Efficacy and safety of interim oncology treatments introduced for solid cancers during the COVID-19 pandemic in England: a retrospective evidence-based analysis

Background: The COVID-19 global pandemic placed unprecedented pressure on cancer services, requiring new interim Systemic Anti-Cancer Treatments (SACT) options to mitigate risks to patients and maintain cancer services. In this study we analyse interim COVID-19 SACT therapy options recommended in England, evaluating the evidence supporting inclusion and delineating how these have been integrated into routine cancer care. Methods: We performed a retrospective analysis of interim Systemic Anti-Cancer Treatments endorsed by NHS England during the COVID-19 pandemic. Interim therapy options were compared to baseline (replacement) therapies by comparing data from the key pivotal trial(s) in terms of clinical efficacy and potential benefits (e.g., reduced immunosuppression or improved adverse effect profile) within the context of the pandemic. Furthermore, we evaluated the evolution of these interim SACT options, exploring if these have been integrated into current treatment pathways or are no longer accessible at the pandemic end. Findings: 31 interim oncology treatment options, across 36 indications, for solid cancers were endorsed by NHS England between March 2020 and August 2021. Interim therapies focused on the metastatic setting (83%; 30/36), allowing greater utilisation of immune checkpoint inhibitors (45%; 14/31) and targeted therapies (26%; 8/31), in place of cytotoxic chemotherapy. Overall, 36% (13/36) of therapies could not have efficacy compared with baseline treatments due to a paucity of evidence. For those which could, 39% (9/23) had superior efficacy (e.g., overall survival), 26% (6/23) had equivocal efficacy and 35% (8/23) lower efficacy. 53% (19/36) of interim therapies had better or equivocal toxicity profiles (when assessable), and/or were associated with reduced immunosuppression. Almost half (47%; 17/36) of interim therapies did not have UK market authorisation, being classified as ‘off label’ use. Analysing access to interim options at the end of the pandemic (May 2023) identified 19 (53% 19/36) interim options were fully available, and a further four (11% 4/36) therapies were partially available. Interpretation: Interim SACT options, introduced in England, across a range of solid cancers supported delivery of cancer services during the pandemic. Most interim therapies did not demonstrate superior efficacy, but provided other important benefits (e.g., reduced immunosuppression) in the context of the pandemic

Axon radius estimation with Oscillating Gradient Spin Echo (OGSE) diffusion MRI

The estimation of axon radius provides insights into brain function [1] and could provide progression and classification biomarkers for a number of white matter diseases [2-4]. A recent in silico study [5] has shown that optimised gradient waveforms (GEN) and oscillating gradient waveform spin echo (OGSE) have increased sensitivity to small axon radius compared to pulsed gradient spin echo (PGSE) diffusion MR sequences. In a follow-up study [6], experiments with glass capillaries show the practical feasibility of GEN sequences and verify improved pore-size estimates. Here, we compare PGSE with sine, sine with arbitrary phase, and square wave OGSE (SNOGSE, SPOGSE, SWOGSE, respectively) for axon radius mapping in the corpus callosum of a rat, ex-vivo. Our results suggest improvements in pore size estimates from OGSE over PGSE, with greatest improvement from SWOGSE, supporting theoretical results from [5] and other studies [7-9]

Cardiovascular Magnetic Resonance Imaging in Experimental Models

Cardiovascular magnetic resonance (CMR) imaging is the modality of choice for clinical studies of the heart and vasculature, offering detailed images of both structure and function with high temporal resolution

Neoadjuvant chemotherapy and trastuzumab versus neoadjuvant chemotherapy followed by post-operative trastuzumab for patients with HER2-positive breast cancer

Neoadjuvant chemotherapy plus trastuzumab (NCT) increases the rate of pathological complete response (pCR) and event-free survival (EFS) compared to neoadjuvant chemotherapy (NC) alone in women with HER2 positive breast cancer (BC). pCR in this setting is associated with improved EFS. Whether NCT preferentially improves EFS in comparison to NC followed by adjuvant trastuzumab initiated postoperatively (NCAT) has not been addressed. Using clinical data from women with HER2 positive BC treated at 7 European institutions between 2007 and 2010 we sought to investigate the impact on breast cancer outcomes of concomitant (NCT) versus sequential (NCAT) treatment in HER2 positive early BC. The unadjusted hazard ratio (HR) for event free survival with NCT compared with NCAT was 0.63 (95% CI 0.37–1.08; p = 0.091). Multivariable analysis revealed that treatment group, tumour size and ER status were significantly associated with EFS from diagnosis. In the whole group NCT was associated with a reduced risk of an event relative to NCAT, an effect that was confined to ER negative (HR: 0.25; 95% CI, 0.10–0.62; p = 0.003) as opposed to ER positive tumours (HR: 1.07; 95% CI, 0.46–2.52; p = 0.869). HER2 positive/ER negative BC treated with NC gain greatest survival benefit when trastuzumab is administered in both the neoadjuvant and adjuvant period rather than in the adjuvant period alone. These data support the early introduction of targeted combination therapy in HER2 positive/ER negative BC

Investigating changes in blood-cerebrospinal fluid barrier function in a rat model of chronic hypertension using non-invasive magnetic resonance imaging

Chronic hypertension is a major risk factor for the development of neurodegenerative disease, yet the etiology of hypertension-driven neurodegeneration remains poorly understood. Forming a unique interface between the systemic circulation and the brain, the blood-cerebrospinal fluid barrier (BCSFB) at the choroid plexus (CP) has been proposed as a key site of vulnerability to hypertension that may initiate downstream neurodegenerative processes. However, our ability to understand BCSFB’s role in pathological processes has, to date, been restricted by a lack of non-invasive functional measurement techniques. In this work, we apply a novel Blood-Cerebrospinal Fluid Barrier Arterial Spin Labeling (BCSFB-ASL) Magnetic resonance imaging (MRI) approach with the aim of detecting possible derangement of BCSFB function in the Spontaneous Hypertensive Rat (SHR) model using a non-invasive, translational technique. SHRs displayed a 36% reduction in BCSFB-mediated labeled arterial water delivery into ventricular cerebrospinal fluid (CSF), relative to normotensive controls, indicative of down-regulated choroid plexus function. This was concomitant with additional changes in brain fluid biomarkers, namely ventriculomegaly and changes in CSF composition, as measured by T1 lengthening. However, cortical cerebral blood flow (CBF) measurements, an imaging biomarker of cerebrovascular health, revealed no measurable change between the groups. Here, we provide the first demonstration of BCSFB-ASL in the rat brain, enabling non-invasive assessment of BCSFB function in healthy and hypertensive rats. Our data highlights the potential for BCSFB-ASL to serve as a sensitive early biomarker for hypertension-driven neurodegeneration, in addition to investigating the mechanisms relating hypertension to neurodegenerative outcomes

Using Diffusion-Diffusion Exchange Spectroscopy to observe diffusion exchange in yeast

The permeability of cell membranes varies significantly across both healthy and diseased tissue, and changes in cell membrane permeability can occur during treatment response in tumours. Measurements of cell membrane permeability could therefore be useful for tumour detection and as biomarkers of treatment response in the clinic. As the diffusion of water across the cell membrane is directly dependent on cell membrane permeability, we have investigated the ability of diffusion-diffusion exchange spectroscopy to quantify the diffusion exchange of water in a suspension of yeast, as a first step towards its application in tumours

Chemically treated 3D printed polymer scaffolds for biomineral formation

We present the synthesis of nylon-12 scaffolds by 3D printing and demonstrate their versatility as matrices for cell growth, differentiation, and biomineral formation. We demonstrate that the porous nature of the printed parts makes them ideal for the direct incorporation of preformed nanomaterials or material precursors, leading to nanocomposites with very different properties and environments for cell growth. Additives such as those derived from sources such as tetraethyl orthosilicate applied at a low temperature promote successful cell growth, due partly to the high surface area of the porous matrix. The incorporation of presynthesized iron oxide nanoparticles led to a material that showed rapid heating in response to an applied ac magnetic field, an excellent property for use in gene expression and, with further improvement, chemical-free sterilization. These methods also avoid changing polymer feedstocks and contaminating or even damaging commonly used selective laser sintering printers. The chemically treated 3D printed matrices presented herein have great potential for use in addressing current issues surrounding bone grafting, implants, and skeletal repair, and a wide variety of possible incorporated material combinations could impact many other areas