tbuckley/cabot-search huggingface dataset:
LGG-28. NOVEL BRAF INTRAGENIC DELETION IN A GLIOMA: A CASE REPORT OF A PEDIATRIC PATIENT
Authors: Valerie Cruz Flores, Maxine Sutcliffe, Thomas Geller, Ignacio Gonzalez Gomez, Stephanie Smith, Stacie Stapleton
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Numerous variant BRAF genetic alterations have been associated with malignancies. BRAF activating fusions/mutations are frequently present in low grade gliomas. BRAF intragenic deletions have been reported in melanoma, but have not previously been reported in gliomas. OBJECTIVE To report a BRAF intragenic deletion in a pediatric patient with recurrent low-grade glioma. RESULTS A 3-year-old female underwent a complete resection of a posterior fossa pilocytic astrocytoma. She had recurrences at age 4, and then at age 9; pathology was consistent with pilocytic astrocytoma. Microarray analysis on sample from the first recurrence showed one region of loss encompassing 86 Kbp within the BRAF gene. The deletion breakpoints are within intron 1 and 9, resulting in loss of exons 2 through 9, inclusive. This has been previously described melanoma, but appears to be a novel finding in glioma. It is hypothesized that, since the loss retains the kinase and ATP binding pocket domains but deletes the N-terminal conserved region 1 and 2 (CR1, CR2) of the BRAF gene, it is likely functionally similar to the loss and activation resulting from the more usually described KIAA1549 and BRAF gene fusion. CONCLUSION This is the first BRAF intragenic deletion involving exons 2–9 reported in a glioma. Although 86kbp is small using whole genome microarray technology, it is large using sequencing strategies, and a targeted sequencing approach to investigate the BRAF gene would not readily identify this deletion. It is speculated that the deletion may be under ascertained in the pediatric population.
Development of the phenylpyrazolo[3,4-<i>d</i>]pyrimidine-based, insulin-like growth factor receptor/Src/AXL-targeting small molecule kinase inhibitor
Authors: Ho Jin Lee, Phuong Chi Pham, Honglan Pei, Bumhee Lim, Seung Yeob Hyun, Byungyeob Baek, Byungjin Kim, Yunha Kim, Min-Hwan Kim, Nae-Won Kang, Hye-Young Min, Dae-Duk Kim, Jeeyeon Lee, Ho-Young Lee
Journal: Theranostics (2020)

Rationale: The type I insulin-like growth factor receptor (IGF-1R) signaling pathway plays key roles in the development and progression of numerous types of human cancers, and Src and AXL have been found to confer resistance to anti-IGF-1R therapies. Hence, co-targeting Src and AXL may be an effective strategy to overcome resistance to anti-IGF-1R therapies. However, pharmacologic targeting of these three kinases may result in enhanced toxicity. Therefore, the development of novel multitarget anticancer drugs that block IGF-1R, Src, and AXL is urgently needed. Methods: We synthesized a series of phenylpyrazolo[3,4-d]pyrimidine (PP)-based compounds, wherein the PP module was conjugated with 2,4-bis-arylamino-1,3-pyrimidines (I2) via a copper(I)-catalyzed alkyne-azide cycloaddition reaction. To develop IGF-1R/Src/AXL-targeting small molecule kinase inhibitors, we selected LL6 as an active compound and evaluated its antitumor and antimetastatic effects in vitro and in vivo using the MTT assay, colony formation assays, migration assay, flow cytometric analysis, a tumor xenograft model, the KrasG12D/+ -driven spontaneous lung tumorigenesis model, and a spontaneous metastasis model using Lewis lung carcinoma (LLC) allografts. We also determined the toxicity of LL6 in vitro and in vivo. Results: LL6 induced apoptosis and suppressed viability and colony-forming capacities of various non-small cell lung cancer (NSCLC) cell lines and their sublines with drug resistance. LL6 also suppressed the migration of NSCLC cells at nontoxic doses. Administration of LL6 in mice significantly suppressed the growth of NSCLC xenograft tumors and metastasis of LLC allograft tumors with outstanding toxicity profiles. Furthermore, the multiplicity, volume, and load of lung tumors in KrasG12D/+ transgenic mice were substantially reduced by the LL6 treatment. Conclusions: Our results show the potential of LL6 as a novel IGF-1R/Src/AXL-targeting small molecule kinase inhibitor, providing a new avenue for anticancer therapies.
The Use of Serial Circulating Tumor DNA to Detect Resistance Alterations in Progressive Metastatic Breast Cancer
Authors: Saya Jacob, Andrew A. Davis, Lorenzo Gerratana, Marko Velimirovic, Ami N. Shah, Firas Wehbe, Neelima Katam, Qiang Zhang, Lisa Flaum, Kalliopi P. Siziopikou, Leonidas C. Platanias, William J. Gradishar, Amir Behdad, Aditya Bardia, Massimo Cristofanilli
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Circulating tumor DNA (ctDNA) is a promising tool for noninvasive longitudinal monitoring of genomic alterations. We analyzed serial ctDNA to characterize genomic evolution in progressive metastatic breast cancer. Experimental Design: This was a retrospective cohort between 2015 and 2019 obtained under an Institutional Review Board–approved protocol at Northwestern University (Chicago, IL). ctDNA samples were analyzed with Guardant360 next-generation sequencing (NGS) assay. A total of 86 patients had at least two serial ctDNA collections with the second drawn at first post-NGS progression (PN1) by imaging and clinical assessment. A total of 27 participants had ctDNA drawn at second post-NGS clinical progression (PN2). We analyzed alterations, mutant allele frequency (MAF), number of alterations (NOA), and sites of disease on imaging in close proximity to ctDNA evaluation. Matched pairs' variations in MAF, NOA, and alterations at progression were tested through Wilcoxon test. We identified an independent control cohort at Massachusetts General Hospital (Boston, MA) of 63 patients with serial ctDNA sampling and no evidence of progression. Results: We identified 44 hormone receptor–positive, 20 HER2+, and 22 triple-negative breast cancer cases. The significant alterations observed between baseline and PN1 were TP53 (P &amp;lt; 0.0075), PIK3CA (P &amp;lt; 0.0126), AR (P &amp;lt; 0.0126), FGFR1 (P &amp;lt; 0.0455), and ESR1 (P &amp;lt; 0.0143). Paired analyses revealed increased MAF and NOA from baseline to PN1 (P = 0.0026, and P &amp;lt; 0.0001, respectively). When compared with controls without progression, patients with ctDNA collection at times of progression were associated with increased MAF and NOA (P = 0.0042 and P &amp;lt; 0.0001, respectively). Conclusions: Serial ctDNA testing identified resistance alterations and increased NOA and MAF were associated with disease progression. Prospective longitudinal ctDNA evaluation could potentially monitor tumor genomic evolution.
DDRE-04. miR-149-3p INHIBITS THE GSC PHENOTYPE AND RE-SENSITIZES THERAPY-RESISTANT GBM CELLS
Authors: Hernando Lopez-Bertoni
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Intra-tumor heterogeneity presents one of the biggest challenges in the development of solid cancer therapeutics. Cells within the same tumor display distinct phenotypes that affect their growth rate, survival, migration, therapy-response, and tumor-propagating capacity. We now understand cancer stem cells (CSCs) play critical roles in driving intra-tumor cellular heterogeneity by establishing dynamic cellular transitions within tumors. GBM are highly aggressive tumors that display a poorly differentiated cell phenotype. Lineage-tracing experiments show that stem-like cells are responsible for GBM re-growth after therapy and this process is in part mediated by known drivers of stemness (e.g. Sox2). PURPOSE Understand the contribution of stem-cell driving mechanisms to the therapy-resistant phenotype of GBM. METHODS We used human GBM-derived neurosphere lines as cell models. miRNA expression was performed using commercially available mimics. Change in self-renewal capacity were measured via neurosphere formation assays, and levels of miRNA and stem cell markers were quantified by qRT-PCR. RESULTS We show that GBM cells expressing transgenic Oct4 and Sox2 are more resistant to ionizing radiation (IR) treatment and exposing GBM neurospheres to temozolomide (TMZ) and IR gives rise to a cell sub-set with higher gene expression levels of Oct4 and Sox2 compared to untreated cells. The clinical relevance of this phenotype is supported by multi-dimensional transcriptome analyses that identifies a group of genes induced by Oct4 and Sox2 enriched in recurrent GBM. We identified miR-149-3p as a high-priority candidate capable of simultaneously inhibiting several transcripts induced by Oct4/Sox2 in recurrent GBM. Transient expression of miR-149-3p decreases the capacity of GSCs to self-renew as spheres and re-sensitized therapy-resistant GSCs to TMZ treatment. CONCLUSION These results show that GSC-driving mechanisms induce a subset of genes that give rise to therapy-resistant GBM cells and suggests that miR-149-3p can be developed as a therapeutic for recurrent GBM.
NIMG-01. MRI VIRTUAL BIOPSY AND TREATMENT OF PRIMARY OR BRAIN METASTATIC TUMORS WITH TARGETED NANOBIOCONJUGATES
Authors: Vladimir Ljubimov, Rameshwar Patil, Eggehard Holler, Julia Ljubimova, Keith Black
Journal: Neuro-Oncology (2020)

Abstract Differential diagnosis of brain magnetic resonance imaging (MRI) enhancement(s) remains a significant problem, which may be difficult to resolve without biopsy that can be often dangerous or even impossible. Such MRI enhancement(s) can result from metastasis of primary tumors such as lung or breast, radiation necrosis, infections or a new primary brain tumor (glioma, meningioma). Neurological symptoms are often the same on initial presentation. METHODS: We present a noninvasive tumor-specific imaging approach “MRI virtual biopsy” by engineering new nano imaging agents (NIA) on polymalic acid polymer (PMLA) scaffold containing linear-Gd-DOTA or star-Gd-DOTA moieties for differential diagnosis of brain tumors. The strategy is that after non-invasive MRI diagnosis recognizing the brain lesion on the basis of its molecular signatures, the primary cancer or brain metastasis (BM) is suppressed by tumor-specific molecular inhibitor(s), which is structurally similar to the used NIA. Anti-TfR antibody or Angiopep-2 (AP-2) peptide used to cross blood-brain barrier (BBB) by receptor-mediated transcytosis, and targeting antibody against EFGR- or HER2-overexpressing tumors were covalently attached to PMLA to recognize the tissues of interest. Delivery of contrast agents across BBB was studied by optical imaging. MRI signals in healthy brain and tumors were quantified using 9.4-Tesla MRI system. RESULTS: High specific signal values prevailed for 3 hours for NIA, in comparison with clinical Gd (MultiHance) that declined rapidly. In newly developed double tumor xenogeneic mouse models of brain metastasis this method allowed differential diagnosis of HER2- and EGFR-expressing brain tumors. After MRI diagnosis, breast and lung cancer brain metastases were successfully treated with similar tumor-targeted nanoconjugates carrying molecular inhibitors of EGFR or HER2 instead of imaging contrast agent. The treatment resulted in significant increase of animal survival and markedly reduced immunostaining for several cancer stem cell markers. Support: NIH grants: R01 CA188743, R01 CA206220, R01 CA209921
COVID-19 as the Leading Cause of Death in the United States
Authors: Steven H. Woolf, Derek A. Chapman, Jong Hyung Lee
Journal: JAMA (2020)

This Viewpoint uses CDC data to compare the COVID-19 mortality rate in 2020 with prior leading causes of death (heart disease, cancer, lung disease, and injury) to put into context the cost of the infection in loss of life in the United States.
A soft hood improves maneuverability in narrow spaces during pharyngeal endoscopic submucosal dissection
Authors: Kotaro Waki, Takashi Kanesaka, Ryu Ishihara, Muneaki Miyake, Tomoki Michida, Takashi Fujii
Journal: Endoscopy (2020)

Endoscopic submucosal dissection (ESD) is a minimally invasive treatment for superficial pharyngeal cancer [1]. However, maneuvering the scope is more difficult in working spaces that are narrowed by anatomical features, such as the larynx and thyroid cartilage, or by equipment, such as intubation tubes, laryngoscopes, and grasping forceps. Transparent hoods are widely used for ESD in all gastrointestinal sections to secure the visual field and provide traction, but their long tips and larger outer diameters can obstruct surrounding structures during a pharyngeal ESD. We therefore used a soft, bendable transparent hood (Space adjuster; TOP Corporation, Tokyo, Japan) for pharyngeal ESDs to improve maneuverability in tight working spaces ([Video 1]).
DNA Polymerase and Mismatch Repair Exert Distinct Microsatellite Instability Signatures in Normal and Malignant Human Cells
Authors: Jiil Chung, Yosef E. Maruvka, Sumedha Sudhaman, Jacalyn Kelly, Nicholas J. Haradhvala, Vanessa Bianchi, Melissa Edwards, Victoria J. Forster, Nuno M. Nunes, Melissa A. Galati, Martin Komosa, Shriya Deshmukh, Vanja Cabric, Scott Davidson, Matthew Zatzman, Nicholas Light, Reid Hayes, Ledia Brunga, Nathaniel D. Anderson, Ben Ho, Karl P. Hodel, Robert Siddaway, A. Sorana Morrissy, Daniel C. Bowers, Valérie Larouche, Annika Bronsema, Michael Osborn, Kristina A. Cole, Enrico Opocher, Gary Mason, Gregory A. Thomas, Ben George, David S. Ziegler, Scott Lindhorst, Magimairajan Vanan, Michal Yalon-Oren, Alyssa T. Reddy, Maura Massimino, Patrick Tomboc, An Van Damme, Alexander Lossos, Carol Durno, Melyssa Aronson, Daniel A. Morgenstern, Eric Bouffet, Annie Huang, Michael D. Taylor, Anita Villani, David Malkin, Cynthia E. Hawkins, Zachary F. Pursell, Adam Shlien, Thomas A. Kunkel, Gad Getz, Uri Tabori
Journal: Cancer Discovery (2020)

Although replication repair deficiency, either by mismatch repair deficiency (MMRD) and/or loss of DNA polymerase proofreading, can cause hypermutation in cancer, microsatellite instability (MSI) is considered a hallmark of MMRD alone. By genome-wide analysis of tumors with germline and somatic deficiencies in replication repair, we reveal a novel association between loss of polymerase proofreading and MSI, especially when both components are lost. Analysis of indels in microsatellites (MS-indels) identified five distinct signatures (MS-sigs). MMRD MS-sigs are dominated by multibase losses, whereas mutant-polymerase MS-sigs contain primarily single-base gains. MS deletions in MMRD tumors depend on the original size of the MS and converge to a preferred length, providing mechanistic insight. Finally, we demonstrate that MS-sigs can be a powerful clinical tool for managing individuals with germline MMRD and replication repair-deficient cancers, as they can detect the replication repair deficiency in normal cells and predict their response to immunotherapy. SIGNIFICANCE: Exome- and genome-wide MSI analysis reveals novel signatures that are uniquely attributed to mismatch repair and DNA polymerase. This provides new mechanistic insight into MS maintenance and can be applied clinically for diagnosis of replication repair deficiency and immunotherapy response prediction.This article is highlighted in the In This Issue feature, p. 995.
ETMR-07. ETANTR: A RARE TUMOR IN A RESOURCE-LIMITED SETTING
Authors: Julieta Hoveyan, Manushak Avagyan, Anna Avagyan, Ruzanna Papyan, Samvel Iskanyan, Samvel Danielyan, Garik Hovhannisyan, Parandzem Khachatryan, Gevorg Tamamyan, Samvel Bardakhchyan
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Embryonal tumor with abundant neuropil and true rosettes (ETANTR) is a rare aggressive brain tumor with low survival rates. There are about 80 cases reported in literature since 2000 when it was first described. There is no standard treatment scheme for ETANTR yet. CASE REPORT: A 2 years old boy presented with a month-long of headache and inability to hold his head. CT scan and MRI revealed a large mass in the right frontal lobe with midline shift. Subtotal tumor resection was done. Histological and immunohistochemical analyses was consistent with ETANTR in one laboratory and PNET in another. The second opinion suggested by the Center of Pediatric Oncology, Hematology and Immunology in Moscow the diagnosis ETANTR was confirmed. Taking into account certain similarities with medulloblastoma was decided to provide treatment according to HIT-2014 protocol. Control MRI done after 2 cycles of Block SKK Carboplatin/Etoposide found tumor progression and for that reason patient underwent second surgical resection. Considering the age of the child radiation therapy was not expedient and the decision was to continue treatment with HIT 2014 intensified regimen, which includes Cisplatin, Vincristine, Etoposide, Cyclophosphamide and intravenous High dose Methotrexate with intrathecal Methotrexate. Aiming to evaluate the effectiveness of treatment we are planning to perform MRI after this 2nd cycle of intensified regimen. DISCUSSION There are difficulties in diagnosis of rare types of cancers in Armenia. Since there is no approved treatment for ETANTR, there is a need for ongoing research to improve its prognosis.
A Pilot Study of CX-01 with Azacitidine for Treatment of Hypomethylating Agent-Refractory AML and MDS
Authors: Eric Huselton, Amanda F. Cashen, John F DiPersio, Meagan Jacoby, Iskra Pusic, Rizwan Romee, Geoffrey L. Uy, Peter Westervelt
Journal: Blood (2017)
Abstract 12296: Identification of Five Genetic Variants as Novel Determinants of Type 2 Diabetes Mellitus in Japanese by Exome-wide Association Studies
Authors: Mitsutoshi Oguri, Kimihiko Kato, Tetsuo Fujimaki, Hideki Horibe, Jun Sakuma, Ichiro Takeuchi, Toyoaki Murohara, Yoshiki Yasukochi, Yoshiji Yamada
Journal: Circulation (2017)

Introduction: Genome-wide association studies (GWASs) have identified >80 susceptibility loci for type 2 diabetes mellitus (DM) in individuals of European ancestry. Genetic variants identified in t...
81P Monalizumab in combination with cetuximab post platinum and anti-PD-(L)1 in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN): Updated results from a phase II trial
Authors: J. Fayette, J. Bauman, S. Salas, D. Colevas, C. Even, D. Cupissol, M.R. Posner, G. Lefebvre, E. Saada-Bouzid, M. Bernadach, T. Seiwert, A. Pearson, S. Messouak, S.L. Cornen, P. Andre, F. Rotolo, A. Boyer-Chammard, R.B. Cohen
Journal: Annals of Oncology (2020)
Abstract P409: Thyroid Function and Cognitive Decline in Middle-aged and Older Adults: The Elsa-Brasil Study
Authors: Claudia Szlejf, Claudia K Suemoto, Carolina Janovsky, Paulo A LOTUFO, Isabela M Bensenor
Journal: Circulation (2020)

Introduction: The role of subtle thyroid alterations on cognitive decline is controversial. We aimed to investigate the association of thyrotropin (TSH) and free thyroxine (FT4) with baseline performance on cognitive tests and with cognitive decline in middle-aged and older adults without overt thyroid disease. Methods: This is a longitudinal analysis of the Brazilian Longitudinal Study of Adult Health baseline and second wave, after 4 years of follow-up. We included participants aged ≥ 55 years without over thyroid disease, prevalent stroke and use of drugs that could affect thyroid function and cognition. TSH and FT4 were assessed at baseline. Cognition was evaluated at baseline and at the second wave using delayed word recall test (DWR), semantic verbal fluency test (SVF), and trail making test version B (TMT). Baseline and longitudinal associations of TSH tertiles and FT4 tertiles with cognitive performance were investigated with generalized estimating equations, adjusted for sociodemographic characteristics, lifestyle, cardiovascular risk factors, and depression. Results: The baseline mean age of the 4675 participants was 62.4 ± 5.8 years, 52.3% women (2445 out of 4675). At baseline, TSH levels were not associated with cognitive performance in any test, although the highest FT4 tertile was associated with poorer performance on DWR (β = -0.087, 95% CI = -0.155; -0.019) and SVF (β = -0.076, 95%CI = -0.143; -0.010) after adjustment. Additionally, the lowest FT4 tertile was associated with poorer performance on SVF (β = -0.090, 95%CI = -0.152; -0.028). Cognitive performance did not change after 4 years of follow-up and there was no effect of time on the association of thyroid hormone levels with cognitive performance. Conclusion: At baseline, FT4 levels were associated with worse cognitive performance in a relatively young sample. Neither baseline FT4 nor TSH were associated with cognitive decline after 4 years.
Rapid triage for COVID-19 using routine clinical data for patients attending hospital: development and prospective validation of an artificial intelligence screening test
Authors: Andrew A S Soltan, Samaneh Kouchaki, Tingting Zhu, Dani Kiyasseh, Thomas Taylor, Zaamin B Hussain, Tim Peto, Andrew J Brent, David W Eyre, David A Clifton
Journal: The Lancet Digital Health (2020)

The early clinical course of COVID-19 can be difficult to distinguish from other illnesses driving presentation to hospital. However, viral-specific PCR testing has limited sensitivity and results can take up to 72 h for operational reasons. We aimed to develop and validate two early-detection models for COVID-19, screening for the disease among patients attending the emergency department and the subset being admitted to hospital, using routinely collected health-care data (laboratory tests, blood gas measurements, and vital signs). These data are typically available within the first hour of presentation to hospitals in high-income and middle-income countries, within the existing laboratory infrastructure.
Manganese porphyrin-based metal-organic framework for synergistic sonodynamic therapy and ferroptosis in hypoxic tumors
Authors: Qingbo Xu, Guiting Zhan, Zelong Zhang, Tuying Yong, Xiangliang Yang, Lu Gan
Journal: Theranostics (2020)

Development of efficient therapeutic strategy to incorporate ultrasound (US)-triggered sonodynamic therapy (SDT) and ferroptosis is highly promising in cancer therapy. However, the SDT efficacy is severely limited by the hypoxia and high glutathione (GSH) in the tumor microenvironment, and ferroptosis is highly associated with reactive oxygen species (ROS) and GSH depletion. Methods: A manganese porphyrin-based metal-organic framework (Mn-MOF) was constructed as a nanosensitizer to self-supply oxygen (O2) and decrease GSH for enhanced SDT and ferroptosis. In vitro and in vivo analysis, including characterization, O2 generation, GSH depletion, ROS generation, lipid peroxidation, antitumor efficacy and tumor immune microenvironment were systematically evaluated. Results: Mn-MOF exhibited catalase-like and GSH decreasing activity in vitro. After efficient internalization into cancer cells, Mn-MOF persistently catalyzed tumor-overexpressed H2O2 to in-situ produce O2 to relieve tumor hypoxia and decrease GSH and GPX4, which facilitated the formation of ROS and ferroptosis to kill cancer cells upon US irradiation in hypoxic tumors. Thus, strong anticancer and anti-metastatic activity was found in H22 and 4T1 tumor-bearing mice after a single administration of Mn-MOF upon a single US irradiation. In addition, Mn-MOF showed strong antitumor immunity and improved immunosuppressive microenvironment upon US irradiation by increasing the numbers of activated CD8+ T cells and matured dendritic cells and decreaing the numbers of myeloid-derived suppressor cells in tumor tissues. Conclusions: Mn-MOF holds great potential for hypoxic cancer therapy.