Surgical treatment of nasopharyngeal cancer - a consensus recommendation from two Chinese associations.

BACKGROUND: Surgical treatment is playing an increasingly important role in the management of nasopharyngeal carcinoma (NPC). This consensus focuses on the indications for optimal surgery, and surgical methods in the whole process of treatment for NPC to provide a useful reference to assist these difficult clinical decisions. METHODOLOGY: A thorough review of available literature on NPC and surgery was conducted by the Association for the prevention and treatment of nasopharyngeal carcinoma in China, international exchange and promotion Association for medicine and healthcare, and the Committee on nasopharyngeal cancer of Guangdong provincial anticancer association. A set of questions and a preliminary draft guideline was circulated to a panel of 1096 experienced specialists on this disease for voting on controversial areas and comments. A refined second proposal, based on a summary of the initial voting and different opinions expressed, was recirculated to the experts in two authoritative medical science and technology academic groups in the prevention and treatment of NPC in China for review and reconsideration. RESULTS: The initial round of questions showed variations in clinical practice even among similar specialists, reflecting the lack of high-quality supporting data and resulting difficulties in formulating clinical decisions. Through exchange of comments and iterative revisions, recommendations with high-to-moderate agreement were formulated on general treatment strategies and details of surgery, including indications and surgical approaches. CONCLUSION: By standardizing the surgical indications and practice, we hope not only to improve the surgical outcomes, but also to highlight the key directions of future clinical research in the surgical management of NPC.

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.

Uveal and conjunctival melanomas: disease course and outcomes in Chinese patients.

INTRODUCTION: Epidemiological studies of ocular melanomas have largely focused on Caucasian populations. This study reviewed the course and outcomes of uveal melanoma (UM) and conjunctival melanoma (CM) in Chinese patients. METHODS: This retrospective study included patients with UM and CM who received treatment in a tertiary eye centre in Hong Kong from January 1994 to December 2019. Data were recorded concerning patient demographics, tumour laterality, tumour characteristics, investigations performed, treatment regimen, and final outcomes. RESULTS: During the 25-year study period, there were 13 patients with UM and 11 patients with CM who did not display nodal or systemic involvement at diagnosis. The mean ± standard deviation ages at diagnosis of UM and CM were 59 ± 15.8 and 57 ± 13.9 years, respectively. There were more men among patients with UM than among those with CM (P=0.042). Most patients with UM underwent primary enucleation (n=12; 92.3%), whereas most patients with CM underwent orbital exenteration (n=9; 81.8%). The prognosis was significantly worse for CM than for UM. The median disease-free survival were 5.2 years (range, 0.7-20.5) and 2.1 years (range, 0.1-24.9) for UM and CM, respectively. Melanoma-related mortality was significantly higher among patients with CM than among those with UM (P=0.006). CONCLUSION: Compared with UM, CM has higher rates of systemic metastasis and tumour-related mortality in Hong Kong Chinese patients, regardless of prior definitive treatment.

Oncogenes expand during evolution to withstand somatic amplification.

Background: Cancer-related genes are under intense evolutionary pressure. We conjectured that gene size is an important determinant of amplification propensity for oncogenes and thus cancer susceptibility and therefore could be subject to natural selection. Patients and methods: Gene information, including size and genomic locations, of all protein-coding genes were downloaded from Ensembl (release 87). Quantification of gene amplification was based on Genomic Identification of Significant Targets in Cancer scores obtained from available The Cancer Genome Atlas studies. Results: Oncogenes are larger in size as compared with non-cancer genes (mean size: 92.1 kb versus 61.4 kb; P < 0.0001) in the human genome, which is contributed by both increased total exon size (mean size: 4.6 kb versus 3.4 kb; P < 0.0001) and higher intronic content (mean %: 84.8 versus 78.0; P < 0.01). Such non-random size distribution and intronic composition are conserved in mouse and Drosophila (all P < 0.0001). Stratification by gene age indicated that young oncogenes have been subject to a stronger evolutionary pressure for gene expansion than their non-cancer counterparts. Pan-cancer analysis demonstrated that larger oncogenes were amplified to a lesser extent. Tumor-suppressor genes also moved toward small oncogenes in the course of evolution. Conclusions: Oncogenes expand in size whereas tumor-suppressor genes move closer to small oncogenes in the course of evolution to withstand oncogenic somatic amplification. Our findings have shed new light on the previously unappreciated influence of gene size on oncogene amplification and elucidated how cancers have shaped our genome to its present configuration.

Calcitonin alleviates hyperalgesia in osteoporotic rats by modulating serotonin transporter activity.

Calcitonin may relieve pain by modulating central serotonin activity. Calcitonin partly reversed the hypersensitivity to pain induced by ovariectomy. This suggests that the anti-nociceptive effects of calcitonin in the treatment of osteoporosis may be mediated by alterations in neural serotonin transporter (SERT) activity. INTRODUCTION: This study used a rat model of osteoporosis to evaluate the role of the cerebral serotonin system in the anti-nociceptive effect of calcitonin, a drug used to treat post-menopausal osteoporosis. METHODS: Osteoporosis was induced in rats by ovariectomy (OVX). Rats were then randomized to the following four groups: sham operation, OVX, OVX plus calcitonin, or OVX plus alendronate. RESULTS: OVX led to alterations in bone micro-architecture; alendronate strongly reversed this effect, and calcitonin moderately reversed this effect. OVX increased hyperalgesia (determined as the time for hind paw withdrawal from a heat source); calcitonin reduced this effect, but alendronate had no effect. OVX increased the expression of c-Fos (a neuronal marker of pain) in the thalamus; calcitonin strongly reversed this effect, and alendronate moderately reversed this effect. OVX also reduced SERT but increased 5-HT1A receptor expression and activity; calcitonin aggravated this effect, but alendronate had no effect on recovery of SERT/5-HT1A activity and expression. CONCLUSIONS: Our study of a rat model of osteoporosis suggests that OVX-induced enhancement of the serotonergic system may protect against hyperalgesia. However, the anti-nociceptive effects of calcitonin in osteoporosis may be mediated by decreased neural SERT activity and increased activation of 5-HT1 receptors in the thalamus.

Heterogeneous photo-Fenton reaction on hematite (α-Fe2O3){104}, {113} and {001} surface facets.

The exposed surface facets play an important role in determining the catalytic performance of nanostructured materials. In this study, we report the synthesis of hematite nanoparticles with three varying morphologies with exposure of well-controlled {104}, {113} and {001} surfaces. The better shape control of hematite particles has provided a direct correlation between the surface facets and the photocatalytic performance. The catalytic photodegradation of MB using hematite nanoparticles reveals that the reaction follows the heterogeneous photo-Fenton process under visible light irradiation. The catalytic performance of hematite surface facets follows the order of {113} > {104} > {001}. Density functional theory (DFT) calculations were conducted to demonstrate the atomic surface structures and the corresponding charge distribution. The results indicate that the catalytic activity depends on surface atom arrangements as well as the number and the type of surface terminated hydroxyl groups bonding to underlying Fe atoms, where low valence states of Fe on {104} and {113} planes have the highest probability to be oxidized by H2O2 and the concurrently generated Fe((3+x)+) sites are more electronegative to accept electrons from activated dye molecules. The findings are of fundamental importance to understand the surface-dependence of photocatalytic properties, thus shedding new light on the catalytic application of hematite particles.

Prevalence and clinical profiles of 'autoantibody-negative' systemic sclerosis subjects.

OBJECTIVES: To determine the prevalence of autoantibody negative systemic sclerosis (SSc) and to identify the clinical correlates thereof. METHODS: Clinical data and sera from 874 SSc subjects were collected and autoantibodies were tested in a central laboratory using 1) indirect immunofluorescence (IIF), 2) commercially available ELISA, addressable laser bead immunoassay (ALBIA), and line immunoassay (LIA), and 3) a sensitive immunoprecipitation (IP) assay. RESULTS: Fifteen (15; 1.7%) subjects were autoantibody negative by IIF, ELISA, ALBIA, LIA and IP, and 16 (1.8%) were antinuclear antibody (ANA) positive by IIF but otherwise negative by ELISA, ALBIA, LIA and IP. Thirty-seven (37; 4.2%) were ANA positive by IIF, autoantibody negative by commercially available immunoassays, but had autoantibodies identified by IP (including Th/To in 20). Autoantibody-negative subjects had generally less severe disease than positive subjects. CONCLUSIONS: Autoantibody-negative SSc is rare (<2%) and appears to be associated with a favourable prognosis.

Meteorological factors and El Nino Southern Oscillation are associated with paediatric varicella infections in Hong Kong, 2004-2010.

Varicella accounts for substantial morbidities and remains a public health issue worldwide, especially in children. Little is known about the effect of meteorological variables on varicella infection risk for children. This study described the epidemiology of paediatric varicella notifications in Hong Kong from 2004 to 2010, and explored the association between paediatric varicella notifications in children aged <18 years and various meteorological factors using a time-stratified case-crossover model, with adjustment of potential confounding factors. The analysis found that daily mean temperature, atmospheric pressure and Southern Oscillation Index (SOI) were positively associated with paediatric varicella notifications. We found that an interquartile range (IQR) increase in temperature (8·38°C) at lag 1 day, a 9·50 hPa increase in atmospheric pressure for the current day, and a 21·91 unit increase in SOI for the current day may lead to an increase in daily cases of 5·19% [95% confidence interval (CI) 1·90-8·58], 5·77% (95% CI 3·01-8·61), and 4·32% (95% CI 2·98-5·68), respectively. An IQR increase in daily relative humidity (by 11·96%) was associated with a decrease in daily paediatric varicella (-2·79%, 95% CI -3·84 to -1·73). These findings suggest that meteorological factors might be important predictors of paediatric varicella infection in Hong Kong.

Varicella vaccine uptake and associated factors in children in Hong Kong.

Varicella is a common and highly contagious childhood disease which impacts the public worldwide. Hong Kong children can only be vaccinated against the disease in private practice. The varicella vaccination rate of local children in preschool is uncertain. Therefore a cross-sectional kindergarten-based parent-administered questionnaire survey was conducted in Hong Kong during 2012. Twelve kindergartens were randomly selected from a complete school list from the Education Bureau of Hong Kong. In total, 1285/1538 (83·6%) parents consented to join the study and completed the questionnaires. The overall varicella infection rate was 19·5% and the uptake of varicella vaccination rate was 57·6%. Barriers against varicella vaccination were mostly due to parental uncertainties about the effectiveness of vaccine, lack of recommendations from doctors or government, and adverse side-effects of the vaccine. The government and healthcare professional bodies are strongly recommended to further enhance health education among healthcare professionals, encouraging their active promotion of varicella vaccination for their patients. Furthermore, health education through various stakeholders is crucial to enhance parental awareness of varicella, as well as the effectiveness and safety of varicella vaccine.

High morbidity and mortality in adults hospitalized for respiratory syncytial virus infections.

BACKGROUND: Better understanding of complications and outcomes of adults hospitalized with respiratory syncytial virus (RSV) infection is necessary. METHODS: A retrospective cohort study was conducted on all adults (≥ 18 years) admitted to 3 acute care general hospitals in Hong Kong with virologically confirmed RSV infection during 2009-2011 (N = 607). Adults hospitalized for seasonal influenza during the period were used for comparison (n = 547). Both infections were prospectively diagnosed following a standard protocol. Independent reviews of chest radiographs were performed by radiologists. Main outcome measures were all-cause death, respiratory failure requiring ventilatory support, and hospitalization duration. Cox proportional hazards models were used for analyses. RESULTS: The mean age of RSV patients was 75 (SD, 16) years; 87% had underlying conditions. Lower respiratory and cardiovascular complications were diagnosed in 71.9% (pneumonia, 42.3%; acute bronchitis, 21.9%; chronic obstructive pulmonary disease/asthma exacerbation, 27.3%) and 14.3% of patients, respectively; 12.5% had bacterial superinfections. Supplemental oxygen and ventilatory support were required in 67.9% and 11.1%, respectively. Crude all-cause mortality was 9.1% and 11.9% within 30 days and 60 days, respectively; mean length of stay of survivors was 12 (SD, 13) days. Advanced age, radiographic pneumonia, requirement for ventilation, bacterial superinfection, and elevated urea level and white blood cell count were independently associated with poorer survival. Systemic corticosteroid use was associated with longer hospitalization and secondary infections. The overall outcomes of survival and length of stay were not significantly different from those in influenza. CONCLUSIONS: RSV can cause severe lower respiratory complications in older adults, resulting in respiratory failure, prolonged hospitalization, and high mortality similar to seasonal influenza. Corticosteroids did not seem to improve outcomes. The unmet need for antiviral therapy and vaccination against RSV in adults should be promptly addressed.

Cross-talk between the unfolded protein response and nuclear factor-κB signalling pathways regulates cytokine-mediated beta cell death in MIN6 cells and isolated mouse islets.

AIMS/HYPOTHESIS: Pancreatic beta cell destruction in type 1 diabetes may be mediated by cytokines such as IL-1ß, IFN-γ and TNF-α. Endoplasmic reticulum (ER) stress and nuclear factor-κB (NFκB) signalling are activated by cytokines, but their significance in beta cells remains unclear. Here, we investigated the role of cytokine-induced ER stress and NFκB signalling in beta cell destruction. METHODS: Isolated mouse islets and MIN6 beta cells were incubated with IL-1ß, IFN-γ and TNF-α. The chemical chaperone 4-phenylbutyric acid (PBA) was used to inhibit ER stress. Protein production and gene expression were assessed by western blot and real-time RT-PCR. RESULTS: We found in beta cells that inhibition of cytokine-induced ER stress with PBA unexpectedly potentiated cell death and NFκB-regulated gene expression. These responses were dependent on NFκB activation and were associated with a prolonged decrease in the inhibitor of κB-α (IκBα) protein, resulting from increased IκBα protein degradation. Cytokine-mediated NFκB-regulated gene expression was also potentiated after pre-induction of ER stress with thapsigargin, but not tunicamycin. Both PBA and thapsigargin treatments led to preferential upregulation of ER degradation genes over ER-resident chaperones as part of the adaptive unfolded protein response (UPR). In contrast, tunicamycin activated a balanced adaptive UPR in association with the maintenance of Xbp1 splicing. CONCLUSIONS/INTERPRETATION: These data suggest a novel mechanism by which cytokine-mediated ER stress interacts with NFκB signalling in beta cells, by regulating IκBα degradation. The cross-talk between the UPR and NFκB signalling pathways may be important in the regulation of cytokine-mediated beta cell death.

A randomized non-inferiority study comparing the addition of exenatide twice daily to sitagliptin or switching from sitagliptin to exenatide twice daily in patients with type 2 diabetes experiencing inadequate glycaemic control on metformin and sitagliptin.

AIMS: To test the hypothesis that glycaemic control achieved when switching sitagliptin to exenatide twice daily plus metformin is non-inferior to adding exenatide twice daily to sitagliptin and metformin. METHODS: Patients with Type 2 diabetes inadequately controlled with sitagliptin plus metformin were randomly assigned to 20 weeks of treatment with twice-daily exenatide plus placebo and metformin (SWITCH, n = 127) or twice-daily exenatide plus sitagliptin and metformin (ADD, n = 128). RESULTS: Non-inferiority (0.4% margin) of SWITCH to ADD treatment, measured by change in HbA(1c) from baseline to week 20, was not shown {between-treatment difference in least-squares mean [95% CI 3 mmol/mol (0.30%)] [0.8-5.8 (0.07-0.53)]}. A greater reduction (P = 0.012) in HbA(1c) [least-squares mean (se)] was experienced by patients in the ADD group {-7 mmol/mol [-0.68%] [0.9 (0.08)]}, compared with those in the SWITCH group {-4 mmol/mol [-0.38%] [1.0 (0.09)]} and a greater proportion (P = 0.027) of patients in the ADD group (41.7%) reached < 7.0% (< 53 mmol/mol) HbA(1c) target, compared with those in the SWITCH group (26.6%) by week 20. Patients in the ADD group experienced greater fasting serum glucose (P = 0.038) and daily mean postprandial self-monitored blood glucose (P = 0.048) reductions, compared with patients in the SWITCH group, by week 20. Patients in both groups experienced a lower incidence of nausea and vomiting compared with previous exenatide studies. CONCLUSIONS: Non-inferiority of SWITCH to ADD treatment was not supported by the results of this study. In patients with Type 2 diabetes inadequately controlled with sitagliptin plus metformin, adding exenatide provided better glycaemic control than switching to exenatide. These results are consistent with the clinical approach that adding is better than switching to another oral anti-hyperglycaemic medication.