tbuckley/cabot-search huggingface dataset:
Clinical Validation of a Machine-learning–derived Signature Predictive of Outcomes from First-line Oxaliplatin-based Chemotherapy in Advanced Colorectal Cancer
Authors: Jim P. Abraham, Daniel Magee, Chiara Cremolini, Carlotta Antoniotti, David D. Halbert, Joanne Xiu, Phillip Stafford, Donald A. Berry, Matthew J. Oberley, Anthony F. Shields, John L. Marshall, Mohamed E. Salem, Alfredo Falcone, Axel Grothey, Michael J. Hall, Alan P. Venook, Heinz-Josef Lenz, Anthony Helmstetter, W. Michael Korn, David B. Spetzler
Journal: Clinical Cancer Research (2020)

FOLFOX, FOLFIRI, or FOLFOXIRI chemotherapy with bevacizumab is considered standard first-line treatment option for patients with metastatic colorectal cancer (mCRC). We developed and validated a molecular signature predictive of efficacy of oxaliplatin-based chemotherapy combined with bevacizumab in patients with mCRC.A machine-learning approach was applied and tested on clinical and next-generation sequencing data from a real-world evidence (RWE) dataset and samples from the prospective TRIBE2 study resulting in identification of a molecular signature, FOLFOXai. Algorithm training considered time-to-next treatment (TTNT). Validation studies used TTNT, progression-free survival, and overall survival (OS) as the primary endpoints.A 67-gene signature was cross-validated in a training cohort (N = 105) which demonstrated the ability of FOLFOXai to distinguish FOLFOX-treated patients with mCRC with increased benefit from those with decreased benefit. The signature was predictive of TTNT and OS in an independent RWE dataset of 412 patients who had received FOLFOX/bevacizumab in first line and inversely predictive of survival in RWE data from 55 patients who had received first-line FOLFIRI. Blinded analysis of TRIBE2 samples confirmed that FOLFOXai was predictive of OS in both oxaliplatin-containing arms (FOLFOX HR, 0.629; P = 0.04 and FOLFOXIRI HR, 0.483; P = 0.02). FOLFOXai was also predictive of treatment benefit from oxaliplatin-containing regimens in advanced esophageal/gastro-esophageal junction cancers, as well as pancreatic ductal adenocarcinoma.Application of FOLFOXai could lead to improvements of treatment outcomes for patients with mCRC and other cancers because patients predicted to have less benefit from oxaliplatin-containing regimens might benefit from alternative regimens.
SURG-13. LASER INTERSTITIAL THERMAL THERAPY FOR RECURRENT GLIOBLASTOMA: A REVIEW OF SURVIVAL OUTCOMES COMPARED TO A MATCHED SURGICAL COHORT
Authors: Hassan Fadel, Sameah Haider, Jacob Pawloski, Hesham Zakaria, Farhan Chaudhry, Seamus Bartlett, Michael Bazydlo, Steven Kalkanis, Ian Lee
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Glioblastoma (GBM) is uniformly associated with a poor prognosis and inevitable recurrence. Management of recurrent GBM remains unclear, with repeat surgery often employed with varying degrees of success. We evaluated the efficacy of Laser Interstitial Thermal Therapy (LITT) for recurrent GBM when compared to a carefully matched cohort of patients treated with repeat surgical resection. METHODS A retrospective single-institution database was used to identify patients who underwent LITT or surgical resection of recurrent GBM between 2014-2019. LITT patients were matched with surgical resection patients according to baseline demographics, comorbidities, tumor location, and eloquence. Subgroup analysis matching similar patients for tumor volume was also completed. Overall survival (OS) and progression-free survival (PFS) were the primary endpoints. RESULTS A LITT cohort of 20 patients was matched to 50 similar patients who underwent repeat surgical resection. Baseline characteristics were similar between both cohorts apart from tumor volume, which was larger in the surgical cohort (17.5 cc vs. 4.7 cc, p&amp;lt; 0.01). On long-term follow-up, there was no difference in OS (HR, 0.72; 95%CI, 0.36-1.45) or PFS (HR, 0.67; 95%CI, 0.29-1.53) between the LITT and surgical cohorts when controlling for tumor volume. Subgroup analysis of 23 LITT patients matched according to tumor volume with 23 surgical patients with similar clinical characteristics also found no difference in OS (HR, 0.66; 95%CI, 0.33-1.30) or PFS (HR, 0.58; 95%CI, 0.90-1.05) between the cohorts. LITT patients had shorter length of stays (1 vs. 4 days, p&amp;lt; 0.001) and a higher rate of home discharge (84% vs. 67%, p=0.172) compared to the surgical cohort. CONCLUSION After matching for demographic, clinical, and tumor characteristics, there was no difference in outcomes between patients undergoing LITT compared to surgical resection for recurrent GBM. LITT patients had similar survival outcomes yet shorter hospital stays and more favorable dispositions, potentially mitigating post-treatment complications.
Abstract P115: Atrial Fibrillation And The Risk Of Subsequent Fracture
Authors: Jason Sherer, Qiuxi Huang, Douglas Kiel, Emelia J Benjamin, Ludovic Trinquart
Journal: Circulation (2020)

Background: There is conflicting evidence regarding the association between atrial fibrillation (AF) and the risk of subsequent fractures. Methods: We included participants aged 45 years or older from the Framingham Heart Study Offspring, Third Generation, New Offspring Spouse, Omni 1, and Omni 2 cohorts. We prespecified analyzing index age 65 years as our primary analysis; we repeated analyses for index age 45, 55, and 75 years. The primary outcome was any bone fracture, except finger, toe, foot, skull, and facial fractures. We assessed the association between time-varying AF and subsequent fractures by an illness-death model that accounted for the competing risk of death. We estimated hazard ratios (HR) adjusted for age, sex, body mass index, smoking, diabetes, alcohol intake, and prior fracture. Results: We included 3,403 participants (mean age of 68 years, 53.3% female) in the analysis at index age 65 years and above. In all, 525 (15%) participants developed incident fractures during follow-up. The HR between AF and subsequent fracture was 1.36 95%CI (1.05-1.77). There was no evidence of effect modification by sex (HR 1.63, 95%CI 1.05-2.23 in men; HR 1.22, 95%CI 0.84-1.76; interaction p value 0.27). Results were consistent at other index ages. Conclusion: AF was associated with increased risk of incident fracture in the community-based Framingham Heart Study.
IMMU-23. CLINICAL AND IMMUNOLOGICAL CHARACTERIZATION OF IMMUNE CHECKPOINT MOLECULE LIGHT IN HUMAN GLIOMAS
Authors: Mingzhi Han, Xingang Li
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Dysregulation of immune checkpoint molecules leads to immune evasion in human tumors but has become a viable target for tumor therapy. Here, we examined expression of LIGHT (TNFSF14), an immune checkpoint molecule, in human glioblastoma (GBM) to assess its potential as a molecular target for treatment. METHODS Molecular and clinical data from publicly available genomic databases containing WHO grade II-IV human glioma cases were analyzed. Immunohistochemistry was applied to assess LIGHT protein levels in primary tumor sections. Statistical analysis was performed using Matlab and R language. FINDINGS LIGHT was found to be elevated in aggressive gliomas, particularly in the mesenchymal molecular subtype and isocitrate dehydrogenase (IDH) wild-type GBM. LIGHT exhibited potential as a prognostic marker based on Cox regression and nomogram models. LIGHT displayed intra-tumor heterogeneity and was more highly expressed in peri-necrotic and microvascular regions. Gene ontology and pathway analysis revealed enrichment of LIGHT in multiple immune regulatory processes. Finally, in cell lineage analysis, LIGHT was found to be tightly associated with several infiltrating immune and stromal cell types which localized to the tumor microenvironment. INTERPRETATION Our data highlights the importance of LIGHT in the development of GBM and as a potential molecular target in combination with current immune checkpoint blockades for treatment of GBM.
Senior Adult Oncology Clinical Practice Guidelines in Oncology
Authors: Lodovico Balducci, Harvey Jay Cohen, Paul F Engstrom, David S Ettinger, Jeffrey Halter, Leo I Gordon, Krystyna Kiel, Andrew Kneier, Dean Lim, Stephen H Petersdorf, Ronnie Rosenthal, Rebecca Silliman, Julie M Vose, Michael J Walker, Babu Zachariah
Journal: Journal of the National Comprehensive Cancer Network (2005)

By 2030, researchers estimate that 20% of the U.S. population will be 65 years or older. More than 50% of all new cancers in the United States occur in this patient population. In addition, the increased incidence and prevalence of cancer in older patients and the increased lifespan of older adults mean that cancer in older individuals is becoming an increasingly common problem. Specific issues include geriatric screening and assessment, preventing or decreasing complications from therapy, accounting for disease-specific issues, and managing patients who cannot tolerate standard treatment. The NCCN Senior Adult Oncology Panel has developed guidelines for addressing these issues and for assessing the risks and benefits of treatment in older patients with cancer. For the most recent version of the guidelines, please visit NCCN.org
Comparison of Lesional Juvenile Myositis and Lupus Skin Reveals Overlapping Yet Unique Disease Pathophysiology
Authors: Jessica L. Turnier, Lauren M. Pachman, Lori Lowe, Lam C. Tsoi, Sultan Elhaj, Rajasree Menon, Maria C. Amoruso, Gabrielle A. Morgan, Johann E. Gudjonsson, Celine C. Berthier, J. Michelle Kahlenberg
Journal: Arthritis & Rheumatology (2020)

Objective Skin inflammation heralds systemic disease in juvenile myositis, yet we lack an understanding of pathogenic mechanisms driving skin inflammation in this disease. We undertook this study to define cutaneous gene expression signatures in juvenile myositis and identify key genes and pathways that differentiate skin disease in juvenile myositis from childhood‐onset systemic lupus erythematosus (SLE). Methods We used formalin‐fixed paraffin‐embedded skin biopsy samples from 15 patients with juvenile myositis (9 lesional, 6 nonlesional), 5 patients with childhood‐onset SLE, and 8 controls to perform transcriptomic analysis and identify significantly differentially expressed genes (DEGs; q ≤ 5%) between patient groups. We used Ingenuity Pathway Analysis (IPA) to highlight enriched biologic pathways and validated DEGs by immunohistochemistry and quantitative real‐time polymerase chain reaction. Results Comparison of lesional juvenile myositis to control samples revealed 221 DEGs, with the majority of up‐regulated genes representing interferon (IFN)–stimulated genes. CXCL10 , CXCL9 , and IFI44L represented the top 3 DEGs (fold change 23.2, 13.3, and 13.0, respectively; q &lt; 0.0001). IPA revealed IFN signaling as the top canonical pathway. When compared to childhood‐onset SLE, lesional juvenile myositis skin shared a similar gene expression pattern, with only 28 unique DEGs, including FBLN2 , CHKA , and SLURP1 . Notably, patients with juvenile myositis who were positive for nuclear matrix protein 2 (NXP‐2) autoantibodies exhibited the strongest IFN signature and also demonstrated the most extensive Mx‐1 immunostaining, both in keratinocytes and perivascular regions. Conclusion Lesional juvenile myositis skin demonstrates a striking IFN signature similar to that previously reported in juvenile myositis muscle and peripheral blood. Further investigation into the association of a higher IFN score with NXP‐2 autoantibodies may provide insight into disease endotypes and pathogenesis.
CTNI-59. FIRST SAFETY ANALYSIS OF ANAPLASTIC MENINGIOMA PATIENTS TREATED WITH TUMOR TREATING FIELDS (TTFIELDS)
Authors: Christian Mawrin
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Anaplastic meningioma (AM) is a rare and aggressive intracranial tumor with very limited treatment options. TTFields is an established therapy and indicated for the treatment of newly diagnosed and recurrent glioblastoma (GBM) patients. The phase 3 study METIS tests the application in another intracranial cancer type, more specifically brain metastases of non-small cell lung cancer. First preclinical data show that TTFields can reduce proliferation of patient-derived meningioma cells and one first case report of a GBM patient with an in-field meningioma was published. First clinical trials are underway to investigate the safety and efficacy in meningioma patients (NCT02847559). Here, we describe first surveillance data on anaplastic meningioma patients treated with the TTFields device indicated for GBM treatment. METHODS Global post-market surveillance data of patients with anaplastic meningioma were assessed employing the MedDRA body system (System organ class (SOC) and preferred terms) with data cut-off in April 2020. RESULTS A total of 29 patients with AM were treated since 2015 to date. The median age is 57y (range 26-74y; based on YOB). Of those 9 (31%) were female and 20 (69%) were male. 15 (52 %) patients with AM reported at least one adverse event (AE). A total of 51 AEs were reported, of those 32 were assessed by the manufacturer as potentially related to TTFields treatment. Most commonly reported were skin reactions beneath the transducer arrays (n=15). No serious adverse events related to TTFields were reported. CONCLUSION Here we present the first post-market surveillance data of anaplastic meningioma patients treated with TTFields. Clinical studies are warranted to investigate the safety and efficacy for the use of TTFields in anaplastic meningioma patients.
Response to: ‘Correspondence on ‘Jan Gösta Waldenströmand rheumatology’’ by Moutsopoulos
Authors: Frank A Wollheim
Journal: Annals of the Rheumatic Diseases (2020)

Gösta Waldenströmand rheumatology'' by MoutsopoulosIt was an exquisite pleasure to read the succinct tribute that Moutsopoulos is contributing on my mentor Jan Waldenström. 1 2 It brings back memories of countless educational ward rounds in Malmö attended by 10 or more people learning from Dr Waldenström's interaction with individual patients; however, not kneeling but often sitting on their bed.His prompt and relevant reactions when confronted with novel information mentioned can be illustrated by the following anecdotes.When I told him of my work on secretory IgA in Minneapolis 3 his reflection was 'Now I understand why dogs lick their wounds'.When listening to a talk on visualising intrauterine movements where it was shown that the fetus stopped moving when the mother smoked, 4 he remarked 'Then mothers should stop smoking and eat an apple instead'.I can also add that when staying in the 'Stone House' at National Institutes of Health Dr Waldenström enjoyed the company of his friend Sir George Pickering, the emeritus Region Professor from Oxford UK. 5 6 They were among the last guests in the premises enjoying the lovely garden surrounding it.The guest rooms was soon converted into offices.
Inhibiting glycolysis rescues memory impairment in an intellectual disability Gdi1-null mouse
Authors: Patrizia D'Adamo, Anemari Horvat, Antonia Gurgone, Maria Lidia Mignogna, Veronica Bianchi, Michela Masetti, Maddalena Ripamonti, Stefano Taverna, Jelena Velebit, Maja Malnar, Marko Muhič, Katja Fink, Angela Bachi, Umberto Restuccia, Sara Belloli, Rosa Maria Moresco, Alessia Mercalli, Lorenzo Piemonti, Maja Potokar, Saša Trkov Bobnar, Marko Kreft, Helena H. Chowdhury, Matjaž Stenovec, Nina Vardjan, Robert Zorec
Journal: Metabolism (2020)

GDI1 gene encodes for αGDI, a protein controlling the cycling of small GTPases, reputed to orchestrate vesicle trafficking. Mutations in human GDI1 are responsible for intellectual disability (ID). In mice with ablated Gdi1, a model of ID, impaired working and associative short-term memory was recorded. This cognitive phenotype worsens if the deletion of αGDI expression is restricted to neurons. However, whether astrocytes, key homeostasis providing neuroglial cells, supporting neurons via aerobic glycolysis, contribute to this cognitive impairment is unclear.We carried out proteomic analysis and monitored [18F]-fluoro-2-deoxy-d-glucose uptake into brain slices of Gdi1 knockout and wild type control mice. d-Glucose utilization at single astrocyte level was measured by the Förster Resonance Energy Transfer (FRET)-based measurements of cytosolic cyclic AMP, d-glucose and L-lactate, evoked by agonists selective for noradrenaline and L-lactate receptors. To test the role of astrocyte-resident processes in disease phenotype, we generated an inducible Gdi1 knockout mouse carrying the Gdi1 deletion only in adult astrocytes and conducted behavioural tests.Proteomic analysis revealed significant changes in astrocyte-resident glycolytic enzymes. Imaging [18F]-fluoro-2-deoxy-d-glucose revealed an increased d-glucose uptake in Gdi1 knockout tissue versus wild type control mice, consistent with the facilitated d-glucose uptake determined by FRET measurements. In mice with Gdi1 deletion restricted to astrocytes, a selective and significant impairment in working memory was recorded, which was rescued by inhibiting glycolysis by 2-deoxy-d-glucose injection.These results reveal a new astrocyte-based mechanism in neurodevelopmental disorders and open a novel therapeutic opportunity of targeting aerobic glycolysis, advocating a change in clinical practice.
RARE-23. NOVEL NF1 MUTATIONS IN TWO OCCURRENCES OF GLIOBLASTOMA MULTIFORM IN A PATIENT WITH CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY SYNDROME
Authors: Kaylyn Utley, Jens Reuter, Lei Li, Devon Evans, Jeffrey Florman, Stanley Chaleff
Journal: Neuro-Oncology (2020)

Abstract Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare cancer predisposition syndrome in children. Its main associated tumor types include brain and CNS tumors, hematologic malignancies, intestinal polyps and colorectal tumors, and other malignancies. Tumor genesis within this population is highly complex and poorly understood. We describe a case of a patient with two occurrences of glioblastoma multiforme (GBM), each with unique NF1 mutations. The patient is a female with CMMRD who was first diagnosed with GBM of the right frontal lobe in 2015. She subsequently underwent gross total resection, radiation to the field and concomitant and maintenance therapy with Temozolomide and Everolimus, due to high suspicion for NF-1. Genetic studies didn’t show NF-1, instead revealing a diagnosis of CMMRD. Molecular testing of the GBM showed a high mutational burden and an NF1 mutation. Later, screening revealed stage IV colon cancer, for which she underwent subtotal colectomy, partial liver resection and chemotherapy. Molecular testing from the colon cancer found a hypermutant malignancy without mutations in NF1. Surveillance imaging detected a mass at the original site of her GBM, for which she had a resection. Notably, the genetic profile of the second tumor substantially different from the original tumor and the colon cancer sample, but had new mutations in NF-1. These findings highlight the significant variability in the genetic profiles of tumors in the context of CMMRD. It is also worth considering that NF1 is one of the first in a cascade of mutations leading to GBM in these patients.
QOLP-03. NEURO-ONCOLOGY PALLIATIVE CARE SURVEY OF PHYSICIANS IN SUB-SAHARAN AFRICA
Authors: Ramya Tadipatri, Amir Azadi, Madison Cowdrey, Samuel Fongue, Paul Smith, Evangelia Razis, Maria Boccia, Ekokobe Fonkem
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Early access to palliative care is a critical component of treating patients with advanced cancer, particularly for glioblastoma patients who have low rates of survival despite optimal therapies. Additionally, there are unique considerations for primary brain tumor patients given the need for management of headaches, seizures, and focal neurological deficits. METHODS We conducted a survey of 109 physicians in Sub-Saharan Africa in order to determine level of understanding and skill in providing palliative care, types of palliative care therapies provided, role of cultural beliefs, availability of resources, and challenges faced. Demographic data including age, gender, and prior training was collected and analyzed using ANOVA statistical testing. RESULTS Among the participants, 48% felt comfortable in providing palliative care consultations, 62% have not had prior training, 52% believed that palliative care is only appropriate when there is irreversible deterioration, 62% expressed having access to palliative care, 49% do not have access to liquid opioid agents, 50% stated that cultural beliefs held by the patient or family prevented them from receiving, palliative care, and 23% stated that their own beliefs affected palliative care delivery. Older providers (age &amp;gt; 30) had a clearer understanding of palliative care (p = 0.004), were more comfortable providing consultation (p = 0.052), and were more likely to address mental health (p &amp;lt; 0.001). CONCLUSIONS Palliative care delivery to glioblastoma patients in Sub-Saharan Africa is often delayed until late in the disease course. Barriers to adequate palliative care treatment identified in this survey study include lack of training, limited access to liquid opioid agents, and cultural beliefs. Challenges most often identified by participants were pain management and end-of-life communication skills, but also included patient spirituality and psychological support, anxiety and depression, terminal dyspnea, ethics, and intravenous hydration and non-oral feeding.
Response to Ponatinib Is Not Related to the Drug Plasma Levels in Chronic Phase CML
Authors: Franck Emmanuel Nicolini, Delphine Rea, Vincent Alcazer, Francoise Huguet, Laurence Legros, Gaelle Fossard, Elodie Grockowiak, Stephane Morisset, Pierre Sujobert, Mohamad Sobh, Mauricette Michallet, Francois Parant, Marie-Claude Gagnieu
Journal: Blood (2017)
TMOD-28. NEW APPROACHES FOR ELUCIDATING MEDULLOBLASTOMA DEVELOPMENT VIA HINDBRAIN BLASTOCYST COMPLEMENTATION
Authors: Christin Schmidt, Annika Carlson, William Weiss, Bjoern Schwer
Journal: Neuro-Oncology (2020)

Abstract Understanding the etiology of brain cancers requires elucidation of developmental origins, genetic drivers, and the tumor microenvironment. This requires reliable in vivo approaches, which are currently lacking. Current in vivo models for pediatric brain tumors rely on generation of xenografts or allografts in immunodeficient mice or generation of transgenic mice. These approaches have severe limitations, including lack of a functional immune system, a restricted developmental time window defined by the cell of origin, or time-consuming workflows for the generation of transgenic mice. We recently developed neural blastocyst complementation (NBC), an organogenesis approach for the forebrain. NBC involves injection of donor mouse embryonic stem cells (ESC) into genetically-engineered blastocysts that are programmed to ablate dorsal telencephalic progenitors. This results in the formation of a donor-cell derived, intact forebrain. Based on this general approach, we are developing an in vivo platform for studies of brain cancer. We will report on our efforts and progress toward the generation of an organogenesis approach for the hindbrain and related studies that aim to define developmental origins and drivers of medulloblastoma.