Shigeru Saijo

Distribution of HRP in the Inner Ear after Injection into the Middle Ear Cavity

The distribution patterns of horseradish peroxidase (HRP) reaction products in the inner ears of guinea pigs were studied after injections into the middle ear cavities and perilymphatic and subarachnoid spaces. The normal round window membrane resisted HRP penetration from the middle ear side, but when it became pathological after repeated applications, its permeability increased. HRP deposits were found in the cochlear and vestibular sensory cells and in the lumen of the endolymphatic sac. HRP reaction products were minimal at the cochlear apex even after long survival times, suggesting that perilymph flow, if it exists, is rather weak toward this direction. Whereas the stria vascularis is impermeable to HRP, the vestibular dark cells were accessible; thus, the metabolic activity of the dark cells can be more readily controlled by drug applications through the middle ear cavity. The finding of HRP deposits on the scala vestibuli surface of Reissners membrane and the absence of HRP in the upper portion of the spiral ligament at the basal turn suggests that the oval window is a secondary route of passage for these particles from the middle ear cavity to the inner ear. In order to determine the route of HRP into the endolymphatic sac from the middle ear cavity or scala tympani, the cochlear and/or vestibular aqueducts were obliterated singly or together. The route of HRP was determined to be the vestibular aqueduct. HRP is believed to enter the sac lumen through Reissners and saccular membranes and the sac epithelium. Drugs and other large molecular substances instilled in or gaining access to the middle ear cavity may reach the endolymphatic sac causing its functional alteration.

Plasma-membrane-associated sialidase (NEU3) differentially regulates integrin-mediated cell proliferation through laminin- and fibronectin-derived signalling

We have found previously that human plasma-membrane-associated sialidase (NEU3), a key glycosidase for ganglioside degradation, was markedly up-regulated in human colon cancers, with an involvement in suppression of apoptosis. To elucidate the molecular mechanisms underlying increased NEU3 expression, in the present study we investigated its role in cell adhesion of human colon cancer cells. DLD-1 cells transfected with NEU3 exhibited increased adhesion to laminins and consequent cell proliferation, but decreased cell adhesion to fibronectin and collagens I and IV, compared with control cells. When triggered by laminins, NEU3 clearly stimulated phosphorylation of FAK (focal adhesion kinase) and ERK (extracellular-signal-regulated kinase), whereas there was no activation on fibronectin. NEU3 markedly enhanced tyrosine phosphorylation of integrin beta4 with recruitment of Shc and Grb-2 only on laminin-5, and NEU3 was co-immunoprecipitated by an anti-(integrin beta4) antibody, suggesting that association of NEU3 with integrin beta4 might facilitate promotion of the integrin-derived signalling on laminin-5. In addition, the promotion of phosphorylation of integrin beta1 and ILK (integrin-linked kinase) was also observed on laminins. G(M3) depletion as the result of NEU3 overexpression, assessed by TLC, appeared to be one of the causes of the increased adhesion on laminins and, in contrast, of the decreased adhesion on fibronectin - NEU3 probably having bimodal effects. These results indicate that NEU3 differentially regulates cell proliferation through integrin-mediated signalling depending on the extracellular matrix and, on laminins, NEU3 did indeed activate molecules often up-regulated in carcinogenesis, which may cause an acceleration of the malignant phenotype in cancer cells.

Combined therapy after superselective arterial cisplatin infusion to treat maxillary squamous cell carcinoma.

Objective We sought to assess the efficacy of combined therapy after superselective arterial cisplatin infusion (SACI) therapy to treat the maxillary squamous cell carcinoma. Study Design We conducted a retrospective chart review of 50 patients. After completion of two courses of SACI, 25 of the patients were successively treated by concurrent SACI and radiotherapy (AR), while the other 25 patients were treated by surgery with postoperative radiotherapy (ASR). Results Patients with surgery (ASR) had an 88% local control rate with 75% disease-free survival rate at 60 months by Kaplan-Meier analysis, compared with 62% disease-free survival rate for patients with AR treatment. A particularly good outcome was obtained in T4 cases of the ASR group (n = 8) whose 5-year survival rate was 87% and local control rate was 100%. Conclusion/Significance Combined SACI therapy is very effective for the treatment of maxillary squamous cell carcinomas and contributes to the improving prognoses of patients and organ preservation rates.

A novel G106D alteration of the SDHD gene in a pedigree with familial paraganglioma

Head and neck paragangliomas are tumors derived from parasympathetic paraganglia. Familial cases account for 10% or more of these tumors, and mutations of the genes encoding subunits for the mitochondrial respiratory chain complex II, SDHD, SDHB, and SDHC, have been reported. We analyzed mutations in the all four SDH genes, SDHA through SDHD, in a Japanese family with cervical paraganglioma that include a father with bilateral tumors and his daughter with a malignant left carotid body tumor with nodal metastasis. This pedigree harbored a germline G106D alteration in exon 4 of the SDHD gene that has not previously been reported to date. The tumors of the father expressed biallelic SDHD, but the SDHD expression was highly suppressed by an unknown mechanism(s) in tumors of his daughter, and the wild‐type allele was predominantly suppressed in the metastatic node. These results suggest that the missense dysfunction of SDHD prepares neoplastic condition and that expressional silencing, particularly of the wild‐type allele, plays an important role in the malignant transformation of the paragangliomas. Our results may lead to a better understanding of this disease and to the development of methods for prevention of this disease.

CD271 Defines a Stem Cell-Like Population in Hypopharyngeal Cancer

Cancer stem cells contribute to the malignant phenotypes of a variety of cancers, but markers to identify human hypopharyngeal cancer (HPC) stem cells remain poorly understood. Here, we report that the CD271+ population sorted from xenotransplanted HPCs possesses an enhanced tumor-initiating capability in immunodeficient mice. Tumors generated from the CD271+ cells contained both CD271+ and CD271− cells, indicating that the population could undergo differentiation. Immunohistological analyses of the tumors revealed that the CD271+ cells localized to a perivascular niche near CD34+ vasculature, to invasive fronts, and to the basal layer. In accordance with these characteristics, a stemness marker, Nanog, and matrix metalloproteinases (MMPs), which are implicated in cancer invasion, were significantly up-regulated in the CD271+ compared to the CD271− cell population. Furthermore, using primary HPC specimens, we demonstrated that high CD271 expression was correlated with a poor prognosis for patients. Taken together, our findings indicate that CD271 is a novel marker for HPC stem-like cells and for HPC prognosis.

Malignant melanoma of the head and neck: A multi‐institutional retrospective analysis of cases in Northern Japan

Mucosal melanoma of the head and neck is rare and is associated with a poor prognoses because of locoregional failure and distant metastasis. The aim of our study was to review the characteristics of these patients in northern Japan and to analyze their outcomes.

miR-34a is downregulated in cis-diamminedichloroplatinum treated sinonasal squamous cell carcinoma patients with poor prognosis.

For the purpose of analyzing mechanisms related to the cis‐diamminedichloroplatinum resistance in head and neck squamous cell carcinoma, we analyzed RPMI2650 and its derived previously established cis‐diamminedichloroplatinum resistant cell line RPMI2650CR. To identify resistant phenotype‐related microRNAs, we compared microRNA expressions between RPMI2650CR and RPMI2650 by microarray. One of the microRNAs as downregulated, miR‐34a, was further investigated. Decreased expression of miR‐34a in RPMI2650CR was confirmed by quantitative reverse transcription‐polymerase chain reaction, but introduction of the miR‐34a precursor into RPMI2650CR or the inhibitor of miR‐34a into RPMI2650 did not change cis‐diamminedichloroplatinum sensitivities. However, 24 patients with sinonasal squamous cell carcinomas treated with intra‐arterial infusion of cis‐diamminedichloroplatinum showed a significant association between decreased expression of miR‐34a and poor disease specific survival (P = 0.0015), poor disease free survival (P = 0.0019), and poor local control rates (P = 0.017) (median follow‐up period: 53 months). Furthermore, multivariate analyses demonstrated significant associations between miR‐34a expression and the hazard ratios of disease free survival at 0.005 (95% confidence interval [CI] 0.00–0.29, P = 0.011) and local control rate at 0.008 (95% CI 0.00–0.44, P = 0.019), although other parameters such as age, gender, treatment method, T and N stages did not show any similar association. These results strongly suggest that miR‐34a expression can be an independent prognostic biomarker in patients with sinonasal squamous cell carcinoma who are undergoing treatment with cis‐diamminedichloroplatinum.

Complication-Free Laryngeal Surgery after Irradiation Failure with Prostaglandin E1 Administration

To examine the usefulness and efficacy of administration of prostaglandin E1 (PGE1) after laryngeal surgery in patients who were previously treated with radiotherapy, we retrospectively examined the clinical data of 12 patients who had undergone partial laryngectomy and 21 patients who had undergone total laryngectomy. Complications were observed in 5 of the 7 cases treated with partial laryngectomy without PGE1 administration, while no complications were observed in the 5 cases treated with PGE1 after operation. Also, complications, including major leakage, were observed in 6 of the 15 patients who underwent total laryngectomy without PGE1, and no complications were observed in the 6 patients who received PGE1. The hospital stay was shorter for the patients treated with PGE1 than for those not receiving such treatment. Although this study was a small, nonrandomized pilot trial, the results indicated that PGE1 administration may be useful and effective for patients who undergo laryngeal surgery after irradiation failure, in decreasing the risk of postoperative complications and increasing the quality of life of the patients.

A Case of Carcinoid Tumor of the Middle Ear Producing Peptide Hormones

We report 6th case of carcinoid tumor of the middle ear in a 16-year-old man. The clinical, histologic, immunohistochemical and ultrastructural features are discussed. The tumor in the attic and the tympanic cavity was successfully excised by radical mastoidectomy. Microscopically, the argyrophilic property and neurosecretory granules which are characteristic of carcinoid tumor were found in the cytoplasm of tumor cells. Furthermore, peptide hormones were confirmed immunohistochemically in this case. This tumor should be considered in the differential diagnosis when biologically lowgrade tumor with glandular and trabecular architectures are encountered in the middle ear.

Foreign bodies in the tracheobronchial tree

ZusammenfassungZwischen 1966 und 1974 wurden 110 Fremdkörper im Tracheo-Bronchialbaum unter Allgemeinnarkose und Beatmungsbronchoskopie entfernt. Die Methode hat sich auch bei Kindern bewährt. Bei der Hälfte der Fälle handelt es sich um Erdnüsse. Die Fremdkörper fanden sich vorwiegend im rechten Hauptbronchus. Nur bei Kindern unter sechs Jahren war der linke Hauptbronchus bevorzugt.SummaryDuring the period from 1966 to 1974, 110 cases of foreign bodies in the tracheobronchial tree were treated in our clinic using the ventilation bronchoscope under general anesthesia, and good results were obtained. Upon reviewing the case records, the ventilation bronchoscope was evaluated to be safe even for infants.Of the 110 cases, male predominance was 2 to 1, and 76 infants were under 3 years of age. Although, various types of foreign bodies were removed, almost half of the cases involved peanuts. Generally, the right bronchus was obstructed more frequently than the left. However, in children under 6 years of age, this tendency was inverted especially in 53 cases involving peanuts. The relationships between the age factor and the location of the foreign bodies are discussed.