Laryngeal granuloma in experimental rats with gastroesophageal reflux disease and mechanically injured vocal cord mucosa.

OBJECTIVE: This study was undertaken to elucidate the mechanisms underlying laryngeal granuloma formation in a rat model of gastroesophageal reflux disease (GERD) with mechanically injured vocal cord mucosa. METHODS: The rat model of GERD was surgically created by tying the pyloric sphincter and ligating the transitional region between the forestomach and the glandular portion (limiting ridge). The control rats received only a midline incision. In all the animals, a plastic bar was inserted into the trachea, and moved vertically thrice in 3 seconds to cause mechanical injury of the vocal cord mucosa. The rats were sacrificed 2 weeks postsurgically, and their pharynx and larynx were observed histologically. RESULTS: Granulomas were observed in the vocal cord mucosa of the GERD group (3 of 5 animals); they presented a similar pathological structure to that of human laryngeal granulomas. In contrast, only abrasions and blisters were observed on the vocal cord mucosa in the control group (all 5 animals). CONCLUSIONS: The development of laryngeal granuloma may involve both mechanical injury and gastric acid reflux.

[Time course of changes in gustatory function test results and subjective symptoms, and predictive factors for response in patients with taste disorder receiving 24-week zinc replacement treatment].

In a taste disorder, an agreement between patients' complaints and gustatory function test results is not necessarily found both at the initial hospital visit and during the course of treatment; therefore, it is difficult to assess treatment responses and review treatment strategies based on the assessed treatment responses. The present study investigated the time course of changes in disc gustometry results and subjective symptom scores measured at 4-week intervals in 44 patients with a taste disorder who were considered eligible for zinc replacement treatment and who received polaprezinc at a dose of 150 mg/day (equivalent to a 34 mg/day dose of zinc) for up to 24 weeks. The study also examined the potential differences in treatment outcomes according to the predictive factors for response such as patient background and assessed disc gustometry results during the course of treatment. Results indicated that disc gustometry results and subjective symptom scores showed different time courses of changes. The response rate as measured by disc gustometry was 47.7% at week 12 of treatment, and showed a subsequent slow increase to 56.8% at week 24. On the other hand, subjective symptom scores showed a time-proportional improvement up to week 24. Among the patients included in the present study, a clear difference was found according to the presence or absence of an improving trend as determined by disc gustometry at week 12 of treatment, although there were no differences in ultimate treatment responses, including categories of taste disorder, according to patient background. Patients showing a trend toward improvement had significantly better treatment responses in terms of both ultimate response rates and subjective symptom scores, whereas patients showing no trend toward improvement were less likely to respond to the subsequent 12-week continued treatment.

Innate immune reactions in locally limited tonsillar cancer.

Tonsillar cancers often present as locally limited tumors but with cervical metastases. When the primary tumors of tonsillar cancers with cervical metastases are as small as clinically occult, the clinical features are diagnosed as primary-unknown cervical metastases. However, little is known as to why small tonsillar cancers establish cervical metastases. The aim of this study was to investigate a possibility that innate immune reactions might suppress the growth of tumors arising in the palatine tonsils, because the palatine tonsils contain various immune effector cells. Infiltration of natural killer (NK) cells and macrophages, which are major innate immune cells, in surgically removed tumors from patients with locally limited tonsillar cancers and tongue cancers was immunohistochemically studied by using anti-CD57 and anti-CD68 antibodies. Phagocytosis of the tumor cells by macrophages was also studied by dual immunofluorescence labeling. The number of infiltrating CD57+ NK cells and CD68+ macrophages was significantly increased in locally limited tonsillar cancers in comparison to normal tonsils and tongue cancers. The phagocytosis of tumor cells by CD68+ macrophages was observed significantly more frequently in tonsillar cancers than in tongue cancers. These results indicated that the innate immune reactions were more strongly induced in locally limited tonsillar cancers than in tongue cancers, and might therefore suppress the growth of primary tumors in palatine tonsils. The innate immune reactions against cancers in palatine tonsils were suggested to be one of the possible etiologies for the developing of primary-unknown cervical metastases.

[The effect of zinc agent in 219 patients with zinc deficiency-inductive/ idiopathic taste disorder: a placebo controlled randomized study].

Diagnosis and treatment of taste disorders are challenging because the disorder can only be determined by the awareness of the patient. Hence, these disorders still require comprehensive evidence. We conducted a randomized, placebo-controlled double-blind study to investigate the effect of polaprezinc, a zinc-containing agent, in 219 patients with either zinc deficiency-inductive or an idiopathic taste, disorder. As a result, the zinc-treated arm experienced a statistically significant improvement against the placebo-treated arm in the perceptible threshold scores of the filter-paper disk method 8 weeks after the administration of the investigational drug. Moreover, the effect lasted for 4 weeks after discontinuation of the drug. However, the effective ratios based on the initial criteria were 55.6% in the treatment group and 43.2% in the placebo, where no statistical significance was recorded. Sex and degree of depression could be two of the potential factors to explain this discrepancy. Furthermore, the effect was not significant among male patients and patients with a high depression score based on the Self-rating Depression Scale (SDS) test. These results indicate that determining the symptom among such patients remains undisclosed. Whereas, in approximately 77%, or 168 patients with "normal" SDS scores and with completely impaired taste qualities, the ratio of effective cases reached 60.9% in the zinc-treated group, the ratio of the placebo-treated group reached 39.5%, resulting in a statistical significance. This may be partly because of a problem in the adaption of male subjects to the gustatory analyses, especially to the identification of saltiness and sourness. Care must also be taken regarding the depressive state of patients when diagnosing and treating taste disorders. Taste disorders caused by depression may not be cured by zinc supplementation due in part to the fact that the symptom is based on a mental issue, and due in part to the conservative responding bias generated by the depression itself, which may inhibit accurate and precise diagnosis of the disorder. In conclusion, administration of a zinc agent is effective for patients with taste disorders, provided selection of appropriate patients is performed, and that proper examination and evaluation are conducted. The present study also indicated that examining depressiveness based on the SDS scores and investigating disturbance of each taste quality using the filter-paper disk method are recommended for the diagnosis and determination of the treatment effect of a taste disorder.

Endotoxin tolerance attenuates airway allergic inflammation in model mice by suppression of the T-cell stimulatory effect of dendritic cells.

Prior exposure of dendritic cells (DCs) and monocytes/macrophages to LPS causes unresponsiveness to subsequent LPS stimulation, a phenomenon called endotoxin tolerance (ET). ET impairs antigen presentation of these cells to T cells by down-regulating expression of MHC class II and co-stimulatory molecules such as CD86 and CD40. Some epidemiological studies have shown that endotoxin acts as a protective factor for allergic diseases. Accordingly, LPS has beneficial effects on the onset of airway allergic inflammation in model animals by T(h)1 skewing or induction of regulatory T cells. However, results derived from asthma model animals are controversial, probably due to the difficulty of handling LPS. We previously generated a monoclonal agonistic antibody against Toll-like receptor (TLR) 4, named UT12, which mimics the biological activities of LPS, exhibiting more potent and sustained ET than does LPS. In this study, we took advantage of UT12 to generate prolonged ET to explore the possibility that ET is involved in the inhibitory effects of the TLR4 signals on asthma model mice. Induction of ET by UT12 inhibited the capacity of DCs to expand ovalbumin (OVA)-specific T(h)2 and T(h)17 cells, without inducing T(h)1 cell or regulatory T-cell populations or producing inhibitory cytokines. Accordingly, administration of UT12 before the OVA sensitization significantly suppressed airway allergic inflammation by OVA inhalation. Taken together, these results demonstrate that ET induced by activating TLR4 signals attenuates airway allergic inflammation through direct suppression of the T-cell stimulatory effect of DCs in asthma model mice.

Relationship between squamous cell carcinoma antigen and the clinical severity of allergic rhinitis caused by Dermatophagoides farinae and Japanese cedar pollen.

OBJECTIVES: Allergic rhinitis is known to be related to the Th2-type immune response, but no sensitive biomarker of severity yet exists. Serum squamous cell carcinoma antigen (SCCA) is clinically used as a popular tumor biomarker. We have demonstrated that SCCA is related to allergic diseases such as asthma. The purpose of the present study was to clarify the relationship between allergic rhinitis and SCCA, which had not yet been investigated. METHODS: We compared the serum SCCA levels in patients with allergic rhinitis due to Japanese cedar pollen and Dermatophagoides farinae with those in normal subjects. Thereafter, the correlations between the clinical severity of allergic rhinitis and the serum levels of SCCA were investigated. Furthermore, the influence of 8 variables (serum levels of SCCA, immunoglobulin E, eosinophil cationic protein, and eosinophils; age; gender; oral administration of antiallergic or antihistaminic agents; and use of nasal drops) in regard to the severity of allergic rhinitis was studied by a multiple regression analysis. RESULTS: The SCCA levels of the D farinae group were statistically higher than those of the control group, and they correlated with the severity of rhinitis. Among the 8 variables, only the SCCA level was found to be a predictive factor of severity on a multiple regression analysis. No relationship between SCCA level and Japanese cedar pollen allergy was demonstrated. CONCLUSIONS: These results suggest that the serum SCCA level may be a useful biomarker to evaluate the severity of allergic rhinitis caused by D farinae.

[A comparative study of concurrent chemoradiotherapy with S-1 or CDDP for pharyngeal or laryngeal cancer].

Adverse events and therapeutic effects were analyzed in patients with pharyngeal or advanced laryngeal squamous cell carcinomas(SCCs)receiving concurrent chemoradiotherapy (CCRT) with S-1 or weekly CDDP between 2004 and 2007. Low-dose CDDP (25 mg/m2) was administered once a week and S-1 (65 mg/m2) was administered for 3 weeks with one-week rest during conventional radiation with 2 Gy/fraction. Both of the two CCRT regimens showed little toxicity with grade 4 toxicities in less than 5%of the patients. However, CCRT with S-1 more frequently induced grade 3 and 4 oral mucositis than CCRT with CDDP. As a result, the completion rate of CCRT with S-1 was lower than that of CCRT with CDDP. The two regimens achieved a similar complete response rate of the primary sites, local control rate(LCR)and larynx preservation rate; the LCR for T1 and 2 disease was more than 70%. However, the LCR for T3 or 4 disease by the two regimens was less than 50%. CCRT with S-1 showed significantly higher LCR in patients with poorly or undifferentiated SCCs than those with well or moderately-differentiated SCCs. It is suggested that the two CCRT regimens are useful treatment modalities for patients with locally(primary site)non-advanced pharyngeal or laryngeal SCCs, and that CCRT with S-1 is highly sensitive to poorly or undifferentiated SCCs. In order to achieve local control and larynx preservation, more intensive CCRT might be necessary for patients with locally(primary site)advanced pharyngeal or laryngeal SCCs.

[Cepharanthin effect on radiation-induced xerostomia and taste disorder in patients with head and neck cancer].

In evaluating the effect of cepharanthin on xerostomia and taste disorder in 40 patients undergoing radiotherapy for head and neck cancer, we administered cepharanthin intravenously during chemoradiotherapy to 22 patients, with 18 others as a control group. Cepharanthin did not significantly affect salivary secretion during and after chemoradiotherapy, although taste disorder and oral discomfort were alleviated. Cepharanthin may thus be effective in maintaining the quality of life of patients with head and neck cancer.

Helicobacter pylori in the palatine tonsils of patients with IgA nephropathy compared with those of patients with recurrent pharyngotonsillitis.

Helicobacter pylori infection is acquired by oral ingestion. However, the morphology and microscopic localization of H pylori in the human oral cavity and pharynx are unknown. In the present study, we performed immunohistochemistry, immunoelectron microscopy, in situ hybridization, and polymerase chain reaction to identify H pylori in the palatine tonsils of 32 patients with immunoglobulin A nephropathy (IgAN) and 141 patients with recurrent pharyngotonsillitis (RPT). H pylori in coccoid form was present in bacterial colonies and horny layers of the stratified squamous epithelium in tonsillar crypts. We described for the first time the morphology of H pylori in palatine tonsils. Most bacterial colonies were sulfur granules with Actinomyces israelii (A israelii), and A israelii showed significant coexistence with H pylori (P=.011). The prevalence of H pylori in palatine tonsils of the RPT group increased steeply with age, but one fourth of the patients were found not to have tonsillar H pylori in adulthood. All patients with IgAN had H pylori in palatine tonsils. The prevalence of H pylori was greater in the IgAN group than in the RPT group, and the difference was statistically significant (P<.001). In contrast, A israelii was unrelated to age and clinical diagnosis (P=.722). In conclusion, our results demonstrate that H pylori in coccoid form is present in palatine tonsils and may indicate that H pylori in palatine tonsils is among the antigens causative of IgAN.

Hypopharyngeal squamous cell carcinoma bordering ectopic gastric mucosa "inlet patch" of the cervical esophagus.

OBJECTIVE: Ectopic gastric mucosa of the cervical esophagus, referred to as inlet patch (IP), is considered to be a common development abnormality of the esophagus. We report here a case of hypopharyngeal squamous cell carcinoma bordering on IP of the cervical esophagus. METHODS: A 44-year-old female underwent partial pharyngectomy, total laryngectomy, cervical esophagectomy, and bilateral neck dissection under the diagnosis of hypopharyngeal carcinoma. RESULTS: Resected specimens of the hypopharynx revealed a well-differentiated squamous cell carcinoma in the ulcerative tumorous lesion (3.5 cm x 0.5 cm). A brown patch (2 cm x 1.5 cm) bordering the anal aspect of the tumor comprised ectopic gastric mucosa of fundic type epithelium. Immunohistochemistry revealed the surface mucosal cells of this lesion were strongly positive for human gastric mucin (HGM) and the fundic cells were positive for gastrin. CONCLUSION: The hypopharyngeal squamous cell carcinoma likely developed in association with chronic irritation due to gastric acid from the IP. To our knowledge, this is the first reported case of squamous cell carcinoma related to IP.

[A case of follicular carcinoma of thyroid gland with concurrent tuberculous lymphadenitises].

We report a case of follicular carcinoma of the thyroid gland with concurrent tuberculous lymphadenitises as neck lymph node metastases of thyroid carcinoma. A 71-year-old woman presented with multiple painless masses in the thyroid gland and painless lymphadenopathies in the right neck. She and her family had no previous history of tuberculosis. A diagnosis of thyroid cancer with lymph node metastases was made, and the patient underwent total thyroidectomy with neck dissection. Lymph nodes were hard and severely adhered to the internal jugular vein. The histopathological diagnosis was follicular carcinoma and multiple nodes of adenomatous goiter of the thyroid gland, and tuberculous lymphadenitises of lymph nodes in the right neck. There was no findings of coexisting pulmonary tuberculosis. The possibility of coexisting tuberculous lymphadenitis must thus be ruled out when we find painless lymph node swelling in aged patients with head and neck cancer including thyroid cancer.

Diffuse expression of laminin gamma2 chain in disseminating and infiltrating cancer cells indicates a highly malignant state in advanced tongue cancer.

The expression of laminin (LN)gamma2 chain in the primary lesions of 20 patients with advanced tongue cancer was analyzed. Positive expressions of LNgamma2 were noted in all of the primary tissue specimens, however, the expression patterns clearly differed according to the mode of growth and invasion of cancer cells. In tumor nests where cancer cells preserved cell-cell adhesiveness and showed polar differentiation, LNgamma2 was expressed only in the peripheral cells of the tumor nests; peripheral expression. On the other hands when cancer cells diminished their cell-cell adhesiveness and strongly infiltrated through stroma, almost all of the cancer cells diffusely expressed LNgamma2; diffuse expression. The peripheral expression of LNgamma2 were noted in 13 patients and the diffuse expressions were noted in 7 patients. The rates of positive cervical metastases according to the expression type were 7/13 for the peripheral expression and 7/7 for the diffuse expression (p = 0.02). The diseases specific 3-year survival rates for the patients with the peripheral expression and the diffuse expression were 68% and 14%, respectively (p = 0.02). The diffuse expression of LNgamma2 in the disseminating and infiltrating cancer cells might indicate a highly malignant state in advanced tongue cancer. Therefore, a more intensive treatment modality would be necessary for the patients with advanced tongue cancer showing the diffuse LNgamma2 expression.

Squamous cell carcinoma arising from Stensen's duct.

We report a case of squamous cell carcinoma presumably arising from the left Stensen's duct. The tumor was discovered during management of recurrent left parotitis. Ultrasonography, computed tomography, and magnetic resonance imaging were useful for estimating the tumor and coexisting obstructive parotitis. Relapsing symptoms and the presence of parotitis seemed to be characteristic of tumors of Stensen's duct. For a mass accompanied by obstructive parotitis or relapsing parotitis without salivary calculus, a tumor of Stensen's duct should be included in the differential diagnosis.

A case of an upper cervical bronchogenic cyst in an adult.

We herein report a case of a rare cervical cystic lesion, namely a congenital bronchogenic cyst, which presented as an asymptomatic upper cervical mass in a 22-year-old female. Although cervical bronchogenic cysts are rare lesions in adults which are very difficult to accurately diagnose preoperatively, they deserve inclusion in the differential diagnosis of cervical cystic lesions.

Basal cell adenoma and lymphoepithelial cyst as recurrent tumors of pleomorphic adenoma of the parotid gland.

Basal cell adenoma of the parotid gland is a rare benign tumor. Lymphoepithelial cyst of the parotid gland is also a rare benign tumor-like lesion. We report an elderly woman, who previously underwent a removal of pleomorphic adenoma, with multiple masses in the left parotid gland. Physical, MR and intra-operative examination suggested the masses as multiple recurrences of the previous pleomorphic adenoma. A total parotidectomy with facial nerve preservation was performed. The histological examination revealed that the masses were two basal cell adenomas and one lymphoepithelial cyst. These rare tumors should be considered in the differential diagnosis of recurrent masses after a removal of pleomorphic adenoma of the parotid gland.

Expression of laminin 5 basement membrane components in invading and recurring adenoid cystic carcinoma of the head and neck.

OBJECTIVE: Adenoid cystic carcinoma (ACC) of the head and neck grows slowly with structural differentiation, however, this tumor nevertheless also shows a highly invasive potential and a high recurrence rate. Extracellular matrices have been suggested to play an important role in the differentiation and growth of ACC. The aim of this study is to understand the roles of laminin 5 basement membrane (BM) components, including collagen IV and laminin gamma2 for the high degree of invasiveness and the recurrence of ACC. METHODS: Collagen IV and laminin gamma2 were immunohistochemically localized in tissue sections from nine patients with ACCs. RESULTS: Cribriform structures with pseudocysts were preserved in small invading tumor nests, and the expression of both of collagen IV and laminin gamma2 was observed in the inner border of the pseudocysts and the surrounding area of the tumor nests. In areas of perineural invasion, the BM components continued to be expressed around the long tumor nests. Recurrent tumors consisted of multiple small nests with a few tumor cell layers, and the expression of the BM components was observed on both the inside of the inner tumor cells and the outside of the outer tumor cells, which was an obviously different appearance from that of the primary tumor. CONCLUSION: ACC appears to possibly grow and invade using the laminin 5 BM matrices while also preserving their differentiated architecture. The laminin 5 BM matrices might play an important role not only in the differentiation and growth, but also in the invasion and recurrence of ACC of the head and neck.

[Blood concentration of laminin gamma2 chain in patients with head and neck cancer].

Laminin gamma2 chain (LN gamma2), expressed in human cancer cells and correlated with cancer malignancy, is cleaved by proteases and secreted into circulation. We measured the blood concentration of LN gamma2 in patients with head and neck cancer by an immuno-fluorescence assay using monoclonal antibodies against human LN gamma2. The normal blood concen- showed normal LN gamma2 concentration less than 50 ng/ml and 20 (33%) increased concentration exceeding 50 ng/ml. The relative ratio of the number of patients who showed increased LN gamma2 concentration correlated with the clinical stages of cancer. The blood concentration of LN gamma2 in 24 who initially showed normal concentrations did not change after radical treatments. Five who initially showed increased LN gamma2 concentration showed decreased concentration of less than 50 ng/ml after radical treatment. Four showed increased LN gamma2 concentration after treatment, and presented residual cancer, which killed them. Three of the 4 patients showed marked increase in LN gamma2 concentration exceeding 100 ng/ml and developed multiple distant metastases to the lung, liver, bone, and skin. The blood concentration of LN gamma2 in patients with head and neck cancer may thus indicate the amount of highly malignant cancer cells expressing LN gamma2. The blood concentration of LN gamma2 could therefore serve as a new tumor marker that might indicate the malignancy of and efficacy of treatments for head and neck cancer.

Identification of a novel human cancer/testis antigen, KM-HN-1, recognized by cellular and humoral immune responses.

PURPOSE: We used serologic screening of a cDNA expression library of human testis to identify novel cancer/testis antigens that elicit both humoral and cellular immune responses in cancer patients. EXPERIMENTAL DESIGN AND RESULTS: We identified a novel gene designated KM-HN-1 the expression of which is testis-specific among normal tissues; it contains coiled coil domains and a leucine zipper motif and encodes a putative protein consisting of 833 amino acids. KM-HN-1 expression was observed in various cancer tissues and cancer cell lines at both mRNA and protein levels. Immunofluorescence staining of an esophageal cancer cell line revealed that KM-HN-1 protein was present exclusively in the nucleus during mitosis. Recombinant KM-HN-1 protein was produced, and used for ELISA to quantitate levels of IgG antibody specific to KM-HN-1. Higher levels of IgG antibodies specific to KM-HN-1 were detected in many types and numbers of cancer patients but not in healthy donors. The CTL lines specific to KM-HN-1, generated from HLA-A*2402-positive healthy donors and cancer patients, killed human leukocyte antigen (HLA)-A24-positive cancer cells expressing KM-HN-1 but not cell lines that did not express either KM-HN-1 or HLA-A24. CONCLUSIONS: We identified a novel cancer/testis antigen, KM-HN-1, which elicited humoral immune responses in patients with various types of cancer. Furthermore, KM-HN-1-specific CTLs could be generated from both healthy donors and cancer patients, which indicated that KM-HN-1 can be a candidate for an ideal target for cancer immunotherapy.

A new in vitro model for analyzing the biological behavior of well-differentiated squamous cell carcinoma.

A suitable model analyzing the behavior of well-differentiated squamous cell carcinoma has not yet been established. We tried to establish such a system using a reconstructed oral mucosa, in which T3M-1 squamous cell carcinoma cells were cultured on 3T3 fibroblast-containing collagen gel. Fibroblasts promoted the stratification and keratinization of T3M-1 cells. During growth, the Ki-67 index of T3M-1 cells with fibroblasts was higher than that of T3M-1 cells alone. Fibroblasts increased the expression of involucrin, a differentiating marker of keratinocytes, in T3M-1 cells. They also promoted the invasion of T3M-1 cells into the gel. When T3M-1 cells alone were cultured in a fibroblast-conditioned (FC) medium, the fibroblast-induced phenomena mentioned above were almost replicated. In addition, epidermal growth factqr (EGF) promoted T3M-1 cells growth, but not the invasion. cDNA microarray analysis showed that FC medium increased the expression of EGF receptor and several other mRNAs of T3M-1 cells. The data suggest that T3M-1 cells, under cancer-stromal fibroblast interaction, undergo invasive growth with their well-differentiated squamous phenotype, and that this interaction may be mediated partly by soluble molecules (e.g., EGF) in an autocrine or paracrine pathway. Our system will probably provide a useful model for analyzing the biological behavior of well-differentiated squamous cell carcinoma.

Taste disorders: a survey of the examination methods and treatments used in Japan.

CONCLUSIONS: In Japan, the number of patients seeking treatment for taste disorders from otolaryngologists is approximately 240 000/year, and this number has almost doubled in the last 13 years. Taste examinations are routinely conducted in almost all university hospitals; testing is not as common in private clinics. Administration of zinc is the main treatment for taste disorders in Japan. OBJECTIVES: To investigate the number of patients who visited otolaryngologists for treatment of taste disorders between 2000 and 2002. In addition to determining changes in the number of patients that had occurred in the 13 years since the last study in 1990, the survey also sought to find out what types of taste examination were used to diagnose taste disorders in Japan and what therapies were used to treat them. MATERIAL AND METHODS: A questionnaire was mailed to 1559 members of the Japan Society of Stomato-pharyngology. RESULTS: The average number of patients with taste disorders who visited otolaryngological clinics between 2000 and 2002 was 244 858/year. This number is 1.77-fold greater than the number of patients reported by the last study in 1990 (138 575). Electrogustometry was used in 99% of university hospitals and in 20% of private clinics. The filter-paper disk method was also used in 57% of university hospitals and in 27% of private clinics. The main treatment was zinc administration. Most doctors (70%) prescribed polaprezinc, a zinc-containing drug that is used to treat peptic ulcers. Of these doctors, 78% stated that it effectively treated taste disorders and 11% that it did not.