Feasibility of abdominal fat quantification on MRI and impact on effectiveness of abdominal compression for radiotherapy motion management.

The impact of fat on abdominal compression effectiveness in abdominal cancers was determined using magnetic resonance imaging (MRI). Visceral and subcutaneous fat were delineated on T2W 3D MRI, and motion change with compression was measured on 2D cine MRI. Results from 16 participants showed no correlation between fat percentage, body mass index (BMI), and motion change. Median BMI was 28.7 (SD, 4.9). Mean motion reduction was 7.8 mm (IQR, 5.0; p = 0.001) with compression. While no direct link was found between fat, BMI, and compression effectiveness, abdominal compression remains crucial for motion management in radiotherapy planning, providing dosimetric benefits.

Changes in Magnetic Resonance Imaging Radiomic Features in Response to Androgen Deprivation Therapy in Patients with Intermediate- and High-risk Prostate Cancer.

AIMS: The benefits of neoadjuvant androgen deprivation therapy (nADT) in the management of intermediate- and high-risk prostate cancer patients have been well-established. The aim of this study was to identify radiomic prognostic features derived from routine anatomic magnetic resonance imaging (MRI) sequences that can predict the response of the prostate cancer to nADT. MATERIALS AND METHODS: Patients with intermediate- and high-risk prostate cancer (with one of clinical stage ≥ T2c, Gleason score ≥7 or presenting prostate-specific antigen ≥10) who received 3 months of ADT prior to radical external beam radiotherapy were enrolled into this study. The relative blood volume and the relative blood flow were used as dynamic MRI kinetic parameters to quantify vascular changes as responses to nADT. For all pre- and post-nADT data sets, a combination of T2-weighted and contrast-enhanced T1-weighted anatomic images were used to define regions of interest (ROI) as the dominant malignant nodules (DMNs) and the benign prostate (the entire prostate with the summed DMNs being subtracted). MRI textural radiomic features associated with prostate cancer response in the literature of energy and homogeneity were selected. Pyradiomics was used to extract textural features of the ROIs. A Wilcoxon signed-rank test was carried out to investigate if there were statistically significant differences in values of radiomic features between: (i) benign prostate ROI and DMN pre-nADT; (ii) pre- and post-nADT of benign prostate ROI; (iii) pre- and post-nADT of DMN. Changes in radiomic features and dynamic MRI kinetic parameters were correlated using the Spearman correlation test. RESULTS: Twenty prostate cancer patients were recruited into the study. The median time between the first baseline scan and the first on-treatment scan was 91.5 days (range 82-105). One patient had no discernible tumour visible, leaving 19 patients with evaluable data for the analysis. Baseline homogeneity and energy values differed significantly between benign and malignant tissue (P < 0.01). In response to nADT, homogeneity and energy showed reciprocal changes, significantly increased in benign prostate while decreasing in the DMN. The reduction in tumour homogeneity and energy feature values showed a positive association with the decline in tumour blood flow and tumour blood volume induced by androgen deprivation as derived from dynamic MRI parameters. CONCLUSION: Energy and homogeneity radiomic features derived from MRI of benign and malignant prostate showed significant reciprocal changes in response to nADT. This study confirms the potential of these radiomic features to act as surrogate markers of tumour androgen sensitivity due to their strong association with ADT-induced physiological effects in prostate tumours.

Evaluation of Prognostic and Predictive Models in the Oncology Clinic.

Predictive and prognostic models hold great potential to support clinical decision making in oncology and could ultimately facilitate a paradigm shift to a more personalised form of treatment. While a large number of models relevant to the field of oncology have been developed, few have been translated into clinical use and assessment of clinical utility is not currently considered a routine part of model development. In this narrative review of the clinical evaluation of prediction models in oncology, we propose a high-level process diagram for the life cycle of a clinical model, encompassing model commissioning, clinical implementation and ongoing quality assurance, which aims to bridge the gap between model development and clinical implementation.

Inter- and intra-fractional stability of rectal gas in pelvic cancer patients during MRIgRT.

PURPOSE: Due to the electron return effect (ERE) during magnetic resonance imaging guided radiotherapy (MRIgRT), rectal gas during pelvic treatments can result in hot spots of over-dosage in the rectal wall. Determining the clinical impact of this effect on rectal toxicity requires estimation of the amount and mobility (and stability) of rectal gas during treatment. We therefore investigated the amount of rectal gas and local inter- and intra-fractional changes of rectal gas in pelvic cancer patients. METHODS: To estimate the volume of gas present at treatment planning, the rectal gas contents in the planning computed tomography (CT) scans of 124 bladder, 70 cervical and 2180 prostate cancer patients were calculated. To estimate inter- and intra-fractional variations in rectal gas, 174 and 131 T2-w MRIs for six cervical and eleven bladder cancer patients were used. These scans were acquired during four scan-sessions (~20-25 min each) at various time-points. Additionally, 258 T2-w MRIs of the first five prostate cancer patients treated using MRIgRT at our center, acquired during each fraction, were analyzed. Rectums were delineated on all scans. The area of gas within the rectum delineations was identified on each MRI slice using thresholding techniques. The area of gas on each slice of the rectum was used to calculate the inter- and intra-fractional group mean, systematic and random variations along the length of the rectum. The cumulative dose perturbation as a result of the gas was estimated. Two approaches were explored: accounting or not accounting for the gas at the start of the scan-session. RESULTS: Intra-fractional variations in rectal gas are small compared to the absolute volume of rectal gas detected for all patient groups. That is, rectal gas is likely to remain stable for periods of 20-25 min. Larger volumes of gas and larger variations in gas volume were observed in bladder cancer patients compared with cervical and prostate cancer patients. For all patients, local cumulative dose perturbations per beam over an entire treatment in the order of 60 % were estimated when gas had not been accounted for in the daily adaption. The calculated dose perturbation over the whole treatment was dramatically reduced in all patients when accounting for the gas in the daily set-up image. CONCLUSION: Rectal gas in pelvic cancer patients is likely to remain stable over the course of an MRIgRT fraction, and also likely to reappear in the same location in multiple fractions, and can therefore result in clinically relevant over-dosage in the rectal wall. The over-dosage is reduced when accounting for gas in the daily adaption.

Cardiovascular mortality and morbidity following radical radiotherapy for lung cancer: Is cardiovascular death under-reported?

BACKGROUND: Lung cancer is the most common malignancy worldwide. Radical radiotherapy is an essential treatment in the management of early and locally advanced lung cancer. Cardiac events are known to occur following radical radiotherapy for lung cancer. This study examines the burden of cardiac events post radiotherapy, and estimates the accuracy of death certification in patients who received radical radiotherapy for lung cancer. METHODS: We conducted a retrospective observational cohort study for all patients receiving radical radiotherapy for non-small cell lung cancer (NSCLC) at a large cancer centre between 01/01/2010 to 31/12/2016. Baseline cardiovascular disease and cancer status and treatment data were collected, along with hospital admission data and documented cause of death from the national registry for a median follow-up period of 34 months. RESULTS: Of 1224 patients included in the analysis, 378 (30.9%) patients had cardiovascular disease at baseline, including 140 (11.4%) with prior myocardial infarction. In the 846 patients without known cardiovascular disease, 451 (53.3%) had a QRISK2 predicted 10-year cardiovascular risk >20% over 10 years. During follow-up, 215 hospitalisations occurred (Incidence rate 6.2 per hundred patient years) which were classified as primarily cardiac, and 622 patients died (18 per 100 patient-years). However, death certificates stated a primary cardiac cause of death in only 33 cases (5.3% of deaths). Notably, 29% of patients dying out of hospital and certified as cancer death did not have documented cancer relapse prior to death, and 61% had no community palliative care input prior to death, implying these events may have been sudden and unexpected. CONCLUSION: There is a high prevalence of baseline cardiovascular disease in people undergoing radiotherapy for NSCLC, accompanied by significant rates of post-radiotherapy cardiovascular hospitalisation. However, only a small proportion of deaths are attributed to cardiovascular disease, together with the large amount of sudden deaths observed, this suggests that cardiovascular death is greatly under-reported in official statistics.

Experimental verification the electron return effect around spherical air cavities for the MR-Linac using Monte Carlo calculation.

PURPOSE: Dose deposition around unplanned air cavities during magnetic resonance-guided radiotherapy (MRgRT) is influenced by the electron return effect (ERE). This is clinically relevant for gas forming close to or inside organs at risk (OARs) that lie in the path of a single beam, for example, intestinal track during pelvic treatment. This work aims to verify Monte Carlo calculations that predict the dosimetric effects of ERE around air cavities. For this, we use GafChromic EBT3 film inside poly-methyl methacrylate (PMMA) -air phantoms. METHOD: Four PMMA phantoms were produced. Three of the phantoms contained centrally located spherical air cavities (0.5, 3.5, 7.5 cm diameter), and one phantom contained no air. The phantoms were split to sandwich GafChromic EBT3 film in the center. The phantoms were irradiated on an Elekta Unity system using a single 10 × 10 cm2 7-MV photon beam under the influence of a 1.5-T transverse magnetic field. The measurements were replicated using the Elekta Monaco treatment planning system (TPS). Gamma analysis with pass criteria 3%/3 mm was used to compare the measured and calculated dose distributions. We also consider 3%/2 mm, 2%/3 mm, and 2%/2 mm pass criteria for interest. RESULTS: The gamma analysis showed that >95% of the points agreed between the TPS-calculated and measured dose distributions, using 3%/3 mm criteria. The phantom containing the largest air cavity had the lowest agreement, with most of the disagreeing points lying inside the air cavity (dose to air region). CONCLUSIONS: The dose effects due to ERE around spherical air cavities are being calculated in the TPS with sufficient accuracy for clinical use.

The Challenges of Using MRI During Radiotherapy.

In this article we aim to introduce the main considerations in integrating magnetic resonance imaging (MRI) into the radiotherapy workflow. We will cover the use of MRI for improved delineation, considerations regarding MRI-only workflows, and the potential of functional imaging techniques. The challenges of implementing each of these will be discussed to ensure safe usage in radiotherapy.

The Potential Value of MRI in External-Beam Radiotherapy for Cervical Cancer.

The reference standard treatment for cervical cancer is concurrent chemoradiotherapy followed by magnetic resonance imaging (MRI)-guided brachytherapy. Improvements in brachytherapy have increased local control rates, but late toxicity remains high with rates of 11% grade ≥3. The primary clinical target volume (CTV) for external-beam radiotherapy includes the cervix and uterus, which can show significant inter-fraction motion. This means that generous margins are required to cover the primary CTV, increasing the radiation dose to organs at risk and, therefore, toxicity. A number of image-guided radiotherapy techniques (IGRT) have been developed, but motion can be random and difficult to predict prior to treatment. In light of the development of integrated MRI linear accelerators, this review discusses the potential value of MRI in external-beam radiotherapy. Current solutions for managing pelvic organ motion are reviewed, including the potential for online adaptive radiotherapy. The impacts of the use of MRI in tumour delineation and in the delivery of stereotactic ablative body radiotherapy (SABR) are highlighted. The potential role and challenges of using multi parametric MRI to guide radiotherapy are also discussed.

Benefit of using motion compensated reconstructions for reducing inter-observer and intra-observer contouring variation for organs at risk in lung cancer patients.

BACKGROUND AND PURPOSE: In lung cancer patients, accuracy in contouring is hampered by image artefacts introduced by respiratory motion. With the widespread introduction of 4DCT there is additional uncertainty caused by the use of different reconstruction techniques which will influence contour definition. This work aims to assess both inter- and intra-observer contour variation on average and motion compensated (mid-position) reconstructions. MATERIAL AND METHODS: Eight early stage non-small cell lung cancer patients that received 4DCT were selected and these scans were reconstructed as average and motion compensated datasets. 5 observers contoured the organs at risk (trachea, oesophagus, proximal bronchial tree, heart and brachial plexus) for each patient and each reconstruction. Contours were compared against a STAPLE volume with distance to agreement metrics. Intra-observer variation was assessed by redelineation after 4 months. RESULTS: The inter-observer variation was significantly smaller using the motion compensated datasets for the trachea (p = 0.006) and proximal bronchial tree (p = 0.004). For intra-observer variation, a reduction in contour variation was seen across all organs at risk in using motion compensated reconstructions. CONCLUSIONS: This work shows that there is benefit in using motion compensated reconstructions for reducing both inter-observer and intra-observer contouring variations for organs at risk in lung cancer patients.

RR-Lyrae-type pulsations from a 0.26-solar-mass star in a binary system.

RR Lyrae pulsating stars have been extensively used as tracers of old stellar populations for the purpose of determining the ages of galaxies, and as tools to measure distances to nearby galaxies. There was accordingly considerable interest when the RR Lyrae star OGLE-BLG-RRLYR-02792 (referred to here as RRLYR-02792) was found to be a member of an eclipsing binary system, because the mass of the pulsator (hitherto constrained only by models) could be unambiguously determined. Here we report that RRLYR-02792 has a mass of 0.26 solar masses M[symbol see text] and therefore cannot be a classical RR Lyrae star. Using models, we find that its properties are best explained by the evolution of a close binary system that started with M[symbol see text] and 0.8M[symbol see text]stars orbiting each other with an initial period of 2.9 days. Mass exchange over 5.4 billion years produced the observed system, which is now in a very short-lived phase where the physical properties of the pulsator happen to place it in the same instability strip of the Hertzsprung-Russell diagram as that occupied by RR Lyrae stars. We estimate that only 0.2 per cent of RR Lyrae stars may be contaminated by systems similar to this one, which implies that distances measured with RR Lyrae stars should not be significantly affected by these binary interlopers.

Quantum-dot-based saturable absorber for femtosecond mode-locked operation of a solid-state laser.

A quantum-dot-based saturable absorber has been demonstrated to initiate the generation of femtosecond pulses from a passively mode-locked solid-state laser. Control and tuning of the pulse duration from 58 ps to 158 fs was achieved. The 158 fs transform-limited pulses at 1280 nm are the shortest pulses that were produced from the Cr:forsterite laser passively mode locked by an InAs/InGaAs quantum-dot semiconductor saturable absorber mirror.

Trypsin induces activation and inflammatory mediator release from human eosinophils through protease-activated receptor-2.

Protease-activated receptors (PARs) are a unique class of G protein-coupled receptors, which are activated by proteolytic cleavage of the amino terminus of the receptor itself. PARs are most likely involved in various biological responses, such as hemostasis and regulation of muscle tone; however, the roles of PARs in the functions of inflammatory and immune cells are poorly understood. Because eosinophils are most likely involved in allergic inflammation and are exposed to a variety of proteases derived from allergens and other inflammatory cells, we investigated whether PARs regulate effector functions of eosinophils. Human eosinophils constitutively transcribe mRNA for PAR2 and PAR3, but not those for PAR1 and PAR4. The expression of PAR2 protein was confirmed by flow cytometry. When trypsin, an agonist for PAR2, was incubated with eosinophils, it potently induced superoxide anion production and degranulation; 5 nM trypsin induced responses that were 50-70% of those induced by 100 nM platelet-activating factor, a positive control. In contrast, thrombin, an activator for PAR1, PAR3, and PAR4, showed minimal effects. The stimulatory effect of trypsin was dependent on its serine protease activity and was blocked 59% by anti-PAR2 Ab. Furthermore, a specific tethered peptide ligand for PAR2 potently induced superoxide production and degranulation; the effects of peptide ligands for PAR1, PAR3, and PAR4 were negligible. These findings suggest that human eosinophils express functional PAR2, and serine proteases at the inflammation site may play important roles in regulating effector functions of human eosinophils. The expression and functional relevance of other PARs still need to be determined.

Acute laryngotracheitis in the rat induced by Sendai virus: the influx of six different types of immunocompetent cells into the laryngeal mucosa differs strongly between the subglottic and the glottic compartment.

OBJECTIVES: Acute laryngotracheitis is a disease in which mainly the subglottic area is infected, whereas adjacent parts of the larynx, especially the narrow glottic fold, remain unaffected. The reason for the difference between these two directly adjacent regions is unknown. Therefore, in the present study the influx of dendritic cells, neutrophils, T and B lymphocytes, natural killer cells, and macrophages into the mucosa of different laryngeal compartments was investigated after Sendai virus infection in the rat. The aims were to study both the influx of immunocompetent cells and the adhesion of the pathogen and to correlate them to the different reactions of the laryngeal areas during pseudocroup. METHODS: Acute laryngotracheitis was induced by intranasal application of Sendai virus in brown Norway rats. This virus is exclusively pneumotropic in rodents and belongs to the parainfluenza virus type 1, the main pathogen of acute laryngotracheitis in children. The numbers of dendritic cells, neutrophils, T and B lymphocytes, natural killer cells, and macrophages were determined in the supraglottic, glottic, subglottic, and tracheal mucosa on days 2, 5, 7, and 14 after virus application. Furthermore, the nucleoprotein of the virus and major histocompatibility complex (MHC) Class II expression were detected immunohistologically on the laryngeal epithelium. RESULTS: All cell subsets entered the laryngeal mucosa during inflammation. The highest influx was detected among dendritic cells subglottically. This was accompanied by a strong virus adhesion and MHC Class II expression on the subglottic epithelium. In contrast, only a few immunocompetent cells entered the adjacent glottic mucosa, and on the glottic epithelium staining for virus nucleoprotein and MHC Class II expression was weak. CONCLUSIONS: The inflammatory response of the laryngeal mucosa shows great regional differences in this animal model during experimental viral infection. The response was characterized by a strong subglottic and a weak glottic reaction. A possible reason for this difference might be region-specific viral adhesion on the epithelium of the laryngeal areas, as well as differences in MHC Class II expression. Thus, these data agree with the clinical observation during acute laryngotracheitis and may explain why the subglottic part of the larynx is affected preferentially during pseudocroup. The molecular mechanisms mediating the different reactions await clarification.

Ontogeny of rat pulmonary alveolar macrophage function: evidence for a selective deficiency in il-10 and nitric oxide production by newborn alveolar macrophages.

Alveolar macrophages (AM) play a crucial role in host defence by secretion of a large repertoire of biological response modifiers (BRM) following challenge. Newborns manifest increased susceptibility to lung infections, suggesting a deficiency in AM-mediated host defence. Thus, we investigated the ontogeny of BRM production by resting and stimulated AM. We analysed the capacity of rat AM to produce mRNA specific for a range of cytokines including tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, IL-10, IL-12, IL-18, and the enzyme inducible nitric oxide synthase, in response to in vitro lipopolysaccharide (LPS) challenge. We report that production of nitric oxide by newborn AM under conditions of maximal stimulation was impaired. In addition, expression of IL-10 was only minimally upregulated in AM from newborns in response to LPS compared to adults. Inability to upregulate expression of IL-10 appeared to be influenced by microenvironmental factors, since peritoneal macrophages from newborns responded to LPS with significant upregulation of IL-10. Furthermore, when newborn AM were precultured in vitro, IL-10 responsiveness to LPS was partially restored. In contrast, cytokines such as TNF-alpha, IL-1, IL-6, IL-12 and IL-18 appeared to be expressed at adult levels by newborn AM. These results demonstrate that there may be functional differences in AM of newborns compared to adults, and these may be specific to the tissue compartment.

Failure of MHC class II expression in neonatal alveolar macrophages: potential role of class II transactivator.

Neonatal peritoneal and blood macrophages are known to be ineffective in antigen-presentation functions, and this manifests as inefficient MHC class II expression in response to IFN-gamma. The underlying mechanisms responsible for this maturational deficiency have not been elucidated. We show here that MHC class II expression in alveolar macrophages (AM) from neonates is also refractory to IFN-gamma stimulation. Furthermore, by examining the intracellular pathway leading to MHC class II expression, we demonstrate that the site of the impairment is at the level of transcription. Thus, expression of mRNA encoding the class II transactivator (CIITA), MHC class II (RT1.B) and invariant chain (Ii) was low or undetectable in neonatal AM stimulated with concentrations of IFN-gamma that induced adult AM to up-regulate MHC class II expression. The failure of AM from young animals to express MHC class II was not due simply to deficient IFN-gamma receptor function since IFN-gamma-responsive genes such as IRF-1, IRF-2 and IP-10 were up-regulated in a dose-dependent manner from animals of all ages investigated. Importantly, the responsiveness of neonatal AM to IFN-gamma, as determined by MHC class II expression, could be modulated to adult levels when pre-cultured in vitro. This suggests that microenvironmental factors operative in vivo may play a role in suppressing the expression of MHC class II in AM from young animals. We have investigated the role of type I interferons but did not find them to be responsible for the inability of AM from young animals to induce MHC class II in response to IFN-gamma.

Regulation of dendritic cell recruitment into resting and inflamed airway epithelium: use of alternative chemokine receptors as a function of inducing stimulus.

Dendritic cells (DC) were purified by flow cytometry from rat tracheal mucosa; they exhibited the phenotypic characteristics of immature DC including high endocytic activity, low CD80/86 expression, and in vitro responsiveness to a broad range of CC chemokines. Daily treatment of adult rats with the selective CCR1 and CCR5 antagonist Met-RANTES reduced baseline numbers of tracheal intraepithelial DC by 50-60%, and pretreatment of animals with Met-RANTES before inhalation of aerosol containing heat-killed bacteria abolished the rapid DC influx into the epithelium that occurred in untreated controls, implicating CCR1 and CCR5 and their ligands in recruitment of immature DC precursors into resting airway tissues and during acute bacterial-induced inflammation. Comparable levels of DC recruitment were observed during airway mucosal Sendai virus infection and after aerosol challenge of sensitized animals with the soluble recall Ag OVA. However, Met-RANTES did not affect these latter responses, indicating the use of alternative chemokine receptors/ligands for DC recruitment, or possibly attraction of different DC subsets, depending on the nature of the eliciting stimulus.

Endogenous function and biological significance of aeroallergens: an update.

Significant advances have been made in delineating the structure and function of the clinically important aeroallergens. Most have now been characterized at the molecular level, and their endogenous function determined. In the period of review, however, several novel allergens have been identified. They include the house dust mite lipophorins and gelsolins, and the birch isoflavone reductase. In addition, the functions of previously described allergens have now been established or inferred on the basis of homology studies. For example, cat Fel d 1 and the grass pollen group 1 allergens possess proteolytic activity and the thaumatin-like plant and pollen allergens possess endo-beta1,3-glucanase activity. Similarly, the lipocalin allergens may possess endonuclease activity, and the mite group 2 allergens may bind cholesterol. The three-dimensional structure of the horse dander lipocalin Equ c 1 and the honey bee Api m 2 allergens have also been determined during the review period. Finally, in this period, a variety of novel or improved immunotherapeutic allergen reagents designed to redirect the host immune response from a T-helper-2 to a T-helper-1 cell phenotype have been described, in particular, allergen and immunostimulatory CpG motif conjugates.