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Background: The objectives of this study were to demonstrate anti-metastatic effect of BioKnife, uPA activity-dependent oncolytic Sendai virus, after BioKnife treatment for primary tumor, and analyze its mechanisms in a simulated metastasis mouse model of head and neck squamous cell carcinoma (HNSCC)., Methods: We established a simulated metastasis mouse model using a murine HNSCC cell line "SCCVII." We assessed a tumor size and an induction of tumor-specific immunoresponses using cytotoxic T-lymphocyte (CTL) assay, flow cytometry (FCM) in spleen and immunohistochemistry (IHC) in secondary tumor., Results: Secondary tumors were significantly smaller in BioKnife-treated group. CTL activities were significantly improved in BioKnife group. FCM revealed that induction of dendritic cells and CD4 + /CD8 + lymphocytes was significantly higher in BioKnife group. IHC showed that CD8 + lymphocytes invaded secondary tumor., Conclusion: Tumor-specific immunoresponses induced by BioKnife has great potential to be a novel, safe, and less invasive option for control and prevention of metastasis., (© 2019 Wiley Periodicals, Inc.)

Objective: To evaluate the feasibility of Transoral Videolaryngoscopic Surgery (TOVS) for radiorecurrent supraglottic and hypopharyngeal cancer, and to compare survival and complications between primary and radiorecurrent cases., Methods: Twelve cases of salvage TOVS for radiorecurrent cancer and 53 cases of TOVS as an initial treatment (primary cases) were evaluated. Days to resume soft diet, Functional Outcomes of Swallowing Scale (FOSS), postoperative complications, epithelization days and survival outcomes were assessed by retrospective chart review., Results: FOSS score was significantly worse in salvage cases compared with primary cases. Bleeding and airway compromise was slightly greater in salvage cases than in primary cases; however, this was not statistically significant. Wound healing was significantly delayed in salvage cases compared with primary cases (P<0.001). In primary cases, wounds were re-epithelized within 60 days in 83% of patients and within 90 days in almost all patients, while in salvage cases 42% of patients required more than 90 days for wound healing. In salvage cases, the 5-year overall survival, disease specific survival rate, local control rate, and laryngeal preservation rate was 85.7%, 85.7%, 62.5%, and 78.0%, respectively, and 85.7%, 98.0%, 91.3%, and 97.8%, respectively, for primary cases. Local control rate was significantly better in primary cases than in salvage cases., Conclusion: Salvage TOVS was feasible in highly selected cases. After serial transoral surgery, the final laryngeal preservation rate was satisfactory. Swallowing function in salvage cases tended to be worse than in primary cases, and a significantly longer time was required for wound healing., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background/aim: Podoplanin is a candidate cancer stem cell marker in squamous cell carcinoma (SCC). Several studies have reported the prognostic value of podoplanin expression in tumor cells in lung SCC but few have focused on its expression in cancer-associated fibroblasts (CAFs). The aim of this study was to analyze the prognostic significance of podoplanin expression, with special reference to the expression pattern in both tumor cells and CAFs., Patients and Methods: Immunohistochemical analyses using anti-podoplanin antibody were performed on 126 resected specimens of lung SCC. When more than 10% of tumor cells or CAFs showed immunoreactivity with podoplanin levels as strong as those of the positive controls, the specimens were classified as a podoplanin-positive., Results: Podoplanin-positive status in tumor cells (n=54) was correlated with a lower incidence of lymphatic invasion (p=0.031) but there were no significant differences in disease-free survival (DFS) and disease-specific survival (DSS) by the log-rank test. Podoplanin-positive status in CAFs (n=41) was correlated with more advanced stage (p=0.008), higher frequency of pleural invasion (p=0.002) and both shorter DFS (p=0.006) and DSS (p=0.006). In Cox's multivariate analysis, podoplanin-positive status in CAFs was an independent negative prognostic factor for DFS (p=0.027) and DSS (p=0.027)., Conclusion: Podoplanin expression in CAFs might be an independent unfavorable prognostic indicator in patients with lung SCC, irrespective of the expression status of tumor cells., (Copyright© 2017 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background The aim of this study is to evaluate cases with locoregional recurrence after video-assisted thoracoscopic surgery (VATS) for primary lung cancer. Methods We reviewed 248 patients with primary lung cancer who underwent lobectomy or segmentectomy with mediastinal lymph node dissection by VATS between January 2005 and December 2011. Locoregional recurrence is defined as per its occurrence in (1) bronchial stump or lung parenchymal cut end, (2) ipsilateral pleura, and (3) ipsilateral hilar and mediastinal lymph nodes, and we analyzed recurrence rate and significant associated factors for locoregional recurrence by logistic regression analysis. Results There were 47 cases of postoperative recurrence, which consisted of 26 distant, 6 locoregional and distant, and 15 locoregional recurrences. The locoregional recurrence rate was 6.0%. Of the 15 locoregional recurrence cases, there were two cases of bronchial stump and lung parenchyma cut end (0.4%), five cases of ipsilateral pleura (2.0%), and eight cases of ipsilateral hilar and mediastinal lymph nodes (3.2%). Pleural and lymphovascular invasion and advanced stages were significant associated factors in univariate analysis. Multivariate analysis revealed that advanced stages were only a significant associated factor for locoregional recurrence (p < 0.01, odds ratio: 3.3). Conclusion Although locoregional recurrence rates of our surgical treatments for primary lung cancer by VATS might be acceptable, we should explore more effective modalities against pathologically proven local advanced lung cancer for preventing not only distant but also locoregional recurrences., (Georg Thieme Verlag KG Stuttgart · New York.)

Aims: Maspin is known to be a tumour suppressor protein, and its prognostic significance in patients with several types of cancer, including lung squamous cell carcinoma (SCC), has been reported. However, its prognostic impact on lung SCC has been controversial. We explored the prognostic value of maspin expression with particular reference to its subcellular localization in patients with lung SCC., Methods and Results: Paraffin-embedded tissue samples from 101 curatively resected patients with lung SCC were analysed immunohistochemically using an antibody for maspin. Maspin positivity was defined as strong expression in only the cytoplasm and observed in 25 patients (24.6%). It correlated significantly with the presence of lymph node metastasis (P = 0.006) and higher pathological stage (P = 0.003). The patients were followed-up for 2-119 months (median: 50 months), and the maspin-positive group had shorter disease-free survival (DFS) and disease-specific survival (DSS) by log-rank test (P = 0.002, P = 0.016, respectively). Multivariate analysis revealed that the status of maspin was the only independent prognostic factor for DFS and DSS (P = 0.017, P = 0.047, respectively)., Conclusions: Cytoplasmic expression of maspin could be an independent unfavourable prognostic indicator in patients with lung SCC., (© 2015 John Wiley & Sons Ltd.)

Improved therapies for individuals with head and neck squamous cell carcinoma (HNSCC) may be developed by identification of appropriate biomarkers. The aim of this study was to evaluate the usefulness of serum midkine measurement as a biomarker for HNSCC. Pretreatment serum midkine concentrations were measured in 103 patients with HNSCC and 116 control individuals by enzyme-linked immunosorbent assay. Midkine expression in tumor tissues from 33 patients with HNSCC who underwent definitive surgical resection without preoperative treatment was examined by immunohistochemistry. The cut-off serum midkine concentrations for predicting the presence of head and neck malignancy and chemosensitivity to induction chemotherapy, as determined using receiver operating characteristic curves, were 482 and 626 pg/mL, respectively. Spearman bivariate correlations showed positive correlations between serum midkine levels and immunohistochemistry staining score (r = 0.612, P < 0.001). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of serum midkine concentration for detection of HNSCC were 57.3, 85.3, 77.6, 69.2, and 72.1%, respectively. However, for predicting the response to induction chemotherapy, the values were 84.6, 60.9, 71.0, 77.8, and 73.5%, respectively. Serum midkine concentration was identified as an independent prognostic factor by multivariate analysis, using Cox's proportional hazards model (P = 0.027). Overexpression of serum midkine yielded a relative risk of death of 3.77, with 95% confidence limits ranging from 1.15 to 17.0. Serum midkine levels in patients with HNSCC were associated with malignancy, chemosensitivity, and prognosis. Serum midkine may be a useful, minimally invasive biomarker for early detection, therapeutic decision-making, and predicting prognosis., (© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

In this retrospective cohort study, we evaluated the oncological and functional outcomes of transoral videolaryngoscopic surgery (TOVS). Using distending laryngoscope and videolaryngoscope, wide operative field and working space could be obtained and tumor could be resected in en bloc. Sixty patients with T1, T2, and selected T3 laryngeal or pharyngeal squamous cell carcinomas (Stage I: n = 17, Stage II: n = 16, Stage III: n = 7, Stage IV: n = 20 cases) were enrolled and followed up for at least 24 months or until the patient's death. Fifty-three patients underwent initial treatment, and seven patients had recurrent cancer after chemoradiation. In principle, node-positive patients underwent a simultaneous neck dissection. Patients with multiple nodal metastases or a positive surgical margin received postoperative radiotherapy. For initial treatment, the 5-year overall survival and disease-specific survival rates were 77 and 95 %, respectively. For supraglottic and hypopharyngeal cancers, the 5-year laryngeal preservation rates were 89 and 96 %, respectively. For salvage surgery, the overall survival, disease-specific survival, and laryngeal preservation rates were 75, 75, and 80 %, respectively. The median times before patients could resume eating and swallowing a soft diet were 6 and 9 days, respectively. The patients' Functional Outcome Swallowing Scale stages were 0-2 in 93.3 % of the cases and 3 or 4 in 6.7 % of the cases. A percutaneous endoscopic gastrostomy was indicated for 1 (1.7 %) patient. Four (6.7 %) patients received transient tracheostomy. TOVS is a satisfactory and minimally invasive treatment option for laryngeal and pharyngeal cancers.

The search for new strategies to improve patient outcome and organ preservation is of great clinical interest in head and neck squamous cell carcinoma (HNSCC) treatment, and gene therapy is expected to play a promising role. In this study, we demonstrated the value of laser-induced stress waves (LISWs) as a novel method for nonviral gene transfer for gene therapy in HNSCC. The in vitro and in vivo transfection efficiency as well as in vitro cytotoxicity for HNSCC was investigated. Green fluorescent protein (GFP) expression and cell viability were analyzed in vitro after administration of a GFP-expressing plasmid or cationically modified GFP-expressing plasmid with LISW application. Luciferase expression in xenograft tumors was also quantitatively analyzed in vivo. The GFP gene was successfully transfected into HNSCC cells in vitro by LISW application. The cationically modified plasmid demonstrated enhanced transfection efficiency. LISWs are not associated with adverse effects after application to cells in vitro. The reporter genes were also successfully transfected into HNSCC tumors in vivo by LISW application. This technique is site specific, safe, and easily applicable for practical purposes. LISW gene therapy with therapeutic factors that inhibit tumor growth therefore has the potential as a future treatment for HNSCC.

Chronic inflammation plays important roles at different stages of cancer development, including carcinogenesis, tumor invasion, and metastasis, but molecular mechanisms linking inflammation to cancer development have not been fully clarified. Here, we report that expression of angiopoietin-like protein 2 (Angptl2), recently identified as a chronic inflammation mediator, is highly correlated with the frequency of carcinogenesis in a chemically induced skin squamous cell carcinoma (SCC) mouse model. Furthermore, Angptl2 expression in SCC is highly correlated with the frequency of tumor cell metastasis to distant secondary organs and lymph nodes. When SCC was induced in transgenic mice expressing Angptl2 in skin epithelial cells, epithelial-to-mesenchymal transitions in SCC as well as tumor angiogenesis and lymphangiogenesis were significantly increased, resulting in increased tumor cell metastasis and shortened survival compared with wild-type mice. Conversely, in a chemically induced SCC mouse model, carcinogenesis and metastasis were markedly attenuated in Angptl2 knockout mice, resulting in extended survival compared with wild-type mice. Overall, we propose that Angptl2 contributes to increased carcinogenesis and metastasis and represents a novel target to antagonize these pathologies.

Background: Recently, several transoral approaches for minimally invasive surgery have been developed for oropharyngeal cancer. However, all approaches have certain disadvantages. Therefore, we built and examined new surgical environments for improving the situation., Methods: Endoscopic transoral resection using a pharyngeal retractor or distending laryngoscope, rigid videoendoscope, and laparoscopic surgical instruments was performed in 17 patients with oropharyngeal squamous cell carcinoma. Postoperative results regarding oncology and function as well as complications were documented., Results: The 2-year relapse-free survival rate was 100%. Postoperative swallowing and speech function were satisfactory: 94.1% of cases scored ≤1 on the functional outcome swallowing scale (FOSS) and ≤1 on the communication score. Further, no perioperative mortality occurred., Conclusions: The improved surgical environment made it possible to perform a safe and reliable en bloc resection with a wide field of view and sufficient working space. Our system can be useful, although further studies on additional cases are required., (Copyright © 2010 Wiley Periodicals, Inc.)

Background: Radiofrequency ablation (RFA) is a minimally invasive tumor destruction technique and can provide the antigen source initiating tumor immunity. However, induced immune response is weak and requires additional immunotherapy for optimized RFA treatment against cancer., Methods: A murine orthotopic model of head and neck squamous cell carcinoma (HNSCC) was established to investigate the efficacy and mechanism of an RFA + interleukin-2 (IL-2) combination adenoviral gene therapy among 6 groups. Tumor volume change, apoptosis, in situ macrophage recruitment, cytotoxic T lymphocyte (CTL) activity, migration of dendritic cells into the regional lymph nodes, and systemic antitumor immunity were examined., Results: RFA + IL-2 therapy induced the highest levels of macrophage recruitment and dendritic cell migration resulting in enhanced CTL activity, increased tumor apoptosis, enhanced systemic antitumor immunity, and the best inhibition of tumor growth among all groups., Conclusion: RFA + IL-2 combination therapy generates potent tumor immunity to suppress tumor growth in HNSCC., (Copyright © 2010 Wiley Periodicals, Inc.)

Background: The relationship between the histological parameters of primary lesions and lymph node metastasis in supraglottic and hypopharyngeal cancers has not been elucidated. This analysis is important to evaluate the requirement for additional elective neck dissection when clinically node-negative cancers are treated by transoral surgery., Methods: This study included 40 previously untreated patients with supraglottic and hypopharyngeal cancers who underwent transoral en bloc tumor resection in two academic tertiary referral centers. Nodal status was confirmed by neck dissection for cases with findings or suspicion of lymph node metastases or by observation of clinically node-negative cases for more than 1 year. Patients' medical records and pathological features were analyzed retrospectively. The correlation of histological parameters with lymph node metastases, including occult metastases, was evaluated by univariate and multiple logistic regression analyses., Results: Univariate analysis showed that lymph node metastasis was correlated with tumor depth (P = 0.00087) and venous invasion (P = 0.027). Multiple logistic regression analysis showed that it was significantly correlated only with tumor depth (P = 0.007)., Conclusions: Tumor depth is the most useful parameter for predicting lymph node metastases. In clinically node-negative cases, when tumor depth exceeds 1 mm, elective neck dissection must be considered and, when it is less than 0.5 mm, regular clinical follow-up is recommended. Patients with tumor depth between 0.5 and 1 mm should be carefully observed, since they also have a chance of developing nodal metastasis. Venous invasion also indicates high rates of nodal metastasis, therefore elective neck dissection must be considered for these cases.

Background: a fibroblast growth factor 2 (FGF2)-targeted adenoviral system can alter viral tropism and allow for improved transduction and reduced systemic toxicity. This study is to investigate if the FGF2-targeted adenoviral mutant Nijmegen breakage syndrome 1 (FGF2-Ad-NBS1) gene transfer can enhance cisplatin chemosensitisation not only by targeting DNA repair, but also through the induction of antiangiogenesis, whereas at the same time reducing toxicities in treating head and neck squamous cell carcinoma (HNSCC)., Methods: the human HNSCC cell line was treated in vitro and in a nude mouse xenograft model. We conducted verification of binding ability of mutant NBS1 and downregulation of MRN complex, evaluation of transduction efficiency and combined antitumour activities. The antiangiogenesis mechanism was also investigated. Finally, we estimated the distribution of adenoviral vector in the liver., Results: the mutant NBS1 protein retains the binding ability and effectively suppresses the expression level of the MRN in infected cells. Transduction efficiency in vitro and cisplatin chemosensitisation were upregulated. The FGF2-Ad-NBS1 also showed detargeting the viral vectors away from the liver. The downregulation of NF-κB expression was supposed to correlate with increased antiangiogenesis., Conclusions: FGF2-targeted adenoviral system enhances the cisplatin chemosensitisation of mutant NBS1 and may avoid viral-associated liver toxicities., (2010 Cancer Resaerch UK.)

Background: In this study, we tested the ability of a novel poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor, 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de]-anthracen-3-one (GPI-15427), to enhance the effect of radiotherapy in a xenograft model of human head and neck squamous cell carcinoma (HNSCC)., Methods: Human xenograft HNSCC tumors were established in female nude mice: animals were treated with orally administered GPI-15427 at varied doses prior to tumor irradiation. In vitro and in vivo apoptosis analyses and neutral single-cell gel electrophoresis (comet) assay were performed, with the "tail moment" calculated to evaluate DNA double-strand break damage., Results: Orally administered GPI-15427 given before radiation therapy significantly reduced tumor volume, and cells demonstrated significantly elevated mean tail moments (indicative of DNA damage) and enhanced apoptosis both in vitro and in vivo, compared with radiation-alone and control groups., Conclusions: Use of the PARP-1 inhibitor GPI-15427 induced significant sensitization to radiotherapy, representing a promising new treatment in the management of HNSCC.

Objective: The current treatment for advanced head and neck squamous cell carcinoma continues to result in poor outcomes. The purpose of this study is to investigate the benefit of fibroblast growth factor 2-targeted adenovirus-mediated mutant-Rad50 (FGF2-Ad-Rad50) gene transfer in enhancing chemosensitization for head and neck squamous cell carcinoma and reducing chemotoxicity., Study Design: Randomized controlled laboratory study., Setting: University of Pennsylvania, Philadelphia, PA., Subjects and Methods: Human head and neck squamous cell carcinoma tumor cells and a mouse model with human head and neck squamous cell carcinoma were used for this study. There were five mice in each study group. FGF2-fab' molecule was conjugated with an adenoviral mutant-Rad50 construct. FGF2-targeted transgene expression efficiency was evaluated in vitro. Tumor cytotoxicity and growth inhibition were examined after combined FGF2-Ad-Rad50 with cisplatin treatment in vitro and in vivo. Anti-tumor mechanisms were investigated., Results: FGF2-targeted gene transfer approach significantly improved transgene expression in head and neck squamous cell carcinoma tumor cells over a nontargeted approach (207.51+/-33.62 vs 51.44+/-8.28, respectively). FGF2-Ad-Rad50 with cisplatin demonstrated a superior tumor suppression effect (264.5+/-124.1 mm3 vs 567.1+/-267.6 mm3), increased DNA double-strand breaks (1349+/-51.67 vs 774+/-28.56), and anti-angiogenesis (%ROI: 0.76%+/-0.38% vs 2.10%+/-1.66%) in tumor cells over nontargeted adenovirus., Conclusion: Combination of FGF2-Ad-Rad50 with cisplatin significantly improves anti-tumor effect by targeting DNA repair systems and tumor angiogenesis. The great benefit of this strategy supports clinical trial for novel treatment of head and neck squamous cell carcinoma.

Platinum-based drugs that induce DNA damage are commonly used first-line chemotherapy agents for testicular, bladder, head and neck, lung, esophageal, stomach, and ovarian cancers. The inherent resistance of tumors to DNA damage often limits the therapeutic efficacy of these agents, such as cisplatin. An enhanced DNA repair and telomere maintenance response by the Mre11/Rad50/Nbs1 (MRN) complex is critical in driving this chemoresistance. We hypothesized therefore that the targeted impairment of native cellular MRN function could sensitize tumor cells to cisplatin. To test this, we designed what we believe to be a novel dominant-negative adenoviral vector containing a mutant RAD50 gene that significantly downregulated MRN expression and markedly disrupted MRN function in human squamous cell carcinoma cells. A combination of cisplatin and mutant RAD50 therapy produced significant tumor cytotoxicity in vitro, with a corresponding increase in DNA damage and telomere shortening. In cisplatin-resistant human squamous cell cancer xenografts in nude mice, this combination therapy caused dramatic tumor regression with increased apoptosis. Our findings suggest the use of targeted RAD50 disruption as what we believe to be a novel chemosensitizing approach for cancer therapy in the context of chemoresistance. This strategy is potentially applicable to several types of malignant tumors that demonstrate chemoresistance and may positively impact the treatment of these patients.

Purpose: To assess whether adenovirus-mediated retinoblastoma 94 (Ad-RB94) transgene expression enhances efficacy of radiation therapy (XRT) of human head and neck squamous cell carcinoma (HNSCC)., Experimental Design: The HNSCC cell lines (JHU006 and JHU012) were treated in vitro and in a nude mouse xenograft model with Ad-RB94, Ad-DL312 control vector, or untreated as mock control. Cell viability and tumor growth were evaluated and combined RB94/XRT antitumor activity was analyzed by measuring DNA double-strand breaks, apoptosis-associated early DNA fragmentation, and levels of RB-regulated cell cycle progression E2F1 transcription factor., Results: Ad-RB94/XRT resulted in significant HNSCC cell growth inhibition compared with XRT alone or Ad-RB94 alone in vitro and caused significant tumor regression compared with XRT alone and Ad-DL312/XRT in JHU006 and with XRT alone, Ad-DL312/XRT and Ad-RB94 alone in JHU012 in vivo. Neutral comet analysis revealed that DNA damage was significantly elevated in cells treated with Ad-RB94 alone and Ad-RB94/XRT. Tumors treated with Ad-RB94 alone showed a striking increase in early apoptosis DNA fragmentation, and DNA fragmentation was further enhanced with XRT. In addition, levels of E2F1 were up-regulated by Ad-RB94/XRT combination, whereas Ad-RB94 alone did not affect E2F1 levels and XRT alone led to down-regulation of E2F1., Conclusions: A potent antitumor effect has been observed after Ad-RB94/XRT combination treatment in HNSCC xenograft tumors. Enhanced tumor regression correlated with increased apoptosis. Ad-RB94 treatment enhances the efficacy of XRT through tumor cell sensitization by arresting the cells at the radiation-sensitive G(2)-M cell cycle and via E2F1 up-regulation.

Objective: It has been reported that akathisia is a neurological side effect induced by antiemetic drugs and/or antipsychotics. Akathisia can occur in any area of the body, but respiratory akathisia is an unusual type of akathisia. Cases of respiratory akathisia in cancer patients taking antiemetic drugs have not previously been reported., Methods: We report on a case of a cancer patient taking prochlorperazine as an antiemetic drug who experienced dyspnea accompanied by severe restlessness associated with respiration. By administration of biperiden, his restlessness in respiration and dyspnea promptly disappeared., Results: This finding led us to conclude that this cancer patient was experiencing respiratory akathisia., Significance of Results: Respiratory akathisia is uncommon. It is important for cancer patients that dyspnea induced by disease progression be ruled out as a cause of the respiratory restlessness. It is necessary to consider the possibility of akathisia in patients that complain of vague anxiety, chest discomfort, or dyspnea following antipsychotic medication.

Laryngeal carcinoma presenting as a cervical abscess is rare, so that its diagnosis is not easy. We described a case of laryngeal squamous cell carcinoma presenting as a prelaryngeal large abscess. Markedly swollen false vocal fold inhibited fiberscopic examination of the vocal folds. CT scan indicated destruction of the thyroid cartilage. Although biopsies from the abscess did not reveal malignancy, laryngeal squamous cell carcinoma was confirmed by laryngomicrosurgery with laryngeal vestibulectomy. The patient was treated by total laryngectomy with neck dissection followed by radiotherapy. The abscess was thought to be formed not by direct extension and necrosis of the tumor, but by the leakage of air and mucus through the fistula on the destroyed thyroid cartilage. Precise observation and biopsy under directscopic vestibulectomy played an important role in diagnosis of malignancy inherent in severe inflammatory tissues.

Cyclo-oxygenase (COX) is a key enzyme in the conversion of arachidonic acid to prostanoids. The expression of its isoforms, COX-1 and -2 is found in many human malignancies. This study analyzed the correlation between COX expression and the pathobiological nature of human oral mucosa, dysplasias and squamous cell carcinomas (SCCs). We examined 9 specimens of normal oral epithelia, 65 lesions with dysplasias and 50 SCCs. Labeling indices (LIs) for COX-1, COX-2, Ki-67 and P53, microvessel density (MVD) and apoptotic index (AI) were evaluated using immunohistochemistry and TUNEL methods. Western blot analysis of COX-1 and -2 was performed on four human oral SCC cell lines, all of which showed expression. The LIs for COX-1 and -2 were higher for the dysplasias than the SCCs. LIs of COX-2 but not COX-1 correlated with the histological grade of dysplasia, being highest for the severe dysplasias (p < 0.05). In contrast, the COX-2 LIs as well as COX-1 were significantly (p < 0.05) inversely correlated with the histological differentiation of the SCCs. COX-2 expression was significantly correlated with LIs of COX-1 for dysplasia (p < 0.05), but not for the SCCs. In addition no significant relationship was noted between COX-2 expression and the Lis of Ki-67, P53, AI as well as MVD for the dysplasias and SCCs. The expression of COX-1 and -2 is correlated with early stage tumorigenesis and cellular differentiation of SCCs in the oral dysplasia-carcinoma sequence.

Background/aims: The multiple occurrence of primary squamous cell carcinoma of the esophagus is often observed, and most such occurrences are double cancers. There have also been some cases with three or more intra-esophageal cancers, however, no detailed clinicopathologic study has yet been performed in the literature., Methodology: Two hundred and fifty patients of primary esophageal squamous cell carcinoma without preoperative treatment that underwent esophageal resection were re-evaluated by serial histopathologic investigations and we analyzed the data of ten patients with three or more intraesophageal cancers., Results: The clinical and histopathologic characteristics were as follows; 1) all but one of the cases were male, 2) all patients had a history of both heavy smoking and drinking but only one case had a family history of esophageal cancers among their siblings, 3) the depth of invasion in the carcinomas was restricted to within the submucosal layer of the esophageal wall, which was defined as superficial esophageal carcinoma, almost all (90%) of the cases accompanied esophageal squamous epithelial dysplasia., Conclusions: Based on these prominent characteristics of considerable multiple intra-esophageal cancers, a new clinical entity of "esophageal field cancers" could thus be suggested.

It is well known that cyclooxygenase (COX) -2 is expressed in a variety of human malignant solid tumors, associated with tumor angiogenesis, cell proliferation and inhibition of apoptosis. Here, we examined the effect of NS398, a selective COX-2 inhibitor, on two human esophageal squamous cell carcinoma (SCC) cell lines, TE-1 and TE-12. Western blot analysis confirmed the expression of COX-2 in TE-12, but not in TE-1. Treatment with 100microM NS398 suppressed the cell viability in TE-12 (48.6% of control) after 48 hours, in contrast to showing no effects in TE-1. The apoptotic index was extremely low in both cell lines after the treatment. NS398 clearly increased the number of cells in the G2/M phase and decreased the cells in the G1 and S phases in TE-12, but not TE-1. A pre-G1 fraction was not noted in either cell line. Moreover, TE-12 cells showed a decrease in the expression levels of cyclin B1 and an increase in p27Kip1. These findings suggest that NS398 inhibits cell growth and induces G2/M arrest in human SCC cells expressing COX-2.

Reported frequencies for microsatellite instability (MSI) in oesophageal cancer differ widely in the literature, perhaps due to the high incidence of loss of heterozygosity (LOH) in this cancer. Using high-resolution fluorescent microsatellite analysis (HRFMA), we analysed microsatellite alterations in detail in 50 Japanese and 50 Chinese patients with squamous cell carcinoma in the oesophagus. In HRFMA, several devices have been developed to improve the detection characteristics, reproducibility of polymerase chain reaction and the migration accuracy of electrophoresis. All the alterations observed were separable into MSI, LOH and alterations ambiguous for both. MSI was rare in these panels of oesophageal carcinomas. The frequencies of MSI in the Japanese and Chinese subjects were 8 and 4%, respectively. All the alterations were mild (within 2 base pairs) and were observed in a limited number of markers. More drastic types of MSI, such as those typical in colorectal cancer, were not observed. On the other hand, the incidence of LOH was high, reaching 50% for the Japanese and 70% for the Chinese subjects. In many of these cases, LOH was observed in multiple microsatellite markers. The frequency of LOH in each marker was not apparently biased. Although in many cases MSI and LOH were clearly distinguished with use of the sensitive and quantitative fluorescent assay, theoretically indistinguishable patterns were noted in some cases. In conclusion, MSI is rare and LOH predominates in squamous cell carcinoma in the oesophagus., (2004 S. Karger AG, Basel.)

Objective: Posttranscriptional modification involving phosphorylation of wild-type p53 has been considered to play a role in the stabilization of p53. Little is known, however, about the role of phosphorylation of mutant p53 overexpressed in tumors. The aim of this study is to determine the phosphorylation state of p53 in tumors and its contribution to tumor development., Methods: Using immunohistochemical techniques, we examined the phosphorylation of Ser392 and 15 sites in p53 overexpressed in 137 esophageal squamous cell carcinomas (ESCCs). The relationships between the phosphorylation and the expression of cell cycle regulators, Ki-67 labeling index (LI), apoptotic index, clinicopathological factors, and patient prognosis were tested statistically., Results: Of the 137 samples examined, staining for Ser392 phosphospecific p53 antibody was detected in 53 (38.7%) cases, corresponding to 58.9% of 90 p53-positive cases, whereas only 3 (2.2%) were positive for Ser15 phosphospecific p53 antibody. A significant correlation was identified between Ser392 phosphorylation and high levels of Ki-67 LI (p = 0.0271), lymphatic invasion (p = 0.0246), and poorer prognosis for patients with stage II and III advanced tumors (p = 0.0136). Using multivariate analysis, Ser392 phosphorylation was recognized as an independent prognostic factor (p = 0.0136)., Conclusions: These findings suggest that p53 protein overexpressed in ESCCs is frequently phosphorylated at Ser392, and that the Ser392 phosphorylation might contribute to tumor progression of ESCCs., (2004 S. Karger AG, Basel.)

A supracricoid laryngectomy with cricohyoidoepiglottopexy (CHEP) consists of the resection of the whole thyroid cartilage and paraglottic space, while preserving the cricoid cartilage, the hyoid bone, most of the epiglottis and the arytenoids. Laryngeal reconstruction is achieved be suturing the cricoid cartilage and the hyoid bone. This procedure is mainly indicated for large T2 glottic carcinomas and provides a complete resection and laryngeal preservation without requiring a permanent tracheostomy. Although bilateral arytenoids are usually preserved to ensure better laryngeal function after CHEP, we unavoidably had to remove the arytenoid on the tumor-bearing side during a complete resection performed in a 56-year-old male with a rT2 tumor who had undergone radiation and demonstrated impaired vocal fold motion. Despite the resection of one arytenoid, the final laryngeal function proved to be satisfactory. CHEP should be utilized as an alternative surgical modality for conventional vertical partial laryngectomies or total laryngectomies. CHEP with the total removal of the arytenoid on the tumor-bearing side may be a useful laryngeal preservation procedure for the treatment of patients with glottic carcinoma associated with an impaired vocal fold motion or a fixed vocal fold.

Background: This study examined the immunohistochemical expression of cell-cycle related molecules as well as cell proliferation and pathologic findings in oral squamous cell carcinoma (SCC) in order to clarify their pathobiologic and prognostic significance., Methods: A total of 46 oral SCC specimens were analyzed using Ki-67, minichromosome maintenance 2 (MCM2), p53, p27, p21, and TUNEL. Aspects including tumor differentiation, mode of carcinoma invasion, tumor metastasis, and patient prognosis were compared among the specimens., Results: A significantly higher MCM2 labeling index (LI) was observed in the moderately differentiated SCCs when compared to the well-differentiated SCCs (P<0.05). The higher MCM2 LI was correlated with mode of invasion Grade 4 (infiltrative growth) and patient prognosis. In contrast, the LIs of Ki-67, TUNEL-signal, p53, p27, and p21 were not correlated with patient prognosis., Conclusion: Higher MCM2 LI provides useful information for patient prognosis in oral SCCs.

Background and Objectives: We have reported that both lifestyle and family history might be related to multiplicity of carcinoma in the upper aerodigestive tract (UADT). The aim of this study was to elucidate the relationship between the number of carcinomas and risk factors., Methods: A serial histologic evaluation of the entire non-irradiated esophagus was performed in 114 males with esophageal cancer who were divided into three groups (group I: 88 cases with solitary cancer, group II: 11 with double cancers, group III: 15 with three or more cancers). As controls, 228 males with benign diseases were selected., Results: Among group III patients, both the incidence of heavy smoking and that of heavy drinking were 67% and 60%, which were significantly higher than those of group I (28% and 30%) and control subjects (14% and 10%, respectively). Heavy drinkers who were also heavy smokers were observed in 2, 10, 27, and 47% in control subjects, groups I, II, and III, respectively. Regarding family history, 27% of group III had a close relative with UADT or lung cancer, while the incidence was 7% in the control., Conclusions: These findings strongly support the hypothesis that heavy smoking and heavy drinking, as well as a family history of both UADT and lung cancer, might be risk factors for multicentric occurrence of UADT cancer., (Copyright 2003 Wiley-Liss, Inc.)

Squamous cell carcinoma of the lung can be divided into two types according to the location of the primary site: the central type and the peripheral type. The clinicopathologic factors in the peripheral type of lung squamous cell carcinoma have not yet been fully evaluated. A total of 204 surgically resected lung squamous cell carcinomas were reviewed with special reference to their location, histologic characteristics based on tumor growth patterns, and clinicopathologic factors. The central type and the peripheral type accounted for 95 and 109 cases, respectively. Although the patient population of the peripheral type was older, with a lower pathologic stage, lower lymphatic vessel involvement, and lymph node metastasis, the Kaplan-Meier survival proportions did not differ significantly between these two groups. Based on the histologic growth pattern, the peripheral type was classified under three subgroups as follows: 1). the alveolar space-filling type, 2). the expanding type, and 3). the combined type. Among these three types, the alveolar space-filling type showed neither lymphatic vessel invasion nor lymph node metastasis and had the most favorable prognosis. The central and peripheral types of lung squamous cell carcinoma have different clinicopathologic characteristics and should be classified under respectively different categories.

Nitric oxide (NO) produced by the NO synthase (NOS), a family of enzymes such as inducible NOS (iNOS), has been suggested to play an important role in tumor bioloty. We immunohistochemically examined iNOS and p53 protein expression in 105 patients with esophageal squamous cell carcinoma (ESCC). Direct sequence analysis for the p53 gene was performed in 51 of 105 tumors. In total, 56 of 105 (53.3%) tumors exhibited intracytoplasmic staining for anti-iNOS antibody, including 17 (16.2%) cases of homogeneous and intense immunostaining (++) and 39 (37.1%) of heterogeneous staining (+). Of 62 p53 protein-positive tumors, 40 (63.5%) were positive for iNOS, and of 43 p53 protein-negative tumors, 27 (62.8%) were negative for iNOS. Of 34 iNOS-positive tumors, 23 (67.6%) carried a p53 gene mutation, and of 17 iNOS-negative tumors, 12 (70.6%) had wild-type p53 gene. There was a significant relationship between iNOS immunoreactivity and p53 protein overexpression (p = 0.0058) as well as p53 mutation frequency (p = 0.0163). No association was found between iNOS immunoreactivity and p53 mutation type, any clinicopathological factor and patient prognosis. Our in vivo findings suggest that iNOS activity might be associated with p53 alteration and contribute to tumorigenesis in ESCC., (Copyright 2003 S. Karger AG, Basel)

Background: The increase of glucose transport is a distinguishing marker of tumor cells. We hypothesized that a hypopharyngeal carcinoma, characterized by high frequency of lymph node spread or distant metastasis, was associated with glucose transporter 1 (Glut 1) overexpression., Materials and Methods: We investigated the incidence of Glut1 expression by immunostaining in 99 patients with hypopharyngeal carcinoma, and revealed the correlation with the clinical characteristics., Results: The analysis showed 46 patients (46%) of Glut1 overexpression (> 70% tumor cell stained). Glut1 expression did not correlate with gender, subsite, histological grade, tumor size, lymph node status or stage grouping. The 5-year relapse-free survival (RFS) rate of patients with Glut1 overexpression (> 70%) (35%) was significantly lower than that of patients with low Glut1 expression (< or = 70%) (57%) (p = 0.047). Multivariate analysis showed that advanced tumor stage (stages III and IV) and Glut1 overexpression were predictors of reduced RFS (p = 0.031 and 0.021, respectively)., Conclusion: Glut1 expression is an indicator for predicting the prognosis of hypopharyngeal carcinoma.

Background: Endoscopic mucosal resection (EMR) is a less invasive localized treatment for patients with esophageal carcinoma. However, indications for EMR use in cases of superficial esophageal carcinoma are controversial. The authors evaluated histopathologic risk factors for lymph node metastasis and recurrence., Methods: In the specimens resected, the authors examined depth, the superficial area and the area attached to or infiltrating the lamina muscularis mucosa., Results: The authors found that the superficial area and the attached or infiltrated area reflected the depth of the tumor. However, there was a recurrence of esophageal carcinoma even in m3 cases attached only to the lamina muscularis mucosa., Conclusions: The authors concluded that ml and m2 esophageal carcinoma had almost no risk of lymph node metastasis and recurrence no matter how extensive the superficial area. In addition, sm2 and sm3 carcinoma have a high frequency of lymph node metastasis and recurrence. M3 and sm1 carcinoma run the risk of lymph node metastasis and recurrence however small the superficial area and the area attached to or infiltrating the lamina muscularis mucosa. Treatment strategies for patients with superficial esophageal carcinoma, including EMR, should take the above findings into account.

To clarify mechanisms involved in the carcinogenesis of multiple oesophageal squamous cell carcinoma, the expression of p53 protein in 46 lesions surgically excised from 13 Japanese patients was investigated immunohistochemically and the relation of p53 protein accumulation to the patient's history of alcohol consumption and cigarette smoking was analyzed. p53 protein accumulation was observed in 13 main lesions, that is in 6 (85.7%) of 7 subjects with a history of heavy drinking and smoking, but only in 1 (16.7%) of 6 with no such history (Fisher's exact test, p = 0.025). As regards the 46 lesions, p53 protein accumulation was evident in 22 (88.0%) of 25 lesions of the high-risk patients, but in 7 (33.3%) of 21 lesions of the other subjects (Fisher's exact test, p < 0.001). p53 protein accumulation was similarly recognized in all oesophageal lesions in 5 of 7 high-risk patients. Thus, use of both alcohol and cigarettes is clearly associated with a high frequency of p53 protein accumulation in multiple oesophageal squamous cell carcinoma present at the same time. These findings are considered to support the concept of field carcinogenesis of the oesophagus., (Copyright 2002 S. Karger AG, Basel)

Purpose: Lymphocyte infiltration (LI) around cancerous lesions is an important immune response. The purpose of this study is to evaluate the prognostic significance of LI after preoperative treatment for esophageal cancer., Methods and Materials: Preoperative chemoradiotherapy (CR therapy), either bleomycin 30 mg or cisplatin 120 mg/m(2) plus radiation 30 Gy, was performed on 51 cases with esophageal cancer, while hyperthermo-chemoradiotherapy (HCR therapy) was also indicated in 71 cases. Using resected specimens, both the histopathologic effectiveness and degree of LI to cancerous lesions were evaluated., Results: The incidences of the cases in which preoperative treatment was effective were 56% and 92.3% in LI (-) and LI (++) group (p < 0.05). The presence of LI resulted in favorable prognosis; the 5-year survival rates of LI (++) and LI (+) patients were 75.5% and 46.1%, both of which were significantly better than LI (-) (27.8%, p < 0.05 and p < 0.01, respectively). Especially among cases whose preoperative treatment was moderately effective, a multivariate analysis revealed LI to be a favorable prognostic factor independent of other clinicopathologic factors (p = 0.0171). Regarding the preoperative treatment, the incidence of LI (++) was higher in the HCR group (16.9%) than in the CR group (2.0%, p < 0.01)., Conclusions: LI appears to be a prognostic predictor after preoperative CR therapy while, in addition, simultaneous hyperthermia may stimulate LI in cases with esophageal cancer.

To clarify the prognostic factors in patients with submucosal carcinoma of the oesophagus, we examined the results of surgical treatment for 78 cases over the last decade. The clinicopathological factors including age, sex, location of the tumour, length of the tumour, histological differentiation, subclassification of depth, lymphatic or blood vessel invasion, intramural metastasis and lymph node metastasis were all analysed. Then the correlation between these factors and prognosis was investigated. As a result, significant differences were observed in the survival rates between the groups regarding lymphatic vessel invasion (P = 0.0003), intramural metastasis (P = 0.0051) and lymph node metastasis (P = 0.0026). According to a multivariate analysis, intramural metastasis (P = 0.0038, relative risk 9.17), vessel invasion (P = 0.0033, relative risk 6.25) and lymph node metastasis (P = 0.0187, relative risk 3.62) were found to be independent prognostic factors. The prognosis of the patients with at least one of these factors was significantly poorer than that without. The five-year survival rate of the patients without these factors was as good as that with mucosal carcinoma of the oesophagus. Based on our findings, vessel invasion, intramural metastasis and lymph node metastasis are thus considered to be significant prognostic factors in patients with submucosal carcinoma of the oesophagus., (Copyright 2000 Cancer Research Campaign.)

We investigated levels of p53 protein expression in Japanese patients with oesophageal squamous cell carcinoma. A significantly larger proportion of heavy alcohol drinkers and cigarette smokers was evident in the p53-positive group. The combination of drinking and smoking was associated with a high frequency of p53 protein accumulation.

Human papillomavirus type 16/18 (HPV-16/18) is implicated in the pathogenesis of squamous cell carcinoma (SCC) of the cervix and esophagus. The arginine allele at codon 72 of p53 was found to be more susceptible to degradation by HPV E6 protein than is the proline allele in vivo, thus resulting in a high frequency of cervical SCC in individuals homozygous for arginine at the codon. There are controversial results from several clinical studies of cervical SCC. In the present study, encoding regions of p53 codon 72 and HPV-16/18 E6 were directly sequenced, using pairs of primary esophageal SCC tissue and corresponding normal mucosa, which were from 75 patients (Japanese, n = 38; Chinese, n = 37). The arginine allele alone was detected in 70.6% (12 of 17) of HPV-positive cases but only in 43.1% (25 of 58) of HPV-negative cases (P < 0.05). In contrast, such a significant correlation between p53 polymorphism and HPV infection was not evident in corresponding normal mucosae. Because our findings between tumor specimens and the normal mucosae differed, we suggest that the frequent loss of proline allele in HPV-associated carcinogenesis of the esophagus major plays some role. The particular type of p53 polymorphism may indicate a potential candidate for HPV-associated SCC.

An examination of the occurrence of skin cancers and precancerous lesions among residents of Kasai City (34 degrees 56' N) since 1992, and of le-island (25 degrees 10' N) since 1993, has been conducted to characterize the prevalence and incidence of skin cancers in Japanese people and to evaluate risk and preventive factors. The mean prevalence of actinic keratosis (AK) in residents of Kasai City and le-island was 203.33 and 756.26, respectively, indicating that twice the dose of UVB radiation causes a 3-4 fold higher incidence of AK, although life styles, including types of occupations, differ in these two locations. Working outdoors, having skin type I and/or a history of severe sunburns during childhood were found to be important risk factors, while the use of cosmetics after 20 years of age was a protective factor, for AK and possibly for skin cancers. Further, sunscreen use among males over 60 years of age in Kasai City from 1994 through 1998 suggested that sunscreen use may reduce AK development in older people. Four and 12 cases of skin cancers were found in residents of Kasai City (from 1992 to 1997) and on le-island (from 1993 to 1998), respectively. These numbers are too small to establish the prevalence of skin cancer in Japanese, but indicate that people living in areas of higher ambient solar radiation have a higher incidence of skin cancer. This epidemiological study strongly indicates that sun protection is the major modality to reduce sun-induced cutaneous tumors in Japanese.

Objective: To assess the diagnostic accuracy of panoramic radiography (PR), panoramic radiography combined with intraoral radiography (PR+IR), and CT in detecting the supero-inferior extent of tumor invasion of the mandible by gingival carcinoma., Method: PR, PR+IR, and CT images of the mandible in 37 patients with gingival carcinoma were evaluated by five oral radiologists for the supero-inferior extent of bone invasion using ROC analysis. The mean ROC curve area (Az) of each observer for the different imaging modalities was analysed by nonparametric two-way ANOVA. P<0.05 was considered statistically significant., Results: The mean Az for the detection of bone invasion were 0.88+/-0.03 for PR, 0.77+/-0.12 for PR+IR, and 0.87+/-0.03 for CT (P=0.0907). The mean Az for the detection of bone invasion beyond the alveolus was 0.89+/-0.07 for PR, 0.85+/-0.08 for PR+IR, and 0.83+/-0.06 for CT (P=0.5438). The mean Az for the detection of bone invasion beneath the mandibular canal were 0.94+/-0.04 for PR, 0.94+/-0.02 for PR+IR, and 0.91+/-0. 04 for CT (P=0.2466). No statistically significant differences were observed in Az between PR, PR+IR, and CT., Conclusion: We consider that PR+IR should be adopted as the initial imaging modality to determine the extent of supero-inferior invasion of the mandible in gingival carcinoma.

Background: p27, a cyclin-dependent kinase inhibitor, regulates progression from G1 to S phase. There have been a few clinical reports of low p27 expression associated with poor survival among patients with cancer; however, there have been no reports of such an association in cases of head and neck cancer. The authors investigated whether p27 expression in patients with oral tongue squamous cell carcinoma was associated with their prognosis., Methods: Ninety-four patients with oral tongue squamous cell carcinoma were analyzed. The authors performed p27 immunohistochemistry on all patients and Western blot analysis on 19 available patients. Cox proportional hazards regression analysis that included gender, history of smoking and alcohol usage, presence of multiple primary cancers, stage, histologic grade, and p27 status was used to identify the multivariate predictive value of prognostic factors., Results: Twenty-six patients had high p27 expression (> or =50% tumor cell nuclei positive), and 68 patients had low p27 expression (<50%) by immunohistochemistry. In those with low p27 expression, N(+) and advanced T (T3 or T4) were significantly higher than in those with high p27 expression (P = 0.02 and 0.04). The 5-year survival rate in the low p27 group was 44%, whereas that in the high p27 group was 68%, indicating a significant difference (P = 0.04). p27 expression was inferred from Western blot analysis, and an arbitrary quantity (<1, 1-5, or > or =5) from the ratio of tumor to normal tissue density was used to characterize, resulting in 8 (42%), 3 (16%), and 8 (42%) patients in the low (<1-fold), intermediate (1-5-fold), and high (> or =5-fold) groups, respectively. Results of immunohistochemical analysis for p27 were significantly correlated with those of Western blot analysis (P = 0.02). Multivariate analysis revealed that low intensity of p27 expression and advanced stage (Stage III or IV) were predictors of reduced survival (P = 0.02 and 0.001)., Conclusions: Low p27 expression was associated with increasing lymph node metastasis and stage of tumor and resulted in a poor prognosis for patients with oral tongue squamous cell carcinoma. p27 is apparently a significant predictor of survival.

Some esophageal diseases such as carcinoma, esophagitis, and collagen diseases have often been reported to show a diffusely thickened esophageal wall in the roentogenogram findings. In the current report, a preoperative upper gastrointestinal series and an endoscopic examination showed a diffusely infiltrative type carcinoma, but other examinations did not suggest any diseases such as esophagitis or collagen diseases which might cause a thickening of the esophageal wall or a constriction of the esophagus. A postoperative histological examination revealed the primary carcinoma to remain only within the mucosal layer, while a large degree of lymphatic vessel permeation reached the adventitia over a wide area. An extraordinary degree of lymphatic permeation spread through the esophageal wall, and stromal fibrosis developed as a result of such lymphatic permeation. These histological phenomena might thus have led to the macroscopic appearance of infiltrative type esophageal carcinoma.

Background: Recently the HPV genome has been detected in 75-80% of uterine cervical squamous cell carcinomas. High-risk HPV 16,18,31,33, and 45 are frequently associated with invasive carcinoma of the oral cavity, oropharynx, larynx, and nasal cavity. In this study we investigated the association of HPV16 and 18 in head and neck squamous cell carcinomas (HNSCC) using PCR-based methods., Materials and Methods: Ninety-eight fresh frozen tissues from HNSCC were collected. The samples were consisted of 26 cases from the larynx, 19 from the nasal and paranasal sinus, 16 the hypopharynx, 14 the oral cavity, 13 the oropharynx, and 10 from the nasopharynx. The presence of HPV genome was examined by PCR using HPV16 and 18 specific primers encoding E7 ORF., Results: HPV16-DNA was detected in 23% of all cases (23/98), 31% (8/26) larynx, 16% (3/19) nasal and paranasal sinus, 19% (3/16) hypopharynx, 21% (3/14) oral cavity, 38% (5/13) oropharynx, and 10% (1/10) nasopharynx. HPV18-DNA was detected in 4% of all cases (4/98), 8% (2/26) larynx, and 15% (2/13) oropharynx. 54% (7/13) in oropharynx and 38% (10/26) in larynx showed rather high prevalence in the head and neck., Conclusions: HPV 16 and 18 play an important role in carcinogenesis of the head and neck, especially, in the oropharynx and larynx.

From 1979 to 1993, 151 patients with resectable oesophageal cancer underwent preoperative hyperthermo-chemo-radiotherapy (HCR) followed by a subtotal esophagectomy. All resected specimens were histopathologically evaluated, and then were classified into two groups according to the efficacy of the preoperative HCR. Group A included 33 patients whose resected oesophagus was free of any cancer cells (grade 3). Group B included 118 patients, in which viable cancer cells remained in the resected specimens to various degrees (grade 1,2). The incidence of patients with well differentiated squamous cell carcinoma, node negative cases, or TNM stage I/II was significantly higher in group A than in group B (27.3% versus 9.3%, 72.7% versus 50.8%, 72.7% versus 50.8%, respectively). The recurrence rate was 33.3% (11/33) in group A, while it was 65.3% (77/118) in group B (p < 0.005). There was no case with any local recurrence in the former, while it was 8.5% (10/118) in the latter. The 1-, 3- and 5-year survival rates were 87.2%, 65.9% and 46.1% in group A, while they were 54.8%, 26.7% and 18.8% in group B (p < 0.005), respectively. Preoperative HCR may be expected of decreasing in the recurrence rate, including regional relapse when a grade 3 is obtained. Complete local control would further positively influence the prognosis.

Objectives: To clarify the diagnostic utility of CT in the evaluation of carcinoma of the maxillary gingiva and hard palate., Methods: The CT scans of 27 patients with squamous cell carcinoma of the upper gingiva and hard palate were reviewed. Tumor extent and bone destruction were compared with the surgical and histopathological findings to estimate the sensitivity, specificity and accuracy of CT., Results: The primary tumor was detected by CT in 89% of patients. The grade of bone destruction determined by CT correlated well with that verified at surgery or by histopathological examination. The sensitivity, specificity, and accuracy of CT for invasion to the buccal mucosa were 64%, 89% and 75% respectively. For maxillary sinus invasion, CT showed low specificity but high sensitivity. The accuracy was 86% when the criterion for sinus invasion was the presence of an enhanced mass continuous with the primary tumor., Conclusion: CT is helpful for the evaluation of tumor extent in the upper gingiva and hard palate carcinoma. However, invasion of the maxillary sinus should be considered carefully, because CT findings suggestive of destruction of the floor of the maxillary sinus are not always consistent with sinus invasion.

The expression of cyclin A protein was retrospectively investigated in 124 patients with human esophageal squamous cell carcinoma with immunohistochemical techniques using antibody to cyclin A protein (BF683). Of 124 tumors, 49 (39.5%) exhibited positive staining in cancer cells with this antibody. Staining was observed predominantly but not exclusively in the nucleus. A significantly higher degree of association of immunoreactivity with this antibody was detected for advanced types of tumors (stages I, II, III, and IV) than for early tumors (stage 0; P < 0.05). Patients with cyclin A immunopositivity had a significantly poorer survival rate than did other patients (P < 0.01). These findings provide the first evidence for frequent and unscheduled overexpression of cyclin A protein in human esophageal cancer and suggest the possibility that alteration of cyclin A overexpression is associated with tumor progression and patient prognosis for esophageal cancers.

The distribution of HLA-DR-positive dendritic cells (DR+DCs) and tumor infiltrating lymphocytes (TILs) was investigated in 67 patients with squamous cell carcinoma of the esophagus. DR+DCs were chiefly present among the cancer cell nests, and few were seen in the stroma. As clusters, UCHL-1-positive T-cells (UCHL1-Ts) were detected in the tissue around the cancer cell nests and as individual cells within tumor nests. Some UCHL1-Ts in the tumor nests showed direct contact with DR+DCs. In addition, a few OPD4-positive helper/inducer T cells were found among cancer cells, and were densely present in the stroma. A correlation was demonstrated between the number of DR+DCs and UCHL1-Ts in each patient (R = 0.4547, p < 0.01). In addition, dense tumor infiltration by both DR+DCs and UCHL1-Ts within the cancer cell nests was related to a better prognosis (p < 0.01).

The distribution of immunohistochemically labeled HLA-DR antigen- and S-100 protein-positive dendritic cell (DR+DC and S100+DC) was investigated in 59 human esophageal squamous cell carcinomas (SCCs). A dense infiltration of both DR+DC and S100+DC was detected in 11, only DR+DC in two, and only S100+DC in one. In the remaining 45 tumors infiltrating DC were sparse. By means of double immunostaining or the mirror section method, three different types of DC, namely S-100-negative and HLA-DR-positive DC(S100-DR+DC), S-100-positive and HLA-DR-negative DC(S100+DR-DC) and double-positive DC(S100+DR+DC) were clearly identified. With regard to postoperative survival, these patients with tumors in which there was a dense infiltration of DR+DCs and/or S100+DCs showed a significantly better survival rate than those in which DC were sparse (DR+DCs - P less than 0.001; S100+DCs - P less than 0.01). These results indicate that DC infiltration may be a prognostic factor in esophageal SCCs.