tbuckley/cabot-search huggingface dataset:
SURG-41. BLOOD-BRAIN BARRIER DISRUPTION WITH HIGH-FREQUENCY ELECTROPORATION IN VIVO: A PRELIMINARY INVESTIGATION DEMONSTRATING THE EFFECTS OF VARIED PULSE WIDTHS AND INTRA-PHASE DELAYS
Authors: Melvin Lorenzo, Sean Thomas, Scott Verbridge, John Robertson, John Rossmeisl, Rafael Davalos
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE Treatment of CNS disorders suffer from the inability to deliver large therapeutic agents to the brain parenchyma due to protection from the blood-brain barrier (BBB). High-frequency electroporation (HFE) employs a series of high voltage pulsed electric fields to disrupt the BBB and/or ablate tumor tissue while sparring proteinaceous structures. Pulsing parameters pulse width and intra-phase delay can be modulated to reduce excitation of muscle and nervous tissues, though this is inherently accompanied by an increase in thresholds for ablation in non-CNS tissues. Here, we investigate the effects of pulse width and intra-phase delay on intracranial tissue for BBB disruption (BBBD) in an in vivo healthy rodent model. METHODS 18 male Fisher rats underwent craniectomy procedure and two blunt tipped monopolar electrodes were advanced into the brain for HFE therapy. 200 bursts of HFE were delivered at a voltage-to-distance ratio 600 V/cm. BBBD was verified with contrast enhanced T1W MRI (gadopentetate dimeglumine) and pathologically (Evans blue dye). RESULTS Gross pathological sections and contrast enhanced T1W scans demonstrated BBBD for 2-2-2 µs (n = 4, 36.6 ± 9.4 mm3, 36.7 ± 13.0 mm3), 2-5-2 µs (n = 4, 74.1 ± 7.7 mm3, 74.7 ± 9.8 mm3), 5-2-5 µs (n = 4, 53.9 ± 8.1 mm3, 59.2 ± 10.8 mm3), 5-5-5 µs (n = 4, 81.2 ± 7.9 mm3, 84.1 ± 8.7 mm3), and 10-1-10 µs (n = 2, 61.0 ± 2.8 mm3, 60.0 ± 4.2 mm3) HFE. Histologically, tissue damage was restricted to electrode insertion tracks. BBBD was induced with minimal muscle contractions and minimal cell death attributed to HFE. Numerical modeling indicated the threshold for HFE-mediated BBBD as low magnitude electric fields (&amp;lt; 201 V/cm). These data suggest HFE-mediated BBBD is only modestly affected by changes in pulse width and intra-phase delay.
GCT-47. TREATMENT STRATEGIES FOR GIANT IMMATURE TERATOMAS IN INFANTS
Authors: Tomoru Miwa, Maya Kono, Haruko Shima, Hiroyuki Shimada, Kazunari Yoshida
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Immature teratomas are the most frequent fetal brain tumors and show a poor prognosis. At onset, the tumor is often already giant with deep origins such as suprasellar or pineal region, and easy bleeding is also considered to be a cause of poor prognosis. On the other hand, it is also known that the prognosis is improved in total removal cases. METHODS We investigated the best treatment strategy based on two cases of total removal of giant immature teratomas in infants. RESULTS 1.5 month after birth at onset (median), maximum diameter of 75 mm (median). A giant tumor centered around the third ventricle with hydrocephalus. First, biopsy (+septostomy) was performed using an endoscope. The tumor showed easily bleeding. In addition, external ventricular drainage was taken out of the lower abdomen subcutaneously by long tract. After chemotherapy (carboplatin and etoposide), tumor removal was performed by using drainage tract. Both cases showed not easily bleeding at that time and the tumor was safely removed. Regarding the deep blind spot, using a flexible endoscope was effective. They showed no recurrence after total removal (median 50 months). DISCUSSION There have been reports of cases in which chemotherapy for immature teratomas suppressed tumor growth and reduced bleeding and safely removed totally. In infants giant immature teratomas, chemotherapy before tumor removal can be expected to reduce bleeding, and further increase body weight during that period. In addition, long-term placement of ventricular drainage by long tract during the chemotherapy can prevent brain development delay due to hydrocephalus.
Atezolizumab Plus Chemotherapy for First-Line Treatment of Nonsquamous NSCLC: Results From the Randomized Phase 3 IMpower132 Trial
Authors: Makoto Nishio, Fabrice Barlesi, Howard West, Simon Ball, Rodolfo Bordoni, Manuel Cobo, Pascale Dubray Longeras, Jerome Goldschmidt, Silvia Novello, Francisco Orlandi, Rachel E. Sanborn, Zsuzsanna Szalai, Grigoriy Ursol, Diana Mendus, Lijia Wang, Xiaohui Wen, Mark McCleland, Tien Hoang, See Phan, Mark A. Socinski
Journal: Journal of Thoracic Oncology (2020)

IntroductionWe report the final results of the phase 3 IMpower132 study evaluating atezolizumab plus carboplatin or cisplatin plus pemetrexed (APP) in patients with nonsquamous NSCLC.MethodsChemotherapy-naive patients with stage IV nonsquamous NSCLC without sensitizing EGFR or ALK genetic alterations were randomized in a one-to-one ratio to receive four or six cycles of carboplatin or cisplatin plus pemetrexed (PP) or APP every 3 weeks, followed by maintenance therapy with atezolizumab plus pemetrexed or pemetrexed alone. Co-primary end points were overall survival (OS) and investigator-assessed progression-free survival (PFS).ResultsThe intention-to-treat population included 578 patients (APP, n = 292; PP, n = 286). At the primary PFS analysis (May 22, 2018; median follow-up, 14.8 mo), APP exhibited significant PFS improvement versus PP (median = 7.6 versus 5.2 mo, stratified hazard ratio [HR] = 0.60, 95% confidence interval [CI]: 0.49–0.72, p < 0.0001). OS for the APP group was numerically better but not statistically significant at the interim (May 22, 2018; median = 18.1 versus 13.6 mo, stratified HR = 0.81, 95% CI: 0.64–1.03, p = 0.0797) and final analyses (July 18, 2019; median = 17.5 versus 13.6 mo; stratified HR = 0.86, 95% CI: 0.71–1.06, p = 0.1546). The OS and PFS results favored APP versus PP across subgroups. Grade 3 or 4 treatment-related adverse events occurred in 54.6% (APP) and 40.1% (PP) of patients; grade 5 treatment-related events occurred in 3.8% and 2.9%, respectively.ConclusionsIMpower132 met its co-primary PFS end point but not its co-primary OS end point, with numerical improvement for OS in the APP arm. APP had a manageable safety profile, with no new or unexpected safety signals identified.
Will the asthma revolution fostered by biologics also benefit adult ICU patients?
Authors: Arnaud Bourdin, Jérémy Charriot, Clément Boissin, Engi Ahmed, Carey Suehs, Arthur De Sevin, Mathilde Volpato, Laurie Pahus, Delphine Gras, Isabelle Vachier, Laurence Halimi, Dominic Hamerlijnck, Pascal Chanez
Journal: Allergy (2020)

Abstract Purpose Asthma exacerbations are inflammatory events that rarely result in full hospitalization following an ER visit. Unfortunately, certain patients require prolonged support, including occasional external lung support through ECMO or ECCOR (with subsequent further exposure to other life‐threatening issues), and some die. In parallel, biologics are revolutionizing severe asthma management, mostly in T2 high patients. Methods We extensively reviewed the current unmet needs surrounding ICU‐admitted asthma exacerbations, with a focus on currently available drugs and the underlying biological processes involved. We explored whether currently available T2‐targeting drugs can reasonably be seen as potential players not only for relapse prevention but also as candidate drugs for a faster resolution of such episodes. The patient's perspective was also sought. Results About 30% of asthma exacerbations admitted to the ICU do not resolve within five days. Persistent severe airway obstruction despite massive doses of corticosteroids and maximal pharmacologically induced bronchodilation is the main cause of treatment failure. Previous ICU admission is the main risk factor for such episodes and may eventually be considered as a T2 surrogate marker. Fatal asthma cases are hallmarked by poorly steroid‐sensitive T2‐inflammation associated with severe mucus plugging. New, fast‐acting T2‐targeting biologics (already used for preventing asthma exacerbations) have the potential to circumvent steroid sensitivity pathways and decrease mucus plugging. This unmet need was confirmed by patients who reported highly negative, traumatizing experiences. Conclusions There is room for improvement in the management of ICU‐admitted severe asthma episodes. Clinical trials assessing how biologics might improve ICU outcomes are direly needed.
Prevalence, progression and impact of chronic cough on employment in Northern Europe
Authors: Henrik Johansson, Ane Johannessen, Mathias Holm, Bertil Forsberg, Vivi Schlünssen, Rain Jõgi, Michael Clausen, Eva Lindberg, Andrei Malinovschi, Össur Ingi Emilsson
Journal: European Respiratory Journal (2020)

We investigated the prevalence of chronic cough and its association with work ability and sick leave in the general population. Data were analysed from the Respiratory Health In Northern Europe (RHINE) III cohort (n=13 500), of which 11 252 participants had also participated in RHINE II 10 years earlier, a multicentre study in Northern Europe. Participants answered a questionnaire on chronic cough, employment factors, smoking and respiratory comorbidities. Nonproductive chronic cough was found in 7% and productive chronic cough in 9% of the participants. Participants with nonproductive cough were more often female and participants with productive cough were more often smokers and had a higher body mass index (BMI) than those without cough. Participants with chronic cough more often reported &gt;7 days of sick leave in the preceding year than those without cough (“nonproductive cough” 21% and “productive cough” 24%; p&lt;0.001 for comparisons with “no cough” 13%). This pattern was consistent after adjusting for age, sex, BMI, education level, smoking status and comorbidities. Participants with chronic cough at baseline reported lower work ability and more often had &gt;7 days of sick leave at follow-up than those without cough. These associations remained significant after adjusting for cough at follow-up and other confounding factors. Chronic cough was found in around one in six participants and was associated with more sick leave. Chronic cough 10 years earlier was associated with lower work ability and sick leave at follow-up. These associations were not explained by studied comorbidities. This indication of negative effects on employment from chronic cough needs to be recognised.
GCT-40. PROGNOSTIC FACTORS FOR PATIENTS WITH RELAPSED CENTRAL NERVOUS SYSTEM (CNS) NON-GERMINOMATOUS GERM CELL TUMORS (NGGCTs)
Authors: Mohammad H Abu-Arja, Diana S Osorio, Joseph R Stanek, Jonathan L Finlay, Mohamed S AbdelBaki
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Patients with relapsed CNS NGGCTs experience poor outcomes. Our aim to explore prognostic factors that may guide future clinical trials. METHODS A review of clinical trials that included patients with relapsed CNS NGGCTs was performed. RESULTS Seventy-four patients were identified; only 14 patients (19%) were long-term survivors. Patients who relapsed &amp;gt;24 months after initial diagnosis had a survival rate of 47% compared with 15% of patients who relapsed in &amp;lt;24 months after initial diagnosis (p= 0.015). Patient with serum/cerebrospinal fluid (CSF) alpha-fetoprotein (AFP) level &amp;lt;25 ng/ml at relapse had a survival rate of 40% compared with 0% among patients with serum/CSF AFP level &amp;gt;25 ng/ml at relapse (p= 0.0015). Patients who achieved complete response/continued complete response (CR/CCR) by the end of therapy had a survival rate of 59% compared with 3% among patients who had less than CR/CCR by the end of therapy (p= 0.0001). Patients who received marrow-ablative chemotherapy followed by autologous hematopoietic cell rescue (HDCx/AuHCR) at relapse had a survival rate of 33% compared with 9% of patients who did not receive HDCx/AuHCR at relapse (p=0.056). The extent of surgical resection, receiving radiotherapy, and beta-human chorionic gonadotropin levels at relapse were not statistically associated with improved outcomes. CONCLUSION Timing of relapse (&amp;gt;24 months after initial diagnosis), serum/CSF AFP &amp;lt;25 ng/ml at relapse, achieving CR/CCR after treatment were associated with a positive impact on survival. Receiving HDCx/AuHCR at relapse was associated with an improved outcome trend among the patients.
EPCT-12. PNOC015: PHASE 1 STUDY OF MTX110 (AQUEOUS PANOBINOSTAT) DELIVERED BY CONVECTION ENHANCED DELIVERY (CED) IN CHILDREN WITH NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) PREVIOUSLY TREATED WITH RADIATION THERAPY
Authors: Sabine Mueller, Cassie Kline, Javier Villanueva-Meyer, Carly Hoffman, Shannon Raber, Erin Bonner, Javad Nazarian, Shannon Lundy, Annette M Molinaro, Michael Prados, Mariella Filbin, Nalin Gupta
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE To determine safety and distribution of MTX110 delivered by CED in newly diagnosed DIPG patients. METHODS DIPG patients (3–21 years) were enrolled after radiation. CED of MTX110 combined with gadoteridol was completed based on dose levels (DL) (30–90 µM with volumes ranging from 3 cc (single dose) to 2 consecutive doses of 6 cc; total number of DL=7). Catheter position was chosen to maximize tumor coverage. Distribution of infusate was monitored with real-time MR imaging. Repeat CED was performed every 4–8 weeks if tolerated. Quality of life (QOL) assessments using PedsQL Generic Core and Brain Tumor modules were obtained at baseline (n=5), 3-months (n=3), and end of therapy (n=2). Single-cell RNA sequencing and analysis of histone modifications was performed to assess pharmacodynamic effects on DIPG cells. RESULTS Between May 2018-Dec 2019, 6 patients were enrolled (median age 8 years, range 5–21). Dose limiting toxicities included: grade 3 gait disturbance (DL7; cycle 1); grade 3 muscle weakness/vagus nerve disorder (DL5; cycle 4) and grade 2 intolerable dysphagia (DL7; cycle 4). Twelve CED procedures were completed at DL7 and repeated cycles ranged from 2 to 7. Infusion to distribution volume ratio was approximately 1:3.5. There were no significant changes in self-reported QOL. Parent ratings of patients’ worry (p = 0.04) and overall QOL (p = 0.03) significantly decreased at 3-months. CONCLUSION Repeat CED of MTX110 at the highest dose is tolerable. Tissue concentrations are likely to be substantially higher compared to oral dosing. Pharmacodynamic effects will be presented.
BIOM-06. CLINICAL AND PROGNOSTIC SIGNIFICANCE OF KRAS MUTATIONS FOR BRAIN METASTASES FROM COLORECTAL ADENOCARCINOMA IN THE UNITED STATES
Authors: Nayan Lamba, Timothy Smith, Bryan Iorgulescu
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND KRAS mutations in colorectal adenocarcinomas have been associated with metastatic involvement of the brain (BM); and predict a lack of benefit to EGFR-targeted antibodies. Herein we leverage national data to evaluate the prevalence and impact of KRAS mutations on colorectal BMs. METHODS Newly-diagnosed patients with stage 4 colorectal adenocarcinoma were identified from the National Cancer Database, comprising &amp;gt;70% of newly-diagnosed cases in the U.S. from 2010–2016. Multivariable logistic regression was used to evaluate predictors of brain involvement, including KRAS mutation status. Overall survival (OS) was estimated with Kaplan-Meier techniques, and compared by logrank test and multivariable Cox regression. RESULTS Of 86,719 patients newly presenting with stage 4 colorectal adenocarcinoma, 1.5% (n=1,318) had BMs. 39.7% of BM cases had KRAS mutation testing, in which 57.9% (n=361) of BM cases were KRAS-mutant, as opposed to only 45.6% (n=13,259) of non-BM cases (p&amp;lt; 0.001). Mutant KRAS persisted as independently associated with BMs (OR 1.37, 95%CI: 1.09–1.72, p=0.006) following adjustment for age at diagnosis, sex, AJCC cT and cN status, and metastatic lung, liver, or bone involvement. Overall, BM patients displayed a median OS of 5.3 months (95%CI: 4.6–6.1): 7.5 months (95%CI: 5.7–10.6) if KRAS-wildtype vs. 12.0 months (95%CI: 10.4–15.4) if KRAS-mutant (p=0.01). The improved OS associated with KRAS-mutant BMs also persisted (HR 0.63, 95%CI: 0.47–0.84, p=0.001) after adjusting for the aforementioned clinical variables, in addition to comorbidity index, chemoradiotherapy, metastasectomy, and treating hospital type. CONCLUSIONS Nationally, testing colorectal BM patients for KRAS mutation status—a predictive biomarker for EGFR-mab therapy—remains underutilized. KRAS-mutant colorectal adenocarcinomas were more likely to have metastatic brain involvement, with KRAS-wildtype BMs demonstrating significantly worse OS than KRAS-mutant BMs. Our data suggest that KRAS mutation testing is underutilized in colorectal BM patients and provides useful prognostic information.
PATH-35. A SCALABLE MOLECULARLY INTEGRATED CLASSIFIER FOR MENINGIOMA OUTPERFORMS WHO CLASSIFICATION
Authors: Wenya Linda Bi, Joseph Driver, Sherwin Tavakol, Samantha Hoffman, Eleanor Woodward, Malak Abedalthagafi, Ossama Al-Mefty, Keith Ligon, Rameen Beroukhim, Azra Ligon, Adrian Dubuc, Ian Dunn, Sandro Santagata
Journal: Neuro-Oncology (2020)

Abstract The clinical behavior of meningiomas often belies their histopathologic grade. Increasing data suggest that molecular features augment classic World Health Organization (WHO) classification in predicting recurrent risk. We investigated the influence of histopathology, chromosome copy number, and treatment on meningioma outcome to construct a simple, scalable, molecularly integrated classifier. METHODS: We analyzed 684 meningiomas with genome-wide chromosomal copy-number profiling for clinical features, pre-/post-operative tumor volume, histopathology, and recurrence. We devised a point-based molecularly-integrated classification system (IC 1-3), incorporating mitotic count and nine common molecular alterations consistently associated with risk of recurrence across four independent statistical tests. We used brier curves, time-dependent area-under-the-curve, and average precision to assess model performance. We added treatment variables, including primary or recurrent status, tumor size, and extent of resection, to the Integrated class to formulate a nomogram of recurrence risk at 5 years. RESULTS: The Integrated Class significantly associated with recurrence in a multivariate model (IC Class 2 vs 1: HR 3.60, 95% CI 2.19-5.91; Class 3 vs 1: HR 5.15, 95% CI 3.28-8.09) and outperformed WHO grade in predicting recurrence (by integrated brier score, 0.093 vs 0.178, internally and independently validated). WHO Grade I and IC-1 exhibited 86% concordance, 31.5% between Grade II and IC-2, and 64% between Grade III and IC-3. WHO grade I meningiomas with IC 2-3 fared significantly worse than WHO grade II-III meningiomas with IC-1 designation. Each additional molecular feature incrementally strengthens the classifier, allowing for application of single-arm FISH or combinatorial genome-wide signatures based on available resources. Intriguingly, receipt of adjuvant radiation in newly diagnosed WHO Grade II-III or IC 2-3 meningiomas was associated with greater propensity for recurrence, after controlling for extent of resection. CONCLUSION: We present a scalable, molecularly-integrated classification for meningioma that better predicts recurrence compared to classic histopathologic grades to aid in clinical management.
Impairment in the Mesenchymal Bone-Marrow Niche of Beta-Thalassemia Patients and Association with Prolonged Iron Exposure
Authors: Stefania Crippa, Valeria Rossella, Laura Silvestri, Annamaria Aprile, Samantha Scaramuzza, Silvia Rivis, maria Antonietta Avanzini, Marco Zecca, Sarah Marktel, Fabio Ciceri, Alessandro Aiuti, Giuliana Ferrari, Maria Ester Bernardo
Journal: Blood (2017)
TMOD-13. RESEARCH RESOURCES FOR OLIGODENDROGLIOMA NOW AVAILABLE TO RESEARCH COMMUNITY
Authors: Brock Greene, Mario Suva, Daniel Cahill, Michelle Monje, Jeremy Rich, Duane Mitchell, Roel Verhaak, Bob Abraham
Journal: Neuro-Oncology (2020)

Abstract There are ~1,400 oligodendroglioma diagnoses in the U.S. annually, with up to 15,000 persons living with this disease today. However, there have not been any new treatments approved for oligodendroglioma in the past 25 years. A lack of funding and advocacy has contributed to this, but the lack of reagents allowing researchers to study the disease may be the most critical factor. Oligodendroglioma tissue and disease models, including cell lines and xenograft models, are crucial resources needed for researchers to understand oligodendroglioma biology, identify new treatment strategies, and perform preclinical research. Oligo Nation has created a collection of oligo tissue large enough to enable adequately-sized studies and meet the needs of researchers interested in studying Oligodendroglioma. Oligo Nation is also investing in developing new models of the disease as well as acquiring existing models to make them easily accessible to the research community. A number of resources are now available to support academic researchers: An oligodendroglioma biobank with over 100 patient tissue samples; WGS and RNA sequencing data, including long reads for these samples; An oligodendroglioma cell line repository with 3 lines available (to date) to researchers; An oligodendroglioma PDX repository will be available in the coming year through the NCI Patient Derived Model Repository; GEMM models that include both IDH1 (R132) and CIC mutations, two of the most common mutations in oligodendroglioma, will be available by the end of 2020. Extensive analysis including high-throughput and CRISPR knockout screens will be performed on all existing and new cell lines. The data generated on these models will be stored in a public repository and made available to the research community. Making these reagents available to the research community will hopefully increase research in oligodendroglioma, and will set us on a path to discover improved and ultimately curative treatments for this disease.