EGFR mutation status affects intra-tumoural heterogeneity of PD-L1 expression but not agreement between assays in resectable non-small cell lung cancer.

Background: The predictive value of PD-L1 to select patients for immunotherapy in resectable NSCLC remains imprecise, confounded by different assays used across trials and intra-tumoural heterogeneity (ITH). We sought to compare the concordance between 3 PD-L1 antibodies stratified by EGFR mutation status, evaluate ITH and implications on survival outcomes.

Methods: Tissue microarrays were constructed from stage IA-IIIA NSCLC with 3 tumour cores per patient.

Impact of educational videos and user guide on indwelling pleural catheter caregiver training and unplanned healthcare encounters.

Background: Indwelling pleural catheters (IPCs) are an effective first line option for the management of symptomatic malignant pleural effusions. However, patients with IPCs often require unplanned healthcare encounters (UHEs) due to complications or concerns with IPC care and drainage.

Local Problem: There is a lack of readily accessible IPC-specific educational material to support caregiver training (CGT).

KCL TEST: an open-source inspired asymptomatic SARS-CoV-2 surveillance programme in an academic institution.

Rapid and accessible testing was paramount in the management of the COVID-19 pandemic. Our university established KCL TEST: a SARS-CoV-2 asymptomatic testing programme that enabled sensitive and accessible PCR testing of SARS-CoV-2 RNA in saliva. Here, we describe our learnings and provide our blueprint for launching diagnostic laboratories, particularly in low-resource settings.

Implementation of an optimised tele-medicine platform for stroke in South Australia improves patient care.

Background: Patients with a large vessel occlusion require a transfer from a primary stroke centre to access thrombectomy, often over significant distances in regional areas. We sought to optimise stroke care access in the regional South Australian Tele-Strokeservice (SATS) to improve patient access to thrombectomy.

Methods: We undertook a 24-month interventional historically controlled cohort study comparing acute stroke care metrics in the SATS.

Real-world outcomes of pemetrexed-platinum chemotherapy plus osimertinib after progression on first-line osimertinib in advanced EGFR-mutated NSCLC.

Objectives: First-line pemetrexed-platinum chemotherapy + osimertinib(Pem-Plat-Osi) improves progression-free survival as compared to osimertinib alone in advanced epidermal growth factor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, many patients are hesitant to commence chemotherapy upfront. We describe outcomes to Pem-Plat-Osi after first-line osimertinib failure.

Transcriptome Deconvolution Reveals Absence of Cancer Cell Expression Signature in Immune Checkpoint Blockade Response.

Unlabelled: Immune checkpoint therapy (ICB) has conferred significant and durable clinical benefit to some patients with cancer. However, most patients do not respond to ICB, and reliable biomarkers of ICB response are needed to improve patient stratification. Here, we performed a transcriptome-wide meta-analysis across 1,486 tumors from ICB-treated patients and tumors with expected ICB outcomes based on microsatellite status.

The cost-effectiveness of including liquid biopsy into molecular profiling strategies for newly diagnosed advanced non-squamous non-small cell lung cancer in an Asian population.

Objectives: Liquid biopsy is complementary to tissue biopsy for lung cancer profiling, yet evidence of the cost-effectiveness is limited. This could retard implementation and reimbursement in clinical practice. The aim of this study is to estimate the cost-effectiveness of profiling strategies that include liquid biopsy and to identify the optimal profiling approach for newly diagnosed advanced non-squamous non-small cell lung cancer (NSCLC) in an Asian population using Singapore as an example.

Soluble immune-checkpoint factors: a potential immunotherapy biomarker.

There is unmet need for additional biomarkers to better select patients with non-small cell lung cancer (NSCLC) that are likely to benefit from immunotherapy in order to improve patient outcomes, reduce patient toxicity, and relieve the growing burden of healthcare costs. In this issue of the JCI, Hayashi and colleagues evaluated soluble forms of the immune checkpoint molecules PD-L1, PD-1, and CTLA-4 in the plasma of patients with advanced NSCLC who had been treated with anti-PD-1/L1 therapy. The findings suggest that these soluble immune-checkpoint factors may provide a complementary biomarker to PD-L1 IHC, although application into the clinic may not be straightforward.

Detection of circulating tumor DNA with ultradeep sequencing of plasma cell-free DNA for monitoring minimal residual disease and early detection of recurrence in early-stage lung cancer.

Background: In early-stage non-small cell lung cancer (NSCLC), recurrence is frequently observed. Circulating tumor DNA (ctDNA) has emerged as a noninvasive tool to risk stratify patients for recurrence after curative intent therapy. This study aimed to risk stratify patients with early-stage NSCLC via a personalized, tumor-informed multiplex polymerase chain reaction (mPCR) next-generation sequencing assay.

Brief Report: Droplet Digital Polymerase Chain Reaction Versus Plasma Next-Generation Sequencing in Detecting Clearance of Plasma EGFR Mutations and Carcinoembryonic Antigen Levels as a Surrogate Measure.

Introduction: To compare the performance of droplet digital polymerase chain reaction (ddPCR) and plasma next-generation sequencing (NGS) in detecting clearance of plasma EGFR (pEGFR) mutations.

Methods: Patients with treatment-naive advanced EGFR-mutated lung cancer treated with first-line tyrosine kinase inhibitors (TKIs) were included. pEGFR were measured at baseline and first response assessment using ddPCR and NGS.

Harnessing the disruption on medical trainee education due to COVID-19 in New South Wales, Australia.

The coronavirus disease (COVID-19) pandemic has caused disruption and uncertainty for junior medical doctor training and education. This has compounded the existing stress experienced by this cohort. However, by choosing appropriate educational models, as well as using novel educational approaches and advancing our online technology capabilities, we may be able to provide acceptable and even, superior solutions for educational training moving forward, as well as promote trainee wellbeing during these uncertain times.

Potent pan huACE2-dependent sarbecovirus neutralizing monoclonal antibodies isolated from a BNT162b2-vaccinated SARS survivor.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern such as Omicron hampered efforts in controlling the ongoing coronavirus disease 2019 pandemic due to their ability to escape neutralizing antibodies induced by vaccination or prior infection, highlighting the need to develop broad-spectrum vaccines and therapeutics. Most human monoclonal antibodies (mAbs) reported to date have not demonstrated true pan-sarbecovirus neutralizing breadth especially against animal sarbecoviruses. Here, we report the isolation and characterization of highly potent mAbs targeting the receptor binding domain (RBD) of huACE2-dependent sarbecovirus from a SARS-CoV survivor vaccinated with BNT162b2.

Implementation of the South Australian Regional Telestroke service is associated with improved care quality and lower stroke mortality: A retrospective cohort study.

Introduction: Stroke in Regional Australia may have worse outcomes due to difficulties accessing optimal care. The South Australian Regional Telestroke service aimed to improve telestroke neurologist access, supported by improved ambulance triage.

Objective: To assess stroke care quality and patient mortality pre- and postimplementation of a vascular neurologist-led Telestroke service.

Structural insights into HIV-1 polyanion-dependent capsid lattice formation revealed by single particle cryo-EM.

The HIV-1 capsid houses the viral genome and interacts extensively with host cell proteins throughout the viral life cycle. It is composed of capsid protein (CA), which assembles into a conical fullerene lattice composed of roughly 200 CA hexamers and 12 CA pentamers. Previous structural analyses of individual CA hexamers and pentamers have provided valuable insight into capsid structure and function, but detailed structural information about these assemblies in the broader context of the capsid lattice is lacking.

Two structural switches in HIV-1 capsid regulate capsid curvature and host factor binding.

The mature HIV-1 capsid protects the viral genome and interacts with host proteins to travel from the cell periphery into the nucleus. To achieve this, the capsid protein, CA, constructs conical capsids from a lattice of hexamers and pentamers, and engages in and then relinquishes multiple interactions with cellular proteins in an orchestrated fashion. Cellular host factors including Nup153, CPSF6, and Sec24C engage the same pocket within CA hexamers.

Evasion of toll-like receptor recognition by is mediated via population level regulation of flagellin production.

Uropathogenic is a major cause of urinary tract infections. Analysis of the innate immune response in immortalized urothelial cells suggests that the bacterial flagellar subunit, flagellin, is key in inducing host defenses. A panel of 48 clinical uro-associated .

The Enduring Effects of COVID for Cancer Care: Learning from Real-Life Clinical Practice.

For three years, COVID-19 has circulated among our communities and around the world, fundamentally changing social interactions, health care systems, and service delivery. For people living with (and receiving treatment for) cancer, pandemic conditions presented significant additional hurdles in an already unstable and shifting environment, including disrupted personal contact with care providers, interrupted access to clinical trials, distanced therapeutic encounters, multiple immune vulnerabilities, and new forms of financial precarity. In a 2020 perspective in this journal, we examined how COVID-19 was reshaping cancer care in the early stages of the pandemic and how these changes might endure into the future.

Unraveling the Impact of Intratumoral Heterogeneity on EGFR Tyrosine Kinase Inhibitor Resistance in -Mutated NSCLC.

The advent of tyrosine kinase inhibitors (TKIs) for treating epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) has been a game changer in lung cancer therapy. However, patients often develop resistance to the drugs within a few years. Despite numerous studies that have explored resistance mechanisms, particularly in regards to collateral signal pathway activation, the underlying biology of resistance remains largely unknown.

Bystander CD4 T cells infiltrate human tumors and are phenotypically distinct.

Tumor-specific T cells likely underpin effective immune checkpoint-blockade therapies. Yet, most studies focus on Treg cells and CD8 tumor-infiltrating lymphocytes (TILs). Here, we study CD4 TILs in human lung and colorectal cancers and observe that non-Treg CD4 TILs average more than 70% of total CD4 TILs in both cancer types.

Exploring the in situ evolution of nitrofurantoin resistance in clinically derived uropathogenic Escherichia coli isolates.

Background: Nitrofurantoin has been re-introduced as a first-choice antibiotic to treat uncomplicated acute urinary tract infections in England and Wales. Highly effective against common uropathogens such as Escherichia coli, its use is accompanied by a low incidence (<10%) of antimicrobial resistance. Resistance to nitrofurantoin is predominantly via the acquisition of loss-of-function, step-wise mutations in the nitroreductase genes nfsA and nfsB.

PD-L1 score as a prognostic biomarker in asian early-stage epidermal growth factor receptor-mutated lung cancer.

Aim: To determine the prognostic value of programmed death-ligand 1 (PD-L1) score in early-stage epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), contrasted against EGFR-wildtype NSCLC.

Methods: Consecutive patients with Stage IA-IIIA NSCLC diagnosed 1st January 2010-31st December 2019 at National Cancer Centre Singapore with evaluable EGFR and PD-L1 status were included. Co-primary end-points were 2-year disease-free survival (DFS) and 5-year overall survival (OS) by Kaplan-Meier method.