In vitro inhalation/ingestion bioaccessibility, health risks, and source appointment of airborne particle-bound elements trapped in room air conditioner filters

Abstract

The airborne particle-bound elements (Ca, Fe, Al, Mg, K, Na, Zn, Mn, P, Pb, Cu, Sr, Ti, Ba, Cr, Ni, As, Sb, Cd, Co, and V) trapped in room air conditioners' filters (filter dusts) during recirculating indoor air from different types of rooms were analyzed, and the objectives of this study were to assess the potential sources of those elements and their potential health risks via inhalation/ingestion exposure. Main crustal elements such as Ca, Fe, Al, Mg, and K with an average value of 60.6, 17.9, 11.3, 7.58, and 6.90 mg g⁻¹, respectively, are the preponderant elements, and the mean values of main toxic elements were 2230, 344, 508, 85.7, 71.5, 36.0, 8.02, and 16.9 mg kg⁻¹ for Zn, Cu, Pb, Cr, Ni, As, Cd, and Sb, respectively. The enrichment factors indicated the significant enrichment of Cd, Pb, Cr, Cu, Sb, and Zn in the filter dusts. Four potential sources with the contributions of 33.5, 29.1, 22.6, and 14.8%, respectively, were identified by absolute principal component scores-multiple linear regression analysis (APCS-MLR). Enrichment factor and APCS-MLR model reveal the outdoor input of toxic elements. In vitro inhalation and ingestion bioaccessibility of toxic elements showed elemental and in vitro procedure dependence. There are potential carcinogenic risks via ingestion exposure and no non-carcinogenic risks to both children and adults based on bioaccessible contents of toxic elements. This study reveals the potential health risks posed by the particle-bound elements.

Optimization of preparation of monolithic carbon foam from rice husk char for benzene leakage emergency

Abstract

In the aim of BTEX leakage emergency, monolithic carbon foam (MCF) was designed and prepared via a simple method. Rice husk char (RHC) was chosen as raw material, polyurethane sponge (PUS) was used as sacrificed template to form inner channel, and corn starch and ZnO were employed as binder and reinforcing filler, respectively. The optimized preparation parameter was determined by adopting of Taguchi experimental design method. Both MCF-RHC and MCF-CAC were made from RHC and commercial activated carbon (CAC) under the same condition, and three reported monolithic carbon adsorbents were selected for comparative study with MCFs. The surface and structural properties were characterized by XRD, SEM, and N₂ adsorption/desorption isotherm analyses. XRD analysis results reveal that MCF-RHC was the composites of carbon, SiO₂, and ZnO, and MCF-RHC and MCF-CAC have good potential in organic adsorption. Hierarchical structure of MCF was constructed by inner macro-channel from burning up of PUS and micro- and meso-pores from resultant carbon composite, and these inner macro-channels play a more important role in benzene rapid adsorption. Specific surface area of MCF-RHC was 465.5 m² g⁻¹, which included micro- and meso-pores, which mainly come from RHC during the carbonization process. Adsorption kinetics study demonstrated that the benzene equilibrium uptake of MCF-RHC and MCF-CAC was similar, and both of data well fitted the pseudo-second-order kinetic model. However, MCF-RHC has the ability to absorb benzene more quickly, which meets the demand of absorbent utilizing in benzene leakage emergency.

Evaluation and Diagnosis of Salivary Gland Neoplasms

Salivary gland tumors are an uncommon heterogeneous group of neoplasms that vary in their anatomic site, histology and biologic behavior. Pleomorphic adenoma is the most common benign tumor and mucoepidermoid and adenoid cystic carcinoma are the most common malignant tumors. Evaluation and diagnosis of these tumors includes not only a complete history and head and neck exam, but also biopsy and imaging of the tumors. Controversy remains regarding the necessity and type of biopsy to be performed and the usefulness of imaging.

Financial instability and CO 2 emissions: the case of Saudi Arabia

Abstract

This study aims to investigate the nexus between financial instability and CO₂ emissions within the multivariate framework in Saudi Arabia's economy over 1971–2016. Autoregressive Distributed Lag (ARDL) model is used to estimate long-run dynamics followed by Vector Error Correction Model (VECM) to detect the direction of causality. The result of the study reveals that financial instability has an insignificant impact on CO₂ emissions. However, electricity consumption has an adverse impact on environmental quality by producing a huge amount of CO₂ emissions in the atmosphere. The coefficients of oil and non-oil GDPs also suggest that both oil and non-oil GDPs contribute to producing a massive amount of CO₂ emissions. Bi-directional causality is observed among all the core variables of the study. Moreover, the reliability and validity are confirmed by applying several diagnostic tests. This study provides novel findings which not only help to advance the existing literature but can be a particular interest to the country's policymakers regarding financial sector and its role in environmental degradation.

Regulation on the toxicity of microcystin-LR target to protein phosphatase 1 by biotransformation pathway: effectiveness and mechanism

Abstract

Biotransformation was an important pathway to regulate the toxicity of microcystins (MCs) targeted to protein phosphatases (PPs). To explore the regulation effectiveness and mechanism, several typical biothiol transformation products originated from MCLR were prepared by nucleophilic addition reaction. The reduced inhibition effect of MCLR transformation products on PP1 was evaluated and compared with their original toxin. Though molecular simulation showed the introduced biothiols enhanced the total combination areas and energies for target complexes, the steric hindrance of introduced biothiols inhibited the combination between the key action sites (Mdha⁷ and Adda⁵ residues) and PP1. Furthermore, the introduced biothiols also weakened the hydrogen bonds for some key interaction sites and altered the ion bonds between PP1 and the two Mn²⁺ ions in the catalytic center. The discrepant regulation effect for biothiols on the toxicity of MCLR was closely related to above indexes and influenced by molecular sides.

Odorous emission reduction from a waste landfill with an optimal protection system based on fuzzy logic

Abstract

Effective landfill management and operation require an accurate evaluation of the occurrence and extent of odour emission events, which are among the main causes of resident complaints and concerns, in particular in densely urbanised areas. This paper proposes a fuzzy optimal protection system (FOPS) based on fuzzy logic to manage odour production from a municipal solid waste (MSW) landfill. The case study is a MSW landfill in an old quarry site located 6 km north-west of Naples city centre (Italy). The aim is to reduce the odour nuisance in the area surrounding the landfill where there are several sensitive receptors. FOPS is based on logical relationships between local atmospheric dynamics, number and intensity of odour pollution events detected by certain fixed receptors and odour emission rate via an optimal fuzzy approach. Such system allows to start, in real time, established mitigation actions required to further reduce the odorous emissions from the landfill itself (e.g. spraying of perfumed substances and activation of extraction wells), especially when weather conditions might not be favourable and cause by causing a higher odour perception. The fuzzy system was coupled with the air pollutant transport software CALPUFF to simulate the odour dispersion in the considered area taking into account both different odour emission rates and local weather conditions. FOPS results show that this approach can be very useful as, by measuring the odour concentrations, a significant reduction of the odour exceedances over the thresholds fixed, to minimise the olfactory harassment, was observed in the whole area studied.

CO 2 emission thresholds for inclusive human development in sub-Saharan Africa

Abstract

We provide policy-relevant critical masses beyond which, increasing CO₂ emissions negatively affects inclusive human development. This study examines how increasing CO₂ emissions affects inclusive human development in 44 sub-Saharan African countries for the period 2000–2012. The empirical evidence is based on fixed effects and Tobit regressions. In order to increase the policy relevance of this study, the dataset is decomposed into fundamental characteristics of inclusive development and environmental degradation based on income levels (low income versus (vs.) middle income); legal origins (English common law vs. French civil law); religious domination (Christianity vs. Islam); openness to sea (landlocked vs. coastal); resource-wealth (oil-rich vs. oil-poor) and political stability (stable vs. unstable). All computed thresholds are within policy range. Hence, above these thresholds, CO₂ emissions negatively affect inclusive human development.

Biomonitoring of atmospheric particulate pollution via chemical composition and magnetic properties of roadside tree leaves

Abstract

Particulate matter (PM) is a main atmospheric pollution which threats human health and well-being. In this research, we chemically and magnetically analysed roadside tree leaves, collected from three tree species in two main roads (from two different cities) and a reference area, for 28 elements and the saturation isothermal remanent magnetisation. Comparison of unwashed and washed leaves revealed that deposited particles on the leaf surface contain various elements including Al, Ca, Fe, Mg, Mn, Na, Si, Ti, Ba, Co, Cr, Cu, Ni, Rb, V, Zn and Zr. Moreover, there was no significant difference between washed/unwashed leaves in Cl, K, P, S, As, Cd, Cs, Pb, Sn and Sr concentrations, which indicates tree leaves may not be a suitable biomonitor for these elements. Our results showed that site and tree species are important factors which affect atmospheric elements deposition. Among the three considered tree species, Chamaecyparis lawsoniana showed the highest potential for atmospheric particle accumulation. The PCA results revealed that Al, Fe, Ti, Co, Cr, Cu, Ni, Rb, Si, V, Zn and Zr indicated emissions from road traffic activities and soil dust; Ca, Mg and Na from sea salts and Mn and Sb from industrial activity. The biplot results showed that the site effect was much stronger than the species effect for all elements and saturation isothermal remanent magnetisation (SIRM) values. Moreover, elements from traffic, industrial activity and soil dust are significantly correlated with leaf SIRM indicating that leaf SIRM can be a suitable bioindicator of exposure to traffic-derived particles and soil dust, and not from sea salts. It is concluded that chemical composition and SIRM of urban tree leaves can serve as a good indicator of atmospheric PM pollution in Iran and anywhere else where the studied trees grow.

Fermented camel milk by Lactococcus lactis subsp. cremoris attenuates erythrocytes oxidative stress-induced hematological and immunological damage in CCl 4 -intoxicated mice

Abstract

Fermented camel by Lactococcus lactis subsp. cremoris has been recently discovered to protect against the toxic effect of carbon tetrachloride (CCl₄), but its beneficial effects in the presence of oxidative stress in the erythrocytes have not been established. In the present study, 28 mice were randomly divided into four groups: control group; CCl₄ group: intoxicated by a single intraperitoneal injection (ip) of CCl₄; group FCM-LLC + CCl₄: pretreated with FCM-LLC daily during 14 days, and received a single dose of CCl₄. FCM-LLC group received FCM-LLC alone. The occurrence of oxidative stress in erythrocytes was evidenced by an increase in lipid peroxidation, protein carbonyl, and changes in antioxidant enzyme activities and non-enzymatic antioxidant. The oxidative injury induced by CCl₄ in the erythrocytes was confirmed by modifications in hematological parameters and decreases in protein, albumin, and globulin content in the serum of intoxicated mice. Therefore, CCl₄ caused a significant decrease in immunotoxic indices, including immunoglobulin G (IgG), immunoglobulin M (Ig M), and immunoglobulin A (IgA) levels, and an increase of inflammatory markers such as C-reactive protein (CRP) level. Meanwhile, FCM-LLC effectively restored the parameters cited above to near-normal values. It can be suggested that fermented camel milk could regulate deviant physiological effects induced by CCl₄ which is due to its powerful antioxidant and immunomodulatory and anti-inflammatory capacity.

Late gadolinium enhancement of colorectal liver metastases post-chemotherapy is associated with tumour fibrosis and overall survival post-hepatectomy

Abstract

Purpose

To determine whether late gadolinium MRI enhancement of colorectal liver metastases (CRCLM) post-chemotherapy is associated with tumour fibrosis and survival post-hepatectomy.

Materials and methods

The institutional review board approved this retrospective cohort study and waived the requirement for informed consent. A cohort of 121 surgical patients who received preoperative MRI after chemotherapy between 2006-2012 was included in this study. Target tumour enhancement (TTE), defined as the mean contrast-to-noise ratio of up to two target lesions on late-phase gadobutrol-enhanced MRI, was determined by two independent raters. The average TTE was correlated with tumour fibrosis on post-hepatectomy specimens using Spearman correlation and with survival post-hepatectomy using Kaplan-Meier and Cox regression. Inter-rater reliability was determined using relative intra-class correlation coefficients.

Results

In the surgical cohort (mean age: 63.0 years; male: 58%), TTE was associated with tumour fibrosis (r = 0.43, p < 0.001). Strong TTE was associated with improved survival compared to weak TTE (3-year survival: 88.4% vs. 58.8%, p = 0.003) with a hazard ratio of 0.32 (95% CI: 0.14-0.75, p = 0.008), after taking into account known prognostic variables. Inter-rater reliability was very good with a relative intraclass correlation of 0.84 (95% CI: 0.77-0.89).

Conclusion

Late gadolinium MRI enhancement of CRCLM post-chemotherapy is associated with tumour fibrosis and survival.

Key Points

• MRI enhancement of colorectal liver metastases is associated with survival post-hepatectomy

• MRI enhancement of chemotherapy-treated colorectal liver metastases correlates with tumour fibrosis

• Measuring late MRI enhancement using target tumour enhancement is reliable

Forensic age assessment by 3.0T MRI of the knee: proposal of a new MRI classification of ossification stages

Abstract

Purpose

To explore the possibility of determining majority via a morphology-based examination of the epiphyseal-diaphyseal fusion by 3.0 T magnetic resonance imaging (MRI), a prospective cross-sectional study developing and applying a new stage classification was conducted.

Materials and methods

344 male and 350 female volunteers of German nationality between the ages of 12-24 years were scanned between May 2013 and June 2015. A 3.0 T MRI scanner was used, acquiring a T1-weighted (T1-w) turbo spin-echo sequence (TSE) and a T2-weighted (T2-w) TSE sequence with fat suppression by spectral pre-saturation with inversion recovery (SPIR). The gathered information was sifted and a five-stage classification was formulated as a hypothesis. The images were then assessed using this classification. The relevant statistics were defined, the intra- and interobserver agreements were determined, and the differences between the sexes were analysed.

Results

The application of the new classification made it possible to correctly assess majority in both sexes by the examination of the epiphyses of the knee joint. The intra- and interobserver agreement levels were very good (κ > 0.80). The Mann-Whitney-U Test implied significant sex-related differences for most stages.

Conclusion

Applying the presented MRI classification, it is possible to determine the completion of the 18th year of life in either sex by 3.0 T MRI of the knee joint.

Key points

• Based on prospective referential data a new MRI classification was formulated.

• The setting allows assessment of the age of an individual's skeletal development.

• The classification scheme allows the reliable determination of majority in both sexes.

• The staging shows a high reproducibility for instructed and trained professional personnel.

• The proposed classification is likely to be adaptable to other long bone epiphyses.

MRI-based detection of renal artery abnormalities related to renal denervation by catheter-based radiofrequency ablation in drug resistant hypertensive patients

Abstract

Objectives

Endovascular renal denervation (RDN) using catheter-based radiofrequency (RF) ablation has emerged as a potential treatment option for drug-resistant hypertension. Its efficacy is currently under debate. We aimed to evaluate the capability of contrast-enhanced magnetic resonance imaging (MRI) to assess the effects of RDN on the renal arterial wall in patients presenting with drug-resistant hypertension.

Methods

Patients were included prospectively following institutional review board approval and written informed consent. Renal arteries were imaged using a two-dimensional T1-weighted TSE sequence pre- and post-administration of a gadolinium-based contrast agent, before (D0), 2 days (D2) and 6 months (M6) after RDN. Mean enhancement of the wall (mENH) and mean wall thickness (mWT) were compared across time using an ANOVA with repeated measures and post-hoc paired t-test.

Results

Follow-up was completed for 23 patients (median age, 57 years; 16 men). The mENH at D2 (96.3 ± 36.0 %) was significantly higher than at D0 (61.1 ± 26.3%, p < 0.001) and M6 (66.1±22.7%, p < 0.001). Similarly, mWT was significantly higher at D2 (3.1 ± 0.4 m) than at D0 (2.7 ± 0.4mm, p < 0.001) and M6 (2.9 ± 0. 5 mm, p = 0.002).

Conclusions

MRI demonstrated abnormalities of the arterial wall 2 days after RDN that had resolved at 6 months.

Key Points

• Contrast-enhanced MRI provides anatomic evidence of renal artery RF ablation

• Temperature increase related to RF ablation induces transient arterial wall inflammation

• Morphological effects observed 2 days post RF ablation are not visible after 6 months

Imaging complex ventral hernias, their surgical repair, and their complications

Abstract

Complex ventral hernia (CVH) describes large, anterior, ventral hernias. The incidence of CVH is rising rapidly due to increasing laparotomy rates in ever older, obese and co-morbid patients. Surgeons with a specific interest in CVH repair are now frequently referring these patients for imaging, normally computed tomography scanning. This review describes what information is required from preoperative imaging and the surgical options and techniques used for CVH repair, so that radiologists understand the postoperative appearances specific to CVH and are aware of the common complications following surgery.

Key Points

• Complex ventral hernia (CVH) describes large abdominal wall hernias (e.g. width ≥10cm).

• CVH patients are being referred increasingly for preoperative and postoperative imaging.

• Imaging is pivotal to characterise preoperative morphology and quantify loss of domain.

• Postoperative imaging appearances are contingent on the surgical methods used for CVH repair.

• Postoperative complications are depicted easily by imaging.

Magnetic resonance with diffusion-weighted imaging improves assessment of focal liver lesions in patients with potentially resectable pancreatic cancer on CT

Abstract

Purpose

To investigate added value of MRI to preoperative staging MDCT for evaluation of focal liver lesions (FLLs) in potentially resectable pancreatic ductal adenocarcinomas (PDACs).

Materials and methods

In patients with potentially resectable PDACs after staging MDCT (n=167), characteristics of FLLs were scored as benign, indeterminate or metastases on an MDCT set and combined MDCT and MRI set by two readers, independently. Size of hepatic lesions was measured and detection rate of hepatic metastasis unsuspected by MDCT and diagnostic yield of MRI for FLLs were assessed.

Results

Reader-averaged figure-of-merit (FOM) of the combined set was significantly higher than that of MDCT alone (0.94 vs. 0.86, p=.028). In the negative-on-CT group, the diagnostic yield of MRI was 1.5–2.3% (2/133 and 3/133 for readers 1 and 2, respectively). In the indeterminate-on-CT group, MRI yield was 10.5–13.6% (2/19 and 3/22) and in patients with suspicious-metastasis-on-CT, 8.3–26.7% (1/12 and 4/15). All lesions with false-positive and false-negative CT findings were ≤1 cm.

Conclusion

In potentially resectable PDACs, addition of MRI with DWI can provide significantly better diagnostic performance in characterization of focal liver lesions, especially for small-sized (≤ 1 cm) MDCT-indeterminate or suspicious metastasis lesions, aiding in determination of appropriate operation candidates.

Key Points

• Addition of MRI provides better diagnostic performance in characterization of liver lesions.

• Combined interpretation of MRI and MDCT provided less frequent indeterminate liver lesions.

• Diagnostic yield of MRI was high in CT-indeterminate or suspicious metastatic lesions.

• Operation candidates can be determined with greater confidence in potentially resectable PDACs.

Progressive supranuclear palsy and idiopathic Parkinson’s disease are associated with local reduction of in vivo brain viscoelasticity

Abstract

Objectives

To apply three-dimensional multifrequency MR-elastography (3DMRE) for the measurement of local cerebral viscoelasticity changes in patients with Parkinson's disease (PD) and progressive supranuclear palsy (PSP).

Methods

T1-weighted anatomical imaging and 3DMRE were performed in 17 PD and 20 PSP patients as well as 12 controls. Two independent viscoelasticity parameters, |G*| and φ, were reconstructed combining seven harmonic vibration frequencies (30–60 Hz). Spatially averaged values were compared by one-way ANOVA, groups were compared using unpaired t test and Mann-Whitney test, respectively. Correlation between clinical data and parameters of brain elasticity and volume were calculated by Pearson's correlation coefficient.

Results

In patients, |G*| was significantly reduced in the frontal and mesencephalic regions (p < 0.05). Beyond that, reduced mesencephalic |G*| discriminated PSP from PD (p < 0.05). Neurodegeneration causes significant brain atrophy (p < 0.01) and is pronounced in PSP patients (p < 0.05 vs. PD). Reduced brain viscoelasticity is correlated with brain atrophy in PSP (r=0.64, p=0.002) and PD (r=0.65, p=0.005) patients but not in controls.

Conclusions

MRE-measured viscoelasticity reflects local structural changes of brain tissue in PSP and in PD and provides a useful parameter to differentiate neurodegenerative movement disorders based on imaging examinations.

Key points

• 3D multifrequency MR-elastography reveals diffuse regional changes in brain viscoelasticity in neurodegenerative disorders.

• Reduced mesencephalic viscoelasticity separates PD and PSP.

• Reduced brain viscoelasticity and brain atrophy as independent hallmarks of neurodegeneration hypothesized.

Contrast media injection protocol optimization for dual-energy coronary CT angiography: results from a circulation phantom

Abstract

Objectives

To investigate the minimum iodine delivery rate (IDR) required to achieve diagnostic coronary attenuation (300 HU) with dual-energy coronary CTA.

Methods

Acquisitions were performed on a circulation phantom with a third- generation dual-source CT scanner. Contrast media was injected for a fixed time whilst IDRs varied from 1.0 to 0.3 gI/s in 0.1-gI/s intervals. Noise-optimized virtual monoenergetic imaging (VMI+) reconstructions from 40 to 90 keV in 5 keV increments were generated. Contrast-to-noise ratio (CNR) and coronary HU were measured for each injection.

Results

VMI+ from 40–70 keV reached diagnostic attenuation with at least one IDR. The minimum IDR achieving a diagnostic attenuation ranged from 0.4 gI/s at 40 keV (312.8 HU) to 1.0 gI/s at 70 keV (334.1 HU). Attenuation values reached with IDR of 1.0 gI/s were significantly higher at each keV level (p<0.001). CNR showed a near perfect correlation with the IDR (ρ≥0.962; p<0.001), the IDR of 1.0 gI/s provided the highest CNR at each keV level, achieving the highest overall value at 40 keV (54.0±3.1).

Conclusions

IDRs from 0.4–1.0 gI/s associated with VMI+ from 40–70 keV provide diagnostic coronary attenuation with dual-energy coronary CTA.

Key Points

• Iodine delivery rate (IDR) is a major determinant of contrast enhancement.

• Low-keV noise-optimized monoenergetic images (VMI+) maximize iodine attenuation.

• Low-keV VMI+ allows for lower IDRs while maintaining adequate coronary attenuation.

• Lowest IDR to reach 300 HU was 0.4 gI/s, 40 keV VMI+.

Experimental feasibility of spectral photon-counting computed tomography with two contrast agents for the detection of endoleaks following endovascular aortic repair

Abstract

Objectives

After endovascular aortic repair (EVAR), discrimination of endoleaks and intra-aneurysmatic calcifications within the aneurysm often requires multiphase computed tomography (CT). Spectral photon-counting CT (SPCCT) in combination with a two-contrast agent injection protocol may provide reliable detection of endoleaks with a single CT acquisition.

Methods

To evaluate the feasibility of SPCCT, the stent-lined compartment of an abdominal aortic aneurysm phantom was filled with a mixture of iodine and gadolinium mimicking enhanced blood. To represent endoleaks of different flow rates, the adjacent compartments contained either one of the contrast agents or calcium chloride to mimic intra-aneurysmatic calcifications. After data acquisition with a SPCCT prototype scanner with multi-energy bins, material decomposition was performed to generate iodine, gadolinium and calcium maps.

Results

In a conventional CT slice, Hounsfield units (HU) of the compartments were similar ranging from 147 to 168 HU. Material-specific maps differentiate the distributions within the compartments filled with iodine, gadolinium or calcium.

Conclusion

SPCCT may replace multiphase CT to detect endoleaks without sacrificing diagnostic accuracy. It is a unique feature of our method to capture endoleak dynamics and allow reliable distinction from intra-aneurysmatic calcifications in a single scan, thereby enabling a significant reduction of radiation exposure.

Key Points

• SPCCT might enable advanced endoleak detection.

• Material maps derived from SPCCT can differentiate iodine, gadolinium and calcium.

• SPCCT may potentially reduce radiation burden for EVAR patients under post-interventional surveillance.

Prediction of rupture risk in anterior communicating artery aneurysms with a feed-forward artificial neural network

Abstract

Objectives

Anterior communicating artery (ACOM) aneurysms are the most common intracranial aneurysms, and predicting their rupture risk is challenging. We aimed to predict this risk using a two-layer feed-forward artificial neural network (ANN).

Materials and method

594 ACOM aneurysms, 54 unruptured and 540 ruptured, were reviewed. A two-layer feed-forward ANN was designed for ACOM aneurysm rupture-risk analysis. To improve ANN efficiency, an adaptive synthetic (ADASYN) sampling approach was applied to generate more synthetic data for unruptured aneurysms. Seventeen parameters (13 morphological parameters of ACOM aneurysm measured from these patients' CT angiography (CTA) images, two demographic factors, and hypertension and smoking histories) were adopted as ANN input.

Results

Age, vessel size, aneurysm height, perpendicular height, aneurysm neck size, aspect ratio, size ratio, aneurysm angle, vessel angle, aneurysm projection, A1 segment configuration, aneurysm lobulations and hypertension were significantly different between the ruptured and unruptured groups. Areas under the ROC curve for training, validating, testing and overall data sets were 0.953, 0.937, 0.928 and 0.950, respectively. Overall prediction accuracy for raw 594 samples was 94.8 %.

Conclusion

This ANN presents good performance and offers a valuable tool for prediction of rupture risk in ACOM aneurysms, which may facilitate management of unruptured ACOM aneurysms.

Key Points

• A feed-forward ANN was designed for the prediction of rupture risk in ACOM aneurysms.

• Two demographic parameters, 13 morphological aneurysm parameters, and hypertension/smoking history were acquired.

• An ADASYN sampling approach was used to improve ANN quality.

• Overall prediction accuracy of 94.8 % for the raw samples was achieved.

Vessel architecture in human knee cartilage in children: an in vivo susceptibility-weighted imaging study at 7 T

Abstract

Objectives

To evaluate the clinical feasibility of ultrahigh field 7-T SWI to visualize vessels and assess their density in the immature epiphyseal cartilage of human knee joints.

Methods

7-T SWI of 12 knees (six healthy volunteers, six patients with osteochondral abnormalities; mean age 10.7 years; 3 female, 9 male) were analysed by two readers, classifying intracartilaginous vessel densities (IVD) in three grades (no vessels, low IVD and high IVD) in defined femoral, tibial and patellar zones. Differences between patients and volunteers, IVDs in different anatomic locations, differences between cartilage overlying osteochondral abnormalities and corresponding normal zones, and differences in age groups were analysed.

Results

Interrater reliability showed moderate agreement between the two readers (κ = 0.58, p < 0.001). The comparison of IVDs between patients and volunteers revealed no significant difference (p = 0.706). The difference between zones in the cartilage overlying osteochondral abnormalities to corresponding normal zones showed no significant difference (p = 0.564). IVDs were related to anatomic location, with decreased IVDs in loading areas (p = 0.003). IVD was age dependent, with more vessels present in the younger participants (p = 0.001).

Conclusions

The use of SWI in conjunction with ultrahigh field MRI makes the in vivo visualization of vessels in the growing cartilage of humans feasible, providing insights into the role of the vessel network in acquired disturbances.

Key Points

• SWI facilitates in vivo visualization of vessels in the growing human cartilage.

• Interrater reliability of the intracartilaginous vessel grading was moderate.

• Intracartilaginous vessel densities are dependent on anatomical location and age.

Are growth patterns on MRI in small (< 4 cm) solid renal masses useful for predicting benign histology?

Abstract

Purpose

To evaluate previously described growth patterns in < 4 cm solid renal masses.

Materials and Methods

With IRB approval, 63 renal cell carcinomas (RCC; clear cell n = 22, papillary n = 28, chromophobe n = 13) and 36 benign masses [minimal-fat (mf) angiomyolipoma (AML) n = 13, oncocytoma n = 23) from a single institution were independently evaluated by two blinded radiologists (R1/R2) using T2-weighted MRI for (1) the angular interface sign (AIS), (2) bubble-over sign (BOS), (3) percentage (%) exophytic growth and (4) long-to-short axis ratio. Comparisons were performed using ANOVA, chi-square and multi-variate regression.

Results

AIS was present in 11.1% (7/63) -9.5% (6/63) R1/R2 RCC compared to 13.9% (5/36) -19.4% (7/36) R1/R2 benign masses (p = 0.68 and 0.16). BOS was present in 11.1% (7/63) -3.2% (2/63) R1/R2 RCC compared to 16.7% (6/36) -8.3% (3/36) R1/R2 benign masses (p = 0.432 and 0.261). Agreement was moderate (K = 0.50 and 0.55). mf-AML [66 ± 32% (range 0-100%)] and oncocytoma [53 ± 26% (0-90%)] had larger % exophytic growth compared to RCC [32 ± 23% (0-80%)] (p < 0.001). No RCC had 90-100% exophytic growth, present in 38.5% (5/13) mf-AMLs and 17.4% (4/23) oncocytomas. The long-to-short axis did not differ between groups (p = 0.053).

Conclusions

Benign masses show greater % exophytic growth whereas other growth patterns are not useful. Future studies evaluating % exophytic growth using multi-variate MR analysis in renal masses are required.

Key Points

• Greater exophytic growth is associated with benignity among solid renal masses.

• Only minimal fat AMLs and oncocytomas had 90-100% exophytic growth.

• The angular interface sign was not useful to differentiate benign masses from RCC.

• The bubble-over sign was not useful to differentiate benign masses from RCC.

• Subjective analysis of growth patterns had fair-to-moderate agreement.

Sequential high intensity focused ultrasound (HIFU) ablation in the treatment of benign multinodular goitre: an observational retrospective study

Abstract

Objectives

Assessing the efficacy and safety of sequential high-intensity focused ultrasound (HIFU) ablation in a multinodular goitre (MNG) by comparing them with single HIFU ablation.

Methods

One hundred and four (84.6%) patients underwent single ablation of a single nodule (group I), while 19 (15.4%) underwent sequential ablation of two relatively-dominant nodules in a MNG (group II). Extent of shrinkage per nodule [by volume reduction ratio (VRR)], pain scores (by 0-10 visual analogue scale) during and after ablation, and rate of vocal cord palsy (VCP), skin burn and nausea/vomiting were compared between the two groups.

Results

All 19 (100%) sequential ablations completed successfully. The 3- and 6-month VRR of each nodule were comparable between the two groups (p > 0.05) and in group II, the 3- and 6-month VRR between the first and second nodules were comparable (p = 0.710 and p = 0.548, respectively). Pain score was significantly higher in group II in the morning after ablation (2.29 vs 1.15, p = 0.047) and nausea/vomiting occurred significantly more frequently in group II (15.8% vs 0.0%, p = 0.012). However, VCP and skin burn were comparable (p > 0.05).

Conclusions

Sequential ablation had comparable efficacy and safety as single ablation. However, patients undergoing sequential ablation are at higher likelihood of pain in the following morning and nausea/vomiting after ablation.

Key Points

• Sequential HIFU ablation is well-tolerated in patients with two dominant thyroid nodules

• More pain is experienced in the morning following sequential HIFU ablation

• More nausea/vomiting is experienced following sequential HIFU ablation

Diffusion tensor magnetic resonance imaging of breast cancer: associations between diffusion metrics and histological prognostic factors

Abstract

Objectives

To investigate whether quantitative diffusion metrics derived from diffusion tensor imaging (DTI) are associated with histological prognostic factors in breast cancer patients.

Methods

This retrospective study was approved by the institutional review board, and informed consent was waived. Between 2016 and 2017, 251 consecutive women (mean age, 53.8 years) with breast cancer (230 invasive, 21 in situ) who underwent preoperative magnetic resonance (MR) imaging with DTI were identified. Diffusion gradients were applied in 20 directions (b values, 0 and 1,000 s/mm²). DTI metrics – mean diffusivity (MD) and fractional anisotropy (FA) – were measured for breast lesions and contralateral normal breast by two radiologists and were correlated with histological findings using the Mann-Whitney U-test and linear regression analysis.

Results

MD and FA were significantly lower for breast cancers than for normal fibroglandular tissues (1.03 ± 0.25×10⁻³ mm²/s vs. 1.60 ± 0.19×10⁻³ mm²/s, p < 0.001 and 0.29 ± 0.09 vs. 0.33 ± 0.06, p < 0.001, respectively). Significant differences were observed in MD between invasive cancer and ductal carcinoma in situ lesions (p < 0.001). Multivariate linear analysis showed that larger size (>2 cm) (p = 0.007), high histological grade (grade 3) (p = 0.045) and axillary node metastasis (p = 0.009) were significantly associated with lower MD in invasive breast cancer patients. Larger size (p < 0.001) and high histological grade (p = 0.025) were significantly associated with lower FA.

Conclusions

DTI-derived diffusion metrics, such as MD and FA, are associated with histological prognostic factors in breast cancer patients.

Key points

• MD was significantly lower for breast cancers than for normal breast tissues.

• FA was significantly lower for breast cancers than for normal breast tissues.

• Reduced DTI metrics were associated with poor prognostic factors of breast cancer.

• DTI may provide valuable information concerning biological aggressiveness in breast cancer.

Correction to: A predictive model for distinguishing radiation necrosis from tumour progression after gamma knife radiosurgery based on radiomic features from MR images

Abstract

The original version of this article, published on 24 November 2017, unfortunately contained a mistake.

Mammographic density changes following discontinuation of tamoxifen in premenopausal women with oestrogen receptor-positive breast cancer

Abstract

Objectives

To evaluate the changes in mammographic density after tamoxifen discontinuation in premenopausal women with oestrogen receptor-positive breast cancers and the underlying factors

Methods

A total of 213 consecutive premenopausal women with breast cancer who received tamoxifen treatment after curative surgery and underwent three mammograms (baseline, after tamoxifen treatment, after tamoxifen discontinuation) were included. Changes in mammographic density after tamoxifen discontinuation were assessed qualitatively (decrease, no change, or increase) by two readers and measured quantitatively by semi-automated software. The association between % density change and clinicopathological factors was evaluated using univariate and multivariate regression analyses.

Results

After tamoxifen discontinuation, a mammographic density increase was observed in 31.9% (68/213, reader 1) to 22.1% (47/213, reader 2) by qualitative assessment, with a mean density increase of 1.8% by quantitative assessment compared to density before tamoxifen discontinuation. In multivariate analysis, younger age (≤ 39 years) and greater % density decline after tamoxifen treatment (≥ 17.0%) were independent factors associated with density change after tamoxifen discontinuation (p < .001 and p = .003, respectively).

Conclusions

Tamoxifen discontinuation was associated with mammographic density change with a mean density increase of 1.8%, which was associated with younger age and greater density change after tamoxifen treatment.

Key Points

• Increased mammographic density after tamoxifen discontinuation can occur in premenopausal women.

• Mean density increase after tamoxifen discontinuation was 1.8%.

• Density increase is associated with age and density decrease after tamoxifen.

Comparison of image quality and radiation dose between split-filter dual-energy images and single-energy images in single-source abdominal CT

Abstract

Objectives

To compare image quality and radiation dose of abdominal split-filter dual-energy CT (SF-DECT) combined with monoenergetic imaging to single-energy CT (SECT) with automatic tube voltage selection (ATVS).

Methods

Two-hundred single-source abdominal CT scans were performed as SECT with ATVS (n = 100) and SF-DECT (n = 100). SF-DECT scans were reconstructed and subdivided into composed images (SF-CI) and monoenergetic images at 55 keV (SF-MI). Objective and subjective image quality were compared among single-energy images (SEI), SF-CI and SF-MI. CNR and FOM were separately calculated for the liver (e.g. CNR_liv) and the portal vein (CNR_pv). Radiation dose was compared using size-specific dose estimate (SSDE). Results of the three groups were compared using non-parametric tests.

Results

Image noise of SF-CI was 18% lower compared to SEI and 48% lower compared to SF-MI (p < 0.001). Composed images yielded higher CNR_liv over single-energy images (23.4 vs. 20.9; p < 0.001), whereas CNR_pv was significantly lower (3.5 vs. 5.2; p < 0.001). Monoenergetic images overcame this inferiority in CNR_pv and achieved similar results compared to single-energy images (5.1 vs. 5.2; p > 0.628). Subjective sharpness was equal between single-energy and monoenergetic images and diagnostic confidence was equal between single-energy and composed images. FOM_liv was highest for SF-CI. FOM_pv was equal for SEI and SF-MI (p = 0.78). SSDE was significant lower for SF-DECT compared to SECT (p < 0.022).

Conclusions

The combined use of split-filter dual-energy CT images provides comparable objective and subjective image quality at lower radiation dose compared to single-energy CT with ATVS.

Key points

• Split-filter dual-energy results in 18% lower noise compared to single-energy with ATVS.

• Split-filter dual-energy results in 11% lower SSDE compared to single-energy with ATVS.

• Spectral shaping of split-filter dual-energy leads to an increased dose-efficiency.

MRI-based decision tree model for diagnosis of biliary atresia

Abstract

Objectives

To evaluate MRI findings and to generate a decision tree model for diagnosis of biliary atresia (BA) in infants with jaundice.

Methods

We retrospectively reviewed features of MRI and ultrasonography (US) performed in infants with jaundice between January 2009 and June 2016 under approval of the institutional review board, including the maximum diameter of periportal signal change on MRI (MR triangular cord thickness, MR-TCT) or US (US-TCT), visibility of common bile duct (CBD) and abnormality of gallbladder (GB). Hepatic subcapsular flow was reviewed on Doppler US. We performed conditional inference tree analysis using MRI findings to generate a decision tree model.

Results

A total of 208 infants were included, 112 in the BA group and 96 in the non-BA group. Mean age at the time of MRI was 58.7 ± 36.6 days. Visibility of CBD, abnormality of GB and MR-TCT were good discriminators for the diagnosis of BA and the MRI-based decision tree using these findings with MR-TCT cut-off 5.1 mm showed 97.3 % sensitivity, 94.8 % specificity and 96.2 % accuracy.

Conclusions

MRI-based decision tree model reliably differentiates BA in infants with jaundice. MRI can be an objective imaging modality for the diagnosis of BA.

Key Points

• MRI-based decision tree model reliably differentiates biliary atresia in neonatal cholestasis.

• Common bile duct, gallbladder and periportal signal changes are the discriminators.

• MRI has comparable performance to ultrasonography for diagnosis of biliary atresia.

Have we forgotten imaging prior to and after kidney transplantation?

Key Points

• The number of publications on imaging and kidney transplantation is low.

• These publications are poorly cited, as compared with other fields of imaging.

• Conversely, there is a clinical need for evidence-based recommendations.

• Innovative advances for the use of imaging and kidney transplantation are essential.

• An increased focus and adequate research funding are highly anticipated by clinicians.

The role of breast tomosynthesis in a predominantly dense breast population at a tertiary breast centre: breast density assessment and diagnostic performance in comparison with MRI

Abstract

Objectives

To compare breast density measured on digital breast tomosynthesis (DBT) (BI-RADS-based breast composition and fully-automatic estimation) and magnetic resonance imaging (MRI) (BI-RADS amount of fibroglandular tissue), and to evaluate the diagnostic performance in terms of sensitivity and specificity of DBT and MRI in a predominantly dense breast population.

Methods

Between 2015 and 2016, 152 women with 103 breast malignancies, who underwent 3-T breast MRI and DBT within 2 months' time, were enrolled in this study. Breast composition/fibroglandular tissue and findings on DBT (two readers) and MRI were reported using BI-RADS 5th edition. Digital mammography images were analysed for breast percent density (PD) using the Libra software tool.

Results

A majority of women had dense breasts as categorised by breast composition c (heterogeneously dense) (68%) and d (extremely dense) (15%). The mean PD was 44% (range, 18-89%) and the correlation between breast composition and PD was r = 0.6. The diagnostic performance of MRI was significantly higher compared to DBT for one reader as described by the area under the receiver operating characteristic (ROC) curve (p = 0.004) and of borderline significance for the other reader (p = 0.052).

Conclusions

MRI had higher diagnostic performance than DBT in a dense breast population in the tertiary setting.

Key Points

• MRI had higher diagnostic performance than DBT in a dense breast population

• Diagnostic performance of DBT was comparable to MRI in women with fatty breasts

• MRI was superior to DBT in preoperative breast cancer size assessment

Overall and Sex-specific Associations between Fetal Adversity and Child Development at One Year: Evidence from Brazil

Abstract

A growing body of epigenetic research suggests that in-utero adaptations to environmental changes display important sex-specific variation. We test this heterogeneous adaptation hypothesis using data from 900 children born at the University Hospital in São Paulo, Brazil, between October 2013 and April 2014. Adjusted and unadjusted linear models were used to quantify the associations between prematurity, small for gestational age and children's physical and mental development at 12 months of age. Prematurity was negatively associated with neuropsychological development in fully adjusted models (z-score difference -0.42, 95% confidence intervals: -0.71, -0.14), but associations did not vary significantly by sex. For small for gestational age, associations with height-for-age, weight-for-age and neuropsychological development were also negative, but systematically larger for male than for female infants (p-values all <0.05). These results suggest that male fetuses may be more vulnerable to intra-uterine adversity than females; further research will be needed to better understand the mechanisms underlying these sex-specific associations.

Ixekizumab provides superior efficacy compared to ustekinumab over 52-weeks of treatment: results from IXORA-S, a phase 3 study

The IL-17 antagonist ixekizumab is effective in the clearance of plaque psoriasis. The superior efficacy of ixekizumab over ustekinumab observed at earlier time points is maintained through Week 52 and is associated with greater quality of life improvements. Over 52 weeks, the overall safety of ixekizumab and ustekinumab was comparable.

The Use of a Tympanoplasty Blade for Tumor Extirpation of the Auricle

Natural History of Disease Activity and Damage in Patients with Cutaneous Lupus Erythematosus

There are few longitudinal studies characterizing disease activity and damage of CLE patients. This study utilizes the CLASI to delineate the disease course of CLE patients on standard-of-care treatments. Having high baseline disease activity, minority race, or CLE disease duration <1 year predict CLE activity improvement.

Choosing the Right Biologic for Psoriatic Patients May Be in the Cards

Preliminary Analysis of Pulsed Radiofrequency Therapy Combined with Carpal Tunnel Release for Reducing the Pain in Postoperative Period: Early Outcomes

Carpal tunnel release (CTR) surgery is the main treatment used for moderate and severe CTS. However, despite this treatment, symptoms of pain may continue into the early postoperative period in some cases1.

Reply to the Editor: The pedicled internal pudendal artery perforator (PIPAP) flap for ischial pressure sore reconstruction: Technique and long-term outcome of a cohort study

It is with great interest that we have read the recent publication of Legemate CM et al. on the technique and long-term outcome of the pedicled internal pudendal artery perforator (PIPAP) flap for ischial pressure sore reconstruction.1 First described by Hashimoto et al., this flap is an interesting option due to its rich vascular network, easy dissection, feasible primary closure of the donor site, and the fact that the pudendal artery perforators are close to the location of the ischial defect.

Patients with Abdominal-based Free Flap Breast Reconstruction a Decade after Surgery - A Comprehensive Long-term Follow-up Study

Abdominal-based free flap breast reconstruction has increasingly become the gold standard, however long-term evidence of aesthetic outcome and quality of life is lacking. Our study aims to gain an overview of patients with abdominal-based free flap breast reconstructions in a long-term perspective.

Optimization of the method of the content‐containing interaction evaluation for cosmetic products by gas chromatography–mass spectrometry

International Journal of Cosmetic Science, EarlyView.

Radiomics signature: a biomarker for the preoperative discrimination of lung invasive adenocarcinoma manifesting as a ground-glass nodule

Abstract

Objectives

To identify the radiomics signature allowing preoperative discrimination of lung invasive adenocarcinomas from non-invasive lesions manifesting as ground-glass nodules.

Methods

This retrospective primary cohort study included 160 pathologically confirmed lung adenocarcinomas. Radiomics features were extracted from preoperative non-contrast CT images to build a radiomics signature. The predictive performance and calibration of the radiomics signature were evaluated using intra-cross (n=76), external non-contrast-enhanced CT (n=75) and contrast-enhanced CT (n=84) validation cohorts. The performance of radiomics signature and CT morphological and quantitative indices were compared.

Results

355 three-dimensional radiomics features were extracted, and two features were identified as the best discriminators to build a radiomics signature. The radiomics signature showed a good ability to discriminate between invasive adenocarcinomas and non-invasive lesions with an accuracy of 86.3%, 90.8%, 84.0% and 88.1%, respectively, in the primary and validation cohorts. It remained an independent predictor after adjusting for traditional preoperative factors (odds ratio 1.87, p < 0.001) and demonstrated good calibration in all cohorts. It was a better independent predictor than CT morphology or mean CT value.

Conclusions

The radiomics signature showed good predictive performance in discriminating between invasive adenocarcinomas and non-invasive lesions. Being a non-invasive biomarker, it could assist in determining therapeutic strategies for lung adenocarcinoma.

Key Points

• The radiomics signature was a non-invasive biomarker of lung invasive adenocarcinoma.

• The radiomics signature outweighed CT morphological and quantitative indices.

• A three-centre study showed that radiomics signature had good predictive performance.

Dynamic contrast-enhanced CT for the assessment of tumour response in malignant pleural mesothelioma: a pilot study

Abstract

Objectives

The aim of this pilot study was to investigate the utility of haemodynamic parameters derived from dynamic contrast-enhanced computed tomography (DCE-CT) scans in the assessment of tumour response to treatment in malignant pleural mesothelioma (MPM) patients.

Methods

The patient cohort included nine patients undergoing chemotherapy and five patients on observation. Each patient underwent two DCE-CT scans separated by approximately 2 months. The DCE-CT parameters of tissue blood flow (BF) and tissue blood volume (BV) were obtained within the dynamically imaged tumour. Mean relative changes in tumour DCE-CT parameters between scans were compared between the on-treatment and on-observation cohorts. DCE-CT parameter changes were correlated with relative change in tumour bulk evaluated according to the modified RECIST protocol.

Results

Differing trends in relative change in BF and BV between scans were found between the two patient groups (p = 0.19 and p = 0.06 for BF and BV, respectively). No significant rank correlations were found when comparing relative changes in DCE-CT parameters with relative change in tumour bulk.

Conclusions

Differing trends in the relative change of BF and BV between patients on treatment and on observation indicate the potential of DCE-CT for the assessment of pharmacodynamic endpoints with respect to treatment in MPM. A future study with a larger patient cohort and unified treatment regimens should be undertaken to confirm the results of this pilot study.

Key Points

• CT-derived haemodynamic parameters show differing trends between malignant pleural mesothelioma patients on treatment and patients off treatment

• Changes in haemodynamic parameters do not correlate with changes in tumour bulk as measured according to the modified RECIST protocol

• Differing trends across the two patient groups indicate the potential sensitivity of DCE-CT to assess pharmacodynamic endpoints in the treatment of MPM

Bioadsorption of trivalent and hexavalent chromium from aqueous solutions by sericin-alginate particles produced from Bombyx mori cocoons

Abstract

In this study, particles produced from sericin-alginate blend were used as non-conventional bioadsorbent for removing Cr(III) and Cr(VI) from aqueous solutions. Besides chromium mitigation, the use of sericin-alginate particles as bioadsorbent aims to offer an environmental solution of added value for sericin, which is a by-product from silk industry. Sericin-alginate particles in natura and loaded with Cr(III) and Cr(VI) were characterized using N₂ physical adsorption analysis, optical microcopy, mercury porosimetry, helium pycnometry, scanning electron microscope coupled with energy dispersive X-ray spectrometer, Fourier transform infrared spectrometer, and X-ray diffraction. Kinetic studies on the removal of Cr(III) (at pH = 3.5) and Cr(VI) (at pH = 2) indicate the ion exchange mechanism with Ca(II) and the predominance of external mass transfer resistance. Cr(VI) uptake occurs through an adsorption-coupled reduction process, and bioadsorption equilibrium is reached after ~ 1000 min. Cr(III) bioadsorption occurs faster (~ 210 min). The Cr(VI) bioadsorption is endothermic, as bioadsorption capacity increases with temperature: 0.0783 mmol/g (20 °C), 0.1960 mmol/g (30 °C), 0.4570 mmol/g (40 °C), and 0.7577 mmol/g (55 °C). The three-parameter isotherm model of Tóth best represents the equilibrium data of total chromium. From Langmuir isotherm model, the maximum bioadsorption capacity is higher for total chromium, 0.25 mmol/g (30 °C), than for trivalent chromium, 0.023 mmol/g (30 °C). The comparison of bioadsorption capacities with different biomaterials confirms sericin-alginate particles as potential bioadsorbent of chromium.

Magnetic flocculants synthesized by Fe 3 O 4 coated with cationic polyacrylamide for high turbid water flocculation

Abstract

A novel magnetic flocculant (CPAMF) was synthesized by using Fe₃O₄ coated with cationic polyacrylamide (CPAM) for flocculation of high turbid water. The surface morphology and chemical structures of CPAMF were confirmed by Fourier transform infrared spectroscopy (FTIR) and thermo-gravimetric analysis (TGA). X-ray diffraction (XRD) was employed to verify the crystal structure of CPAMF. The magnetic property of CPAMF was compared with Fe₃O₄ in this study. The flocculation performance by using flocculants CPAMF was evaluated in high turbid water treatment. The maximum transmittance 92.4% of kaolin suspension was achieved at corresponding optimal flocculation conditions. The result indicated that CPAMF was efficient in high turbid water flocculation. Analysis of FTIR, XRD of flocs, and zeta potential (ZP) of supernatant were accomplished for flocculation mechanism investigation. Because of low recovery factor in reflocculation under the effect of shear force on flocs, the bridging effect was found to be dominant in both acidic and alkaline conditions. Sedimentation experiments under the role of permanent magnet indicated that nano-Fe₃O₄ could effectively improve the settling property of CPAM.

Graphical abstract

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A retrospective analysis of surgical resection of large ear keloids

Australasian Journal of Dermatology, EarlyView.

Multinuclear and Ground Glass-Formed Cells Detected in the Peritoneal Dialysate

(See pages 312–3 for the Answer to the Photo Quiz.)

News

Multinuclear and Ground Glass-Formed Cells Detected in the Peritoneal Dialysate

herpes simplex virusimmunosuppressionperitoneal dialysisbullous pemphigoid

In the Literature

Cover

Copy number profiling across glioblastoma populations has implications for clinical trial design

Abstract

Background

Copy number alterations form prognostic molecular subtypes of glioblastoma with clear differences in median overall survival. In this study, we leverage molecular data from several glioblastoma cohorts to define the distribution of copy number subtypes across random cohorts as well as cohorts with selection biases for patients with inherently better outcome.

Methods

Copy number subtype frequency was established for four glioblastoma patient cohorts. Two randomly selected cohorts include The Cancer Genome Atlas (TCGA) and German Glioma Network (GGN). Two more selective cohorts include the phase II trial ARTE in elderly patients with newly diagnosed glioblastoma and a multi-institutional cohort focused on paired resected initial/recurrence glioblastoma. The paired initial/recurrence cohort also had exome data available, which allowed for evaluation of multidimensional scaling analysis.

Results

Smaller selective glioblastoma cohorts are enriched for copy number subtypes that are associated with better survival, reflecting the selection of patients who do well enough to enter a clinical trial or who are deemed well enough to undergo resection at recurrence. Adding exome data to copy number data provides additional data reflective of outcome.

Conclusions

The overall outcome for diffuse glioma patients is predicted by DNA structure at initial tumor resection. Molecular signature shifts across glioblastoma populations reflect the inherent bias of patient selection towards longer survival in clinical trials. Therefore it may be important to include molecular profiling, including copy number, when enrolling patients for clinical trials in order to balance arms and extrapolate relevance to the general glioblastoma population.

Differences of Cd uptake and expression of MT family genes and NRAMP2 in two varieties of ryegrasses

Abstract

In order to understand the mechanism of the difference of Cd absorption and Cd enrichment in different ryegrass varieties, pot experiment was conducted to study on the response of two varieties of ryegrass (Bond and Abbott) to Cd stress as well as the differences of Cd uptake and expression of MT family genes and NRAMP2. Results showed that root dry weights of two varieties and shoot dry weights of Abbott increased first and then decreased with the increase of Cd level in soil. When exposed to 75 mg kg⁻¹ Cd, shoot dry weight and plant dry weight of Abbott both reached maximum values (10.92 and 12.03 g pot⁻¹), which increased by 11.09 and 10.67% compared with the control, respectively. Shoot dry weight and plant dry weight of Bond decreased with the increase of Cd level in soil. When the Cd level in soil was 75 mg kg⁻¹, shoot Cd concentrations of the two varieties were 111.19 mg kg⁻¹ (Bond) and 133.69 mg kg⁻¹ (Abbott), respectively, both of which exceeded the critical value of Cd hyperaccumulator (100 mg kg⁻¹). The expression of MT gene family and NRAMP2 in the leaf of Bond variety significantly increased at the Cd level of 75 mg kg⁻¹ and reached maximum value (except MT2C) at Cd level of 150 mg kg⁻¹. The expression of MT gene family in the stem of Bond variety showed a double-peak pattern, while the expression of NRAMP2 was a single-peak pattern. The expression of MT gene family and NRAMP2 in Abbott variety was consistent with single-peak pattern. The expression of MT gene family and NRAMP2 in leaf both significantly increased at Cd level of 150 mg kg⁻¹, while that in stem and root significantly increased at Cd level of 75 mg kg⁻¹. For both varieties of ryegrass, the expression amount of MT family genes and Nramp2 in leaf was higher than that in root and stem, indicating the Cd tolerance of ryegrass can be improved by increasing the expression levels of MT family genes and Nramp2 in stem and root. There was significant genotypic difference in the expression of MT gene family and NRAMP2 between the two varieties of ryegrass, and the expression of MT gene family and NRAMP2 in leaves and stems of Bond variety was higher than that in Abbott variety, while the expression of MT gene family and NRAMP2 in roots of Abbott variety was higher than that in Bond variety. The two gene families investigated in this study may be closely related to Cd uptake, but not related to Cd transport from root to leaf and Cd enrichment in shoot.

Drug-induced Anaphylaxis Documented in Electronic Health Records

Publication date: Available online 30 June 2018
Source:The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Neil Dhopeshwarkar, Aziz Sheikh, Raymond Doan, Maxim Topaz, David W. Bates, Kimberly G. Blumenthal, Li Zhou
BackgroundAlthough drugs represent a common cause of anaphylaxis, few large studies of drug-induced anaphylaxis have been performed.ObjectiveTo describe the epidemiology and validity of reported drug-induced anaphylaxis in the electronic health records (EHRs) of a large United States healthcare system.MethodsUsing EHR drug allergy data from 1995-2013, we determined the population prevalence of anaphylaxis including anaphylaxis prevalences over time, and the most commonly implicated drugs/drug classes reported to cause anaphylaxis. Patient risk factors for drug-induced anaphylaxis were assessed using a logistic regression model. Serum tryptase and allergist visits were used to assess the validity and follow up of EHR-reported anaphylaxis.ResultsAmong 1,756,481 patients, 19,836 (1.1%) reported drug-induced anaphylaxis: Penicillins (45.9 per 10,000), sulfonamide antibiotics (15.1 per 10,000), and nonsteroidal anti-inflammatory drugs (NSAIDs) (13.0 per 10,000) were most commonly implicated. Patients with white race (odds ratio [OR] 2.38, 95% CI 2.27-2.49), female sex (OR 2.20, 95% CI 2.13-2.28), systemic mastocytosis (OR 4.60, 95% CI 2.66-7.94), Sjögren's syndrome (OR 1.94, 95% CI 1.47-2.56), and asthma (OR 1.50, 95% CI 1.43-1.59) had an increased odds of drug-induced anaphylaxis. Serum tryptase was performed in 135 (<1%) anaphylaxis cases and 1,587 patients (8.0%) saw an allergist for follow-up.ConclusionEHR-reported anaphylaxis occurred in approximately 1% of patients, most commonly from penicillins, sulfonamide antibiotics, and NSAIDs. Females, whites, and patients with mastocytosis, Sjögren's syndrome, and asthma had increased odds of reporting drug-induced anaphylaxis. The low observed frequency of tryptase testing and specialist evaluation emphasize the importance of educating providers on anaphylaxis management.

LTBK-01. UPDATES ON THE PHASE II AND RE-TREATMENT STUDY OF AZD6244 (SELUMETINIB) FOR CHILDREN WITH RECURRENT OR REFRACTORY PEDIATRIC LOW GRADE GLIOMA: A PEDIATRIC BRAIN TUMOR CONSORTIUM (PBTC) STUDY

Abstract

The PBTC is conducting a phase II study (NCT01089101) evaluating selumetinib (AZD6244, ARRY-142886), a MEK I/II inhibitor, in children with recurrent/refractory LGG assigned to 6 strata. We present the updated data on Stratum 2 and 5. Also, data on subsequent progression after treatment completion in patients enrolled on Stratum 1 and 3 will be discussed. Finally, we present details on the re-treatment study (PBTC-029C). Both stratum 2 (pilocytic astrocytoma [PA] without common BRAF aberrations) and Stratum 5 (non-pilocytic LGG with BRAF aberrations) met response criteria for expansion (> 2 objective responses in 16 patients), and accrual to a total of 25 patients on each stratum is ongoing. Among 50 patients treated on Stratum 1 (PA with BRAF aberrations) or Stratum 3 (NF-associated LGG), 21 have progressed. Thirteen of 21 have progressed after stopping therapy. The median time to progression for these 13 patients is 119 days (10–928). The re-treatment study has enrolled 25 patients who received a median of 12 re-treatment courses (2–36). The most common attributable toxicities after re-treatment were grade 1 CPK elevation (44%), diarrhea (44%), hypoalbuminemia (40%), elevated AST (36%), rash (36%) and fatigue (32%). The most common grade 3/4 attributable toxicities were grade 3 paronychia (8%), CPK elevation (4%), AST elevation (4%), decreased ejection fraction (4%), neutropenia (4%), elevated triglycerides (4%), peripheral neuropathy (4%) and grade 4 CPK elevation (4%). There is not a significant difference between the toxicities observed during original therapy versus re-treatment. The most current response and patient demographic data will be presented.

CRAN-34. TRANSCRIPTOMIC AND PROTEOMIC COMPARISON OF PEDIATRIC AND ADULT ADAMANTINOMATOUS CRANIOPHARYNGIOMA

Abstract

Adamantinomatous craniopharyngioma (ACP) is a biologically benign but clinically aggressive lesion that has a significant impact on quality of life. The incidence of the disease has a bimodal distribution with peaks occurring in children and adults. Our group previously published the results of a transcriptome analysis of pediatric ACPs that identified several genes that were consistently overexpressed relative to other brain tumors. We now present the results of a transcriptome analysis of both pediatric and adult ACP to identify biological differences between these groups that may provide novel therapeutic insights, or support the assertion that potential therapies identified through the study of pediatric ACP may also have a role in adult ACP. Following bulk RNA sequencing, we explored the differential expression of adult ACP versus pediatric ACPs via geneset enrichment analysis. Preliminary studies identified a decreased cytokine gene expression profile in adult ACP that may correspond to a reduced senescence-associated secretory phenotype (SASP), which has recently been described in pediatric ACP. Additionally, our results corroborate our previous work demonstrating an increase in IL-6 expression and overall inflammatory response in pediatric tumors. To further characterize age-associated transcriptomic differences, we performed immunohistochemistry, immunoblotting, and other proteomic studies. Our results demonstrate phenotypic similarities and differences between pediatric and adult ACP.

IMMU-08. PHASE I TRIAL (NCT02457845) SAFETY, TOLERABILITY AND PRELIMINARY EFFICACY OF IMMUNOVIROTHERAPY WITH HSV G207 IN CHILDREN WITH PROGRESSIVE MALIGNANT SUPRATENTORIAL BRAIN TUMORS

Abstract

BACKGROUND

Outcomes for children with progressive malignant supratentorial brain tumors are dismal. Preclinical evidence indicates that pediatric brain tumors are highly sensitive to genetically engineered oncolytic HSV-1 G207, which lacks genes essential for replication in normal brain. We report on this first-in-children oncolytic virotherapy brain tumor trial of G207.

DESIGN/METHODS

A 3 + 3 design was used to evaluate the safety, tolerability and preliminary efficacy of G207 at two doses (10⁷ and 10⁸ plaque-forming units). After informed consent, patients underwent biopsy to confirm viable tumor followed by placement of up to four silastic intratumoral catheters. The following day, G207 was infused by convection enhanced delivery over 6 hours. Patients were assessed for viral shedding and viremia by PCR and response by serial MRIs.

RESULTS

Six subjects have been treated (5 glioblastoma; 1 anaplastic astrocytoma). No dose limiting toxicities, serious adverse events, or ≥ grade 2 toxicities related to G207 have occurred. No G207 shedding or viremia was detected in the saliva, conjunctiva or blood at any time. Evidence of radiographic responses to G207 were seen in 5 of 6 patients including a patient >12 months post-G207 with an ongoing response and improvement in performance score from 80 to 100.

CONCLUSION

G207 delivered intratumorally is safe and tolerable in children with progressive malignant supratentorial brain tumors. Preliminary evidence of efficacy is very promising to date. The next phase of the study (NCT02457845) will test the safety of G207 combined with a single 5 Gy dose of radiation within 24 hours of virus inoculation.

EMBR-14. RECLASSIFICATION OF CENTRAL NERVOUS SYSTEM PRIMITIVE NEUROECTODERMAL TUMOR (CNS-PNET) INTO ENTITIES REFLECTS OUTCOME: RESULTS FROM THE PROSPECTIVE SJYC07 AND SJMB03 TRIALS

Abstract

BACKGROUND

Central nervous system primitive neuroectodermal tumor (CNS-PNET) was removed from the WHO classification after DNA-methylation profiling unveiled its underlying heterogeneity. Here we describe the makeup and outcome of patients histopathologically diagnosed as CNS-PNET treated on 2 multi-center, prospective trials.

METHODS

Patients <3yr received chemotherapy with/without focal irradiation (SJYC07). Patients ≥3yr received risk-adapted craniospinal-irradiation (23.4Gy for localized disease, 36–39.6Gy for metastatic) and chemotherapy (SJMB03). DNA-methylation was performed using Infinium MethylationEPIC BeadChip and profiled on DKFZ molecularneuropathology2.0 classifier.

RESULTS

Fifty-six patients were enrolled (SJYC07=32; SJMB03=24) with median age 2.86yr (range: 0.64–19.47). Sixteen were stratified as high-risk including 10 with metastasis. Histopathological diagnosis upon central review was CNS-PNET (n=34), ETMR (n=17), CNS-neuroblastoma/ganglioneuroblastoma (n=3) and HGNET (n=2). 42/56 cases were methylation-profiled into ETMR (N=13), GBM (N=3), MB_group3 (N=2), CNS-NB-FOXR2 (N=3), CNS-EFT-CIC (N=1), EPN-RELA (N=1), choroid plexus tumor (pediatric B) (N=1), PB_groupB (N=1), normal tissue (N=3), and "no match" (calibrated scores <0.9) (N=14). Median duration of follow-up was 2.24yr (range: 0.06–12.7). 5yr-OS/PFS in SJMB03-AR and -HR patients were 46.7 ± 12.9%/46.7 ± 12.9% and 33.3 ± 15.7%/33.3 ± 15.7% (OS p=0.503; PFS p=0.494). 5yr-OS/PFS in SJYC07-IR and -HR patients were 46.8 ± 10.6%/44.7 ± 10.4% and 57.1 ± 18.7%/14.3 ± 13.2% respectively (OS p=0.973; PFS p=0.046). Patients methylation-profiled as ETMR/GBM/MB had 5yr-OS/PFS of 24.1 ± 10.4%/14.8 ± 8.9% compared to 90.0 ± 9.5%/80.0 ± 12.6% in the other entities (OS p=0.001; PFS p<0.001). Age, metastasis, extent of surgery and treatment protocol did not significantly impact outcome. Classification by DNA-methylation profiling (p=0.037), histopathological diagnosis (p=0.019) and radiation use (p<0.001) were predictive of PFS.

CONCLUSION

Outcome of pediatric CNS-PNET varied but better conformed to convention when assigned a new entity.

ATRT-07. MURINE SOX2-POSITIVE EARLY PRECURSOR CELLS GIVE RISE TO RHABDOID TUMORS WITH FEATURES OF THE HUMAN ATRT-MYC GROUP

Abstract

PURPOSE

Atypical teratoid rhabdoid tumors (ATRT), characterized by SMARCB1 loss, have been classified by DNA methylation and gene expression profiling into three distinct molecular subgroups (ATRT-SHH, -MYC, -TYR). We hypothesize that ATRT from distinct subgroups have a different cell of origin.

METHODS

Multiple precursor cell specific, constitutive and inducible Smarcb1 knockout mouse strains were established by using a Cre-loxP system. Murine tumors were analyzed by histology and gene expression profiling. Unsupervised hierarchical clustering and differential expression analyses were performed.

RESULTS

Rhabdoid tumor (RT) development was detected only when Smarcb1 abrogation occurred in a very restricted time frame during embryonic development and only under the control of an ubiquitous (Rosa26) or Sox2 promoter. Unsupervised hierarchical clustering of Affymetrix gene expression profiles of these murine and of published human ATRT classified tumors of the Rosa26cre^ERT2::Smarcb1^Fl/Fl model either as ATRT-MYC or as ATRT-SHH. In contrast, ATRT of Sox2cre^ERT2::Smarcb1^Fl/Fl mice were assigned to the ATRT-MYC subgroup only. Mouse strains in which the Smarcb1 knockout was driven by Nestin-, hGFAP-, Math1-, Olig1- Cre recombinase presented other phenotypes but not RT.

CONCLUSION

Subgroup-specific RT genesis depends on the cell of origin. Here we identify early Sox2-positive progenitors as precursor cells of ATRT-MYC subgroup. We further demonstrate that Smarcb1 abrogation during a specific, short time period and in a specific targeted cell population is crucial for induction of ATRT-MYC.

DIPG-41. IDENTIFICATION OF BIRC5 AS A NOVEL THERAPEUTIC TARGET FOR DIFFUSE INTRINSIC PONTINE GLIOMA

Abstract

Diffuse Intrinsic Pontine Glioma (DIPG) remains to be a lethal type of pediatric brain tumor to date, indicating an urgent need of finding novel therapeutic strategy. Through screening of a collection of anti-tumor agents against a patient-derived DIPG primary tumor cell line, we identified a few novel therapeutic candidates for treating DIPG, among which BIRC5 inhibitor YM155 was the top potent agent. Next, we confirmed that YM155 could selectively inhibit multiple DIPG primary cell lines with IC50 less than 10nM. Moreover, our gene expression analyses showed that BIRC5 was significantly upregulated in DIPG primary tumor tissues and paired normal cortex tissues from the same patient. Genetically targeting of BIRC5 with CRISPR-Cas9 or RNAi approach could also effectively disrupt the growth of multiple DIPG cell lines, confirming BIRC5 as a valid therapeutic target for treating DIPG. Mechanistically, BIRC5 inhibition could cause cell cycle arrest, shut off proliferation and induce massive apoptosis. Furthermore, we tested the combinatory inhibitory effects of YM155 plus chemotherapy or targeted therapy drugs with proven anti-DIPG activity, including THZ1, JQ1, Gemcitabine, Panobinostat, GSK-J4 and et al. The preliminary results demonstrated YM155 could work synergistically with a few of above-mentioned drugs in vitro. We are also testing the in vivo inhibitory effects of targeting BIRC5 against DIPG preclinical PDX models. Together, our study identified BIRC5 inhibition as a novel therapeutic strategy against DIPG.

GERM-15. A PHASE 2 TRIAL OF RESPONSE-BASED RADIATION THERAPY FOR PATIENTS WITH LOCALIZED CENTRAL NERVOUS SYSTEM GERM CELL TUMORS (CNS GCT): A CHILDREN’S ONCOLOGY GROUP (COG) STUDY

Abstract

Intracranial germ cell tumors represent 3-5% of pediatric CNS tumors. Non-germinomatous germ cell tumors (NGGCT) have worse outcomes compared to germinomas, however, improved survivals were achieved on COG ACNS0122 utilizing a combination of chemotherapy and craniospinal irradiation (CSI). Since CSI is associated with significant late effects, a Phase 2 study was undertaken to determine whether irradiation could be reduced without impacting survival in a subgroup of NGGCT patients. Patients with localized disease who achieved a complete (CR) or partial response (PR) to chemotherapy were eligible for reduced irradiation to 30.6Gy whole ventricular field (WVI) and 54Gy tumor-bed boost as compared to 36Gy CSI plus tumor-bed boost as used on ACNS0122. Between 5/2012 and 11/2016, 107 eligible patients were accrued. Median age was 11 years (range: 4-22) and 75% were male. Tumor location was pineal in 58, suprasellar in 37, ventricular in 6 and bifocal in 6 patients. Sixty-six patients achieved CR/PR post-induction and received reduced irradiation. The 2-year progression-free survival (PFS) was 89% (95% CI: 81%-97%) and overall survival was 92% (95% CI: 86%- 99%). Eight patients progressed; seven had a distant relapse (outside the irradiation field) and one patient had a local plus distant relapse. Alpha-fetoprotein and beta-human chorionic gonadotropin levels were not associated with PFS. There were no unexpected treatment-related adverse events or deaths. Although these survival data are encouraging, distant relapses noted in all of the patients who progressed are concerning. Longer follow-up of the ACNS1123 cohort may better inform our recommendations in the future.

CRAN-01. QUALITY OF LIFE AND GROWTH AFTER CHILDHOOD CRANIOPHARYNGIOMA: RESULTS OF THE MULTINATIONAL TRIAL KRANIOPHARYNGEOM 2007

Abstract

CONTEXT

Quality of life (QoL) after childhood-onset craniopharyngioma (CP) is frequently impaired due to tumor and/or treatment-related factors such as endocrine deficits and hypothalamic involvement/lesions. PATIENTS AND

METHODS

In a multinational trial, we prospectively analyzed parental and self-assessment of CP patient QoL at 3 months, one and 3 years after CP diagnosis related to growth hormone (GH) substitution. 47 of 194 CP recruited between 2007 and 2015 in KRANIOPHARYNGEOM 2007 were analyzed for QoL one and 3 years after CP diagnosis. QoL was assessed by Pediatric Quality of Life (PEDQOL) questionnaire and PEDQOL scores of parental and self-assessed QoL during 3 years follow-up after CP diagnosis were analyzed.

RESULTS

Parents estimated QoL of their children worse than patients did themselves. GH substitution had no relevant effect on short-term weight and height development. CP patients GH-treated at 3 years follow-up presented at baseline (one year after diagnosis, before GH substitution) with reduced self-assessed QoL when compared with GH non-treated CP. QoL stabilized during 1–3 years of follow-up in GH-treated patients, whereas non GH-treated patients experienced decreases in autonomy (p=0.03), cognition (p=0.01), and physical function (p=0.04).

CONCLUSIONS

Parents assess QoL in CP survivors worse than their children. GH substitution should be considered as a therapeutic option to ameliorate imminent impairments of QoL after CP.

DIPG-09. HDAC INHIBITION IN THALAMIC AND SPINAL CORD H3K27M+ DIFFUSE MIDLINE GLIOMA

Abstract

BACKGROUND

Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), are the leading cause of brain tumor-related deaths in children. There are no effective treatments and median survival remains dismal. Genomics identified a mutation in the majority of DMGs, a lysine to methionine substitution (K27M) in histones 3.1 and 3.3, which causes changes in gene expression that promote gliomagenesis. Panobinostat, a multiple histone deacetylase (HDAC) inhibitor, was one of the most effective agents against patient-derived DIPG cell cultures and xenograft models in previous studies and is presently in clinical trial for DIPG. HDAC inhibition with panobinostat may also exhibit activity against H3K27M+ DMG of the thalamus and spinal cord.

METHODS

Patient-derived thalamic and spinal cord H3K27M+ DMG cell cultures were treated with single agent panobinostat at a range of concentrations. Cell viability was evaluated using the CellTiter-Glo assay. Panobinostat was systemically administered to murine models of luciferase-expressing spinal cord H3K27M+ DMG. Response to panobinostat was evaluated with IVIS in vivo imaging.

RESULTS

HDAC inhibition with panobinostat significantly decreases cell proliferation with an IC50 of 30 nM and 41 nM in the spinal cord and thalamic glioma patient-derived cell cultures respectively. Panobinostat slowed tumor growth in spinal cord glioma orthotopic xenografts compared to vehicle controls.

CONCLUSION

This study suggests that HDAC inhibition with panobinostat may also be beneficial for thalamic and spinal cord H3K27M+ DMG.

DIPG-74. DNA METHYLATION STOCHASTICITY IN DIPG

Abstract

Diffuse intrinsic pontine glioma (DIPG) is a childhood brainstem tumor with a dismal prognosis and no effective treatment. Recent studies point to a critical role for epigenetic dysregulation in this disease. Nearly 80% of DIPGs harbor mutations in histone H3 encoding replacement of lysine 27 with methionine (K27M), leading to global loss of the repressive histone H3K27 trimethylation mark, global DNA hypomethylation, and a unique gene expression profile. Recent studies across diverse cancers have highlighted the role of epigenetic variability as a driving force in tumor evolution. Epigenetic variability may underlie the heterogeneity and phenotypic plasticity of cancer cells and allow for the selection of cellular traits that promote survival and resistance to therapy. Our group has recently described a novel mathematical framework for analyzing variability of DNA methylation directly from whole-genome bisulfite sequencing data by modeling stochastic Markov processes, allowing rigorous computation of DNA methylation entropy at precise genomic locations. We have carried out genome-wide characterization of DNA methylation at single-base resolution in DIPG in order to generate comprehensive genome-wide maps of DNA methylation entropy. We find a global increase in DNA methylation entropy in DIPG. Dissection of the targets of this perturbation highlights specific genes and regulatory regions under epigenetic control in DIPG cells. We assess the effect of pharmacologic DNA methyltransferase inhibition on the DNA methylation landscape and on gene expression in DIPG patient-derived neurosphere cell lines. We find that DNA methyltransferase inhibition alters expression of genes involved in cell death, differentiation, cellular defense, and immune signaling.

EPEN-30. HISTONE H3 LYSINE 4 TRIMETHYLATION IS A POTENTIAL TARGET TO IMPROVE CHEMOTHERAPEUTIC EFFICACY FOR PEDIATRIC PRIMARY EPENDYMOMAS

Abstract

Ependymomas are the third most common form of brain tumors in children. These tumors are resistant to chemotherapy and despite genomic sequencing, there is a lack of effective molecular treatment targets. Efficient treatment targets need to be identified. Increasing evidence shows epigenetic alterations including posttranslational histone modifications (PTMs), associated with malignancy, chemotherapeutic resistance and prognosis in pediatric ependymomas. In this study we examined histone PTMs in ependymomas and identified potential targets to improve chemotherapeutic efficacy. Global levels of trimethylation at lysine 4 on histone H3 (H3K4me3), detected with immunohistochemistry and western blots, positively correlated with malignancy in pediatric primary ependymomas. Micro-array analysis of 22 pediatric ependymomoas identified upregulated candidate drug resistance genes. Promoter H3K4me3 occupancy was examined for two of these genes, CCND1 and ERBB2. Chromatin-immunoprecipitation with H3K4me3 coupled with real-time PCR, showed higher levels of H3K4me3 at these genes in grade III tumors, in comparison to grade II ones. When H3K4me3 levels were reduced in primary cultured ependymoma cells in vitro, cell response to chemotherapy increased. In summary, these results indicate that H3K4me3 levels are high at promoters of genes which confer chemotherapeutic resistance. Consequently, a novel treatment regimen which targets H3K4me3 in combination with traditional protocols may increase chemotherapeutic efficacy and improve prognosis for children who present with ependymoma.

TBIO-04. A CENTRALIZED MOLECULAR DIAGNOSTIC SERVICE FOR PEDIATRIC BRAIN TUMORS IN JAPAN

Abstract

Molecular tests have now become an essential part of clinical management of pediatric brain tumor patients. We have established a central diagnosis system for pediatric brain tumors in Japan to provide standardized molecular diagnostic service. Tumor specimen are accepted from centers participating Japan Children's Cancer Group (JCCG). The JCCG Datacenter at National Center for Child Health and Development (NCCHD) manages all patients' specimen and information. Histology is centrally reviewed at Gunma University Hospital. Molecular tests are performed at either Osaka National Hospital (medulloblastoma), Gunma University Hospital (ETMR) or National Cancer Center (all the others). Medulloblastomas are classified by expression profiling using the nanostring technology, and mutations of CTNNB1, TP53 and TERT determined. Gliomas are examined for mutations of BRAF, H3F3A, HIST1H3B, FGFR1, IDH1/2 and TERT using pyrosequencing, as well as for BRAF fusion by RT-PCR as necessary. Supratentorial ependymomas are examined for the presence of RELA fusion by RT-PCR, and posterior fossa ependymomas are classified as PFA or PFB by DNA methylation analysis. Those tumors negative for the routine analyses may be subjected to RNA sequencing or targeted sequencing for 93 genes known to be mutated in brain tumors. As of August 2017, over 200 tumors have been molecularly diagnosed and the integrated diagnosis reported to each center. Our system is affordable utilizing minimum amount of high throughput technologies, and will hopefully improve the standard of diagnosis for pediatric brain tumors.

HGG-22. PHASE 1b STUDY POLIO VACCINE SABIN-RHINOVIRUS POLIOVIRUS (PVSRIPO) FOR RECURRENT MALIGNANT GLIOMA IN CHILDREN

Abstract

BACKGROUND

Prognosis of recurrent World Health Organization (WHO) grade IV malignant glioma (GBM) in children is dismal with no effective therapy. We have recently performed a dose-finding and toxicity study within adults with GBM, evaluating the recombinant non-pathogenic polio/rhinovirus chimera (PVSRIPO) by intratumoral convection-enhanced delivery (CED). PVSRIPO recognizes the poliovirus receptor CD155, which is widely expressed in neoplastic cells of solid tumors and in major components of tumor stroma. We have commenced a Phase Ib study to evaluate feasibility, safety, and preliminary evidence of efficacy of the optimal adult dose in a pediatric population.

METHODS

Patients with a recurrent supratentorial WHO Grade III malignant glioma (anaplastic astrocytoma, anaplastic oligoastrocytoma, anaplastic oligodendroglioma, anaplastic pleomorphic xanthoastrocytoma, ependymoma) or WHO Grade IV malignant glioma (glioblastoma, gliosarcoma) based on imaging studies with measurable disease (≥ 1 cm and ≤ 5.5 cm of contrast-enhancing tumor) will be enrolled. A stereotactic biopsy will be performed prior to virus administration. Immediately following the stereotactically-guided tumor biopsy, a catheter will be implanted in the operating room. PVSRIPO will then be delivered intratumorally by CED, using the catheter placed within the enhancing portion of the tumor, at a dose of 5 x 10⁷ TCID over 6.5 hours.

CONCLUSION

We will confirm the activity of intratumoral PVSRIPO infusion in recurrent WHO grade III or IV malignant glioma in the absence of neurovirulent potential in children.

TBIO-21. ANALYSIS OF PAIRED BRAFV600E MUTANT GLIOMA PATIENT SAMPLES IDENTIFIES NOVEL RESISTANCE MECHANISMS TO TARGETED BRAF INHIBITION

Abstract

BRAF^V600E mutations occur in a variety of gliomas and BRAF^V600E targeted therapies have provided new treatment options. Trials in melanoma and colorectal cancer, as well as early results in CNS tumors, indicate a high risk for the development of resistance. To date there is little data available for resistance mechanisms in glioma patients treated with BRAF^V600E inhibition. To identify molecular and pathway alterations driving resistance, we performed targeted next-generation DNA sequencing, RNA sequencing, and Ingenuity Pathway Analysis (IPA) on paired pre-treatment and post-resistance primary pediatric glioma samples (n=10) and cell lines (n=2). Unique genetic alterations likely driving tumor recurrence and resistance to BRAF inhibition were identified. Novel mutations in post-resistance samples included a de novo mutation in the CBL gene within the RING finger domain of the E3 ubiquitin ligase protein that has been recurrently found in myeloid neoplasms, a frameshift mutation in the RB1 tumor suppressor gene, and a nonsense mutation in ERRFI1, which encodes a negative regulator of EGFR signaling. IPA analysis demonstrated significant pathway activation differences in post-resistance samples. There was a predominance of upregulated receptor tyrosine kinase pathways including EGFR, NTRK2, TGFB1, estrogen receptor, ERBB2, and PI3K. Expected up-regulation of MEK, MAPK1, MAP2k1 and ERK1/2 pathways were found. The altered pathways were unique for each paired set. These data suggest that pediatric gliomas develop resistance to BRAF inhibition using a multitude of genetic and transcriptional mechanisms that are potentially distinct in each tumor, and with novel resistance mutations not found in resistant melanoma or colorectal cancers.

ATRT-24. CHROMATIN SEGMENTATION IN ATRT REVEALS AN IMPORTANT ROLE FOR RESIDUAL SWI/SNF MEMBERS

Abstract

Although SMARCB1 mutations represent the only recurrent genetic aberration in atypical teratoid/rhabdoid tumors (ATRT), a comprehensive assessment of the epigenetic effect of SMARCB1 loss has not been attempted so far. To achieve this, we performed ChIP-sequencing for six histone marks (H3K4me1, H3K4me3, H3K27me3, H3K27Ac, H3K9me3, H3K36me3) and EZH2 in 11 primary ATRTs, encompassing all three molecular subgroups of ATRT.Chromatin segmentation analyses revealed that across all three subgroups a high percentage of ATRT epigenomes resides in a quiescent state and active enhancer states are significantly underrepresented as compared to non-neoplastic brain. We validated these findings in a SMARCB1-reexpressing ATRT cell line and also found an overall deincrease of H3K27Ac and H3K27me3 upon SMARCB1 reexpression. Interestingly, by comparing the genome wide distribution of EZH2 and H3K27me3, we also identified classes of ATRT-specific active genes bound by EZH2, but lackingH3K27me3, pointing at a non-canonical role of EZH2 in gene activation. ChIP-Sequencing of SMARCA4 in these samples revealed that many of these „EZH2 only" genes display a high signal of of this protein. Many of these genes (such as e.g. CCND2) were downregulated upon knock-down of SMARCA4 in ATRT cell lines. Adding to the overall characterization of the epigenome, we have shown that a number of genes - despite being bound by EZH2- are maintained in an active state by residual SWI/SNF complex binding. This sheds new light on the role of residual SWI/SNFSMARCA4 still being present in AT/RT and elucidates a mechanism by which AT/RT keep important tumor-genes in an active state.

CRAN-18. CASE SERIES OF INTRACRANIAL NON-GERMINOMATOUS GERM CELL TUMOR: A SINGLE INSTITUTION EXPERIENCE

Abstract

Intracranial non-germinomatous germ cell tumors are a rare, heterogenous group of neoplasms, commonly occurring in the pineal and/or suprasellar regions. The subtypes include yolk sac tumor (YST) or endodermal sinus tumor (EST), embryonal carcinoma (EC), choriocarcinoma (CHC), and mixed malignant subtypes. Diagnosis is usually made without a biopsy, through detection of elevated levels of Alpha-fetoprotein (AFP) and/or beta-human chorionic gonadotropin (βHCG) in the serum and/or cerebrospinal fluid. Three patients with intracranial NGGCT were treated at our institution, using a combination of surgery, chemotherapy, and/or radiation therapy. The clinical presentation of all cases included signs and symptoms of obstructive hydrocephalus. Patient #1 was diagnosed with malignant teratoma at birth via neuroimaging; she died from complications due to surgical resection. Patient #2 was diagnosed with choriocarcinoma of the pituitary gland at age 5 years via elevated AFP in serum and CSF; he was treated with alternating cycles of carboplatin/etoposide and ifosfamide/etoposide, followed by whole ventricle radiation therapy. He is now 28 months off-therapy, without evidence of disease. Patient #3 was diagnosed with choriocarcinoma of the pineal and suprasellar regions at the age 7 years, via elevated beta-HCG in serum and CSF, with evidence of bimodal disease. Treatment included 6 cycles of risk-adapted chemotherapy followed by whole ventricle radiation therapy. Neuroimaging continues to show no evidence of disease with normalization of tumor markers, at 24 months off-therapy. Patients #2 and #3 have residual neuroendocrine and neuropsychological deficits, but remain neurodevelopmentally appropriate. Combination of chemotherapy and radiation therapy is required for optimal prognosis.

DEV-11. OUTCOMES OF MALIGNANT BRAIN TUMORS IN YOUNG CHILDREN TREATED WITH CHEMOTHERAPY AND DELAYED RADIOTHERAPY IN A RESOURCE LIMITED SETTING

Abstract

METHODOLOGY

A retrospective analysis of children less than 3 years diagnosed with malignant brain tumors was conducted from January 2011 to December 2016. Children with malignant brain tumors were treated with cyclophosphamide, etoposide and carboplatin (CEJ) upto 36months of age or till disease progression. Low grade gliomas were excluded from the analysis. An intention to treat analysis was performed to determine the outcomes and delay in radiotherapy (RT).

RESULTS

ninety four children (median age: 26 months, median follow-up: 18.9 months) were diagnosed with malignant brain tumors of which 59 received the CEJ regimen. Twenty six children (44.0%) underwent a complete resection, 23 (38.9%) partial resection, and 10 (16.9%) debulking/biopsy. Progression free survival (PFS) and overall survival (OS) at 24months was 53.8% (95% CI: 38.6% - 66.9%) and 64.0% (95% CI: 48.7%- 78.8%) respectively.41 children (69.5%) received RT with a median time to delaying RT of 9.3months (inter-quartile range 6.5 -13.4 months). Among 39 cases of medulloblastoma (MB), molecular data was available in 24 (wnt-0, shh-11, group 3 and group4 – 13). The outcomes with shh and non-shh were similar.

CONCLUSIONS

Chemotherapy regimens like CEJ are effective in delaying radiotherapy in young children with malignant brain tumors. This approach may be used in resource limited countries to improve the outcomes of young children with malignant brain tumors.

DIPG-25. A KINOME-WIDE shRNA SCREEN UNCOVERS VRK3 AS AN ESSENTIAL GENE FOR DIPG SURVIVAL

Abstract

Diffuse Intrinsic Pontine Glioma (DIPG) remains the most fatal form of pediatric brain tumor. The specific somatic mutation (H3K27M) in the H3 histone gene was found in around 95% of patients making this alteration as the initial oncogenic event. However, until now this alteration cannot be targeted. Consequently, we conducted a RNAi-based loss-of-function screen targeting the human kinome to decipher vulnerabilities in DIPG, unravel their biology and provide therapeutic opportunities in this devastating disease. An integrative lentiviral pooled library of 7450 shRNAs against 770 kinases was used to transduce four GSC (glioma stem cells) cultures harboring either H3.1 (n=2) or H3.3-mutation (n=2) in order to cover the diversity observed in patients, and 2 control NSC (neural stem cell) cultures. The entire set of shRNAs was identified by sequencing 40 hours and 22 days after transduction. Genes required for cell expansion over 22 days of outgrowth in GSC but with limited deleterious effect on NSC proliferation were identified. Among those, we selected the target genes with at least 3 distinct shRNAs presenting a significant decrease in their abundance and identified in particular VRK3 (Vaccinia-Related Kinase 3) as one of the top scoring kinases whose extinction was lethal to DIPG. This serine-threonine kinase was recently linked to cell cycle progression, DNA repair and neuronal differentiation. The role of this protein in DIPG biology is currently assessed especially to identify actionable downstream targets. Drugs mimicking the effect of VRK3 extinction will be evaluated in our vitro and vivo models of DIPG.

DIPG-57. A COMPREHENSIVE GENE/PROTEIN INVESTIGATION OF THE TUMOUR MICROENVIRONMENT IN DIFFUSE MIDLINE GLIOMA IN CHILDREN

Abstract

Pediatric diffuse midline glioma (pDMG) is a rare aggressive childhood malignancy. While much is known concerning molecular genomics, our focus is on understanding the tumour microenvironment and how this influences cancer growth. We hope to learn how interaction and communication between host cells, tumour cells and extracellular matrix proteins (ECM) promote the pDMG growth. We conducted bioinformatic analysis using data obtained from R2: Genomics Analysis and Visualization Platform of pDMG tissue samples (GSE26576). In parallel, fixed-formalin paraffin embedded tissue (FFPE) was obtained from post-mortem brain. RNA was extracted from tumour core, adjacent and 'normal' tissue. Following quality control experiments to ensure RNA integrity, RNA was then used for a focused ECM array. Eighty ECM related genes were chosen for bioinformatics analyses to make indirect comparisons to the ECM focused RT2 profiler. Preliminary bioinformatic analyses indicate that 15 of the 80 genes were significantly up-regulated in pDMG tumours compared to normal brainstem (p<0.05). The most significantly differentially expressed include, Matrix Metalloproteinase1 (MMP1), Collagen type XI alpha 1 (COL11A1), and Matrix Metalloproteinase 16 (MMP16) (p<0.0001). In preliminary analyses of data obtained from FFPE tissue, tumour adjacent RNA was compared to 'normal' brain. Out of 80 genes, 7 were differentially expressed and include COL11A1, Collagen type VI alpha 2 (COL6A2) and Laminin alpha 3 (LAMA3). We believe that by identifying key host/tumour interactions that drive pDMG growth, this knowledge will help lead to improved therapeutics for this devastating childhood brain cancer.

EAPH-13. PHASE I STUDY OF INTRAVENTRICULAR INFUSIONS OF AUTOLOGOUS EX VIVO EXPANDED NK CELLS IN CHILDREN WITH RECURRENT/REFRACTORY MALIGNANT POSTERIOR FOSSA TUMORS OF THE CENTRAL NERVOUS SYSTEM

Abstract

Prognosis of recurrent/refractory medulloblastoma, ependymoma and atypical teratoid/rhabdoid neoplasms (AT/RT) remains dismal. Preclinical data showing efficacy of activated/propagated NK cells to lyse and kill these tumor cells in culture and in mice have been demonstrated, along with feasibility and safety of infusions of biologic agents into the ventricles. The ongoing phase I trial evaluates for the first time in humans, safety of infusions of autologous NK cells directly into the ventricles of patients with these tumors. Assessment of antitumor activity, and correlative biologic studies are being evaluated to define the immunophenotype and function of expanded NK cells. Patients receive three cycles of NK-cell infusions over 12 weeks through an Ommaya reservoir. To date, 9 patients have been enrolled, 8 patients achieved successful expansion of their NK cells, and 7 patients received up to 27 infusions each of NK cells at doses up to 3x10e7/m2/infusion. Currently this study is enrolling patients in the last cohort. This phase I study has so far demonstrated safety with no dose-limiting toxicity attributable to the infused NK cells. Significant CSF pleocytosis is seen in patients receiving NK cells with the increased dosage, with no evidence of infection. Influx of CD4⁺ and CD8⁺ T cells into the CSF in noted. This could suggest a proinflammatory environment induced by higher doses of NK cell infusion. This study also intends to evaluate the migration and persistence of NK cells with novel neuroimaging techniques to correlate efficacy outcome and the pharmacokinetics of NK cells.

Impact of PM 10 and meteorological factors on the incidence of hand, foot, and mouth disease in female children in Ningbo, China: a spatiotemporal and time-series study

Abstract

Hand, foot, and mouth disease (HFMD) is a viral illness that is considered a critical public health challenge worldwide. Previous studies have demonstrated that meteorological parameters are significantly related to the incidence of HFMD in children; however, few studies have focused only on female children. This study quantified the associations of HFMD incidence with meteorological parameters and PM₁₀ (particulate matter with an aerodynamic diameter of 10 μm) among female children. Data were collected on daily HFMD cases, meteorological variables, and PM₁₀ levels in Ningbo, China, from January 2012 to December 2016. Data were assessed using a distributed lag nonlinear model (DLNM) with Poisson distribution. A total of 59,809 female children aged 0−15 years with HFMD were enrolled. The results showed that highest relative risk (RR) of HFMD for temperature was 3 °C and the lag effect was 3 days. The highest RR for PM₁₀ was 80 mg/m³ and the lag effect was 5 days. Spatial analysis showed that female HFMD incidence was mainly concentrated in the suburban of Ningbo city indicating that female children in this area should be more paid attention on avoiding this disease outbreak. Our findings suggest that HFMD prevention strategies should focus more attention on local meteorological parameters.

Modelling local uncertainty in relations between birth weight and air quality within an urban area: combining geographically weighted regression with geostatistical simulation

Abstract

In this study, we combine known methods to present a new approach to assess local distributions of estimated parameters measuring associations between air quality and birth weight in the urban area of Sines (Portugal). To model exposure and capture short-distance variations in air quality, we use a Regression Kriging estimator combining air quality point data with land use auxiliary data. To assess uncertainty of exposure, the Kriging estimator is incorporated in a sequential Gaussian simulation algorithm (sGs) providing a set of simulated exposure maps with similar spatial structural dependence and statistical properties of observed data. Following the completion of the simulation runs, we fit a geographically weighted generalized linear model (GWGLM) for each mother's place of residence, using observed health data and simulated exposure data, and repeat this procedure for each simulated map. Once the fit of GWGLM with all exposure maps is finished, we take the distribution of local estimated parameters measuring associations between exposure and birth weight, thus providing a measure of uncertainty in the local estimates. Results reveal that the distribution of local parameters did not vary substantially. Combining both methods (GWGLM and sGs), however, we are able to incorporate local uncertainty on the estimated associations providing an additional tool for analysis of the impacts of place in health.