楯谷 一郎

<title>Abstract</title> Background The aims of this study were to perform a four-dimensional assessment of velopharyngeal closure function in pediatric patients with cleft palate using 320-row area detector computed tomography (CT), and to estimate the organ-absorbed doses using Monte Carlo simulation. Methods We evaluated CT image data obtained between July 2018 and August 2019 from five pediatric patients with cleft palate (four boys and one girl; age range, 4–7 years) at Fujita Health University Hospital. The presence of velopharyngeal insufficiency (VPI), patterns of velopharyngeal closure (VPC), and cross-sectional area of VPI were evaluated. In addition, organ-absorbed doses were assumed in the Monte Carlo simulation. However, we did not perform statistical analysis because of the insufficient number of patients enrolled in this study. Results The existence of VPI and hypernasality were completely concordant. The VPC patterns were circular (two patients), circular with Passavant’s ridge (one patient), and unevaluable (two patients). The organ-absorbed doses were relatively lower than those in past reports. Conclusions Our method could be an alternative for patients who refuse the conventional nasopharyngoscopic evaluation.

声帯結節と竹節状声帯を呈した全身性エリテマトーデス(systemic lupus erythematosus:SLE)例を経験した.症例は29歳女性.嗄声を認め当科受診した.声の酷使があり喉頭所見では両声帯膜様部中央に声帯結節を認めたほか,それとは別に膜様部中央と声帯突起のほぼ中間に乳白色状の竹節状の結節を認め,ストロボスコピーで左右位相のずれ,声門上部の前後径短縮が見られた.音声治療を実施したところ器質的病変に顕著な変化は見られなかったが,自覚的・他覚的に嗄声が改善した.本症例の機序として,声の酷使によってまず声帯結節が膜様部中央に出現し,そのため声帯結節のある声帯膜様部中央と声帯突起のほぼ中間部の振動が大きくなり,免疫複合体が沈着して竹節状の結節が出現したと考えられた.音声治療は竹節状声帯への直接的な効果は期待できないが,声の酷使など機能性要因がある場合は積極的に考慮すべきと考えられた.(著者抄録)

Objectives: Transoral approaches for laryngeal/pharyngeal malignancies have been widely accepted as minimally invasive treatment options; however, hypopharyngeal lesions treated by transoral surgery have rarely been reported due to the difficulties in visualizing the hypopharynx. Since 2010, we have treated superficial hypopharyngeal lesions with endoscopic laryngopharyngeal surgery (ELPS), and herein report the outcomes of this transoral procedure. Materials and Methods: One hundred and eighteen patients with superficial hypopharyngeal lesions were treated by ELPS from February 2010 to February 2017, and the clinical courses of the patients were reviewed. Results: Four females and 114 males (average: 65.6 y-o) were included in this study. Some patients had multiple lesions and a total of 154 superficial hypopharyngeal lesions (dysplasia: 29, Tis: 52, T1: 44, T2: 20, T3: 9) were treated with ELPS. Ten patients had only dysplasia and no carcinoma. Five patients presented with nodal metastases and 11 patients had simultaneous oropharyngeal lesions. In all cases, the hypopharynx was well visualized with sufficient working space, and no cases required a change in surgical approach. All post-operative complications were safely managed. In regard to the oncological outcomes, of the 108 patients with malignant lesions, the 3-year and 5-year overall survival (OS) rate was 93.6% and 85.5%, respectively. Conclusions: During ELPS, the hypopharynx was well visualized providing sufficient working space for the resection. The procedure was safe and feasible for superficial hypopharyngeal lesions and exhibited very good oncological outcomes. ELPS is thought to be a very effective surgical alternative for superficial hypopharyngeal lesions.

The tracheal lumen is essential for conducting air to the lung alveoli and for voice production. However, patients with severe tracheal stenosis and malignant tumors invading the trachea often require tracheal resection. Recently, various reported tissue engineering methods for tracheal reconstruction show that regeneration of ciliated epithelium in the reconstructed areas, as well as preservation of the luminal structure is possible. However, only few studies report on the mucociliary transport function in reconstructed tracheae. We investigated mucociliary transport function within rat tracheal epithelium, reorganized after autologous adipose tissue-derived stem cell (ASC) transplantation. Rat ASCs were expanded in culture, and then seeded in a collagen sponge, which was physically supported with a polypropylene framework. The ASC-seeded collagen sponge was transplanted into the rat tracheal defect. We then examined the motility and transport function of cilia generated in the transplanted area using ciliary beat frequency (CBF) and microsphere movement analyses. Our data suggested that autologous ASC transplantation promoted ciliogenesis, consistent with previous reports. The CBF analysis revealed that motility of the cilia generated in the ASC group was comparable to that observed in the normal rat tracheal epithelium. Transport function in the ASC group was higher than that in the control group. These data suggested that autologous ASC transplantation increased ciliated cells in the reconstructed area without significantly disrupting cilia motility, thereby promoting transport function regeneration. Autologous ASC transplantation is expected to be beneficial in morphological and functional regeneration of tracheal epithelium. Anat Rec, 303:471–477, 2020. © 2019 American Association for Anatomy.

Objective: Salivary gland carcinoma is rare among head and neck cancers. Sublingual gland carcinoma, a type of salivary gland carcinoma, is even rarer; therefore, the number of cases at a single institute is too small for sufficient evaluation of tumor characteristics. We conducted a multicenter, retrospective analysis of sublingual gland carcinomas in patients who visited 12 institutions associated with the Kyoto Hospital and Affiliated Facilities Head and Neck Clinical Oncology Group. Methods: Thirteen previously untreated patients who visited the institutions between 2006 and 2015 were enrolled. The overall survival (OS) and disease-free survival (DFS) rates for all patients and by disease stage were analyzed. Statistical analyses were performed for all patients with respect to disease stage. Results: Eight of thirteen patients were diagnosed with adenoid cystic carcinoma on pathological study. A significant difference in OS rate was observed between patients with Stage I–III and Stage IV disease; however, the difference in DFS rate by disease stage was not significant. Conclusion: Stage IV disease was identified as a poor prognostic factor in patients with sublingual gland carcinoma. However, even patients with Stage I–III disease experienced relatively short DFS. Distant metastasis is a serious problem among patients with sublingual gland carcinoma.

Objective: To develop a summary of the first version of the Clinical Practice Guideline of Voice Disorders for Diagnosis, Management, and Treatment in Japan by the Clinical Practice Guideline Committee of the Japan Society of Logopedics and Phoniatrics and The Japan Laryngological Association. The 2018 recommendations, based on a review of the scientific literature, are intended to serve as clinical practice guidelines for the diagnosis, management, and treatment of voice disorders in Japan. Methods: A summary of the original version of the Clinical Practice Guideline of Voice Disorders for Diagnosis, Management, and Treatment in Japan was described. Recommendations for the diagnosis, management, and treatment of voice disorders were prepared. Twelve clinical questions (CQs) regarding the diagnosis, management, treatment, and effectiveness of therapy for voice disorders were also prepared. Results: A summary of the first version of the clinical practice guidelines for the diagnosis, management, and therapy of voice disorders was prepared and is presented. Additionally, answers to the 12 CQs on the diagnosis, management, treatment, and effectiveness of voice disorder therapy were prepared, and include evidence-based recommendations. Conclusion: These guidelines present a summary of the standard approaches for the diagnosis and treatment of voice disorders and relevant CQs that consider the medical environments in Japan. We hope that the guidelines will assist physicians in clinical settings for patients with voice disorders.

Robotic surgery is ushering in a new era in surgery by offering patients better outcomes and has already become one of the standard modalities in urology and gynecology. In the head and neck field, after the FDA clearance in 2009, transoral robotic surgery (TORS) has now been widely adopted by head and neck surgeons for treatment of benign and malignant conditions of the pharynx and larynx. Another use of surgical robots in the head and neck is thyroidectomy and neck surgery. Robotic thyroidectomy has been developed mainly by Korean surgeons and the technique has evolved into robotic neck dissection. In Japan, multi-institutional clinical study of TORS using da Vinci Surgical System had been conducted and PMDA clearance was obtained in 2018. Japan Society for Head and Neck Surgery has announced recommendations and credentials for head and neck robotic surgery in January 2019 and advance course for TORS has been held every month in Fujita Health University since May. Recent progress of surgical robots and future directions of robots and surgery in the head and neck are also discussed.

The authors experienced a case of vocal fold bamboo nodes which appeared along with vocal nodules in a 29-year-old woman who was diagnosed as systemic lupus erythematosus (SLE). The patient visited our outpatient clinic complaining of hoarseness. She exhibited a strong tendency of daily vocal abuse. An initial flexible laryngeal endoscopic examination revealed bilateral vocal fold nodules in the middle portion of the vocal folds and bilateral white bamboo nodes in the posterior third portion of the vocal folds. Stroboscopic examination showed asymmetrical vibratory phases of the mucosal wave and mild anteroposterior narrowing of the supraglottic space. To treat her functional problems, voice therapy was provided. Post-therapy examination demonstrated improvements in both self-evaluation and instrumental/clinical measures, although the vocal lesions remained the same. The causes of the bamboo nodes in this patient are suspected as follows: 1) The patient's vocal abuse caused vocal nodules in the middle portion of the vocal fold mucosa. 2) The presence of the vocal nodules increased the vibration of the membranes between the nodules and the process. 3) The increased vibration led to accumulation of immune complexes and subsequent bamboo nodes in the posterior third of the membranous vocal folds. This case report indicates that, in patients with SLE, although voice therapy does not solve the organic aspects of the problems, it is important for identifying functional components of the voice problems. We therefore view voice therapy as a valuable treatment option.

16歳男性。8歳時より当院小児科にて僧帽弁閉鎖不全症の経過観察中であった。今回、嗄声を主訴に当科を受診、所見では左声帯は傍正中位固定しており、左声帯萎縮を認めたが、誤嚥の症状は認めず、経過観察とした。しかし、19歳時に嗄声の増悪を認め、臨床経過および画像所見より、僧帽弁閉鎖不全症に起因した左反回神経麻痺(Cardiovocal syndrome)と診断され、甲状軟骨形成術I型および披裂軟骨内転術が施行された。その結果、術後は5ヵ月間の音声治療を行い、最長発声持続時間、GRBASスコア、Jitter、PPQ、APQ、vF0の改善が認められた。

当科でバセドウ病に対し甲状腺全摘術、もしくは甲状腺亜全摘術を施行した55例をT3優位型16例(男性4例、女性12例)と通常型39例(男性11例、女性28例)に分け、比較検討した。その結果、T3優位型は通常型と比較して、術前TRAb値が高く、甲状腺重量が大きく、手術時間が長く、術中出血量が多かった。また、甲状腺重量と手術時間・術中出血量との間には正の相関がみられた。一方、T3優位型は通常型に比べ、抗甲状腺薬内服治療に抵抗性であり、長期の内服継続により甲状腺の腫大および手術合併症リスクの増加をまねく恐れがあるため、早期に外科的治療ないしは放射線ヨウ素内用療法を考慮する必要があると考えられた。

Objectives: The indication of transoral robotic surgery for hypopharyngeal cancer is limited because of poor accessibility. The aim of this study was to explore the efficacy of a curved laryngopharyngoscope used in combination with a next-generation flexible robotic surgical system for accessing and resecting the hypopharynx. Methods: A comparative evaluation of the curved laryngopharyngoscope versus standard straight-blade retractors using the flexible robotic surgical system was conducted on 2 cadavers. End points measured included visualization, accessibility, and ease of dissection for accessing and resecting the hypopharynx. Results: Visualization, accessibility, and dissection were superior with the curved laryngopharyngoscope in all subareas of the hypopharynx. The advantages of accessibility and visualization were much more evident in the cadaver with a high body mass index. Conclusions: These preclinical data suggest that using a curved laryngopharyngoscope in combination with a flexible robotic surgical system may lead to technical innovations concerning transoral surgery of the hypopharynx.

Liposarcoma is one of the most common soft tissue tumors that affect adults. Liposarcoma is typically identified in the retroperitoneum, trunk and extremities as a slow-growing mass, yet is rare in the thyroid gland. Herein, we report a case of dedifferentiated liposarcoma that developed in the thyroid gland, and performed a literature review. A 66-year-old male with a history of well-differentiated liposarcoma in the thymus presented with a rapidly enlarging mass in the thyroid gland. Malignancy was suspected due to the local extension of the tumor, and complete resection of the tumor was achieved. Tissue diagnosis from the tumor following surgery revealed that dedifferentiated liposarcoma, and tumor progression was difficult to control with adjuvant radiation and chemotherapy. This is, to the best of our knowledge, the first case to report dedifferentiated liposarcoma in the thyroid gland, and the difficulty in initial diagnosis as well as the aggressive features of dedifferentiated liposarcoma are highlighted.

Recently, a global phase III study demonstrated that nivolumab markedly improved patient outcomes in recurrent or metastatic head and neck carcinoma (RMHNC). However, the effcacy of nivolumab in patients who are ineligible for clinical trials is unknown. We investigated nivolumab eeecacy in real-world patients and prognostic factors associated with the response to nivolumab. This study was conducted at 11 institutes associated with Kyoto University and its Affliated Hospitals-Head and Neck Oncology Group. In total, 95 patients withRMHNCwho received nivolumab between May 2017 and May 2018 were retrospectively reviewed. Objective response rate (ORR), overall survival, and progression-free survival (PFS) were evaluated. Univariate and multivariate analyses were performed to identify prognostic factors. The ORRs in patients with squamous cell carcinoma (SCC) and non-SCC were 21.8% and 0%, respectively. In patients with SCC and non-SCC, the 1-year PFS rates were 28.7% and 8.9%, respectively. The hazard ratio (HR) for risk of PFS events (SCC versus non-SCC) was 2.28 (95% confidence interval: 1.21–4.1; log-rank p = 0.007). Univariate and multivariate analyses revealed radiotherapy history, platinum-refractory carcinoma, and treatment-related adverse events (TRAEs) as important prognostic factors associated with PFS in patients with SCC. In a real-world setting, non-SCC and platinum-refractory carcinoma were associated with a poorer prognosis, and a history of radiotherapy to the primary tumor, and the occurrence of TRAEs were associated with a better prognosis. These findings could be useful for clinicians and patients when selecting a treatment strategy.

Tracheal resection is often performed for malignant tumours, congenital anomalies, inflammatory lesions, and traumatic injuries. There is no consensus on the best approach for the restoration of tracheal functionality in patients with tracheal defects. Artificial grafts made of polypropylene and collagen sponge have been clinically used by our group. However, 2 months are required to achieve adequate epithelialization of the grafts in humans. This study aimed to investigate the feasibility of transplantation therapy using an artificial trachea with human-induced pluripotent stem cell (hiPSC)-derived multiciliated airway cells (hiPSC-MCACs). Collagen vitrigel membrane, a biocompatible and absorbable material, was used as a scaffold to cover the artificial trachea with hiPSC-MCACs. Analyses of hiPSC-MCACs on collagen vitrigel membrane were performed by immunocytochemistry and electron microscopy and by assessing ciliary beat frequency. Along with the artificial trachea, hiPSC-MCACs were transplanted into surgically created tracheal defects of immunodeficient rats. The survival of transplanted cells was histologically evaluated at 1 and 2 weeks after the transplantation. The hiPSC-MCACs exhibited motile cilia on collagen vitrigel membrane. The surviving hiPSC-MCACs were observed in the endotracheal epithelium of the tracheal defect at 1 and 2 weeks after transplantation. These results suggest that hiPSC-MCAC is a useful candidate for tracheal reconstruction.

Tracheal epithelia have barrier and mucociliary clearance functions that prevent invasion of extraneous particles and infectious materials. Hence, following tracheal reconstructions, functional and morphological regeneration of epithelia is required to prevent respiratory declines and infectious diseases. Although growth factors (GFs) promote the regeneration of tracheal epithelial morphologies, it remains unclear whether tracheal grafts containing GFs are beneficial for regeneration of tracheal epithelial functions. Thus, we fabricated collagen sponge scaffolds containing insulin-like GF-1 (IGF-1) and the basic fibroblast, hepatocyte, and epidermal GFs (bFGFs, HGFs, and EGFs, respectively), and we evaluated the effects of the grafts on the functional regeneration of tracheal epithelia. Partial tracheal defects were imposed surgically, and collagen sponges containing IGF-1, bFGF, HGF, or EGF were then transplanted to defect sites. Subsequent immunofluorescence studies suggested that EGF and bFGF contribute to regular distributions of tight junction molecules, and tracer permeability assays suggested that EGF and bFGF promote regeneration of barrier function. Increased ciliogenesis was also observed using scanning electron microscopy in reconstructed regions treated with EGF- and bFGF-supplemented collagen sponges. However, bFGF-supplemented collagen sponges led to greater microsphere transport than did EGF-supplemented sponges. The present data suggested that collagen sponge scaffold containing bFGF promotes functional regeneration of tracheal epithelial tissues.

Objectives: Macrophages are prominent inflammatory cells in wounds, and their phenotypes are altered during wound healing. They are reported to contribute to not only inflammatory responses but also tissue remodeling. However, few studies in vocal fold biology have focused on the function of macrophages. The purpose of this study was to investigate macrophage polarization and distribution in injured murine vocal folds. Study Design: Animal experiments with controls. Method: Unilateral vocal fold stripping was performed on C57BL/6 mice, and larynges were harvested 1, 3, 5, 7, and 14 days postinjury. Immunohistochemical analysis of the vocal fold lamina propria was performed to detect the expression of classically activated (M1) and alternatively activated (M2) macrophage markers (inducible nitric oxide synthase [iNOS] and CD206, respectively) in F4/80 + macrophages. Results: The proportion of F4/80 + iNOS + cells out of all F4/80 + cells tended to increase from day 1. F4/80 + iNOS + cell percentage tended to be high at days 1 through 7 and declined to close to a normal level by day 14. F4/80 + CD206 + cell percentage tended to decrease at day 1 and then to increase the rest of the time. In the normal vocal fold, the majority of F4/80 + macrophages were only positive for CD206. F4/80 + iNOS + CD206 + cells were observed at days 1 through 7. Conclusion: The main population of injured sites gradually shifted from M1 to M2 marker-positive macrophages in murine vocal folds. However, coexistence of M1 and M2 markers in the same macrophages was observed. Our results suggest that macrophage phenotypes are regulated by complex tissue-derived signals and exhibit dynamic changes during wound healing. Level of Evidence: NA Laryngoscope, 129:E135–E142, 2019.

Cytotoxic chemotherapy after exposure to nivolumab (nivo), an anti-programmed death-1 (PD-1) antibody, has been associated with good response compared with historical data in various cancers including head and neck squamous cell carcinoma (HNSCC). In a previous report, different chemotherapy regimens were used before and after treatment with nivo. This HNSCC case is the first report of a good response when the same cytotoxic chemotherapy regimen was used before and after nivo. In addition, the efficacy of anti-epidermal growth factor receptor antibody after nivo treatment may be better than without exposure to nivo.

Objective: Due to the rising number of elderly patients and advances in endoscopic devices, early laryngeal and pharyngeal cancers are increasingly found in elderly patients. In these cases, minimally invasive endoscopic larygo-pharyngeal surgery (ELPS) may be indicated. However, the safety and efficacy of ELPS in elderly populations has not been established. The purpose of this study was to investigate the safety, outcomes and feasibility of ELPS in very elderly patients. Methods: Between February 2010 and April 2016, 29 pharyngeal cancerous or pre-cancerous lesions in 19 patients aged 75 years or older were treated with ELPS. Twenty-six resections were performed in total, and the patients’ clinical courses were reviewed. Results: Sixteen patients had multiple comorbidities and moderate to severe comorbidities were observed in 17 patients. The average surgical time and hospitalization period was 54.3 min and 18.8 days, respectively. On average, oral intake began 4.4 days after the procedure, and all patients eventually received nourishment by mouth; no percutaneous endoscopic gastrostomy dependency was observed. Complications included post-operative bleeding and aspiration pneumonia in two cases each, and all complications were safely managed. The 3-year overall survival rate was 90.2% and the 3-year disease-specific survival rate was 100%. Conclusion: ELPS was safely performed in elderly patients, suggesting that it is a feasible treatment option for pharyngeal lesions in very elderly patients.

Objectives/Hypothesis: To elucidate the aging physiology of the vocal folds, we examined the characters of aged vocal fold fibroblasts (VFFs) in various conditions. Study Design: In vitro study. Methods: VFFs from young (12-week-old) and aged (19-month-old) Sprague-Dawley rats were compared. Proliferative capacity, ratio of myofibroblast to fibroblast, myofibroblast function, and extracellular matrix production were examined in the following conditions: naïve, basic fibroblast growth factor (bFGF) supplemented, and hepatocyte growth factor (HGF) supplemented. Results: Aged VFFs demonstrated reduced proliferation by cell counting, though the ratio of Ki-67–positive cells showed no difference. Aged VFFs exhibited an increased expression of α-smooth muscle actin (α-SMA); however, they demonstrated no enhanced contractile ability in a gel contraction assay. Type I collagen protein was increased age dependently, accompanied with decreased Mmp1 and unchanged Col1a1 transcription. Type I collagen protein and α-SMA represented quite similar reduction patterns to bFGF or HGF administration. Conclusions: The following possible characteristics of aged VFFs were implied: long duration of mitosis, increased myofibroblast population size with certain dysfunctions, reduced type I collagen turnover, and correlation between α-SMA expression and type I collagen metabolism. Further investigations of these features will help to clarify presbyphonia's pathology and establish treatment strategies. Level of Evidence: NA Laryngoscope, 129:E94–E101, 2019.

Congenital malformations of the larynx, which is crucial for breathing and swallowing, are rare. To enable a better understanding of congenital laryngeal malformations, the prenatal development of the trachea and larynx is summarized, based on the classification described by Henick. It is followed by a review of the molecular-biological findings in recent studies focused on the development of trachea and larynx. The molecular mechanism of laryngeal development has not been well documented and needs to be elucidated by future research using conditional knockout mouse lines specific to the larynx.

Objective: Clinical studies demonstrating the prognostic factors in submandibular gland carcinoma are limited because the tumor is relatively rare. The aim of this study was to identify clinical outcomes and prognostic factors in submandibular gland carcinoma. Methods: The study included 65 patients with submandibular gland carcinoma who underwent initial surgical treatment at the Kyoto University and its affiliated hospitals. Results: The 3-year overall survival (OS), disease specific survival, locoregional control (LRC), and no distant metastasis (NDM) rates were 74.2%, 74.2%, 90.0%, and 64.8%, respectively. In the current follow-up study, 16 patients died of the disease, 5 patients were alive with recurrence, 43 patients were alive without disease, and 1 patient died of unrelated disease without recurrence. All patients who died of the disease had developed distant metastasis. Based on univariate analysis, tumor grade (high grade) and lymph node metastases (≥N2) were significant prognostic factors for OS and LRC. It also revealed tumor grade (high grade), T classification (≥T3), and lymph node metastases (≥N2) were significant for distant metastasis. Multivariate analysis showed the following significant prognostic factors: lymph node metastases (≥N2) for OS, LRC, and NDM, and high tumor grade for NDM. Conclusion: Our study suggested death of submandibular gland carcinoma occurred mainly due to distant metastasis. The significant predictors of distant metastasis were lymph node metastases (≥N2) and tumor grade (high grade).

Objectives/Hypothesis: Endoscopic laryngopharyngeal surgery (ELPS), a hybrid of head and neck surgery and gastrointestinal endoscopic treatment, has been attracting attention as a new therapeutic modality for superficial laryngopharyngeal cancers. Although this technique is less invasive than traditional open procedures, some complications including postoperative bleeding, subcutaneous emphysema, or aspiration pneumonia can occur after treatment. The purpose of this study was to investigate the complications associated with ELPS to better understand the indications for this procedure. Study Design: Retrospective medical chart review. Methods: One hundred five patients with 159 laryngeal or pharyngeal lesions were treated with ELPS between August 2009 and September 2015 at Kyoto University Hospital. In total, 147 resections were performed, and complications after the resections were reviewed. Results: Of the 147 resections, postoperative bleeding, subcutaneous emphysema, and aspiration pneumonia were observed in 10, 17, and 10 cases, respectively. All cases with postoperative bleeding and aspiration pneumonia occurred in patients over 65 years of age. A history of taking anticoagulation/platelet medications, and macroscopic 0–IIa lesions were shown to correlate with postoperative bleeding after ELPS. Resection of lesions in the pyriform sinus was found to be associated with subcutaneous emphysema. Conclusions: All complications after ELPS were safely managed. A history of taking anticoagulation/platelet medications and macroscopic 0–IIa lesions were identified as risk factors for postoperative bleeding, whereas resection of pyriform sinus lesions was found to be a risk factor for subcutaneous emphysema. These risk factors should be carefully considered when treating pharyngeal and laryngeal lesions by ELPS. Level of Evidence: 4. Laryngoscope, 128:1546–1550, 2018.

Objectives: The management of patients with cervical metastasis in head and neck cancer of unknown primary (HNCUP) remains controversial. This current multicenter retrospective study investigated the treatment outcomes of patients with HNCUP. Methods: The study included patients who were treated curatively at 12 institutions in Japan from January 2006 to December 2015. Results: Eighty patients with HNCUP were included. The median follow-up period was 34 months. The three-year overall survival (OS), disease-specific survival (DSS), regional relapse-free survival (RRFS), local progression-free survival (LPFS), and distant metastasis-free survival (DMFS) rates were 72.5%, 80.3%, 74.0%, 89.7%, and 86.9%, respectively. Nodal status was a significant factor for OS, DSS, RRFS, and DMFS; and extracapsular extension (ECE) was significant for OS and DSS. There was a distinct difference between the survival rates of patients with N1–2a and N2b–3 disease. RT was a significant positive factor for LPFS (3-year LPFS, RT 93.0% vs. no RT 83.0%, p =.043). Conclusions: For N2a as well as N1 disease without ECE, a single treatment modality, including ND or RT alone is acceptable. When ND alone is performed, thorough monitoring should be continued during follow-up to identify the emergence of the primary lesion.

はじめに:耳下腺癌と顎下腺癌は比較的まれな疾患である。耳下腺癌、顎下腺癌症例を集積し、後ろ向きに比較検討した。対象:2006年から2015年に、京都大学医学部附属病院とその関連病院にて初回根治治療を行った260例(耳下腺癌195例、顎下腺癌65例)。結果:病理組織型の悪性度について、高悪性の割合は耳下腺癌44%、顎下腺癌58%であった。穿刺吸引細胞診(FNA)の悪性に対する感度は、耳下腺癌50%、顎下腺癌75%であった。平均観察期間3.6年における3年全生存率/特異的生存率/局所頸部制御率/遠隔制御率は、耳下腺癌85%/89%/85%/87%、顎下腺癌74%/74%/90%/65%であった。疾患特異的生存率と遠隔制御率については、統計学的有意差をもって顎下腺癌の成績が不良であった。結論:顎下腺癌は耳下腺癌と比較して遠隔制御率が低く、疾患特異的生存率が不良であった。(著者抄録)

Vocal fold scar and sulcus are intractable diseases with no effective established treatments. Hepatocyte growth factor (HGF) has preclinically proven to have potent antifibrotic and regenerative effects on vocal fold scar. The current Phase I/II clinical trial aims to examine the safety and effectiveness of intracordal injection of a recombinant human HGF drug for patients with vocal fold scar or sulcus. This is an open-label, dose-escalating, first-in-human clinical trial. Eighteen patients with bilateral vocal fold scar or sulcus were enrolled and divided into three groups: Step I received 1 μg of HGF per vocal fold; Step II received 3 μg of HGF; and Step III received 10 μg of HGF. Injections were administered once weekly for 4 weeks. The protocol treatment was performed starting with Step I and escalating to Step III. Patients were followed for 6 months post-treatment. Local and systemic safety aspects were examined as primary endpoints, and therapeutic effects were assessed as secondary endpoints using voice handicap index-10; maximum phonation time; vocal fold vibratory amplitude; grade, rough, breathy, asthenic, strained scale; and jitter. The results indicated no serious drug-related adverse events in either the systemic or local examinations. In whole-subject analysis, voice handicap index-10, vocal fold vibratory amplitude, and grade, rough, breathy, asthenic, strained scale were significantly improved at 6 months, whereas maximum phonation time and jitter varied. There were no significant differences in phonatory data between the step groups. In conclusion, intracordal injection of a recombinant human HGF drug was safe, feasible, and potentially effective for human patients with vocal fold scar or sulcus.

Objectives/Hypothesis: The vocal fold epithelium that includes tight junction (TJ)-based barrier function protects underlying connective tissues from external insults. TJs play an important role to control paracellular permeability of not only solutes but also ions, and preserve the vocal fold homeostasis. However, the distribution of TJs and paracellular diffusion barrier across the entire vocal fold epithelium are still unknown. The aim of this study was to identify the distribution of TJs in the vocal fold epithelium and to characterize the recovery process of TJ-based paracellular diffusion barrier in a rat model of vocal fold injury. Study Design: Animal experiments with controls. Methods: Normal and vocal fold–injured rats were used. Larynges were harvested for immunohistochemical examination of TJ proteins. For functional analysis, a tracer permeability assay was performed using EZ-Link Sulfo-NHS-LC-Biotin. Results: TJ proteins occludin and zonula occludens 1 signals were localized to the junctional regions of the most luminal cell layers of the vocal fold epithelium. The injured region had been recovered with epithelium at 5 days postinjury, but the paracellular diffusion barrier assays revealed that biotinylation reagents diffused into the lamina propria at 5 days postinjury, and were blocked at the epithelium at 14 and 28 days postinjury. Conclusions: It was strongly suggested that TJs in the vocal fold epithelium exist at the junctional regions of the first layer of stratified squamous epithelium. TJ-based paracellular diffusion barrier following vocal fold injury is recovered by 14 days postinjury, and this period corresponds with the time course of structural changes in the regenerating epithelium layer. Level of Evidence: NA. Laryngoscope, 128:E150–E156, 2018.

Background: Planar cell polarity (PCP) coordinates the patterning and orientation of cells and their structures along tissue planes, and although its acquisition during the formation of airway epithelium has been described, the mechanisms for its maintenance and reconstruction are poorly understood. We aimed to clarify whether ambient environment change by orthotropic autologous transplantation affected PCP at the cellular level. Methods: We performed orthotropic autologous transplantation by inverting tracheal segments in rats, and then performed morphological evaluation by microscopy. The PCP of the tracheal epithelium was assessed over time by analyzing the directions of mucociliary transport and ciliary beat, the positional relationship between the basal body and basal foot, and the bias of Vang-like protein 1 (Vangl1) at 2, 4, and 6 months postoperatively. Results: After 2 months, the directions of mucociliary transport and ciliary beat were preserved toward the lung in the inverted tracheal segments. The positional relationship between the basal body and the basal foot, and the bias of Vangl1, also indicated preservation of PCP in the inverted tracheal segments. Similar results were obtained at 6 months. Conclusion: The PCP of ciliated epithelium was preserved in reversed trachea, even after long-term observation.

Background: Adenoid cystic carcinoma of the head and neck (ACCHN) is rare and difficult to study effective treatment at one institute. Our aim is to identify prognostic factors for this disease by conducting a multicenter study at 11 institutions in Japan. Methods: A retrospective multicenter study of ACCHN was performed. One hundred and three patients were identified between 2006 and 2015. The overall survival (OS) rate for all patients was calculated, and OS, locoregional control (LRC) rate, or no distant metastasis (NDM) rate was calculated for patients in that the surgery was performed without distant metastasis (DM). Statistical analyses were performed. Results: A significant difference with multivariate analysis was observed in patients in sublingual glands, stage IV and the use of radiation therapy ≥60Gy (sufficient RT) in OS for all patients. A significant difference was observed in the use of sufficient postoperative RT in the OS and the LRC rate, and in pathological surgical margins in the NDM rate. Conclusion: Sublingual glands or stage IV was a poorer, and sufficient RT was a better prognostic factor for ACCHN. Sufficient RT was effective to prevent local recurrence after surgical resection. Positive surgical margins caused an increase in DM.

More than 10 years have passed since the da VinciⓇ Surgical System (Intuitive Surgical Inc.) was introduced to head and neck cancer treatment. It has spread all over the world very quickly and the indications for this procedure have been expanding. Trans-oral robotic surgery (TORS) was initially applied to oropharyngeal cancer (anterior wall and lateral wall), and is now widely used for naso-and hypo-pharyngeal cancer treatment. Although its indications remain open to discussion, TORS demonstrates good accessibility and operability for nasopharyngeal cancer. As for hypopharyngeal cancer, it is still difficult to obtain good exposure of the hypopharynx. However, new instruments have been shown to work in the hypopharynx, and the difficulty of exposing the hypopharynx will be addressed by making the instruments smaller. In Japan, a multi-institutional clinical study of TORS was completed last year, and the use of surgical robots has just been approved in the field of otolaryngology. Currently, in order to ensure the quality and safety of TORS, related societies are preparing rules and systems for conducting TORS.

Background Parotid gland carcinoma is a rare malignancy, comprising only 1–4% of head and neck carcinomas; therefore, it is difficult for a single institution to perform meaningful analysis on its clinical characteristics. The aim of this study was to update the clinical knowledge of this rare disease by a multi-center approach. Methods The study was conducted by the Kyoto University Hospital and Affiliated Facilities Head and Neck Clinical Oncology Group (Kyoto-HNOG). A total of 195 patients with parotid gland carcinoma who had been surgically treated with curative intent between 2006 and 2015 were retrospectively reviewed. Clinical results including overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS), local control rate (LCR), regional control rate (RCR), and distant metastasis-free survival (DMFS) were estimated. Univariate and multivariate analyses were performed to identify prognostic factors. Results The median patient age was 63 years old (range 9–93 years), and the median observation period was 39 months. The OS, DFS, DSS, LCR, RCR, and DMFS at 3 years were 85%, 74%, 89%, 92%, 88%, and 87%, respectively. Univariate analysis showed age over 74, T4, N +, preoperative facial palsy, high grade histology, perineural invasion, and vascular invasion were associated with poor OS. N + and high grade histology were independent factors in multivariate analysis. In subgroup analysis, postoperative radiotherapy was associated with better OS in high risk patients. Conclusion Nodal metastases and high grade histology are important negative prognostic factors for OS. Postoperative radiotherapy is recommended in patients with advanced high grade carcinoma.

Background: The purpose of this cadaveric study was to determine the efficacy of a flexible, next-generation robotic surgical system for transoral robotic hypopharyngectomy. Methods: A comparative evaluation study of the flexible versus rigid robotic surgical systems for the hypopharynx was conducted using 3 cadavers. Endpoints for assessment were visualization of the hypopharynx, access to the hypopharynx, and difficulty of dissection. Hypopharyngectomy was performed on 3 other cadavers using the da Vinci Sp surgical system. Results: Access to the apex of the pyriform sinus and the esophageal inlet was easier with the da Vinci Sp than with the da Vinci Si. Dissection with the da Vinci Sp was easier in all areas of the hypopharynx than with the da Vinci Si. Robotic hypopharyngectomy was successfully completed on all cadavers using the da Vinci Sp surgical system. Conclusion: Preclinical testing in human cadavers suggests that flexible robotic surgery may facilitate successful transoral hypopharyngectomy.

Objectives/Hypothesis: This study aimed to reveal the effects of adipose-derived mesenchymal stromal cells (ASCs) on prevention of vocal fold scarring by investigating how the immediate ASCs transplantation into the injured rat vocal fold affect the levels of gene transcription and translation. Study Design: Prospective animal experiments with controls. Methods: ASCs harvested from green fluorescent protein transgenic rat (ASCs group) or saline (sham group) were injected into the thyroarytenoid muscle of Sprague-Dawley rats immediately after stripping the vocal fold. For histological examinations, larynges were extirpated at 3, 14, and 56 days after the injection. Quantitative real-time polymerase chain reaction (PCR) analyses were performed at 3 and 14 days after the injection. Results: Transplanted ASCs were detected only in larynges at day 3. At days 14 and 56, histological examination showed significantly higher amounts of hyaluronic acid and lower deposition of collagen in the ASCs group compared to the sham group. Real-time PCR revealed that the ASCs group showed low expression of procollagen (Col)1a1, Col1a3, matrix metalloproteinase (Mmp)1 and Mmp8 in each time points. The ASCs group showed high expression of fibroblast growth factor (Fgf)2 and Hepatocyte growth factor (Hgf) compared to the sham group at day 14. Conclusions: ASCs increased expressions of Fgf2 and Hgf, and suppressed excessive collagen deposition during vocal fold wound healing. Given the fact that ASCs survived no more than 14 days, ASCs were thought to induce upregulations of growth factors' genes in surrounding cells. These results suggested that ASCs have potential to prevent vocal fold scarring. Level of Evidence: NA. Laryngoscope, 128:E33–E40, 2018.