Nasal NK/T-cell lymphoma (N-NKTL) is characterized by progressive unrelenting ulceration and necrosis of the nasal cavity and midline facial tissues. The etiology of the lymphoma is closely associated with Epstein-Barr virus (EBV). Phenotypic finding dual positive for pan-T-cell antigens CD2 and the NK-cell antigen CD56 is important for diagnosis. Recently we found that serum EBV DNA is the most useful tumor marker for diagnosis, disease monitoring and prediction of prognosis in this lymphoma. Previous treatment with systemic chemotherapy followed by radiotherapy was not an effective method, with median survival of only 6 months. Recently, we performed radiochemotherapy including local irradiation with total dose of 56 Gy along with concomitant intra-maxillary arterial infusion of chemotherapy reagents. For concomitant radiochemotherapy, we planned a new regimen of MPVIC-P (VP-16 100 mg/m² on days 1 and 15, ifosfamide (IFM) 1500 mg/m² on days 1 and 15, carboplatin (CBDCA) 100 mg/m² on days 8 and 22, methotrexate 325 mg/m² with leucovorin rescue on day 8, peplomycin 10 mg/m² on day 22, and predonisolone 75 mg/body first 3 days on the week) was employed in 3 cycles. We treated 4 patients with concomitant radiochemotherapy, and all of them were alive and tumor free.

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Ninety-eight patients with malignant maxillary sinus tumors, since 1979, were analyzed retrospectively. There were 63 males and 35 females, with a median age of 61 years. The mean follow-up period was 78 months. All of the patients underwent multi-modality therapy including surgery through a sublabial incision, radiotherapy, and regional chemotherapy. The 5- and 10-year cause-specific survival rates were both 77%. The 5-year local control rate for patients with T2 lesions was 89% ; that for patients with T3 lesions was 91% ; that for patients with T4a lesions was 66%, and that for patients with T4b lesions was 62%. Local control rates were significantly worse in patients with pathology other than SCC. So, in 80 patients with squamous cell carcinoma, the 5-year local control rate for patients with T2 lesions was 100% ; that for patients with T3 lesions was 93% ; that for patients with T4a lesions was 78%, and that for patients with T4b lesions was 69%. Local control rates were significantly worse in patients with orbital apex involvement compared with patients without orbital apex involvement. Among 89 patients with T3 or T4 lesions, 72 patients demonstrated adequate ocular function. Multi-modality therapy with conservative surgery, radiotherapy, and regional chemotherapy is an effective method for local control and preservation of ocular function. Nonetheless, performing this procedure in patients with orbital apex invasion or with non-SCC tumors must be considered very carefully.

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We conducted a prospective study of an alternative chemoradiation protocol comprising CDDP (50mg/m²/day, 2 days), 5FU (800mg/m²/day, 5days) and radiotherapy (66Gy in 36 fractions) for locally advanced nasopharyngeal cancer (stage II-IV). We treated 67 patients (stage II-III : 41 patients, IV : 26) using this protocol. Fifty-seven patients (85%) received the full-course, three-cycle chemotherapy. Three-year overall survival rate of all patients was 90.5%, and 3-year disease-free survival rate was 78.3%. The recurrent sites were the primary site in four patients, neck lymph node in two and distant metastasis in eight. Severe myelosuppression (grade 3-4) was observed in half of the patients, and severe mucositis (grade 3-4) in about 30%. Chemotherapy induced severe dysfunction of liver or kidney (grade 3-4) was seen in three patients. This treatment strategy may be very useful, but careful medical management is essential.

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The purpose of this study was to determine the efficacy of surgical treatment for tongue cancer. We reviewed our experience in the treatment of tongue cancer with surgery as a single definitive treatment modality.
METHOD : Two-hundred and seventy-four patients with squamous cell carcinoma of the tongue received all of their treatment at the Division of Head and Neck Surgery of the National Cancer Center Hospital East from July 1992 to June 2000. They were 172 males and 102 females, whose ages ranged from 20 to 93 years (median 59) and the median follow-up period for living patients was 65 months.
RESULTS : Clinically, there were 54 patients with Stage I, 125 patients with Stage II, 55 patients with Stage III, and 40 patients with Stage IV. Advanced stage (Stages III and IV) was diagnosed in 35% of patients at presentation. Nodal metastasis was noted in 76 cases (28%) at the first treatment. About 30% patients underwent primary resection surgery with pull-through method and free flap reconstruction. Ninety-five percent of patients received surgical treatment only. The incidence of tumor recurrence was 38%, 47%, 56% and 61% for Stage I, Stage II, Stage III and Stage IV, respectively. Recurrence in the neck lymph node was twice as common as primary site recurrence. Seventy-one percent of recurrences occurred within the first 12 months. The estimated Kaplan-Meier 5-year cause-specific survival rate for all patients was 69%. The 5-year cause-specific survival rates for Stage I, Stage II, Stage III and Stage IV disease were 85%, 75%, 62% and 43%, respectively.
CONCLUSION : Significant decrease in cause-specific survival rate was observed in patients with advanced stages, positive clinical node and tumor recurrence. Close monitoring in the first year is recommended because of the high incidence of tumor recurrence.

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To prevent laryngeal dysfunction after a partial laryngopharyngectomy for hypopharyngeal carcinoma, we developed a new method in which the supraglottis is reconstructed using a bone-muscle pedicle flap. After removing the epiglottis and arytenoid on the affected side, half of the hyoid bone connecting to the sternohyoid muscle was fixed to the thyroid and epiglottic cartilages to reconstruct the epiglottis. A protrusion of the arytenoid was formed with the sternohyoid muscle sutured to the excised end of the arytenoid on the unaffected side. Using a free forearm flap, the supraglottis was covered and the pharyngeal lumen was reconstructed.
This surgery was performed on five patients with T2 hypopharyngeal carcinoma. In all of the patients, the tracheal stoma was successfully closed and the voice was conserved. Postoperative swallowing function was almost normal in two patients, fair in two, and poor in one. Bilateral radical neck dissection, circumferential resection of the pharynx, and preoperative stenosis of the digestive tract due to previous cancer surgery, were factors for the deterioration of swallowing function. These results suggested that our method is useful to conserve laryngeal functions in pharyngolaryngectomy for hypopharyngeal carcimona.

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Seventy-five hypopharyngeal cancer patients without lymph-node metastasis, treated with radiotherapy at Kyushu University Hospital from 1976 through 2003, were evaluated. T category was 10 in T1, 41 in T2, 13 in T3, and 11 in T4. Median total doses of radiation therapy were 62.5Gy (range : 60-74Gy) in radical intent, and 30Gy (28.5-41.4Gy) in the preoperative setting. Patient selection as to radical radiotherapy or preoperative irradiation plus surgery was performed at 30-40Gy by an oncologist of head and neck surgery and a radiation oncologist, according to the tumor response to radiation therapy. Most patients were treated with radiotherapy combined with concurrent chemotherapy including 5-fluorouracil (5-FU) and Vitamin A. As the result, radical radiotherapy was selected for 48 patients (T1, 9 ; T2, 30 ; T3, 4 ; T4, 5), and preoperative irradiation plus surgery was selected for 27 patients (T1, 1 ; T2, 11 ; T3, 9 ; T4, 6) For 75 T1-4 cancer patients, the 5-year overall and cause-specific survival rates were 62% and 75%, respectively. The 5-year cause-specific survival (5y-CSS) rates were 100% for T1, 85% for T2, 83% for T3, and 30% for T4. For patients with T1-2 cancers, there was no significant difference in survival between the RT+Surgery group and the RT group ; 5-year CSS was 92% vs. 85%, respectively. In the RT group, however, the prognosis of patients with T3-4 cancers (5-year CSS : 29%) was significantly poor compared with that of patients with T1-2 cancers. The 5-year local progression-free survival with laryngeal preservation was 65% in T1-2 cancers, 6% in T3-4 cancers, and 45% in all patients. Radiotherapy has an advantage for the preservation of laryngeal function compared with surgery. For stage I-II cancers, therefore, radiotherapy should be first considered as a radical treatment option. For T3-4 cancers, however, the combination of radiotherapy and surgery was thought to be proper treatment.

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Thirteen patients received a partial pharyngectomy for hypopharyngeal carcinoma. T classification of the patients was T1, 3 cases ; T2, 8 cases ; and T3, 2 cases). As such, the majority of the primary lesions were early and small. However, N classification of the patients involved the advanced state with N2, 4 cases, and N3, 1 case. The majority of the patients received a hemi-lateral neck dissection, a partial pharyngectomy, and a free jejunum transfer. Nine patients underwent adjuvant radiation therapy. The median of duration for de-canulation and removal of the nasogastric tube was almost 30 days. The difference of postoperative function by primary tumor, surgery, and adjuvant radiation was unclear. There were four patients with local recurrence. Six of seven disease-free patients had a functional larynx. Three of six patients who died had a functional larynx until death. The indication for partial pharyngectomy is mainly T1 and T2 hypopharyngeal carcinoma, even in N advanced cases. Our next object is reduction of local recurrence and increasing the ratios of survival and laryngeal preservation.

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Between 1989 and 2003, we treated 129 patients with T1 and T2 laryngeal cancers. The purpose of this study was to estimate the management of T1 and T2 laryngeal cancers, referring to the relationship with the T classification, subtype, treatment, prognosis and laryngeal preservation. The treatment plan for T1 and T2 laryngeal cancers is fundamentally radiotherapy. To raise the laryngeal preservation rate, concurrent chemoradiotherapy by FAR therapy, CBDCA, DOC and laser treatment was performed for the T2 cases. The 5-year survival rates of the T1 and T2 cases were 94.7% and 94.8%, respectively. The 5-year laryngeal preservation rates of the T1 and T2 cases were 97.1% and 72.3%, respectively. The 5-year survival rates of the glottic cancer and supraglottic cancer cases were 96.7% and 87.0% and the 5-year laryngeal preservation rates of these cases were 97.1% and 57.2%, respectively. Particularly in T2 supraglottic laryngeal cancer, the laryngeal preservation rate is not improved even with concurrent chemoradiotherapy by CBDCA and FAR therapy. To improve the laryngeal preservation rate in T2 supraglottic laryngeal cancer, it is necessary to consider concurrent chemoradiotherapy by DOC or hyperfractionation.

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Serum levels of calcitonin and CEA represent useful tumor markers for medullary thyroid carcinoma (MTC). CEA secretion-rich MTCs are considered more aggressive than calcitonin-rich tumors. We examined the significance of the ratio of serum calcitonin (pg/ml) to CEA (ng/ml) as a prognostic factor for MTC. Between 1986 and 2002, a total of 20 patients with MTC underwent surgery at our institute. Tumor type was sporadic in 13 cases, and hereditary in 7 patients from 3 families. Tumors were recurrent in 5 patients, and the 5-year disease-free survival was 80%. Recurrences occurred in the mediastinum in 4 patients, cervical lymph nodes in 3, and liver in 2. The 2 patients with hepatic recurrence died of the disease, and the 5-year disease-specific survival was 88%. Preoperative calcitonin/CEA ratio ≤10 and ≥10 pathological metastatic nodes represented significant prognostic factors for disease-free survival. No recurrence was found in 13 patients with biochemical cure (normalization of both serum calcitonin and CEA) after surgery. These 13 patients were the same patients with preoperative calcitonin/CEA>10. The preoperative serum calcitonin/CEA ratio can be used as a prognostic factor for patients with MTC.

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For patients with head and neck malignant tumors involving the carotid artery, surgical extirpation of all adjacent soft tissue, including the artery, has been challenged in efforts to obtain the best chance of loco-regional control. Although controversial, these patients should be offered surgical resection if the risk of complications or death is acceptable. To analyze the complications of carotid resection and the oncological results, the authors performed a retrospective review of their 29-year experience of carotid artery resection with or without revascularization at the Cancer Institute Hospital in Tokyo. We have used revascularization technique for the carotid artery since 1985. Until then, ligation of the carotid artery was performed for all patients who received carotid resection. Recently, our practice has been to reconstruct the artery whenever possible. Sixty-two charts were reviewed. Thirty-five patients had the carotid artery ligated, and 27 patients had the artery reconstructed, at the time of resection. Strokes occurred in 13 patients. Survival and recurrence were evaluated in 34 patients with squamous cell carcinoma in the head and neck region. The 50% disease-specific survival was 12 months. The 5-year disease-free survival rate was 13%. Thirty-nine percent of the patients died from loco-regional recurrence. The high risk of complications and mortality must be balanced against the natural history of the disease if left untreated.

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In the last 18 years, 24 patients with adenoid cystic carcinoma of the head and neck were treated in our department. There were 16 males and 8 females ; average age was 58.3 years old. Salivary glands were the most common site of origin. When classified by histological grade, 7 patients were grade I ; 10 patients grade II ; and 7 patients grade III. Nine patients had perineural invasion. Local recurrence and distant metastasis were present in 5 patients. The overall 5-year and 10-year survival rates calculated by Kaplan-Meier analysis were 64.3% and 53.6%, respectively. The prognosis of patients with stage III and IV was worse than that of patients with stage I and II. There was no statistical significance in prognosis compared with each histological grade. Because the prognosis of patients with perineural invasion was significantly poor, we consider that some post-operative therapies should be done to them.

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Thirty-two patients with adenoid cystic carcinomas were treated at our hospital over 15 years. Twenty-seven cases (85%) occurred in the head and neck. Cumulative 5- and 10-year survival rates of 24 cases that were treated in otorhinolaryngology were 86.2% and 57.9%, respectively. In our study, T stage and positive margins of excision were found to be of prognostic significance. Recurrences were seen in nine of 19 cases (47.4%) of complete treatment, and six involved the primary site. In four of the six cases, recurrences at the primary site occurred after more than five years. These reflected the slow growth that is characteristic of adenoid cystic carcinoma. One patient lived for elght years and two months, despite impossibility of adequate treatment. On the other hand, there are cases in which the terminal stage is prolonged. We consider adenoid cystic carcinoma to be a difficult neoplasm for which appropriate treatment is needed according to each case.

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Clinical features of multiple squamous cell carcinoma (SCC) cases within the head and neck that were treated in our department during the recent 10 years are discussed. Multiple SCCs arose in 6.6% of the cases with primary SCC ; 67% of the cases had two carcinomas, and 33% had more than three carcinomas. The most common site of the multiple SCCs was the oral cavity (54%). The most frequent interval between treatment of previous carcinoma and diagnosis of subsequent carcinoma was simultaneous, but more than 5 years' interval was observed in 36% of the patients. The most common initial treatment of the carcinoma was irradiation, but the ratio of surgery increased for subsequent carcinomas. Prognosis of the patients with more than three carcinomas was not worse than that of patients with two carcinomas. Therefore, early diagnosis of the subsequent carcinomas based on careful long-term observation in the head and neck is necessary for follow-up of the patients with SCC of the head and neck. Treatment strategies considering the treatment of subsequent carcinomas are needed for the patients with primary head and neck SCC.

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Twenty-six patients with head and neck cancer (27 lesions) underwent radical radiotherapy by gold grains with or without external irradiation from April 1999 to June 2004. There were 23 tongue cancers, two cancers of the floor of the mouth, one right buccal cancer, and one cancer of the soft palate. Eighteen lesions were treated by gold grains alone and nine lesions were treated by combined external irradiation and gold grains. The 2-year primary control rate was 92%. One lesion recurred at four months after treatment and one lesion persisted as a residual tumor. The treatment for head and neck cancers by gold grains with or without external irradiation was safe, less invasive, and effective.

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Radiation therapy (RT) for head and neck cancer patients exerts a prominent effect not only on tumor regression but also on functional preservation of the head and neck region. In human salivary glands affected by RT, acinar (water-permeable) cells are lost ; however, duct (water-impermeable) cells preferentially survive these circumstances. Regarding the water-permeability in acinar cells, the membrane water channel aquaporin-5 (AQP) plays an important role in the outflow of water from these cells. On the other hand, DNA methylation in the promoters of certain genes is associated with transcriptional silencing. In this study, we demonstrate that an immortalized normal human salivary gland duct cell (NS-SV-DC) line, lacking expression of AQP5, acquires AQP5 gene expression in response to treatment with 5-aza-2'-deoxycytidine (5-Aza-CdR), a DNA demethylating agent. The expressed AQP5 protein was functionally active, since the following seems instead to be proof that it was active. AQP5 expression resulted in a significant increase in the osmotically directed net fluid rate across monolayers of NS-SV-DC cells. By analysis of bisulfite sequencing of CpG islands in the AQP5 promoter, hypermethylation within the consensus Sp1-binding sites was commonly observed in parental cell clones, whereas demethylation at the CGs : one in the second consensus Sp1 element, and the other outside of the third consensus Sp1 element in the AQP5 promoter, was detected in NS-SV-DC cells after treatment with 5-Aza-CdR. By analyzing the luciferase activity of transfected AQP5 promoter vectors, it became evident that demethylation at the CGs cooperatively functions between these two sites to induce AQP5 expression. Our data suggest that hypomethylation, both in the second consensus Sp1-binding site and around the third consensus Sp1-binding site in the AQP5 promoter, may result in expression of the AQP5 gene, leading to increased fluid secretion from NS-SV-DC duct cells.

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Docetaxel (DOC) is one of the most promising drugs for head and neck cancer (HNSCC). A phase II trial of concurrent DOC and radiation for HNSCC was conducted to evaluate the therapeutic benefit based on the response and toxicity of the recommended dose schedule. We also studied the prognosis of patients. Patients with squamous cell carcinoma of the head and neck were entered. All of the patients received radiation with 2.0Gy single daily fractions up to 60Gy. DOC was administered weekly for six consecutive weeks during radiotherapy. The recommended dose was decided to be 10mg/m² in a previousy reported phase I study. Thirty-nine patients with stage II, III or IV were registered ; 35 patients were eligible ; 32 patients were evaluable for response, and 34 were evaluable for toxicity. The overall response rate was 96.9%. The prognoses of the CR patients were statistically better compared with the PR patients. Grade 3 or 4 adverse events consisted of lymphopenia in 64.7%, stomatitis, in 41.2% and anorexia in 20.6% of the patients. Thirty-two of the 35 eligible patients showed high compliance of over 90%, and their toxicities were manageable. Even low-dose DOC shows a strong effect on HNSCC in combination with radiation. The CR patients showed a high survival rate, though the prognosis of non-CR patients was poor. Further treatment for non-CR patients with advanced HNSCC will be needed.

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In order to distinguish benign from malignant nodules within the dissected neck area in patients with oral cancer during the follow-up period, we retrospectively evaluated the frequency and characteristic findings of fusiform-shaped nodules along the internal carotid artery observed by follow-up sonography.
From 1997 to 2003, 52 patients with oral cancer, who underwent radical neck dissections, were enrolled in this study. The study cohort consisted of 33 males and 19 females ranging in age from 29 to 84 years (mean, 62.0 years). After neck dissection, every patient was examined repeatedly with sonography during the follow-up period at an interval of one month. CT and/or MRI were performed when clinically required. Any patient with recurrent neck mass was excluded from this study. In the 52 patients, fusiform-shaped nodules were observed in 10 patients (19%) by the follow-up sonography. The nodules were homogenously hypoechoic and the margin was well-demarcated except for the upper end. A hyperechoic core was clearly observed in every nodule, which showed a fatty density on post-contrast CT. On post-contrast MRI, the nodules enhanced markedly and the core showed hypointensity on fat saturated images.
In conclusion, it was suggested that the fusiform-shaped nodules observed by follow-up sonography within the dissected neck area might be the superior cervical ganglion of sympathetic trunk. However, further studies are needed to disclose the true character of the nodules.

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We investigated the usefulness of FDG-PET for early detection of recurrent advanced head and neck cancer after intra-arterial chemotherapy combined with radiotherapy. We examined 56 lesions (43 cases) suspected of recurrence after the chemoradiotherapy. In all cases, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of FDG-PET were 91%, 85%, 80%, 94%, and 88%, respectively. CT/MRI showed sensitivity of 88%, but poor specificity of 33% due to many false positive lesions. The specificity, accuracy, and positive predictive value of FDG-PET (85%, 88%, 80%, respectively) were significantly (p<0.05) higher than those of MRI/CT (32%, 48%, 41%). In one to two months after the combined therapy, the sensitivity, specificity, PPV, NPV, and accuracy of FDG-PET were 50%, 67%, 50%, 67%, and 60%, respectively. Between two and three months after the therapy, the sensitivity, specificity, PPV, NPV, and accuracy of FDG-PET were 100%, 93%, 89%, 100%, and 96%, respectively. FDG-PET was a better modality for the detection of recurrence after the chemoradiotherapy for advanced head and neck cancer. Two to three months after the therapy is thought to be the best timing of FDG-PET for early detection of relapse.

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Molecular target therapy has recently been a noticeable field of therapy for human cancer. We reported previously that the suppression of histone deacetylase 3 (HDAC3) enhanced the apoptosis induced by hyperthermia at low pH, by radiation, and by cisplatin, in head and neck cancer cells. In this report, we show that the suppression of HDAC3 up-regulated the apoptosis induced by paclitaxel (TAXOL) remarkably. It is possible that HDAC3 can play an important role in the resistance of cancers to various anticancer drugs. Since the suppression of HDAC3 has no cell-killing effect itself, HDAC3 is expected to be a new target of molecular target therapy for head and neck cancers.

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RAGE is a membrane binding multi-ligand receptor which belongs to the immunoglobulin superfamily. Major ligands of RAGE are amphoterin, AGE, and S100 proteins. RAGE is known to be closely associated with invasive and metastatic ability of cancer, and we previously reported a significant correlation between expression of RAGE and progression or metastasis in gastric, colon, and prostate adenocarcinoma. In the present study, the relationship between RAGE expression and clinicopathological parameters was examined in 74 patients with oral squamous cell carcinoma. Expression of RAGE was strongly associated with tumor progression and recurrence, and RAGE-positive patients showed significantly shorter disease-free survival. These results indicate that RAGE expression is a useful marker for tumor progression and disease recurrence in patients with oral squamous cell carcinoma.

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S100A2 is a member of the S100 calcium-binding proteins, but the mechanism of its action is not clear. The expression of this protein has been reported to be associated with the prognosis in patients with laryngeal squamous cell carcinoma and to be accompanied by malignant changes in an in vitro bronchial epithelial carcinogenesis model. To know whether S100A2 has a tumor suppressive function in this model system, we applied RNA interference to suppress the S100A2 expression in 1799 immortalized human bronchial epithelial cells. The cells transfected with the vector expressing small hairpin RNA specific to the S100A2 gene showed the depletion of S100A2. The 1799 cells without S100A2 expression exhibited malignant phenotypes such as a colony forming ability and resistance to anoikis. These results support the hypothesis that S100A2 serves as a tumor suppressor in this system. (134 words)

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We measured the activity of dihydropyrimidine dehydrogenase (OPD), the amount of thymidylate synthase (TS), and the activity of orotate phosphoribosyl transferase (OPRT) in order to study the contribution of these substances to the effects of the pyrimidine fluoride anticancer drug 5-fluorouracil (5-FU). We also examined the correlation between these three enzymes and clinical pathophysiologic features such as tissue type, extent of tumor invasion, and extent of metastasis to the lymph nodes in 14 head and neck cancer patients. Poorly differentiated squamous cell carcinoma showed significantly higher DPD activity than the other histological type. DPD activity significantly increased as the invasiveness of the tumor increased, and was also higher in patients with lymph nodes metastasis. TS enzyme levels showed a significant correlation with tumor size. OPRT activity showed no significant relationship with the clinical pathophysiologic features. An increase in DPD activity and TS enzyme levels in tumor tissue is a possible cause for the equivocal results of 5-FU based chemotherapy in advanced head and neck squamous cell carcinoma.

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