tbuckley/cabot-search huggingface dataset:
CTNI-10. MAINTENANCE CHEMOTHERAPY USING BEVACIZUMAB FOR NEUROFIBROMATOSIS 2 PATIENTS WITH HEARING LOSS AND PROGRESSIVE VESTIBULAR SCHWANNOMAS: AN NF CLINICAL TRIALS CONSORTIUM STUDY (NF104)
Authors: Scott Plotkin, James Tonsgard, Nicole Ullrich, Jeffrey Allen, Jaishri Blakeley, Girish Dhall, Jian Campian, Wade Clapp, Michael Fisher, Gary Cutter, Bruce Korf, Roger Packer, Coretta Thomas, Lloyd Edwards, Matthias Karajannis
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Bevacizumab treatment at 2.5–5 mg/kg/week is associated with hearing improvement and tumor shrinkage in about 40% of patients with neurofibromatosis 2 (NF2) and progressive vestibular schwannomas (VS). Treatment-emergent hypertension and proteinuria are common with prolonged treatment, and data supporting strategies to maintain hearing and minimize toxicity are lacking. METHODS We conducted a multicenter, phase II, open-label study of bevacizumab for subjects (≥6 years old) with NF2, hearing loss, and progressive VS. After 6 months of induction therapy (10 mg/kg every 2 weeks), subjects received low dose bevacizumab at 5 mg/kg every 3 weeks during maintenance therapy (18 months). Hearing decline was defined as a significant decrease in word recognition score below baseline. Progressive disease was defined as ≥20% increase in tumor volume from baseline. RESULTS Twenty of 22 subjects (median age=23 years) were treated with maintenance bevacizumab. The proportion of subjects free from hearing decline at 6, 12, and 18 months was 88%, 94%, and 85%, respectively; the proportion free from tumor progression at 6, 12, and 18 months from baseline was 88%, 94%, and 85%, respectively. Three subjects (15%) experienced hearing loss during maintenance and required dose escalation. Maintenance chemotherapy with bevacizumab was well tolerated: 1 subject discontinued due to perirectal abscess and 2 discontinued by choice. Grade 3 hypertension occurred in 2 subjects (10%). Adverse events of interest included hypertension (55%), proteinuria (20%), and irregular menstruation (6/13, 46%). CONCLUSIONS Maintenance chemotherapy with bevacizumab at 5 mg/kg every 3 weeks is associated with prolonged hearing and tumor stability that surpasses historical controls. A minority of subjects require dose escalation during low dose bevacizumab treatment.
Gluconeogenesis, But Not Glycogenolysis, Contributes to the Increase in Endogenous Glucose Production by SGLT-2 Inhibition
Authors: Peter Wolf, Paul Fellinger, Lorenz Pfleger, Hannes Beiglböck, Patrik Krumpolec, Chiara Barbieri, Amalia Gastaldelli, Jürgen Harreiter, Matthäus Metz, Thomas Scherer, Maximilian Zeyda, Sabina Baumgartner-Parzer, Rodrig Marculescu, Siegfried Trattnig, Alexandra Kautzky-Willer, Martin Krššák, Michael Krebs
Journal: Diabetes Care (2020)

OBJECTIVE Recent studies indicate that sodium-glucose cotransporter 2 (SGLT-2) inhibition increases endogenous glucose production (EGP), potentially counteracting the glucose-lowering potency, and stimulates lipid oxidation and lipolysis. However, the acute effects of SGLT-2 inhibition on hepatic glycogen, lipid, and energy metabolism have not yet been analyzed. We therefore investigated the impact of a single dose of dapagliflozin (D) or placebo (P) on hepatic glycogenolysis, hepatocellular lipid (HCL) content and mitochondrial activity (kATP). RESEARCH DESIGN AND METHODS Ten healthy volunteers (control [CON]: age 30 ± 3 years, BMI 24 ± 1 kg/m2, HbA1c 5.2 ± 0.1%) and six patients with type 2 diabetes mellitus (T2DM: age 63 ± 4 years, BMI 28 ± 1.5 kg/m2, HbA1c 6.1 ± 0.5%) were investigated on two study days (CON-P vs. CON-D and T2DM-P vs. T2DM-D). 1H/13C/31P MRS was performed before, 90–180 min (MR1), and 300–390 min (MR2) after administration of 10 mg dapagliflozin or placebo. EGP was assessed by tracer dilution techniques. RESULTS Compared with CON-P, EGP was higher in CON-D (10.0 ± 0.3 vs. 12.4 ± 0.5 μmol kg−1 min−1; P &amp;lt; 0.05) and comparable in T2DM-D and T2DM-P (10.1 ± 0.7 vs. 10.4 ± 0.5 μmol kg−1 min−1; P = not significant [n.s.]). A strong correlation of EGP with glucosuria was observed (r = 0.732; P &amp;lt; 0.01). The insulin-to-glucagon ratio was lower after dapagliflozin in CON-D and T2DM-D compared with baseline (P &amp;lt; 0.05). Glycogenolysis did not differ between CON-P and CON-D (−3.28 ± 0.49 vs. −2.53 ± 0.56 μmol kg−1 min−1; P = n.s.) or T2DM-P and T2DM-D (−0.74 ± 0.23 vs. −1.21 ± 0.33 μmol kg−1 min−1; P = n.s.), whereas gluconeogenesis was higher after dapagliflozin in CON-P compared with CON-D (6.7 ± 0.6 vs. 9.9 ± 0.6 μmol kg−1 min−1; P &amp;lt; 0.01) but not in T2DM. No significant changes in HCL and kATP were observed. CONCLUSIONS The rise in EGP after SGLT-2 inhibition is due to increased gluconeogenesis, but not glycogenolysis. Changes in glucagon and the insulin-to-glucagon ratio are not associated with an increased hepatic glycogen breakdown. HCL and kATP are not significantly affected by a single dose of dapagliflozin.
LGG-03. INCIDENCE AND OUTCOME OF PEDIATRIC IDH-MUTANT GLIOMA
Authors: Kee Kiat Yeo, Sanda Alexandrescu, Chantel Cacciotti, Emily Krzykwa, Jessica Clymer, Christine Chordas, Mary Ann Zimmerman, Susan Chi, Katherine Warren, Karen Wright
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION The incidence of IDH mutations in pediatric glioma is unclear. Recent publications suggest rates ranging between 0–20%. Therapy poses challenges as it is unclear if the biology and prognosis of pediatric IDH-mutant gliomas are identical to adults. METHODS We performed an IRB approved, systematic retrospective search for IDH-mutant gliomas in the Dana-Farber Cancer Institute/Boston Children’s Hospital database between 2009–2018, analyzing incidence, demographics, histology, co-occurring genetic alterations and outcome. RESULTS We identified 575 patients with glioma, ages 0–21 years. Of these, 394 underwent biopsy/resection (0–9 years:n=204; 10–21 years:n=190), with 294 genetic testing. Fifteen of 294 tumors (5%) were IDH1-mutant. Among patients 0–9 years and 10–21 years, 1/156 (0.6%) and 14/138 (10%) had IDH1-mutant tumors, respectively. Among patients 10–21 year old, 13/115 low-grade gliomas were IDH1-mutant (11%). High-grade gliomas accounted for the remaining 23, with one IDH1-mutant glioma (4%). Most common co-occurring genetic alterations for diffuse astrocytoma (n=12) were TP53 (n=9) and ATRX (n=2). Three patients with IDH1-mutant oligodendrogliomas had 1p/19q deletion. Eleven IDH1-mutant patients were evaluable for outcomes with median follow-up of five years. Five-year radiation-free, progression-free and overall survival for patients with low-grade histology were 76% and 100%, respectively. One patient with high-grade glioma recurred 1.2 years after upfront chemo-radiation and died soon after recurrence. CONCLUSION IDH-mutant gliomas comprise a small proportion of pediatric gliomas. Incidence rate is higher in the second decade of life. Comparative analyses between pediatric IDH-mutant gliomas and adult historical cohorts are currently underway, evaluating outcomes, radiation therapy and frequency of malignant transformation.
Unbiased Detection of Driver Mutations in Extramammary Paget Disease
Authors: Yoshihiro Ishida, Nobuyuki Kakiuchi, Kenichi Yoshida, Yoshikage Inoue, Hiroyuki Irie, Tatsuki R. Kataoka, Masahiro Hirata, Takeru Funakoshi, Shigeto Matsushita, Hiroo Hata, Hiroshi Uchi, Yuki Yamamoto, Yasuhiro Fujisawa, Taku Fujimura, Ryunosuke Saiki, Kengo Takeuchi, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Atsushi Otsuka, Satoru Miyano, Kenji Kabashima, Seishi Ogawa
Journal: Clinical Cancer Research (2020)

Extramammary Paget disease (EMPD) is an uncommon skin malignancy whose genetic alterations are poorly characterized. Previous reports identified mutations in chromatin remodeling genes and PIK3CA. In order to unambiguously determine driver mutations in EMPD, we analyzed 87 EMPD samples using exome sequencing in combination with targeted sequencing.First, we analyzed 37 EMPD samples that were surgically resected using whole-exome sequencing. Based on several in silico analysis, we built a custom capture panel of putative driver genes and analyzed 50 additional formalin-fixed, paraffin-embedded samples using target sequencing. ERBB2 expression was evaluated by HER2 immunohisotochemistry. Select samples were further analyzed by fluorescence in situ hybridization.A median of 92 mutations/sample was identified in exome analysis. A union of driver detection algorithms identified ERBB2, ERBB3, KMT2C, TP53, PIK3CA, NUP93, AFDN, and CUX1 as likely driver mutations. Copy-number alteration analysis showed regions spanning CDKN2A as recurrently deleted, and ERBB2 as recurrently amplified. ERBB2, ERBB3, and FGFR1 amplification/mutation showed tendency toward mutual exclusivity. Copy-number alteration load was associated with likelihood to recur. Mutational signatures were dominated by aging and APOBEC activation and lacked evidence of ultraviolet radiation. HER2 IHC/fluorescence in situ analysis validated ERBB2 amplification but was underpowered to detect mutations. Tumor heterogeneity in terms of ERBB2 amplification status was observed in some cases.Our comprehensive, unbiased analysis shows EMPD is characterized by alterations involving the PI3K-AKT pathway. EMPD is distinct from other skin cancers in both molecular pathways altered and etiology behind mutagenesis.
Abstract 10820: Real-world Characteristics of Patients With Heart Failure in China: Baseline Results From The Retrospective Non-interventional Nationwide Study (REPRESENT-HF)
Authors: Jingmin Zhou, Xinli Li, Yugang Dong, Jiefu Yang, Yong Huo, Junbo Ge
Journal: Circulation (2019)

Background: Heart failure (HF) represents a major public health problem in China with an estimated prevalence of approximately 0.9%. There is paucity of data on the clinical characteristics, diagno...
In patients at high CV risk receiving simvastatin, the Myopathy Risk Score predicted statin-related myopathy
Authors: Michelle D. Kelsey, L. Kristin Newby
Journal: Annals of Internal Medicine (2020)

Hopewell JC, Offer A, Haynes R, et al. Independent risk factors for simvastatin-related myopathy and relevance to different types of muscle symptom. Eur Heart J. 2020;41:3336-42. 32702748.
MBCL-21. GERMLINE ELONGATOR MUTATIONS IN SONIC HEDGEHOG MEDULLOBLASTOMA
Authors: Giles W Robinson, Sebastian M Waszak, Brian L Gudenas, Kyle S Smith, Antoine Forget, Marija Kojic, Garcia-Lopez Jesus, Jennifer Hadley, Kayla V Hamilton, Emilie Indersie, Ivo Buchhalter, Natalie Jager, Tanvi Sharma, Tobias Rausch, Marcel Kool, Dominic Sturm, David T W Jones, Ruth Tatevossian, Berangere Lombard, Damarys Loew, Daniel Bowers, Anne Bendel, Sonia Partap, Murali Chintagumpala, John Crawford, Nicholas G Gottardo, Amy Smith, Christelle Dufour, Stefan Rutkowski, Michael Grotzer, Mark Remke, Stephanie Puget, Kristian W Pajtler, Till Milde, Olaf Witt, Marina Ryzhova, Andrey Korshunov, Brent A Orr, David W Ellison, Laurence Brugieres, Peter Lichter, Kim E Nichols, Amar Gajjar, Brandon J Wainwright, Olivier Ayrault, Jan O Korbel, Paul A Northcott, Stefan M Pfister
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Our previous analysis of established cancer predisposition genes in medulloblastoma (MB) identified pathogenic germline variants in ~5% of all patients. Here, we extended our analysis to include all protein-coding genes. METHODS Case-control analysis performed on 795 MB patients against &amp;gt;118,000 cancer-free children and adults was performed to identify an association between rare germline variants and MB. RESULTS Germline loss-of-function variants of Elongator Complex Protein 1 (ELP1; 9q31.3) were strongly associated with SHH subgroup (MBSHH). ELP1-associated-MBs accounted for ~15% (29/202) of pediatric MBSHH cases and were restricted to the SHHα subtype. ELP1-associated-MBs demonstrated biallelic inactivation of ELP1 due to somatic chromosome 9q loss and most tumors exhibited co-occurring somatic PTCH1 (9q22.32) alterations. Inheritance was verified by parent-offspring sequencing (n=3) and pedigree analysis identified two families with a history of pediatric MB. ELP1-associated-MBSHH were characterized by desmoplastic/nodular histology (76%; 13/17) and demonstrated a favorable clinical outcome when compared to TP53-associated-MBSHH (5-yr OS 92% vs 20%; p-value=1.3e-6) despite both belonging to the SHHα subtype. ELP1 is a subunit of the Elongator complex, that promotes efficient translational elongation through tRNA modifications at the wobble (U34) position. Biochemical, transcriptional, and proteomic analyses revealed ELP1-associated-MBs exhibit destabilization of the core Elongator complex, loss of tRNA wobble modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response. CONCLUSIONS We identified ELP1 as the most common MB predisposition gene, increasing the total genetic predisposition for pediatric MBSHH to 40%. These results mark MBSHH as an overwhelmingly genetically-predisposed disease and implicate disruption of protein homeostasis in MBSHH development.
Abstract 13684: Depressive Symptoms, Cardiac Function, and Risk of Heart Failure With Preserved or Reduced Ejection Fraction in Late Life: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Katja Vu, Janice E Williams, Brian Claggett, Jenine E John, Hicham Skali, Scott D Solomon, Thomas Mosley, Anna Kucharska-Newton, Tor Biering-Soerensen, Amil M Shah
Journal: Circulation (2019)

Background: Depressive symptoms are associated with heightened risk of heart failure (HF) independent of cardiovascular comorbidities, but their association with cardiac function and incident HF wi...
QOLP-15. QUALITATIVE STUDY OF DIFFERENTIAL QUALITY OF LIFE (QOL) IN SUPRASELLAR MENINGIOMA PATIENTS TREATED VIA ENDOSCOPIC ENDONASAL APPROACH VERSUS OPEN CRANIOTOMY
Authors: Adham Khalafallah, Shirley Fung, Sharon Kozachik, Benita Valappil, Hussam Abou Al Shaar, Eric Wang, Georgios Zenonos, Carl Snyderman, Paul Gardner, Gary Gallia, Nicholas Rowan, Debraj Mukherjee
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND The optimal surgical treatment of suprasellar meningiomas remains controversial. While successful surgery has historically been measured by extent of tumor resection (EOR), surgeons must also balance tumor- and patient-specific characteristics with quality of life (QoL) outcomes when considering either an open craniotomy or endoscopic endonasal approach (EEA). METHODS We conducted 28 in-depth individual interviews with patients diagnosed with suprasellar meningioma and treated via EEA (n=14) or craniotomy (n=14). We used a structured interview script and the transcribed interviews were independently coded by two researchers. Consensus was used to identify themes and domains of interest. RESULTS The overall sample (80% between 40-69 years old, 70% female, and 82% white) was largely similar between craniotomy and EEA cohorts. Tumor volumes were not different between both cohorts (p=0.2), with a combined average of 4.4 cm3 (standard error ± 0.7). Suprasellar meningiomas caused a wide range of symptoms with 21 concepts elicited. The most frequently endorsed concepts were “Vision” (n=22), “Headaches” (n=11), “Fatigue” (n=11), “Cognitive Symptoms” (n=10), “Pituitary Dysfunction – including Trouble Sleeping and Frequent Urination” (n=9), “Sinus Problems” (n=7), and “Personality Changes” (5). Both surgical approaches demonstrated improvements in vision (69.2% EEA, 66.7% craniotomy) and headaches (100% EEA, 80% craniotomy). Compared to EEA, craniotomy yielded a longer list of complications (3 vs.14) and surgery-specific symptoms (9 vs.16). More craniotomy patients reported having negative emotions (5 vs.1), new depression and anxiety (6 vs.1), financial difficulties (3 vs.1), and reduced desire/ability to pursue fun activities (12 vs.7) after surgery relative to EEA counterparts. CONCLUSION Suprasellar meningiomas can be debilitating with significantly impact on patients’ health and QoL. Our findings demonstrate differential effects upon patients’ post-operative QoL associated with type of surgery. Our findings support the need for measuring patient-centered, disease-specific QoL outcomes in patients undergoing craniotomy versus EEA for suprasellar meningioma resection.
CTNI-11. CC-115 IN NEWLY DIAGNOSED MGMT UNMETHYLATED GLIOBLASTOMA IN THE INDIVIDUALIZED SCREENING TRIAL OF INNOVATIVE GLIOBLASTOMA THERAPY (INSIGHT): A PHASE II RANDOMIZED BAYESIAN ADAPTIVE PLATFORM TRIAL
Authors: Rifaquat Rahman, Lorenzo Trippa, Geoffrey Fell, Eudocia Lee, Isabel Arrillaga-Romany, Mehdi Touat, Christine McCluskey, Jennifer Brunno, Sarah Gaffey, Jan Drappatz, Andrew Lassman, Evanthia Galanis, Manmeet Ahluwalia, Howard Colman, Louis Nabors, Jaroslaw Hepel, Heinrich Elinzano, David Schiff, Ugonma Chukwueke, Rameen Beroukhim, Lakshmi Nayak, Jose Mcfaline-Figueroa, Tracy Batchelor, Mikael Rinne, Thomas Kaley, Christine Lu-Emerson, Wenya Linda Bi, Omar Arnaout, Daphne Haas-Kogan, Shyam Tanguturi, Daniel Cagney, Ayal A Aizer, Mary Welch, Lisa Doherty, Maria Lavallee, Brittany Fisher-Longden, Shanna Dowling, Jack Geduldig, Fiona Watkinson, Sandro Santagata, David Meredith, E Antonio Chiocca, David Reardon, Keith Ligon, Brian Alexander, Patrick Wen
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND CC-115 is an oral, CNS-penetrant, selective inhibitor of mammalian target of rapamycin kinase (mTOR) and deoxyribonucleic acid-dependent protein kinase (DNA-PK). Both targets are important in glioblastoma; PI3K/Akt/mTOR signaling is hyperactive in most glioblastomas, and DNA-PK is integral to repair of radiotherapy-mediated DNA damage. To investigate CC-115 in newly diagnosed glioblastoma and explore potential genomic biomarker associations, CC-115 was evaluated in the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial, an adaptive platform trial designed to efficiently test experimental agents. METHODS Adults with newly diagnosed MGMT-unmethylated glioblastoma, with genomic data available, are eligible for this ongoing trial. Patients are adaptively randomized to one of several experimental arms or the control arm: standard radiotherapy with concurrent and adjuvant temozolomide. The primary endpoint is overall survival (OS). Patients randomized to CC-115 (10mg po BID) received it concurrently with radiotherapy and as adjuvant monotherapy. As the first in-human use of CC-115 with radiation, a safety lead-in 3 + 3 design was used. RESULTS Twelve patients were randomized to CC-115; seven patients had possible treatment-related CTCAE grade &amp;gt; 3 toxicity, including four pre-specified dose-limiting toxicities: liver function abnormality (n=1), hyperlipidemia (n=1), lipase elevation (n=1) and cerebral edema (n=1). There was no significant difference in progression-free survival (PFS, median 4.2 months [CC-115] vs. 5.2 months, p=0.9) or OS (median 10.1 months [CC-115] vs. 14.5 months, p=0.9) compared to the 50 patients randomized to the control arm. Based on early PFS results, randomization probability to CC-115 decreased from 25% to &amp;lt; 10% at time of the trial arm closure. CONCLUSION Concurrent and adjuvant CC-115 was associated with toxicity and failed to improve PFS or OS. The INSIGhT trial design allowed for more efficient testing of CC-115, decreasing patients and resources allocated to a therapy that was discontinued due to concerns about toxicity and unfavorable risk-to-benefit ratio.
MBCL-36. HOW TO INCREASE SURVIVAL IN 7 TO 10% OF PATIENTS WITH AVERAGE-RISK MEDULLOBLASTOMA WITHOUT NEW THERAPIES: EARLY PROSPECTIVE NEURORADIOLOGY SCREENING EXPERIENCE FROM THE CHILDREN’S ONCOLOGY GROUP
Authors: Nicholas Gottardo, Sarah Leary, Guolian Kang, Jeffrey Gossett, Maryam Fouladi, Sandy Kessel, Noah Sabin, Alok Jaju, Julie Harreld
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Previous Children’s Oncology Group (COG) average-risk medulloblastoma studies retrospectively identified that 7 to 10% of patients were wrongly staged; either due to the presence of unequivocal residual disease greater than 1.5cm2 or metastatic disease. Notably, these patients had an inferior survival. The current COG front-line average-risk study for WNT-driven medulloblastoma patients, ACNS1422, is a reduced-intensity therapeutic protocol. Given the potentially devastating consequences of dose reduction in a wrongly staged patient, ACNS1422 is utilizing optimized MRI sequences, including thin slices with no gap and post contrast T2 FLAIR sequences, combined with a rapid central neuroradiology review. RESULTS The study opened on October 2 2017. As of 31 December 2019, a total of 34 patients have undergone central neuroradiology review. In 27/34 (79%) repeat scans were requested due to technically inadequate sequences (majority due to missing post contrast T2 FLAIR, slice thickness and gap issues). Of 19 repeat scans received, four patients (12%) were wrongly staged as average-risk; three patients were identified with residual disease &amp;gt;1.5cm2 (in 2 residual disease was confirmed at second resection) and one patient had widespread spinal metastases previously obscured by motion. In addition, metastatic disease was excluded in another patient, reported as having metastatic disease. CONCLUSION Our data is consistent with previous reports revealing that approximately 10% of patients are wrongly staged as average-risk. The early experience of ACNS1422 reveals that the optimized MRI sequences combined with a rapid central neuroradiology review are very valuable in a cooperative group setting to more accurately stage patients.
<i>Staphylococcus aureus</i> internalisation enhances bacterial survival through modulation of host immune responses and mast cell activation
Authors: Timothy C. Biggs, Rana S. Abadalkareem, Stephen M. Hayes, Rebecca E. Holding, Laurie C. Lau, Philip G. Harries, Raymond N. Allan, Sylvia L. F. Pender, Andrew F. Walls, Rami J. Salib
Journal: Allergy (2020)

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