Language：Japanese   Publisher：(公社)神奈川県医師会  

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Language：Japanese   Publisher：耳鼻咽喉科臨床学会  

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Language：Japanese   Publisher：(一社)日本頭頸部癌学会  

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Language：Japanese   Publisher：(一社)日本頭頸部癌学会  

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Language：Japanese   Publisher：(一社)日本頭頸部癌学会  

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Language：Japanese   Publisher：(NPO)日本気管食道科学会  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J01054&link_issn=&doc_id=20240502250045&doc_link_id=10.2468%2Fjbes.75.126&url=https%3A%2F%2Fdoi.org%2F10.2468%2Fjbes.75.126&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Nivolumab paved a new way in the treatment of patients with recurrent or metastatic (RM) head and neck squamous cell carcinoma (RM-HNSCC). However, the limited rates of long-term survivors (< 20%) demand a robust prognostic biomarker. This nationwide multi-centric prospective study aimed to identify a plasma exosome (PEX) mRNA signature, which serves as a companion diagnostic of nivolumab and provides a biological clue to develop effective therapies for a majority of non-survivors. METHODS: Pre-treatment plasmas (N = 104) of RM-HNSCC patients were subjected to comprehensive PEX mRNA analyses for prognostic marker discovery and validation. In parallel, paired treatment-naïve tumor and plasma samples (N = 20) were assayed to elucidate biological implications of the PEX mRNA signature. RESULTS: Assays for pre-treatment blood samples (N = 104) demonstrated that a combination of 6 candidate PEX mRNAs plus neutrophil-to-lymphocyte ratio precisely distinguished non-survivors from >2-year survivors (2-year OS; 0% vs 57.7%; P = 0.000124) with a high hazard ratio of 2.878 (95% CI 1.639-5.055; P = 0.0002348). Parallel biological assays demonstrated that in the paired treatment-naïve HNSCC tumor and plasma samples (N = 20), PEX HLA-E mRNA (a non-survivor-predicting marker) was positively corelated with overexpression of HLA-E protein (P = 0.0191) and the dense population of tumor-infiltrating NK cells (P = 0.024) in the corresponding tumor, suggesting that the HLA-E-NKG2A immune checkpoint may inhibit the antitumor effect of PD-1blockade. CONCLUSION: The PEX mRNA signature could be useful as a companion diagnostic of nivolumab. The combination of an anti-NKG2A antibody (i.e., monalizumab) and nivolumab may serve as a treatment option for non-survivors predicted by a RT-qPCR-based pre-treatment measurement of PEX mRNAs.

DOI： 10.3389/fimmu.2024.1464419

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: In view of improving biomarkers predicting the efficacy of immunotherapy for head and neck squamous cell carcinoma (R/M HNSCC), this multicenter retrospective study aimed to identify clinical, tumor microenvironmental, and genomic factors that are related to therapeutic response to the anti- Programmed cell death protein 1 (PD-1) antibody, nivolumab, in patients with R/M HNSCC. METHODS: The study compared 53 responders and 47 non-responders, analyzing formalin-fixed paraffin-embedded samples using 14-marker multiplex immunohistochemistry and targeted gene sequencing. RESULTS: Of 100 patients included, responders had significantly lower smoking and alcohol index, higher incidence of immune related adverse events, and higher PD-1 ligand (PD-L1) expression in immune cells as well as PD-L1 combined positive score (CPS) than non-responders. The frequency of natural killer cells was associated with nivolumab response in patients with prior cetuximab use, but not in cetuximab-naïve status. Age-stratified analysis showed nivolumab response was linked to high CPS and lymphoid-inflamed profiles in patients aged ≥ 65. In contrast, lower NLR in peripheral blood counts was associated with response in patients aged < 65. Notably, TP53 mutation-positive group had lower CPS and T cell densities, suggesting an immune-excluded microenvironment. Patients with altered tumor suppressor gene pathways, including TP53, CDKN2A, and SMAD4 mutations, had lower CPS, higher smoking index, and were associated with poor responses. CONCLUSION: Nivolumab treatment efficacy in HNSCC is influenced by a combination of clinical factors, age, prior treatment, immune environmental characteristics, and gene mutation profiles.

DOI： 10.3389/fimmu.2024.1390873

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BACKGROUND: Our previous research showed that a high rate of secondary carcinogenesis is observed during follow-up after transoral surgery in patients with early-stage laryngeal, oropharyngeal, and hypopharyngeal cancers. We speculate that the contributing factors are alcohol drinking, smoking, and aging; however, we could not provide clear evidence. In this study, we aimed to identify the risk factors for secondary carcinogenesis in patients with these cancers, particularly factors associated with drinking and/or smoking. METHODS: The medical records of all-stage laryngeal, oropharyngeal, and hypopharyngeal cancer patients who had undergone definitive treatment were retrospectively analyzed. Assessments included visual and endoscopic observations of the primary site, enhanced cervical CT or US of the primary site and regional lymph nodes, PET-CT, and enhanced whole-body CT. Clinical characteristics were compared in patients with and without secondary carcinogenesis and in patients with hypopharyngeal cancer and patients with other cancers. RESULTS: Hypopharyngeal cancer was an independent risk factor for secondary cancer. The 5-year incidence rate of secondary cancer was 25.5%, 28.6%, and 41.2% in laryngeal, oropharyngeal, and hypopharyngeal cancers, respectively. Radiotherapy was defined as an independent risk factor in hypopharyngeal cancer patients with secondary cancers. No direct correlation was found between secondary carcinogenesis and alcohol consumption, smoking, or aging. CONCLUSIONS: Patients with hypopharyngeal cancer require close follow-up as they are at high risk of developing secondary cancer, possibly because out-of-field radiation exposure may induce systemic secondary carcinogenesis in hypopharyngeal cancer patients with genetic abnormality induced by alcohol consumption.

DOI： 10.1007/s10147-023-02433-8

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Transoral robotic surgery (TORS), introduced by Weinstein et al. in 2005, has been widely adopted as a minimally invasive procedure, particularly for the treatment of patients with early stage oropharyngeal cancer. TORS is typically performed using the da Vinci Surgical System, similar to robot-assisted surgeries for other malignancies. The main difference between TORS and these other robot-assisted surgeries is that it is performed through the natural orifice of the mouth, which limits the surgical working space, and that it progresses from the lumen of the pharynx to the deeper tissues. The advantages of TORS are mainly due to the benefits of using the da Vinci Surgical System, such as three-dimensional high-definition images, magnification, multiple forceps articulation, tremor-stabilization function and motion scale function. To date, many big data and meta-analyses have shown that TORS is superior to conventional surgeries, such as open surgery, in terms of oncological outcomes, post-operative functionality and quality of life. In Japan, TORS is expected to spread across the country, as it has been covered by health insurance since April 2022. This review highlights the procedures of TORS, its unique aspects, its unparalleled advantages as a minimally invasive surgery for treating laryngeal and pharyngeal cancers, and its current status in Japan.

DOI： 10.1093/jjco/hyad168

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Language：Japanese   Publisher：(株)全日本病院出版会  

咽喉頭癌に対する低侵襲手術である経口的切除術の一つにtransoral robotic surgery(TORS;経口的ロボット支援手術)がある.米国を中心に広く行われており,その有用性と安全性が多く報告されている.本邦でも2022年4月に咽喉頭癌に対するTORSが保険診療の適用となり,今後急速に普及していくことが予想される.TORSに対して現在薬事承認されているda Vinciサージカルシステムは三次元ハイビジョン画像,拡大視,鉗子の多関節機能,手振れ防止機能,モーションスケール機能といった特徴を有し,従来の経口的切除の技術的欠点を補うことが可能である.一方で,鉗子を介した触覚はなく,豊富な視覚情報で補う必要がある.そのため,TORSでは良好な術野展開と術野に出血がない,クリーンな状態保持が重要である.本稿ではこれらの点を含めたTORSの手術手技の実際と,そのコツについて述べる.(著者抄録)

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BACKGROUND: Total pharyngolaryngectomy (TPL) is standard treatment for hypopharyngeal cancer. However, extensive thyroidectomy and paratracheal nodal dissection (PTND) can cause hypoparathyroidism. We sought to determine the optimum extent of resection. METHODS: We analyzed the clinicopathological information of 161 pyriform sinus cancer patients undergoing TPL from 25 Japanese institutions. Rates of recurrence and risk factors for hypoparathyroidism, as well as incidence of pathological contralateral level VI nodal metastasis and stomal recurrence, were investigated. RESULTS: The extent of thyroidectomy and nodal dissection were not independent risk factors for recurrence. Incidences of contralateral level VI nodal involvement and stomal recurrence were 1.8% and 1.2%, respectively. Patients undergoing hemithyroidectomy/ipsilateral PTND did not develop stomal recurrence and had the lowest incidence of hypoparathyroidism. Prognosis in patients without tracheostomy prior to hemithyroidectomy/ipsilateral PTND was comparable to that with more extensive resections. CONCLUSIONS: Hemithyroidectomy/ipsilateral PTND may be sufficient for pyriform sinus cancer cases without tracheostomy.

DOI： 10.1002/hed.27572

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Language：Japanese   Publisher：日本唾液腺学会  

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: The aim of this study is to assess the impact of lymph node ratio (LNR) and number of positive lymph nodes (NPLN) on mortality and recurrence rates in patients with laryngeal squamous cell carcinoma. MATERIALS AND METHODS: We conducted a retrospective multicenter international study involving 24 Otorhinolaryngology-Head and Neck Surgery divisions. Disease-specific survival (DSS) and disease-free survival (DFS) were evaluated as the main outcomes. The curves for DSS and DFS according to NPLN and LNR were analyzed to identify significant variations and establish specific cut-off values. RESULTS: 2507 patients met the inclusion criteria. DSS and DFS were significantly different in the groups of patients stratified according to LNR and NPLN. The 5-year DSS and DFS based on LNR and NPLN demonstrated an improved ability to stratify patients when compared to pN staging. CONCLUSION: Our data demonstrate the potential prognostic value of NPLN and LNR in laryngeal squamous cell carcinoma.

DOI： 10.1002/hed.27471

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND/AIM: This study aimed to identify key molecules associated with the survival of patients with hypopharyngeal squamous cell carcinoma (HpSCC) by combining in silico and in vitro analyses. MATERIALS AND METHODS: Differentially expressed genes (DEGs) were screened using the Gene Expression Omnibus database. For DEGs, we performed functional enrichment and protein-protein interaction network analyses to identify potential biological functions and hub genes. Functional analysis of HpSCC cell lines verified the critical roles of the hub genes. RESULTS: DEGs were associated with the extracellular matrix. Among the hub genes, high expression of prolyl 4-hydroxylase subunit alpha 1 (P4HA1) was significantly associated with shorter survival. In addition, P4HA1 knockdown inhibited cell migration and colonization. Suppression of cell proliferation was demonstrated using P4HA1-selective inhibitors. CONCLUSION: P4HA1 may be a useful therapeutic target for the treatment of HpSCC.

DOI： 10.21873/anticanres.16424

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DOI： 10.21037/tcr-23-48

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: We previously established a patient-derived xenograft (PDX) model, patient-derived organoids (PDOs), and PDX-derived organoids (PDXOs) for salivary duct carcinoma (SDC). Using these models, this study examined the therapeutic effect of human epidermal growth factor receptor 2 (HER2) blockade on HER2-positive SDC. METHODS: The therapeutic effect of lapatinib was assessed in SDC PDXOs with regards to cell growth, receptor/downstream signaling molecule expression, phosphorylation levels, and apoptosis. Effect of lapatinib treatment was evaluated in vivo in SDC PDX mice. RESULTS: The siRNA knockdown of HER2 and lapatinib suppressed cell proliferation in SDC PDXOs. Lapatinib inhibited the phosphorylation of HER2 and its downstream targets, and induced apoptosis in SDC PDXOs. Lapatinib also significantly reduced tumor volumes compared with that of the control in SDC PDX mice. CONCLUSION: For the first time, we demonstrated the efficacy of anti-HER2 therapy in HER2-positive SDC using preclinical models of SDC PDX and PDXO.

DOI： 10.1002/hed.27395

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Language：Japanese   Publisher：(一社)日本頭頸部癌学会  

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Language：Japanese   Publisher：日本外科系連合学会  

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科頭頸部外科学会  

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科頭頸部外科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Research Square Platform LLC  

Abstract

Purpose: Salivary gland carcinoma (SGC) has poor prognosis depending on the histological subtype. However, due to the scarcity of preclinical experimental models, its molecular biology remains largely unknown, hampering the development of new treatment modalities for patients with these malignancies. The aim of this study is to generate human SGC experimental models for multiple histological subtypes using patient-derived xenograft (PDX) and organoid culture techniques. Methods: Tumor specimens from surgically resected SGC were proceeded for the preparation of PDX and patient-derived organoid (PDO). Specimens from SGC PDX were also proceeded for PDX-derived organoid (PDXO). in vivo tumorigenicity was assessed by orthotopic transplantation of SGC organoids. The pathological characteristics of each model were compared to those of the original tumor by Immunohistochemistry analysis. The genetic traits of PDO samples were analyzed by RNA-seq. Results: A series of SGC PDOs, PDX and PDXO models using human SGC tumor section for salivary duct carcinoma, mucoepidermoid carcinoma, and myoepithelial carcinoma were successfully generated. Through passaging, each model was confirmed to almost maintain the pathological characteristics of the original tumor and the genetic traits including transcription profiles, genomic variation and the presence of fusion genes of corresponding histological subtypes. Conclusion: We here described success in the generation of in vitro and in vivo SGC models of multiple histological subtypes using organoid culture and PDX, recapitulating the histological and genetical characteristics of original tumor. Thus, our experimental models of SGC could be a powerful resource for the development of novel therapeutic agents and investigating the molecular biology of these malignancies.

DOI： 10.1007/s13402-022-00758-6

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Other Link： https://www.researchsquare.com/article/rs-1621957/v1.html

Language：Japanese   Publisher：耳鼻と臨床会  

症例は73歳、男性。嗄声を主訴に受診した。左声帯白板症の経過観察中、初診から13ヵ月後に右声帯前方にポリープ様腫瘤が出現し、全身麻酔下での切除生検時の病理所見と術後の画像診断で紡錘細胞癌(T1aN0M0)と診断した。切除断端が陰性であったため、追加治療は施行しない方針とした。治療後1年6ヵ月経過し、再発なく経過している。紡錘細胞癌は扁平上皮癌と紡錘形細胞の2相性細胞で構成されるものであり、扁平上皮癌の亜型とされている。頭頸部領域では発生部位は喉頭が最多であるが、その発生頻度は喉頭悪性腫瘍の1%程度とまれである。喉頭紡錘細胞癌はポリープ様,外向性発育を示すことが特徴であり、良性病変との鑑別が重要である。治療は手術を施行されることが多いが、症例数が少ないことから放射線治療や薬物治療のエビデンスが乏しく、治療標的を含む分子生物学的な特徴の解明が必要である。(著者抄録)

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Language：Japanese   Publisher：(株)東京医学社  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J01814&link_issn=&doc_id=20230217060016&doc_link_id=%2Faq9johne%2F2023%2F003903%2F016%2F0289-0292%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Faq9johne%2F2023%2F003903%2F016%2F0289-0292%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(一社)日本耳鼻咽喉科頭頸部外科学会  

局所進行頭頸部扁平上皮癌の術後再発高リスク患者を対象としたJCOG1008試験において,weeklyシスプラチンのtri-weeklyシスプラチンに対する全生存期間の非劣性が示された.Weeklyシスプラチンの導入にあたり,治療の標準化と効率化,有害事象対策の強化,患者の理解の促進を図るためクリニカルパスを作成し,運用した.1泊2日を基本とする短期入院でも十分な輸液ができるよう配慮した.当科でtri-weeklyシスプラチン併用放射線治療を受けた患者とweeklyシスプラチン併用放射線治療を受けた患者を後ろ向きに比較したところ,シスプラチン総投与量に有意差は認められなかったが,weeklyシスプラチン群では入院泊数が有意に短く,1泊あたりの診療群分類包括評価(DPC)点数が有意に高かった.Weeklyシスプラチン併用放射線治療の導入は,安全性と治療強度を損なうことなく入院期間の短縮と入院単価の増加が得られる可能性があり,患者,医療者,病院それぞれにとってメリットがある方法であると考えられた.また,クリニカルパスについてはバリアンスに関するデータを蓄積および解析し,改良を続ける必要がある.(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J07551&link_issn=&doc_id=20230301320007&doc_link_id=%2Fdz0tokei%2F2023%2F012602%2F007%2F0121-0127%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdz0tokei%2F2023%2F012602%2F007%2F0121-0127%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND/AIM: The prognosis of recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) is poor, although immune checkpoint inhibitors (ICIs), such as nivolumab, have been shown to prolong survival. We investigated the factors that predict the efficacy of nivolumab when selecting an appropriate treatment strategy for patients with R/M SCCHN. PATIENTS AND METHODS: Forty-four Japanese patients with R/M SCCHN treated with nivolumab between May 2017 and October 2021 were analyzed. The primary endpoint of the study was overall survival (OS). We defined pre-treatment tumor size (PTS) as the sum of the size of all measurable lesions, and tumor growth rate (TGR) as the total growth rate of the largest tumor diameter on CT scans taken to determine treatment response, divided by the interval between CT scans. Receiver operating characteristic (ROC) curves were used to identify the cutoff points of PTS and TGR for OS. Cox proportional hazards regression analysis was performed to examine the relationships between various factors, including patient characteristics, PTS, and TGR, as well as treatment outcomes. RESULTS: In multivariate analysis, Eastern Cooperative Oncology Group (ECOG) performance status (PS) score ≥1, progressive disease (PD) as best overall response (BOR), and TGR >0.60%/day were independent risk factors for poor OS in patients with R/M-SCCHN. CONCLUSION: Higher TGR, poor PS, and PD as BOR may be prognostic factors in patients with R/M SCCHN.

DOI： 10.21873/invivo.13378

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Language：Japanese   Publisher：日本喉頭科学会  

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Language：Japanese   Publisher：日本喉頭科学会  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J02852&link_issn=&doc_id=20230111160004&doc_link_id=10.5426%2Flarynx.34.65&url=https%3A%2F%2Fdoi.org%2F10.5426%2Flarynx.34.65&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：日本唾液腺学会  

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Language：Japanese   Publisher：日本唾液腺学会  

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Language：Japanese   Publisher：(有)科学評論社  

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Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: To evaluate the feasibility of narrow-field supracricoid partial laryngectomy with cricohyoidoepiglottopexy (NF-SCPL-CHEP). METHODS: Between 2019 and 2020, five patients with glottic cancers underwent NF-SCPL-CHEP. The mean durations of surgical drains, tracheostomy canula, and nasogastric tube use were evaluated. Length of stay following NF-SCPL-CHEP was compared with that of our open SCPL historical controls. A case summary is provided for the first patients, with detailed information about postoperative management and function. RESULTS: All five patients achieved uneventful postoperative recoveries without major complications. The average time for surgical drains, tracheostomy canula, and nasogastric tube use were 2, 15, and 46 days, respectively. The mean overall hospitalization period was 36 days for NF-SCPL-CHEP patients. The mean period of hospitalization based on our early experiences between 1997 and 2005 with classical open SCPL was 72 days. All patients were fully functional and local recurrences or distant metastases were not encountered during a mean observation period of 39 months. CONCLUSIONS: NF-SCPL-CHEP with 6 cm cervical access appeared technically feasible and oncologically sound in this initial clinical experience. An extra 2 cm incision, which enabled lateral neck dissection, was not felt to detract from the overall minimally invasive basis of NF-SCPL-CHEP. The clinical results were encouraging with limited complications and predictable postoperative recovery. The length of stay for patients undergoing NF-SCPL was half that of open SCPL historical controls. Less damages to local circulation may associate with the positive influences. Further study with a large patient sample across multiple institutions are needed to carefully evaluate long-term functional and oncological outcomes.

DOI： 10.1016/j.anl.2022.09.011

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：English   Publisher：(一社)日本癌学会  

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Language：English   Publisher：(一社)日本癌学会  

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BACKGROUND/AIM: This Japanese single-center retrospective cohort study aimed to evaluate the real-world therapeutic outcomes of pembrolizumab or pembrolizumab plus chemotherapy (pembrolizumab regimen) as first-line therapy for patients with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). PATIENTS AND METHODS: Thirty-two Japanese patients with R/M SCCHN treated with the pembrolizumab regimen between January 2020 and January 2022 were analyzed. The primary endpoint of the study was overall survival. RESULTS: The median follow-up duration was 9.8 months (range=1.6-25.1 months). Fourteen patients received pembrolizumab alone, whereas the others received pembrolizumab with chemotherapy. The 1-year overall and progression-free survival rates were 64.5% (95% CI=38.9-81.6) and 54.9% (95% CI=33.9-71.8), respectively. The objective response rate was 56.2%. The Kaplan-Meier analysis showed that patients with favorable objective responses and an Eastern Cooperative Oncology Group performance status of 0 had longer survival. Immune-related adverse events (irAEs) occurred in 16 out of 32 patients (50.0%) during treatment; however, there were no irAEs greater than grade 4. CONCLUSION: The observed therapeutic efficacy and safety of pembrolizumab in real-world clinical practice was consistent with the data of the KEYNOTE-048 trial.

DOI： 10.21873/anticanres.15948

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Many types of cancer have metabolic alterations with increased glycolysis. Identification of alternative sweeteners that do not fuel cancer is a novel approach to cancer control. The present study aimed to investigate the effects of xylitol on tumor growth and survival of mice bearing orthotopic xenograft of tongue cancers. The results showed that partial substitution of glucose with xylitol (glucose 0.35 g plus xylitol 2.06 g/kg body weight) non-significantly reduced tumor volume, and significantly prolonged the median survival time from 19 days in the control to 30.5 days in the xylitol group. Immunohistochemical data of the tongue tissue shows significantly lower intense-to-mild staining ratios of the proliferation marker Ki-67 in the xylitol than those of the control group (p = 0.04). Furthermore, the xylitol substitution significantly reduced the expression of the rate-limiting glycolytic enzyme, phosphofructokinase-1 (PFK-1) (p = 0.03), and showed a non-significant inhibition of PFK activity. In summary, partial substitution of glucose with xylitol at the equivalent dose to human household use of 10 g/day slows down tumor proliferation and prolongs survival of mice bearing an orthotopic oral cancer xenograft, possibly through glycolytic inhibition, with minimal adverse events. The insight warrants clinical studies to confirm xylitol as a candidate sweetener in food products for cancer survivors.

DOI： 10.3390/nu14102023

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Salivary gland malignancies are rare neoplasms that have a broad histological spectrum and a variety of biologic behaviors. Salivary gland malignancies are known as chemo-resistant tumors, which render optimal treatment challenging. This review summarizes the role of systemic therapy for salivary gland malignancies. To date, the advantage of adding concurrent chemotherapy has remained undefined for both postoperative and inoperable locally advanced salivary gland malignancy patients undergoing radiotherapy. For recurrent/metastatic disease, local and/or systemic treatment options should be discussed in a multidisciplinary setting with consideration to both patient needs and tumor factors. For symptomatic patients or those who may compromise organ function, palliative systemic therapy can be a reasonable option based on the results of phase II studies. Platinum combination regimens as first-line therapy have been widely accepted. Personalized therapies have become established options, particularly for androgen receptor-positive, HER2-positive and NTRK fusion-positive salivary gland malignancies (i.e. androgen receptor and HER2 in salivary duct carcinoma and NTRK3 in secretory carcinoma). For patients with adenoid cystic carcinoma, multi-targeted tyrosine kinase inhibitors have also been developed. Anti-PD1 checkpoint inhibitors have shown limited activity to date. Investigation of active systemic treatments for salivary gland malignancy remains a significant unmet need. Future directions might include a more comprehensive genomic screening approach (usually next-generation sequencing-based) and combination strategies using immune checkpoint inhibitors. These are rare malignancies that require ongoing effort in the conduct of high-quality clinical trials.

DOI： 10.1093/jjco/hyac008

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It was not until around 2000 that human papillomavirus-related oropharyngeal carcinoma was recognized as carcinoma with clinical presentations different from nonrelated head and neck carcinoma. Twenty years after and with the revision of the tumor-node-metastasis classification in 2017, various clinical trials focused on human papillomavirus-related oropharyngeal carcinoma to improve the prognosis and quality of life of patients with this disease. However, the incidence of human papillomavirus-related cancers is increasing, which is expected to be particularly prominent in Japan, where human papillomavirus vaccination is not widely available. In this review, we describe the current status of clinical trials (mainly focused on initial surgery and radiation dose reduction) for, primary and secondary prevention of, and the present status of human papillomavirus-related oropharyngeal carcinoma in Japan.

DOI： 10.1093/jjco/hyac049

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BACKGROUND: We previously identified hypopharyngeal cancer as an independent risk factor for the incidence of newly diagnosed secondary cancers after the treatment of early-stage laryngeal, oropharyngeal, and hypopharyngeal cancers. We subsequently used a different patient cohort to validate the usefulness of this factor during the follow-up period in these patients. METHODS: Patients who underwent transoral surgery (TOS) as a definitive treatment between April 1, 2016, and September 30, 2020, were included. The incidence of secondary cancer was evaluated in hypopharyngeal and other cancers. Overall survival (OS), recurrence-free survival (RFS), and disease-free survival (DFS) outcomes were evaluated. Statistical analyses based on the risk factors were also performed. RESULTS: Incidence of new secondary cancer was 30% in hypopharyngeal cancer patients as compared to 11% in other cancer patients, and the risk was 3.60-fold (95% confidence interval 1.07-12.10) higher after definitive treatment for initial head and neck cancers. The 3-year OS, RFS, and DFS rates were 98%, 86%, and 67%, respectively. CONCLUSIONS: Among patients with early-stage laryngeal, oropharyngeal, and hypopharyngeal squamous cell carcinoma, who were initially treated with TOS, hypopharyngeal cancer patients had a higher risk of newly diagnosed secondary cancers as observed during the follow-up period.

DOI： 10.1007/s10147-021-02080-x

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BACKGROUND: We have previously reported the effectiveness and safety of nivolumab in patients with head and neck cancer (HNC) in real-world clinical practice in Japan. Here, we report long-term outcomes from this study in the overall population and subgroups stratified by subsequent chemotherapy. METHODS: In this multicenter, retrospective observational study, Japanese patients with recurrent or metastatic (R/M) HNC receiving nivolumab were followed up for 2 years. Effectiveness endpoints included overall survival (OS), OS rate, progression-free survival (PFS), and PFS rate. Safety endpoints included the incidence of immune-related adverse events (irAEs). RESULTS: Overall, 256 patients received a median of 6.0 doses (range: 1-52) of nivolumab over a median duration of 72.5 days (range: 1-736). Median OS was 9.5 months [95% confidence interval (CI) 8.2-12.0] and median PFS was 2.1 months (95% CI 1.8-2.7). A significant difference between 2-year survivors (n = 62) and non-2-year survivors was observed by median age (P = 0.0227) and ECOG PS (P = 0.0001). Of 95 patients who received subsequent chemotherapy, 54.7% received paclitaxel ± cetuximab. The median OS and PFS from the start of paclitaxel ± cetuximab were 6.9 months (95% CI 5.9-11.9) and 3.5 months (95% CI 2.3-5.5), respectively. IrAEs were reported in 17.2% of patients. Endocrine (7.0%) and lung (4.3%) disorders were the most common irAEs; kidney disorder (n = 1) was newly identified in this follow-up analysis. CONCLUSIONS: Results demonstrated the long-term effectiveness of nivolumab and potential effectiveness of subsequent chemotherapy in patients with R/M HNC in the real-world setting. Safety was consistent with that over the 1-year follow-up.

DOI： 10.1007/s10147-021-02047-y

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BACKGROUND: We had previously identified the following risk factors for insufficient control of early T-stage head and neck cancer by transoral surgery (TOS): (1) tumor thickness > 7 mm on enhanced computed tomography (CT), and (2) poor differentiation in pathological examination. We subsequently used a different patient cohort to validate the usefulness of these factors in determining the need for adaptation of TOS. STUDY SETTING: A prospective observational study METHODS: Patients who received TOS as a definitive treatment between April 1, 2016 and September 30, 2020 were included. Primary control rates (by single TOS and TOS alone) in relation to the above-mentioned risk factors were calculated. Overall (O), recurrence-free (RF), and disease-free (DF) survival (S) outcomes were evaluated. A combination analysis based on the number of risk factors was also performed. RESULTS: Patients with tumor thickness > 7 mm had a 2.88-fold [95% confidence interval (CI) 1.01-8.51] higher risk of incomplete primary resection by single TOS, while patients who showed poor differentiation on pathological assessments had a 13.14-fold (95% CI 3.66-47.14) higher risk of insufficient primary control by TOS alone. The 3 year OS, RFS, and DFS rates were 99%, 83%, and 63%, respectively. Patients with both risk factors had a 93.00-fold (95% CI 4.99-1732.00) higher risk of incomplete primary control by TOS alone. CONCLUSIONS: Among patients with early-stage laryngeal, oropharyngeal, and hypopharyngeal squamous cell carcinoma, primary control by TOS alone may not be achieved in patients with both risk factors, that is, tumor thickness > 7 mm as measured by enhanced CT and poor differentiation on pathological examination.

DOI： 10.1007/s10147-021-01992-y

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Language：English   Publisher：(一社)日本癌治療学会  

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Elevated angiotensin-converting enzyme 2 (ACE2) expression in organs that are potential targets of severe acute respiratory syndrome coronavirus 2 may increase the risk of coronavirus disease 2019 (COVID-19) infection. Previous reports show that ACE2 alter its tissue-specific expression patterns under various pathological conditions, including renal diseases. Here, we examined changes in pulmonary ACE2 expression in two mouse chronic kidney disease (CKD) models: adenine-induced (adenine mice) and aristolochic acid-induced (AA mice). We also investigated changes in pulmonary ACE2 expression due to renin-angiotensin system (RAS) blocker (olmesartan) treatment in these mice. Adenine mice showed significant renal functional decline and elevated blood pressure, compared with controls. AA mice also showed significant renal functional decline, compared with vehicles; blood pressure did not differ between groups. Renal ACE2 expression was significantly reduced in adenine mice and AA mice; pulmonary expression was unaffected. Olmesartan attenuated urinary albumin excretion in adenine mice, but did not affect renal or pulmonary ACE2 expression levels. The results suggest that the risk of COVID-19 infection may not be elevated in patients with CKD because of their stable pulmonary ACE2 expression. Moreover, RAS blockers can be used safely in treatment of COVID-19 patients with CKD.

DOI： 10.1038/s41598-021-96294-8

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Language：Japanese   Publisher：(株)癌と化学療法社  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J00296&link_issn=&doc_id=20210720430008&doc_link_id=issn%3D0385-0684%26volume%3D48%26issue%3D7%26spage%3D900&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0385-0684%26volume%3D48%26issue%3D7%26spage%3D900&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

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BACKGROUND/AIM: We evaluated the impact of FosL1, a member of the activated protein-1 family, on the pathways leading to regional metastasis of head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: We examined the influence of small interfering RNA (siRNA) and short heparin RNA (shRNA) mediated knockdown of FosL1 on cell migration, invasion, and proliferation in vitro as well as on regional metastasis in vivo. The prognostic significance of FosL1 was also analyzed using the Kaplan- Meier plotter using data from an HNSCC patient database. RESULTS: Down-regulation of FosL1 inhibited cell migration, invasion, and proliferation in vitro, decreased the incidence of regional metastases, and prolonged the survival of mice in vivo. We also determined that HNSCC patients with higher expression levels of FosL1 had a significantly shorter survival time than those with low expression of FosL1. CONCLUSION: FosL1 plays a crucial role in promoting cell migration, invasion, and proliferation in HNSCC.

DOI： 10.21873/anticanres.15119

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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BACKGROUND: To examine the effect of prior use of cetuximab and neck dissection on the effectiveness of nivolumab, we conducted a large-scale subgroup analysis in Japanese patients with recurrent/metastatic head and neck cancer. METHODS: Data on the effectiveness of nivolumab were extracted from patient medical records. All patients were analyzed for effectiveness by prior cetuximab use. In the analyses for prior neck dissection, only patients with locally advanced disease were included. RESULTS: Of 256 patients analyzed, 155 had received prior cetuximab. Nineteen of 50 patients with local recurrence underwent neck dissection. The objective response rate was 14.7 vs 17.2% (p = 0.6116), median progression-free survival was 2.0 vs 3.1 months (p = 0.0261), and median overall survival was 8.4 vs 12 months (p = 0.0548) with vs without prior cetuximab use, respectively. The objective response rate was 23.1 vs 25.9% (p = 0.8455), median progression-free survival was 1.8 vs 3.0 months (p = 0.6650), and median overall survival was 9.1 vs 9.9 months (p = 0.5289) with vs without neck dissection, respectively. CONCLUSIONS: These findings support the use of nivolumab for patients with recurrent/metastatic head and neck cancer regardless of prior cetuximab use or neck dissection history. TRIAL REGISTRATION NUMBER: UMIN-CTR (UMIN000032600), Clinicaltrials.gov (NCT03569436).

DOI： 10.1007/s10147-021-01900-4

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Language：Japanese   Publisher：(一社)日本頭頸部癌学会  

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Language：Japanese   Publisher：(一社)日本頭頸部癌学会  

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DOI： 10.1007/s10147-021-01879-y

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Language：Japanese   Publisher：(株)東京医学社  

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Language：Japanese   Publisher：(一社)日本頭頸部癌学会  

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The incidence of oropharyngeal cancer (OPC) is increasing remarkably among all head and neck cancers, mainly due to its association with the human papillomavirus (HPV). Most HPVs are eliminated by the host's immune system; however, because HPV has developed an effective immune evasion mechanism to complete its replication cycle, a small number of HPVs are not eliminated, leading to persistent infection. Moreover, during the oncogenic process, the extrachromosomal HPV genome often becomes integrated into the host genome. Integration involves the induction and high expression of E6 and E7, leading to cell cycle activation and increased genomic instability in the host. Therefore, integration is an important event in oncogenesis, although the associated mechanism remains unclear, especially in HPV-OPC. In this review, we summarize the current knowledge on HPV-mediated carcinogenesis, with special emphasis on immune evasion and integration mechanisms, which are crucial for oncogenesis.

DOI： 10.3390/microorganisms9050891

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BACKGROUND: To fill the data gap between clinical trials and real-world settings, this study assessed the overall effectiveness and safety of nivolumab in patients with head and neck cancer (HNC) during Japanese real-world clinical practice. METHODS: This was a multicenter, retrospective study in Japanese patients with recurrent or metastatic HNC who received nivolumab for the first time between July and December 2017. Data on the clinical use, effectiveness, and safety of nivolumab were extracted from patient medical records. RESULTS: Overall, 256 patients were enrolled in this study. The median duration of nivolumab treatment was 72.5 days, with patients receiving a median of 6.0 (range 1-27) doses. Median overall survival (OS) was 9.5 (95% confidence interval [CI] 8.2-12.0) months and the estimated 12-month OS rate was 43.2%. The objective response rate (ORR) was 15.7% overall and 21.1%, 7.1%, and 13.6% in patients with primary nasopharynx, maxillary sinus, and salivary gland tumors, respectively, who had been excluded from CheckMate 141. Grade ≥ 3 immune-related adverse events occurred in 5.9% of patients. No new safety signals were identified compared with adverse events noted in CheckMate 141. CONCLUSIONS: The effectiveness and safety of nivolumab in real-world clinical practice are consistent with data from the CheckMate 141 clinical trial. Therapeutic response was also observed in the groups of patients excluded from CheckMate 141. TRIAL REGISTRATION NUMBER: UMIN-CTR (UMIN000032600), Clinicaltrials.gov (NCT03569436).

DOI： 10.1007/s10147-020-01829-0

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: The aim of this multicenter retrospective cohort study was to compare efficacy and subsequent postoperative treatment between transoral robotic surgery (TORS) and any non-robotic transoral surgery in Japanese patients with early oropharyngeal squamous cell carcinoma (OPSCC), hypopharyngeal SCC (HPSCC), or supraglottic SCC (SGSCC). MATERIALS AND METHODS: Clinical information and surgical outcomes were compared between patients with early-stage OPSCC, HPSCC, and SGSCC who underwent TORS (TORS cohort) and those who underwent non-robotic transoral surgery, including transoral videolaryngoscopic surgery (TOVS), endoscopic laryngopharyngeal surgery (ELPS), and transoral laser microsurgery (TLM) (non-robotic cohort). The data of the Head and Neck Cancer Registry of Japan (registry cohort) were used to validate the comparison. The main outcomes were the presence of positive margins under pathology and the requirement for postoperative therapy, including radiotherapy or chemoradiotherapy. RESULTS: Sixty-eight patients in the TORS cohort, 236 patients in the non-robotic cohort, and 1,228 patients in the registry cohort were eligible for this study. Patients in the TORS cohort were more likely to have oropharyngeal tumor disease and T2/3 disease than those in the other cohorts (P<0.001 and P=0.052, respectively). The TORS cohort had significantly fewer patients with positive surgical margins than the non-robotic cohort (P=0.018), as well as fewer patients who underwent postoperative treatment, although the difference was not significant (P=0.069). In the subgroup analysis of patients with OPSCC, a total of 57 patients in the TORS cohort, 73 in the non-robotic cohort, and 171 in the registry cohort were eligible for the present study. Patients with OPSCC who underwent TORS were more likely to have lateral wall lesions than those in the other cohorts (P=0.003). The TORS cohort also had significantly fewer patients with positive surgical margins than the non-robotic cohort (P=0.026), and no patients in the TORS cohort underwent any postoperative treatment for OPSCC, although the difference was not significant (P=0.177). CONCLUSIONS: Our results suggest that TORS leads to fewer positive surgical margins than non-robotic transoral surgeries. The clinical significance of TORS may be further validated through the results of all-case surveillance for patients who underwent TORS running in Japan in the future.

DOI： 10.1016/j.anl.2021.01.024

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In order to maximize the benefit of induction chemotherapy, practice based on a comprehensive interpretation of a large number of clinical trials, as in this review, is essential. The standard treatment for locally advanced squamous cell carcinoma of the head and neck is surgery or chemoradiation. However, induction chemotherapy followed by (chemo) radiotherapy may be used in some circumstances. Although many clinical trials of induction chemotherapy have been conducted, a rationale other than to preserve the larynx is still controversial. Selection of this modality should therefore be made with care. The current standard regimen for induction chemotherapy is docetaxel, cisplatin and 5-FU, but concerns remain about toxicity, cost and the duration of treatment. Regarding treatment after induction chemotherapy, it is also unclear whether radiation alone or chemoradiation is the better option. Furthermore, there is no answer as to what drugs should be used in combination with radiation therapy after induction chemotherapy. Several new induction chemotherapy treatment developments are currently underway, and future developments are expected. This review article summarizes the current position of induction chemotherapy for head and neck squamous cell carcinoma, based on the evidence produced to date, and discusses the future prospects for this treatment.

DOI： 10.1093/jjco/hyaa220

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BACKGROUND/AIM: We previously presented the real-world treatment outcomes of the EXTREME regimen as a first-line therapy for recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). This study aimed to evaluate the prognostic significance of pretreatment inflammatory biomarkers in patients with R/M-SCCHN treated with the EXTREME regimen as first-line therapy as a supplementary study of our previous retrospective cohort study. PATIENTS AND METHODS: The treatment outcomes of 100 patients with R/M-SCCHN treated with the EXTREME regimen as first-line therapy were compared according to patient characteristics and pretreatment inflammatory biomarkers using a Cox proportional hazards regression model. Survival was evaluated using the Kaplan-Meier method. RESULTS: In multivariate analysis, a lymphocyte-to-monocyte ratio (LMR) of <1.944 and Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1 were independent risk factors for poor overall and progression-free survival. Furthermore, we found that the PS-LMR score based on the ECOG PS and LMR could stratify patients to extract the poor prognostic characteristics of R/M-SCCHN patients treated with the EXTREME regimen as first-line therapy. CONCLUSION: Further evaluation is warranted to study the reliability and applicability of this novel scoring system in predicting the prognosis of R/M-SCCHN patients in the future.

DOI： 10.21873/cdp.10047

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As the laryngopharynx is closely related to swallowing, speech, and phonation, it is necessary to consider not only disease control but also a minimally invasive approach for the treatment of laryngopharyngeal cancer. Transoral surgery has been reported to be a minimally invasive method for treating these diseases. Transoral videolaryngoscopic surgery (TOVS) and endoscopic laryngo-pharyngeal surgery (ELPS) have been developed in Japan and recently emerged as treatments for patients with early stage pharyngeal and laryngeal cancers. However, securing an appropriate field of view and a narrow operating space during TOVS or ELPS are critical issues to be resolved for these surgeries. The clinical significance and safety of transoral robotic surgery (TORS) using the da Vinci Surgical System have been widely reported to provide surgeons with increased visualization and magnification, resulting in precise surgical margins and rapid functional recovery. In this context, a multi-institutional clinical study was conducted to evaluate the treatment outcomes of TORS for the treatment of laryngopharyngeal cancer in Japan, and the da Vinci Surgical System for oral robot-assisted surgery for these diseases was approved by the Pharmaceutical Affairs Agency in August 2018. This review provides an overview of the therapeutic effects of TOVS, ELPS, and TORS, with a particular focus on these therapeutic results in Japan.

DOI： 10.3389/fonc.2021.804933

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Language：Japanese   Publisher：日本喉頭科学会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J02852&link_issn=&doc_id=20210108280013&doc_link_id=10.5426%2Flarynx.32.151&url=https%3A%2F%2Fdoi.org%2F10.5426%2Flarynx.32.151&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：Japanese   Publisher：日本喉頭科学会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J02852&link_issn=&doc_id=20210108280007&doc_link_id=10.5426%2Flarynx.32.116&url=https%3A%2F%2Fdoi.org%2F10.5426%2Flarynx.32.116&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：English   Publisher：(一社)日本癌学会  

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Language：Japanese   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：(NPO)日本頭頸部外科学会  

咽喉頭がんにおける経口的ロボット支援手術に対するda Vinciサージカルシステムの追加薬事承認が2018年8月になされ,2019年4月より全国で経口的ロボット支援手術の導入が始まった。著者らの施設でも「頭頸部癌に対するda Vinciサージカルシステムを用いた経口的切除術」が院内の先進医療推進事業として採用され,頭頸部ロボット支援手術委員会が定めるトレーニングの修了後に咽喉頭がんに対する経口的ロボット支援手術を開始している。本稿では咽喉頭がん治療に対して保険未収載であるda Vinciサージカルシステムによる経口的ロボット支援手術の施設内導入について著者らの施設を1例に記す。(著者抄録)

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Language：English   Publisher：(一社)日本癌学会  

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Language：Japanese   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：(一社)日本癌治療学会  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

To generate a reliable preclinical model system exhibiting the molecular features of salivary adenoid cystic carcinoma (ACC) whose biology is still unclear due to the paucity of stable cell cultures. To develop new in vitro and in vivo models of ACC, the techniques of organoid culture and patient-derived tumor xenograft (PDX), which have attracted attention in other malignancies in recent years, were applied. Tumor specimens from surgically resected salivary ACC were proceeded for the preparation of PDX and organoid culture. The orthotopic transplantation of patient-derived or PDX-derived organoids was demonstrated into submandibular glands of NSG mice and those histology was evaluated. PDX-derived organoid cells were evaluated for the presence of MYB-mediated fusion genes and proceeded for in vitro drug sensitivity assay. Human ACC-derived organoids were successfully generated in three-dimensional culture and confirmed the ability of these cells to form tumors by orthotopic injection. Short-term organoid cell cultures from two individual ACC PDX tumors were also established that maintain the characteristic MYBL1 translocation and histological features of the original parent and PDX tumors. Finally, the establishment of drug sensitivity tests on these short-term cultured cells was confirmed using three different agents. This is the first to report an approach for the generation of human ACC-derived organoids as in vitro and in vivo cancer models, providing insights into understanding of the ACC biology and creating personalized therapy design for patients with ACC.

DOI： 10.1002/ijc.33315

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BACKGROUND: Our prospective study of patients with early T-stage head and neck cancer indicated a high incidence of newly diagnosed secondary malignancies during the follow-up period. We aimed to determine the incidence rate and risk factors of secondary malignancies in early-stage head and neck cancer patients. METHODS: We sub-analyzed the patient data of a previous study focusing on secondary cancer incidence. The endpoints were statistical analyses of risk factors and survival and incidence rates. RESULTS: The incidence rate of secondary cancer was 37%, the crude incidence of second primary cancers was 10.6 per 100 person-years, and the 5 year secondary cancer-free survival rate was 63%. The hypopharynx as the primary site was an independent significant predictive factor (odds ratio 3.96, 95% confidence interval 1.07-14.6, p = 0.039). CONCLUSIONS: Early stages of laryngeal, oropharyngeal, and hypopharyngeal cancer had a risk of secondary cancer, especially hypopharyngeal cancer. Attention to the secondary cancer has to be paid during the follow-up period after controlling the early-stage disease. These findings highlight the need for awareness of the incidence of secondary cancer in cases of early-stage primary head and neck cancer.

DOI： 10.1007/s10147-020-01779-7

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科学会  

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科頭頸部外科学会  

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科学会  

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科学会  

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科学会  

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Squamous cell carcinoma of the head and neck is characterized by an immunosuppressive environment and evades immune responses through multiple resistance mechanisms. A breakthrough in cancer immunotherapy employing immune checkpoint inhibitors has evolved into a number of clinical trials with antibodies against programmed cell death 1 (PD-1), its ligand PD-L1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) for patients with squamous cell carcinoma of the head and neck. CheckMate141 and KEYNOTE-048 were practice-changing randomized phase 3 trials for patients with platinum-refractory and platinum-sensitive recurrent or metastatic squamous cell carcinoma of the head and neck, respectively. Furthermore, many combination therapies using anti-CTLA-4 inhibitors, tyrosine kinase inhibitors and immune accelerators are currently under investigation. Thus, the treatment strategy of recurrent or metastatic squamous cell carcinoma of the head and neck is becoming more heterogeneous and complicated in the new era of individualized medicine. Ongoing trials are investigating immunotherapeutic approaches in the curative setting for locoregionally advanced disease. This review article summarizes knowledge of the role of the immune system in the development and progression of squamous cell carcinoma of the head and neck, and provides a comprehensive overview on the development of immunotherapeutic approaches in both recurrent/metastatic and locoregionally advanced diseases.

DOI： 10.1093/jjco/hyaa139

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BACKGROUND: Although the American Joint Committee on Cancer TNM classification has been amended to include human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) as an independent entity, to the authors' knowledge the optimized de-escalating treatment modality has not been established to date. METHODS: The authors conducted a retrospective, nationwide, observational study in patients with HPV-related OPSCC who were treated from 2011 to 2014 in Japan to determine the best treatment modality. RESULTS: A total of 688 patients who were newly diagnosed with HPV-related OPSCC who were treated with curative intent at 35 institutions and had coherent clinical information and follow-up data available were included in the current study. In patients with T1-T2N0 disease (79 patients), both the 3-year recurrence-free survival and overall survival (OS) rates were 100% in the group treated with radiotherapy (RT) as well as the group receiving concurrent chemoradiotherapy (CCRT). The 3-year OS rates were 94.4% (for patients with T1N0 disease) and 92.9% (for patients with T2N0 disease) among the patients treated with upfront surgery. In patients with stage I to stage II HPV-related OPSCC, the 5-year recurrence-free survival and OS rates were 91.4% and 92%, respectively, in the patients treated with CCRT with relatively high-dose cisplatin (≥160 mg/m2 ; 114 patients) and 74.3% and 69.5%, respectively, in the patients treated with low-dose cisplatin (<160 mg/m2 ; 17 patients). CONCLUSIONS: Despite it being a retrospective observational trial with a lack of information regarding toxicity and morbidity, the results of the current study demonstrated that patients with T1-T2N0 HPV-related OPSCC could be treated with RT alone because of the equivalent outcomes of RT and CCRT, and patients with stage I to stage II HPV-related OPSCC other than those with T1-T2N0 disease could be treated with CCRT with cisplatin at a dose of ≥160 mg/m2 .

DOI： 10.1002/cncr.33062

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Language：Japanese   Publisher：(一社)日本頭頸部癌学会  

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FLCN is a tumor suppressor gene which controls energy homeostasis through regulation of a variety of metabolic pathways including mitochondrial oxidative metabolism and autophagy. Birt-Hogg-Dubé (BHD) syndrome which is driven by germline alteration of the FLCN gene, predisposes patients to develop kidney cancer, cutaneous fibrofolliculomas, pulmonary cysts and less frequently, salivary gland tumors. Here, we report metabolic roles for FLCN in the salivary gland as well as their clinical relevance. Screening of salivary glands of BHD patients using ultrasonography demonstrated increased cyst formation in the salivary gland. Salivary gland tumors that developed in BHD patients exhibited an upregulated mTOR-S6R pathway as well as increased GPNMB expression, which are characteristics of FLCN-deficient cells. Salivary gland-targeted Flcn knockout mice developed cytoplasmic clear cell formation in ductal cells with increased mitochondrial biogenesis, upregulated mTOR-S6K pathway, upregulated TFE3-GPNMB axis and upregulated lipid metabolism. Proteomic and metabolite analysis using LC/MS and GC/MS revealed that Flcn inactivation in salivary gland triggers metabolic reprogramming towards the pentose phosphate pathway which consequently upregulates nucleotide synthesis and redox regulation, further supporting that Flcn controls metabolic homeostasis in salivary gland. These data uncover important roles for FLCN in salivary gland; metabolic reprogramming under FLCN deficiency might increase nucleotide production which may feed FLCN-deficient salivary gland cells to trigger tumor initiation and progression, providing mechanistic insight into salivary gland tumorigenesis as well as a foundation for development of novel therapeutics for salivary gland tumors.

DOI： 10.1016/j.bbrc.2019.11.184

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科学会  

嚥下機能評価法としての兵頭スコアの有用性の検証を行うとともに、臨床所見などほかの評価項目を含めた誤嚥の予測因子の検索を行った。2013年1月〜2016年7月に兵頭スコアを用いた嚥下内視鏡検査を施行した528症例を対象に、兵頭スコアによるスコアリングを行い、嚥下内視鏡検査時の誤嚥の有無を評価した。兵頭スコア4点以下は332例(62.9%)、5〜8点は153例(29.0%)、9点以上は43例(8.1%)、嚥下内視鏡検査の際に誤嚥を認めた症例数は133例(25.2%)であった。ROC解析により、誤嚥の有無における兵頭スコアのカットオフ値は6点と算出され、AUC 0.842、感度0.863、特異度0.654であった。誤嚥の有無との関連において、単変量解析では兵頭スコア>6点、年齢≧80歳、血清アルブミン値<3.3g/Dl、誤嚥性肺炎の既往歴あり、声帯麻痺あり、JCS≧1、PS≧3で有意差を認めた。多変量解析では、兵頭スコア>6点、誤嚥性肺炎の既往歴あり、声帯麻痺あり、PS≧3で有意差を認めた。

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J01099&link_issn=&doc_id=20200129320014&doc_link_id=%2Fdz0jibik%2F2020%2F012301%2F016%2F0085-0086%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdz0jibik%2F2020%2F012301%2F016%2F0085-0086%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND/AIM: This Japanese multiple-center retrospective study aimed to examine the real-world treatment outcomes of the EXTREME regimen as a first-line therapy for recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). PATIENTS AND METHODS: A total of 100 R/M SCCHN patients treated with the EXTREME regimen as first-line therapy were analyzed. The treatment outcomes were evaluated to compare patient and treatment characteristics with overall survival. RESULTS: Patients treated with carboplatin-based EXTREME regimen showed similar overall survival with less adverse effects compared to that of patients using cisplatin. The post-progression survival was significantly longer in patients treated with second-line treatment following the EXTREME regimen than in those without second-line treatment. CONCLUSION: The carboplatin-based EXTREME regimen was more feasible with similar treatment outcomes compared to cisplatin-based EXTREME regimen. In addition, subsequent lines of therapy contributed to improvement of survival for R/M SCCHN patients.

DOI： 10.21873/anticanres.13898

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Transoral surgery (TOS) has been widely applied for early T-stage head and neck cancer (HNC). The resection is performed with a minimum safety margin for function preservation under a limited surgical field; therefore, it is difficult to have a strong conviction about the complete resection. This study aims to evaluate the completeness of the initial TOS procedure; possibility of primary control by TOS alone; and predictive factors in patients with early T-stage laryngeal, oropharyngeal, and hypopharyngeal cancer. METHODS: Patients were treated by TOS at the primary site with or without neck dissection. The patients were divided into two groups based on the pathological evaluation of their surgical specimens: the control (observation) group, in that the resection was considered complete and the intervention (second-look procedure) group, in that incomplete tumor resection was suspected. The predictive factors for the possibility and/or limitations of complete resection by TOS were then analyzed. RESULTS: The study enrolled 26 and 25 patients in the control and intervention group, respectively. The success rate for single resection was 66% and the predictive factor was tumor depth obtained by enhanced computed tomography (CT) examination (odds ratio, 7.870, P = .0243). The success rate for definitive therapy by TOS alone was 83% and the predictive factor was poor differentiation observed on pathological examination (odds ratio, 6.800, P = .0248). CONCLUSIONS: TOS has the potential for both definitive resection and function preservation with minimal invasiveness. Identification of the risk factors for TOS is advantageous for accurate treatment selection in patients with early T-stage HNC.

DOI： 10.1002/cam4.2588

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: This multicenter retrospective cohort study aimed to evaluate the significance of adding S-1 to radiotherapy (RT) for the treatment of T2N0 glottic cancer using a propensity score matched analysis in Japan. MATERIALS AND METHODS: This study was conducted on 287 patients with T2N0 glottic cancer who were treated with definitive RT or chemoradiotherapy with S-1 (S-1 RT) between April 2007 and March 2017. Propensity score matched analysis was performed to ensure the well-balanced characteristics of the groups of patients who received RT alone and S-1 RT. Overall, progression-free and laryngectomy-free survivals and local control and laryngeal preservation rates were compared. RESULTS: Fifty-four pairs of patients were selected after performing propensity score matched analysis. Clinical characteristics were well-balanced between the two groups. The overall survival of patients in the S-1 RT group was significantly better than those in the RT alone group (P = 0.008). The progression-free and laryngectomy-free survivals of patients in the S-1 RT group were also better than those in the RT alone group; however, the differences were not significant. In contrast, patients in the S-1 RT group had slightly lower local control and laryngeal preservation rates compared with those in the RT alone group. The incidence of dermatitis in the S-1 RT group was significantly higher than that in the RT alone group in the matched population (P = 0.013). CONCLUSIONS: The addition of S-1 to RT for the treatment of T2N0 glottic cancer was not associated with better local control and laryngeal preservation rates in this study.

DOI： 10.1016/j.oraloncology.2019.104454

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Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: In this study, we examine the relationship between developmental insufficiency of mastoid air cells and abnormal morphology of the paranasal sinuses in patients with chronic otitis media (COM) and acquired middle ear cholesteatoma (AMEC) using precise image assessment, in order to evaluate whether the anatomical features of paranasal sinuses has any impact on the pathogenesis in COM and AMEC. METHODS: A total of 127 patients, including 45 COM patients and 82 AMEC patients, were enrolled for this study. The existence of nasal septal deviation, the existence of paranasal sinus opacification, the modified Lund-Mackay score, the diameters of the paranasal sinuses, the Vidic classification, mastoid development, and cranial size were assessed by CT examination. A further 76 adult patients who underwent high-resolution CT imaging of their skull bone for other diseases were enrolled as the control. RESULTS: The AMEC group showed a significantly shorter sphenoid length (P < 0.01) and lower Vidic classification score (P < 0.01) compared to the control group in this study. In addition, we observed that patients with AMEC had less pneumatization of the mastoid air cells compared to the control individuals, and that the sphenoid length of the poor MC score group was significantly shorter than that of the good MC score group. CONCLUSION: Our results suggested that the developmental deficiency in sphenoid length caused by long-standing pediatric rhinosinusitis might indicate the potential of chronic middle ear inflammation in childhood and impact the pneumatization of mastoid air cells. Therefore, chronic rhinosinusitis during the childhood and adolescence might play a role in the pathophysiology of AMEC.

DOI： 10.1016/j.anl.2019.09.008

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Ireland Ltd  

Erroneous Table 1 has been published in the original article. The corrected table is given in this correction. Table 1 Clinicopathological characteristics. [Table presented] Abbreviations: RT, radiation therapy
CRT, chemoradiotherapy
ND, neck dissection
IJV, internal jugular vein
SAN, spinal accessory nerve
SCM, sternocleidomastoid muscle.

DOI： 10.1016/j.anl.2019.05.004

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Language：English   Publisher：(一社)日本癌学会  

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科頭頸部外科学会  

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Publishing type：Research paper (scientific journal)   Publisher：Oto-Rhino-Laryngological Society of Japan, Inc.  

DOI： 10.3950/jibiinkoka.123.251

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japan Society for Head and Neck Cancer  

Preclinical animal xenograft tumor models are widely used for modeling the growth and spread of disease in translational cancer research. In particular, orthotopic xenograft models of head and neck cancer, by implanting head and neck cancer cell lines into the tongue of the mouse, have advantages for their ability to mimic local tumor growth and recapitulate the pathways of cervical lymph node metastasis seen in human head and neck cancers. However, these animal models have limitations due to the issues related with using established cell lines, suggesting that it is difficult for these animal models to recapitulate tumor heterogeneity and microenvironment. This review summarizes the advantages and limitations of animal models for head and neck cancers and discusses the future directions of the role of animal models in translational cancer research.

DOI： 10.5981/jjhnc.45.366

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Oto-Rhino-Laryngological Society of Japan Inc.  

The aim of this retrospective study was to assess whether the possibility of oral intake could be estimated with an endoscopic swallowing examination(VE)in patients with dysphagia after surgery for digestive diseases. The study subjects were 28 patients who had dysphagia after surgery for digestive diseases in Yokohama City University Hospital between January, 2013 and September, 2017. Oral intake status(possibility of oral intake and dependence on alternative nutrition)was evaluated up to 80 days after the first VE. The relationship between oral intake status and patient characteristics (age, sex, history of aspiration pneumonia, presence of tracheostomy, presence of vocal cord paralysis, American Society of Anesthesiologists physical status, operative time), the Hyodo score and the presence of aspiration during VE were examined. The time course for oral intake status(the start of oral intake and the transition from alternative nutrition) was also evaluated by the Kaplan-Meier method according to the Hyodo score(with a cut-off value of 6)and aspiration during VE. In the followup period for up to 80 days after the first VE, 26 patients started oral intake and the remaining 2 did not. Nine patients were dependent on alternative nutrition and 19 were not. There were no statistical differences on the final oral intake status according to the patient characteristics. At the first VE, 19 and 9 patients had a Hyodo score of≤6 and &gt
6, respectively. The numbers of patients with and without aspiration were 10 and 18, respectively. There were no statistical differences on the final oral intake status according to the indexes at the first VE. The Kaplan-Meier estimation revealed that patients with a Hyodo score &gt
6 experienced a later start of oral intake and a slower transition from alternative nutrition than patients with a Hyodo score ≤6. Patients with aspiration at the first VE had a longer dependence on alternative nutrition than those without. Although the first VE after the surgery for digestive diseases was not a definitive predictor of the final oral intake status, it could predict the time course for the transition from alternative nutrition as well as the start of oral intake.

DOI： 10.3950/jibiinkoka.122.1304

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AME Publishing Company  

DOI： 10.21037/tcr.2019.04.02

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OBJECTIVE: The Hyodo scoring system during the endoscopic procedure has been proposed as a new tool for evaluating oral intake feasibility. However, the effectiveness of the information obtained from this procedure in predicting aspiration is not fully elucidated. The aim of this study was to assess the significance of clinical factors, including Hyodo scores, for predicting the risk of aspiration. METHODS: Five hundred and twenty-eight endoscopic swallowing examinations were performed. Clinical factors, including age, sex, disease type, history of aspiration pneumonia, cognitive function, presence of tracheostomy, presence of vocal cord paralysis, consciousness level on the Japan Coma Scale, ECOG Performance Status, serum albumin level and Hyodo score, were obtained for each examination. The relationship between each of these factors and the presence of aspiration during endoscopic procedure was evaluated. RESULTS: Three hundred and thirty-two patients (62.9%) were scored less than 5, 153 (29.0%) were scored between 5 and 8, and 43 (8.1%) were scored above 8. The number of patients with aspiration was 133 (25.2%). ROC analysis revealed that a cut-off point of 6 for Hyodo score was effective for predicting aspiration, with a sensitivity of 0.65 and a specificity of 0.86. History of aspiration pneumonia (OR 1.87, P<0.001), vocal cord paralysis (OR 2.23, P<0.001), PS≥3 (OR 2.47, P<0.001) and Hyodo score>6 (OR 9.08, P<0.001) were found to be independent predictive factors for aspiration. CONCLUSION: The Hyodo scoring method was easy for otolaryngologists to perform and the scores were useful for predicting aspiration with moderate sensitivity and high specificity. Hyodo score>6, history of aspiration pneumonia, vocal cord paralysis, and PS≥3 were independent predictive factors for aspiration and that a Hyodo score above 6 was the statistically strongest predictor for aspiration.

DOI： 10.1016/j.anl.2018.03.005

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND/AIM: The purpose of this study is to investigate the prognostic significance of the pretreatment F-NLR score, which is based on fibrinogen (F) and neutrophil-to-lymphocyte ratio (NLR) in patients with advanced hypopharyngeal carcinoma (HPC). MATERIALS AND METHODS: A total of 111 advanced HPC patients treated with radiotherapy, chemoradiotherapy, or bioradiotherapy were classified into three groups: F-NLR score of 2 (fibrinogen ≥341 mg/dl and NLR≥3.59), score of 1 (fibrinogen ≥341 mg/dl or NLR≥3.59), and score of 0 (fibrinogen <341 mg/dl and NLR<3.59). RESULTS: F-NLR score of 2 was an independent prognostic factor for overall (OS) and progression-free survival (PFS) in patients with advanced HPC in the multivariate analysis. Both OS and PFS were significantly lower in patients with an F-NLR score of 2 than in those with an F-NLR score of 0. CONCLUSION: F-NLR score was useful to stratify patients to extract poor prognostic characteristics in patients with advanced HPC.

DOI： 10.21873/anticanres.12859

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BACKGROUND: We confirmed the safety of postoperative bio-chemoradiotherapy using cetuximab and docetaxel in a small number of patients with cis-platinum-intolerant core high-risk head and neck cancer. OBJECTIVE: To assess treatment efficacy, we planned a phase 2 study of postoperative bio-chemoradiotherapy for patients with cis-platinum-intolerant core high-risk head and neck cancer and will compare the results to those of previously collected radiotherapy data. METHODS: Patients who underwent definitive surgery for oral cavity, laryngeal, oropharyngeal, or hypopharyngeal advanced cancer, whose postoperative pathological results indicated core high risk for recurrence (eg, positive margin in the primary site or extranodal extension) and who were cis-platinum-intolerant, will undergo postoperative bio-chemoradiotherapy. The primary end point is 2-year disease-free survival. RESULTS: The expected 2-year disease-free survival is set at 55%, and the calculated sample size is 35 patients, according to a statistical analysis based on previous reports. CONCLUSIONS: This treatment method is expected to improve the survival rate of patients with severe head and neck cancer. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000031835; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ ctr_view.cgi?recptno=R000036355 (Archived by WebCite at http://www.webcitation.org/71fejVjMr).

DOI： 10.2196/11003

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Background: The purpose of this study was to elucidate the efficacy of concurrent chemotherapy and analyze prognostic factors in the radiation-based therapy for early stage laryngeal squamous cell carcinoma (ELSCC). Methods: The records of 97 patients with ELSCC treated by radiation-based therapy from 2004 to 2016 were retrospectively reviewed. Eighty-one patients were treated with the combined-agent regimens during the treatment. Of the 81 patients, 58 were treated with S-1 regimen and 23 with other regimens. Clinical factors, such as concurrent chemotherapy, non-glottic subsite and the incidence of second primary cancer (SPC) were analyzed for their association with survival. Results: From the analysis of all patients, the 5-year overall survival (OS) rates were found to be significantly poorer for patients with non-glottic cancer compared to those with glottic cancer (P < 0.001), and non-glottic subsite was shown to be the only poor prognostic factor for OS by the multivariate analysis (P=0.006). SPC was responsible for two-thirds of all deaths. In the analysis of patients with stage II ELSCC, the 5-year disease-free survival (DFS) rates were significantly better for patients treated by concurrent chemoradiotherapy (CCRT) with S-1 compared to those treated by the other treatment methods, and a combination with the S-1 regimen was shown to be the only good prognostic factor for DFS by the multivariate analysis (P=0.015). Conclusions: Non-glottic subsite and SPC were associated with worsened survival. CCRT with S-1 can be a useful treatment option for stage II ELSCC.

DOI： 10.21037/tcr.2018.06.15

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: The purpose of this study is to validate the concept of lymph node ratio (LNR) in head and neck squamous cell carcinoma (HNSCC). METHODS: A total of 63 patients with HNSCC who underwent resection of the primary tumor combined with neck dissection in our institution were analyzed in this study. LNR was defined as the number of positive lymph nodes divided by the total number of lymph nodes excised. LNR was categorized into two groups (<0.068 and ≥0.068) according to the results of receiver-operating characteristic plots for determination of the cut-off value. RESULTS: LNR≥0.068 was associated with poor overall survival (OS), progression-free survival (PFS) and locoregional recurrence-free survival (LRFS) after resection of the primary tumor combined with neck dissection in patients with HNSCC. Univariate and multivariate data analysis showed that LNR≥0.068 was an independent prognostic factor for OS, PFS and LRFS. Both pathological T stage status (pT3 or 4) and ≥3 positive LNs were also an independent prognostic factors for PFS in patients with HNSCC in our univariate and multivariate analysis. CONCLUSION: These results suggested that LNR could be useful tools in identifying HNSCC patients with poor outcomes.

DOI： 10.1016/j.anl.2017.11.015

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: The purpose of this study is to validate the applicability of new TNM classification for human papillomavirus (HPV)-related oropharyngeal cancer (OPC) in the 8th edition of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) TNM staging system in Japan. METHODS: A total of 91 OPC patients treated with radiation-based therapy between November 2001 and July 2015 were analyzed retrospectively in this study. HPV infection status was evaluated using tumor p16 expression. RESULTS: 40 OPC patients (44.0%) had HPV-positive disease in this study. The distribution of disease stage of HPV-positive OPC patients dramatically changed from the 7th edition to the 8th edition of AJCC/UICC TNM classification. However, neither the 8th edition nor the 7th edition of the AJCC/UICC TNM staging system could adequately predict outcomes of HPV-positive OPC patients in our patient series. On the other hand, our multivariate analysis indicated that matted nodes and age ≥63 were independent prognostic factors for progression-free survival. In addition, HPV-positive OPC patients with stage I without matted nodes showed significantly better overall and progression-free survival compared with those with stage I with matted nodes and stages II and III in the 8th edition of the AJCC/UICC TNM staging system (P=0.008, and P=0.043, respectively). CONCLUSION: Our results suggested that matted nodes of HPV-positive OPC patients might be additionally examined to apply the 8th edition of AJCC/UICC TNM classification for more adequate predicting outcomes of HPV-positive OPC patients.

DOI： 10.1016/j.anl.2017.07.010

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AME Publishing Company  

Background: Although dihydropyrimidine dehydrogenase (DPD) expression has been reported to correlate with 5-fluorouracil (5-FU) resistance in several cancers, the relationship between DPD expression and chemotherapeutic resistance to 5-FU remains unclear in head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to determine the impact of DPD expression on 5-FU sensitivity and survival in HNSCC patients receiving 5-FU-based treatment. Methods: To study the correlation between DPD expression and clinical outcome of HNSCC patients who had undergone concurrent chemoradiotherapy with 5-FU-based regimens, we first examined DPD mRNA expression of these patient samples. We next developed a 5-FU-resistant HNSCC cell line (HSC-3R) to clarify the association between DPD expression and 5-FU resistance. Clonogenic survival assay was performed to determine the sensitivity of HSC-3 cells and HSC-3R cells to 5-FU. DPD expression levels in parental HSC-3 and HSC-3R cell lines were then examined by Western blotting and real-time quantitative polymerase chain reaction analysis. Lastly, we performed WST-8 assay to examine the effects of 5-Chloro-2,4-dihydroxypyridine (CDHP), a 5-FU modulator to competitively inhibit DPD, on 5-FU cytotoxicity in the HSC-3 and HSC-3R cells, to evaluate if inhibition of DPD can restore the sensitivity of HNSCC cells to 5-FU. Results: Nineteen HNSCC patients who had undergone concurrent chemoradiotherapy with 5-FU-based regimens were enrolled in this study. The cut-off value for DPD mRNA expression calculated from the ROC curve was 8.53 against cancer-specific survival of these patients. The high-level DPD expression group showed significantly shorter overall and cancer-specific survival compared to the low-level DPD expression group (P=0.0018 and 0.0004, respectively). Both of protein and mRNA expression levels were greater in the HSC-3R cells than that in the HSC-3 cells. While HSC-3R cells showed 12.64-fold greater resistance to 5-FU compared with HSC-3 cells, the combination of 5-FU with CDHP had a significant inhibitory effect on 5-FU cytotoxicity in HSC-3R cells in CDHP exposure. Conclusions: In this study, we clarified that the high-level DPD expression group of HNSCC patients undergoing concurrent chemoradiotherapy with 5-FU-based regimens showed significantly shorter overall survival. The 5-FU-resistant cells established from HNSCC cells showed increased DPD expression and attenuated 5-FU resistance induced by CDHP. Our results suggested that a high level of DPD expression was correlated with 5-FU resistance and that DPD expression level might be a predictive biomarker in 5-FU-based chemoradiotherapy for HNSCC patients.

DOI： 10.21037/tcr.2018.03.38

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科頭頸部外科学会  

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OBJECTIVE: The preservation of residual hearing after conventional cochlear implantation (CI) is frequently observed when atraumatic soft surgery is adopted. The purpose of this study was to elucidate the predictive factors for residual hearing preservation after atraumatic CI. PATIENTS: This study included 46 patients who underwent CI based on an atraumatic technique using a standard-length flexible electrode implant through a round window approach. MAIN OUTCOME MEASURE: Cochlear volume was measured using magnetic resonance imaging (MRI). Cochlear duct length (CDL) was taken as the length of the scala media measured using computed tomography (CT). The association between residual hearing preservation and cochlear volume/CDL was then examined. RESULT: Cochlear volume and CDL were significantly larger in patients with complete hearing preservation than in those with hearing loss. Multivariate logistic regression analysis revealed that cochlear volume was a significant predictive factor for residual hearing preservation. CONCLUSION: Residual hearing preservation after conventional CI was observed in patients with a larger cochlear volume and longer CDL. Cochlear volume could be a predictive factor for residual hearing preservation after conventional CI.

DOI： 10.1080/00016489.2017.1393840

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BACKGROUND: Transoral videolaryngoscopic surgery (TOVS) has been widely applied for early T stage head and neck cancer. The resection is performed with a minimum safety margin for function preservation under a limited surgical field of view, making it difficult to be certain of complete resection. OBJECTIVE: Our aim is the evaluation of the completeness of resection by initial TOVS resection, and the possibility of primary control by TOVS alone, allowing for repeat procedures for function preserving treatment in early T stage laryngeal, oropharyngeal, and hypopharyngeal cancer patients. METHODS: Patients are treated by TOVS for the primary site with or without neck dissection. Patients are divided in two groups based on the results of the pathological evaluation of the surgical specimen; the control group in which the resection is considered to be complete, and the intervention (second-look procedure) group in which incomplete tumor resection is suspected. The predictive factors for the possibility of complete resection by TOVS will then be analyzed. RESULTS: Patient enrollment started on January 1, 2014, and closed on March 31, 2016, with 54 patients. The control group consists of 27 patients, the intervention group is 21 patients, and 6 patients were excluded. There were no clinical differences between the control and intervention groups. The observation period will end on December 31, 2018. CONCLUSIONS: TOVS has potential for both definitive resection and function preservation with minimal invasiveness. Identifying the limitations of TOVS is beneficial to ensure accurate treatment selection in early T stage head and neck cancer patients. TRIAL REGISTRATION: UMIN Clinical Trials Registry: UMIN000012485; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi? recptno=R000014472 (Archived by WebCite at http://www.webcitation.org/6v1b741Iw).

DOI： 10.2196/resprot.8907

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

To confirm the efficacy and safety of cetuximab and docetaxel in postoperative radiotherapy for high-risk head and neck cancer patients who cannot to be administered high-dose cisplatin.
The eligibility criteria required stage III-IVB head and neck cancer patients who had undergone total resection, and for whom pathological evaluation revealed positive or close margins in the primary site and/or extracapsular nodal extension and/or two or more nodal metastases. In each case, the patients general condition prevented the use of high-dose cisplatin. Instead, they received cetuximab and docetaxel every week during a 66.6 Gy course of postoperative radiotherapy.
Eleven patients were enrolled; the median follow-up period was 22 months, and the 1- and 2-year disease free survival rates were 91 and 55%, respectively. Grade 3 adverse events included oral mucositis, radiation dermatitis, reduced white blood cell and neutrophil counts, lung infection, aspiration, and hyponatremia; however, no grade 4 adverse events were observed.
Administration of cetuximab and docetaxel during postoperative radiotherapy for high-risk poor condition head and neck cancer patients in poor general condition was both feasible and tolerable. With the safety of this treatment confirmed, we propose a phase trail to further clarify the efficacy of cetuximab and docetaxel use for high-risk cisplatin-intolerant patients.

DOI： 10.1007/s00280-017-3352-3

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Language：Japanese   Publisher：(NPO)日本気管食道科学会  

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Language：Japanese   Publisher：(一社)日本頭頸部癌学会  

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Recent studies showed that human papillomavirus (HPV) integration contributes to the genomic instability seen in HPV-associated head and neck squamous cell carcinoma (HPV-HNSCC). However, the epigenetic alterations induced after HPV integration remains unclear. To identify the molecular details of HPV16 DNA integration and the ensuing patterns of methylation in HNSCC, we performed next-generation sequencing using a target-enrichment method for the effective identification of HPV16 integration breakpoints as well as the characterization of genomic sequences adjacent to HPV16 integration breakpoints with three HPV16-related HNSCC cell lines. The DNA methylation levels of the integrated HPV16 genome and that of the adjacent human genome were also analyzed by bisulfite pyrosequencing. We found various integration loci, including novel integration sites. Integration loci were located predominantly in the intergenic region, with a significant enrichment of the microhomologous sequences between the human and HPV16 genomes at the integration breakpoints. Furthermore, various levels of methylation within both the human genome and the integrated HPV genome at the integration breakpoints in each integrant were observed. Allele-specific methylation analysis suggested that the HPV16 integrants remained hypomethylated when the flanking host genome was hypomethylated. After integration into highly methylated human genome regions, however, the HPV16 DNA became methylated. In conclusion, we found novel integration sites and methylation patterns in HPV-HNSCC using our unique method. These findings may provide insights into understanding of viral integration mechanism and virus-associated carcinogenesis of HPV-HNSCC.

DOI： 10.1002/ijc.30589

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Objective/HypothesisWe previously reported that the metabolic tumor volume (MTV) of a primary tumor was an independent prognostic factor for survival in laryngeal carcinoma treated by radiotherapy (RT)-based protocol. The purpose of this study was to evaluate the difference in survival outcomes between surgery-based and RT-based treatment in patients with a MTV laryngeal cancer.
Study DesignAn individual retrospective cohort study.
MethodsWe reviewed the records of 63 patients with laryngeal cancer showing a primary tumor with a high MTV value ( 4.9 mL). The patients were separated into two groups by primary treatment strategy: 22 patients were included in the surgery group, and 41 patients were included in the RT group. Clinical factors and treatment modalities were analyzed for their association with survival.
ResultsMultivariate analysis, including age, sex, subsite, T classification, nodal metastasis, and treatment modality, showed that the subsite (hazard ratio [HR] 2.55, P = 0.043) and treatment modality (HR 3.98, P = 0.019) were independent predictors for survival. The Kaplan-Meier curves for 2-year relapse-free survival rates and overall survival rates for patients in the surgery and RT groups were 74.2% versus 38.8% (P = 0.025) and 80.1% versus 66.7% (P = 0.078).
ConclusionsPatients with a high metabolic volume laryngeal cancer treated by a surgery-based protocol showed better relapse-free survival and overall survival than did those undergoing RT-based treatment. Pretreatment MTV assessment could be useful in planning the treatment strategy for patients with a laryngeal cancer.
Level of Evidence2b. Laryngoscope, 127:862-867, 2017

DOI： 10.1002/lary.26233

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Language：Japanese   Publisher：(公社)神奈川県医師会  

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BACKGROUND: The purpose of this study was to elucidate the prognostic significance of the pretreatment metabolic tumor volume (MTV) in patients with piriform sinus carcinoma treated by radiation-based therapy. METHODS: This retrospective study included 100 patients with piriform sinus carcinomas who had received treatment by radiation-based therapy. The MTV values were obtained from pretreatment positron emission tomography (PET). The association between clinical factors, including the MTV, and survival was analyzed. RESULTS: Kaplan-Meier estimates revealed the 5-year disease-free survival (DFS) rates were significantly poorer for patients with a high MTV compared to those with a low MTV. In the multivariate analysis, MTV (p < .001), nodal metastasis (p = .011), and applied chemotherapy regimen (p = .004) were found to be independent prognostic factors for DFS. CONCLUSION: The locoregional MTV is a prognostic factor for DFS in patients with piriform sinus carcinoma treated by radiation-based therapy. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1708-1716, 2016.

DOI： 10.1002/hed.24488

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

For primary organ preservation, concurrent chemoradiotherapy (CCRT) is performed for advanced squamous cell carcinoma of the head and neck (SCCHN). In this organ-preservation setting with CCRT, surgery is reserved as a salvage treatment in cases of locoregional failure after CCRT. The purpose of the study was to review our experience with salvage surgery after CCRT for patients with SCCHN and to evaluate the effectiveness and prognostic factors affecting survival.
The records of patients with stage II-IVB SCC of the larynx, oropharynx, or hypopharynx treated with salvage surgery after CCRT between 1998 and 2012 were reviewed.
A total of 645 patients with previously untreated, resectable SCC of the larynx, oropharynx, or hypopharynx received CCRT. Salvage surgery was performed for 78 of 225 patients with residual or recurrent tumors. The 5-year overall survival (OS) and disease-specific survival rates for patients who received salvage surgery were 61.0 and 65.5 %, respectively. Stage IV, poorly differentiated, synchronous double cancer, and surgical complications were significant predictors of unfavorable OS on multivariate analysis. Postoperative complications were observed in 30 patients (38.5 %).
Salvage surgery is the best therapeutic option for failure after CCRT for SCCHN because of its good survival rate, although a high surgical complication rate is seen. Patients with initial stage IV tumors, poorly differentiated SCC, or synchronous double cancer are considered for further adjuvant treatment.

DOI： 10.1007/s10147-016-0964-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Recently, the incidence of oropharyngeal cancer (OPC) has increased markedly in comparison to that of HNSCC, which is associated with the use of tobacco or alcohol or both. This increase has resulted mainly from the global rise in the number of human papillomavirus (HPV)-related oropharyngeal cancers (HPV-OPCs). HPV-OPC has several unique characteristics, including presentation in younger patients, better response rates to treatment, and better prognosis compared to alcohol- and smoking-related HNSCC. HPV infection status is now an independent prognostic factor for survival in patients with OPC. In general, HPV oncoproteins E6 and E7 are the primary viral factors responsible for the initiation and progression of HPV-related cancers via the inactivation of p53 and pRb. However, alterations in additional factors, including genomic instability, HPV DNA integration, and epigenetic alterations, could be equally important for neoplastic transformation and tumor progression. The impact of genomic instability and external environmental factors on the initiation of cervical cancer development through high-risk HPV infection has been well characterized, although less is known about the mechanism underlying HPV-induced carcinogenesis in HNSCC. This review provides an overview of the biology and molecular mechanisms of HPV-related cancers, including a particular focus on several recent studies on the comprehensive characterization of genomic alterations in HPV-associated HNSCC.

DOI： 10.1007/s10147-016-1005-x

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BACKGROUND: Definitive chemoradiotherapy (CRT) is used to treat lymph node metastatic head and neck cancer patients. Regional control of the neck disease is important to improve the prognosis, and the accuracy of the method used to evaluate the metastatic lymph node(s) after CRT is crucial to the decision-making process for any following salvage surgery. METHODS: Patients undergoing CRT were divided in two groups of patients of those showing complete clinical response (CR) and those showing clinical non-response (non-CR), as assessed by computed tomography (CT) and/or magnetic resonance imaging (MRI), ultrasonography, fluorodeoxyglucose-positron emission tomography (FDG-PET), and fine needle aspiration cytology. The responses (CR vs. non-CR) were compared with the actual clinical outcomes. For the interim analysis, the study period was broken down into two periods, namely, the exploratory phase (patients treated between January 2002 and April 2012) and the validating phase (patients treated between May 2012 and January 2014). RESULTS: The sensitivity, specificity, and accuracy were as follows: CT and/or MRI, 66.7, 73.8, and 72.8 %, respectively, in the exploratory phase; ultrasonography, 91.7, 70.6, and 73.4 %, respectively, in the exploratory phase and 80.0, 82.8, and 82.4 %, respectively, in the validating phase; FDG-PET, 50.0, 97.5, and 91.3 %, respectively, in the exploratory phase and 60.0, 100, and 94.1 %, respectively, in the validating phase; cytology, 68.4, 95.9, and 90.3 %, respectively, in the exploratory phase and 66.7, 100, and 85.7 %, respectively, in the validating phase. CONCLUSIONS: Based on our results, CT and/or MRI appear to be inadequate methods for the evaluation of the response of lymph node(s) to CRT. In contrast, ultrasonography appears to be a highly sensitive and useful tool for positive screening at 6-8 weeks after CRT, and FDG-PET appears to be a highly specific and useful tool for negative screening at 8-12 weeks after CRT.

DOI： 10.1007/s10147-015-0936-y

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Language：English   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2016-4054

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Language：Japanese   Publisher：神奈川県医師会  

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PURPOSE: Although locally advanced head and neck squamous cell carcinoma (HNSCC) can be effectively treated using chemoradiotherapy (CRT) with docetaxel (DTX), and cisplatin (CDDP) plus 5-fluorouracil (TPF-CRT), severe adverse events (especially neutropenia) can limit treatment adherence. Therefore, we evaluated the safety and efficacy of a new chemotherapy regimen that consisted of DTX and CDDP plus cetuximab (Cmab) with concurrent radiotherapy. METHODS: Bio-chemoradiotherapy (B-CRT) using DTX, CDDP, and Cmab was administrated to patients with locally advanced HNSCC, and its safety and efficacy were evaluated. RESULTS: Interim analysis of nine patients revealed severe neutropenia in five patients (56 %) and leukopenia in seven patients (78 %); hence, the study was terminated. One patient experienced disease-free survival using only B-CRT. CONCLUSIONS: Neutropenia was equally severe for B-CRT, compared to TPF-CRT. Based on the limited sample size, it is impossible to conclude that B-CRT has non-inferior efficacy, compared to TPF-CRT.

DOI： 10.1007/s00280-016-3052-4

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科頭頸部外科学会  

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Both central giant cell granuloma (CGCG) and ossifying fibroma (OF) are relatively common diseases. The synchronous presentation of CGCG and OF is, however, an extremely rare occurrence. We present an unusual case with the synchronous presentation of these two diseases in the maxilla and introduce a surgical strategy based on a combination of the stereolithographic model and navigation system for the treatment of gigantic OF with secondary CGCG.

DOI： 10.1016/j.anl.2015.08.003

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Language：English   Publisher：SPANDIDOS PUBL LTD  

DOI： 10.3892/or.2016.4573

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BACKGROUND: Chemoradiotherapy (CRT) is used to treat cervical lymph node(s) metastatic head and neck cancer patients. Evaluation and treatment of lymph node(s) after CRT is important to improve the prognosis. METHODS: Prior to CRT, we determined the TNM stage by visual and imaging examinations. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were calculated from the results of fluorodeoxyglucose-positron emission tomography (FDG-PET). After CRT, the patients were divided in two groups-complete response (CR) and non-CR-and their responses were compared with the clinical characteristics. RESULTS: T4, N2b, N2c and TLG2.5 ≥ 18.8 were statistically significant predictive indices before CRT. The odds ratio, 95 % confidence interval and p value were, respectively-T4: 2.73, 1.15-6.51, 0.0230; N2b: 6.96, 1.50-32.3, 0.0132; N2c: 11.80, 2.37-58.50, 0.00258; and TLG2.5 ≥ 18.8: 6.25, 2.17-18.00, 0.000672. CONCLUSIONS: TLG was found to be a good predictive factor for metastatic lymph node(s) prior to CRT treatment. After CRT treatment, FDG-PET was found to be highly specific and useful for negative screening.

DOI： 10.1007/s10147-015-0890-8

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BACKGROUND: While treatment failure in cases of head and neck squamous cell carcinoma (HNSCC) frequently takes the form of locoregional recurrences and distant metastasis, our understanding of the mechanisms of metastasis in HNSCC is limited. We initially performed the upstream and key nodes analysis together with whole gene microarray analysis characterized by distant metastatic potential in vivo with HNSCC cell lines and identified JunB, a member of the activator protein-1 (AP-1) family, as a key molecule in the regulation of the pathways related to distant metastasis in HNSCC. We have therefore tested the hypothesis that JunB plays a crucial role in distant metastasis in HNSCC. METHODS: To study the role of JunB on metastatic potential of HNSCC, small interfering RNA (siRNA)-mediated knockdown and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (cas9) system (CRISPR/Cas9)-mediated knockout of JunB in HNSCC cells were established and the abilities of cell invasion and migration in vitro were examined. The efficacy of knockout of JunB was also examined using an experimental lung metastatic mouse model of HNSCC. In addition, to study if the role of JunB in HNSCC cell migration and invasiveness is related to epithelial-to-mesenchymal transition (EMT), cell morphology and expression of mesenchymal or epithelial marker on siRNA mediated JunB knockdown in HNSCC cells were examined with or without TGF-β stimulation. RESULTS: siRNA knockdown and sgRNA knockout of JunB in metastatic HNSCC cells significantly suppressed both cell invasion and migration in vitro. In addition, the knockout of JunB in metastatic HNSCC cells significantly repressed the incidence of lung metastases and prolonged the survival in vivo. However, we did not observe any change in cell morphology with the down-regulation of mesenchymal markers and up-regulation of epithelial markers in response to siRNA-mediated JunB knockdown in HNSCC cells. CONCLUSION: These results suggested that JunB could play an important role in promoting cell invasion, migration and distant metastasis in HNSCC via pathways other than EMT and that the down-regulation of JunB may become an effective strategy for patients with invasive HNSCC.

DOI： 10.1186/s13046-016-0284-4

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: While treatment failure in cases of head and neck squamous cell carcinoma (HNSCC) frequently takes the form of locoregional recurrences and distant metastasis, our understanding of the mechanisms of metastasis in HNSCC is limited. We initially performed the upstream and key nodes analysis together with whole gene microarray analysis characterized by distant metastatic potential in vivo with HNSCC cell lines and identified JunB, a member of the activator protein-1 (AP-1) family, as a key molecule in the regulation of the pathways related to distant metastasis in HNSCC. We have therefore tested the hypothesis that JunB plays a crucial role in distant metastasis in HNSCC.
Methods: To study the role of JunB on metastatic potential of HNSCC, small interfering RNA (siRNA)-mediated knockdown and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (cas9) system (CRISPR/Cas9)-mediated knockout of JunB in HNSCC cells were established and the abilities of cell invasion and migration in vitro were examined. The efficacy of knockout of JunB was also examined using an experimental lung metastatic mouse model of HNSCC. In addition, to study if the role of JunB in HNSCC cell migration and invasiveness is related to epithelial-to-mesenchymal transition (EMT), cell morphology and expression of mesenchymal or epithelial marker on siRNA mediated JunB knockdown in HNSCC cells were examined with or without TGF-beta stimulation.
Results: siRNA knockdown and sgRNA knockout of JunB in metastatic HNSCC cells significantly suppressed both cell invasion and migration in vitro. In addition, the knockout of JunB in metastatic HNSCC cells significantly repressed the incidence of lung metastases and prolonged the survival in vivo. However, we did not observe any change in cell morphology with the down-regulation of mesenchymal markers and up-regulation of epithelial markers in response to siRNA-mediated JunB knockdown in HNSCC cells.
Conclusion: These results suggested that JunB could play an important role in promoting cell invasion, migration and distant metastasis in HNSCC via pathways other than EMT and that the down-regulation of JunB may become an effective strategy for patients with invasive HNSCC.

DOI： 10.1186/s13046-016-0284-4

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT INST ANTICANCER RESEARCH  

Background/Aim: Several randomized trials have shown that concurrent chemoradiotherapy (CCRT) either with or without adjuvant chemotherapy is more effective than radiotherapy-alone for treating nasopharyngeal carcinoma (NPC). The present study retrospectively evaluated the efficacy and toxicity of CCRT with docetaxel, cisplatin, and 5-fluorouracil (TPF) chemotherapy in patients with NPC. Patients and Methods: The study regimen consisted of two cycles of TPF chemotherapy [docetaxel (90 mg/m(2)), cisplatin (60 mg/m(2)), and continuous 5-fluorouracil (600 mg/m(2)/day: 5 days)] during definitive radiotherapy. Radiotherapy was performed 5 days a week with a single daily fraction of 1.8 or 2.0 Gy totalling to 70-Gy doses. A total of 24 patients with NPC were enrolled and evaluated. Results: Treatment completion rate was 70.8%, with an overall response rate of 100%. The 5-year overall survival rate was 82.4%, and 5-year progression-free survival rate was 78.3%. Conclusion: CCRT with TPF resulted in excellent survival rates for patients with NPC.

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Language：English   Publisher：(一社)日本癌学会  

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Background. The precise comparison of the voice characteristics of Parkinson disease (PD) patients with age-matched normal subjects is still one of the important research projects. The present study aimed at comparing the voice characteristics in sustained phonations of PD patients with an age-matched control group.
Methods. The subjects were 30 Japanese PD patients (15 males and 15 females). The control group consisted of 30 age-matched normal Japanese subjects (15 males and 15 females). Each subject was required to phonate into a mouthpiece attached to Vocal Function Analyzer (PS-77E; Nagashima Medical Instrumental Corporation, Tokyo, Japan) with the airway interruption system, and expiratory lung pressure, mean flow rate, fundamental frequency and intensity of voice, and pitch range were measured. Maximum phonation time was also assessed.
Results. The highest pitch level was significantly lower in the PD group than that of the control group in both sexes, whereas the lowest pitch level was significantly higher in the PD group only in males. In both sexes, the pitch range was significantly narrower in the PD group than in the control group. There was no significant difference in intensity, mean flow rate, expiratory pressure, or maximum phonation time between the two groups, for both males and females.
Conclusion. Only remarkable difference in the voice characteristics between PD patients and age-matched normal elderlies was limited to the narrowing of the pitch range in PD patients. The restriction in pitch regulation in PD patients was considered to be because of difficulty in reciprocal control of the laryngeal muscles secondary to latent rigidity.

DOI： 10.1016/j.jvoice.2014.08.012

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TP53 is the most frequently altered gene in head and neck squamous cell carcinoma, with mutations occurring in over two-thirds of cases, but the prognostic significance of these mutations remains elusive. In the current study, we evaluated a novel computational approach termed evolutionary action (EAp53) to stratify patients with tumors harboring TP53 mutations as high or low risk, and validated this system in both in vivo and in vitro models. Patients with high-risk TP53 mutations had the poorest survival outcomes and the shortest time to the development of distant metastases. Tumor cells expressing high-risk TP53 mutations were more invasive and tumorigenic and they exhibited a higher incidence of lung metastases. We also documented an association between the presence of high-risk mutations and decreased expression of TP53 target genes, highlighting key cellular pathways that are likely to be dysregulated by this subset of p53 mutations that confer particularly aggressive tumor behavior. Overall, our work validated EAp53 as a novel computational tool that may be useful in clinical prognosis of tumors harboring p53 mutations. (C)2015 AACR.

DOI： 10.1158/0008-5472.CAN-14-2735

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科頭頸部外科学会  

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Purpose
To evaluate the predictive and prognostic value of pretreatment metabolic tumor volume (MTV) in patients with treated by radiotherapy (RT) or concurrent chemoradiotherapy (CCRT).
Methods
We reviewed the records of 118 patients with newly diagnosed laryngeal carcinoma, who had been treated by RT or CCRT. Pretreatment positron emission tomography (PET) was performed, and MTV values were obtained by contouring margins of standardized uptake value. Clinical factors and MTV were analyzed for their association with survival.
Results
Patients with residual disease showed a significantly higher MTV than those with a complete response (CR) after primary treatment. Univariate analysis showed that the patients with a high MTV had a significantly lower disease-free survival (DFS) (p &lt; 0.001). Subsite (p = 0.010), T-stage (p &lt; 0.001), nodal metastasis (p &lt; 0.001) and clinical stage (p &lt; 0.001) also correlated significantly with DFS. In the multivariate analysis, MTV and clinical stage were both found to be independent prognostic factors for DFS (p = 0.001, p = 0.034, respectively). The 3-year DFS for patients with a high MTV were significantly poorer than those with a low MTV (p &lt; 0.001).
Conclusions
MTV of the primary tumor is a significant prognostic factor for DFS in patients with laryngeal carcinoma treated by RT or CCRT. The results imply that MTV could be an important factor when planning treatment and follow-up for patients with laryngeal carcinoma.

DOI： 10.1371/journal.pone.0117924

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

The goals of treatment for head and neck cancer are cure and organ-function preservation. For organ preservation, primary treatment via radiotherapy alone is thought to be insufficient for Stage II squamous cell carcinoma of the larynx, oropharynx or hypopharynx. The objective of the present study was to investigate the efficacy and safety of concurrent chemoradiotherapy with S-1 for patients with Stage II squamous cell carcinoma of the pharynx or larynx for primary organ preservation.
Previously untreated patients with Stage II squamous cell carcinoma of the larynx, oropharynx or hypopharynx received three courses of S-1 (40 or 50 mg twice a day; 2 weeks of administration followed by 1 week of rest every 3 weeks) during conventional radiotherapy (a single daily fraction of 1.8 Gy) to a total dose of 70.2 Gy. The primary endpoint was the local control rate at 3 years.
From August 2009 to October 2012, 37 patients were evaluated for the study. The overall response rate was 100%. The 3-year local control rate was 89.0% (95% confidence interval, 78.9-99.2%), and the 3-year overall survival rate was 97.2% (95% confidence interval, 91.8-100%). Mucositis and dermatitis in the radiation field were the most common acute adverse events observed. The rates of Grade 3 mucositis and dermatitis were 27 and 35%, respectively. No patients experienced Grade 4 acute adverse events. The treatment completion rate was 89.2%.
Concurrent chemoradiotherapy with S-1 was safe and effective in improving local control for Stage II squamous cell carcinoma of the pharynx or larynx.

DOI： 10.1093/jjco/hyu154

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

BackgroundThe purpose of this study was to identify mechanisms of innate resistance to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, erlotinib, in a panel of head and neck squamous cell carcinoma (HNSCC) cell lines. Specifically, we analyzed the role of HRAS mutations in erlotinib resistance.
MethodsErlotinib sensitivity was determined by methyl thiazolyl-tetrazolium (MTT) assays. Molecular signaling pathways and somatic mutations were examined. Changes in sensitivity after modulation of HRAS expression were evaluated.
ResultsAll 7 cell lines were wild-type for EGFR and KRAS regardless of erlotinib sensitivity; however, 1 erlotinib-resistant cell line (HN31) harbored an HRAS G12D mutation. Downregulation of HRAS expression by small interfering RNA (siRNA) or short hairpin RNA (shRNA) in HN31 led to increased erlotinib sensitivity in vitro and in vivo. Transfection of activating HRAS-mutant (G12D and G12V) constructs into erlotinib-sensitive cell lines made them more resistant to erlotinib.
ConclusionActivating HRAS mutations can confer erlotinib resistance in an HRAS mutant HNSCC cell line. (c) 2014 Wiley Periodicals, Inc. Head Neck 36: 1547-1554, 2014

DOI： 10.1002/hed.23499

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Language：English   Publisher：(一社)日本癌学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Purpose: Tumor metastasis is the leading cause of death in patients with cancer. However, the mechanisms that underlie metastatic progression remain unclear. We examined TMEM16A (ANO1) expression as a key factor shifting tumors between growth and metastasis.
Experimental Design: We evaluated 26 pairs of primary and metastatic lymph node (LN) tissue from patients with squamous cell carcinoma of the head and neck (SCCHN) for differential expression of TMEM16A. In addition, we identified mechanisms by which TMEM16A expression influences tumor cell motility via proteomic screens of cell lines and in vivo mouse studies of metastasis.
Results: Compared with primary tumors, TMEM16A expression decreases in metastatic LNs of patients with SCCHN. Stable reduction of TMEM16A expression enhances cell motility and increases metastases while decreasing tumor proliferation in an orthotopic mouse model. Evaluation of human tumor tissues suggests an epigenetic mechanism for decreasing TMEM16A expression through promoter methylation that correlated with a transition between an epithelial and a mesenchymal phenotype. These effects ofTMEM16A expression on tumor cell size and epithelial-to-mesenchymal transition (EMT) required the amino acid residue serine 970 (S970); however, mutation of S970 to alanine does not disrupt the proliferative advantages of TMEM16A overexpression. Furthermore, S970 mediates the association of TMEM16A with Radixin, an actin-scaffolding protein implicated in EMT.
Conclusions: Together, our results identify TMEM16A, an eight transmembrane domain Ca2+-activated Cl- channel, as a primary driver of the "Grow" or "Go" model for cancer progression, in which TMEM16A expression acts to balance tumor proliferation and metastasis via its promoter methylation. (C) 2014 AACR.

DOI： 10.1158/1078-0432.CCR-14-0363

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Language：Japanese   Publisher：神奈川県医師会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CELL PRESS  

Many mutant p53 proteins (mutp53s) exert oncogenic gain-of-function (GOF) properties, but the mechanisms mediating these functions remain poorly defined. We show here that GOF mutp53s inhibit AMP-activated protein kinase (AMPK) signaling in head and neck cancer cells. Conversely, downregulation of GOF mutp53s enhances AMPK activation under energy stress, decreasing the activity of the anabolic factors acetyl-CoA carboxylase and ribosomal protein S6 and inhibiting aerobic glycolytic potential and invasive cell growth. Under conditions of energy stress, GOF mutp53s, but not wild-type p53, preferentially bind to the AMPK alpha subunit and inhibit AMPK activation. Given the importance of AMPK as an energy sensor and tumor suppressor that inhibits anabolic metabolism, our findings reveal that direct inhibition of AMPK activation is an important mechanism through which mutp53s can gain oncogenic function.

DOI： 10.1016/j.molcel.2014.04.024

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

The purpose of the study is to review our experience with concurrent chemoradiotherapy (CCRT) for patients with advanced resectable squamous cell carcinoma (SCC) of the hypopharynx and to evaluate the factors affecting survival and larynx preservation.
Retrospective study.
The records of 102 patients with Stage III or IV resectable SCC of the hypopharynx treated with CCRT between January 1998 and August 2010 were reviewed. Of the 102 patients, 62 were treated with high-dose regimens including cisplatin, 5-fluorouracil, methotrexate, leucovorin or docetaxel, cisplatin, and 5-fluorouracil. The remaining 40 were treated with low-dose regimens including carboplatin and uracil-tegafur, weekly docetaxel, or S-1. Radiotherapy was delivered 5 days a week using a single daily fraction of 1.8-2.0 Gray (Gy), to a total dose of 64.8-70.2 Gy. Overall survival (OS), disease-specific survival (DSS), and DSS with larynx preservation were estimated using Kaplan-Meier methods. The log-rank test and Cox proportional hazards regression were used to identify significant prognostic factors for OS, DSS, and DSS with larynx preservation.
The 5-year OS and DSS for all patients treated with CCRT were 51.3 and 64.3 %, respectively. The 5-year DSS with larynx preservation was 55.5 %. On multivariate analysis, the content of chemotherapy was a significant predictor of OS and DSS for patients undergoing CCRT; N stage was a significant prognostic factor for DSS and larynx preservation.
The treatment method including the indication for CCRT may be determined by the contents of the chemotherapy and the N stages of SCC of the hypopharynx.

DOI： 10.1007/s00280-014-2448-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Objective: Compared with radiotherapy alone, concurrent chemoradiotherapy significantly improves survival rates for patients with squamous cell carcinoma of the head and neck. The aim of this study was to retrospectively evaluate the efficacy, toxicity and long-term prognosis of concurrent chemoradiotherapy with docetaxel, cisplatin and 5-fluorouracil chemotherapy.
Methods: A total of 140 patients were enrolled and evaluated. Patients were received two cycles of docetaxel, cisplatin and 5-fluorouracil chemotherapy (docetaxel [50 mg/m(2) : Day 1], cisplatin [60 mg/m(2): Day 4] and continuous 5-fluorouracil [600 mg/m(2)/day: Days 1-5]) during definitive radiotherapy.
Results: The overall response rate was 97.1%. The 3 and 5-year overall survival rates were 83.3 and 79.2%, respectively. The 3 and 5-year disease-specific survival rates were 84.2 and 80.0%, respectively. Among patients with laryngeal or hypopharyngeal carcinoma, the 5-year laryngectomy-free survival rate was 64.9%.
Conclusions: Concurrent chemoradiotherapy with docetaxel, cisplatin and 5-fluorouracil showed excellent survival and organ preservation rates for the patients with locally advanced squamous cell carcinoma of the head and neck.

DOI： 10.1093/jjco/hyu026

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Language：Japanese   Publisher：(一社)日本頭頸部癌学会  

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BACKGROUND: Radioresistance remains a critical issue in the use of radiotherapy for the treatment of head and neck squamous cell carcinoma (HNSCC). This study evaluated the efficacy of combination treatment with OBP-301, a telomerase-specific replication-selective adenovirus, and radiotherapy in overcoming radioresistance by examining its effect on radiation-resistant HNSCC cells. METHODS: Radiation-resistant HNSCC cells were treated with OBP-301 and radiation in vitro and in an orthotopic nude mouse model in vivo and synergism was assessed. Apoptosis and expression of MRN complex, which plays a key role in DNA repair machinery, were also analyzed. RESULTS: Infection with OBP-301 was found to enhance the antitumor efficacy of radiation both in vitro and in vivo by inhibiting MRN complex expression and increasing apoptosis induction. CONCLUSION: Combined OBP-301 and radiation therapy seems to overcome radioresistance in HNSCC cells by inhibiting DNA repair machinery, and may thus be a novel therapeutic strategy for treating HNSCC.

DOI： 10.1002/hed.23309

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Purpose: Signal transducer and activator of transcription 3 (STAT3) has shown to play a critical role in head and neck squamous cell carcinoma (HNSCC) and we have recently completed clinical trials of STAT3 decoy oligonucleotide in patients with recurrent or metastatic HNSCC. However, there is limited understanding of the role of STAT3 in modulating other aspects of tumorigenesis such as angiogenesis. In this study, we aimed to examine the effects of STAT3 decoy oligonucleotide on tumor angiogenesis.
Experimental Design: A STAT3 decoy oligonucleotide and small interfering RNA (siRNA) were used to inhibit STAT3 in endothelial cells in vitro and in vivo. The biochemical effects of STAT3 inhibition were examined in conjunction with the consequences on proliferation, migration, apoptotic staining, and tubule formation. Additionally, we assessed the effects of STAT3 inhibition on tumor angiogenesis using murine xenograft models.
Results: STAT3 decoy oligonucleotide decreased proliferation, induces apoptosis, decreased migration, and decreased tubule formation of endothelial cells in vitro. The STAT3 decoy oligonucleotide also inhibited tumor angiogenesis in murine tumor xenografts. Lastly, our data suggest that the antiangiogenic effects of STAT3 decoy oligonucleotide were mediated through the inhibition of both STAT3 and STAT1.
Conclusions: The STAT3 decoy oligonucleotide was found to be an effective antiangiogenic agent, which is likely to contribute to the overall antitumor effects of this agent in solid tumors. Taken together with the previously demonstrated antitumor activity of this agent, STAT3 decoy oligonucleotide represents a promising single agent approach to targeting both the tumor and vascular compartments in various malignancies.

DOI： 10.1371/journal.pone.0081819

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Language：Japanese   Publisher：神奈川県医師会  

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Language：English   Publisher：The Society of Practical Otolaryngology  

Orbital infection mainly develops as a complication of sinusitis, and often disturbs the functions of the eye by raising orbital pressure due to abscess formation. We herein report on a case of an intraorbital abscess in the upper-lateral part of the orbit following acute sinusitis occurred in a 59-year-old male. At presentation, the sinusitis itself had already been improved and the abscess did not have contact with frontal or the ethmoid sinuses. A quick and correct diagnosis of sinusitis followed by orbital infection is essential. An urgent surgical drainage along with an adequate use of antibiotics is required to preserve the eyesight.

DOI： 10.5631/jibirinsuppl.140.54

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

To review our experience with concurrent chemoradiotherapy (CCRT) for patients with advanced resectable squamous cell carcinoma (SCC) of the larynx and to evaluate the factors affecting survival and larynx preservation.
Retrospective study.
The records of 102 patients with stage III or IV resectable SCC of the larynx treated with CCRT between February 1994 and March 2009 were reviewed. Of 102 patients, 59 were treated with high-dose regimens, including cisplatin, 5-fluorouracil (5-FU), methotrexate, and leucovorin or docetaxel, cisplatin, and 5-FU, and 43 were treated with low-dose regimens, including carboplatin and uracil-tegafur or S-1. Radiotherapy was delivered 5 days a week using a single daily fraction of 1.8-2.0 Gray (Gy), to a total dose of 66.0-70.2 Gy. Overall survival (OS), disease-specific survival (DSS), and DSS with larynx preservation were estimated using Kaplan-Meier methods. The log-rank test and Cox proportional hazards regression were used to identify significant prognostic factors for DSS and DSS with larynx preservation.
The 5-year OS and DSS for all patients treated with CCRT were 63.9 and 70.7 %, respectively. The 5-year DSS with larynx preservation was 54.1 %. On multivariate analysis, N stage, synchronous multiple primary cancers, and the contents of chemotherapy were significant predictors of OS for patients undergoing CCRT; T stage, N stage, and the contents of chemotherapy were significant prognostic factors for larynx preservation.
The treatment method including the indication for CCRT may be determined by the contents of the chemotherapy and the T and N stages of laryngeal SCC. It is important to diagnose multiple synchronous primary cancers before CCRT.

DOI： 10.1007/s00280-013-2261-3

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Language：English   Publisher：(一社)日本癌学会  

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Objectives Bevacizumab, a monoclonal antibody to VEGF-A, is under active clinical evaluation in head and neck squamous cell carcinoma (HNSCC) and appears to be a promising therapy in at least a subset of patients. However, there are no reliable predictive biomarkers to identify those patients most likely to benefit. In this study, we assessed the efficacy of bevacizumab in HNSCC xenograft models to characterize escape mechanisms underlying intrinsic resistance and identify potential biomarkers of drug response. Materials and methods We evaluated the angiogenic profile of HNSCC cells from sensitive and resistant cell lines using antibody array. We further examined the role of interleukin-8 (IL-8) in contributing to resistance both in vitro and in vivo, using a loss- and gain-of-function approach. Results Angiogenic profiling indicated that resistant cells expressed higher levels of proangiogenic factors including IL-8, interleukin-1α (IL-1α), vascular endothelial growth factor (VEGF), fibroblast growth factor-a (FGF-a), and tumor necrosis factor-α (TNF-α). IL-8 was the most differentially expressed protein. IL-8 signaling compensated for VEGF inhibition in endothelial cells. Downregulation of IL-8 resulted in sensitization of resistant tumors to bevacizumab by disrupting angiogenesis and enhancing endothelial cell apoptosis. Overexpression of IL-8 in sensitive tumors conferred resistance to bevacizumab. Serum analysis of HNSCC patients treated with a bevacizumab-containing regime revealed high baseline IL-8 levels in a subset of patients refractory to treatment but not in responders. Conclusions These results implicate IL-8 in mediating intrinsic resistance to bevacizumab in HNSCC. Hence, co-targeting of VEGF and IL-8 may help overcome resistance and enhance therapeutic efficacy. © 2013 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.oraloncology.2013.03.452

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Objectives/Hypothesis: Mutation of the TP53 gene occurs in more than half of cases of head and neck squamous cell carcinoma (HNSCC). However, little is known about how specific TP53 mutations affect tumor progression. The objective of this study is to determine the gain of function of mutant p53 with a proline-to-serine substitution at codon 151.
Study Design: Laboratory-based study.
Methods: A panel of HNSCC cell lines was determined with anoikis assays, and orthotopic mouse experiments were performed. TP53 was sequenced. The shRNA knockdown and overexpression approaches were used for testing mutant p53 functions. The crystal structure of the p53 protein was analyzed using an in silico approach.
Results: An anoikis-resistant cell line, Tu138, was found to have a proline-to-serine substitution at codon 151 of TP53, which results in loss of wild-type p53 transcriptional activity. Moreover, the mutant p53 was shown to promote anoikis resistance and soft agar growth. Using an in silico approach based on the crystal structure of wild-type p53 protein, substitution of proline by serine at position 151 would create a cavity in a hydrophobic pocket, the loss of van der Waals contacts, and the thermodynamically unfavorable placement of a polar group, the hydroxyl oxygen atom of the serine, within a hydrophobic region, all of which likely cause a locally altered structure.
Conclusions: Our data suggest that mutation at position 151 leads to a structural alteration, which results in significant functional changes in the p53 protein that impact tumor progression.

DOI： 10.1002/lary.23846

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Language：Japanese   Publisher：(一社)日本頭頸部癌学会  

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Language：Japanese   Publisher：(一社)日本頭頸部癌学会  

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科頭頸部外科学会  

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科学会  

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科学会  

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科学会  

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科学会  

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Background. The local-regional failure of advanced oral squamous cell carcinoma (OSCC) after surgery results from the regrowth of residual tumor cells that may be stimulated by epidermal growth factor receptor (EGFR) ligands during the wound healing process.
Methods. The level of EGFR ligands in human drain fluids (DFs) from OSCC resection and remote flap donor site were determined. A mouse model of microscopic residual OSCC was established and treated with cetuximab to measure tumor growth, survival, and cervical lymph node metastases. A mouse model of wound healing was also established to assess the effect of an EGFR antibody on the wound healing process.
Results. EGFR ligands are found in sites from OSCC resection. EGFR targeted therapy can delay tumor regrowth in a microscopic residual disease model of OSCC without significant effects on local wound healing.
Conclusion. These results provide a strong rationale for clinical evaluation of this approach to treat patients with local-regionally advanced OSCC. (C) 2012 Wiley Periodicals, Inc. Head Neck 35: 321-328, 2013

DOI： 10.1002/hed.22961

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：URBAN & VOGEL  

Background and purpose. Primary subglottic cancer is a rare malignancy. We investigated the efficacy and toxicity of radiotherapy for subglottic cancer.
Patients and methods. Nineteen patients with primary squamous cell carcinoma of the subglottis received radiotherapy, 14 of whom also underwent chemotherapy. Of the 19 patients, 15 received definitive radiotherapy to the gross tumors with total doses of 70-70.2 Gy in 35-39 fractions, and 4 underwent preoperative radiotherapy with total doses of 37.8-55.8 Gy in 21-31 fractions, followed by total laryngectomy.
Results. Of the 19 patients, 5 developed local progression and 2 developed distant metastasis at the median follow-up period of 5 years. The 5-year local control and disease-free rates were 74 and 63%, respectively. Three patients died of tumor progression, and the 5-year overall and disease-free survival rates were 80 and 63%, respectively. Regarding acute toxicities, transient mucositis and dermatitis of grade 3 or lower were observed in all patients, but there were no late toxicities of grade 3 or higher.
Conclusion. Radiotherapy is a safe and effective treatment for patients with primary squamous cell carcinoma of the subglottis. The use of chemotherapy together with radiotherapy may enhance treatment efficacy and contribute to larynx preservation through good local control.

DOI： 10.1007/s00066-012-0178-0

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Language：English   Publisher：(一社)日本癌学会  

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Language：English   Publisher：(一社)日本癌学会  

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科頭頸部外科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

Current chemotherapeutics are characterized by efficient tumor cell-killing and severe side effects mostly derived from off-target toxicity. Hence targeted delivery of these drugs to tumor cells is actively sought. In an in vitro system, we previously demonstrated that targeted drug delivery to cancer cells overexpressing epidermal growth factor receptor (EGFR+) can be achieved by poly(ethylene glycol)-functionalized carbon nanovectors simply mixed with a drug, paclitaxel, and an antibody that binds to the epidermal growth factor receptor, cetuximab. This construct is unusual in that all three components are assembled through noncovalent interactions. Here we show that this same construct is effective in vivo, enhancing radiotherapy of EGFR+ tumors. This targeted nanovector system has the potential to be a new therapy for head and neck squamous cell carcinomas, deserving of further preclinical development.

DOI： 10.1021/nn204885f

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：2  

BACKGROUND: Concurrent chemoradiotherapy (CCRT) is used to treat advanced head and neck cancer. The accuracy of evaluating lymph nodes metastases following CCRT is important for subsequent therapy. PATIENTS AND METHODS: Patients were divided into two groups, the complete response (CR) and the non-CR groups, as determined by imaging and fine-needle aspiration cytology (FNAC) performed 4-8 weeks after the CCRT, and the findings were compared with the clinical characteristics. RESULTS: The sensitivity and the specificity of each evaluation method were as follows: 52.9% and 74.2%, respectively, for computer tomography (CT) and magnetic resonance imaging (MRI); 88.2% and 66.1% for ultrasonography (US); 35.3% and 96.0% for fluorodeoxyglucose-positron emission tomography (FDG-PET) or PET-CT; and 71.4% and 95.6% for FNAC. CONCLUSION: To evaluate the response of lymph node(s) treated by CCRT, US is useful as a positive screening tool and FDG-PET and PET-CT as negative screening tools. FNAC is useful in evaluating suspicious lymph nodes in both positive and negative cases.

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Language：Japanese   Publisher：神奈川県医師会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Purpose: Human cell lines are useful for studying cancer biology and preclinically modeling cancer therapy, but can be misidentified and cross-contamination is unfortunately common. The purpose of this study was to develop a panel of validated head and neck cell lines representing the spectrum of tissue sites and histologies that could be used for studying the molecular, genetic, and phenotypic diversity of head and neck cancer.
Methods: A panel of 122 clinically and phenotypically diverse head and neck cell lines from head and neck squamous cell carcinoma, thyroid cancer, cutaneous squamous cell carcinoma, adenoid cystic carcinoma, oral leukoplakia, immortalized primary keratinocytes, and normal epithelium was assembled from the collections of several individuals and institutions. Authenticity was verified by carrying out short tandem repeat analysis. Human papillomavirus (HPV) status and cell morphology were also determined.
Results: Eighty-five of the 122 cell lines had unique genetic profiles. HPV-16 DNA was detected in 2 cell lines. These 85 cell lines included cell lines from the major head and neck primary tumor sites, and close examination shows a wide range of in vitro phenotypes.
Conclusions: This panel of 85 genomically validated head and neck cell lines represents a valuable resource for the head and neck cancer research community that can help advance understanding of the disease by providing a standard reference for cell lines that can be used for biological as well as preclinical studies. Clin Cancer Res; 17(23); 7248-64. (C)2011 AACR.

DOI： 10.1158/1078-0432.CCR-11-0690

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Purpose: To characterize tumor growth and metastatic potential in head and neck squamous cell carcinoma (HNSCC) cell lines in an orthotopic murine model of oral tongue cancer and to correlate TP53 mutation status with these findings.
Experimental Design: Cells from each of 48 HNSCC cell lines were orthotopically injected into the oral tongues of nude mice. Tumor volume, cervical lymph node metastasis, and mouse survival were recorded. Direct sequencing of the TP53 gene and Western blot analysis for the p53 protein after induction with 5-fluorouracil was conducted. Cell lines were categorized as either mutant TP53 or wild-type TP53, and lines with TP53 mutation were further categorized on the basis of type of mutation (disruptive or nondisruptive) and level of p53 protein expression. The behavior of tumors in these different groups was compared.
Results: These 48 HNSCC cell lines showed a wide range of behavior from highly aggressive and metastatic to no tumor formation. Mice injected with cells harboring disruptive TP53 mutations had faster tumor growth, greater incidence of cervical lymph node metastasis, and shorter survival than mice injected with cells lacking these mutations.
Conclusions: HNSCC cell lines display a wide spectrum of behavior in an orthotopic model of oral cancer. Cell lines with disruptive TP53 mutations are more aggressive in this system, corroborating clinical reports that have linked these mutations to poor patient outcome. Clin Cancer Res; 17(21); 6658-70. (C)2011 AACR.

DOI： 10.1158/1078-0432.CCR-11-0046

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Chemotherapeutic regimens incorporating taxanes significantly improve outcomes for patients with squamous cell carcinomas of the head and neck (SCCHN). However, treatment with taxanes is limited by toxicities, including bone marrow suppression and peripheral neuropathies. We proposed that conjugating taxanes to targeting carrier molecules would increase antitumor efficacy and decrease toxicity. The cell surface proteoglycan, CD44, is expressed on most SCCHNs, and we hypothesized that it is an attractive candidate for targeted therapy via its natural ligand, hyaluronic acid (HA). We determined whether HA-paclitaxel conjugates were able to decrease tumor growth and improve survival in orthotopic nude mouse human SCCHN xenograft models. HA-paclitaxel concentration-dependent growth inhibition of human SCCHN cell lines OSC-19 and HN5 in vitro, very similarly to free paclitaxel treatment. Tumor cell uptake of FITC-labeled HA-paclitaxel was significantly blocked with free HA, indicating the dependence of uptake on CD44. HA-paclitaxel administered intravenously once per week for three weeks at 120 mg/kg paclitaxel equivalents, far above the paclitaxel maximum tolerated dose, exerted superior tumor growth control to that of paclitaxel in both orthotopic OSC-19-luciferase and HN5 xenograft models in vivo. Mouse survival following HA-paclitaxel administration was prolonged compared with that of controls in mice implanted with either of these xenografts. Mice treated with HA-paclitaxel displayed increased TUNEL(+) cells in tumor tissue, as well as markedly reduced microvessel density compared to those treated with free paclitaxel. No acute histopathological changes were observed in mice treated with HA-paclitaxel. Thus, we conclude that HA-paclitaxel effectively inhibits tumor growth in human SCCHN xenografts via an HA-mediated mechanism and this conjugate should be considered for further preclinical development for this disease. (C) 2011 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.oraloncology.2011.07.029

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

Current chemotherapeutics are characterized.-by efficient tumor cell-killing and severe side effects mostly derived from off-target toxicity. Hence targeted delivery of these drugs. to tumor cells is actively sought. We previously demonstrated that poly(ethylene glycol)-functionalized carbon nanovectors are able to sequester paclitaxel, a widely used hydrophobic cancer drug, by simple physisorption and thereby deliver the drug for killing of cancer cells. The cell-killing When these drug-loaded carbon nanoparticles were used was, equivalent to. when a commercial formulation of paclitaxel was used.. Here we show that by further mixing the. drug-loaded nanoparticles with Cetuximab, a monodonal antibody that recognizes the epidermal growth factor receptor (EGFR), paclitaxel is preferentially targeted to EGFR+ tumor cells in vitro. This supports progressing to in vivo studies. Moreover, the construct Is unusual In that all three components are assembled through noncovalent interactions. Such noncovalent assembly could enable high-throughput screening of drug/antibody combinations.

DOI： 10.1021/nn2021293

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Purpose: Anaplastic thyroid carcinoma (ATC) is one of the most lethal human cancers with a median survival of 6 months. The inhibition of epidermal growth factor receptor (EGFR) alone, or with VEGF receptor 2 (VEGFR2), represents an attractive approach for treatment of ATC. Several reports have examined agents that target these receptors. However, with the misidentification of as many as 60% of all commonly used ATC cell lines, the significance of these past findings is unclear.
Experimental Design: Cell lines authenticated by short tandem repeat profiling were selected to establish xenograft tumors in an orthotopic murine model of ATC. These mice were then treated with vandetanib to evaluate its effects on ATC tumor growth. Dynamic contrast-enhanced (DCE) MRI was utilized to measure the impact of vandetanib on tumor vasculature.
Results: Vandetanib inhibited tumor growth of the ATC cell lines Hth83 and 8505C in vivo by 69.3% (P &lt; 0.001) and 66.6% (P &lt; 0.05), respectively, when compared with control. Significant decreases in vascular permeability (P &lt; 0.01) and vascular volume fraction (P &lt; 0.05) were detected by DCE-MRI in the orthotopic xenograft tumors after 1 week of treatment with vandetanib as compared with control.
Conclusion: The inhibition of EGFR and VEGFR2 by vandetanib and its tremendous in vivo antitumor activity against ATC make it an attractive candidate for further preclinical and clinical development for the treatment of this particularly virulent cancer, which remains effectively untreatable. Vandetanib disrupts angiogenesis and DCE-MRI is an effective method to quantify changes in vascular function in vivo. Clin Cancer Res; 17(8); 2281-91. (C) 2011 AACR.

DOI： 10.1158/1078-0432.CCR-10-2762

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Purpose: We investigated whether vandetanib, an inhibitor of the tyrosine kinase activities of vascular endothelial growth factor receptor-2 (VEGFR-2), epidermal growth factor receptor (EGFR), and rearranged during transfection (RET), could augment the antitumor activity of radiation with or without cisplatin in preclinical in vitro and in vivo models of human head and neck squamous cell carcinoma (HNSCC).
Experimental Design: OSC-19 and HN5 HNSCC cells that were cisplatin and radioresistant were treated with vandetanib, cisplatin, and radiation alone or in combination in vitro and in vivo using an orthotopic nude mouse model. Treatment effects were assessed using clonogenic survival assay, tumor volume, bioluminescence imaging, tumor growth delay, survival, microvessel density, tumor and endothelial cell apoptosis, and EGFR and Akt phosphorylation data.
Results: Vandetanib plus cisplatin radiosensitized HNSCC cells in vitro and in vivo. The combination treatment with vandetanib, cisplatin, and radiation was superior to the rest of treatments (including the double combinations) in antitumoral effects, prolonging survival, decreasing cervical lymph node metastases in vivo. It also increased both tumor and tumor-associated endothelial cell apoptosis and decreased microvessel density in vivo. An analysis of tumor growth delay data revealed that vandetanib plus cisplatin enhanced radioresponse in vivo. All vandetanib-containing treatments inhibited EGFR and Akt phosphorylation in vitro and in vivo.
Conclusion: The addition of vandetanib to combination therapy with cisplatin and radiation was able to effectively overcome cisplatin and radioresistance in in vitro and in vivo models of HNSCC. Further study of this regimen in clinical trials may be warranted. Clin Cancer Res; 17(7); 1815-27. (C) 2011 AACR.

DOI： 10.1158/1078-0432.CCR-10-2120

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Background: Squamous cell carcinoma of the head and neck (SCCHN) is the seventh most common cancer worldwide. Unfortunately, the survival of patients with SCCHN has not improved in the last 40 years, and thus new targets for therapy are needed. Recently, elevations in serum level of interleukin 6 (IL-6) and expression of Twist in tumor samples were found to be associated with poor clinical outcomes in multiple types of cancer, including SCCHN. Although Twist has been proposed as a master regulator of epithelial-mesenchymal transition and metastasis in cancers, the mechanisms by which Twist levels are regulated post-translationally are not completely understood. Tumor progression is characterized by the involvement of cytokines and growth factors and Twist induction has been connected with a number of these signaling pathways including IL-6. Since many of the effects of IL-6 are mediated through activation of protein phosphorylation cascades, this implies that Twist expression must be under a tight control at the post-translational level in order to respond in a timely manner to external stimuli.
Methodology/Principal Findings: Our data show that IL-6 increases Twist expression via a transcription-independent mechanism in many SCCHN cell lines. Further investigation revealed that IL-6 stabilizes Twist in SCCHN cell lines through casein kinase 2 (CK2) phosphorylation of Twist residues S18 and S20, and that this phosphorylation inhibits degradation of Twist. Twist phosphorylation not only increases its stability but also enhances cell motility. Thus, post-translational modulation of Twist contributes to its tumor-promoting properties.
Conclusions/Significance: Our study shows Twist expression can be regulated at the post-translational level through phosphorylation by CK2, which increases Twist stability in response to IL-6 stimulation. Our findings not only provide novel mechanistic insights into post-translational regulation of Twist but also suggest that CK2 may be a viable therapeutic target in SCCHN.

DOI： 10.1371/journal.pone.0019412

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Background. We investigated the effects of vandetanib, an inhibitor of vascular endothelial growth factor receptor 2 (VEGFR-2) and epidermal growth factor receptor (EGFR), alone and in combination with paclitaxel in an orthotopic mouse model of human head and neck squamous cell carcinoma (HNSCC).
Methods. The in vitro effects of vandetanib (ZACTIMA) were assessed in 2 HNSCC cell lines on cell growth, apoptosis, receptor and downstream signaling molecule expression, and phosphorylation levels. We assessed in vivo effects of vandetanib and/or paclitaxel by measuring tumor cell apoptosis, endothelial cell apoptosis, microvessel density, tumor size, and animal survival.
Results. In vitro, vandetanib inhibited the phosphorylation of EGFR and its downstream targets in HNSCC cells and inhibited proliferation and induced apoptosis of HNSCC cells and extended survival and inhibited tumor growth in nude mice orthotopically injected with human HNSCC.
Conclusion. Vandetanib has the potential to be a novel molecular targeted therapy for HNSCC. (C) 2010 Wiley Periodicals, Inc. Head Neck 33: 349-358, 2011

DOI： 10.1002/hed.21455

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

Many new drugs have low aqueous solubility and high therapeutic efficacy. Paclitaxel (PTX) is a classic example of this type of compound. Here we show that extremely small (&lt;40 nm) hydrophilic carbon clusters (HCCs) that are PEGylated (PEG-HCCs) are effective drug delivery vehicles when simply mixed with paclitaxel. This formulation of PTX sequestered in PEG-HCCs (PTX/PEG-HCCs) is stable for at least 20 weeks. The PTX/PEG-HCCs formulation was as effective as PTX in a clinical formulation in reducing tumor volumes in an orthotopic murine model of oral squamous cell carcinoma. Preliminary toxicity and biodistribution studies suggest that the PEG-HCCs are not acutely toxic and, like many other nanomaterials, are primarily accumulated in the liver and spleen. This work demonstrates that carbon nanomaterials are effective drug delivery vehicles in vivo when noncovalently loaded with an unmodified drug.

DOI： 10.1021/nn100975c

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Language：Japanese   Publisher：Japan Society for Head and Neck Cancer  

TS-1 is a novel oral fluorouracil antitumor drug that combines three pharmacological agents: FT, a prodrug of 5FU; CDHP, an inhibitor of DPD, and Oxo, a reducer of gastro intestinal toxicity. TS-1 has safe and potent anti-tumor effects in oral cancer via these respective functions.<br>TS-1 increased the effect of irradiation therapy for cancer.<br>We report here a patient who had undergone hemodialysis because of chronic renal failure, with advanced upper gingival cancer in which preoperative concurrent chemoradiotherapy with TS-1was performed.<br>The patient was a 62-year-old male who had a 40×25mm tumor mass around the left posterior buccal sulcus, which invaded to the pterygopalatine fossa (T4N1M0, Stage IVA). TS-1 therapy tends to increase the adverse events for patients with an impaired renal function due to excessively high blood concentration of 5FU, because CDHP is mainly excreted into the urine.<br>The optimum dose of TS-1 for the treatment of upper gingival cancer in a chronic dialysis patient was estimated by monitoring the blood concentrations of 5FU (therapeutic drug monitoring (TDM)) during administration of TS-1. In this treatment protocol, TS-1 was administered 15 times at a daily dose of 25 mg every other day immediately after dialysis. Radiation was given for a total of 40Gy.<br>The treatment could be safely continued without the development of any severe adverse events such as myelosuppression. After this treatment, PR was achieved. The tumor was responded to preoperative concurrent chemoradiotherapy, so curative resection was possible.<br>Histological evaluation after surgery according to General Rules for Clinical Studies on Head and Neck Cancers classification showed grade II.<br>The TS-1 combination with radiotherapy adjusted doses of TS-1 according to the results of pharmacokinetics studies may provide therapeutic safety and high efficacy in gingival carcinoma, in chronic dialysis patients.

DOI： 10.5981/jjhnc.36.19

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Other Link： http://search.jamas.or.jp/link/ui/2010195464

Language：Japanese   Publisher：(一社)日本耳鼻咽喉科頭頸部外科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Purpose: Aberrant expression of inflammatory molecules, such as inducible nitric oxide (NO) synthase (iNOS), has been linked to cancer, suggesting that their inhibition is a rational therapeutic approach. Whereas iNOS expression in melanoma and other cancers is associated with poor clinical prognosis, in vitro and in vivo studies suggest that iNOS and NO can have both protumor and antitumor effects. We tested the hypothesis that targeted iNOS inhibition would interfere with human melanoma growth and survival in vivo in a preclinical model.
Experimental Design: We used an immunodeficient non-obese diabetic/severe combined immunodeficient xenograft model to test the susceptibility of two different human melanoma lines to the orally-given iNOS-selective small molecule antagonist N(6)-(1-iminoethyl)-L-lysine-dihydrochloride (L-nil) with and without cytotoxic cisplatin chemotherapy.
Results: L-nil significantly inhibited melanoma growth and extended the survival of tumor-bearing mice. L-nil treatment decreased the density of CD31+ microvessels and increased the number of apoptotic cells in tumor xenografts. Proteomic analysis of melanoma xenografts with reverse-phase protein array identified alterations in the expression of multiple cell signaling and survival genes after L-nil treatment. The canonical antiapoptotic protein Bcl-2 was downregulated in vivo and in vitro after L-nil treatment, which was associated with increased susceptibility to cisplatin-mediated tumor death. Consistent with this observation, combination therapy with L-nil plus cisplatin in vivo was more effective than either drug alone, without increased toxicity.
Conclusions: These data support the hypothesis that iNOS and iNOS-derived NO support tumor growth in vivo and provide convincing preclinical validation of targeted iNOS inhibition as therapy for solid tumors. Clin Cancer Res; 16(6); 1834-44. (C) 2010 AACR.

DOI： 10.1158/1078-0432.CCR-09-3123

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER MEDICAL ASSOC  

Objective: To evaluate the therapeutic effect of treatment with a combination of the monoclonal antibodies to the vascular endothelial growth factor receptor (DC101) and the epidermal growth factor receptor (cetuximab) in an orthotopic nude mouse model of metastatic squamous cell carcinoma of the oral tongue (SCCOT).
Design: In vivo study.
Setting: A translational research laboratory at a comprehensive cancer center.
Subjects: Male athymic nude mice aged 8 to 12 weeks.
Intervention: To develop orthotopic nude mouse models of SCCOT, OSC-19 cells or luciferase (Luc)-expressing OSC-19-Luc and JMAR-Luc cells were injected into the tongues of nude mice. Animals were randomly divided into 4 groups: DC101 alone, cetuximab alone, DC101 plus cetuximab, or placebo, and all treatments were administered twice per week for 4 weeks. The in vivo antitumor activity was monitored noninvasively by bioluminescence imaging. Tumors were resected at necropsy, and immunohistochemical and immunofluorescent staining were performed.
Main Outcome Measures: Tumor size, bioluminescence, animal survival, and percentage of animals with lymph node metastasis.
Results: At the conclusion of the treatment period, the mean tumor volumes in the cetuximab alone and the DC101 plus cetuximab groups had decreased significantly compared with those that received the placebo control (68% [P=.002] and 84% [P&lt;.001], respectively). Significant effects of the treatment were also observed in bioluminescence imaging. Mice treated with DC101 plus cetuximab also lived longer and had a lower incidence of neck lymph node metastases compared with the control group (P=.003).
Conclusions: Treatment with DC101 plus cetuximab inhibited the growth of SCCOT and decreased the incidence of the neck lymph node metastases in vivo. These results suggest that this combination treatment may be an effective strategy against metastatic SCCOT and warrants further preclinical trials.

DOI： 10.1001/archoto.2009.14

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPANDIDOS PUBL LTD  

The ephB4-ephrinB2 system plays an important role in the interaction of tumor cells with endothelial cells (ECs). To assess the role of ephB4 in the in vivo growth of head and neck squamous cell carcinoma (HNSCC), we used ephrinB2-Fc, a fusion protein consisting of the extracellular domain of ephrin-B2 and the Fc portion of human IgG1, as the soluble ligand for ephB4. EphrinB2-Fc injection into HNSCC xenografted mice significantly suppressed xenograft growth, accompanied by a decrease in vessel cross-sectional area, but there was no change in vessel number. EphrinB2-Fc: injection also induced the formation of mature blood vessels rich in alpha-smooth muscle actin positive pericytes in the xenograft tissue. In vitro assays revealed that ephrinB2-Fc inhibited the proliferation of human umbilical vein ECs (HUVECs) but not tumor cells. Furthermore, real-time quantitative RT-PCR showed that ephrinB2-FC down-regulated matrix metalloproteinase-2 mRNA expression in HUVECs and vascular endothelial growth factor-A in tumor cells. These data suggest that treatment with ephrinB2-Fc, the soluble ligand of ephB4, inhibited the growth of HNSCC through vessel maturation/stabilization, preventing leakiness and endothelial sprout formation.

DOI： 10.3892/ijo_00000154

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Language：English   Publisher：BIOMED CENTRAL LTD  

Head and neck cancers are among the most prevalent tumors in the world. Despite advances in the treatment of head and neck tumors, the survival of patients with these cancers has not markedly improved over the past several decades because of our inability to control and our poor understanding of the regional and distant spread of this disease. One of the factors contributing to our poor understanding may be the lack of reliable animal models of head and neck cancer metastasis. The earliest xenograft models in which human tumor cells were grown in immunosuppressed mice involved subcutaneous implantation of human head and neck cancer cell lines. Subcutaneous xenograft models have been popular because they are easy to establish, easy to manage, and lend themselves to ready quantitation of the tumor burden. More recently, orthotopic xenograft models, in which the tumor cells are implanted in the tumor site of origin, have been used with greater frequency in animal studies of head and neck cancers. Orthotopic xenograft models are advantageous for their ability to mimic local tumor growth and recapitulate the pathways of metastasis seen in human head and neck cancers. In addition, recent innovations in cell labeling techniques and small-animal imaging have enabled investigators to monitor the metastatic process and quantitate the growth and spread of orthopically implanted tumors. This review summarizes the progress in the development of murine xenograft models of head and neck cancers. We then discuss the advantages and disadvantages of each type of xenograft model. We also discuss the potential for these models to help elucidate the mechanisms of regional and distant metastasis, which could improve our ability to treat head and neck cancers.

DOI： 10.1186/1758-3284-1-32

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPANDIDOS PUBL LTD  

Telomelysin is a telomerase-specific replication-competent adenovirus with telomerase reverse transcriptase (hTERT) promoter, which has shown strong anti-tumor effects on a variety of human cancer cells. Human head and neck squamous cell carcinoma (HNSCC) cell lines and a murine HNSCC (NR-S 1) model were used to investigate whether telomelysin (OBP-301) had a therapeutic efficacy for HNSCC. We examined the cell killing effects of telomelysin and the induction of tumor cell apoptosis by telomelysin in vitro. Based on these data, we examined whether telomelysin therapy produced therapeutic benefits in vivo. The results demonstrated that the treatment of telomelysin led to significant tumor regression on the side with subcutaneous NR-S I tumor. We first confirmed the direct anti-tumor effect of intratumoral telomelysin injections in a murine HNSCC model. Further analyses of the augmented anti-tumor effects revealed that telomelysin increased the source of tumor antigens for immune cells, resulting in the induction of CD4(+) and CD8(+) T cells responsible for the in vivo tumor regression of treated and untreated tumors. Subsequently, an elevated IFN-gamma production of spleen cells was observed in mice treated with telomelysin. These results raise the possibility that telomelysin enhances the immune response in addition to its direct tumor cell killing activity. These findings suggest that telomelysin is a potent agent for the treatment of HNSCC patients with multiple metastases.

DOI： 10.3892/or_00000153

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Language：English   Publisher：(一社)日本癌学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Purpose: Adenoid cystic carcinoma (ACC) can often be controlled with surgery and postoperative adjuvant radiotherapy but is also characterized by late local recurrence and distant metastasis. No effective systemic therapeutic agents have been found to alter the natural history of ACC. Therefore, new therapeutic approaches are needed. In this study, we evaluated whether vandetanib (Zactima), a potent inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR) tyrosine kinases, had antitumor efficacy in vitro and in an orthotopic nude mouse model of human ACC.
Experimental Design: The in vitro effects of vandetanib were assessed in three ACC cell lines on cell growth, apoptosis, and VEGFR-2 and EGFR phosphorylation levels. The in vivo antitumor activity of vandetanib was examined in nude mice bearing parotid gland ACC tumors. The mice were treated for 4 weeks with vandetanib (50 mg/kg/d) or placebo (control). Tumors were resected at necropsy, and immunohistochemical and immunofluorescence staining were done.
Results: In vitro, vandetanib caused dose-dependent inhibition of VEGFR-2 and EGFR phosphorylation in ACC cells. Vandetanib also inhibited the cell proliferation and induced their dose-dependent apoptosis. In vivo, mice in the vandetanib group had tumor volumes significantly lower than those in the control group (P &lt; 0.01). In addition, immunohistochemical staining showed a decrease in microvessel density and an increase in apoptosis of both tumor cells and endothelial cells within the tumor xenografts.
Conclusion: These results suggest that vandetanib inhibits the growth of ACC in vitro and in vivo, making it a promising novel agent for the treatment of ACC.

DOI： 10.1158/1078-0432.CCR-08-0245

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PROFESSOR D A SPANDIDOS  

The overexpression of EGFR and/or HER-2 is associated with tumor cell resistance to chemotherapy, radiotherapy, disease progression and poor prognosis in patients with a variety of malignant tumors. Treatment combining the EGFR-targeting drug, gefitinib (ZD 1839, Iressa) with the HER-2-targeting drug, trastuzumab (Herceptin) has been reported to improve therapeutic efficacy in patients with breast cancer. The purpose of this study was to examine the antitumor effect of this combination on head and neck squamous cell carcinoma (HNSCC) in vitro. Cell proliferation was inhibited significantly in two cell lines. Although IC50 of gefitinib alone against some cell lines was not reached, it was achieved after being combined with trastuzumab. Furthermore, IC50 was lower for the combination than for gefitinib alone in several cell lines. These results suggest that the combination may improve efficacy against HNSCC.

DOI： 10.3892/or_00000017

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科頭頸部外科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PROFESSOR D A SPANDIDOS  

Epidermal growth factor receptor (EGFR) gene mutations are associated with the sensitivity of non-small cell lung carcinomas (NSCLCs) to gefitinib, but such findings have not been reported in squamous cell carcinomas of the head and heck (SCCHNs). Accordingly, we determined whether EGFR gene expression and mutations correlate with the in vitro efficacy of gefitinib in SCCHN cell lines. EGFR status was analyzed in 16 different SCCHN cell lines by polymerase chain reaction (PCR) and direct sequencing for activating mutations, by real-time quantitative RT-PCR, and by Western blot analysis for RNA and protein expression. Using direct sequencing of PCR products from exons 18-23 of 9 SCCHN cell lines, we found a heterozygous EGFR mutation (EGFR(mut)) with a 2607G A transition in exon 20 (G/A genotype). The 9 different cell lines that showed this mutation also showed higher sensitivity (lower IC50 values) to gefitinib than cell lines with wild-type EGFR (EGFR(wt): G/G genotype) (p=0.016). EGFR protein levels correlated robustly (r=0.76) and significantly (p=0.0007) with EGFR mRNA levels and with IC50 values for gefitinib (r=0.65, p=0.0067). EGFR mRNA correlated with IC50 values (r=0.67, p=0.0046). Our conclusion was that the heterozygous and synonymous transition of the EGFR gene and low EGFR expression levels of mRNA and protein in SCCHN may be reliable predictors of high sensitivity in SCCHN patients to gefitinib.

DOI： 10.3892/or.19.1.65

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Language：English   Publisher：ELSEVIER SCI LTD  

Objective: Nafamostat mesilate (FUT-175), a synthetic serine protease inhibitor, has antitumor activities toward adenocarcinoma, e.g., colon cancer. However, its antitumor effects on other types of cancer have been less extensively studied. We investigated the biological activities of Nafamostat mesilate on cell proliferation, cell-invasive potential and growth factor production in head and neck squamous cell carcinoma (HNSCC).
Methods: Two human HNSCC cell lines established in our department, YCU-L891 and -H891, and a human vulvar squamous cell carcinoma cell line, A431, were examined for the effect of Nafamostat mesilate. The effects on cell growth were evaluated using the MTT assay. The effects on the relative expression levels of mRNA were measured by quantitative RT-PCR. Cytokine secretion was analyzed by enzyme-linked immunosorbent assay.
Results: Nafamostat mesilate inhibited the proliferation of two HNSCC cell lines, YCU-L891 and YCU-H891, and A431. In these cell lines, Nafamostat mesilate down-regulated both matrix metalloproteinase (MMP)-2 and -9. In addition, it reduced the productions of vascular endothelial growth factor (VEGF) and transforming growth factor betal (TGF-betal) by the tumor cells.
Conclusion: Our results suggest that Nafamostat mesilate has potential for use as a treatment against local growth, invasion and metastasis of squamous cell carcinoma. (c) 2007 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.anl.2006.12.002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PROFESSOR D A SPANDIDOS  

Human tumors are dependent on angiogenesis for growth, and the vascular endothelial growth factor (VEGF) is a major regulator of this process. Bevacizumab (Avastin (R)), a monoclonal antibody directed against VEGF, has shown promise in treating a variety of cancers. In this study, we first examined the anti-tumor effects of bevacizumab on head and neck squamous cell carcinoma (HNSCC). Then we examined the effects of bevacizumab combined with paclitaxel, a chemotherapeutic agent, in HNSCC. This is the first demonstration of the anti-tumor effects of bevacizumab on HNSCC. In vitro, bevacizumab did not show any antiproliferative effects against the HNSCC cell lines. However, in vivo, bevacizumab showed dramatic anti-tumor effects against HNSCC tumor xenografts in mice. In addition, treatment with a bevacizumab-paclitaxel combination resulted in a remarkable inhibition of the HNSCC tumor xenografts, compared to the effects of each agent separately. A decreased blood vessel density and an increased apoptotic index were seen in the shrunken tumors. These results suggest that bevacizumab in combination with paclitaxel could have useful clinical application in HNSCC.

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科頭頸部外科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PROFESSOR D A SPANDIDOS  

Angiogenesis is required for tumor growth and metastasis and, therefore, represents a target for cancer treatment. While many factors have been implicated in promoting angiogenesis, vascular endothelial growth factor (VEGF) plays a key role in tumor angiogenesis. ZD6474 is a potent VEGF receptor-2 (VEGFR-2) tyrosine kinase inhibitor which also has activity against the epidermal growth factor receptor (EGFR) tyrosine kinase. The purpose of this study was to investigate the sensitivity of head and neck squamous cell carcinoma (HNSCC) cell lines to ZD6474, and to evaluate its antitumor efficacy on HNSCC xenografts. This is the first demonstration of antitumor effects of ZD6474 on HNSCC. In vitro ZD6474 displayed antiproliferative effects on HNSCC cells and inhibition of VEGFR-2 and EGFR pathways. In vivo ZD6474 displayed antitumor activity, induced apoptosis and antiangiogenic activity on nude mice bearing an established xenograft of YCU-H891 cells. These results suggest that ZD6474 has the potential to inhibit two key pathways in tumor growth via inhibition of VEGF-dependent tumor angiogenesis and via inhibition of EGFR-dependent tumor cell proliferation.

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Language：Japanese   Publisher：(株)癌と化学療法社  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

Myxofibrosarcoma is common in the extremities, but rare in the head and neck region. Hypopharyngeal myxofibrosarcoma has not been reported previously. We report the first case of a patient with myxofibrosarcoma of the hypopharynx. We examined this patient once a month after the operation, and there has been no local recurrence and no distant metastasis. Sarcomas are rare in the hypopharynx, but we have to bear in mind their possibility. Though a low-grade myxofibrosarcoma is a low-grade malignancy, complete resection should be done. We have to pay more attention planning the treatment for neoplastic diseases. (C) 2005 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.anl.2005.07.004

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

Objective: Since maxillary sinus is composed of bone structure, the main symptoms of maxillary sinus carcinoma are related to the anatomical feature and the destructive lesion of the bony wall, such as cheek pain and nasal obstruction.
Methods: We report a female case with undifferentiated carcinoma in the right maxillary Sinus, only appearing cervical swelling which was revealed as lymph node metastasis.
Results: CT and MRI findings showed just maxillary sinusitis with minor bone destruction. However, fluorine 18-labelled deoxyglucose positron emission tomography (FDG-PET) was useful for the detection of the primary site. The patient received concomitant chemoradiotherapy, and showed a complete response both in the primary site and neck lymph nodes. She has no recurrence for 18 months after the primary therapy.
Conclusion: The main symptoms of maxillary sinus carcinoma are related to the local progression, and known to have less cervical lymph node metastasis. However, like the present case, there is a rare case that has no symptom and organic features associated with the local mass. With the best use of advanced diagnostic technique, e.g., FDG-PET, we could diagnose and treat atypical maxillary sinus carcinoma patients. (C) 2005 Elsevier Ireland Ltd. All fights reserved.

DOI： 10.1016/j.anl.2005.05.014

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PROFESSOR D A SPANDIDOS  

Taxanes, a new class of antitumor drugs, are effective against a large number of human tumors, although there are problems with drug resistance. The novel taxane, IDN5109, is characterized by its high tolerability, antitumor efficacy, ability to overcome multidrug resistance, and oral bioavailabilty. We investigated the cellular response of IDN5 109 to head and neck squamous cell carcinoma (HNSCC), and compared the antitumor activity of IDN5109 with that of paclitaxel. This is the first demonstration of antitumor effects of IDN5109 on HNSCC. In in vitro experiments, IDN5109 showed anti proliferative effects against HNSCC cell lines. After treatment with IDN5109, Bcl-2 and Bcl-XL were down-regulated, Bax was upregulated, and caspase-3 was activated. After treatment with IDN5 109, concentrations of both VEGF and IL-8 in the culture supernatant of HNSCC cells decreased. In in vivo experiments, the oral administration of IDN5109 showed antitumor effects against HNSCC tumor xenografts. immunohistochemistry showed that IDN5109 inhibited tumor angiogenesis and induced apoptosis in HNSCC cells, producing a decreased blood vessel density and increased apoptosis index. On the basis of these results, IDN5109 is useful as a chemotherapeutic agent against HNSCC.

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Language：Japanese   Publisher：(株)癌と化学療法社  

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Language：Japanese   Publisher：(一社)日本癌学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS AS  

Metastatic carcinomas in the larynx are uncommon, and laryngeal tumors originating from the colon are extremely rare. We report a case of metastatic laryngeal tumor originating from a colon adenocarcinoma in an 81-year-old female. Only a tracheostomy was performed because the patient presented with multiple metastases in other regions. The diagnosis, route of metastasis, treatment and prognosis of metastatic laryngeal tumors are discussed.

DOI： 10.1080/00016480410022930

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Society of Practical Otolaryngology  

A 22-year-old female, who had been diagnosed with aortitis syndrome five years earlier, consulted our clinic in May 1992 complaining of hearing loss and tinnitus in the right ear. Since the first onset of hearing loss, pure-tone audiogram was performed many times over a period of twelve years. Hearing fluctuated with no relation to the dose of steroid hormone during the initial three years, but hearing improvement thereafter depended on the dose of steroid hormone. During long-term follow-up, hearing disturbance gradually progressed. A tendency for CRP to become elevated and the sedimentation rate to increase just before hearing worsened was found. It appeared that hearing loss was one of the symptoms of aortitis syndrome. Cases of sensorineural hearing loss with aortitis syndrome should be followed for a long time, because in some cases previously reported hearing disturbance progresses.

DOI： 10.5631/jibirin.97.1043

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Language：Japanese   Publisher：Society of Oto-rhino-laryngology Tokyo  

We reported a case of a 35-year-old man with an intractable recurrent ulcer of the hypopharynx. Ulcers in the oral cavity and pharynx may be involved Behçet's disease or malignant tumors, but we should rule out Behçet's disease or malignant tumors from intractable recurrent ulcers. Intractable recurrent ulcer in the oral cavity and pharynx is defined as irregular ulcerating lesions limited to the oral cavity and pharynx without specific clinical abnormalities ; such ulcers recur frequently and may be resistant to treatments for more than one month. Although intractable recurrent ulcer etiology in the oral cavity and pharynx remains unknown, immunologic disorders are thought to be related. Long-term follow-up is needed because some recurrent ulcers in the oral cavity and pharynx have been reported to be a partial symptom of Behçet's disease. Although many reports have shown that steroids are the most effective medication for intractable recurrent ulcer, steroids should not be used as the first choice if we are to avoid side effects of steroids and difficulty in abstinence from them. In the present case, we did not adminisiter steroids because local treatment was effective.

DOI： 10.11453/orltokyo1958.47.243

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Language：Japanese  

CiNii Research

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Publisher：東京医学社  

DOI： 10.24479/ohns.0000000836

CiNii Research

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Language：Japanese   Publisher：(株)癌と化学療法社  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J00296&link_issn=&doc_id=20230725250006&doc_link_id=%2Fab8gtkrc%2F2023%2F005007%2F007%2F0775-0780%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2023%2F005007%2F007%2F0775-0780%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(株)東京医学社  

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Language：Japanese   Publisher：(NPO)日本気管食道科学会  

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2022&ichushi_jid=J01054&link_issn=&doc_id=20220608270022&doc_link_id=%2Fea4broes%2F2022%2F007302%2F027%2F0098-0101%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fea4broes%2F2022%2F007302%2F027%2F0098-0101%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(株)東京医学社  

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Language：Japanese   Publisher：(株)羊土社  

がん微小環境において、神経ががんの進展に関与することがわかってきた。がん関連神経はがん細胞と相互作用を起こすだけでなく、血管内皮細胞や免疫細胞といった多様な因子と協調して、がん細胞の生存と進展にかかわっている。がん関連神経と他の細胞とのコミュニケーションには成長因子やケモカインだけでなく、細胞外小胞が重要な役割を担っている。がん関連神経はさまざまながんの予後予測因子となることが報告されているほか、画期的で有望な治療標的として研究が進められている。(著者抄録)

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Language：Japanese   Publisher：(株)東京医学社  

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Language：Japanese   Publisher：(株)癌と化学療法社  

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J00296&link_issn=&doc_id=20210720430008&doc_link_id=%2Fab8gtkrc%2F2021%2F004807%2F009%2F0900-0902%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2021%2F004807%2F009%2F0900-0902%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞POINT ▼ヒト乳頭腫ウイルス(HPV)対する感染予防ワクチン(2価,4価,9価)がすでに本邦で製造販売承認されている。▼HPVワクチン接種が広く実施されている諸外国では,HPV感染や子宮頸癌の前癌病変の発症減少が報告されている。▼頭頸部領域では中咽頭癌,特に扁桃・舌根原発の癌とHPV感染との関連が確実視されている。▼口腔内HPV感染がHPV関連中咽頭癌の発症に先行すると考えられる。▼HPV関連中咽頭癌が好発する中高年男性の口腔内HPV16陽性率は低く,効果的なワクチン接種の時期・年齢について今後検討されなければならない。

DOI： 10.11477/mf.1411202732

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Language：Japanese   Publisher：日本耳鼻咽喉科免疫アレルギー感染症学会  

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Language：Japanese   Publisher：JIBI TO RINSHO KAI  

A 62-year-old man who was initially diagnosed with Stage IVa squamous cell cancer of the hypopharynx, received concurrent chemoradiotherapy with cisplatin. As local recurrence was subsequently observed, he underwent total laryngopharyngectomy with free flap reconstruction. However, unresectable cervical lymph node metastasis was observed 3 months after the surgery. He was therefore treated with nivolumab as first-line therapy. As disease progression was observed after 4 courses of nivolumab, he was then treated with paclitaxel plus cetuximab as second-line therapy. He suddenly lost consciousness at home 2 days after 8 courses of the chemotherapy (11 months after the first administration of nivolumab). As elevated CK was observed in the laboratory test on admission, immune-related adverse events were initially suspected. The patient died without showing a response to steroid therapy, ventilator management, continuous hemodiafiltration and other treatments. The autopsy revealed a lack of cross-striation of skeletal muscle, indicating the existence of rhabdomyolysis. Although there have been few reports on rhabdomyolysis after nivolumab treatment date, this immune-related adverse events (irAEs) may be a potentially fatal adverse event.

DOI： 10.11334/jibi.67.3_193

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Language：Japanese   Publisher：(株)全日本病院出版会  

根治治療の対象とならない再発・転移性頭頸部扁平上皮癌に対する現在の標準的な一次治療はCDDP+5FU療法(PF療法)にセツキシマブを加えた、いわゆるEXTREMEレジメンである。さらに、プラチナ製剤使用歴のある再発・転移性頭頸部癌に対してニボルマブが近年本邦でも承認された。EXTREMEレジメンはプラチナ製剤を含むため、再発・転移性頭頸部扁平上皮癌に対する薬物療法における化学療法と免疫療法の最適化にはプラチナ抵抗性の判断が重要となる。さらに、比較的低い奏効率、奏効するまでやや時間を要するといった免疫阻害薬が有する特徴や、免疫阻害薬に特有の免疫関連有害事象なども考慮し、化学療法と免疫療法の最適化を図る必要がある。(著者抄録)

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科学会  

Stress Velopharyngeal Insufficiency/Incompetence(SVPI;吹奏楽器の演奏時のみ呼気が鼻腔より抜けることで演奏に支障を来す病態)の1例を経験したので報告する。症例は19歳、男性。クラリネット演奏時のみ鼻から空気が漏れ、吹き続けられないため、当科を受診した。ファイバースコピーでは、頬ふくらまし時にアデノイドの小隆起の左側より呼気の漏出を認めた。全身麻酔下、上咽頭脂肪注入を施行したところ、呼気の漏出と症状は消失し、術後1年再発を認めていない。本邦において耳鼻咽喉科医師の中でも認知度が低いと思われるSVPIについて文献的考察を加え、症例提示する。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J01099&link_issn=&doc_id=20200409390010&doc_link_id=%2Fdz0jibik%2F2020%2F012303%2F010%2F0251-0256%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdz0jibik%2F2020%2F012303%2F010%2F0251-0256%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(一社)日本耳鼻咽喉科学会  

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Language：Japanese   Publisher：日本喉頭科学会  

初回根治手術として喉頭摘出術、咽頭喉頭摘出術を施行した局所進行喉頭・下咽頭扁平上皮癌患者76例を対象に、炎症性バイオマーカーの予後予測における有用性について検討した。その結果、治療前CAR(CRP/アルブミン値比)が予後予測因子として有用である可能性が示唆された。

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J02852&link_issn=&doc_id=20200106280025&doc_link_id=%2Fea7kotou%2F2019%2F003102%2F025%2F0157-0162%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fea7kotou%2F2019%2F003102%2F025%2F0157-0162%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：日本喉頭科学会  

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Language：Japanese   Publisher：(一社)日本頭頸部癌学会  

基礎研究から臨床への橋渡しを担うトランスレーショナルリサーチにおいて、細胞レベルの研究で得られた結果を確認、検証する際に動物モデルが広く用いられている。がん研究で汎用される皮下担癌モデルに対して、癌の浸潤・転移パターンを反映することが可能となる同所性担癌モデルが開発されており、我々は以前より同モデルを用いた頭頸部がんトランスレーショナルリサーチに取り組んできた。一方、同所性担癌モデルを含む動物モデルは樹立した細胞株を通常は用いて作製するため、平面培養により維持されている細胞株の限界、すなわちがん組織の不均一性や、がん周囲の微小環境の再現が困難という実験系の限界が存在する。本稿では、頭頸部がんトランスレーショナルリサーチにおける同所性担癌モデルの有用性、並びに従来の担癌モデルの限界に対する我々の取り組みについて述べる。(著者抄録)

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Language：Japanese   Publisher：(一社)日本頭頸部癌学会  

基礎研究から臨床への橋渡しを担うトランスレーショナルリサーチにおいて、細胞レベルの研究で得られた結果を確認、検証する際に動物モデルが広く用いられている。がん研究で汎用される皮下担癌モデルに対して、癌の浸潤・転移パターンを反映することが可能となる同所性担癌モデルが開発されており、我々は以前より同モデルを用いた頭頸部がんトランスレーショナルリサーチに取り組んできた。一方、同所性担癌モデルを含む動物モデルは樹立した細胞株を通常は用いて作製するため、平面培養により維持されている細胞株の限界、すなわちがん組織の不均一性や、がん周囲の微小環境の再現が困難という実験系の限界が存在する。本稿では、頭頸部がんトランスレーショナルリサーチにおける同所性担癌モデルの有用性、並びに従来の担癌モデルの限界に対する我々の取り組みについて述べる。(著者抄録)

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Language：Japanese   Publisher：耳鼻と臨床会  

早期舌癌治療の大きな論点となっている潜在的頸部リンパ節転移を予測する上で、腫瘍が転移能を獲得する十分な時間経過を有するという観点から原発巣の進達度、また腫瘍が実際に遊走能・浸潤能を獲得しているという観点から腫瘍深部浸潤先端部における浸潤様式が重要と考えられる。本稿では早期舌癌における潜在的頸部リンパ節転移の予測因子としてのdepth of invasionを含めた腫瘍の深達度や、YK分類や大腸癌における簇出や低分化胞巣を含めた腫瘍深部浸潤先端部における浸潤様式の有用性について述べる。(著者抄録)

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科学会  

消化器疾患術後の嚥下障害患者において、初回嚥下内視鏡検査(以下VE)の結果から経口摂取の予後予測が可能か検討する。2013年1月〜2017年9月までに、当院消化器外科で施行された全身麻酔下手術症例のうち、術後嚥下機能評価目的に当科に紹介された28症例を対象とした。初回VE時から最長80日後までの経口摂取状況を追跡調査し、1)経口摂取の可否、2)代替栄養離脱の可否について、患者背景(年齢、性別、術前の嚥下性肺炎既往の有無、気管切開の有無、声帯麻痺の有無、ASA-PS分類、手術時間)、初回嚥下内視鏡検査のスコア評価法(以下兵頭スコア)、VE時の誤嚥の有無との関連を単変量解析(Fisher検定)にて検討した。また、Kaplan-Meier法を用いて、初回兵頭スコアの高低別(cut off値6点)および初回VE時の誤嚥の有無別の経口摂取開始率と代替栄養離脱率を検討した。有意差検定にはlog-rank検定を用いた(p<0.05)。初回VE時から最長80日後までの経過観察において、経口摂取可能例26例、不能例2例、代替栄養離脱例19例、依存例9例であった。初回兵頭スコア≦6点群19例、兵頭スコア<6点群9例、初回VE時に誤嚥あり10例、誤嚥なし18例であった。経口摂取・代替栄養離脱の可否別の単変量解析において、患者背景因子、初回兵頭スコア、VE時の誤嚥の有無について有意差を認めなかった。しかし、兵頭スコア高値群は兵頭スコア低値群と比較し、経口摂取開始や代替栄養離脱までに有意に長い日数を要した。またVE時の誤嚥の有無別においても、経口摂取開始までに有意差は認めなかったが、代替栄養離脱までに有意に長い日数を要した。消化器疾患術後の嚥下機能評価として初回VE時の兵頭スコアおよび誤嚥の有無は、最終的な経口摂取可否の予測因子にはならないが、代替栄養離脱までの期間を予測する因子であることが示された。(著者抄録)

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Language：Japanese   Publisher：(株)東京医学社  

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Language：Japanese   Publisher：(株)癌と化学療法社  

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科学会  

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J01099&link_issn=&doc_id=20190724450014&doc_link_id=1390282763132634112&url=https%3A%2F%2Fcir.nii.ac.jp%2Fcrid%2F1390282763132634112&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_3.gif

Language：Japanese   Publisher：(株)癌と化学療法社  

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Language：Japanese   Publisher：(一社)日本頭頸部癌学会  

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Language：Japanese   Publisher：(株)東京医学社  

症例は72歳男性で、1ヵ月前からの嚥下困難を認め近医を受診した。下咽頭に腫瘍性病変を認め、生検で扁平上皮癌と診断、重複癌検索目的で施行した上部消化管内視鏡検査で切歯より18〜25cmの部位に3型食道癌を認めたため当院紹介となった。咽頭喉頭摘出食道抜去、非開胸後縦隔胃管再建、両側頸部郭清術、腸瘻造設術を施行した。術後2日目に淡血性の口腔出血を認めた。喉頭ファイバーでは縫合部を含め、活動性出血を認めず、挙上胃管はややうっ血気味であったが組織壊死を積極的に疑う所見は認めなかった。しかし、術後28日目より永久気管孔近傍に瘻孔形成を認め、喉頭ファイバーでは挙上胃管の組織壊死を疑う白色調の色調変化を認めた。再建胃管の壊死と判断し、遊離空腸による再建術を施行した。再手術後の経過は良好であり、下咽頭造影でリークを認めず、初回手術後77日後、経口摂取可能な状態で退院となった。

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Language：Japanese   Publisher：(一社)日本頭頸部癌学会  

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Language：Japanese   Publisher：(一社)日本頭頸部癌学会  

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科学会  

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Language：Japanese   Publisher：(株)医学書院  

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科学会  

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科学会  

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科学会  

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科学会  

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Language：Japanese   Publishing type：Book review, literature introduction, etc.   Publisher：Oto-Rhino-Laryngological Society of Japan Inc.  

DOI： 10.3950/jibiinkoka.122.1009

Scopus

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Language：Japanese   Publisher：日本喉頭科学会  

初回根治治療として放射線治療、化学放射線治療を行ったStage IV下咽頭扁平上皮癌88例(年齢中央値67歳、観察期間中央値22ヵ月)を対象として、進行下咽頭扁平上皮癌における炎症性マーカーの有用性を後方視的に検討した。患者背景、各種炎症性バイオマーカーや小野寺らのprognostic nutritional index(PNI)と予後との関連について単変量解析、多変量解析、カプランマイヤー生存曲線解析を行った。その結果、好中球数/リンパ球数比(NLR)は全生存期間(OS)と無増悪生存期間(PFS)の増悪に、F-NLR scoreはPFSの増悪に、TPFレジメンの併用はPFSの改善にそれぞれ有意に寄与していた。また、独立した予後予測因子として治療前NLRとF-NLR scoreが示されたが、血清アルブミン値やPNIの有用性は明らかでなかった。

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Language：Japanese   Publisher：(株)東京医学社  

症例は72歳男性で、胸部食道癌に対して開胸胸部食道亜全摘術、3領域郭清、後縦隔経路頸部吻合、胃管再建、腸瘻増設を施行した。術後2日目に人工呼吸器を離脱し、理学療法を開始した。術後3日目にICUを退室した。術後8日目、吻合部造影検査時の飲水テストで著明なムセ込みを認めた。口腔期嚥下機能は保たれており、声帯麻痺・鼻咽腔閉鎖不全・早期咽頭流入などの随伴所見は認めなかった。しかし、嚥下内視鏡検査(VE)では嚥下内視鏡検査スコア(VEスコア)12点と高度嚥下障害を認めた。喉頭挙上が起こらず、非嚥下時に唾液の高度誤嚥を認めた。間接訓練を開始し、嚥下体操やアイスマッサージについて指導し、以降はパンフレットに基づき看護師のサポートのもと訓練を継続した。術後14日目、VEスコア5点と咽喉頭知覚の改善を認め、直接訓練開始可能と判断した。術後15日目、吻合部造影検査でマイナーリークを認め直接訓練は中断したが、術後24日目に縫合不全改善と判断し、直接訓練を再開した。術後27日目から嚥下調整食摂取を、術後32日目に全粥摂取を開始した。術後38日目、経管栄養や経口栄養剤を要せずに自宅退院した。

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Language：English   Publisher：日本癌学会  

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Language：Japanese   Publisher：特定非営利活動法人 日本頭頸部外科学会  

Esophageal carcinosarcoma is a rare malignant tumor. We report a case of carcinosarcoma in the cervical esophagus treated by radical surgery. A 73-year-old male complaining of dysphagia visited a clinic. Esophagogastroscopy revealed a longitudinally-spread tumor in the cervical esophagus, extending from the hypopharynx to the upper thoracic esophagus. He was diagnosed as having stage Ⅳ esophageal cancer and was referred to our hospital. A biopsy specimen showed histology of carcinosarcoma. He underwent total pharyngo-laryngo-esophagectomy with bilateral neck dissection. Histological examination of the resected tumor showed the presence of both spindle-shaped atypical cells and squamous carcinoma cells, and the transition of the two components was also observed. The final diagnosis was carcinosarcoma. The tumor invasion was limited within muscularis propria, and no regional lymph node metastatis was detected. The pathological TNM was T2N0M0. He has been disease-free for three years after the radical surgery.

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科学会  

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Language：Japanese   Publisher：(NPO)日本頭頸部外科学会  

咽頭腔外異物は位置同定が困難であり摘出に外切開を要する例もあるが、経口腔的に摘出し得た下咽頭粘膜下(咽頭腔外)魚骨異物の1例を経験したので報告する。症例は72歳女性で、カレイを摂取した翌日に当科を受診した。咽喉頭ファイバースコピーで異物を同定できなかったが、CTで下咽頭後壁右側から正中に向かって走行する魚骨を疑わせる所見を認め手術の方針とした。佐藤式彎曲型咽喉頭直達鏡で下咽頭を展開し、CT所見を参考に下咽頭粘膜を切開剥離して異物を同定し摘出し得た。異物周囲に感染がなかった事、CTが異物の位置を正確に反映していた事、下咽頭の広範な視野を確保できた事が経口腔的摘出成功の理由として考えられた。(著者抄録)

DOI： 10.5106/jjshns.27.325

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Language：Japanese   Publisher：(NPO)日本頭頸部外科学会  

咽頭腔外異物は位置同定が困難であり摘出に外切開を要する例もあるが、経口腔的に摘出し得た下咽頭粘膜下(咽頭腔外)魚骨異物の1例を経験したので報告する。症例は72歳女性で、カレイを摂取した翌日に当科を受診した。咽喉頭ファイバースコピーで異物を同定できなかったが、CTで下咽頭後壁右側から正中に向かって走行する魚骨を疑わせる所見を認め手術の方針とした。佐藤式彎曲型咽喉頭直達鏡で下咽頭を展開し、CT所見を参考に下咽頭粘膜を切開剥離して異物を同定し摘出し得た。異物周囲に感染がなかった事、CTが異物の位置を正確に反映していた事、下咽頭の広範な視野を確保できた事が経口腔的摘出成功の理由として考えられた。(著者抄録)

DOI： 10.5106/jjshns.27.325

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Language：English   Publisher：日本癌学会  

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Language：Japanese   Publisher：神奈川県臨床細胞学会  

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Language：Japanese   Publisher：(NPO)日本頭頸部外科学会  

上顎全摘術では、外切開による軟部組織の処理、骨削開を行い、翼状突起の切断にはノミが使用される。しかし、良好な視野が得られない中での操作になることや頭蓋底が近いことによる恐怖心のために切除ラインが術前の想定通りとならない可能性が指摘されてきた。上顎全摘術において、外切開に先立ち内視鏡下で鼻腔内の粘膜切断、骨削開を施行することにより、術前に予定した切除ラインで摘出が可能であった上顎洞悪性腫瘍例を経験した。内視鏡併用により、鼻腔内の軟部組織だけでなく、翼状突起、蝶形骨と厚い部分の骨削開を内視鏡下の良好な視野であらかじめ行っておくことで、外側から想定通りの骨切りラインでの切断が容易になると考えられた。(著者抄録)

DOI： 10.5106/jjshns.27.129

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Language：Japanese  

J-GLOBAL

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Language：Japanese   Publisher：日本音声言語医学会  

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Language：Japanese   Publisher：Japan Society for Head and Neck Cancer  

While concurrent chemoradiotherapy has been used as one of the main larynx preservation strategies for patients with locally advanced laryngeal or hypopharyngeal cancer for whom surgical treatment would require a total laryngectomy, unfortunately there are some patients with residual or recurrent lesions after radiotherapybased treatment. It is therefore necessary to plan an adequate treatment strategy for these patients. This paper reviews the impact of metabolic tumor volume (MTV), a volumetric parameter of FDG-PET, as an important factor when planning the treatment strategy for patients with laryngeal cancer, and the role of lymph node ratio when selecting suitable patients with advanced HNSCC for receiving postoperative intensive adjuvant therapy.

DOI： 10.5981/jjhnc.43.320

Scopus

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Language：Japanese   Publisher：Oto-Rhino-Laryngological Society of Japan Inc.  

Orbital infection often disturbs the functioning of the eyes because of the increase of the orbital pressure caused by the inflammatory reaction and abscess formation. Herein, we report the case of a 68-year-old woman who developed an intraorbital abscess as a complication of acute dacryocystitis while receiving methotrexate therapy. We performed endonasal endoscopic drainage of the intraorbital abscess and didn't find orbital complications. In such cases, it is necessary to establish quick and close cooperation with ophthalmologists and perform urgent surgical drainage to preserve the functioning of the eyes.

DOI： 10.3950/jibiinkoka.120.722

Scopus

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Language：Japanese   Publisher：(NPO)日本気管食道科学会  

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Language：Japanese   Publisher：(NPO)日本気管食道科学会  

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Language：English   Publisher：日本癌学会  

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Language：English   Publisher：日本癌学会  

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Language：Japanese   Publisher：日本耳鼻咽喉科感染症・エアロゾル学会  

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Language：Japanese   Publisher：(株)東京医学社  

J-GLOBAL

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科学会  

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Language：Japanese   Publisher：神奈川県医師会  

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Language：Japanese  

J-GLOBAL

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Language：Japanese   Publisher：日本耳鼻咽喉科感染症・エアロゾル学会  

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Language：Japanese   Publisher：耳鼻咽喉科展望会  

ヒト乳頭腫ウイルス(HPV)陽性中咽頭癌は多量の喫煙歴や飲酒歴がない比較的若年者に発生し、早期に所属リンパ節転移を起こすものの、放射線や化学療法に対する感受性が高く、従来型の中咽頭癌と比較して有意に予後良好であるなど異なる臨床像を呈する。HPVについて、HPVによる発癌、HPVと頭頸部癌、北海道大学での中咽頭癌症例におけるHPV検出、HPV関連中咽頭癌の臨床像・治療成績と予後、HPV陽性中咽頭癌の治療成績が良好である理由について述べた。

DOI： 10.11453/orltokyo.58.4_194

J-GLOBAL

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Language：Japanese  

DOI： 10.5106/jjshns.25.99

J-GLOBAL

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Language：Japanese   Publisher：日本頭頸部癌学会  

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科学会  

DOI： 10.3950/jibiinkoka.118.606

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科学会  

DOI： 10.3950/jibiinkoka.118.581

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Language：Japanese   Publisher：JAPAN SOCIETY FOR HEAD AND NECK SURGERY  

Myxofibrosarcoma is common in the extremities, but rare in the head and neck region, and myxofibrosarcoma arising from the temporal muscle has not been reported previously. We report the first case of a patient with temporal muscle myxofibrosarcoma. The treatment was complete resection and the patient has been alive for 8 months without disease. Sarcomas in the temporal muscle are rare, but their possibility must be considered. Though a low-grade myxofibrosarcoma is a low-grade malignancy, complete resection should be performed. Greater attention should be paid to planning the treatment for neoplastic diseases.

DOI： 10.5106/jjshns.24.311

J-GLOBAL

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Language：Japanese   Publisher：神奈川県医師会  

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Language：Japanese   Publisher：神奈川県医師会  

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Language：Japanese   Publisher：(NPO)日本気管食道科学会  

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Language：Japanese  

DOI： 10.11334/jibi.60.Suppl.1_S70

J-GLOBAL

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Language：Japanese  

J-GLOBAL

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Language：Japanese  

J-GLOBAL

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Language：Japanese  

DOI： 10.3950/jibiinkoka.117.502

J-GLOBAL

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Language：Japanese   Publisher：耳鼻咽喉科臨床学会  

症例は59歳男性で、右眼球突出、右視力低下を主訴に、頭部CTにて右眼窩内膿瘍を疑われ、同日当院眼科紹介となった。初診時、右上眼瞼が発赤腫脹し、自力で開瞼不能であり、画像所見にて鼻性視神経炎を疑われ、同日当科コンサルタントとなった。当科初診時の鼻内腔所見・MRI所見および血液検査所見より、副鼻腔炎による眼窩感染症と診断し、右鼻茸切除および右鼻前頭管開放術を施行したが、前頭洞内からの膿汁はわずかであった。第7病日に入院し、イミペネム/シラスタチン投与を開始し、第8病日に右内視鏡下で前頭洞篩骨洞根本術を施行したが、眼窩内膿瘍の排膿が困難であったため、経皮的に右眼窩内膿瘍切開術を行った。培養結果にて前頭洞膿瘍、眼窩内膿瘍ともにStaphylococcus aureusを認め、急性副鼻腔炎から波及した右眼窩内膿瘍と診断した。術後、プレドニゾロンの漸減投与を行い、術後、眼瞼腫脹は著明に改善し、自力での開瞼が可能となった。術後5ヵ月の時点で、右眼視力は術前100cmの手動弁から術後は0.05(矯正不能)となり、視野は下方のみえる範囲がわずかに回復した。

DOI： 10.5631/jibirin.107.117

CiNii Books

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Other Link： https://jlc.jst.go.jp/DN/JALC/10028169511?from=CiNii

Language：Japanese   Publisher：Oto-Rhino-Laryngological Society of Japan Inc.  

Background: Concurrent chemoradiotherapy (CCRT) is used to treat advanced head and neck cancer. The accuracy of evaluating lymph nodes metastases following CCRT is important for subsequent therapy. Patients and Methods: Patients were divided into two groups according to the nodal status, the complete response (CR) and the non-CR groups, as determined by imaging and fine-needle aspiration cytology (FNAC) performed 4-8 weeks after the CCRT, and the findings were compared with the status 6 months after the treatment completion. Results: The sensitivity, the specificity, positive predictive value, negative predictive value and accuracy of each evaluation method were as follows: 66.7%, 73.5%, 26.7%, 93.8% and 72.5%, respectively, for computer tomography (CT) and magnetic resonance imaging (MRI)
91.7%, 69.9%, 30.6%, 98.3% and 72.6% for ultrasonography (US)
50.0%, 96.4%, 66.7%, 93.0% and 90.5% for fluorode-oxyglucose-positron emission tomography (FDG-PET) or PET-CT
and 68.4%, 96.1%, 81.3%, 92.5% and 90.6% for FNAC. Conclusion: To evaluate the response of lymph node (s) treated by CCRT, US is useful as a positive screening tool and FDG-PET and PET-CT as negative screening tools. FNAC is useful in evaluating suspicious lymph nodes in both positive and negative cases.

DOI： 10.3950/jibiinkoka.117.899

Scopus

PubMed

J-GLOBAL

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Language：Japanese   Publisher：Japan Society for Head and Neck Cancer  

Salivary duct carcinoma (SDC) is considered to be a high-grade malignant tumor with morphological resemblance to invasive ductal carcinoma of the breast, and develops high mortality. We retrospectively investigated the outcomes of 7 SDC cases (1 stageI, 1 stageII and 5 stageIVa) treated in Yokohama City University from 2003 to 2011. The treatment consisted of definitive surgery, postoperative concurrent chemoradiotherapy and adjuvant chemotherapy. The five-year disease specific survival rate was 83.3%, which was better than those of previous reports. Our multidisciplinary regimen might be an effective therapeutic option for SDC.

DOI： 10.5981/jjhnc.40.71

Scopus

J-GLOBAL

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Language：Japanese   Publisher：日本耳鼻咽喉科免疫アレルギー学会  

患者自身の希望があれば受けることが可能と考えられる癌免疫療法として、養子免疫療法、ワクチン療法、BRM(生物学的反応修飾物質)製剤について概説した。養子免疫療法にはLAK療法、TIL療法、αβT細胞療法、γδT細胞療法、NK細胞療法、癌ワクチン療法にはペプチドワクチン療法、DCワクチン療法がある。BRMにはOK-432、漢方薬の十全大補湯、補中益気湯、人参養栄湯が用いられる。試験管レベルで期待された効果が得られない一因として腫瘍免疫回避機構があり、腫瘍細胞側の要因とリンパ球側の要因が考えられている。

DOI： 10.5648/jjiao.31.237

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2013&ichushi_jid=J01987&link_issn=&doc_id=20140521400001&doc_link_id=%2Fch6menek%2F2013%2F003104%2F001%2F0237-0246%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fch6menek%2F2013%2F003104%2F001%2F0237-0246%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科学会  

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Language：Japanese  

J-GLOBAL

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Language：Japanese   Publisher：Oto-Rhino-Laryngological Society of Japan Inc.  

Cerebrospinal fluid (CSF) otorrhea, leakage of CSF through the ear structures, may occur from a traumatic or operative defect in the skull, tumor, cholesteatoma, or congenital anomalies. A case of repeated CSF otorrhea is uncommon. In this report, we presented a case of a repeated CSF otorrhea which occurred a decade after the first middle ear surgery for chronic otitis media. The first CSF leakage, which might have been due to bone defects in the tegmen at the first middle ear sutgery, was surgically repaired using a transmastoid approach. However, CSF leakage with a meningoencephalocele occurred again 8 years after our first surgery for the CSF and the fistula was repaired using a transmiddle cranial fossa approach. Although 2 years have passed since the surgery, the CSF leakage has not recurred.

DOI： 10.3950/jibiinkoka.116.161

Scopus

J-GLOBAL

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Language：Japanese  

CiNii Books

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Other Link： http://search.jamas.or.jp/link/ui/2009301120

Language：English   Publishing type：Book review, literature introduction, etc.   Publisher：SPRINGER  

Squamous cell carcinoma of the oral tongue (SCCOT) is one of the most prevalent tumors of the head and neck region. Despite advances in treatment, the survival of patients with SCCOT has not significantly improved over the past several decades. Most frequently, treatment failure takes the form of local and regional recurrences, but as disease control in these areas improves, SCCOT treatment failures are occurring more often as distant metastasis. The presence of cervical lymph node metastasis is the most reliable adverse prognostic factor in patients with SCCOT, and extracapsular spread (ECS) of cervical lymph nodes metastasis is a particularly reliable predictor of regional and distant recurrence and death from disease. Decisions regarding the elective and therapeutic management of cervical lymph node metastases are made mainly on clinical grounds as we cannot always predict cervical lymph node metastasis from the size and extent of invasion of the primary tumors. Therefore, the treatment of these metastases in the management of SCCOT remains controversial. The promise of basing treatment decisions on biomarkers has yet to be fully realized because of our poor understanding of the mechanisms of regional and distant metastases of SCCOT. Here we summarize the current status of investigations of SCCOT metastases and the potential of these studies to have a positive impact on the clinical management of SCCOT in the future.

DOI： 10.1007/s10555-007-9082-y

Web of Science

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Language：Japanese  

CiNii Books

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Other Link： http://search.jamas.or.jp/link/ui/2007211079

Event date： 2019.3

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