tbuckley/cabot-search huggingface dataset:
CMET-24. NEXT-GENERATION EPIDERMAL GROWTH FACTOR RECEPTOR TYROSINE KINASE INHIBITORS FOR LEPTOMENINGEAL CARCINOMATOSIS
Authors: Kate Grimsrud, Maciej Mrugala
Journal: Neuro-Oncology (2018)

EGFR mutation status is strongly correlated with leptomeningeal carcinomatosis in non-small-cell lung cancer. Historically, patients were treated with first-generation EGFR tyrosine kinase inhibitors, however most would eventually develop resistance and disease progression. Therefore, recent interest has sparked in investigating next-generation EGFR- TKI monotherapy. We report two patients treated with next-generation EGFR-TKI monotherapy, independent of whole brain radiotherapy, with favorable response and outcome. CASE 1: A 70-year-old woman with non-small cell lung adenocarcinoma in status post resection and erlotinib was in remission until 10 years later when she presented with findings of intracranial hypertension. Imaging demonstrated an enhancing right frontal lesion and leptomeningeal disease. After six months on afatinib 30 mg daily, she had near-complete resolution of symptoms and significant decrease in leptomeningeal enhancement. CASE 2: A 54-year-old woman with non-small-cell lung adenocarcinoma underwent resection and presented two years later with multifocal right frontotemporal hemorrhagic metastases and leptomeningeal enhancement. Pathology from brain tumor resection showed pulmonary adenocarcinoma with EGFR exon 19 mutation. She received a single pulsed dose of erlotinib 1500 mg followed by osimertinib 80 mg daily with significant improvement in symptoms and complete resolution on repeat neuroimaging two months later. Systemic chemotherapy alone has traditionally been ineffective in patients with CNS metastasis, likely due to poor penetration of the blood brain barrier by early-generation EGFR-TKIs and evolving drug resistance. The next-generation EGFR-TKIs may have improved success in treatment of leptomeningeal metastases in non-small-cell lung adenocarcinoma when compared to the first- and second-generation EGFR-TKIs. This could be particularly true in patients with documented exon 19 deletions, as in our second case. Next-generation EGFR-TKI monotherapy could be considered in select patients with leptomeningeal metastases from lung adenocarcinoma. More research is needed to review this potential therapeutic option, especially for use as first-line therapy.
MNGI-41. LARGE VOLUME RE-IRRADIATION FOR RECURRENT MENINGIOMA WITH PULSED REDUCED DOSE RATE RADIOTHERAPY
Authors: Jacob Witt, Hima Musunuru, Adam Bayliss, Steven Howard
Journal: Neuro-Oncology (2018)

Meningiomas comprise up to 30% of primary brain tumors. The majority of meningioma patients enjoy high rates of control after conventional therapies. However, patients with recurrent disease previously treated with radiotherapy have few options for salvage treatment, and systemic interventions have proven largely ineffective. The aim of this study was to determine whether PRDR radiotherapy was well tolerated and effective in patients with recurrent meningioma. We retrospectively identified 8 patients with recurrent intracranial meningioma treated with PRDR from April 2013 to August of 2017 at a single institution. All patients had radiographic and/or pathologic evidence of progression prior to treatment and had previously completed conventional radiotherapy. Relevant patient, tumor, and treatment characteristics were abstracted from the electronic medical record. Acute and late toxicities were graded based on CTCAE 4.0. Of 8 patients, 6 had histologically confirmed atypical meningiomas upon recurrence. All patients were re-treated with IMRT at an apparent dose rate of 0.0667 Gy/min. Median time between radiation courses was 7.7 years. Median PRDR dose was 54 Gy in 27 fractions to a median volume of 261.6 cm3. Two patients (25%) had in field failure with a median follow up of 23.3 months. PFS at 6 months was 100%. All but one (87.5%) patient was still alive at last follow up. No patient experienced grade ≥2 acute or late toxicities. PRDR re-irradiation is a viable option for patients with recurrent meningioma previously treated with radiotherapy. A phase II trial to assess this prospectively is in development.
Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome
Authors: Gregory G. Schwartz, P. Gabriel Steg, Michael Szarek, Deepak L. Bhatt, Vera A. Bittner, Rafael Diaz, Jay M. Edelberg, Shaun G. Goodman, Corinne Hanotin, Robert A. Harrington, J. Wouter Jukema, Guillaume Lecorps, Kenneth W. Mahaffey, Angèle Moryusef, Robert Pordy, Kirby Quintero, Matthew T. Roe, William J. Sasiela, Jean-François Tamby, Pierluigi Tricoci, Harvey D. White, Andreas M. Zeiher
Journal: New England Journal of Medicine (2018)

Patients who have had an acute coronary syndrome are at high risk for recurrent ischemic cardiovascular events. We sought to determine whether alirocumab, a human monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9), would improve cardiovascular outcomes after an acute coronary syndrome in patients receiving high-intensity statin therapy.We conducted a multicenter, randomized, double-blind, placebo-controlled trial involving 18,924 patients who had an acute coronary syndrome 1 to 12 months earlier, had a low-density lipoprotein (LDL) cholesterol level of at least 70 mg per deciliter (1.8 mmol per liter), a non-high-density lipoprotein cholesterol level of at least 100 mg per deciliter (2.6 mmol per liter), or an apolipoprotein B level of at least 80 mg per deciliter, and were receiving statin therapy at a high-intensity dose or at the maximum tolerated dose. Patients were randomly assigned to receive alirocumab subcutaneously at a dose of 75 mg (9462 patients) or matching placebo (9462 patients) every 2 weeks. The dose of alirocumab was adjusted under blinded conditions to target an LDL cholesterol level of 25 to 50 mg per deciliter (0.6 to 1.3 mmol per liter). The primary end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization.The median duration of follow-up was 2.8 years. A composite primary end-point event occurred in 903 patients (9.5%) in the alirocumab group and in 1052 patients (11.1%) in the placebo group (hazard ratio, 0.85; 95% confidence interval [CI], 0.78 to 0.93; P<0.001). A total of 334 patients (3.5%) in the alirocumab group and 392 patients (4.1%) in the placebo group died (hazard ratio, 0.85; 95% CI, 0.73 to 0.98). The absolute benefit of alirocumab with respect to the composite primary end point was greater among patients who had a baseline LDL cholesterol level of 100 mg or more per deciliter than among patients who had a lower baseline level. The incidence of adverse events was similar in the two groups, with the exception of local injection-site reactions (3.8% in the alirocumab group vs. 2.1% in the placebo group).Among patients who had a previous acute coronary syndrome and who were receiving high-intensity statin therapy, the risk of recurrent ischemic cardiovascular events was lower among those who received alirocumab than among those who received placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; ODYSSEY OUTCOMES ClinicalTrials.gov number, NCT01663402 .).
HCV-Associated Liver Fibrosis and <i>HSD17B13</i>
Authors: Frédégonde About, Laurent Abel, Aurélie Cobat
Journal: New England Journal of Medicine (2018)

Variant HSD17B13 and HCV-Associated Liver Fibrosis A loss-of-function variant in HSD17B13 (rs72613567:TA) has been found to be associated with protection against chronic liver disease. This study s...
GENE-27. GENOME-WIDE DNA METHYLATION PROFILING IN GRADE II AND III GLIOMAS REVEALS A SUBSET OF GENES WITH PROGNOSTIC SIGNIFICANCE CONTROLLED BY PROMOTER METHYLATION
Authors: Wei Meng, Erica Hlavin Bell, Rajbir Singh, Joseph McElroy, Ilinca Popp, Jessica Fleming, Benjamin Johnson, Ori Staszewski, Marco Prinz, Saikh Jaharul Haque, Anca-Ligia Grosu, Arnab Chakravarti
Journal: Neuro-Oncology (2018)

This study sought to identify promoter-CpG methylation sites that are significantly correlated with overall survival and gene expression regulations in grade II/III gliomas. Fifty-six LGG specimens collected from the University Medical Center Freiburg were profiled using the Methylation 450K array, in a discovery cohort, which was followed by analysis of 471 LGG cases from The Cancer Genome Atlas (TCGA) in a validation cohort. Association between each CpG probe and patient overall survival (OS) was assessed in a Cox model with IDH1/2 mutations using false discovery rate (FDR) < 0.05. Probes were selected based on training association (FDR < 0.05) and being located on promoter regions. Genes were selected based on their correlation of expression and methylation (TCGA dataset only). The prognostic values of the selected genes were determined using univariable Cox model in the TCGA LGG cohort. The correlation of CpG-methylation and gene expression was determined using Pearson Correlation method. 40% of total CpG probes from the Freiburg cohort were found significantly associated with OS of LGG patients in the univariable Cox model, and 53970 CpG probes were validated in the TCGA cohort. 18.3% of 53970 probes are located on promoter regions. 99.7% of transcription start site (TSS) probes show that high promoter methylation levels predict better OS. After incorporating TCGA RNA seq dataset, 2145 CpG probes and 1331 genes were identified, which associate with OS. There was no probe significantly associated with OS in multivariable Cox model with IDH mutation status as co-variate. We identified genes whose promoter methylation regulate their expressions and are associated with favorable LGG patient outcome by controlling cancer cell movement, death and survival, and proliferation. Further studies are underway to identify select genes as therapeutic targets in LGGs, employing both in vitro and in vivo preclinical models.
CADD-53. GLIOBLASTOMA TUMORIGENESIS <i>–</i> LESSONS FROM REPRODUCTIVE IMMUNOLOGY
Authors: Na Tosha Gatson
Journal: Neuro-Oncology (2018)

There is no cure for glioblastoma (GBM), the most lethal primary brain tumor in adults. Despite decades of research aimed to improve outcomes, median survival is only 14–16 months. While promising discoveries in molecular genetics and immunotherapy continuously enhance our understanding of GBM and inspire new treatment approaches, challenges related to tumor-heterogeneity, inevitable recurrence, and poor patient tolerance limit treatment. The emergent need for paradigm-shifting approaches to to improve GBM-targeting is evident. Although never previously comprehensively reported, pregnancy/fetal-development shares striking similarities with gliobastomagenesis. Developing in an immune-deviated host, within an immune-privileged compartment, shielded and maintained by a proficiently adaptable microenvironment, both glioblastoma and fetal development thrive. After nine-months of pregnancy, biological and immune processes give-way to delivery (fetal-allograft rejection); however, GBM clearance is not so well orchestrated. By investigating the stages of these biologically reminiscent conditions, earlier events of glioblastomagenesis may be uncovered and potentially drive new treatment paradigms in neuro-oncology. While large cohort studies have not found a causal relationship between pregnancy and incidence of glioma, retrospective reviews of pregnancy concurrent with glioma consistently report increased aggressive glioma characteristics during the mid-late pregnancy period. These changes can in-part be ascribed to the influence of pregnancy hormones and growth factors accessing the CNS. In addition, (1) Pregnancy-mediated systemic immunosuppression and cellular re-education supporting glioma immune evasion; (2) Pregnancy hormones influence tumor-promoting cellular pathways; and (3) Fetal-maternal microchimerism allows for nesting of fetal cells within the glioma, offers local immunosuppression, and promotes glioma vascular neogenesis as quasi-stem-cells. Implementing the current knowledge of reproductive processes might offer new insight into GBM implantation and development. This abstract seeks a platform to discuss the potential to exploit overlapping concepts in reproductive immunology with that of neuro-oncology to develop clinical and biologic correlates between the two disciplines and drive innovative and paradigm-shifting multidisciplinary research.
DRES-03. EGFR-TARGETED THERAPY-INDUCED RESISTANCE MECHANISM IN MALIGNANT GLIOMAS
Authors: Inah Hwang, Lingxiang Wu, Dongqing Cao, Baoli Hu, Jun Yao, Yao Yu, Qianghu Wang, Hongwu Zheng, Jihye Paik
Journal: Neuro-Oncology (2018)

Epidermal growth factor receptor (EGFR) is frequently amplified, mutated and overexpressed in malignant gliomas. Our investigation of the proximal and distal responses to EGFR inhibition identified the molecular mechanisms for the therapeutic resistance of EGFR inhibition in gliomas. Oncogenic EGFRviii-dependent gliomas initially showed cytotoxic responses upon removal of oncogenic cue. However, during the initial regression, a subset of tumor cells with activated mesenchymal subtype gene expression program emerged by lineage reprogramming which promoted tumor relapse in the absence of EGFRviii signaling. This lineage switch is dependent on YAP1 activation as a response to therapy, and is a key to EGFRviii independent tumor growth. YAP signature stratifies overall survival of recurrent glioma patients. Inhibition of YAP1 activation suppressed mesenchymal gene expression and significantly delayed recurrence of gliomas. Our findings provide mechanisms underlying inefficacies of EGFR targeted therapy in glioblastoma and suggest a new combinatorial targeting of EGFR and YAP for deeper and more durable responses.
EXTH-61. PARTNERSHIP FOR DEFINING THE IMPACT OF 12 SELECT RARE CNS TUMORS: A REPORT FROM CBTRUS AND THE NCI-CONNECT
Authors: Gabrielle Truitt, Haley Gittleman, Quinn Ostrom, Carol Kruchko, Alexander Boscia, Terri Armstrong, Mark Gilbert, Jill Barnholtz-Sloan
Journal: Neuro-Oncology (2018)

Measuring tumor-specific incidence, prevalence, and survival is essential to evaluate the contribution of specific tumor-types to overall cancer burden in the United States population. Central nervous system tumors are rare, with specific tumor types rarer than others. NCI-Connect was developed to understand tumor biology, patient outcomes, and develop standards of care for 12 select rare CNS Tumors. The aim of this study was to determine the incidence, prevalence, and survival of specific rare brain tumors by histology, age, race, and sex in this subset. Data derived from CBTRUS was used to examine age-adjusted incidence rate (AAIR) per 100,000 and data derived from SEER was used to examine prevalence and survival statistics from 2000–2014 (all with 95% confidence intervals). The data was then used to compare specific rare brain tumors overall and by sex, age group, race, and ethnicity. The total AAIR was 6.57/100,000 for these specific brain tumor types combined; with the highest AAIR at 0.4/100,000 for oligodendroglioma. Overall, the specified tumors were most incident in males, adults (age 40+), white individuals, and non-Hispanic individuals. Ependymomas were most prevalent at 4.11 cases per 100,000; followed by brain stem and midline gliomas at 1.98 cases per 100,000. Relative survival at 1-, 5-, and 10-years was 59.7%, 33.3%, and 27.7% respectively for all subtypes. Ependymomas had the highest relative survival rate (94.2%, 83.9%, and 78.6%) and gliosarcomas had the lowest relative survival rate (42.5%, 5.6%, 2.9%) at all three time points. Overall incidence and prevalence of these brain tumors was very low and varied considerably by each tumor type. Survival also varied by tumor type. The comparison of incidence, prevalence, and survival of rare brain and CNS tumors is critical for measuring the clinical impact of these diseases and for determining future research and clinical care.
PATH-55. CLINICAL AND MOLECULAR RECURSIVE PARTITIONING ANALYSIS OF HIGH-GRADE GLIOMA TREATED WITH IMRT
Authors: Philip Sutera, Ronny Kalash, John Flickinger, Johnathan Engh, Dwight Heron
Journal: Neuro-Oncology (2018)

Despite multimodal treatment for high-grade gliomas, prognosis remains grim. Since the development of the RTOG-RPA, high-grade gliomas have seen the widespread introduction of temozolomide and tumor onco-genetics. We aimed to determine whether the RTOG-RPA retained prognostic significance in the context of modern treatment paradigm, as well as generate an updated RPA incorporating both clinical and genetic variables. Patients with histologically-proven high-grade gliomas treated with IMRT between 2004–2017 were reviewed. The primary endpoint was overall survival from date of diagnosis. Primary analysis compared actual survival rates to that expected of corresponding RTOG-RPA class. Secondary analysis utilized the rpart function to recursively partition overall survival by numerous clinical and genetic pre-treatment and treatment-related variables. A tertiary analysis recursively partitioned a subset of patients in which the status of all genetic markers were known. We identified 878 patients with a median overall survival of 14.2 months (95% CI: 13.1–15.3). Our cohort validated the relative prognostic ordering of the RTOG RPA survival classes except class II. Our new RPA created 7 significantly different survival classes (p2 = 584) with median survival ranging from 96.4 to 2.9 months based on age, histology, MGMT methylation, radiation fractions, tumor location, radiation dose, temozolomide, and resection. Our second RPA of our genetic subset (291 patients) generated 5 significantly different survival classes (p2 = 166) with survival ranging from 65.3 to 5.6 months based on age, IDH1 mutation, MGMT methylation, neurologic functional classification, IMRT hospitalization, temozolomide, and KPS. This series represents a large RPA analyzing clinical and genetic factors and generated 7 distinct survival classes. Further assessment of patients with fully available genetic markers generated 5 distinct survival classes. These classifications need to be validated by a prospective dataset and compared against the RTOG-RPA to determine if they provide improved prognostic power.
A Population-Based Study of Outcomes in Surgically Resected T3N0 Non–Small Cell Lung Cancer in The Netherlands, Defined Using TNM-7 and TNM-8; Justification of Changes and an Argument to Incorporate Histology in the Staging Algorithm
Authors: Hans Blaauwgeers, Ronald Damhuis, Birgit I. Lissenberg-Witte, Adrianus J. de Langen, Suresh Senan, Erik Thunnissen
Journal: Journal of Thoracic Oncology (2018)
RTHP-23. HEARING AND FACIAL PRESERVATION FOR VESTIBULAR SCHWANNOMAS TREATED WITH STEREOTACTIC RADIOSURGERY OR FRACTIONATED STEREOTACTIC RADIOTHERAPY
Authors: Komal Preet, Isabelle Kwan, Methma Udawatta, Thien Nguyen, Vera Ong, John Sheppard, Courtney Duong, Quinton Gopen, Isaac Yang
Journal: Neuro-Oncology (2018)

Vestibular schwannomas (VS) are benign intracranial neoplasms arising from the eighth cranial nerve. In recent years, advancing radiological techniques have provided successful non-invasive alternatives for VS therapy. RESEARCH QUESTION: How do the long-term clinical outcomes vary for the three current radiation modalities of stereotactic radiosurgery (SRS), fractionated stereotactic radiotherapy (FSRT), and hypofractionated stereotactic radiotherapy (hypoFSRT)? A retrospective chart review was conducted for all patients with unilateral VS at a single academic medical center from 2000 to 2017. Audiograms, physical examinations, and patient-reported symptoms were extracted to assess hearing, facial function and sensation, and statuses of tinnitus, vertigo, and imbalance. Sixty patients were identified (33 FSRT cases, 21 SRS cases, and 6 hypoFSRT cases). Post-operative onset of vertigo and tinnitus demonstrated significant difference between the three modalities (p = 0.035, 0.005). Survival rate analysis revealed the survival time to tinnitus onset also varied significantly when comparing SRS and FSRT (p = 0.050). SIGNIFICANCE: This study aims to elucidate the hearing and facial preservation of the three radiological interventions, thus enabling physicians to optimize patient care.
Third-space endoscopy – can we see light at the end of the tunnel?
Authors: Amol Bapaye
Journal: Endoscopy (2018)

“Third-space endoscopy” as a term was coined by Khashab and Pasricha in 2013 [1]. Also called “submucosal endoscopy,” this endoscopic procedure is unique in that it utilizes the principle of a mucosal-flap valve to create a tunnel in the potential submucosal layer via a proximally placed mucosal incision. This access route is then used to operate in the deeper layers of the gastrointestinal (GI) tract; following which the incision is closed using endoscopic clips.
Association of a Competency-Based Assessment System With Identification of and Support for Medical Residents in Difficulty
Authors: Shelley Ross, Natalia M. Binczyk, Deena M. Hamza, Shirley Schipper, Paul Humphries, Darren Nichols, Michel G. Donoff
Journal: JAMA Network Open (2018)

<h3>Importance</h3> Competency-based medical education is now established in health professions training. However, critics stress that there is a lack of published outcomes for competency-based medical education or competency-based assessment tools. <h3>Objective</h3> To determine whether competency-based assessment is associated with better identification of and support for residents in difficulty. <h3>Design, Setting, and Participants</h3> This cohort study of secondary data from archived files on 458 family medicine residents (2006-2008 and 2010-2016) was conducted between July 5, 2016, and March 2, 2018, using a large, urban family medicine residency program in Canada. <h3>Exposures</h3> Introduction of the Competency-Based Achievement System (CBAS). <h3>Main Outcomes and Measures</h3> Proportion of residents (1) with at least 1 performance or professionalism flag, (2) receiving flags on multiple distinct rotations, (3) classified as in difficulty, and (4) with flags addressed by the residency program. <h3>Results</h3> Files from 458 residents were reviewed (pre-CBAS: n = 163; 81 [49.7%] women; 90 [55.2%] aged &gt;30 years; 105 [64.4%] Canadian medical graduates; post-CBAS: n = 295; 144 [48.8%] women; 128 [43.4%] aged &gt;30 years; 243 [82.4%] Canadian medical graduates). A significant reduction in the proportion of residents receiving at least 1 flag during training after CBAS implementation was observed (0.38; 95% CI, 0.377-0.383), as well as a significant decrease in the numbers of distinct rotations during which residents received flags on summative assessments (0.24; 95% CI, 0.237-0.243). There was a decrease in the number of residents in difficulty after CBAS (from 0.13 [95% CI, 0.128-0.132] to 0.17 [95% CI, 0.168-0.172]) depending on the strictness of criteria defining a resident in difficulty. Furthermore, there was a significant increase in narrative documentation that a flag was discussed with the resident between the pre-CBAS and post-CBAS conditions (0.18; 95% CI, 0.178-0.183). <h3>Conclusions and Relevance</h3> The CBAS approach to assessment appeared to be associated with better identification of residents in difficulty, facilitating the program's ability to address learners' deficiencies in competence. After implementation of CBAS, residents experiencing challenges were better supported and their deficiencies did not recur on later rotations. A key argument for shifting to competency-based medical education is to change assessment approaches; these findings suggest that competency-based assessment may be useful.