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 accompanied by malignant changes in an in vitro bronchial epithelial carcinogenesis model. We have reported that the 1799 cells transfected with the vector expressing small hairpin RNA specific to the S100A2 gene exhibited the depletion of S100A2 and malignant phenotypes such as colony forming ability, suggesting that S100A2 serves as a tumor suppressor in this system. In this study, we applied the DNA microarray technique to clarify the changes of gene expression profile resulting from the suppression of S100A2 and identifed the genes whose expression have altered beyond 4-fold compared to the control. The altered expression of E-cadherin, one of such genes, was also confirmed at the protein level.

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It has been reported that TS-1 can exert antitumor effects on human oral squamous cell carcinoma patients in Japan. However, little is known about the mechanisms of the antitumor activity of TS-1. In this study, we examined the mechanism of the antiangiogenic effects of TS-1 on a human oral squamous cell carcinoma cell line, B88. B88 tumor-bearing nude mice were treated with TS-1 (10 mg/kg/day, 5 days/week), which was administered orally for eight weeks. The TS-1 treatment resulted in a significant suppression of tumor growth, and induced the up-regulation of TSP-1 expression, and the down-regulation of VEGF and CD34 expression immunohistochemically. Overall, these results indicate that TS-1 may inhibit the angiogenecity of human oral cancer cells through the up-regulating TSP-1 expression and the down-regulating VEGF expression.

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Tumor markers have clinical significance as a valuable tool for diagnosis and treatment monitoring of human malignancies. Unfortunately, there are no useful tumor markers for oral cancer. In this study, we attempted to identify individual tumor markers in blood RNA of two patients with oral squamous cell carcinoma (OSCC) or salivary gland cancer (SGC) using whole genome-wide gene expression array. We selected genes with more than 3-fold induction in each patient with oral cancer as compared to healthy controls. Among these genes, the individual tumor marker that was expressed at the highest level was identified. Solute carrier family 28 (sodium-coupled nucleoside transporter), member 1 (SLC28A1) in T1 OSCC case and a novel gene in T2 SGC case were identified as the individual tumor markers. These markers were increased 585- and 87-fold, respectively. After resection of the primary tumor, expression levels of these markers were markedly reduced and normalized. These results suggest that we can individualize tumor markers for each patient with cancer and their markers are useful for treatment monitoring.

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It is necessary to seal the defect in the skull base after tumor resection to maintain separation between the brain and the nasal cavity. We usually use a free musculocutaneous flap for the reconstruction of the skull base. It is, however, difficult to seal the defect of the middle skull base without a gap, because it is narrow and complex. In this paper, we describe that a free omental flap was useful for the middle skull base reconstruction.
We performed 29 skull base reconstructions in 5 years. Eight of the cases were middle skull base reconstructions. We used a free flap for the reconstruction of the middle skull base. Five omental flaps and 3 rectus abdominis musculocutaneous flaps were used for reconstructions.
All free flaps were successfully transferred. In one case undergoing repair with an omental flap, liquorrhea occurred, but was successfully managed by conservative treatment. In two cases undergoing rectus abdominis musculocutaneous flap transfer, wound infection occurred. One case was successfully managed by conservative treatment, whereas in the other, a free omental flap was subsequently transferred to the infected wound in a laler surgical procedure.
The defect of middle skull base reconstruction is complex and narrow, so it is difficult to fill the complex dead space with musculocutaneous flaps. We consider that an omental flap is useful for middle skull base reconstruction, because it is flexible and has a long pedicle.

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The maxillary region consists of the nasal and oral cavity, and is an important constituent of facial appearance. Careful consideration is essential for a functional and aesthetic reconstruction.
Our strategy for maxillary reconstruction is as follows, 1) the skin paddle of the rectus abdominis musclocutaneous flap is designed to fulfill the reconstructive issues concerning the orbit, the palate and nasal lining, 2) in the skeletal reconstruction, the methods depend on whether the subcutaneous fat is thick or thin; the former is reconstructed by the rectus abdominis myocutaneous flap combined with vascularized costal cartilages, the latter by artificial bone, and 3) reconstruction the eyelids and eye socket of is carried out in a secondary operation when atrophy of transferred tissue after 1 year has ceased.
As a functional device, we performed the reconstruction of a nasal lining by the mucosal hinged flap which can be elevated in the secondary operation. This method diminished the unpleasant complication caused by the skin paddle.
For aesthetic reasons, dynamic reconstruction is positively performed after reconstruction of the eyelids and eye socket. Natural wrinkles appear in the lateral canthal region by this method, and a nice smile can be obtained.

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Malignant melanoma is a rare disease, which accounts for only 1-2% of sinonasal malignant tumors. Attempts have been made to treat if with a combined modality therapy of surgery, radiotherapy, chemotherapy, and immunotherapy, but the prognoses are poor. We reviewed the clinical courses, treatments, and prognoses of 14 cases which received firstline treatment at the Department of the Head and Neck Surgery in Saitama Cancer Center from 1975 to 2003.
All 14 cases received surgery. The surgical procedure was lateral rhinotomy, i.e. resection of the side wall of the nasal cavity, inner wall of the eye socket, nasal turbinates, and mucosa of the sinuses. If the nasal septum was involved, cartilage and/or mucosa were resected together. In addition, radiotherapy, chemotherapy and immunotherapy were also given for each case accordingly.
The 2-year survival rate (Kaplan-Meier method) was 46.2% and the 5-year survival rate was 23.1%. Both the 2-year and 5-year local control rate were 21.4%. The 2-year survival rate of patients whose tumors were totally removed (A) was 42.9%, and not totally removed (B) was 50%. 5-year survival rate of (A) was 50%, however, nobody of (B) could survive for 5 years.
Surgical treatment with lateral rhinotomy seemed to be effective for patients with a small region, especially when limited to one turbinate, however, it was not efficient for patients with a large or septal region. Other treatments are necessary for them, such as skull-base surgery and/or radiotherapy.

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The cervical lymph node (CLN) status is one of the most important prognostic factors in oral cancer. However, the main method of addressing the CLN depends on diagnostic imaging. Sentinel lymph node (SN) biopsy combined with lymphoscintigraphy may be a minimally invasive technique that samples first-echelon lymph node to predict the need for neck dissection. Focused analysis of the SN is highly accurate in identifying metastases. In this study, we investigate the possibility of identifying the SN in oral cancer and the detection of metastases in SN by HE stain, cytokeratin IHC and cytokeratin 17 RT-PCR. Twenty-four consecutive patients who had clinically negative CLN underwent SN biopsy, followed by elective neck dissection. SNs were detected by means of mapping with isotope labeling ^99mTc-phytate. All lymph nodes were examined by conventional HE staining for evaluating metastasis. In addition, each SN was cut into multiple sections for cytokeratin IHC staining and for RT-PCR for cytokeratin 17. SNs were identified in 24 (100%) of 24 patients by lymphoscintigraphy and gamma probe. One to seven SNs were identified in each patient. Both HE and immunohistochemical staining of SN identified metastasis in 7 patients (29.2%), and the expression of cytokeratin 17 by RT-PCR of SN was positive in 8 patients (34.8%). No metastases were identified using HE, cytokeratin IHC staining in non-SNs. Neck failure has not developed in 23 (95.8%) of 24 patients. The results strongly suggest the usefulness of the SN concept in oral cancer and for better assessing the status of the CLN.

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For the clinicopathological analysis of subsequent contralateral cervical lymph node metastasis in stage I squamous cell carcinoma of the oral tongue, 64 cases with muscular invasion, initially treated by partial glossectomy alone, were reviewed.
Twenty-two patients developed subsequent cervical node metastasis. Contralateral neck metastasis was diagnosed in 7 cases (32%), 4 of which had simultaneous bilateral metastases. In the remaining three with delayed contralateral metastasis, the time lapse between glossectomy and contralateral neck metastases ranged from a little less than 2 months to 31 months. In cases with contralateral spread, the submandibular, jugular and middle nodes were involved.
The presence of contralateral metastases resulted in a 5-year cause-specific survival rate of 50% and 67% for patients with simultaneous metastases and delayed contralateral metastases, respectively.
In two of the three cases with carcinomas arising from the sublingual surface, contralateral metastasis developed. With regard to ipsilateral node metastasis, of the 13 patients with single node metastasis only one developed metastasis contralaterally, however of the 5 patients with multiple node metastasis (≥3), two developed on the contralateral side. In the four patients with metastatic submental node, three had contralateral metastasis.
The depth of the primary lesion itself, as well as the size, did not play a substantial role in the occurrence of contralateral metastasis. However, the primary lesion with poor and/or non keratinization in the muscular layer appeared to be significantly associated with contralateral metastasis.
Therefore, it is suggested that stage I tongue carcinoma patients with sublingual surface origin, submental node metastasis, multiple node metastases of the ipsilateral side, poor and/or non keratinization in the muscular layer should be followed up more carefully.

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Late cervical metastasis after treatment for the primary tumor influences the prognosis of N0 cases of tongue cancer. We retrospectively investigated 192 patients with previously untreated N0 squamous cell carcinoma of the tongue who underwent partial resection via the mouth without elective neck dissection at the Maxillofacial Surgery Department, Graduate School, Tokyo Medical and Dental University, between 1987 and 2001. Patients with recurrence at the primary site were excluded. Late cervical metastasis occurred in 30 (15.6%) of the 192 patients, of whom 18 (60%) were salvaged by neck dissection. Among patients who died, loco-regional recurrence was seen in 5 (17%), and 7 patients (23%) died as a result of distant metastasis. Eleven (68.8%) of the 16 patients who had poorly differentiated squamous cell carcinoma of the tongue developed late cervical metastasis. Twenty-two patients had extracapsular spread in their metastatic lymph nodes, and 11 of these patients died due to loco-regional recurrence or distant metastasis. Four (80%) of 5 patients who developed late cervical metastasis in the area of level II died due to loco-regional recurrence. To salvage patients with late cervical metastasis after treatment of primary tongue cancer, it is important to detect cervical metastasis as early as possible, and to undertake salvage surgery immediately. However, control of distant metastasis in patients who are free of disease at loco-regional sites is still problematic.

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There are various indications of neck dissection for tongue carcinoma. The treatments for many diseases have been standardized, and we considered that neck dissection for tongue carcinoma. The subjects were 110 patients with tongue carcinoma in 9 hospitals from 1998 to 1999. Based on retrospective data we determined treatment protocols for tongue carcinoma. Elective neck dissection for patients with T1N0 and early T2N0 was not necessary, but that for patients with late T2N0 and T3N0 was necessary. The necessity of neck dissection of level I to IV was confirmed for patients with TN1 or N2a. The extent of neck dissection for patients with TN2b, N2c, or N3 was not prescribed, because these cases include a variety of tumors. The rate of death caused by cervical metastasis for patients with T1N0, early T2N0, late T2N0, or T3N0 was 3%, 6%, 23%, and 13%, respectively however the rate of cervical metastasis for these groups was 19%, 33%, 31%, and 36%, respectively. Based on these results, this protocol for N0 patients was adequate. The pathological sites of cervical metastasis in patients with TN1 were all in the area of level I to III. The adequate area of neck dissection for patients with TN1 was level I to III. The pathological cervical metastatic sites of patients with TN2b, N2c, or N3 were all in the area of level I to IV. The adequate area of neck dissection for those with TN2b, N2c, and N3 was level I to IV.

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Subjects were 32 patients, 30 men and 2 women, with squamous cell carcinoma of the hypopharynx. Their median age was 61 years, ranging from 41 to 71 years. Subsites were the piriform sinus in 28, and the post-cricoid area in 4. Eight had stage III disease and 24 had stage IV disease. The twenty-six cases were resectable and 6 cases were unresectable. These patients were treated with concurrent chemoradiotherapy. The treatment regimen consisted of 5-fluorouracil (5-FU) and cisplatin (CDDP). 5-FU was given at 1000 mg/m² per day as a continuous infusion during 4 days, and 60 mg/m² of CDDP was given on day 4 after the beginning of 5-FU administration. Two courses of chemotherapy were performed, on day 1 and on day 35. Radiation was given in a single daily fraction of 2 Gy and 5 fractions per week to a total dose of 60 to 70 Gy. A radiation break was scheduled from day 26 to 35. The median total delivered dose of radiation was 66 Gy. Toxicities included mucositis (grade 3, 21.9%, grade 4, 28.1%), vomiting (grade 3, 6.3%), and leukopenia (grade 3, 12.5%). Twenty-nine patients (90.6%) received scheduled treatment. Nine (28.1%) had a complete response and 22 (71.9%) partial response. Mean overall survival was 23.5 months (4.7-61.6) and progression-free survival (PFS) was 20.8 months (4.7-61.6). The preservation rate of the hypopharynx without recurrent sites was 58.8% of patients during two years. The two-year overall survival rate (OS) was 67.0% and PFS rate was 54.0%. Two-year OS was 75.9% and PFS rate was 57.9% in resectable cases. Failure patterns showed in 9 cases with locoregional recurrence and 1 with distant metastasis. Based on the results, concurrent chemoradiotherapy is effective in preserving the hypopharynx in a high percentage of patients and improving two-year OS and PFS rates without compromising QOL.

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In the last five years, 16 out of 49 patients with hypopharyngeal cancer (HPC) treated in Kyoto University Hospital had esophageal cancer (EC). In nine of the 16 patients, the HPC was detected 50 months on average after treatment for EC. The staging of HCP was classified as early (stage 1 or 2) in five cases and the larynx was conserved in five cases. All these cases had been observed in this hospital after EC treatment. In 16 patients of double cancer, the 3-year overall survival rate was 62%. Three of five the dead cases died of EC. There was no patient who died of HPC. Out of 11 live patients, seven cases lost their voice, one case needed a tracheal canulla and six cases had serious dysfunctions in swallowing. The most contributing factor to the prognosis in double cancer of HPC and EC may be the treatment of EC. Swallowing function tended to be worse as both cancers were treated synchronously or metachronously.

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Thirty-three cases with previously untreated submandibular gland cancer and sublingual gland cancer received definite operation in our hospital from November 1979 to February 2000. In this report we evaluated the results of the treatment and clinical features. Histopathological classification was composed of 16 cases with adenoid cystic carcinoma, 7 cases with adenocarcinoma, 6 cases with mucoepidermoid carcinoma and 4 cases with others. Of the cases, 2 cases were T1, 14 cases were T2, 15 cases were T3, 2 cases were T4, 13 cases were stage I, 11 cases were stage II, 1 case was stage III, and 8 cases were stage IV. Primary control rates in 5 years and 10 years were 75.5% and 61.8%. Cause -specific cumulative survival rates in 5 years and 10 years were 52.2% and 47.5%. We believe that it is important to achieve en bloc resection with adequate surgical margin. On the other hand, it is considered that neck lymph node metastasis is one of the critical factors which influence prognosis. Nineteen out of the 33 cases developed recurrence and almost all of them showed poor prognosis because of distant metastasis. Therefore, effective adjuvant treatment for distant metastasis is considered to be the key to improve the survival rate.

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Shoulder syndrome, a sequelae of cutting the spinal accessory nerve during neck dissection, remarkably decreases QOL of the patients. We examined post-operative shoulder funtions in 43 patients who underwent total neck dissection in our hospital from 1999 to 2004.
All of the subjective symptoms, objective findings and degree of shoulder abduction were significantly better in the patient group with the spinal accessory nerve preserved (preserved group, n=25) than in the group with the nerve resected without reconstruction (resected group, n=11). The patient group with the nerve reconstructed either by re-anastomosis or nerve-grafting (n=4) showed a similar shoulder function to the preserved group. The patient group with the nerve reconstructed by nerve-grafting between the central cut-end of the cervical plexus (C2 or C3) and the peripheral cut-end of the accessory nerve (n=3) showed better fnctional results than the resected group.

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Patients with head and neck cancer having large or multiple cervical lymph nodes metastasis generally require radical neck dissection (RND) including internal jugular vein resection. However, histological examination sometimes reveals no direct invasion of the metastasis into the jugular vein, even though pre-operative examinations indicate direct invasion. Preservation of the internal jugular vein is a critical issue in reconstructive head and neck surgery in order to select the reconstructive procedure and to secure a drainage vein for vascular anastomosis of a free flap. In the present study, pathological invasion of lymph node metastasis into the jugular vein was examined in patients with head and neck cancer who underwent RND and the influence on the prognosis was investigated. Further, the clinical course after surgery of those patients was compared with that of patients who underwent modified RND (mRND) preserving the internal jugular vein. The results showed that recurrence of cervical lymph node metastasis was more frequently observed in patients who underwent RND compared to the patients who underwent mRND, irrespective of pathological invasion of the metastasis into the internal jugular vein. The ratio of distant metastasis was higher in patients having vascular invasion than in those without the invasion. These findings suggest that the presence of extra-nodal dissemination should always be considered in cases showing vascular adhesion to the internal jugular vein in pre-operative examination regardless of pathological invasion.

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Severe systemic complications developed in 48 of 2,426 patients undergoing reconstruction after resection of head and neck cancers at the East and Tokyo hospitals of the National Cancer Center, Japan, from June 1980 through December 2003. To identify causative factors, we reviewed 11 cases of upper airway obstruction, 8 cases of brain infarction, 5 cases of gastrointestinal hemorrhage, and 2 cases of pulmonary thromboembolism. We identified many possible causes of upper airway obstruction; tracheostomy should be performed when defects are large, when bilateral neck dissection has been done, and when patients are elderly. Most patients with brain infarction had a history of hypertension poorly controlled despite treatment with multiple agents. Appropriate blood pressures should be maintained during and after surgery in all patients. The stress of re-operation and treatment with nonsteroidal anti-inflammatory agents were believed to be the main causes of gastrointestinal hemorrhage. Although the incidence of pulmonary thromboembolism after head and neck reconstruction is low (0.08%), anticoagulants are indicated, especially for obese patients.

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Patients undergoing reconstructive microsurgery after head and neck cancer ablation are at risk of postoperative delirium because they have a prevalence of several problems such as advanced age and long operation time. To prevent anastomotic thrombosis, bed rest used to be forced upon the patients after microsurgery. To improve the activity of daily life (ADL) in patients after microsurgery, bed rest was removed from our postoperative clinical path and patients were allowed to walk without restriction. As a result, incidences of postoperative delirium decreased.

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Boron neutron capture therapy (BNCT) is a tumor-cell targeted radiotherapy. When ¹⁰B absorbs thermal neutrons, the alpha and ⁷Li particles generated by the ¹⁰B (n, α) ⁷Li reaction are high LET particles, and carry high kinetic energy (2.34 MeV), and have short ranges (4-9 micron-meters) of approximately one-cell diameter, resulting in a large RBE and selective destruction of tumor cells containing ¹⁰B. We have, for the first time in the world, used BNCT to treat 11 patients with recurrent head and neck malignancies (HNM) after a standard primary therapy since 2001. The 11 patients were composed of 6 squamous cell carcinomas, 3 salivary gland tumors and 2 sarcomas. The results of BNCT were as follows. (1) Regression rates (volume %) were CR: 2 cases, >90%: 5 cases, 73%: 1case, 54%: 1 case, PD: 1 case, NE (not evaluated): 1 case. The response rate was 82%. (2) Improvement of QOL was recognized, such as disappearance of tumor ulceration and covering with normal skin: relief of severe pain, bleeding, trismus and dyspnea: improvement of PS (from 4 to 2) allowing the patients to return to work and elongate his survival period. (3) Survival periods after BNCT were 1-38 months (mean: 8.5 months). The survival rate was 36% (4 cases). (4) There are a few side-effects such as transient mucositis and alopecia less than Grade-2.
These results indicate that BNCT represents a new and promising treatment approach even for a huge or far-advanced HNM.

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Recently, a clinical pathway has been rapidly introduced to many medical fields, but not sufficiently for the treatment of head and neck cancer because patients show different pathology and disease courses. If the process of diagnosis and treatment is segmentalized into small steps and a clinical pathway for each step is created, clinical pathways will be also more easily introduced to diseases with diversity, such as head and neck cancer. This study shows an example of our clinical pathway with segmentalized treatment procedures, a clinical pathway for inpatient chemotherapy. It is suggested that the introduction of a clinical pathway for chemotherapy is useful for improved operational efficiency and informed consent, enhanced risk management, and the practice of team medicine.

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We report a case of parotid pleomorphic adenoma metastatic to sternum with benign pathology and discuss the mechanism of metastasis by reviewing the literature about metastasizing pleomorphic adenoma. The patient was a 41-year-old woman, who underwent parotid gland surgery for parotid tumor in February 1992, and total parotidectomy for recurrent parotid tumor in February 2002. Both of the pathological diagnoses were benign pleomorphic adenoma. She visited the orthopaedic department with chest pain in October 2003 and was diagnosed as sternum tumor, and operated on in November 2003. The pathological diagnosis was also pleomorphic adenoma with no malignancy and seemed to be the same as the previous ones. She has been followed up at the outpatient department with no recurrence.

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IκB kinase (IKK) complex consisting of two related catalytic subunits (IKK-α and IKK-β) and one regulatory subunit with a scaffold function (IKK-γ) has been shown to participate in the cytoplasmic signaling pathway that activates NF-κB. NF-κB plays an important role in the regulation of survival process, which protects cells from a wide variety of apoptotic signals. In addition to the cytoplasmic role of IKK complex, recent studies revealed that one of its components, IKK-α, shuttles between cytoplasm and cell nucleus. However, the nuclear function of IKK-α remains largely unknown. The present study showed that cisplatin treatment results in the activation of ATM in association with a significant nuclear accumulation of IKK-α. The cisplatin-mediated nuclear accumulation of IKK-α was blocked by a potent inhibitor of ATM. In addition, cisplatin treatment decreased in the amounts of ubiquitinated forms of IKK-α. Furthermore, IKK-α-deficient MEFs displayed a decreased sensitivity to cisplatin as compared with wild-type MEFs. Taken together, these results strongly suggest that nuclear IKK-α is regulated in an ATM-dependent manner, and plays a pivotal role in the cisplatin-induced apoptosis.

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We report three cases of maxillary carcinomatreated with total maxillectomy following preoperative superselective arterial embolization.
Patient 1, a 56-year-old woman, was referred to our department because of hypoesthesia of the right face. Under the diagnosis of a recurrence of adenoid cystic carcinoma in the right maxilla we performed a total maxillectomy 3 days after superselective arterial embolization. Total blood loss was 380 ml. Patient 2, a 63-year-old man, received a right total maxillectomy and supraomohyoid neck dissection 1 day after superselective arterial embolization under the diagnosis of a squamous cell carcinoma in the right maxillary sinus. Total blood loss was 160 ml. Patient 3, a 72-year-old woman, received a left total maxillectomy 2 days after superselective arterial embolization under the diagnosis of a left maxillary liposarcoma. Total blood loss was 660 ml. It is suggested that superselective transcatheter maxillary artery embolization is effective for reduction of blood loss for total maxillectomy.

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SCL-CHEP and CHP are indicated for early stage and selected advanced stage laryngeal cancers. In this subtotal laryngeal surgery, voice and swallowing functions can be preserved without altering the upper respiratory pathway. Between 1997 and 2004, 24 patients received this procedure at our hospital and we have accumulated knowledge regarding postoperative care and complications. Because of the nature of the organ preservation technique, many factors can influence the outcome of this surgery. By reviewing these factors, we feel it would be beneficial to introduce a clinical pathway to manage the complicated postoperative care of this surgery. Hospitalization was subdivided into two stages, the healing stage and the swallowing rehabilitation stage. Related factors, such as wound care, bed rest period, airway management, and nutritional care were summarized and precisely determined in this 20^- to 28^- days pathway. We believe the introduction of a clinical path will facilitate communication between different medical staff members and offer high quality patient care.

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