BACKGROUND:Salivary gland carcinomas are uncommon malignancies with various histological subtypes harboring fusion genes. The EWSR1::ATF1 fusion gene, resulting from a translocation between chromosomes 12 and 22, is frequently observed in hyalinizing clear cell carcinoma (HCCC). However, the role of this fusion gene in HCCC oncogenesis remains unclear. METHODS:We generated EWSR1::ATF1 transgenic mice by introducing an EWSR1::ATF1 fusion gene with a breakpoint in HCCC. These mice were crossed with Lama parotid secretory protein (PSP)-Cre transgenic mice, expressing Cre recombinase in salivary glands, to produce salivary gland-specific EWSR1::ATF1 transgenic mice. Tumor samples were analyzed using Western blotting, histopathology, and RNA sequencing. RESULTS:We generated salivary gland-specific EWSR1::ATF1 transgenic mice, and tumors developed in major salivary glands in three mice. These tumors exhibited more malignant characteristics than human HCCC. CONCLUSIONS:These results suggest that salivary gland-specific expression of EWSR1::ATF1 plays an important role in malignant tumor formation in major salivary glands.

PURPOSE:Salivary gland carcinoma (SGC), particularly salivary duct carcinoma (SDC), is a rare and aggressive malignancy with no standard systemic treatment. Androgen receptor (AR) expression is frequently detected in SDC, which suggests inhibition of the AR pathway as a therapeutic strategy. We conducted a prospective phase II trial of the efficacy and safety of darolutamide, a second-generation AR signaling inhibitor, as monotherapy or in combination with goserelin, in patients with AR-positive unresectable locally advanced (LA) or recurrent/metastatic (R/M) SGC. METHODS:DISCOVARY was a multicenter, single-arm, phase II trial conducted in Japan. Patients with unresectable LA or R/M AR-positive SGC were enrolled into two sequential cohorts, a monotherapy cohort (darolutamide 600 mg orally twice daily) and a combination cohort (darolutamide plus goserelin 3.6 mg subcutaneously once every 28 days). The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), overall survival (OS), safety, and health-related quality of life. RESULTS:Fifty-seven patients were enrolled (monotherapy, n = 24; combination, n = 33). In the monotherapy cohort, the confirmed ORR was 8.3% (90% CI, 1.5 to 24.0) and the median PFS was 5.7 months. In the combination cohort, ORR was 45.2% (90% CI, 29.7 to 61.3) and the median PFS was 13.1 months. Twelve-month OS rates were 91.3% and 87.0%, respectively. Most adverse events were grade 1 or 2 in severity, with no treatment-related deaths. Quality of life was preserved. No clear association between AR expression level or Ki-67 index and treatment response was evident in exploratory analysis. CONCLUSION:Darolutamide demonstrated antitumor activity in AR-positive SGC, with numerically more favorable outcomes with goserelin. Darolutamide plus goserelin may represent a chemotherapy-sparing option in this rare malignancy.

Based on the results of the JCOG1212 trial, superselective intra-arterial infusion chemoradiotherapy (IA-CRT) has become a standard treatment option for patients with locally advanced maxillary sinus carcinoma (LA-MSC), especially those with T4a disease, in Japan. This study aimed to evaluate the real-world effectiveness of IA-CRT compared with systemic intravenous chemoradiotherapy (IV-CRT) in patients with LA-MSC. We retrospectively analyzed data from patients with T3 and T4 N0M0 maxillary sinus carcinoma who were treated with IA-CRT or IV-CRT between 2011 and 2017, using data from the Head and Neck Cancer Registry of Japan. The primary endpoint was the 5-year local control rate (LCR), and the secondary endpoints were overall survival (OS) and progression-free survival (PFS). Survival analyses were performed using inverse probability of treatment weighting (IPTW) adjustment. Among 1,329 registered patients, 507 received definitive chemoradiotherapy as initial treatment, including 373 patients treated with IA-CRT (median follow-up, 46 months) and 134 treated with IV-CRT (median follow-up, 31 months). After IPTW adjustment, the 5-year LCR was significantly higher in the IA-CRT group than in the IV-CRT group (67.0

OBJECTIVE:In this nationwide retrospective study, we sought to evaluate the oncologic and functional outcomes and safety of transoral surgery (TOS) for hypopharyngeal and laryngeal squamous cell carcinomas in Japan and to clarify the appropriate indications for various TOS modalities. METHODS:Data were obtained from the Head and Neck Cancer Registry of Japan. Patients who underwent transoral or endoscopic resection between 2011 and 2016 were selected. Detailed clinical information was collected from 55 institutions using web-based case report forms. Surgical modalities analyzed included endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), endoscopic laryngopharyngeal surgery (ELPS), transoral laser microsurgery (TLM), and transoral videolaryngoscopic surgery (TOVS). RESULTS:In total, 1825 patients were included (hypopharyngeal cancer, 62.5 %; laryngeal cancer, 37.5 %). Most cases (77.5 %) were T1 or lower, and 90.8 % were Stage II or earlier. TLM is predominantly used for glottic cancers, ELPS/ESD for superficial hypopharyngeal lesions, and TOVS for more advanced tumors, reflecting distinct indications for each modality. The 5-year disease-specific survival (DSS), recurrence-free survival (RFS), and overall survival (OS) were 97.1 %, 84.3 %, and 85.4 %, respectively. The laryngeal preservation rate was 98.2 %. Tracheostomy was performed in 5.0 % of cases, mainly for airway protection; major complications, including pneumonia (2.4 %), hemorrhage (1.1 %), fistula formation (0.4 %), and vocal cord fixation (2.6 %), occurred in <3 % of patients. Postoperative functional outcomes were favorable, with persistent dysphagia (Functional Outcome Swallowing Scale stage ≥ 3) in 1.6 % and tube feeding dependence in 1.8 %. CONCLUSION:Non-robot-assisted TOS demonstrated excellent oncologic control and functional preservation of the larynx with low complication rates in early-stage hypopharyngeal and laryngeal cancers. Each surgical modality has distinct indications depending on the tumor site, depth of invasion, and institutional expertise. These findings support the use of TOS as a safe and effective treatment option for selected patients. Further procedural standardization and data accumulation are required to refine the indications and facilitate their broader adoption in clinical practice.

It is difficult to accurately predict occult cervical lymph node metastasis, a major factor that significantly influences treatment outcomes in patients with clinical stage I/II tongue cancer. This study aimed to develop a predictive model for occult cervical lymph node metastasis in patients with stage I/II tongue cancer based on clinical and histopathological findings. This multicenter cross-sectional study analyzed the archived pathological specimens and clinical records of patients diagnosed with stage I/II tongue cancer between January 2012 and March 2020 at seven institutions in Japan. All patients underwent transoral partial glossectomy with elective neck dissection, and the histological depth of invasion (DOI) was confirmed to be 3–10 mm. The clinicopathological features of the primary tumors were compared with those of occult cervical lymph node metastases. Predictive factors for occult cervical lymph node metastasis were identified using the least absolute shrinkage and selection operator (LASSO) regression model, and the model performance was evaluated using receiver operating characteristic (ROC) analysis. In total, 106 patients were included in this study. The LASSO regression analysis identified three significant predictors of occult cervical lymph node metastasis: vascular invasion, poorly differentiated clusters (PDC), and DOI. The predictive model incorporating these factors achieved an area under the curve (AUC) of 0.713. Vascular invasion, PDC, and DOI are the key histopathological predictors of occult cervical lymph node metastasis in early-stage tongue cancer. External validation in larger cohorts is warranted to validate the utility of the predictive model developed in this study.

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

Clinical reasoning skills are essential competencies for medical students; therefore, effective, evidence-informed teaching methodologies are needed worldwide. This study investigated the benefits of team-based learning (TBL) for developing the skills in medical students. A mixed-methods sequential explanatory design was used to investigate the effectiveness of TBL for medical students acquiring clinical reasoning skills. The study participants comprised 92 fourth-year medical students at Yokohama City University School of Medicine, participating in TBL sessions that covered 10 major clinical symptoms identified in the core curriculum. Each session lasted 240 min. Before and after the educational intervention, student performance was measured using the script concordance test (SCT) on a 30-point scale, and self-assessed clinical reasoning competency was measured on a 7-point Likert scale. The SCT included pre-tests and post-tests of 30 questions each, with students randomly assigned to one of two test sets. Following the quantitative evaluation, a qualitative content analysis was conducted to explore the advantages of TBL for learning clinical reasoning skills. The analytic categories were set according to the six levels of Fink’s taxonomy of significant learning. Student performance improved significantly after the educational intervention (A test: 16.5 ± 4.4 to 18.7 ± 4.5, p = 0.019; B test: 18.1 ± 3.7 to 19.8 ± 4.4, p = 0.028). After the educational intervention, self-assessed clinical reasoning competency was significantly higher in “recalling appropriate physical examination and tests on clinical hypothesis generation,” “recalling appropriate differential diagnosis from patient’s chief complaint,” “verbalizing points that fit/don’t fit the recalled differential diagnosis appropriately,” “verbalizing and reflecting appropriately on own mistakes,” “selecting keywords from the whole aspect of the patient,” and “practicing the appropriate clinical reasoning process” (all p < 0.001). The content analysis extracted 23 subcategories and 233 codes of the advantages of TBL for learning clinical reasoning skills, covering all six levels of Fink’s taxonomy of significant learning: Foundational knowledge (7 codes); Application (40 codes); Integration (69 codes); Human dimension (89 codes); Caring (8 codes); and Learning how to learn (20 codes). This study demonstrates that TBL supports the acquisition of critical clinical reasoning skills among medical students.

Advances in narrowband imaging (NBI) have revealed that squamous epithelial lesions form alongside changes in squamous epithelial cells and intrapapillary capillary loops (IPCLs) in the head and neck. However, the molecular interactions between squamous epithelial cells and endothelial cells (ECs) that promote IPCL proliferation are unclear. This study aimed to identify the mechanisms of cooperation between parenchymal squamous cells and stromal IPCLs during the formation of head and neck squamous cell carcinoma (SCC). We investigated ligand-receptor interactions between squamous epithelial and endothelial cells of IPCLs using Visium analysis on frozen, formalin-fixed and paraffin-embedded (FFPE) tissues from hypopharyngeal squamous epithelial lesions. We examined the protein expression in hypopharyngeal superficial squamous epithelial lesions using immunohistochemistry and immunofluorescence. mRNA expression levels of these genes in SCC and non-tumor tissues were analyzed using RT-qPCR. Phenotypic changes were analyzed by inducing candidate genes into SCC cell lines via a lentivirus system. Visium analysis revealed that Fibronectin 1 (FN1) acted as a ligand in endothelial cells, Cellular communication network factor 1 (CCN1) as a ligand in SCC cells, and Integrin subunit alpha V (ITGAV) as a receptor for both FN1 and CCN1. The expression of these three candidates increased in low-grade dysplasia, an early stage of neoplastic lesions, and was significantly higher in invasive SCCs, except for CCN1. When ITGAV was introduced into SCC cell lines (FaDu and Detroit 562) and HaCaT cells treated with FN1, the cells showed increased proliferation ability. SCC develops via ligand-receptor molecular interactions between squamous epithelial and vascular endothelial cells in IPCLs.

The prognosis for T2N0 glottic squamous cell carcinoma (SCC) is generally favorable, with a 5-year overall survival rate of 79%-96% achieved with radiotherapy (RT), the standard nonsurgical treatment for this condition. However, the local control rate for T2N0 glottic SCC treated with RT remains suboptimal, with a 5-year local control rate of only 65%-80%. Local residual disease or recurrence following RT for T2N0 glottic SCC often leads to difficulties in laryngeal preservation. When total laryngectomy is performed as a salvage surgery in such cases, patients lose their physiological ability to speak. Therefore, improving local control and laryngeal preservation rates through RT could substantially improve the quality of life of these patients. Attempts have been made to combine cytotoxic anticancer agents with RT to achieve better local control in patients with T2N0 glottic SCC. In Japan, several studies have evaluated the effects of combining S-1, an oral fluorinated pyrimidine, with RT in these patients. This review highlights the importance of adding chemotherapy to RT in the treatment of patients with T2N0 glottic SCC.

6007 Background: No standard treatment exists for unresectable locally advanced (LA) or recurrent/metastatic (R/M) salivary gland cancer (SGC). Previous findings suggest that combined androgen blockade (CAB) provides promising clinical activity in patients with androgen receptor (AR)-positive SGC. However, no AR-targeted drug is currently approved for SGC. This multi-center phase 2 study investigated two approaches in patients with unresectable LA or R/M SGC: darolutamide monotherapy followed by the combination of darolutamide and goserelin. In the monotherapy phase, darolutamide showed an objective response rate (ORR) of 20.8% as determined by independent central review (ICR) with tolerable toxicity (ASCO 2023). We now report the results from the combination phase. Methods: Eligible patients had histologically confirmed AR-positive LA or R/M SGC, ECOG performance status (PS) 0–2, adequate organ function, and no local therapy options. Patients received darolutamide orally at 1,200mg daily, combined with goserelin at 3.6 mg every four weeks. The primary endpoint was ORR by ICR in patients verified to have AR positivity through central assessment. Secondary endpoints included clinical benefit rate (CBR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety profiles. Results: Between Sep 2022 and Aug 2023, 33 patients were enrolled in the combination phase. Median age was 63 years; 26 were male; ECOG PS 0/1/2 in 28/4/1. Histology included salivary duct carcinoma (n=32) or adenocarcinoma not otherwise specified (n=1). Prior treatment included surgery (n=23), radiotherapy (n=21), and chemotherapy (n=15). The ORR by ICR was 45.2% (14/31; 95% CI, 27.3–64.0), meeting the primary endpoint. CBR was 51.6% (95% CI, 33.1–69.8), and DCR was 64.5% (95% CI, 45.4–80.8). At a median follow-up of 13.7 months, the median PFS was 13.1 months (95% CI, 2.0– not calculable [NC]). Thirteen patients continued treatment at the data cutoff (August 9, 2024). Median OS was not reached (95% CI, 20.0–NC), and 12 months OS rate was 87%(95% CI, 68.9–94.9). Treatment was generally well tolerated, with six patients (18.2%) experiencing grade 3 adverse events. Conclusions: This is the first prospective CAB trial in SGC which has met its primary endpoint. Darolutamide plus goserelin demonstrated clinically meaningful efficacy and a favorable safety profile, suggesting it may be a compelling option before initiating chemotherapy, which can significantly diminish a patient’s quality of life. Clinical trial information: NCT05694819 .

Introduction: Surgical extirpation of a cholesterol granuloma in the petrous apex, located dorsal to the petrous part of the internal carotid artery (ICA), is challenging. Herein, we report a pediatric case of a cholesterol granuloma of the petrous apex treated using the endoscopic contralateral transmaxillary (CTM) approach. Case Presentation: A 13-year-old boy presented with a left-sided headache, slight hypoesthesia in the left V1 area, and severe neuralgia of the left auriculotemporal nerve. Magnetic resonance imaging (MRI) revealed a high-intensity mass without gadolinium enhancement. The patient's headache was unresponsive to various medications. After careful evaluation, an endoscopic CTM approach was selected for the extirpation of the granuloma. Postoperatively, the patient did not experience headache or associated neurological complications. MRI at 46 months revealed no recurrence. Conclusion: The endoscopic CTM approach can be used for excising cholesterol granulomas of the petrous apex located posterior to the petrous part of the ICA without causing severe complications. This approach can be considered useful for pediatric cases in which granulomas are not accessible via the transnasal endoscopic transsphenoidal approach. .

BACKGROUND:The AJCC cutoff value of 2 mm for the extranodal extension (ENE) distance was determined from an analysis of patients with or without adjuvant therapy. The purpose of this study was to find out the ENE distance that reflects prognosis only in patients with head and neck squamous cell carcinoma (SCC) who received adjuvant therapy. METHODS:The ENE distance was defined for 109 patients who underwent surgery for SCC of larynx or hypopharynx as a primary tumor. RESULTS:To standardize patient conditions, only 26 patients who received additional postoperative treatment were analyzed. Receiver operating characteristic analysis of the ENE distance for overall survival (OS) and recurrence-free survival (RFS) yielded a cutoff value of 4250 μm. Multivariate analysis showed that the ENE distance was an independent poor prognostic factor for OS and RFS. CONCLUSION:The optimal ENE distance cutoff for OS and RFS in postoperatively treated patients was 4250 μm.

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

6068 Background: Photoimmunotherapy is a novel anticancer treatment developed by the NCI and has been covered by insurance in Japan since January 2021 for patients with unresectable, locally advanced or locally recurrent head and neck cancers. Over 400 patients have been treated with photoimmunotherapy in Japan, including 19 cases with recurrent nasopharyngeal carcinoma. Photoimmunotherapy uses an antibody-drug conjugate, cetuximab sarotalocan sodium, comprising cetuximab, a chimeric monoclonal antibody (IgG1) that targets human EGFR, and a light-sensitive dye, IRDye 700DX (IR700). The conjugate exhibits a strong affinity for cells expressing EGFR, which is enhanced in HNSCC. When exposed to a 690 nm (red) laser beam from the BioBlade laser system, the dye is activated, resulting in selective and rapid death of cells to which the conjugate is bound. The mechanism involves: (i) activation of the antibody conjugate by laser illumination, (ii) damage to the cell membrane, (iii) increased transmembrane water flux, and (iv) cell rupture and necrosis. The entire process occurs rapidly following laser illumination. Nasopharyngeal carcinoma is primarily treated with radiation therapy; however, if it persists, therapy becomes challenging. Surgical intervention for local recurrence or residual disease can be difficult due to the anatomical characteristics of the disease. Drugs and re-irradiation have limited effectiveness and significant adverse events have been reported. Photoimmunotherapy is considered more effective for nasopharyngeal carcinoma than other treatment sites. Methods: Nineteen patients with recurrent residual nasopharyngeal carcinoma following irradiation, who were treated with photoimmunotherapy at 15 centers across Japan, were reviewed. The study analyzed patients’ previous treatment regimens, laser irradiation methods employed in photoimmunotherapy, and pathological characteristics before and after treatment. Results: The mean observation duration was 368 days (median 302 days). A total of 10 patients received photoimmunotherapy once, 5 received it twice, 2 received it three times, and 2 received it four times. Final local control was achieved in 14 patients with CR, 3 with PR and 1 with SD. Regrettably, 3 patients developed distant metastases after the start of photoimmunotherapy. At the end of the observation period, 11 patients were disease-free, 6 were alive with cancer, and 2 died of carotid artery rupture despite achieving local tumor control. The overall survival rate at 1 year was 88.2 %. Conclusions: The outcomes of the photoimmunotherapy demonstrated successful local control of recurrent nasopharyngeal carcinoma. This innovative therapeutic approach holds significant potential for addressing nasopharyngeal cancer recurrence. However, it is crucial to carefully evaluate patients who can safely be treated using this method.