Transoral surgery for superficial head and neck cancer: National Multi-Center Survey in Japan.

Head and neck cancers, especially in hypopharynx and oropharynx, are often detected at advanced stage with poor prognosis. Narrow band imaging enables detection of superficial cancers and transoral surgery is performed with curative intent. However, pathological evaluation and real-world safety and clinical outcomes have not been clearly understood. The aim of this nationwide multicenter study was to investigate the safety and efficacy of transoral surgery for superficial head and neck cancer. We collected the patients with superficial head and neck squamous cell carcinoma who were treated by transoral surgery from 27 hospitals in Japan. Central pathology review was undertaken on all of the resected specimens. The primary objective was effectiveness of transoral surgery, and the secondary objective was safety including incidence and severity of adverse events. Among the 568 patients, a total of 662 lesions were primarily treated by 575 sessions of transoral surgery. The median tumor diameter was 12 mm (range 1-75) endoscopically. Among the lesions, 57.4% were diagnosed as squamous cell carcinoma in situ. The median procedure time was 48 minutes (range 2-357). Adverse events occurred in 12.7%. Life-threatening complications occurred in 0.5%, but there were no treatment-related deaths. During a median follow-up period of 46.1 months (range 1-113), the 3-year overall survival rate, relapse-free survival rate, cause-specific survival rate, and larynx-preservation survival rate were 88.1%, 84.4%, 99.6%, and 87.5%, respectively. Transoral surgery for superficial head and neck cancer offers effective minimally invasive treatment. Clinical trials registry number: UMIN000008276.

Adequate Number of Swallows for Pharyngeal Pressure Measurement of a Subject using High-resolution Manometry.

Introduction The number of pressure measurements that need to be recorded using high-resolution manometry (HRM) for the accurate evaluation of pharyngeal function is not well established. Objective The purpose of this study is to clarify the number of swallows required to obtain an accurate pharyngeal manometric profile of a person. Methods Forty healthy adults performed a dry swallow and bolus swallows using 3-, 5-, or 10 ml of water and underwent measurements using the Starlet HRM system. Each subject underwent 10 swallows for each of the four bolus volume conditions. Results The mean of up to seven measurements of maximum pre-swallow upper esophageal sphincter pressure with 10 ml of swallow was close to the mean of up to eight measurements in 95% of the subjects. Similarly, the rate of change of the average for the eighth and ninth measurements and the rate of change for the average of the ninth and tenth measurements were less than 5%. When the other parameters were similarly measured up to the sixth measurement, no major change in the average value was observed even if more measurements were taken. Conclusion A minimum of six measurements are required, and seven swallows are sufficient for evaluating the pharyngeal manometric profile of a single person. This number of measurements can be a useful criterion when performing HRM measurements on individual subjects.

Adequate Number of Swallows for Pharyngeal Pressure Measurement of a Subject using High-resolution Manometry

Abstract Introduction The number of pressure measurements that need to be recorded using high-resolution manometry (HRM) for the accurate evaluation of pharyngeal function is not well established. Objective The purpose of this study is to clarify the number of swallows required to obtain an accurate pharyngeal manometric profile of a person. Methods Forty healthy adults performed a dry swallow and bolus swallows using 3-, 5-, or 10 ml of water and underwent measurements using the Starlet HRM system. Each subject underwent 10 swallows for each of the four bolus volume conditions. Results The mean of up to seven measurements of maximum pre-swallow upper esophageal sphincter pressure with 10 ml of swallow was close to the mean of up to eight measurements in 95% of the subjects. Similarly, the rate of change of the average for the eighth and ninth measurements and the rate of change for the average of the ninth and tenth measurements were less than 5 %. When the other parameters were similarly measured up to the sixth measurement, no major change in the average value was observed even if more measurements were taken. Conclusion A minimum of six measurements are required, and seven swallows are sufficient for evaluating the pharyngeal manometric profile of a single person. This number of measurements can be a useful criterion when performing HRM measurements on individual subjects.

Matched-pair analysis of patients with advanced hypopharyngeal cancer: surgery versus concomitant chemoradiotherapy.

BACKGROUND: The aim of this study was to compare the therapeutic outcomes of total pharyngolaryngectomy with those of concomitant chemoradiotherapy in advanced hypopharyngeal cancer. METHODS: This is a retrospective multi-institutional study. The medical records of 979 patients with hypopharyngeal cancer, who were initially treated between 2006 and 2008, were reviewed. In this study, we matched a group of total pharyngolaryngectomy patients with a second group of chemoradiotherapy patients, according to age, gender, subsite, arytenoid fixation, cartilage invasion, and N classification, and analyzed overall survival, disease-specific survival, and locoregional control rates. RESULTS: The matched-pair analysis included 254 patients. The 5-year overall survival, disease-specific survival, and locoregional control rates were 58.5% and 53.5% (P = 0.30), 68.9% and 68.0% (P = 0.80), and 82.2% and 63.6% (P < 0.01), respectively, for patients in the total pharyngolaryngectomy and chemoradiotherapy groups. For T4a patients with cartilage invasion, the matched-pair analysis included 46 patients. The 5-year overall survival, disease-specific, and locoregional control rates were 56.5% and 26.0% (P = 0.092), 56.5% and 41.3% (P = 0.629), and 43.0% and 42.5% (P = 0.779), respectively, for patients in the total pharyngolaryngectomy and chemoradiotherapy groups. CONCLUSIONS: The data from this large-scale multi-institutional joint research program of hypopharyngeal cancer in Japan suggest that chemoradiotherapy may provide adequate survival benefit for hypopharyngeal cancer patients with the distinct advantage of larynx preservation. Our data also suggest that chemoradiotherapy is as beneficial as total pharyngolaryngectomy for the local control of locally advanced hypopharyngeal cancer.

Association of impaired renal function and poor prognosis in oropharyngeal squamous cell carcinoma.

BACKGROUND: Renal function influences decisions regarding treatment for patients with oropharyngeal squamous cell carcinoma (SCC). However, the importance of renal function in oropharyngeal SCC has not yet been reported. METHODS: Four hundred sixty patients with oropharyngeal SCC treated with curative intent between April 2005 and March 2007 in 12 institutions in Japan were analyzed retrospectively. RESULTS: Four hundred three patients (87.6%) showed a creatinine clearance (CrCl) ≥50 mL/min and 57 (12.4%) with a CrCl <50 mL/min. Age was associated with worse overall survival (OS), whereas stage IVB, radiotherapy (RT), and CrCl <50 were associated with worse OS on univariate analyses. Surgery and hypertension were associated with better OS on univariate analyses. On multivariate analysis, age, stage, hypertension, and CrCl were also found to be significantly associated with OS. CONCLUSION: Based on this retrospective study, impaired renal function is an independent predictor of increased risk of death in patients with oropharyngeal SCC. © 2016 Wiley Periodicals, Inc. Head Neck 38: First-1500, 2016.

The role of initial neck dissection for patients with node-positive oropharyngeal squamous cell carcinomas.

BACKGROUND: The current study sought to assess the role of initial neck dissection (ND) for patients with node-positive oropharyngeal squamous cell carcinomas (OPSCC). METHODS: The data for 202 patients with previously untreated node-positive OPSCC were gathered from 12 institutions belonging to the Head and Neck Cancer Study Group in the Japan Clinical Oncology Group. These patients were categorized into two groups, consisting of the initial ND group and the wait-and-see group, according to treatment policy. RESULTS: Regional recurrence was observed in 17 of 93 patients undergoing initial ND, whereas, recurrent or persistent diseases were observed in 40 of 109 patients who did not undergo initial ND. The 4-year overall survival rates (OS) for the wait-and-see group and initial ND groups were 74.0% and 78.7%, respectively, and the 4-year regional control rates (RC) for each group were 77.6% and 84.9%. There were no significant differences in either OS or RC (p=0.3440 and p=0.2382, respectively). However, for patients with N3 disease, the 4-year OS of the initial ND group (100%) was favorable. For patients with N2a disease, the 4-year RC of the initial ND group was higher than that of the wait-and-see group statistically (100% vs 62.5%, p=0.0156). CONCLUSIONS: The role of initial ND was limited in patients with node-positive OPSCC. The treatment strategy not involving initial ND is considered feasible and acceptable when nodal evaluation after definitive radiotherapy or chemoradiotherapy is applied adequately. However, it is possible that initial ND improves outcomes in patients with resectable large-volume nodal disease.

Lymph node metastasis in t4 maxillary sinus squamous cell carcinoma: incidence and treatment outcome.

BACKGROUND: The purpose of this study was to evaluate the incidence of lymph node metastasis among patients with T4 maxillary sinus squamous cell carcinoma (MS-SCC) as well as the delayed metastasis rate and the treatment outcome for untreated N0 neck in patients with T4 MS-SCC. METHODS: Consecutive series of all patients (n = 128) with previously untreated T4 maxillary sinus SCC between 2006 and 2007 were obtained from 28 institutions belonging to or cooperating in the Head and Neck Cancer Study Group of the Japan Clinical Oncology Group. RESULTS: Of the 128 patients, 28 (21.9 %) had lymph node metastasis, and six patients (4.7 %) had distant metastasis at diagnosis. Among the 111 patients who were treated with curative intent, 98 had clinically N0 neck disease and did not receive prophylactic neck irradiation. A total of 11 patients (11.2 %) subsequently developed evidence of lymph node metastasis, of whom eight were among the 83 patients with an N0 neck and had not received elective neck treatment. There were 15 patients who received an elective neck dissection as part of the initial treatment, of whom three had pathologically positive for lymph node metastases. Of 11 patients, six patients with nonlateral retropharyngeal lymph node metastasis without primary or distant disease were successfully salvaged. CONCLUSIONS: This study identified the incidence of lymph node metastasis among patients with T4 MS-SCC as well as the delayed metastasis rate and the treatment outcome for untreated N0 neck in patients with T4 MS-SCC. These results will be of assistance in selecting treatment strategy for T4 MS-SCC in the future.

Free skin flap reconstruction after partial hypopharyngectomy with laryngeal preservation.

Surgical resection of hypopharyngeal cancer often affects laryngeal function. The aim of this study is to assess the reliability and efficacy of free skin flap transfer after partial hypopharyngectomy with laryngeal preservation. This study designs a retrospective analysis. The subjects were 54 patients who underwent free skin flap reconstruction immediately after partial pharyngolaryngectomy or hypopharyngectomy with laryngeal preservation. The defects were classified into four types based on the location of the hypopharyngeal defect. Functional results were evaluated by routine physical examination findings and parameters related to swallowing function and X-ray barium deglutition examination. Perioperative mortalities and morbidities were reviewed. There were no perioperative mortalities and 98% of the flaps survived. Forty-three patients (80%) were able to eat an unrestricted diet and experienced no aspiration. Restriction of the diet was significantly associated with the extent of oesophageal mucosal resection. In conclusion, free skin flap reconstruction is confirmed to be a safe and effective strategy to maintain laryngeal function and good quality-of-life.

Distinct effects of alcohol consumption and smoking on genetic alterations in head and neck carcinoma.

BACKGROUND: Tobacco and alcohol consumption are risk factors for head and neck squamous cell carcinoma (HNSCC). Recently, whole-exome sequencing clarified that smoking increased TP53 and other mutations in HNSCC; however, the effects of alcohol consumption on these genetic alterations remain unknown. We explored the association between alcohol consumption and somatic copy-number alterations (SCNAs) across the whole genome in human papillomavirus (HPV)-negative HNSCCs, and compared with the effects of smoking on genetic alterations. METHODS: SCNA and TP53 mutations in tumor samples were examined by high-resolution comparative genomic hybridization microarray 180K and by direct sequencing, respectively, and statistically analyzed for associations with alcohol consumption and smoking during the 20 years preceding diagnosis of HNSCC. Probes with a corrected p-value (=q-value) less than 0.05 and fold change greater than 1.2 or less than -1.2 were considered statistically significant. RESULTS: A total of 248 patients with HNSCC were enrolled. In the HPV-negative patients (n=221), heavy alcohol consumption was significantly associated with SCNAs of oncogenes/oncosuppressors that were previously reported to occur frequently in HNSCCs: CDKN2A (q=0.005), FHIT (q=0.005), 11q13 region including CCND1, FADD and CTTN (q=0.005), ERBB2 (HER2) (q=0.009), 3q25-qter including CCNL1, TP63, DCUN1D1 and PIK3CA (q=0.014), and CSMD1 (q=0.019). But, TP53 mutations were not affected. In contrast, smoking was associated with increased risk of TP53 mutations, but did not induce any significant SCNAs of oncogenes/oncosuppressors. CONCLUSION: These results suggest that both alcohol consumption and smoking had distinct effects on genetic alterations in HNSCCs. Heavy alcohol consumption may trigger previously known and unknown SCNAs, but may not induce TP53 mutation. In contrast, smoking may induce TP53 mutation, but may not trigger any SCNAs.

[Dysphagia screening on resumption of oral intake in inpatients predictive factor for the resumption of oral intake].

There is much concern about the acute phase of restarting an oral diet for hospital inpatients who have been prohibited from any oral intake. We found predictive factors for the successful resumption of oral intake in such patients. A total of 186 subjects who had been hospitalized without oral intake were screened for dysphagia between January 1st and December 31st in 2010 (mean age 80.9 years), and formed the study population. We observed them from the initial consultation day until the discharge. (mean days 32.6) We examined factors of age, sex, appetite, gag reflex, tongue activity, the repetitive saliva swallowing test (RSST), obeying commands, the status of the laryngopharynx, laryngeal sensation and the 3 ml water swallowing test under endoscopy. We excluded those who died in hospital after dysphagia screening because they were obviously lost to follow-up. One hundred and twelve patients (60.2%) could resume oral intake, 54 patients could not and 20 (10.8%) died. Logistic regression analysis identified seven significant factors in predicting the resumption of oral intake : 1) age (p = 0.01, OR = 0.938, 95% CI 0.903-0.976); 2) sex (p = 0.21, OR = 2.15, 95% CI 1.124-4.128); 3) appetite (p = 0.041, OR = 1.983, 95% CI 1.029-3.821); 4) gag reflex (p = 0.06, OR = 1.932, 95% CI 0.971-3.844); 5) tongue activity (P = 0.002, OR = 3.825, 95% CI 1.647-8.883); 6) RSST (P = 0.013, OR = 2.284, 95% CI 1.186-4.397); 7) obeying commands (p = 0.02, OR = 3.005, 95% CI 1.507-5.993); 8) the status of the laryngopharynx (P = 0.668, OR = 0.668, 95% CI 0.351-1.272); 9) laryngeal sensation (P = 0.081, OR = 1.841, 95% CI 0.928-3.650); and the 3 ml water swallowing test under endoscopy (P = 0.000, OR = 0.226, 95% CI 0.102-0.499). These predictive factors could be very useful for dysphagia screening to help forecast the successful resumption of oral intake in affected patients. When the likelihood of dysphagia and the onset of aspiration pneumonia are suggested by dysphagia screening, these factors must be taken into careful consideration when oral intake is to be resumed.

Multidisciplinary therapy including proton beam radiotherapy for a Ewing sarcoma family tumor of maxillary sinus in a 4-year-old girl.

BACKGROUND: Although complete resection offers the best chance for controlling head and neck Ewing sarcoma family tumors (ESFTs), it is occasionally unfeasible because of possible functional and cosmetic side effects. Planning multidisciplinary treatment for head and neck ESFT is challenging. METHODS AND RESULTS: A 4-year-old girl had left-sided excessive tearing, nasal obstruction, and exophthalmos for 4 months. A CT scan showed a mass filling the left maxillary sinus and extending to the left orbital wall. After a diagnosis of ESFT was established with biopsy, the patient was treated with vincristine, doxorubicin, cyclophosphamide/ifosfamide etoposide (VDC/IE) regimen over 50 weeks; partial maxillectomy was performed at week 15 and was followed by proton radiotherapy. The patient has remained tumor-free for 16 months, with preservation of facial form and function. CONCLUSION: Partial resection combined with proton radiotherapy may enable maximal tumor control and minimal functional and cosmetic side effects in children with head and neck ESFT.

Matched-pair analysis in patients with advanced oropharyngeal cancer: surgery versus concurrent chemoradiotherapy.

OBJECTIVE: The current study aimed to compare the therapeutic outcomes of surgery with those of chemoradiation for patients with advanced oropharyngeal cancer (OPC). METHODS: The data for 523 patients with previously untreated OPC were obtained from 12 institutions belonging to the Head and Neck Cancer Study Group in the Japan Clinical Oncology Group from April 2005 to March 2007. In this study, we matched a group of patients who underwent surgery with a second group treated with chemoradiation according to age, gender, subsite, and T and N classification, and analyzed the overall survival, progression-free survival, local control and swallowing function. RESULTS: The final matched-pair analysis included 186 patients. The 5-year overall survival, progression-free survival and local control rates were 69.8 and 71.4% (p = 0.762), 51.0 and 54.4% (p = 0.531), and 75.2 and 80.3% (p = 0.399), respectively, in patients treated with surgery and those treated with chemoradiation. Swallowing function in patients treated with chemoradiation was significantly better than that in patients treated with surgery (p = 0.015). CONCLUSION: Although this study was not randomized, this matched-pair analysis of patients treated with surgery or chemoradiation showed that chemoradiation is as effective as surgery in the treatment of OPC.

Salvage surgery for recurrent oropharyngeal cancer after chemoradiotherapy.

BACKGROUND: The current study aimed to assess the role of salvage surgery for failure cases of oropharyngeal cancer (OPC) undergoing initial chemoradiotherapy (CRT). METHODS: The data for 523 patients with previously untreated OPC were gathered from 12 institutions belonging to the Head and Neck Cancer Study Group in Japan Clinical Oncology Group (JCOG). RESULTS: Of the 170 patients who received CRT, 35 patients (21%) had local recurrence or residual disease. Only 11 patients underwent further salvage surgery, and 24 patients received nonsurgical treatment. There were statistically significant differences between the two groups in terms of patient age and the presence of a simultaneous regional recurrence. The 5-year overall survival rates for the patients who underwent salvage surgery were 49.1%, whereas those for the patients who received nonsurgical treatment were 16.3%. CONCLUSION: The initial treatment method for OPC should be decided carefully and the limitations of salvage surgery should be fully considered.

Copy number amplification of the PIK3CA gene is associated with poor prognosis in non-lymph node metastatic head and neck squamous cell carcinoma.

BACKGROUND: Deregulation of the EGFR signaling pathway is one of the most frequently observed genetic abnormalities that drives cancer development. Although mutations in the downstream components of the EGFR signaling pathway, including KRAS, BRAF and PIK3CA, have been reported in numerous cancers, extensive mutation and copy number analysis of these genes in clinical samples has not been performed for head and neck squamous cell carcinoma (HNSCC). METHODS: We examined the mutations and copy number alterations of KRAS, BRAF and PIK3CA in 115 clinical specimens of HNSCC obtained from surgically treated patients.We used DNA sequencing to detect mutations and the copy number changes were evaluated by qPCR and array comparative genomic hybridization (CGH) analysis. RESULTS: We examined the mutations and copy number alterations of KRAS, BRAF and PIK3CA in 115 clinical specimens of HNSCC obtained from surgically treated patients. We identified 3 mutations (2.6%) in K-RAS and 3 mutations (2.6%) in PIK3CA. Copy number amplification was found in 37 cases (32.2%) for PIK3CA, 10 cases (8.7%) for K-RAS and 2 cases (1.7%) for BRAF. Kaplan-Meier survival analysis revealed that copy-number amplification of PIK3CA was markedly associated with cancer relapse in patients without lymph node metastasis. (Log-rank test, p = 0.026) CONCLUSIONS: Copy number amplification of the PIK3CA gene is associated with poor prognosis in HNSCC patients without lymph node metastasis. The PIK3CA copy number status will serve as a marker of poor prognosis in patients with HNSCC.

Functional mutation analysis of EGFR family genes and corresponding lymph node metastases in head and neck squamous cell carcinoma.

Tumors with certain mutations in the epidermal growth factor receptor (EGFR) family genes dramatically respond to EGFR inhibitors. Therefore, these mutations are important factors that influence disease progression and patient survival. We previously studied the mutation status of EGFR in patients with head and neck squamous cell carcinoma (HNSCC). However, the mutation status of lymph node metastases and the frequency of mutations in EGFR family genes have not been extensively studied. In this study, we sequenced the catalytic domains of the three other members of the EGFR family, HER2, HER3, and HER4 in 92 clinical samples of HNSCC. We identified a HER2 mutation (K716E) in one sample but no mutations were found in HER3 or HER4. Next to investigate the relationship between EGFR mutations and tumor metastasis, we compared the DNA sequences of the EGFR gene between the primary tumor and the lymph node metastasis in 31 clinical samples. Only one of the patients with an EGFR mutation in the primary HNSCC carried the same mutation (L858R) in the lymph node metastasis. Finally, we explored the tumorigenic potential of the EGFR mutations that we had previously identified and their sensitivity to two different EGFR tyrosine kinase inhibitors (CL-387785, OSI-420). Ba/F3 cells transformed with mutant EGFR genes were sensitive to treatment with lower concentrations of CL-387785 than of OSI-420. These results contribute to our understanding of the genetic basis of drug sensitivity and will help design drugs that specifically target different subtypes of HNSCC.

Diagnostic utility of narrow-band imaging endoscopy for pharyngeal superficial carcinoma.

AIM: To investigate the endoscopic features of pharyngeal superficial carcinoma and evaluate the utility of narrow-band imaging (NBI) for this disease. METHODS: In the present prospective study, 335 patients underwent conventional white light (CWL) endoscopy and non-magnified/magnified NBI endoscopy, followed by an endoscopic biopsy, for 445 superficial lesions in the oropharynx and hypopharynx. The macroscopic appearance of superficial lesions was categorized as either elevated (< 5 mm in height), flat, or depressed (not ulcerous). Superficial carcinoma (SC) was defined as a superficial lesion showing high-grade dysplasia or squamous cell carcinoma on histology. The color, delineation, and macroscopic appearances of the lesions were evaluated by CWL endoscopy. The ratio of the brownish area/intervascular brownish epithelium (IBE), as well as microvascular proliferation, dilation, and irregularities, was determined by non-magnified/magnified NBI endoscopy. An experienced pathologist who was unaware of the endoscopic findings made the histological diagnoses. By comparing endoscopic findings with histology, we determined the endoscopic features of SC and evaluated the diagnostic utility of NBI. RESULTS: The 445 lesions were divided histologically into two groups: a non-SC group, including non-neoplasia and low-grade dysplasia cases, and an SC group. Of the 445 lesions examined, 333 were classified as non-SC and 112 were classified as SC. There were no significant differences in age, gender, or the location of the lesions between the patients in the two groups. The mean diameter of the SC lesions was significantly greater than that of non-SC lesions (11.0 ± 7.6 mm vs 4.6 ± 3.6 mm, respectively, P < 0.001). Comparisons of CWL endoscopy findings for SC and non-SC lesions by univariate analysis revealed that the incidence of redness (72% vs 41%, respectively, P < 0.001) and a flat or depressed type of lesion (58% vs 44%, respectively, P = 0.013) was significantly higher in the SC group. Using non-magnified NBI endoscopy, the incidence of a brownish area was significantly higher for SC lesions (79% vs 57%, respectively, P < 0.001). On magnified NBI endoscopy, the incidence of IBE (68% vs 33%, P < 0.001) and microvascular proliferation (82% vs 51%, P < 0.001), dilation (90% vs 76%, P = 0.002), and irregularity (82% vs 31%, P < 0.001) was also significantly higher for the SC compared with the non-SC lesions. Multivariate analysis revealed that the incidence of redness (P = 0.022) on CWL endoscopy and IBE (P < 0.001) and microvascular irregularities (P < 0.001) on magnified NBI endoscopy was significantly higher in SC than non-SC lesions. Redness alone exhibited significantly higher sensitivity and significantly lower specificity for the diagnosis of SC compared with redness plus IBE and microvascular irregularities (72% vs 52%, P = 0.002; and 59% vs 92%, P < 0.001, respectively). The accuracy of redness plus IBE and irregularities for the diagnosis of SC was significantly greater than using redness alone (82% vs 62%, respectively, P < 0.001). CONCLUSION: Redness, IBE, and microvascular irregularities appear to be closely related to SC lesions. Magnified NBI endoscopy may increase the diagnostic accuracy of CWL endoscopy for SC.

Prognostic significance of vitamin D receptor polymorphisms in head and neck squamous cell carcinoma.

BACKGROUND: In patients with advanced non-small-cell lung cancer, vitamin D receptor (VDR) polymorphisms and haplotypes are reported to be associated with survival. We hypothesized that a similar association would be observed in patients with head and neck squamous-cell carcinoma (HNSCC). METHODS: In a post-hoc analysis of our previous prospective cohort study, VDR polymorphisms including Cdx2 G/A (rs11568820), FokI C/T (rs10735810), BsmI A/G (rs1544410), ApaI G/T (rs7976091), and TaqI T/C (rs731236) were genotyped by sequencing in 204 consecutive patients with HNSCC who underwent tumor resection. Progression-free survival was compared between VDR polymorphisms using Kaplan-Meier survival curves with log-rank tests and Cox proportional hazard models adjusting for age, gender, smoking status, primary tumor sites, postoperative stages, existence of residual tumor, and postoperative treatment with chemotherapy or radiotherapy. RESULTS: During a median follow-up of 1,047 days, tumor progression and death occurred in 76 (37.3%) and 27 (13.2%) patients, respectively. The FokI T/T genotype was associated with poor progression-free survival: median survival for T/T was 265 days compared with 1,127 days for C/C or C/T (log-rank test: P = 0.0004; adjusted hazard ratio, 3.03; 95% confidence interval, 1.62 to 5.67; P = 0.001). In contrast, the other polymorphisms (Cdx2, BsmI, ApaI, TaqI) showed no significant association with progression-free survival. The A-T-G (Cdx2-FokI-ApaI) haplotype demonstrated a significant association with a higher progression rate (P = 0.02). CONCLUSION: These results suggest that VDR polymorphisms and haplotypes may be associated with prognosis in patients with HNSCC, although the sample size is not large enough to draw definitive conclusions.

Endoscopic endonasal surgery in the management of selected malignant naso-ethmoidal tumors.

OBJECTIVE: The objective of this study was to report the cases of three patients with sinonasal malignant tumors who underwent en bloc tumor resection using endoscopic endonasal approaches, and to discuss the advantages and limitations of endoscopic endonasal tumor resection. METHODS: Three patients with malignant naso-ethmoidal tumors underwent en bloc resection with endoscopic endonasal approach. RESULTS: In very carefully selected cases of naso-ethmoidal malignant tumors that were preoperatively evaluated on endoscopic findings and magnetic resonance imaging to be limited to within the nasal cavity and/or ethmoid sinus and to have some safe margins between the tumor and skull base and/or lamina papyracea, tumors were resected en bloc using endoscopic endonasal approaches. A case of cerebrospinal fluid leakage was safely managed with the endoscopic approach. CONCLUSIONS: In selected T1-T2 naso-ethmoidal malignant tumors with some safe margins, endoscopic endonasal surgery may offer a satisfactory alternative to external procedures.

Prognostic significance of epidermal growth factor receptor phosphorylation and mutation in head and neck squamous cell carcinoma.

The molecular status of the epidermal growth factor receptor (EGFR) has not been as well studied in head and neck squamous cell carcinoma (HNSCC) as in lung cancer. We examined the frequencies of EGFR mutations as well as the expression/phosphorylation status of the EGFR protein in HNSCC patients. Moreover, we tried to elucidate associations between EGFR molecular status and patient characteristics and disease-free survival. In this prospective cohort study, clinical data and samples were obtained from 82 consecutive patients who had not been treated with EGFR molecular targeting therapy. Full-length EGFR was sequenced, and expression and phosphorylation of the EGFR protein were measured by Western blotting. Four novel mutations (E709K, V765G, Ins770G, and G1022S) and one mutation well-known in lung cancer (L858R) were identified in six HNSCC samples (7%), but we could not find any mutations in the extracellular domain of EGFR, such as EGFRvIII, in this study. E709K and Ins770G as well as L858R appear to be functional mutations based on the use of Ba/F3 cells. In terms of patient characteristics, the number of metastatic lymph nodes and node stage were associated with phosphorylation of EGFR. No patients with EGFR mutations relapsed during the study period. Excluding mutated cases, patients whose tumor samples showed phosphorylated EGFR relapsed significantly earlier than those without phosphorylated EGFR. This finding was still significant after adjusting for mutation and overexpression of EGFR protein using the Cox proportional hazard model. In conclusion, phosphorylated EGFR without mutations may be a marker of poor prognosis in patients with HNSCC.