Brusatol attenuated proliferation and invasion induced by KRAS in differentiated thyroid cancer through inhibiting Nrf2.

BACKGROUND: Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) can be developed from differentiated thyroid cancer, and this dedifferentiated transformation leads to poor prognosis and high mortality. The role of Nrf2 in the dedifferentiation of differentiated thyroid cancer (DTC) induced by KRAS remains unclear. METHODS AND MATERIALS: In this study, two DTC cell lines, BCPAP and WRO, were used to evaluate the function of Nrf2 in the dedifferentiation caused by wild-type KRAS (KRAS-WT) and G12V point mutation KRAS (KRAS-G12V). RESULTS: The overexpression of KRAS-WT and KRAS-G12V increased the proliferative and invasive ability of BCPAP and WRO cells. Aggressive morphology was observed in KRAS-WT and KRAS-G12V overexpressed WRO cells. These results suggested that overexpression of KRAS-WT or KRAS-G12V may induce dedifferentiation in DTC cells. The expression of Nrf2 was increased by KRAS-WT and KRAS-G12V in DTC cells. In addition, compared with normal thyroid tissues, the expression of Nrf2 protein was considerably higher in thyroid cancer tissues on immunohistochemistry (IHC) staining, and the increased expression of Nrf2 indicated a poor prognosis of thyroid cancer. These results indicated that Nrf2 is the KRAS downstream molecule in thyroid cancer. Functional studies showed that the Nrf2 inhibitor Brusatol counteracted the proliferative and invasive abilities induced by KRAS-WT and KRAS-G12V in BCPAP and WRO cells. In addition, the xenograft assay further confirmed that Brusatol inhibits tumor growth induced by KRAS-WT and KRAS-G12V. CONCLUSION: Collectively, this study suggests that Nrf2 could be a promising therapeutic target in KRAS-mediated dedifferentiation of thyroid cancer.

Psychometric properties of the Chinese (Cantonese) Tinnitus Handicap Inventory.

OBJECTIVES: To establish the reliability and validity of the Chinese (Cantonese) version of the Tinnitus Handicap Inventory to measure the self-perceived handicapping effect and severity of the condition in patients with chronic tinnitus. DESIGN: Cross-sectional psychometric validation study. SETTING: Audiology clinics in a hospital setting. PARTICIPANTS: Subjects were 114 adult Chinese who attended the audiology clinics with a complaint of tinnitus. MAIN OUTCOME MEASURES: Test-retest and internal consistency reliability; construct validity. RESULTS: The Chinese version of the Tinnitus Handicap Inventory and its subscales showed good internal consistency reliabilities (alpha = 0.72-0.94) that are comparable to those of the original version. High correlations were observed between the Tinnitus Handicap Inventory and psychological distress, tinnitus-related problem ratings and severity ratings. Factor analysis showed that the Chinese version of the Tinnitus Handicap Inventory has a unifactorial structure. A high degree of test-retest reliability was observed (intraclass correlation coefficient = 0.88). CONCLUSIONS: The results suggest that the Chinese (Cantonese) version of the Tinnitus Handicap Inventory is a reliable and valid measure of general tinnitus-related distress that can be used in clinical settings to quantify the impact of tinnitus on daily life.

The accuracy of parent and teacher reports in assessing the vocabulary knowledge of Chinese children with hearing impairment.

PURPOSE: This study aimed to investigate (a) the accuracy of adult reports in assessing the vocabulary knowledge of Cantonese-speaking children with hearing impairment (HI) and (b) the factors that are associated with the accuracy of those reports. METHOD: The first participant group consisted of 47 children and their mothers. The second group consisted of 47 children and 21 teachers. All of the children had profound HI, with a mean age of 57 months. The ratings of the adults were compared with the children's test scores in a standardized test. RESULTS: Both adult groups reported children's performance with satisfactory accuracy. Mother and teacher ratings showed fair to good agreement with each other. Two factors significantly associated with the accuracy of the report were (a) the difficulty of the vocabulary and (b) the child's vocabulary ability as determined by the standardized norm-referenced receptive vocabulary test. The mothers' education level, occupation, and socioeconomic status, and the teachers' teaching experience and length of time they had trained the child, were not significant factors. CONCLUSION: The results suggest that employing adult reports to collect data on the word knowledge of children with HI is applicable to a broad spectrum of the Cantonese-speaking Chinese population.

A region of homozygous deletion on chromosome 9p21-22 in primary nasopharyngeal carcinoma.

Using 21 microsatellite polymorphic markers spanning both p and q arms, we have performed detailed deletion mapping on chromosome 9 in 18 primary nasopharyngeal carcinomas. All 18 tumors were informative at multiple loci. Eleven of the 18 cases (61%) demonstrated allelic deletion of chromosome 9. Among these 11, 6 cases are likely to be tumors with monosomy of chromosome 9. The other 5 cases demonstrated partial deletion by showing multiple areas of allelic loss. In one of the 5 cases, a homozygous deletion region was identified which includes D9S126, D9S171, and IFNA loci at 9p21-22, situated between loci D9S161 (9p21) and D9S162 (9p21-22). The presence of a homozygous deletion strongly suggests the presence of tumor suppressor gene(s) involved in the tumorigenesis of nasopharyngeal carcinoma. The same region has been reported to include some potential tumor suppressor gene loci in other cancers. This is the first reported finding of frequent genetic loss observed on chromosome 9 in nasopharyngeal carcinomas in addition to allelic loss on chromosome 3p at specific regions. Our results suggest that tumorigenesis and progression of nasopharyngeal carcinomas, like other solid tumors, involves multiple genetic changes associated with the inactivation of tumor suppressor genes.

Lexical tone perception in native speakers of Cantonese.

PURPOSE: This study aimed at investigating (1) tone perception development among typically-developing Cantonese speakers and (2) the hierarchy of tone perception difficulty among the 15 tone contrasts. METHOD: Two-hundred typically-developing children aged 3-10 and a group of 25 normal hearing adults were recruited. They were tested on a pool of 75-item calibrated recorded speech signals. Participants responded to each stimulus by pointing at the corresponding picture displayed on a computer screen from a choice of four. RESULT: There was a gradual increase in tone perception accuracy from children aged 3-6. After age 6, tone perception accuracy was similar to adults with an average error rate of 3-8%. The two tone contrasts that listeners consistently found difficult to distinguish were T2T5 (high-rising vs low-rising) and T3T6 (mid-level vs low-level). In addition, all children groups also showed difficulty in T4T6 identification (low-falling vs low-level). CONCLUSION: Tone perception is not error-free even among native Cantonese-speaking adults. Overall tone identification performance improved steadily from age 3 to age 6. Based on the participants' performance, a three-tier set of tone groups, with an increasing level of difficulty for identification, is proposed for rehabilitation purposes. These tone groups are (1) Easy: T1T2, T1T3, T1T4, T1T5, T1T6, and T2T3, (2) Medium: T2T4, T2T6, T3T4, and T4T5, and (3) Hard: T2T5, T3T5, T3T6, T4T6, and T5T6.

Resistance to apoptosis of HPV 16-infected laryngeal cancer cells is associated with decreased Bak and increased Bcl-2 expression.

Human papillomavirus type 16 (HPV 16) plays an etiological role in human laryngeal carcinoma. Apoptosis is closely associated with various biological processes including oncogenesis. This study investigated how HPV 16 oncoproteins E6 and E7 affect apoptosis in human laryngeal cancer cells. We established two human laryngeal cancer cell lines that expressed HPV 16 E6 and E7, respectively. Using these two cell lines, we found that both E6 and E7 exhibited an inhibitive effect on apoptosis induced by tumor necrosis factor alpha and cycloheximide. In both transfected cell lines, the expression of pro-apoptotic Bak was reduced and that of anti-apoptotic Bcl-2 was over-expressed. However, the expression of caspase-3 and caspase-8 was not significantly different between the E6- and E7-transfected cells and the control cells without HPV 16. p53 Protein was not detected in either the transfected or the non-transfected cells. Our study indicates that: (1) HPV 16 E6 and E7 oncoproteins are capable of inhibiting apoptosis in laryngeal squamous carcinoma cells; (2) the mechanism modulated by E6 and E7 involves the over-expression of Bcl-2 and the down-regulation of Bak; (3) the anti-apoptotic pathway is not related to the level of p53, caspase-3, or caspase-8. These results suggest that the dysregulation of apoptotic molecules Bak and Bcl-2 by HPV 16 E6 and E7 plays a role in the prolongation of cell survival, which may subsequently contribute to the development of human laryngeal cancer.

Adult croup.

Adult croup is a distinct disease entity that probably represents a heterogeneous clinical syndrome. Three cases of adult laryngotracheitis characterized by upper airway infection and progression to airway obstruction are illustrated. Close observation and prompt decisions regarding airway intervention are critical in effective management, and complete resolution is expected.

Diagnosis of nasopharyngeal tuberculosis by detection of tuberculostearic acid in formalin fixed, paraffin wax embedded tissue biopsy specimens.

The use of gas chromatography and mass spectrometry with selected ion monitoring detected tuberculostearic acid (TBSA) in 10 of 12 formalin fixed, paraffin wax embedded nasopharyngeal and head and neck biopsy specimens from patients with confirmed tuberculosis and carcinoma, and in one of 50 control specimens (giving a sensitivity of 83% and a specificity of 98%). The two false negative cases had very small tissue fragments and the patient with a false positive result may have had pulmonary tuberculosis. Tuberculostearic acid (TBSA) was also detected in nine of 16 specimens from the head and neck region with non-caseating granulomas suspected, but not confirmed, to be tuberculosis. It is concluded that nasopharyngeal tuberculosis is relatively common in Hong Kong and should be considered when biopsy specimens show granulomas. The detection of TBSA in tissue biopsy specimens is a useful, rapid method for the diagnosis of tuberculosis and other mycobacterial infections, and can be conveniently performed within two days on formalin fixed and paraffin wax embedded material.

Late swallowing and aspiration problems after esophagectomy for cancer: malignant infiltration of the recurrent laryngeal nerves and its management.

One hundred eleven patients who underwent esophagectomy for squamous carcinoma of the esophagus were followed up during a 42-month period. Forty-three patients who had normal swallowing in the postoperative period had recurrent dysphagia on follow-up. The causes were benign anastomotic stricture (n = 15), malignant anastomotic recurrence (n = 2), recurrent laryngeal nerve palsy (n = 22), and no known cause (n = 4). Twenty-six patients were assessed by laryngoscopy and 15 were deemed suitable for Teflon injection of the vocal cord. All but one patient had improved swallowing and phonation after the procedure. Mean survival time after Teflon injection was 5 1/2 months. A significant proportion of swallowing problems after esophagectomy are not caused by mechanical obstruction. Teflon injection of a unilateral paralyzed vocal cord provides good palliation in these patients.

Fatal haemoperitoneum as a result of liver metastases from nasopharyngeal cancer.

Spontaneous rupture of hepatic metastases is rare, there being only 22 cases documented in the literature. We report here the first such case owing to nasopharyngeal carcinomatous metastases. This is of interest because in South East Asia ruptured hepatocellular carcinoma is the usual cause of fatal haemoperitoneum.

Lugol's iodine dye-enhanced endoscopy in patients with cancer of the oesophagus and head and neck.

Lugol's iodine dye indicates the presence of unsuspected early oesophageal cancers during endoscopy at which such cancers fail to show the characteristic black colour change. We evaluated Lugol's iodine dye-enhanced endoscopy in 17 patients with oesophageal cancer. In a further 37 patients with head and neck cancer we examined the use of Lugol's iodine since these patients have a 29% risk of synchronous oesophageal cancer. The oesophagus was sprayed with Lugol's iodine (1.5%) during endoscopy. Any areas not turning black were biopsied. In 13 patients with oesophageal cancer discrete areas beyond the macroscopically obvious primary tumour showed no change in colour. Biopsy revealed cancer in all cases. Six synchronous cancers were found in the head and neck group, one of which was identified only by the use of Lugol's iodine. Lugol's iodine augmented the information gained about the oesophageal mucosa during endoscopy. It revealed unsuspected cancer which altered the management of patients with primary oesophageal cancer as well as those with head and neck cancer. We recommend the routine use of Lugol's iodine-enhanced endoscopy for surveillance of all 'at risk' oesophageal cases.

Detection of the tumour suppressor gene p53 in nasopharyngeal carcinoma in Hong Kong Chinese.

This study has investigated the expression of the p53 tumour suppressor gene in 41 cases of primary nasopharyngeal carcinomas (NPC) using the p53 monoclonal antibody BP53-12. Moderate p53 expression was found in 54% and strong expression in 12% of the specimens. There was no correlation between p53 expression and any of the clinicopathological parameters or survival. Surprisingly, three research groups have investigated p53 mutations in NPC and found no fresh tumour specimens to contain p53 mutations in exons 4-8 of the gene. It may be argued that as p53 overexpression has been demonstrated in 70% of the patients investigated in this study, that the mutations lie outside the 4-9 exon region. We are in the process of testing this hypothesis.

A case of neonatal stridor.

A case is reported of a retropharyngeal abscess in a neonate who presented with increasing stridor since birth. Group B streptococcus was cultured from the abscess contents and the maternal birth tract.

Diagnosing nasopharyngeal cancer.

When nasopharyngeal carcinoma is suspected clinically, an adequate tissue sample should be taken at the patient's first visit. Should the initial tissue sample be nondiagnostic, depending on the index of suspicion in the individual case, the process may be repeated under either local or general anesthesia. It is important that a detailed examination of the nasopharynx be undertaken in the outpatient setting. Biopsy should be performed accurately under direct visualization. Large biopsy forceps are essential to obtain an adequate tissue sample. Biopsy under local anesthesia is safe, easy to perform, well tolerated by the patient, and should be undertaken in the outpatient clinic. This direct diagnostic approach achieves a rapid diagnosis in patients with nasopharyngeal carcinoma.

Endoscopic terminal dacryocystorhinostomy.

OBJECTIVE: Traditional endoscopic dacryocystorhinostomy (DCR) involves creation of a lacrimal sac side hole that may close down in the presence of a partially patent lower lacrimal drainage system. Endoscopic terminal DCR is a modified DCR procedure designed to prevent this problem. METHODS: From September 1996 to June 1999, 16 patients (17 sides) had endoscopic terminal DCR that involved resection of the lacrimal sac-duct junction to achieve total separation of the lacrimal sac from the nasolarcrimal duct and creation of a terminal DCR opening. RESULTS: Ten of the 17 DCRs were primary and 7 were revisions. The follow-up ranged from 3 to 36 months. There were two failures. One failure was due to canalicular obstruction and the other was due to prolapse of orbital fat hindering proper fashioning of the mucosal flap. The overall success rate was 88%. CONCLUSIONS: Instead of creating a side hole in the lacrimal sac as proposed by most endoscopic DCR studies, we advocate total diversion of tear flow by performing a terminal DCR opening that would further improve the success rate of endoscopic DCR, particularly in cases of idiopathic and partial obstruction.

A technique of mastoidectomy and meatoplasty that minimizes factors associated with a discharging mastoid cavity.

OBJECTIVES: To present and assess a surgical technique designed to minimize the known causes of a discharging mastoid cavity. STUDY DESIGN: A temporal bone dissection to establish the anatomical relationships on which the surgical technique is based. A presentation of the proposed surgical technique and a prospective assessment of the technique in twenty consecutive mastoidectomies. METHODS: Five temporal bone dissections were performed to establish the relationship between the chorda tympani and the facial nerve when these structures are approached from above. The surgical technique is presented and the mastoid cavities of twenty consecutive patients assessed. The assessment included measurement of the facial ridge height, "kidney-shape" of the cavity, size of the cavity, size of the meatus, and state of the tympanic membrane. RESULTS: In the temporal bone dissections the vertical height between the chorda tympani and the facial nerve at 3/9 o'clock was a mean of 2.01 mm. Nineteen of the 20 consecutive mastoid cavities (95%) performed with the presented technique remained well healed and dry. The mean facial ridge height was 2.7 mm at 3/9 o'clock and 4.8 mm at 6 o'clock. The kidney-shaped measurement was 1.45 mm. The mean size of the cavities was 2.6 mm and 18 of the 20 patients (90%) had an intact tympanic membrane. The mean largest diameter of the meatus was 10.1 mm. CONCLUSIONS: The surgical technique presented produces a mastoid cavity with a low facial ridge and oval shape. These two factors have been previously identified as important in the outcome of mastoid surgery.

New guidelines for endoscopic localization of the anterior ethmoidal artery: a cadaveric study.

OBJECTIVES: To determine objective data to improve the methods of identification of the anterior ethmoidal artery during endoscopic dissection. STUDY DESIGN: Cadaveric dissection of adult human heads. METHODS: A 0 degrees, 4-mm rigid endoscope was used to guide uncinectomy and frontoethmoidectomy. The location of the anterior ethmoidal artery was first determined visually and then confirmed by passing a needle through the anterior ethmoidal foramen from the orbit into the nose in all cases. The distances were endoscopically measured using a simple ruler between two nasal landmarks and the anterior ethmoidal artery. RESULTS: Fifty-six nasal fossae in 28 cadavers were dissected endoscopically. The median distance between the artery and the "axilla" formed by the anterior attachment of the middle turbinate to the lateral nasal wall was 20 mm (range, 17-25 mm), irrespective of the side. The measurement differed by less than 2 mm between the sides in the same individual. The median distance between the artery and the "axilla" formed by the medial and lateral crura of the lower lateral cartilage (superomedial edge of the nostril) was 62 mm (range, 55-75 mm) for both sides. The artery was found to be in direct alignment with the two "axillae" formed by the middle turbinate and the nostril edge. CONCLUSIONS: The distance between the ethmoidal artery and the axilla of the middle turbinate showed the least intraindividual and interindividual variations. The tip of the endoscope (or the ruler) points directly at the anterior ethmoidal artery in the fovea ethmoidalis when its edge is aligned with the two nasal landmarks. These simple guidelines can aid the identification of the artery in endoscopic frontoethmoidectomy.

In vivo diagnosis of nasopharyngeal carcinoma using contact rhinoscopy.

OBJECTIVES: To evaluate the potential use of contact endoscopy for the diagnosis of nasopharyngeal carcinoma (NPC). STUDY DESIGN: Prospective study to examine the nasopharynx of 30 patients with nasopharyngeal carcinoma and 18 subjects with normal nasopharynx in a clinic setting using contact rhinoscopes (Karl Storz, Tuttlingen, Germany, 7215 AA, 00 and 7215 BA, 300; 23 cm long; 4 mm in diameter). METHODS: The superficial cells of the normal nasopharynx and the nasopharyngeal tumors were stained with 1% methylene blue and examined with contact rhinoscopes at high magnifications (x 60 and x 150). The areas under examination were then biopsied. The contact endoscopic images were compared with the corresponding hematoxylin and eosin-stained histologic sections of the biopsied tissues. RESULTS: Sixty-six procedures were performed in 48 patients. The images of normal pseudostratified ciliated epithelium and squamous epithelium were readily recognized by contact endoscopy in all subjects with normal nasopharynx (10 men and 8 women; mean age, 51.9 y). Twenty-six of 30 patients with NPC (86.6%; 18 men and 8 women; mean age, 50.6 y) were successfully examined by contact endoscopy under local anesthesia. In these 26 patients, two patterns of malignant cells were identified with contact endoscopy. The patterns of contact endoscopic images corresponded well with the histologic findings. CONCLUSION: Contact endoscopy is an accurate and reliable office-based procedure, which allows for in-vivo diagnosis of nasopharyngeal carcinoma.

Excision of the preauricular sinus: a comparison of two surgical techniques.

OBJECTIVES: To compare the long-term recurrence rate of the standard technique (simple sinectomy) and the supra-auricular approach (wide local excision) for the surgical management of preauricular sinuses. STUDY DESIGN: Retrospective cohort. METHODS: Fifty-four patients with a preauricular sinus excised between May 1986 and December 1996 were included in this study. All patients were categorized into one of two groups based on the type of surgery performed: the standard technique or the supra-auricular approach. The medical records were then reviewed and the latest information concerning the recurrence of a preauricular sinus were updated by phone interview. The recurrence rate of these two groups was statistically analyzed by the Fisher exact test. RESULTS: Forty-nine of 54 patients were successfully contacted with data updated and analyzed. The 32% recurrence rate of the standard excision (n = 25) was significantly higher than the 3.7% recurrence rate of the supraauricular approach (n = 27; two-tailed test, P = .01). CONCLUSION: The supra-auricular approach for excision of a preauricular sinus has a statistically lower recurrence rate in comparison to the standard technique.