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.

Phytoremediation of Mn-contaminated paddy soil by two hyperaccumulators ( Phytolacca americana and Polygonum hydropiper ) aided with citric acid

Abstract

The purpose of this study was to investigate the phytoremediation potential of two hyperaccumulator plants, Phytolacca americana L. and Polygonum hydropiper L., on manganese-contaminated paddy soils. The biomass growth, Mn concentrations in plant tissues, and potential Mn removal efficiency from soils of these two plants were studied with citric acid, and the mechanisms of citric acid on these two plants were analyzed by examining the root activity, the activities of superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT) in leaves, as well as the concentrations of O₂·⁻ and H₂O₂ in leaves. The results showed that the biomass of these two plants were both promoted under low level of citric acid (3 mmol kg⁻¹). The concentration of Mn in the plants and the amount of Mn removed from the soil by the plants through harvesting were enhanced at low and intermediate (10 mmol kg⁻¹) citric acid application levels. The results also showed that root activity was enhanced at the low citric acid level and significantly inhibited under the intermediate and high levels (15 mmol kg⁻¹), which indicates the facilitative function of the low level of citric acid and the inhibitive function of the high level of citric acid application on plant biomass growth. Under the low and intermediate levels of citric acid application, O₂·⁻ in the plant leaves increased sharply, and the SOD, POD, and CAT activities also increased sharply, which made the level of H₂O₂ very similar to that of the control, ensuring the health of the plants. At the high level of citric acid application, however, the O₂·⁻ continued to rise sharply, while the activity of the three antioxidant enzymes declined sharply, causing the concentration of hydrogen peroxide to be much higher than that in the control, thus endangering the plants. The present study shows the potential of P. hydropiper for use in the phytoremediation of soil contaminated with a relatively low level of manganese.

Placa anular pigmentada submentoniana

Publication date: Available online 30 June 2018
Source:Actas Dermo-Sifiliográficas
Author(s): F.J. Navarro-Triviño, M.J. Naranjo-Díaz, R. Ruiz-Villaverde

Síndrome de Stewart-Bluefarb: caso clínico y revisión de la literatura

Publication date: Available online 30 June 2018
Source:Actas Dermo-Sifiliográficas
Author(s): V.E. García Blanco, E. Dóiz Artázcoz, M.C. Galera Martínez, M. Rodríguez Piñero

Utilidad de la microscopía confocal de reflectancia para el diagnóstico in vivo de los sebomatricomas

Publication date: Available online 30 June 2018
Source:Actas Dermo-Sifiliográficas
Author(s): S. Burillo-Martínez, R. Gamo, F. Pinedo, J.L. López-Estebaranz

Medición del impacto psicológico en pacientes con psoriasis en tratamiento sistémico

Publication date: Available online 30 June 2018
Source:Actas Dermo-Sifiliográficas
Author(s): M.B. Madrid Álvarez, G. Carretero Hernández, A. González Quesada, J.M. González Martín
Antecedentes y objetivosEl impacto negativo que la psoriasis tiene en la calidad de vida del paciente puede ser tan importante como sus consecuencias físicas. Podríamos suponer que el blanqueamiento de la enfermedad conllevaría también una mejoría de su impacto psicosocial. El presente estudio valora el estado psicológico de los pacientes con psoriasis controlados con tratamiento sistémico en una Unidad de Psoriasis, especialmente en aquellos con una afectación leve o nula de la enfermedad.MétodosEstudio epidemiológico observacional y trasversal, sin intervención, con dos cohortes (casos y controles). Los pacientes autocompletaron datos demográficos y 4 cuestionarios (Cuestionario de autoestima de Rosenberg, Skindex-29, HADS y COPE-28) en una única visita.ResultadosSe reclutaron 111 pacientes diagnosticados de psoriasis y 109 pacientes control. En autoestima, el promedio y la desviación estándar (DE) del grupo de psoriasis fue de 33,5 (4,8) y de 33,3 (6,7) para el grupo control, sin diferencias significativas. En el Skindex-29, la puntuación media del grupo de pacientes con psoriasis fue casi 3 veces mayor que la media del grupo control (30 vs. 11). Se encontraron diferencias significativas en las puntuaciones del HADS de ambos grupos (12,7 vs. 9,0; p<0,001). Las puntuaciones promedio del HADS-A fueron de 8,0 (4,78) en el grupo de psoriasis frente a 5,7 (3,8) en el grupo control (p<0,001), mientras que las del HADS-D fueron de 4,7 (3,9) frente a 3,2 (3,1) (p<0,004), respectivamente.ConclusionesLos resultados obtenidos indican que es necesario medir el estado psicológico de nuestros pacientes con psoriasis, pues incluso con un control casi total de la enfermedad la afectación psicológica permanece.Background and objectivesThe negative impact of psoriasis on patient quality of life can be as important as the physical consequences of the disease. We could assume that clearance of the disease would also lead to an improvement in its psychosocial impact. The present study assesses the psychological state of patients with psoriasis receiving systemic treatment in a psoriasis unit, especially those with mild or no disease involvement.MethodsWe performed a cross-sectional, observational, noninterventional epidemiological study of 2 cohorts (cases and controls). The patients self-completed demographic data and 4 questionnaires (Rosenberg Self-Esteem Scale, Skindex-29, HADS, and COPE-28 questionnaire) at a single visit.ResultsWe recruited 111 patients diagnosed with psoriasis and 109 control patients. In self-esteem, the mean and standard deviation (SD) score was 33.5 (4.8) for the psoriasis group and 33.3 (6.7) for the control group, with no significant differences. In the Skindex-29, the mean score for the psoriasis group was almost 3 times higher than that of the control group (30 vs. 11). Significant differences were found in the HADS scores of both groups (12.7 vs. 9.0, P<.001). The mean HADS-A scores were 8.0 (4.78) for the psoriasis group compared with 5.7 (3.8) for the control group (P<.001). In the case of HADS-D, the scores were 4.7 (3.9) compared with 3.2 (3.1) (P<.004), respectively.ConclusionsOur findings indicate that it is necessary to assess the psychological state of patients with psoriasis, because psychological effects persist even in cases where the disease is almost totally controlled.

Graphical abstract

Tumoración frontal que aumenta de tamaño con maniobra de Valsalva

Publication date: Available online 30 June 2018
Source:Actas Dermo-Sifiliográficas
Author(s): A. Catalán Griffiths, F. Alfagueme Roldán, I. Salgüero Fernández, M.G. Ragusa

Lesiones de rascado… sin rascado

Publication date: Available online 30 June 2018
Source:Actas Dermo-Sifiliográficas
Author(s): J.L. Ramírez-Bellver, A. Alegre-Sánchez

Silicon improves salt tolerance of Glycyrrhiza uralensis Fisch. by ameliorating osmotic and oxidative stresses and improving phytohormonal balance

Abstract

Si has a beneficial effect on improving plant tolerance to salt stress. Nevertheless, the mechanisms of Si in mediating the stress responses are still poorly understood. Glycyrrhiza uralensis Fisch. (G. uralensis), a well-known medicinal plant, possesses vast therapeutic potentials. In the present study, a pot experiment was conducted to investigate the long-term effects of Si on growth and physiobiochemical characteristics in 2-year-old G. uralensis subjected to different levels of salinity. Si markedly affected G. uralensis growth in a salt concentration-dependent manner and had no effect on G. uralensis growth under 6 g/kg NaCl. However, it partly reversed the reduction effect induced by 9 g/kg NaCl. In addition, Si significantly increased the contents of soluble sugar and protein but deceased proline content and thus increased water relations; Si markedly increased the activities of SOD, peroxidase, and CAT and further resulted in decreased MDA content and membrane permeability. Moreover, Si altered the levels of phytohormones and their balances. With correlation analysis and principal component analysis (PCA), root biomass had a significant negative correlation with MDA and membrane permeability while a positive correlation with indole-3-acetic acid and GA₃. The PCA partitioned the total variance into three PCs contributing maximum (88.234%) to the total diversity among the salt stress with or without Si due to the study of various traits. In conclusion, Si exerts a beneficial property on salt-induced harmful effects in G. uralensis by relieving osmotic stress, improving water relations, and alleviating oxidative stress; thus, altering the levels and balance of phytohormones results in improved growth of salt-stressed G. uralensis.

Ecotoxicological evaluation of electrochemical oxidation for the treatment of sanitary landfill leachates

Abstract

In this study, the efficiency of electrochemical oxidation to treat a sanitary landfill leachate was evaluated by the reduction in physico-chemical parameters and in ecotoxicity. The acute toxicity of the sanitary landfill leachates, before and after treatment, was assessed with the model organism Daphnia magna. Electrochemical oxidation treatment was effective in the removal of organic load and ammonium nitrogen and in the reduction of metal ions concentrations. Furthermore, a reduction of 2.5-fold in the acute toxicity towards D. magna after 36 h of treatment was noticed. Nevertheless, the toxicity of the treated leachate is still very high, and further treatments are necessary in order to obtain a non-toxic effluent to this aquatic organism. Toxicity results were also compared with others described in the literature for different leachate treatments and test organisms.

The spatial distribution of phosphorus and their correlations in surface sediments and pore water in Lake Chaohu, China

Abstract

The study presents the spatial distribution of different forms of phosphorus in the sediments in Lake Chaohu, a large eutrophic Chinese lake, and their correlation with phosphorus content in pore water. The sediment and pore water samples were taken from 19 sampling sites. A sequential extraction was used to determine the contents of different forms of phosphorus in the sediments. The compositions and spatial distribution of different forms of phosphorus in the sediments and their correlation with orthophosphate and total phosphorus content in the pore water were studied. The following results were obtained: (1) the mean content of total phosphorus was 474.7 ± 20.5 mg/kg, with 390.8 ± 82.4 mg/kg for the eastern lake (N = 5), 469.0 ± 53.9 mg/kg for the western lake (N = 5), and 524.5 ± 185.3 mg/kg for rivers (N = 9); (2) the order of the proportions of the different forms of phosphorus was occluded phosphorus (Oc-P, 52.4%) > debris phosphorus (De-P, 14.2%) > auto-calcium-bound phosphorus (ACa-P, 13.5%) > aluminum-bound phosphorus (Al-P, 9.8%) > organic phosphorus (Or-P, 6.8%) > exchangeable phosphorus (Ex-P, 2.1%) > iron-bound phosphorus (Fe-P, 1.3%); (3) Ex-P, Al-P, and Fe-P had significantly positive correlations with orthophosphate and total phosphorus content in pore water, which showed that these forms of phosphorus were released more easily and had an indirect impact on lake eutrophication.

Association between prenatal nickel exposure and preterm low birth weight: possible effect of selenium

Abstract

There is a proposed link between prenatal nickel (Ni) exposure and preterm low birth weight (PLBW); however, this association remains unclear. Selenium (Se) may modify this relationship by protecting against Ni toxicity. Concentrations of Ni and Se were measured in urine samples collected from 408 pregnant women (102 PLBW cases and 306 matched controls) in China. Conditional logistic regression was utilized to explore the association between Ni levels and PLBW, as well as the effect modification by Se on this association. A significant association was observed between higher maternal urinary Ni levels and risk of PLBW [adjusted odds ratio (OR) = 2.80 (95% confidence interval (CI): 1.44, 5.44) for the highest tertile], and this association was more apparent among female infants than that among male infants. Further analyses showed that mothers with high urinary Ni and low urinary Se levels had a significantly increased risk for PLBW [adjusted OR = 2.87 (95% CI: 1.09, 7.56)] compared with the mothers with low urinary Ni and high urinary Se levels. Our study indicates that prenatal exposure to Ni was a risk factor for PLBW. Se might provide protection against the toxicity of Ni.

Impact of waste-derived organic and inorganic amendments on the mobility and bioavailability of arsenic and cadmium in alkaline and acid soils

Abstract

In agriculture, more and more frequently waste-derived amendments are applied to soil to improve physical and chemical properties. Nevertheless, in soils polluted by potentially toxic metal(loid)s, this agricultural practice may significantly affect the mobility and bioavailability of pollutants modifying the risks for biota and human health. This work was aimed to assess the influence of poultry manure, biochar and coal fly ash on the mobility and bioavailability of As and Cd spiked in two Australian soils with different pH and texture: Mount Gambier (MGB)-alkaline sandy clay loam and Kapuda (KPD)-acid loamy sand. After 4 weeks of incubation from spiking and another 4 weeks from amendment addition, the soils were analysed for pH and amounts of As and Cd in pore-water and following 1 M NH₄NO₃ extraction. Bioavailable amounts were assessed by plant uptake, using Zea mays L. as test crop. In the alkaline MGB soil, the availability of Cd was reduced, while that of As increased. An opposite behaviour was observed in the acid KPD soil. All amendments, when added to KPD soil, increased pH and consequently reduced the mobility of Cd and increased the mobility of As. In MGB, the amendment addition had an effect only on As mobility and bioavailability, which increased likely as a result of the increased competition for adsorption with DOC released by organic compounds. These trends were confirmed by the amounts of Cd and As uptaken by maize plants.

Varying concentrations of soil chromium (VI) for the exploration of tolerance thresholds and phytoremediation potential of the oregano ( Origanum vulgare )

Abstract

Varying concentrations of soil Cr(VI) were used in order to explore the tolerance thresholds and phytoremediation potential of Greek oregano (Origanum vulgare), in a pot experiment conducted outdoors. Oregano exhibited a rather exceptional capacity to bioaccumulate Cr in both the aerial part (up to 1200 mg of total Cr kg⁻¹ DM) and the root—reaching 4300 mg kg⁻¹ DM when grown in soil [Cr(VI)] of 150–200 mg kg⁻¹. Plant responses indicated that there was a threshold set at 100 mg Cr(VI) kg⁻¹ in the soil, above which the following results were recorded: (i) a restriction of Cr translocation from below- to above-ground plant part, (ii) a raise of the soil-to-root Cr transfer, and (iii) the Cr(III) evolution from the reduction of Cr(VI) was significantly decelerated in the root and accelerated in the aerial part. Soil [Cr] that surpassed this threshold challenged plant tolerance, resulting in a dose-dependent reduction of growth and antioxidant phenolics pool. Nonetheless, the significant Cr uptake capacity at plant level accounted for the considerably short remediation time (i.e., 29 years at soil [Cr(VI)] of 150 mg kg⁻¹) calculated according to these results. The overall performance of oregano indicated that phytoremediation would be feasible at sites with Cr contamination levels ranging within the above-defined thresholds.

The carotenoid Bixin found to exhibit the highest measured carotenoid oxidation potential to date consistent with its practical protective use in cosmetics, drugs and food

Publication date: Available online 30 June 2018
Source:Journal of Photochemistry and Photobiology B: Biology
Author(s): Sefadzi Tay-Agbozo, Shane Street, Lowell Kispert
The electrochemical oxidation potentials of cis bixin correspond to the production of the carotenoid radical cation, Car⁺ and dication Car⁺⁺. The oxidation is a two-electron process with oxidation potentials at ~0.94 and ~1.14 V vs SCE (reference to ferrocene at 0.528 V) in THF. These potentials are higher than that of symmetrical canthaxanthin at 0.775 V and 0.972 V and for β-carotene at 0.634 V and 0.605 V respectively. The second oxidation potential for canthaxanthin is higher by 0.20 V than the first. Similar difference is observed for bixin. In contrast, the second oxidation potential for β-carotene is lower by 30 mV than that of the first. Reduction potentials were found to occur at ~−0.69 and ~−1.22 V vs SCE. The lifetime of the radical cation of cis bixin, Car⁺, is short and decays rapidly at ambient temperature. The suggested scavenging ability of cis bixin towards reactive oxidative oxygen species is estimated to be 44. On the other hand, that of β-carotene, symmetrical canthaxanthin and the dicyano substituted carotenoid which exhibit oxidation potentials of 0.634 V, 0.775 V and 0.833 V vs SCE were measured to be 0.64, 1.96 and 23.60 respectively. The non-reversible electrochemical measurements suggest the tendency for bixin to react with trace amounts of reactive oxygen species (OH, O2⁻, OOH).

Graphical abstract

Photobiomodulation improved stereological parameters and sperm analysis factors in streptozotocin-induced type 1 diabetes mellitus

Publication date: Available online 30 June 2018
Source:Journal of Photochemistry and Photobiology B: Biology
Author(s): Sara Dadras, Mohammad-Amin Abdollahifar, Hamid Nazarian, Seyed Kamran Ghoreishi, Somyeh Fallahnezhad, Parvaneh Naserzadeh, Vahid Jajarmi, Sufan Chien, Mohammad Bayat
The aim of this study was to evaluate the effect of photobiomodulation (PBM) on testicular tissues and fresh sperm analysis factors in streptozotocin (STZ)-induced type one diabetes mellitus (T1DM) mice.T1DM was induced in 15 male Syrian mice by injection of 200 mg/kg STZ. After one month, mice were divided randomly into three groups, harboring 5 mice each: 1, control group; 2, first laser group (890 nm, 80 Hz, 0.03 J/cm²) and 3, second laser group (0.2 J/cm²). Then the mice were euthanized and testicles were dissected for stereological studies, and both epididymis and vas deferens were removed for fresh sperm analysis. Data were analyzed by statistical methods.A significant increase was observed in the Sertoli cell count in both PBM groups, compared to the control group. In addition, the second PBM group shows a significant increase in the Sertoli cell count, compared to the first PBM group. Both PBM groups show significant increase in the Leydig cell count, compared to the control group. There were significant increases of the length in the seminiferous tubules in both PBM groups, compared to the control group. In addition, the second PBM group showed a significant increase of the length in the seminiferous tubules, compared to the first PBM group. The second PBM group showed a significant increase in the sperm count, compared to the control, and first PBM groups. The first PBM group showed a significant increase in sperm count, compared to the control group. The sperm motility and count were significantly increased in the second PBM group, compared to the control and first PBM groups. The sperm motility was significantly increased in the first PBM group, compared to the control group.PBM with 0.2 J/cm² and 0.03 J/cm² energy densities significantly improved the stereological parameters and fresh sperm analysis factors, compared to the control group in STZ-induced T1DM in mice. Moreover, the PBM with 0.02 J/cm² energy density was statistically more effective, compared to the 0.03 J/cm².

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

Publication date: Available online 30 June 2018
Source:Journal of Plastic, Reconstructive & Aesthetic Surgery
Author(s): Gokce Yildiran, Osman Akdag, Inci Kara, Mehtap Karamese

The unexpected diversity of microbial communities associated with black corals revealed by high-throughput Illumina sequencing

Abstract

The microbes associated with black corals remain poorly studied. The present study is the first attempt to investigate microbial community structure in the black corals Antipathes ceylonensis and A. dichotoma from the South China Sea by using high-throughput Illumina sequencing. A total of 52 bacterial and 3 archaeal phyla were recovered in this study, suggesting the black corals harboured highly diverse microbial communities. Among the 55 microbial phyla, Proteobacteria, Firmicutes, Bacteroidetes, Chloroflexi, Acidobacteria and Actinobacteria dominated in the two black corals from the South China Sea. Although most of the microbial phyla recovered from the two black corals have been reported in previous studies on coral-associated microbes, eight bacterial phyla including Synergistetes, Thermi, AncK6, GNO2, NKB19, NC10, WWE1 and GAL15, and the archaeal phylum Parvarchaeota are reported for the first time from corals in this study, which expands our knowledge about the diversity of coral-associated microbes. The comparison of microbial communities in the different black coral species indicated that A. ceylonensis harboured few abundant bacterial genera such as Citrobacter and Pseudomonas, whereas a high diversity of rare bacterial genera (<1% abundance), such as Winogradskyella and Rubricoccus, was detected only in A. dichotoma. These results suggested that the microbial community in black corals exhibited species-specific variation.

Transport and metabolic engineering of the cell factory Corynebacterium glutamicum

Abstract

Corynebacterium glutamicum has a long and successful history in the biotechnological production of the amino acids l-glutamate and l-lysine. In the recent years, C. glutamicum has been engineered for the production of a broad catalog of value-added compounds including organic acids, vitamins, terpenoids and proteins. Moreover, this bacterium has been engineered to realize a flexible carbon source concept enabling product formation from various second generation feedstocks without competing uses in human and animal nutrition. In this review, we highlight transport engineering to improve product export and substrate uptake or to avoid loss of intermediates by excretion as well as the application of new metabolic engineering concepts for C. glutamicum strain development including the use of designed synthetic E. coli-C. glutamicum consortia. As examples, pathway extension of l-lysine and l-glutamate biosynthesis to produce derived value-added chemicals is described. The described examples of C. glutamicum strain engineering reflect strategies to cope with the increasing complexity of biotechnological processes that are required for successful applications in the bioeconomy.

Educating in antimicrobial resistance awareness: adaptation of the Small World Initiative program to service-learning

Abstract

The Small World Initiative (SWI) is a consolidated and successful education program rooted in the USA that tackles the antibiotic crisis by a crowdsourcing strategy. Based on active learning, it challenges young students to discover novel bioactive-producing microorganisms form environmental soil samples. Besides its pedagogical efficiency to impart Microbiology contents in academic curricula, SWI promotes vocations on research and development in Experimental Sciences and, at the same time, disseminates the antibiotic awareness guidelines of the World Health Organization (WHO). We have adapted the SWI program to the Spanish academic environment by a pioneering hierarchic strategy based on service-learning that involves two education levels (higher education and high school) with different degrees of responsibility. Along the academic year, 23 SWI teams each consisting of 3–7 undergraduate students led by one faculty member have coordinated off-campus programs in 22 local high schools, involving 597 secondary/high school students as researchers. Post-survey-based evaluation of the program reveals a satisfactory achievement of goals: acquiring scientific abilities and general or personal competencies by university students, as well as promoting academic decisions to inspire vocations for science- and technology-oriented degrees in younger students, and successfully communicating scientific culture in antimicrobial resistance to a young stratum of society.

Insights into the phylogeny of false-branching heterocytous cyanobacteria with the description of Scytonema pachmarhiense sp. nov. isolated from Pachmarhi Biosphere Reserve, India

Abstract

A false branching cyanobacterium (strain 10A1_PS) was isolated from a freshwater body of the Pachmarhi Biosphere Reserve, India and was characterized using the polyphasic approach. The detailed morphological examination indicated that the strain belonged to the complex genus Scytonema as it exhibited typical false branching character whose frequency increased with age of the culture. As the family Scytonemataceae and the genus Scytonema has been shown to be polyphyletic in many studies, we provide deep insights into the phylogenetic complexities within the family Scytonemataceae based on 16S rRNA gene phylogeny along with complete morphological, molecular and phylogenetic characterization of the strain. The 16S rRNA gene phylogenetic tree inferred by Bayesian Inference, Neighbor-Joining and Maximum Parsimony methods showed that the strain clustered within the Scytonema sensu stricto clade. The phylogenetic distance and the positioning of the strain clearly indicated it to be different from other Scytonema species. Further analysis using rbcL phylogeny, folded secondary structures of the 16S-23S ITS, p-distance and percentage pairwise similarity matrix clearly distinguished the strain 10A1_PS from the other closely related species. In accordance with the International Code of Nomenclature of Algae, Fungi and Plants we propose the name of the new species to be Scytonema pachmarhiense.

The influence of sigma factors and ribosomal recognition elements on heterologous expression of cyanobacterial gene clusters in Escherichia coli

Abstract

Cyanobacterial natural products offer new possibilities for drugs and lead compounds but many factors can inhibit the production of sufficient yields for pharmaceutical processes. While Escherichia coli and Streptomyces sp. have been used as heterologous expression hosts to produce cyanobacterial natural products, they have not met with resounding success largely due to their inability to recognize cyanobacterial promoter regions. Recent work has shown that the filamentous freshwater cyanobacterium Anabaena sp. strain PCC 7120 recognizes various cyanobacterial promoter regions and can produce lyngbyatoxin A from the native promoter. Introduction of Anabaena sigma factors into E. coli might allow the native transcriptional machinery to recognize cyanobacterial promoters. Here, all 12 Anabaena sigma factors were expressed in E. coli and subsets were found to initiate transcription from several cyanobacterial promoters based on transcriptional fusions to the chloramphenicol acetyltransferase (CAT) reporter. Expression of individual Anabaena sigma factors in E. coli did not result in lyngbyatoxin A production from its native cyanobacterial gene cluster, possibly hindered by deficiencies in recognition of cyanobacterial ribosomal binding sites by native E. coli translational machinery. This represents an important step toward engineering E. coli into a general heterologous expression host for cyanobacterial biosynthetic gene cluster expression.

An approach to the heating dynamics of residues from greenhouse-crop plant biomass originated by tomatoes ( Solanum lycopersicum , L.)

Abstract

The most representative of greenhouse-crop plant biomass residues of tomatoes (Solanum lycopersicum L.) were selected for this study by using X-ray fluorescence spectrometry (XRF) and X-ray powder diffraction (XRD). The heating dynamics in air in the 600–1150 °C range of these residues for the production of renewable energy and the resultant ashes have been investigated. A total of 11 elements were determined by XRF in the biomass ashes and some minor elements. The content of alkaline elements and chlorides decreased as increasing heating temperature and disappeared at 1150 °C. Alkaline salts, NaCl and KCl, were volatilized by heating since 800 °C. The total contents of S and P in the biomass ashes were associated to CaSO₄, and a complex phosphate identified by XRD. CaCO₃ present at 600 °C was decomposed to CaO with disappearance at 1000 °C. By heating, new silicates were formed by solid-state reactions in the biomass residue. The minor elements have been found in a relative proportion lower than 0.9 wt.% and they characterized the obtained ashes, with potential use as micronutrients.

Harmonization of Respiratory Data From Nine US Population-Based Cohorts: The NHLBI Pooled Cohorts Study

Abstract

Chronic lower respiratory diseases (CLRD) are the fourth leading cause-of-death in the US. To support investigations into CLRD risk determinants and new approaches to primary prevention, we aimed to harmonize and pool respiratory data from US general population-based cohorts. Data were obtained from prospective cohorts that performed pre-bronchodilator spirometry, which was harmonized following 2005 ATS/ERS standards. In cohorts conducting follow-up for non-cardiovascular events, CLRD events were defined as hospitalizations/deaths adjudicated as CLRD-related or assigned relevant administrative codes. Coding and variable names were applied uniformly. The pooled sample included 65,251 adults in nine cohorts followed-up for CLRD-related mortality over 653,380 person-years from 1983-2016. Average baseline age was 52 years; 56% were female; 49% were never-smokers; and racial/ethnic composition was 44% White, 22% Black, 28% Hispanic/Latino, and 5% American-Indians. Over 96% had complete data on smoking, clinical CLRD diagnoses, and dyspnea. After excluding invalid spirometry exams (13%), there were 105,696 valid exams (median 2 per participant). Of 29,351 participants followed-up for CLRD hospitalizations, median follow-up was 14 years; only 5% were lost-to-follow-up at 10 years. Hence, the NHLBI Pooled Cohorts Study provides a harmonization standard applied to a large, US population-based sample that may be used to advance epidemiologic research on CLRD.

¿Qué tipo de guantes debemos utilizar en la cirugía dermatológica? Recomendaciones sobre los guantes a emplear

Publication date: Available online 29 June 2018
Source:Actas Dermo-Sifiliográficas
Author(s): X. Bosch-Amate, D. Morgado-Carrasco, J. Riera-Monroig, J. Ferrando

Removal of bisphenol A by Fe-impregnated activated carbons

Abstract

A commercial wood-based activated carbon and the oxidized counterpart were impregnated with iron. The two Fe-impregnated carbons were prepared and characterized for their iron content, textural characteristics, surface chemistry, and their performance for bisphenol A adsorption. Batch adsorption experiments were conducted to study the effect of pH, ionic strength, kinetics, and thermodynamic equilibrium. Equilibrium adsorption data were described by both Langmuir and Freundlich isotherms. The iron impregnated activated carbon and the oxidized impregnated activated carbon presented maximum adsorption capacities of 785.65 and 469.78 mg/g, respectively, while adsorption followed second-order rate kinetics for both impregnated carbons. According to the thermodynamic parameters (ΔΗο, ΔSo, ΔGo), the adsorption is a spontaneous, exothermic, and physical process. Fenton-driven experiments conducted at different molar ratios of [H₂O₂]/[BPA] showed efficient degradation of BPA in spent Fe-impregnated carbons up to 82–95%, with traces of hydroxylated products.

S olubilization of insoluble zinc compounds by zinc solubilizing bacteria (ZSB) and optimization of their growth conditions

Abstract

In this research, the optimum growth conditions for two zinc solubilizing bacteria (ZSB) have been studied for their potential application as bioinoculants to overcome Zn unavailability in soils. For this purpose, a laboratory-scale experiment was carried out to evaluate the zinc solubilizing ability of 80 plant growth promoting bacteria (PGPB) strains isolated from the rhizosphere of barley and tomato plants. To select effective ZSB, isolates were evaluated on Tris-mineral medium supplemented separately with zinc oxide, zinc carbonate, and zinc phosphate at a concentration of 0.1%. Two strains (Agrobacterium tumefaciens and Rhizobium sp.) were selected, based on a clear halo zone around their colonies in the solid medium supplemented with zinc oxide after 10 days of incubation at 29 °C. Results of solubilization at different pH values showed that these strains had solubilization activity in the range of pH 8–10 while no solubilization was observed at pH 6 and 7. The maximum Zn solubilization values were noted at pH 9: 51.4 mg L⁻¹ (Agrobacterium tumefaciens) and 72.1 mg L⁻¹ (Rhizobium sp). According to findings, bacterial growth was affected by different NaCl concentrations under in vitro condition. The salt concentration required for 50% inhibition of absorbance was 2.11 and 2.27% NaCl for Agrobacterium tumefaciens and Rhizobium sp., respectively. The maximum bacterial growth was observed at about 0.8% NaCl concentration.

Evaluating the effect of biochar addition on the anaerobic digestion of swine manure: application of Py-GC/MS

Abstract

The anaerobic digestion process of swine manure was studied when char was used as supplement for improving performance. The use of pyrolysis-gas chromatography/mass spectrometry (Py-GC/MS) was proposed for assessing the organic matter degradation. The assessment on biogas production was carried out using samples of swine manure (SM) supplemented with char in one case and pre-treated by microwave irradiation in the other. This experimental set-up allows for the comparison of the biological degradation observed under these two different configurations and therefore aids in understanding the effect of char particles on the process. Results showed similar performance for both systems, with an average improvement of 39% being obtained in methane production when compared to the single digestion of SM. The analysis of digestate samples by Fourier transform infrared (FTIR) spectroscopy and Py-GC/MS showed improved degradation of proteins, with the Py-GC/MS technique also capable of identifying an increase in microbial-derived material when char was added, therefore highlighting the relevant role of carbon conductive particles on biological systems. Py-GC/MS along with the use of FTIR spectroscopy has proven to be useful tools when evaluating anaerobic digestion.

A new concept for risk analysis relating to the degradation of water reservoirs

Abstract

This paper presents a proposal for a procedure by which to analyse the risk of reservoirs being degraded. The body of water assessed for its susceptibility to degradation in line with the proposed procedure is Myczkowce Reservoir, SE Poland. This reservoir has a maximum capacity of ten million m³ and helps provide hydropower, by serving as a surge tank located above the main Solina Reservoir. On the basis of an assessment of its morphometric and hydrological parameters, Myczkowce Reservoir was assigned to the low-resilience category where risk of degradation was concerned. The primary factors responsible for that are limited capacity in relation to shoreline length, a lack of thermal stratification, and a high value for the Schindler index. These and other environmental parameters provided for Myczkowce's assignment to the category of susceptible to the impact of matter supplied by its catchment, with this reflecting the instantaneous nature of the basin, high values for the Ohle coefficient, average catchment slope, and the lack of a septic system. The designated risk level supported Myczkowce's assignment to a category characterised by an "unacceptable" risk of degradation. The proposed method taking two parameters (resilience and susceptibility) into account represents the first universal method for assessing reservoirs without reference to risks such as drought, flooding, or lack of water supply for human consumption. The risk depends only on the reservoir and catchment parameters.