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Introduction: This study aimed to determine whether prescribed molar intrusion, with or without virtual occlusal bite-blocks (BB), resulted in actual molar intrusion and assisted with anterior open bite (AOB) correction in adult patients treated with Invisalign clear aligners (Align Technology, Santa Clara, Calif)., Methods: A retrospective study was conducted with 36 adult patients with AOB. Subjects were divided into 2 treatment groups: planned molar intrusion (PMI) and no-PMI (No-PMI). PMI was obtained from the tooth movement tables in the ClinCheck software. Patients with PMI were further categorized by the presence or absence of virtual posterior BB (PMI-BB and PMI-No BB, respectively). Treatment success was determined on the basis of positive vertical incisor overlap in posttreatment cephalograms. Treatment changes were assessed using pretreatment and posttreatment cephalometric radiographs (Welch 2-sample t test, 95% confidence interval, P = 0.05). Finally, treatment stability was assessed at least 1-year posttreatment using the Photographic Open Bite Severity Index (POSI)., Results: There were 15 patients with No-PMI and 21 without PMI (total n = 36). The mean overbite change was 2.5 ± 1.0 mm for No-PMI and 3.2 ± 1.8 mm for patients with PMI (P = 0.12). All patients had positive vertical incisor overlap in posttreatment cephalograms, indicating 100% treatment success. Open bites were corrected primarily by incisor retroclination and extrusion in both treatment groups. The average measured molar intrusion for the PMI group was 0.71 mm greater than the change for the No-PMI group, but the difference was not statistically significant after controlling for potentially confounding variables (P = 0.074). A total of 14 patients from the original sample were assessed for stability using the POSI analysis. Of those, 12 (85.7%) had a POSI score of 0., Conclusions: Regardless of whether the molar intrusion was planned or not, the modality of AOB correction with Invisalign clear aligners was primarily incisor extrusion and retroclination. Overall, aligners are an effective appliance for the treatment of adult AOB. Based on our limited sample, treatment stability was similar to that reported for fixed appliances., (Copyright © 2024 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.)

Intratumoral hypoxia not only promotes angiogenesis and invasiveness of cancer cells but also creates an immunosuppressive microenvironment that facilitates tumor progression. However, the mechanisms by which hypoxic tumor cells disseminate immunosuppressive signals remain unclear. In this study, we demonstrate that a hypoxia-induced long noncoding RNA HIF1A Antisense RNA 2 (HIF1A-AS2) is upregulated in hypoxic tumor cells and hypoxic tumor-derived exosomes in head and neck squamous cell carcinoma (HNSCC). Hypoxia-inducible factor 1 alpha (HIF1α) was found to directly bind to the regulatory region of HIF1A-AS2 to enhance its expression. HIF1A-AS2 reduced the protein stability of major histocompatibility complex class I (MHC-I) by promoting the interaction between the autophagy cargo receptor neighbor of BRCA1 gene 1 (NBR1) protein and MHC-I, thereby increasing the autophagic degradation of MHC-I. In HNSCC samples, the expression of HIF1A-AS2 was found to correlate with hypoxic signatures and advanced clinical stages. Patients with high HIF1α and low HLA-ABC expression showed reduced infiltration of CD8+ T cells. These findings define a mechanism of hypoxia-mediated immune evasion in HNSCC through downregulation of antigen-presenting machinery via intracellular or externalized hypoxia-induced long noncoding RNA., (©2024 The Authors; Published by the American Association for Cancer Research.)

Objectives: To compare vertical and transverse changes in mixed dentition patients treated with the Invisalign First System (IFS) to those treated with a banded hyrax expander with fixed appliances (Hyrax) and control groups, and to assess the efficiency rate of dental arch expansion with IFS., Materials and Methods: The study included 80 mixed dentition patients, with 40 in each group (IFS and Hyrax) and 40 controls from the American Association of Orthodontists Foundation Craniofacial Growth Legacy Collection. Skeletal and dental vertical dimension changes and arch width changes between pretreatment (T1) and posttreatment (T2) were evaluated., Results: Age at T1, time interval (T1-T2), sex, and Angle class did not significantly differ among the groups. Mandibular plane angle changes showed a similar reduction for the control and IFS groups, with no changes in the Hyrax group. However, the differences among the three groups did not reach statistical significance (P = .06). The Hyrax group showed significantly greater expansion in maxillary intermolar width compared to the IFS group, 4.4 vs 2.5 mm, respectively. The efficiency of maxillary expansion using IFS ranged from 52.3% to 76.87%., Conclusions: During the mixed dentition stage, no significant changes occurred in vertical dimensions among the control, Hyrax, and IFS groups. Although there was a trend suggesting a greater reduction in mandibular plane angle in the IFS group compared to the Hyrax group, this may not be clinically significant given the less than 1° difference. IFS can be a viable option for addressing mild arch width deficiencies, with a predictable increase in intermolar width of approximately 2.5 mm., (© 2024 by The EH Angle Education and Research Foundation, Inc.)

Background: Treatment options are limited, and the prognosis is poor for patients with platinum-resistant recurrent metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). This study evaluated the efficacy and safety of a paclitaxel and ifosfamide (TI) regimen in patients with R/M HNSCC whose disease had progressed following platinum-based therapy., Patients and Methods: In this retrospective study, we included 53 patients with R/M HNSCC who underwent at least one cycle of TI-based therapy, post platinum failure, between February 2020 and August 2023. Some patients received the TI regimen in combination with immunotherapy and/or cetuximab. Key metrics assessed included the objective response rate (ORR), disease control rate, and progression-free as well as overall survival., Results: The study observed an ORR of 15.8% and a disease control rate of 36.8%. The median progression-free survival for the entire cohort was 3.3 months, and the median overall survival was 9.6 months. Notably, the combination of TI with immunotherapy yielded a higher ORR of 30.8%, compared to 14.3% with TI alone. The most prevalent grade 1-2 adverse events were anemia (81%), weight loss (68%) and hypernatremia (55%)., Conclusion: The TI-based regimen demonstrated favorable efficacy and safety profile in treating R/M HNSCC. Enhanced outcomes may be attainable when combining it with immunotherapy. This study suggests that TI-based therapy could serve as a potential salvage option for this specific patient group., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The presence of p16 and neck disease is important predictors of prognosis for oropharyngeal squamous cell carcinoma (OPSCC). Patients who are p16-negative and have clinically node-positive (cN+) disease generally have worse oncologic outcomes. This study aimed to investigate whether upfront neck dissection (UFND) could provide potential benefits for patients with cN+ p16-negative OPSCC., Methods: Through this retrospective study, 76 patients with cN+ p16-negative OPSCC were analyzed, those who received either definite concurrent chemoradiotherapy (CCRT group) or UFND followed by chemoradiotherapy (UFND group). The primary endpoints were regional recurrence-free survival (RRFS), disease-specific survival (DSS), and overall survival (OS). Factors associated with survival were evaluated by univariate and multivariate analysis. Survival between the two groups was compared by propensity score-matched analysis., Results: Matched 23 patients in each group through propensity analysis, the UFND group showed a significantly better 5-year RRFS (94.1% vs 61.0%, p = 0.011) compared to the CCRT group. Univariate analysis revealed that UFND was the sole factor associated with regional control (hazard ratio [HR] = 0.110; 95% CI, 0.014-0.879; p = 0.037). Furthermore, the study found that the CCRT group was associated with a higher dose of radiotherapy and exhibited a significantly higher risk of mortality due to pneumonia., Conclusion: The study indicated that UFND followed by CCRT may be a potential treatment option for patients with cN+ p16-negative OPSCC, as it can reduce the risk of regional recurrence. Additionally, the study highlights that definite CCRT is connected to a larger dose of radiotherapy and a higher risk of fatal pneumonia. These findings could be beneficial in informing clinical decision-making and improving treatment outcomes for patients with OPSCC., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article, (Copyright © 2024, the Chinese Medical Association.)

Background: Esophageal squamous cell neoplasms (ESCNs) are common second primary tumors in patients with head and neck cancer. Image-enhanced endoscopy (IEE) with Lugol chromoendoscopy or magnifying narrow-band imaging both increase the detection of early ESCNs. No evidence-based ESCN surveillance program for head and neck cancer patients without a history of synchronous ESCNs exists. We aimed to evaluate the performance of an IEE surveillance program with magnifying narrow-band imaging endoscopy and Lugol chromoendoscopy., Methods: From April 2016, we routinely used IEE with magnifying narrow-band imaging and Lugol chromoendoscopy to evaluate patients with head and neck cancer history. All patients who were negative for ESCNs at the first surveillance endoscopy and received at least 2 IEEs through December 2019 were included. Demographic profiles, clinical data, cancer characteristics, IEE results and pathology reports were analyzed., Results: A total of 178 patients were included. Only 4 patients (2.2%) developed metachronous ESCNs during follow-up, all of whom received curative resection treatment. The interval for the development of metachronous ESCNs was 477 to 717 days. In multivariate Firth logistic regression and Kaplan‒Meier survival curve analysis, Lugol's voiding lesion type C had an increased risk of esophageal cancer development (adjusted odds ratio = 15.71; 95% confidence interval, 1.33-185.87, p = 0.029). Eight patients died during the study period, and none of them had metachronous ESCNs., Conclusions: IEE with magnifying narrow-band imaging and Lugol chromoendoscopy is an effective surveillance program in head and neck cancer patients without a history of ESCNs. Annual surveillance can timely detect early ESCNs with low ESCN-related mortality., (© 2024. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Purpose: The prevalence of atopic diseases has increased in recent decades. A possible link between antibiotic use during pregnancy and childhood atopic disease has been proposed. The aim of this study is to explore the association of antibiotic exposure during pregnancy with childhood atopic diseases from a nationwide, population-based perspective., Methods: This was a nationwide population-based cohort study. Taiwan's National Health Insurance Research Database was the main source of data. The pairing of mothers and children was achieved by linking the NHIRD with the Taiwan Maternal and Child Health Database. This study enrolled the first-time pregnancies from 2004 to 2010. Infants of multiple delivery, preterm delivery, and death before 5 years old were excluded. All participants were followed up at least for 5 years. Antenatal antibiotics prescribed to mothers during the pregnancy period were reviewed. Children with more than two outpatient visits, or one admission, with a main diagnosis of asthma, allergic rhinitis, or atopic dermatitis were regarded as having an atopic disease., Results: A total of 900,584 children were enrolled in this study. The adjusted hazard ratios of antibiotic exposure during pregnancy to childhood atopic diseases were 1.12 for atopic dermatitis, 1.06 for asthma, and 1.08 for allergic rhinitis, all of which reached statistical significance. The trimester effect was not significant. There was a trend showing the higher the number of times a child was prenatally exposed to antibiotics, the higher the hazard ratio was for childhood atopic diseases., Conclusions: Prenatal antibiotic exposure might increase the risk of childhood atopic diseases in a dose-dependent manner., (© 2024. The Author(s).)

Introduction: The objective of this study was to compare the skeletal and dental changes of patients with a Class II relationship treated with clear aligner mandibular advancement (MA) and Herbst appliances followed by comprehensive orthodontic treatment., Methods: The participants included 20 patients treated with MA and 20 with the Herbst appliance. Orthodontic records were taken before treatment, after the functional appliance, and completion of phase II treatment. The skeletal and dental changes across the 3-time periods were evaluated using a matched paired t test for each treatment. A 2-sample t test was used to examine the changes across periods between 2 treatment groups (P <0.05)., Results: Significant reduction in overjet, overbite, and change in molar relationship were obtained by both appliances with similar skeletal and dental contributions. This was contributed by a forward movement of the mandible and mandibular molars, backward movement of the maxillary molars, and retraction of the maxillary incisors. After phase II treatment, both appliances could maintain the skeletal and dental changes achieved during the advancement phase. Greater change in overbite (2.4 mm vs 1.4 mm), an eruption of maxillary incisors (0.9 mm vs 0.1 mm), and proclination of mandibular incisors were found with the Herbst group (3.9° vs -2.1°). The average total treatment time was similar with the 2 appliances., Conclusions: Both functional appliances were equally effective in reducing the overjet and overbite and achieving a Class I molar relationship with a similar length of treatment time. The Herbst design lacked control of the mandibular incisor proclination, and clear aligners offered better vertical control and management of the mandibular incisor inclination., (Copyright © 2023 American Association of Orthodontists. All rights reserved.)

Introduction: Near-infrared imaging (NIRI) has been proposed as an alternative to radiographs and uses nonionizing radiation in the near-infrared spectrum to differentially scatter light off tooth surfaces and generate images allowing interproximal caries detection. The new iTero 5D Element Scanner (Align Technology, Santa Clara, Calif) has integrated NIRI capture and viewing technology but has not been specifically studied in a pediatric population. Therefore, this study aimed to assess clinicians' abilities to detect and characterize caries in pediatric patients using this instrument., Methods: Bitewing (BW) radiographs and an intraoral scan were captured on 17 pediatric patients (344 surfaces were analyzed). Data were randomized and graded by 5 calibrated clinicians individually with 2 different rounds of grading., Results: The reliability of lesion characterization (ie, grade) among examiners was poor to fair in both systems, whereas the reliability of caries detection was moderate. Both systems had a high specificity and low sensitivity. The reliability of the characterization of the combined dataset was moderate to substantial, whereas, for detection, it was substantial., Conclusions: When using either BW or NIRI analysis, reliability is relatively poor, and clinicians are more likely to correctly identify a healthy tooth surface when compared with a carious surface. There is a small difference in error rate between BW and NIRI systems that is not likely to be clinically significant. When NIRI and BW data are combined, clinician agreement for both lesion characterization and detection increases significantly., (Copyright © 2023 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.)

Most studies for comprehensive molecular profiling of papillary thyroid carcinoma (PTC) have been performed before the 2017 World Health Organization (WHO) classification, in which the diagnostic criteria of follicular variants of PTC have been modified and noninvasive follicular thyroid neoplasm with papillary-like nuclear features has been introduced. This study aims to investigate the shift in the incidence of BRAF V600E mutations in PTCs following the 2017 WHO classification and to further characterize the histologic subtypes and molecular drivers in BRAF-negative cases. The study cohort consisted of 554 consecutive PTCs larger than 0.5 cm between January 2019 and May 2022. Immunohistochemistry for BRAF VE1 was performed for all cases. Compared with a historical cohort of 509 PTCs from November 2013 to April 2018, the incidence of BRAF V600E mutations was significantly higher in the study cohort (86.8% vs 78.8%, P = .0006). Targeted RNA-based next-generation sequencing using a FusionPlex Pan Solid Tumor v2 panel (ArcherDX) was performed for BRAF-negative PTCs from the study cohort. Eight cribriform-morular thyroid carcinomas and 3 cases with suboptimal RNA quality were excluded from next-generation sequencing. A total of 62 BRAF-negative PTCs were successfully sequenced, including 19 classic follicular predominant PTCs, 16 classic PTCs, 14 infiltrative follicular PTCs, 7 encapsulated follicular PTCs, 3 diffuse sclerosing PTCs, 1 tall cell PTC, 1 solid PTC, and 1 diffuse follicular PTC. Among them, RET fusions were identified in 25 cases, NTRK3 fusions in 13 cases, BRAF fusions in 5 cases including a novel TNS1::BRAF fusion, NRAS Q61R mutations in 3 cases, KRAS Q61K mutations in 2 cases, NTRK1 fusions in 2 cases, an ALK fusion in 1 case, an FGFR1 fusion in 1 case, and an HRAS Q61R mutation in 1 case. No genetic variants, from our commercially employed assay, were detected in the remaining 9 cases. In summary, the incidence of BRAF V600E mutations in PTCs significantly increased from 78.8% to 86.8% in our post-2017 WHO classification cohort. RAS mutations accounted for only 1.1% of the cases. Driver gene fusions were identified in 8.5% of PTCs and were clinically relevant given the emerging targeted kinase inhibitor therapy. Of the 1.6% of cases for which no driver alteration was detected, the specificity of drivers tested and tumor classification require further investigation., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Objectives: To compare palatal dimensions and molar inclinations after Invisalign First System (IFS) to those in patients treated with slow maxillary expansion (SME) and normal controls., Materials and Methods: Twenty-three mixed dentition patients treated with IFS were gender- and dental age-matched to another two groups: Haas-type SME and control group. The intercanine width (ICW), intermolar width (IMW), palatal surface area (SA), volume (V), and first molar buccolingual inclinations (MI) were measured before (T1) and after (T2) treatment. Analysis of variance was used to compare the differences among the three groups., Results: The ICW increased significantly by 3.10 mm after IFS, 4.77 mm with SME, and 0.54 mm in controls; the difference among the groups was statistically significant (P < .001). The IMW increased by 1.95 mm in IFS, 4.76 mm in SME, and 0.54 mm in controls, with significant intra- and intergroup differences. Palatal SA and volume increased by 43.50 mm2 and 294.85 mm3 in the IFS group, which differed significantly from SME, but was similar to controls. The right and left MI increased 0.24° and 0.08° buccally, respectively, in the IFS group, which was comparable to controls, while significantly increased buccal MI was observed in the SME group., Conclusions: IFS expands the upper arch with increased ICW and IMW compared to controls, but the expansion amount is smaller than SME. Unlike SME, IFS has no effects on palatal dimensions and molar inclinations., (© 2023 by the EH Angle Education and Research Foundation, Inc.)

Purpose: This study evaluated the efficacy of a 4-week straw phonation in water (SPW) exercise program on aging-related vocal fold atrophy (VFA), with a secondary objective to examine the immediate effects of SPW exercises., Method: Thirty-eight older adults aged 60 years and above formally diagnosed with aging-related VFA were randomly assigned into an experimental group undergoing SPW exercises with an 8-cm depth of straw submersion into water for 4 weeks plus vocal hygiene practice ( n = 20), and a control group with only vocal hygiene practice ( n = 18). Outcome measures included laryngeal endoscopic measures of glottal gap, auditory-perceptual ratings of voice quality, acoustic measures, aerodynamic measures, and standardized self-assessment questionnaire scores. An additional round of acoustic and aerodynamic assessment following 20 min of SPW exercises was conducted to examine the immediate effects., Results: Significant improvements in normalized glottal gap area, perceptual rating of breathiness, smoothed cepstral peak prominence, harmonics-to-noise ratio (HNR), mean oral airflow, subglottal pressure and laryngeal airway resistance at comfortable loudness, Voice-related Quality of Life scores, and Chinese Vocal Fatigue Index Factor 3 scores were observed in the experimental group relative to the control group. There were also significant immediate effects for HNR, mean oral airflow, subglottal pressure, and laryngeal airway resistance., Conclusions: These findings suggested significant immediate improvements in vocal function following SPW exercises, with additional significant improvements in vocal function as well as significant improvements in quality of life following the 4-week SPW exercise program. Further studies with more long-term follow-up are recommended to better understand the efficacy of SPW exercises with deep levels of straw submersion into water as an effective clinical option for the management of hypofunctional dysphonia associated with aging-related VFA.

As a type of immunogenic cell death, ferroptosis participates in the creation of immunoactive tumor microenvironments. However, knowledge of spatial location of tumor cells with ferroptosis signature in tumor environments and the role of ferroptotic stress in inducing the expression of immune-related molecules in cancer cells is limited. Here the spatial association of the transcriptomic signatures is demonstrated for ferroptosis and inflammation/immune activation located in the invasive front of head and neck squamous cell carcinoma (HNSCC). The association between ferroptosis signature and inflammation/immune activation is more prominent in HPV-negative HNSCC compared to HPV-positive ones. Ferroptotic stress induces PD-L1 expression through reactive oxygen species (ROS)-elicited NF-κB signaling pathway and calcium influx. Priming murine HNSCC with the ferroptosis inducer sensitizes tumors to anti-PD-L1 antibody treatment. A positive correlation between the ferroptosis signature and the active immune cell profile is shown in the HNSCC samples. This study reveals a subgroup of ferroptotic HNSCC with immune-active signatures and indicates the potential of priming HNSCC with ferroptosis inducers to increase the antitumor efficacy of immune checkpoint inhibitors., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Objective: We investigated the effects of different treatment modalities and clinical stage for hypopharyngeal carcinoma (HPC) patients., Methods: Between February 2004 and December 2012, 167 HPC patients were reviewed. We calculated overall survival (OS), progression-free survival (PFS), local failure-free survival (LFFS), regional failure-free survival (RFFS), and distant metastasis failure-free survival (DMFFS) using the Kaplan-Meier method and compared various survival outcomes between definitive chemoradiotherapy (CRT) and surgery-based therapy (SBT)., Results: There were no significant differences in baseline characteristics between SBT (n = 102) and definitive CRT (n = 65) groups. The 5-year rates of OS (59.7% vs. 24.0%, p < 0.0001) and PFS (49.9% vs. 22.6%, p = 0.0002) were significantly better in patients who received SBT than in those who received definitive CRT. The SBT group also obtained better LFFS (p < 0.0001), RFFS (p = 0.0479), and DMFFS (p = 0.0110). We did similar analyses by different T-classification (T1-2, T3, and T4) and found that SBT had better OS (p < 0.0001 and p = 0.0020), PFS (p < 0.0001 and p = 0.0513), LFFS (p = 0.0002 and p = 0.0075), RFFS (p = 0.1949 and p = 0.0826), and DMFFS (p = 0.0248 and p = 0.0436) in the T4 and T1-2 subgroups but similar OS (p = 0.9598), PFS (p = 0.5052), RFFS (p = 0.9648), and DMFFS (p = 0.8239) in T3 patients. Analyses by different overall stages revealed no differences between definitive CRT and SBT for stage III patients but significantly better results for stage IV patients who received SBT., Conclusions: SBT can obtain significant survival benefits when compared with definitive CRT for the whole cohort of patients. Definitive CRT has similar survival outcomes compared with SBT only for T3 tumors or overall stage III disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lin, Lee, Hsu, Tai, Wang, Yang and Chu.)

Hepatocellular carcinoma (HCC) is one of the most critical health problems in the world. For proper treatment, it is important to identify the grade of cancer morbidity from HCC biopsy image. The diagnostic work is not only time-consuming but also subjective. The same biopsy image may be diagnosed as of different grades by different doctors, due to lack of experience or difference in opinion. In this work, we proposed an automatic grading system with classification accuracy matching to an experienced doctor, to help augment the diagnosis process. First, we proposed a segmentation method to isolate all nucleus-like objects present in a biopsy image. Non-target objects (here the target is a single HCC nucleus) present in the biopsy image are isolated too in the segmentation process. To eliminate such non-target objects, we proposed clustering of segmented images and a novel method to filter out target objects. Next, we proposed a two track neural network, where input consists of 2 different images. It combines a single segmented nucleus and a random cropped texture patch of the biopsy image to which the nucleus belongs. At this classifier output, we grade the single nucleus. Finally, a majority voting method is used to identify the grade of the whole biopsy image. We achieved an accuracy of 99.03% for nucleus image grading and 99.66% accuracy for grading biopsy images.

A patient with a Class II division 2 malocclusion is presented, illustrating the application of a modified double J retractor (DJR) and palatal miniscrews along with clear aligners to correct the malocclusion and normalize the incisor torque. In terms of incisor torque recovery, a nonextraction approach might be a good choice if the Class II correction could be successfully achieved with total arch distalization. When maxillary molar distalization was limited by anatomical boundaries, the treatment plan was changed to bilateral maxillary first premolar extractions, which led to even more retroclination of the maxillary incisors after space closure. Anterior interdental miniscrews were used to intrude the maxillary incisors. A modified DJR and palatal miniscrews were used to regain torque and achieve palatal root movement of the maxillary incisors. The treatment effects and biomechanical designs were evaluated for torque recovery of the retroclined maxillary incisors., (© 0000 by The EH Angle Education and Research Foundation, Inc.)

Background: Recurrent/ metastatic squamous cell carcinoma of head and neck (R/M SCCNH) is still a difficult-to-treat disease with poor clinical outcomes and limited treatment choices. In view of locoregional recurrent versus distant metastatic SCCHN, the therapeutic efficacy of cetuximab-containing regimen and relevant prognostic factors for these two groups may be different. Thus, the aim of this study was to explore the treatment outcomes of cetuximab-containing regimen in locoregional recurrent and distant metastatic SCCHN groups, and to identify clinical factors correlated with better survival outcomes., Methods: From 2016 to 2020, patients with R/M SCCHN who received cetuximab-containing regimen in our institute were enrolled in this study. Clinical outcomes including overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) were evaluated in both locoregional recurrence and distant metastasis groups. Exploratory analysis were conducted to investigate major clinical features associated with better outcomes., Results: A total of 107 patients with locoregional recurrent SCCHN (N = 66) and distant metastatic SCCNH (N = 41) who received cetuximab-containing regimen were enrolled in this retrospective study. Patients with oral cavity cancer and patients with disease recurrence within 6 months after radiation therapy were significantly increased in locoregional recurrence group. The median OS (15.6 vs. 9.7 months, P = 0.004) and PFS (5.8 months vs. 4.2 months, P = 0.008) were longer in locoregional recurrence group than in distant metastasis group. In multivariate analysis of clinical features, locoregional recurrence was still an important risk factor associated with better OS (Hazzard ratio (HR) 0.64, p = 0.06) and PFS (HR 0.67, p = 0.075). In addition, a trend of favorable disease control rate (DCR; 62.5% vs. 45.0%, p = 0.056) was noted in locoregional recurrence group. In locoregional recurrence group, prior salvage surgery was associated with longer OS (HR = 0.24, P = 0.008) and PFS (HR = 0.30, P = 0.005)., Conclusion: SCCHN with locoregional recurrence is associated with better disease control and survival outcomes comparing to distant metastatic SCCHN when treated with cetuximab-containing regimen. Salvage surgery for locoregional recurrence may further improves clinical outcome., (© 2022. The Author(s).)

Fine-needle aspiration biopsy (FNAB) is a routine diagnostic test for thyroid nodules. The use of local anesthesia (LA) before the procedure is still controversial. This prospective study aimed to evaluate the degree of pain and specimen adequacy in liquid-based cytology (LBC) for FNAB of thyroid nodules with and without LA. A total of 100 consecutive patients with thyroid nodules who underwent FNAB with and without LA between January and December 2020 were included. Patients who received LA had a significantly lower immediate pain scale score (P = 0.01). Multivariate analysis demonstrated that no use of LA (odds ratio [OR] = 3.48, 95% confidence interval [CI] = 1.50-8.10, P = 0.004) and lesion abutting the trachea (OR = 6.14, 95% CI = 1.56-24.12, P = 0.009) were independently and significantly associated with pain degree immediately after FNAB. A higher proportion of patients who previously underwent FNAB thought that LA was helpful and should be performed prior to FNAB. However, the use of LA did not improve the specimen adequacy (P = 0.075). The results showed that administration of LA with a proper technique before ultrasound-guided FNAB might reduce immediate pain after the procedure, and patients may experience more pain when the aspirated nodules abut the trachea., (© 2022. The Author(s).)

Introduction: Orthodontists, surgeons, and patients have taken an interest in using clear aligners in combination with orthognathic surgery. This study aimed to evaluate the accuracy of tooth movements with clear aligners during presurgical orthodontics using novel 3-dimensional superimposition techniques., Methods: The study sample consisted of 20 patients who have completed presurgical orthodontics using Invisalign clear aligners. Initial (pretreatment) digital dental models, presurgical digital dental models, and ClinCheck prediction models were obtained. Presurgical models were superimposed onto initial ones using stable anatomic landmarks; ClinCheck models were superimposed onto presurgical models using surface best-fit superimposition. Five hundred forty-five teeth were measured for 3 angular movements (buccolingual torque, mesiodistal tip, and rotation) and 4 linear movements (buccolingual, mesiodistal, vertical, and total scalar displacement). The predicted tooth movement was compared with the achieved amount for each movement and tooth, using both percentage accuracy and numerical difference., Results: Average percentage accuracy (63.4% ± 11.5%) was higher than in previously reported literature. The most accurate tooth movements were buccal torque and mesial displacement compared with lingual torque and distal displacement, particularly for mandibular posterior teeth. Clinically significant inaccuracies were found for the buccal displacement of maxillary second molars, lingual displacement of all molars, intrusion of mandibular second molars, the distal tip of molars, second premolars, and mandibular first premolars, buccal torque of maxillary central and lateral incisors, and lingual torque of premolars and molars., Conclusions: Superimposition techniques used in this study lay the groundwork for future studies to analyze advanced clear aligner patients. Invisalign is a treatment modality that can be considered for presurgical orthodontics-tooth movements involved in arch leveling and decompensation are highly accurate when comparing the simulated and the clinically achieved movements., (Copyright © 2022 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.)

Background: Compared with the precise targeting of drug-resistant mutant cancer cells, strategies for eliminating non-genetic adaptation-mediated resistance are limited. The pros and cons of the existence of inflammasomes in cancer have been reported. Nevertheless, the dynamic response of inflammasomes to therapies should be addressed., Methods: Tumor-derived exosomes were purified by differential ultracentrifugation and validated by nanoparticle tracking analysis and transmission electron microscopy. A proximity ligation assay and interleukin-1β (IL-1β) level were used for detecting activation of NLRP3 inflammasomes. RNA sequencing was used to analyze the exosomal RNAs. MIR21 knocked out human monocytic THP cells and mir21 knocked out murine oral cancer MTCQ1 cells were generated for confirming the exosomal delivery of microRNA (miR)-21. Syngeneic murine models for head and neck cancer (C57BLJ/6J), breast cancer (BALB/C) and lung cancer (C57BL/6J) were applied for examining the impact of Snail-miR21 axis on inflammasome activation in vivo. Single-cell RNA sequencing was used for analyzing the tumor-infiltrated immune cells. Head and neck patient samples were used for validating the findings in clinical samples., Results: We demonstrated that in cancer cells undergoing Snail-induced epithelial-mesenchymal transition (EMT), tumor cells suppress NLRP3 inflammasome activities of tumor-associated macrophages (TAMs) in response to chemotherapy through the delivery of exosomal miR-21. Mechanistically, miR-21 represses PTEN and BRCC3 to facilitate NLRP3 phosphorylation and lysine-63 ubiquitination, inhibiting NLRP3 inflammasome assembly. Furthermore, the Snail-miR-21 axis shapes the post-chemotherapy tumor microenvironment (TME) by repopulating TAMs and by activating CD8 + T cells. In patients with head and neck cancer, the Snail-high cases lacked post-chemotherapy IL-1β surge and were correlated with a worse response., Conclusions: This finding reveals the mechanism of EMT-mediated resistance beyond cancer stemness through modulation of post-treatment inflammasome activity. It also highlights the dynamic remodeling of the TME throughout metastatic evolution., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The antiepidermal growth factor receptor (EGFR) monoclonal antibody cetuximab and immune checkpoint inhibitors (ICIs) are the current front-line treatment for recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC). However, understanding of the efficacy of cetuximab-containing regimens in patients who fail ICI treatments is limited. In this study, we present the efficacy of cetuximab-based regimens in heavily pretreated R/M HNSCC patients after progression to ICIs., Methods: This was a retrospective study that analyzed patients diagnosed with R/M HNSCC who progressed after ICIs and then received their first-time cetuximab-based regimens at Taipei Veterans General Hospital from January 2017 to December 2020. The response rate, overall survival, and progression-free survival were measured., Results: A total of 28 patients were included in this study. Most patients had received pembrolizumab as an ICI. The median duration of cetuximab-based regimens prescribed was 4.5 months. The objective response rate (ORR) was 32.1% (95% confidence interval [CI], 17.9%-50.6%), and the disease control rate (DCR) was 53.6% (95% CI, 42.4%-76.4%). The median overall survival and median progression-free survival were 9.1 months (95% CI, 1.3-16.8) and 2.9 months (95% CI, 2.2-3.5), respectively. The incidence of cetuximab-related adverse events was reported as 39.2%., Conclusion: A cetuximab-based regimen is still an effective and tolerable treatment for R/M HNSCC after progression on ICIs. Future prospective studies are needed to identify better treatments for previously ICI-treated or heavily treated R/M HNSCC patients., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2022, the Chinese Medical Association.)

Background: To assess the feasibility of tongue conservation treatment with induction chemotherapy (ICT), tongue conservation surgery, and risk-adapted postoperative adjuvant therapy in oral tongue squamous cell carcinoma (OTSCC)., Methods: Patients with newly diagnosed OTSCC cT2-4 N0-2 M0 were recruited. The ICT with a regimen of docetaxel, cisplatin, and oral tegafur/uracil (DCU) was administrated every 21 days. After the first cycle of ICT (DCU1), patients with a more than 30% decrease in the longest diameter of primary tumor underwent a second cycle of ICT (DCU2). Tongue conservation surgery was performed after ICT, and risk-adapted adjuvant therapy was organized based on pathological features., Results: From July 2011 to December 2015, a total of 23 patients were enrolled, 87% of whom were classified as stage III-IV. Clinical responders to DCU1 and DCU2 were determined in 90.5% (19/21) and 88.2% (15/17) of patients. Tongue conservation surgery was performed in 16 responders to ICT. Only one patient had a positive margin (6.3%), and a complete pathologic response was achieved in eight patients (50%). Only one patient developed local recurrence after a median follow-up of 58.6 months (range, 7.9-105.2). The 5-year overall survival (0% vs. 87.5%, P = 0.001) and disease-specific survival (0% vs. 93.3%, P = 0.000) were significantly different between the DCU1 nonresponders and responders., Conclusion: Tongue conservation treatment with ICT, followed by conservation surgery and risk-adapted adjuvant therapy, is feasible for patients with OTSCC who are good responders to ICT. However, the outcomes of nonresponders are dismal. Further study in a larger patient population is warranted., (© 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Postoperative adjuvant therapy has been indicated by advanced T classification for T3-4 oral squamous cell carcinoma (OSCC) and the significance of perineural invasion (PNI) and lymphovascular invasion (LVI) in treatment for T3-4 OSCC remains unclear. Ninety-eight cumulative patients with T3-4 OSCC who underwent curative surgery between Jan 2002 and Dec 2010 were recruited and analyzed. Twenty-seven (27.6%) patients were PNI/LVI double positive. PNI/LVI double positive demonstrated independent predictive values for higher neck metastasis (LN+), higher distant metastasis (DM) and low 5-year disease-specific survival (DSS) rates (p < 0.001, p = 0.017, and p < 0.001, respectively) after controlling for other pathologic features of the primary tumors. A high DM rate of 33.3% was noted in PNI/LVI double-positive patients. Among the PNI/LVI double negative, single positive to double positive subgroups, increasing LN+, DM rates and decreasing DSS rate were observed. Among the 44 LN+ patients, PNI/LVI double positive remained associated with a markedly high DM rate of 42.9% and a poor 5-year DSS of 27.7%. PNI/LVI double positive plays important roles in prognostication and potential clinical application for T3-4 OSCC by independently predicting LN+, DM, and poor DSS, and can be used as a good marker to select DM high-risk patients for novel adjuvant therapy trials., (© 2021. The Author(s).)

Background: Esophageal second primary neoplasms (ESPNs) are common in hypopharyngeal squamous cell carcinoma (HPSCC) patients and are associated with poor prognoses. The effectiveness of image-enhanced endoscopy (IEE) has not been well established., Methods: We reviewed the patients between April 2016 and April 2018 with HPSCC receiving ESPNs screening via white-light imaging, narrow-band imaging, and Lugol chromoendoscopy., Results: Of 99 eligible patients, ESPNs prevalence was 31%. Of the 69 patients assigned to the follow-up group, 23 with positive findings showed significantly increased previous histories of second primary malignancies in the upper aerodigestive tract. Among them, patients without symptoms at the time of IEE screening showed less advanced T stages and higher percentages of receiving minimal invasive therapy., Conclusion: The present study represented the clinical utility of routine IEE screening in HPSCC patients and proposed routine surveillance may help identify and properly manage early-stage ESPN., Competing Interests: Conflicts of interest: Dr. Ming-Chih Hou, an editorial board member at Journal of the Chinese Medical Association, had no role in the peer review process of or decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2021, the Chinese Medical Association.)

Background: Angiopoietin-Tie2 and nitric oxide pathway is crucial in tumor angiogenesis and closely correlates with tumor development, growth, and metastasis. This study aimed to investigate the angiopoietin-Tie2 and nitric oxide signaling of the erythrocyte membrane in response to surgical trauma in head and neck cancer., Methods: We prospectively enrolled the patients with histology-proven head and neck squamous cell carcinoma undergoing surgical resection of primary tumors at the medical center between August and November 2019. We measured the preoperative and postoperative levels of angiopoietin-1, angiopoietin-2 in plasma using enzyme-linked immunosorbent assays, nitric oxide in plasma using nitrate/nitrite colorimetric assays, and Tie2 phosphorylation in erythrocyte membrane using Western blotting., Results: The plasma angiopoietin-1 was downregulated from the median 971.3 pg/mL (interquartile range [IQR] 532.1-1569.3) to 417.9 (IQR 270.5-597.3) after tumor resection (p = 0.0020). Conversely, the plasma angiopoietin-2 was enhanced from 1173.6 pg/mL (IQR 977.7-1450.2) to 2353.7 (IQR 1352.4-2954.3) after surgery (p = 0.0021), with a concomitant increase in plasma nitric oxide level from 7.73 μM (IQR 5.39-10.06) to 10.50 (IQR 7.65-14.18) after surgical resection (p = 0.0093). Subgroup analyses further showed the angiopoietin-Tie2 and nitric oxide signaling was significant only in stage III and IV cancer., Conclusions: The dynamic change of angiopoietin-Tie2 signaling in the erythrocyte membrane along with the enhanced nitric oxide in plasma after tumor resection suggests erythrocytes play a significant role in modulating surgery-induced angiogenesis, which may provide a novel marker for cancer surveillance and control.

Early enzyme replacement therapy (ERT) improve long-term outcomes in patients with infantile-onset Pompe disease (IOPD). Our cohort of patients with IOPD at Taipei Veterans General Hospital (TVGH) joined Taiwan Pompe newborn screening program from 2008, testing more than one million newborns until 2018. By 2010, we had established rapid diagnostic strategies. Now, the average age of ERT initiation starts at an average age of <10 days-old, the earliest group in the world. However, they still presented some airway problems. We present a retrospective study focused on airway abnormalities in these patients along 8 years of observation. Fifteen patients with IOPD, who received very early treatment at a mean age of 8.94 ± 3.75 days, underwent flexible bronchoscopy (FB) for dynamic assessment of the whole airway. Long-term clinical outcomes and relevant symptoms of the upper airway were assessed. All patients in the study had varying degrees of severity of upper airway abnormalities and speech disorders. The three oldest children (Age 94, 93, and 88 months, respectively) had poor movement of the vocal cords with reduced abduction and adduction and had silent aspiration of saliva through the glottis during respiration. This is the largest cohort study presented to date about airway abnormalities in very early treated patients with IOPD patients by FB. Despite very early treatment, we observed upper airway abnormalities in these IOPD patients. In IOPD, upper airway abnormalities seem inevitable over time. We suggest early and continuous monitoring for all IOPD patients, even with early and regular treatment., (© 2020 Wiley Periodicals, Inc.)

Objectives: Perineural invasion (PNI) is a poor prognostic pathologic feature of oral squamous cell carcinoma (OSCC). The mechanisms of PNI remain poorly understood, and nerve-tumour interactions have been implicated for its pathogenesis., Design and Setting: Systematic investigation of nerve-tumour interactions was performed using fresh human peripheral nerve. In vitro and in vivo models were used to determine the ability of human peripheral nerves to enhance OSCC migration/invasion. Retrospective cohort study was also carried out in one medical centre from 2001 to 2009., Participants: 314 T1-2 OSCC patients., Main Outcome Measures: In the transwell migration/invasion assay, the cells in five representative fields were counted. In the nerve implantation model, tumour size was estimated. PNI quantification by PNI focus number was carried out in the OSCC patients to correlate with cervical lymph node metastasis and oncologic outcomes., Results: The transwell migration/invasion assay demonstrated that human peripheral nerves, compared with subcutaneous soft tissue, significantly enhanced the migration/invasion abilities of OSCC. Moreover, the enhanced migration was dose-dependent with increased length or number of peripheral nerve segments. The nerve implantation model showed that human peripheral nerve also enhanced OSCC growth in vivo. Finally, increased PNI focus number was found dose-dependently associated with increased cervical lymph node metastasis and decreased 5-year disease-specific survival rates., Conclusions: These results clearly indicated the presence of nerve-tumour interaction that involved paracrine influences leading to aggressiveness of OSCC. Further investigations are required to explore key cell types and molecules involved in nerve-tumour interactions for future therapeutic targeting of PNI in OSCC., (© 2019 John Wiley & Sons Ltd.)

Purpose : The first aim of this study was to compare inferior tear meniscus height (TMH) measured by keratography and swept-source optical coherence tomography (OCT). Effect of locations of fluorescein instillation and subjects' subjective sensation, and the TMH results were also investigated. Methods : Forty-one eyes from 41 healthy adults had TMH randomly measured by keratography (K5M, Oculus, Germany) and swept-source OCT (Casia SS-1000, Tomey Corp, Japan) at baseline, followed by touching either the inferior bulbar or inferior palpebral conjunctiva, randomly assigned, with a moistened fluorescein strip. Two-way analysis of variance (ANOVA) was used to compare TMH obtained from the two devices and three measurement conditions. Subjective sensation of conjunctival touch was obtained through a 4-point scale with zero representing no sensation, and one to three representing ocular sensation in an ascending order. Results : Two-way ANOVA revealed no significant difference in TMH between keratography and swept-source OCT (Factor (devices): F = 0.579, p = .451) while there was a significant difference among fluorescein instillations (Factor (conditions): F = 10.146, p < .001). Baseline TMH was around 0.25 mm, and increased to around 0.28 mm after instillation of fluorescein sodium. Ocular sensation was similar between the two conjunctival touch, and TMH was not significantly associated with ocular sensation. Conclusions : Keratography and swept-source OCT provided similar TMH results. Applying fluorescein sodium through moistened fluorescein strip could over-estimate TMH by around 0.03 mm. Applying moistened fluorescein strip at bulbar or palpebral conjunctival led to similar subjective sensations and did not affect TMH measurement.

In the version of Supplementary Fig. 3c originally published with this Article, the authors mistakenly duplicated a blot from Supplementary Fig. 3b. The correct versions of these figures are shown below. In addition, two independent repeats of the experiments presented in Supplementary Figs. 3b and 3c, showing results consistent with those originally reported, have been deposited in Figshare ( 10.6084/m9.figshare.7545263 ).

Objective: Perineural invasion (PNI) has been an established poor prognostic feature for T1-T2 oral squamous cell carcinoma (OSCC). Different presentations and amounts of PNI are commonly observed, but PNI is currently recorded as being present or absent. This study asked whether the quantification of PNI provides additional information for early OSCC., Study Design: Retrospective cohort study., Setting: Tertiary referral medical center., Subjects and Methods: Pathologic reevaluations were performed for 314 patients with T1-T2 OSCC who underwent curative surgery from June 2001 to August 2009. A novel parameter, PNI focus number, was defined for PNI quantification. With 5 PNI foci as the cutoff, patients were categorized into 3 groups: no PNI (0 PNI foci), low PNI (PNI foci, 1-5), and high PNI (PNI foci >5). Rate of cervical lymph node metastasis (LN+), 5-year disease-specific survival (DSS), and 5-year overall survival (OS) were analyzed among these groups., Results: PNI focus number independently predicted for LN+, poor DSS, and poor OS in multivariate analysis after controlling for T classification, lymphovascular invasion, differentiation, margin, and tumor thickness. The 5-year DSS demonstrated a dose-dependent decrease among the 3 groups (no PNI, 88.6%; low PNI, 75.2%; high PNI, 33.8%; P < .001). Moreover, the 5-year DSS of the high PNI group was significantly worse than that of the low PNI group., Conclusion: PNI focus number can be a novel parameter for PNI quantification in early OSCC. Although optimal quantification methods still require further investigation, this study offers clear clinical support for the nerve-tumor interaction hypothesis and advocates further mechanistic research for the exploration of PNI-related treatment concepts for OSCC.

Epithelial-mesenchymal transition (EMT) is a pivotal mechanism for cancer dissemination. However, EMT-regulated individual cancer cell invasion is difficult to detect in clinical samples. Emerging evidence implies that EMT is correlated to collective cell migration and invasion with unknown mechanisms. We show that the EMT transcription factor Snail elicits collective migration in squamous cell carcinoma by inducing the expression of a tight junctional protein, claudin-11. Mechanistically, tyrosine-phosphorylated claudin-11 activates Src, which suppresses RhoA activity at intercellular junctions through p190RhoGAP, maintaining stable cell-cell contacts. In head and neck cancer patients, the Snail-claudin-11 axis prompts the formation of circulating tumour cell clusters, which correlate with tumour progression. Overexpression of snail correlates with increased claudin-11, and both are associated with a worse outcome. This finding extends the current understanding of EMT-mediated cellular migration via a non-individual type of movement to prompt cancer progression.

A favorable interplay between cancer cells and the tumor microenvironment (TME) facilitates the outgrowth of metastatic tumors. Because of the distinct initiating processes between primary and metastatic tumors, we investigate the differences in tumor-associated macrophages (TAMs) from primary and metastatic cancers. Here we show that dual expression of M1 and M2 markers is noted in TAMs from primary tumors, whereas predominant expression of M2 markers is shown in metastatic TAMs. At metastatic sites, TAMs secrete interleukin-35 (IL-35) to facilitate metastatic colonization through activation of JAK2-STAT6-GATA3 signaling to reverse epithelial-mesenchymal transition (EMT) in cancer cells. In primary tumors, inflammation-induced EMT upregulates IL12Rβ2, a subunit of the IL-35 receptor, in cancer cells to help them respond to IL-35 during metastasis. Neutralization of IL-35 or knockout of IL-35 in macrophages reduces metastatic colonization. These results indicate the distinct TMEs of primary and metastatic tumors and provide potential targets for intercepting metastasis.

Epithelial-mesenchymal transition (EMT) is a major event during cancer progression and metastasis; however, the definitive role of EMT in remodeling tumor microenvironments (TMEs) is unclear. Tumor-associated macrophages (TAMs) are a major type of host immune cells in TMEs, and they perform a wide range of functions to regulate tumor colonization and progression by regulating tumor invasiveness, local tumor immunity, and angiogenesis. TAMs are considered to have an M2-like, i.e., alternatively activated, phenotype; however, how these EMT-undergoing cancer cells promote M2 polarization of TAMs as a crucial tumor-host interplay during cancer progression is unclear. In this study, we investigated the mechanism of EMT-mediated TAM activation. Here, we demonstrate that the EMT transcriptional factor Snail directly activates the transcription of MIR21 to produce miR-21-abundant tumor-derived exosomes (TEXs). The miR-21-containing exosomes were engulfed by CD14 + human monocytes, suppressing the expression of M1 markers and increasing that of M2 markers. Knockdown of miR-21 in Snail-expressing human head and neck cancer cells attenuated the Snail-induced M2 polarization, angiogenesis, and tumor growth. In head and neck cancer samples, a high expression of miR-21 was correlated with a higher level of SNAI1 and the M2 marker MRC1. This study elucidates the mechanism of EMT-mediated M2 polarization through delivery of the miR-21-abundant exosomes, which may serve as a candidate biomarker of tumor progression and provide a potential target for intercepting EMT-mediated TME remodeling., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Overexpression of ALDH is associated with cancer stem-like features and poor cancer prognosis. High ALDH activity has been observed in cancer stem-like cells. There are a total of 19 human ALDH isoforms, all of which are associated with reducing oxidative stress and protecting cells from damage. However, it is unknown whether all ALDHs are associated with poor cancer prognosis and which ones play a significant role in cancer progression. In this study, we used RNA sequencing data from The Cancer Genome Atlas (TCGA) to evaluate the differential expression of 19 ALDH isoforms in 5 common human cancers. The 19 ALDH genes were analyzed with an integrating meta-analysis of cancer prognosis. Genotyping and next-generation RNA sequencing for 30 pairwise samples of head and neck squamous cell carcinoma were performed and compared with the TCGA cohort. The analysis showed that each ALDH isoform had a specific differential expression pattern, most of which were related to prognosis in human cancer. A lower expression of ALDH2 in the tumor was observed, which was independent from the ALDH2 rs671 SNP variant and the expression of other mitochondria-associated protein coding genes. This study provides new insight into the association between ALDH expression and cancer prognosis.

PD-L1 expression is critical in helping tumor cells evade the immune system. However, the level of PD-L1 expression in non-oropharyngeal head and neck squamous cell carcinoma (non-OPHNSCC) and its association with patient prognosis remains unclear. A retrospective clinicopathological analysis was performed on 106 patients with non-OPHNSCC diagnosed between 2007 and 2014. In the current study, tissue arrays from paraffin-embedded non-OPHNSCC samples obtained from patients were constructed, and PD-L1 and p16 INK4A expression were determined using immunohistochemistry. Systemic inflammatory factors, including C-reactive protein, serum white blood cell, neutrophil, monocyte and lymphocyte counts were also analyzed. The current study demonstrated that PD-L1 was overexpressed in 32.1% (34/106) and p16 INK4A in 20.8% (22/106) of patients. The expression of PD-L1 was associated with p16 INK4A expression (P<0.01) but was not associated with levels of systemic inflammatory factors. Tumor stage was determined to be a significant prognostic value (stage I/II vs. III/IV, P=0.03), however, PD-L1, p16 INK4A or other clinicopathological factors were not. The current study identified an association between PD-L1 and p16 INK4A expression in non-OPHNSCC. This may facilitate the development of anti-PD1/PDL1 therapies to treat patients with head and neck cancer.

Backgrounds: The aim of this study is to introduce pterygomandibular suspension suture as a simple modification of uvulopalatopharyngoplasty for severe obstructive sleep apnea in dealing with lateral pharyngeal wall and retropalatal space collapse., Methods: This retrospective study was conducted at Taipei Veterans General Hospital, Taiwan. Ten adult patients underwent modified uvulopalatopharyngoplasty with pterygomandibular suspension suture according to following inclusion criteria: severe obstructive sleep apnea (apnea-hypopnea index [AHI] > 30 events/h), type I Fujita with lateral pharyngeal wall collapse, and failure for continuous positive airway pressure (CPAP) therapy. The philosophy of this modification technique is to create a firm anterolateral suspension of the lateral pharyngeal wall and soft palate by sutures., Results: The mean operative time of modified uvulopalatopharyngoplasty with pterygomandibular suspension suture was 60 min. The mean AHI decreased significantly from 77.2 ± 25.0 preoperatively to 28.7 ± 18.8 postoperatively (P = 0.005) and the lowest oxygen saturation increased from 69.9 ± 11.4 to 81.1 ± 7.19% (P = 0.005). No major perioperative complication such as massive bleeding or respiratory distress was noted. No patient experienced a swallowing disturbance, taste change, or voice change 6 months postoperatively. The mean period for resuming a normal diet was 15 days., Conclusion: Modified uvulopalatopharyngoplasty with pterygomandibular suspension suture is a simplified and effective surgical approach with satisfactory functional recovery for selective patients with severe obstructive sleep apnea.

Background: To evaluate the failure pattern and identify predictors of locoregional control in lateralized buccogingival cancer after postoperative radiotherapy (RT) at a single institution., Methods: We retrospectively reviewed the clinical data of 150 patients with lateralized oral squamous cell carcinoma, including carcinoma of the buccal mucosa, gingiva and retromolar trigone. All patients underwent radical surgery followed by postoperative RT with or without concurrent chemotherapy. We registered planning computer tomography images with images obtained at recurrence and categorized the failure pattern as in-field, marginal, or out-field recurrence., Results: The median follow-up duration was 47 months (range, 2-131 months). Twenty-eight patients (19%) experienced locoregional failure, including 20 local failure, 5 regional failure and 3 with both. Among the 24 patients who had image studies at recurrence, 15 patients had in-field recurrence, 5 were marginal recurrence and 4 were out-field recurrence. Seven patients (5%) had contralateral neck failure. Four of 5 patients with marginal failure had recurrent tumors in the infratemporal fossa. In multivariate analysis, extracapsular spread and positive or close surgical margin were associated with poor locoregional control., Conclusion: Local in-field recurrence is the most common failure pattern in lateralized buccogingival cancer after postoperative RT. The infratemporal fossa is a risk area for marginal failure and should be encompassed adequately in the postoperative RT field. Extracapsular spread and positive or close margin are predictors of locoregional control for lateralized oral cancer. Patients exhibiting such adverse features require more aggressive treatment., (Copyright © 2017. Published by Elsevier Taiwan LLC.)

Purpose: In head and neck squamous cell carcinoma (HNSCC), the incidence of RAS mutation, which is the major cause of cetuximab resistance, is relatively rare compared with the other types of cancers, and the mechanism mediating acquired resistance is unclear compared with the driver gene mutation-mediated de novo resistance. Here, we investigated the driver gene mutation-independent mechanism for cetuximab resistance in HNSCC. Experimental Design: We used the in vitro -selected and in vivo -selected cetuximab-resistant sublines of HNSCC cell lines for investigating the mechanism of acquired resistance to cetuximab. Zebrafish model was applied for evaluating the synergistic effect of combinatory drugs for overcoming cetuximab resistance. Results: The cetuximab-resistant HNSCC cells undergo a Snail-induced epithelial-mesenchymal transition. Mechanistically, Snail induces the expression of lymphotoxin-β (LTβ), a TNF superfamily protein that activates NF-κB, and protein arginine methyltransferase 1 (PRMT1), an arginine methyltransferase that methylates EGFR. LTβ interacts with methylated EGFR to promote its ligand-binding ability and dimerization. Furthermore, LTβ activates the NF-κB pathway through a LTβ receptor-independent mechanism. Combination of an EGFR tyrosine kinase inhibitor and a NF-κB inhibitor effectively suppressed cetuximab-resistant HNSCC and interfering with the EGFR-LTβ interaction reverses resistance. Conclusions: Our findings elucidate the mechanism of driver gene mutations-independent mechanism of acquired resistance to cetuximab in HNSCC and also provide potential strategies for combating cetuximab resistance. Clin Cancer Res; 23(15); 4388-401. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background: Inoperable oral cavity squamous cell carcinoma (SCC) is a highly invasive disease associated with the extensive destruction of locoregional tissues and a dismal prognosis. Management strategies for these patients are limited., Methods: This study was a single arm, prospective, open-label phase II trial. A regimen consisting of cetuximab-docetaxel, cisplatin, and fluorouracil (C-TPF) followed by bio-chemoradiotherapy (bio-CRT) with cisplatin and cetuximab was administered to patients who responded to induction chemotherapy. The objective response rate to C-TPF was the primary endpoint., Results: Forty-three patients were enrolled in this study. The objective response rate of C-TPF was 88.4%; 88.9% (32/36) of the responders completed the full bio-CRT course, and the objective response rate of bio-CRT was 64.7%. The most common grade 3/4 adverse events for induction chemotherapy were leucopenia (32.6%) and febrile neutropenia (14.0%). The 1-year progression-free survival (PFS) and overall survival (OS) rates were 43% and 68%, respectively., Conclusion: C-TPF is an effective and tolerable induction chemotherapy regimen for inoperable oral cavity SCC., (© 2017 Wiley Periodicals, Inc.)

Objective: This paper aims to comprehensively document a rare case of thyroid carcinoma with rhabdoid phenotype and literature review of this disease., Methods: A 59-year-old man presented with a rapidly enlarging, painful left lateral cervical mass. CT scan revealed a tumor over the left the thyroid gland with multiple left cervical lymphadenopathy over left level II-IV and level VI. Fine-needle aspiration cytology reported carcinoma, type undetermined. Total thyroidectomy with central compartment and left neck dissection was performed., Results: Pathology report showed rhabdoid phenotype of thyroid carcinoma. Final staging was pT4N1M1., Conclusions: Although WHO classification of thyroid tumor histology does not define this disease entity, few cases were reported. In the last 20 years, English literature review revealed only 12 cases about thyroid carcinoma with rhabdoid phenotype. Major treatment of thyroid carcinoma with rhabdoid phenotype is surgery, and the benefit of adjuvant therapies as radiotherapy or systemic chemotherapy is not clear. The prognosis of thyroid carcinoma with rhabdoid phenotype is extremely poor, with mean survival of only 6 months., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Chemoradiotherapy (CRT) has become the mainstay of treatment for tonsillar squamous cell carcinoma (SCC). Pre-CRT tonsillectomy is frequently performed, mostly for small primary tumors (T1-T2). However, the benefits of pre-CRT tonsillectomy remain unclear., Methods: A retrospective review was performed in 66 patients with T1-T2 tonsillar SCCs treated by CRT from 1997 to 2009. The efficacy of pre-CRT tonsillectomy was analyzed with regard to oncological and functional outcomes., Results: Thirty patients (45.5%) received tonsillectomy (pre-CRT tonsillectomy group), and 36 patients (54.5%) did not (CRT group). Except for a trend toward more T1 cases (33.3% vs. 13.9%, p = 0.061) and significantly less chemotherapy use (60% vs. 86.1%, p = 0.016) in the pre-CRT tonsillectomy group, there were no differences between the two groups in terms of age, gender, N classification (nodal status), overall stage, radiation dose, duration, or technique. In the pre-CRT tonsillectomy group, eight cases (26.7%) achieved an adequate operative margin judged by the surgeon, and only one (12.5%) had a negative pathological margin. In long-term follow-up, there were no statistically significant differences between the two groups regarding local (93.3% vs. 91.7%, p = 0.82) or regional control (93.3% vs. 94.4%, p = 0.84). The pre-CRT tonsillectomy group did not have a better 5-year disease-specific survival rate (83.3% vs. 94.4%, p = 0.177) or 5-year overall survival rate (70% vs. 94.4%, p = 0.017). There were no differences in complications or functional results (feeding tube and tracheostomy dependence), and quality of life demonstrated no significant difference., Conclusion: Pre-CRT tonsillectomy contributes little to oncological and functional outcomes in patients with T1-T2 tonsillar SCC., (Copyright © 2016. Published by Elsevier Taiwan LLC.)

Objectives: Perineural invasion (PNI) is an established poor prognostic pathological feature for oral squamous cell carcinoma (OSCC). The purpose of this study was to analyze the role of pretreatment parameters in predicting PNI for OSCC., Materials and Methods: We prospectively enrolled into our study 102 newly diagnosed OSCC patients, who were surgically treated from 2011 to 2012. Before treatment, patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire H&N35 and the visual analogue scale (VAS) for cancer pain. Pathological examination was performed to ascertain PNI status in all patients. Patients were divided into two groups, those with PNI and without PNI. Pretreatment parameters were compared between the two groups., Results: In univariate analysis, clinical T classification (P<0.001), painkiller use (P=0.001), problem with social eating (P<0.001) and social contact (P=0.002), VAS scores of primary pain (P<0.001) and referred pain (P=0.004) were found to be associated with PNI. Multivariate logistic regression analysis further revealed VAS score of primary pain (P=0.001, OR 2.014) and T3-4 classification (P=0.014, OR 6.422) were independent predictors of PNI. A regression equation incorporating pretreatment pain was developed to predict the probability of having PNI., Conclusion: PNI can be predicted by higher pretreatment VAS score of primary pain, as well as more advanced clinical T classification. Careful evaluation of pretreatment pain of primary tumor can thus be helpful in improving treatment decision making for OSCC., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Let-7 is crucial for both stem cell differentiation and tumor suppression. Here, we demonstrate a chromatin-dependent mechanism of let-7 in regulating target gene expression in cancer cells. Let-7 directly represses the expression of AT-rich interacting domain 3B (ARID3B), ARID3A, and importin-9. In the absence of let-7, importin-9 facilitates the nuclear import of ARID3A, which then forms a complex with ARID3B. The nuclear ARID3B complex recruits histone demethylase 4C to reduce histone 3 lysine 9 trimethylation and promotes the transcription of stemness factors. Functionally, expression of ARID3B is critical for the tumor initiation in let-7-depleted cancer cells. An inverse association between let-7 and ARID3A/ARID3B and prognostic significance is demonstrated in head and neck cancer patients. These results highlight a chromatin-dependent mechanism where let-7 regulates cancer stemness through ARID3B., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Posttranslational modifications to the intracellular domain of the EGFR are known to regulate EGFR functions; however, modifications to the extracellular domain and their effects remain relatively unexplored. Here, we determined that methylation at R198 and R200 of the EGFR extracellular domain by protein arginine methyltransferase 1 (PRMT1) enhances binding to EGF and subsequent receptor dimerization and signaling activation. In a mouse orthotopic colorectal cancer xenograft model, expression of a methylation-defective EGFR reduced tumor growth. Moreover, increased EGFR methylation sustained signaling activation and cell proliferation in the presence of the therapeutic EGFR monoclonal antibody cetuximab. In colorectal cancer patients, EGFR methylation level also correlated with a higher recurrence rate after cetuximab treatment and reduced overall survival. Together, these data indicate that R198/R200 methylation of the EGFR plays an important role in regulating EGFR functionality and resistance to cetuximab treatment.

Background: Triweekly cisplatin-based postoperative concurrent chemoradiotherapy (CCRT) has high intolerance and toxicities in locally advanced head and neck cancer (LAHNC). We evaluated the effect of a modified weekly cisplatin-based chemotherapy in postoperative CCRT., Methods: A total of 117 patients with LAHNC were enrolled between December 2007 and December 2012. Survival, compliance/adverse events, and independent prognostic factors were analyzed., Results: Median follow-up time was 30.0 (3.1-73.0) months. Most patients completed the entire course of postoperative CCRT (radiotherapy ≥ 60 Gy, 94.9%; ≥ 6 times weekly chemotherapy, 75.2%). Only 17.1% patients required hospital admission. The most common adverse effect was grade 3/4 mucositis (28.2%). No patient died due to protocol-related adverse effects. Multivariate analysis revealed the following independent prognostic factors: oropharyngeal cancer, extracapsular spread, and total radiation dose. Two-year progression-free survival and overall survival rates were 70.9% and 79.5%, respectively., Conclusion: Modified weekly cisplatin-based chemotherapy is an acceptable regimen in postoperative CCRT for LAHNC.

Snail is primarily known as a transcriptional repressor that induces epithelial-mesenchymal transition by suppressing adherent proteins. Emerging evidence suggests that Snail can act as an activator; however, the mechanism and biological significance are unclear. Here, we found that CREB-binding protein (CBP) is the critical factor in Snail-mediated target gene transactivation. CBP interacts with Snail and acetylates Snail at lysine 146 and lysine 187, which prevents the repressor complex formation. We further identified several Snail-activated targets, including TNF-α, which is also the upstream signal for Snail acetylation, and CCL2 and CCL5, which promote the recruitment of tumor-associated macrophages. Here, we present our results on the mechanism by which Snail induces target gene transactivation to remodel the tumor microenvironment., (Copyright © 2014 Elsevier Inc. All rights reserved.)

We recently reported that low NM23-H1 expression of head and neck squamous cell carcinoma (HNSCC) correlated with poor patients' prognosis. Growing evidence has indicated that high tumor NM23-H1 expression contributes to a good response to chemotherapy. Therefore, we investigated the role of NM23-H1 in susceptibility of HNSCC cells to cisplatin and its clinical significance, as well as the in vitro study for validation was performed. Using immunohistochemistry, we analyzed NM23-H1 expression in surgical specimens from 46 HNSCC patients with cervical metastases receiving surgery and adjuvant chemoradiotherapy. Low tumor NM23-H1 expression correlated with locoregional recurrence of HNSCC following postoperative cisplatin-based therapy (p = 0.056) and poor patient prognosis (p = 0.001). To validate the clinical observation and the effect of NM23-H1 on cisplatin cytotoxicity, we established several stable clones derived from a human HNSCC cell line (SAS) by knockdown and overexpression. Knockdown of NM23-H1 attenuated the chemosensitivity of SAS cells to cisplatin, which was associated with reduced cisplatin-induced S-phase accumulation and downregulation of cyclin E1 and A. Overexpression of NM23-H1 reversed these results, indicating the essential role of NM23-H1 in treatment response to cisplatin. NM23-H1 may participate in HNSCC cell responses to cisplatin and be considered a potential therapeutic target.