Published papers

Background: The efficacy and safety of human epidermal growth factor receptor 2 (HER2)-targeted therapy and androgen deprivation therapy (ADT) for locally advanced or recurrent or metastatic (LA/RM) salivary duct carcinoma (SDC) have been reported in prospective studies. However, the survival benefit of these therapies to conventional therapy remains controversial, and whether HER2-targeted therapy or ADT should be chosen in HER2- and androgen receptor (AR)-positive SDC patients remains unknown. Methods: Overall, 323 LA/RM SDC patients treated at seven institutions between August 1992 and June 2020 were retrospectively enrolled. The primary aim was to analyze the effect of HER2-targeted therapy and ADT on overall survival from the diagnosis of LA/RM disease to death from any cause (OS1). The secondary indicators included the overall response rate (ORR), clinical benefit rate (CBR), overall survival from therapy initiation for LA/RM disease (OS2), progression-free survival (PFS), time to second progression (PFS2), duration of response (DoR), and duration of clinical benefit (DoCB) of HER2-targeted therapy or ADT as first-line therapy for HER2-positive/AR-positive SDC. Results: Patients treated with HER2-targeted therapy or ADT had longer OS1 than those treated without these therapies (Median OS1: historical control, 21.6 months; HER2-targeted therapy, 50.6 months; ADT, 32.8 months; HER2-targeted therapy followed by ADT, 42.4 months; and ADT followed by HER2-targeted therapy, 45.2 months, p < 0.001). Among HER2-positive/AR-positive SDC patients, although HER2-targeted therapy had better ORR, CBR, and PFS than those of ADT as first-line therapy, we found no significant differences between HER2-targeted therapy and ADT regarding OS2, PFS2, DoR, and DoCB. Conclusion: Patients treated with HER2-targeted therapy and ADT showed longer survival in LA/RM SDC. HER2-targeted therapy can be recommended prior to ADT for HER2-positive/AR-positive SDC. It is warranted to establish a biomarker that could predict the efficacy of clinical benefit or better response in ADT.

Objective: Salivary 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 Methods: The 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). Results: EZH2 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. Conclusions: A 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.

Background: In recent years, transcanal endoscopic ear surgery (TEES) is known as an innovative and minimally invasive surgery. Aims: To clarify the usefulness of TEES for the ossicular malformation, we performed a retrospective study. Material and methods: We examined cases of ossicular malformation performed using TEES at our hospital between April 2015 and April 2020. Results: The hearing level results were countable for 16 cases. Post-operative hearing levels were significantly improved. Transient nausea, tongue paralysis, and taste disorders were observed; however, no other complications were observed. In 2015–2018, some of the cases required the assistance of a surgical microscope. In contrast, all the cases were performed by TEES after 2019 using a powered device to curve the canal. Conclusions and significance: TEES requires considerable training, and the sensation of depth is difficult to acquire. However, this less invasive method is also helpful for ossicular malformation cases.

Background: The spinal accessory nerve (SAN) has several anatomical variations, which may be a pitfall in neck dissection (ND). These include the trapezius muscle branch (TB), which stems from the common trunk before entering the sternocleidomastoid muscle (SCM). Aims/Objectives: To investigate the prevalence of this variation and suggest a protocol for preventing unexpected injury of the TB in ND. Materials and methods: We conducted a retrospective cohort study for 93 patients who had undergone neck dissection (117 sides) without resection of the SCM nor SAN. We recorded the division of the TB after and before penetration of the SCM by the common trunk (penetrating type TB [PTB]) and non-penetrating type TB [NPTB], respectively). Results: Among NDs, PTB and NPTB were observed in 61 (52%) and 56 (48%) sides, respectively. In the subgroup of 24 cases with bilateral ND, PTB/PTB, NPTB/NPTB, and NPTB/PTB were observed in eight (33%), nine (38%), and seven (29%) cases, respectively. The prevalence of PTB/NPTB did not differ according to age, sex, or laterality. Conclusions and significance: NPTB is a common anatomical variation. The presence or absence of a branch from the common trunk must be initially checked to avoid unexpected damage to the TB.

Purpose: Carotid artery invasion by metastatic lymph nodes in head and neck squamous cell carcinoma (HNSCC) is one of the diagnostic criteria for unresectable tumors. However, to date, the diagnostic criteria for carotid artery invasion have not been well documented. This study investigated the utility of computed tomography (CT) findings as a predictor of carotid artery invasion by metastatic lymph nodes in HNSCC. Methods: Twenty-eight patients who had metastatic lymph nodes of HNSCC attached to the carotid artery as seen on CT images before neck dissection from January 2011 to November 2017 were included. Five imaging parameters (angle of contact [AC], length of contact [LC], haziness of the carotid artery wall [HW], size of the lymph node, and involvement of the bifurcation of the carotid artery [IB]) were assessed using CT to predict carotid artery invasion. Furthermore, the utility of the combination of these five parameters was evaluated. Results: There were significant differences in AC, LC, and IB between patients with and without carotid artery invasion. There were significant differences in all combinations of the two image findings between patients with and without carotid artery invasion. In particular, the combinations of LC and HW, and LC and IB could clearly predict carotid artery invasion. Conclusion: AC, LC, and IB were useful predictors of carotid artery invasion of metastatic lymph nodes in HNSCC. This study is the first to report that IB is a useful predictor of carotid artery invasion in HNSCC.

Surgery for vestibular schwannoma includes various techniques such as the middle cranial fossa, suboccipital, translabyrinthine, and retrolabyrinthine approaches. The retrolabyrinthine approach does not impair the labyrinth and allows postoperative hearing preservation. Previously, we reported an endoscope-assisted retrolabyrinthine approach under reinforced continuous intraoperative monitoring for preservation of hearing and facial nerve function. However, the hearing preservation rate was relatively low in patients with long-wave V latency in the auditory brainstem response or poor otoacoustic emission response under this approach. Thus, the hearing preservation rate in such patients remains to be improved. To overcome this limitation, we modified the previous approach. In 26 of the 33 consecutive cases (79%) over the last three years, preservation of hearing equivalent to that before surgery or improved hearing was achieved. Postoperative deafness was observed in only two of the 33 cases (6%). According to previous reports, the rate of hearing preservation using the retrolabyrinthine approach is approximately 30–50%. Therefore, we have achieved a higher hearing preservation rate than that previously reported using the endoscopy-assisted retrolabyrinthine approach under reinforced continuous intraoperative monitoring. These improvements in our department are considered to be helpful for hearing preservation.

Objectives: Evaluation of sarcopenia accompanied by systemic inflammation status is a more beneficial prognostic marker than sarcopenia alone in various cancers. However, few studies have focused on this combination in patients with head and neck squamous cell cancer (HNSCC). In this study, we investigated how the combination of sarcopenia and systemic inflammation could affect survival in patients with HNSCC. Moreover, we explored which systemic inflammation markers could be better prognostic indicators when accompanied by sarcopenia. Materials and methods: We retrospectively reviewed the medical records of patients with HNSCC treated between 2012 and 2016. Sarcopenia was defined by the skeletal muscle area measured on a computed tomography image slice at the level of the third cervical vertebra. The neutrophil/lymphocyte, platelet/lymphocyte, and lymphocyte/monocyte ratios (NLR, PLR, and LMR, respectively) were used as systemic inflammation markers that were combined with sarcopenia to evaluate prognosis. Results: A total of 100 patients were enrolled, and 71 patients were considered sarcopenia. Patients with sarcopenia had significantly lower LMR and higher NLR and PLR. They also showed worse overall survival (OS) and progression-free survival (PFS). The comparative assessment of multiple combination patterns of sarcopenia and systemic inflammation indices proved that sarcopenia plus LMR considered as most reliable indicator for prognosis in HNSCC patients. Sarcopenia plus low LMR was a significantly poor prognostic factor both for OS and PFS with greater HR values than sarcopenia alone. Conclusions: The combination of sarcopenia and LMR was considered the most sensitive prognostic factor in patients with HNSCC, suggesting it might be beneficial for identifying poor outcome risks.

Objective: Febrile neutropenia (FN) is the most serious toxicity in patients with head and neck squamous cell carcinoma (HNSCC) treated with induction chemotherapy (IC). Although it is well-known that sarcopenia is a risk factor for severe toxicity of (chemo)radiotherapy, the data on the association between sarcopenia and FN during IC in HNSCC patients is rare. This study determined the impact of sarcopenia on FN during IC. Methods: IC-treated patients with HNSCC were enrolled in this study. Skeletal muscle mass (SMM) at the C3 vertebral body was used to define sarcopenia from computed tomography (CT) scans. To determine the predictive effect of low SMM on FN, logistic regression analysis was performed. Results: In this study, 71 patients were included, of whom 28 had low SMM and 14 experienced FN. In multivariate analysis, low SMM and high CRP were the independent predictive factors for FN. The combination index of sarcopenia and CRP showed a greater odds ratio than sarcopenia alone suggesting a more significant predicting indicator. Conclusions: Sarcopenia defined by CT imaging is associated with FN in patients with HNSCC treated with IC. The combination of sarcopenia and high CRP is a more significant risk factor, and it helps determine patients at risk of FN during IC.

Background: Cluttering is a speech disorder distinct from stuttering. Despite this distinction, there is no established method to clearly differentiate the two disorders. This study aimed to use objective criteria to differentiate cluttering from stuttering in Japanese speakers. Methods: Participants were 32 consecutive native-Japanese speakers who visited the Keio University Hospital between July 2020 and January 2023 with a chief complaint of speech disfluency. One physician and two speech-language-hearing therapists concurred on a stuttering or cluttering diagnosis of the 32 patients based on recordings of the Kitsuon kensa-ho test. The frequencies of stuttering-like disfluencies (SDF) and normal disfluencies (NDF) were calculated from the Kitsuon kensa-ho, and the ratio of disfluencies (RDF) was calculated as the ratio of SDF to NDF. Differences between the cluttering and stuttering groups in the RDF and the mean articulatory rate (MAR) for oral reading and a monologue task were tested using the Mann–Whitney U test. ROC curves were used to determine the sensitivity and specificity that well-distinguished subjects with cluttering from those with stuttering; the experts’ diagnosis was the gold standard. Results: Of the 32 participants, 12 (38%) were diagnosed with cluttering and 20 (62%) with stuttering. The cluttering and stuttering groups were comparable in demographic characteristics. The RDF on monologue task had the highest sensitivity in diagnosing cluttering, and the MAR on monologue task had the highest specificity. Adopting provisional criteria of a monologue RDF greater than 1.2 and a monologue MAR greater than 7.5 produced a sensitivity of 0.92 and a specificity of 0.95. Conclusion: We conclude that combining monologue RDF and monologue MAR well-distinguished cluttering from stuttering. This method provides new objective diagnostic criteria, which can aid clinicians, therapists, and basic researchers.

The Japanese Clinical Practice Guidelines for Head and Neck Cancer – 2025 Edition were developed to provide clear evidence-based recommendations that reflect recent advancements and evolving clinical needs in head and neck cancer care. Advances in immunotherapy, targeted therapies, surgical techniques, and genomic medicine have expanded treatment options and added new complexities. This edition offers practical, up-to-date guidance to support consistent decision making across diverse clinical scenarios. Compared with the 2022 edition, the guidelines have been substantially expanded to 63 clinical questions (CQs) across 14 categories. A new feature is the inclusion of commentary columns that address clinically important topics not suited to the CQ format, such as special patient populations, novel therapies, and rare malignancies. To reflect the growing role of precision oncology, updated recommendations for molecular-targeted treatments have been added based on specific genomic alterations, in alignment with the current approvals in Japan. While maintaining the structure of previous editions, this edition addresses the changing clinical environment while also helping to inform future discussions and directions in head and neck cancer care.

Many researchers have focused on the role of the autonomic nervous system in the tumor microenvironment. Autonomic nerves include the sympathetic and parasympathetic nerves, which are known to induce cancer growth and metastasis. However, in salivary duct carcinoma (SDC), a rare and highly malignant tumor, the issue should be investigated from both biological and therapeutic perspectives. We explored the clinicopathological and prognostic implications of the autonomic nerves in 129 SDCs. Immunohistochemistry was performed to determine the nature of each nerve using antibodies against S100, tyrosine hydroxylase (TH) as a sympathetic marker, and vesicular acetylcholine transporter (VAChT) as a parasympathetic marker. The area of each marker-positive nerve was digitized and evaluated quantitatively. Double immunofluorescence for TH and VAChT was performed in selected cases. The expression of the secreted neurotrophins was also examined. S100-positive nerves were present in the cancer tissue in 94 of 129 cases (72.9%). Among them, TH-positive sympathetic nerves and/or VAChT-positive parasympathetic nerves were identified in 92 cases (97.9%), and 59 cases (62.8%) had TH/VAChT-co-expressing nerves. Double immunofluorescence revealed a mosaic pattern of sympathetic and parasympathetic fibers in co-expressing nerve bundles. The presence of autonomic nerves, regardless of their area, was significantly associated with aggressive histological features, advanced T/N classification, and a poor prognosis, with shorter disease-free and overall survival. There was an association between some tumor immune microenvironment-related markers and the autonomic nerve status, but not the latter and the secreted neurotrophin expression. This study suggests that autonomic nerves might play a role in the progression of SDC.

Objectives: Recent advances in systemic therapy for salivary duct carcinoma (SDC) have been driven by the development of HER2- and androgen receptor (AR)-targeted therapies. Trastuzumab deruxtecan has proven effective not only in HER2-positive but also HER2-low breast and gastro-esophageal cancers. However, the significance of HER2-low expression in SDC remains unknown. This study aimed to investigate the clinicopathologic characteristics, prognostic implications, and impact on efficacy to AR-targeted therapy in HER2-low SDC. Materials and Methods: This was a multi-center, observational study. HER2 status was reclassified as follows: HER2-positive (IHC3+ or 2+/ISH+ ), HER2-low (IHC1+ or 2+/ISH-), and HER2-zero (IHC0). The subjects were compared in three groups: total population, curative treatment cohort, and AR-targeted therapy cohort. Results: The total population consisted of 526 patients, of whom, 271 (52 %), 184 (35 %), and 71 (13 %) had HER2-positive, -low, and -zero tumors, respectively. Sex, M category, histological origin, Ki67, and p53 expression differed significantly between the HER2-low and HER2-positive cases. No differences in relapse-free or overall survival were observed for HER2 status in the curative treatment cohort; however, in the AR-targeted therapy cohort, the HER2-low group had significantly better response rates (41.6 % vs. 18.9 %, Odds ratio = 0.30, P = 0.012) and longer median progression-free survival (6.9 vs. 4.2 months, Hazard ratio = 1.61, P = 0.029) than those of the HER2-positive group. Conclusion: HER2-low showed different clinicopathologic features from HER2-positive cases, with no prognostic differences observed in patients who underwent curative treatment. Still, HER2-low may be associated with the efficacy of AR-targeted therapy.

Objective Sarcopenia and systemic inflammatory markers predict prognosis in various cancers, including head and neck cancer (HNC) treated with surgery or chemoradiotherapy. Their significance in patients receiving immune checkpoint inhibitors (ICIs), however, remains unclear. This study aims to determine whether skeletal muscle loss and systemic inflammation influence treatment response and survival in ICI-treated HNC, and whether composite indices provide prognostic value. Methods A retrospective cohort of 179 patients with histologically confirmed recurrent or metastatic (R/M) HNC who received ICI therapy between April 2017 and July 2024 was analyzed. Sarcopenia was assessed using the lumbar skeletal muscle index (LSMI), calculated from cervical CT images. Inflammatory markers such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) were derived from pre-treatment blood samples. Overall survival (OS) and progression-free survival (PFS) were evaluated using Kaplan–Meier estimates, and prognostic factors were identified through Cox regression analysis. Results Among the 179 patients, 98 (54.7%) were classified as sarcopenic. These patients had significantly shorter median OS compared to non-sarcopenic patients (12.1 vs. 39.8 months; p < 0.001). Univariate analysis identified sarcopenia, BMI, NLR, and PLR as significant predictors of OS. However, multivariate Cox analysis revealed that only sarcopenia remained an independent prognostic factor for both OS (HR 1.94; 95% CI: 1.15–3.27; p = 0.013) and PFS (HR 1.92; 95% CI: 1.33–2.75; p < 0.001). Inflammatory markers and their composite indices failed to retain prognostic significance in adjusted models. Conclusion Sarcopenia independently predicts poor survival outcomes in patients with R/M HNC undergoing ICI therapy, whereas conventional inflammatory markers such as NLR, PLR, and LMR, alone or in combination with sarcopenia, lack independent prognostic value. Routine pre-treatment evaluation of skeletal muscle mass using CT imaging may offer a practical and effective tool for patient risk stratification.

Human papillomaviruses (HPV) infect epithelial tissues and induce a variety of proliferative lesions. A subset of HPV types are also the causative agents of many anogenital as well as oropharyngeal cancers. Following infection of basal epithelial cells, HPVs establish their genomes as episomes in undifferentiated cells and require differentiation for their productive life cycles. During HPV infections, viral oncoproteins alter cellular pathways such as those for DNA damage repair and innate immune surveillances to regulate their productive life cycles. These pathways provide potential targets for therapeutic intervention.

Purpose: Lenvatinib achieves favorable therapeutic outcomes for patients with radioactive iodine therapy refractory differentiated thyroid cancer (DTC); however, its use is associated with a high incidence of adverse events. To avoid severe adverse events, planned drug holidays (PDH) have been proposed. This study aimed to evaluate treatment effects, identify prognostic factors, and investigate the usefulness of PDH in patients with unresectable DTC who received lenvatinib across the multi-institutions. Methods: Fifty-one patients with unresectable DTC treated with lenvatinib were evaluated retrospectively. Overall survival (OS) and progression-free survival (PFS) were calculated, and prognostic factors were assessed. OS, PFS, and time to treatment failure (TTF) were compared between patients with and without PDH. Lenvatinib administration schedule was evaluated in PDH. Results: The 3-year OS and PFS rate were 53.5% and 42.1%, respectively. Multivariate analysis revealed that presence of maximum size of lung metastasis ≥10 mm was independent prognostic factor for poorer OS and PFS, and histology other than papillary thyroid carcinoma was the independent prognostic factor for poorer PFS. Twenty-five patients (49%) treated with PDH. There were significant differences in OS, PFS, and TTF between patients with and without PDH. Various schedules were used in PDH. Eight (32%) patients required switch to the different administration schedule. Conclusion: Our results suggest that PDHs may extend OS, PFS, and TTF. In patients with PDH, various schedules used for lenvatinib administration highlight the difficulty in determining a uniform administration schedule. Therefore, it is crucial to consider the optimal lenvatinib administration schedule on a case-by-case basis.

Do adults who stutter have abnormally high social anxiety? Is it related to maladaptive cognition? As these are persistent, unresolved questions in stuttering research, it behooves clinicians to at least assess and attempt to identify social anxiety in patients who stutter and its basis before decisions are made about stuttering treatment. The Unhelpful Thoughts and Beliefs About Stuttering (UTBAS) scale is a self-administered questionnaire that measures the degree of non-adaptive cognition in people who stutter (PWS) due to social anxiety. The 66-item UTBAS is time-consuming to complete, prompting the development of a shorter 6-item version, the UTBAS-6, which is in English. Here, we aimed to assess some psychometric properties of the Japanese version of the UTBAS-6, the UTBAS-6-J, which has not been done to date. In 56 adult patients (mean 32.6 ± 11.1 years) who stutter, we quantified the reliability, the internal consistency, and the concurrent validity of the UTBAS-6-J. Along with the UTBAS-6-J, patients also were administered the Overall Assessment of the Speaker’s Experience of Stuttering – Japanese version (OASES-A-J), the Modified Erickson Communication Attitude Scale – Japanese version (S-24-J), and the Liebowitz Social Anxiety Scale – Japanese version (LSAS-J). Cronbach’s alpha for UTBAS-6-J total scores was 0.974, indicating excellent internal consistency. UTBAS-6-J scores were significantly correlated with scores on the OASES-A-J, the S-24-J, and the LSAS-J (all p < 0.005). Concurrent validity of the UTBAS-6-J with these three questionnaires was confirmed. The UTBAS-6-J has good internal consistency and concurrent validity, which will aid clinical decision-making about stuttering treatments.

Objective: Previous studies have evaluated various markers as prognostic predictors in patients with many types of cancers. However, the influence of such factors on the outcomes of patients with parotid gland carcinoma (PGC) is unknown. This study investigated the roles of alternative markers in the prognoses of patients with PGC. Methods: Overall, 101 patients who underwent curative treatment for PGC were retrospectively evaluated, and their 5-year overall and disease-free survival rates were calculated. The prognostic values of clinical and pathologic factors were determined. Results: The 5-year overall and disease-free survival rates were 73.1% and 62.8%, respectively. Multivariate analysis revealed that a low lymphocyte-to-monocyte ratio (LMR), high T classification, high N classification, and perineural invasion were independent predictors of poor prognosis. Conclusions: Thus, we identified LMR as an independent prognostic factor for patients with PGC. Patients with low LMRs who are amenable to treatment may require adjuvant treatment to improve their prognoses. Level of Evidence: 4 Laryngoscope, 131:E864–E869, 2021.