tbuckley/cabot-search huggingface dataset:
PATH-59. HISTOPATHOLOGICAL INVESTIGATION OF THE 1p/19q-CODELETED GLIOMAS RESECTED FOLLOWING ALKYLATING AGENTS CHEMOTHERAPY
Authors: Tokunori Kanazawa, Kentaro Ohara, Kazunari Yoshida, Hikaru Sasaki
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Little is known about histopathological changes after chemotherapy in lower-grade gliomas (LrGGs). METHODS We investigated 15 1p/19q-codeleted gliomas resected following tumor volume decrease after alkylating agents chemotherapy in comparison with their pre-chemotherapy specimens. Histopathological changes by chemotherapy were evaluated by hematoxilyn-eosin staining and immunohistochemistry for Ki-67/MIB-1, CD68 as pan macrophage/monocyte marker, CD163 as presumed marker of M2 polarity, and nestin and CD133 as markers of glioma stem cells (GSCs). RESULTS Histologically, there were several presumed chemotherapy-related changes in the post-chemotherapy specimens, with the most frequent findings being sparse glial background and abundant foamy cell infiltration. The Ki-67/MIB-1 indices significantly decreased, and CD68+ cells significantly increased after chemotherapy. The increasing rate of CD68+ cells in the post-/pre-chemotherapy specimens was prone to be associated with patients’ progression-free survival (PFS) and overall survival (OS), but not tumor response. The number of CD163+ cells and the ratio of nestin+ cells and CD133+ cells significantly increased after chemotherapy. The number of CD163+ cells, the ratio of nestin+ cells and CD133+ cells, and M2 (CD163+)/M1+M2 (CD68+) ratio in the post-chemotherapy specimens were negatively correlated with patients’ PFS and OS. There was no difference between chemotherapy regimens (temozolomide versus nitrosourea-based) in the number of CD163+ cells and the ratio of nestin+ and CD133+ cells. CONCLUSIONS GSCs in conjunction with M2 macrophages constitute the mechanism of resistance to and recurrence after alkylating agents chemotherapy in LrGGs.
DDIS-22. DRUG SCREEN IN PATIENT-DERIVED IDHMUT GLIOMA STEM CELLS IDENTIFIES SEVERAL FDA-APPROVED ANTINEOPLASTIC AGENTS
Authors: Philip Dao Trong, Stefan Pusch, Andreas Unterberg, Christel Herold-Mende, Rolf Warta
Journal: Neuro-Oncology (2019)

Abstract OBJECTIVE The discovery of the Isocitrate Dehydrogenase (IDH) mutation in glioma has led to a paradigm shift on how we see glioma biology. While it is clear, that IDH mutated (IDHmut) and wildtype (IDHwt) tumors have to be viewed as separate entities, the underlying biological differences are still matter of extensive research. Difficulties in cultivating IDHmut glioma stem cells (GSC) have led to a paucity of preclinical models in IDHmut glioma making the discovery of new effective chemotherapeutic agents problematic. We therefore sought to perform a repurposing drug screen in five patient-derived IDHmut GSC lines to discover potential effective antineoplastic agents, already approved by the FDA. METHODS Patient tumor tissue was obtained in our neurosurgical department to isolate and establish IDHmut GSC lines. (D)-2-hydroxyglutarate (2HG) levels were measured in the cell culture supernatant of IDHmut GSCs using an enzymatic diaphorase/resazurin system. The drug library provided by the Developmental Therapeutics Program (DTP) of the National Cancer Institute (NCI) consisting of 146 FDA-approved drugs was used for the screen. Cell viability was assessed with the CellTiterGlo assay (Promega). RESULTS Despite several passages, the IDHmut GSCs showed stable production of 2HG and were therefore suitable for the drug screen. Cells were cultured as neurospheres and subjected to the test compounds for 72h in concentrations ranging from 0.1nM – 1µM. We identified several compounds in two IDHmut GSC lines (NCH551b, NCH1681) that had a half maximal inhibitory concentration (IC50) below 1µM and could confirm its cytotoxic potential in additional three IDHmut GSC lines (NCH612, NCH620, NCH3763). CONCLUSION In this study, we present a feasible preclinical model for a high-throughput drug screen in patient-derived IDHmut GSCs and identified several FDA-approved antineoplastic agents which warrant further investigations.
Aurora Kinase a/MDM2-Mediated SETD2 Loss of Function in Chronic Myeloid Leukemia Patients in Blast Crisis Can be Therapeutically Targeted Inducing Apoptotic Cell Death in a Caspase-Dependent Way
Authors: Manuela Mancini, Sara De Santis, Cecilia Monaldi, Luana Bavaro, Margherita Martelli, Gabriele Gugliotta, Fausto Castagnetti, Gianantonio Rosti, Maria Chiara Fontana, Samantha Bruno, Elisa Dan, Barbara Sinigaglia, Alessandra Iurlo, Nicola Orofino, Elisabetta Abruzzese, Marzia Salvucci, Patrizia Pregno, Antonella Gozzini, Monica Crugnola, Francesco Albano, Massimiliano Bonifacio, Elisabetta Calistri, Mario Tiribelli, Gianni Binotto, Annalisa Imovilli, Elena Trabacchi, Sara Galimberti, Claudia Baratè, Elena Tenti, Michele Baccarani, Giovanni Martinelli, Michele Cavo, Simona Soverini
Journal: Blood (2019)
CD117 Expression Is Associated with Cytogenetic and Molecular Profiles and Outcome in Pediatric Acute Myeloid Leukemia
Authors: Katherine Tarlock, Lisa Eidenschink Brodersen, Todd A. Alonzo, Yi-Cheng Wang, Robert B. Gerbing, Laura Pardo, Fangyan Dai, Alan S Gamis, Richard Aplenc, Jessica A. Pollard, Michael R. Loken, Soheil Meshinchi
Journal: Blood (2019)
King’s College London clarifies details of inquiry into publications by Eysenck and Grossarth-Maticek
Authors: Ian P Everall
Journal: BMJ (2019)

The BMJ ’s news article on Rod Buchanan’s claims regarding papers by Hans Eysenck and Ronald Grossarth-Maticek1 contains allegations that the King’s College London inquiry into publications authored by Eysenck with Grossarth-Maticek omitted papers on which Eysenck was the sole author to “imply diminished responsibility” of Eysenck or to absolve …
Distinct Gene Expression Profiles and Mutations Associate with Outcome in Younger Adults with De Novo Cytogenetically Normal Acute Myeloid Leukemia (CN-AML) (Alliance)
Authors: Christopher J. Walker, Ann-Kathrin Eisfeld, Hatice G Ozer, Jessica Kohlschmidt, Deedra Nicolet, Krzysztof Mrózek, Dimitrios Papaioannou, Luke K Genutis, Bayard L Powell, Geoffrey L. Uy, Jonathan E. Kolitz, Andrew J. Carroll, Richard Stone, Ramiro Garzon, John C. Byrd, Albert de la Chapelle, Clara D. Bloomfield
Journal: Blood (2019)
The Distinctive Metabolic Environment of the Bone Marrow Niche Drives Leukemia Chemoresistance
Authors: Nick van Gastel, Jessica B. Spinelli, Azeem Sharda, Amir Schajnovitz, Ninib Baryawno, Catherine S Rhee, Toshihiko Oki, Eliane Grace, Heather J. Soled, Charles Vidoudez, Sunia A. Trauger, Marcia C. Haigis, David T. Scadden
Journal: Blood (2019)
Stuart B Levy: antibiotic resistance researcher and advocate for “prudent use” of antibiotics
Authors: Ned Stafford
Journal: BMJ (2019)

Photo credit/copyright: Alonso Nichols/Tufts University

In 1963 in Paris the young Stuart Levy was introduced, as he would describe it four decades later, “to the phenomenon of antibiotic resistance.”1 At the time, he had completed only two years of medical study in the US and had taken a fellowship in Paris to research radiation genetics at the Pasteur Institute.

Levy was introduced to antibiotic resistance during a “journal club” meeting, where he and others discussed the latest papers published in scientific journals. Tsutomu Watanabe, who with his colleagues in Japan was pioneering drug resistance research, had in early 1963 published a landmark paper in English on “infective heredity” of multidrug resistance in bacteria.2

“I was fascinated to learn about R factors, curious means of drug resistance transfer among bacteria of different genera,” Levy later recalled. “I decided to understand first hand the findings in this area.”1

Levy wrote a letter to Watanabe, asking to work in his laboratory at Keio University in Tokyo for a few months. Watanabe agreed, and Levy’s fate was sealed. He would spend the rest of his life focusing on antibiotic resistance as a pioneering medical researcher and as an impassioned advocate, working tirelessly over decades to convince his fellow doctors that antibiotics should be prescribed only when absolutely necessary.

Put more simply, and in his own words, he advocated the “prudent use” of antibiotics. He also called for advanced diagnostics to identify diseases earlier and more accurately, better to target appropriate antibiotic use.

“The difficulties we face today,” he wrote in The BMJ in 1998, “derive from misguided efforts to try to sterilise our environment by indiscriminately destroying bacteria when we should reserve our killing capabilities for cases when health is threatened by infectious strains. We should act now to restore and maintain the healthy balanced microbiology …
Extracellular vesicle-mediated delivery of miR-101 inhibits lung metastasis in osteosarcoma
Authors: Kailiang Zhang, Chuan Dong, Ming Chen, Tongtao Yang, Xin Wang, Yongheng Gao, Lijuan Wang, Yanhua Wen, Guanyin Chen, Xinli Wang, Xiuchun Yu, Yinglong Zhang, Pingshan Wang, Mingfu Shang, Kang Han, Yong Zhou
Journal: Theranostics (2019)

Rationale: Extracellular vesicles (EVs) have emerged as novel mediators of cell-to-cell communication that are capable of the stable transfer of therapeutic microRNAs (miRNAs), and thus, EVs hold immense promise as a miRNA delivery system for cancer therapy. Additionally, as miRNA-containing EVs are secreted into circulation, miRNAs contained within plasma EVs may represent ideal biomarkers for diseases. The objective of this study was to characterize a potential tumor suppressor miRNA, miR-101, and explore the potential of miR-101 delivery via EVs for in vivo therapy of metastatic osteosarcoma as well as the potential value of plasma EV-packaged miR-101 (EV-miR-101) level for predicting osteosarcoma metastasis. Methods: The relationship of miR-101 expression and osteosarcoma progression was investigated in osteosarcoma specimens by in situ hybridization (ISH), and the potential inhibitory effect of miR-101 was further investigated using in vivo models. Using prediction software analysis, the mechanism of action of miR-101 in osteosarcoma was explored using quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blotting and dual-luciferase assay. Adipose tissue-derived mesenchymal stromal cells (AD-MSCs) were transduced with lentiviral particles to obtain miR-101-enriched EVs. A Transwell assay and lung metastasis models of osteosarcoma were used to observe the effect of miR-101-enriched EVs on osteosarcoma invasiveness and metastasis. Detection of plasma EV-miR-101 levels was carried out in osteosarcoma patients and healthy controls by qRT-PCR. Results: miR-101 expression was markedly lower in metastatic osteosarcoma specimens compared to non-metastatic specimens. Significantly fewer metastatic lung nodules were formed by Saos-2 cells overexpressing miR-101 and SOSP-9607 cells overexpressing miR-101 injected into mice. With increased miR-101 expression, B cell lymphoma 6 (BCL6) mRNA and protein expression levels were reduced, and miR-101 was found to exert its effects by directly targeting BCL6. AD-MSCs were successfully engineered to secrete miR-101-enriched EVs. Once taken up by osteosarcoma cells, these EVs showed suppressive effects on cell invasion and migration in vitro, and systemic administration of these EVs effectively suppressed metastasis in vivo with no significant side effects. Finally, the EV-miR-101 level was lower in osteosarcoma patients than in healthy controls and even lower in osteosarcoma patients with metastasis than in those without metastasis. Conclusion: Our data support the function of miR-101 as a tumor suppressor in osteosarcoma via downregulation of BCL6. AD-MSC derived miR-101-enriched EVs represent a potential innovative therapy for metastatic osteosarcoma. EV-miR-101 also represents a promising circulating biomarker of osteosarcoma metastasis.
The Outcome of Modified St. Jude Total XV Protocol in Turkish Children with Newly Diagnosed Acute Lymphoblastic Leukemia
Authors: Hulya Yilmaz, Selin Aytac, Barış Kuşkonmaz, Duygu Çetinkaya, Sule Unal, Fatma Gumruk, Mualla Çetin
Journal: Blood (2019)
CSIG-06. DEPATUXIZUMAB MAFODOTIN (ABT-414)-INDUCED GLIOBLASTOMA CELL DEATH REQUIRES EGFR OVEREXPRESSION, BUT NOT PHOSPHORYLATION
Authors: Caroline von Achenbach, Vincent Blot, William Weiss, Michael Weller
Journal: Neuro-Oncology (2019)

Abstract Glioblastomas commonly (40%) exhibit epidermal growth factor receptor (EGFR) amplification, half of these tumors carry the EGFRvIII deletion variant characterized by an in-frame deletion of exons 2–7, resulting in constitutive EGFR activation. Although EGFR tyrosine kinase inhibitors had only modest effects in glioblastoma, novel therapeutic agents targeting amplified EGFR or EGFRvIII continue to be developed. Depatuxizumab mafodotin (ABT-414) is an antibody drug conjugate consisting of the monoclonal antibody 806 and, as its toxic payload, monomethyl auristatin F, designed to target EGFR-overexpressing tumor cells. Since long-term glioma cell lines and patient-derived glioma-initiating cell lines appeared to express too little EGFR in vitro to be sensitive to ABT-414, we generated glioma sublines overexpressing EGFR or EGFRvIII to explore the determinants of ABT-414-induced glioma cell death. Overexpression of EGFRvIII induces sensitization to ABT-414 more readily than overexpression of EGFR. There is no bystander killing of cells devoid of EGFR or EGFRvIII expression. Surprisingly, either exposure to EGF or to EGFR tyrosin kinase inhibitors reduce EGFR protein levels and are thus no strategies to promote ABT-414-induced cell killing. Furthermore, glioma cells overexpressing kinase-dead EGFR or EGFRvIII retain binding of mAb 806 and sensitivity to ABT-414, allowing to dissociate EGFR phosphorylation from the emergence of the “active” EGFR conformation required for ABT-414 binding. The combination of EGFR-targeting antibody drug conjugates with EGFR tyrosine kinase inhibitors carries a high risk of failure. Promoting mere EGFR expression rather than phosphorylation should result in glioblastoma cell sensitization to ABT-414 or related agents.
A Phase I Study of Duvelisib and Venetoclax in Patients with Relapsed or Refractory CLL / SLL
Authors: Jennifer L. Crombie, Svitlana Tyekucheva, Alexandra Savell, Karen Francoeur, Mark Choiniere, Josie Montegaard, Jacob D. Soumerai, Jon E. Arnason, David C. Fisher, Jennifer R. Brown, Matthew S. Davids
Journal: Blood (2019)
Use of cystatin C as a marker to detect renal insufficiency in head and neck cancer patients with cisplatin-based chemotherapy
Authors: E. Bölke, S. Gripp, C. Matuschek, D. Hermsen, M. Peiper, W. Budach
Journal: Journal of Clinical Oncology (2009)

e17048 Background: Knowledge of the usefulness of cystatin C measurement in the detection of chronic kidney disease in patients with head and neck cancer (HNC) is scant. The purpose of this study was to evaluate the ability of plasma cystatin C- and creatinine-based methods to predict glomerular filtration rate (GFR) and classify chronic kidney disease in HNC patients before receiving cisplatin based chemotherapy. Methods: The study population consisted of 43 HNC patients aged 39–76 years. Comparisons were made between measured plasma creatinine, cystatin C, creatinine clearance and GFR estimated by the Modification of Diet in Renal Disease (MDRD) formula. The plasma clearance of (51)Cr-EDTA served as a reference method. Results: The Pearson correlation coefficients between plasma clearance of (51)Cr-EDTA and the markers of GFR were calculated. The correlation coefficients were 0.765 for cystatin C, 0.688 for plasma creatinine, 0.585 for GFR values estimated by MDRD and 0.568 for plasma creatinine clearance. Conclusions: We recommend using cystatin C for the estimation of the GFR of HNC patients instead of solely creatinine or creatinine clearance in clinical practice. No significant financial relationships to disclose.
ACTR-07. LONG-TERM OUTCOMES FROM INTERGROUP NCCTG 86-72-51 (ALLIANCE): FINAL REPORT OF A PHASE III PROSPECTIVE RANDOMIZED TRIAL OF HIGH DOSE VERSUS LOW DOSE RADIATION IN ADULT SUPRATENTORIAL LOW-GRADE GLIOMA
Authors: William Breen, S Keith Anderson, Xiomara Carrero, Paul Brown, Karla Ballman, Brian O’Neill, Walter Curran, Ross Abrams, Nadia Laack, Ralph Levitt, Evanthia Galanis, Jan Buckner, Edward Shaw
Journal: Neuro-Oncology (2019)

Abstract PURPOSE To provide a final update on oncologic and cognitive outcomes of high dose versus low dose radiation for low-grade glioma. METHODS Between 1986 and 1994, 203 patients with supratentorial low grade glioma were randomized to 50.4 Gy in 28 fractions versus 64.8 Gy in 36 fractions after any degree of resection. Histologic subtype was oligodendroglioma (71%) or astrocytoma (29%). Primary outcome was overall survival (OS). Cognitive status was followed using Folstein Mini-Mental State Examination (MMSE). RESULTS For the entire cohort of 203 patients, median OS was 8.4 years (95% CI: 7.2 – 10.8). Median progression-free survival (PFS) was 5.2 years (95% CI: 4.3 – 6.6). Median follow-up is 17.2 years for the 33 patients still alive. High-dose radiation did not improve OS (15-yr OS: 22.4% vs. 24.9%, log rank p=0.978) or PFS (15-yr PFS: 15.2% vs. 9.5%, p=0.7142). OS was significantly better for patients with pre-operative tumor diameter &lt; 5 cm (15-yr OS: 39.4% vs. 15.2%, p&lt; 0.001), baseline MMSE &gt; 27 (15-yr OS: 27.3% vs. 9.8%, p=0.001), and for patients who underwent gross total resection (GTR) (15-yr OS: 39.3% GTR vs. 16.4% subtotal resection vs. 24.5% biopsy only, p=0.0119). PFS was improved for patients with oligodendroglioma versus astrocytoma (15-yr PFS: 13.8% vs. 8.6%, p=0.0221). PFS was also improved for patients with pre-operative tumor diameter &lt; 5 cm, patients who had GTR, and patients with baseline MMSE &gt; 27. For patients who had normal MMSE at baseline, at 7 years only 1 patient (5%) had a clinically significant decrease in MMSE from the previous time point, with the remainder (95%) stable. None had decrease in MMSE at 10, 12, or 15 years. CONCLUSIONS Long-term follow-up indicates no benefit to high-dose over low-dose radiation for low-grade gliomas. Minimal late decline in cognitive function after radiation was seen by MMSE. SUPPORT: U10CA180821,U10CA180882. https://acknowledgments.alliancefound.org
Low-Dose Azacitidine, Pioglitazone and All-Trans Retinoic Acid Versus Standard-Dose Azacitidine in Patients ≥ 60 Years with Acute Myeloid Leukemia Refractory to Standard Induction Chemotherapy (AMLSG 26-16/AML-ViVA): Results of the Safety Run-in Phase I
Authors: Daniel Heudobler, Sebastian Klobuch, Florian Lüke, Joachim Hahn, Matthias Grube, Stephan Kremers, Thomas Südhoff, Jörg Westermann, Marie-Luise Huetter-Kroenke, Peter Paschka, Gauthier Bouche, Hartmut Döhner, Wolfgang Herr, Simone Thomas, Albrecht Reichle
Journal: Blood (2019)
Transient receptor potential vanilloid-4 contributes to stretch-induced hypercontractility and time-dependent dysfunction in the aged heart
Authors: Adam B Veteto, Deborah Peana, Michelle D Lambert, Kerry S McDonald, Timothy L Domeier
Journal: Cardiovascular Research (2019)

Abstract Aims Cardiovascular disease remains the greatest cause of mortality in Americans over 65. The stretch-activated transient receptor potential vanilloid-4 (TRPV4) ion channel is expressed in cardiomyocytes of the aged heart. This investigation tests the hypothesis that TRPV4 alters Ca2+ handling and cardiac function in response to increased ventricular preload and cardiomyocyte stretch. Methods and results Left ventricular maximal pressure (PMax) was monitored in isolated working hearts of Aged (24–27 months) mice following preload elevation from 5 to 20mmHg, with and without TRPV4 antagonist HC067047 (HC, 1 µmol/L). In preload responsive hearts, PMax prior to and immediately following preload elevation (i.e. Frank–Starling response) was similar between Aged and Aged+HC. Within 1 min following preload elevation, Aged hearts demonstrated secondary PMax augmentation (Aged&amp;gt;Aged+HC) suggesting a role for stretch-activated TRPV4 in cardiac hypercontractility. However, after 20 min at 20 mmHg Aged exhibited depressed PMax (Aged&amp;lt;Aged+HC) suggestive of TRPV4-dependent contractile dysfunction with sustained stretch. To examine stretch-induced Ca2+ homeostasis at the single-cell level, isolated cardiomyocytes were stretched 10–15% of slack length while measuring intracellular Ca2+ with fura-2. Uniaxial longitudinal stretch increased intracellular Ca2+ levels and triggered Ca2+ overload and terminal cellular contracture in Aged, but not Aged+HC. Preload elevation in hearts of young/middle-age (3–12 months) mice produced an initial PMax increase (Frank–Starling response) without secondary PMax augmentation, and cardiomyocyte stretch did not affect intracellular Ca2+ levels. Hearts of transgenic mice with cardiac-specific TRPV4 expression exhibited PMax similar to 3- to 12-month control mice prior to and immediately following preload elevation but displayed secondary PMax augmentation. Cardiomyocytes of mice with transgenic TRPV4 expression were highly sensitive to mechanical stimulation and exhibited elevated Ca2+ levels, Ca2+ overload, and terminal contracture upon cellular attachment and stretch. Conclusion TRPV4 contributes to a stretch-induced increase in cardiomyocyte Ca2+ and cardiac hypercontractility, yet sustained stretch leads to cardiomyocyte Ca2+ overload and contractile dysfunction in the aged heart.
Updated Meta-Analysis to Evaluate the Incidence of Atrial Fibrillation and Major Bleeding in Patients with Hematologic Malignancies Treated with Ibrutinib
Authors: Sriman Swarup, Anita Sultan, Lukman Tijani, Thura Win Htut, Nicholas D'Cunha, Sariya Wongsaengsak, Donald P. Quick, Khaing Khaing Htwe, Pwint Phyu Hlaing, Myat Min Han, Yin Mon Myat, Akshar Dash, Fred Hardwicke, Kyaw Zin Thein
Journal: Blood (2019)
Palliative radiotherapy
Authors: Katie Spencer, Rhona Parrish, Rachael Barton, Ann Henry
Journal: BMJ (2018)

What you need to know• Palliative radiotherapy offers effective symptom control for focal disease due to cancer• Increased analgesia, anti-emetics, and in some cases corticosteroids can help to reduce discomfort and side effects• Acute side effects of radiotherapy usually resolve within 4-6 weeks of completing treatment• Symptoms of cancer may deteriorate before improvement• For patients in the final weeks of life, the side effects and disruption of palliative radiotherapy may outweigh the benefits, and holistic palliative care may be more appropriate