tbuckley/cabot-search huggingface dataset:
QOLP-06. PHENOMENOLOGICAL EXPLORATION OF THE LIVED EXPERIENCE OF QUALITY OF LIFE FOR PATIENTS WITH GLIOBLASTOMA AND THEIR PRIMARY CARE PARTNERS
Authors: Meghan Tierney, Cynthia Peden-McAlpine
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Quality of life (QOL) should be included among the important outcomes of brain tumor treatment. QOL is often reduced to a measure of treatment tolerability, resulting in a lack of understanding of how patients experience this phenomenon. There is also limited knowledge surrounding the meaning of QOL for family care partners. The research (in progress) aims to explore the meaning of lived experience of QOL during treatment for glioblastoma (GBM) for both patients and their primary care partners. It will also examine similarities and differences in QOL perceptions within patient-care partner dyads. METHODS Using a phenomenological approach, this study is recruiting patients receiving treatment for GBM and their care partners. Participants complete a timeline depicting significant events impacting QOL from the time of the patient’s diagnosis to the present. They then complete an individual, unstructured interview describing their experience of QOL. Interviews are recorded and transcribed. The research team reviews and completes a thematic analysis on transcripts. RESULTS Numerous themes are emerging from the data. One theme among patients is: Feeling Uncertain About the Future. Patients discussed feeling uncertain about their prognosis during their course of treatment. They talked about the need to adjust to multiple changes in their lives over time. This uncertainty extended to concern for their QOL in the future. One theme among care partners is: Challenges in Relationship with Spouse. Care partners reported relationship conflict stemming from both personality changes in their spouse and role changes resulting in increased responsibilities for the care partner. CONCLUSION This study is providing insight into the meaning and experience of QOL for patients undergoing treatment for GBM, along with meaning and experience of QOL for their care partners. The findings will have implications for clinical practice and generate insights for future research.
DIPG-71. SELECTIVE HDAC INHIBITOR RG2833 INDUCES DIPG CELL DEATH VIA DOWNREGULATION OF THE NFĸB PATHWAY
Authors: Katherine Barnett, Orlandi Novak, Charles Eberhart, Eric Raabe
Journal: Neuro-Oncology (2020)

Abstract Histone deacetylase (HDAC) inhibitor panobinostat demonstrated activity against diffuse intrinsic pontine glioma (DIPG) in vitro, but its efficacy in vivo was limited by toxicity and poor blood brain barrier penetration. RG2833 (RGFP109) is a selective HDAC1/3 inhibitor that has established brain penetration. In clinical trials, the Cmax (plasma) of RG2833 was 32uM. RG2833 demonstrated cytotoxicity against temozolomide-resistant glioblastoma and downregulated the NFĸB pathway. Because this pathway is overexpressed in DIPG and may play a role in DIPG cell growth and survival, we hypothesized that RG2833 would kill DIPG cells. Treatment of DIPG cell lines with RG2833 as a single agent suppresses cell proliferation in the 5–10μM range (MTS assay for HSJD007 p=0.0004 10μM vs DMSO, JHH-DIPG1 p=0.001 10μM vs DMSO, SF-7761 p=0.04 10μM vs DMSO, SU-DIPG13 p=0.01 10μM vs DMSO by t-test). RG2833 induces apoptosis by 48 hours as measured by Western blot for cPARP and cleaved caspase 3 immunofluorescence (HSJD007 p&amp;lt;0.003 8μM vs DMSO, JHH-DIPG1 p=0.0026 10μM vs DMSO by t-test). RG2833 also slows cell proliferation as measured by Western blot for pRb and immunofluorescence for BrdU (HSJD007 p=0.008 8μM vs DMSO, JHH-DIPG1 p=0.0002 10μM vs DMSO by t-test). Western blot confirmed a dose-dependent increase in histone 3 acetylation with RG2833 treatment at 5 hours. We detected increased acetylated p65 and decreased expression of the NFĸB regulated pro-survival genes BCL2, BCL-xL, and XIAP with RG2833 treatment. Together, this data shows that HDAC inhibitor RG2833 may be a promising therapeutic candidate for DIPG via downregulation of the NFĸB pathway.
MBRS-10. QUIESCENT SOX9-POSITIVE CELLS BEHIND MYC DRIVEN MEDULLOBLASTOMA RECURRENCE
Authors: Sara Bolin, Vasil Savov, Anna Borgenvik, Gabriela Rosén, Karl Holmberg Olausson, Miao Zhao, Alexandra Garancher, Aldwin Suryo Rahmanto, Sonja Hutter, Oliver Mainwaring, Jessica Rusert, Anders Sundstrom, Stacey Richardson, Grammatiki Fotaki, Rebecca M Hill, Adrian M Dubuc, Antonia Kalushkova, Marc Remke, Matko Čančer, Helena Jernberg-Wiklund, Vijay Ramaswamy, Xingqi Chen, Michael D Taylor, Olle Sangfelt, Ulrich Schüller, Steve C Clifford, Robert J Wechsler-Reya, Holger Weishaupt, Fredrik J Swartling
Journal: Neuro-Oncology (2020)

Abstract Tumor recurrence is the leading cause of death in medulloblastoma, the most frequent malignant pediatric brain tumor. Recurrence occurs when subpopulations of cancer cells evade standard therapy by acquiring features of immune escape, metastatic spread, and treatment resistance. The transcription factor SOX9 correlated with treatment resistance and dissemination in aggressive Group 3 medulloblastoma. By studying paired primary-recurrent medulloblastoma samples and patient-derived xenograft models, we identified rare SOX9-positive slow-cycling, therapy-resistant tumor cells that accumulate in relapses and in metastases. In an inducible transgenic Group 3 tumor model, doxycycline treatment kills all tumor cells by turning MYC off. However, when MYC expression was redirected to the SOX9 promoter, recurrences from rare, dormant SOX9-positive cells developed with 100% penetrance. Expression profiling revealed that recurrences were more inflammatory, metastatic, and showed elevated MGMT methyltransferase levels which depleted recurrent cells when selectively inhibited. Our model explains how recurrences develop from SOX9-induced quiescence in MYC-driven brain cancer.
NCOG-15. PREGNANCY AND GLIOMA
Authors: Andrew Rodriguez, Michael Ruff
Journal: Neuro-Oncology (2020)

Abstract Improvements in treatments and prognosis in glioma patients has led patients the opportunity for pregnancy despite their diagnosis. In this retrospective case series of 13 patients evaluated at Mayo Clinic, we identified patients who were pregnant at or after glioma diagnosis from 1998-2019. Clinical information was obtained through the electronic medical record. Tumor grade, treatments, peripartum complications, and pediatric outcomes were analyzed. Median follow-up for pregnant patients was 13.5 years (range, 0-24). Of the 13 patients, 2 patients received temozolomide and radiation during pregnancy for glioblastoma and had no peripartum complications. Median survival time in these patients after further treatments was 23.5 months (range, 23.3-23.8). Two children from these pregnancies had no fetal malformations or pediatric developmental delays with median follow-up of 8.8 years (range, 4.7-12.8). Three patients received radiation during pregnancy for high grade gliomas and had no fetal malformations or peripartum complications. Eight patients had one or multiple pregnancies with median 2 (range, 1-3) children at or after diagnosis with 14 children total. Eleven of the 14 children had no fetal malformations or peripartum complications and were conceived without reproductive assistive technologies. Two children, who were identical twins, were born with a placental malformation but otherwise had normal pediatric development. One child was born pre-term and had long-term developmental delays.
A Very Long-Acting PARP Inhibitor Suppresses Cancer Cell Growth in DNA Repair-Deficient Tumor Models
Authors: Shaun D. Fontaine, Gary W. Ashley, Peter J. Houghton, Raushan T. Kurmasheva, Morgan Diolaiti, Alan Ashworth, Cody J. Peer, Ryan Nguyen, William D. Figg, Denis R. Beckford-Vera, Daniel V. Santi
Journal: Cancer Research (2020)

PARP inhibitors are approved for treatment of cancers with BRCA1 or BRCA2 defects. In this study, we prepared and characterized a very long-acting PARP inhibitor. Synthesis of a macromolecular prodrug of talazoparib (TLZ) was achieved by covalent conjugation to a PEG40kDa carrier via a β-eliminative releasable linker. A single injection of the PEG∼TLZ conjugate was as effective as ∼30 daily oral doses of TLZ in growth suppression of homologous recombination-defective tumors in mouse xenografts. These included the KT-10 Wilms' tumor with a PALB2 mutation, the BRCA1-deficient MX-1 triple-negative breast cancer, and the BRCA2-deficient DLD-1 colon cancer; the prodrug did not inhibit an isogenic DLD-1 tumor with wild-type BRCA2. Although the half-life of PEG∼TLZ and released TLZ in the mouse was only ∼1 day, the exposure of released TLZ from a single safe, effective dose of the prodrug exceeded that of oral TLZ given daily over one month. μPET/CT imaging showed high uptake and prolonged retention of an 89Zr-labeled surrogate of PEG∼TLZ in the MX-1 BRCA1-deficient tumor. These data suggest that the long-lasting antitumor effect of the prodrug is due to a combination of its long t1/2, the high exposure of TLZ released from the prodrug, increased tumor sensitivity upon continued exposure, and tumor accumulation. Using pharmacokinetic parameters of TLZ in humans, we designed a long-acting PEG∼TLZ for humans that may be superior in efficacy to daily oral TLZ and would be useful for treatment of PARP inhibitor-sensitive cancers in which oral medications are not tolerated. SIGNIFICANCE: These findings demonstrate that a single injection of a long-acting prodrug of the PARP inhibitor talazoparib in murine xenografts provides tumor suppression equivalent to a month of daily dosing of talazoparib.
RARE-57. PEDIATRIC CHORDOMA: WHOLE EXOME SEQUENCING OF 11 PEDIATRIC CHORDOMA SAMPLES
Authors: Katrina O’Halloran, Moiz Bootwalla, Daria Merkurjev, Kristiyana Kaneva, Alex Ryutov, Jennifer Cotter, Jianling Ji, Dejerianne Ostrow, Jaclyn A Biegel, Xiaowu Gai
Journal: Neuro-Oncology (2020)

Abstract Chordoma is a rare tumor and while SMARCB1 alterations have been observed in poorly differentiated chordomas, conventional chordomas are not well understood. We interrogated nuclear and mitochondrial genomes of 11 chordoma samples from 7 children. Frozen tumor tissue DNA was extracted and whole exome libraries generated using Agilent SureSelect Human All Exon V6 kit plus mtDNA genome capture kit. Libraries were sequenced using Illumina Nextseq 500. MuTect2, VarDict and LUBA variant callers were used with allele frequency cutoff 2%. Potential germline variants were filtered bioinformatically. In total, 656±74 high-confidence somatic variants, including 368±43 nonsynonymous variants per sample were detected. Of 2,607 combined unique nonsynonymous variants, 95% were missense. Remaining high impact variants were frameshift (37%), stop gain (39%), splice acceptor/donor (22%), start and stop loss (2%). Of the unique nonsynonymous variants, 137 fall within Cosmic Cancer Census Genes, including high impact variants in SETD2, MLLT4. No previously reported TBXT, CDKN2A, PI3K, LYST mutations identified. Tumor Mutation Burden/Megabase was 10±1. The mitochondrial analysis revealed heteroplasmic m.11727C&amp;gt;T MT-ND4 missense variants in three tumors resected at different time points from the same patient, and another heteroplasmic m.1023C&amp;gt;T rRNA mutation from the primary and recurrent tumors of another patient. Intriguingly, two Children’s Brain Tumor Tissue Consortium patients with chordoma had identical heteroplasmic m.10971G&amp;gt;A MT-ND4 nonsense mutations. Pediatric chordomas appear to lack somatic nuclear mutations. Observing recurrent mitochondrial mutations across multiple tumors from the same and/or different patients is striking, suggesting they may be implicated in tumorigenesis and be potential diagnostic markers.
How the (Pediatric) Heart Works When It Contracts: Application of Left Ventricular “Isovolumic Acceleration” as a Load-Independent Index of Contractility⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Sándor J. Kovács
Journal: Journal of the American College of Cardiology (2011)
Spleen plays a major role in DLL4-driven acute T-cell lymphoblastic leukemia
Authors: Huizhong Xiong, Maicol Mancini, Michael Gobert, Shiqian Shen, Glaucia C. Furtado, Sergio A. Lira, Christopher N. Parkhurst, Veronique Garambois, Muriel Brengues, Carlos E. Tadokoro, Thomas Trimarchi, Gonzalo Gómez-López, Amartya Singh, Hossein Khiabanian, Sonia Minuzzo, Stefano Indraccolo, Camille Lobry, Iannis Aifantis, Daniel Herranz, Juan J. Lafaille, Antonio Maraver
Journal: Theranostics (2020)

The Notch pathway is highly active in almost all patients with T-cell acute lymphoblastic leukemia (T-ALL), but the implication of Notch ligands in T-ALL remains underexplored.Methods: We used a genetic mouse model of Notch ligand delta like 4 (DLL4)-driven T-ALL and performed thymectomies and splenectomies in those animals.We also used several patient-derived T-ALL (PDTALL) models, including one with DLL4 expression on the membrane and we treated PDTALL cells in vitro and in vivo with demcizumab, a blocking antibody against human DLL4 currently being tested in clinical trials in patients with solid cancer.Results: We show that surgical removal of the spleen abrogated T-ALL development in our preclinical DLL4-driven T-ALL mouse model.Mechanistically, we found that the spleen, and not the thymus, promoted the accumulation of circulating CD4 + CD8 + T cells before T-ALL onset, suggesting that DLL4-driven T-ALL derives from these cells.Then, we identified a small subset of T-ALL patients showing higher levels of DLL4 expression.Moreover, in mice xenografted with a DLL4-positive PDTALL model, treatment with demcizumab had the same therapeutic effect as global Notch pathway inhibition using the potent γ-secretase inhibitor dibenzazepine.This result demonstrates that, in this PDTALL model, Notch pathway activity depends on DLL4 signaling, thus validating our preclinical mouse model.Conclusion: DLL4 expression in human leukemic cells can be a source of Notch activity in T-ALL, and the spleen plays a major role in a genetic mouse model of DLL4-driven T-ALL.
Association of Physician Burnout With Suicidal Ideation and Medical Errors
Authors: Nikitha K. Menon, Tait D. Shanafelt, Christine A. Sinsky, Mark Linzer, Lindsey Carlasare, Keri J. S. Brady, Martin J. Stillman, Mickey T. Trockel
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Addressing physician suicide requires understanding its association with possible risk factors such as burnout and depression. <h3>Objective</h3> To assess the association between burnout and suicidal ideation after adjusting for depression and the association of burnout and depression with self-reported medical errors. <h3>Design, Setting, and Participants</h3> This cross-sectional study was conducted from November 12, 2018, to February 15, 2019. Attending and postgraduate trainee physicians randomly sampled from the American Medical Association Physician Masterfile were emailed invitations to complete an online survey in waves until a convenience sample of more than 1200 practicing physicians agreed to participate. <h3>Main Outcomes and Measures</h3> The primary outcome was the association of burnout with suicidal ideation after adjustment for depression. The secondary outcome was the association of burnout and depression with self-reported medical errors. Burnout, depression, suicidal ideation, and medical errors were measured using subscales of the Stanford Professional Fulfillment Index, Maslach Burnout Inventory–Human Services Survey for Medical Personnel, and Mini-Z burnout survey and the Patient-Reported Outcomes Measurement Information System depression Short Form. Associations were evaluated using multivariable regression models. <h3>Results</h3> Of the 1354 respondents, 893 (66.0%) were White, 1268 (93.6%) were non-Hispanic, 762 (56.3%) were men, 912 (67.4%) were non–primary care physicians, 934 (69.0%) were attending physicians, and 824 (60.9%) were younger than 45 years. Each SD-unit increase in burnout was associated with 85% increased odds of suicidal ideation (odds ratio [OR], 1.85; 95% CI, 1.47-2.31). After adjusting for depression, there was no longer an association (OR, 0.85; 95% CI, 0.63-1.17). In the adjusted model, each SD-unit increase in depression was associated with 202% increased odds of suicidal ideation (OR, 3.02; 95% CI, 2.30-3.95). In the adjusted model for self-reported medical errors, each SD-unit increase in burnout was associated with an increase in self-reported medical errors (OR, 1.48; 95% CI, 1.28-1.71), whereas depression was not associated with self-reported medical errors (OR, 1.01; 95% CI, 0.88-1.16). <h3>Conclusions and Relevance</h3> The results of this cross-sectional study suggest that depression but not physician burnout is directly associated with suicidal ideation. Burnout was associated with self-reported medical errors. Future investigation might examine whether burnout represents an upstream intervention target to prevent suicidal ideation by preventing depression.
LINC-27. PAEDIATRIC SUPRASELLAR TUMOURS: CLINICAL EXPERIENCE FROM A SINGLE TERTIARY CENTRE IN KUALA LUMPUR, MALAYSIA
Authors: Hamidah Alias, C-Khai Loh
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION The outcome of suprasellar tumours in children varies with the diagnosis and morbidity is significant. We herein report the clinical features of children with suprasellar tumours treated at our centre. METHODS Clinical data were collected by retrospective review from January 2000 to December 2019. The patients were identified from the paediatric haematology and oncology unit registry. RESULTS There was a total of 103 children with brain tumour and suprasellar tumours comprise of 14.6% (n=15). Median age at presentation was 7 years old. Male to female ratio was 3:2. Majority of cases was low grade glioma, 40% (n=6) and germ cell tumour(GCT) 33.3% (n=5) followed by craniopharyngioma, 13.3% (n=2) and Rathke cleft cyst, 6.7% (n=1). All patients had tissue diagnosis except one with secreting GCT and one with unsatisfactory tissue sample. Mean duration of follow up was 7.4 years. One patient with germinoma was lost to follow-up after radiotherapy. Three out of 13 (23%) patients died; 2 with GCT from disease progression; 1 craniopharyngioma after 11 years of unknown cause. All survivors have significant morbidity; 70% have moderate to severe visual impairment, 90% have at least two pituitary hormones deficiency, 20% have neurological deficit and 1 was surgically related. Two boys have precocious puberty not related to disease progression. Two with GCT with diabetes insipidus had history of thromboembolism (stroke and pulmonary embolism). CONCLUSIONS Suprasellar tumours in children at our centre pose a significant long-term complications and multidisciplinary team management and follow up is required to improve the morbidity.
MNK Inhibition Sensitizes <i>KRAS</i>-Mutant Colorectal Cancer to mTORC1 Inhibition by Reducing eIF4E Phosphorylation and c-MYC Expression
Authors: John R.P. Knight, Constantinos Alexandrou, George L. Skalka, Nikola Vlahov, Kathryn Pennel, Leah Officer, Ana Teodosio, Georgios Kanellos, David M. Gay, Sebastian May-Wilson, Ewan M. Smith, Arafath K. Najumudeen, Kathryn Gilroy, Rachel A. Ridgway, Dustin J. Flanagan, Rachael C.L. Smith, Laura McDonald, Craig MacKay, Anne Cheasty, Kerri McArthur, Emma Stanway, Joshua D. Leach, Rene Jackstadt, Joseph A. Waldron, Andrew D. Campbell, Georgios Vlachogiannis, Nicola Valeri, Kevin M. Haigis, Nahum Sonenberg, Christopher G. Proud, Neil P. Jones, Martin E. Swarbrick, Heather J. McKinnon, William J. Faller, John Le Quesne, Joanne Edwards, Anne E. Willis, Martin Bushell, Owen J. Sansom
Journal: Cancer Discovery (2020)

Abstract KRAS-mutant colorectal cancers are resistant to therapeutics, presenting a significant problem for ∼40% of cases. Rapalogs, which inhibit mTORC1 and thus protein synthesis, are significantly less potent in KRAS-mutant colorectal cancer. Using Kras-mutant mouse models and mouse- and patient-derived organoids, we demonstrate that KRAS with G12D mutation fundamentally rewires translation to increase both bulk and mRNA-specific translation initiation. This occurs via the MNK/eIF4E pathway culminating in sustained expression of c-MYC. By genetic and small-molecule targeting of this pathway, we acutely sensitize KRASG12D models to rapamycin via suppression of c-MYC. We show that 45% of colorectal cancers have high signaling through mTORC1 and the MNKs, with this signature correlating with a 3.5-year shorter cancer-specific survival in a subset of patients. This work provides a c-MYC–dependent cotargeting strategy with remarkable potency in multiple Kras-mutant mouse models and metastatic human organoids and identifies a patient population that may benefit from its clinical application. Significance: KRAS mutation and elevated c-MYC are widespread in many tumors but remain predominantly untargetable. We find that mutant KRAS modulates translation, culminating in increased expression of c-MYC. We describe an effective strategy targeting mTORC1 and MNK in KRAS-mutant mouse and human models, pathways that are also commonly co-upregulated in colorectal cancer. This article is highlighted in the In This Issue feature, p. 995
BIOM-41. GENETIC MARKERS CORRELATED WITH PROGRESSION-FREE SURVIVAL TIMES IN GLIOBLASTOMA PATIENTS UNDERGOING TREATMENT WITH TUMOR TREATING FIELDS
Authors: Caitlin Monson, Megan Tipps, Kelsey Jackson, Meghan Tierney, Nilanjana Banerji, John Trusheim
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Despite advances in surgical approaches, followed by chemo-radiotherapy protocols, the overall prognosis for patients with glioblastoma remains poor. Clinical trials have demonstrated that the use of low intensity alternating electric fields, known as Tumor Treating Fields (TTFields), via the Optune™ device extends overall survival times when combined with standard chemotherapy. However, the response to TTFields varies across patients, and it is currently unclear why some patients show increased time to tumor progression with TTFields treatment while others do not. One possible answer lies in the biological diversity of the tumors themselves. Genetic alterations are known to impact survival times and chemotherapy sensitivity in glioblastoma, suggesting that certain markers may also predict responsiveness to TTFields. Here, we compare the genetic profile of primary glioblastoma tumors with progression times in patients receiving TTFields treatment. METHODS Patients with primary glioblastoma who chose treatment with the Optune™ device were prospectively enrolled and a sample from their primary tumor resection was sent for FoundationONE CDx™ testing. Genetic alteration results, including mutation burden and copy number alterations, were then compared with clinical data and tumor progression times. RESULTS Mutations and/or copy number changes in genes that regulate cell growth/proliferation, apoptosis, and interactions with DNA were among the most common alterations observed in our cohort. For patients that recurred within 12 months, we found a common pattern of alterations that includes CDKN2A/2B co-deletion, MTAP deletion, and PIK3 mutations. This pattern was not observed in patients that recurred after 12 months. CONCLUSION The identification of genetic markers that predict treatment responsiveness may help direct patients toward optimal treatment options. Ongoing work is aimed at expanding our sample size, correlating these genetic markers with overall patient survival, and determining if this pattern of expression is specifically related to TTFields treatment response.