The Impact of COVID-19 on Radiotherapy Services in Scotland, UK: A Population-based Study.

AIMS: The effect of the COVID-19 pandemic on cancer radiotherapy services is largely unknown. The aim of the present study was to investigate the impact of the resultant contingency plans on radiotherapy cancer services in Scotland. MATERIALS AND METHODS: Detailed data of radiotherapy activity at our centre were collected from 1 April 2019 to 31 March 2021. Differences in mean weekly radiotherapy courses, dose and fractionation patterns and treatment intent were compared with corresponding pre-pandemic months for all treatment sites. Qualitative data were collected for a subgroup of radical radiotherapy patients. RESULTS: Total radiotherapy courses decreased from 6968 to 6240 (-10%) compared with the previous year, prior to the pandemic. Average weekly radiotherapy courses delivered were 134 (standard deviation ±13), decreasing by 10% to 120 (standard deviation 15) (Welch's t-test, P < 0.001). The greatest decrease in new start treatment courses was observed from May to August 2020 (-7.7%, -24.0%, -16.7% and -18.7%) compared with the corresponding months in 2019. A significant reduction was seen for female patients <70 years (-16%) compared with females >70 years (-8%) or their male counterparts (-7% and -6%, respectively). By diagnosis, the largest reductions between pre- and post-pandemic levels were for anal (-26%), breast (-18%) and prostate (-14%) cancer. Contrarily, a significant increase was found for bladder (28%) and oesophageal (11%) cancers. CONCLUSIONS: Over the first 12 months of the COVID-19 pandemic, radiotherapy activity significantly decreased compared with the 12 months prior. Due to issued guidance, the use of hypofractionated regimens increased, contributing to the reduction in treatments for some tumour sites. An increase in other tumour sites can probably be attributed to the reduction or cancellation of surgical interventions. These results will inform our understanding of the indirect consequences of the pandemic on radiotherapy services.

Evaluating potential of multi-parametric MRI using co-registered histology: Application to a mouse model of glioblastoma.

BACKGROUND: Conventional MRI fails to detect regions of glioblastoma cell infiltration beyond the contrast-enhanced T1 solid tumor region, with infiltrating tumor cells often migrating along host blood vessels. PURPOSE: MRI is capable of generating a range of image contrasts which are commonly assessed individually by qualitative visual inspection. It has long been hypothesized that better diagnoses could be achieved by combining these multiple images, so called multi-parametric or multi-spectral MRI. However, the lack of clinical histology and the difficulties of co-registration, has meant this hypothesis has never been rigorously tested. Here we test this hypothesis, using a previously published multi-dimensional dataset consisting of registered MR images and histology. STUDY TYPE: Animal Model. SUBJECTS: Mice bearing orthotopic glioblastoma xenografts generated from a patient-derived glioblastoma cell line. FIELD STRENGTH/SEQUENCES: 7 Tesla, T1/T2 weighted, T2 mapping, contrast enhance T1, diffusion-weighted, diffusion tensor imaging. ASSESSMENT: Immunohistochemistry sections were stained for Human Leukocyte Antigen (probing human-derived tumor cells). To achieve quantitative MRI-tissue comparison, multiple histological slices cut in the MRI plane were stacked to produce tumor cell density maps acting as 'ground truth'. STATISTICAL TESTS: Sensitivity, specificity, accuracy and Dice similarity indices were calculated. ANOVA, t-test, Bonferroni correction and Pearson coefficients were used for statistical analysis. RESULTS: Correlation coefficient analysis with co-registered 'ground truth' histology showed interactive regression maps had higher correlation coefficients and sensitivity values than T2W, ADC, FA, and T2map. Further, the interaction regression maps showed statistical improved detection of tumor volume. DATA CONCLUSION: Voxel-by-voxel analysis provided quantitative evidence confirming the hypothesis that mpMRI can, potentially, better distinguish between the tumor region and normal tissue.

Stacked in-plane histology for quantitative validation of non-invasive imaging biomarkers: Application to an infiltrative brain tumour model.

BACKGROUND: While it is generally agreed that histopathology is the gold standard for assessing non-invasive imaging biomarkers, most validation has been by qualitative visual comparison. To date, the difficulties involved in accurately co-registering histology sections with imaging slices have prevented a voxel-by-voxel assessment of imaging modalities. By contrast with previous studies, which focus on improving the registration algorithms, we have taken the approach of improving the quality of the histological processing and analysis. NEW METHOD: To account for imaging slice orientation and thickness, multiple histology sections were cut in the MR imaging plane and averaged to produce stacked in-plane histology (SIH) maps. When combined with intensity sensitive staining this approach gives histopathology maps, which can be used as the gold standard to validate imaging biomarkers. RESULTS: We applied this pipeline to a patient-derived mouse model of glioblastoma multiforme (GBM). Increasing the number of stacked histology sections significantly increased SIH measured tumour volume. The SIH technique proposed here resulted in reduced variability of volume measurements and this allowed significant improvements in the quantitative volumetric assessment of multiple MRI modalities. Further, high quality registration enabled a voxel-wise comparison between MRI and histopathology maps. Previous approaches to the validation of imaging biomarkers with histology, have been either qualitative or of limited accuracy. Here we propose a pipeline that allows for a more accurate validation via co-registration with SIH maps, potentially allowing validation in a voxel-wise mode. CONCLUSION: This work demonstrates that methodically produced SIH maps facilitate the quantitative histopathologic assessment of imaging biomarkers.

Focused very high-energy electron beams as a novel radiotherapy modality for producing high-dose volumetric elements.

The increased inertia of very high-energy electrons (VHEEs) due to relativistic effects reduces scattering and enables irradiation of deep-seated tumours. However, entrance and exit doses are high for collimated or diverging beams. Here, we perform a study based on Monte Carlo simulations of focused VHEE beams in a water phantom, showing that dose can be concentrated into a small, well-defined volumetric element, which can be shaped or scanned to treat deep-seated tumours. The dose to surrounding tissue is distributed over a larger volume, which reduces peak surface and exit doses for a single beam by more than one order of magnitude compared with a collimated beam.

Quantitative histopathologic assessment of perfusion MRI as a marker of glioblastoma cell infiltration in and beyond the peritumoral edema region.

BACKGROUND: Conventional MRI fails to detect regions of glioblastoma cell infiltration beyond the contrast-enhanced T1 solid tumor region, with infiltrating tumor cells often migrating along host blood vessels. PURPOSE: To quantitatively and qualitatively analyze the correlation between perfusion MRI signal and tumor cell density in order to assess whether local perfusion perturbation could provide a useful biomarker of glioblastoma cell infiltration. STUDY TYPE: Animal model. SUBJECTS: Mice bearing orthotopic glioblastoma xenografts generated from a patient-derived glioblastoma cell line. FIELD STRENGTH/SEQUENCES: 7T perfusion images acquired using a high signal-to-noise ratio (SNR) multiple boli arterial spin labeling sequence were compared with conventional MRI (T1 /T2 weighted, contrast-enhanced T1 , diffusion-weighted, and apparent diffusion coefficient). ASSESSMENT: Immunohistochemistry sections were stained for human leukocyte antigen (probing human-derived tumor cells). To achieve quantitative MRI-tissue comparison, multiple histological slices cut in the MRI plane were stacked to produce tumor cell density maps acting as a "ground truth." STATISTICAL TESTS: Sensitivity, specificity, accuracy, and Dice similarity indices were calculated and a two-tailed, paired t-test used for statistical analysis. RESULTS: High comparison test results (Dice 0.62-0.72, Accuracy 0.86-0.88, Sensitivity 0.51-0.7, and Specificity 0.92-0.97) indicate a good segmentation for all imaging modalities and highlight the quality of the MRI tissue assessment protocol. Perfusion imaging exhibits higher sensitivity (0.7) than conventional MRI (0.51-0.61). MRI/histology voxel-to-voxel comparison revealed a negative correlation between tumor cell infiltration and perfusion at the tumor margins (P = 0.0004). DATA CONCLUSION: These results demonstrate the ability of perfusion imaging to probe regions of low tumor cell infiltration while confirming the sensitivity limitations of conventional imaging modalities. The quantitative relationship between tumor cell density and perfusion identified in and beyond the edematous T2 hyperintensity region surrounding macroscopic tumor could be used to detect marginal tumor cell infiltration with greater accuracy. LEVEL OF EVIDENCE: 1 Technical stage: 2 J. Magn. Reson. Imaging 2019;50:529-540.

SYSTEMS-2: A randomised phase II study of radiotherapy dose escalation for pain control in malignant pleural mesothelioma.

SYSTEMS-2 is a randomised study of radiotherapy dose escalation for pain control in 112 patients with malignant pleural mesothelioma (MPM). Standard palliative (20 Gy/5#) or dose escalated treatment (36 Gy/6#) will be delivered using advanced radiotherapy techniques and pain responses will be compared at week 5. Data will guide optimal palliative radiotherapy in MPM.

The Challenges Faced in Developing Novel Drug Radiation Combinations in Non-small Cell Lung Cancer.

Lung cancer is the most common cancer diagnosed in the UK. Outcomes for patients with this disease remain poor and new strategies to treat this disease require investigation. One potential option is to combine novel agents with radiotherapy in clinical studies. Here we discuss some of the important issues to consider when combining novel agents with radiotherapy, together with potential solutions as discussed at a recent Clinical Translational Radiotherapy Group (CTRad) workshop.

DNA repair and resistance to topoisomerase I inhibitors: mechanisms, biomarkers and therapeutic targets.

Irinotecan and topotecan are derivatives of the naturally occurring cytotoxic compound camptothecin that are used in the treatment of patients with colorectal cancer, either as single agents or in combination with radiotherapy and/or other chemotherapy drugs. They are inhibitors of DNA topoisomerase I (Top I) and exert their cytotoxic effects in replicating cells by inducing DNA strand breaks. A wide range of DNA repair proteins is involved in the recognition and repair of these breaks, and depletion or inhibition of some of these proteins increases the cytotoxic effects of Top I inhibitors. Building on these laboratory observations, ongoing translational research is aiming to establish whether this mechanistic information can be used to improve the treatment of patients with certain types of cancer. Two potential strategies are under investigation: (1) individualising treatment by evaluating levels and/or patterns of expression of DNA repair proteins that predict clinical response to Top I inhibitors, and (2) developing small molecule inhibitors of these repair enzymes to overcome tumour resistance and improve outcomes. This review summarises the current status of these research endeavours, focusing on the key roles of tyrosyl DNA phosphodiesterase 1 (Tdp1) and poly(ADP-ribose) polymerase (PARP), and examines the pre-clinical and clinical data that support the potential value of these and other DNA repair proteins as predictive markers and therapeutic targets. Since irinotecan is increasingly being combined with radiotherapy, the potential for these proteins to act as predictive biomarkers for both Top I inhibitors and radiation is proposed, and the possibility of synergistic potentiation of chemoradiation regimes by Tdp1 and/or PARP inhibitors is considered.

Topoisomerase I inhibition in colorectal cancer: biomarkers and therapeutic targets.

The topoisomerase I (Top 1) poison irinotecan is an important component of the modern treatment of colorectal cancer. By stabilising Top 1-DNA complexes, irinotecan generates Top 1-linked DNA single-strand breaks that can evolve into double-strand breaks and ultimately cause cell death. However, cancer cells may overcome cell killing by releasing the stalled topoisomerase from DNA termini, thereby reducing the efficacy of Top 1 poisons in clinics. Thus, understanding the DNA repair mechanisms involved in the repair of Top 1-mediated DNA damage provides a useful tool to identify potential biomarkers that predict response to this class of chemotherapy. Furthermore, targeting these pathways could enhance the therapeutic benefits of Top 1 poisons. In this review, we describe the cellular mechanisms and consequences of targeting Top 1 activity in cells. We summarise preclinical data and discuss the potential clinical utility of small-molecule inhibitors of the key proteins.

Low-dose hyper-radiosensitivity: a consequence of ineffective cell cycle arrest of radiation-damaged G2-phase cells.

This review highlights the phenomenon of low-dose hyper- radiosensitivity (HRS), an effect in which cells die from excessive sensitivity to small single doses of ionizing radiation but become more resistant (per unit dose) to larger single doses. Established and new data pertaining to HRS are discussed with respect to its possible underlying molecular mechanisms. To explain HRS, a three-component model is proposed that consists of damage recognition, signal transduction and damage repair. The foundation of the model is a rapidly occurring dose-dependent pre-mitotic cell cycle checkpoint that is specific to cells irradiated in the G2phase. This checkpoint exhibits a dose expression profile that is identical to the cell survival pattern that characterizes HRS and is probably the key control element of low-dose radiosensitivity. This premise is strengthened by the recent observation coupling low- dose radiosensitivity of G2-phase cells directly to HRS. The putative role of known damage response factors such as ATM, PARP, H2AX, 53BP1 and HDAC4 is also included within the framework of the HRS model.

Poly(ADP-ribose) polymerase-1 and ionizing radiation: sensor, signaller and therapeutic target.

Poly(ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear enzyme that binds rapidly to single and double-strand breaks in DNA and consequently modifies a range of nuclear proteins involved in the cellular response to ionising radiation. PARP-1 knockout mice are highly sensitive to ionising radiation, and inhibition or depletion of PARP-1 brings about modest sensitisation of cells in culture to radiation doses of 2 Gy and above. In certain cell lines, chemical inhibition of PARP activity is also associated with marked sensitisation to very low doses of radiation (<0.5 Gy). The mechanisms underlying these effects are discussed, and possible therapeutic applications of PARP-1 manipulation in combination with ionising radiation are considered.

Nuchal aggressive fibromatosis in childhood: two instructive case reports.

Aggressive fibromatosis is a rare, benign tumour with a capacity for infiltration of surrounding structures and a propensity for local recurrence. The cornerstone of therapy is surgery, with various other treatment modalities having ill-defined roles. Assessment of the efficacy of these interventions is difficult. The natural history of the condition is variable and different treatment modalities are often used concurrently. Childhood cases pose particular management problems because of their tendency to occur in the head and neck region and the potential for treatment-related morbidity. Two children presented after surgery with recurrent disease threatening the airway. One remitted spontaneously and remains disease free at 20 years. The other achieved a complete remission with radiotherapy and toremifene. The role of non-surgical treatment, particularly radiotherapy, is reviewed.