bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of lysyl oxidase like 1 in regulation of postpartum connective tissue metabolism in the mouse vagina†
Authors: Borazjani Ali , Couri Bruna M , Kuang Mei , Balog Brian M , Damaser Margot S
Published: August 2019

Pelvic organ prolapse (POP) in lysyl oxidase like-1 knockout (Loxl1 KO) mice occurs primarily in parous mice and is rare in nulliparous mice. We determined the effect of Loxl1 deficiency on postpartum regulation of connective tissue metabolism genes and degradative enzyme activity in the vagina at 20 days gestation or 4 h, 48 h, 7 days, 15 days, 25 days, 7 weeks, or 12 weeks postpartum. Nulliparous Loxl1 KO and wildtype (WT) mice aged 11, 18, or 23 weeks were controls. Gene expression and enzyme activity were assessed using real-time quantitative reverse transcription PCR and fluorescein conjugated gelatin zymography, respectively. Parity, but not aging, had a significant influence on gene expression both with time postpartum and between KO and WT mice. Mmp2, Timp1, Timp2, Timp3, Timp4, Col1a1, Col3a1, Acta2, and Bmp1 were differentially expressed between KO and WT mice. Correlational analysis of gene-gene pairs revealed 10 significant differences between parous KO and WT groups, 5 of which were due to lack of co-expression of Bmp1 in KO mice. The overall enzyme activity that could be attributed to MMPs was significantly higher in WT compared to KO mice both 25 days and 12 weeks postpartum, and MMP activity was significantly lower 15 days and 25 days postpartum compared to KO nulliparous controls, but not WT. These findings suggest that Loxl1 deficiency combined with parity has a significant impact on postpartum regulation of connective tissue metabolism, particularly as it relates to co-expression of Bmp1 and altered proteolytic activity.
Fibrinogen in equine pregnancy as a mediator of cell adhesion, an epigenetic and functional investigation
Authors: Grant Danielle M , Macedo Alysson , Toms Derek , Klein Claudia
Published: August 2019

Preimplantation equine embryos synthesize and secrete fibrinogen, which is a peculiar finding as fibrinogen synthesis almost exclusively occurs in the liver. This study investigated the hypothesis that conceptus-derived fibrinogen mediates cell adhesion during fixation. On day 21 of pregnancy, five integrin subunits, including ITGA5, ITGB1, ITGAV, and ITGB1, displayed significantly higher transcript abundance than on day 16 of pregnancy. Endometrial epithelial cells adhered to fibrinogen in an integrin-dependent manner in an in vitro cell adhesion assay. Bilaminar trophoblast and allantochorion expressed fibrinogen transcript, indicating that fibrinogen expression persists past fixation. Preimplantation-phase endometrium, conceptuses, and microcotyledonary tissue expressed components of the clotting cascade regulating fibrin homeostasis, leaving open the possibility that fibrinogen is converted to fibrin. Fibrinogen is likely to have functions beyond mediating cell adhesion, such trapping growth factors and triggering signaling cascades, and has remarkable parallels to the expression of fibrinogen by some tumors. The deposition of fibrinogen within tumor stroma is characteristic of breast carcinoma, and tumor-derived fibrinogen has been implicated in the metastatic potential of circulating tumor cells. DNA methylation of the fibrinogen locus in equine conceptuses was examined in comparison to liver and endometrium, and across the full gene cluster, was significantly higher for endometrium than liver and conceptus. DNA methylation of regulatory regions did not differ between liver and conceptus, and was significantly lower than in endometrium. These results, therefore, support the hypothesis of DNA methylation being a regulator of fibrinogen expression in the conceptus.
The effects of income distribution and fiscal policy on aggregate demand, investment and the budget balance: the case of Europe
Authors: Obst Thomas , Onaran Özlem , Nikolaidi Maria
Published: August 2019

This paper develops a multi-country post-Kaleckian model that incorporates the role of the government. One key novelty of the model is that it integrates cross-country effects of changes in both income distribution and fiscal policy. The model is used to estimate econometrically the effects of income distribution and fiscal policy on the components of aggregate demand and the budget balance in EU15 countries. The results show that a simultaneous increase in the wage share in all EU15 countries would increase demand and the primary budget balance in all countries. A simultaneous increase in government spending turns out to boost economic activity in all the EU15 countries, indicating the positive economic effects of expansionary fiscal policy. Moreover, a progressive tax policy that would be implemented simultaneously at the EU level would lead to an increase in output in all countries.
Staged surgical intervention to treat dysphagia caused by Kommerell’s diverticulum
Authors: Hashimoto Makoto , Nishida Hidefumi , Milner Ross , Ota Takeyoshi
Published: August 2019

Kommerell’s diverticulum is a rare congenital vascular anomaly. Dysphagia is one indication for surgical intervention. We report on 4 consecutive patients who presented with dysphagia caused by Kommerell’s diverticulum and underwent staged surgical treatment. The key to surgical treatment for such patients is to remove the vascular structure completely from the vicinity of the oesophagus.
Hippocampus Mediates the Effect of Emotional Support on Cognitive Function in Older Adults
Authors: Kim Grace Eun , Han Ji Won , Kim Tae Hui , Suh Seung Wan , Bae Jong Bin , Kim Jae Hyoung , Kim Ki Woong
Published: August 2019

Background

Despite strong evidence that emotional support has a protective effect on cognitive decline, the neural basis for how an individual’s emotional support is associated with cognition is unknown. We investigated if the hippocampus mediates the relationship between emotional support and cognition in older adults.

Method

Four hundred and ten nondemented Korean older adults were classified into two groups according to their Medical Outcomes Study–Social Support Survey emotional support scores: the poor emotional support (score ≤ 25th percentile of entire sample) and normal emotional support (score > 25th percentile of entire sample) groups. Cognitive function was assessed using the Verbal Memory Score and Consortium to Establish a Registry for Alzheimer’s Disease Assessment Packet Neuropsychological Assessment Battery total score (CERAD-TS). Left and right hippocampal volume were obtained using 3T T1-weighted magnetic resonance images. Mediation analyses were conducted.

Results

In the association of emotional support with Verbal Memory Score, left hippocampal volume played a mediating role (indirect effect = 0.40, SE = 0.21, bias-corrected 95% confidence interval = 0.04, 0.86). In the association of emotional support with CERAD-TS, both left (indirect effect = 0.82, SE = 0.45, bias-corrected 95% confidence interval = 0.09, 1.83) and right (indirect effect = 0.51, SE = 0.32, bias-corrected 95% confidence interval = 0.02, 1.24) HPVs played mediating roles.

Conclusions

The hippocampus may mediate the association between emotional support and cognition. Higher levels of emotional support may be associated with better verbal memory and global cognition via larger HPV.
Hurry Up and Get Out of the Way! Exploring the Limits of Muscle-Based Latch Systems for Power Amplification
Authors: Abbott Emily M , Nezwek Teron , Schmitt Daniel , Sawicki Gregory S
Published: August 2019

Animals can amplify the mechanical power output of their muscles as they jump to escape predators or strike to capture prey. One mechanism for amplification involves muscle–tendon unit (MT) systems in which a spring element (series elastic element [SEE]) is pre-stretched while held in place by a “latch” that prevents immediate transmission of muscle (or contractile element, CE) power to the load. In principle, this storage phase is followed by a triggered release of the latch, and elastic energy released from the SEE enables power amplification (PRATIO=PLOAD/PCE,max >1.0), whereby the peak power delivered from MT to the load exceeds the maximum power limit of the CE in isolation. Latches enable power amplification by increasing the muscle work generated during storage and reducing the duration over which that stored energy is released to power a movement. Previously described biological “latches” include: skeletal levers, anatomical triggers, accessory appendages, and even antagonist muscles. In fact, many species that rely on high-powered movements also have a large number of muscles arranged in antagonist pairs. Here, we examine whether a decaying antagonist force (e.g., from a muscle) could be useful as an active latch to achieve controlled energy transmission and modulate peak output power. We developed a computer model of a frog hindlimb driven by a compliant MT. We simulated MT power generated against an inertial load in the presence of an antagonist force “latch” (AFL) with relaxation time varying from very fast (10 ms) to very slow (1000 ms) to mirror physiological ranges of antagonist muscle. The fastest AFL produced power amplification (PRATIO=5.0) while the slowest AFL produced power attenuation (PRATIO=0.43). Notably, AFLs with relaxation times shorter than ∼300 ms also yielded greater power amplification (PRATIO>1.20) than the system driving the same inertial load using only an agonist MT without any AFL. Thus, animals that utilize a sufficiently fast relaxing AFL ought to be capable of achieving greater power output than systems confined to a single agonist MT tuned for maximum PRATIO against the same load.
Coordinated control strategy of DC microgrid with hybrid energy storage system to smooth power output fluctuation
Authors: Wu Tiezhou , Ye Fanchao , Su Yuehong , Wang Yubo , Riffat Saffa
Published: August 2019

As the fossil energy crisis and environmental pollution become more and more serious, clean renewable energy becomes the inevitable choice of energy structure adjustment. The power system planning and operation has been greatly influenced by the instability of the power output of distributed renewable energy systems such as solar energy and wind energy. The hybrid energy storage system composed of accumulator and supercapacitor can solve the above problems. Based on the analysis of the energy storage requirements for the stable operation of the DC microgrid, battery–supercapacitor cascade approach is adopted to form hybrid energy storage system, in a single hybrid energy storage subsystem for battery and supercapacitor and in the microgrid system of different hybrid energy storage subsystem, respectively, and puts forward the corresponding power allocation method to realize the smooth control of the battery current, to reduce the battery charge and discharge times, to prolong the service life of battery and to improve the running stability of the microgrid.
In vitro antimicrobial combination testing of and evolution of resistance to the first-in-class spiropyrimidinetrione zoliflodacin combined with six therapeutically relevant antimicrobials for Neisseria gonorrhoeae
Authors: Foerster Sunniva , Drusano George , Golparian Daniel , Neely Michael , Piddock Laura J V , Alirol Emilie , Unemo Magnus
Published: August 2019

Objectives

Resistance in Neisseria gonorrhoeae to all gonorrhoea therapeutic antimicrobials has emerged. Novel therapeutic antimicrobials are imperative and the first-in-class spiropyrimidinetrione zoliflodacin appears promising. Zoliflodacin could be introduced in dual antimicrobial therapies to prevent the emergence and/or spread of resistance. We investigated the in vitro activity of and selection of resistance to zoliflodacin alone and in combination with six gonorrhoea therapeutic antimicrobials against N. gonorrhoeae.

Methods

The international gonococcal reference strains WHO F (WT) and WHO O, WHO V and WHO X (strains with different AMR profiles) were examined. Zoliflodacin was evaluated alone or combined with ceftriaxone, cefixime, spectinomycin, gentamicin, tetracycline, cethromycin or sitafloxacin in chequerboard assays, time–kill curve analysis and selection-of-resistance studies.

Results

Zoliflodacin alone or in combination with all six antimicrobials showed rapid growth inhibition against all examined strains. The time–kill curve analysis indicated that tetracycline or cethromycin combined with zoliflodacin can significantly decrease the zoliflodacin kill rate in vitro. The frequency of selected zoliflodacin-resistance mutations was low when evaluated as a single agent and further reduced for all antimicrobial combinations. All resistant mutants contained the GyrB mutations D429N, K450T or K450N, resulting in zoliflodacin MICs of 0.5–4 mg/L.

Conclusions

Zoliflodacin, alone or in combination with sexually transmitted infection therapeutic antimicrobials, rapidly kills gonococci with infrequent resistance emergence. Zoliflodacin remains promising for gonorrhoea oral monotherapy and as part of dual antimicrobial therapy with low resistance emergence potential. A Phase III trial evaluating efficacy and safety of zoliflodacin for uncomplicated gonorrhoea treatment is planned in 2019.
Lack of KBTBD4 Mutations in Molecularly Classified Brazilian Medulloblastomas
Authors: Leal Letícia Ferro , Cavagna Rodrigo de Oliveira , Campanella Nathalia Cristina , Mançano Bruna , Almeida Gisele Caravina , Matsushita Marcus , Almeida Junior Carlos Roberto , Saggioro Fabiano , Stavale João Norberto , Malheiros Suzana M F , Lima Matheus , Hajj Glaucia N M , Neder Luciano , Reis Rui Manuel
Published: August 2019

Medulloblastoma is the most frequent malignant brain tumor in children, representing 20% of all childhood brain tumors. Currently, medulloblastomas are molecularly classified in 4 subgroups that are associated with distinctive clinicopathological features. KBTBD4 mutations were recently described in a subset of MBGRP3 and MBGRP4 medulloblastomas subgroups. However, no other studies reported KBTBD4 mutations in medulloblastomas. Thus, our aim was to investigate KBTBD4 mutations in a Brazilian series of medulloblastoma. We evaluated 128 medulloblastoma patients molecularly classified from 4 Brazilian reference centers. DNA from formalin-fixed, paraffin-embedded samples was screened for KBTBD4 hotspot mutations by Sanger sequencing. Most of the patients were male, average age was 16.5 years old and average overall survival was 55.9 months. The predominant histological subtype was the classic subtype, followed by nodular/desmoplastic, and the predominant medulloblastoma molecular subtype was the MBSHH subgroup (46%), followed by MBGRP3 and MBGRP4 (19%/each), and MBWNT (16%). Among the 128 samples, 111 were successfully sequenced. No KBTBD4 mutations were identified in 111 samples. Our findings suggest that KBTBD4 mutations are uncommon in Brazilian MBGRP3 and MBGRP4 medulloblastomas subgroups. Further studies in a larger series of MBGRP3 and MBGRP4 medulloblastomas are warranted to better assess role of KBTBD4 mutations.
MicroRNA Alteration in Developing Rat Oligodendrocyte Precursor Cells Induced by Hypoxia-Ischemia
Authors: Su Xiaojuan , Xiao Dongqiong , Huang Lingyi , Li Shiping , Ying Junjie , Tong Yu , Ye Qianghua , Mu Dezhi , Qu Yi
Published: August 2019

microRNAs (miRNAs) are involved in the pathogenesis of white matter injury (WMI). However, their roles in developing rat brains under hypoxia-ischemia (HI) insult remain unknown. Here, we examined the expression profiles of miRNAs in oligodendrocyte precursor cells using microarray analysis. We identified 162 miRNAs and only 6 were differentially regulated in HI compared with sham. Next, we used these 6 miRNAs and 525 extensively changed coding genes (fold change absolute: FC(abs) ≥2, p < 0.05) to establish the coexpression network, the result revealed that only 3 miRNAs (miR-142-3p, miR-466b-5p, and miR-146a-5p) have differentially expressed targeted mRNAs. RT-PCR analysis showed that the expression of the miRNAs was consistent with the microarray analysis. Further gene ontology and KEGG pathway analysis of the targets of these 3 miRNAs indicated that they were largely associated with neural activity. Furthermore, we found that 2 of the 3 miRNAs, miR-142-3p, and miR-466b-5p, have the same target gene, Capn6, an antiapoptotic gene that is tightly regulated in the pathogenesis of neurological diseases. Collectively, we have shown that a number of miRNAs change in oligodendrocyte precursor cells in response to HI insult in developing brains, and miR-142-3p/miR-466b-5p/Capn6 pathway might affect the pathogenesis of WMI, providing us new clues for the diagnosis and therapy for WMI.
Effects of long-wavelength fluctuations in large galaxy surveys
Authors: Klypin Anatoly , Prada Francisco
Published: August 2019

In order to capture as much information as possible large galaxies surveys have been increasing their volume and redshift depth. To face this challenge theory has responded by making cosmological simulations of huge computational volumes with equally increasing numbers of dark matter particles and supercomputing resources. Thus, it is taken for granted that the ideal situation is when a single computational box encompasses the whole volume of the observational survey, e.g. $\sim 50\, h^{-3}\,{\rm Gpc}^3$ for the DESI and Euclid surveys. Here we study the effects of missing long waves in a finite volume using several relevant statistics: the abundance of dark matter haloes, the probability distribution function (PDF), the correlation function and power spectrum, and covariance matrices. Finite volume effects can substantially modify the results if the computational volumes are less than $\sim (500\mbox{$\, h^{-1}$Mpc})^3$. However, the effects become extremely small and practically can be ignored when the box size exceeds ∼1 Gpc3. We find that the average power spectra of dark matter fluctuations show remarkable lack of dependence on the computational box size with less than 0.1 per cent differences between $1$ and $4\mbox{$\, h^{-1}\,$Gpc}$ boxes. No measurable differences are expected for the halo mass functions for these volumes. The covariance matrices are scaled trivially with volume, and small corrections due to supersample modes can be added. We conclude that there is no need to make those extremely large simulations when a box size of $1-1.5\mbox{$\, h^{-1}$Gpc}$ is sufficient to fulfil most of the survey science requirements.
WHO grade has no prognostic value in the pediatric high-grade glioma included in the HERBY trial
Authors: Varlet Pascale , Le Teuff Gwénaël , Le Deley Marie-Cécile , Giangaspero Felice , Haberler Christine , Jacques Thomas S , Figarella-Branger Dominique , Pietsch Torsten , Andreiuolo Felipe , Deroulers Christophe , Jaspan Tim , Jones Chris , Grill Jacques
Published: August 2019

Background

The World Health Organization (WHO) adult glioma grading system is questionable in pediatric high-grade gliomas (pHGGs), which are biologically distinct from adult HGGs. We took advantage of the neuropathological review data obtained during one of the largest prospective randomized pHGG trials, namely HERBY (NCT01390948), to address this issue in children with newly diagnosed non-brainstem HGG.

Methods

HGG diagnosis was confirmed by pre-randomization, real-time central pathology review using WHO 2007 criteria, followed by a consensus review blinded to clinical factors and outcomes. We evaluated association between WHO 2007 grade and other clinical/radiological/biological characteristics and the prognostic value of WHO 2007 grade, midline location, and selected biomarkers (Ki-67 index/Olig2/CD34/EGFR/p53/H3F3A K27M mutation) on overall survival.

Results

Real-time central neuropathological review was feasible in a multicenter study, with a mean time of 2.4 days, and led to the rejection of HGG diagnosis in 20 of 163 cases (12.3%). The different grading criteria and resulting WHO grade were not significantly associated with overall survival in the entire population (n = 118) or in midline and non-midline subgroups. H3F3A K27M mutation was significantly associated with poor outcome. No significant prognostic value was observed for grade, even after regrading H3F3A K27M-mutated midline glioma as grade IV (WHO 2016). Midline location and a high Ki-67 index (≥20%) were associated with poor outcome (P = 0.004 and P = 0.04, respectively). A 10% increase in Ki-67 index was associated with a hazard ratio of 1.53 (95% CI: 1.27–1.83; P < 0.0001).

Conclusion

Our findings suggest that WHO grade III versus IV has no prognostic value in pediatric HGG.
BSCI-06. FREQUENCY OF BRAIN METASTASIS FROM BREAST AND LUNG CANCER IN THE UNITED STATES -- A POPULATION-BASED ASSESSMENT
Authors: Ostrom Quinn , Ascha Mustafa , Kruchko Carol , Barnholtz-Sloan Jill
Published: August 2019

BACKGROUND: Brain metastases (BM) are the most common central nervous system tumor in the United States and occur with increasingly frequency due to improved screening and therapeutics leading to improved survival. Current estimates of frequency of BM vary significantly by cancer site and are typically not population-based. Population-based estimates of incidence have recently become possible due to collection of data on BM identified at diagnosis (“synchronous” BM, SBM). BM may occur at any point after cancer diagnosis. We report our recent population-based estimates of SBM and period incidence of BM (PBM) from breast (BC) and lung cancer (LC). METHODS: Data from Surveillance, Epidemiology, and End Results (SEER, 2010–2016 diagnoses) were used to estimate SBM and linked data from SEER-Medicare (2008–2012 diagnoses for individuals 65+, with 2007–2014 claims) were used to estimate PBM, for BC and LC overall and by BC and LC subtypes. RESULTS: Within the SEER data, 10.9% of LC cases presented with SBM (15.5% in small cell LC [SCLC], and 10.8% in non-small cell LC [NSCLC]); 0.4% of BC cases presented with SBM, 0.7% in triple negative (TNBC), 0.8% for HER2+, and 0.2% for ER+\PR+\HER2-. Within the SEER-Medicare data, 13.5% of LC overall had LBM with 23.1% for SCLC and 15.3% for NSCLC; 1.8% of BC overall had LBM with 4.2% in triple negative (TNBC), 3.1% for HER2+, and 1.1% for ER+\PR+\HER2. CONCLUSION: Frequency of synchronous and period BM varies by originating site as well as subtype. The new SBM variable in SEER allows for estimation of this important statistic, while the SEER-Medicare linked data allows for estimation of PBM, both on a population-level for the US population. These estimates are useful to clinical practice and critical for estimating morbidity and mortality due to BM.
BSCI-12. COMPREHENSIVE GENOMIC ANALYSIS OF BRAIN METASTASES FROM MULTIPLE CANCER TYPES
Authors: Fukumura Kazutaka , Mao Xizeng , Song Xingzhi , Fischer Grant , Yang Jie , Sulman Erik , Davies Michael , Zhang Jianhua , Huse Jason
Published: August 2019

PURPOSE: Brain metastases occur in approximately 8–10% of patients with cancer, and the incidence has increased over the past decades. The most common primary tumors responsible for brain metastases are lung cancer, melanoma, renal cell carcinoma (RCC), breast cancer and colorectal cancer. The precise mechanisms by which genomic and transcriptional abnormalities drive the formation of brain metastases remain unclear. Here, we conducted comprehensive genomic and transcriptional analysis with paired primary tumor tissue (or extracranial metastasis tissue) and brain metastasis tissue using whole-exome sequencing (WES), mRNA-Seq and global methylation profiling. METHODS: Frozen, paired brain metastasis tissue and primary tumor tissue (or extracranial metastasis tissue) and white blood cells were acquired from RCC (n=12), breast cancer (n=17), lung cancer (n=15) and melanoma (n=14) patients, followed by extraction of DNA and RNA. WES and mRNA-Seq were performed on the Illumina HiSeq4000 platform. For methylation profiling, DNA was analyzed using Illumina Infinium MethylationEPIC Beadchip arrays. RESULTS: Somatic mutations or methylation of VHL gene were identified in 81.8% of RCC patients. Gene Set Enrichment Analysis revealed significant enrichment for hypoxia pathway transcripts in RCC brain metastases relative to primary tumors. The most common alterations in breast and lung cancer patients were TP53 mutations with frequencies of 50.0% and 73.3%, followed by ERBB2 alterations (43.8%) in breast cancer patients and mutually exclusive alterations of EGFR (33.3%) and KRAS (26.7%) in lung cancer patients. Mutually exclusive alterations of NRAS (42.9%) and BRAF (42.9%) were also observed in melanoma patients. Gene expression and epigenetic analysis revealed characteristics of brain metastases depending on primary cancer types. CONCLUSIONS: Comprehensive genomic analysis of brain metastases from four different cancer types revealed that brain metastasis tissues have unique genomic, transcriptional and epigenetic profiles according to histopathology groups. Therefore, the therapeutic strategies should be designed based at least in part on tumor histiogenesis.
BSCI-14. SYNTHETIC METASTATIC BRAIN DISEASE MRI IMAGES CREATED USING A GENERATIVE ADVERSARY NETWORK TO OVERCOME DEEP MACHINE LEARNING CHALLENGES IN HEALTHCARE
Authors: Dai Zhenzhen , Snyder James , Wen Ning
Published: August 2019

Deep Machine Learning (DML) in commercial applications such as recognizing animal species in photographs occurred through analyzing large volumes of public data. To achieve similar success in brain tumor imaging, additional factors must be addressed such as the need to follow strict regulatory protocols, work with limited datasets, and protect patient privacy. Generative adversary network (GAN) restricted to intracranial disease is one possibility to overcome these challenges and enable training on small annotated datasets to synthesize new samples. Large fabricated brain metastases (BM) training datasets derived from patient MRI using GAN models may enable DML of BM MRI studies. METHOD: We randomly selected 82 glioma patient imaging studies from the MICCAI BraTS 2018 Challenge1. All patients underwent contouring of GD-enhancing tumor (C+), peritumoral T2 (pT2), necrotic and non-enhancing tumor core (NCR/NET). Images are co-registered to the anatomical template and skull-stripped. Our network consists of a GAN and a discriminative network. The generative model works to synthesize images from labels. Labels comprise the normal brain mask as well as the contoured C+, pT2 and NCR/NET. Normal brain mask is extracted from threshold segmentation on T2-weighted image (T2WI). A discriminative network compares the difference between synthetic and real patient image in both pixel and perceptual difference. The generative model is trained to minimize the difference from the discriminative network. This method was refined in the glioblastoma dataset and applied to BM MRI. RESULTS: Figure 1. Synthetic BM MRI images derived from human brain MRI studies using the GAN model with four modalities (T2, T2 FLAIR, T1 contrasted image, and T1 non-contrasted Image). CONCLUSION: Training DML in BM disease using GAN MRI models may overcome limitations in applying DML to healthcare, namely volume of high-quality data and patient privacy. GAN based modeling for BM needs to be further refined and validated.
BSCI-19. EFFECT OF STEREOTACTIC RADIOSURGERY ON NON-SMALL CELL LUNG CANCER BRAIN METASTASIS: CORRELATIVE RADIOBIOLOGIC ANALYSIS FROM PHASE-II CLINICAL TRIAL NCT03398694
Authors: Huff Wei , Shireman Jack , Monaco Gina , Agrawal Namita , Park Cheol , Saathoff Miranda , Henriquez Mario , Watson Gordon , Ahmed Atique , Dey Mahua
Published: August 2019

BACKGROUND: Stereotactic radiosurgery (SRS) is an increasingly common modality used with or without surgery for brain metastases (BM). However, biological effect of SRS to tumors in vivois not known. METHODS: Patients were treated with SRS prior to surgery as per the clinical trial protocol. The resected tumor was divided into two groups: ‘center’ and ‘periphery’ with respect to the center of SRS treatment with periphery within 50%-isodose-line. Tissue was analyzed by whole exome sequencing (WES) and compared between the two groups as well as to non-radiated control tissues. RESULTS: All sequenced samples contained greater than 95% clean reads with an average read density of 100 base pairs and mapping efficiency of >99%. Preliminary analysis focused on SNP and Indel detection. In pooled groups with n=7 replicates there was no statistically significant differences in total mutation burden in either SNP’s or Indels compared between controls and both treatment locations. Delving deeper intronic, frameshift, missense, and nonsense mutations all also showed insignificant changes between controls and center or peripheral tumor locations (p >0.5, p >0.1, p >0.4, p >0.3 respectively) hinting that at a pooled biological level there are not significant mutational burdens between treatment locations. However, at the individual level, matched comparison of SRS samples originating from the center or periphery of the same tumor showed total mutational burden differences. 6 out of 7 (86%) patients showed decreased total number of indels in peripheral vs. center and 5 out of 7 (71%) patients showed decreased number of SNP’s in peripheral vs. center locations. CONCLUSION: Ultimately, these data demonstrate the power of matched patient controls over bulk analysis in order to elucidate smaller but possibly biologically meaningful effects, and point to a possible location dependency in treatment associated mutation burden within a single patient and single tumor that may be masked at a population level.
BSCI-22. IDENTIFICATION OF ACTIONABLE TYROSINE KINASE-REGULATED NETWORKS REQUIRED FOR LUNG AND BREAST CANCER BRAIN METASTASIS
Authors: Pendergast Ann Marie , McKernan Courtney , Hoj Jacob , Anders Carey , Force Jeremy , Fecci Peter
Published: August 2019

Brain metastases are a common consequence of advanced lung and breast cancer resulting in functional impairment, cranial neuropathies, and decline in quality of life. Current therapies for brain metastasis, such as whole brain radiation therapy, can result in cognitive impairment, while targeted therapies and chemotherapy are largely ineffective due, in part, to the emergence of resistance and inability to reach effective concentrations in the central nervous system (CNS). We have uncovered a role for the Abelson (ABL) family of tyrosine kinases, ABL1 and ABL2, in lung and breast cancer metastasis to the brain. We show that cancer cells increase ABL expression upon colonization of the brain. Notably, we found that genetic inactivation or pharmacological inhibition of the ABL kinases suppressed lung and breast cancer metastasis to the brain. ABL allosteric inhibitors effectively cross the blood-brain barrier (BBB), inhibit ABL kinases and downstream targets in brain metastases, and markedly impair metastatic colonization of the brain. Further, treatment with an ABL allosteric inhibitor increased recruitment of Iba1+ macrophages/microglia to breast cancer brain metastases. Current studies are aimed at identifying the molecular mechanisms by which ABL kinase signaling regulates the crosstalk between cancer cells and macrophages/microglia, with the aim of disrupting metastatic colonization of the brain parenchyma. These data reveal, for the first time, a role for ABL kinases in promoting brain colonization by metastatic tumors, and demonstrate that ABL allosteric inhibitors efficiently penetrate the BBB and inhibit intracranial growth of breast and lung cancer metastases.
BSCI-23. TISSUE FACTOR SIGNALING ENHANCES METASTATIC BRAIN CANCER MALIGNANCY
Authors: Unruh Dusten , Mirkob Snezana , James C David , Horbinski Craig
Published: August 2019

Brain metastases are on the rise and remain one of the most refractory malignancies worldwide. Currently, the standard approach for therapy involves surgery and radiation. However, this approach usually produces only a modest increase in survival. We recently discovered that Tissue Factor (TF) strongly enhances the malignancy of gliomas via protease-activated receptor 2 (PAR2) signaling, though its role in brain metastases is not as well understood. In this study, we further explored the significance of TF in lung cancer brain metastases, showing that genetic and pharmacological targeting of TF-PAR2 signaling may decrease malignancy and increase the efficacy of radiotherapy. Studies were performed using patient-derived brain metastases coming from lung carcinoma. Markers of malignancy were measured by BrdU incorporation for cell proliferation, Matrigel-coated transwell migration, soft agar colony formation for anchorage-independent growth, limiting dilution assay for tumor initiation capacity, and clonogenic cell survival assay to measure radiation sensitivity. Low transcription of the TF gene is a favorable prognostic marker for overall survival in TCGA lung cancer patients (54.7 vs 41.9 months, P=0.0053), with 74% longer progression-free survival (102.7 vs 59.1 months, P=0.0012). TF knockdown significantly reduced tumor malignancy as determined by cell proliferation, invasion, colony formation, and in vivo growth. Conversely, TF overexpression increased tumor malignancy and promoted cancer stem-like behavior, as indicated by CD44 and CD133 expression, extreme limiting dilution assay, and anchorage-independent growth. A PAR2 antagonist, I-191, inhibited TF-mediated signaling and reduced cell proliferation by 51.3% (P< 0.001). TF knockdown and I-191 increased radiation sensitivity. Exogenous treatment of lung cancer cells with recombinant TF suppressed radiation-induced apoptosis, and this effect was blocked with I-191. These data show that TF-PAR2 signaling may represent a novel therapeutic strategy to reduce the malignancy of brain metastasis and increase the efficacy of radiation.
BSCI-26. COMPARATIVE METHYLATION PROFILING OF EGFR MUTANT LUNG ADENOCARCINOMA AND PAIRED BRAIN METASTASIS
Authors: Mamatjan Yasin , Zuccato Jeffrey , Karimi Shirin , Cabanero Michael , Weiss Jessica , Sorotsky Hadas , Tsao Ming , Shepherd Frances , Aldape Kenneth , Zadeh Gelareh
Published: August 2019

BACKGROUND: Adenocarcinomas (ADC) are the most common lung tumours and EGFR-mutant lesions have a higher risk of brain metastasis development, which confers poorer survival. Genetic and epigenetic signatures of brain metastasis have not been comprehensively identified. The aim of this study is to compare the methylome of EGFR-mutant primary lung tumor and matched brain metastasis to identify mechanisms of brain metastasis and new treatment targets. METHOD: Seven matched primary to brain metastasis tumours were profiled using the Illumina Infinium MethylationEPIC BeadChip array. Hierarchical clustering and principal component analyses (PCA) were performed using most variable CpG sites. Supervised analyses were performed between lung and brain tumour samples. Copy number variation (CNV) plots identified alterations between pairs along with Leukocytes unmethylation for purity (LUMP) score and prediction lymphocyte proportion analyses to measure immune infiltration. RESULTS: Unsupervised clustering showed that the fourteen tumours clustered according to patient with similar methylation profiles between each of seven matched pairs. On the supervised analysis using 83K significant CpG sites, the fourteen samples clustered into two groups based on tumour site being lung or brain. Of these 83K CpG sites, 2.4K were either hypermethylated or hypomethylated in all lung samples. One quarter of these 2.4K CpG sites were located in promoter regions. CNV analyses showed losses of FGFR1, C19MC, CDKN2A, PTCH1, and MYCN genes with higher deep deletions in brain versus lung primary samples. Immune infiltration measures were similar between lung and brain metastasis pairs (LUMP-score=0.64) consistent with high immune cell infiltration. CONCLUSION: In this EGFR-mutant lung adenocarcinomas and matched brain metastases, differentially methylated CpG sites and CNV alterations are identified that distinguish lung from brain samples. Further work with additional matched samples may further elucidate signatures specific to brain metastasis and aid in our understanding of the mechanisms of brain metastasis.
LPTO-07. CARCINOEMBRYONIC ANTIGEN OF CEREBROSPINAL FLUID PREDICT PROGNOSIS OF LEPTOMENINGEAL METASTASIS FROM NON-SMALL CELL LUNG CANCER
Authors: Zhen Junjie , Wen Lei , Li Shaoqun , Lai Mingyao , Zhou Cheng , Cai Linbo
Published: August 2019

BACKGROUND: Leptomeningeal metastasis (LM) is a detrimental complication of patients with non-small cell lung cancer (NSCLC) and its incidence has increased due to recent improvements in survival. The aim of this study was to identify the clinicolpathological features and prognostic factors related to overall survival in NSCLC patients with LM. METHODS: Seventy-four consecutive patients diagnosed with LM from NSCLC between 2009 and 2018 in Guangdong Sanjiu Brain Hospital were retrospectively reviewed. RESULTS: Median KPS at diagnosis of LM were 60 (range, 20–90). Forty-seven (63.5%) patients harboring epidermal growth factor receptor (EGFR) or anaplasticlymphoma kinase (ALK) mutation while other twenty-seven patients (36.5%) were wild type or unknown status. Local treatment for LM consisted of whole-brain radiotherapy (WBRT) (52.7%), ventriculoperitoneal (VP) shunt (6.8%) and external drainage (6.8%). Systematic therapy for LM included EGFR or ALK tyrosine kinase inhibitors (TKI) (59.5%), chemotherapy (40.5%) and bevacizumab (8.1%). The median overall survival from diagnosis of LM to death was 8.1 months (95% confidence interval: 5.2 to 11.0). Patients with high Cerebrospinal Fluid (CSF) carcinoembryonic antigen (CEA) level (＞50ng/ml) had worse prognosis compared with those low CSF CEA level (≤50ng/ml) ones (p=0.02). However, there was no significant difference in survival between patients with high serum CEA and those with low serum CEA (p=0.645). EGFR/ALK mutation and EGFR/ALK TKI after LM were also identified as variables that had prognostic influence on survival, while KPS, concurrent brain metastasis, WBRT and chemotherapy had no prognostic value for survival. CONCLUSION: Median overall survival was higher than historical experience in this retrospective analysis. It is CSF CEA level, but not serum CEA level that correlated with prognosis for LM from NSCLC.
TRLS-10. MITIGATING NEUROCOGNITIVE DEFICITS FROM WHOLE-BRAIN RADIOTHERAPY IN PATIENTS WITH NUMEROUS BRAIN METASTASES VIA A NOVEL SUPEROXIDE DISMUTASE MIMETIC: RATIONALE & DESIGN OF A CLINICAL TRIAL
Authors: Kirkpatrick John , Franklin Heather , Torok Jordan , Floyd Scott , Anders Carey , Fecci Peter , Salama April , Clarke Jeffrey , George Daniel , Crapo James , Peters Katherine
Published: August 2019

BACKGROUND: Patients with a large number of brain metastases (BM) and/or micrometastatic disease in the brain present a clinical challenge. While technical innovations in stereotactic radiosurgery (SRS) have extended the number of BM that can be effectively treated, SRS does not treat occult disease and distant brain failure (DBF) post-SRS remains high. Immuno- and targeted therapies show promise in treating metastatic disease to the brain, though response rates are variable. In contrast, whole-brain radiotherapy (WBRT) provides high rates of local control and, compared to SRS, reduces the risk of distant brain failure. Unfortunately, WBRT is also associated with substantial neurocognitive deficits and neither altered fractionation nor the use of available neuroprotectants has adequately addressed this issue. An agent that safely minimizes the adverse effects of WBRT while preserving or enhancing tumor control would provide meaningful clinical benefit. TRIAL DESIGN: BMX-001, a novel Mn-porphyrin superoxide dismutase mimetic, has been shown to protect normal tissues from ionizing radiation in preclinical trials, reducing neurocognitive adverse effects as well as enhancing tumor response. Based on the first-in-human trial of this agent in patients with high-grade gliomas, we have instituted a clinical trial of WBRT +/- BMX-001 in adult patients with more than 10 BM from melanoma, non-small-cell lung, breast and renal cancer. Following a safety lead-in of 5 patients, all of whom will receive WBRT and BMX-001, 69 patients will be randomized to WBRT (3Gy/fraction x 10 fractions) with or without BMX-001 administered subcutaneously before, twice weekly during and once after WBRT (6 injections total.) The primary endpoint is cognition, as measured by the Hopkins Verbal Learning, Trailmaking A/B and Controlled Oral Word Association tests. Secondary endpoints include health-related quality-of-life, overall and progression-free survival, rates of radiation necrosis, DBF and neurologic death. Enrollment began January 2019. (ClinicalTrials.gov Identifier: NCT03608020.)
THER-02. IMPACT OF SYSTEMIC THERAPY IN MELANOMA BRAIN METASTASIS
Authors: Sagar Soumya , Lauko Adam , Barnett Addison , Wei Wei , Chao Samuel , Peereboom David , Stevens Glen , Angelov Lilyana , Yu Jennifer , Murphy Erin , Mohammadi Alireza , Suh John , Barnett Gene , Ahluwalia Manmeet
Published: August 2019

BACKGROUND: Melanoma brain metastasis is associated with a median overall survival (OS) of approximately 9 months. In recent years, management of melanoma brain metastases (MBM) by surgery and radiation [stereotactic radiosurgery (SRS) and whole brain radiation therapy (WBRT)] has been bolstered by targeted therapy and immune checkpoint inhibitors (ICI). METHODS: 351 patients, who underwent treatment for MBM at our tertiary care center from 2000 to 2018, were grouped into those that received chemotherapy, ICI, or targeted therapy. Thirty-four percent of patients treated with ICI had received other systemic therapies as well as part of their management. OS was calculated from the date of diagnosis of the brain metastases. The Kaplan Meier analysis was utilized to determine median OS and difference in OS was determined by utilizing the Cox proportional hazard model. RESULTS: The median survival after the diagnosis of brain metastasis was 10.4, 11.96, and 7.06 months in patients who received ICI, chemotherapy and targeted therapy respectively. A multivariate model was developed including the type of systemic therapy, presence of extracranial metastases, age, KPS and number of intracranial lesions. 114 patients underwent SRS alone, 56 underwent SRS and WBRT, 43 underwent SRS and surgical removal, 28 had surgical removal, SRS and WBRT, and 78 had no intracranial therapy. Compared to patients who received chemotherapy, patients who received immunotherapy had a hazard ratio, HR = 0.628 (confidence interval = 0.396 – 0.994, p-value = 0.047). Presence of EC metastases (HR= 1.25, p-value < .001), lower KPS (HR = .97, p-value < .0001) and multiple brain lesions (HR = 1.117, p-value < .0001) were associated with significantly worse OS. CONCLUSIONS: Addition of ICI significantly improves the OS in MBM compared to chemotherapy. Lower performance status, multiple brain metastases, and EC metastases are associated with poor OS.
THER-03. USING SUCCESSIVE EGF RECEPTOR ANTAGONISTS TO TREAT A PATIENT WITH EXTENSIVE METASTATIC DISEASE: CASE REPORT AND REVIEW OF THE LITERATURE
Authors: Megyesi Joseph , Macdonald David
Published: August 2019

INTRODUCTION: EGFR-targeted agents can be useful in the treatment of systemic metastatic cancer including that which has spread to the brain. We present the case of a patient with two different EGFR mutations that responded to receptor blockade. CASE REPORT: A 38 year old right-handed female presented with a one week history of progressive left-sided weakness and focal seizures. Neuroimaging revealed multiple enhancing brain lesions and a lesion in the left maxillary antrum. Body imaging revealed a right lung mass, hilar and mediastinal nodes and multiple bony lesions. Biopsy of the maxillary antrum lesion showed metastatic poorly differentiated adenocarcinoma, TTF-1 positive, suggesting a lung primary. ALK was not mutated but there was an EGFR mutation (exon 19 deletion). The patient underwent treatment with dexamethasone, levetiracetam, whole brain radiation and afatinib, an oral EGFR-targeted agent. Most of the brain lesions responded completely with only two small residual lesions. Seizures were controlled. There was major partial response from the systemic lesions. Two years later the patient was clinically well but the lung lesion, mediastinal nodes and bony lesions were all enlarging. A new pituitary lesion was identified on brain MRI. A liquid biopsy (blood) revealed a T790M mutation and the patient underwent stereotactic body radiation and EGFR-targeted therapy with osimertinib. All lesions responded to treatment and four years after initial diagnosis the patient is clinically well with stable disease. DISCUSSION: Successful treatment of widespread metastatic disease is possible with the use of multiple EGFR-targeted agents in certain patients.
THER-06. GENOMIC AND IMMUNE CHARACTERIZATION OF TRIPLE NEGATIVE BREAST CANCER BRAIN METASTASES
Authors: Vincent Benjamin , Sambade Maria , Chai Shengjie , Siegel Marni , Cuaboy Luz , Holye Alan , Parker Joel , Perou Charles , Anders Carey
Published: August 2019

INTRODUCTION: Approximately 50% of patients with metastatic triple negative breast cancer (TNBC) will develop brain metastases (BM). Routinely treated with radiotherapy and/or surgery, survival is generally less than one year. There are no approved systemic therapies to treat TNBC BM. We characterized the genomic and immune landscape of TNBC BM to foster the development of effective brain permeable anti-cancer agents, including immunotherapy. EXPERIMENTAL PROCEDURES: A clinically-annotated BCBM biobank of archival tissues was created under IRB approval. DNA (tumor/normal) and RNA (tumor) were extracted from TNBC primaries and BM; whole exome (WES) and RNA sequencing (RNASeq) was performed. Mutations were determined from WES as those co-identified by two variant callers (Strelka|Cadabra). Immune gene signature expression, molecular subtype identification, and T cell receptor repertoires were inferred from RNAseq. RESULTS: 32 TNBC patient tissues (14 primaries, 18 BCBM, 6 primary-BCBM matched), characterized as basal-like by PAM50, were analyzed. Top exome mutation calls included ten genes in ≥19% of BCBMs including TP53, ATM, and PIK3R1, and four genes in ≥18% of primaries including TP53 and PIK3R1. Many immune gene signatures were lower in BM compared to primaries including B cell, dendritic cell, regulatory T cell, and IgG cluster (p< 0.05). A signature of PD-1 inhibition responsiveness was higher in BM compared with primaries (p< 0.05). BCBM T cell receptor repertoires showed higher evenness and lower read count (both p < 0.01) compared to primaries. CONCLUSIONS: TNBC BM compared to primaries that metastasize to the brain show lower immune gene signature expression, higher PD-1 inhibition response signature expression, and T cell receptor repertoire features less characteristic of an active antigen-specific response. Mutations common to TNBC BM and primaries include TP53 and PIK3R1. Given that non-BCBM (i.e. lung and melanoma) show response to checkpoint inhibitors, these findings collectively support further study of immunotherapy for TNBC BM.