Routine image-enhanced endoscopic surveillance for metachronous esophageal squamous cell neoplasms in head and neck cancer patients.

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.

A Shift in Molecular Drivers of Papillary Thyroid Carcinoma Following the 2017 World Health Organization Classification: Characterization of 554 Consecutive Tumors With Emphasis on BRAF-Negative Cases.

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.

Treatment outcomes of cetuximab-containing regimen in locoregional recurrent and distant metastatic head and neck squamous cell carcinoma.

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.

Airway abnormalities in very early treated infantile-onset Pompe disease: A large-scale survey by flexible bronchoscopy.

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.

Stage-dependent angiopoietin-Tie2 and nitric oxide signaling of erythrocytes in response to surgical trauma in head and neck cancer.

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.

Nerve-tumour interaction enhances the aggressiveness of oral squamous cell carcinoma.

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.

Pterygomandibular suspension suture: a simple modification of uvulopalatopharyngoplasty for severe obstructive sleep apnea.

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.

Decoy receptor 3 enhances tumor progression via induction of tumor-associated macrophages.

Tumor-associated macrophages (TAMs) are the major component of tumor-infiltrating leukocytes. TAMs are heterogeneous, with distinct phenotypes influenced by the microenvironment surrounding tumor tissues. Decoy receptor 3 (DcR3), a member of the TNFR superfamily, is overexpressed in tumor cells and is capable of modulating host immunity as either a neutralizing decoy receptor or an effector molecule. Upregulation of DcR3 has been observed to correlate with a poor prognosis in various cancers. However, the mechanisms underlying the DcR3-mediated tumor-promoting effect remain unclear. We previously demonstrated that DcR3 modulates macrophage activation toward an M2-like phenotype in vitro and that DcR3 downregulates MHC class II expression in TAMs via epigenetic control. To investigate whether DcR3 promotes tumor growth, CT26-DcR3 stable transfectants were established. Compared with the vector control clone, DcR3-transfectants grew faster and resulted in TAM infiltration. We further generated CD68 promoter-driven DcR3 transgenic (Tg) mice to investigate tumor growth in vivo. Compared with wild-type mice, macrophages isolated from DcR3-Tg mice displayed higher levels of IL-10, IL-1ra, Ym1, and arginase activity, whereas the expression of IL-12, TNF-α, IL-6, NO, and MHC class II was downregulated. Significantly enhanced tumor growth and spreading were observed in DcR3-Tg mice, and the enhanced tumor growth was abolished by arginase inhibitor N-ω-hydroxy-l-norarginine and histone deacetylase inhibitor sodium valproate. These results indicated that induction of TAMs is an important mechanism for DcR3-mediated tumor progression. Our findings also suggest that targeting DcR3 might help in the development of novel treatment strategies for tumors with high DcR3 expression.

Decoy receptor 3 suppresses TLR2-mediated B cell activation by targeting NF-κB.

Decoy receptor 3 (DcR3) is a soluble protein in the TNFR superfamily. Its known ligands include Fas ligand, homologous to lymphotoxin, showing inducible expression, and competing with HSV glycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes, TNF-like molecule 1A, and heparan sulfate proteoglycans. DcR3 has been reported to modulate the functions of T cells, dendritic cells, and macrophages; however, its role in regulating B cell activation is largely unknown. In this study, we found that the DcR3.Fc fusion protein bound to human and mouse B cells and suppressed the activation of B cells. DcR3.Fc attenuated Staphylococcus aureus, IgM-, Pam(3)CSK(4)-, and LPS-mediated B cell proliferation but did not affect cytokine-induced B cell growth. In the presence of these mitogens, DcR3.Fc did not induce B cell apoptosis, suggesting that DcR3 may inhibit the signal(s) important for B cell activation. Because the combination of Fas.Fc, LT-ßR.Fc (homologous to lymphotoxin, showing inducible expression, and competing with HSV glycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes receptor), and DR3.Fc (TNF-like molecule 1A receptor) did not suppress B cell proliferation and because the biological effect of DcR3.Fc on B cells was not blocked by heparin, we hypothesize that a novel ligand(s) of DcR3 mediates its inhibitory activity on B cells. Moreover, we found that TLR2-stimulated NF-κB p65 activation and NF-κB-driven luciferase activity were attenuated by DcR3.Fc. The TLR2-induced cytokine production by B cells was consistently reduced by DcR3. These results imply that DcR3 may regulate B cell activation by suppressing the activation of NF-κB.

Paclitaxel-Ifosfamide-based Therapy as Salvage Treatment in Platinum-resistant Recurrent/Metastatic Head and Neck Cancer.

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.

Hypoxia-induced long non-coding RNA HIF1A­AS2 regulates stability of MHC class I protein in head and neck cancer.

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 non-coding RNA (lncRNA) HIF1A Antisense RNA 2 (HIF1A-AS2) is upregulated in both hypoxic tumor cells and hypoxic tumor-derived exosomes (TEXs) in head and neck squamous cell carcinoma (HNSCC). Hypoxia-inducible factor 1 alpha 1 (HIF-1α) 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 protein (NBR1) 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 HIF-1α 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 lncRNA.

Enhancing regional control in p16-negative oropharyngeal cancer: A propensity score-matched analysis of upfront neck dissection and definitive chemoradiotherapy.

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.

Repression of bone morphogenetic protein 4 by let-7i attenuates mesenchymal migration of head and neck cancer cells.

The movement modes of epithelial cancer cells in three-dimensional (3D) environments include the mesenchymal mode, which is associated with local invasion, and the amoeboid mode, which facilitates distant metastasis. The migratory behavior of individual cancer cells is critical for tumor dissemination; however, the mechanism underlying regulation of the switch between movement modes is not clearly understood. For head and neck squamous cell carcinoma (HNSCC), local invasion is the major route of dissemination. We previously demonstrated that, in HNSCC cells, Twist1 represses let-7i expression to elicit mesenchymal-mode movement through activation of Ras-related C3 botulinum toxin substrate 1 (RAC1). In this study, we discover another important target gene of let-7i for regulating HNSCC migration. Using bioinformatic tools, we identified bone morphogenetic protein 4 (BMP4) as a candidate target of let-7i. Further experiments, including 3'-untranslated region (UTR) reporter assays, quantitative RT-PCR and western blotting, confirmed that BMP4 is a bona fide target repressed by let-7i. In the HNSCC cell line OECM-1, knockdown of BMP4 reduced mesenchymal-mode migration and invasion in 3D culture. In clinical HNSCC samples, let-7i expression was inversely correlated with BMP4 expression. Our results revealed that let-7i attenuates mesenchymal-mode migration of HNSCC cells through repression of a novel target, BMP4.

Perineural invasion as a major determinant for the aggressiveness associated with increased tumor thickness in t1-2 oral tongue and buccal squamous cell carcinoma.

BACKGROUND: Neck management for cN0 neck remains controversial for T1-2 oral tongue and buccal squamous cell carcinoma (SCC). Increased tumor thickness and perineural invasion (PNI) are two pathologic features that correlated with cervical lymph node (LN) metastasis and poor survival. However, the relationships between these two features remain unclear. METHODS: Detailed histologic reevaluation under hematoxylin and eosin staining was performed in tumors of 212 consecutive patients with T1-2, cN0 oral tongue and buccal SCC. The interrelationships between the impacts of tumor thickness and PNI on cervical LN metastasis and disease-specific survival (DSS) were analyzed. RESULTS: Increased tumor thickness (>6 mm) correlated with higher LN metastasis and poor 5-year DSS rates in univariate analysis. However, only PNI independently predicted both in multivariate analysis (P = 0.004 and P = 0.039, respectively). When stratified by PNI status, increased tumor thickness did not correlate with higher LN metastasis rate in either PNI-negative or PNI-positive groups (P = 0.337 and P = 0.730). Compared to patients with thin tumors (≤6 mm), patient with thick tumors revealed significantly higher LN metastasis rate (41.9 vs. 16.4 %, P = 0.001) and lower 5-year DSS rate (77.5 vs. 93.7 %, P = 0.006) only at the presence of PNI. CONCLUSIONS: PNI can be a major determinant for higher LN metastasis and poor 5-year DSS rates associated with increased tumor thickness in T1-2 oral tongue and buccal SCC. Careful evaluation of PNI should be mandatory in routine pathologic examination, aside from the measurement of tumor thickness.

Predisposing factors, management, and prognostic evaluation of acute carotid blowout syndrome.

BACKGROUND: Massive hemorrhages occur in 6%-10% of patients with advanced cancer. Acute carotid blowout syndrome is the most severe massive hemorrhagic complication in head and neck cancer patients. METHODS: This was a single institute, retrospective, case control study. A total of 45 patients were enrolled in this study. The predisposing factors, management, and prognosis of acute carotid blowout syndrome were evaluated. RESULTS: Among the baseline characteristics, the site of the primary tumor (P = .003), origin of bleeding (P = .048), method of intervention (P = .005), and time to intervention (P = .006) were significantly different factors between survivor and nonsurvivor patients. After 24 hours of onset, a Glasgow Coma Scale score (P = .000), the use of inotropic agents (P = .007), and neutrophil-to-lymphocyte ratio (P = .019) were significantly predicting factors for outcome. Multivariate logistic regression analyses revealed bleeding from common carotid artery was an independent factor for long-term survival (odds ratio, 25.951; 95% confidence interval [CI], 1.373-490.441; P < .030). The median overall survival of survivors and nonsurvivors were 12.1 (range, 3.7-118.7; 95% CI, 4.33-54.87) and 11.9 (range, 0.7-53.5; 95% CI, 5.78-25.69) months, respectively (P = .092). CONCLUSIONS: Early and aggressive intervention is important for the successful management of acute carotid blowout syndrome. The Glasgow Coma Scale score, the use of inotropic agents, and neutrophil-to-lymphocyte ratio 24 hours after the onset were predictive factors for patients' outcomes. Bleeding from common carotid artery is an independent prognostic factor in multivariate analysis. Long-term survival can be achieved after successful management.

Serum albumin is an important prognostic factor for carotid blowout syndrome.

OBJECTIVE: Carotid blowout syndrome is a severe complication of head and neck cancer. High mortality and major neurologic morbidity are associated with carotid blowout syndrome with massive bleeding. Prediction of outcomes for carotid blowout syndrome patients is important for clinicians, especially for patients with the risk of massive bleeding. METHODS: Between 1 January 2001 and 31 December 2011, 103 patients with carotid blowout syndrome were enrolled in this study. The patients were divided into groups with and without massive bleeding. Prognostic factors were analysed with proportional hazard (Cox) regressions for carotid blowout syndrome-related prognoses. Survival analyses were based on the time from diagnosis of carotid blowout syndrome to massive bleeding and death. RESULTS: Patients with massive bleeding were more likely to have hypoalbuminemia (albumin <3.5 g/dl; P = 0.023). Univariate analysis of carotid blowout syndrome-related massive bleeding showed that treatment for carotid blowout syndrome (best supportive care, P = 0.000; embolization, P = 0.000), monocytosis (monocytes >1000 cells/µl, P = 0.041) and hypoalbuminemia (P = 0.010) were important to prognosis. Concurrent chemoradiotherapy (P = 0.007), elevated lactate dehydrogenase (>250 U/l; P = 0.050), local recurrence (P = 0.022) and hypoalbuminemia (P = 0.038) were related to poor prognosis in carotid blowout syndrome-related death. In multivariate analysis, best supportive care and hypoalbuminemia were independent factors for both carotid blowout syndrome-related massive bleeding (P = 0.000) and carotid blowout syndrome-related death (P = 0.013), respectively. CONCLUSION: Best supportive care and serum albumin are important prognostic factors in carotid blowout syndrome. It helps clinicians to evaluate and provide better supportive care for these patients.

A 4-Week Straw Phonation in Water Exercise Program for Aging-Related Vocal Fold Atrophy.

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.

Survival analyses of different treatment modalities and clinical stage for hypopharyngeal carcinoma.

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.

Ferroptosis Signature Shapes the Immune Profiles to Enhance the Response to Immune Checkpoint Inhibitors in Head and Neck Cancer.

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.

Treatment for T1-2 oral squamous cell carcinoma with or without perineural invasion: neck dissection and postoperative adjuvant therapy.

BACKGROUND: Although perineural invasion (PNI) has been a poor prognostic factor for head and neck cancers, few studies have focused on oral squamous cell carcinoma (OSCC). The independent significance of PNI in early T1-2 OSCC and the benefit of treatment modification based on PNI status have not been assessed. This study investigated the role of PNI in T1-2 OSCC patients, with focus on the controversial issues of neck management and postoperative adjuvant therapy. METHODS: PNI status was re-reviewed under hematoxylin and eosin staining in tumors of 307 consecutive T1-2 OSCC patients. Oncologic and survival outcomes were analyzed by univariate and multivariate analyses. RESULTS: PNI was identified in 84 (27.4%) patients, correlating with several established poor prognostic factors. In multivariate analysis, PNI remained an independent predictor for neck metastasis, neck recurrence, and a worse 5-year disease-specific survival. Elective neck dissection contributed to a significantly better 5-year disease-specific survival only in cN0 patients with PNI-positive tumors (P = 0.0071) but not in those with PNI-negative tumors (P = 0.3566). In low-risk patients who were treated by surgery alone, including neck dissection, the 5-year disease-specific survival rates were almost the same in those with PNI-positive tumors and those with PNI-negative tumors (92.0 vs. 92.9%; P = 0.9104). CONCLUSIONS: Elective neck dissection is indicated for cN0 patients with PNI-positive tumors for the efficacy of improving disease-specific survival as well as neck control. However, low-risk PNI-positive patients who undergo neck dissection do not need postoperative adjuvant therapy, because the residual risk from PNI is minimal.