Cardiac Substructure Dose and Survival in Stereotactic Radiotherapy for Lung Cancer: Results of the Multi-Centre SSBROC Trial.

BACKGROUND AND PURPOSE: Stereotactic ablative body radiotherapy (SABR) is increasingly used for early-stage lung cancer, however the impact of dose to the heart and cardiac substructures remains largely unknown. The study investigated doses received by cardiac substructures in SABR patients and impact on survival. MATERIALS AND METHODS: SSBROC is an Australian multi-centre phase II prospective study of SABR for stage I non-small cell lung cancer. Patients were treated between 2013 and 2019 across 9 centres. In this secondary analysis of the dataset, a previously published and locally developed open-source hybrid deep learning cardiac substructure automatic segmentation tool was deployed on the planning CTs of 117 trial patients. Physical doses to 18 cardiac structures and EQD2 converted doses (α/ß = 3) were calculated. Endpoints evaluated include pericardial effusion and overall survival. Associations between cardiac doses and survival were analysed with the Kaplan-Meier method and Cox proportional hazards models. RESULTS: Cardiac structures that received the highest physical mean doses were superior vena cava (22.5 Gy) and sinoatrial node (18.3 Gy). The highest physical maximum dose was received by the heart (51.7 Gy) and right atrium (45.3 Gy). Three patients developed grade 2, and one grade 3 pericardial effusion. The cohort receiving higher than median mean heart dose (MHD) had poorer survival compared to those who received below median MHD (p = 0.00004). On multivariable Cox analysis, male gender and maximum dose to ascending aorta were significant for worse survival. CONCLUSIONS: Patients treated with lung SABR may receive high doses to cardiac substructures. Dichotomising the patients according to median mean heart dose showed a clear difference in survival. On multivariable analyses gender and dose to ascending aorta were significant for survival, however cardiac substructure dosimetry and outcomes should be further explored in larger studies.

Dosimetric Impact of Delineation and Motion Uncertainties on the Heart and Substructures in Lung Cancer Radiotherapy.

AIMS: Delineation variations and organ motion produce difficult-to-quantify uncertainties in planned radiation doses to targets and organs at risk. Similar to manual contouring, most automatic segmentation tools generate single delineations per structure; however, this does not indicate the range of clinically acceptable delineations. This study develops a method to generate a range of automatic cardiac structure segmentations, incorporating motion and delineation uncertainty, and evaluates the dosimetric impact in lung cancer. MATERIALS AND METHODS: Eighteen cardiac structures were delineated using a locally developed auto-segmentation tool. It was applied to lung cancer planning CTs for 27 curative (planned dose ≥50 Gy) cases, and delineation variations were estimated by using ten mapping-atlases to provide separate substructure segmentations. Motion-related cardiac segmentation variations were estimated by auto-contouring structures on ten respiratory phases for 9/27 cases that had 4D-planning CTs. Dose volume histograms (DVHs) incorporating these variations were generated for comparison. RESULTS: Variations in mean doses (Dmean), defined as the range in values across ten feasible auto-segmentations, were calculated for each cardiac substructure. Over the study cohort the median variations for delineation uncertainty and motion were 2.20-11.09 Gy and 0.72-4.06 Gy, respectively. As relative values, variations in Dmean were between 18.7%-65.3% and 7.8%-32.5% for delineation uncertainty and motion, respectively. Doses vary depending on the individual planned dose distribution, not simply on segmentation differences, with larger dose variations to cardiac structures lying within areas of steep dose gradient. CONCLUSION: Radiotherapy dose uncertainties from delineation variations and respiratory-related heart motion were quantified using a cardiac substructure automatic segmentation tool. This predicts the 'dose range' where doses to structures are most likely to fall, rather than single DVH curves. This enables consideration of these uncertainties in cardiotoxicity research and for future plan optimisation. The tool was designed for cardiac structures, but similar methods are potentially applicable to other OARs.

Validation of a Fully Automated Hybrid Deep Learning Cardiac Substructure Segmentation Tool for Contouring and Dose Evaluation in Lung Cancer Radiotherapy.

BACKGROUND AND PURPOSE: Accurate and consistent delineation of cardiac substructures is challenging. The aim of this work was to validate a novel segmentation tool for automatic delineation of cardiac structures and subsequent dose evaluation, with potential application in clinical settings and large-scale radiation-related cardiotoxicity studies. MATERIALS AND METHODS: A recently developed hybrid method for automatic segmentation of 18 cardiac structures, combining deep learning, multi-atlas mapping and geometric segmentation of small challenging substructures, was independently validated on 30 lung cancer cases. These included anatomical and imaging variations, such as tumour abutting heart, lung collapse and metal artefacts. Automatic segmentations were compared with manual contours of the 18 structures using quantitative metrics, including Dice similarity coefficient (DSC), mean distance to agreement (MDA) and dose comparisons. RESULTS: A comparison of manual and automatic contours across all cases showed a median DSC of 0.75-0.93 and a median MDA of 2.09-3.34 mm for whole heart and chambers. The median MDA for great vessels, coronary arteries, cardiac valves, sinoatrial and atrioventricular conduction nodes was 3.01-8.54 mm. For the 27 cases treated with curative intent (planned target volume dose ≥50 Gy), the median dose difference was -1.12 to 0.57 Gy (absolute difference of 1.13-3.25%) for the mean dose to heart and chambers; and -2.25 to 4.45 Gy (absolute difference of 0.94-6.79%) for the mean dose to substructures. CONCLUSION: The novel hybrid automatic segmentation tool reported high accuracy and consistency over a validation set with challenging anatomical and imaging variations. This has promising applications in substructure dose calculations of large-scale datasets and for future studies on long-term cardiac toxicity.

Evidence of Small Airways Disease and the Immediate Effects of Lumacaftor/Ivacaftor in Children with Cystic Fibrosis.

Aim The aim of this study was to explore risk factors for acute changes in lung function following initiation of lumacaftor/ivacaftor (LUM/IVA) in children with cystic fibrosis. Methods Retrospective review of all children commenced on LUM/IVA treatment over a one-year period. CT Thorax images were reviewed for evidence of air trapping using the Brody score. Results Data was collected from 15 children. A transient decline in ppFEV1 was observed after initiation of LUM/IVA in 93% (n=14) of patients with an absolute mean decline of -10.8%. There was a statistically significant inverse relationship between ΔFEV1 and baseline ppFEV1. There was no relationship between air trapping score and ΔFEV1 (p=0.41). Conclusion Pre-existing small airways disease is not a risk factor for acute changes in lung function following initiation of LUM/IVA. Our results suggest that a LUM/IVA-related decline in lung function is more significant in CF children with higher baseline FEV1.

Primary External Ventricular Drains in the Management of Open Myelomeningocele Repairs in the Neonatal Setting in Ireland

Aim The aim of this study is to outline the role of primary external ventricular drains (EVD) in the management of open myelomeningoceles in the neonatal setting in Ireland. Methods Retrospective cohort study involving all infants who underwent open myelomeningocele repair in a teritary centre in Ireland between January 2009 and April 2016. Medical charts and laboratory data was reviewed on all infants meeting the inclusion criteria. Results One hundred and forty-three neonates underwent open myelomeningocele repair in the 6.5 year period. EVD were inserted at the time of primary wound closure in 19 cases (13%). EVD were used to aid in wound closure and as a primary method of cerebrospinal fluid (CSF) diversion. They remained in place for a median of 8 days, ranging from 1-22 days. All EVD, apart from one, in our series were replaced by a ventricular-peritoneal (VP) shunt at some stage. Conclusion EVD were used in 13% of cases of open myelomeningocele repairs from Jan 2009-Apr 2016 as a primary measure to aid in management. Compared to the cohort in whom an EVD was not inserted at the time of surgery, there was a decrease in the rate of infections. However, there was an increased rate of wound dehiscence/leak and a later need for VP shunt insertion.

High-level expression and stabilization of recombinant human chitinase produced in a continuous constitutive Pichia pastoris expression system.

A continuous fermentation process has been developed in Pichia pastoris (P. pastoris) with the glyceraldehyde-3-phosphate dehydrogenase (GAP) promoter in order to produce large quantities of recombinant human chitinase (rh-chitinase) for preclinical studies as a potential high-dose antifungal drug. Expression levels of about 200 to 400 mg/L have been demonstrated in fed-batch fermentations using strains with either the traditional methanol-inducible or the constitutive GAP promoter. Proteolytic degradation of the enzyme was typically seen in fed-batch fermentations. Continuous production of the enzyme by P. pastoris with the GAP promoter was demonstrated in a 1.5-L working volume fermentor using either glucose or glycerol as the carbon source. The fermentation could be extended for >1 month with a steady-state protein concentration of approximately 300 mg/L. Cell densities were >400 g/L wet cell weight (WCW) (approximately 100 g/L dry cell weight [DCW]) at a dilution rate (D) of 0.83 day(-1) or 1.2 volume exchanges per day (VVD). No proteolytic degradation of the enzyme was seen in the continuous fermentation mode.

FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate.

Oncogenic osteomalacia (OOM), X-linked hypophosphatemia (XLH), and autosomal dominant hypophosphatemic rickets (ADHR) are phenotypically similar disorders characterized by hypophosphatemia, decreased renal phosphate reabsorption, normal or low serum calcitriol concentrations, normal serum concentrations of calcium and parathyroid hormone, and defective skeletal mineralization. XLH results from mutations in the PHEX gene, encoding a membrane-bound endopeptidase, whereas ADHR is associated with mutations of the gene encoding FGF-23. Recent evidence that FGF-23 is expressed in mesenchymal tumors associated with OOM suggests that FGF-23 is responsible for the phosphaturic activity previously termed "phosphatonin." Here we show that both wild-type FGF-23 and the ADHR mutant, FGF-23(R179Q), inhibit phosphate uptake in renal epithelial cells. We further show that the endopeptidase, PHEX, degrades native FGF-23 but not the mutant form. Our results suggest that FGF-23 is involved in the pathogenesis of these three hypophosphatemic disorders and directly link PHEX and FGF-23 within the same biochemical pathway.

Skewed autonomy-relatedness in preadolescents' conceptions of their relationships with mother, father, and best friend.

Healthy adaptation within all close relationships--whether with parents, friends, or romantic partners--involves striking a balance between connectedness to and independence from the relationship partner. For some individuals, adaptation within one or more relationships is skewed, or characterized by either an excessive concern for closeness that impedes autonomy (preoccupied stance) or an excessive concern for autonomy that inhibits closeness (avoidant stance). In this study with boys and girls aged 9-14 years, children who reported a preoccupied or avoidant stance toward their mother displayed increased social impairment in the peer group over time. There were predictable associations among children's stances toward mother, father, and best friend. Children resembled their best friend in relationship stance. The study illustrates the advantages of applying common relationship constructs (e.g., autonomy-relatedness) to the study of diverse close relationships.

Victimization by peers: associations with children's reports of mother-child interaction.

Children who are chronically victimized by peers are at risk for personal difficulties. This study examined whether victimization is associated with mother-child interaction at home. Preadolescents (N = 184; mean age = 11.7 years) reported on their mother's child-rearing practices and on how they cope during conflicts with their mother. Peers reported on victimization at school. Sex-specific links between perceived family interaction and peer victimization were found. For boys, victimization was associated with perceived maternal overprotectiveness, especially when boys reported reacting with fear during mother-child conflict. For girls, victimization was associated with perceived maternal rejection and with girls' reports of aggressive coping during mother-child conflict. Results support the theory that parenting that hinders children's development of gender-salient competencies (autonomy for boys and communion for girls) places children at risk for peer victimization.

Characterization of cyclic AMP efflux from swine adipocytes in vitro.

OBJECTIVE: A variety of cell types transport cyclic AMP (cAMP) to the extracellular fluid; the purpose of this study was to determine if and how this process occurs in adipocytes. RESEARCH METHODS AND PROCEDURES: Adipocytes were isolated from 3-month-old swine and incubated with stimulators of adenylate cyclase for 2 to 120 minutes to promote cAMP synthesis and efflux. Efflux was characterized in the presence of agents that inhibit ATP production, anion transport, intracellular cAMP metabolism, and extracellular cAMP metabolism. Extracellular cAMP was measured by enzyme immunoassay, then corrected for cell lysis by measuring lactate dehydrogenase release. RESULTS: cAMP efflux averaged 24.7 fmol/min/cm2 adipocyte surface area, was linear for 2 hours, and was proportional to adipocyte surface area (r=0.94, p<0.05). Efflux was reduced by approximately 35% in cells incubated with 1 microM antimycin, an inhibitor of ATP synthesis (p<0.05), and by approximately 55% in cells incubated with 2 mM probenecid, an anion-specific transport blocker (p<0.05). Extracellular cAMP levels more than doubled by the addition of 1 microM 1,3-dipropyl-8-p-sulfophenylxanthine, a purported inhibitor of extracellular phosphodiesterase. DISCUSSION: Our data demonstrate that cAMP is transported from swine adipocytes by an energy-dependent anion transporter and can be metabolized extracellularly. Future studies will evaluate extracellular cAMP as a potential source of extracellular adenosine, a potent inhibitor of adipocyte lipolysis.