Understanding the Benefit of Magnetic Resonance-guided Adaptive Radiotherapy in Rectal Cancer Patients: a Single-centre Study.

AIMS: Neoadjuvant chemoradiotherapy followed by surgery is the mainstay of treatment for patients with rectal cancer. Standard clinical target volume (CTV) to planning target volume (PTV) margins of 10 mm are used to accommodate inter- and intrafraction motion of target. Treating on magnetic resonance-integrated linear accelerators (MR-linacs) allows for online manual recontouring and adaptation (MRgART) enabling the reduction of PTV margins. The aim of this study was to investigate motion of the primary CTV (CTVA; gross tumour volume and macroscopic nodes with 10 mm expansion to cover microscopic disease) in order to develop a simultaneous integrated boost protocol for use on MR-linacs. MATERIALS AND METHODS: Patients suitable for neoadjuvant chemoradiotherapy were recruited for treatment on MR-linac using a two-phase technique; only the five phase 1 fractions on MR-linac were used for analysis. Intrafraction motion of CTVA was measured between pre-treatment and post-treatment MRI scans. In MRgART, isotropically expanded pre-treatment PTV margins from 1 to 10 mm were rigidly propagated to post-treatment MRI to determine overlap with 95% of CTVA. The PTV margin was considered acceptable if overlap was >95% in 90% of fractions. To understand the benefit of MRgART, the same methodology was repeated using a reference computed tomography planning scan for pre-treatment imaging. RESULTS: In total, nine patients were recruited between January 2018 and December 2020 with T3a-T4, N0-N2, M0 disease. Forty-five fractions were analysed in total. The median motion across all planes was 0 mm, demonstrating minimal intrafraction motion. A PTV margin of 3 and 5mm was found to be acceptable in 96 and 98% of fractions, respectively. When comparing to the computed tomography reference scan, the analysis found that PTV margins to 5 and 10 mm only acceptably covered 51 and 76% of fractions, respectively. CONCLUSION: PTV margins can be reduced to 3-5 mm in MRgART for rectal cancer treatment on MR-linac within an simultaneous integrated boost protocol

A randomised controlled trial of Caphosol mouthwash in management of radiation-induced mucositis in head and neck cancer.

Purpose This phase III, non-blinded, parallel-group, randomised controlled study evaluated the efficacy of Caphosol mouthwash in the management of radiation-induced oral mucositis (OM) in patients with head and neck cancer (HNC) undergoing radical (chemo)radiotherapy.Patients and methods Eligible patients were randomised at 1:1 to Caphosol plus standard oral care (intervention) or standard oral care alone (control), stratified by radiotherapy technique and use of concomitant chemotherapy. Patients in the intervention arm used Caphosol for 7weeks: 6weeks during and 1-week post-radiotherapy. The primary endpoint was the incidence of severe OM (CTCAE ⩾grade 3) during and up to week 8 post-radiotherapy. Secondary endpoints include pharyngeal mucositis, dysphagia, pain and quality of life.Results The intervention (n=108) and control (n=107) arms were well balanced in terms of patient demographics and treatment characteristics. Following exclusion of patients with missing data, 210 patients were available for analysis. The incidence of severe OM did not differ between the intervention and control arms (64.1% versus 65.4%, p=0.839). Similarly, no significant benefit was observed for other secondary endpoints. Overall, compliance with the recommended frequency of Caphosol was low.Conclusion Caphosol did not reduce the incidence or duration of severe OM during and after radiotherapy in HNC

Roadmap on commercialization of metal halide perovskite photovoltaics

Perovskite solar cells (PSCs) represent one of the most promising emerging photovoltaic technologies due to their high power conversion efficiency. However, despite the huge progress made not only in terms of the efficiency achieved, but also fundamental understanding of the relevant physics of the devices and issues which affect their efficiency and stability, there are still unresolved problems and obstacles on the path toward commercialization of this promising technology. In this roadmap, we aim to provide a concise and up to date summary of outstanding issues and challenges, and the progress made toward addressing these issues. While the format of this article is not meant to be a comprehensive review of the topic, it provides a collection of the viewpoints of the experts in the field, which covers a broad range of topics related to PSC commercialization, including those relevant for manufacturing (scaling up, different types of devices), operation and stability (various factors), and environmental issues (in particular the use of lead). We hope that the article will provide a useful resource for researchers in the field and that it will facilitate discussions and move forward toward addressing the outstanding challenges in this fast-developing field

MicroRNA-145 Regulates Human Corneal Epithelial Differentiation

Epigenetic factors, such as microRNAs, are important regulators in the self-renewal and differentiation of stem cells and progenies. Here we investigated the microRNAs expressed in human limbal-peripheral corneal (LPC) epithelia containing corneal epithelial progenitor cells (CEPCs) and early transit amplifying cells, and their role in corneal epithelium.Human LPC epithelia was extracted for small RNAs or dissociated for CEPC culture. By Agilent Human microRNA Microarray V2 platform and GeneSpring GX11.0 analysis, we found differential expression of 18 microRNAs against central corneal (CC) epithelia, which were devoid of CEPCs. Among them, miR-184 was up-regulated in CC epithelia, similar to reported finding. Cluster miR-143/145 was expressed strongly in LPC but weakly in CC epithelia (P = 0.0004, Mann-Whitney U-test). This was validated by quantitative polymerase chain reaction (qPCR). Locked nucleic acid-based in situ hybridization on corneal rim cryosections showed miR-143/145 presence localized to the parabasal cells of limbal epithelium but negligible in basal and superficial epithelia. With holoclone forming ability, CEPCs transfected with lentiviral plasmid containing mature miR-145 sequence gave rise to defective epithelium in organotypic culture and had increased cytokeratin-3/12 and connexin-43 expressions and decreased ABCG2 and p63 compared with cells transfected with scrambled sequences. Global gene expression was analyzed using Agilent Whole Human Genome Oligo Microarray and GeneSpring GX11.0. With a 5-fold difference compared to cells with scrambled sequences, miR-145 up-regulated 324 genes (containing genes for immune response) and down-regulated 277 genes (containing genes for epithelial development and stem cell maintenance). As validated by qPCR and luciferase reporter assay, our results showed miR-145 suppressed integrin β8 (ITGB8) expression in both human corneal epithelial cells and primary CEPCs.We found expression of miR-143/145 cluster in human corneal epithelium. Our results also showed that miR-145 regulated the corneal epithelium formation and maintenance of epithelial integrity, via ITGB8 targeting

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Optimising head and neck radiotherapy treatment using adaptive radiotherapy

Radiotherapy delivery in head and neck cancer (HNC) has dramatically improved recently with the introduction of advanced techniques such as intensity-modulated radiation therapy (IMRT) and image-guided radiation therapy (IGRT). The aim of IGRT is to correct for setup errors such as positional shifts without modifying the original treatment plan. Intra-treatment structural and spatial changes are not corrected using IGRT. In contrast, adaptive radiotherapy (ART) is an exciting concept that aims to modify the radiotherapy treatment plan in response to temporal changes to the anatomy and tumour. In an anatomy-adapted ART, repeat planning is based on intra-treatment structural changes to reduce organs at risk (OARs) planned dose deviations and improve dose homogeneity to preserve target coverage. Treatment can be individualised further by adapting to a changing target volume in a response-adapted ART. Improved soft tissue contrast with magnetic resonance (MR) guidance has made the latter a real possibility. This thesis lays the groundwork for the introduction of ART at our institution. To assist with the increased clinician workload, I first demonstrate the utility of using deformable image registration (DIT) for contour propagation during repeat planning. This improves delineation efficiency by significantly reducing clinician delineation time. Whilst intra-treatment changes are evident in CT-based studies, there are few magnetic resonance imaging (MRI) studies reporting this. This thesis demonstrates that these intra-treatment changes in target volume and OARs are evident on MR imaging and that MR-guided response-adapted ART leads to AOR dose reduction and improves target volume coverage. The clinical introduction of a hybrid MRI and linear accelerator (MR-Linac) has made daily MR-guided ART possible but this has important practical differences to a conventional linear accelerator. Patient selection is crucial due to a restricted carniocaudal treatment field length and a longer treatment time. A hyo-sternal neck length <14.6 cm in a neutral neck position can be optimised using an oral cavity constraint, allaying concerns about increased oral cavity doses. Finally, this thesis reports the first HNC patient to be treated on the MR-Linac using a simple online adapted worflow. Whilst certain findings in this thesis such as the utility of DIR for contour propagation can be applied to current clinical practice, the response-adapted ART findings remain investigative and lay the groundwork for future randomised controlled studies

A convolutional neural network for contouring metastatic lymph nodes on diffusion-weighted magnetic resonance images for assessment of radiotherapy response.

Background and purpose Retrieving quantitative parameters from magnetic resonance imaging (MRI), e.g. for early assessment of radiotherapy treatment response, necessitates contouring regions of interest, which is time-consuming and prone to errors. This becomes more pressing for daily imaging on MRI-guided radiotherapy systems. Therefore, we trained a deep convolutional neural network to automatically contour involved lymph nodes on diffusion-weighted (DW) MRI of head and neck cancer (HNC) patients receiving radiotherapy.Materials and methods DW-images from 48 HNC patients (18 induction-chemotherapy + chemoradiotherapy; 30 definitive chemoradiotherapy) with 68 involved lymph nodes were obtained on a diagnostic 1.5 T MR-scanner prior to and 2-3 timepoints throughout treatment. A radiation oncologist delineated the lymph nodes on the b = 50 s/mm2 images. A 3D U-net was trained to contour involved lymph nodes. Its performance was evaluated in all 48 patients using 8-fold cross-validation and calculating the Dice similarity coefficient (DSC) and the absolute difference in median apparent diffusion coefficient (ΔADC) between the manual and generated contours. Additionally, the performance was evaluated in an independent dataset of three patients obtained on a 1.5 T MR-Linac.Results In the definitive chemoradiotherapy patients (n = 96 patients/lymphnodes/timepoints) the DSC was 0.87 (0.81-0.91) [median (1st-3rd quantiles)] and ΔADC was 1.9% (0.8-3.4%) and both remained stable throughout treatment. The network performed worse in the patients receiving induction-chemotherapy (n = 65), with DSC = 0.80 (0.71-0.87) and ΔADC = 3.3% (1.6-8.0%). The network performed well on the MR-Linac data (n = 8) with DSC = 0.80 (0.75-0.82) and ΔADC = 4.0% (0.6-9.1%).Conclusions We established accurate automatic contouring of involved lymph nodes for HNC patients on diagnostic and MR-Linac DW-images

The impact of restricted length of treatment field and anthropometric factors on selection of head and neck cancer patients for treatment on the MR-Linac.

OBJECTIVE:This study investigates the impact of a restricted craniocaudal (CC) field length of <20 cm on the selection of head and neck cancer (HNC) patients who can be treated on the MR-Linac using a single isocentre technique. We also assess the effects of anthropometric factors and the neck position on the CC field length. METHODS:110 HNC patients who underwent radical primary or adjuvant radiotherapy were retrospectively analysed. We assessed the proportion of treatment fields with a CC length of <20 cm and the effects of gender, height, hyo-sternal neck length (distance from superior surface of hyoid to sternal notch measured on the coronal reconstruction of the planning CT) and neck position on CC length. RESULTS:95% of HNC patients had a CC field length <20 cm. Female patients showed a significantly shorter median CC length than male patients in both extended (p = 0.0003) and neutral (p = 0.008) neck positions. Neck position influenced the median CC length with neutral neck being significantly shorter than extended neck (p = 0.0119). Patient height and hyo-sternal neck length showed positive correlation with the CC length, with neck length in neutral position having the strongest correlation (r = 0.65, p = 0.0001 and r = 0.63, p < 0.0001, respectively for extended neck; r = 0.55, p = 0.0070 and r = 0.80, p < 0.0001, respectively for neutral neck). A hyo-sternal neck length of <14.6 cm predicted a CC length of <20 cm in neutral neck position. CONCLUSION:The majority of patients with HNC at the Royal Marsden Hospital have anthropometric features compatible with their being treated on the MR-Linac using a single isocentre technique. The absolute CC field size may vary according to primary tumour site, patient factors and neck position. A hyo-sternal neck length cut-off of 14.6 cm in the neutral neck position can be used as a surrogate marker for suitability of treatment on MR-Linac. ADVANCES IN KNOWLEDGE:This paper highlights the potential impact of a restricted CC field in HNC patient selection for the MR-Linac treatment. This is the first report to suggest the use of neck length as a surrogate marker for suitability of treatment on the MR-Linac

Medically Documented Suicide Ideation Among U.S. Army Soldiers

We used administrative data to examine predictors of medically documented suicide ideation (SI) among Regular Army soldiers from 2006 through 2009 (N = 10,466 ideators, 124,959 control person-months). Enlisted ideators (97.8% of all cases) were more likely than controls to be female, younger, older when entering service, less educated, never or previously deployed, and have a recent mental health diagnosis. Officer ideators were more likely than controls to be female, younger, younger when entering service, never married, and have a recent mental health diagnosis. Risk among enlisted soldiers peaked in the second month of service and declined steadily, whereas risk among officers remained relatively stable over time. Risk of SI is highest among enlisted soldiers early in Army service, females, and those with a recent mental health diagnosis. In recent years, there have been several large-scale efforts to understand the sharp increase in fatal (LeardMann et al., 2013; Reger et al., 2015; Schoenbaum et al., 2014) and nonfatal (Nock et al., 2014; Ursano, Kessler, Heeringa, et al., 2015; Ursano, Kessler, Stein, et al., 2015) suicidal behaviors among U.S. military personnel that occurred during the wars in Iraq and Afghanistan. Suicide ideation (SI) is an important outcome both as an indicator of distress and as a predictor of more serious suicidal behavior (Kessler, Borges, & Walters, 1999; Nock et al., 2014; Ursano, Heeringa, et al., 2015). The lifetime prevalence of SI is approximately 14% among active duty Regular Army soldiers (Nock et al., 2014). The sociodemographic correlates of ideation in service members, including female gender, younger age, and non-Hispanic White race and ethnicity (Nock et al., 2014; Ursano, Kessler, Heeringa, et al., 2015) are consistent with those of the U.S. general population (Borges, Angst, Nock, Ruscio, & Kessler, 2008; Kessler, Berglund, Borges, Nock, & Wang, 2005). Risk of attempting or dying by suicide is higher among enlisted soldiers in their first tour of duty (Gilman et al., 2014; Ursano, Kessler, Stein, et al., 2015), but the relationship of time in service with SI is not yet known. Although the influence of deployment on adverse mental health outcomes is well supported (Bray et al., 2010; Gadermann et al., 2012; Jacobson et al., 2008; Shen, Arkes, & Williams, 2012; Wells et al., 2010), the association of deployment with suicidal thoughts and behaviors has generated inconsistent results (Bryan et al., 2015). Prior mental disorders are a robust predictor of both fatal (Black, Gallaway, Bell, & Ritchie, 2011) and nonfatal (Ursano, Kessler, Stein, et al., 2015) suicidal behaviors in service members, findings in line with a large body of civilian research (Harris & Barraclough, 1997; Nock, Hwang, Sampson, & Kessler, 2010)

Investigation of the High-energy Emission from the Magnetar-like Pulsar PSR J1119-6127 after the 2016 Outburst

PSR J1119-6127 is a radio pulsar that behaved with magnetar-like bursts, and we performed a comprehensive investigation of this pulsar using the archival high-energy observations obtained after its outburst in 2016 July. After the 2016 outburst, specific regions on the neutron star (NS) surface were heated up to &gt;0.3 and &gt;1 keV from similar to 0.2 keV. A hard nonthermal spectral component with a photon index &lt;0.5 related to the magnetospheric emission can be resolved from the NuSTAR spectra above 10 keV. We find that the thermal emitting regions did not cool down and gradually shrank by about 20%-35% 4 months after the outburst. Hard X-ray pulsations were detected with NuSTAR immediately after the outburst at a 5 sigma confidence level and with a background-subtracted pulsed fraction of 40% +/- 10%. However, the signal became undetectable after a few days. Using Fermi data, we found that the gamma-ray emission in 0.5-300 GeV was suppressed along with the disappearance of the radio pulsations. This is likely caused by a reconfiguration of the magnetic field. We also discovered that the timing noise evolved dramatically, and the spin-down rate significantly increased after the 2016 glitch. We proposed that postoutburst temporal and spectral behaviors from radio to gamma-ray bands were caused by changes of the magnetosphere structure, pair plasma injection, and the shrinking emission sites on the NS