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.

Covid-19 dermatoses: Acral vesicular pattern evolving into bullous pemphigoid.

Bullous pemphigoid (BP) appears to be rising in incidence across the Western World, especially in the elderly. Some of the pathogenetic mechanisms involving antigen mimicry and antibody cross-reactivity have been elucidated for cases associated with neurological disease and certain drugs. There have been reports of cutaneous manifestations of Covid-19 (SARS-Cov2 infection) as the pandemic has raged across the world. We report here a case of prolonged Covid-19, symptomatic with dermatoses only, which was seen to evolve initially from a maculo-papular exanthema with acral vesicular dermatitis, into classical BP disease. This was confirmed histologically by positive skin autoantibody serology, direct IMF on peri-lesional skin and also salt-split IMF. Although possible that the development of BP could be a purely co-incidental finding during Covid-19, we suggest that it is more likely that prolonged SARS-Cov2 infection triggered an autoimmune response to the basement membrane antigens, BP 180 and 230. To our knowledge, this is the first case of BP developing during concurrent Covid-19 disease. It will be necessary to continue dermatological surveillance as the pandemic continues, to collate data on BP incidence and to test these patients for Covid-19 disease. As the pandemic continues, even potential and rare associations such as this will be clarified eventually. What's already known about this topic? Covid-19 disease has been associated with a spectrum of dermatosesCommon presentations in up to 20% of patients include exanthema, pseudo-chilblain like acral lesions 'Covid toes', livedo-/retiform purpuric/necrotic vascular lesions, acute urticarial lesions, and vesicular/varicella-like lesionsA multi-system inflammatory syndrome in children akin to Kawasaki syndrome has been described What does this study add? To our knowledge, this is the first description of classic Bullous Pemphigoid evolving from vesicular lesions caused by prolonged SARS-Cov2 induced skin inflammation.

Advancing Care for Head and Neck Cancers in a Multidisciplinary Tumour Board in the East.

Managing head and neck cancers is an excellent example of the importance of teamwork, with head and neck surgeons, clinical oncologists, radiologists, pathologists and other allied health professionals specialised in this disease site working together. The reliable imaging and dedicated pretreatment work-up entailing the comprehensive anatomical description of tumour involvement by the radiologists, the expertise of surgeons in performing en-bloc gross tumour resection, the uneventful speedy postoperative rehabilitation and recovery by the speech therapists and nutritionists, as well as the dedicated treatment planning of clinical oncologists in delivering precise preoperative or postoperative (chemo)radiotherapy to maximise the therapeutic potentials are the pillars of treatment success. A multidisciplinary tumour board involving all of these key players is essential to provide the highest level of recommendation based on evidence-based medicine and to bring patients new hopes and the best chance of cure. This review illustrates the seamless collaborative teamwork within a well-established multidisciplinary tumour board in managing one of the most intractable cancers in the East, taking enlightenment and inspiration from the West.

Effects of Salivary Mg on Head and Neck Carcinoma via TRPM7.

Magnesium (Mg) has been known to play vital roles in regulating growth and various metabolic processes. In recent years, the association between Mg and tumorigenesis has raised more and more attention. However, the effects of Mg on the progression of head and neck carcinoma (HNC), as well as the mechanism behind it, remain undefined. In this study, the roles of Mg in tumorigenic activities were tested in CAL27 and FaDu cells as well as in a xenograft tumor model in nude mice. We demonstrated that a moderate increase in extracellular Mg contributed to the proliferation, migration, and invasion of 2 HNC cell lines, while the addition of Mg in drinking water promoted the growth of xenograft tumors in mice without altering their serum Mg levels. Moreover, TRPM7, a major Mg transporter, was shown to be essential for the tumorigenic activities of HNC and the Mg-induced promotive effects on HNC cells and was further shown to be associated with the activation of AKT/mTOR (mammalian target of rapamycin) signaling. In a preliminary clinical study, we determined the Mg ion concentrations in the stimulated saliva from 72 patients with nasopharynx carcinoma and 12 healthy individuals. Our data revealed that the salivary Mg levels of subjects with nasopharynx carcinoma were significantly higher than those of the healthy controls. This is correlated with our finding showing TRPM7 to be overexpressed in tumor tissues harvested from 9 patients with HNC. Therefore, we can conclude that salivary Mg level, within a certain range, could act as a risk factor for the progression of HNC, which involves the activation of AKT/mTOR signaling pathways through the TRPM7 channel. The control of salivary Mg level and the intervention of TRPM7 should not be ignored during the study of HNC.

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.

Evidence against a role for NLRP3-driven islet inflammation in db/db mice.

OBJECTIVES: Type 2 diabetes (T2D) is associated with chronic, low grade inflammation. Activation of the NLRP3 inflammasome and secretion of its target interleukin-1ß (IL-1ß) have been implicated in pancreatic ß cell failure in T2D. Specific targeting of the NLRP3 inflammasome to prevent pancreatic ß cell death could allow for selective T2D treatment without compromising all IL-1ß-associated immune responses. We hypothesized that treating a mouse model of T2D with MCC950, a compound that specifically inhibits NLRP3, would prevent pancreatic ß cell death, thereby preventing the onset of T2D. METHODS: Diabetic db/db mice were treated with MCC950 via drinking water for 8 weeks from 6 to 14 weeks of age, a period over which they developed pancreatic ß cell failure. We assessed metabolic parameters such as body composition, glucose tolerance, or insulin secretion over the course of the intervention. RESULTS: MCC950 was a potent inhibitor of NLRP3-induced IL-1ß in vitro and was detected at high levels in the plasma of treated db/db mice. Treatment of pre-diabetic db/db mice with MCC950, however, did not prevent pancreatic dysfunction and full onset of the T2D pathology. When examining the NLRP3 pathway in the pancreas of db/db mice, we could not detect an activation of this pathway nor increased levels of its target IL-1ß. CONCLUSIONS: NLRP3 driven-pancreatic IL-1ß inflammation does not play a key role in the pathogenesis of the db/db murine model of T2D.

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.

Systematic review with meta-analysis: faecal occult blood tests show lower colorectal cancer detection rates in the proximal colon in colonoscopy-verified diagnostic studies.

BACKGROUND: The performance of faecal occult blood tests (FOBTs) to screen proximally located colorectal cancer (CRC) has produced inconsistent results. AIM: To assess in a meta-analysis, the diagnostic accuracy of FOBTs for relative detection of CRC according to anatomical location of CRC. METHODS: Diagnostic studies including both symptomatic and asymptomatic cohorts assessing performance of FOBTs for CRC were searched from MEDINE and EMBASE. Primary outcome was accuracy of FOBTs according to the anatomical location of CRC. Bivariate random-effects model was used. Subgroup analyses were performed to evaluate test performance of guaiac-based FOBT (gFOBT) and immunochemical-based FOBT (iFOBT). RESULTS: Thirteen studies, with 17 cohorts, reporting performance of FOBT were included; a total of 26 342 patients (mean age 58.9 years; 58.1% male) underwent both colonoscopy and FOBT. Pooled sensitivity, specificity, positive likelihood ratio and negative likelihood ratio of FOBTs for CRC detection in the proximal colon were 71.2% (95% CI 61.3-79.4%), 93.6% (95% CI 90.7-95.7%), 11.1 (95% CI 7.8-15.8) and 0.3 (95% CI 0.2-0.4) respectively. Corresponding findings for CRC detection in distal colon were 80.1% (95% CI 70.9-87.0%), 93.6% (95% CI 90.7-95.7%), 12.6 (95% CI 8.8-18.1) and 0.2 (95% CI 0.1-0.3). The area-under-curve for FOBT detection for proximal and distal CRC were 90% vs. 94% (P = 0.0143). Both gFOBT and iFOBT showed significantly lower sensitivity but comparable specificity for the detection of proximally located CRC compared with distal CRC. CONCLUSION: Faecal occult blood tests, both guaiac- and immunochemical-based, show better diagnostic performance for the relative detection of colorectal cancer in the distal colon than in the proximal bowel.

Disruption of insulin receptor function inhibits proliferation in endocrine-resistant breast cancer cells.

The insulin-like growth factor (IGF) system is a well-studied growth regulatory pathway implicated in breast cancer biology. Clinical trials testing monoclonal antibodies directed against the type I IGF receptor (IGF1R) in combination with estrogen receptor-α (ER) targeting have been completed, but failed to show benefits in patients with endocrine-resistant tumors compared to ER targeting alone. We have previously shown that the closely related insulin receptor (InsR) is expressed in tamoxifen-resistant (TamR) breast cancer cells. Here we examined if inhibition of InsR affected TamR breast cancer cells. InsR function was inhibited by three different mechanisms: InsR short hairpin RNA, a small InsR-blocking peptide, S961 and an InsR monoclonal antibody (mAb). Suppression of InsR function by these methods in TamR cells successfully blocked insulin-mediated signaling, monolayer proliferation, cell cycle progression and anchorage-independent growth. This strategy was not effective in parental cells likely because of the presence of IGFR /InsR hybrid receptors. Downregulation of IGF1R in conjunction with InsR inhibition was more effective in blocking IGF- and insulin-mediated signaling and growth in parental cells compared with single-receptor targeting alone. Our findings show TamR cells were stimulated by InsR and were not sensitive to IGF1R inhibition, whereas in tamoxifen-sensitive parental cancer cells, the presence of both receptors, especially hybrid receptors, allowed cross-reactivity of ligand-mediated activation and growth. To suppress the IGF system, targeting of both IGF1R and InsR is optimal in endocrine-sensitive and -resistant breast cancer.

Comparing staging by positron emission tomography with contrast-enhanced computed tomography and by pathology in head and neck squamous cell carcinoma.

OBJECTIVE: This study aimed to evaluate the ability of positron emission tomography with contrast-enhanced computed tomography to correctly stage head and neck squamous cell carcinomas, in comparison with pathological staging. METHODS: Positron emission tomography computed tomography was used to determine the tumour-node-metastasis classification and overall cancer stage in 85 head and neck squamous cell carcinoma patients who underwent pre-operative imaging using this modality and primary surgery between July 2010 and January 2013. Staging by positron emission tomography computed tomography was retrospectively compared with staging using pathological specimens. Agreement between imaging stage and pathological stage was examined by univariate and multivariate analysis both overall and for each primary tumour site. RESULTS: This imaging modality was 87.5 per cent sensitive and 44.8 per cent specific in identifying regional cervical metastases, and had false positive and false negative rates of 18.8 per cent and 8.2 per cent, respectively. The positive predictive and negative predictive values were 75.4 per cent and 65.0 per cent, respectively. Univariate and multivariate analyses revealed a significant agreement between positron emission tomography computed tomography and pathological node classification in older patients and for the oral cavity primary tumour site. There was significant agreement between both methods in the overall classification only for tumours classified as T3 or greater. CONCLUSION: Positron emission tomography computed tomography should be used with caution for the pre-operative staging of head and neck cancers because of its high false positive and false negative rates.