Toshiki Tomita

Mucoepidermoid Carcinoma of the Head and Neck : Clinical Analysis of 43 Patients

OBJECTIVE It is well known that mucoepidermoid carcinoma (MEC) displays a variety of biological behaviors. While the high-grade type is a highly aggressive tumor, its low-grade counterpart usually demonstrates a more benign nature and several systems have, therefore, been proposed to grade this neoplasm. METHODS This report analyzes 43 patients suffering from head and neck MEC, who were treated in our department during the period from 1989 to 2005. The relationship between clinical and pathologic characteristics and survival rate was investigated. RESULTS The 5-year overall and disease-free survival rate was 62.3 and 57.2%. Multivariate analysis demonstrated that the parameters that significantly affected survival were the patients age (P = 0.040) and treatment method (P = 0.011). CONCLUSIONS The patients age and treatment method is the prognostic parameter in this study. Although complete surgical resection is the standard treatment for MEC, we should aggressively consider adjunctive radiotherapy in those cases that have a high risk of recurrence and poor prognosis.

Granulocyte-macrophage colony-stimulating factor upregulates matrix metalloproteinase-2 (MMP-2) and membrane type-1 MMP (MT1-MMP) in human head and neck cancer cells.

Matrix metalloproteinase-2 (MMP-2) and membrane type 1-MMP (MT1-MMP) play an important role in the invasion and metastasis of head and neck squamous cell carcinoma (HNSCC), but the mechanism of their regulation is not clearly understood. Recently, granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to be associated with cancer invasion and metastasis. We hypothesized that GM-CSF may upregulate MMP-2 and/or MT1-MMP expression in HNSCC cells, and may thereby influence their ability to invade and metastasize. We studied the effects of GM-CSF on the production of MMP-2 and MT1-MMP in HNSCC cell lines SAS and HSC-2. Gelatin zymography of conditioned media derived from HNSCC cells revealed a major band of 68 kDa, which was characterized as proMMP-2. GM-CSF stimulated the production of proMMP-2 in both cell lines in a dose-dependent manner. Treatment with 50 ng/ml GM-CSF for 24 h increased the proMMP-2 activity 3.4-fold in SAS cells and 2.3-fold in HSC-2 cells compared with untreated controls. Northern blot analyses demonstrated that GM-CSF led to elevated mRNA levels of MMP-2 and MT1-MMP in both cell lines. The results identify GM-CSF as a regulator of MMP-2 and MT1-MMP expression in certain types of HNSCC, and suggest that GM-CSF may contribute to the invasiveness of HNSCC through the regulation of MMP-2 and MT1-MMP expression.

Restoration of E-cadherin expression by selective Cox-2 inhibition and the clinical relevance of the epithelial-to-mesenchymal transition in head and neck squamous cell carcinoma

BackgroundThe epithelial-to-mesenchymal transition (EMT) accompanied by the downregulation of E-cadherin has been thought to promote metastasis. Cyclooxygenase-2 (Cox-2) is presumed to contribute to cancer progression through its multifaceted function, and recently its inverse relationship with E-cadherin was suggested. The aim of the present study was to investigate whether selective Cox-2 inhibitors restore the expression of E-cadherin in head and neck squamous cell carcinoma (HNSCC) cells, and to examine the possible correlations of the expression levels of EMT-related molecules with clinicopathological factors in HNSCC.MethodsWe used quantitative real-time PCR to examine the effects of three selective Cox-2 inhibitors, i.e., celecoxib, NS-398, and SC-791 on the gene expressions of E-cadherin (CDH-1) and its transcriptional repressors (SIP1, Snail, Twist) in the human HNSCC cell lines HSC-2 and HSC-4. To evaluate the changes in E-cadherin expression on the cell surface, we used a flowcytometer and immunofluorescent staining in addition to Western blotting. We evaluated and statistically analyzed the clinicopathological factors and mRNA expressions of Cox-2, CDH-1 and its repressors in surgical specimens of 40 patients with tongue squamous cell carcinoma (TSCC).ResultsThe selective Cox-2 inhibitors upregulated the E-cadherin expression on the cell surface of the HNSCC cells through the downregulation of its transcriptional repressors. The extent of this effect depended on the baseline expression levels of both E-cadherin and Cox-2 in each cell line. A univariate analysis showed that higher Cox-2 mRNA expression (p = 0.037), lower CDH-1 mRNA expression (p = 0.020), and advanced T-classification (p = 0.036) were significantly correlated with lymph node metastasis in TSCC. A multivariate logistic regression revealed that lower CDH-1 mRNA expression was the independent risk factor affecting lymph node metastasis (p = 0.041).ConclusionsThese findings suggest that the appropriately selective administration of certain Cox-2 inhibitors may have an anti-metastatic effect through suppression of the EMT by restoring E-cadherin expression. In addition, the downregulation of CDH-1 resulting from the EMT may be closely involved in lymph node metastasis in TSCC.

Diagnosis and management of cervical sympathetic chain schwannoma: A review of 9 cases

Conclusions. Cervical sympathetic chain schwannoma (CSCS) sometimes mimics carotid body tumor (CBT). Differential diagnosis between these tumors is sometimes difficult using MRI alone. MRA, color Doppler ultrasonography, and fine needle aspiration (FNA) after imaging may be helpful to rule out CBT. Surgical resection of CSCS is relatively effortless, and Horners syndrome is an expected but acceptable postoperative complication. Intratumoral hemorrhage and vasodilation may be the main reasons for significant enhancement on MRI. Objectives. CSCSs are rare and known to mimic carotid body tumors. We report 9 cases of CSCS with an emphasis on imaging, surgical management, and pathological findings. Moreover, we describe the differential diagnosis of CSCS and CBT, and speculate the reasons behind significant enhancement on MRI. Patients and methods. Nine cases of CSCS treated at a tertiary referral center between 1996 and 2008 were reviewed. Results. MRI revealed 3 of 9 cases (33%) splayed the carotid bifurcation and displayed marked contrast enhancement with gadolinium. All patients underwent surgical excision of the mass with minimal blood loss. Postoperative Horners syndrome was encountered in all patients, which required no treatment. Marked gadolinium enhancement tended to be associated with histological findings such as intratumoral hemorrhage and vasodilation.

Palliative radiotherapy for lingual metastasis of renal cell carcinoma

The report is of a 50-year-old man with renal cell carcinoma (RCC) who had rapidly progressing metastasis to the tongue at 10 months after the left radical nephrectomy. The metastatic lingual tumor was not resectable, therefore treated with radiation (50 Gy). The tumor disappeared macroscopically after the radiation therapy, but enlarged again 4 months later. The patient died of respiratory failure due to multiple lung metastases 12 months after the appearance of the lingual metastasis. Radiation therapy is an acceptable palliative strategy for advanced lingual metastasis of RCC.

Phase I/II Study of S-1 plus Cisplatin Combination Chemotherapy in Patients with Advanced/Recurrent Head and Neck Cancer

OBJECTIVE The objectives of this study were to determine the maximum tolerated dose (MTD) and recommended dose (RD) of S-1 plus cisplatin (CDDP) and to evaluate safety and efficacy using the defined RD in advanced/recurrent head and neck cancer (HNC). METHODS S-1 was administered orally at 40 mg/m(2) twice daily for 14 consecutive days, and CDDP was infused on day 8 at a dose of 60 and 70 mg/m(2). Each course was repeated every 4 weeks. RESULTS A total of 38 patients were registered, 10 patients for the Phase I study and an additional 28 patients for the Phase II study. Although no dose-limiting toxicity (DLT) was observed in the CDDP 60 mg/m(2) (Level 1) group, two of six patients in the CDDP 70 mg/m(2) (Level 2) group exhibited DLT (fatigue/diarrhea). The MTD was not achieved in the Phase I study. Level 2 was therefore determined as the RD. In the Phase II study, 34 patients, including 6 patients from the Phase I study, were evaluated. At the termination of treatment, the confirmed response rate was 44.1% (15/34, 95% CI: 27.4-60.8). The best response rate without an adequate duration time was 67.6% (95% CI: 51.9-83.4). The median survival period was 16.7 months, and the 1-year survival rate was 60.1%. The main toxicities of Grade 3 or above were anorexia (26.5%), nausea (14.7%), neutropenia/thrombocytopenia (11.8%) and anemia/fatigue (8.8%). CONCLUSIONS This is considered to be an effective regimen with acceptable toxicities for HNC.

Tracheoesophageal diversion versus total laryngectomy for intractable aspiration

This study evaluates the outcome and surgical stress associated with surgery for intractable aspiration. A retrospective review was conducted to compare the results between tracheoesophageal diversion and total laryngectomy. The operative time, intra-operative bleeding, time until drain removal, feeding conditions and surgical complications were compared between the two groups. Of the 19 patients, 31.6 per cent underwent tracheoesophageal diversion and 68.4 per cent received total laryngectomy. The operative time and drain insertion periods were statistically shorter in the tracheoesophageal diversion group, while the amount of intra-operative blood loss was smaller in the tracheoesophageal diversion group. The complication rate and the feeding conditions before and after surgery for the two groups did not show any statistically significant difference. Tracheoesophageal diversion was thus found to be a simple, safe, and reliable therapeutic modality for the control of intractable aspiration. Moreover, it induced less surgical stress than total laryngectomy.

Clinicopathological Significance of Expression of CD44 Variants in Head and Neck Squamous Cell Carcinoma

Splice variants of the cell surface glycoprotein CD44 have been reported to be associated with the progression of various human tumors. The aim of this study is to determine the correlation between the expression of CD44 isoforms, especially CD44 variant 2 (CD44v2), and the clinicopathological features of head and neck squamous cell carcinomas (HNSCCs). The expression of CD44 isoforms was evaluated immunohistochemically in paraffin‐embedded tissues from 89 primary lesions, using monoclonal antibodies against CD44 standard (CD44st), CD44 variant 6 (CD44v6) and CD44v2. Cancer tissues from 89 (100%), 85 (95.5%) and 59 (66.3%) patients showed positive immunoreactivity for CD44st, CD44v6 and CD44v2, respectively. A significant correlation was observed between the down‐regulation of CD44v2 and poorer differentiation of the tumor cells (P=0.02). We could not find any significant correlation between the expression of CD44v2 and T stage or N stage (lymph node status). However, the rate of positive cervical lymph node metastasis tended to increase with reduced expression of CD44v2 (P=0.08). Down‐regulation of CD44v2 expression was correlated with shorter overall survival (P=0.01). Furthermore, Coxs multivariate analysis revealed that only CD44v2 expression and lymph node status were independent prognostic factors. These findings suggest that down‐regulation of CD44v2 expression may be one of the biological markers for the degree of malignancy in HNSCCs.

Weekly Low-Dose Docetaxel–Based Chemoradiotherapy for Locally Advanced Oropharyngeal or Hypopharyngeal Carcinoma: A Retrospective, Single-Institution Study

PURPOSE To retrospectively assess the efficacy, toxicity, and prognostic factors of weekly low-dose docetaxel-based chemoradiotherapy for Stage III/IV oropharyngeal or hypopharyngeal carcinoma. METHODS AND MATERIALS Between 2001 and 2005, 72 consecutive patients with locally advanced oropharyngeal or hypopharyngeal carcinoma were treated with concurrent chemoradiotherapy (CCR; radiation at 60 Gy plus weekly docetaxel [10 mg/m(2)]). Thirty of these patients also received neoadjuvant chemotherapy (NAC; docetaxel, cisplatin, and 5-fluorouracil) before concurrent chemoradiotherapy. Survival was calculated according to the Kaplan-Meier method. The prognostic factors were evaluated by univariate and multivariate analyses. RESULTS The median follow-up was 33 months, with overall survival, disease-free survival, and locoregional control rates at 3 years of 59%, 45%, and 52%, respectively. Thirty-six patients (50%) experienced more than one Grade 3 to 4 acute toxicity. Grade 3 mucositis occurred in 32 patients (44%), Grade 4 laryngeal edema in 1 (1%). Grade > or =3 severe hematologic toxicity was observed in only 2 patients (3%). Grade 3 dysphagia occurred as a late complication in 2 patients (3%). Multivariate analyses identified age, T stage, hemoglobin level, and completion of weekly docetaxel, but not NAC, as significant factors determining disease-free survival. CONCLUSIONS Docetaxel is an active agent used in both concurrent and sequential chemoradiotherapy regimens. Mucositis was the major acute toxicity, but this was well tolerated in most subjects. Anemia was the most significant prognostic factor determining survival. Further studies are warranted to investigate the optimal protocol for integrating docetaxel into first-line chemoradiotherapy regimens, as well as the potential additive impact of NAC.

Primary dural closure and anterior cranial base reconstruction using pericranial and nasoseptal multi-layered flaps in endoscopic-assisted skull base surgery

IntroductionDural and anterior cranial base reconstruction is essential in the surgical resection of a craniofacial tumor that extends from the paranasal sinuses to the subdural space. Watertight reconstruction of vascularized tissue is essential to prevent postoperative liquorrhea, especially under conditions that prevent wound healing (e.g., postoperative irradiation therapy).MethodWe successfully treated two cases of olfactory neuroblastoma by endoscopic-assisted craniotomy with primary dural closure and anterior cranial base reconstruction using a multi-layered flap technique. Dural defects were closed using temporal fascia or fascia lata in a conventional fashion, immediately after detaching the subdural tumor, in order to isolate and prevent contamination of subdural components and cerebrospinal fluid (CSF) from the tumor and nasal sinuses. Tumor removal and anterior cranial base reconstruction were performed without any concern of CSF contamination after dural closure by craniotomy and endoscopic endonasal approach (EEA). Vascularized pericranial flaps (PCF) and nasoseptal flaps (NSF) were used simultaneously as doubled-over layers for reconstruction.ResultsThe tumor was completely removed macroscopically and the anterior cranial base was reconstructed in both cases. CSF leak and postoperative meningitis were absent. Postoperative and irradiation therapy courses were successful and uneventful.ConclusionsThis multi-layered anterior cranial base reconstruction consisted of three layers: a fascia for dural plasty and double-layered PCF and NSF. This surgical reconstruction technique is suitable to treat craniofacial tumors extending into the subdural space through the anterior cranial base dura mater.