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ObjectiveSalivary duct carcinoma (SDC) is a highly aggressive and uncommon tumor arising not only de novo but also in pleomorphic adenoma. Androgen receptor (AR)- and HER2-targeted therapy have recently been introduced for SDC as promising treatment options; however, no predictive biomarkers have yet been established. EZH2 and H3K27me3 are closely linked to the development and progression of various cancers, and EZH2 is also expected to be a desirable therapeutic target. We therefore explored the clinicopathological and prognostic implications of EZH2 and H3K27me3 in a large cohort of SDC patients, focusing on their impact on the therapeutic efficacy of AR- or HER2-targeted therapy.Materials and MethodsThe EZH2 and H3K27me3 immunohistochemical expression and EZH2 Y646 gain-of-function mutation status were examined in 226 SDCs, and the relationship with the clinicopathological factors as well as clinical outcomes were evaluated within the three groups depending on the treatment: AR-targeted (combined androgen blockade with leuprorelin acetate and bicalutamide; 89 cases), HER2-targeted (trastuzumab and docetaxel; 42 cases), and conventional therapy (112 cases).ResultsEZH2 and H3K27me3 were variably immunoreactive in most SDCs. A positive correlation was found between the expression of EZH2 and H3K27me3. The EZH2 expression in the SDC component was significantly higher than that in the pre-existing pleomorphic adenoma component. EZH2 Y646 was not identified in any cases. EZH2-high cases more frequently had an advanced clinical stage and aggressive histological features than EZH2-low cases. An EZH2-high status in patients treated with AR-targeted therapy was associated with a significantly shorter progression-free and overall survival as well as a lower objective response rate and clinical benefit rate. In addition, a H3K27me3-high status in patients treated with AR-targeted therapy was related to a shorter overall survival. Conversely, there was no association between the EZH2 and H3K27me3 expression and the clinical outcomes in the conventional or HER2-targeted therapy groups.ConclusionsA high expression of EZH2 and H3K27me3 in SDC might be a predictor of a poor efficacy of AR-targeted therapy. Our data provide new insights into the role of EZH2 and H3K27me3 in therapeutic strategies for SDC.

Molecular targets and predictive biomarkers for prognosis in salivary duct carcinoma (SDC) have not been fully identified. We conducted comprehensive molecular profiling to discover novel biomarkers for SDC. A total of 67 SDC samples were examined with DNA sequencing of 464 genes and transcriptome analysis in combination with the clinicopathological characteristics of the individuals. Prognostic biomarkers associated with response to combined androgen blockade (CAB) treatment were explored using mRNA expression data from 27 cases. Oncogenic mutations in receptor tyrosine kinase (RTK) genes or genes in the MAPK pathway were identified in 55 cases (82.1%). Alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway were identified in 38 cases (56.7%). Interestingly, patient prognosis could be predicted using mRNA expression profiles, but not genetic mutation profiles. The risk score generated from the expression data of a four-gene set that includes the ADAMTS1, DSC1, RNF39, and IGLL5 genes was a significant prognostic marker for overall survival in the cohort (HR = 5.99, 95% confidence interval (CI) = 2.73–13.1, p = 7.8 × 10−6). Another risk score constructed from the expression of CD3E and LDB3 was a strong prognostic marker for progression-free survival for CAB treatment (p = 0.03). Mutations in RTK genes, MAPK pathway genes, and PI3K/AKT pathway genes likely represent key mutations in SDC tumorigenesis. The gene expression profiles identified in this study may be useful for stratifying patients who are good candidates for CAB treatment and may benefit from additional systemic therapies.

Salivary duct carcinoma (SDC) is a rare, aggressive malignancy that histologically resembles high-grade mammary duct carcinoma. Because of the rarity of this entity, data verifying the association between histologic features and patient survival are limited. We conducted a comprehensive histologic review of 151 SDC cases and performed an analysis of the association between various histomorphologic parameters and the clinical outcome with the aim of developing a histologic risk stratification model that predicts the prognosis of SDC patients. A multivariate analysis revealed that prominent nuclear pleomorphism (overall survival [OS]: P=0.013; progression-free survival [PFS]: P=0.019), ≥30 mitoses/10 HPF (PFS: P=0.013), high tumor budding (OS: P=0.011; PFS: P

Cluster of acute flaccid paralysis and cranial nerve dysfunction was associated with a 2014 outbreak of enterovirus D68 (EV-D68) respiratory illness in US. We describe a 33 year-old male patient of refractory dysphagia due to EV-D68-induced brainstem encephalitis successfully treated by surgery. Following acute upper respiratory tract infection, he developed dysphagia and bilateral facial paralysis. A coughing reflex was readily produced when the laryngopharyngeal fiberscope touched the epiglottis, however, water infusion induced only very weak and slow swallowing reflex, suggesting that only motor component was impaired but sensory function was preserved during swallowing. Despite eight months-conservative rehabilitations, Food Intake Level Scale (FILS) remained level 4. Therefore, corrective surgeries including cricopharyngeal myotomy, laryngeal suspension, and pharyngeal flap were performed. Thirty-six days after surgery, FILS rapidly and dramatically improved to level 8. This is the first report describing a successful surgical intervention for EV-D68-induced refractory dysphagia. Surgical treatment was suitable for EV-D68-induced dysphagia, perhaps because sensory function was preserved and only motor disturbance was present during the pharyngeal stage of swallowing.

The molecular characteristics of therapeutically-relevant targets and their clinicopathological implications in salivary duct carcinomas (SDCs) are poorly understood. We investigated the gene alterations and the immunoexpression of crucial oncogenic molecules in 151 SDCs. The mutation rates that were identified, in order of frequency, were as follows: TP53, 68%; PIK3CA, 18%; H-RAS, 16%; BRAF, 4%; and AKT1, 1.5%. PIK3CA/H-RAS/BRAF mutations were more common in de novo SDC than in SDC ex-pleomorphic adenoma. Furthermore, these mutations were mutually exclusive for HER2 overexpression/amplification. TP53 mutations were frequently detected in cases with the aberrant p53 expression, and TP53 missense and truncating mutations were associated with p53-extreme positivity and negativity, respectively. DISH analysis revealed no cases of EGFR amplification. The rates of PI3K, p-Akt, and p-mTOR positivity were 34%, 22%, and 66%, respectively; PTEN loss was observed in 47% of the cases. These expressions were correlated according to the signaling axis. Cases with PI3K negativity and PTEN loss appeared to show a lower expression of androgen receptor. In the multivariate analysis, patients with SDC harboring TP53 truncating mutations showed shorter progression-free survival. Conversely, p-Akt positivity was associated with a favorable outcome. This study might provide information that leads to advances in personized therapy for SDC.

// Soichiro Takase 1, 2, * , Satoshi Kano 3, * , Yuichiro Tada 4, * , Daisuke Kawakita 5 , Tomotaka Shimura 2, 6 , Hideaki Hirai 2 , Kiyoaki Tsukahara 1 , Akira Shimizu 1 , Yorihisa Imanishi 7 , Hiroyuki Ozawa 7 , Kenji Okami 8 , Yuichiro Sato 9 , Yukiko Sato 10 , Chihiro Fushimi 4 , Takuro Okada 1 , Hiroki Sato 1 , Kuninori Otsuka 7 , Yoshihiro Watanabe 7 , Akihiro Sakai 8 , Koji Ebisumoto 8 , Takafumi Togashi 9 , Yushi Ueki 9 , Hisayuki Ota 9 , Toyoyuki Hanazawa 11 , Hideaki Chazono 11 , Robert Yoshiyuki Osamura 12 and Toshitaka Nagao 2 1 Department of Otolaryngology Head and Neck Surgery, Tokyo Medical University, Tokyo, Japan 2 Department of Anatomic Pathology, Tokyo Medical University, Tokyo, Japan 3 Department of Otolaryngology-Head and Neck Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan 4 Department of Head and Neck Oncology and Surgery, International University of Health and Welfare Mita Hospital, Tokyo, Japan 5 Department of Otolaryngology Head and Neck Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan 6 Department of Otorhinolaryngology, Showa University School of Medicine, Tokyo, Japan 7 Department of Otorhinolaryngology-Head and Neck Surgery, Keio University School of Medicine, Tokyo, Japan 8 Department of Otolaryngology Head and Neck Surgery, Tokai University School of Medicine, Isehara, Japan 9 Department of Head and Neck Surgery, Niigata Cancer Center Hospital, Niigata, Japan 10 Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan 11 Department of Otolaryngology, Head and Neck Surgery, Chiba University Graduate School of Medicine, Chiba, Japan 12 Diagnostic Pathology Center, International University of Health and Welfare Mita Hospital, Tokyo, Japan * These authors contributed equally to this work Correspondence to: Toshitaka Nagao, email: nagao-t@tokyo-med.ac.jp Keywords: salivary duct carcinoma, androgen receptor, p53, CK5/6, HER2 Received: June 22, 2017 Accepted: July 26, 2017 Published: August 02, 2017 ABSTRACT Salivary duct carcinoma (SDC) is an uncommon, aggressive malignant neoplasm histologically resembling high-grade mammary ductal carcinoma. SDC can arise de novo or ex pleomorphic adenoma. To clarify the correlation of biomarker immunoprofile with clinicopathological findings and clinical outcome of SDC, we conducted immunohistochemistry for EGFR, HER2, HER3, AR, CK5/6, p53, and Ki-67, along with HER2 fluorescence in situ hybridization in 151 SDCs. SDCs ex pleomorphic adenoma more commonly overexpressed EGFR, HER2, HER3, and Ki-67 than de novo SDCs ( P = 0.015, < 0.001, 0.045, and 0.02, respectively). In multivariate analysis, AR− and CK5/6+ were associated with shorter progression-free survival ( P = 0.027 and 0.004, respectively). Moreover, patients with p53-extreme negative/positive demonstrated poorer overall survival ( P = 0.007). On assessing the revised classification by the combination of biomarker expression, the percentages of each subtype were as follows: ‘apocrine A’ (AR+/HER2−/Ki-67-low) (24%), ‘apocrine B’ (AR+/HER2−/Ki-67-high) (18%), ‘apocrine HER2’ (AR+/HER2+) (35%), ‘HER2-enriched’ (AR−/HER2+) (12%), and ‘double negative’ (AR−/HER2−) (11%). ‘Double negative’ was further subclassified into ‘basal-like’ (EGFR and/or CK5/6+) (7%) and ‘unclassified’ (3%). Consequently, patients with ‘apocrine A’ showed a better progression-free survival than those with any other subtypes. Our revised immunoprofiling classification was valuable for predicting the survival and might be useful in personalized therapy for patients with SDC.

AIMS Salivary duct carcinoma (SDC) is an uncommon, aggressive tumour that, histologically, resembles high-grade mammary ductal carcinoma, and is characterised by the expression of androgen receptor (AR). The androgen signalling pathway, a potential therapeutic target, can be regulated by FOXA1. This study aimed to evaluate the clinicopathological implications of FOXA1 in SDC. METHODS AND RESULTS We examined the relationship between the immunoexpression of FOXA1 and FOXA1 mutations and clinicopathological factors, including the biomarker status and clinical outcome, in 142 SDCs. FOXA1 was expressed in 128 SDCs (90.1%); the immunoexpression was heterogeneous. SDCs with a higher FOXA1 labelling index (LI) (≥20%) more frequently showed less advanced tumors on T classification (P = 0.002). FOXA1 LI was correlated positively with the AR expression value (r = 0.430, P

Objective Recent data indicated that concurrent chemoradiotherapy (CCRT) using high dose cisplatin (CDDP) is the most useful treatment for advanced head and neck squamous cell carcinoma (SCC). Regarding the dose of CDDP, 100 mg/m2 is most recommended in Western countries. However, in terms of a balance of efficacy and adverse events, appropriate dose of cytotoxic drugs such as CDDP may be different among the different ethnic groups. In this multicenter phase I/II study, we aimed to identify the optimal dose of CDDP in CCRT for patients with advanced head and neck SCC in the Japanese. Methods Patients were eligible for inclusion if they had head and neck SCC that was treated with radical CCRT comprising whole-neck irradiation of the primary lesion and level II–IV lymph nodes on both sides. For the phase I study, a CDDP dose was 70 mg/m2 for level 0, 80 mg/m2 for level 1, and 100 mg/m2 for level 2. Maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) were examined by phase I trial, by which CDDP dose for phase II was determined. The primary endpoint for the phase II was CCRT completion rate, and the secondary endpoint was full-dose-CCRT completion rate, the percentage of patients receiving a total CDDP dose of ≥200 mg/m2, response rate, and incidences of adverse events. Results A CDDP dose of 100 mg/m2 was the MTD for phase I, and the recommended dose for phase II was 80 mg/m2. Forty-seven patients were evaluated in the phase II trial. CCRT completion rate, full-dose-CCRT rate, and the percentage of patients receiving a total CDDP dose of ≥200 mg/m2, were 93.6%, 78.7%, and 93.6%, respectively. One patient (2.1%) developed grade 2 renal dysfunction, and no patient developed febrile neutropenia or a grade 4 adverse event. Conclusion The present phase I study indicated that a CDDP dose of 80 mg/m2 is the optimal dose in terms of safety. The phase II study revealed that CCRT completion rate, response rate, and rates of adverse events were not inferior for a CDDP dose of 80 mg/m2 as compared with a dose of 100 mg/m2, and a dose of 80 mg/m2 is therefore recommended in CCRT for the Japanese. This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; identification No. UMIN000010369).

Papillary thyroid carcinoma (PTC) often metastasizes to the central and lateral neck lymph nodes, but rarely affects retropharyngeal nodes (RPN). We retrospectively reviewed 12 patients (three men, nine women) with PTC who underwent dissection of RPN metastases between 1994 and 2012. Mean age at dissection was 65 years (range 23–77). Dissection was performed with the initial surgery for PTC in eight patients, while the remaining four patients underwent dissection as secondary surgery. RPN metastases arose from an ipsilateral primary in nine patients, bilateral in two, and contralateral in one, with primaries located at the superior pole of the thyroid lobe in nine patients. All patients showed simultaneous or previous lymph node metastases in the upper jugular chain. A transcervical approach was applied for RPN dissection in 11 patients, while a transcervical-transparotid approach was applied in the remaining patient. No patients needed mandibulotomy or showed severe complications. Median duration of follow-up after RPN dissection was 48 months (range 3–206). No recurrences in the retropharyngeal space were identified. Two patients died of the disease, one died from other carcinoma, and five survived with distant metastases from PTC. The remaining four patients remain free of the disease as at the time of writing. If lymph node metastases are identified in the upper jugular chain, the possibility of RPN metastases should be checked. Most RPN metastases from PTC can be dissected safely without mandibulotomy. In particular, low-risk patients can expect favorable outcomes.

// Daisuke Kawakita 1 , Yuichiro Tada 2 , Yorihisa Imanishi 3 , Shintaro Beppu 1 , Kiyoaki Tsukahara 4 , Satoshi Kano 5 , Hiroyuki Ozawa 3 , Kenji Okami 6 , Yuichiro Sato 7 , Akira Shimizu 4 , Yukiko Sato 8 , Chihiro Fushimi 2 , Soichiro Takase 4 , Takuro Okada 2 , Hiroki Sato 4 , Kuninori Otsuka 3 , Yoshihiro Watanabe 3 , Akihiro Sakai 6 , Koji Ebisumoto 6 , Takafumi Togashi 7 , Yushi Ueki 7 , Hisayuki Ota 7 , Tomotaka Shimura 9 , Toyoyuki Hanazawa 10 , Shingo Murakami 1 , Toshitaka Nagao 9 1 Department of Otorhinolaryngology, Head and Neck Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan 2 Department of Head and Neck Oncology and Surgery, International University of Health and Welfare Mita Hospital, Tokyo, Japan 3 Department of Otorhinolaryngology-Head and Neck Surgery, Keio University School of Medicine, Tokyo, Japan 4 Department of Otolaryngology, Tokyo Medical University School of Medicine, Tokyo, Japan 5 Department of Otorhinolaryngology-Head and Neck Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan 6 Department of Otolaryngology-Head and Neck Surgery, Tokai University School of Medicine, Isehara, Japan 7 Department of Head and Neck Surgery, Niigata Cancer Center Hospital, Niigata, Japan 8 Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan 9 Department of Anatomic Pathology, Tokyo Medical University School of Medicine, Tokyo, Japan 10 Department of Otolaryngology, Head and Neck Surgery, Chiba University Graduate School of Medicine, Chiba, Japan Correspondence to: Daisuke Kawakita, email: dk200811@gmail.com Keywords: salivary duct carcinoma, survival, mGPS, CRP, NLR Received: August 26, 2016 Accepted: November 09, 2016 Published: November 24, 2016 ABSTRACT The prognostic role of modified Glasgow Prognostic Score (mGPS), neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in patients with salivary duct carcinoma (SDC) remains unclear. We conducted a multi-institutional retrospective cohort study of 140 SDC patients. The survival impact of these hematological markers was evaluated using multivariate proportional hazard models.High mGPS (≥1) was significantly associated with worse survival (3-year overall survival (OS): 16.7% vs 66.1%, p -value=0.003; 3-year progression-free survival (PFS): 0.0% vs 27.9%, p -value

Salivary duct carcinoma (SDC) has a poor prognosis owing to the high incidence of distant metastasis. Approximately 40 % of SDCs are positive for human epidermal growth factor receptor 2 (HER2), suggesting that anti-HER2 therapy for cases with distant metastasis may be effective. However, the pathological response of SDC metastases to anti-HER2 therapy has not been reported. A 44-year-old man was diagnosed with HER2-positive SDC of the submandibular gland with multiple distant metastases. After six cycles of trastuzumab/docetaxel therapy, the patient achieved clinical partial response for the primary tumor and complete response for the neck and distant metastases. Subsequently, the patient underwent submandibular gland resection and neck dissection. On histopathological examination, very few viable cancer cells were identified in the resected primary tumor. Unfortunately, the patient died of multiple distant metastases 12 months after initial treatment. Trastuzumab/docetaxel therapy can elicit a clinical and pathological response in HER2-positive SDC.

We report a rare case of first and second branchial arch syndrome with fistula originated from the first pharyngeal pouch. A 10-day-old female was referred to our clinic with a complaint of left microtia with fistula at the mandibular angle. On preoperative examinations, X-ray with angiography flexible wire inserted into the fistula and computed tomography with contrast enhancement of the fistula revealed that the fistula was connected to the middle ear cavity. Fistulectomy was performed at the age of 7. Pathological examinations demonstrated that the fistula consisted of a single layer of cylindrical epithelium, suggesting that it originated from the endoderm. Based on surgical, imaging, and pathological findings, the fistula originated from first pharyngeal pouch. Preoperative X-ray with angiography flexible wire inserted into the fistula and the computed tomography with contrast enhancement of the fistula were useful for planning operation.