The role of radiotherapy in tumor immunity and the potential of PET/CT in detecting the expression of PD-1/PD-L1.

Upregulation of PD-1/PD-L1 allows cancer cells to escape from host immune systems by functionally inactivating T-cell immune surveillance. Clinical blockade strategies have resulted in an increased prevalence of patients with late-stage cancers. However, many cancer patients had limited or no response to current immunotherapeutic strategies. Therefore, how to improve the sensitivity of immunotherapy has become the focus of attention of many scholars. Radiotherapy plays a role in the recruitment of T cells in the tumor microenvironment, increases CD4 + and CD8 + T cells, and increases PD-L1 expression, resulting in the synergistically enhanced antitumor effect of irradiation and PD-L1 blockade. Radiotherapy can cause changes in tumor metabolism, especially glucose metabolism. Tumor glycolysis and tumor immune evasion are interdependent, glycolytic activity enhances PD-L1 expression on tumor cells and thus promotes anti-PD-L1 immunotherapy response. Therefore, the mechanism of radiotherapy affecting tumor immunity may be partly through intervention of tumor glucose metabolism. Furthermore, some authors had found that the uptake of 2'-deoxy-2'-[18F]fluoro-D-glucose(18F-FDG) was correlated with PD-1/PD-L1 expression. Positron emission tomography/computed tomography (PET/CT) is a non-invasive detection method for PD-1/PD-L1 expression and has several potential advantages over immunohistochemical (IHC), PET/CT can dynamically reflect the expression of PD-1/PD-L1 inside the tumor and further guide clinical treatment.

The role of interleukin 36γ in the epithelial-mesenchymal transition process of chronic rhinosinusitis: A pilot study.

PURPOSE: Epithelial-mesenchymal transition (EMT) is an important characteristic in the remodelling of chronic rhinosinusitis with nasal polyps (CRSwNP). IL-36γ and fibroblast activation protein (FAP) may exacerbate remodelling in CRS. Here, we aimed to determine whether IL-36γ and FAP expression are associated with EMT and may be a predictor for CRSwNP prognosis. METHODS: Fifty-two non-Eos CRSwNP patients and 12 control patients were obtained and were followed up for more than 1 year after surgery. IL-36γ, FAP and EMT markers expression were evaluated by real-time polymerase chain reaction and western blot. Masson trichrome staining was adopted to assess tissue fibrotic changes. Furthermore, the soluble form of IL-36γ and FAP in nasal secretions was detected by ELISA. RESULTS: While basal expression of E-cadherin decreased, the expression of IL-36γ, vimentin and FAP increased in nasal polyps. In well-prognosis patients, the expression of IL-36γ, vimentin and FAP were significantly decreased than in poor-prognosis patients, while the protein expression of E-cadherin was increased. The protein expression of IL-36γ was notably increased in recurrent nasal polyps than in preoperation specimens. A positive relationship between IL-36γ and FAP expression, a negative relationship between IL-36γ and E-cad expression was noted. The soluble form of IL-36γ and FAP increased during the development of non-Eos CRSwNP, with the highest level in poor-prognosis patients after surgery. CONCLUSION: Non-Eos CRSwNP have partially undergone EMT under baseline conditions. IL-36γ and FAP expression were related with EMT, the soluble form of IL-36γ and FAP in nasal secretions may predict the prognosis of patients.

Effect of Glut-1 and HIF-1α double knockout by CRISPR/CAS9 on radiosensitivity in laryngeal carcinoma via the PI3K/Akt/mTOR pathway.

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 18 F-fluorodeoxyglucose radioactivity. A tumour xenograft model was established by subcutaneous injection of Tu212 cells. Tumour histopathology was determined by haematoxylin and eosin staining, immunohistochemical staining, and TUNEL assays. Signalling transduction was evaluated by Western blotting. We found that hypoxia induced radioresistance in Tu212 cells accompanied by increased glucose uptake capability and activation of the PI3K/Akt/mTOR pathway. Inhibition of PI3K/Akt/mTOR activity abolished hypoxia-induced radioresistance and glucose absorption. Mechanistic analysis revealed that hypoxia promoted higher expressions of HIF-1α and Glut-1. Moreover, the PI3K/Akt/mTOR pathway was a positive mediator of HIF-1α and/or Glut-1 in the presence of irradiation. HIF-1α and/or Glut-1 knockout significantly reduced cell viability, glucose uptake and PI3K/Akt/mTOR activity, all of which were induced by hypoxia in the presence of irradiation. In vivo analysis showed that knockout of HIF-1α and/or Glut-1 also inhibited tumour growth by promoting cell apoptosis, more robustly compared with the PI3K inhibitor wortmannin, particularly in tumours with knockout of both HIF-1α and Glut-1. HIF-1α and/or Glut-1 knockout also abrogated PI3K/Akt/mTOR signalling transduction in tumour tissues, in a manner similar to wortmannin. HIF-1α and/or Glut-1 knockout facilitated radiosensitivity in laryngeal carcinoma Tu212 cells by regulation of the PI3K/Akt/mTOR pathway.

The role of Glut-1 and H+/K+-ATPase expression in hyperplasia of mice laryngeal epithelium induced by pepsin.

PURPOSE: To explore the role played by Glut-1 and H+/K+-ATPase in pepsin-induced, mouse laryngeal epithelial proliferation, growth, and development. METHODS: We established a mouse model of laryngopharyngeal reflux and measured Glut-1 and H+/K+-ATPase expression levels in mouse laryngeal epithelium treated with artificial gastric juice containing pepsin. RESULTS: Artificial pepsin-containing gastric juice induced significant hyperplastic changes in mouse laryngeal epithelium compared to control mice at 15, 30, and 45 days. Inhibition of Glut-1 expression by 2-DG significantly suppressed such hyperplasia compared to mice exposed to artificial gastric juice containing pepsin at 15, 30, and 45 days. After treatment with pepsin-containing artificial gastric juice, RT-PCR and Western blotting showed that the levels of Glut-1 and H+/K+-ATPase α, ß increased significantly. CONCLUSIONS: Pepsin-containing artificial gastric juice promoted mouse laryngeal epithelial hyperplasia associated with abnormal expression of Glut-1 and H+/K+-ATPase α, ß.

Role and mechanism of Glut-1 and H+/K+-ATPase expression in pepsin-induced development of vocal cord leukoplakia.

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 < 0.01). With increasing duration of exposure to pepsin, the proportion of VSCLCs in G0/G1 phase decreased and the proportions in the S and G2/M phases significantly increased (p < 0.05). After treatment with pepsin-containing artificial gastric juice, RT-PCR and Western blotting showed that the expression of Glut-1 and H+/K+-ATPase α, ß significantly increased in HVCLCs compared to in the absence of pepsin (p < 0.05). The expression of Glut-1 and H+/K+-ATPase α, ß gradually increased from vocal cord leukoplakia (VLC) to laryngeal carcinoma (p < 0.05). Lentivirus-mediated inhibition of Glut-1 expression in VCL significantly inhibited the cells' migration and proliferation (p < 0.05) but enhanced their apoptosis (p < 0.05). Also, inhibition of Glut-1 expression resulted in an increased proportion of cells in G0/G1 phase and a significantly decreased proportion in G2/M phase (p < 0.05). 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.

Radiosensitizing effects of curcumin alone or combined with GLUT1 siRNA on laryngeal carcinoma cells through AMPK pathway-induced autophagy.

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.

The Systemic Immune-Inflammation Index and Albumin as Prognostic Predictors in Laryngeal Carcinoma.

BACKGROUND: Systemic inflammation via host-tumor interactions is currently recognized as the seventh cancer hallmark. The purpose of this study was to detect whether pretreatment peripheral indexes were associated with aggressive behavior and prognosis of laryngeal carcinoma patients. METHODS: The pretreatment peripheral indexes such as albumin and systematic immune-inflammation index (SII) in 338 patients with laryngeal carcinoma were retrospectively recorded, the relationships between them and clinicopathological features and prognosis were analyzed. RESULTS: A high SII value was significantly positively associated with age (P = 0.01), N stage (P = 0.022) and tumor differentiation (P = 0.001). A low albumin value was significantly negatively associated with age (P = 0.01), tumor location (P = 0.001) and T stage (P = 0.015), N stage (P = 0.001) and tumor differentiation (P = 0.001). Univariate and multivariate survival analysis showed that a high SII (HR: 2.415, 95% CI 1.400-4.184; P = 0.002), a low blood albumin content (HR: 3.194, 95% CI 2.030-5.025; P = 0.001) independently predicted poor overall survival (OS). However, neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and platelet distribution width (RDW) were not independent prognostic factors. CONCLUSION: Pretreatment peripheral indexes SII and albumin could function as inexpensive indicators of aggressive behavior and be feasible and promising predictive biomarkers for prognosis in laryngeal carcinoma patients. Quantification of pretreatment SII and albumin may help physicians to design more effective management and follow-up strategies in laryngeal carcinoma patients.

Epstein-Barr Virus-Positive Langerhans Cell Sarcoma: Is There a Link? A Case Report.

Langerhans cell sarcoma (LCS) is an extremely rare, malignant neoplasm that originates from Langerhans cells (LCs). Fewer than 70 cases have been reported in the English-language literature. LCS typically involves multiple organs, including the skin, lymph nodes, lungs, bone, bone marrow, liver, spleen, and soft tissues. Several etiological factors for LCS have been proposed, including immunosuppression, virus infection, and prior hematological disease. We report a rare case of LCS with Epstein-Barr virus (EBV) infection; bilateral cervical giant cysts were the initial manifestation. To our knowledge, this is the first report of LCS with EBV infection. The case information was complete, and the relevant literature was reviewed to gain insight into LCS. The case raises new questions on the oncogenic character of EBV.

Telecommuting during the coronavirus pandemic: Future time orientation as a mediator between proactive coping and perceived work productivity in two cultural samples.

This study examines the relationship between proactive coping, future time orientation, and perceived work productivity during the coronavirus (COVID-19) pandemic, based on the work-from-home experience of employees in Taiwan and the United States (U.S.). It draws on the conservation of resources (COR) theory, which posits that proactive coping and future time orientation are crucial personal resources that affect the capacity of an individual to adapt to stressful situations. The results show that in the relationship between proactive coping and perceived work productivity, future time orientation acts as a full mediator in Taiwan and a partial mediator in the U.S. The study extends the application of the COR theory to the context of the COVID-19 pandemic and offers important insights that will enable professionals to assess the role of proactive coping and future time orientation in their productivity evaluations of working tasks and to design appropriate training sessions.

Role of GLUT-1 in the Upregulation of PD-L1 Expression After Radiotherapy and Association of PD-L1 with Favourable Overall Survival in Hypopharyngeal Cancer.

PURPOSE: The alteration of tumor immunity after radiotherapy (RT) has been widely studied in recent years. However, the mechanism through which RT mediates tumor immunity and the involvement of glycolysis in this mediation in hypopharyngeal cancer remain unclear. This study investigated whether RT regulates programmed cell death ligand 1(PD-L1) partly via glucose transporter 1(GLUT-1) expression and whether PD-L1 expression predicts overall survival (OS) in patients with hypopharyngeal cancer. METHODS: The expression of PD-L1 and Glut-1, and the numbers of CD4+, CD8+ T cells were detected by immunohistochemical analysis on 47 pre-RT and 25 post-RT specimens of hypopharyngeal cancer. Changes in these indicators before and after RT were compared, and their association with the OS of patients was analyzed. Moreover, we used siRNA-GLUT-1 to inhibit GLUT-1 expression and examined whether GLUT-1 was a key factor involved in the mediation of PD-L1 expression by RT in vitro. RESULTS: In the multivariate analysis, patients with higher PD-L1 expression (p=0.037), higher CD4+ T cell infiltration (p=0.016) and earlier clinical stage (p=0.019) had favourable OS. The expression of PD-L1, and the CD4+ and CD8+ T cells was markedly increased following RT. PD-L1 expression was correlated with Glut-1 pre-RT (p=0.002), but not after RT (p=0.051). The expression of PD-L1 in FaDu cells was upregulated after RT, especially at 96h after RT in vitro. However, the expression of PD-L1 in siRNA-GLUT-1 FaDu cells was markedly decreased at 96h after RT compared with that measured in FaDu cells. CONCLUSION: Patients with high PD-L1 expression and CD4+ T cell infiltration may have favourable OS in hypopharyngeal cancer. RT may increase PD-L1 expression and alter tumor immunity. The expression of PD-L1 was correlated with Glut-1, and inhibition of GLUT-1 expression may decrease the expression of PD-L1. GLUT-1 may participate in the alteration of tumor immunity after RT.

Three unusual parapharyngeal space masses resected via the endoscopy-assisted transoral approach: case series and literature review.

Tumors of the parapharyngeal space (PPS) are rare, most originate from salivary and neurogenic tissues, and most are benign. However, there are some rarer masses in the PPS, with just a few published reports in the literature worldwide, and we may not consider them in the differential diagnosis of PPS neoplasms. We report three cases of rare masses in the PPS: Warthin's tumor, branchial cleft cyst, and carcinoma ex pleomorphic adenoma. The three patients were admitted to our department with complaints of painless swelling in the lower side of the right face or a long history of snoring; diagnoses were confirmed histopathologically. An endoscopy-assisted transoral approach was used that allowed wide visibility for safe resection and resulted in a short hospitalization time and good functional and cosmetic outcomes. All patients have been followed to the current time, and there have been no recurrences. The transoral endoscopy-assisted approach appears to be safe, effective, and less invasive for excision of masses in the PPS.

Effect of combination of curcumin and GLUT-1 AS-ODN on radiosensitivity of laryngeal carcinoma through regulating autophagy.

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.

Relationships between expression of glucose transporter protein-1 and hypoxia inducible factor-1α, prognosis and 18F-FDG uptake in laryngeal and hypopharyngeal carcinomas.

BACKGROUND: We investigated the relationships between glucose transporter protein-1 (GLUT-1) and hypoxia inducible factor-1α (HIF-1α) expression, 2-deoxy-2-[18F]-fluoro-D-glucose (18F-FDG) uptake and prognosis in laryngeal and hypopharyngeal carcinomas patients. METHODS: Levels of GLUT-1 and HIF-1α proteins were examined by immunohistochemistry in 55 patients with laryngeal and hypopharyngeal carcinomas. All patients underwent 18F-FDG positron emission tomography-computed tomography (PET/CT) before surgery. RESULTS: Levels of GLUT-1 and HIF-1α in laryngeal and hypopharyngeal carcinomas were significantly higher than in vocal cord polyps. GLUT-1 expression was correlated with HIF-1α expression (r=0.571, P<0.001) and SUVmax (r=0.495, P<0.001). HIF-1α expression was not correlated with SUVmax (P=0.199). HIF-1α expression was correlated with tumor size (r=0.351, P=0.009). Multivariate analysis demonstrated that treatment method (P=0.025), tumor size (P=0.008), GLUT-1 expression (P=0.032), and HIF-1α expression (P=0.032) were correlated with overall survival (OS). CONCLUSIONS: Treatment method, tumor size, GLUT-1 and HIF-1α levels were correlated with prognosis in laryngeal and hypopharyngeal carcinomas patients.

Predicting response to radiotherapy in tumors with PET/CT: when and how?

Radiotherapy is one of the main methods for tumor treatment, with the improved radiotherapy delivery technique to combat cancer, there is a growing interest for finding effective and feasible ways to predict tumor radiosensitivity. Based on a series of changes in metabolism, microvessel density, hypoxic microenvironment, and cytokines of tumors after radiotherapy, a variety of radiosensitivity detection methods have been studied. Among the detection methods, positron emission tomography-computed tomography (PET/CT) is a feasible tool for response evaluation following definitive radiotherapy for cancers with a high negative predictive value. The prognostic or predictive value of PET/CT is currently being studied widely. However, there are many unresolved issues, such as the optimal probe of PET/CT for radiosensitivity prediction, the selection of the most useful PET/CT parameters and their optimal cut-offs such as total lesion glycolysis (TLG), metabolic tumor volume (MTV) and standardized uptake value (SUV), and the optimal timing of PET/CT pre-treatment, during or following RT. Different radiosensitivity of tumors, modes of radiotherapy action and fraction scheduling may complicate the appropriate choice. In this study, we will discuss the diverse methods for evaluating radiosensitivity, and will also focus on the selection of the optimal probe, timing, cut-offs and parameters of PET/CT for evaluating the radiotherapy response.

Construction of a GLUT-1 and HIF-1α gene knockout cell model in HEp-2 cells using the CRISPR/Cas9 technique.

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.

Second branchial cleft anomalies in children: a literature review.

Branchial cleft anomalies are the second most common head and neck congenital lesions in children. It may sometimes be a part of branchio-oto-renal (BOR) syndrome, so in patients with branchial cleft anomalies associated with a complaint of auricular deformity or a similar history and findings in other family members, we should take an additional examination to find the possibility of BOR syndrome. Complete excision is essential for good prognosis. For the management of branchial cleft anomalies, various methods have been reported. Endoscopically assisted dissection technique and transoral robot-assisted surgery were used in the management of fistula and allowed excellent visualization of the pharyngeal component of the lesion and a minimally invasive approach. It is essential for the surgeon to fully comprehend the congenital lesions to attain the correct preoperative diagnosis and plan for an appropriate surgical approach to prevent the most common complication and recurrence in these lesions. The following sections discuss the anatomy, common presentation, auxiliary examination, differential diagnosis, the current principles of surgical treatment and prognosis for second branchial cleft anomalies in children, and discussed the branchio-oto-renal syndrome.

Basal cell adenoma in the parapharyngeal space resected via trans-oral approach aided by endoscopy: Case series and a review of the literature.

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 3-5 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.

In vivo evaluation of the effects of simultaneous inhibition of GLUT-1 and HIF-1α by antisense oligodeoxynucleotides on the radiosensitivity of laryngeal carcinoma using micro 18F-FDG PET/CT.

PURPOSE: Hypoxia-inducible factor 1α (HIF-1α) and glucose transporter-1 (GLUT-1) are two important hypoxic markers associated with the radioresistance of cancers including laryngeal carcinoma. We evaluated whether the simultaneous inhibition of GLUT-1 and HIF-1α expression improved the radiosensitivity of laryngeal carcinoma. We explored whether the expression of HIF-1α and GLUT-1 was correlated with 2'-deoxy-2'-[18F]fluoro-D-glucose (18F-FDG) uptake and whether 18F-FDG positron emission tomography-computed tomography (PET/CT) was appropriate for early evaluation of the response of laryngeal carcinoma to targeted treatment in vivo. MATERIALS AND METHODS: To verify the above hypotheses, an in vivo model was applied by subcutaneously injecting Hep-2 (2 × 107/mL × 0.2 mL) and Tu212 cells (2 × 107/mL × 0.2 mL) into nude mice. The effects of HIF-1α antisense oligodeoxynucleotides (AS-ODNs) (100 µg) and GLUT-1 AS-ODNs (100 µg) on the radiosensitivity of laryngeal carcinoma were assessed by tumor volume and weight, microvessel density (MVD), apoptosis index (AI) and necrosis in vivo based on a full factorial (23) design. 18F-FDG-PET/CT was taken before and after the treatment of xenografts. The relationships between HIF-1α and GLUT-1 expression and 18F-FDG uptake in xenografts were estimated and the value of 18F-FDG-PET/CT was assessed after treating the xenografts. RESULTS: 10 Gy X-ray irradiation decreased the weight of Hep-2 xenografts 8 and 12 days after treatment, and the weights of Tu212 xenografts 8 days after treatment. GLUT-1 AS-ODNs decreased the weight of Tu212 xenografts 12 days after treatment. There was a synergistic interaction among the three treatments (GLUT-1 AS-ODNs, HIF-1α AS-ODNs and 10Gy X-ray irradiation) in increasing apoptosis, decreasing MVD, and increasing necrosis in Hep-2 xenografts 8 days after treatment (p < 0.05) and in Tu212 xenografts 12 days after treatment (p < 0.001). Standardized uptake value (tumor/normal tissue)( SUVmaxT/N) did not show a statistically significant correlation with GLUT1 and HIF-1α expression and therapeutic effect (necrosis, apoptosis). CONCLUSIONS: Simultaneous inhibition of HIF-1α and GLUT-1 expression might increase the radiosensitivity of laryngeal carcinoma, decreasing MVD, and promoting apoptosis and necrosis. 18F-FDG-PET/CT wasn't useful in evaluating the therapeutic effect on laryngeal cancer in this animal study.