tbuckley/cabot-search huggingface dataset:
RARE-21. A DESCRIPTIVE REPORT OF PATIENTS WITH RARE CENTRAL NERVOUS SYSTEM (CNS) CANCERS ON AN NCI-CONNECT CANCER MOONSHOT IMMUNE CHECKPOINT INHIBITOR TRIAL
Authors: Lisa Boris, Christine Bryla, Elizabeth Vera, Orwa Aboud, Nancy Garren, Deric Park, Christine Siegel, Brett Theeler, Jing Wu, Terri Armstrong, Mark Gilbert
Journal: Neuro-Oncology (2018)

There is increasing interest in the use of immunotherapy in rare CNS tumors, but limited experiences in the clinical evaluation of imaging findings and treatment toxicity in these patients. A phase II clinical trial of Nivolumab, a PD-1 inhibitor, in eleven rare CNS tumors was developed by NCI-Connect program. The purpose of this report is to describe both patient-reported outcome (PRO) and standardized assessment of these patients treatment toxicities and correlate with imaging findings. Patients were evaluated using standardized CTCAE (version 4.0) for toxicity grading and M.D. Anderson Symptom Inventory-Brain/Spine Tumor Module (MDASI-BT/SP) for PRO scoring. The item change scores (>1 point) in individual symptoms, overall symptom burden, and interference from symptoms were calculated at the time of imaging changes and classified as improved, stable or worsened. Of thirteen patients, male (n=10), median age 43 (24–74), brain location (n=10), spine location (n=4), the most common diagnosis was Ependymoma (n=4). An average of 4 cycles of nivolumab was received, with three grade 3 or higher adverse events: one grade 3 colitis and two grade 3 lymphopenia. Radiographic disease progression was declared in all, confirmed by pathological diagnosis in 8/13. Per MDASI-BT/SP, mean symptom severity was stable in all cases; interference score was worse in 3/8 cases. Significant worsening in disease-related symptoms included walking (50%) and pain (25%). Autonomic function worsened in 2/3 spine patients; concentration/memory and seizures worsened in 60% and 20% respectively in brain tumor patients. Nivolumab was well tolerated with no CNS specific adverse events. MRI changes were not associated with change in symptom burden, but was associated with significant worsening in patient-reported interference, specifically in walking, pain, seizures, cognitive or autonomic symptoms. Evaluation of cardinal symptoms associated with progression on immunotherapy may be meaningful diagnostic adjuncts in patients with rare CNS tumors.
NIMG-25. MOLECULAR PHYSIOLOGY OF CONTRAST ENHANCEMENT IN GLIOBLASTOMAS: AN ANALYSIS OF THE CANCER IMAGING ARCHIVE (TCIA)
Authors: Ali Alattar, Jeffrey Treiber, Tyler Steed, Kunal Patel, Michael Brandel, Anders Dale, Bob Carter, Clark Chen
Journal: Neuro-Oncology (2018)

The biologic processes that contribute to contrast enhancement on magnetic resonance imaging of glioblastoma patients remain poorly understood. Glioblastoma tumors from The Cancer Imaging Archive were segmented using iterative probabilistic voxel labeling. Three parameters of contrast enhancement (CE) were calculated: intensity (CEi), heterogeneity (CEh), and volumetric ratio to necrosis (CEr). Associations between these parameters and gene expression from The Cancer Genome Atlas were examined to gain insights into their underlying biologic process. Glioma CpG island methylator phenotype glioblastomas (G-CIMP) were poorly enhancing. No differences in CE parameters were found between proneural, neural, mesenchymal, and classical glioblastomas. Increased CEi was associated with expression of genes that mediate inflammatory immune responses. High CEh was associated with increased genes required for tumor migration and invasion, including those that modulate extracellular matrix (ECM) and endothelial vascularity. High CEr was associated increased gene expression associated with stressful metabolic states, including hypoxia and starvation. Our results indicate aspects of CE are associated with distinct underlying biology. Integrative analysis of these CE parameters may yield meaningful information pertaining to the biologic state of glioblastomas and guide future therapeutic paradigms.
Surgery for WPW Syndrome
Authors: ANDREW G. WALLACE, WILL C. SEALY, JOHN J. GALLAGHER, ROBERT H. SVENSON, HAROLD C. STRAUSS, JACK KASELL
Journal: Circulation (1974)

EDITORhad no further episodes of tachycardia and has undergone one pulse generator replacement.She continues to conduct through the anomalous pathway with the pacemaker cap- turing only rarely.We do, however, feel committed to life- long replacement of the pacemaker power source since the reliability of the accessory pathway as a permanent A-V con- nection is questionable.Since this first case we have treated 2 other Type A WPW patients in the same manner.One is now 3 years postoperative and another 3 months postoperative.Both are free of their tachycardias.If in future patients an accessory A-V pathway cannot be found and divided, then division of the His bundle with implantation of a permanent demand pacemaker is an acceptable alternate approach to the surgical management of patients with Type A Wolff-Parkinson-White svndrome and re- entrant atrial tachycardias.
Novel locus for atopic dermatitis in African Americans and replication in European Americans
Authors: Berta Almoguera, Lyam Vazquez, Frank Mentch, Michael E. March, John J. Connolly, Peggy L. Peissig, James G. Linneman, María del Carmen Plaza-Serón, Maria Pino-Yanes, Esteban G. Burchard, Murray Brilliant, Patrick Sleiman, Hakon Hakonarson
Journal: Journal of Allergy and Clinical Immunology (2018)
CSIG-44. TREATMENT WITH THE CASEIN KINASE 2 INHIBITOR, CX-4945, SENSITIZES MEDULLOBLASTOMA TO TEMOZOLOMIDE
Authors: Ryan Nitta, Gordon Li
Journal: Neuro-Oncology (2018)

Medulloblastoma (MB) is the most common malignant pediatric brain tumor, accounting for ~20% of all cases. While current treatments result in a cure rate of 70–75%, the surviving patients are afflicted with neurocognitive impairment, endocrine dysfunction, and a severe decrease in quality of life. Consequently, better and more effective treatments are needed to treat these young patients. Casein kinase 2 (CK2) is an intriguing therapeutic target because MB patients with elevated levels of CK2 expression have a significantly worse prognosis. To elucidate the role of CK2 in MB, we modulated CK2 expression in multiple MB cell lines (Daoy and Med1-MB). We discovered that exogenous expression of either CK2 isoform, CK2a or CK2b, increased MB cell growth and significantly decreased survival in mice that were injected intracranially with the modulated cell lines. Consistently, we demonstrated that knocking down CK2 expression using CRISPR-Cas9 or inhibiting CK2 activity using the CK2 inhibitor, CX-4945, decreased MB growth. We conducted a high throughput to identify new compounds that could work synergistically with CX-4945. We screened over 4,000 FDA approved compounds and determined that temozolomide (TMZ) enhanced the efficacy of CX-4945. We corroborated these findings when we verified that knocking out CK2a or CK2b sensitized Daoy cells to TMZ treatment. Interestingly we also determined that combinatorial treatment of CX-4945 and TMZ enhanced MB apoptosis and decreased cell growth. To elucidate the mechanism by which CK2 inhibition sensitized MB cells to TMZ we analyzed the expression of b-catenin, a known regulator of O-6-methylguanine-DNA methyltransferase (MGMT) activity. We determined that inhibition or loss of CK2 activity reduced b-catenin expression, which in turn lead to a decrease in MGMT expression. Together, our findings suggest that CK2 is a novel therapeutic target for MB and that combining CX-4945 and TMZ can lead to a promising new MB therapy.
TMIC-36. LOCAL TISSUE BIOMARKERS OF RESPONSE TO THERAPY FOR GLIOBLASTOMA
Authors: Karishma Rajani, Ian Olson, Joshua Jacobs, Slobodan Macura, Jann Sarkaria, Terry Burns
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is a common deadly malignant brain cancer of the central nervous system (CNS), with a median survival of 12–15 months. Scientific advancements are lacking in developing effective therapies for both primary GBM, as well as secondary GBMs, that typically originate as malignant transformation of lower-grade isocitrate dehydrogenase (IDH)-mutant tumors. The unique metabolomic profile of IDH-mutant tumors may present opportunities to develop biomarker signatures of therapeutic efficacy. Microdialysis is an extracellular fluid sampling collection technique utilizing a perfused semipermeable catheter to permit diffusion of molecules between brain interstitium and the perfusate. We hypothesized that microdialysis may identify a metabolomics-based biomarker response to therapy in IDH-mutant tumors. To test this hypothesis, orthotopic xenografts were generated from two patient-derived GBM lines harboring mutations in IDH1. Perfusates were collected from intra-cranial tumors in aythmic nude mice sampled at baseline, 24h and 72h time-points post treatment with temozolomide, an oral alkylating agent used to treat IDH-mutant gliomas, compared with vehicle treatment, and TMZ-treated non-tumor bearing animals. Perfusates were analyzed via unsupervised metabolomic profiling using both gas and liquid chromatography-mass spectrometry (GC/LC-MS). Results of metabolic signatures will be presented. This study aims to demonstrate proof-of-principle and the feasibility of using microdialysis as an approach to identify local tissue biomarkers of tumor response to drug therapy. This work will be complemented by parallel analysis of non-IDH-mutant and TMZ-resistant xenografts, as well as signatures of response to other therapies to yield predictive in vivo tissue biomarkers of drug responsiveness translatable to clinical practice.
QOLP-21. THE RELATIONSHIP BETWEEN CAREGIVING BURDEN AND ANXIETY SYMPTOMS IN CAREGIVERS OF PATIENTS WITH MALIGNANT GLIOMAS
Authors: Katharine Quain, Ryan Nipp, Joseph Greer, Areej El-Jawahri, Tracy Batchelor, Jennifer Temel, Deborah Forst
Journal: Neuro-Oncology (2018)

Patients with malignant gliomas have a poor prognosis and high symptom burden. Caregivers of these patients face significant challenges due to the impact of the cancer on their loved ones neurological and mental faculties. We have previously shown that rates of clinically significant anxiety symptoms in caregivers of this population are high (50%). We sought to evaluate whether caregiving burden was associated with anxiety symptoms in caregivers of patients with malignant gliomas. We conducted a prospective study in patients with newly diagnosed malignant gliomas and their caregivers, collecting caregivers self-report data within 6 weeks of diagnosis. We assessed caregivers anxiety symptoms with the Hospital Anxiety and Depression Scale, with subscale scores >7 considered clinically significant. We evaluated caregiving burden using the Caregiver Reaction Assessment (CRA) subscales, with the following domains: impact on schedule, caregivers esteem, lack of family support, impact on health, and impact on finances. We used a linear regression model to identify associations between the CRA subscales and anxiety symptoms. Fifty percent (38/76) of caregivers experienced clinically significant anxiety symptoms. Caregiving burden was significantly associated with anxiety symptoms F(5, 69)=11.525, p<0.001, R^2=0.455. Impact on schedule (B=2.273, p<0.001), impact on health (B=2.177, p=0.011), and impact on finances (B=1.374, p=0.002) added significantly to the model. CONCLUSIONS: Half of caregivers of patients with malignant gliomas experience clinically significant anxiety symptoms within 6 weeks of the patients diagnosis. Caregiving burden accounted for a substantial proportion (45.5%) of the variance in anxiety symptoms, with impact on the caregivers schedule, health, and finances demonstrating significant relationships with anxiety. These results suggest that caregivers who report a greater caregiving burden that impacts their schedule, health, and finances are also at risk for heightened anxiety symptoms. Interventions to reduce caregiving burden and decrease caregiver anxiety are needed.
PDTM-23. CD57 DEFINES A NOVEL MARKER OF GLIOBLASTOMA STEM CELLS THAT DRIVES THE INVASION OF GBM
Authors: Lin Qi, Yuchen Du, Mari Kogiso, Frank Braun, Holly Lindsay, Huiyuan Zhang, Sibo Zhao, Sarah Injac, Patricia Baxter, Jack Su, Michael Mancini, Oliver Hampton, Murali Chintagumpala, Clifford Stephan, Peter Davies, Xiao-Nan Li
Journal: Neuro-Oncology (2018)

Glioblastoma multiforme (GBM) is the most lethal brain tumor. Diffuse invasion is one of the important biologic features that make GBM particularly difficult to treat. While existing studies on GBM invasion are primarily conducted in tumor core tissues from surgical resections, it is unclear whether infiltrative GBM cells would be more informative for studying their invasive nature, and little is known if and which cancer stem cell populations are driving GBM invasion. To address these issues, we utilized 6 patient tumor-derived orthotopic xenograft mouse models to isolate invasive GBM cells (GBMINV, infiltrating normal mouse brain parenchyma) and tumor core GBM cells (GBMTC) and compared their biological features. Our result showed that the GBMINV cells have stronger neurosphere forming efficiency in vitro, more tumorigenic capacity in vivo, even some invasion-related genes also be detected to be changed in GBMINV cells. In the further study, gene profiling showed that CD57 is higher expressed in mostly GBM models and in patient tissues; CD57+ cells have stronger neurosphere formation ability with compared to CD57- cells; The survival time of mice injected with CD57+ cells decreases compared with mice with CD57- cells. Furthermore, CD57+ cells in GBMINV is higher expressed in PDOX invasive tumor cells than the expression of GBMTC cells; CD57+ cells in GBMINV cells are enriched (>2 folds) and have stronger neurosphere formation ability and more invasive with compared to GBMTC cells in mostly GBM models; The survival time of mice injected with GBMINV cells decreases compared with mice with GBMTC cells. We found that CD57+ cells expressed high levels of self-renewal genes (BMI1 and Nanog). In conclusion, we showed that invasive GBM cells were not biologically identical to the matched tumor core cells and identified CD57 as a novel stem cell marker that was associated with GBM infiltration.
ATIM-07. WINDOW-OF-OPPORTUNITY CLINICAL TRIAL OF PEMBROLIZUMAB IN RECURRENT GLIOBLASTOMA PATIENTS
Authors: John de Groot, Marta Penas-Prado, Jacob Mandel, Barbara O’Brien, Shiao-Pei Weathers, Monica Loghin, Carlos Kamiya-Matsuoka, Shouhao Zhou, Rivka Colen, Kathy Hunter, Gregory Fuller, Jason T Huse, Ganesh Rao, Jeffrey Weinberg, Sujit Prabhu, Sherise Ferguson, Ying Yuan, Luis Vence, James Allison, Padmanee Sharma, Amy Heimberger
Journal: Neuro-Oncology (2018)

A window-of-opportunity trial was used to ascertain the immune modulatory properties of pembrolizumab in recurrent GB patients. In an open label, single-center, single-arm Phase 2 trial, 15 patients with recurrent GBM, were treated with up to two doses of pembrolizumab prior to surgery and afterwards received pembrolizumab until disease progression or the development of unacceptable toxicities. The co-primary objectives of the study were to evaluate immune effector function in resected GBM tissue and to determine progression free survival at 6 months (PFS6). We screened 21 patients, of whom 15 were enrolled and received at least one dose of pembrolizumab. The most common adverse event was grade 1 or 2 fatigue in 40% of patients followed by headache in 27%. There were five grade 3 or 4 adverse events including one with cerebral edema requiring surgery. There were no treatment-related deaths; 5 (33%) of 15 patients died because of progression of disease. The median follow-up time for all patients was 12 months (95% CI3-31). Based on iRANO, 10 patients had progressive disease, 3 had a partial response and 1 had stable disease. The longest ongoing duration of response exceeded 34 months in two patients. Median PFS was 7 months (95% CI 4–16) and PFS6 was 53% (95% CI 33%-86%). Median OS was not reached (95% CI 15 to not reached), with an estimated 1-year overall survival of 72% (52%–99.6%). CyTOF and IHC immune analysis revealed that GBM tumors were markedly enriched with CD68+ macrophages but had a paucity of effector T cells. Although pembrolizumab was well tolerated, a high predominance of immunosuppressive CD68+ myeloid cells and a marked scarcity of T cells within the tumor microenvironment may be limiting the activity of PD-1 blockade.
Abstract 17760: Maintaining High Quality CPR With an Integrated Manual/Mechanical Resuscitation Protocol
Authors: Taro Irisawa, Tyler Vadeboncoeur, Cameron Hypes, Annemarie Silver, Robyn McDannold, Margaret Mullins, Dan Spaite, Bentley Bobrow
Journal: Circulation (2015)

Background: High quality manual chest compressions (CC) can be achieved on scene during resuscitation of cardiac arrest patients, but manual CC quality can deteriorate during patient extrication and transport. The purpose of this study was to describe the effect on CC quality of an integrated manual/mechanical chest compression protocol developed to maintain CC quality and patient/provider safety throughout resuscitation. Methods: CC quality was monitored using a monitor with accelerometer-based CC sensing (E Series/X Series, ZOLL Medical) during the treatment of consecutive out-of-hospital cardiac arrest patients between 3/1/2013-4/30/2015. The EMS agency performed manual CC guided by real-time audiovisual feedback on scene but deployed the AutoPulse load-distributing band CC device (LDB, ZOLL Medical) in a choreographed manner for extrication and transport. The LDB was also placed prophylactically on patients after ROSC. Descriptive statistics are reported as median (IQR). Results: A total of 71 OHCA patients were treated (median age 58 yrs, 66 % male) of which 39 received only manual CC and 32 received both manual and LDB CCs (22 with LDB deployed during ongoing manual CC and 10 with LDB placed after ROSC). With real-time CC feedback, high quality CCs were performed [depth 2.38 in (2.17-2.64), rate 100.3 cpm (99.2-102.5), CC fraction 87.0% (83.8-89.5)]. For patients requiring transport, the LDB was started after 14.2 min (11.6-19.2) of manual CC and was placed with minimal interruptions- total of 27.5 sec (23-42) pause time in 2 minutes prior to LDB deployment. During transport, CC fraction remained high (91.7%; 89.3-95.4) with use of LDB. Seven of 10 patients prophylactically placed on the LDB rearrested, 3 rearrested during transport. Conclusion: A choreographed and rehearsed integrated chest compression protocol featuring both manual and mechanical compressions, allows for high quality resuscitation with minimal compression interruptions. Placement of a mechanical device on patients after ROSC may be beneficial as over two-thirds of patients in this study rearrested, one-third of which occurred during transport when delivery of manual compressions is difficult and potentially dangerous.
HOUT-24. DURAMATRIX-ONLAY® PLUS IN CRANIAL SURGERY IS ASSOCIATED WITH AN ACCEPTABLE COMPLICATION PROFILE: A CASE SERIES
Authors: Methma Udawatta, Carlito Lagman, John Sheppard, Thien Nguyen, Giyarpuram Prashant, Isaac Yang
Journal: Neuro-Oncology (2018)

DuraMatrix Onlay® Plus (Stryker, Kalamazoo, Michigan) is a collagen dura membrane derived from purified bovine Achilles tendon. The matrix provides a scaffold for collagen synthesis and is intended to be used as an onlay without the need for dural sutures. To describe our experience with 33 consecutive patients who underwent a duraplasty procedure using the novel DuraMatrix Onlay® Plus collagen dura membrane. This is a retrospective case series of consecutive patients who underwent a duraplasty procedure at a single academic hospital in Los Angeles, California between May 2016 and March 2017. The primary outcome is the rate of cerebrospinal fluid (CSF) leak. Secondary outcomes include the rates of dural substitute complication, infection, and removal. Thirty-three patients underwent a duraplasty procedure using the DuraMatrix Onlay® Plus material. The average age of the patients was 41 ± 21 years (range 2–75 years). There were 18 females and 15 males. The majority of procedures were elective and for resection of a lesion (n = 19, 58%), with the average size of material used measured at 18 ± 14 cm2. There were no secondary CSF leaks at an average follow-up of 3 months. The rates of dural substitute complication, infection, and removal were 6%, 6%, and 3%, respectively. In one patient, the dural substitute was removed for concern of infection. DuraMatrix-Onlay® Plus is associated with an acceptable complication profile, including a low rate of CSF leak.
Angiotensin–Neprilysin Inhibition in Acute Decompensated Heart Failure
Authors: Eric J. Velazquez, David A. Morrow, Adam D. DeVore, Carol I. Duffy, Andrew P. Ambrosy, Kevin McCague, Ricardo Rocha, Eugene Braunwald
Journal: New England Journal of Medicine (2018)

Acute decompensated heart failure accounts for more than 1 million hospitalizations in the United States annually. Whether the initiation of sacubitril-valsartan therapy is safe and effective among patients who are hospitalized for acute decompensated heart failure is unknown.We enrolled patients with heart failure with reduced ejection fraction who were hospitalized for acute decompensated heart failure at 129 sites in the United States. After hemodynamic stabilization, patients were randomly assigned to receive sacubitril-valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) or enalapril (target dose, 10 mg twice daily). The primary efficacy outcome was the time-averaged proportional change in the N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration from baseline through weeks 4 and 8. Key safety outcomes were the rates of worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema.Of the 881 patients who underwent randomization, 440 were assigned to receive sacubitril-valsartan and 441 to receive enalapril. The time-averaged reduction in the NT-proBNP concentration was significantly greater in the sacubitril-valsartan group than in the enalapril group; the ratio of the geometric mean of values obtained at weeks 4 and 8 to the baseline value was 0.53 in the sacubitril-valsartan group as compared with 0.75 in the enalapril group (percent change, -46.7% vs. -25.3%; ratio of change with sacubitril-valsartan vs. enalapril, 0.71; 95% confidence interval [CI], 0.63 to 0.81; P<0.001). The greater reduction in the NT-proBNP concentration with sacubitril-valsartan than with enalapril was evident as early as week 1 (ratio of change, 0.76; 95% CI, 0.69 to 0.85). The rates of worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema did not differ significantly between the two groups.Among patients with heart failure with reduced ejection fraction who were hospitalized for acute decompensated heart failure, the initiation of sacubitril-valsartan therapy led to a greater reduction in the NT-proBNP concentration than enalapril therapy. Rates of worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema did not differ significantly between the two groups. (Funded by Novartis; PIONEER-HF ClinicalTrials.gov number, NCT02554890 .).