray examination often fails to show the characteristic nidus that is typically seen in extra-articular osteoid osteoma and therefore can result in a delayed diagnosis. We herein present a case of intra-articular osteoid osteoma arising in the knee joint, which was successfully treated by arthroscopy, and review the reported cases of intra-articular osteoid osteoma arising in the knee.

Background: Epstein-Barr Virus (EBV)-associated nasopharyngeal carcinoma (NPC) is distinctive among head-and-neck cancers in its undifferentiated histopathology and highly metastatic character. We have recently investigated the involvement of epithelial–mesenchymal transition (EMT) in NPC. In a previous study, we found a close association of expression of LMP1, the principal EBV oncoprotein, with expression of Twist and induction of EMT. Methods: We analysed expression of Snail in 41 NPC tissues by immunohistochemistry. The role of Twist as well as Snail in EMT of NPC was investigated by using NP69SV40T human nasopharyngeal cells. Results: In NPC tissues, overexpression of Snail is associated with expression of LMP1 in carcinomatous cells. In addition, expression of Snail positively correlated with metastasis and independently correlated inversely with expression of E-cadherin. Expression of Twist had no association with expression of E-cadherin. Further, in a human nasopharyngeal cell line, LMP1 induces EMT and its associated cellular motility and invasiveness. Expression of Snail is induced by LMP1 in these cells, and small hairpin RNA (shRNA) to Snail reversed the cellular changes. By contrast, Twist did not produce EMT in these nasopharyngeal cells. Conclusions: This study strengthens the association of EMT with the metastatic behaviour of NPC. These results suggest that induction of Snail by the EBV oncoprotein LMP1 has a pivotal role in EMT in NPC.

The aim of this study was to visualize the human olfactory transport pathway to the brain by performing imaging after nasal thallium-201 ((201)Tl) administration.Healthy volunteers were enrolled in this study after giving informed consent (five males, 35-51 years old). The subjects were nasally administered (201)TlCl into either the olfactory cleft. Twenty-four hours later, uptake of (201)Tl was detected by a single photon emission computed tomography (SPECT)/X-ray computed tomography hybrid system. For each subject, an MRI image was obtained and merged with the SPECT image.The peak of the (201)Tl uptake entered into the olfactory bulb in the anterior skull base through the cribriform lamina 24 h after nasal administration of (201)Tl. No participant had olfactory disturbance after treatment.Nasal (201)Tl administration was safely used to assess the direct pathway to the brain via the nose in healthy volunteers with normal olfactory threshold.

IL-27 was first discovered as a factor supporting initial Th1 immune responses. Subsequent studies revealed that this cytokine has pleiotropic effects, including inhibition of certain immune cells, a regulatory role in hemopoietic stem cell differentiation, and antitumor activities. However, the role of human IL (hIL)-27 in human osteoclast precursors and inflammatory bone disease is unclear. Here, we examined the direct effect of hIL-27 on human osteoclastogenesis. Human bone marrow cells cultured in MethoCult medium containing human (h) GM-CSF, human stem cell factor, and hIL-3 expressed Mac-1, c-kit, and c-Fms. These cells, called hCFU-GMs, also expressed the IL-27 receptor, an IL-27Rα (WSX-1)/gp130 heterodimer. Cultivation in hM-CSF and human receptor activator of NF-κB ligand induced the differentiation of tartrate-resistant acid phosphatase-positive multinucleated cells (osteoclasts) from hCFU-GMs, and hIL-27 inhibited this osteoclastogenesis in a dose-dependent manner. hIL-27 also repressed bone resorption by osteoclasts on a dentine slice. hIL-27 caused a remarkable increase in STAT1 phosphorylation and enhanced the STAT1 protein level. It also inhibited the expression of receptor activator of NF-κB ligand-induced c-Fos and cytoplasmic, calcineurin-dependent 1 NFAT (NFATc1), which are indispensable transcription factors for osteoclastogenesis. Fludarabine, a STAT1 inhibitor, and STAT1 small interfering RNA partially rescued the inhibition of osteoclastogenesis by IL-27. A WSX-1 deficiency caused severe inflammatory bone destruction primed by Escherichia coli cell wall lysate in vivo. Therefore, hIL-27 may act as an anti-inflammatory cytokine in human bone destruction, by inhibiting osteoclastogenesis from hCFU-GMs via STAT1-dependent down-regulation of the transcription factor c-Fos. Our results suggest that hIL-27 may prove useful as a therapeutic target for inflammatory bone destruction.

1-Alpha, 25-dihydroxy vitamin D(3) (1alpha,25(OH)(2)D(3)), an active form of vitamin D(3), plays a critical role in calcium and bone metabolism. Although 1alpha,25(OH)(2)D(3) has been used for osteoporosis therapy, the direct role of 1alpha,25(OH)(2)D(3) on human osteoclastogenesis has not been well characterized. Here we show that 1alpha,25(OH)(2)D(3) treatment significantly inhibited human osteoclast formation at the early stage of differentiation in a concentration-dependent manner. 1alpha,25(OH)(2)D(3) inhibited the expression of nuclear factor of activated T cells c1 (NFATc1, also referred as NFAT2), an essential transcription factor for osteoclast differentiation, and upregulated the expression of interferon-beta (IFN-beta), a strong inhibitor of osteoclastogenesis in osteoclast progenitors. Inhibitory effects of 1alpha,25(OH)(2)D(3) on osteoclastogenesis and NFATc1 expression were restored by treatment with an antibody against IFN-beta, suggesting that upregulation of IFN-beta by 1alpha,25(OH)(2)D(3) treatment results in inhibition of NFATc1 expression, in turn interfering with osteoclast formation. Thus, our study may provide a molecular basis for the treatment of human bone diseases by 1alpha,25(OH)(2)D(3) through regulation of the IFN-beta and NFATc1 axis.

Juzen-taiho-to (JTT, TJ-48), a Japanese herbal medicine that improves immune function, was found to be effective in otitis-prone in children.To evaluate the efficacy of JTT against intractable and recurrent infections in immature immune systems, we administered JTT to otitis-prone infants and investigated clinical changes before and during JTT administration.Twenty-four otitis-prone infants were administered JTT at 0.10-0.14 g/kg/day twice a day for 3 months. We compared clinical course, such as frequency of acute otitis media (AOM), duration of fever and antibiotics administration, and hospital visits for the periods before and during JTT administration.Medication compliance rate was 87.5%, and administration of JTT led to remission in 95.2% patients. No apparent side effects were observed. The frequency of AOM decreased significantly (Wilcoxon signed rank test, p=0.000) with JTT. The duration of fever (p=0.000) and administration of antibiotics (p=0.001), as well as the number of hospital visits (p=0.001) and emergent hospital visits (p=0.000) showed significant decreases after JTT administration. After the end of the JTT period, 14 of 21 (66.7%) patients started to take it again, as they experienced purulent otitis media and/or other infections after discontinuation. The frequency of AOM increased significantly after stopping JTT (p=0.004) and decreased again with JTT resumption (p=0.005).

金沢大学附属病院耳鼻咽喉科, Objectives: Although organ-preserving radiotherapy or chemoradiotherapy has offered good locoregional control, many patients still experience recurrent disease requiring salvage laryngectomy. The pharyngocutaneous fistula (PCF) is a common and troublesome complication in the early post-operative period after laryngectomy. Here, we evaluated the cause of PCF after laryngectomy, with special emphasis on radiotherapy and/or chemotherapy. Patients and methods: A total of 63 consecutive patients undergoing salvage total laryngectomy for squamous cell carcinoma of the larynx at Kanazawa University Hospital from 1990 to 2005 were reviewed. Forty of the 63 had received primary total laryngectomy (PL). Ten patients underwent radiotherapy alone (SL-RT) and 13 patients underwent concurrent chemoradiotherapy (SL-CRT) followed by salvage laryngectomy. Results: Overall, 17 of the 63 patients (27.0%) developed PCF after laryngectomy. Fisher's exact test showed a significant increase of PCF formation in SL-CRT (7/13, 53.8%) compared with PL (7/40, 17.5%) (p = 0.0252). There were non-significant increases of PCF formation both in SL-CRT (7/13, 53.8%) compared with SL-RT (3/10, 30.0%) (p = 0.4015), and also in SL-RT (3/10, 30.0%) compared with PL (7/40, 17.5%) (p = 0.3969). The Mann-Whitney U-test showed that the duration of PCF was significantly longer for SL-CRT PCF (121.2 ± 95.0 days) compared with those for PL (39.0 ± 55.3 days) (p = 0.0298) or SL-RT (28.0 ± 16.2 days) (p = 0.0325). However, we did not find a significant difference in the duration of PCF with respect to PL (39.0 ± 55.3 days) and SL-RT (28.0 ± 16.2 days) (p = 0.4367). Conclusions: Although radiotherapy or chemotherapy has only a limited impact on PCF formation, concurrent chemoradiotherapy significantly increases PCF formation. The addition of chemotherapy to irradiation delays PCF closure. © 2007 Elsevier Ireland Ltd. All rights reserved.

金沢大学附属病院耳鼻咽喉科・頭頸部外科, Conclusions. The GG genotype of MDM2 SNP309 is associated with an earlier onset of head and neck squamous cell carcinoma (HNSCC) in the Japanese population. SNP309 may be a key factor in the tumorigenesis of HNSCC as well as other hereditary or sporadic tumors. Objective. This study was designed to evaluate the association between the single nucleotide polymorphism (SNP) 309 in the MDM2 gene with HNSCC. An MDM2 protein down-regulates the p53 pathway. Recently, an important SNP was discovered in the MDM2 promoter region, which could affect the tumorigenesis of HNSCC by attenuation of the p53 pathway. Patients and methods. Patients with 103 HNSCCs were genotyped using direct sequencing and real-time PCR. The relationship between the SNP309 genotypes and the clinicopathological features was statistically analyzed. Results. The number of patients genotyped to TT, TG, and GG was 29 (28%), 46 (44.7%), and 28 (27.2%), respectively. The average age at tumor onset was 65.6 years for TT, 62.9 years for TG, and 56.7 years for GG. The patients with the GG genotype had a significantly earlier tumor onset in comparison to those with the TT genotype (p=0.032). © 2008 Taylor & Francis.全文公開200907

金沢大学附属病院耳鼻咽喉科, Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV) associated malignant tumor. Recently, cidofovir, an anti-viral drug which is an acyclic nucleoside analogue, has been reported to have an anti-tumor potential. Two patients with NPC, who had previously received multi-round therapy, were treated with cidofovir. Cidofovir was topically injected in and around the tumor once every 3 weeks (originally 75 mg/ml sulution, diluted to 15 mg/ml just before injection, 37.5 mg of cidofoviratatime).Tumorgrowth was suppressed for several months around the injection site in each patient. EBV-encoded RNAs in situ hybridization revealed the reduction of the tumor cell population; however, the EBER expression was still maintained in the NPC tumor cells. Although the anti-tumor mechanism remains unclear, these results suggest that cidofovir is actually an effective and safe agent for the treatment of NPC. © 2008 Wiley-Liss, Inc.

The results of this study suggest that the administration of vitamin E and vitamin C to patients with idiopathic sudden sensorineural hearing loss (ISSHL) has beneficial effects by reducing the level of reactive oxygen metabolites produced by inner ear ischaemia and reperfusion injury after treatment.The purpose of this study was to investigate the efficacy of antioxidant vitamin E and vitamin C in the treatment of ISSHL.In a retrospective chart review, a total of 87 patients were enrolled who fulfilled the following inclusion criteria: 1) sudden onset of sensorineural hearing loss, 2) cause of hearing loss unknown, 3) hearing loss did not fluctuate, 4) arithmetic mean of hearing levels at 250, 500, 1000, 2000 and 4000 Hz exceeded 40 dB and 5) treatment was started within 14 days from the onset of hearing loss. All the patients were treated with steroids and/or alprostadil. In the study group, patients additionally received vitamin E (tocopherol nicotinate, 600 mg/day) and vitamin C (1200 mg/day) orally.The hearing gain after therapy was 29.4 dB and the improvement rate was 63.3% in the study group, compared with 18.5 dB and 44.0% in the control group. Significant improvement was seen in the hearing gain and recovery rate in the study group.

Objectives: This study was designed to evaluate the efficacy and feasibility of our intra-arterial chemotherapy protocol with a lower amount and frequency of cisplatin delivery than in RADPLAT for the treatment of resectable advanced head and neck cancer. Methods: Fifty-one patients with advanced squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx were included in this prospective study. The patients were treated with 3 courses of cisplatin (100 mg at 1 treatment, intra-arterial) and sodium thiosulfate (28 g at 1 treatment, intravenous) once every 2 weeks during concurrent radiotherapy (66 to 70 Gy, 2 Gy per fraction, daily for 5 days over 7 weeks). Nodal metastases larger than 3 cm in diameter were treated with an additional 50 mg of cisplatin. The patients with less than 50% tumor reduction after 40 Gy and 2 courses of chemotherapy were treated with surgery. Results: The protocol was completed for 49 patients. All living patients had a minimum follow-up period of 2 years. Including the 3 patients with salvage surgery, local disease-free control was achieved in 39 patients (80%). For 36 patients (73.5%), disease-free primary organs were preserved at 2 years after treatment. Locoregional disease-free control for 2 years was obtained for 38 patients (77.6%), in 30 of them without salvage surgery. The patients treated with surgery had an overall survival rate similar to that of the patients with a complete response (80% and 84.6%, respectively). The patients with a partial response had a worse prognosis (40%; p = 0069). Conclusions: This treatment regimen is feasible and effective for advanced resectable head and neck cancer.

An aberrant internal carotid artery (ICA) is a rare vascular anomaly and causes to objective pulsatile tinnitus and retrotympanic mass. In the past, it was often diagnosed during ear surgery or biopsy, which may lead to massive bleeding. We present a case of 37-year-old woman complaining of pulsatile tinnitus. The tinnitus was objectively audible at the right ear through an otoscope. Previously, MRA plays a pivotal role in the evaluation of the aberrant ICA. But in this case, the resolution of magnetic resonance angiography (MRA) was not enough to portray the course of the ICA, because dephasing of the spins due to turbulence may cause loss of the signal intensity on MRA. Computed tomography (CT) of the temporal bone revealed aberrant internal carotid artery passing through the middle ear. It is important to diagnose approximately this anomaly using with combination of high-resolution CT, MRI, and MRA.

Cell motility plays a crucial role in invasion and metastasis of malignant tumors. Both AMFR and c-Met, known as key factors in up-regulation of cell motility, are overexpressed in a variety of malignant solid tumors. This study was designed to analyze the role of cell motility and its prognostic value in tongue squamous cell carcinoma (SCC). In addition, the expression of Ets-1, known as a transcription factor that regulates cell motility, was also studied to elucidate its relationship with c-Met and AMFR expression. The expression of c-Met, AMFR, and Ets-1 protein was analyzed by immunohistochemistry in 99 patients with tongue SCC. Then, the expression score of these proteins and their association with clinical factors was retrospectively evaluated. The expression level of both c-Met and AMFR was significantly correlated with local and distant metastatic tumor recurrence. Moreover, patients with increased expression of both c-Met and AMFR had significantly worse disease-free survival. The expression score of Ets-1 was also strongly correlated with that of c-Met, whereas it was weakly correlated with AMFR. Pathologically advanced tumor status (pT4), advanced node (pN2 and pN3), stage IV, c-Met and AMFR were significant hazards in univariate analysis. In multivariate analysis among stage IV, c-Met, and AMFR, AMFR expression remained a significant prognostic factor. This study suggests that Ets-1 contributes to the invasive phenotype through overexpression of c-Met. The evaluation of AMFR and c-Met in tongue SCC is valuable in identifying patients at high risk for recurrences and who should be treated as more advanced cases.

The purpose of this study was to elucidate the role of the superior thyroid artery in intra-arterial infusion chemotherapy for laryngeal and hypopharyngeal cancers. Thirty-nine patients with laryngeal cancer and 29 patients with hypopharyngeal cancer underwent intra-arterial infusion chemotherapy. We performed a retrospective analysis of the feeding arteries confirmed by computed tomography during selective arteriography and compared the results with the extent of the tumors. In 14 of 39 laryngeal and 15 of 29 hypopharyngeal cancers, the tumor did not cross the midline (group 1). In the remaining 25 and 14 cancers, respectively, the tumor crossed the midline or located in the center (group 2). For 13 of 14 laryngeal and 7 of 15 hypopharyngeal cancers in group 1 and for 6 of 25 laryngeal cancers in group 2, the entire tumor was contrast enhanced by the ipsilateral superior thyroid and/or superior laryngeal artery. For 12 of 25 laryngeal and 1 of 14 hypopharyngeal cancers in group 2, the entire tumor was contrast enhanced by the bilateral superior thyroid artery. For the other patients, infusion via the other arterial branches such as the inferior thyroid and the lingual arteries were needed to achieve contrast enhancement of the entire tumor. Superselective intra-arterial chemotherapy for laryngeal cancer from the superior thyroid artery is appropriate, whereas that for hypopharyngeal cancer is less sufficient. To accomplish contrast enhancement of the entire tumor, additional intra-arterial infusion from other arteries such as the inferior thyroid artery is often necessary.

金沢大学がん研究所がん病態制御, Amyloid-β precursor protein (APP) was identified on expression cloning from a human placenta cDNA library as a gene product that modulates the activity of membrane-type matrix metalloproteinase-1 (MT1-MMP). Co-expression of MT1-MMP with APP in HEK293T cells induced cleavage and shedding of the APP ectodomain when co-expressed with APP adaptor protein Fe65. Among the MT-MMPs tested, MT3-MMP and MT5-MMP also caused efficient APP shedding. The recombinant APP protein was cleaved by MT3-MMP in vitro at the A463-M 464, N579-M580, H622-S 623, and H685-Q686 peptide bonds, which included a cleavage site within the amyloid β peptide region known to produce a C-terminal fragment. The Swedish-type mutant of APP, which produces a high level of amyloid β peptide, was more effectively cleaved by MT3-MMP than wild-type APP in both the presence and absence of Fe65; however, amyloid β peptide production was not affected by MT3-MMP expression. Expression of MT3-MMP enhanced Fe65-dependent transactivation by APP fused to the Gal4 DNA-binding and transactivation domains. These results suggest that MT1-MMP, MT3-MMP and MT5-MMP should play an important role in the regulation of APP functions in tissues including the central nervous system. © 2006 The Japanese Biochemical Society.

Objectives/Hypothesis: The authors recently demonstrated that interleukin-8 (IL-8) is induced by Epstein-Barr virus encoding latent membrane protein 1 and that IL-8 is overexpressed in tumor cells and correlates significantly with angiogenesis in nasopharyngeal carcinoma. The present objective was to investigate the expressions and the roles of IL-8 receptors in nasopharyngeal carcinoma. Study Design: Retrospective patient file review and immunohistochemical study of tissues of patients with nasopharyngeal carcinoma. Methods: The authors examined the expressions of two high-affinity IL-8 receptors, IL-8 receptor A (IL8RA) and IL-8 receptor B (IL8RB), in 30 patients with nasopharyngeal carcinoma by immunohistochemical analysis. Results: As expected, both IL-8 receptors were expressed on microvessels in tumor nests and surrounding stroma. Interestingly, they were also abundantly expressed on tumor cells. The expressions of IL8RA and IL8RB had no associations with gender, metastasis, or clinical stage. However, the expression of IL8RA in tumors significantly correlated with a shorter overall survival rate (P = .0045). Although the estimated 5-year overall survival rate for IL8RA-negative patients was 68.2%, that in IL8RA-positive patients was only 33.3%. Conclusion: The study results suggest that the expression of IL8RA in tumor cells becomes an important indicator of poor prognosis in nasopharyngeal carcinoma.

Since the need for laparotomy in harvesting the omentum is the most significant drawback, the omentum has not been the tissue of choice for reconstructive surgery. To compensate for this drawback, we started laparoscopic harvesting of the omentum and clarified the advantages and disadvantages of this procedure. Ten patients underwent laparoscopic harvesting of the omentum by abdominal surgeons, followed by reconstruction of head and neck defects. Surgery was conducted in 5 cases of defect reconstructions for parotid gland tumor surgery and 5 of oropharyngeal defect after cancer surgery. The average harvesting time was 107 minutes (55-140 minutes) and used the omentum and different amounts and length of the vascular pedicle. Although the omentum was successfully transplanted in 9 of 10 cases, 2 cases showed partial peripheral necrosis and 1 total necrosis. With the advantage of laparoscopic harvesting of the omentum, we could obtain appropriate omental size for the defect size. Especially after total parotidecomy, the omentum was useful to fill in the defect, reducing the patients' worries about postoperative deformity. In one case, the omentum was used to treat Frey syndrome, successfully relieving the symptoms. In oropharyngeal reconstruction, the omentum is used to fill dead space and prevented postoperative infection. Although mild abdominal pain was observed a few days after surgery, no major abdominal complications such as intestinal perforation or ileus occurred in the 8 to 39 months following laparoscopic harvest of the omentum. Since the omentum is pliable and easily fills a complicated defect, the omentum is considered satisfactory for reconstructing defects of the lateral face after parotid tumor surgery and small defects after oropharyngeal tumor surgery.

医薬保健研究域医学系, We compared the amount of serum Epstein-Barr virus DNA (EBV-DNA) detected in patients with nasopharyngeal carcinoma (NPC) in a high-incidence area, represented by Taiwan, and a low-incidence area, represented by Japan, using real-time quantitative PCR. The median serum EBV-DNA value in 41 Japanese NPC cases was 5450 copies/ml, and that in in 23 Taiwanese cases was 2125 copies/ml. The median serum EBV-DNA value in all 64 NPC cases was significantly higher than in control groups. Using receiver-operating-characteristic (ROC) curves, the sensitivity and specificity of EBV-DNA quantification were determined (cut-off point, 6.87 copies/ml; sensitivity, 0.855; specificity, 0.885) and compared with those of EBV-viral-capsid-antigen (VCA) titers; the results showed that EBV-DNA was a more sensitive and specific parameter than EBV-VCA titer. Then, we analyzed 19 NPC patients in whom recurrence developed (11 Japanese and 8 Taiwanese), and 26 NPC patients in continuous remission. Although there was no significant difference in EBV-DNA values between Japanese and Taiwanese patients, the value was significantly higher in the 19 patients with recurrence than in those in remission. ROC analysis again revealed a higher diagnostic value of EBV-DNA than EBV-VCA. These results suggest EBV-DNA is a more reliable tumor marker than EBV-VCA in both high-incidence and low-incidence areas of NPC.

Background/Objectives: Nasopharyngeal carcinoma (NPC) is a highly invasive and metastatic malignant tumor and is associated with Epstein-Barr virus (EBV) infection that exhibits type II latency. Angiogenesis is essential for tumor growth, invasion, and metastasis. Our previous studies have indicated that interleukin (IL)-8 was over-expressed in many NPC tissues and was found to be significantly correlated with angiogenesis by immunohistochemistry. Study Design: In vitro design. Methods: The influence of the EBV genome for IL-8 gene expression was studied using the EBV–genome-positive and -negative epithelial/NPC hybrid cell line NPC-KT. The EBV-positive and -negative clones were selected by polymerase chain reaction and in situ hybridization. Results: EBV-positive clones expressed abundant IL-8 mRNA compared with EBV-negative clones. This result indicated that over-expression of IL-8 depended on the presence of EBV genomes in NPC-KT cells. Two encoded genes, latent membrane protein (LMP)1 and EBV-encoded small RNAs (EBERs), expressed in NPC were transfected in EBV-negative NPC-KT cells. LMP1 transactivated the IL-8 promoter, whereas EBERs did not. Moreover, the nuclear factor (NF)- κB binding site in the IL-8 promoter was essential for the response to LMP1, and the activator protein (AP)-1 binding site played only a partial role. Conclusions: LMP1 induces IL-8 mainly through the activation of NF-κB and partly through AP-1 in NPC model cell lines, NPC-KT, and this suggests that LMP1 plays an important role in the angiogenesis of NPC.

The odor stick identification test for Japanese (OSITJ) is the latest in measuring olfactory identification. It consists of 13 odorants familiar to the Japanese population. We studied the relationship between the Japanese standard olfactory test (T & T olfactometer) and the OSITJ in 182 patients with olfactory disturbance. The identification ratio in 2 of OSITJ tests using 13 odorants was correlated significantly negatively with the detection and recognition threshold measured by the T & T olfactometer. A high correlation between identification ratio and olfactory thresholds was maintained even when the number of odorants in the OSITJ was reduced to 2. For each odorant used, the identification ratio correlated significantly with olfactory thresholds. Results from the OSITJ provide a measure of the degree of olfactory deficit because the ratio of correct answers obtained by the OSITJ decreased gradually with of the severity of olfactory disturbance. Compared to the T & T olfactometer, the OSITJ has several advantages for use in the clinic. These include minimal odor pollution of the test room, simplicity of use, and shorter clinical time needed to administer the test. The OSITJ may be ideal for use in screening due to the minimum number of odorants needed. In conclusion, the OSITJ is useful for detecting and evaluating olfactory disturbance in Japanese people.

The transmembrane heparan sulfate proteoglycan syndecan-1 was identified from a human placenta cDNA library by the expression cloning method as a gene product that interacts with membrane type matrix metalloproteinase-1 (MT1-MMP). Co-expression of MT1-MMP with syndecan-1 in HEK293T cells promoted syndecan-1 shedding, and concentration of cell-associated syndecan-1 was reduced. Treatment of cells with MMP inhibitor BB-94 or tissue inhibitor of MMP (TIMP)-2 but not TIMP-1 interfered with the syndecan-1 shedding promoted by MT1-MMP expression. In contrast, syndecan-1 shedding induced by 12-O-tetradecanoylphorbol-13-acetate treatment was inhibited by BB-94 but not by either TIMP-1 or TIMP-2. Shedding of syndecan-1 was also induced by MT3-MMP but not by other MT-MMPs. Recombinant syndecan-1 core protein was shown to be cleaved by recombinant MT1-MMP or MT3-MMP preferentially at the Gly245-Leu246 peptide bond. HT1080 fibrosarcoma cells stably transfected with the syndecan-1 cDNA (HT1080/SDC), which express endogenous MT1-MMP, spontaneously shed syndecan-1. Migration of HT1080/SDC cells on collagen-coated dishes was significantly slower than that of control HT1080 cells. Treatment of HT1080/SDC cells with BB-94 or TIMP-2 induced accumulation of syndecan-1 on the cell surface, concomitant with further retardation of cell migration. Substitution of Gly245 of syndecan-1 with Leu significantly reduced shedding from HT1080/SDC cells and cell migration. These results suggest that the shedding of syndecan-1 promoted by MT1-MMP through the preferential cleavage of Gly245-Leu246 peptide bond stimulates cell migration.

We present a very rare case of mucosal melanoma with osteocartilaginous differentiation (MMOD). This is the first report of MMOD originating in the sinonasal cavity. Preoperative diagnosis of this tumor from specimens resected for biopsy alone is very difficult, because it has 2 histopathologic components: a primary melanoma site and the part of the melanoma with osteocartilaginous differentiation. The immunohistochemical technique is useful in histopathologic diagnosis of this tumor. Malignant melanoma usually shows reactivity with MelanA (melanoma tumor antigen) and S-100 proteins. We diagnosed this case as MMOD because both regions in this tumor were stained with MelanA and S-100 proteins. Magnetic resonance imaging provides the best clinical ability to detect malignant melanoma in the sinonasal region. In this case, the melanotic melanoma site in the posterior ethmoid sinus appeared hyperintense to gray matter on T1-weighted image magnetic resonance imaging. Thus, it would have been possible to diagnose this case as MMOD before operation, even though we could not obtain a biopsy specimen from the posterior ethmoid sinus lesion.

Intravenous olfaction is a unique stimulation method often used in Japan to diagnose olfactory disturbances. Odorant is injected into a vein and transported by blood flow and respiration to the upper air tract. The intravenous olfaction might allow the potential at the frontal scalp to be recorded without contamination from electromyograms, such as those caused by sniffing. We injected Alinamin (thiamine propyldisulphide) into healthy subjects according to a standard protocol for clinical intravenous olfaction testing and we simultaneously recorded potential changes at the frontal scalp. When Alinamin was injected into the right median cubital vein over a 20 s period, the potential changes with gamma-band oscillations were detected 17.6 +/- 6.7 s (mean +/- SD) after the start of the injection. The main frequency component of this gamma-band oscillation is 30-160 Hz. The gamma-band oscillation elicited by intravenous olfactory stimulation (VOP) was similar to the induced wave of the olfactory bulb. Mapping the VOPs on the frontal scalp of a subject with less developed frontal sinuses and the relation between the thickness of the frontal sinuses and VOP amplitude suggest an intracranial source, possibly the olfactory bulb. The gamma-band potential at the frontal scalp is a useful measure of central disturbance.

To investigate the importance of tyrosine recognition by the AP-1B clathrin adaptor subunit μ1B for basolateral sorting of integral membrane proteins in polarized epithelial cells, we have produced and characterized a mutant form of μ1B. The mutant (M-μ1B) contains alanine substitutions of each of the four conserved residues, which in the AP-2 adaptor subunit μ2 are critical for interacting with tyrosine-based endocytosis signals. We show M-μ1B is defective for tyrosine binding in vitro, but is nevertheless incorporated into AP-1 complexes in transfected cells. Using LLC-PK1 cells expressing either wild type or M-μ1B, we find that there is inefficient basolateral expression of membrane proteins whose basolateral targeting signals share critical tyrosines with signals for endocytosis. In contrast, membrane proteins whose basolateral targeting signals are distinct from their endocytosis signals (transferrin and low-density lipoprotein receptors) accumulate at the basolateral domain normally, although in a manner that is strictly dependent on μ1B or M-μ1B expression. Our results suggest that μ1B interacts with different classes of basolateral targeting signals in distinct ways.

Olfactory evoked potential is considered a useful method of electrophysiological olfactometry for the diagnosis of olfactory disturbance. However, electrophysiological olfactometry is not as widely used as electrophysiological audiometry, such as the auditory brain stem response, because odor stimulation is difficult to perform. In contrast, electrical pulse stimulation is easy to perform, and its evoked potential is also easily recorded by the averaging method. We recorded olfactory evoked potentials from the scalp produced by electrical stimulation on the olfactory mucosa and investigated the relationship between this electrical olfactory evoked potential (EOEP) and the results of Toyoda and Takagi's perfumist's strip method (T&T) olfactometry, which is a standard Japanese means of psychophysical olfactometry. In EOEP-detectable cases, the detection and cognitive thresholds of T&T olfactometry were 1.32 ± 1.99 (mean ± SD; n = 10) and 3.02 ± 1.64 (n = 10), respectively. But in the undetectable cases, the thresholds were 4.67 ± 2.03 (n = 8; 5.8 means off the scale) and 5.80 ± 0.00 (n = 8), respectively. The differences between the T&T thresholds of EOEP-detectable and -undetectable cases were significant. We concluded that EOEP is suitable for electrophysiological olfactometry.

Malignant myoepitheliomas of the salivary gland are very rare tumors which may either arise de novo or develop in a pre-existing pleomorphic adenoma. We report a case of malignant myoepithelioma of the minor salivary gland that progressed from benign pleomorphic adenoma. The original pleomorphic adenoma was resected in 1979 (the '79 tumor). The first recurrent tumor was operated in 1995 (the '95 tumor). The '95 tumor was diagnosed as pleomorphic adenoma. Although the myoepithelial tumor component was more prevalent in the '95 tumor, histological features of the first recurrent tumor were similar to the '79 tumor. The second recurrent tumor showed more aggressive clinical features (the '98 tumor). It also showed massive growth of myoepithelial tumor cells with bone invasion, which led to the diagnosis of the '98 tumor as malignant myoepithelioma. With adequate surgical margin, the patient has been free from tumor recurrence for 20 months.

Cyclooxygenase-2 (COX-2) is an inducible form of COX and is overexpressed in diverse tumors, raising the possibility of a role for COX-2 in carcinogenesis. In addition, COX-2 contributes to angiogenesis. The Epstein–Barr virus (EBV) oncoprotein, latent membrane protein 1 (LMP1), is detected in at least 70% of nasopharyngeal carcinoma (NPC) and all EBV-infected preinvasive nasopharyngeal lesions. We found that in specimens of LMP1-positive NPC, COX-2 is frequently expressed, whereas LMP1-negative NPC rarely express the enzyme. We next found that expression of LMP1 in EBV-negative nasopharyngeal epithelial cells induced COX-2 expression. Coexpression of IκBα(S32A/S36A), which is not phosphorylated and prevents NF-κB activation, with LMP1 showed that NF-κB is essential for induction of COX-2 by LMP1. We also demonstrate that NF-κB is involved in LMP1-inducedcox-2promoter activity with the use of reporter assays. Two major regions of LMP1, designated CTAR1 and CTAR2, are signal-transducing domains of LMP1. Constructs expressing either CTAR1 or CTAR2 induce COX-2 but to a lesser extent than wild-type LMP1, consistent with the ability of both regions to activate NF-κB. Furthermore, we demonstrate that LMP1-induced COX-2 is functional because LMP1 increased production of prostaglandin E2in a COX-2-dependent manner. Finally, we demonstrate that LMP1 increased production of vascular endothelial growth factor (VEGF). Treatment of LMP1-expressing cells with the COX-2-specific inhibitor (NS-398) dramatically decreased production of VEGF, suggesting that LMP1-induced VEGF production is mediated, at least in part, by COX-2. These results suggest that COX-2 induction by LMP1 may play a role in angiogenesis in NPC.

Nasopharyngeal carcinoma (NPC), which is closely associated with the Epstein-Barr virus (EBV), is a highly metastatic malignant tumor. An important activity in tumor invasion and metastasis is that of the 92-kDa type IV collagenase or gelatinase, matrix metalloproteinase 9 (MMP-9), which mediates the degradation of the basement membrane and extracellular matrix. The expression of MMP-9 has been shown to be enhanced by the EBV oncoprotein, latent membrane protein 1 (LMP-1). LMP-1, which is expressed in NPC, has two essential signaling domains within the carboxy terminus, termed C-terminal activation regions 1 (CTAR-1) and CTAR-2. This study reveals that either signaling domain can activate the MMP-9 promoter and induce MMP-9 activity; however, LMP-1 deletion mutants lacking either CTAR-1 or CTAR-2 had a decreased ability to induce MMP-9 expression. The deletion of both activation regions completely abolished the induction of MMP-9 activity, while the cotransfection of both the CTAR-1 and CTAR-2 deletion mutants restored MMP-9 activity to levels produced by wild-type LMP-1. The NF-κB and activator protein 1 (AP-1) binding sites in the MMP-9 promoter were essential for the activation of MMP-9 gene expression by both CTAR-1 and CTAR-2. The induction of MMP-9 expression by LMP-1 and both CTAR-1 and CTAR-2 mutants was blocked by the overexpression of IκB. The tumor necrosis factor receptor-associated factor (TRAF) pathway also contributed to the activation of the MMP-9 promoter as shown by the use of TRAF-2 and TRAF-3 dominant-negative constructs. These data indicate that the activation of both the NF-κB and AP-1 pathways by LMP-1, CTAR-1, and CTAR-2 is necessary for the activation of MMP-9 expression. In NPC, LMP-1 may contribute to invasiveness and metastasis through the induction of MMP-9 transcription and enzymatic activity.

Although patient death due to nasopharyngeal carcinoma (NPC) is increasing, few epidemiological analyses of NPC in Japan have been conducted since Sawaki's report in 1979. To determine the current incidence of NPC in Japan we examined NPC case in the Chubu area from 1986 to 1995. The leaders and reporting representatives of all otorhinolaryngological groups in the area were asked for their support of this epidemiological research. A total of 607 cases (445 male and 162 female NPC patients) were analyzed epidemiologically, histologically, serologically and clinically in this study. The incidence of NPC gradually increased with age. The mean age of the patients was 54.1 years. The age-standardized annual incidence in the Chubu region was 0.28 per 10(5) persons per year. The incidence in prefectures bordering Japan Sea (0.36) was significantly higher than that of prefectures facing the Pacific Ocean (0.21, P

Well differentiated squamous cell carcinoma of the nasal septum developed in a 55-year old man with Wegener's granulomatosis. It is suggested that the malignancy was induced by immunosuppressive state from an increased and prolonged use of cyclophosphamide and corticosteroids. Although the efficacy of the therapeutic concept using cyclophosphamide and corticosteroids is well established, there have been some few reports that cyclophosphamide could be implicated in the genesis of malignancies. The pathophysiology of Wegener's granulomatosis should be better understood, and effective and less toxic alternative protocol should be established.

Matrix metalloproteinases (MMPs) are frequently expressed in malignant tumor cells and are thought to play crucial roles in tumor invasion and metastasis. Here we report that expression of MMP9 is increased in Epstein-Barr virus (EBV)-infected type III latency lymphoma cell lines, but not in type I lines where latent viral gene expression is highly restricted. Type III cell lines express abundant EBV latent membrane protein 1 (LMP1), the principal EBV oncoprotein, as well as the other latency proteins including the transcriptional factor, EBV nuclear antigen 2, which is also required for cell immortalization. Transfection of an LMP1 expression plasmid in the C33A cell line increased MMP9 expression, whereas overexpression of EBV nuclear antigen 2 did not. Three motifs, homologous to the binding sites of NF-kappaB, SP-1, and AP-1 proteins, contribute to induction of the MMP9 promoter by 12-O-tetradecanoyl-phorbol-13-acetate and tumor necrosis factor alpha. Here we report that binding sites for NF-kappaB, SP-1, and AP-1 also contribute to induction of the MMP9 promoter by the viral protein, LMP1, mainly through the NF-kappaB and, to a lesser extent, the SP-1 and AP-1 sites. Moreover the AP-1 binding site is essential in that mutation of it abolished reporter gene induction by LMP1. The enhancement of MMP9 expression was blocked by cotransfection of an IkappaB expression plasmid. Thus in addition to its transforming properties, the oncoprotein LMP1 may contribute to invasiveness and metastasis of EBV-associated tumors such as nasopharyngeal carcinoma.

金沢大学医学部附属病院耳鼻咽喉科, A 54-year-old man complained of severe throat pain and showed subglottic oedema on fibre-optic endoscopy with a distinctly narrowed subglottic space on anteroposterior radiography of the neck and dense linear opacity at the level of the cricoid cartilage on lateral plain radiography. These findings suggested a foreign body just posterior to the cricopharyngeus, but a computed tomography (CT) scan demonstrated a dense calcified ridge on the posterior lamina of the cricoid cartilage but no foreign body.The patient improved symptomatically with systemic antibiotics and topical steroids, and gastrointestinal endoscopy did not detect any foreign body. This is a rare case of vertical ossification of the cricoid lamina masquerading as a foreign body.

Most physiological studies of the human olfactory system have concentrated on the cortical level; the olfactory bulbar level has been studied rarely. We attempted to stimulate the human olfactory mucosa by electrical pulse to detect the bulbar potentials. Electrical stimulation (2 mA, 0.5 ms) of the human olfactory mucosa evoked a change in potential recorded from the frontal sector of the head. A negative peak of the evoked potential that occurred at 19.4 ms (grand means, n = 5) after stimulation was the clearest. The highest amplitude of the potential was recorded from the frontal sector of the head on the stimulated side. Our findings were similar to the experimental results obtained from the olfactory bulbs of animals. This evoked potential was considered to be the human olfactory bulbar potential. When the subjects were stimulated by applying electricity to the olfactory mucosa, no sensation of smell occurred even though evoked potentials were recorded. Evoked potentials were recorded only when the stimulating electrode was located in the olfactory cleft. When the stimulating electrode was outside the olfactory cleft, the stimulation caused pain. The trigeminal nerve seemed to be stimulated by electricity. Olfactory evoked potentials produced by the electrical stimulation of the human olfactory mucosa should aid the research on human olfactory physiology, and may be applicable to clinical tests of olfactory dysfunction.

BACKGROUND Three types of membrane type-matrix metalloproteinases (MT-MMPs) have been identified as activators of pro-MMP2 (gelatinase A/72-kilodalton Type IV collagenase), which is believed to be crucial for tumor invasion and metastasis. MT1-MMP has been shown to be widely expressed in various tissues and to be overexpressed in lung and gastric carcinomas. METHODS Activation of pro-MMP2 was examined in head and neck squamous cell carcinoma (HNSCC) by gelatin zymography. The expression of the MT1-MMP mRNA transcript was studied by Northern hybridization and that of MT1-MMP protein by immunohistochemical staining with a monoclonal antibody against MT1-MMP. RESULTS Activation of pro-MMP2 was observed in ten of ten HNSCC tissues. Increased expression of the MT1-MMP mRNA transcript was also detected in eight of eight of these tissues. MT1-MMP positive cells were detected at the tumor cell lesions in the majority of these carcinoma tissues by immunohistochemical staining (24 of 27). MT1-MMP expression was more intense in moderately and well differentiated tumors than in poorly differentiated ones (P < 0.05). CONCLUSIONS These results suggest that MT1-MMP is involved in the activation of pro-MMP2 in HNSCC. These findings suggest that MT1-MMP is significant not only as a tumor marker but as a new target for chemotherapy against HNSCC. Cancer 1997; 79:139-44. © 1997 American Cancer Society.

We report a rare case of relapsing polychondritis with an initial symptom of inner ear involvement. This 53-year-old Japanese man experienced a hearing difficulty, tinnitus in both ears, and dizziness of sudden onset, but lacked auricular chondritis at that time, which is the most frequent finding in relapsing polychondritis. Thus it was difficult to reach a correct diagnosis. Steroid therapy, with oral prednisolone 15 mg daily, was effective. Almost two months after we began the steroid therapy, the patient complained of losing interest in his work and reported a hallucination vision on the TV screen, so the dose of prednisolone was decreased to 10 mg. The hallucinations then disappeared, but the serum level of C-reactive protein increased highly. To reduce the dose of prednisolone, we tried low-dose oral methotrexate. However, we had to discontinue it when the patient experienced severe vomiting and diarrhoea. As adjuvant therapy, we then administered Sho-saiko-to, Chinese herbal medicines with few side effects. Symptoms and laboratory abnormalities then improved markedly.

The treatment of sialolithiasis is discussed in this report. Generally, stones within the distal salivary duct are easily removed by transoral ductotomy, although proximal stones are usually treated by excision of the salivary gland and its duct. Since 1980, extracorporeal shock wave lithotripsy (ESWL) has been in clinical use for the treatment of renal and gallbladder stones. We used this technique as a treatment for sialolithiasis. We undertook ESWL on 14 submandibular gland stone patients, 1 parotid gland stone patient, and 3 submandibular duct stone patients. In 10 of 14 submandibular gland stone patients and 1 parotid gland stone patient, clinical symptoms such as pain and swelling disappeared without excision of the affected salivary gland. Stones larger than 10 mm seem to have a tendency to form Steinstrassen. Although computed tomography findings correlate with success in breaking up gallstones, they did not predict success for salivary stones. We conclude that sialolithiasis is treated successfully without adverse effects by ESWL in selected patients.

The fact that in vitro culture of murine organ allografts prior to transplantation enhances graft survival is commonly accepted. In this study, we examined the possibility of thyroid allotransplantation for the therapy of total thyroidectomy in the rat model. Transplanted thyroid function was determined by 125I uptake ratio and evaluated by immunohistochemical and microautoradiographical assessments. Fully allogeneic thyroid glands cultured for 8-24 hr in Hank's balanced salt solution (HBSS) at pH 6.3 or 7.2 were transplanted to rats under the kidney capsule. Five weeks after allotransplantation, thyroid glands cultured for 16 hr in HBSS at pH 6.3 presented prolonged survival. This procedure could be used as an initial therapy not only for total thyroidectomized patients but also for patients with primary hypothyroidism.

Extracorporeal shock wave lithotripsy (ESWL) was undertaken on 11 patients with sialolithiasis. In three patients, fragmented calculi were excreted via the duct of the gland. In four patients, though fragmented calculi were excreted from the gland to the duct, complete disappearance was not achieved. It was therefore necessary to remove the fragmented calculi by intraoral ductotomy. However, without ESWL, submandibular glandectomy would have been unavoidable. As for the two patients who had an intraducted stone and the one patient who had a 20 mm stone in his submandibular gland, ESWL was not effective. No severe complications occurred either during or after ESWL. ESWL is beneficial for the treatment of salivary stones, especially of the intraglandular and transitional zone type, and for stones smaller than 10 mm.

A rare case of extramedullary plasmacytoma in the sino-nasal cavity is presented. During a prolonged clinical course, the tumor has recurred several times after irradiation, chemotherapy and surgery, and presented in the clavicular bone as well. Immunohistochemical staining of each tumor showed IgA kappa phenotype, and immunoelectrophoresis of the serum showed overproduction of IgA with kappa light chains. Although an elevation of serum IgA persists, the patient has remained well without evidence of overt multiple myeloma.

The prevalence of MHL in 202, 1 to 6 year-old children with communication disorders who visited our clinic in 1991 was investigated. 1) 31% of the subjects had MHL bilaterally. The prevalence of MHL was 44% at age 1 year, 20% at age 2 years, 36% at age 3 years, 24% at age 4 years, 39% at age 5 years, 33% at age 6 years. 2) 88% of children with MHL had OME, 10% had mild sensorineural hearing loss, and 2% had cerminous plug. 3) The prevalence of MHL in children with mental retardation and autistic disorders was 9%, that with stuttering was 9%, that of OME accompanied by moderate and severe hearing disorders was 6%. 4) The primary causes in 191, except for those with stuttering, were as follows; the prevalence of MHL was 30%, that of mental retardation and autistic disorders was 24%, and that of articulation disorders was 28%. 5) On the other hand, the prevalence of MHL in children with retarded language development and articulation disorders was 30%, which was significantly higher than that of the other communication disorders. Accordingly, the results of this study suggest that MHL in early childhood greatly influences communication disorders.