Inhibition of NOTCH3 signalling significantly enhances sensitivity to cisplatin in EBV-associated nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) is an EBV-associated epithelial malignancy which is prevalent in south-east Asia and southern China. Despite the multiple genetic and epigenetic changes reported, the contribution of dysregulated signalling pathways to this distinct type of head and neck cancer is not well understood. Here we demonstrate the up-regulation of NOTCH ligands (JAG1 or DLL4) and effector (HEY1) in the majority of EBV-positive tumour lines and primary tumours. Among the NOTCH receptors, NOTCH3 was over-expressed in all EBV-positive tumour lines and 92.5% of primary tumours. Aberrant activation of NOTCH3 signalling was consistently detected in all these samples. These findings imply that NOTCH3 may play an crucial role in the development of NPC. By NOTCH3 specific siRNA, NOTCH3 signalling was suppressed and thereby significant growth inhibition and apoptosis induction occurred in NPC cells. Down-regulation of a number of targets involved in cell proliferation, eg CCND1, C-MYC,NFKB1, and survival, eg BCL2, BCL-XL, SURVIVIN, was confirmed in the NOTCH3 knockdown NPC cells. Importantly, NOTCH3 knockdown highly enhanced the sensitivity of NPC cells to cisplatin treatment. Furthermore, we revealed that the ability of NPC cells to form spheroids in vitro and tumours in nude mice was also significantly decreased after knockdown of NICD3 expression. These findings indicate that activation of NOTCH3 pathway is a critical oncogenic event in NPC tumourigenesis. Targeting NOTCH3 signalling may serve as a potential therapeutic approach for treating patients suffering from EBV-associated NPC. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.link_to_subscribed_fulltex

Single-nucleotide polymorphism (SNP) of excision repair cross complementation group 1 (ERCC1) in nasopharynx cancer (NPC): A companion biomarker study to Hong Kong NPC Study Group 0502 trial

Poster Highlights Session - Head and Neck Cancer: abstract no. 6029Background: Polymorphisms at ERCC1 has been linked to platinum sensitivity and treatment outcome. We hypothesized that ERCC1 SNP at codon 118 and C8092A is predictive of relapse free survival (RFS) in NPC, and correlates with ERCC1 protein/mRNA in paired tumor samples. Methods: 0502 is a multi-center prospective clinical trial to assess adjuvant chemotherapy in NPC pts with detectable plasma EBV-DNA (pEBV) following primary radiotherapy (RT) or cisplatin-RT (CRT) (NCT00370890). Eligible pts with biopsy proven NPC, AJCC stage IIB-IVB, no persistent locoregional disease or distant metastasis, ECOG 0-1, adequate organ function, were screened by pEBV at 6-8 weeks after completing RT/CRT. Post-RT pEBV -ve pts received no further treatment. pEBV +ve pts underwent work-up and randomization to adjuvant chemotherapy or observation. We tested our hypothesis using samples collected in the 0502 screening cohort. Primary endpoint is relapse free survival (RFS). ERCC1 genotyping was by TaqMan real time PCR. 450 pts is planned to detect a hazard ratio (HR) of 1.5 for the weaker ERCC1 SNP at 80% power and 2-side 5% alpha level. In subset with available tumor biopsies, we quantified ERCC1 protein expression by immunohistochemistry (IHC) or Western blot (WB) with mouse monoclonal antibody (clone 8F1), and ERCC1 mRNA by quantitative RT-PCR. Results: ERCC1 SNP was analyzed in peripheral blood lymphocytes from 478 pts. Median follow up was 3.61 years (90% C.I. 3.36-3.88). 31% pEBV +ve, 17% randomized. ERCC1 genotype distribution at codon 118: 54% CC, 39% CT, 7% TT; C8092A: 38% CC, 50% CA, 12% AA. There was no significant association of ERCC1 SNP with 3-year RFS or overall survival. No significant correlation was observed in ERCC1 SNP and tumor ERCC1 expression by IHC, WB or mRNA. In subset evaluated by ERCC1 IHC (n=79), pts with ERCC1+ve tumor (H-score > median) had worse RFS (HR 2.34, 95% C.I. 1.06-5.16, p=0.036). Multivariate analysis showed pEBV was the most significant adverse prognosticator for all clinical endpoints. Conclusions: We found no association of ERCC1 SNP with NPC survival. pEBV remained the most significant prognostic biomarker in NPC

Managing ICU surge during the COVID-19 crisis: rapid guidelines.

Given the rapidly changing nature of COVID-19, clinicians and policy makers require urgent review and summary of the literature, and synthesis of evidence-based guidelines to inform practice. The WHO advocates for rapid reviews in these circumstances. The purpose of this rapid guideline is to provide recommendations on the organizational management of intensive care units caring for patients with COVID-19 including: planning a crisis surge response; crisis surge response strategies; triage, supporting families, and staff