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Hypoxic resistance is the main obstacle to radiotherapy for laryngeal carcinoma. Our previous study indicated that hypoxia-inducible factor 1α (HIF-1α) and glucose transporter 1 (Glut-1) double knockout reduced tumour biological behaviour in laryngeal carcinoma cells. However, their radioresistance mechanism remains unclear. In this study, cell viability was determined by CCK8 assay. Glucose uptake capability was evaluated by measurement of

To explore the Fibroblast-epithelial metabolic coupling among laryngeal cancers and its prognostic roles METHODS: We reviewed the clinical information of patients with laryngeal cancer in our department. Paraffin-embedded tissues from included patients were immune-stained with antibodies towards MCT4 and TOMM20 and evaluated for stromal and epithelial expression. Survival analysis and Cox regression analysis were applied to investigate the prognostic factor of laryngeal squamous cell carcinoma. TCGA database was used to validate our result.Stromal MCT4 and TOMM20 were both significantly associated with each other among laryngeal cancer tissues. High expression of both Stromal MCT4 and TOMM20 is related to poor prognosis in laryngeal cancer. Stromal MCT4 expression was an independent prognostic indicator for laryngeal cancer. Furthermore, cancer cell MCT4 expression has no relationship with the clinical characteristics of laryngeal cancer.Our results support that the phenomenon of metabolic symbiosis was exist in the laryngeal cancer tissue. In addition, TOMM20 and stromal MCT4 could be used as new therapeutic targets for laryngeal cancer.

Thyroglossal duct cysts (TDCs) are generally single cyst, multiple TDCs are rare. We describe a case of multiple TDCs, discuss its characteristic features and management, and provide a review of the literature, to improve clinical diagnosis and treatment. We report an extremely rare case of multiple TDCs containing five cysts, together with a review of the relevant English medical literature. To the best of our knowledge, this is the first reported case of TDCs containing more than three cysts in the anterior cervical region. The five cysts were completely excised in a Sistrunk operation. Histological examination of the cystic lesions revealed TDCs. The patient recovered well and no recurrence was found during the 6-year of follow-up. Multiple TDCs are extremely rare, and may be misdiagnosed as a single cyst. Clinicians should be aware of the possibility of multiple thyroglossal duct cysts. Adequate preoperative radiological examinations should be performed, and careful interpretation of the CT or MRI scans is important to diagnosis and surgery.

Purpose The presence of extra-gastric H+/K+ ATPases may explain the clinically significant effect of proton pump inhibitor (PPI) pharmacotherapy in patients with chronic laryngitis related to laryngopharyngeal reflux disease (LPRD) but without gastroesophageal reflux disease (GERD) symptoms. Given the need for a better understanding of GERD and LPRD, we review the various proton pumps with respect to their classification, function, and distribution. We then consider the potential role of the laryngeal H+/K+ ATPase pump in LPRD. Methods We searched databases of PubMed, EMBASE, and Web of Science to achieve related published before September 15, 2020. Results There were only seven English-literatures meeting inclusive criteria about laryngeal H+/K+ ATPases. Some studies provide convincing evidence of a laryngeal H+/K+ ATPase in normal laryngeal tissues but also suggest the potential role of the proton pump in the abnormal mucus secretion frequently seen in patients with chronic laryngitis. Conclusion A laryngeal H+/K+ ATPase expresses in normal laryngeal tissues. These findings question the current understanding of GERD and LPRD.

Background Several studies have suggested that laryngopharyngeal reflux disease (LPRD) or gastroesophageal reflux disease (GERD) is an independent risk factor for laryngeal carcinoma. However, it remains unclear whether either condition affects the level of H+/K+-ATPase expression in laryngeal carcinoma. Materials and Methods Immunohistochemistry, real-time RT-PCR, and Western blotting were used to explore the distributions of proton pump (H+/K+-ATPase) α- and β-subunits in normal laryngeal tissue and laryngeal carcinoma. Results Messenger RNAs encoding both the α- and β-subunits were found in the normal epiglottic, ventricular fold, vocal fold, and arytenoid mucosae, as well as epiglottic cartilage. The distributions and expression levels of H+/K+-ATPase α-subunits in various laryngeal subregions did not significantly differ in IHC, RT-PCR, or Western blotting. However, Western blotting revealed a significant difference between the expression level of the β-subunit protein in the epiglottic cartilage and the levels in other sites. The expression levels of both subunits were significantly higher in carcinomatous than in paracarcinomatous tissue and normal laryngeal tissue. The mean follow-up duration was 66.2 months (range, 17–162 months). In all, 4 patients died during follow-up, 4 were lost to follow-up, and 22 were alive and free of disease at the end of follow-up. Two patients developed lung metastases and six developed disease recurrences (at 2, 8, 14, 16, 36, and 41 months). The 3- and 5-year overall survival (OS) rates were 93.0% and 77.0%, respectively. Univariate analyses showed that the 5-year OSs were significantly associated with the T, N, and clinical stages but not with age, alcohol use, pathological differentiation, or the expression levels of the α- or β-subunits (as revealed by IHC, RT-PCR, or Western blotting). However, in multivariate regression analyses, the 5-year OSs were not significantly associated with any clinicopathological factor or the expression levels of either subunit. Conclusion H+/K+-ATPase is expressed in the normal larynx, including in the epiglottic cartilage and the mucosae of the epiglottis, ventricular fold, and arytenoid vocal fold. The expression levels of the H+/K+-ATPase α- and β-subunits in laryngeal carcinomas were higher than in normal laryngeal tissues.

We describe a case of laryngeal angioleiomyoma, discuss its characteristic features and management, and provide a review of the literature, to improve clinical diagnosis and treatment. We report the oldest patient with a laryngeal angioleiomyoma to date and analyze the clinicopathological features reported in the literature. To the best of our knowledge, a total of 36 cases have been described in the English and Chinese medical literature (including our case). The male-to-female ratio was 5:1 and the mean age was 53.89 years. The most common laryngeal site was the supraglottic region (23 cases; 63.89%), followed by the subglottic region (8 cases; 22.22%), and glottis (5 cases; 13.89%). The most common and serious intra- and postoperative complication was massive bleeding. Angioleiomyoma is a benign tumor that rarely occurs in the larynx. Biopsy of this lesion should not be performed; complete surgical resection is the best treatment. Recurrence and malignant transformation are extremely rare.

Bao YY, Jiang Q, Li ZW, et al. Onco Targets Ther. 2020;13:12919–12931. Page 12920, Materials and Methods, Specimens section, second paragraph, lines 3 and 8, the text “60 paracarcinoma tissue samples” should read “57 paracarcinoma tissue samples” and “30 and 60 specimens” should read “30 and 20 specimens”, respectively. Page 12921, Table 1, Paracarcinoma Tissues from 20 of 30 Patients column, the value “60” should read “57” and the values for RT-PCR and WB are incorrect. The correct Table 1 is shown in Download Article. Additionally, the authors have advised due to an error that occurred inadvertently at the time of figure assembly, Figure 3 on page 12925 is incorrect. The correct Figure 3 is shown in Download Article. The authors apologize for these errors and advise they do not affect the conclusion of the article. Read the original article

Purpose We investigated the role of Glut-1 and H+/K+-ATPase expression in pepsin-induced development of human vocal cord leukoplakia cells (HVCLCs). Next, we analyzed the relationship between Glut-1 and H+/K+-ATPase expression with the clinicopathological features of laryngeal carcinoma. Methods Glut-1 and H+/K+-ATPase expression levels in HVCLCs were determined after treatment with artificial gastric juice containing pepsin and laryngeal carcinoma tissues. Results Exposure to pepsin-containing artificial gastric juice significantly enhanced the migration and proliferation of VSCLCs in a time-dependent manner. The apoptotic rate of VSCLCs decreased over time after exposure to pepsin and reached a nadir on day 7 (p p +/K+-ATPase α, β significantly increased in HVCLCs compared to in the absence of pepsin (p +/K+-ATPase α, β gradually increased from vocal cord leukoplakia (VLC) to laryngeal carcinoma (p p p p Conclusions Elevated Glut-1 expression may promote the development of VCL by upregulating laryngeal H+/K+-ATPase expression to reactivate absorbed pepsin, thus damaging the laryngeal mucosa.

Jiang-Tao Zhong,1 Qi Yu,1 Shui-Hong Zhou,1 Er Yu,1 Yang-Yang Bao,1 Zhong-Jie Lu,2 Jun Fan3 1Department of Otolaryngology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, People’s Republic of China; 2Department of Radiotherapy, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, People’s Republic of China; 3State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, People’s Republic of ChinaCorrespondence: Shui-Hong ZhouDepartment of Otolaryngology, The First Affiliated Hospital, College of Medicine, Zhejiang University, 310003, People’s Republic of ChinaTel +86-571-87236894Fax +86-571-87236895Email 1190051@zju.edu.cnBackground: Radiotherapy does not show good efficacy against laryngeal cancer due to radioresistance. Cancer stem cells (CSCs) are considered among the causes of radioresistance. Inhibition of glucose transporter-1 (GLUT-1) using GLUT-1 small interfering RNA (siRNA) may enhance the radiosensitivity of laryngeal cancer cells, but the underlying cellular mechanisms remain unclear.Methods: The CD133+-Hep-2R cell line was established with repeated irradiation and magnetic-activated cell sorting. The effects of irradiation on CD133+-Hep-2R cells were examined by CCK-8 assay, Transwell assay, quantitative real-time polymerase chain reaction (RT-PCR), and Western blotting. The effects of GLUT-1 siRNA on the radiosensitivity of CD133+-Hep-2/2R cells were examined by RT-PCR, Western blotting, CCK-8 assay, colony formation assay, and Transwell assay in vitro and in a xenograft tumor model in nude mice. The cellular mechanism of enhanced radiosensitivity associated with GLUT-1 siRNA was investigated. The cell cycle and apoptosis rate were analyzed by flow cytometry, and the repair capability was examined by determining the levels of RAD51 and DNA-PKcs.Results: CD133+-Hep-2/2R cells showed stronger proliferation, lower apoptosis rate, lower percentage of G0/G1 phase cells, higher percentages of S and G2/M phase cells, and higher expression levels of GLUT-1 than Hep-2/2R cells. Transfection with GLUT-1 siRNA inhibited the proliferation and invasive capability of CD133+-Hep-2R cells by inhibiting GLUT-1 expression, which also caused a redistribution of the cell cycle (higher proportion of cells in the G0/G1 phase and lower proportion in the S and G2/M phases), increased the apoptosis rate, and reduced DNA repair capability by suppressing RAD51 and DNA-PKcs expression.Conclusion: The results of this study suggest that GLUT-1 siRNA can enhance the radiosensitivity of CD133+-Hep-2R cells by inducing a redistribution of cell cycle phases, inhibiting DNA repair capability, and increasing apoptosis. Inhibition of GLUT-1 may have therapeutic potential for interventions to increase the radiosensitivity of laryngeal CSCs.Keywords: glucose transporter-1, small interfering RNA, laryngeal cancer stem cells, radioresistance, DNA double-strand break

Background Glucose transporter (GLUT)-mediated glucose uptake is an important process in the development of laryngeal carcinoma, one of the most common malignancies of the head and neck. GLUT-1, together with HIF-1α, is also an indicator of hypoxia. Both proteins play a critical role in glucose uptake and glycolysis in laryngeal carcinoma cells under hypoxic stress. A double gene knockout model in which HIF-1α and GLUT-1 are no longer expressed can provide important information about carcinogenesis in laryngeal carcinoma. Purpose In this study we used the CRISPR/Cas 9 system to induce HIF-1α and GLUT-1 double gene knockout in HEp-2 cells and then used the knocked-out cells to study the role of these markers in laryngeal carcinoma, including in chemoradioresistance. Methods High-grade small-guide RNAs (sgRNAs) of HIF-1α and GLUT-1 were designed using an online tool and inserted into the pUC57-T7-gRNA vector. The recombinant plasmids were transfected into HEp-2 cells and positive cells were screened using the dilution method. Gene mutation and expression were determined by sequence analysis and immunoblotting. Results In HIF-1α and GLUT-1 double gene knockout HEp-2 cells, a 171-bp deletion in the HIF-1α genomic sequence was detected, whereas multiple base insertions resulted in frameshift mutations in the GLUT-1 gene. Neither HIF-1α nor GLUT-1 protein was expressed in positive cells. The proliferation, migration, and invasion of HEp-2 cells were significantly decreased afterward. The possible mechanism may be that the inhibition PI3K/AKT/mTOR pathway by HIF-1α and GLUT-1 double gene knockout using CRISPR/Cas9 technique lead to reduction of glucose uptake and lactic acid generation. Conclusion Our HIF-1α and GLUT-1 double gene knockout HEp-2 cell model, obtained using a CRISPR/Cas9-based system, may facilitate studies of the pathogenesis of laryngeal carcinoma.

BACKGROUND Collision carcinoma is rare in clinical practice, especially in the head and neck region. In this paper, we report a case of squamous cell carcinoma (SCC) and neuroendocrine carcinoma (NEC) colliding in the larynx and review 12 cases of collision carcinoma in the head and neck to further understand collision carcinoma, including its definition, diagnosis, and treatment. CASE SUMMARY A 61-year-old man presented with a 1-year history of hoarseness. Contrast-enhanced magnetic resonance imaging of the larynx revealed that the right vocal cord had a nodule-like thickening with obvious enhancement. Laryngoscopy revealed a neoplasm on the right vocal cord, and a malignant tumor was initially considered. A frozen section of right vocal cord was performed under general anesthesia. The pathological result showed a malignant tumor in the right vocal cord. The tumor was excised with a CO2 laser (Vc type). Routine postoperative pathology showed moderately differentiated SCC with small cell NEC in the right vocal cord. No metastatic lymph nodes or distant metastases were found on postoperative positron emission tomography/computed tomography. Because of the coexistence of SCC and NEC, the patient received adjuvant chemotherapy and radiotherapy. The patient was followed for 8 mo, and no recurrence or distant metastasis was found. CONCLUSION The treatment of collision carcinoma in the head and neck region is uncertain due to the small number of cases.

Ingested foreign bodies occasionally migrate to the paraglottic space. The external transcervical approach is almost always required to extract completely embedded foreign bodies. We report a case of an ingested fishbone embedded in the paraglottic space, which was successfully removed through transcervical exploration of the paraglottic space via the posterolateral approach. The posterolateral approach is safe and effective for the removal of foreign bodies completely embedded in the paraglottic space.

A thyroglossal duct cyst is the most common congenital disease in the neck. There are two age groups usually associated with thyroglossal duct cysts: 1–11 years in children and 30–60 years in adults. These midline neck masses are typically located anteriorly in the neck, inferior to the hyoid bone. We report an extremely rare case of an intralaryngeal thyroglossal duct cyst without a neck mass, presenting with hoarseness as the sole symptom. A 64-year-old man presented with a 3-month history of hoarseness. On physical examination, no neck mass or swelling was observed during cervical palpation. Laryngostroboscopy revealed a large submucosal mass in the right glottis and supraglottis, and mobility of the right vocal cord was restricted. Surgery was performed via an external approach to completely resect the cyst, together with the middle part of the hyoid bone. Histopathologic examination of the cyst led to a diagnosis of thyroglossal duct cyst. The patient recovered well and his voice returned to normal. Attention should be paid to the occurrence of rare types of thyroglossal duct cyst in unusual clinical sites. Adequate radiological examinations should be performed, and reading the computed tomography or magnetic resonance imaging scans carefully before surgery is important to avoid misdiagnosis.

In this study, we investigated the ability of curcumin alone or in combination with GLUT1 siRNA to radiosensitize laryngeal carcinoma (LC) through the induction of autophagy. Protein levels in tumour tissues and LC cells were measured by immunohistochemistry and Western blotting. In vitro, cell proliferation, colony formation assays, cell death and autophagy were detected. A nude mouse xenograft model was established through the injection of Tu212 cells. We found that GLUT1 was highly expressed and negatively associated with autophagy-related proteins in LC and that curcumin suppressed radiation-mediated GLUT1 overexpression in Tu212 cells. Treatment with curcumin, GLUT1 siRNA, or the combination of the two promoted autophagy. Inhibition of autophagy using 6-amino-3-methypourine (3-MA) promoted apoptosis after irradiation or treatment of cells with curcumin and GLUT1 siRNA. 3-MA inhibited curcumin and GLUT1 siRNA-mediated non-apoptotic programmed cell death. The combination of curcumin, GLUT1 siRNA and 3-MA provided the strongest sensitization in vivo. We also found that autophagy induction after curcumin or GLUT1 siRNA treatment implicated in the AMP-activated protein kinase-mTOR-serine/threonine-protein kinase-Beclin1 signalling pathway. Irradiation primarily caused apoptosis, and when combined with curcumin and GLUT1 siRNA treatment, the increased radiosensitivity of LC occurred through the concurrent induction of apoptosis and autophagy.

Background: Although laryngopharyngeal reflux (LPR) has been implicated in various upper aerodigestive tract and laryngeal diseases, the underlying mechanisms remain elusive. In this study, we investigated the role of gastric acidified pepsin in laryngeal precancerosis. Methods: The in vitro and in vivo effects of acidified pepsin on H+/K+-ATPase expression and autophagy/mitophagy induction in mouse laryngeal epithelial cells were assessed by hematoxylin and eosin staining, immunohistochemistry, CCK-8 assay, flow cytometry, Western blotting, and quantitative real-time PCR. Additionally, the levels of pepsin and H+/K+-ATPase α and β subunits in 31 human laryngeal mucosal specimens were assessed by immunohistochemical staining. Results: Acidified pepsin (pH=3) enhanced the growth and survival of mouse laryngeal epithelial cells in vitro and promoted laryngeal mucosal thickening and laryngeal epithelial cell growth in vivo. Furthermore, acidified pepsin promoted autophagy/mitophagy induction, accompanied by a significant decrease in mitochondrial membrane potential (MMP). Inhibition of autophagy by chloroquine abolished the ability of acidified pepsin to promote mitophagy and cell growth in laryngeal epithelial cells. Additionally, chloroquine promoted cell apoptosis and further reduced MMP in laryngeal epithelial cells treated with acidified pepsin. The expression levels of pepsin and H+/K+-ATPase α and β subunits in 31 human laryngeal mucosa specimens were 51.6%, 48.4%, and 48.4%, respectively. Importantly, the pepsin level was correlated with the H+/K+-ATPase β subunit level. H+/K+-ATPase upregulation in laryngeal epithelial cells in response to acidified pepsin was essential for the mitophagy-promoting effect of acidified pepsin. H+/K+-ATPase knockout or inhibition further reduced MMP in the presence of acidified pepsin. Conclusions: Our findings suggest that in an acidic environment, pepsin promotes laryngeal epithelial cell growth and survival by upregulating H+/K+-ATPase and activating mitophagy, potentially leading to laryngeal precancerosis.

To measure pepsin expression in patients with vocal fold leukoplakia and elucidate its clinical significance.Retrospective analysis of pathologic archive specimens.Affiliated university hospital.The study included 45 patients with vocal fold leukoplakia and 19 with vocal fold polyps who underwent surgical treatment between December 2013 and July 2016. Masses were detected on both vocal cords in 5 patients with vocal fold leukoplakia and in 1 patient with vocal fold polyps. Immunohistochemistry was used to assess pepsin expression. In addition, the relationship of pepsin expression level with clinical characteristics of vocal fold leukoplakia was assessed.The rate of pepsin expression was high in the polyp group (75%) and the leukoplakia group (68%); however, the difference between groups was not significant (Our study suggests that pepsin was associated with the grade of dysplasia of vocal cord leukoplakia. Further investigation with appropriate control groups and controlling for other risk factors, such as smoking or alcohol consumption, is needed.

ObjectiveGlut-1 is a key regulator in the process of glucose uptake. Previous studies have shown that Glut-1 affects autophagy. However, it is unclear whether there is a correlation between Glut-1 and autophagy in the progression of laryngeal carcinoma. This study was performed to investigate the role of Glut-1 in the development of laryngeal carcinoma.MethodsA stable HEp-2 cell model was constructed by Glut-1 and Beclin-1 shRNA lentiviral infection. The autophagosome was measured by transmission electron microscopy. Protein levels of LC3, ATG5, CyclinD1, Bcl-2, Caspase-3, and c-Myc were determined by Western blotting. CCK8 assay and Transwell assays were used to determine cell viability and migration rate of HEp-2 cells, respectively. Flow cytometry was performed to analyze the rate of apoptosis. Immunofluorescence was performed to determine the expression distribution of LC3.ResultsGlut-1 knockdown significantly promoted autophagosome formation by upregulating the ratio of LC3-II/LC3-I as well as the role of rapamycin (RAP) and Beclin-1 overexpression on autophagy flux in HEp-2 cells. Glut-1 inhibition also reduced the viability of HEp-2 cells followed by the decreases in expression of cyclinD1 and c-Myc. In addition, Glut-1 depletion increased the number of apoptotic HEp-2 cells accompanied by activation of caspase-3 and downregulation of Bcl-2. Glut-1 knockdown also reduced the migration rate of HEp-2 cells by promoting the expression of N-cadherin and inhibiting the expression of E-cadherin. Beclin-1 consumption significantly reversed Gult-1 knockdown-mediated autophagy activation, resulting in promotion of both proliferation and migration and inhibition of apoptosis.ConclusionsGlut-1 knockdown-induced autophagy inhibits the proliferation and migration of HEp-2 cells, and promotes apoptosis of HEp-2 cells partly by regulating autophagy.

ObjectiveCarcinosarcoma consists of carcinomatous and sarcomatous tissues and is an aggressive malignant tumor. It is rarely reported in the hypopharynx.MethodsA 72-year-old man presented with dysphagia and dyspnea. Laryngoscopy, computed tomography (CT), and18F-fluorodeoxyglucose positron emission tomography/CT (18F-FDG PET/CT) showed a neoplasm on the left posterior hypopharyngeal wall. The patient underwent bilateral neck dissection and excision of the hypopharyngeal cancer followed by postoperative radiation therapy.ResultsImmunohistochemistry revealed carcinomatous cells with membrane positivity for cytokeratin, glucose transporter-1 (GLUT-1), phosphoinositide-3 kinase (PI3K), hypoxia-inducible factor-1α (HIF-1α), and hexokinase-II as well as sarcomatous cells with membrane positivity for smooth muscle actin, GLUT-1, HIF-1α, and PI3K. Histopathology and immunohistochemistry revealed a true carcinosarcoma of the hypopharynx (pT3N0M0, Stage III).ConclusionsThorough immunohistochemistry is required for a correct diagnosis of hypopharyngeal carcinosarcoma.18F-FDG PET/CT may help to distinguish hypopharyngeal carcinosarcoma from benign tumors.

Objective The treatment of laryngotracheal stenosis is a major therapeutic challenge. Various treatments include observation, medical management, and surgical management. The most effective surgical management is resection and reconstruction. To the authors’ knowledge, no reports have described the use of xenogenic acellular dermal matrix (ADM) for laryngotracheal stenosis. Methods A 27-year-old man presented with hemoptysis of the neck due to a traffic accident. Emergency orotracheal intubation was performed. Tracheostomy was then performed under local anesthesia. Computed tomography revealed fractures of the right thyroid cartilage and posterior arc of the cricoid cartilage and stenosis of the subglottis and first and second tracheal rings. We used a composite hyoid–sternohyoid osseomuscular flap with xenogenic ADM and a straight silicone tube as a lumen stent to reconstruct the laryngotracheal stenosis. Results Surgical recovery was uneventful. The tracheotomy opening was changed to a metal tube 5 days postoperatively. Four months postoperatively, the silicone tube was endoscopically removed under local anesthesia. The patient was decannulated 20 days later. The patient satisfied with his voice, respiration, and deglutition at the 16-month postoperative follow-up. Conclusion The use of ADM for laryngotracheal stenosis may reduce the growth of granulation tissues and promote the repair process.

Background This study is to explore the role of curcumin and GLUT-1 antisense oligodeoxynucleotides (AS-ODN) on autophagy modulation-initiated radiosensitivity. Methods BALB/c mice were employed to establish xenograft model using Tu212 cell. The expression of autophagy- and apoptosis-related proteins was determined by WB. Autophagosome was observed under transmission electron microscope. Apoptosis of tumor tissue were detected by TUNEL staining. Results Combinations of curcumin and GLUT-1 AS-ODN with 10 Gy inhibited the tumor growth by inducing apoptosis of laryngeal cancer cells followed with the enhancement of autophagy. 3-MA also had a promotion effect on irradiation-mediated growth inhibition possibly by depressing PI3K and on curcumin/GLUT-1 AS-ODN-mediated growth inhibition potentially by regulating autophagic events. Of note, a de-escalation of radiotherapy dose (5 Gy) along with curcumin, GLUT-1 AS-ODN or 3-MA produced a stronger effect than high dosage of radiotherapy (10 Gy) alone. Conclusions Curcumin and GLUT-1 AS-ODN improve the radiosensitivity of laryngeal carcinoma through regulating autophagy and inducing apoptosis.

Background Glucose transporter (GLUT)-mediated glucose uptake is an important process in the development of laryngeal carcinoma, one of the most common malignancies of the head and neck. GLUT-1, together with HIF-1α, is also an indicator of hypoxia. Both proteins play a critical role in glucose uptake and glycolysis in laryngeal carcinoma cells under hypoxic stress. A double gene knockout model in which HIF-1α and GLUT-1 are no longer expressed can provide important information about carcinogenesis in laryngeal carcinoma. Purpose In this study we used the CRISPR/Cas 9 system to induce HIF-1α and GLUT-1 double gene knockout in HEp-2 cells and then used the knocked-out cells to study the role of these markers in laryngeal carcinoma, including in chemoradioresistance. Methods High-grade small-guide RNAs (sgRNAs) of HIF-1α and GLUT-1 were designed using an online tool and inserted into the pUC57-T7-gRNA vector. The recombinant plasmids were transfected into HEp-2 cells and positive cells were screened using the dilution method. Gene mutation and expression were determined by sequence analysis and immunoblotting. Results In HIF-1α and GLUT-1 double gene knockout HEp-2 cells, a 171-bp deletion in the HIF-1α genomic sequence was detected, whereas multiple base insertions resulted in frameshift mutations in the GLUT-1 gene. Neither HIF-1α nor GLUT-1 protein was expressed in positive cells. The proliferation, migration, and invasion of HEp-2 cells were significantly decreased afterward. The possible mechanism may be that the inhibition PI3K/AKT/mTOR pathway by HIF-1α and GLUT-1 double gene knockout using CRISPR/Cas9 technique lead to reduction of glucose uptake and lactic acid generation. Conclusion Our HIF-1α and GLUT-1 double gene knockout HEp-2 cell model, obtained using a CRISPR/Cas9-based system, may facilitate studies of the pathogenesis of laryngeal carcinoma.

Objective Magnetic resonance imaging (MRI) provides important information regarding tumors in the parapharyngeal space (PPS), revealing their origin, whether they are benign or malignant, and their relationships with surrounding structures. Methods Twelve tumors in the PPS were completely excised using an endoscopically assisted transoral approach (EATA). The MRI features were analyzed. Results Ten pleomorphic adenomas confirmed on postoperative pathological examination had the parotid pedicle sign. A fat space between the tumor and parotid gland may distinguish such a tumor from a tumor arising from a minor salivary gland in the prestyloid space and a tumor arising from the deep lobe of the parotid gland. Both the jugular vein and carotid artery were displaced posteriorly in all 10 cases of pleomorphic adenomas. The principal features of the two schwannomas confirmed on postoperative pathological examination were separation of the internal carotid artery and internal jugular vein and anteromedial displacement of the internal carotid artery, suggesting that the tumors originated in the poststyloid space. In this review, 95 tumors were excised by the EATA in the English-language literature. Conclusions MRI renders differential diagnosis possible. PPS tumors may be completely excised via an EATA guided by tumor features evident on preoperative MRI.

Rationale: Basal cell adenoma (BCA) is a rare benign salivary gland tumor. It is difficult to be completely resected when arising in parapharyngeal space. A contemporary trend is to develop minimally invasive approaches on the premises of safety and complete resection. Patient concerns: Three patients were referred to our ENT Outpatient Department with the chief complaint of an uncomfortable throat. CT or MRI revealed a unilateral mass in the parapharyngeal space, round or oval in shape, with well-defined borders. Diagnoses: CT and MRI provided useful information for the preoperative evaluation. The appearance of large-scale cystic components may be an important clue for the diagnosis of BCA. PET/CT images were also available in one case. The final diagnoses were all basal cell adenomas (tubular type) in parapharyngeal space according to the regular histopathological examination after surgery. Interventions: All three cases were completely resected by a trans-oral approach. The average operative time and estimated blood loss were 86 (range, 61–106) min and 116.7 (range, 50–200) mL, respectively. Endoscopy was used in the largest case to further assess the residual cavity after the complete resection and hemostasis. Outcomes: Postoperative recovery courses were quick and uneventful, with no neurovascular complication. Patients were discharged on the 3rd–5th day after surgery on an oral diet. One patient reported symptoms of velopharyngeal incompetence, manifested as mild slurred speech and nighttime salivation, for up to 3 months, which recovered spontaneously thereafter. There was no evidence of recurrence in the follow-up period. Lessons: In our experience, the trans-oral approach appeared to be effective, safe, and less invasive for extirpation of selected basal cell adenomas in the parapharyngeal space. An assistance of endoscopy facilitates the surgery.

The aim of the present study was to assess the role of diffusion-weighted magnetic resonance imaging (DWI) and apparent diffusion coefficient (ADC) values in hypopharyngeal carcinoma. A total of 40 hypopharyngeal carcinoma tissues and 15 benign lesion tissues were retrospectively analyzed. DWI, and T1- and T2-weighted magnetic resonance imaging (MRI) was performed. The sensitivity, specificity and accuracy of conventional MRI were 97.5, 66.7, and 89.1%, respectively. The mean ADC value [diffusion sensitive factor (b)=1,000× sec/mm2) for hypopharyngeal carcinomas was (1.0285±0.0328)×10−3 mm2/sec, which was significantly lower than the mean ADC value for benign lesions [(1.5333±0.1061)×10−3 mm2/sec; P(1.0285±0.0328)×10−3 mm2/sec]. The 2-year survival rates of the two groups were 55.6 and 100.0%, respectively (P=0.024). ADC values may aid in distinguishing hypopharyngeal carcinomas from benign lesions and differentiating metastatic lymph nodes of hypopharyngeal squamous cell carcinomas from reactive cervical lymph nodes. In conclusion, mean ADC values may be useful prognostic factors in univariate analysis of hypopharyngeal carcinoma.

Apigenin is a natural phyto-oestrogen flavonoid, which exerts various biological effects, including anti‑oxidative, anti‑inflammatory and anticancer activities. In addition, apigenin has recently been reported to target hypoxic markers; however, there are currently no studies regarding the association between apigenin and glucose transporter‑1 (GLUT‑1) in adenoid cystic carcinoma (ACC). The present study investigated whether apigenin inhibits the proliferation of ACC cells or suppresses the expression of GLUT‑1 in ACC cells. The results of the present study demonstrated that apigenin inhibits ACC‑2 cell growth in a dose‑ and time‑dependent manner. Treatment with apigenin also induced apoptosis and G2/M‑phase arrest in a dose‑ and time‑dependent manner. Corresponding with the above results, the expression levels of GLUT‑1 were significantly decreased following treatment in a dose- and time-dependent manner. These results suggest that the inhibition of ACC-2 cell growth by apigenin may be due to the decreased expression of GLUT-1.

The current study presents a case of extranodal follicular dendritic cell sarcoma (FDCS) of the tonsil and reviews the relevant literature. In the present case, a 59-year-old male presented with a globus sensation in the right pharynx for 6 weeks. On clinical examination, a painless non-ulcerated enlarged right tonsil was identified; the tonsil was covered with a normal mucus membrane. A right tonsillectomy was performed under general anesthesia. The final pathological diagnosis was follicular dendritic cell sarcoma of the right tonsil. Postoperatively, the patient received radiotherapy. The patient remains alive without disease recurrence or metastasis 44 months after tonsillectomy. To the best of our knowledge, only 42 cases of FDCS of the tonsil have been reported to date. Of the 42 cases, 41 patients underwent surgery and one patient refused treatment. A total of 23 (54.7%) received surgery alone. Adjuvant treatment was administered for 18 patients (42.9%). Six patients (14.3%) experienced local recurrences and two patients (4.8%) succumbed to the disease 24 months after treatment. The three-, five-, and eight-year overall survival rates for the entire group were 86.5, 77.8 and 77.8%, respectively. Furthermore, a tumor diameter of ≥4 cm was prognostic upon univariate analysis (χ2=4.634; P=0.031; excluding incomplete data). Tonsillar FDCS is rare and is associated with high rates of recurrence and metastasis, therefore, adjuvant treatment should be prescribed.

A 67-year-old male presented with a metastatic carcinoma in the right side of the neck from an unknown primary site. 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography showed increased 18F-FDG uptake in the right larynx and right neck lymph nodes. A smooth lesion was identified in the submucosa of the right supraglottic region via a suspension laryngoscopy under general anaesthesia. A biopsy was performed and a frozen section revealed a small-cell (SC) carcinoma. A total laryngectomy and bilateral neck dissection were performed simultaneously, and the pathological results demonstrated a SC neuroendocrine carcinoma. The patient received chemo-radiotherapy postoperatively, however, succumbed due to distant metastasis one year following surgery.

High fluorodeoxyglucose (FDG) uptake by human carcinomas, including head and neck cancers, is associated with a poor prognosis. Glucose transporter-1 (Glut-1) is believed to be an intrinsic marker of hypoxia in malignant tumors. The expression of hypoxia-inducible factor-1α (HIF-1α) and correlated target genes, including Glut-1, is regulated by the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway. However, it remains unclear whether the PI3K/Akt signaling pathway is involved in regulating FDG uptake directly. In the present study, 24 consecutive patients with laryngeal carcinoma were examined pre-operatively and the standardized uptake values (SUV) of the laryngeal carcinomas were determined. Glut-1, HIF-1α, PI3K and phosphorylated-Akt (p-Akt) expression was detected by immunohistochemical staining of paraffin sections from the tumor specimens. Associations among SUVmax, Glut-1, HIF-1α, PI3K and p-Akt protein expression and the other clinical parameters were analyzed. The univariate analyses revealed a significantly shorter survival time along with higher HIF-1α (P=0.018) and PI3K (P=0.008) expression, but the survival time was not significantly correlated with Glut-1 or p-Akt expression. The multivariate analysis demonstrated that higher SUVmax (P=0.043) and PI3K expression (P=0.012) were significantly correlated with a poor survival time. Spearman’s rank analysis showed significant correlations between SUVmax and HIF-1α (r=0.577; P=0.003), PI3K (r=1.0; P

Metastasis from a malignant tumor to the palatine tonsils is rare, accounting for only 0.8% of all tonsillar tumors, with only 100 cases reported in the English-language literature. Various malignant lung carcinomas may metastasize to the tonsils. A few cases of tonsillar metastasis from neuroendocrine lung carcinoma have been reported. A 67-year-old female underwent a right tonsillectomy because of a sore throat and an enlarged right tonsil. The postoperative pathology showed right tonsillar small cell neuroendocrine carcinoma (SCNC). Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) demonstrated metabolic activity in the lower lobe of the right lung. In addition, hypermetabolic foci were noted in the lymph nodes of the right neck and mediastinum. A needle biopsy of the pulmonary mass showed SCNC. The patient received chemotherapy and died of multiple distant metastases after 6 months. This is the first report using PET/CT to evaluate tonsillar metastasis from lung SCNC.

Background. Synovial sarcoma is common in the extremities. Our search revealed only 17 cases of synovial sarcoma of the larynx in the English-language literature. Case report. We report an additional case of a 37-year-old man with primary laryngeal synovial sarcoma who underwent positron emission tomography/computed tomography (PET/CT) following the treatment. Although the patient received comprehensive therapy including surgery, radiotherapy, repeated chemotherapies, and targeted therapies, he had an unfavourable outcome and died of distant metastases. Conclusions. In synovial sarcoma of the larynx, PET/CT can detect recurrence and metastasis. PET/CT can also predict the treatment effect in patients with synovial sarcoma.

Objective To investigate the expression of interleukin (IL) 17A in Chinese patients with chronic rhinosinusitis (CRS) and analyse its correlation with clinical parameters. Methods Patients undergoing functional endoscopic sinus surgery and matched controls were included in this retrospective study. Clinical assessments (using a visual analogue scale of symptom severity, Johansson endoscopic score and Lund–Mackay computed tomography score) were performed preoperatively. Mucosal specimens were analysed for inflammatory infiltration and IL-17A expression, using immunohistochemistry. Results In total, 40 patients undergoing functional endoscopic sinus surgery and 16 controls were included in the study. IL-17A levels were significantly higher in tissues from patients with CRS (with or without nasal polyps) than in control tissues. In CRS, IL-17A expression tended to be higher in tissues with infiltrating neutrophils than in those with infiltrating eosinophils, but this difference was not significant. IL-17A expression in CRS was positively correlated with symptom severity, endoscopic findings and radiological appearance. Conclusions Expression of IL-17A was higher in Chinese patients with CRS than in controls, and was associated with infiltrating inflammatory cells, symptom severity, endoscopic findings and radiological appearance. These findings suggest that IL-17A may play a role in CRS pathogenesis and remodelling of nasal polyps.

The incidence of cutaneous and subcutaneous metastases from atypical laryngeal carcinoids is approximately 20%. However, the pathogenesis and natural history of, and prognostic factors for, the condition remain poorly understood. We reported a 54-year-old female presented with cutaneous and subcutaneous metastases from atypical laryngeal carcinoid. Laryngoscopy revealed a 0.5 × 1.5-cm reddish mass on the laryngeal surface of the epiglottis. Under general anesthesia, a biopsy sample was obtained via suspension laryngoscopy. Routine pathology revealed atypical laryngeal carcinoid. Immunohistochemical staining of the sections of primary tumor was positive for cytokeratin, chromogranin A, synaptophysin, hypoxia-inducible factor-1α, P53, and CD56. GLUT-1, p-Akt, and PI3K were negative. The Ki-67 index was 15%. Supraglottic laryngectomy and selective right-neck dissection were performed. After 6 months, the patient complained of pain in the right wall of the chest; multiple cutaneous and subcutaneous nodules were evident at that site and in the abdomen. An abdominal nodule was biopsied and pathology revealed that the atypical metastatic carcinoid had metastasized to both cutaneous and subcutaneous areas of the abdomen. Chemotherapy was then prescribed. Currently, the intrathecal drug delivery system remains in place. No local recurrence has been detected. Furthermore, we systematically reviewed clinical manifestations of the disease, pathogenesis, prognostic factors, and treatment. The metastasis rate (cutaneous and subcutaneous) was approximately 12.2%. Thirty patients (62.5%) with cutaneous and subcutaneous metastases exhibited contemporaneous lymph node invasion. The 3-, 5-, and 10-year survival rates were 44.0%, 22.0%, and 13.0%, respectively. The prognosis of patients with atypical laryngeal carcinoids was poor. Relevant prognostic factors included the level of p53, human papilloma virus status, certain hypoxic markers, and distant metastasis. No optimal treatment for such metastases has yet been defined.

Background and Aims Glucose transporter protein-1 (Glut-1) is correlated with biological behaviors of malignant tumors. However, there was no evidence that overexpression of Glut-1 mechanistically lead to invasion or metastasis of cancer cells. We hypothesized that Glut-1 regulates the expression of membrane type 1-MMP (MT1-MMP) and matrix metalloproteinase-2 (MMP-2). Methods Analysis of the expression of Glut-1, MMP-2, β-actin, and MT1-MMP was performed using RT-PCR. Expression of Glut-1 protein, MMP-2, and MT1-MMP was detected by Western blotting. Results At mRNA and protein levels, Glut-1 and MMP-2 were co-expressed in the Hep-2 laryngeal carcinoma cell line. After transfection, Glut-1 antisense oligodeoxynucleotide (AS-ODN) decreased the expression of MMP-2 mRNA and protein as well as Glut-1 mRNA and protein. Glut-1 AS-ODN also decreased the expression of MT1-MMP mRNA. Conclusions Co-expression of Glut-1 and MMP-2 in Hep-2 laryngeal carcinoma cells and Glut-1 may regulate MMP-2 and MT1-MMP expression.

Hypoxia is an important factor in radioresistance of laryngeal carcinoma. Glucose transporter-1 (GLUT-1) is an important hypoxic marker in malignant tumors, including laryngeal carcinoma. Apigenin is a natural phytoestrogen flavonoid that has potential anticancer effects. Various studies have reported that the effects of apigenin on lowering GLUT-1 expression were involved in downregulation of the PI3K/Akt pathway. Thus, apigenin may improve the radiosensitivity of laryngeal carcinoma by suppressing the expression of GLUT-1 via the PI3K/Akt pathway. The effect of GLUT-1 and PI3K/Akt pathway-related factor expressions by apigenin or antisense oligonucleotides (AS-ODNs) on the radiosensitivity of laryngeal carcinoma in vivo was assessed. The xenograft volume, xenograft weight and apoptosis detection were performed to determine radiosensitivity. The results showed that apigenin or apigenin plus GLUT-1 AS-ODNs improved the radiosensitivity of xenografts. Apigenin or apigenin plus GLUT-1 reduced the expression of GLUT-1, Akt, and PI3K mRNA after X-ray radiation. We found similar results at the protein level. The results suggest that the effects of apigenin on inhibiting xenograft growth and enhancing xenograft radiosensitivity may be associated with suppressing the expression of GLUT-1 via the PI3K/Akt pathway. In addition, apigenin may enhance the effects of GLUT-1 AS-ODNs via the same mechanism.

In the present study, we investigated the role of GLUT-1 and PI3K/Akt signaling in radioresistance of laryngeal carcinoma xenografts. Volume, weight, radiosensitization, and the rate of inhibition of tumor growth in the xenografts were evaluated in different groups. Apoptosis was evaluated by TUNEL assay. In addition, mRNA and protein levels of GLUT-1, p-Akt, and PI3K in the xenografts were measured. Treatment with LY294002, wortmannin, wortmannin plus GLUT-1 AS-ODN, and LY294002 plus GLUT-1 AS-ODN after X-ray irradiation significantly reduced the size and weight of the tumors, rate of tumor growth, and apoptosis in tumors compared to that observed in the 10-Gy group (p

A paucity of data exists concerning the presentation, natural course and outcome of extramedullary plasmcytoma (EMP). It is difficult to determine the optimal treatment strategy and prognostic factors for EMP. We present an additional case of laryngeal EMP and systemic review relevant reports in the English and Chinese literature. We found, to our knowledge, 147 cases in larynx in the English-language literature and Chinese-literature. The most common treatment modality was radiotherapy alone. The mean survival duration was ~184 months, and the 5- and 10- year survival rates were 76.1% and 67.4%, respectively. The univariate analysis suggested that progression to multiple myeloma and amyloid deposits may be poor prognostic factors. The multivariate analysis suggested that only progression to multiple myeloma may be a poor prognostic factor. Laryngeal EMP is uncommon. Progression to multiple myeloma may be a poor prognostic factor.

Obstructive sleep apnea syndrome (OSAS) is always caused by anatomic abnormalities, including nasal cavity, pharynx, and neuromuscular dysfunctions, leading to airway narrowing. OSAS associated with a mass in the aerodigestive tract is rare. In the present study, we report OSAS caused by 9 cases of preoperative uncommon tumors in the aerodigestive tract. Two tumors in the parapharyngeal space were pleomorphic adenoma, one oropharyngeal tumor was mucoepidermoid carcinoma, one tumor in the right tonsil was schwannoma, and five tumors were non-Hodgkin’s lymphoma (NHL). Of the five NHL cases, one in the nasopharynx was diffuse large B-cell lymphoma, two were mantle cell lymphoma, one was chronic lymphocytic leukemia/small lymphocytic lymphoma, and one was NHL. Tumors in the aerodigestive tract should be considered in the differential diagnosis of OSAS upon exacerbation of snoring or sudden gasping. Further examinations should be performed, including a routine workup (computed tomography (CT) and magnetic resonance imaging) and positron emission tomography/CT.

Glucose transporter-1 (GLUT-1) and PI3K/Akt are known to be closely involved in resistance to chemotherapy. Co-targeted therapy reducing GLUT-1 expression and PI3K/Akt pathway activity may overcome the chemoresistance of human cancers. Apigenin may inhibit the expression of GLUT-1 and the PI3K/Akt pathway. We hypothesized that over-expression of GLUT-1 and p-Akt was associated with the resistance to cisplatin of laryngeal carcinoma Hep-2 cells. We explored whether apigenin inhibited GLUT-1 and p-Akt, resulting in sensitization of laryngeal carcinoma Hep-2 cells to cisplatin. Real-time RT-PCR and Western blotting confirmed the presence of GLUT-1 mRNA, and GLUT-1 and p-Akt proteins in Hep-2 cells. We found that resistance or insensitivity of Hep-2 cells to cisplatin might be associated with such expression. Apigenin markedly enhanced the cisplatin-induced suppression of Hep-2 cell growth. This effect was concentration- and time-dependent. Thus apigenin may significantly reduce the levels of GLUT-1 mRNA, and GLUT-1 and p-Akt proteins, in cisplatin-treated Hep-2 cells, in a concentration- and time-dependent manner. To conclude, overexpression of GLUT-1 mRNA may be associated with the resistance to cisplatin of laryngeal carcinoma Hep-2 cells. Apigenin may enhance the sensitivity to cisplatin of laryngeal carcinoma cells via inhibition of GLUT-1 and p-Akt expression.

A 67-year-old male presented with a metastatic carcinoma in the right side of the neck from an unknown primary site. 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography showed increased 18F-FDG uptake in the right larynx and right neck lymph nodes. A smooth lesion was identified in the submucosa of the right supraglottic region via a suspension laryngoscopy under general anaesthesia. A biopsy was performed and a frozen section revealed a small-cell (SC) carcinoma. A total laryngectomy and bilateral neck dissection were performed simultaneously, and the pathological results demonstrated a SC neuroendocrine carcinoma. The patient received chemo-radiotherapy postoperatively, however, succumbed due to distant metastasis one year following surgery.

Apigenin, a natural phytoestrogen flavonoid, has potential biological effects, including antioxidative, anti-inflammatory and anticancer activities. The mechanisms of anticancer activities of apigenin are unknown. Some studies have found that apigenin inhibits GLUT-1 mRNA and protein expression in cancer cells. Thus, we hypothesized that apigenin exerts similar effects on head and neck cancers through its inhibition of GLUT-1 expression. In this article, we review the anticancer mechanism of apigenin and the implications of GLUT-1 expression in head and neck cancers. In addition, we describe the current state of knowledge about the relationship between apigenin and GLUT-1 expression in head and neck cancers.

Purpose: Laryngeal carcinomas always resist to radiotherapy. Hypoxia is an important factor in radioresistance of laryngeal carcinoma. Glucose transporter-1 (GLUT-1) is considered to be a possible intrinsic marker of hypoxia in malignant tumors. We speculated that the inhibition of GLUT-1 expression might improve the radiosensitivity of laryngeal carcinoma. Methods: We assessed the effect of GLUT-1 expression on radioresistance of laryngeal carcinoma and the effect of GLUT-1 expressions by antisense oligodeoxynucleotides (AS-ODNs) on the radiosensitivity of laryngeal carcinoma in vitro and in vivo. Results: After transfection of GLUT-1 AS-ODNs: MTS assay showed the survival rates of radiation groups were reduced with the prolongation of culture time (p