tbuckley/cabot-search huggingface dataset:
Upregulation of amplified in breast cancer 1 contributes to pancreatic ductal adenocarcinoma progression and vulnerability to blockage of hedgehog activation
Authors: Licen Li, Jiaolin Bao, Haitao Wang, Josh Haipeng Lei, Cheng Peng, Jianming Zeng, Wenhui Hao, Xu Zhang, Xiaoling Xu, Chundong Yu, Chu-Xia Deng, Qiang Chen
Journal: Theranostics (2020)

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and devastating cancers without effective treatments. Amplified in breast cancer 1 (AIB1) is a member of the steroid receptor coactivator family that mediates the transcriptional activities of nuclear receptors. While AIB1 is associated with the initiation and progression of multiple cancers, the mechanism by which AIB1 contributes to PDAC progression remains unknown. In this study, we aimed to explore the role of AIB1 in the progression of PDAC and elucidate the underlying mechanisms. Methods: The clinical significance and mRNA level of AIB1 in PDAC were studied by database analysis. To demonstrate whether AIB1 mediates the malignant features of PDAC cells, namely, proliferation, migration, invasion, we performed real-time PCR and Western blot analysis, established xenograft models and used in vivo metastasis assay. With insights into the mechanism of AIB1, we performed RNA sequencing (Seq), ChIP-Seq, luciferase reporter assays and pull-down assays. Furthermore, we analyzed the relationship between AIB1 expression and its target expression in PDAC cells and patients and explored whether PDAC cells with high AIB1 levels are sensitive to inhibitors of its target. Results: We found that AIB1 was significantly upregulated in PDAC and associated with its malignancy. Silencing AIB1 impaired hedgehog (Hh) activation by reducing the expression of smoothened (SMO), leading to cell cycle arrest and the inhibition of PDAC cell proliferation. In addition, AIB1, via upregulation of integrin αv (ITGAV) expression, promoted extracellular matrix (ECM) signaling, which played an important role in PDAC progression. Further studies showed that AIB1 preferably bound to AP-1 related elements and served as a coactivator for enhancing the transcriptional activity of MafB, which promoted the expression of SMO and ITGAV. PDAC cells with high AIB1 levels were sensitive to Hh signaling inhibitors, suggesting that blocking Hh activation is an effective treatment against PDAC with high AIB1 expression. Conclusions: These findings reveal that AIB1 is a crucial oncogenic regulator associated with PDAC progression via Hh and ECM signaling and suggest potential therapeutic targets for PDAC treatment.
The Art of Losing—Three Poems for the COVID-19 Pandemic
Authors: Rafael Campo, Elisa New
Journal: JAMA (2020)

This Arts and Medicine essay features 3 poems—Elizabeth Bishop's "One Art," Marilyn Chin's "Hospital in Oregon," and Edward Hirsch's "What the Last Evening Will Be Like"—as sources of wisdom and insight in the turmoil and pain of the COVID-19 pandemic.
LINC-24. CHARACTERISTICS OF PEDIATRIC BRAIN TUMORS AT DEPARTMENT OF CHILD HEALTH FACULTY OF MEDICINE UNIVERSITAS INDONESIA-DR. CIPTO MANGUNKUSUMO TERTIARY GENERAL HOSPITAL, JAKARTA, INDONESIA
Authors: Dwi Putro Widodo, Irawan Mangunatmadja, Marsintauli Siregar, Hardiono Pusponegoro, Setyo Handryastuti, Amanda Soebadi, Achmad Rafli
Journal: Neuro-Oncology (2020)

Abstract Brain tumors are still the second leading cause of death among cancers in children. Based on data from National Brain Tumor Society (2019), in United States, there are 28.000 children living with brain tumor with varied clinical, radiological, and histopathological features. The most prevalent children’s brain tumor types in US are gliomas (ependymal tumors, pilocytic astrocytomas) and embroyonal tumors, including medulloblastoma. From 1993–1994 at Department of Child Health Faculty of Medicine Universitas Indonesia-Dr. Cipto Mangunkusumo Tertiary General Hospital, Jakarta, Indonesia, there are 19 patients with brain tumors hospitalized with most of patients with astrocytoma 8 patients (42%), 4 patients (21%) medulloblastoma, 2 patients (11%) neuroblastoma, 2 patients (11%) ependymoma, 2 patients (11%) craniopharyngioma, and one patient (4%) meningioma. Retrospective cohort study (2010–2015) with subjects 100 children revealed that based on the radiographs, the brain tumors were located mostly in the cerebellum (24%) and the suprasellar region (10%); based on the histopathology, the most common types of brain tumor were astrocytomas (18%), medulloblastoma (21%), and gliomas (17%). The most common symptom of brain tumors was headache and impaired vision. Survival patients with brain tumors for 5 years in the age group aged 3 years and above was better than that in children aged under 3 years (60% vs 55% and 17% vs 14%). This report can serve as one of basic data for profile children’s brain tumors in Indonesia. Keywords: brain; tumor; children; survival; Indonesia
GCT-16. LONG-TERM CLINICAL OUTCOMES OF GERM CELL TUMORS
Authors: Kenichiro Matsuda, Kaori Sakurada, Takamasa Kayama, Yukihiko Sonoda
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Intracranial germ cell tumors (GCT) are mainly arising in adolescent term and treated with chemotherapy concomitant with radiation therapy. There is accumulating evidence that the progress of treatment. Besides, long-term outcome and adverse effects are major problem in treatment. So, we must grasp the influence of these outcomes on daily and social life. Then we investigated in clinical outcome in cases of GCT treated in our institution. METHOD: We reviewed the clinical features and outcomes of 52 cases of intracranial GCT in 1975 to 2019. Ages on diagnosis are 5–35 years old (median 14 years old), consisted with 44 male cases. The pathological distributions are these: pure germinoma: 40 cases, non-germinomatous germ cell tumor (NGGCT): 10 cases (mature teratoma: 4, mixed germ cell tumors: 3, and one cases of choriocarcinoma, embryonal carcinoma, yolk sac tumor), unidentified pathology: 2 cases. Almost all cases have biopsied and treated by chemotherapy and radiation therapy. RESULTS Chemotherapy with ICE regimen (ifosphamide, cisplatin, etoposide) or CARE regimen (carboplatin, etoposide) concomitant with radiation therapy (mainly, extended local irradiation) have done in almost cases by the era. Clinical outcomes are relatively well in our cases, but 10 cases experienced recurrence. 3 cases have dead. Some cases with suprasellar involvement have need hormone replacement in long term. There are 10 cases at work. CONCLUSION Almost cases have gained better outcome and ADL. But there is slightly lower rate in work or marriage. Serial evaluation in outcome, and higher brain functions should be performed in follow up.
Genetic Heterogeneity of MET-Aberrant NSCLC and Its Impact on the Outcome of Immunotherapy
Authors: Anna Kron, Matthias Scheffler, Carina Heydt, Lea Ruge, Carsten Schaepers, Anna-Kristina Eisert, Sabine Merkelbach-Bruse, Richard Riedel, Lucia Nogova, Rieke Nila Fischer, Sebastian Michels, Diana S.Y. Abdulla, Sophia Koleczko, Jana Fassunke, Anne M. Schultheis, Florian Kron, Frank Ueckeroth, Gabriele Wessling, Juliane Sueptitz, Frank Beckers, Jan Braess, Jens Panse, Christian Grohé, Michael Hamm, Hans-Joachim Kabitz, Kato Kambartel, Britta Kaminsky, Stefan Krueger, Clemens Schulte, Joachim Lorenz, Johann Lorenzen, Wolfram Meister, Andreas Meyer, Jutta Kappes, Niels Reinmuth, Bernhard Schaaf, Wolfgang Schulte, Monika Serke, Reinhard Buettner, Jürgen Wolf
Journal: Journal of Thoracic Oncology (2020)
DIPG-77. TREATMENT EXTENT AND THE EFFECT ON SURVIVAL IN DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Joshua Baugh, Niclas Colditz, Geert Janssens, Stefan Dietzsch, Darren Hargrave, André von Bueren, Rolf-Dieter Kortmann, Brigitte Bison, Dannis van Vuurden, Sophie Veldhuijzen van Zanten, Christof Kramm
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Front line radiotherapy for diffuse intrinsic pontine glioma (DIPG) remains the only standard of care. Is this still appropriate? PATIENTS AND METHODS We examined survival outcomes across six treatment modalities including I) no treatment (n=19), II) radiotherapy alone (n=38), III) radio-chemotherapy (n=101), IV) radiotherapy and relapse chemotherapy (n=35), V) radio-chemotherapy and relapse chemotherapy (n=163), and VI) radio-chemotherapy and relapse chemotherapy, plus reirradiation (n=54). Data were collected retrospectively using the Society of Pediatric Oncology and Hematology (GPOH) and the SIOPE DIPG Registry. 410 patients were included with radiologically centrally reviewed DIPG, mostly unbiopsied. Of note, the untreated patients and radiotherapy only cohorts chose limited treatment voluntarily. RESULTS Median overall survival (MOS) of the whole cohort was 11 months and progression free survival (PFS) 7 months. PFS was not significantly different between the treatment groups. OS and post-progression survival (PPS) were significantly different between cohorts. For the respective treatment groups, median OS was 3 months (I), 7 months (II), 8 months (III), 13 months (IV), 13 months (V), and 15 months (VI). For only front line vs at least one second line therapy, MOS was 8 months vs 14 months and PPS 2 months vs 5 months. CONCLUSIONS Although subject to biases to some extent, it seems that additional therapies beyond radiation therapy are of benefit to extending survival in DIPG patients. This is at least partially caused by the introduction of reirradiation regimens. To what extent other therapies contribute to survival and quality of life is subject to further investigation.
Transcatheter Pulmonary Valve Replacement With the Sapien Prosthesis
Authors: Shabana Shahanavaz, Evan M. Zahn, Daniel S. Levi, Jamil A. Aboulhousn, Sebastien Hascoet, Athar M. Qureshi, Diego Porras, Gareth J. Morgan, Holly Bauser Heaton, Mary Hunt Martin, Britton Keeshan, Jeremy D. Asnes, Damien Kenny, Jeremy M. Ringewald, Jenny E. Zablah, Margaret Ivy, Brian H. Morray, Alejandro J. Torres, Darren P. Berman, Matthew J. Gillespie, Kasey Chaszczewski, Jeffrey D. Zampi, Kevin P. Walsh, Plessis Julien, Bryan H. Goldstein, Shyam K. Sathanandam, Clement Karsenty, David T. Balzer, Doff B. McElhinney
Journal: Journal of the American College of Cardiology (2020)
CTNI-53. SINGLE ARM, OPEN-LABEL, MULTICENTER PHASE II STUDY OF THE RADIONUCLIDE 177LU-DOTATATE (LUTATHERA) IN ADULTS WITH ADVANCED INTRACRANIAL MENINGIOMA
Authors: Sylvia Kurz, Elcin Zan, Jasone Gurewitz, Christine Cordova, Andrea B Troxel, Zacharia Sawaged, Hector Sevillano-Torres, Joshua S Silverman, Matija Snuderl, David Zagzag, John Golfinos, Douglas Kondziolka, Erik Sulman
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Meningiomas are the most common primary intracranial neoplasm. Once surgical and radiotherapeutic options are exhausted, there are no effective medical treatments available. A majority of meningiomas express somatostatin receptor 2 (SSTR2), representing a promising treatment target. 177Lu-DOTATATE is a SSTR2-targeting radionuclide that has been successful in SSTR2-expressing neuroendocrine tumors. Here we hypothesize that 177Lu-DOTATATE is effective in treating progressive intracranial meningiomas. METHODS In this ongoing phase II study (NCT03971461), adults with advanced intracranial meningiomas received 177Lu-DOTATATE 7.4 GBq (200 mCi) every 8 weeks for 4 doses. 68Ga-DOTATATE PET-MRI was obtained before and at the end of treatment (EOT). The primary endpoint was progression-free survival at 6 months (PFS-6). Correlative studies evaluated the association of PFS-6, objective response rate, progression-free survival, overall survival with radiographic tumor measurements, 68Ga-DOTATATE uptake on PET-MRI, SSTR2 expression in tumor, and meningioma methylation subclass. RESULTS Nine patients (F = 7, M = 2) with progressive meningiomas (WHO I = 2, II = 6, III = 1) have been enrolled. Median age was 63 (range 49–78) years. All patients previously underwent tumor resection and at least one course of radiation. Treatment with 177Lu-DOTATATE was well tolerated, although CTCAE grade 3/4 electrolyte derangements and cytopenias were observed. Six patients reached PFS-6, three patients experienced progressive disease. Four patients had EOT 68Ga-DOTATATE PET-MRI evaluations in which anatomic measurements and 68Ga-DOTATATE standardized uptake values (SUV) pre- and post-treatment were assessed: one patient had reduced SUV measurements in all target lesions indicating altered SSTR2 expression and functional treatment response, one patient had stable disease, one patient had a mixed treatment response, and one patient experienced progressive disease. CONCLUSIONS SSTR2-targeting 177Lu-DOTATATE represents a promising treatment option for patients with progressive intracranial meningiomas. Treatment is well tolerated and can lead to functional alteration of tumoral SSTR2 expression by 68Ga-DOTATATE PET-MR imaging.
EXTH-53. A BRAIN-PENETRANT MICROTUBULE-TARGETING AGENT THAT DISRUPTS HALLMARKS OF GLIOMA TUMORIGENESIS
Authors: Eric Horne, Juan J Vicente Ruiz, Patrick Cimino, Erik Jung, Cong Xu, Philippe Diaz, Ernest Hamel, Debra K Kumasaka, Michael J Wagenbach, Frank Winkler, Linda G Wordeman, Eric Holland, Nephi Stella
Journal: Neuro-Oncology (2020)

Abstract Most cancer therapeutics developed to date are excluded from the brain and are therefore ineffective in treating glioma, the most devastating type of brain cancer in adults. Microtubule targeting agents (MTAs) are indispensable medicines to treat a wide range of solid and hematopoietic tumors, and evidence suggests that glioma is sensitive to MTAs; but most MTAs do not cross the blood-brain-barrier. To address this limitation, we developed a brain-penetrant MTA, ST-401, that inhibited the growth of human glioma in culture at nanomolar concentrations. ST-401 bound to the colchicine site, inhibited tubulin assembly and reversibly reduced microtubule (MT) dynamics. Testing of ST-401 on the NCI 60 cancer cell panel indicated that its anti-tumor activity does not correlate with any of the compounds tested thus far through this platform but showed weak correlations for two MTA that work through distinct mechanisms: taxol (p=0.46) and vinblastine (p=0.34). Thus, ST-401 may kill cancer cells through a novel mechanism related to disruption of MT function. We discovered that ST-401 killed patient-derived (PD) glioma isolates in both mitosis and interphase, and inhibited the formation of tumor microtubes, MT-rich structures that connects glioma cells to a network that is resistant to standard therapies. Pharmacokinetic analysis of ST-401 in mice shows brain penetration reaching antitumor concentrations, and in vivo testing of ST-401 in a xenograft model demonstrated significant antitumor activity. In an immunocompetent mouse model of platelet-derived growth factor B-driven glioma, ST-401 significantly enhanced the therapeutic efficacies of standard care therapies temozolomide and radiation therapy. Our study identified novel aspects of glioma tumorigenesis that exhibit enhanced sensitivity to MTAs and shows that the brain-penetrant MTA, ST-401, represents a promising chemical scaffold to develop therapeutics for the treatment of patients diagnosed with glioma.
DIPG-53. CHARACTERIZING THE ROLE OF PPM1D MUTATIONS IN THE PATHOGENESIS OF DIFFUSE INTRINSIC PONTINE GLIOMAS (DIPGS)
Authors: Prasidda Khadka, Zachary Reitman, Sophie Lu, Graham Buchan, Rachel Hartley, Heather Bear, Yoahnna Georgis, Spandana Jarmale, Kathleen Schoolcraft, Peter Miller, Elizabeth Gonzalez, Gabrielle Gionet, Kenin Qian, Randy Melanson, Hasmik Keshishian, Diana Carvalho, Alexandra Condurat, Amy Goodale, Tanaz Abid, Federica Piccioni, Susan Chi, Steven Carr, Daphne Haas-Kogan, Benjamin Ebert, Mark Kieran, Chris Jones, Keith Ligon, Rameen Beroukhim, Timothy Phoenix, Pratiti Bandopadhayay
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION We have previously found that up to 15% of all DIPGs harbor mutations in PPM1D, resulting in the expression of an activated and truncated PPM1D (PPM1Dtr). Here we evaluate the mechanisms through which PPM1Dtr enhances glioma formation and identify its associated therapeutic vulnerabilities. METHODS We have developed multiple in vitro and in vivo models of PPM1D-mutant DIPGs and applied quantitative proteomic and functional genomic approaches to identify pathways altered by PPM1Dtr and associated dependencies. RESULTS PPM1D mutations are clonal events that are anti-correlated to TP53 mutations. We find ectopic expression of PPM1Dtr to be sufficient to enhance glioma formation and to be necessary in PPM1D-mutant DIPG cells. In addition, endogenous truncation of PPM1D is sufficient to enhance glioma formation in the presence of mutant H3F3A and PDGFRA. PPM1Dtr overexpression attenuates g-H2AX formation and suppresses apoptosis and cell-cycle arrest in response to radiation treatment. Deep scale phosphoproteomics analyses reveal DNA-damage and cell cycle pathways to be most significantly associated with PPM1Dtr. Furthermore, preliminary analysis of genome-wide loss-of-function CRISPR/Cas9 screens in isogenic GFP and PPM1Dtr overexpressing mouse neural stem cells reveal differential dependency on DNA-damage response genes in the PPM1Dtr overexpressing cells. Consistent with PPM1D’s role in stabilizing MDM2, PPM1D-mutant DIPG models are sensitive to a panel of MDM2 inhibitors (Nutlin-3a, RG7388, and AMG232). CONCLUSION Our study shows that PPM1Dtr is both an oncogene and a dependency in PPM1D- mutant DIPG, and there are novel therapeutic vulnerabilities associated with PPM1D that may be exploited.
LGG-20. CLINICAL FEATURES AND TREATMENT RESULTS FOR PEDIATRIC OPTICO-HYPOTHALAMIC ASTROCYTOMA
Authors: Koji Yoshimoto, Nobuhiro Hata, Nayuta Higa, Hajime Yonezawa, Hiroyuki Uchida, Tatsuki Oyoshi, Masahiro Mizoguchi
Journal: Neuro-Oncology (2020)

Abstract Current consensus for the treatment of optico-hypothalamic astrocytoma (OHA) is a chemotherapy-first policy, limiting the role of surgery for histopathological diagnosis and partial decompression. However, a subgroup of OHA patients show resistance to chemotherapy and have a worse prognosis. In this study, we retrospectively analyzed our clinical experiences of the treatment of patients with OHA in two university hospitals. We have extracted and analyzed the medical charts of 15 pediatric OHA patients treated in two university hospitals since 1990. NF-1-associated OHA patients were excluded. Patient ages ranged from 10 months to 21 years (median 7 years). Out of 15 cases, 12 patients had a tumor larger than 3 cm and classified as Dodge 3. The final histopathological diagnosis was pilocytic astrocytoma in 13 cases. Three patients with tumors classified as Dodge 1 or 2 show good prognosis only by biopsy or partial resection. However, regarding Dodge 3 tumor, patient prognosis is worse regardless of chemotherapy and radiotherapy. After the initial surgery, chemotherapy was administered in 11 cases and radiotherapy in 5 cases. Multiple surgeries are needed for tumor control in 7 patients. Four patients died of tumor progression or treatment-associated complications. When the initial tumor is large enough to cause neurological deterioration, a chemotherapeutic tumor suppressive effect might be limited in a subset of large OHA cases. Therefore, it is important to consider the proper timing of safe surgical decompression in the early phase when a large tumor does not respond to chemotherapy.
TAMI-21. MALIGNANT GLIOMAS REMODEL FUNCTIONAL NEURAL CIRCUITS THROUGH PARACRINE SIGNALING WHICH CONFERS A NEGATIVE PROGNOSIS
Authors: Saritha Krishna, Abrar Choudhury, Lijun Ni, Kyounghee Seo, Sofia Kakaizada, Anne Findlay, Anthony Lee, Rasika Sudharshan, Caroline Cao, Humsa Venkatesh, Hannes Vogel, Joanna Phillips, Nyle Almeida, Srikantan Nagarajan, Mitchel Berger, David Raleigh, David Brang, Michelle Monje, Shawn Hervey-Jumper
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Unlike cancers affecting many solid organs, gliomas exist within the context of complex neural circuitry. It remains unknown whether glioma-neuron interactions play a role in maintaining functional circuits underlying cognition. We test the hypothesis that malignant gliomas remodel functional circuits through glioma-neuron interactions. METHODS Using language processing as a model for functional circuit dynamics, we enrolled 53 patients with dominant hemisphere IDH-wild-type glioblastoma. Task related circuit dynamics were measured using electrocorticography. Magnetoencephalography measures of functional connectivity identified intratumoral connectivity (HFC) and suppressed connectivity (LFC) regions. Primary patient samples and cultures from HFC and LFC-sites were assessed by single-cell RNA sequencing, pre/post-synaptic marker expression, cocultured with murine hippocampal neurons, and induced neuron organoids. Hippocampal tumor xenografts were created. Language/survival statistics were performed to correlate with functional connectivity measures. RESULTS Speech production evokes neuronal population spikes within the entire area of tumor-infiltrated cortex, far beyond the cortical territory normally involved in expressive language. Primary patient samples from HFC-regions are enriched for glioblastoma cells with a synaptogenic profile as characterized by pre-and post-synaptic marker expression at both tissue and cellular levels. RNA-sequencing and proteomic analyses from HFC samples revealed a neurogenic signature including thrombospondin-1 originating from glioma cells in HFC-regions and non-tumor astrocytes in LFC-regions. HFC xenografts demonstrated increased total number of synapses. Importantly, when compared with gliomas without intratumoral functional connectivity, connected gliomas have worse language task performance (r= -0.54,p=0.03) and shorter OS (medianOS-64 weeks compared with 107-weeks,p=0.04). CONCLUSION Glioma infiltrated regions generate task-relevant neural responses, with speech production evoking neuronal activity throughout tumor-involved cortex in the dominant hemisphere. An enriched population of synaptogenic glioma cells are organized within functionally connected intratumoral regions and this confers negative functional and survival outcomes. Together, these findings indicate that malignant gliomas can functionally remodel neural circuitry, thereby impairing neurological function and promoting tumor progression.