We investigated cytokine production and mRNA expression by human adenoidal and tonsillar epithelial cells cultured in vitro. The cells with epithelioid morphology were established from all adenoidal and tonsillar tissues tested. The mRNA of the IL-1 α or β, IL-6, IL-8 and TNF-α were determined by reverse transcription-polymerase chainreaction (RT-PCR) on the adenoidal and tonsillar epithelial cells cultured in vitro . IL-1 α or, β IL-6, IL-8 and TNF-α were detected in the supernatant culture fluids of the ade noidal and tonsillar epithelial cells . Among these cytokines, the highest level was IL-8 and the level decreased in the order of IL-6, IL-1 α or β, TNF-α. The IL-6 level was significantly higher in the supernatant culture fluids of tonsillar epithelial cells than in those of adenoidal epithelial cells. The IL-1 β level in the supernatant culture fluids of the adenoidal epithelial cells was significantly higher in the non-OME group than in the OME group.These data suggest adenoidal and tonsillar epithelial cells play an immunoregulatory role through the secretion of a number of cytokines .

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Immunoglobulin (Ig) isotype switching is the process whereby B cells initially expressing IgM and/or IgD on their surface switch to other Ig heavy-chain loci and thereby provide antibodies with different effector functions but the same antigen specificity. In this study, we determined a switching factor for IgA by human tonsillar B cells. As a result of the study, we demonstrated in vitro switching via the generation of switch circular DNA (Sα/Sμ) following stimulation with vasoactive intestinal peptide (VIP) and transforming growth factor-β (TGF-β) in the presence of CD40 mAb. In addition, TGF-β alone, CD40 mAb alone, and VIP alone could induce a germ-line transcripts in human IgD⁺B cells. A significant amount of IgA production was also found from the supernatant of IgD+B cultured with VIP plus CD40 mAb and IL-10 plus CD40 mAb. These data demonstrate that VIP, TGF-β and IL-10, in the presence of CD40 mAb, can induce isotype switching for IgA in human tonsillar B cells.

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A sophisticated common mucosal immunity system is provided in the nasopharyngeal mucosal linings, as previously shown by a large number of studies on animals and humans. Homing theory is now settled down for explaining the recruitments of primed lymphocytes from inductive sites to various distant mucosal sites. However, it still remains to be investigated how these precursor B and T cells recruit to the distant mucosal sites and how final effector antibody-producing B cells differentiate and conduct a clonal expansion. To challenge this issue, we have done a transfer study of human tonsillar lymphocytes into NOD/LtSz-scid/scid mice and obtained successful results in which human leukocytes (CD45⁺), T cells (CD3⁺) and B cells (CD20) are engrafted in the spleens and other nonlymphoid organs such as lung and liver. In a flow cytometric analysis, human CD45⁺, CD3⁺, CD4⁺ (helper/inducer), and CD8⁺ (suppressor/cytotoxic) cells were detected in various degrees (up to 57% of whole spleen cells) in the spleens of NOD/LtSz-scid/scid mice at a 4-week interval after human tonsillar mononuclear cells (1×108) were inoculated intraperitoneally into the mice. However, there was no engraftment of human tonsillar cells in CB-17 scid mice (0/11). An immunohistochemical study revealed that human leukocytes were present in the spleen, thymus, lung, and liver, but not in normal (not inflammatory) nasopharyngeal or tubotympanal mucosae. In NOD-scid mice engrafted with human tonsillar lymphocytes obtained from patients carrying α Streptococcus, M-protein (α Streptococcus, group A type 3, derived)-specific human IgG and IgA antibody activities were detected in the sera of these mice. Upon an intranasal immunization of 100μg of M-protein and 1μg of choleratoxin to these mice, M-proteins-pecific human IgA antibody titers in nasal washings were higher than those of mice without the intranasal challenge of M-proteins. In an immunostaining study, human T and B cells were recruited to the nasal mucosae around the nasopharyngeal lymphoreticular tissue (NALT) of those mice having higher M-protein-specific human IgA antibody titers.
These results may allow us to use this model as a promising tool for evaluating the lymphocyte homing and mechanism of the final differentiation of recruiting precursor lymphocytes for mounting antigen-specific immune response in peripheral mucosal sites such as the nasopharynx and tubotympanum.

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In order to investigate the immunological role of palatine tonsils in the upper aerodigestive tract, we investigated the immune responses of tonsillar lymphocytes against the P6 of nontypeable Haemophilus influenzae (NTHi) and the M-protein of Streptococcus pyogenes after intratonsillar or intranasal immunization with OK-432. Nasal secretions and sera were obtained from the patients who underwent tonsillectomy and the antibody titers against P6 or M-protein were determined by ELISA. Mononuclear cells were isolated from palatine tonsils by discontinuous gradient centrifugation and the number of antigen-specific antibodysecreting cells was determined by ELISPOT. CD4⁺T cells isolated by use of anti-CD4 microbeads were incubated with P6 or M-protein and the production of cytokines was deter mined by ELISA. The results showed that the number of P6-specific IgA-secreting cells was greater in the samples having no NTHi than that in the samples having the bacteria. The number of P6-specific IgA-secreting cells in tonsils was significantly correlated to the IgA antibody titers in nasal secretions. Intratonsillar as well as intranasal immunization with OK-432 increased the number of M-protein-specific antibody-secreting cells in tonsils and antigen-specific antibody activity in nasal secretions. CD4⁺T cells produced Th2-and Th1-type cytokines in response to stimulation with P6 or M-protein. These findings suggest that palatine tonsils play an important role as an effector site and an inductive site for mucosal immune responses, and prevent bacterial infection in the upper aerodigestive tract.

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The nasal mucosa is the first site of contact with inhaled antigens for the induction of IgA response. A major aim of this study was to characterize Th1 and Th2 cytokine expression by mucosal T cells residing in nasal-associated lymphoid tissue (NALT) and analyze NALT immunity as IgA inductive sites at transcriptional and cellular levels. The application of single-cell RT-PCR for the analysis of Th1 (IFN-γ) and Th2 (IL-4 and IL-6) cytokine-specific mRNA revealed the presence of CD4⁺T cells with a Th0 profile. NALT CD4⁺T cells did not provide a helper function for the induction of antibody-forming cells including IgA isotype in B-cell cultures. However, intranasally-immunized mice showed an increase of memory T cells and germinal center formation in NALT, and selected Th2-type cytokine expressing CD4⁺T cells were induced in NALT, which possessed a helper function for B cells. These findings suggest that NALT is characterized as a Th0 environment which can become Th1 and/or Th2 phenotype and has the capacity to be an IgA inductive site for nasopharyngeal mucosal immunity.

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Apnea index (AI) was used to evaluate the long-term status of sleep apnea patients following UPPP. Twenty-three patients, who were observed in a sleep study of more than one year after UPPP, were selected as the UPPP group.The control group consisted of 23 patients who received conservative treatment for more than a year. AI before the treatments was 20.7 for the UPPP group and 8.9 for the control group.The patients from the UPPP group usually reached and maintained improved AI (improvement rate over 50%) for more than 3 years after surgery, whereas AI did not change much for the patients in the control group.For a few patients in the UPPP group, AI deteriorated after a temporary improvement subsequent to surgery. In those patients, increased body weight was one of the reasons for the deterioration. The number of patients with extended long-term follow up is still limited. Based on the knowledge that aging might deteriorate the symptom of sleep apnea, we feel the necessity of follow-up on post-UPPP patients for more than 10 years.

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The supine sleeping position and overweight are well known to contribute to the development of apneic episodes. Sixty-eight obstructive sleep apnea cases (average age: 47.2 years, obesity index: 120.5%) were examined by polysomnography including upper airway pressure monitoring. Respiratory related parameters were analyzed according to the sleeping position and degree of obesity. The subjects were divided into three group according to their obesity; Normal weight group, obesity index less than 110%; mild obese group, between 110%-120%; and obese group, more than 120%.
Apnea+hypopnea index (AHI) in the obese group was 47.1/hr. in the supine position, which was significantly higher than those in the normal weight group (32.6/hr.) and in mild obese group (31.3/hr.). The value of lowest oxygen saturation in the supine position was lowest in the obese group (80.1%). The value of intraesophageal pressure change in the supine position was 45.4 cm H₂O in the obese group, 32.5 cm H₂O in the mild obese groupand 33.5 cm H₂O in the normalweight group.In the lateral sleeping position, the values of AHI, lowest oxygen saturation and intraesophageal pressure change were more severe in the obese group than those in the normal weight and mild obese groups. In 30 cases out of 67, the AHI and intraesophageal pressure showed more than 50% reduction by changing body position from supine to lateral.

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Dividing OSAS patients into UPPP responders and nonresponders, we examined whether the responders can be distinguished from nonresponders by air-flow resistance examination before operation.
Furthermore, we made clear the criteria for UPPP indications and studied what kind of operation shuld be indicated for the type of case; that is, criteria for selecting operations.
As a result, we were able to distinguish them by the upper respiratory resistance calculated by subtracting the respiratory resistance through the nose from the respiratory resistance through the mouth.
UPPP is indicated when the upper respiratory resistance is higher than 3.0 cm H₂O/l/sec. When the upper respiratory resitance is lower than 3.0 cm H₂O/l/sec, it was considered to be indicative for an operation on the base of the tongue. Furthermore, when the nasal resistance is higher than 3.6 cm H₂O/l/sec, operation on the nasal cavity is considered necessary.

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In order to examine the indication and long-term results of UPPP, we performed nocturnal polysomnography (n-PSG) and questionnaire surveys. The subjects were obstructive sleep apnea syndrome (OSAS) patients with obstructed mesopharynx more than two years after UPPP.
As a result, apneic deterioration occurred in 30% of 26 OSAS patients questioned, and 45% of 11 OSAS patients with PSG. The causes were attributed to post-operative overweight.
In addition, we analyzed the preoperative cephalometric characteristics of 10 OSAS patients with n-PSG to study various causes. In conclusion, our cephalometoric data showed that post-operative apneic deteriorative patients had more stenotic upper airway than non-apneic deteriorative patients.

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Rationale for the treatment of obstructive sleep apnea is based on increased morbidity and mortality, suggesting the importance of long-term follow-up after therapy. We evaluated the long-term outcome of uvulopalatopharyngoplasty (UPPP) for sleep-disordered breathing (SDB) by questionnaire and nocturnal oximetry. In addition to body habitus, clinical symptoms such as excessive daytime sleepiness, witnessed apnea, snoring and morning headache were assessed by a questionnaire given to 54 pationts with SDB who had UPPP at our hospital more than 12 months before the reassessment (12-82 months). Overall satisfaction to the treatment was also asked to the patients. A similar assessment was conducted using patients with SDB who had been treated by ental appliance (DA, n=30) or nasal CPAP (n=15). For 17 of the UPPP patients, we evaluated nocturnal oxygenation by pulse oximetry. The results of these long-term assessments were compared with those obtained before UPPP and immediately after UPPP. Compared to patients treated by DA, UPPP patients presented significantly less excessive daytime sleepiness, and UPPP patients were reported to snore significantly louder than those treated by nasal CPAP. The incidence of witnessed apnea and morning headache did not differ among the treatments. The acore of overall satisfaction to the treatment was significantly higher for UPPP than the other treatments. The intensity of snoring sound was reported to increase after UPPP, although it was still quieter than preoperative snoring. Similarly, nocturnal oxygenation was significantly worsened after initial improvement of the oxygenation immediately after UPPP, although it was significantly better than the preoperative condition.
Body mass index (BMI) didnot change significantly before or aftre UPPP, whereas we found a minor reduction of BMI at the time of discharge, indicating that the observed aggravation of nocturnal breathing after UPPP is possibly explained by factors other than weight gain. In conclusion, our results strongly suggest the recurrence of sleep-disordered breathing after UPPP, and the importance of long-term follow-up after surgery.

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A questionaire was sent to 208 adult patients suffering from obstructive sleep apnea. These patients were diagnosed by pilysomnograph during sleep and were treated surgically. One-hundred-nineteen patients replied to the questionaire. Respondants were aged from 20 to 69 years old. The average age was 47. One-hundred-five males and 14 females responded. Uvulo-palato-pharyngoplasty (UPPP) was performed on 109 patients, chonch otomy on 60, deviatomy on 39, laser midline glossectomy (LMG) on 5 and other surgery on 6 patients.
Total cases were divided into 3 groups.(A, B and C);
Group A consisted of patients who underwent surgery 6 months to 3 years prior to filling out the questionaire (46 respondents); Group B of patients who underwent surgery 3 to 5 years prior to filling out the questionaire (38 respondents); and Group C of patients who underwent surgery more than 5 years prior to filling out the questionaire (35 respondents).
Subjects of the questionaire were snoring, apnea during sleep, sleep arousal, difficulty of sleeping, excessive daytime sleepiness and overall satisfication of treatment. The questionaire asked patients about their presurgical, 1 month post-surgical and present day (time of survey) conditions.
In regards to snoring, apnea during sleep, sleep arousal, difficulty of sleeping, and excessive daytime sleepiness, the difference was slight between 1 month on the group A and B post-surgical and present day (time of survey) conditions. Long-term results of upper symptoms were excellent. The group C reported the aggravation of 14-16% on the upper 5 symptoms between 1 month post-surgical and present day (time of survey) conditions.
In regards to overall satisfication of surgical treatment, complete, considerable or reasonable satisfication was reported by 85% of group A, 84% of group B and 71% of group C at the time of the questionaire.

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The etiology of ulcers which develop in the oral cavity and pharynx involves various diseases, including Behcet's disease, Crohn's disease and T-cell lymphoma. Other than these, intractable recurrent ulcers of unknown etiology have also been reported.
To clarify the pathogenesis of intractable recurrent ulcers in the oral cavity and pharynx, the authors examined clinicopathologically 7 intractable recurrent ulcers; 2 Behcet's disease, one Crohn's disease and 2 T-cell lymphomas; and 10 other non-specific ulcers found in the oral cavity and pharynx. The specimens were studied immunohistochemically for the development of collagen fiber and expression of superoxide dismutase (SOD) in the ulcerative lesions. Furthermore, serum values of vitamin C and prostaglandin E2 were analysed for 3 intractable recurrent ulcers and one Behcet's disease.
Clinically, abnormal serum findings of immunoglobulin, CHSO, C3, and C4 were noted in most cases of intractable recurrent ulcers, the 2 Behcet's diseases patients and one Crohn's disease patient. Of interest, all examples of intractable recurrent ulcers and Behcet's disease indicated abnormal elevated levels of antinuclear antibody (ANA). On the other hand, there were no differences in the expression of SOD or development of collagen fiber between the ulcerative diseases studied. A decrease in the serum value of vitamin C was noted for 1 of the 3 intractable recurrent ulcers. This study indicates that it is impossible to differentiate an intractable recurrent ulcer from Behcet's disease when an ulcer occurs as a first symptom in the oral cavity and pharynx. Further examinations in a large group of patients are necessary to study whether or not the intractable recurrent ulcer of the oral cavity and pharynx is an entity.

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To clarify the clinical findings of intractable recurrent ulcers of the oral cavity and pharynx, we sent out questionnaires to 696 hospitals all over the country. We asked them to investigate about this disease over a 5-year period (from January 1992 to December 1996). Information was obtained from 162 institutions. In this paper, 138 cases reported from 69 hospitals were studied.
The consultation rate was about 1.3-1.4 to 10, 000 first-visit outpatients. The ratio of males to females was 1: 1. The age of patients was distributed from 15 to 80 years old, and the average age of male patients was 45.1 years old and that of female patients was 51.6. For younger age, male patients were dominant; and for older age, female patients were dominant. There was no relation to drinking, smoking or medication. There were no particular diseases in previous history, family history or complications. Most of the chief complaints were sore throat and pain in swallowing. Most of the ulcers were occurred on the tongue, soft palate, palatine tonsil, posterior arch of the soft palate, vallecula, epiglottis or arytenoid, but few cases were associated with the nasopharynx or glottis.
There were two types of ulcer form (single and multiple). A large number of single and multiple ulcers occurred in the oral cavity, but in the pharynx, most of the ulcers were single. Many patients had up to triple recurrences of ulcers, and some patients had recurrence of more than 20 times. Days required to cure the ulcers ranged from 25.5 days (shortest average) to 80 days (longest average). For the therapy of ulcer steroids was the most effective medication for half of the cases. Scar or stenosis formation after healing was found in 30% of the cases. As an abnormality in laboratory examinations, an increase in the number of WBCs was found in 35% (41/114), positive CRP was found in 40% (44/110) and an increase of BSR was found in 63% (29/46). An increased level of IgG was found in 16% (10/63) and the level of IgA increased in 32% (20/63). There were no significant abnormalities in the examinations of liver function, electrolytes, metals in serum, ASO, ASK, bacterias, fungi, HLA typing and histopathology. There were 14 cases with reports of positive antinuclear antibody. We could not find a definite tendency about this disease in the present general study. The fact of such a conclusion suggests that, to obtain a definite clinical finding of this disease, we must analyze the cases after dividing them into some groups.

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The injury or sacrifice of the facial nerve and further recurrences are the main problems in managing recurrent pleomorphic adenoma of the parotid gland. Seven cases of benign recurrent pleomorphic adenoma with multiple tumors (1 male, 6 females) were studied. A single operation for three cases and multiple operations for four cases had already been performed elsewhere. Two of the patients had facial nerve paralysis. The procedure for treatment of the patients in the same manner, namely, to remove recurrent tumor, was total parotidectomy and excision of the previous scar. Pathologically, all cases had multiple recurrent tumors. Postsurgically, all patients showed facial nerve paralysis including transient cases. It was possible to preserve of the facial nerve in two cases. Two other cases required resection of the nerve branch. In the other three cases, including two cases with preoperative facial nerve paralysis, the whole facial nerve was completely embedded in the tumor and then resected. Revision surgery was successful in all cases with no further recurrences. It is nessesary to get a patient's informed consent to make plans for revision surgery.

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We reported five patients with multiple recurrence of pleomorphic adenoma, especially a deep tumor of the parotid gland, and investigated their therapeutic problems. The recurrence of pleomorphic adenoma of the parotid gland is a difficult problem, both in prevention and management. Since pleomorphic adenoma is a benign tumor, we should basically preserve the facial nerve even if the tumor exists in the deep lobe. However, recurrent tumor is thought to have high tumor activity, so it is required that an en bloc resection be performed within an adequate margin of the normal gland. The approach to recurrent pleomorphic adenoma of the parotid gland consists of total residual parodectomy with facial nerve preservation. However it is sometimes impossible to resect without sacrificing the facial nerve due to scaring and the location of the recurrent tumor, although the resultant facial nerve function after nerve grafting is not sufficient. Therefore, the type of surgery must be individually selected for each case.

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Thirteen patients with mucoepidermoid carcinoma of the parotid gland, treated mainly by operation in Oita Medical University Hospital from 1981 to 1997, were reviewed with special attention to histopathological malignancy and prognosis. The five-year cumulative survival rate was 100% for low-and intermediate-grade malignancies, and the three-year survival rate was 25% for high-grade malignancy. The 5-year survival rate was 89% for HER-2/neu weak-positive or negative and 25% for strong-positive carcinomas. Local recurrence was found in 5 patients. Two cases showing high-grade malignancy HER-2/neu strong-positive staining died within 3 years after the initial treatment. In three cases showing low-or intermediate-grade malignancy, two of the patients died in the 8th and 10th years after the first treatment. Insufficient resection of the facial nerve and surround-ing structures was considered to be the cause of local recurrence. Unilateral radical neck dissection was carried out on 9 patients including 5 NO patients. False-negatives were found for 2 ofthe 5 patients. Involvement of regional lymph nodes was seen histopathologically in 5 patients. All of them showed high-grade malignancy and 3 of them showed HER-2/neu strong-positive staining. Cervical recurrence and distant metastasis were seen in 2 patients. Both of them showed high-grade malignancy and HER-2/neu strong-positive staining. The results indicate that overexpression of HER-2/neu as well as high-grade malignancy might be a factor of poor prognosis. To improve the results of therapy, complete surgical resection is necessary. Resection of the facial nerve should be considered even if the nerve has barely come in contact with a tumor. In addition, surrounding st ructures should be resected as extensively as possible. Unilateral radical neck dissection might be essential when the carcinoma turns out to be a high-grade malignancy.

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A study was performed on the treatment for invasive adenoid cystic carcinoma (ACC) of the parotid gland, based upon 53 cases of parotid cancer in our hospital, including 2 cases with adenoid cystic carcinoma. Also, a questionnaire which was sent to major hospitals in Japan was used regarding treatment policy for ACC. Initial surgical resection with a wide safety margin is primarily important. Careful preoperative clinical examination should be performed to evaluate tumor malignancy and its invasiveness.
However it could be difficult to take the safety margin in cases with perineural invasion. Histological confirmation by the use of frozen section during surgery will be indispensable.
Invasion toward the skull base is a problem to be overcome. In order to obtain a better result, a team approach to combat with this tumor is enevitable from now on. Postoperative irradiation or chemotherapy should be performed for selected cases considering risk factors of the recurrence.

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Salivary duct carcinoma (SDC) is a high-grade aggressive malignant tumor of the major salivary gland. Many studies have been published on SDC stressing its agressive biological behavior and poor prognosis. In this paper, according to the 1991 WHO's histological typing of salivary gland tumors, we reviewed the clinical courses and the prognoses of our SDC patients comparing them with those of other types of adenocarcinomas. We also studied the clinical features, diagnostic imaging, treatment and outcome of every SDC case.
The 5-year survival rate for patients with SDC was only 16.7%, whereas the rate for patients as a whole was 41.2%. Five out of 8 patients with SDC died of local recurrence or distant metastases less than 4 years after initial treatment, although they underwent aggressive treatment such as total parotidectomy, post-operative irradiation and so on.
These results suggest that appropriate surgical treatment includes extended radical parotidectomy and neck dessection with recontruction using free myocutaneous flaps in order to improve locoregional control. Preoperative irradiation seems to be worth performing if SDC can be diagnosed using FNA before surgical removal.

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We studied the clinical problems of malignant parotid tumors in children and adolescents by analyzing questionnaires. Fifty-six patients with parotid cancer who were under 19 years of age were registered in 40 out of 159 hospitals in Japan. Mucoepidermoid carcinoma was the most common histologic cell type, which was 35 out of 56 patients (62.5%). Most patients showed an early stage of carcinoma without lympnode neck metastasis. The possibility of facial nerve paralysis by the surgical removal of primary tumor was esitimated to be 41%. However, most paralysis was reversed after the treatment. Recurrence was observed in 10 patients (15.3%). Two out of 10 patients died of carcinoma, suggesting good prognosis. These results indicate that the local-regional treatment at the primary stage is recommended.

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