Jenn-Ren Hsiao

Background/Objectives: To investigate laryngeal elevation velocity (LEV) as a candidate physiological marker of swallowing safety in post-radiotherapy dysphagia patients with cricopharyngeal muscle dysfunction (CPMD), we examined its association with airway safety and whether the LEV–upper esophageal sphincter (UES) opening relationship differed before versus after botulinum toxin injection, used here as a within-subject physiological perturbation. Methods: This retrospective cohort study included 18 post-radiotherapy patients with nasopharyngeal carcinoma (NPC) and CPMD who underwent botulinum toxin injection into the cricopharyngeal muscle (median total dose, 30 U; range, 20–40 U) and completed videofluoroscopic swallowing studies (VFSSs) before and after intervention. Primary outcomes were the Penetration–Aspiration Scale (PAS) and UES opening diameter; secondary outcomes included the Functional Oral Intake Scale (FOIS), laryngeal elevation (LE) and LEV. Associations were evaluated using generalized estimating equations (GEEs) with LEV × treatment interaction terms to assess whether they differed across pre- and post-injection states. Results: Following botulinum toxin injection, FOIS scores improved significantly (median, 4 to 5; p < 0.001), with concurrent increases in LEV (median, 149.86 to 201.12 C2–4%/s; p = 0.027) and UES diameter (median, 21.10 to 23.30 C2–4%; p = 0.039); PAS scores and laryngeal elevation displacement did not change significantly. Higher LEV was associated with lower odds of unsafe airway invasion (PAS 5–8) in univariate analysis (odds ratio per 100-unit increase, 0.38; 95% confidence interval [CI], 0.17–0.86; p = 0.021). A significant LEV × treatment interaction was observed for UES diameter (p = 0.021). Conclusions: In post-radiotherapy NPC patients with CPMD, higher LEV was associated with airway safety, and the LEV–UES relationship differed across pre- and post-injection states. Although the study design does not permit conclusions about treatment efficacy, LEV may represent a candidate load-sensitive marker of swallowing safety, warranting further investigation.

Background: Oral squamous cell carcinoma (OSCC), primarily caused by high exposure to betel quid, tobacco, and alcohol, remains a major public health burden in Taiwan. Although key mutations have been identified in OSCC, the population‐specific mutational landscape and its clinical relevance remain underexplored. Methods: A total of 106 OSCC tumors from Taiwanese patients were subjected to targeted gene sequencing with the Oncomine Comprehensive Assay v3 platform. High‐confidence exonic, nonsynonymous variants were identified from 161 cancer‐related genes. The resulting mutational landscape was compared with publicly available data from The Cancer Genome Atlas. Gene‐ and pathway‐level alterations were further correlated with clinicopathological parameters. Results: A total of 317 exonic, nonsynonymous variants were identified in 73 OSCC‐related genes, of which 52 were classified as driver genes. In addition to commonly mutated genes (e.g., TP53 , CDKN2A , NOTCH1 , HRAS , and PIK3CA ), PIK3R1 and MSH6 exhibited high mutation frequencies. A higher number of mutated genes per tumor was significantly correlated with poorer local‐relapse‐free survival (hazard ratio: 1.17, 95% CI: 1.04–1.31, p = 0.010). In the 83 advanced‐stage OSCC tumors, TP53 mutation was strongly associated with positive cervical lymph nodal metastasis ( p < 0.001). An inverse relationship was noted between nodal metastasis and NOTCH1 , HRAS , and PIK3CA mutations, possibly due to the mutually exclusive pattern observed between TP53 and NOTCH1 / HRAS mutations. Alteration of the cell cycle oncogene pathway was significantly associated with poor survival in advanced‐stage OSCC patients, which was subsequently confirmed as an independent prognostic factor for disease‐specific survival (hazard ratio: 3.2, 95% CI: 1.05–9.75, p = 0.040) in 89 patients with advanced‐stage OSCC from The Cancer Genome Atlas. Conclusions: This study uniquely illustrates the mutational landscape of OSCC in Taiwanese patients, highlighting clinically relevant genomic alterations that hold promise as prognostic biomarkers and candidates for targeted intervention.

Results of retinoid-based therapies in head and neck cancer (HNC) are generally disappointing, indicating a lack of understanding of retinoic acid signaling. The role of retinoic acid receptor gamma (RARγ) and its isoforms in HNC is yet to be established. In this study, we found that RARγ1, 2, 4 are the predominant RARγ isoforms expressed in various types of human cancers, including HNC. The mechanistic study revealed that RARγ1, 2, 4 enhanced the proliferation of HNC cells by accelerating cell cycle progression through interaction with vinexin-β, as well as by ligand-dependent activation of EGFR with downstream Akt, ERK, Src, and YAP signaling pathways. Retinoic acid binding and CDK7-dependent phosphorylation on specific serine residue at the AF-1 domain are mandatory for RARγ-mediated growth promotion of HNC. Knockdown of RARγ abolished proliferation of cultured HNC cells, and completely prevented tumor growth in xenografted nude mice. Similar effects were observed in various human cancer types other than HNC. Our results indicate that RARγ-targeting approach could be a promising therapeutic and chemopreventive strategy for human cancers.

Exosomal microRNAs (miRNAs) from cancer cells play a key role in mediating the oral squamous cell carcinoma (OSCC) microenvironment. The objective aimed to investigate how long non-coding RNA (lncRNA) MEG3 affects OSCC angiogenesis through exosomal miR-421. Global miRNA microarray analysis and quantitative real-time PCR (qRT-PCR) were performed to determine the level of miRNAs in OSCC cells-derived exosomes. Cell migration, invasion, tube formation, immunohistochemistry and hemoglobin concentration were used to study the effects of exosomal miR-421 in angiogenesis. Western blotting was used to determine the expression level of HS2ST1 and VEGFR2-related downstream proteins. MiRNA array and qRT-PCR identified upregulation of miR-421 in OSCC cell-derived exosomes. Furthermore, exosome-miR-421 can be taken up by human umbilical vein endothelial cells (HUVEC) and then targets HS2ST1 through VEGF-mediated ERK and AKT phosphorylation, thereby promoting HUVEC migration, invasion, and tube formation. Additionally, enforced expression of lncRNA MEG3 in OSCC cells reduced exosomal miR-421 levels and then increased HS2ST1 expression, thereby reducing the VEGF/VEGFR2 pathway in HUVEC. Our results demonstrate a novel mechanism by which lncRNA MEG3 can act as a tumor suppressor and regulate endothelial angiogenesis through the exosomal miR-421/HS2ST1 axis, which provides a potential therapeutic strategy for OSCC angiogenesis.

(1) Background: Salivary gland tumors are rare in the head and neck. To determine the need and extent of surgical intervention, fine needle aspiration (FNA) is a widely accepted tool to approach salivary gland lesions. However, the FNA cytology varies between entities, while the lack of uniform terminology makes diagnosis more challenging. Since establishing the Milan system for reporting salivary gland cytopathology (MSRSGC) has become an increasingly accepted reporting standard, further examination and detailed recommendations were needed. (2) Methods: Between April 2013 and October 2021, 375 cases with FNA and salivary gland resection were retrospectively collected. All FNA specimens were reclassified according to the criteria of MSRSGC. After surgical excision, the FNA data were compared with the histological diagnosis to estimate the risk of malignancy (ROM), the risk of neoplasm (RON), and the diagnostic accuracy for each diagnostic category. (3) Results: Our cohort’s distribution of ROM and RON was similar to the MSRSGC’s recommendation. Carcinoma ex pleomorphic adenoma (CXPA) has the highest rate (66.7%) of misdiagnosed as a nonneoplastic lesion or benign salivary gland tumor. Pleomorphic adenoma (PA) and Warthin’s tumor were the most common benign salivary gland tumors, while the cytology diagnosis of Warthin’s tumor seems more challenging than PAs. (4) Conclusions: Despite the convenience and effectiveness of MSRSGC, we suggest close follow-up, re-biopsy, or surgical removal for salivary lesions even in Milan IVA-Benign for possibly missing FNA of malignancy, mixed lesions, or prevention of malignant transformation.

Background: To cure advanced hypopharyngeal squamous cell carcinoma (HPSCC), primary operation followed by adjuvant (chemo-)radiotherapy (OP-CRT) or definitive chemoradiation (CCRT) are the two primary options. This study aimed to compare the failure patterns and long-term survival outcomes of HPSCC patients treated with these two strategies. Patients and Methods: From 2007 to 2015, 198 pathologically confirmed HPSCC patients receiving either OP-CRT or CCRT were retrospectively reviewed. Failure patterns and survival outcomes stratified by the 7th American Joint Committee on Cancer staging system and treatment modalities were compared. Results: One hundred and eighty-nine patients (95.4%) were stage III/IV and 62 patients (31.3%) received OP-CRT. Median follow-up duration was 4.9 years. Compared with CCRT, OP-CRT provided better 3-year local relapse-free survival for T3 (93 vs 48%, p < 0.0001), T4a (88 vs 37%, p = 0.0005) and better 3-year regional relapse-free survival for N2b+2c (93 vs 60%, p < 0.0001). Of note, for stage IVA subjects, OP-CRT provided better 3-year loco-regional relapse-free survival (85 vs 37%, p < 0.0001), marginal poor 3-year distant metastasis-free survival (62 vs 79%, p = 0.06), but comparable 3-year OS (52 vs 44%, p = 0.37) and 5-year OS (44 vs 31%, p = 0.15) compared with CCRT. Conclusions: For patients with advanced HPSCC, although OP-CRT and CCRT provided similar overall survival, failure patterns were distinct. OP-CRT provided better loco-regional control but was more likely to encounter distant metastases than CCRT. The detailed analysis of failure patterns will pave the way to improve this devastating disease.

Background: Information regarding the design and usage of inferiorly based nasolabial flap for lower lip and commissural defect reconstruction following ablative cancer surgery remains limited. This study aimed to provide our design and experiences for such reconstructive purpose. Methods: Patients with lower lip or oral commissural cancer who received curative surgery involving reconstruction with inferiorly based nasolabial flap were included. The demographic data and clinical outcomes of these patients were obtained by retrospective chart review. Results: A total of eight patients were enrolled in this study. All patients received ablative surgery at the National Cheng Kung University Hospital during May 2019 to May 2021, with their surgical defects reconstructed with unilateral inferiorly based nasolabial flap successfully. Among the five patients with lower lip cancer, one had a limited area of necrosis at flap tip. Another patient had a small orocutaneous fistula that healed spontaneously. No trismus or oral incompetence was noted following recovery. For the three patients with commissural cancer, a second stage commisuroplasy was needed after primary reconstruction. One patient had limited wound dehiscence at mouth angle following surgery, resulting in mild oral incompetence. Although mild trismus was noted in these three commissural cancer patients, all patients resumed normal diet during follow-up. Conclusion: Inferiorly based nasolabial flap is an excellent local flap for lower lip reconstruction following cancer ablative surgery. It is also a viable option for reconstruction of oral commissural defects. Minimal donor side morbidity, good functional recovery, and esthetic outcomes can be achieved with meticulous flap design.