With recent developments in plastic and reconstructive surgery, reconstruction of a relatively large defect in the mandible after oral tumor excision has become feasible by the transplantation of vascularized complex tissues containing bone, muscles, and skin; however, transplantation for large defects requires significant invasion and morbidity of the donor site, usually resulting in severe oral dysfunction. The concept of distraction osteogenesis was established in the 1950s by the Russian orthopedist, G.A. Ilizarov. After corticotomy of the long bone in the lower limb and rigid fixation with external device, a callus develops between bone segments by gradual traction of the distraction gap, and the newly formed callus matures to bone by fixation after the completion of lengthening. Ilizarov also developed the bone transport method for new bone formation of intermediate defective regions caused by injury, tumor excision, or other acquired disorders. In this method, the transport segment is prepared by osteotomising the disk of the healthy long bone adjacent to the defective region, and slowly moving to the other healthy stump produces new bone and surrounding tissues. The new bone is regenerated within the regions through which the transport segment has passed, resulting in tissue regeneration in the intermediate defective region. There is also a bifocal distraction method, in which a transport segment is produced and moved through the entire defective region, and a trifocal distraction method, in which transport segments are produced at both ends of the defect region, and moved in opposite directions. In summary, we performed distraction osteogenesis using a combination of the bone transport method and transplantation of a small volume of bone, and achieved reconstruction of mandibular defects. The treatment period is long, but functionally and morphologically good results are obtained without significant invasion of other regions, suggesting that our methods could be used as an effective reconstruction method in the future.

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Aberrant promoter hypermethylation of tumor suppressor genes is considered to be a common feature of primary cancer cells. In this study, we checked the methylation status of Cyclin A1 in cancer cell lines by bisulfite sequencing analysis, showing that four of seven head and neck (57%), six of ten esophagus (60%), and none of six lung (0%) cancer cell lines were methylated. RT-PCR analysis revealed that the expression of Cyclin A1 correlated with the methylation status very well. Then we checked several kinds of primary cancer tissue by quantitative methylation-specific PCR (QMSP). QMSP analysis revealed that Cyclin A1 methylation was detected in 22 samples (44%) of 50 head and neck cancer, 6 (30%) of 20 esophageal cancer and 7 (23%) of 30 lung cancer. In addition, we examined serum DNA from 23 patients with head and neck cancer and found that little methylation was detected in these samples.
In this study, we found that Cyclin A1 is methylated very frequently in cancer tissue suggesting that promoter hypermethylation of Cyclin A1 is an important alteration in carcinogenesis of head and neck cancer.

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In response to replication perturbation or damage of DNA, cell-cycle checkpoint is activated, which leads to mutually exclusive, two consequences: cell cycle arrest and repair of damaged DNA, or induction of apoptosis. Although previous studies have suggested that a checkpoint molecule, human Rad9, is involved in the process, the exact mechanism remains to be investigated. Here, we studied the role of Rad9 in DNA damage response through the tumor suppressor p53 pathway. Rad9 bound specifically to a p53-consensus DNA-binding sequence in the P21^WAF1 promoter, which increased after exposure to UV. The immunoprecipitation and in vitro binding assay indicated p53 associated with Rad9 regardless of phosphorylation status. Taken together with the assessment of immunohistochemistry showing overexpression of Rad9 in head and neck squamous cell carcinoma cell line, the present study demonstrates overexpression of Rad9 leads to dysregulation of checkpoint response after DNA damage occurs in head and neck cancer.

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A new approach to maxillary cancer using the extended lateral rhinotomy and hemicoronal flap is described. In comparison with the classic Weber-Fergusson incision, the new approach has several advantages: 1) avoids lower eyelid complications and fistula formation, 2) allows to approach the infratemporal fossa, permitting safe resection, especially visualization of the base of the pterygoid process and 3) allows easy use of the flap for reconstruction of the orbital floor, such as temporoparietal flap with or without calvarial bone. Our experience with this approach has been very satisfactory. This approach combined with a versatile approach to the mid-facial skeleton and hemifacial dismasking flap, provides good exposure and good cosmetic outcome without undue technical difficulty.

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Two hundred and sixty-four patients with squamous cell carcinoma of the tongue were analyzed retrospectively.
One hundred and eighty-two of these patients were treated by methods similar to the recommended protocol of Asakage et al. 2005. The cases that showed histological cervical lymph node metastasis at the time of initial treatment or developed secondary cervical lymph node metastasis without recurrence of primary tumor were 17/138 (12%), in T1 or early T2 N0 group, 2/5 (40%) in late T2 or T3 N0 group, 8/10 (80%) in any T N1 group and 25/29 (86%) in any T N2 group.
All N0 cases with T1-3 that did or did not follow recommended protocol were also analyzed. A high occurrence rate of cervical lymph node metastasis was observed in late T2 patients with endophytic type growth. This result suggests that addition of growth pattern is useful criteria for late T2 such as an indication of elective neck dissection.

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Thymidine phosphorylase (TP) is an enzyme involved in fluoropyrimidine anti-tumor agent metabolism, but little is known about the relation between TP and response to the anti-tumor agent. To examine its influence on response to anti-tumor agent, we quantified and localized TP expression using immunohistochemistry and image analysis in oral squamous cell carcinoma tissue of 31 patients before neoadjuvant chemotherapy, then assessed the influence of TP including other tumor related factors by multivariate analysis (discriminant analysis). A criterion variable was designed between the response group and the non-response group. We could significantly discriminate between the two groups. Significant explanatory variables selected for the prediction of discrimination were thymidylate synthase (TS), TP, PCNA and nuclear polymorphism. Furthermore, TS, TP and PCNA contributed to discrimination. Accuracy rate for the response group was 0.86 and that for the non-response group was 0.76. In the response group, the accuracy could be excellent. In conclusion, TP next to TS might be an important factor for predicting the response to anti-tumor agent.

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In elderly patients with head and neck cancer, a safe and radical treatment with which the incidence of systemic side effects is low is required. We developed a new combination intra-arterial and intra-venous chemotherapy with docetaxel (TXT), cisplatin (CDDP), peplomycin (PEP), and 5-FU (TCPF intra-arterial chemotherapy), and evaluated its usefulness and safety in such patients.
From March 2002 to May 2005, 10 patients aged over 75 years with oral squamous cell carcinoma were treated with TCPF intra-arterial chemotherapy. The patients consisted of 5 males and 5 females aged from 75 to 84 years (median age, 80 years). The tumors were located in the tongue or oral floor in 8 patients, the buccal mucosa in one, and the upper gingiva in one. A catheter for intra-arterial administration was inserted via the superficial temporal artery or occipital artery. Continuous intra-arterial administration of 15 mg/m² TXT (day 1-5) and 10 mg/body PEP (day 6-10), intra-arterial administration of 7-15 mg/m² TXT (day 3) and 7-15 mg/m² CDDP (day 4, 5), and continuous intravenous administration of 250 mg/body/day 5FU (day 1-10) were performed as 1 course. The second course was performed 4 weeks after the completion of the first course in patients for whom it was required. Radiotherapy was additionally performed in one patient. Excision biopsy in 7 patients, and radical excision in 2 were performed after the completion of this treatment.
The effects of this method on the primary lesions were CR 8/10 (80%), PR 2/10 (20%), and pathological CR 6/9 (67%). As side effects, no cerebrovascular disorder was detected, but grades 2-3 mucositis and alopecia on the intra-arterial administration side were observed, without marked systemic disorders. These results indicated that this chemotherapy is useful and safe, and can be applied to as a radical treatment method elderly patients with high risks.

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This study was conducted on 106 patients who received interstitial brachytherapy for Stage I, II squamous cell carcinoma of the tongue over the past 15 years and whose primary tumor was controlled. Late cervical lymph node metastasis occurred in 38 patients (35.8%), with the time until metastasis ranging from 2 months to 7 years and 8 months. Among the 38 patients, 34 patients underwent neck dissection and 23 of them could be salvaged. The 5-year disease-specific survival rate did not differ between stages T1 (73%) and T2 (62%). When classified according to the criteria of Yamamoto and Kohama of the mode of invasion, the 5-year survival rate was 100% in Grade 2, 96% in Grade 3, 63.1% in Grade 4C, and 0% in Grade 4D. The survival rate of Grade 4C and 4D differed from that of Grade 2 and 3. Patients with Stage I, II squamous cell carcinoma of the tongue and late cervical lymph node metastasis, regardless of their T-stage, had a 5-year survival rate of 65.6% and their prognosis was worse than that of metastasis-free patients who had a 5-year survival rate of 100%. During follow-up, early detection of late cervical lymph node metastasis by taking into consideration the mode of invasion is considered important.

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To evaluate the association of the features of subsequent cervical lymph node metastasis and prognostic factors in stage I·II squamous cell carcinoma of the oral tongue, 50 patients with subsequent cervical node metastases from 243 cases initially treated by partial glossectomy alone, between 1987 and 2002, were reviewed. Of those, 26 had uneventful prognosis, and the remaining 24 had poor prognosis, including recurrence deep in the floor of the mouth in two, ipsilateral neck failure in ten, late contralateral neck metastases in three, and distant metastases in nine. The three-year disease-free survival rates in relation to each of the prognostic factors were as follows: the number of metastatic nodes: single node metastasis: 18 (78%) vs. two nodes: 3 (38%) vs. more than three: 5 (28%), respectively; the number of involved levels: single level: 18 (78%) vs. two levels: 8 (42%) vs. more than three: 0 (0%), respectively; as the most far involved level: level I: 13 (81%) vs. II or III: 13 (43%) vs. IV or V: 0 (0%), respectively; capsular destruction: slight and/or moderate: 12 (75%) vs. severe: 12 (38%). The size of the metastatic deposits itself was not related to poor prognosis, however, lesions without keratinization in the nodes appeared to be significantly associated with poor prognosis.
Therefore, if the presence of high-risk features mentioned above are identified when examining neck dissection specimens from stage I·II tongue carcinoma patients, postsurgical treatments should be considered.

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This study evaluated the usefulness of epithelial dysplasia on surgical margin in squamous cell carcinoma of the tongue with Stage I, II. Fifty patients seen between 1995 and 2000 with surgical treatment only were reviewed. Epithelial dysplasia on surgical margin occurred in 26 patients (52%). The clinicopathologic prognosis factors significantly associated with the epithelial dysplasia on surgical margin was tumor growth type, tumor size, tumor thickness, and postoperative local recurrence. Moreover, postoperative local recurrence was positively associated with tumor size, tumor thickness, and epithelial dysplasia on surgical margin. In a multivariate logistic regression analysis, patients with an epithelial dysplasia score of ≥4 points had a predictive value for postoperative local recurrence.

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Background: This study was undertaken to analyze salvage treatment, larynx conservation rates and survival rates in radiation-failures of early glottic carcinoma.
Methods: From 1988 to 2002, 186 patients with previously untreated T1 (135 patients) and T2 (51 patients) glottic carcinoma were treated by radiotherapy. Radiation-failures occurred in 33 patients (local rest in 5 patients, and local recurrence in 28 patients). All patients were male with an average age of 66 years, ranged from 52 to 81.
Results: Radiation-failure rate was 12.6% in T1 (17 of 135 patients) and 31.4% in T2 (16 of 51 patients) cases. The salvage treatment at rT2 stage after radiotherapy was total laryngectomy, but no one underwent partial laryngectomy. The 5-year larynx conservation rate after radiation-failure was 21.6% (66.7% in rT1, 16.7% in rT2, and 0% in rT3-4). The 5-year survival rate was 75% in rT1, 100% in rT2, and 33.3% in rT3-4.
Conclusion: In order to improve the 5-year larynx conservation rate, it is important to try partial laryngectomy in patients with rT2-stage glottic carcinoma. More careful follow-up is necessary for patients to detect recurrent carcinoma in the early stage.

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The standard treatment for advanced laryngeal cancer has been shifting from total laryngectomy to various organ preservation therapies such as subtotal laryngectomy and chemoradiotherapy. Robbins showed remarkable results with RADPLAT, the superselective intra-arterial infusion of supradose cisplatin (150mg/m²), against advanced head and neck cancer. However, the volume of laryngeal cancer is smaller than those of the other sites of head and neck cancers, and so a swaller less dose of cisplatin could save advanced laryngeal cancer patients. It may be reasonable to treat these subtypes of laryngeal cancer with a different modality. Thirty-five patients with laryngeal cancer were treated with tri-weekly intra-arterial infusion of cispatin (100mg/body). A 200 times molar excessive amount of sodium thiosulfate was intravenously infused to reduce the toxicity of cisplatin. Ten of 16 patients with glottic cancer and 10 of 19 patients with supraglottic cancer were followed for more than 2 years. Larynx preservation rate of glottic and supraglotiic cancer was 80% and 70%, and progression-free survival rate was 80% and 50%, respectively. Grade III and IV toxic events were less frequent than with RADPLAT or systemic administration of a similar dose of cisplatin. Glottic and supraglottic cancers show different clinical behaviors. Our protocol with less cisplatin than RADPLAT is especially effective for glottic cancer.

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The oropharynx sustains important functions such as respiration, phonation, and deglutition in our upper airway. It is crucial to understand both the anatomy which sustains functions and the clinical behaviors of the cancer to obtain optimal functional results in the treatment of oropharyngeal cancers. The authors reported on the surgical technique and the indication for this transoral approach referred to as transoral lateral oropharymgectomy (TLO). Before surgery, a meticulous clinical examination including palpation of the tumor is needed. CT scan and MRI are particularly important to evaluate the deep margin of the tumor and the relationship with important anatomical tissue such as the carotid artery. Surgery should be done under a good visual exposure in order to properly identify the anatomical landmarks, such as the medial pterygoid muscle and parapharyngeal fat layer. We have performed TLO in five patients. Although the observation period is still short, all patients are maintaining good function and are surviving without disease. Further study is needed to fully elucidate the clinical usefulness of TLO.

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Reconstruction of surgical defects of the lateral and superior oropharynx is complicated and frequently results in velopharyngeal dysfunction. We review the long-term results of reconstruction with the Gehanno method to investigate postoperative function.
During the past 9 years, we performed the Gehanno method on 33 patients with carcinoma of the oropharynx. After two years or more among 8 of these patients, we conducted a detailed evaluation of postoperative function.
All of the 8 patients had satisfactory function including normal nasal breathing, swallowing without aspiration and nasopharyngeal regurgitation.
Narrowing of the velopharyngeal space is important for obtaining satisfactory functional results. We created a velopharyngeal port as wide as the fifth finger. Postoperative articulatory dysfunction resulting from velopharyngeal insufficiency was within the acceptable range. However, gradual velopharyngeal dysfunction caused by the fore-arm flap was seen a few cases.
This reconstructive procedure preserves the good postoperative function of the oropharynx over a long period of time without technical difficulty.

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The application of iodine solution to the epithelium of the hypopharynx before cutting the surgical margin off was studied to determine its feasibility as an aid to resection.
From 1997 to 2006, 82 cases of hypopharynx carcinoma were treated at Fukushima Medical University Hospital, of which 43 cases underwent laryngo-pharyngectomy. These 43 cases were selected for the present study. In 32 of these cases, marginal sections were diagnosed pathologically during operation by frozen-section. In 23 of the 32 cases, iodine stained samples were examined, and the unstained area was restricted to the area of resection. In the other 11 cases, the margin of resection was determined by gross view.
One case developed marginal recurrence, whose margin of resection was determined by visual examination. There were no cases of marginal recurrence, whose margin of resection was determined in frozen-section pathologically.
In 32 cases, margins of resection were diagnosed by frozen-section, although further excision was added until the margin became negative. A significant difference in the incidence of positive margin at the first resection was observed between the cases with iodine staining (2 of 23 cases) and those without iodine staining (4 of 9 cases). In 23 cases with iodine staining, four cases were skipped to unstained areas and these pathological diagnoses were as follows; invasive carcinoma, carcinoma-in-situ, dysplasia, and granulation.
Iodine staining for laryngo-pharyngectomy showed hidden malignant lesions and aids accurate resection of hypopharyngeal carcinoma.

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There is no standard reconstructive technique for cancer ablation in head and neck lesions. The wide variety of reconstructive techniques results in big differences in outcomes among each institution, so we carried out a multi-institutional study of reconstructive techniques, and investigated the outcomes for 10 years. In order to standardize the range of ablation, only patients who had a reconstruction after pharyngolaryngoesophagectomy for hypopharyngeal cancer were included in this study. 764 patients were enrolled, of whom 715 patients (93.7%) were reconstructed with jejunum. There were differences among each institution's situation regarding the ratio of preoperative radiation and chemotherapy, total operation time, total volume of bleeding, ratio of abscess formation and fistula formation, duration of fast and hospital stay after operation.
There was a correlation between long operation time and much bleeding. There was also a correlation between a large number of operations and short operation time. There was no correlation between the use of PGE1 and the risk of thrombosis. Preoperative radiation delayed wound healing significantly. We studied a multivariate analysis on each factor. The use of penrose drain and long operation time were significant risk factors of abscess or fistula formation. Based on these results, we would like to standardize reconstructive technique.
This research was supported by a Grant-in-Aid for Cancer Research (grant 17-15) from the Ministry of Health and Welfare of Japan.

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In surgical treatment of parotid gland carcinoma, the facial nerve should often be resected due to tumor extension. In particular, when the main branch of a facial nerve is excised, reconstruction of the facial nerve is rather difficult. We reviewed the records of 5 parotid gland carcinoma patients who received radical extirpation of the entire parotid gland and also received primary reconstruction with nerve graft using the cervical plexus at Kurume University Hospital between 2001 and 2005. After the reconstruction, the facial paralysis recovered gradually and the median score of facial paralysis was 32 points. Because the cervical plexus has multiple branches, it is easy to remove during surgery of the neck. In conclusion, primary reconstructive surgery with nerve graft from the cervical plexus is highly recommended in the event of facial nerve extirpation.

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The clinical features of 123 patients (66 men, 57 women; mean age, 61 years) with malignant major salivary gland tumors treated between 1986 to 2004 were retrospectively investigated. In this report we evaluated the results of the treatment and clinical as well as histopathologic features. According to the TNM Classification of 1997, 10 patients were classified as T1, 21 as T2, 23 as T3, and 69 as T4. Seventy-eight cases were staged as N0, 15 as N1, 28 as N2 and 2 as N3. Histopathologically, 16 tumor types were observed; mucoepidermoid carcinoma was the most common. As a treatment, surgery was done in all patients.
The five-year and ten-year cause-specific survival rates determined using the Kaplan-Meier method were 61% and 50%. The factors influencing a poor outcome were T4 classification (p=0.0131), N+ stage (p<0.0001) and stage IV (p=0.0046). As for the major histopathologic types, the five-year suvival rates were 61% for mucoepidermoid carcinoma, 62% for adenoid cystic carcinoma, 52% for adenocarcinoma, 83% for malignant mixed tumor and 100% for acinic cell carcinoma.
Thirty-two (26%) out of the 123 cases developed local recurrence. Twelve (13%) out of the 90 cases developed neck recurrence after neck dissection. Two (6%) out of the 33 cases without neck dissection developed nodal metastasis. Twenty-five (20%) out of the 123 cases developed distant metastasis. There was a statistically significant difference between extra-capsular spread of the metastatic lymph node and distant metastasis (p<0.05).

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We experienced two rare cases of carcinoma of the parotid gland in a child aged under ten years old. In a review of 1649 patients with malignant tumors from 1958 to 1996 in Japan, 9 patients were under ten years old. We experienced rare cases in which we performed total resection of the parotid gland and facial nerve graft. Histologically, these two cases were low grade mucoepidermoid carcinoma. Post-operative course of the two patients was uneventful with satisfactory recovery of the facial palsy.

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Although extrathyroidal invasion is one of the most significant risk factors for patients with papillary thyroid carcinoma (PTC), minimal, superficial adhesion does not affect their prognosis. The General Rules for the Description of Thyroid Cancer by the Japanese Society of Thyroid Surgery classifies minimal extrathyroidal invasion as Ex1, and massive invasion as Ex2. However, this definition is sometimes inconsistent between institutions or surgeons. We have defined only patients who had preoperative palsy of the recurrent laryngeal nerve, or patients with invasion of the mucosa of the trachea or esophagus as Ex3. When we can shave tumors off the laryngotracheal structures, the esophagus, or the recurrent laryngeal nerve, the condition is considered to be Ex2. From 1993 to 2004, among 562 patients with primary PTC (microcarcinomas were excluded), there were 272 patients with Ex0, 149 with Ex1, 81 with Ex2, and 60 with Ex3. Their 10-year disease-free survivals were 94%, 81%, 56% and 41%, respectively. There was a statistically significant difference between Ex1 and Ex2. However, as for 10-year disease-specific survivals which were 99%, 94%, 91% and 65%, respectively, a significant difference existed between Ex2 and Ex3. In conclusion, this novel definition of extrathyroidal invasion for patients with PTC leaves no room for confusion and is valuable in predicting their prognosis.

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To better understand ways to improve the preservation of function of the parathyroid glands in surgery for advanced malignancy of the larynx and hypopharynx, we did a retrospective analysis of 59 patients. These patients underwent total laryngectomy or total pharyngo-laryngectomy and bilateral neck dissection with preservation of the contnalateral thyroid gland and parathyroid glands. Results of preserving the parathyroid function were evaluated at 3 months after surgery based on the necessity of calcium replacement.
The rates of successful preservation of the function of the parathyroid glands post-operatively were not significantly different between those who underwent surgery for laryngeal cancer and hypopharyngeal cancer. There were also no significant differences based on the surgery of the primary sites. T-stage and N-stage were not useful indicators. Most importantly for discriminating between success and failure, were the findings during surgery. Our analysis demonstrated that the function of the parathyroid glands was preserved in only 44.4% of the patients with insufficient preservation of the superior thyroid vein and 20.0% of the patients with congestion of the preserved thyroid glands.
These results indicate that sufficient preservation of the superior thyroid vein and avoidance of congestion of the preserved thyroid gland were crucial for the post-operative functional management of the parathyroid glands in surgery for advanced malignancy of the larynx and hypopharynx.

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Primary lymphoma of the salivary gland is rare, accounting for 4.7% of lymphomas overall. Furthermore, lymphomas arising in the submandibular gland are reported to comprise 9-16% of all salivary gland lymphomas. Among lymphomas originating from salivary glands, the ratio of follicular lymphoma is very low. A 58-year-old woman was referred to our hospital with a painless mass in the submandibular gland. Fine-needle aspiration biopsy showed class I findings. However, histological diagnosis indicated follicular lymphoma grade 1. The disease was considered stage IVA. Eight courses of chemotherapy were performed with rituximab, cyclophosphamide, adriamycin, vincristine, and prednisolone. This case achieved complete remission, but the patient should be followed carefully hereafter.

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