Hisayuki Kato

Purpose: Rapidly metabolizing tumor cells have elevated levels of nicotinamide phosphoribosyltransferase, an enzyme involved in NAD(+) biosynthesis, which serves as an important substrate for proteins involved in DNA repair. GMX1777, which inhibits nicotinamide phosphoribosyltransferase, was evaluated in two human head and neck cancer models in combination with radiotherapy. Experimental Design: Effects of GMX1777-mediated radiosensitization were examined via metabolic and cytotoxicity assays in vitro; mechanism of action, in vivo antitumor efficacy, and radiosensitization were also investigated. Results: IC(50) values of GMX1777 for FaDu and C666-1 cells were 10 and 5 nmol/L, respectively, which interacted synergistically with radiotherapy. GMX1777 induced a rapid decline in intracellular NAD(+) followed by ATP reduction associated with significant cytotoxicity. These metabolic changes were slightly increased with the addition of radiotherapy, although poly(ADP-ribose) polymerase activity was significantly reduced when GMX1777 was combined with radiotherapy, thereby accounting for the synergistic cytotoxicity of these two modalities. Systemic GMX1777 administration with local tumor radiotherapy caused complete disappearance of FaDu and C666-1 tumors for 50 and 20 days, respectively. There was also significant reduction in tumor vascularity, particularly for the more sensitive FaDu model. [(18)F]FDG-positron emission tomography/computed tomography images showed reduction in [(18)F]-FDG uptake after GMX1777 administration, showing decreased glucose metabolism in vivo. Conclusions: Our data represent the first report showing that GMX1777 plus radiotherapy is an effective therapeutic strategy for head and neck cancer, mediated via pleiotropic effects of inhibition of DNA repair and tumor angiogenesis, while sparing normal tissues. Therefore, GMX1777 combined with radiotherapy definitely warrants clinical evaluation in human head and neck cancer patients. Clin Cancer Res; 16(3); 898-911. (C) 2010 AACR.

We investigated the prevalence of high-risk human papillomavirus (HR-HPV) in squamous cell carcinoma of the tonsil and tongue-base region, and evaluated its clinical features and prognostic implications according to HPV status and p16 and p53 expression. HR-HPV was positive in 16 (53%) of 30 samples. Of these positive cases, 15 (94%) carried HPV 16 sequences and only 1 (6%) carried a HPV58 sequence. Among the HPV-positive patients, the frequency of heavy smokers and drinkers was significantly lower than among the HPV-negative patients. Among the 30 patients, p16 was overexpressed in 16 (53%), and this overexpression was strongly associated with the presence of HR-HPV (P &lt 0.0001). In contrast, HPV-negative patients were more likely to have p53 overexpression (75%). On univariate analysis, both HPV-positive status (86% vs. 48% P = 0.029) and p16 overexpression (100% vs. 31% P &lt 0.001) significantly improved the overall survival (OS), respectively. On the other hand, p53 overexpression was significantly associated with inferior OS (42% vs. 83% P = 0.004). These results indicate that it will be necessary to use these HPV-related biomarkers for decisions on staging and therapeutic strategy. © 2010, Japan Society for Head and Neck Cancer. All rights reserved.

We investigated the prevalence of high-risk human papillomavirus (HR-HPV) in squamous cell carcinoma of the tonsil and tongue-base region, and evaluated its clinical features and prognostic implications according to HPV status and p16 and p53 expression. HR-HPV was positive in 16 (53%) of 30 samples. Of these positive cases, 15 (94%) carried HPV 16 sequences and only 1 (6%) carried a HPV58 sequence. Among the HPV-positive patients, the frequency of heavy smokers and drinkers was significantly lower than among the HPV-negative patients. Among the 30 patients, p16 was overexpressed in 16 (53%), and this overexpression was strongly associated with the presence of HR-HPV (P &lt 0.0001). In contrast, HPV-negative patients were more likely to have p53 overexpression (75%). On univariate analysis, both HPV-positive status (86% vs. 48% P = 0.029) and p16 overexpression (100% vs. 31% P &lt 0.001) significantly improved the overall survival (OS), respectively. On the other hand, p53 overexpression was significantly associated with inferior OS (42% vs. 83% P = 0.004). These results indicate that it will be necessary to use these HPV-related biomarkers for decisions on staging and therapeutic strategy. © 2010, Japan Society for Head and Neck Cancer. All rights reserved.

Purpose A significant proportion of oropharyngeal squamous cell carcinomas (OSCC) are associated with the human papilloma virus (HPV), particularly HPV16. The optimal method for HPV determination on archival materials however, remains unclear. We compared a quantitative real-time polymerase chain reaction (qRT-PCR) assay for HPV16 mRNA to a DNA in situ hybridization (ISH) method, and evaluated their significance for overall (OS) and disease-free (DFS) survival. Patients and Methods Matched, archival biopsies from 111 patients with OSCC were evaluated for HPV16 using a qRT- PCR for E6 mRNA and ISH for DNA. Immunohistochemistry for p16, p53, and epidermal growth factor receptor were also performed. Results HPV16 E6 mRNA was positive in 73 (66%) of 111 samples; ISH was positive in 62 of 106 samples (58%), with 86% concordance. P16 was overexpressed in 72 samples (65%), which was strongly associated with HPV16 status by either method. E6 mRNA presence or p16 overexpression were significantly associated with superior OS; E6 mRNA, HPV16 ISH, or p16 were all significantly associated with DFS. On multivariate analysis adjusted for age, stage, and treatment, positive E6 mRNA was the only independent predictor for superior OS; for DFS, p16 expression or HPV16 status determined by either method was significant. Conclusion The prevalence of HPV16 in OSCC ranges from 58% to 66%, in a recently treated Canadian cohort. Classification of HPV-positivity by HPV16 E6 mRNA, HPV16 ISH or p16 immunohistochemistry (IHC) is associated with improved DFS. However, the latter two assays are technically easier to perform; hence, HPV16 ISH or p16 IHC should become standard evaluations for all patients with OSCC.

It has become clear that superselective intraarterial infusion therapy has demonstrated extremely high effectiveness for advanced head and neck cancer in combination with radiation therapy. It is expected to contribute in particular to improvement of patients' quality of life following treatment and improvement of the prognosis through organ preservation. However, some problems currently rto be solved, such as indications or complications. We report herein on our cases and those in the literature, and discuss superselective intraarterial infusion therapy in Japan.

It has become clear that superselective intraarterial infusion therapy has demonstrated extremely high effectiveness for advanced head and neck cancer in combination with radiation therapy. It is expected to contribute in particular to improvement of patients' quality of life following treatment and improvement of the prognosis through organ preservation. However, some problems currently rto be solved, such as indications or complications. We report herein on our cases and those in the literature, and discuss superselective intraarterial infusion therapy in Japan.

To detect probable mechanisms of local heated aerosol inhalation in nasal allergy, we measured nasal resistance before and after house dust antigen challenge to the nasal mucosa in 13 patients with perennial allergic rhinitis treated with local hyperthermia for 2 weeks and in 15 untreated patients. Mean nasal resistance either on expiration or inspiration 15min. and 8 hours after antigen challenge in treated patients was significantly lower than in untreated patients. We measured nasal resistance before and after histamine challenge to the nasal mucosa in 9 perennial allergic rhinitis patients before and after hyperthermial treatment and 6 voluntary healthy subjects. Mean nasal resistance right after histamine challenge either on expiration or inspiration in patients before treatment was significantly higher than in patients after treatment or healthy subjects. The frequency of sneezing due to histamine challenge to the nasal mucosa in patients after treatment was significantly lower than in patients before treatment, and no significant difference in frequency of sneezing was seen between patients after local hyperthermia and healthy subjects. Local heated aerosol therapy for more than 1 week, twice a day, may suppress both early- and late- phase allergic reaction and nonspecific hypersensitivity by histamine in the allergic nasal mucosa.

A case of mucoepidermoid carcinoma in the maxillary sinus is reported. The patient was an 88-year-old female who complained of swelling of the left cheek. CT scan showed a low density tumor mass in the left maxillary sinus, and the tumor infiltrated into the hard palate. Histopathological examination revealed a high grade mucoepidermoid carcinoma. Although partial maxillectomy performed, she relapsed with a lesion in the maxillary sinus 6 months after the operation. We performed radiotherapy for a total of 50Gy, and the relapsed tumor disappeared completely after irradiation. However, she died of bone metastasis 12 months after radiotherapy.

1. Five cases of parotid cancer are reported, in which the patients underwent parotidectomy under diagnosis of benign tumor in another hospital or department, were postoperatively diagnosed with malignant tumor, and then received reoperation in our department.<br>2. The age and sex distribution of the cases was 3 males and 2 females with a mean age of 40 years, ranging from 10 to 77 years, including 2 child cases under 15 years.<br>3. Histopathologically, the cancer was classified as adenoid cystic carcinoma in 2 cases, mucoepider-moidcarcinoma in 2 cases, and acinic cell carcinoma in 1 case, and one each of adenoid cystic carcinoma and mucoepidermoid carcinoma occurred in the children.<br>4. The patients underwent reoperation within 8 weeks after the first surgery. The surgical technique was total parotidectomy in 1 case and superficial lobectomy in the remaining 4 cases, with the facial nerve being preserved in all 5 patients.<br>5. Palpation in the examinations conducted at follow-up in our department detected no localized tumor remnant, but the tumor was still found to be histologically residual in 4 of the 5 cases.<br>6. The postoperative clinical course was found to be excellent, without recurrence or metastasis of the cancer.

An epithelioid sarcoma is a malignant soft tissue tumor that has a high frequency of occurrence in the extremities of a young adult males. Occurrence of the diseases in the head and neck region is rare, about 1%. We report here an experience of epithelioid sarcoma which occurred in the buccal mucosa of a 12-years-old boy.<BR>The patient has complained of pain in the buccal region for one month and visited Gamagori City Hospital. In the initial diagnosis, we recognized a tumor of 15×10mm in the left buccal mucosa, and it was diagnosed as an epithelioid sarcoma by biopsy. We performed tumorectomy from an oral cavity. It was free of margin in pathological diagnosis; test result being cytokeratin, CEA positive, and EMA slightly positive. The post-operative area did not epithelialize for about two months, and recurrence was diagnosed because a tumor almost similar to that preoperative formed. Therefore, the patient was introduced our hospital and tumorectomy was performed again. Inflammatory granulation and scar tissue comprised of a fibrosis tissue were observed in the pathological diagnosis of pecimen extraction. There was no recurrence seven months after the operation.

1. Five cases of parotid cancer are reported, in which the patients underwent parotidectomy under diagnosis of benign tumor in another hospital or department, were postoperatively diagnosed with malignant tumor, and then received reoperation in our department. 2. The age and sex distribution of the cases was 3 males and 2 females with a mean age of 40 years, ranging from 10 to 77 years, including 2 child cases under 15 years. 3. Histopathologically, the cancer was classified as adenoid cystic carcinoma in 2 cases, mucoepidermoidcarcinoma in 2 cases, and acinic cell carcinoma in 1 case, and one each of adenoid cystic carcinoma and mucoepidermoid carcinoma occurred in the children. 4. The patients underwent reoperation within 8 weeks after the first surgery. The surgical technique was total parotidectomy in 1 case and superficial lobectomy in the remaining 4 cases, with the facial nerve being preserved in all 5 patients. 5. Palpation in the examinations conducted at follow-up in our department detected no localized tumor remnant, but the tumor was still found to be histologically residual in 4 of the 5 cases. 6. The postoperative clinical course was found to be excellent, without recurrence or metastasis of the cancer.

A case of mucoepidermoid carcinoma in the maxillary sinus is reported. The patient was an 88-year-old female who complained of swelling of the left cheek. CT scan showed a low density tumor mass in the left maxillary sinus, and the tumor infiltrated into the hard palate. Histopathological examination revealed a high grade mucoepidermoid carcinoma. Although partial maxillectomy performed, she relapsed with a lesion in the maxillary sinus 6 months after the operation. We performed radiotherapy for a total of 50 Gy, and the relapsed tumor disappeared completely after irradiation. However, she died of bone metastasis 12 months after radiotherapy.

We report here two cases of spontaneous retropharyngeal and cardiomediastinal emphysema. The patients were a 15-year-old boy, who developed a foreign body sensation in the pharynx after he ran and a 16-year-old boy who developed pain in the anterior neck after he spoke loudly. X-ray and CT examination findings revealed air in the retropharyngeal and cardiomediastional regions in both patients. Antibiotics and a week of rest were prescribed and these complaints disappeared. Sixty-four cases of spontaneous mediastinal emphysema, including our two cases, reported in the Japanese literature in the period between 1992 and 2001 are also reviewed and discussed in this paper.

We report here two cases of spontaneous retropharyngeal arid cardiomediastinal emphysema. The patients were a 15-year-old boy, who developed a foreign body sensation in the pharynx after he ran and a 16-year-old boy who developed pain in the anterior neck after he spoke loudly. X-ray and CT examination findings revealed air in the retropharyngeal and cardiomediastional regions in both patients. Antibiotics and a week of rest were prescribed and these complaints disappeared. Sixty-four cases of spontaneous mediastinal emphysema, including our two cases, reported in the Japanese literature in the period between 1992 and 2001 are also reviewed and discussed in this paper.

We conducted aerodynamic inspection, including subglottic pressure measurement, and clinical evaluation of aerodynamic parameters for various disorders. In total, 1,072 examples were examinas, including normal vocal cords, polyp, reeurrent nerve paralysis and glottic cancor. Phonation function inepection was carried out by measuring height (Hz). sound pressure (dBspl) and mean flow rate (ml/sec). By combining these parameters, the diseased state of glottic vibration was discussed. In particular, measuremenis of subglottic preseure were necessary for direct calculation of larynx resistance, subglottic power and glottal efficiency. Results were characteristic for each diseased state. It is important in terms of evaluating phonation, to observe the vibrational state of the vocal cords and to measure acrodynamic conditions in both normal and disessed vocal cords. It also seems important for disordar chsracterbtion to be detected in conjuaetion with optical and macroscopic observations of the vocal cords. © 1999, The Japan Society of Logopedics and Phoniatrics. All rights reserved.

We conducted aerodynamic inspection, including subglottic pressure measurement, and clinical evaluation of aerodynamic parameters for various disorders. In total, 1,072 examples were examinas, including normal vocal cords, polyp, reeurrent nerve paralysis and glottic cancor. Phonation function inepection was carried out by measuring height (Hz). sound pressure (dBspl) and mean flow rate (ml/sec). By combining these parameters, the diseased state of glottic vibration was discussed. In particular, measuremenis of subglottic preseure were necessary for direct calculation of larynx resistance, subglottic power and glottal efficiency. Results were characteristic for each diseased state. It is important in terms of evaluating phonation, to observe the vibrational state of the vocal cords and to measure acrodynamic conditions in both normal and disessed vocal cords. It also seems important for disordar chsracterbtion to be detected in conjuaetion with optical and macroscopic observations of the vocal cords. © 1999, The Japan Society of Logopedics and Phoniatrics. All rights reserved.

We investigated the proliferative activities in epithelial hyperplasia and dysplasia of the human vocal cords as precancerous lesions, using immunohistochemical staining with anti PCNA and MIB-1 (anti-Ki 67) monoclonal antibody. The series for this study consisted of nine patients with hyperplasia, 12 with mild dysplasia, ten with moderate dysplasia, eight with severe dysplasia, eight with vocal cord polyps, and 14 with invasive squamous cell carcinoma. The following results were obtained : 1) The mean PCNA labeling index was 1.12±1.05 (MEAN±STD%) in polyp, 4.88±2.02 in hyperplasia, 2.76± 1.76 in mild dysplasia, 3.80± 2.03 in moderate dysplasia, 6.12±3.01 in severe dysplasia, and 19.07±10.37 in invasive cancer. 2) The mean MIB-1 positive rates were 5.50±2.47 (MEAN±STD%) in polyp, 13.08±6.86 in hyperplasia, 16.55±7.34 in mild dysplasia, 15.94±6.73 in moderate dysplasia, 21.43±8.16 in severe dysplasia, and 41.48±14.05 in invasive cancer.