Targeting Nrf2 to treat thyroid cancer.

Oxidative stress (OS) is recognized as a contributing factor in the development and progression of thyroid cancer. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a pivotal transcription factor involved in against OS generated by excessive reactive oxygen species (ROS). It governs the expression of a wide array of genes implicated in detoxification and antioxidant pathways. However, studies have demonstrated that the sustained activation of Nrf2 can contribute to tumor progression and drug resistance in cancers. The expression of Nrf2 was notably elevated in papillary thyroid cancer tissues compared to normal tissues, indicating that Nrf2 may play an oncogenic role in the development of papillary thyroid cancer. Nrf2 and its downstream targets are involved in the progression of thyroid cancer by impacting the prognosis and ferroptosis. Furthermore, the inhibition of Nrf2 can increase the sensitivity of target therapy in thyroid cancer. Therefore, Nrf2 appears to be a potential therapeutic target for the treatment of thyroid cancer. This review summarized current data on Nrf2 expression in thyroid cancer, discussed the function of Nrf2 in thyroid cancer, and analyzed various strategies to inhibit Nrf2.

Autophagy regulates anti-angiogenic property of lenvatinib in thyroid cancer.

We aimed to explore the role of lenvatinib-mediated autophagy in papillary thyroid cancer (PTC). K1 and BCPAP, were tested for cell viability, proliferation, and apoptosis after treatment with lenvatinib or chloroquine (CQ) or both. The levels of angiogenesis vascular endothelial growth factor A (VEGFA) were measured by ELISA. Transwell and wound-healing assays were performed using endothelial HUVECs cells. The dynamics of microvessels were detected by tubular formation assay. Western blotting was used to determine the expression of LC3-I/II and Atg-7 and alterations in the PI3K/Akt/mTOR and MEK/ERK pathways. In vivo tumor growth assay and immunohistochemical staining (IHC) was also performed. The results showed that lenvatinib inhibited the viability of K1 and BCPAP cells and caused apoptosis. We further showed that lenvatinib also upregulated autophagy levels in thyroid cancer cells in a dose-dependent manner through the PI3K/Akt/mTOR and MEK/ERK pathways. Co-administration of lenvatinib with CQ resulted in a greater decrease of VEGFA in the tumor supernatant than with either lenvatinib or CQ alone. Autophagy inhibition enhanced the cytotoxicity and anti-angiogenic ability of lenvatinib, which was supported by the HUVECs migration, wound healing, and tube formation assays. Inhibiting autophagy chemically or genetically enhanced lenvatinib's cytotoxic effects and anti-angiogenic efficacy in thyroid cancer cells in vitro and in vivo. In conclusion, lenvatinib inhibited cell viability and induced apoptosis and autophagy in human PTC cells. Significantly, the combination of lenvatinib and autophagy inhibition may represent a novel and effective treatment option for PTC, which may be able to overcome drug resistance.

Applying Rasch model analysis in the development of the cantonese tone identification test (CANTIT).

OBJECTIVE: Applying Rasch analysis to evaluate the internal structure of a lexical tone perception test known as the Cantonese Tone Identification Test (CANTIT). DESIGN: A 75-item pool (CANTIT-75) with pictures and sound tracks was developed. Respondents were required to make a four-alternative forced choice on each item. A short version of 30 items (CANTIT-30) was developed based on fit statistics, difficulty estimates, and content evaluation. Internal structure was evaluated by fit statistics and Rasch Factor Analysis (RFA). STUDY SAMPLE: 200 children with normal hearing and 141 children with hearing impairment were recruited. RESULTS: For CANTIT-75, all infit and 97% of outfit values were < 2.0. RFA revealed 40.1% of total variance was explained by the Rasch measure. The first residual component explained 2.5% of total variance in an eigenvalue of 3.1. For CANTIT-30, all infit and outfit values were < 2.0. The Rasch measure explained 38.8% of total variance, the first residual component explained 3.9% of total variance in an eigenvalue of 1.9. CONCLUSIONS: The Rasch model provides excellent guidance for the development of short forms. Both CANTIT-75 and CANTIT-30 possess satisfactory internal structure as a construct validity evidence in measuring the lexical tone identification ability of the Cantonese speakers.

Endoscopic skull base training using 3D printed models with pre-existing pathology.

Endoscopic base of skull surgery has been growing in acceptance in the recent past due to improvements in visualisation and micro instrumentation as well as the surgical maturing of early endoscopic skull base practitioners. Unfortunately, these demanding procedures have a steep learning curve. A physical simulation that is able to reproduce the complex anatomy of the anterior skull base provides very useful means of learning the necessary skills in a safe and effective environment. This paper aims to assess the ease of learning endoscopic skull base exposure and drilling techniques using an anatomically accurate physical model with a pre-existing pathology (i.e., basilar invagination) created from actual patient data. Five models of a patient with platy-basia and basilar invagination were created from the original MRI and CT imaging data of a patient. The models were used as part of a training workshop for ENT surgeons with varying degrees of experience in endoscopic base of skull surgery, from trainees to experienced consultants. The surgeons were given a list of key steps to achieve in exposing and drilling the skull base using the simulation model. They were then asked to list the level of difficulty of learning these steps using the model. The participants found the models suitable for learning registration, navigation and skull base drilling techniques. All participants also found the deep structures to be accurately represented spatially as confirmed by the navigation system. These models allow structured simulation to be conducted in a workshop environment where surgeons and trainees can practice to perform complex procedures in a controlled fashion under the supervision of experts.

Evaluation and validation of four translated Chinese questionnaires for obstructive sleep apnea patients in Hong Kong.

BACKGROUND: The present study validates and evaluates the sensitivity and specificity of four internationally popular questionnaires, translated into Chinese, for assessing suspected obstructive sleep apnea (OSA) patients, namely, the Berlin questionnaire, the ASA checklist, the STOP questionnaire and the STOP-BANG questionnaire. Their predictive values in OSA risks in patients presenting with OSA symptoms are examined. Questionnaires may be helpful in prioritizing polysomnography (PSG) and in treatment for the more severe cases. METHODS: All patients attending our sleep laboratory for overnight PSG were recruited. They were asked to complete three questionnaires (Berlin, ASA checklist and STOP) 2 weeks before and on the same night as the PSG. STOP-BANG questionnaire, an extended STOP with demographic data, 'B'-body mass index (BMI), 'A'-age, 'N'-neck circumference and 'G'-gender was completed by our technologists using the patient's completed STOP. RESULTS: A number of 141 patients were recruited. The sensitivities and specificities for STOP-BANG with cutoffs at PSG's RDI=5, RDI=15 and RDI=30 were 81% to 86% and 34% to 57%, respectively. The high-risk group patients identified by STOP-BANG had significantly higher respiratory disturbance index and lower minimum oxygen saturation than the low-risk group patients. CONCLUSION: Among the four questionnaires studied, STOP-BANG, with only eight questions and the highest sensitivity, is the best questionnaire of the four for OSA screening. This can potentially assist in prioritizing PSG and can be helpful in clinical or self-evaluation by the general public.

Evaluation of a porcine vascular model to assess the efficacy of various hemostatic techniques.

BACKGROUND: A novel live porcine model replicated the endoscopic surgical field of a carotid arterial injury of the human skull base. Hemostatic techniques were applied to jugular venous and carotid arterial injuries, including muscle patches, hemoclips, and aneurysm clips. Doppler imaging distal to the injury assessed flow through the repaired vessel. MATERIALS AND METHODS: External jugular veins, and internal carotid arteries isolated from seven live anesthetized 100 kg pigs, were placed into a sinus model otorhino neuro trainer for visualization via an endoscopic nasal approach. Vessels were systematically injured and repaired, and Doppler measurements were made to assess flow through the vessels before injury and following repair. RESULTS AND CONCLUSIONS: Blood pressures were maintained within physiological ranges, despite blood losses of up to 4.5 l. Venous injuries were repaired using Floseal, hemoclips, and aneurysm clips, while arterial injuries were repaired with muscle patches and aneurysm clips. Blood flow remained in all vessels after repair. This porcine model was effective for demonstration of arterial and venous injuries during endoscopic skull base surgery. Crushed muscle patch was effective for arterial injuries of 3 mm, and the aneurysm clips for injuries of 5 mm. Jugular venous injuries of 3 mm were repaired using Floseal, 5 mm using hemoclips, and 6 mm using aneurysm clips. Doppler imaging was a noninvasive means of demonstrating ongoing flow through injured and repaired vessels. The model represents a valuable training tool with the potential to train endoscopic skull base teams the skills required to manage an internal carotid artery injury.

Sleep endoscopy with midazolam: sedation level evaluation with bispectral analysis.

OBJECTIVE: This study examines subjects' level of consciousness with bispectral analysis in sedation endoscopy of the upper airway. STUDY DESIGN: A prospective study. SETTING: University hospital. SUBJECTS AND METHODS: Bispectral analysis levels recorded in natural sleep of 43 patients with obstructive sleep apnea during an overnight polysomnographic sleep study were directly compared with the levels recorded during midazolam sedation sleep endoscopy in the same subjects. The possible muscle relaxation effect of midazolam was examined via surface chin electrodes. Supine Müller maneuver findings in 50 patients with obstructive sleep apnea were also compared with soft tissue dynamics during midazolam sedation sleep endoscopy. RESULTS: In our study of the 43 patients with bispectral analysis during natural sleep and midazolam sedation sleep endoscopy, a predominance of bispectral analysis values indicating N1 and N2 sleep was observed during the sedation study. Midazolam failed to achieve deeper levels of sleep with minimal N3 and no convincing rapid eye movement. As N1 and N2 are the stages during which maximal dynamic activities occur, and they make up an average of 70.5% of total sleep time, from 210 sleep studies at our laboratory, the present technique would be ideal as a surgical assessment tool. No muscle relaxation effect could be detected at our protocol dose of midazolam. The supine Müller maneuver findings were significantly different from those observed during sedation sleep. CONCLUSION: These findings support the value of sleep endoscopy as an efficient and informative technique for the examination of upper airway dynamics relevant to focused surgical planning.

Lexical tone perception ability of profoundly hearing-impaired children: performance of cochlear implant and hearing aid users.

OBJECTIVE: In tone languages such as Cantonese, a change in tone denotes a change in lexical meaning. The present study investigates the functional benefit of hearing devices in assisting tone perception among children with profound hearing impairment. SUBJECTS: Fifty-two children with profound hearing loss were categorized into two groups based on their primary type of hearing device - a hearing aid group and cochlear implant group. METHODS: A 75-item tone identification test covering all 15 Cantonese tone contrast pairs was administered to each subject under two conditions - unaided (hearing devices turned off) and aided (devices turned on). The proportion of correct responses was computed as the total score for all items and subtotal contrast scores for each of the 15 tone contrasts. RESULTS: The results indicated no significant differences between the children wearing hearing aids and those with cochlear implants under the unaided or the aided condition (z = -0.91, p = 0.36; z = -0.40, p = 0.69, respectively). Regardless of the type of device used, the total scores under the aided condition were higher than those under the unaided condition (z = -3.55 for the hearing aid group; z = -4.87 for the cochlear implant group, both ps < 0.01). CONCLUSION: Children wearing hearing devices generally have a satisfactory functional gain in tone perception. No major observable difference was noted between children using cochlear implants and those using hearing aids. Tone contrast pairs with dissimilar fundamental frequency at onset and dissimilar tone contour patterns were more easily identified.

Age sensitivity in the acquisition of lexical tone production: evidence from children with profound congenital hearing impairment after cochlear implantation.

OBJECTIVES: This study investigated the effects of implant experience and age at implantation on the Cantonese tone production of children with cochlear implants. The study also examined whether there was a particular age at which children were more responsive to acquiring tones. METHODS: The study included 45 children who had received unilateral cochlear implants at a mean age of 65.56 months. The subjects were grouped according to their age at cochlear implantation and were assessed annually for 5 years thereafter. A picture-naming task was used to measure their tone production performance. RESULTS: A simple effect of age at implantation was significant at all testing intervals except at the preoperative data point. Children who were younger than 4 years of age when they received their implants scored significantly higher than did the 2 older groups at various testing intervals. A significant simple effect of implant experience was also found. Progress was most striking in children who received their implants before the age of 4 years. CONCLUSIONS: For the most effective acquisition of Cantonese lexical tones, children should undergo early cochlear implantation. For children who receive implants before the age of 4 years, benefits are noted in tone production ability in terms of a faster rate of improvement within a shorter period of time.

How reliable is contact endoscopy of the nasopharynx in patients with nasopharyngeal cancer?

OBJECTIVES/HYPOTHESIS: To evaluate diagnostic reliability of contact rhinoscopy in patients with nasopharyngeal carcinoma. STUDY DESIGN: A cross-sectional randomized single-blinded study was carried out to evaluate the reliability of the findings of contact rhinoscopy in patients with nasopharyngeal carcinoma assessed by different observers. METHODS: Random images of contact endoscopy of 157 subjects including normal patients and patients with nasopharyngeal carcinoma, both prior to external beam radiation therapy (RT), the non-RT group, and after external beam radiation therapy, the post-RT group, were available for analysis. Three independent observers of varying clinical experience and histopathologic knowledge viewed the images and made a diagnosis for each image. The diagnosis of each image was correlated with the histology of the biopsy from the corresponding patient. RESULTS: In the non-RT group, Kappa values for inter- and intraobserver reliability to differentiate normal epithelium from primary nasopharyngeal carcinoma were 0.894, 1.000, 0.794 and 0.694, 1.000, 0.776 for the house officer, radiologist, and pathologist, respectively. There were no significant differences in interobserver and intraobserver reliabilities between the assessors. In the post-RT group, Kappa values for the inter- and intraobserver reliability to diagnose recurrent carcinoma or atypia, squamous metaplasia, and radiation change for the three observers were 0.820, 0.718, 0.775 and 0.731, 0.622, 0.734, respectively. There were no significant differences in interobserver and intraobserver reliabilities between the assessors. CONCLUSIONS: The clinical diagnosis of nasopharyngeal carcinoma by contact endoscopy is highly reliable and is not dependent on the clinical experience or knowledge of histopathology of the observers.

Tone perception results with Harmony and HiRes 120 in Cantonese-speaking subjects.

The goal of this study was to examine tonal language perception in adults with cochlear implants who are native speakers of Cantonese. Ten adult subjects were implanted with HiRes 90K devices and participated in the study. Baseline data were obtained with standard HiRes and compared with HiRes 120. Subjects were evaluated using a tone identification test and a questionnaire. While objective outcome measures with the tone identification test did not show significant differences between standard HiRes and HiRes 120, subjective evaluation with the questionnaire showed significant differences in the overall satisfaction perceived by subjects. HiRes 120 received a significantly higher rating and the majority of subjects preferred HiRes 120.

[Treatment of moderately severe hearing loss with totally implantable hearing aid].

OBJECTIVE: To evaluate the safety and effectiveness of totally implantable hearing aid (Carina) was assessed in adult patients with bilateral moderate to severe hearing loss. METHODS: Surgical implantations of Carina were performed in three adult patients with bilateral moderate to severe hearing loss. The safety and effectiveness were evaluated in a more than 12 months follow-up by comparison of outcomes of PTA and speech audiometry pre and post-operatively. The daily usage of implants was observed and compared with traditional hearing aids. RESULTS: The average elevation of unaided threshold elevation on surgical side was 8.3 dB postoperatively. The average functional gain in four speech frequencies of PTA was 35.4 dB HL and the average threshold decrease of speech discrimination was 22.5 dB HL. The subjective scoring of performance of the implants is significantly higher than traditional hearing aid. CONCLUSIONS: Totally implantable hearing aid (Carina) is an ideal implant to treat moderate to severe hearing loss. Long term follow-up is needed to validate the results.

Tone perception in Cantonese-speaking children with hearing aids.

OBJECTIVES: In this study we investigated the benefit of using hearing aids for Cantonese tone perception among children with various degrees of hearing impairment. METHODS: Forty-eight children with moderate to profound hearing loss were investigated. They were required to perform a lexical tone perception test with recorded test stimuli presented at 65 dB in soundproof booths. To allow for comparison, the subjects performed the test under 2 conditions: with their hearing aids turned off (unaided condition) and with them turned on (aided condition). RESULTS: The mean tone perception scores for the aided condition were higher than those for the unaided condition across all of the subject groups. Paired sample t-tests showed statistically significant improvement in tone perception in the moderate and severe hearing loss groups (p = .02 and p = .03, respectively). The result obtained from the moderately severe hearing loss group was marginally significant (p = .058). The improvement in tone perception in the profound hearing loss group was insignificant (p = .55). CONCLUSIONS: The use of a hearing aid is beneficial for Cantonese tone perception in children who have moderate to severe hearing impairment. When a hearing loss is greater than 90 dB, ie, in children who are classified as having profound hearing loss, a hearing aid is not effective in aiding Cantonese tone perception.

The tone production performance of children receiving cochlear implants at different ages.

Sixty prelingually deaf children were tested on Cantonese tone production ability at seven time intervals. Results of linear regression showed children in general improved in tone production performance over time. The magnitude of improvement, nevertheless, was different for children implanted at different ages. For children to acquire tone acquisition satisfactory, a critical age of four to receive implant is suggested. Optimally, children should receive their implant before two where they will be able to achieve around 80% accuracy in tone production within 1 yr of implant use. Children received their implant from two to just below 4 yr old achieved high tone production accuracy but needed a longer duration of implant experience. Children who received their implants at the age of 4 yr or older made little, if any, progress in producing tones correctly even after four to 5 yr of implant use.

The combined olfactory test in a Chinese population.

OBJECTIVE: To establish an olfactory test in the Hong Kong Chinese population. STUDY DESIGN: Prospective analysis of the results of a combined olfactory test (COT) for patients with olfactory dysfunction and for normal subjects attending a secondary and tertiary ear, nose and throat centre. METHOD: Our COT was based on and modified from the Connecticut Chemosensory Research Centre test. It consisted of an odour identification test involving nine substances and a threshold test using a series of threefold dilutions of 1-butanol. From September 1998 to June 2002, 188 Hong Kong Chinese patients with olfactory dysfunction and subjects with normal olfaction were prospectively recruited. The subjects were categorized into normal, hyposmic and anosmic groups. The olfactory function of the main group of subjects (n = 153) was assessed with the COT by a blinded observer and also quantified with a visual analogue scale; the results were analysed to validate the discriminative ability of the COT. Another subgroup of subjects (n = 35) was tested with the COT twice with a two-week interval to evaluate test-retest reliability. RESULTS: There were 42 normal, 68 hyposmic and 43 anosmic subjects within the main group (total n = 153). The identification scores, threshold scores and combined olfactory scores were statistically significantly different between the anosmic, hyposmic and normal groups of subjects (p < 0.001). The combined olfactory score correlated with the visual analogue score and the correlation coefficient was 0.56 (p < 0.01). The mean time spent on each COT was 8.6 minutes (standard deviation = 3.4 minutes). The test-retest reliability of the COT was satisfactory, with a one-way model intraclass correlation coefficient of 0.87 (n = 35). CONCLUSION: The satisfactory discriminative ability and test-retest reliability of the COT have been demonstrated in this study. The COT is a feasible method for assessing sense of smell in the Hong Kong Chinese population.

In vivo real-time diagnosis of nasopharyngeal carcinoma in situ by contact rhinoscopy.

BACKGROUND: Nasopharyngeal dysplasia or nasopharyngeal carcinoma in situ (NPCIS) lesions have rarely been reported. Timely diagnosis of the preinvasive lesion may improve prognosis. Contact endoscopy has been documented to accurately differentiate normal cells of the nasopharynx from malignant cells and allows a real-time diagnosis of primary and recurrent nasopharyngeal carcinoma (NPC) in a clinical setting. However, the role of contact endoscopy in the diagnosis of NPCIS is unknown. METHODS: The superficial cells of the nasopharynx in a patient with NPCIS were examined in vivo under local anaesthesia by use of a contact rhinoscope. The contact endoscopic findings were correlated with the histologic findings of the biopsy. RESULTS: The atypical cells of the lesion were magnified and visualized under contact endoscopy. Histopathologic analysis of the biopsied tissue confirmed the presence of NPCIS staining positively for Epstein-Barr virus (EBV)-encoded RNA (EBER). No cell-free EBV DNA was detected in the sera of the patient. CONCLUSIONS: Contact endoscopy can accurately identify the atypical cells of a tiny preinvasive lesion in the nasopharynx in a clinical setting, which may not be evident in routine imaging examination.

Array-based comparative genomic hybridization analysis identified cyclin D1 as a target oncogene at 11q13.3 in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma is highly prevalent in Southern China and Southeast Asia. To unveil the molecular basis of this endemic disease, high-resolution comparative genomic hybridization arrays were used for systematic investigation of genomic abnormalities in 26 nasopharyngeal carcinoma samples. A comprehensive picture of genetic lesions associated with tumorigenesis of nasopharyngeal carcinoma was generated. Consistent chromosomal gains were frequently found on 1q, 3q, 8q, 11q, 12p, and 12q. High incidences of nonrandom losses were identified on chromosomes 3p, 9p, 11q, 14q, and 16q. In addition to previously characterized regions, we have identified several novel minimal regions of gains, including 3q27.3-28, 8q21-24, 11q13.1-13.3, and 12q13, which may harbor candidate nasopharyngeal carcinoma-associated oncogenes. In this study, gain of 11q13.1-13.3 was the most frequently detected chromosomal aberration and a 5.3-Mb amplicon was delineated at this region. Within this 11q13 amplicon, concordant amplification and overexpression of cyclin D1 (CCND1) oncogene was found in nasopharyngeal carcinoma cell lines, xenografts, and primary tumors. Knockdown of cyclin D1 by small interfering RNA in nasopharyngeal carcinoma cell lines led to significant decrease of cell proliferation. The findings suggest that cyclin D1 is a target oncogene at 11q13 in nasopharyngeal carcinoma and its activation plays a significant role in nasopharyngeal carcinoma tumorigenesis.

Spoken word recognition in children with cochlear implants: a five-year study on speakers of a tonal language.

OBJECTIVES: To study the effects of age at implantation and duration of implant use on the performance of spoken word recognition of pediatric cochlear implantees in a tonal language setting over a period of 5 years. DESIGN: Sixty-four children, given implants between the ages 1:01 and 14:09 (years:months), were divided into three age groups. They were tested on open-set word recognition ability at seven time intervals from before surgery to 5 years after surgery. Analyses of variance with repeated measurements were used to examine the effect of their age at implantation and the duration of implant use. RESULTS: Duration of implant experience was significant in spoken word recognition across the three age groups (p < 0.01). Children given implants below the age of 3 years caught up with the performance of the older children at 12 months after implantation. The difference in score reached statistical significance at 2 and at 3 years after surgery (p = 0.03, p = 0.00). CONCLUSIONS: The performance of Cantonese-speaking children was similar to that of English-speaking children in that better outcomes were associated with longer implant experience as well as when implantation occurred at a younger age. The children implanted before the age of 3 and who had an implant experience of more than 2 years outperformed the children who were given implants after the age of 6 and also sustained these higher scores throughout 5 years of postimplant testing.