Details of a Researcher - Ozawa, Hiroyuki

Papers - Ozawa, Hiroyuki

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Clinical outcomes of transoral videolaryngoscopic surgery for hypopharyngeal and supraglottic cancer

Imanishi, Y., Ozawa, H., Sakamoto, K., Fujii, R., Shigetomi, S., Habu, N., Otsuka, K., Sato, Y., Watanabe, Y., Sekimizu, M., Ito, F., Tomita, T. and Ogawa, K.

Bmc Cancer 17 2017.06

ISSN 1471-2407

Background: Transoral videolaryngoscopic surgery (TOVS) was developed as a new distinct surgical procedure for hypopharyngeal cancer (HPC) and supraglottic cancer (SGC) staged at up to T3. However, long-term treatment outcomes of TOVS remain to be validated. Methods: Under a straight broad intraluminal view provided by combined use of a distending laryngoscope and a videolaryngoscope, we performed en bloc tumor resection via direct bimanual handling of the ready-made straight-form surgical instruments and devices. We retrospectively analyzed functional and oncologic outcomes of 72 patients with HPC (n = 58) or SGC (n = 14) whose minimum follow-up was 24 months or until death. Results: The cohort comprised nine patients of Tis, 23 of T1, 33 of T2, and 7 of T3. Among 36 patients (50%) who underwent neck dissection simultaneously, all but one were pathologically node-positive. Twelve patients underwent postoperative concurrent chemoradiation (CCRT) as adjuvant treatment, and another four patients underwent radiation or CCRT for second or later primary cancer. The endotracheal tube was removed in an operation room in all but two patients who underwent temporary tracheostomy. Pharyngeal fistula was formed transiently in two patients. The median time until patients resumed oral intake and could take a soft meal was 2 and 5 days, respectively. Eventually, 69 patients (96%) took normal meals. The 5-year cause-specific survival (CSS), overall survival (OS), larynx-preserved CSS, and loco-regional controlled CSS were 87.3%, 77.9%, 86.0%, and 88.0%, respectively. Multivariate analysis revealed N2-3 as an independent prognostic factor in both CSS (hazard ratio [HR] = 25.51, P = 0.008) and OS (HR = 4.90, P = 0.022), which indirectly reflected higher risk of delayed distant metastasis. Conclusions: Considering its sound functional and oncological outcomes with various practical advantages, TOVS can be a dependable, less invasive, and cost-effective surgical option of an organ-function preservation strategy for HPC and SGC.

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Impact of hematological inflammatory markers on clinical outcome in patients with salivary duct carcinoma: a multi-institutional study in Japan

Kawakita, D., Tada, Y., Imanishi, Y., Beppu, S., Tsukahara, K., Kano, S., Ozawa, H., Okami, K., Sato, Y., Shimizu, A., Sato, Y., Fushimi, C., Takase, S., Okada, T., Sato, H., Otsuka, K., Watanabe, Y., Sakai, A., Ebisumoto, K., Togashi, T., Ueki, Y., Ota, H., Shimura, T., Hanazawa, T., Murakami, S. and Nagao, T.

Oncotarget 8 ( 1 ) 1083 - 1091 2017.01

ISSN 1949-2553

The prognostic role of modified Glasgow Prognostic Score (mGPS), neutrophil-to- lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in patients with salivary duct carcinoma (SDC) remains unclear. We conducted a multi-institutional retrospective cohort study of 140 SDC patients. The survival impact of these hematological markers was evaluated using multivariate proportional hazard models. High mGPS (>= 1) was significantly associated with worse survival (3-year overall survival (OS): 16.7% vs 66.1%, p-value=0.003; 3-year progression-free survival (PFS): 0.0% vs 27.9%, p-value<0.001). Additionally, high C-reactive protein (CRP) (>= 0.39 mg/dl) was significantly associated with worse survival (3-year OS: 32.1% vs 68.2%, p-value= 0.001; 3-year PFS: 7.1% vs 31.1%, p-value<0.001). These associations were consistent with multivariate analysis adjusted for established prognostic factors. Although we also found significant association of high NLR (>= 2.5) with OS (HR 1.80; 95% confidence interval, 1.05-3.08) in multivariate analysis, this association were inconsistent with the results of PFS. In addition, we found no significant associations of PLR with survival. In conclusion, we found that mGPS, CRP and NLR were identified as prognostic factors associated with survival in SDC patients.

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Endonasal endoscopic approach for a giant cavernous sinus meningioma that extended to the middle cranial fossa with preoperative embolization

Tamura, R., Toda, M., Kohno, M., Ozawa, H., Tomita, T., Akiyama, T., Ogawa, K. and Yoshida, K.

Interdisciplinary Neurosurgery-Advanced Techniques and Case Management 6 20 - 22 2016.12

ISSN 2214-7519

Background: Transcranial surgery is considered more appropriate than an endonasal endoscopic approach (EEA) for a large cavernous sinus meningioma with lateral extension. Case presentation: A 6-cm-diameter hypervascular meningioma around cavernous sinus invaded the orbital apex and infratemporal fossa. 80% of the tumor was removed without too much blood loss via endoscopic endonasal transpterygoidal-infratemporal approach. Preoperative embolization from some feeding arteries was done, and 80% of the tumor staining disappeared. Discussion: Tumor removal rates for giant meningioma are worse with EEA than with the transcranial approach because of various anatomical limitations and blood control. Recently, EEA has become more widely used with approaches such as the transpterygoidal approach. The operation can be done safely with preoperative embolization because the operative view is clear without bleeding. Conclusion: Preoperative embolization for a large hypervascular tumor makes EEA more effective. A giant meningioma can be removed by EEA if the anatomical limitations can be identified and approached safely and effectively. (C) 2016 The Authors. Published by Elsevier B.V.

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CoGAPS matrix factorization algorithm identifies transcriptional changes in AP-2alpha target genes in feedback from therapeutic inhibition of the EGFR network

Fertig, E. J., Ozawa, H., Thakar, M., Howard, J. D., Kagohara, L. T., Krigsfeld, G., Ranaweera, R. S., Hughes, R. M., Perez, J., Jones, S., Favorov, A. V., Carey, J., Stein-O'Brien, G., Gaykalova, D. A., Ochs, M. F. and Chung, C. H.

Oncotarget 7 ( 45 ) 73845 - 73864 2016.11

ISSN 1949-2553

Patients with oncogene driven tumors are treated with targeted therapeutics including EGFR inhibitors. Genomic data from The Cancer Genome Atlas (TCGA) demonstrates molecular alterations to EGFR, MAPK, and PI3K pathways in previously untreated tumors. Therefore, this study uses bioinformatics algorithms to delineate interactions resulting from EGFR inhibitor use in cancer cells with these genetic alterations. We modify the HaCaT keratinocyte cell line model to simulate cancer cells with constitutive activation of EGFR, HRAS, and PI3K in a controlled genetic background. We then measure gene expression after treating modified HaCaT cells with gefitinib, afatinib, and cetuximab. The CoGAPS algorithm distinguishes a gene expression signature associated with the anticipated silencing of the EGFR network. It also infers a feedback signature with EGFR gene expression itself increasing in cells that are responsive to EGFR inhibitors. This feedback signature has increased expression of several growth factor receptors regulated by the AP-2 family of transcription factors. The gene expression signatures for AP-2alpha are further correlated with sensitivity to cetuximab treatment in HNSCC cell lines and changes in EGFR expression in HNSCC tumors with low CDKN2A gene expression. In addition, the AP-2alpha gene expression signatures are also associated with inhibition of MEK, PI3K, and mTOR pathways in the Library of Integrated Network-Based Cellular Signatures (LINCS) data. These results suggest that AP-2 transcription factors are activated as feedback from EGFR network inhibition and may mediate EGFR inhibitor resistance.

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Clinical Outcomes and Prognostic Factors for Salivary Duct Carcinoma: A Multi-Institutional Analysis of 141 Patients

Otsuka, K., Imanishi, Y., Tada, Y., Kawakita, D., Kano, S., Tsukahara, K., Shimizu, A., Ozawa, H., Okami, K., Sakai, A., Sato, Y., Ueki, Y., Sato, Y., Hanazawa, T., Chazono, H., Ogawa, K. and Nagao, T.

Annals of Surgical Oncology 23 ( 6 ) 2038 - 2045 2016.06

ISSN 1068-9265

Among salivary gland malignancies, the prognosis of salivary duct carcinoma (SDC) is assumed to be the poorest. However, because of its low incidence, reliable survival estimates and prognostic factors based on a large number of patients remain to be elucidated, thereby making it impossible to standardize the optimal treatment for SDC. We performed this multi-institutional, retrospective analysis by collecting the clinical information of 141 patients with SDC without distant metastasis who underwent curative surgery as the initial treatment to elucidate overall survival (OS) and disease-free survival (DFS) along with their prognostic factors. The 3-year OS and DFS rates were 70.5 and 38.2 %, respectively. Multivariate analysis revealed that age a parts per thousand yen65 years (p < 0.001) and N1 and N2 (p = 0.047 and < 0.001, respectively) were independent prognostic factors for OS, whereas the primary site of the minor salivary and sublingual gland (p < 0.001) and N2 (p < 0.001) were those for DFS. The most common treatment failure was distant metastasis (55 patients, 39.0 %). For early parotid SDC, neither total parotidectomy in the patients with early T stage nor nerve resection in the patients without facial nerve palsy showed survival benefits. Advanced N stage independently affects both OS and DFS. Partial parotidectomy with facial nerve preservation could be a less invasive standard surgical procedure for parotid gland SDC in the early T stage without facial nerve palsy. Effective systemic therapy is imperative to improve DFS of SDC.

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Sigmoid incision rescue nasoseptal flap technique for endoscopic endonasal skull base surgery

Ozawa, H., Tomita, T., Watanabe, Y., Sekimizu, M., Ito, F., Ikari, Y., Saito, S., Toda, M. and Ogawa, K.

Acta Oto-Laryngologica 136 ( 6 ) 636 - 640 2016.06

ISSN 0001-6489

Conclusion The sigmoid-incision (S-I) rescue flap technique has the advantage of both reduced-invasiveness and providing a sufficient surgical corridor for endoscopic endonasal skull base surgery (EESBS). Objective Skull base reconstruction with nasoseptal flap (NSF) is critically important in managing post-operative cerebrospinal fluid (CSF) leakage after tumor removal by EESBS. The NSF needs to be elevated before sphenoidotomy and posterior septectomy to preserve the pedicle. However, most extradural surgery without CSF leakage does not require NSF and, therefore, NSF preparation is often futile. As a result, a rescue flap technique to overcome this problem has been developed, whereby a new S-I rescue flap method is used that enables wide exposure of the sphenoidal rostrum and smooth manipulation of surgical instruments to preserve the NSF pedicle. Materials and methods Starting in April 2014, 19 cases underwent EESBS with S-I rescue flap. Results All patients underwent tumor resection under an adequate operative field with smooth manipulation of surgical instruments. Two complications were experienced. One patient had CSF leak after removal of the nasal packing, but the leakage was successfully closed by conventional NSF. Another patient had epistaxis from the septal wall, but this was controlled by electrocautery.

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Vascularized middle turbinate flap for the endoscopic endonasal reconstruction of the anterior olfactory groove

Tamura, R., Toda, M., Kohno, M., Watanabe, Y., Ozawa, H., Tomita, T., Ogawa, K. and Yoshida, K.

Neurosurgical Review 39 ( 2 ) 297 - 302 2016.04

ISSN 0344-5607

A vascularized middle turbinate flap (MTF) might be useful in the repair of lesions in the anterior olfactory groove. The sizes of the MTF and inferior turbinate flap (ITF) and these distances up to the frontal base were analyzed by computed tomography (CT) using a picture archiving and communication system (PACS) in 20 patients. The minimum flap measurement to reconstruct the skull base was defined as the distance from the basal plate to the medial slope or lateral slope edge of the MTF and the ITF on the coronal view. Next, we reviewed clinical data from three patients with dural deficits who underwent endoscopic vascularized MTF reconstruction. The distance to the frontal base from the ITF was significantly longer than that from the MTF. The minimum length of the MTF measured by coronal CT was similar to the distance to the frontal base. In contrast, the minimum length of the ITF was shorter than the distance to the frontal base. These results suggest that the MTF might be superior to the ITF for coverage of the anterior frontal base. Three patients who underwent MTF reconstruction for a defect in the anterior olfactory groove had good outcomes and no complications. The MTF is a good option for reconstruction of defects in the anterior part of the olfactory groove.

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Cetuximab activity in dysplastic lesions of the upper aerodigestive tract

Khan, Z., Epstein, J. B., Marur, S., Gillespie, M. B., Feldman, L., Tsai, H. L., Zhang, Z., Wang, H., Sciubba, J., Ferris, R., Grandis, J. R., Gibson, M., Koch, W., Tufano, R., Westra, W., Tsottles, N., Ozawa, H., Chung, C. and Califano, J. A.

Oral Oncology 53 60 - 66 2016.02

ISSN 1368-8375

Background: High risk head and neck mucosal premalignancy has a malignant conversion rate of up to 40%, despite adequate surgical therapy. Epidermal Growth Factor Receptor (EGFR) blocking agents, including cetuximab, have shown activity in head and neck squamous cell carcinoma (HNSCC) and have potential for therapy in high risk premalignancy. Methods: We conducted a randomized, prospective, phase II clinical trial to determine the effects of cetuximab on patients with high risk premalignancy. Patients were randomized to treatment with cetuximab 400 mg/m2 on week one followed by 250 mg/m2 on week 2-8 or observation, with the option for crossover to cetuximab therapy for patients originally randomized to the observation arm. Results: Two of 19 enrolled patients did not complete therapy due to treatment toxicity. Analysis of 17 patients who completed the trial regimen show a trend toward a larger mean decrease in grade of dysplasia in the cetuximab treated group (-1.0) vs. the observation group (-0.2) (P = 0.082, one-sided exact Wilcoxon rank sum test). However, in the observation group, none of the 5 patients (0%) achieved complete resolution of dysplasia; while 4 of 12 (33.3%) cetuximab treated patients had no remaining dysplasia after therapy. Conclusions: Treatment of high risk premalignancy of the upper aerodigestive tract with cetuximab alone may result in significant, durable, and complete clinical and histological resolution of moderate to severe dysplasia in at least a subset of high risk patients. These results warrant further investigation in larger studies with increased statistical power. (C) 2015 Elsevier Ltd. All rights reserved.

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NF-κB and stat3 transcription factor signatures differentiate HPV-positive and HPV-negative head and neck squamous cell carcinoma

Gaykalova Daria A., Manola Judith B., Ozawa Hiroyuki, Zizkova Veronika, Morton Kathryn, Bishop Justin A., Sharma Rajni, Zhang Chi, Michailidi Christina, Considine Michael, Tan Marietta, Fertig Elana J., Hennessey Patrick T., Ahn Julie, Koch Wayne M., Westra William H., Khan Zubair, Chung Christine H., Ochs Michael F., Califano Joseph A.

International Journal of Cancer 137 ( 8 ) 1879 - 1889 2015.10

ISSN 0020-7136

Using high-throughput analyses and the TRANSFAC database, we characterized TF signatures of head and neck squamous cell carcinoma (HNSCC) subgroups by inferential analysis of target gene expression, correcting for the effects of DNA methylation and copy number. Using this discovery pipeline, we determined that human papillomavirus-related (HPV+) and HPV- HNSCC differed significantly based on the activity levels of key TFs including AP1, STATs, NF-κB and p53. Immunohistochemical analysis confirmed that HPV- HNSCC is characterized by co-activated STAT3 and NF-κB pathways and functional studies demonstrate that this phenotype can be effectively targeted with combined anti-NF-κB and anti-STAT therapies. These discoveries correlate strongly with previous findings connecting STATs, NF-κB and AP1 in HNSCC. We identified five top-scoring pair biomarkers from STATs, NF-κB and AP1 pathways that distinguish HPV+ from HPV- HNSCC based on TF activity and validated these biomarkers on TCGA and on independent validation cohorts. We conclude that a novel approach to TF pathway analysis can provide insight into therapeutic targeting of patient subgroup for heterogeneous disease such as HNSCC. What's new? Changes in transcription factor (TF) expression contribute to genetic and epigenetic abnormalities in cancer. In order to capitalize on those changes and advance diagnostic and therapeutic strategies for cancer, researchers must first find a way to detect and quantify changes in TF activity. Here, TF activity was estimated globally in primary head and neck squamous cell carcinoma (HNSCC) using a novel inferential approach that accounted for gene silencing and loss of heterozygosity and homozygosity. Top-scoring pair biomarkers were identified and linked to human papillomavirus (HPV) status, enabling HPV+ and HPV- HNSCC to be distinguished based on TF activity.

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Expression of Oct3/4 and Nanog in the head and neck squamous carcinoma cells and its clinical implications for delayed neck metastasis in stage I/II oral tongue squamous cell carcinoma

Habu, N., Imanishi, Y., Kameyama, K., Shimoda, M., Tokumaru, Y., Sakamoto, K., Fujii, R., Shigetomi, S., Otsuka, K., Sato, Y., Watanabe, Y., Ozawa, H., Tomita, T., Fujii, M. and Ogawa, K.

Bmc Cancer 15 2015.10

ISSN 1471-2407

Background: The side population (SP) of cancer cells is reportedly enriched with cancer stem cells (CSCs), however, the functional role and clinical relevance of CSC marker molecules upregulated in the SP of head and neck squamous carcinoma (HNSCC) cells are yet to be elucidated. Patients with clinical stage I/II (T1-2N0M0) tongue squamous cell carcinoma (TSCC) typically undergo partial glossectomy; however, development of delayed neck metastasis (DNM) tends to reduce their survival. In the present study, we aimed to determine the CSC markers in the SP of HNSCC cells along with their functions in cellular behaviors, and to clarify the association of these markers with DNM. Methods: Flow cytometry was applied to isolate SP from main population (MP) in HNSCC cells. The expression of the CSC markers was examined by semi-quantitative RT-PCR and immunocytochemistry. In vitro proliferation, migration, and invasion assays were performed to assess cellular behaviors. Clinicopathological factors and immunohistochemical expressions of Oct3/4 and Nanog were evaluated using surgical specimens from 50 patients with stage I/II TSCC. Results: SPs were isolated in all three cell lines examined. Expression levels of Oct3/4 and Nanog were higher in SP cells than MP cells. Additionally, cell migration and invasion abilities were higher in SP cells than MP cells, whereas there was no difference in proliferation. Univariate analysis showed that expression of Oct3/4 and Nanog, vascular and muscular invasion, and mode of invasion were significantly correlated with DNM. Multivariate logistic regression revealed that Oct3/4 expression (risk ratio = 14.78, p = 0.002) and vascular invasion (risk ratio = 12.93, p = 0.017) were independently predictive of DNM. Regarding the diagnostic performance, Oct3/4 showed the highest accuracy, sensitivity, and NPV of 82.0 %, 61.5 %, and 86.8 %, respectively, while vascular invasion showed the highest specificity and PPV of 94.6 % and 71.4 %, respectively. Conclusion: These results suggest that Oct3/4 and Nanog represent probable CSC markers in HNSCC, which contribute to the development of DNM in part by enhancing cell motility and invasiveness. Moreover, along with vascular invasion, expression of Oct3/4 can be considered a potential predictor for selecting patients at high risk of developing DNM.

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Decreased SMAD4 expression is associated with induction of epithelial-to-mesenchymal transition and cetuximab resistance in head and neck squamous cell carcinoma

Cheng, H. X., Fertig, E. J., Ozawa, H., Hatakeyama, H., Howard, J. D., Perez, J., Considine, M., Thakar, M., Ranaweera, R., Krigsfeld, G. and Chung, C. H.

Cancer Biology & Therapy 16 ( 8 ) 1252 - 1258 2015.08

ISSN 1538-4047

Epidermal growth factor receptor (EGFR) is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) and cetuximab, a monoclonal antibody targeting this receptor, is widely used to treat these patients. In the following investigation, we examined the role of SMAD4 down-regulation in mediating epithelial-to-mesenchymal transition (EMT) and cetuximab resistance in HNSCC. We determined that SMAD4 downregulation was significantly associated with increased cell motility, increased expression of vimentin, and cetuximab resistance in HNSCC cell lines. In the HNSCC genomic dataset obtained from The Cancer Genome Atlas, SMAD4 was altered in 20/279 (7%) of HNSCC via homozygous deletion, and nonsense, missense, and silent mutations. When SMAD4 expression was compared with respect to human papillomavirus (HPV) status, HPV-positive tumors had higher expression compared to HPV-negative tumors. Furthermore, higher SMAD4 expression also correlated with higher CDKN2A (p16) expression. Our data suggest that SMAD4 down-regulation plays an important role in the induction of EMT and cetuximab resistance. Patients with higher SMAD4 expression may benefit from cetuximab use in the clinic.

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PiCO2 monitoring of transferred jejunum perfusion using an air tonometry technique after hypopharyngeal cancer surgery

Ozawa Hiroyuki, Imanishi Yorihisa, Ito Fumihiro, Watanabe Yoshihiro, Kato Takashi, Nameki Hideo, Isobe Kiyoshi, Ogawa Kaoru

Medicine (United States) 94 ( 11 ) e632 2015.03

ISSN 0025-7974

This study aimed to investigate the usefulness of intraluminal Pco 2 (Pico 2) monitoring by air tonometry for the assessment of the vascular condition of the transferred jejunum after surgery for hypopharyngeal cancer. Pico 2 in the transplanted jejunum of 24 patients was monitored using air tonometry after radical surgery for hypopharyngeal cancer from 2003 to 2010. All but 1 patient, who removed the catheter before monitoring began, were monitored safely. Pico 2 in the transferred jejunum correlated with arterial Pco 2 (Paco 2) that was measured concurrently, and dissociation of Pico 2 from Paco 2 was observed in cases with vascular complication. In those cases without postoperative vascular complication, the Pico 2 value gradually increased for 3 hours but then decreased by 12 hours after surgery. Three patients experienced major vascular complication. All 3 patients had continuous elevation of Pico 2 >100mm Hg, although vascular flow in 1 patient recovered by removal of a venous thrombosis and reanastomosis of the vein 7.5 hours after surgery. Four other patients who experienced elevation of Pico 2 had their skin suture released for decompression of their neck wound, resulting in a decrease in Pico 2 after treatment. The current results demonstrated that continuous monitoring of Pico 2 by air tonometry accurately reflects the vascular condition of the transferred jejunum, and this method is one of the best options for postoperative monitoring of jejunum blood perfusion.

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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

Fujii Ryoichi, Imanishi Yorihisa, Shibata Katsushi, Sakai Nobuya, Sakamoto Koji, Shigetomi Seiji, Habu Noboru, Otsuka Kuninori, Sato Yoichiro, Watanabe Yoshihiro, Ozawa Hiroyuki, Tomita Toshiki, Kameyama Kaori, Fujii Masato, Ogawa Kaoru

Journal of Experimental and Clinical Cancer Research 33 ( 1 ) 2014.05

ISSN 0392-9078

Background: The 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. Methods. We 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). Results: The 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). Conclusions: These 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. © 2014 Fujii et al.; licensee BioMed Central Ltd.

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Clinical outcome and clinicopathological prognostic factors in adenoid cystic carcinoma of the head and neck

Shigetomi Seiji, Imanishi Yorihisa, Shimoda Masayuki, Tomita Toshiki, Ozawa Hiroyuki, Sakamoto Koji, Fujii Ryoichi, Habu Noboru, Otsuka Kuninori, Yamashita Taku, Fujii Masato, Ogawa Kaoru

Journal of Otolaryngology of Japan 117 ( 5 ) 658 - 665 2014

ISSN 0030-6622

We retrospectively reviewed the records of the 30 patients with adenoid cystic carcinoma of the head and neck (ACCHN) who had undergone initial treatment in the Department of Otorhinolaryngology, Head and Neck Surgery, Keio University School of Medicine between 1988 and 2007. The primary tumor site was the parotid gland in 10 patients and the submandibular gland in 4 patients, which account for about a half of the subjects. Thirty patients underwent surgical resection with curative intent as the primary treatment, of which 10 patients had post-operative radiotherapy. The 5- and 10-year disease-specific survival (DSS) was 73.9% and 62.4%, respectively, whereas the 5- and 10-year disease-free survival (DFS) was 64.3% and 59.7%, respectively. A univariate analysis revealed that DSS was significantly correlated with perineural invasion (p = 0.010) and lymphatic invasion (p = 0.036), while DFS was significantly correlated with higher T-stage (p = 0.044), a positive surgical margin (p = 0.012) and perineural invasion (p = 0.019). A multivariate analysis demonstrated that perineural invasion (/> = 0.034, risk ratio = 9.530) was the independent prognostic factor for DSS, whereas for DFS it was a positive surgical margin (p = 0.038, risk ratio = 8.897). The histological grade classification, defined specifically for ACC, showed no correlation with the survival. Extended resection with wider margin and additional resection in cases with positive margin may improve treatment results, however, surgical resection alone can prevent neither the development of local recurrence mainly attributed to undetectable perineural invasion, nor that of delayed distant, metastasis. Therefore, the roles of adjuvant radiotherapy and effective systemic therapies are also significant in ACCHN, although a reliable regimen for the latter has not yet been established. Development of a personalized strategy for the adjuvant therapy, which should be based on the accurate prediction of the long-term prognosis in combination with dependable molecular biomarkers, would be indispensable in the future to improve the clinical outcome of the patients with ACCHN.

A case of igg4-related pharyngolaryngitis

Suzuki Narihisa, Fujioka Masato, Araki Yasutomo, Ozawa Hiroyuki, Kawaura Mitsuhiro

Practica Oto-Rhino-Laryngologica 107 ( 3 ) 227 - 233 2014

ISSN 0032-6313

IgG4-related inflammatory diseases, including autoimmune pancreatitis and Mikulicz syndrome, have become known to physicians as new clinical entities, especially over the past few years. We would like to present a case of IgG4-related oropharyngolaryngitis. We encountered a case with a severe and intractable inflammation distributed exclusively in the hypopharynx and laryngeal surface of the epiglottis. The patient did not spontaneously recover and the disease was resistant to antibiotics and NSAIDs that were administered for 4 weeks. Frequent fiberscope inspections and punch biopsies failed to provide a diagnosis, and were followed by a detailed examination under laryngomicrosurgery, with multiple tissue samplings under general anesthesia. The samples revealed proliferative, non-malignant inflammatory lesions and the pathology showed IgG4-related symptoms; indicated by all of the criteria including blood and local IgG4 elevation being met. Symptoms were quickly suppressed by a week of steroid infusion drips, followed by a gradual tapering of oral steroids in accordance with a regimen for autoimmune pancreatitis. For many years, ENT physicians have often used corticosteroids empirically for atypical pharyngitis, but usage of steroids on conditions with uncertain criteria has always been criticized. This is, as far as we know, the first report of oropharyngolaryngitis to be associated with IgG4-related symptoms. The case is thought-provoking in that some of those recurrent atypical oropharyngolaryngitis cases might be explained in accordance with this information. Moreover, the results suggest that the serum IgG4 level might be a predictive marker for the requirement of corticosteroids administration.

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A phase II study of temsirolimus and erlotinib in patients with recurrent and/or metastatic, platinum-refractory head and neck squamous cell carcinoma

Bauman Julie E., Arias-Pulido Hugo, Lee Sang Joon, Fekrazad M. Houman, Ozawa Hiroyuki, Fertig Elana, Howard Jason, Bishop Justin, Wang Hao, Olson Garth T., Spafford Michael J., Jones Dennie V., Chung Christine H.

Oral Oncology 49 ( 5 ) 461 - 467 2013.05

ISSN 1368-8375

Objectives: The epidermal growth factor receptor (EGFR) is a validated target in head and neck squamous cell carcinoma (HNSCC). In recurrent and/or metastatic (R/M) HNSCC, resistance to anti-EGFR therapy inevitably occurs. Downstream activation of the PI3K/Akt/mTOR pathway is an established resistance mechanism. Concurrent mTOR blockade may improve efficacy of anti-EGFR therapy. Materials and methods: Erlotinib 150 mg daily and temsirolimus 15 mg weekly were administered to patients with platinum-refractory R/M HNSCC and ECOG performance status 0-2. The primary endpoint was progression-free survival (PFS). Correlative studies determined PIK3CA and HRAS mutation status; p16, EGFR, pS6K, pAkt and PTEN expression; and pre- and post-treatment plasma levels of 20 immunomodulatory cytokines. Results: Twelve patients enrolled; six withdrew within 6 weeks due to toxicity or death, prompting early closure of the trial. Grade ≥ 3 toxicities included fatigue, diarrhea, gastrostomy tube infection, peritonitis, pneumonia, dyspnea, and HN edema. Median PFS was 1.9 months. Median overall survival was 4.0 months. Six/12 tumors were p16(+), 9/11 lacked measurable PTEN expression, and 1/12 harbored a PIK3CA mutation. On exploratory analysis, high baseline plasma VEGF and interferon-gamma levels marginally associated with tumor progression. Conclusions: The combination of erlotinib and temsirolimus was poorly tolerated. Low prevalence of PTEN expression and 8% incidence of PIK3CA mutations indicate biological relevance of this pathway in R/M disease. Investigation of more tolerable combinations of EGFR and PI3K/Akt/mTOR pathway inhibitors in selected HNSCC patients is warranted. © 2012 Elsevier Ltd. All rights reserved.

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A case of nasopharyngeal carcinoma ex pleomorphic adenoma

Wasano Koichiro, Ikari Yuichi, Hashiguchi Sayuri, Suzuki Noriomi, Kawasaki Taiji, Ozawa Hiroyuki

Practica Oto-Rhino-Laryngologica 106 ( 12 ) 1083 - 1088 2013

ISSN 0032-6313

Malignant tumors of the minor salivary glands are very rare and most cases occur in the oral cavity, e.g., the palate, tongue, cheek and lip. We report herein on an extremely rare case of carcinoma ex pleomorphic adenoma arising in the fossa of Rosenmuller. An 83-year-old man, who had consulted another clinic with a complaint of hemosputum, was referred to our hospital because of the presence of a nasopharyngeal tumor. The tumor was resected via a transnasal endoscopic procedure without any major complications. The tumor was found to have arisen in the fossa of Rosenmuller and extended to superior lateral side behind the Eustachian tube cartilage. Histological examination showed that the main part of the tumor consisted of a pleomorphic adenoma, however, capsular invasion, nuclear atypia and mitosis were observed in a limited area where the MIB-1 index was high. We diagnosed the lesion as a carcinoma ex pleomorphic adenoma. We did not perform any postoperative therapy, because the area containing malignancy was far from the surgical margin and the patient was rather elderly. Three years and 10 months after the surgery, he remains in follow-up and has not shown any recurrence of the tumor.

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Statistical analysis of 32 patients with nasopharyngeal Carcinoma

Fujii Ryoichi, Imanishi Yorihisa, Tomita Toshiki, Sakamoto Koji, Shigetomi Seiji, Habu Noboru, Ootsuka Kuninori, Sato Yoichiro, Ozawa Hiroyuki, Yamashita Taku, Fujii Masato, Shigematsu Naoyuki, Ogawa Kaoru

Journal of Otolaryngology of Japan 115 ( 8 ) 773 - 782 2012.08

ISSN 0030-6622

In order to assess the clinical outcome and prognostic factors of patients with nasopharyngeal carcinoma (NPC) who were initially treated in the Department of Otorhinolaryngology, Head and Neck Surgery, Keio University School of Medicine between 1997 and 2006, statistical analyses were performed based on the patient medical records. Cause-specific survival (CSS) and disease-free survival (DFS) in all cases (stage I to IV, n = 32) and advanced cases (stage III and IV, n = 22) were estimated using the Kaplan-Meier method. The independent prognostic values of the clinical and therapeutic factors were determined using multivariate Cox proportional hazards models. Results: The 5-year CSS/DFS were 43.4%/34.8% in all cases and 34.596/29.8% in advanced cases. Multivariate analysis revealed that, in all cases, the independent prognostic factors for CSS were age ≥ 61 vs. ≤60, risk ratio (RR) =5.717, p = 0.006), T-stage (3/4 vs. 1/2, RR = 6.957, p = 0.004), and the use of platinum agents (unused vs. used, RR = 3.911, p = 0.012), whereas those for DFS were T-stage (3/4 vs. 1/2, RR=3.499, p = 0.019) and the use of platinum agents (unused vs. used, RR=2.947, p = 0.028). In advanced cases, the use of platinum agents alone was significant for both CSS (RR = 4.503, p = 0.023)and DFS (RR=4.218, p = 0.014). The patients who received neoadjuvant chemotherapy (NAC) showed better CSS and DFS than the patients who did not (p = 0.066 and p = 0.025, respectively) in a univariate analysis (Log-rank test), although no significant difference was seen between these groups in the multivariate analysis. Conclusion: The advantage of the administration of platinum agents in the treatment of NPC was statistically corroborated even in our study with its small sample size. As agents combined with chemoradiotherapy, the efficacy of do-cetaxel alone did not seem comparable to that of platinum agents. The docetaxel-CDDP-5-FU regimen applied as NAC was suggested to be possibly beneficial for advanced cases of NPC.

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Overexpression of SIP1 and downregulation of e-cadherin predict delayed neck metastasis in stage I/II oral tongue squamous cell carcinoma after partial glossectomy

Sakamoto Koji, Imanishi Yorihisa, Tomita Toshiki, Shimoda Masayuki, Kameyama Kaori, Shibata Katsushi, Sakai Nobuya, Ozawa Hiroyuki, Shigetomi Seiji, Fujii Ryoichi, Fujii Masato, Ogawa Kaoru

Annals of Surgical Oncology 19 ( 2 ) 612 - 619 2012.02

ISSN 1068-9265

Background: Patients with clinical stage I/II (T1-2N0M0) oral tongue squamous cell carcinoma (TSCC) usually undergo partial glossectomy alone. However, 14-48% of them develop delayed neck metastasis (DNM), which may lead to an unfavorable course. Recently epithelial-to-mesenchymal transition (EMT) has been thought to play a crucial role in cancer metastasis. The present study aimed to examine the associations of EMT-involved molecular factors and clinicopathological factors with DNM in stage I/II TSCC. Methods: mRNA expression levels of E-cadherin and its transcriptional repressors (snail, SIP1, and twist) in 7 head and neck squamous cell carcinoma (HNSCC) cell lines were evaluated by quantitative real-time PCR. Clinicopathological parameters and immunohistochemical expressions of E-cadherin and its repressors were examined in surgical specimens of 37 stage I/II TSCC patients who underwent partial glossectomy alone. Results: In HNSCC cells, E-cadherin expression was inversely correlated with SIP1 expression (P = 0.023). Univariate analysis of immunohistochemistry showed that overexpression of SIP1 and loss of E-cadherin were significantly correlated with DNM, although no inverse correlation was found between E-cadherin and its repressors. Multiple logistic regression analysis including clinicopathological and molecular factors revealed that overexpression of SIP1 (P = 0.005), loss of E-cadherin (P = 0.046), and vascular invasion (P = 0.024) were independently correlated with DNM. Conclusions: These results suggest that development of DNM in stage I/II TSCC is closely related to induction of EMT in primary tumor cells. Especially, SIP1 and E-cadherin are considered to be the possible markers for selecting patients at high risk of DNM. © 2011 Society of Surgical Oncology.

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Thyroglobulin concentration measurement in fine-needle aspiration fluid from cystic cervical lymph node metastases of papillary thyroid carcinoma

Inagaki Yozo, Sakamoto Koji, Inoue Yasuhiro, Imanishi Yorihisa, Tomita Toshiki, Shinden Seiichi, Ozawa Hiroyuki, Fujii Ryoichi, Shigetomi Seiji, Watabe Takahisa, Yamada Hiroyuki, Ogawa Kaoru

Journal of Otolaryngology of Japan 114 ( 12 ) 912 - 916 2011.12

ISSN 0030-6622

Background: Combining ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI) and fine-needle aspiration cytology (FNAC) usually results in the best preoperative diagnosis of cervical masses, including neoplasms. This may not be tnie, however, especially in occult papillary thyroid carcinoma (PTC) associated with single cystic cervical lymph node metastasis. We assessed the role of thyroglobulin measurement in FNA fluid (FNATg) in differentially diagnosing cystic cervical mass lesions, including PTC cystic lymph node metastasis. Methods: We reviewed the records of 17 subjects with cervical cystic masses undergoing both FNATg measure ment and surgery. FNA was done under ultrasonographic guidance. We also measured FNATg concentrations from extrathyroid lesions, consisting of cystic cervical lymph node metastases and benign cystic lesions. Results: Pathological diagnosis involved 5 PTC lymph node metastases, 3 lateral cervical cysts, 7 thyroglossal duct cysts, and 2 squamous cell carcinoma (lung and oropharynx) lymph node metastases. FNATg of PTC lymph node metastasis was much higher than the reference range of blood serum thyroglobulin, although much lower for the lateral cervical cyst detection threshold. FNAC and FNATg measurement are thought to be mutually complementary in the differential-diagnosis of PTC cystic lymph node metastasis. Conclusion : High concentrations of FNATg in a cystic cervical mass is considered specific to PTC lymph node metastasis, indicating its usefulness in distinguish PTC cystic metastasis from other cystic lesions. Including FNATg measurement with FNAC may thus improve preoperative diagnosis accuracy without additionally stressing subjects with PTC cystic lymph node metastasis.

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