Explore the vast range of titles available.

Mucoepidermoid carcinoma (MEC) is rare, but the most common primary malignancy of the salivary gland and not infrequent in young individuals. CRTC1/3‐MAML2 fusions are frequently detected in MEC and are useful as a diagnostic biomarker. However, there has been debate as to whether the fusions have prognostic significance. In this study, we retrospectively collected 153 salivary gland MEC cases from 11 tertiary hospitals in Japan. As inclusion criteria, the MEC patients in this study had curative surgery as the initial treatment, received no preoperative treatment, and had no distant metastasis at the time of the initial surgery. The MEC diagnosis was validated by a central pathology review by five expert salivary gland pathologists. The CRTC1/3‐MAML2 fusions were detected using FISH and RT‐PCR. In 153 MEC cases, 90 (58.8%) were positive for CRTC1/3‐MAML2 fusions. During the follow‐up period, 28 (18.3%) patients showed tumor recurrence and 12 (7.8%) patients died. The presence of the fusions was associated with favorable tumor features. Of note, none of the fusion‐positive patients died during the follow‐up period. Statistical analysis showed that the presence of the fusions was a prognostic indicator of a better overall survival in the total and advanced‐stage MEC cohorts, but not in the early‐stage MEC cohort. In conclusion, CRTC1/3‐MAML2 fusions are an excellent biomarker for favorable overall survival of patients with salivary gland MEC. Debate exists as to whether CRTC1/3‐MAML2 fusions have a prognostic significance in salivary mucoepidermoid carcinoma (MEC). We undertook a multiinstitutional study including 153 MEC cases, and found that the fusions were an excellent biomarker for better overall survival in the total and advanced‐stage MEC cohorts.

Although videofluorography (VFG) is an effective tool for evaluating swallowing functions, its accurate evaluation requires considerable time and effort. This study aimed to create a deep learning model for automated bolus segmentation on VFG images of patients with healthy swallowing and dysphagia using the artificial intelligence deep learning segmentation method, and to assess the performance of the method. VFG images of 72 swallowing of 12 patients were continuously converted into 15 static images per second. In total, 3910 images were arbitrarily assigned to the training, validation, test 1, and test 2 datasets. In the training and validation datasets, images of colored bolus areas were prepared, along with original images. Using a U-Net neural network, a trained model was created after 500 epochs of training. The test datasets were applied to the trained model, and the performances of automatic segmentation (Jaccard index, Sørensen–Dice coefficient, and sensitivity) were calculated. All performance values for the segmentation of the test 1 and 2 datasets were high, exceeding 0.9. Using an artificial intelligence deep learning segmentation method, we automatically segmented the bolus areas on VFG images; our method exhibited high performance. This model also allowed assessment of aspiration and laryngeal invasion.

ObjectiveTo clarify CT diagnostic performance in extranodal extension of cervical lymph node metastases using deep learning classification.MethodsSeven-hundred and three CT images (178 with and 525 without extranodal extension) in 51 patients with cervical lymph node metastases from oral squamous cell carcinoma were enrolled in this study. CT images were cropped to an arbitrary size to include lymph nodes and surrounding tissues. All images were automatically divided into two datasets, assigning 80% as the training dataset and 20% as the testing dataset. The automated selection was repeated five times. Each training dataset was imported to a deep learning training system “DIGITS”. Five learning models were created after 300 epochs of the learning process using a neural network “AlexNet”. Each testing dataset was applied to each created learning model and resulting five performances were averaged as estimated diagnostic performances. A radiologist measured the minor axis and three radiologists evaluated central necrosis and irregular borders of each lymph node, and the diagnostic performances were obtained.ResultsThe deep learning accuracy of extranodal extension was 84.0%. The radiologists’ accuracies based on minor axis ≥ 11 mm, central necrosis, and irregular borders were 55.7%, 51.1% and 62.6%, respectively.ConclusionsThe deep learning diagnostic performance in extranodal extension was significantly higher than that of radiologists. This method is expected to improve diagnostic accuracy by further study with increasing the number of patients.

Immunotherapy with immune‐checkpoint therapy has recently been used to treat oral squamous cell carcinomas (OSCCs). However, improvements in current immunotherapy are expected because response rates are limited. Transforming growth factor‐β (TGF‐β) creates an immunosuppressive tumor microenvironment (TME) by inducing the production of regulatory T‐cells (Tregs) and cancer‐associated fibroblasts and inhibiting the function of cytotoxic T‐lymphocytes (CTLs) and natural killer cells. TGF‐β may be an important target in the development of novel cancer immunotherapies. In this study, we investigated the suppressive effect of TGF‐β on CTL function in vitro using OSCC cell lines and their specific CTLs. Moreover, TGFB1 mRNA expression and T‐cell infiltration in 25 OSCC tissues were examined by in situ hybridization and multifluorescence immunohistochemistry. We found that TGF‐β suppressed the function of antigen‐specific CTLs in the priming and effector phases in vitro. Additionally, TGF‐β inhibitor effectively restored the CTL function, and TGFB1 mRNA was primarily expressed in the tumor invasive front. Interestingly, we found a significant negative correlation between TGFB1 mRNA expression and the CD8+ T‐cell/Treg ratio and between TGFB1 mRNA expression and the Ki‐67 expression in CD8+ T‐cells, indicating that TGF‐β also suppressed the function of CTLs in situ. Our findings suggest that the regulation of TGF‐β function restores the immunosuppressive TME to active status and is important for developing new immunotherapeutic strategies, such as a combination of immune‐checkpoint inhibitors and TGF‐β inhibitors, for OSCCs. We found that, TGF‐β suppressed the function of antigen‐specific CTLs in the priming and effector phases in vitro. And, we found a significant negative correlation between TGFB1 mRNA expression and the CD8+ T‐cell/Treg ratio. Inhibition of TGF‐β restores the immunosuppressive TME to active status by a mechanism different from that of immune‐checkpoint inhibitors, suggesting that the combination of both may lead to a new therapeutic strategy for OSCCs.

BackgroundOwing to the low incidence of adenoid cystic carcinoma (AdCC), reliable survival estimates and prognostic factors remained unclarified.MethodsIn this multi-institutional retrospective analysis, we collected 192 AdCC cases, and investigated the impact of clinicopathological factors on clinical outcomes of the patients. All AdCC cases were of salivary gland origin and were surgically treated with curative intent. Diagnoses of AdCC were validated by a central pathology review by expert pathologists.ResultsThe 5-year overall survival (OS) and disease-free survival (DFS) rates were 92.5 and 50.0%, respectively. Treatment failure occurred in 89 patients (46%) with the distant failures in 65 (34%). Multivariate analysis indicated that pN2 and a pathologically positive surgical margin were independent prognostic factors for both OS and DFS. Histological grade III was an independent prognostic factor for OS. A primary site in the submandibular gland, pT3/4, pN1, and histological grade II were independent prognostic factors for DFS. Postoperative radiation therapy (PORT) improved the locoregional control (LRC) rate. Prophylactic neck dissection was not associated with a better OS or better LRC among patients with cN0. Facial nerve dissection did not improve clinical outcomes in parotid AdCC cases without facial nerve palsy.ConclusionsA higher TN classification, a pathologically positive surgical margin, and a higher histological grade were associated with a lower OS. PORT improved LRC rates but neck dissection failed to improve clinical outcomes in patients with cN0. As the distant metastasis was frequent, effective systemic therapy is imperative to improve the survival of AdCC patients.

Background: Ensuring effective return to work following acquired brain injuries is crucial from the perspectives of both quality of life and the economy. However, techniques of occupational therapy support for return to work remain relatively unelucidated. Aims/Objectives: To clarify the specific contents of occupational therapy required for work and work support for clients with acquired brain injuries. Material and Methods: An interview-based survey was conducted with participants who had >10 years of occupational therapy experience and had provided work support. We selected participants via snowball sampling. Data were analyzed using thematic analysis. Results: A total of 20 participants (15 women and 5 men; 6, 12, 1, and 1 in their 30s, 40s, 50s, and 60s, respectively) were included. Six concepts were generated on reviewing the support for work items considered important by the occupational therapist as follows: \"Support for vocational life,\" \"Support for interpersonal skills,\" \"Support for work,\" \"Support for illness, disability, and awareness,\" \"Support for utilization of compensation measures,\" and \"Support for goal setting.\" Conclusions: We clarified the specific contents of work support, including support for vocational life and support for work, that is administered by occupational therapists who provide work support for clients with acquired brain injury. The insights from the study improve understanding of OTs' roles and contributions in supporting clients with acquired brain injuries in returning to work.

Three pathological grading systems advocated by Perzin/Szanto, Spiro, and van Weert are currently used for adenoid cystic carcinoma (AdCC). In these systems, the amount or presence of the solid tumor component in AdCC specimens is an important index. However, the “solid tumor component” has not been well defined. Salivary AdCC cases (N = 195) were collected after a central pathology review. We introduced a novel criterion for solid tumor component, minAmax (minor axis maximum). The largest solid tumor nest in each AdCC case was histologically screened, the maximum oval fitting the solid nest was estimated, and the length of the minor axis of the oval (minAmax) was measured. The prognostic cutoff for the minAmax was determined using training and validation cohorts. All cases were evaluated for the four grading systems, and their prognostic impact and interobserver variability were examined. The cutoff value for the minAmax was set at 0.20 mm. Multivariate prognostic analyses showed the minAmax and van Weert systems to be independent prognostic tools for overall, disease‐free, and distant metastasis‐free survival while the Perzin/Szanto and Spiro systems were selected for overall survival but not for disease‐free or distant metastasis‐free survival. The highest hazard ratio for overall survival (11.9) was obtained with the minAmax system. The reproducibility of the minAmax system (kappa coefficient of 0.81) was scored as very good while those of the other three systems were scored as moderate. In conclusion, the minAmax is a simple, objective, and highly reproducible grading system useful for prognostic stratification for salivary AdCC. The amount or presence of the solid tumor component is an important index for histopathological grading of adenoid cystic carcinoma. However, the “solid tumor component” has not been well defined. We introduced a novel objective criterion for solid tumor component, minAmax (minor axis maximum), and showed that the minAmax is a simple, objective, and highly reproducible grading system useful for prognostic stratification for salivary adenoid cystic carcinoma.

Regulatory T-cells (Tregs) play a major role in suppressing anti-tumor immune responses. Mogamulizumab, an anti-CC chemokine receptor type 4 (CCR4) monoclonal antibody, depletes effector Tregs (eTregs). However, the clinical efficacy of mogamulizumab was limited in phase Ia/Ib studies for solid tumors (NCT01929486); the finding suggests that mogamulizumab may also deplete beneficial CCR4 + CD8 + T-cells in patients. Therefore, we focused on CTLs and aimed to identify a way to protect CCR4 + CTLs. Here, we evaluated the association of CCR4 expression in cytotoxic T-lymphocytes (CTLs) with antigen and cytokine stimulations and kinase inhibition using cytomegalovirus antigen instead of tumor antigen. CCR4 expression in CTLs was induced by antigen stimulation (mean 3.14–29.0%), enhanced by transforming growth factor-β1 (TGF-β1) (mean 29.0–51.2%), and downregulated by trametinib with (mean 51.2–11.4%) or without TGF-β1 treatment (mean 29.0–6.98%). Phosphorylation of ERK in CD8 + T-cells was suppressed by trametinib. Regarding the effect on immunological function of CTL, trametinib reduced cytokine production but not affected cytotoxicity. Importantly, trametinib alleviated CTL reduction by anti-CCR4 antibody without affecting eTreg depletion because CCR4 expression in eTregs was not downregulated. In conclusion, combination therapy with trametinib may improve the clinical efficacy of mogamulizumab.

The expression of programmed death ligand-1 (PD-L1) is controlled by complex mechanisms. The elucidation of the molecular mechanisms of PD-L1 expression is important for the exploration of new insights into PD-1 blockade therapy. Detailed mechanisms of the in situ expression of PD-L1 in tissues of oral squamous cell carcinomas (OSCCs) have not yet been clarified. We examined the mechanisms of PD-L1 expression focusing on the phosphorylation of downstream molecules of epidermal growth factor (EGF) and interferon gamma (IFN-γ) signaling in vitro and in vivo by immunoblotting and multi-fluorescence immunohistochemistry (MF-IHC), respectively. The in vitro experiments demonstrated that PD-L1 expression in OSCC cell lines is upregulated by EGF via the EGF receptor (EGFR)/PI3K/AKT pathway, the EGFR/STAT1 pathway, and the EGFR/MEK/ERK pathway, and by IFN-γ via the JAK2/STAT1 pathway. MF-IHC demonstrated that STAT1 and EGFR phosphorylation was frequently shown in PD-L1-positive cases and STAT1 phosphorylation was correlated with lymphocyte infiltration and EGFR phosphorylation. Moreover, the phosphorylation pattern of the related molecules in PD-L1-positive cells differed among the cases investigated. These findings indicate that PD-L1 expression mechanisms differ depending on the tissue environment and suggest that the examination of the tissue environment and molecular alterations of cancer cells affecting PD-L1 expression make it necessary for each patient to choose the appropriate combination drugs for PD-1 blockade cancer treatment.

Congenital tooth agenesis is a common anomaly in humans. We investigated the etiology of human tooth agenesis by exome analysis in Japanese patients, and found a previously undescribed heterozygous deletion (NM_002448.3(MSX1_v001):c.433_449del) in the first exon of the MSX1 gene. The deletion leads to a frameshift and generates a premature termination codon. The truncated form of MSX1, namely, p.(Trp145Leufs*24) lacks the homeodomain, which is crucial for transcription factor function.