Preliminary outcomes of boron neutron capture therapy for head and neck cancers as a treatment covered by public health insurance system in Japan: Real-world experiences over a 2-year period.

PURPOSE: Since June 2020, boron neutron capture therapy (BNCT) has been a health care service covered by health insurance in Japan to treat locally advanced or recurrent unresectable head and neck cancers. Therefore, we aimed to assess the clinical outcomes of BNCT as a health insurance treatment and explore its role among the standard treatment modalities for head and neck cancers. MATERIALS AND METHODS: We retrospectively analyzed data from patients who were treated using BNCT at Kansai BNCT Medical Center, Osaka Medical and Pharmaceutical University, between June 2020 and May 2022. We assessed objective response rates based on the Response Evaluation Criteria in Solid Tumors version 1.1, and adverse events based on the Common Terminology Criteria for Adverse Events, version 5.0. Additionally, we conducted a survival analysis and explored the factors that contributed to the treatment results. RESULTS: Sixty-nine patients (72 treatments) were included in the study, with a median observation period of 15 months. The objective response rate was 80.5%, and the 1-year locoregional control, progression-free survival, and overall survival rates were 57.1% (95% confidence interval [CI]: 43.9%-68.3%), 42.2% (95% CI: 30.1%-53.8%), and 75.4% (95% CI: 62.5%-84.5%), respectively. Locoregional control was significantly longer in patients with earlier TNM staging and no history of chemotherapy. CONCLUSIONS: BNCT may be an effective treatment option for locally advanced or recurrent unresectable head and neck cancers with no other definitive therapies. If definitive surgery or radiation therapy are not feasible, BNCT should be considered at early disease stages.

Investigation of Parotid Cancer Cases Diagnosed as Bell's Palsy at Initial Presentation: The 23 Year Experience of a Single Institution.

Objective: Facial nerve paralysis due to parotid carcinoma is sometimes misdiagnosed as Bell's palsy. This study aimed to compare patients with parotid carcinoma with and without accompanying facial nerve paralysis and to capture the features of patients misdiagnosed with Bell's palsy. Methods: Among 209 patients, 42 (20%) had facial nerve paralysis. Of these 42 patients, 14 had received treatment for facial nerve paralysis without being diagnosed with parotid carcinoma (pretreatment group); the remaining 28 patients had not received any pretreatment and were diagnosed with parotid carcinoma at the initial visit to our hospital (no pretreatment group). This study compared patients with and without facial nerve paralysis and the pretreatment and no pretreatment groups. Results: The 42 patients with facial nerve paralysis had a significantly higher frequency of pain/tenderness and adhesion with surrounding tissues, significantly higher proportions of deep lobe tumors, and a significantly higher proportion of high-grade malignancy. In addition, the disease-specific and disease-free 5 year survival rates were significantly poorer in patients with than in those without facial nerve paralysis. The comparison between the pretreatment and no pretreatment groups revealed no significant differences in any factors nor survival rate. Five patients in the pretreatment group complained of palpable masses or pain/tenderness at the time of their initial treatment for paralysis. Conclusion: Patients with parotid carcinoma who present with facial nerve paralysis at the initial visit have a significantly poorer prognosis. The number of cases in the pretreatment group can be reduced by performing a detailed examination, which can potentially improve the prognosis.

Differential expression of TRKB tyrosine kinase in the two histological types of parotid salivary duct carcinoma with cancer aggressiveness.

Parotid salivary duct carcinoma (SDC) is a rare and aggressive parotid gland carcinoma (PGC). SDC has two origins: de novo and ex pleomorphic adenoma (SDC ex PA); however, because of its rarity, the clinical and molecular features of the two types of SDC are not sufficiently understood. Here, we studied the differences in their clinicopathological and molecular features using clinical specimens while comparing them to those of adenoid cystic carcinoma (AdCC), an intermediate-grade PGC. Clinicopathological analysis of tissues from patients with PGC revealed significant associations between histological types and malignant phenotypes, including nodal metastasis, recurrence, vascular invasion, and neural invasion, and revealed more malignant phenotypes of de novo SDC than of SDC ex PA. The de novo SDC showed a significantly higher frequency of intra-neural invasion (intra-NI) and vascular invasion than AdCC and SDC ex PA. PGCs with high intra-NI were significantly correlated with malignant phenotypes and survival rates. Recently, we observed the overexpression of tropomyosin receptor kinase B (TRKB), a receptor tyrosine kinase, in PGC cells. Here, immunohistochemical and clinicopathological analyses showed that TRKB was highly expressed in SDC cells, particularly de novo SDC cells, and was significantly associated with poor survival and highly malignant phenotypes, including intra-NI and vascular invasion. Collectively, these data show that TRKB expression is significantly elevated in PGC, particularly in de novo SDC, and can be one of the biomarkers of their aggressiveness.

Tumor localization is the important factor for recovery time of postoperative facial nerve paralysis in benign parotid surgery.

OBJECTIVE: Facial nerve paralysis is the most problematic complication of surgery for parotid tumors. This study aimed to examine the progress of recovery from postoperative transient facial nerve paralysis (POFNP). METHODS: Participants were 203 patients who developed POFNP after benign parotid surgery. A Kaplan-Meier showed the progress of recovery from paralysis. Factors involved in recovery were examined. For factors for which a significant difference was found, recovery from paralysis was examined over time. RESULTS: Rates of recovery from paralysis were as follows: 28.6% of patients at 1 month, 58.3% at 3 months, 85.9% at 6 months, and 95.1% at 12 months after surgery. Deep lobe tumors were shown to be significantly associated with delayed recovery from paralysis. The relationship between tumor location and the time of recovery from was that deep lobe tumors had a significantly worse recovery from paralysis at 4 and 5 months after surgery. CONCLUSION: Patients who develop POFNP must be informed about the progress of recovery and factors involved in recovery from paralysis. We believe that the results of the present study are a useful reference to that end.

Facial nerve dissection in parotid surgery: a microscopic investigation study.

In parotid surgery, it is crucial to identify and preserve the facial nerve, which runs through the parotid gland. The purpose of this study was to histologically clarify two clinical questions: whether "superficial" and "deep" lobes exist anatomically and what are the structures surrounding facial nerve. Parotid gland tissues were obtained from dissection of donated cadavers. The gland was cut perpendicular to the facial nerve plane at 5 mm intervals, and the pieces were embedded in paraffin, thinly sliced, and stained. The morphology of the nerve was observed at each site, and the relationships between the thickness of the perineural tissue (defined as the tissue between the groups of nerve fasciculi and the glandular parenchyma), nerve diameter, and distance from the proximal end of the nerve were examined. In addition, the dissection layer was examined histologically in isolated parotid tissues. The interlobular connective tissue was spread like a mesh within the parotid gland and subdivided the glandular parenchyma. The facial nerve was located in the interlobular connective tissue, and its course was not restricted to the boundary plane between the superficial and deep lobes. The thickness of the perineural tissue decreased with increasing distance from the proximal end of the nerve. The dissection layer was clarified that located in the perineural tissue. The perineural tissue is thinner in more distal regions, which may make dissection more difficult there. No particular anatomical structure appears to separate the superficial and deep lobes.

Tracheostomy in otorhinolaryngology education and training programs: A Japanese nationwide survey.

OBJECTIVE: Surgical airway management is one of the most effective techniques for safe airway management. Within the training programs relating to knowledge and skills required by otorhinolaryngologists, tracheostomy and postoperative management are important items that must be fully understood by airway surgeons. We performed a nationwide survey to identify problems within tracheostomy and postoperative management in Japan in order to establish practical and safe guidelines for surgical airway management. METHODS: We conducted a questionnaire survey of the current status of tracheostomy and postoperative management at core institution of otorhinolaryngology training programs in Japan. RESULTS: Responses were obtained from all 101 core training institutions in Japan. Tracheostomy was performed in the operating room at 61.4% of institutions and in the ICU at 26.7%. 89.1% of them performed surgical tracheostomy (ST) in all cases. Even in the remaining 10.9%, percutaneous dilatational tracheostomy (PDT) was performed in less than 10% of cases. The primary surgeon was an otorhinolaryngology resident at 89.1% of institutions. The method of securing the tube immediately after surgery was by securing it with an attached cord at 48.5% of institutions, by suturing to the skin at 25.7%, and using a Velcro band at 24.8%. The first tube change after tracheostomy was performed on the seventh postoperative day at 81.2% of institutions. 87.1% had more than one person performing the first tube change. The tracheostomy postoperative complications within the past year were as follows: tracheostomal granulation: 89.1%; subcutaneous and/or mediastinal emphysema: 62.4%; tube stenosis: 55.4%; accidental tube removal: 50.5%; incorrect tube insertion or misplacement: 15.8%; hemorrhage from tracheal foramen requiring hemostasis in the operating room: 14.9%; pneumothorax: 4.0%; tracheo-innominate arterial fistula: 2.0%; and tracheoesophageal fistula: 1.0%. The method for educating otorhinolaryngology residents about tracheostomy was on-the-job training at 98.0% of institutions. CONCLUSIONS: For airway management in otorhinolaryngology training programs, after learning the basics of ST, PDT should also be well understood. Furthermore, in order to create safe educational programs for intraoperative and postoperative management, it is necessary to train otorhinolaryngologists with accurate knowledge and skills, and to strengthen collaboration with multiple professions in their leadership roles as airway surgeons.

Central node dissection from the perspective of lateral neck node metastasis in papillary thyroid carcinoma.

OBJECTIVES: Controversy exists on how to handle central lymph nodes in papillary thyroid carcinoma, particularly regarding indications for prophylactic central neck dissection (CND). Central node metastases are more difficult to diagnose preoperatively than lateral node metastases. METHODS: We enrolled 493 patients with papillary thyroid carcinoma treated at our department in the past 22 years. Metastatic lymph nodes were diagnosed preoperatively mainly by ultrasonography. In principle, CND was performed for all cases; ipsilateral CND was performed for hemithyroidectomy, and bilateral CND was performed for total thyroidectomy. Lateral neck dissection (levels II to V; LND) was performed for metastases to lateral neck lymph nodes (clinical node (cN) 1b). RESULTS: The cN stage was cN0 in 365 patients, cN1a in 10, and cN1b in 118. Of the 357 patients with stage cN0 who underwent CND, 42.9 % had pathologically positive nodes (pN+) in level VI, and of the 118 with stage cN1b who underwent CND, 78.0 % had pN+ in level VI. Cases with advanced T stage were significantly more common with pN+ in level VI. Level VI metastases were significantly associated with pN+ in level IV. As the total number of pN+ at each level of the lateral neck increased, the rate of patients with pN+ in level VI increased, and in patients with 3 or more pN+, about 85 % had level VI metastases. CONCLUSION: Because about half of the patients with cN0 patients had pN+ in level VI, and the rate of pN+ in level VI in each clinical T stage was 46 to 65 %, prophylactic CND should be performed, considering the various clinical benefits. Central nodes will have metastases in about 80 % of cases with lateral node metastases, requiring more accurate dissection. In lateral node metastases, there is a significant association between metastases in levels IV and VI.

Utility of palliative prognostic index and neutrophil-to-lymphocyte ratio in predicting prognosis of end-stage squamous cell carcinoma of head and neck.

BACKGROUND: The purpose of this study was to examine the factors influencing the prognosis of end-stage head and neck squamous cell carcinoma (HNSCC) and to develop a more useful prognostic index. PATIENTS AND METHODS: This retrospective observational study included 79 patients with end-stage HNSCC. Patients were grouped by patient factors and prognostic indicators, and overall survival from the start of Best Supportive Care was compared for each group. In addition, overall survival was compared between patients with palliative prognostic index (PPI) ≥6 and neutrophil-to-lymphocyte ratio (NLR) ≥10 and patients with PPI <6 or NLR <10. RESULTS: PPI ≥6 and NLR ≥10 were associated with significantly more frequent poor prognoses (p = 0.01 and p = 0.002, respectively). The median survival was 32 days in cases with PPI ≥6 and NLR ≥10, and 64 days for PPI <6 or NLR <10 (p < 0.001). CONCLUSION: The combination of PPI and NLR is a useful indicator for predicting the prognosis of patients with end-stage HNSCC.

Clinicopathological characteristics of four major histological types of high-grade parotid carcinoma.

OBJECTIVE: High-grade parotid carcinoma generally has a poor prognosis, and the histological type is mucoepidermoid carcinoma (MEC), salivary duct carcinoma (SDC), carcinoma ex pleomorphic adenoma (CEPA), or adenoid cystic carcinoma (AdCC) in the majority of cases. METHODS: During the 23-year period from September 1999 to December 2022, 250 patients with parotid carcinoma underwent initial treatment and had the histopathological type of their carcinoma. Retrospective study evaluated 111 MEC, SDC, CEPA, or AdCC cases among 134 patients with high-grade parotid carcinoma. We examined pathological and clinical features and prognosis, evaluated factors associated with recurrence, and performed immunohistological examinations. RESULTS: Pathological and clinical features and factors associated with recurrence were different for each histological type. The 10-year disease-free survival rates were as follows: MEC, 34.9%; SDC, 22.6%; CEPA, 47.1%; and AdCC, 56.3%. Human epidermal growth factor receptor type-2 and androgen receptor were positive in 48% and 56% of patients with SDC, respectively, 38% and 25% of those with CEPA. CONCLUSION: Each histological type has its own pathological and clinical features, recurrence types, and tumor activities, suggesting that differentiating between high-grade parotid carcinomas according to histological type will improve diagnosis, and thus prognosis.

Prognostic scores for patients with salivary adenoid cystic carcinoma without lymph node metastasis.

Adenoid cystic carcinoma (AdCC) of salivary gland grows relatively slowly, but occasionally develops distant metastasis. Although cervical lymph node metastasis (LNM) has been reported as a strong prognostic factor, most of AdCC do not have LNM. In this study, we investigated the prognostic factors to predict disease free survival (DFS), distant metastasis free survival (DMFS), and overall survival (OS) for 175 patients surgically treated for AdCC without LNM, and developed prognostic score (PS) determined as number of positive prognostic factors. The following emerged as significant prognostic factors: positive surgical margin in DFS, pT3/4 and positive surgical margin in DMFS, and positive surgical margin and high-histological grade in OS. 10-year DFS rates were 56.4% in PS0, and 19.1% in PS1 (p < 0.0001). 10-year DMFS rates were 86.3% in PS0, 56.4% in PS1, and 30.7% in PS2 (p < 0.0001). 10-year OS rates were 100% in PS0, 73.3% in PS1, and 38.8% in PS2 (p < 0.0001).

The Landscape of MYB/MYBL1- and Peri-MYB/MYBL1-Associated Rearrangements in Adenoid Cystic Carcinoma.

Approximately 60% of adenoid cystic carcinoma (AdCC) cases are positive for MYB::NFIB or MYBL1::NFIB, whereas MYB/MYBL1 oncoprotein, a key driver of AdCC, is overexpressed in most cases. Juxtaposition of superenhancer regions in NFIB and other genes into the MYB/MYBL1 locus is an attractive oncogenic hypothesis for AdCC cases, either negative or positive for MYB/MYBL1::NFIB. However, evidence supporting this hypothesis is insufficient. We examined 160 salivary AdCC cases for rearrangements in MYB/MYBL1 loci and peri-MYB/MYBL1 areas (centromeric and telomeric areas of 10 Mb each) using formalin-fixed, paraffin-embedded tumor sections. For the detection of the rearrangements, we employed conventional fluorescence in situ hybridization split and fusion assays and a 5 Mb fluorescence in situ hybridization split assay. The latter is a novel assay that enabled us to detect any possible splits within a 5 Mb distance of a chromosome. We found MYB/MYBL1- and peri-MYB/MYBL1-associated rearrangements in 149/160 patients (93%). AdCC cases positive for rearrangements in MYB, MYBL1, the peri-MYB area, and the peri-MYBL1 area numbered 105 (66%), 20 (13%), 19 (12%), and 5 (3%), respectively. In 24 peri-MYB/MYBL1 rearrangement-positive cases, 14 (58%) were found to have a juxtaposition of the NFIB or RAD51B locus into the MYB/MYBL1 loci. On comparing with a tumor group positive for MYB::NFIB, a hallmark of AdCC, other genetically classified tumor groups had similar features of overexpression of the MYB transcript and MYB oncoprotein as detected by semiquantitative RT-qPCR and immunohistochemistry, respectively. In addition, clinicopathological and prognostic features were similar among these groups. Our study suggests that peri-MYB/MYBL1 rearrangements may be a frequent event in AdCC and may result in biological and clinicopathological consequences comparable to MYB/MYBL1 rearrangements. The landscape of MYB/MYBL1 and peri-MYB/MYBL1 rearrangements shown here strongly suggests that juxtaposition of superenhancers into MYB/MYBL1 or peri-MYB/MYBL1 loci is an alteration that acts as a key driver for AdCC oncogenesis and may unify MYB/MYBL1 rearrangement-positive and negative cases.

Management and outcome of adenoid cystic carcinoma of the major salivary glands: the 22-year experience of a single institution.

BACKGROUND: Prognostic factors and survival rate are difficult to determine for adenoid cystic carcinoma(AdCC) of salivary glands. AIMS/OBJECTIVES: To clarify the clinical characteristics of AdCC and examine factors associated with recurrence and prognosis by histopathological grade classification. MATERIALS AND METHODS: Twenty-five patients with AdCC of the parotid gland and 10 patients with AdCC of the submandibular gland were included. We classified AdCC histopathologically by the proportion of solid components. Clinical features, fine-needle aspiration cytology (FNAC), and patient outcomes were examined according to grade. Factors associated with local recurrence and distant metastases were examined. RESULTS: Age was significantly higher in the grade III group than in the grade I group. The grade III group had significantly higher proportions of patients with cN+, pN+, and perineural invasion. In FNAC, lower-grade groups showed higher rates of correct histopathological type. Five-year disease-specific survival and disease-free survival rates were significantly lower in the grade III than in the grade I. Distant metastases were more common among patients with high-stage and perineural invasion. CONCLUSIONS: Five-year survival is significantly worse in patients with grade III.

Increased Chymase-Positive Mast Cells in High-Grade Mucoepidermoid Carcinoma of the Parotid Gland.

It has long been known that high-grade mucoepidermoid carcinoma (MEC) has a poor prognosis, but the detailed molecular and biological mechanisms underlying this are not fully understood. In the present study, the pattern of chymase-positive mast cells, as well as chymase gene expression, in high-grade MEC was compared to that of low-grade and intermediate-grade MEC by using 44 resected tumor samples of MEC of the parotid gland. Chymase expression, as well as chymase-positive mast cells, was found to be markedly increased in high-grade MEC. Significant increases in PCNA-positive cells and VEGF gene expression, as well as lymphangiogenesis, were also confirmed in high-grade MEC. Chymase substrates, such as the latent transforming growth factor-beta (TGF-ß) 1 and pro-matrix metalloproteinase (MMP)-9, were also detected immunohistologically in high-grade MEC. These findings suggested that the increased chymase activity may increase proliferative activity, as well as metastasis in the malignant condition, and the inhibition of chymase may be a strategy to improve the poor prognosis of high-grade MEC of the parotid gland.

Predicting postoperative facial nerve paralysis by using intraoperative nerve monitoring during parotid surgery.

OBJECTIVES: To investigate a method for predicting postoperative facial nerve paralysis (POFNP) during parotid surgery using intraoperative nerve monitoring (IONM). METHODS: We assessed prediction for POFNP by using IONM, comparing between stimulation in the facial nerve trunk and each branch by using facial nerve monitoring. The amplitude response ratio (ARR) was calculated for the trunk/periphery. In addition, we then examined the correlation between ARR and time to recovery of paralyzed branches. RESULTS: 372 branches of 93 patients did not develop POFNP and were classified as group A. Among 20 patients who developed POFNP, 51 branches without POFNP were classified as group B, and 29 branches with POFNP were classified as group C. The ARR was approximately 1 in group A and B. but less than 0.5 in all branches in Group C. When the cut off value of ARR was set at 0.55, the sensitivity, specificity, and accuracy of POFNP diagnosis by ARR were 96.5%, 93.1%, and 96.8%, respectively. CONCLUSION: Using IONM during parotid surgery enables easy prediction of POFNP.

Proposal for a novel classification of benign parotid tumors based on localization.

OBJECTIVE: Postoperative facial nerve paralysis is the most problematic complication after surgical treatment of parotid tumors. Localization of tumors is highly relevant for the surgical approach, but existing classification systems do not focus on the association between localization and surgical technique. Therefore, we created a new localization-based classification system for benign parotid tumors and investigated the characteristics of tumors in each localization and the frequency of postoperative facial nerve paralysis by retrospectively applying the classification to previous cases. METHODS: First, we defined 6 portions of the parotid gland (upper, U; lower, L; posterior, P; anterior, A; superficial, S; deep, D) by dividing the transverse plane into an upper and lower portion at the mandibular marginal branch, the longitudinal plane into a posterior and anterior portion at the midline of the parotid anteroposterior diameter, and the sagittal plane into a superficial and deep portion along the course of the facial nerve. Then, we defined 8 locations by combining the 6 portions in all possible ways (i.e., U-P-S, U-P-D, U-A-S, U-A-D, L-P-S, L-P-D, L-A-S, L-A-D). We used this classification to define the tumor localization in 948 patients who had undergone partial superficial parotidectomy for benign parotid tumors and then investigated the incidence, histopathological type, signs/symptoms, diagnosis, surgery, and complications in each area. RESULTS: Pleomorphic adenomas comprised approximately 70% of tumors in the upper portion but only approximately 35% in the lower portion. The rate of postoperative facial nerve paralysis was significantly higher for tumors in deep locations than in superficial locations (33.9% vs 14.9%, respectively), and the odds ratios for postoperative facial nerve paralysis in the U-P-D and U-A-D locations were 7.6 and 4.8 compared to the L-P-S location. When maximum diameter, operation time, bleeding volume, sex (reference: female), and age were added as control variables, the odds ratios were 4.2 and 3.0. CONCLUSION: Determining tumor localization preoperatively with the new localization-based classification of parotid tumors is helpful not only for predicting the histopathological type but also for predicting surgical complications, particularly postoperative facial nerve paralysis.

Role of Intra-Parotid Lymph Node Metastasis in Primary Parotid Carcinoma.

The parotid gland contains intra-glandular lymph nodes, the distribution of which is crucial for understanding the pathogenesis of intra-parotid lymph node metastases of parotid carcinoma and other head and neck carcinomas. Positive intra-parotid lymph node metastasis predicts the risk of positive cervical nodal metastasis. It is important to establish whether prophylactic neck dissection, including intra-parotid lymph nodes, contributes to treatment outcomes. The presence or absence of intra-parotid lymph nodes or metastasis-positive lymph nodes warrants further study. A preoperative diagnosis by imaging and fine-needle aspiration cytology of intra-parotid lymph nodes is difficult. Although intraoperative frozen section biopsy is performed during surgery, it is challenging to identify intra-parotid lymph nodes. The number of lymph nodes was the largest (47%) in the lower half of the superficial lobe, with 35% of nodes being concentrated in the inferior part of the cervicofacial branch, i.e., the lower pole of the parotid gland. Therefore, superficial parotidectomy and lower pole lobectomy need to be performed in cases in which a malignant tumor localizes to the superficial lobe or a lower pole. When intra-parotid lymph node metastases are detected during surgery, selective neck dissection (at least levels II and III) needs to be simultaneously performed.

Fine-Needle Aspiration Cytology for Parotid Tumors.

Fine-needle aspiration (FNA) cytology is widely used in clinical practice as a simple and minimally invasive test for parotid tumors that allows for preoperative estimation of benignancy and malignancy, histological type, and malignancy grade and can be performed on an outpatient basis. In recent years, cell blocks prepared with core needle biopsy (CNB) and liquid-based cytology (LBC) have increased the reliability of immunostaining and molecular biological testing, leading to improved diagnostic accuracy. In 2018, the Milan System for Reporting Salivary Gland Cytology was introduced, but it does not include malignancy grade or histological type, so we proposed the Osaka Medical College classification as a more clinically based cell classification that includes both types of information, and we have reported on its usefulness. This review gives an overview of the history and use of FNA and describes CNB and LBC and the two classification systems.

Development of the Sphenoid Sinus in Japanese Children: A Retrospective Longitudinal Study Using Three-Dimensional Computed Tomography.

Background: The sphenoid sinus (SS) is located close to vital structures, such as the pituitary gland, and it has significant clinical relevance. This study aimed to clarify the growth pattern of the SS in Japanese children using three-dimensional computed tomography (CT). Methods: Seventy-eight participants with congenital, acquired, or external auditory canal cholesteatoma were recruited and underwent CT more than twice during their treatment. Using the volume-rendered images, the size and volume of the SS were measured. Furthermore, on the scout image, the morphological measurements of the cranial base were determined. Results: The size and volume of the SS increased with age, and peaked at the mean age of 15 years. For males, the volume of the SS was smaller than that of females aged <5 years. The growth rate of the SS was significantly higher in males than in females. The maximum growth rate was detected at the age of 12 years for males and 10 years for females. For females, the increase in the length of the anterior cranial base ceased at approximately 10 years of age and remained constant thereafter. In contrast, for males, the length of the anterior cranial base increased gradually until 15 years of age. Conclusions: Considering the similarity of the periods between the adolescent growth spurt and the maximum growth rate of the SS, changes in the size of the SS may be used as an indicator of the physical growth spurt.

BDNF/TRKB axis provokes EMT progression to induce cell aggressiveness via crosstalk with cancer-associated fibroblasts in human parotid gland cancer.

Parotid gland cancer (PGC) is a rare malignancy and its molecular characteristics remain poorly understood, which has precluded the development of effective drug therapies. Given the poor prognosis of many human cancers in which tropomyosin receptor kinase B (TRKB) is highly expressed, we investigated the involvement of brain-derived neurotrophic factor (BDNF)/TRKB pathway in PGC cells using clinical specimens and observed upregulation of TRKB and BDNF. In primary culture systems of patient-derived PGC cells and cancer-associated fibroblasts (CAFs), PGC cells co-cultured with CAFs exhibited significant upregulation of BDNF and epithelial-mesenchymal transition (EMT). Similar results were observed in PGC cells treated with conditioned medium from co-cultures of PGC cells with CAFs. Administration of TRK inhibitors suppressed BDNF-induced cell migration in PGC cells. Immunohistochemical and clinicopathological analyses of tumors from patients with PGC revealed that BDNF and TRKB were highly expressed in both tumor cells and stromal cells such as CAFs, and TRKB expression levels in PGC cells were significantly correlated with aggressive features, including vascular invasion, nodal metastasis, and poor prognosis. Collectively, these data suggest that the BDNF/TRKB pathway regulates PGC cell aggressiveness via crosstalk with CAFs and is a potential therapeutic target for PGC harboring invasive and metastatic features.