Human Rad9 (hRad9) is a checkpoint molecule involved in processes including cell cycle arrest, repair of damaged DNA, or induction of apoptosis after DNA damage. Previous studies suggested that hRAD9 is frequently amplified in epithelial tumor cells of breast, lung, and head and neck cancer, and participates in regulation of the tumor suppressor p53-dependent transactivation of pro-survival P21^WAF1. Recently, we reported the direct association of Rad9 and p53 results in regulation of the expression of P21 gene. Here we studied the regulation of Rad9 for therapy of head and neck cancer. Overexpression of Rad9 mutant resulted in the reduction of association among p53 and Rad9 protein, and induction of p21 protein. Introduction of Rad9 mutant induced apoptosis in the head and neck cancer cell line. Rad9 inhibition using Rad9 siRNA also induced apoptosis. These results indicate that regulation of Rad9 may be effective for therapy of head and neck cancer.

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In order to define the diagnostic value of cyclin D1 gene (CCND1) numerical aberration as a clonal marker in oral squamous cell carcinomas (OSCCs), we investigated copy number changes of the CCND1 in 32 OSCC primary tumors (PTs) and matched lymph node metastases (LNMs) taken by fine-needle aspiration (FNA) biopsies using fluorescence in situ hybridization (FISH). When CCND1 numerical aberration was detected in PTs, this genetic aberration was determined in the matched LNMs. On the other hand, when cancer cells in PTs did not show CCND1 numerical aberration, no tumor cells in matched LNMs exhibited this genetic abnormality. In 30 of the 32 OSCCs, the genetic status of this gene was identical between PTs and matched LNMs. We conclude that CCND1 numerical aberration develops in carcinogenesis before lymph node metastasis occurs and remains during metastasis. Therefore, CCND1 numerical aberration may be a promising candidate as a clonal marker in OSCCs.

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To evaluate the treatment efficacy of infused dose of cisplatin in intra-arterial chemoradiotherapy for maxillary sinus cancer, patients treated with superselective chemoradiotherapy were divided into a low-dose group (<450mg/body of cisplatin, n=7, follow-up period 5-60 months, median follow-up 26 months) and a high-dose group (>600mg/body of cisplatin, n=8, follow-up period 10-32 months, median follow-up 19 months). Of 22 cases, 15 cases who had received at least 2 courses of intra-arterial infusion of cisplatin were involved in this study. The high-dose group had a better overall survival rate and progression-free survival although it was not statistically significant. However, 5 of 7 patients in the low-dose group received partial maxillectomy or more invasive salvage surgery whereas none of the high-dose group did (p=0.0138). There was no significant difference of adverse effects in the two groups. These results suggest that 450mg of cisplatin is insufficient to control maxillary sinus cancer but 600mg of cisplatin is beneficial.

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One hundred and thirty-five sites of oral carcinoma (118 patients) treated in our department during 15 years (1991 to 2005) were clinically analyzed. Multiple carcinomas within the oral cavity arose in 17 sites. In our department, tongue and oral floor were common subsites, followed by buccal mucosa, gingiva, lip, and hard palate. The number of patients increased according to the elevation of clinical stage. Since the subsites and stage characteristics of our department might be due to patients' distribution among medical and dental clinics, correlation of information among medical and dental schools was considered important. The significance of multiple malignancies in patients with oral carcinoma was confirmed since multiple malignancies within and outside of the oral cavity occurred at a high rate. The five-year survival rate was 73.8% in tongue carcinoma patients and 58.9% in oral floor carcinoma patients, and the prognosis of patients was fair with positive application of surgery. Since the prognosis of patients without surgery was poor, it is important to consider the treatment strategy for patients who reject surgery and to recommend that they visit a clinic before the tumor advances to an unresectable stage.

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The correlation between features of muscular invasion and prognosis after neck dissection for subsequent cervical lymph node metastasis in stage I/II squamous cell carcinoma of the oral tongue was investigated. Fifty-nine patients, initially treated by partial glossectomy alone who underwent neck dissection for subsequent cervical lymph node metastasis at the Division of Head and Neck, Ganken Cancer Institute Hospital, from 1987 to 2003, were reviewed. The prognosis was analyzed, depth of muscular invasion was measured, and cancer pearls were also evaluated as either remarkable (Cancer Pearl type: CP, 18 cases) or not (Dyskeratotic type: DK, 41 cases). In the CP group, none of seven patients with muscular depth ≤ 5 mm died from neck failures. Among patients with muscular depth > 5 mm, 86% (6/7) died of neck failures, and 14% (1/7) died from distant metastasis. In the DK group, among patients with muscular depth ≤ 3 mm, 80% (8/10) died of neck and/or deep to floor of mouth failures, and 20% (2/10) died from distant metastasis. On the other hand, among patients with muscular depth > 3 mm, 25% (2/8) died of failures of the neck, and 75% (6/8) died from distant metastasis. Therefore, It is concluded that aggressive adjuvant therapy following neck dissection may be indicated except for patients with a tumor with muscular depth ≤ 5 mm and CP.

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Cervical lymph node metastasis influences the prognosis of tongue carcinoma. We retrospectively investigated 113 patients with stage I,II tongue carcinoma from 1986 to 2004 at our department. There were 26 patients who underwent elective neck dissection, of whom 8 had primary metastasis. On the other hand, there were 87 patients who did not undergo elective neck dissection. There were 26 patients who had late metastasis. Our results do not necessarily demonstrate a clear correlation between grade of malignancy and cervical lymph node metastasis. On the other hand, mode of invasion was a significant factor for cervical lymph node metastasis. The overall 5-year survival rate was 87.5% in primary metastasis and 57.7% in late metastasis. Among the patients who died, regional lymph node metastasis was seen in 6 patients, and 6 patients died as a result of distant metastasis. The incidence of extra-nodal spread was found only in patients with late metastasis. These results suggested that the mode of invasion and extra-nodal spread are the most important prognostic factors in cervical lymph node metastases. Further studies should assess the indication for neck dissection in cases of stage I,II tongue carcinoma.

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Intra-arterial infusion chemotherapy has been widely used to treat advanced head and neck cancers in order to preserve organs and improve patient QOL. We clinically evaluate and report the efficacy of intra-arterial infusion chemotherapy with cisplatin via the superficial temporal artery with TS-1 medication. Twenty consecutive patients with tongue cancer, 7 T2 (early: 1 and late: 6), 6 T3, 7 T4, underwent intra-arterial chemotherapy between May 2001 and May 2007. No side effects such as cerebrovascular disorder or cessation cases were detected during this therapy. The clinical effects of this method were CR 9/20 (45.0%), PR 11/20 (55%) and the overall response rate was 100%. Eleven patients of PR also received operation or radiotherapy. To date, four patients have died of distant metastasis, local recurrence, or unrelated disease; 16 patients are disease-free in the primary sites, without relapse. No patients who have been treated with this method have functional disorder postoperatively. This method is useful for preserving oral functions.

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Ultrasonography has been introduced in the procedure of implanting Iridium hairpins in interstitial brachytherapy for stage I and II tongue cancer since 2004 to identify the location of the source in and around the tumor. Twenty patients were treated in this manner among 152 patients who were treated between 1994 and 2005. Incidence of both local recurrence and radiation ulcer in each period was examined.
Seventeen patients (13%) out of 132 treated until 2003 experienced local recurrence but only 1 patient (5%) among 20 treated after 2004 did so. Especially, all 14 patients with T2 lesion treated after 2004 were controlled. Radiation ulcers occurred in 64 patients (57%) of 132 treated until 2003 and in 9 patients (47%) among 20 treated after 2004. All radiation ulcers except 1 healed within 6 months by conservative care.
It was considered that these improvements were obtained by the use of ultrasonography which worked as a useful guide for adjusting the position of the source.

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There are many methods of treating laryngeal cancers: definitive irradiation with or without concurrent chemotherapy, endoscopic laser surgery, partial surgery techniques, and total laryngectomy. Few studies have been reported on vocal function and quality of life of patients after the definitive treatment for laryngeal cancer, using single voice related QOL measures. The aim of this study was to examine voice related QOL in patients treated with various modalities using a Voice-Related Quality of Life (V-RQOL) questionnaire as well as Voice Handicap Index-10 (VHI-10) questionnaire. Between August 2006 and May 2007, survey data on voice utilizing the V-RQOL and VHI-10 were obtained from a total of 130 patients who had received definitive treatment for laryngeal cancers with follow-up at the Hokkaido University Hospital, and who were alive with no evidence of malignancy at the time of survey. Mean V-RQOL scores of the patients who received radiation therapy (n=63), chemoradiotherapy (n=29), laser resection (n=14) and total laryngectomy (n=27) as the final treatment for laryngeal cancer were 92.6, 92.9, 85.5, and 68.4, respectively. Mean VHI-10 values were 2.87, 2.34, 5.43, and 11.26. Such measures of quality of life are important endpoints to help judge the overall effectiveness of treatment options for laryngeal cancers.

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Proper evaluation of preoperative cancer extension is important for transoral lateral oropharyngectomy (TLO). Narrow band imaging (NBI) is a new endoscopic technique developed recently by OLYMPUS Co. NBI combined endoscopic observation is useful in diagnosing superficial cancer of the head and neck region. It is capable of evaluating microscopic changes of vasculature of the mucosal surface which are generally difficult to recognize by conventional light evaluation. We report here two cases of superficial oropharyngeal carcinoma excision with NBI assistance. Both lesions manifested a brownish area and a surface pattern of small spots when we performed NBI combined expansive endoscopic observation. Iodine pigment endoscopic examination confirmed that the abscission range matched the brownish area under NBI evaluation. NBI assisted evaluation was useful in performing TLO.

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The cases of 28 consecutive patients with T1, T2 hypopharyngeal carcinoma (HPC) treated in Kyoto University Hospital from 2000 to 2006 were reviewed. Radiotherapy (RT) was performed in 13 patients, surgery with conservation of the larynx (SCL) in 11 and laryngopharyngectomy with cervical esophagotomy in 4 patients. Local recurrence occurred in a patient of RT. There was the complication of persistent severe edema of the larynx in one patient with RT and serious swallowing disturbance in two patients with RT and SCL. Disease-specific 3- and 5-year survival rates were 96% and overall survival rate was 76%. One patient died of lymph node metastasis and three patients of other carcinomas. Both of RT and SCL showed satisfactory results as conservative treatment modalities for T1, T2 HPC. Problems were late complications after RT, swallowing disturbance due to RT or SCL and controls of regional lymph node metastasis and other carcinomas.

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We studied the effect of neoadjuvant chemotherapy (NAC) cisplatin (or nedaplatin)/5FU for 15 patients with locally advanced hypopharyngeal cancer (HPC). Eleven patients who showed complete response (CR) or near CR with NAC were followed by chemoradiotherapy (CRT) using nedaplatin (CDGP), docetaxel (DOC) and TS-1. The other 4 patients were followed by surgical treatment. The regimen of CRT was administration of CDGP 40mg/m² (day1), DOC 40mg/m² (day1) and TS-1 80mg/m² (day1-5). The CR rate of CRT was 100%, but 2 patients had a recurrence after CRT. The rate of larynx which could be preserved was 63.3% by this method. This method demonstrated good efficacy in patients with locoregionally advanced HPC.

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We reviewed 22 cases of non-squamous cell carcinoma (NSCC) of the oral cavity and oropharynx that were treated at the Kurume University Hospital between 1976 and 2005. Two percent of the oral carcinomas and 5% of the oropharyngeal carcinomas were NSCCs. The 5-year and 10-year survival rates of NSCC in the oropharynx were 90%. There was no statistically significant difference in survival rate between squamous cell carcinoma (SCC) and NSCC (p=0.06). The 5-year and 10-year survival rates of NSCC in the oral cavity were 75% and 37%, respectively. There was no statistically significant difference in the survival rate between SCC and NSCC. Survival results well correlated with clinical stages. A significant difference between Stage I, II and III versus Stage IV was found (p=0.04). In contrast, no significant relationship was found between survival and histologic type, or between survival and treatment. Patients with adenoid cystic carcinoma of Grade III, peri-neural invasion or vessel invasion, are recommended to receive adjuvant therapy.

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Reg IV (Regenerating gene type IV) is a member of the Reg gene family which is associated with tissue degeneration, and is known to be up-regulated in inflammatory bowel diseases, gastric and colorectal cancer. The relationship between Reg IV expression and metastatic prostate cancer with refractory of hormone therapy or usefulness of serum marker in early pancreatic ductal carcinoma is reported. In an immunohistochemical examination of Reg IV in 25 cases of adenoid cystic carcinoma of the salivary gland, Reg IV expression was closely associated with nodal metastasis and distant metastasis. These results suggested that Reg IV might be a useful marker for prediction of metastasis and prognosis in adenoid cystic carcinoma.

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Most parapharyngeal space tumors are benign, and malignancies are rare. We report the results of a retrospective review of patients with primary parapharyngeal space malignant tumors treated at our institution from 1994 to 2007. During this period, 42 patients seen at our institution were found to have parapharyngeal space tumors. Six tumors (14.3%) were malignant and 36 (85.7%) were benign. Six of 21 (28.6%) prestyloid tumors were malignant, and malignant tumors were all found in the prestyloid region in MRI. There were three carcinoma ex pleomorphic adenomas and one each of salivary duct carcinoma and liposarcoma and chordoma. Four of the six tumors were diagnosed as benign preoperatively. Prestyloid parapharyngeal space tumors should be indicated for surgery even if they are asymptomatic, because preoperative diagnosis is difficult. It was difficult to deal with tumors that were revealed to be malignant postoperatively. Postoperative adjuvant therapy should be considered case by case by referring to the histology and surgical margin, because malignant parapharyngeal space tumors are heterogeneous. If tumors recur, it is important to follow up strictly to salvage them.

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Calcium replacement therapy is often needed to maintain normal levels of serum calcium postoperatively in cases of advanced pharyngolaryngeal cancer, even if the parathyroid gland is preserved. However, in the majority of these patients, functional preservation of the parathyroid gland is possible. Therefore, there is a need for developing criteria for terminating the calcium replacement therapy. In this study, we tried to create such criteria.
Ten patients with advanced pharyngolaryngeal cancer who underwent pharyngolaryngeal resection and bilateral neck dissection with preservation of the contralateral parathyroid gland were enrolled in this study. The level of iPTH was measured preoperatively, during operation, just after operation, and on day 1, day 3, 1 week, 2 weeks, 1 month and 3 months postoperation.
In 9 patients in whom the parathyroid gland was successfully preserved, the values of iPTH were 38.9 ± 5.9, 12.7 ± 5.9, 10.3 ± 3.7, 10.6 ± 3.8, 10.9 ± 8.6, 9.2 ± 5.0, 22.4 ± 12.7, 26.6 ± 12.4 and 29.3 ± 11.8, respectively. iPTH decreased within one week, but increased significantly at 2 weeks postoperation. These results indicate that the evaluation of parathyroid function at 2 weeks postoperative by measuring the level of iPTH might be a useful criterion for deciding whether or not to stop calcium replacement therapy.

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Since 2000 we have used primary nerve grafts to reconstruct facial nerve defects caused by tumor ablation in a parotid region in 16 patients (12 males and 4 females aged from 31 to 79 years old, 64.3 on average). The extent of sacrificed facial nerves was from 1 branch to total, and the maximum length of the nerve gaps was 11cm. For facial nerve reconstruction, a free nerve graft was used in 5 patients (from the great auricular nerve in 2 patients and the sural nerve in 3 patients) and a vascularized sural nerve graft was used in 11 patients. In 9 patients with vascularized sural nerve grafts, a skin flap or adipofascial flap harvested with the vascularized sural nerve was used to cover or fill the soft tissue defect. Postoperative radiotherapy was applied in 8 patients.
We evaluated the results using Yanagihara's 40-points grading system after more than ten months' follow-up. Eight patients reconstructed by vascularized nerve grafts obtained 20 and 32 points (average 25.3), and 4 patients reconstructed by free nerve grafts obtained 14 and 36 points (average 22.0). The average scores of the patients with total facial nerve defects were 25.0 and 14.0 points in the vascularized and free nerve graft groups, respectively. However, no significant differences were identified between these two groups. Problems encountered were obvious misdirections of the facial nerve in 2 patients with total facial nerve defects.
These results indicated that a vascularized sural nerve graft is preferable for a reliable result when a flap to cover or fill a soft tissue defect is required, because it can be elevated with a skin flap from the posterior calf region.

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