tbuckley/cabot-search huggingface dataset:
CMET-07. FRAILTY PREDICTS MORTALITY AFTER RESECTION OF BRAIN METASTASES
Authors: Saksham Gupta, Wenya Linda Bi, Alexandra Giantini Larsen, Hassan Dawood, Luis Fandino, Timothy R Smith, Ayal Aizer, Ian F Dunn
Journal: Neuro-Oncology (2018)

Brain metastases are the most common type of brain tumor, though determining candidates for resection may be challenging. Patients’ unfavorable prognoses make pre-operative risk stratification critical in the selection of patients that are likely to benefit from resection. Multivariable logistic regression was applied to 3,532 cases of secondary neoplasms of the brain in the American College of Surgeons National Surgical Quality Improvement Program database. The validated 5-criteria modified frailty index (mFI-5) score was utilized to quantify frailty, characterized as an mFI-5 score of 2 or higher. The median age in the cohort was 61 years, and the majority of patients were female (55%). Frailty was present in 17% of patients. The most frequent 30-day post-operative medical complications were venous thromboembolism (3.1%), pneumonia (2.7%), and urinary tract infections (2.2%). Unplanned readmissions and reoperations occurred in 12.2% of patients and 4.9% of patients, respectively. The incidence of death was 4.2% across the cohort, including 1.2% during index hospitalization. Frailty was associated with pneumonia (OR 2.7, p Frailty was associated with post-operative medical complications and death, in particular during the post-discharge phase. Frailty should be used in risk-stratifying patients.
Abstract P140: High Poverty Among Patients With Noncommunicable Diseases in Rural Haiti
Authors: Gene F Kwan, Benito Isaac, Lily Yan, Waking Jean-Baptiste, Densa Belony, Loiune Martineau, Philip Cleophat
Journal: Circulation (2018)

Background: Noncommunicable diseases (NCDs) are a major and growing cause of death and disability in low-income countries, and contribute a substantial portion of outpatient clinic visits. Poverty can be a major barrier to accessing healthcare in rural low-income countries. The objective of this study is to describe the demographics and socioeconomic status of patients attending an NCD clinic in rural Haiti, where poverty is highly prevalent. Methods: We analyzed routinely collected clinic data from adult patients in rural Haiti presenting to the NCD clinic at Hôpital Universitaire de Mirebalais. We collected data during routine initial clinic visits from July 2013 through October 2016. We performed descriptive statistics to assess patient demographics and socioeconomic status using available data. We evaluated poverty based on the Multidimensional Poverty Index by evaluating 9 indicators within three dimensions: health, education, and standard of living - we did not assess electricity. We assessed deprivation within each indicator. The “poorest” patients were defined as those deprived in 4 of the 9 poverty indicators. We also assessed measures of catastrophic health spending. Results: A total of 518 adults were included, with 72% (373/508) women. The mean overall age was 52.8 years (SD 14.7) and 21% (108/518) were 40 years old or younger. Of the patients, 32% had only hypertension, 18% had only diabetes, 32% had both diabetes and hypertension, 5% had heart failure, and 13% had no recorded diagnosis. 45% of patients travel more than 1 hour for clinic visits. Almost half (49%, 146/296) of adults sold belongings and 61% (178/292) borrowed money to pay for healthcare. Among the poverty measures, the top indicators with deprivation were cooking fuel with charcoal or wood (96%, 290/302), child death in household (70%, 169/243), and no household members completing primary school (25%, 83/324), lack of household assets (25%, 79/313), poor sanitation (19%, 59/304), dirt floor (16%, 50/304), and lack of improved drinking water (9%, 29/308). Of all patients, 21% (78/378) were among the poorest. Throughout Haiti, however, 55% of the population are among the poorest. There were more patients among the poorest living closer to the hospital (27%) than living farther away (10%). Interpretation: The great majority of patients were middle-aged women, with predominantly hypertension and/or diabetes. Socioeconomic deprivation was high among many poverty indicators and most patients experienced catastrophic health spending. At this clinic in rural Haiti, the proportion of patients presenting for care who are among the poorest is less than that overall in Haiti. Patients who travel far distances have less poverty. Health systems for chronic disease management in rural low-income countries must account for patient poverty.
TMOD-39. A PLATELET-ACTIVATING FACTOR RECEPTOR ANTAGONIST DELAYS GLIOBLASTOMA GROWTH AND INVASION IN A MOUSE MODEL
Authors: Valerie Cruz Flores, Lindsay Lasseigne, Hemant Menghani, Larissa Khoutorova, Pranab Mukherjee, Ludmila Belayev, Nicolas Bazan
Journal: Neuro-Oncology (2018)

Glioblastoma Multiforme (GBM) is a diffuse malignant brain tumor with rapid growth and infiltration, high resistance to available therapies, and poor survival rate. The current standard of care only provides patients with an average survival of 12–14 months. Platelet-Activating Factor (PAF) is a strong mediator of inflammation, and its receptor, PAF-R, is over-activated in the microenvironment of different tumors as part of an enhanced neuroinflammatory response. PAF-R antagonists are beneficial in experimental ischemic stroke and counteract epileptogenesis. The purpose of this study was to determine if the PAF-R antagonist, LAU-0901, could delay GBM progression and improve survival. U87MG cells were implanted in the right dorsal CA3 hippocampal region of BALB/c (nu/nu) mice. Intracranial tumor growth was quantified using in vivo bioluminescent imaging on days 10 and 25, and then every 2 weeks. Saline (vehicle, n=6) or LAU-0901 (60mg/kg/day; IP, n= 6) was administered daily from days 10 to 15 post GBM implantation. Tumor size before treatment on day 10 was identical in both groups. A large GBM mass was present in saline-treated mice and most of these mice died within 6 weeks; only two animals survived for the 10-week survival period. In contrast, tumor size was dramatically reduced by LAU-0901 treatment during the survival period. LAU-0901 treatment diminished tumor size by 80% on day 25, compared to saline-treated group. In addition, body weight increased by 30–45% in LAU-0901-treated mice at weeks 8 and 10. We have demonstrated that treatment with PAF-R antagonist, LAU-0901, decreased tumor growth, increased body weight and improved survival in a GBM mouse model. This novel experimental therapy can provide future avenues for GBM treatment. ABSTRACTS FROM THE 3rd CNS ANTICANCER DRUG DISCOVERY AND DEVELOPMENT CONFERENCE
TMOD-04. TARGETING A GLIOMA SPECIFIC lncRNA IN A HUMAN BRAIN ORGANOID TUMOR MODEL
Authors: Martina Malatesta, John Liu, Leslie Pedraza, Kyounghee Seo, Elizabeth DiLullo, David Raleigh, Arnold Kriegstein, Erik Ullian, Daniel Lim
Journal: Neuro-Oncology (2018)

Long non-coding RNAs (lncRNAs) are transcripts >200 nucleotides long with essentially no protein coding potential. While certain lncRNAs play key roles in cancer and therefore represent an important class of therapeutic targets, very few lncRNAs have been studied in glioma. Here, we show that knockdown of a primate-specific lncRNA – referred to as GTT1 – selectively inhibits the growth of both adult and pediatric glioma but does not adversely affect the viability of normal human glia and neurons. In a recent genome-scale CRISPR interference (CRISPRi)-based screen, we identified GTT1 as one of 65 lncRNA genes that modify the growth of U87 glioblastoma cells. To prioritize lncRNAs for further study, we next performed a CRISPRi-based screen to identify lncRNA targets that also sensitize tumor cells to radiation. Both CRISPRi-mediated and antisense oligonucleotide (ASO)-mediated knockdown of GTT1 inhibited the propagation of U87 cells in culture, and this effect synergized with radiation treatment. Furthermore, GTT1 knockdown inhibited the growth of patient-derived glioma cells including adult glioblastoma and pediatric diffuse intrinsic pontine glioma (DIPG) in culture. Although GTT1 is expressed in normal human brain, knockdown of this lncRNA in normal human astrocytes, cortical neurons and fetal forebrain tissues did not reduce cell viability. As GTT1 is primate-specific, knockdown of this lncRNA in mouse xenograft models would not fully assess potential adverse effects. We therefore developed a human brain organoid model comprised of mature astrocytes and functional neurons. Patient-derived glioma cells engrafted into these organoids, and tumors grew in an infiltrative manner. GTT1 knockdown in this brain organoid model strongly impaired tumor growth but did not reduce organoid viability. These studies identify GTT1 as a glioma-specific therapeutic target and illustrate how this human brain organoid tumor model can be used to rapidly evaluate the tumor-specificity of novel therapeutics.
Abstract 14953: STAT3 in Vascular Smooth Muscle Cells Protects Aorta From Dissection by Reinforcing Aortic Wall
Authors: Saki Hirakata, Hiroki Aoki, Michihide Nishihara, Satoko Ohno, Aya Furusho, Norifumi Nishida, Sohei Ito, Makiko Hayashi, Yoshihiro Fukumoto
Journal: Circulation (2015)

Aortic dissection (AD) is a common and fatal disease for which pathogenesis is largely unknown. Recently we and others reported that JAK/STAT3-activating cytokines are highly expressed in human and mouse models of AD. In this study, we used a mouse model of AD that was induced by continuous infusion of beta-aminopropionitrile, an inhibitor of lysyl oxidase that cross-links collagen and elastin, and angiotensin II (BAPN+AngII). Mouse AD tissue showed STAT3 activation (phosphorylation) both in inflammatory cells and in vascular smooth muscle cells (VSMCs). We used the smooth muscle-specific knockout mice for SOCS3, a negative feedback regulator of STAT3 (smSOCS3-KO), to activate STAT3 specifically in VSMCs. smSOCS3-KO mice developed less severe AD in the aortic arch (WT; 0.093±0.018 vs. smSOCS3-KO; 0.018±0.013 mm/g body weight, P=0.014), as determined by the lesion length. Immunofluorescence staining showed phospho-STAT3 in medial VSMCs by BAPN+AngII, which was more prominent in smSOCS3-KO as expected. Interestingly, smSOCS3-KO aorta showed more collagen fibers, suggesting that STAT3 activation in VSMCs may augment the tensile strength of aorta. Indeed, direct measurement of the tensile strength of the excised aortic rings indicated that smSOCS3-KO aorta had more tensile strength compared to wild type aorta (WT; 0.171±0.018 vs. smSOCS3-KO; 0.234±0.011 N/mm, P=0.004). Consistently, adventitia of smSOCS3-KO aorta showed more fibroblasts, as determined by ER-TR7 staining, compared to WT aorta. We also examined surgical specimens from AD patients for phospho-STAT3 and collagen deposition. Strong signal of phospho-STAT3 was detected at the site of dissection. However, phospho-STAT3 was reduced where strong collagen deposition was observed, suggesting that STAT3 activity is reduced after the completion of collagen deposition. From these results we concluded that activation of STAT3 in VSMCs reinforces aortic wall by enhancing collagen deposition, thus protecting aorta from dissection. Understanding of the protection mechanism of the aortic walls from dissection would lead to better understanding of the molecular pathogenesis, which is essential for developing novel therapeutic strategy for AD.
DRES-12. FUNCTIONAL GENETIC APPROACHES TO OVERCOME TEMOZOLOMIDE RESISTANCE IN GLIOBLASTOMA
Authors: Paula Nogales-Gomez, Javier Perales-Patón, Alberto Jimenez-Schuhmacher, Alvaro Curiel-Garcia, Fatima Al-Shahrour, Massimo Squatrito
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM), the highest grade of malignant astrocytomas, is the most common and lethal primary central nervous system tumour in the adults. Despite the recent advances in treatment modalities, GBM patients generally respond poorly to all therapeutic approaches and prognosis remain dismal. Radiation and chemo-resistance are characteristic of various cancer types, however it is not clear if this therapy resistance is a consequence of tumour progression or it is intrinsically associated with the genetic events that lead to the tumour formation in the first place. Gaining insights into the pathways that determine this poor treatment response will be instrumental for the development of new therapeutic modalities. Alterations of the DNA damage response (DDR) have been associated with therapy resistance, offering both challenges and opportunities from a treatment prospective. Currently, a number of laboratories are exploring the possibility of manipulating the DDR to cause selective tumour cell death through mitotic catastrophe. In order to identify genes that modulate temozolomide (TMZ) response we have performed a series of in vitro shRNA screenings, using a customized sRNA library against DDR genes and several GBM cell lines with various genetic makeup (e.g.: MGMT+, MGMT-, MMR-proficient and MMR-deficient). Our studies allowed to pinpoint both positive and negative regulators of TMZ sensitivity. Novel approaches to overcome TMZ resistance will be presented.
CBMT-03. A NOVEL METABOLIC PET TRACER STRATEGY TO DETERMINE EARLY EFFECTS OF TUMOR TREATING FIELDS (TTFIELDS)
Authors: Chirag Patel, Corinne Beinat, Yuanyang Xie, Tom Haywood, Surya Murty, Edwin Chang, Sanjiv Gambhir
Journal: Neuro-Oncology (2018)

Pyruvate kinase M2 (PKM2) is a key marker of cancer metabolic reprogramming since it catalyzes the final step in glycolysis. [18F]DASA-23 is a novel radiotracer that measures aberrantly-expressed PKM2 in glioblastoma (GBM). Tumor treating fields (TTFields), the application of alternating electric fields (100–300 kHz, 1–4 V/cm) to tumors, is emerging as the fourth therapeutic modality in GBM after surgery, temozolomide (TMZ) chemotherapy, and radiotherapy. There is an important need to assess early on whether a patient’s GBM is responding to a given therapy. We evaluated the ability of [18F]DASA-23 to detect changes in GBM metabolism in response to standard-of-care (TMZ) and emerging (TTFields) therapies. Human U87 GBM cells were subjected to 200 kHz TTFields, the IC50 of TMZ, or vehicle for three or six days (n≥3/condition), followed by evaluation of [18F]DASA-23 uptake. Immunofluorescence for PKM2 was performed to confirm the [18F]DASA-23 uptake results. Finally, Western blot analysis was performed to determine the effect of TMZ and TTFields exposure on the expression of PKM2 and a downstream enzyme, lactate dehydrogenase (LDH). 2-way ANOVA with multiple comparisons was performed. Data are reported as mean±SD. There was a significant interaction between the treatment (TTFields, TMZ, or vehicle) and treatment duration (3 or 6 days) on PKM2 expression as measured by [18F]DASA-23 uptake (p=0.005) at 30 minutes post-addition of radioactivity. Immunofluorescence independently confirmed reduced PKM2 expression due to TTFields. Western blot analysis revealed reduced PKM2 and LDH (normalized to loading control) without/with TMZ (0.43 ± 0.13 vs. 0.30 ± 0.05 [p=0.14] and 0.61 ± 0.16 vs. 0.43 ± 0.04 [p=0.12], respectively) and without/with TTFields (0.70 ± 0.23 vs. 0.15 ± 0.09 [p=0.01] and 1.14 ± 0.36 vs. 0.54 ± 0.14 [p=0.04], respectively). These data highlight the potential for non-invasive assessment of GBM’s glycolytic response to standard and emerging therapies using [18F]DASA-23. A clinical study is underway to evaluate the ability of [18F]DASA-23 to predict responders vs. non-responders to anti-GBM therapy.
Abstract 19436: First Report of Successful Implantation of a Micra Leadless Pacemaker Through an Inferior Vena Cava Filter and Complex Venous Obstruction
Authors: Erica Flores, Geoffrey J Orme, Andrew Tseng, Emrie Tomaiko, Edward Distler, Adnan Habib, Wilber Su
Journal: Circulation (2017)

Background: This is a clinical case of a leadless pacemaker implantation in the setting of complex vascular anatomy, including a previously placed inferior vena cava filter. Results: The patient is...
Abstract 15732: Impact of Bilateral Mammary Artery Grafting for Coronary Revascularization in the Obese Population, a Retrospective Study
Authors: Emmeline Ruka, François Dagenais, Siamak Mohammadi, Vincent Chauvette, Pierre Voisine
Journal: Circulation (2015)

Context: The prevalence of obesity has increased over the last decade. Although bilateral internal mammary artery (BIMA) grafting for coronary revascularization is associated with better survival in the general population, it is also a risk factor for deep sternal wound infection (DSWI), a complication more frequently seen in the obese population. The aim of this study is to determine the short and long-term outcomes of the use of BIMA in obese patients undergoing cardiac surgery, assessing the impact on survival and the incidence of DSWI. Methodology: This is a single center retrospective cohort study with prospectively collected data. We included obese patients (BMI ≥ 30 kg/m2) undergoing coronary artery bypass grafting (CABG) between April 1991 and April 2014 in our institution. Propensity score matching was conducted for the entire population studied. Results: Results showed that 5608 obese patients underwent CABG during the study period. After propensity scoring, 494 patients receiving BIMA revascularization were matched to 5089 patients receiving single internal mammary artery (SIMA) revascularization. All pre-operative characteristics were comparable except for a higher prevalence of heart failure in the SIMA group. In-hospital post-operative mortality in the two groups was comparable (1.0% BIMA vs 1.8% SIMA, p=0.86). In-hospital DSWI was also comparable (1.2% BIMA vs 1.0% SIMA, p=0.63). However total DSWI (including post-discharge DSWI, median time 19 days) was significantly higher in the BIMA group compared to the SIMA group (3.6% vs 2.2%; p&lt;0.0001). Over a median follow-up of 7.2 years (mean follow-up 7.7 ± 4.2 years), there was no observed long-term survival advantage in the BIMA vs the SIMA group (p=0.22). Conclusion: Using BIMA instead of SIMA increases the risk of DSWI in obese patients. The use of BIMA is not associated with better survival compared to the use of SIMA in this population. These results suggest that the increased short-term risk of post-operative infection associated with BIMA revascularization is not offset by a long-term survival benefit. Given the increased risk of DSWI and absence of mid- to long-term survival benefit, caution should be exerted when selecting the use of BIMA grafting in the obese population.
Prevalence of Severe Maternal Morbidity and Factors Associated With Maternal Mortality in Ontario, Canada
Authors: Joel G. Ray, Alison L. Park, Susie Dzakpasu, Natalie Dayan, Paromita Deb-Rinker, Wei Luo, K. S. Joseph
Journal: JAMA Network Open (2018)

<h3>Importance</h3> Severe maternal morbidity is defined by potentially life-threatening conditions. The association between the number of severe maternal morbidity (SMM) indicators and maternal death is not known. <h3>Objective</h3> To quantify the association between the number of SMM indicators and maternal mortality. <h3>Design, Setting, and Participants</h3> This population-based cohort study used provincial databases for data on all live birth and stillbirth hospital deliveries among women in Ontario, Canada, from April 1, 2002, to February 18, 2017. Excluded from this cohort were those with invalid identification number, non–Ontario residency, maternal age younger than 10 years or older than 55 years or unknown, or gestational age fewer than 20 weeks or unknown as well as any out-of-hospital births, ectopic pregnancies, or spontaneous or induced abortions. <h3>Exposures</h3> Number of SMM indicators identified between 20 weeks' gestation and 42 days after the index delivery. <h3>Main Outcomes and Measures</h3> Maternal death occurring from delivery to 42 days after the index delivery. <h3>Results</h3> Of the 1 953 943 total births among 1 211 396 women, 181 maternal deaths occurred within 42 days after birth, a rate of 9.3 per 100 000 births. Of the 181 women who died, 123 (68.0%) had at least 1 SMM indicator compared with 1.7% (33 152) of women who survived. Standardized differences suggested that women who died, compared with the women who lived, were older (mean [SD] age, 31.0 [6.2] years vs 30.1 [5.5] years; standardized difference, 0.15) and more likely to reside in a lower-income area (99 [54.7%] vs 832 231 [42.6%]; standardized difference, 0.24), be nulliparous (93 [51.4%] vs 880 386 [45.1%]; standardized difference, 0.13), and be of Afro-Caribbean origin (12 [6.6%] vs 64 948 [3.3%]; standardized difference, 0.15). The most frequent SMM indicators were intensive care unit admission (81 [44.8%]), invasive ventilation (77 [42.5%]), cardiac conditions (69 [38.1%]), complications of obstetric surgery or procedures (32 [17.7%]), and postpartum hemorrhage with blood transfusion (31 [17.1%]). The rate of maternal mortality increased exponentially with the number of SMM indicators: 0 indicators (3.0 per 100 000 births), 1 (71.7 per 100 000 births), 2 (385.9 per 100 000 births), 3 (1274.2 per 100 000 births), 4 (2236.8 per 100 000 births), 5 (4285.7 per 100 000 births), and 6 or more (9422.5 per 100 000 births). Adjusted relative risks for maternal death ranged from 20.1 (95% CI, 11.6-34.7) with 1 SMM indicator to 2192.0 (95% CI, 1287.0-3735.0) with 6 or more SMM indicators compared with 0 indicators. <h3>Conclusions and Relevance</h3> Maternal death may be associated with the number of SMM indicators and occur in certain identifiable groups of women; targeting preventable SMM indicators or limiting their progression may reduce the number of maternal deaths.
QOLP-06. BODY IMAGE DISTURBANCE IN PATIENTS WITH PRIMARY BRAIN TUMORS
Authors: Lindsay Rowe, Elizabeth Vera, Alvina Acquaye, Sonja Crandon, María Fletcher Ruiz, Orwa Aboud, Lisa Boris, Miranda Brown, Nancy Garren, Ming Ji, Jason Levine, Megan Mackey, Peter Mathan, Carlos Romo, Jennifer Reyes, Christine Siegel, DeeDee Smart, Jing Wu, Mark Gilbert, Kevin Camphausen, Tito Mendoza, Terri Armstrong
Journal: Neuro-Oncology (2018)

Perception of body image is an important issue for cancer patients, as patients with body image concerns are susceptible to psychosocial consequences such as depression, anxiety, difficulty coping, and poor quality of life (QoL). While this concern has been documented in patients with similar heightened risk due to visible disfigurement and lifestyle alterations, such as in head and neck tumors, currently no data exists of this QoL issue in patients with primary brain tumors (PBT). A cross-sectional survey of 100 PBT patients was conducted as part of an IRB approved prospective protocol using structured questionnaires. Participants completed the 10-item Body Image Scale (BIS) questionnaire to assess the prevalence of body image disturbance. Clinically significant body image disturbance was defined as a BIS score ≥ 10. Cronbach’s alpha was used to assess reliability. The median age was 48 (range 23–74), 86% were Caucasian, and 56% were male. Glioblastoma was the most common diagnosis (32%), with low grade tumors (I-II) representing 30% of the sample. Median time from initial diagnosis was 5 years (range 0–22), and 64% of patients had a KPS of ≥ 90. Overall, the median BIS score was 5 (range 0–27). The prevalence of clinically significant body image disturbance was 28% (95%CI: 19%-37%). Cronbach’s alpha for the BIS in this population was 0.91, with all 10 items contributing to its reliability. CONCLUSIONS: This is the first study to explore altered body image in PBT patients. Clinically significant body image disturbance was present in nearly 1/3 of patients, and was similar to other solid tumor patients felt to be at heightened risk. The BIS demonstrated good internal consistency. This data supports future research into the characteristics and etiology of this QoL issue among PBT patients.