Sodium-iodide symporter and its related solute carriers in thyroid cancer.

The solute carrier (SLC) family is a large group of membrane transport proteins. Their dysfunction plays an important role in the pathogenesis of thyroid cancer. The most well-known SLC is the sodium-iodide symporter (NIS), also known as sodium/iodide co-transporter or solute carrier family 5 member 5 (SLC5A5) in thyroid cancer. The dysregulation of NIS in thyroid cancer is well documented. The role of NIS in the uptake of iodide is critical in the treatment of thyroid cancer, radioactive iodide (RAI) therapy in particular. In addition to NIS, other SLC members may affect the autophagy, proliferation, and apoptosis of thyroid cancer cells, indicating that an alteration in SLC members may affect different cellular events in the evolution of thyroid cancer. The expression of the SLC members may impact the uptake of chemicals by the thyroid, suggesting that targeting SLC members may be a promising therapeutic strategy in thyroid cancer.

The Isoforms of Estrogen Receptor Alpha and Beta in Thyroid Cancer.

The incidence of thyroid cancer was predominant in women, indicating that the sex hormone may have a role in thyroid cancer development. Generally, the sex hormone exerts its function by binding to the correspondent nuclear receptors. Therefore, aberrant of these receptors may be involved in the development of thyroid cancer. Estrogen receptor alpha (ERα) and beta (ERß), two main estrogen receptors, have been reported to have an important role in the pathogenesis of thyroid cancer. When the ERα and ERß genes undergo the alternative RNA splicing, some ERα and ERß isoforms with incomplete functional domains may be formed. To date, several isoforms of ERα and ERß have been identified. However, their expression and roles in thyroid cancer are far from clear. In this review, we summarized the expressions and roles of ERα and ERß isoforms in thyroid cancer, aiming to provide the perspective of modulating the alternative RNA splicing of ERα and ERß against thyroid cancer.

Differential Effects of Estrogen Receptor Alpha and Beta on Endogenous Ligands of Peroxisome Proliferator-Activated Receptor Gamma in Papillary Thyroid Cancer.

Purpose: The inhibition of estrogen receptor alpha (ERα) or the activation of ERß can inhibit papillary thyroid cancer (PTC), but the precise mechanism is not known. We aimed to explore the role of ERα and ERß on the production of endogenous peroxisome proliferator-activated receptor gamma (PPARγ) ligands in PTC. Methods: 2 PTC cell lines, 32 pairs of PTC tissues and matched normal thyroid tissues were used in this study. The levels of endogenous PPARγ ligands 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE), 13-S-hydroxyoctadecadienoic acid (13(S)-HODE), and15-deoxy-Δ12,14-prostaglandin J2 (PGJ2) were measured by ELISA. Results: The levels of PGJ2 and 15(S)-HETE were significantly reduced in PTC, but 13(S)-HODE was not changed. Activation of ERα or inhibition of ERß significantly downregulated the production of PGJ2, 15(S)-HETE and 13(S)-HODE, whereas inhibition of ERα or activation of ERß markedly upregulated the production of these three ligands. Application of endogenous PPARγ ligands inhibited growth, induced apoptosis of cancer cells, and promoted the efficacy of chemotherapy. Conclusion: The levels of endogenous PPARγ ligands PGJ2 and 15(S)-HETE are significantly decreased in PTC. The inhibition of ERα or activation of ERß can inhibit PTC by stimulating the production of endogenous PPARγ ligands to induce apoptosis in cancer cells.

The Knockdown of Nrf2 Suppressed Tumor Growth and Increased the Sensitivity to Lenvatinib in Anaplastic Thyroid Cancer.

Papillary thyroid cancer can dedifferentiate into a much more aggressive form of thyroid cancer, namely into anaplastic thyroid cancer. Nrf2 is commonly activated in papillary thyroid cancer, whereas its role in anaplastic thyroid cancer has not been fully explored. In this study, we used two cell lines and an animal model to examine the function of Nrf2 in anaplastic thyroid cancer. The role of Nrf2 in anaplastic thyroid cancer was investigated by a series of functional studies in two anaplastic thyroid cancer cell lines, FRO and KAT-18, and further confirmed with an in vivo study. The impact of Nrf2 on the sensitivity of anaplastic thyroid cancer cells to lenvatinib was also investigated to evaluate its potential clinical implication. We found that the expression of Nrf2 was significantly higher in anaplastic thyroid cancer cell line cells than in papillary thyroid cancer cells or normal control cells. Knockdown of Nrf2 in anaplastic thyroid cancer cells inhibited their viability and clonogenicity, reduced their migration and invasion ability in vitro, and suppressed their tumorigenicity in vivo. Mechanistically, knockdown of Nrf2 decreased the expression of Notch1. Lastly, knockdown of Nrf2 increased the sensitivity of anaplastic thyroid cancer cells to lenvatinib. As knockdown of Nrf2 reduced the metastatic and invasive ability of anaplastic thyroid cancer cells by inhibiting the Notch 1 signaling pathway and increased the cancer cell sensitivity to lenvatinib, Nrf2 could be a promising therapeutic target for patients with anaplastic thyroid cancer.

Whole-genome profiling of nasopharyngeal carcinoma reveals viral-host co-operation in inflammatory NF-κB activation and immune escape.

Interplay between EBV infection and acquired genetic alterations during nasopharyngeal carcinoma (NPC) development remains vague. Here we report a comprehensive genomic analysis of 70 NPCs, combining whole-genome sequencing (WGS) of microdissected tumor cells with EBV oncogene expression to reveal multiple aspects of cellular-viral co-operation in tumorigenesis. Genomic aberrations along with EBV-encoded LMP1 expression underpin constitutive NF-κB activation in 90% of NPCs. A similar spectrum of somatic aberrations and viral gene expression undermine innate immunity in 79% of cases and adaptive immunity in 47% of cases; mechanisms by which NPC may evade immune surveillance despite its pro-inflammatory phenotype. Additionally, genomic changes impairing TGFBR2 promote oncogenesis and stabilize EBV infection in tumor cells. Fine-mapping of CDKN2A/CDKN2B deletion breakpoints reveals homozygous MTAP deletions in 32-34% of NPCs that confer marked sensitivity to MAT2A inhibition. Our work concludes that NPC is a homogeneously NF-κB-driven and immune-protected, yet potentially druggable, cancer.

The role of microRNA in cisplatin resistance or sensitivity.

INTRODUCTION: Cisplatin is a chemotherapy drug that has been used to treat a number of cancers for decades, and is still one of the most commonly used anti-cancer agents. However, some patients do not respond to cisplatin while other patients who were originally sensitive to cisplatin eventually develop chemoresistance, leading to treatment failure or/and tumor recurrence. AREAS COVERED: Different mechanisms contribute to cisplatin resistance or sensitivity, involving multiple pathways or/and processes such as DNA repair, DNA damage response, drug transport, and apoptosis. Among the various mechanisms, it appears that microRNAs play an important role in determining the resistance or sensitivity. In this article, we analyzed and summarized recent findings in this area, with the aim that these data can aid further research and understanding, leading to the eventual reduction of cisplatin resistance. EXPERT COMMENTARY: microRNAs can positively or negatively regulate cisplatin resistance by acting on molecules or/and pathways related to apoptosis, autophagy, hypoxia, cancer stem cells, NF-κB, and Notch1. It appears that the modulation of relevant microRNAs can effectively re-sensitize cancer cells to cisplatin regimen in certain types of cancers including breast, colorectal, gastric, liver, lung, ovarian, prostate, testicular, and thyroid cancers.

Frontal inverted papillomas: A 25-year study.

OBJECTIVES/HYPOTHESIS: This study analyzes the treatment outcomes of frontal inverted papillomas (FIPs) in an attempt to provide guidelines for surgery selection. STUDY DESIGN: Retrospective case series. METHODS: The treatment results of 29 FIPs classified into five categories were retrospectively analyzed. The five categories are F1, tumor prolapsed into frontal sinus, tumor origin outside frontal sinus; F2, tumor origin inside frontal sinus, medial to the plane of lamina papyracea; F3, tumor origin inside frontal sinus, lateral to the plane of lamina papyracea; F4, bilateral; and F5, extrasinonasal. RESULTS: Of the 11 F1 cases, 73% had Draf I and 27% had Draf IIA procedures. There was one (9%) frontal recurrence and one (9%) frontal stenosis. Of the 10 F2 cases, 10% had Draf I, 40% had Draf IIA, 40% had Draf IIB, and 10% had Draf III surgery with a trephination. One patient (10%) had a frontal recurrence. Of the five F3 cases, 40% had Draf IIA surgery, 20% had external frontoethmoidectomy, and 40% had external frontal sinusotomy. The recurrence rate was 60%, and frontal stenosis rate was 60%. The two F4 cases had external frontal sinusotomies and Draf III surgery with no frontal recurrence or stenosis. The patient with the F5 had a frontal recurrence after Draf IIA surgery and external frontoethmoidectomy. CONCLUSIONS: Draf I or IIA surgery is adequate for most F1 tumors, and Draf II surgery is adequate for most F2 tumors. F3 and F4 tumors can be managed initially by Draf III surgery with external frontal sinusotomy added when required. F5 tumors probably require combined surgical approaches. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:1622-1628, 2020.

MicroRNA-125b Interacts with Foxp3 to Induce Autophagy in Thyroid Cancer.

Thyroid cancer is rapidly increasing in incidence worldwide. Although most thyroid cancer can be cured with surgery, radioactive iodine, and/or chemotherapy, thyroid cancers still recur and may become chemoresistant. Autophagy is a complex self-degradative process that plays a dual role in cancer development and progression. In this study, we found that miR-125b was downregulated in tissue samples of thyroid cancer as well as in thyroid cancer cell lines, and the expression of Foxp3 was upregulated. Further, we demonstrated that miR-125b could directly act on Foxp3 by binding to its 3' UTR and inhibit the expression of Foxp3. A negative relationship between miR-125b and Foxp3 was thus revealed. Overexpression of miR-125b markedly sensitized thyroid cancer cells to cisplatin treatment by inducing autophagy through an Atg7 pathway in vitro and in vivo. Taken together, our findings demonstrate a novel mechanism by which miR-125b has the potential to negatively regulate Foxp3 to promote autophagy and enhance the efficacy of cisplatin in thyroid cancer. miR-125 may be of therapeutic significance in thyroid cancer.

Conservative management of postoperative chylous fistula with octreotide and peripheral total parenteral nutrition.

Postoperative chylous fistula after neck dissection is an uncommon complication associated with significant patient morbidity. Octreotide acetate is a somatostatin analogue established in the treatment of chylothorax; however, its utility in the management of cervical chylous fistulae has not been fully evaluated. The investigators hypothesized that chylous fistula can be managed by a combination of octreotide and peripheral total parenteral nutrition (TPN). A retrospective review of cases compiled at our institution from 2009 to 2015 was conducted. Ten patients, all men, were identified as having a postoperative chylous fistula after a neck dissection. All patients were treated with peripheral TPN and intravenous octreotide. Mean age of the patients was 63.0 years (range 49 to 82). Five (50.0%) had a neck dissection for the management of metastatic nasopharyngeal carcinoma and had previous neck irradiation. In 8 (80%) patients, chylous fistula occurred in the left neck. Seven (70.0%) of the leaks occurred within the first 2 postoperative days. Eight (80%) leaks were controlled using TPN and octreotide, with 2 (20%) patients requiring surgical intervention. No factors were significant in the successful conservative management of chylous fistulae. One patient with a chylous fistula of 1,800 ml/day was managed successfully without surgical intervention. The results of this case series suggest that chylous fistulae may be managed conservatively with octreotide and TPN. However, long-term evaluation is needed to define if and when surgical intervention is required for control.

Effects of electrical stimulation on vocal functions in patients with nasopharyngeal carcinoma.

OBJECTIVES/HYPOTHESIS: This study aimed to evaluate the effects of neuromuscular electrical stimulation (NMES) on vocal functions in patients with nasopharyngeal carcinoma following radiation therapy. STUDY DESIGN: Prospective, randomized controlled trial. METHODS: One hundred forty newly treated NPC patients were recruited and randomized into NMES or traditional swallowing exercise (TE) group. Participants received intensive NMES or traditional swallowing therapy and were followed up until 12 months postrandomization. Fifty-seven participants completed the treatment and all of the follow-up assessments. The Voice Handicap Index-30 (VHI-30) was used to measure the vocal functions of the participants. RESULTS: The NMES group showed no significant changes to their vocal functions, whereas the TE group showed a short-term deterioration of voice functions at the 6-month follow-up. VHI-30 scores returned to the baseline level for both groups at the 12-month follow-up. CONCLUSIONS: NMES is shown to provide a short-term benefit on vocal functions for NPC patients following radiation therapy. LEVEL OF EVIDENCE: 1b Laryngoscope, 127:1119-1124, 2017.

An Application of Item Response Theory and the Rasch Model in Speech Recognition Test Materials.

PURPOSE: The purpose of this study was to describe an attempt to apply item-response theory (IRT) and the Rasch model to construction of speech-recognition tests. A set of word-recognition test items applicable to children as young as 3 years old-with any level of hearing sensitivity, with or without using hearing devices-was developed. METHOD: Test items were constructed through expert consultation and by reference to some established language corpora, validated with 121 participants with various degrees of hearing loss and 255 with typical hearing. IRT and the Rasch model were applied to evaluate item quality. RESULTS: Eighty disyllabic word items were selected in accordance with IRT. The speech-recognition abilities of the 376 young participants are reported. The IRT analyses on this set of data are also discussed. CONCLUSIONS: A new set of speech-recognition test materials in Cantonese Chinese has been developed. Construction of short equivalent lists may be performed in accordance with IRT item qualities. Clinical applications of this test tool in the particular language population are discussed.

If cytology of Warthin tumor is accurate, can management be conservative?

We conducted a retrospective study to assess the accuracy of fine-needle aspiration cytology (FNAC) in the diagnosis of Warthin tumor and to evaluate the subsequent risk of conservative nonsurgical management. We reviewed the records of 75 patients (76 tumors) with a parotid mass that had been diagnosed as a Warthin tumor by FNAC. This patient population was made up of 64 men and 11 women, aged 46 to 93 years (mean: 67). Of the 76 tumors, 40 were treated with surgical excision and 36 with conservative measures. Histology of the 40 excised parotid masses revealed that 38 (95%) were indeed Warthin tumors, 1 (2.5%) was a low-grade adenocarcinoma, and 1 was benign-not otherwise specified. None of the 36 tumors underwent malignant transformation either clinically or on repeat FNAC (if performed) during a follow-up of 4 to 120 months (mean: 55.5 ± 32.2). We conclude that conservative management of Warthin tumors confidently diagnosed on FNAC may be an option for patients who are unwilling or unable to undergo surgical excision.

Expression of Antioxidant Molecules and Heat Shock Protein 27 in Thyroid Tumors.

Oxidative stress-induced DNA damage is a known causing factor for many types of tumors, but information on the role of oxidants and antioxidants in thyroid tumors is limited. The aim of this study was to determine antioxidant levels in thyroid tumors. In this study, tumor and its matched non-tumor thyroid tissue samples were obtained from 53 patients with thyroid tumors. The levels of manganese superoxide dismutase (MnSOD), thioredoxin reductase 2 (TXNRD2), glutathione (GSH), glutathione peroxidase (Gpx), catalase (CAT), and 27 kd heat-shock protein (hsp27) were determined in both thyroid tissue samples and cultured thyroid cells by immunohistochemical staining and western blot. Hydrogen peroxide (H2 O2 ) was used to generate oxidant stress in the cell culture experiments. We found that the levels of MnSOD, TXNRD2, GSH, Gpx, and Hsp27 were increased in both malignant and benign tumors, while the level of CAT was decreased. To verify the results of the tissue study, we treated cultured thyroid cells with H2 O2 and found the same pattern of antioxidant changes. Hsp27 was also increased after H2 O2 treatment. The expression of hsp27 was upregulated by 8.24-, 6.96-, and 3.09-fold in thyroid cancer, follicular adenoma, multinodular goiter, respectively. Collectively, our study demonstrated that the levels of hsp27 together with MnSOD, TXNRD2, GSH, and Gpx were significantly upregulated by H2 O2 in thyroid tumors. The increase of these antioxidants is observed in both malignant and benign tumors, particularly in the former. The upregulation of antioxidants is likely a protective mechanism of tumor cells to maintain their survival and growth. J. Cell. Biochem. 117: 2473-2481, 2016. © 2016 Wiley Periodicals, Inc.

Narrow band imaging endoscopy of the nasopharynx is not more useful than white light endoscopy for suspected nasopharyngeal carcinoma.

Endoscopy is often used to screen for nasopharyngeal carcinoma. A normal nasopharynx on white light endoscopy may yet harbor subclinical or occult malignancy. This study assessed whether the vascular pattern seen on narrow band imaging endoscopy could indicate this and thus be useful for detecting suspected nasopharyngeal carcinoma. The nasopharynx of 156 patients who failed serological screening for or presented with symptoms of nasopharyngeal carcinoma was graded under white light and narrow band imaging endoscopy and a biopsy taken. The accuracy of assessing the nasopharynx as being probably or definitely malignant on white light endoscopy was high (area under the curve = 0.924), as it was of being normal on narrow band imaging endoscopy (=0.799). The sensitivity and specificity of white light and narrow band imaging endoscopy for nasopharyngeal carcinoma was 93 and 22 %, and 92 and 98 %, respectively. Significantly associated with nasopharyngeal carcinoma was a high index of suspicion or definitely malignant grade on white light endoscopy (p < 0.0005, odds 58.978) and vascular tufts on narrow band imaging endoscopy (p = 0.020, odds 41.210). Narrow band imaging endoscopy of vasculature alone for suspected nasopharyngeal carcinoma is not more useful than white light endoscopy of nasopharyngeal morphology, nor does it add to or surpass the diagnostic accuracy of white light endoscopy in this regard.

Contemporary solutions for patients with microtia and congenital aural atresia - Hong Kong experience.

Managing microtia patients is always a challenge. Multidisciplinary approach, good family support, well established doctor-patient relationship and well organised patient-support groups are the essential elements for success. With the advancement of implantable hearing devices, more options will be available for the microtia patients. Otologists play a leading role in the whole management process. They not only provide proper guidance to the patients in choosing the correct path of the treatment, but also play a key role in organising and maintaining a cost-effective multidisciplinary rehabilitation team for the microtia patients.

Estrogen receptor α induces prosurvival autophagy in papillary thyroid cancer via stimulating reactive oxygen species and extracellular signal regulated kinases.

CONTEXT: The incidence of papillary thyroid cancer (PTC) shows a predominance in females, with a male:female ratio of 1:3, and none of the known risk factors are associated with gender difference. Increasing evidence indicates a role of estrogen in thyroid tumorigenesis, but the mechanism involved remains largely unknown. OBJECTIVE: This study aimed to assess the contribution of autophagy to estrogen receptor α (ERα)-mediated growth of PTC. DESIGN: The expression of ERα in thyroid tissue of patients with PTC tissues was analyzed. Cell viability, proliferation, and apoptosis were evaluated after chemical and genetic inhibition of autophagy. Autophagy in PTC cell lines BCPAP and BCPAP-ERα was assessed. RESULTS: ERα expression was increased in PTC tissues compared with the adjacent nontumor tissues. Estrogen induced autophagy in an ERα-dependent manner. Autophagy induced by estrogen/ERα is associated with generation of reactive oxygen species, activation of ERK1/2, and the survival/growth of PTC cells. Chemical and genetic inhibition of autophagy dramatically decreased tumor cell survival and promoted apoptosis, confirming the positive role of autophagy in the growth of PTC. CONCLUSIONS: ERα contributes to the growth of PTC by enhancing an important prosurvival catabolic process, autophagy, in PTC cells. The inhibition of autophagy promotes apoptosis, implicating a novel strategy for the treatment of ERα-positive PTC.

Inhibition of Foxp3 in cancer cells induces apoptosis of thyroid cancer cells.

Foxp3+ regulatory T cells (Tregs) in lymphocytes facilitate the thyroid tumor growth and invasion. Very limited information is available on Foxp3 expression in thyroid cancer cells and its function is totally unknown. This study demonstrated that Foxp3 expression was increased in thyroid cancer cells. Inhibition of Foxp3 decreased cell proliferation and migration, but increased apoptosis, suggesting a positive role of Foxp3 in cancer growth. Interestingly, Foxp3 inhibition enhanced PPARγ expression and activity. In addition, Foxp3 inhibition downregulated NF-κB subunit p65 and cyclin D1 but upregulated caspase-3 levels. These molecular changes are in line with Foxp3 shRNA-mediated alteration of cell functions. Collectively, our study demonstrates that thyroid cancer cells express a high level of functional Foxp3 and that the inhibition of the Foxp3 suppresses the proliferation and migration but promotes apoptosis, suggesting that targeting Foxp3 in thyroid cancer cells may offer a novel therapeutic option for thyroid cancer.

Fish bone impaction in the supraglottis.

The most common sites of fish bone impaction are the tonsils, tonsillar pillars, tongue base, valleculae, and piriform fossa. Impaction in the supraglottic area is extremely uncommon.