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Background/Aim: Chemoradiotherapy (CRT) with high-dose cisplatin has become the standard of care for larynx preservation in patients with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). However, the long-term results are unsatisfactory. Induction chemotherapy (ICT) with docetaxel/cisplatin/5-fluorouracil (TPF) is associated with hematologic toxicity, and a safer therapy with comparable efficacy is desired. We conducted a pilot study to investigate the efficacy and safety of 5-fluorouracil/cisplatin/cetuximab (FPE) therapy as a candidate regimen for ICT in comparison with TPF. Patients and Methods: Patients with stage cN2/3 LA-SCCHN of the larynx/oropharynx/hypopharynx were treated with FPE or TPF followed by radiotherapy. We reviewed patients’ medical records and evaluated treatment efficacy and safety retrospectively. Results: The response rates for ICT and ICT–radiotherapy were 71% and 93%, respectively, in the FPE group and 90% and 89%, respectively, in the TPF group. The 1-year progression-free and overall survival rates were 57% and 100%, respectively, in the FPE group and 70% and 90%, respectively, in the TPF group. TPF was linked to significantly higher rates of Grade 3/4 hematologic toxicity during ICT. The rates of Grade 3 or higher toxicity did not differ between the two groups during radiotherapy. Conclusion: The efficacy of ICT was comparable between the FPE and TPF groups, whereas FPE was associated with less toxicity. It is suggested that FPE therapy is an alternative ICT regimen to TPF therapy, but further long-term follow-up is needed.

The efficacy of programmed cell death 1 (PD-1) inhibitor therapy for patients with recurrent and/or metastatic salivary gland carcinoma (R/M SGC) remains unclear.We retrospectively analyzed 36 patients with R/M SGC treated with PD-1 inhibitor. The expression of programmed cell death ligand 1 (PD-L1) and mismatch repair (MMR) proteins was also analyzed.The objective response rate (ORR) was 11.1%. The histopathological subtypes of patients who achieved complete response or partial response were salivary duct carcinoma (SDC) in three patients and poorly differentiated carcinoma in one patient, all of whom showed a positive PD-L1 expression. The expression of MMR proteins was not associated with the efficacy of PD-1 inhibitors.Although the efficacy of PD-1 inhibitor therapy in R/M SGC is limited, certain patients may respond and achieve long-term disease control. There is a potential therapeutic effect in SDC patients with positive PD-L1 expression.

Background/Aim: Surgery remains the standard treatment for salivary gland carcinoma (SGC). Our study investigated the association between epidermal growth factor receptor (EGFR) status in recurrent/metastatic SGC and the effectiveness of treatment with cisplatin/carboplatin and 5-fluorouracil plus cetuximab (EXTREME). Patients and Methods: We retrospectively collected 19 SGCs from patients treated with the EXTREME regimen. After analyzing EGFR expression and gene copy number gain, we evaluated the correlation between EGFR status and clinicopathological factors and prognosis. Results: EGFR overexpression was detected in 77.8% cases, but not statistically associated with clinicopathological factors or prognosis. EGFR gene copy number gain was detected in 16.7% cases, and statistically positively correlated with lymph node metastasis (p=0.0291). The best overall response was partial response in two cases, stable disease in 15, and progressive disease in one case. The EXTREME regimen was discontinued in all cases. Conclusion: Our results suggest that SGCs are positive for EGFR protein expression but the response rate to the EXTREME regimen was unremarkable.

Background: Papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) are common differentiated thyroid cancers, but the detection of a collision tumor is an extremely rare event. Case Presentation: The patient was a 69-year-old Japanese female with multiple cervical lymph node swellings and a thyroid tumor. Preoperative fine needle aspiration cytology of the enlarged lymph node revealed a cytological diagnosis of papillary thyroid carcinoma (PTC). A total thyroidectomy, right cervical dissection and paratracheal dissection were performed. Histopathological immunohistochemistry (IHC) analyses of resected specimens revealed a collision tumor of PTC and FTC. Multiple metastases of papillary carcinoma were found in the dissected lymph nodes. In the PTC lesion, IHC for BRAF (V600E) was positive but negative for the FTC lesion. Genetic analyses further revealed a TERT prompter C228T mutation in PTC and a NRAS codon 61 mutation in FTC. The patient died of recurrent cancer 8 months after surgery. Conclusions: A case of a collision tumor of PTC and FTC is very rare, and even fewer cases have been subjected to genetic scrutiny. The present case was successfully diagnosed by pathological examination using IHC and genetic analyses. The TERT promoter mutation in the PTC lesion was consistent with the aggressive behavior of the cancer.

Palonosetron, a long-acting 5-HT3 receptor antagonist, is an effective antiemetic agent for chemotherapy-induced nausea and vomiting; however, it sometimes causes severe constipation. The aim of the present study was to evaluate the severity of palonosetron-related constipation. We retrospectively analyzed the incidence and severity of constipation after intravenous administration of 0.75-mg palonosetron in 150 chemotherapy-naive patients who received first-line chemotherapy at Saga University Hospital. Constipation was classified into grades 1–5 according to the Common Terminology Criteria for Adverse Events version 5.0. Multiple logistic regression analysis was performed to identify factors associated with palonosetron-related worsening of constipation to grade 2 or higher. Palonosetron significantly increased the incidence and severity of constipation (incidence: before vs. after palonosetron, 35.4% vs. 74.0%, p < 0.0001, and severity: before vs. after palonosetron, 26.7% and 8.7% in grades 1 and 2, respectively, vs. 46.7%, 23.3%, and 4.0% in grades 1, 2, and 3, respectively, p < 0.0001). Despite the use of laxatives, 4.0% of patients had grade 3 constipation requiring manual evacuation. Combination treatment with aprepitant (odds ratio (OR), 10.9; 95% confidence interval (CI), 1.3–90.0; p = 0.026) and older age (OR, 1.25; 95% CI, 1.01–1.57; p = 0.039) were factors associated with the severity of constipation. Constipation was more severe in patients receiving combination treatment with aprepitant than in those treated with palonosetron alone. Older age was also associated with increased risk of severe palonosetron-related constipation. Identification of risk factors can help target risk-based laxative therapy.

This study investigated the effectiveness of pembrolizumab with or without chemotherapy on advanced-stage head and neck cancer (HNC), including nasopharyngeal, sinonasal cavity and external auditory canal cancer, in a real-world setting.We retrospectively collected data from 97 HNC patients who were treated with pembrolizumab alone (n=60) or with chemotherapy (n=37), and we investigated the association between clinicopathological findings and treatment response or prognosis.Patients treated with pembrolizumab and chemotherapy had a 1-year overall survival (OS) of 72.8%, objective response rate (ORR) of 48.6%, and serious (≥G3) adverse events (AEs) of 29.7%. Patients treated with pembrolizumab alone had a 1-year OS of 51.9%, ORR of 21.7%, and ≥G3 AEs of 6.7%. Both the ORR and disease control rate (DCR) in the pembrolizumab with chemotherapy group were significantly better than those in the pembrolizumab group (p=0.074 and p=0.00101, respectively). Among patients with distant metastasis, patients on pembrolizumab with chemotherapy achieved significantly better OS than pembrolizumab alone (p=0.0039). Among patients in the pembrolizumab group, both AE-positive and better performance status were associated with longer OS (p=0.011 and p=0.0037, respectively).Our real-world experience reinforces the durability and effectiveness of pembrolizumab for HNC patients. Additionally, our results suggest that pembrolizumab with chemotherapy might be recommended for patients with distant metastasis and no prior treatment. Further studies are needed to determine the optimal treatment strategy for HNC.

Background The prognosis of advanced laryngeal cancer is unfavorable despite advances in multidisciplinary therapy. Dendritic cells (DCs) play a central role in antitumor immunity. Tumor-infiltrating CD1a+ DCs have been reported to be associated with clinical outcomes in carcinomas of various organs, but the clinical impact of CD1a+ DCs in laryngeal cancer remains to be unequivocally established. Methods We retrospectively analyzed the cases of 57 patients with Stage III or IV laryngeal cancer who underwent a total laryngectomy. Immunohistochemistry detection of CD1a, S100 and CD8 was performed on representative resected specimens. CD1a+ DCs, S100+ DCs and CD8+ cytotoxic T-lymphocytes (CTLs) were evaluated, and the cases divided into high and low groups according to the cut-off of the median values for each of these 3 parameters. Results Compared to the CD1a-low group, the CD1a-high group had more advanced cases and showed significantly worse disease-specific survival (DSS) (P = 0.008) and overall survival (OS) (P = 0.032). The analyses of S100 DCs and CD8+ CTLs revealed no significant impact on clinical outcomes. However, multivariate analysis revealed that infiltration of CD1a+ DCs was an independent unfavorable prognostic factor for both DSS (P = 0.009) and OS (P = 0.013). Conclusions Our results demonstrated that the infiltration of CD1a+ DCs was associated with unfavorable clinical outcomes in patients with advanced laryngeal cancer who underwent a total laryngectomy as the initial treatment.

Background Eosinophilic chronic rhinosinusitis (ECRS) is often complicated by asthma and can be difficult to diagnose. This study aimed to clarify the usefulness of the self-administered odor questionnaire (SAOQ) and visual analog scale (VAS) to identify olfactory disorders in patients with asthma. Methods This retrospective study was conducted on patients with asthma who were referred to the Otolaryngology clinic between May and September 2018. The treatment step of asthma, asthma control test (ACT), pulmonary function test, peripheral blood eosinophils, and fractional exhaled nitric oxide (FeNO) were analyzed. ECRS was diagnosed based on the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis Study score. Olfactory dysfunction was evaluated using the SAOQ and VAS for olfactory disorders. Results The study included 56 patients (18 males and 38 females), who were divided into two groups; those with ECRS (n = 18) and those without ECRS (n = 38). Age, sex, treatment step, ACT score, and pulmonary function were not significantly different between the groups. The ECRS group had a significantly higher FeNO value (89.1 ppb vs. 39.1 ppb) and a significantly lower SAOQ score (40.1% vs. 96.1%). The area under the receiver operating characteristic curve for the efficacy of ECRS diagnosis was 0.88, 0.889, 0.799, and 0.757 for SAOQ, VAS, blood eosinophil count, and FeNO, respectively. Conclusion The SAOQ and VAS scores were useful tools that presented similar results to the blood eosinophil count and FeNO, and may help to improve the diagnosis of ECRS in patients with asthma.

BACKGROUND The optimal therapeutic strategy in treating thyroid metastasis from renal cell carcinoma (RCC) has not been clearly established. Here we describe a case of didactic surgical experience of the disease which caused massive intraoperative bleeding. CASE SUMMARY A 59-year-old male patient presented with a thyroid left lobe soft mass detected by chest computed tomography scans prior to the surgical treatment of RCC of the left kidney. The thyroid mass was initially considered to be benign, then he underwent left radical nephrectomy. One year after the nephrectomy, stereotactic radiosurgery was performed for brain metastasis. During follow-up, the thyroid nodule gradually grew, and the patient manifested swallowing discomfort. Under a clinical diagnosis of thyroid follicular neoplasm, left hemithyroidectomy was performed. Although hemithyroidectomy is usually a safe and straightforward procedure, massive bleeding from markedly developed tumor vessels made the operation very difficult. The thyroid tumor was finally diagnosed as metastasis from clear cell RCC. CONCLUSION For proper timing of the surgery, a clinician should take into consideration the possibility of thyroid metastasis of RCC when a thyroid lesion is found in patients with RCC or in patients with a previous history of RCC. We recommend that thyroid metastasis of RCC should be resected as early as possible even if a patient has other metastatic sites.

Objective In this study, we evaluated pathological changes in the tooth and pharynx of GERD rats to elucidate the association between gastric acid reflux and oral and pharyngeal diseases. Methods An experimental rat model of chronic acid reflux esophagitis was surgically created. The oral cavities were observed histologically every 2 weeks until 20 weeks after surgery. Results At 10 weeks after surgery, molar crown heights in GERD rats were shorter than that in control rats, and inflammatory cell infiltration by gastric acid reflux was found in the periodontal mucosa of GERD rats. Furthermore, dental erosion progressed in GERD rats at 20 weeks after surgery, and enamel erosion and dentin exposure were observed. During the same period, inflammatory cell infiltration was observed in the mucosa of the posterior part of the tongue. These findings suggest that gastric acid reflux may be one of the exacerbating factors of dental erosion, periodontitis and glossitis. Conclusion We investigated oral changes in an experimental rat model of GERD and observed development of dental erosion, periodontitis and glossitis. Our findings suggested chronic gastric acid reflux may be involved in the pathogenesis of oral disease.

Background: Mammary analogue secretory carcinoma (MASC) of the salivary gland shows morphologic similarities and shares an immunophenotype and characteristic ETV6-NTRK3 translocation with secretory carcinoma of the breast. We present a buccal case of MASC along with a survey-based debate about its cytologic diagnosis by fine-needle aspiration (FNA). Case: FNA of the buccal nodule of a 58-year-old Japanese man was initially performed by 3 cytologists who gave different assessments of the Papanicolaou classification (i.e., class II, III, and V). To investigate the potential for discrepant diagnosis of MASC on a larger scale, we distributed a survey with questions about the cytological diagnosis of the present case to cytologists at other institutions. A total of 109 cytologists completed the survey, providing varying assessments of the Papanicolaou classification: class I/II (14%), class III (53%), and class IV/V (33%). Most of the respondents (72%) could not identify a particular tumor or disease. Even the respondents who identified a particular tumor suggested widely differing diagnoses, from a benign lesion to various malignant tumors. Only 2 respondents correctly identified MASC. Conclusion: Our experience and the results of the survey suggest difficulty in the cytodiagnosis of MASC.

Objective To elucidate the association between gastric acid reflux and respiratory diseases by studying the histological changes of the lower airway in rats with chronic acid reflux esophagitis. Methods An experimental rat model of chronic acid reflux esophagitis was surgically created. The lower airways of these rats were histologically observed for more than 50 weeks. Results Although there were no histological changes which induced gastric acid reflux at 10 weeks after surgery, thickening of the basal laminae and the proliferation of the collagenous fibers were observed in the alveolar epithelium at 20 weeks after surgery. At 50 weeks after surgery, the collagenous fibers obliterated the pulmonary alveoli and bronchial lumen. These findings observed in the GERD rats are similar to the pathological findings of human pulmonary fibrosis. Conclusion In this study, we reported pathological changes in the lower airways of GERD rat models observed for more than 50 weeks. These results suggest that gastric acid reflux may be one of the pathogenic or exacerbating factors of pulmonary fibrosis.

喉頭肉芽腫の発生には胃酸逆流および音声酷使, 慢性咳嗽, 気管内挿管による喉頭粘膜損傷が関与することが指摘されているが, この二つが関与する詳細な機序は不明である。われわれはこれまで逆流性食道炎 (gastro-esophageal reflux disease : GERD) モデルラットを作成し, 喉頭粘膜の形態学的変化を観察してきたが, 喉頭肉芽腫の形成は認めなかった。今回, GERDモデルラット作成時に喉頭粘膜に機械的損傷を加えることにより, ラット喉頭に肉芽腫を形成することができた。GERDモデルラットを作成した直後に, プラスチック製の円柱状の棒を声門から気管内に挿入し, 3秒間に3回の上下運動を行った後に抜去した。術後2週のラット喉頭を観察した結果, 機械的刺激のみを与え胃酸逆流のないコントロール群では, 機械的刺激により声帯遊離縁粘膜が剥離しており, 水疱形成を認めた。それに対し, GERDモデルに機械的刺激を与えた群では, 声帯粘膜に粘膜肥厚と毛細血管の増生・拡張および線維組織の増生を伴った炎症細胞浸潤を呈しており, 肉芽腫形成を認めた。形成された肉芽腫は組織学的にヒト喉頭肉芽腫と同様な病理像を呈した。今回の結果から, 喉頭肉芽腫の形成において機械的刺激と胃酸逆流が大きく関与することが示された。

We report herein a rare case of typical carcinoid occurring primarily in the epiglottis. The patient was a 70-year-old man. On initial examination, a polypoid lesion with irregular surface near the center right-hand side of the laryngeal surface of the epiglottis was observed, and a biopsy was performed. Pathological examination of the specimen suggested the possibility of adenocarcinoma. Surgical excision was performed by means of laryngomicrosurgery. A Weerda-type laryngoscope was used to open the larynx, supplemented by rigid nasal sinus surgery endoscopes, and the right-hand half of the epiglottis were excised was ensured using a CO2laser. Postoperative pathological diagnosis was negative for adenocarcinoma and squamous cell cancer; typical carcinoid was diagnosed according to the World Health Organization criteria. Aspiration occurred postoperatively, swallowing training was therefore provided, and the patient was discharged from hospital 2 months after surgery when he was able to eat normally. As of 4 years after surgery, the patient remains under follow-up observation by means of PET-CT and neck, thoracic, and abdominal CT administered at appropriate intervals, but no findings indicating obvious recurrence or metastasis have been observed, and the patient displays good swallowing function.

本邦におけるHPV関連中咽頭癌の発生率やタイピング，臨床上の特徴などを明らかにするため，多施設による前向き研究を行った。2009年5月から症例の登録が開始され，倫理委員会の承認が得られた21の施設によって，中咽頭癌148例，コントロールの正常口蓋扁桃53例が登録された。PCRによるHPV検出は，中咽頭癌症例では76例（51.4%）に認められ，タイピングの結果はHPV16が69例（90.8%），HPV18：2例（2.6%），HPV58：2例（2.6%），その他HPV31，HPV35，HPV56が各1例（1.3%）であった。HPV陽性中咽頭癌は側壁に多く発生し，非喫煙者，非飲酒者に多い傾向が認められた。正常口蓋扁桃ではHPVの感染は認められなかった。ハイブリッドキャプチャー2法を用いたブラッシングによるHPVの検出はPCRと比較すると，感度90.7%，特異度97.1%であった。

当科では下咽頭癌に対し初治療として化学放射線同時併用療法（chemoradiotherapy；CRT）を行い，CRT 40Gyによる原発巣奏効度がCR（またはほとんどCR）であれば根治的CRTを施行し，PRまでであれば根治切除術に移行するという集学的治療を行ってきた。今回，2000年から2007年の間にこの方針にて治療を行った下咽頭癌症例の治療成績を，生存率と喉頭保存率について検討した。CRTはすべて低容量抗癌剤の併用（低容量CRT）であり，CRT 40Gyで原発巣がCRとなった症例はT1 or 2N0群12例中10例（83%），T1 or 2N1-3群15例中10例（67%），T3 or 4N0-3群22例中7例（32%）であった。各群の疾患特異的5年生存率と喉頭保存率は，それぞれT1 or 2N0群；81%と67%，T1 or 2N1-3群；47%と67%，T3 or 4N0-3群；49%と27%であった。T1 or 2N0-3症例では低容量CRTにより70%程度の喉頭保存率が期待できるが，30%程度の低感受性症例では局所制御のために原発巣切除術や高容量抗癌剤を併用するCRT（高容量CRT）が必要と思われた。また，T1 or 2N1-3症例の生存率向上のためには高容量CRTや頸部郭清術を適切に組み込む必要があると思われた。T3 or 4N0-3症例では根治切除術の必要性が大きいが，30%程度の高感受性症例では低容量CRTでも喉頭保存が期待でき，この群の喉頭保存率をさらに高めるためには高容量CRTや動注CRTなどの強力なCRTが必要と思われた。CRT 40Gyでの原発巣奏効度に基づき治療法を決める集学的治療は，CRTに対する感受性に応じて治療法を選択する治療体系であり，下咽頭癌の根治や喉頭保存を図る有用な方法の一つである。

1991年から2006年の間に佐賀大学医学部附属病院で経験した甲状腺分化癌縦隔進展例15例の治療成績について検討を行った。症例は男性6例,女性9例,平均60歳で,初発例が5例,再発例が10例であった。縦隔進展のパターンは縦隔リンパ節転移が14例,縦隔への直接浸潤が1例であった。縦隔郭清術を施行した症例は7例で,すべて胸骨縦切開法により胸部外科医によって行われた。初発時に頸部手術と縦隔郭清術を行った症例が4例,再発時に縦隔郭清術を行った症例が2例,再発時に頸部手術と縦隔郭清を行った症例が1例であった。縦隔郭清術施行7症例の5年生存率,10年生存率はいずれも85.7%であった。非施行例8例のうち6例は手術不能により根治手術を施行しなかった。これら6例は診断後4年以内に死亡しており,このうち4例は気管狭窄あるいは気管内出血という苦痛の大きな死因であった。このような大きな苦痛を取り除くために,非根治例でも今後は症例によっては縦隔隔清を選択すべきであると考えられた。非施行例のうち2例は手術拒否例であり,1例は診断後89ヶ月,もう1例は120ヶ月になるがいずれも担癌生存中である。縦隔郭清術に伴う合併症として縦隔洞炎と反回神経麻痺が1例ずつみられ,縦隔洞炎は抗生剤投与と縦隔内洗浄で制御できた。甲状腺癌縦隔進展例に対する縦隔郭清術については,耳鼻咽喉科・頭頸部外科医が単独で行う胸骨柄切除や胸鎖関節切除などの術式が一般的であるが,耳鼻咽喉科と胸部外科のチーム医療で臨む胸骨縦切開法は充分な視野が得られ比較的安全に行い得る術式であり,有用な術式の一つであると考えられた。

Objective Ectopic gastric mucosa of the cervical esophagus, referred to as inlet patch (IP), is considered to be a common development abnormality of the esophagus. We report here a case of hypopharyngeal squamous cell carcinoma bordering on IP of the cervical esophagus. Methods A 44-year-old female underwent partial pharyngectomy, total laryngectomy, cervical esophagectomy, and bilateral neck dissection under the diagnosis of hypopharyngeal carcinoma. Results Resected specimens of the hypopharynx revealed a well-differentiated squamous cell carcinoma in the ulcerative tumorous lesion (3.5 cm × 0.5 cm). A brown patch (2 cm × 1.5 cm) bordering the anal aspect of the tumor comprised ectopic gastric mucosa of fundic type epithelium. Immunohistochemistry revealed the surface mucosal cells of this lesion were strongly positive for human gastric mucin (HGM) and the fundic cells were positive for gastrin. Conclusion The hypopharyngeal squamous cell carcinoma likely developed in association with chronic irritation due to gastric acid from the IP. To our knowledge, this is the first reported case of squamous cell carcinoma related to IP.