bluuebunny/crossref_metadata_2025_split huggingface dataset:
Late surgical conversions after abdominal endovascular aortic repair: underlying mechanisms, clinical results and strategies for prevention
Authors: Juraszek Andrzej , Rylski Bartosz , Kondov Stoyan , Scheumann Johannes , Kreibich Maximilian , Morlock Julia , Schröfel Holger , Berger Tim , Kari Fabian , Siepe Matthias , Beyersdorf Friedhelm , Czerny Martin 
Published: August 2019

AbstractOBJECTIVESOur goal was to report our results of late surgical conversion after endovascular aneurysm repair (EVAR).METHODSVariables analysed included baseline data, preinterventional anatomy, type of endovascular intervention, indications for conversion, operative technique, postoperative complications and follow-up survival rate.RESULTSBetween April 2011 and May 2018, 16 patients with late complications after EVAR underwent open surgical conversion at our institution. The mean age was 73.6 [standard deviation (SD) 8.9] years. There were 3 (18.8%) female patients. In 15 patients, the indication for primary EVAR was abdominal aortic aneurysm, and in 1 patient, chronic abdominal aortic dissection. Five patients underwent secondary EVAR service interventions for endoleak treatment between the index EVAR and the final secondary surgical conversion. Thirteen patients underwent surgery in an elective setting and 3 patients underwent emergency surgery. The mean time from EVAR to open surgical conversion was 6.31 (SD 4.0) years (range 1.2–16.0 years). The most common indication for conversion was endoleak formation (n = 12, 75%), followed by 3 cases of aortic rupture (1 patient with primary type 1 endoleak) and 2 cases of stent graft infection—1 with and 1 without an aortoduodenal fistula. One patient died during emergency open surgery of cardiopulmonary instability. Three patients developed postoperative renal dysfunction with recovery of their renal function before discharge. The in-hospital mortality rate was 12.5%. The median follow-up was 16.5 months (interquartile range 21 months). Freedom from death and aortic reintervention was 100%, respectively. After careful review of the index computed tomography scans for EVAR, the majority of failures could have been anticipated due to trade-offs with regard to length, diameter, morphology, shape and angulation of the proximal and/or distal landing zone.CONCLUSIONSDespite being a challenging operation, late surgical conversion after EVAR yields excellent results with regard to outcome and freedom from the need for further aortic interventions. An anticipative strategy adhering to current recommendations for using or refraining from using EVAR in patients with anatomical challenges will help reduce the need for secondary surgical conversions and keep them to minimum.
Energy conservation analysis of regenerative radiator for low-temperature heating
Authors: Li Cuimin , Li Chunying , Wang Lei 
Published: August 2019

Abstract
In this paper, the phase change plate is made of the organic phase change material (PCM) with the phase change temperature of about 30°C. The PCM is installed in the capillary natural convection radiator with the water supply temperature of 30–60°C. A low-temperature natural convection radiator with heat storage function is formed. The mathematic model is established by enthalpy method and solved by line-by-line iteration method. The applicability and economy of the equipment in Shanghai area are calculated. Taking the time ratio and average temperature of the target domain as the limiting parameters, the operation schemes suitable for three representative days are determined, and the optimum thickness of the phase change plate is 0.05 m for use in Shanghai. The regenerative low-temperature heating radiator provides a new idea for the application of PCMs in the field of low-temperature heating. The conclusions obtained provide a basis for further research and application of the equipment.
Cerebrospinal Fluid Shunting Improves Long-Term Quality of Life in Idiopathic Normal Pressure Hydrocephalus
Authors: Israelsson Hanna , Eklund Anders , Malm Jan 
Published: August 2019

Abstract

BACKGROUND
The short- and long-term impact of cerebrospinal fluid shunting on quality of life (QoL) in idiopathic normal pressure hydrocephalus (INPH) is poorly understood.

OBJECTIVE
To investigate QoL in shunted INPH patients compared to the population and to investigate which factors influence QoL in INPH.

METHODS
INPH patients consecutively shunted in Sweden during 2008-2010 were scrutinized. Population-based controls were age- and sex-matched to the patients. Included participants were the following: 176 INPH patients and 368 controls. QoL was assessed using the EuroQol 5-dimension 5-level (EQ5D5L) instrument, which measures overall QoL and health status in 5 dimensions. Independency (accommodation and/or need for in-home care) and comorbidities were assessed. Patients were followed up 6-45 mo after surgery (mean follow-up time: 21 mo).

RESULTS
Shunting improved QoL (P < .001) and health status in all dimensions (P < .005). Shunted INPH patients had lower QoL than controls (P < .001). The patients’ health status in mobility, self-care, daily activities, and anxiety/depression was worse than the controls both before and after surgery (P < .001). The main predictors of low QoL in INPH were symptoms of depression (P < .001) and severity of gait disturbance (P = .001). Fewer INPH patients than controls lived independently (45% vs 85%, P < .001). Time after shunting had no influence on QoL.

CONCLUSION
QoL remains improved in shunted INPH patients at a mean follow-up time of 21 mo, but the patients do not reach the same QoL as the population. Symptoms of depression and severity of gait disturbance are the strongest predictors of low QoL in INPH.
BSCI-02. tGLI1 IS A NOVEL, ACTIONABLE TARGET FOR THE TREATMENT OF BREAST CANCER BRAIN METASTASES
Authors: Doheny Daniel , Sirkisoon Sherona , Rimkus Tadas , Zhu Dongqin , Aguayo Noah , Harrison Alexandria , Anguelov Marlyn , Xing Fei , Metheny-Barlow Linda , Watabe Kounosuke , Thomas Alexandra , Masters Adrianna Henson , Strowd Roy , Lo Hui-Wen 
Published: August 2019

Abstract
Despite improvements in early detection and intervention, breast cancer remains the second leading cause of cancer-related death in women and the second most common cancer to metastasize to the brain. Current standard of care options for breast cancer brain metastases (BCBM) include stereotactic radiosurgery, whole-brain radiotherapy, and surgical resection. Local and distant recurrences are common leading to significant morbidity; effective FDA-approved drugs for these patients remain a significant unmet need. Our laboratory discovered an alternative splice variant of glioma-associated oncogene homolog 1 (GLI1), termed truncated GLI1 (tGLI1) that is a tumor-specific gain-of-function transcription factor preferentially expressed in most BCBM samples and recurrent gliomas. Recent results established that tGLI1 promotes breast cancer stem cells (BrCSCs) and is associated with preferential metastasis to the brain and radioresistance, justifying tGLI1 as an ideal therapeutic target for BCBM patients. To identify tGLI1-targeting agents, we screened 1,520 compounds across three commercial drug libraries and found ketoconazole, an FDA-approved azole antifungal and component of previously studied anti-neoplastic regimens, selectively killed tGLI1-expressing breast cancer cells with heightened efficacy against the CSC subpopulation in vitro. tGLI1 knockdown abolished the ability of ketoconazole to target BrCSCs, indicating that ketoconazole effect is dependent on tGLI1. Intracardiac mouse studies showed ketoconazole selectively inhibited circulating tGLI1-positive breast cancer cells from developing into brain metastases and suppressed the progression of existing brain metastases. Mass spectrometry demonstrated ketoconazole effectively penetrated the blood-brain barrier (BBB) and blood-tumor barrier (BTB). Mechanistic studies suggest that ketoconazole-dependent cell kill is, in part, mediated through disruption of the tGLI1-STAT3 interaction. Collectively, our preclinical results demonstrate that ketoconazole is an effective inhibitor of BrCSCs and brain metastasis of tGLI1-positive breast cancer. Based on these promising preclinical data, we opened a window-of-opportunity study in patients with BCBM and recurrent gliomas to determine if ketoconazole treatment alters tGLI1 signaling in humans (NCT03796273).
BSCI-04. TARGETING TRIPLE-NEGATIVE BREAST CANCER BRAIN METASTASES WITH A RE-ENGINEERED LUPUS AUTOANTIBODY
Authors: Zhang Shenqi , May Christopher , Shirali Anupama , Dubljevic Valentina , Campbell James , Zhou Jiangbing , Hansen James 
Published: August 2019

Abstract
An unusual lupus anti-DNA autoantibody, 3E10, has potential to be used against triple-negative breast cancer (TNBC) brain metastases. 3E10 penetrates live cell nuclei, inhibits DNA repair, and is selectively toxic to cancer cells with the PTEN and/or DNA-damage response (DDR)-deficiencies that are associated with brain metastases in TNBC. The ENT2 nucleoside transporter that 3E10 uses to cross cell membranes is highly expressed in tumors and in brain endothelial cells (BECs) at the blood-brain barrier (BBB), and 3E10 has previously delivered cargo proteins to ischemic brain in a rat stroke model. We have re-engineered 3E10 into an optimized fragment, called Deoxymab-1 (PAT-DX1), that has increased effect on PTEN/DDR-deficient tumor cells. In the present study we tested the ability of PAT-DX1 to cross the BBB and improve outcomes in a mouse model of TNBC brain metastases. PAT-DX1 crossed from apical to basolateral chambers in an hCMEC/D3 Transwell filter model of the BBB, and penetrated the nuclei of and was toxic to the brain-seeking 231-BR subclone of MDA-MB-231 TNBC cells, which harbors a loss of PTEN compared to parental cells. Brain metastases were generated in nude mice by intracardiac injection of 1.75x105 231-BR cells engineered for expression of luciferase, as confirmed by IVIS one week after injection. Mice with brain metastases were treated by tail vein injection of control (PBS, n=7) or DX1 (20 mg/kg, n=7) 3x/week for 4 weeks. Mice were observed for behavior and weights, and brain radiance efficiency was monitored by weekly IVIS to track metastatic tumor growth. PAT-DX1 significantly suppressed growth of brain metastases based on absolute and relative radiance efficiencies in the brain, increased the median survival of the mice from 38 to 52 days (P&lt; 0.02), and was well tolerated. These results provide proof of concept for use of a re-engineered autoantibody against brain metastases.
BSCI-07. BONE MARROW T-CELL SEQUESTRATION IN THE SETTING OF BRAIN METASTASES
Authors: Chongsathidkiet Pakawat , Woroniecka Karolina , Dechant Cosette , Kemeny Hanna , Cui Xiuyu , Wilkinson Daniel , Lorrey Selena , Fecci Peter 
Published: August 2019

Abstract
INTRODUCTION: Brain metastases remain one of the most dreaded consequences of late stage cancer, yet their incidence has risen as survival from primary cancers has improved. We have recently reported that tumors harbored within the brain, specifically, sequester T-cells within the bone marrow as a novel mechanism of immune evasion. Sequestration results from tumor-imposed loss of S1P1 receptor from the T-cell surface. Stabilization of the receptor on T-cells frees T-cells from sequestration and licenses T-cell activating therapies for intracranial tumors. While this phenomenon was initially uncovered in glioblastoma, its role in promoting immune-evasion in brain metastases remains less clear. METHODS: Blood, bone marrow, and tumors were collected from mice bearing intracranial tumors commonly metastatic to the brain, including lung carcinoma (LLC), melanoma (B16F10), or breast carcinoma (E0771) and analyzed by flow cytometry. T-cell S1P1 levels, as well as total T-cell counts were assessed in each compartment. Correlation analyses were conducted between T-cell counts and S1P1 levels on T-cells in the bone marrow across intracranial and subcutaneous murine tumor models. RESULTS: T-cell lymphopenia and accompanying accumulation of T-cells in the bone marrow were observed in the murine models of lung carcinoma, melanoma, and breast carcinoma, but only when these tumor lines were implanted intracranially. Sequestered T-cells in tumor-bearing mice showed decreased surface S1P1 levels in a manner correlating with their sequestration. CONCLUSION: S1P1-mediated bone marrow T-cell sequestration is a novel mode of cancer-induced T-cell dysfunction in intracranial tumors. Preventing receptor internalization abrogates T-cell sequestration and licenses T-cell activating therapies in glioblastoma. Sequestration is now observed in models of brain metastases. Pharmacologic strategies to stabilize S1P1, reverse sequestration, and restore circulating T-cell numbers are anticipated to improve immunotherapeutic efficacy for brain metastases.
BSCI-11. STROMAL PLATELET DERIVED GROWTH FACTOR RECEPTOR-β (PDGFRβ) PROMOTES BREAST CANCER BRAIN METASTASIS
Authors: Thies Katie , Hammer Anisha , Hildreth Blake , Russell Luke , Sizemore Steven , Trimboli Anthony , Kladney Raleigh , Steck Sarah , Das Manjusri , Bolyard Chelsea , Pilarski Robert , Cuitino Maria , Koivisto Christopher , Schoenfield Lynn , Otero Jose , Chakravarti Arnab , Ringel Matthew , Li Zaibo , Kaur Balveen , Leone Gustavo , Ostrowski Michael , Sizemore Gina 
Published: August 2019

Abstract
Stromal platelet-derived growth factor receptor-beta (PDGFRβ) has emerged as an actionable mediator of breast tumor-stromal communication. As a receptor tyrosine kinase, PDGFRβ is activated by its ligand, PDGFB, which is released by neighboring tumor epithelium and endothelium. However, how PDGF signaling mediates breast cancer (BC) initiation, progression, and metastasis remains unclear. To evaluate PDGFRβ in this disease, we developed a mouse model of stromal-specific PDGFRβ activation using the Fsp-cre transgene previously published by our group. Mesenchymal-specific activation of PDGFRβ promotes preferential experimental brain metastasis of PDGFB-expressing mammary tumor cells when injected intravenously and accelerates intracranial tumor growth of these cells. Mammary tumor cells expressing low levels of PDGFB do not exhibit a similar increase in brain metastases in PDGFRβ mutant mice. To our knowledge, this is the first example where genetic manipulation of the stroma leads to an increased incidence of BCBM. Our pre-clinical data suggests that primary breast tumors that express high PDGFB could preferentially metastasize to the brain. To test this in patients, we analyzed PDGFB protein expression in a tissue microarray comprised of HER2-positive and triple negative BC primary tumors. While high PDGFB did not correlate with site-independent metastatic recurrence, it was prognostic of brain metastasis, mirroring our mouse data. Our findings suggest that high primary tumor PDGFB expression defines a subset of BC patients predisposed to brain metastases. These patients may benefit from therapeutic intervention of PDGFRβ signaling. To test this pre-clinically, we treated mice harboring intracranial tumors with the PDGFR-specific inhibitor, crenolanib. Excitingly, crenolanib treatment significantly inhibited the brain tumor burden in these mice. Combined, our findings (1) advocate that primary tumor expression of PDGFB is a novel prognostic biomarker for the development of BCBM and (2) support clinical trial evaluation of PDGFR inhibitors for the prevention and treatment of BCBM.
BSCI-13. TUMOR-SPECIFIC tGLI1 TRANSCRIPTION FACTOR MEDIATES BREAST CANCER BRAIN METASTASIS VIA ACTIVATING METASTASIS-INITIATING CANCER STEM CELLS AND ASTROCYTES IN THE TUMOR MICROENVIRONMENT
Authors: Sirkisoon Sherona , Carpenter Richard , Rimkus Tadas , Doheny Daniel , Zhu Dongqin , Aguayo Noah , Anguelov Marlyn , Arrigo Austin , Regua Angelina , Xing Fei , Chan Michael , Metheny-Barlow Linda , Watabe Kounosuke , Lo Hui-Wen 
Published: August 2019

Abstract
Breast cancer is the second leading cause of brain metastases in women; patients with breast cancer brain metastasis (BCBM) survive only 6–18 months after diagnosis. Mechanisms for BCBM remain unclear, which contributes to ineffective treatments and dismal prognosis. Truncated glioma-associated oncogene homolog 1 (tGLI1) belongs to the GLI1 family of zinc-finger transcription factors and functions as a tumor-specific gain-of-function mediator of tumor invasion and angiogenesis. Whether tGLI1 plays any role in metastasis of any tumor type remains unknown. Using an experimental metastasis mouse model, via intracardiac implantation, we showed that ectopic expression of tGLI1, but not GLI1, promoted preferential metastasis to brain. Conversely, selective tGLI1 knockdown using tGLI1-specific antisense oligonucleotides led to decreased brain metastasis of intracardially inoculated breast cancer cells. Furthermore, intracranial implantation mouse study revealed tGLI1 enhanced intracranial colonization and growth of breast cancer cells. Immunohistochemical staining of patient samples showed that tGLI1, but not GLI1, was increased in lymph node metastases compared to matched primary tumors, and that tGLI1 was expressed at higher levels in BCBM specimens compared to primary tumors. Whether tGLI1 plays any role in radioresistance is unknown; we found radioresistant BCBM cell lines and patient specimens expressed higher levels of tGLI1 than radiosensitive counterparts, and that tGLI1 promotes radioresistance. Since cancer stem cells (CSCs) are highly metastatic and radioresistant, we examined whether tGLI1 promotes BCBM and radioresistance through activating CSCs. Results showed that tGLI1 transcriptionally activates stemness genes CD44, Nanog, Sox2, and OCT4, leading to stem cell activation. Furthermore, we observed that tGLI1-positive CSCs strongly activated and interacted with astrocytes, the most abundant brain tumor microenvironmental cells known to promote tumor growth, in vitro and in vivo. Collectively, our findings establish a novel role of that tGLI1 plays in promoting breast cancer preferential metastasis to brain, radioresistance, and astrocytes in the metastatic niche.
BSCI-15. METASTATIC BRAIN TUMOR TARGETING PEPTIDES ISOLATED THROUGH PHAGE DISPLAY BIOPANNING AGAINST BRAIN METASTASIS-INITIATING CELLS
Authors: Kim JongMyung , Liu James 
Published: August 2019

Abstract
To effectively target metastatic brain tumors (MBTs), the paradigm of treating MBTs after visualization on clinical imaging needs to be shifted to an understanding of the mechanisms that drive the formation and maintenance of brain metastasis-initiating cells (BMICs). Targeting this tumor sub-population, which may form as a result from activation of epithelial-mesenchymal transition, may allow for more effective means of isolating and targeting brain metastasis. In order to isolate BMICs, we have harvested cells from patient derived MBTs originating from lung cancer and cultured the cells using serum-free media conditions. In vivo phage display biopanning was used to isolate 12-amino acid length peptides that specifically target BMICs. Of the peptides recovered, one peptide, LBM4, was tested for specificity of binding to MBTs through in vitro and in vivo binding assays. When comparing patient derived metastatic brain tumors cells against brain metastasis cell lines, we found that both types of cells demonstrated similar morphology when grown in serum media conditions, but when grown in serum-free media, both demonstrated a tumor sphere morphology, similar to a stem cell-like state. LBM4 demonstrated specific binding to MBT cells over primary lung cancer cells in vitro through flow cytometry analysis and immunocytochemistry. Fluorescent tagged LBM4 intravenously injected into mice harboring intracranial BM demonstrated peptide localization to the tumor within the intracranial cavity visualized with live animal imaging. In vivo phage display biopanning is an effective tool that is able to isolate cell specific targeting peptides. MBT targeting peptides can potentially result in a shifting of the clinical treatment paradigm of brain metastases, through the development of more effective targeted therapeutics aimed at BMICs, as well as improving detection of MBT cells which may result in earlier tumor visualization as well as delineation of tumor recurrence versus radiation effects.
TRLS-01. RADIOSURGERY FOLLOWED BY TUMOR TREATING FIELDS (TTFIELDS) FOR BRAIN METASTASES (1–10) FROM NSCLC IN THE PHASE 3 METIS TRIAL
Authors: Mehta Minesh , Gondi Vinai , Ahluwalia Manmeet , Brown Paul 
Published: August 2019

Abstract
Tumor Treating Fields (TTFields) are non-invasive, loco-regional, anti-mitotic treatment comprising alternating electric fields that have demonstrated efficacy in preclinical non-small cell lung cancer (NSCLC) models. TTFields to the brain was safe and extended overall survival in newly-diagnosed glioblastoma. The METIS study [NCT02831959] investigates the efficacy and safety of TTFields in NSCLC patients with brain metastases. NSCLC patients (N=270) with 1–10 brain metastases are randomized 1:1 to stereotactic radio surgery (SRS) followed by continuous TTFields ((150 kHz, &gt; 18 hours/day) within 7 days of SRS or supportive care. The TTFields portable device delivers TTFields to the brain using 4 transducer arrays, while patients receive the best standard-of-care for their systemic disease. Patients are followed every two months until second intracranial progression. Key inclusion criteria: KPS ≥70, new diagnosis of 1 inoperable or 2–10 supra- and/or infratentorial brain metastases from NSCLC amenable to SRS; KPS ≥70; and optimal therapy for extracranial disease. Prior WBRT or surgical resection of metastases, a single resectable lesion or recurrent brain metastases were exclusionary. Primary endpoint was time to 1st intracranial progression. Secondary endpoints included time to neurocognitive failure (HVLT, COWAT and TMT), overall survival, radiological response rate (RANO-BM and RECIST V1.1); quality-of-life; adverse events; time to first/second intracranial progression for patients with 1–4 and 5–10 brain metastases; bi-monthly intracranial progression rate from 2–12 months; and time to second intracranial and distant progression. The sample size (N=270) was calculated using a log-rank test (Lakatos 1988 and 2002) with 80% power at a two sided alpha of 0.05 to detect a hazard ratio of 0.57. In August 2018, an independent Data Monitoring Committee (DMC) performed a review of the METIS trial data collected to that point. The DMC concluded that no unexpected safety issues have emerged on the study, and recommended to continue the METIS study as planned.