tbuckley/cabot-search huggingface dataset:
Real-World (RW) Multiple Myeloma (MM) Patients (Pts) Remain Under-Represented in Clinical Trials Based on Standard Laboratory Parameters and Baseline Characteristics: Analysis of over 3,000 Pts from the Insight MM Global, Prospective, Observational Study
Authors: Vania T.M. Hungria, Hans C. Lee, Rafat Abonour, Robert M. Rifkin, Evangelos Terpos, Xavier Leleu, Caitlin L. Costello, Frits van Rhee, Katja C. Weisel, Noemi Puig, Jesus G. Berdeja, Gordon Cook, Saad Z. Usmani, Michael A. Thompson, Mario Boccadoro, Jeffrey A. Zonder, Andrew Spencer, Roman Hajek, Suzanne R. Fanning, Kevin Boyd, Jim Omel, Mira Armour, Kathryn E. Morgan, Ronak S. Patel, Gary L. Carlson, Renda H. Ferrari, Dawn Marie Stull, Kaili Ren, Dasha Cherepanov, James V. Pottala, Ajai Chari
Journal: Blood (2019)
Engineering a Hematopoietic Stem Cell Niche By Revitalizing Mesenchymal Stem Cells with Five Transcription Factors
Authors: Fumio Nakahara, Sandra Pinho, Daniel K. Borger, Qiaozhi Wei, Maria Maryanovich, Ali H. Zahalka, Masako Suzuki, Cristian Cruz, Zichen Wang, Chunliang Xu, Philip Boulais, Avi Ma'ayan, John M. Greally, Paul S. Frenette
Journal: Blood (2019)
Incidence of Vaso-Occlusive Crisis Does Not Increase with Achieving Higher Hemoglobin Levels on Voxelotor Treatment or after Discontinuation: Analyses of the HOPE Study
Authors: Elliott P. Vichinsky, Paul Telfer, Adlette Inati, Margaret Tonda, Barbara Tong, Irene Agodoa, Joshua Lehrer-Graiwer, Kenneth I. Ataga
Journal: Blood (2019)
A CD19/CD3 Bispecific Antibody Induces Superior T Cell Responses Against Chronic Lymphocytic Leukemia When Combined with Ibrutinib
Authors: Maissa Mhibik, Erika M Gaglione, Amy Blackburn, Keyvan Keyvanfar, Clare Sun, Inhye E Ahn, Maria Joao Baptista, Junpeng Qi, Christoph Rader, Adrian Wiestner
Journal: Blood (2019)
IMMU-41. RNA-MODIFIED T CELLS AS PROFESSIONAL ANTIGEN PRESENTING CELLS
Authors: Fernanda Pohl-Guimarães, Duane Mitchell
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION With the lack of antigen presenting cells (APCs) in the central nervous system (CNS), anti-tumor immune responses from intracranial tumors are believed to be initiated in the peripheral lymph nodes. Recently, studies have shown that intratumoral dendritic cells (DCs), a well-known professional APC, play a crucial role at inducing anti-tumor immunity. Although DCs have been tested in cancer immunotherapy clinical trials for two decades, DC delivery strategies have limited access to the CNS, mainly due to the blood brain barrier (BBB). To bypass the limitations of the lack of intracranial APCs, we investigate the HYPOTHESIS that RNA-modified T cells can express and cross-present single tumor antigens locally within the CNS tumor microenvironment. Since activated T cells have an inherent ability to cross the BBB and can be genetically modified, this strategy makes them an attractive professional antigen presenting cells for cancer cell therapy. METHODS Using electroporation to deliver messenger RNA (mRNA) encoding a model tumor antigen to T cells, we evaluated the expression and cross-presentation capability of RNA-modified T cells. RESULTS We demonstrated that activated T cells can be genetically modified to express tumor antigens in vitro while retaining their inherent effector functions. Compared to unmodified T cells, T cells modified with tumor antigen encoding RNA showed high expression of inflammatory cytokines, including IFN gamma and TNF alpha and enhanced cellular proliferation and IL-2 secretion. Tumor antigen RNA-modified T cells demonstrated potent antigen presentation in vitro and importantly were significantly superior to RNA-loaded DCs in antigen presenting capacity. CONCLUSIONS This study strongly supports the implementation of a non-invasive and efficacious strategy to deliver “APC-like” T cell locally to brain tumors, thereby bypassing the lack of APCs within CNS malignancies.
PATH-57. MRI-LOCALIZED BIOPSIES REVEAL HISTOPATHOLOGIC HETEROGENEITY IN POST-TREATMENT RECURRENT HIGH-GRADE GLIOMA
Authors: Deborah Boyett, Jack Grinband, Kai Canoll, Zachary Englander, Akshay Save, George Zanazzi, Brianna Pereira, Angela Lignelli, Andrew Lassman, Guy McKhann, Jeff Bruce, Peter D Canoll
Journal: Neuro-Oncology (2019)

Abstract Evaluation of recurrence in post-treatment glioma is challenging because contrast-enhancing (CE) lesions are a mixture of tumor and treatment effect. This study characterizes intratumoral heterogeneity using quantitative digital pathology to correlate intraoperative MRI-localized biopsies with histopathology in the post-treatment setting. Findings will inform multiparametric radiographic models of intratumoral heterogeneity. A retrospective review was performed on adult patients with MRI-localized biopsies obtained during resection for post-treatment recurrent high-grade glioma. 68 patients and 170 MRI-localized samples were analyzed (median 2 samples/patient). Immunohistochemistry (IHC) for markers of glioma cells (SOX2), macrophages (CD68), and proliferating cells (KI67) was used to characterize biopsies. Slides were digitized and quantified using an automated cell-counting algorithm. Histopathological criteria based on IHC data was developed to classify biopsies. IHC quantification was compared across histological groups using ANOVA and paired t-tests. Most patients (52/68) yielded multiple biopsies. 75% (39/52) demonstrated heterogeneity in histological classification of all specimens obtained from their lesion. 47/170 (28%) biopsies were predominantly treatment effect, and most were CE (31/47 or 66%). Only 75/170 (44%) biopsies contained recurrent glioma, and 21/75 (28%) were NE. SOX2 labeling index was higher in biopsies containing recurrent tumor (p=5.13E-25). CD68 labeling index was higher in biopsies with predominant treatment effect (p=1.35E-12). IHC data from MRI-localized biopsies informed a multiple linear regression model which demonstrated significant predictive value for determining the distribution of recurrent tumor in the post-treatment setting. Contrast enhancement is not a reliable predictor of tumor in recurrent high-grade glioma. Most patients demonstrated marked intratumoral heterogeneity, highlighting the difficulty of accurate tumor sampling post-treatment glioma. Our histopathological classification significantly distinguished recurrent tumor from treatment effect and informed a multiparametric radiomic model which can guide surgical sampling and assess response to therapy.
Phase I Study of a Novel Bcl-2 Inhibitor, at-101 in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma (RRMM)
Authors: Sikander Ailawadhi, Victoria R. Alegria, Salman Ahmed, Betsy Laplant, Alak Manna, Ricardo Parrondo, Vivek Roy, Taimur Sher, Brett Edwards, Stephanie Lanier, Keisha Jackson, Asher A. Chanan-Khan, Aneel Paulus
Journal: Blood (2019)
CMET-31. WHOLE BRAIN RADIOTHERAPY VERSUS STEREOTACTIC RADIOSURGERY IN POOR-PROGNOSIS PATIENTS WITH 1 – 10 BRAIN METASTASES: A RANDOMIZED FEASIBILITY STUDY
Authors: Alan Nichol, Srinivas Raman, Benjamin Mou, Fred Hsu, Boris Valev, Arthur Cheung, Isabelle Vallières, Laura Beaton, Thomas Rackley, Lovedeep Gondara
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND The clinical advantage of stereotactic radiosurgery (SRS) over whole brain radiotherapy (WBRT) in patients with brain metastases and poor prognosis is controversial. To investigate the feasibility of a phase III clinical trial in a population of patients with poor prognosis, we conducted a randomized feasibility study of WBRT versus SRS. METHODS Patients with Karnofsky performance status (KPS) ≥ 70, life expectancy of 3–6 months, based on both Diagnosis-Specific Graded Prognostic Assessments and attending oncologist opinion, and 1– 10 brain metastases with a diameter ≤ 4 cm were enrolled at six Canadian cancer centers. Patients were randomly assigned to WBRT (20 Gy in 5 fractions) or SRS (15 Gy in 1 fraction). The primary endpoint was the rate of accrual. A secondary endpoint was the ratio of screened subjects to accrued subjects. This trial is registered with ClinicalTrials.gov (NCT02220491). RESULTS Between January 2015 and November 2017, 210 were screened to enroll 22 patients (9.5 screened/participant) and 20 patients were randomized. The accrual rate was 0.63 patients / month. The most common reasons for exclusion were: estimated median survival outside 3–6 months (n = 40), baseline KPS below 70 (n = 28), and &gt; 10 brain metastases (n = 28). The median survival was 7.0 months. The overall survival was 9.5 months (n = 11) for patients who had subsequent systemic therapy, compared to 3.7 months (n = 9) in patients who had none. In both arms, the cumulative incidence of retreatment with brain radiotherapy was 40%. CONCLUSIONS Accrual was slow and the median survival was longer than expected, but a randomized trial evaluating WBRT vs SRS in patients with poor prognosis would likely be feasible by enrolling only patients with no remaining systemic therapy options.
Desaturation Is Related to the Presence of Dense Red Blood Cells in Sickle Cell Patients and Is Reversed By Hydroxyurea
Authors: Gaetana Di Liberto, Laurent Kiger, Michael Marden, Laurent Boyer, Marc Conti, Anoosha Habibi, Marie Georgine Rakotoson, Sanam Khorgami, Benoit Vingert, Bernard Maitre, Frédéric Galacteros, France Noizat-Pirenne, Pablo Bartolucci
Journal: Blood (2014)
Response to: ‘The level of peripheral regulatory T cells is linked to changes in gut commensal microflora in patients with systemic lupus erythematosus’ by Zhang <i>et al</i> and the phylogeny of a candidate pathobiont in lupus nephritis
Authors: Gregg J Silverman, Doua F Azzouz
Journal: Annals of the Rheumatic Diseases (2019)

We appreciate the opportunity to respond to the correspondence from Zhang et al ,1 and fully agree with the importance of elucidating the specific roles of individual taxa in clinical lupus pathogenesis. These authors assert that the candidate pathobiont in our earlier paper ‘is lacking in a precise link with lymphocytes…’. Yet, this is completely erroneous as we showed that lupus patients with expansions of the Ruminococcus gnavus species also had circulating antibodies that recognised strain-restricted lipoglycan antigens in this candidate pathobiont species.2 These peripheral immune responses were also shown to be cross-reactive with …
Signaling Input from Divergent Pathways Subverts Malignant B-Cell Transformation
Authors: Lai N Chan, Mark A. Murakami, Rebecca Caesar, Christian Hurtz, Kohei Kume, Teresa Sadras, Seyedmehdi Shojaee, Petri Pölönen, Amol Ugale, Jaewoong Lee, Kadriye Nehir Cosgun, Huimin Geng, Merja Heinäniemi, Olli Lohi, Arun P. Wiita, Shai Izraeli, David M Weinstock, Markus Müschen
Journal: Blood (2019)
Phylogenomics Identifies an Ancestral Burst of Gene Duplications Predating the Diversification of Aphidomorpha
Authors: Irene Julca, Marina Marcet-Houben, Fernando Cruz, Carlos Vargas-Chavez, John Spencer Johnston, Jèssica Gómez-Garrido, Leonor Frias, André Corvelo, Damian Loska, Francisco Cámara, Marta Gut, Tyler Alioto, Amparo Latorre, Toni Gabaldón
Journal: Molecular Biology and Evolution (2019)

Abstract Aphids (Aphidoidea) are a diverse group of hemipteran insects that feed on plant phloem sap. A common finding in studies of aphid genomes is the presence of a large number of duplicated genes. However, when these duplications occurred remains unclear, partly due to the high relatedness of sequenced species. To better understand the origin of aphid duplications we sequenced and assembled the genome of Cinara cedri, an early branching lineage (Lachninae) of the Aphididae family. We performed a phylogenomic comparison of this genome with 20 other sequenced genomes, including the available genomes of five other aphids, along with the transcriptomes of two species belonging to Adelgidae (a closely related clade to the aphids) and Coccoidea. We found that gene duplication has been pervasive throughout the evolution of aphids, including many parallel waves of recent, species-specific duplications. Most notably, we identified a consistent set of very ancestral duplications, originating from a large-scale gene duplication predating the diversification of Aphidomorpha (comprising aphids, phylloxerids, and adelgids). Genes duplicated in this ancestral wave are enriched in functions related to traits shared by Aphidomorpha, such as association with endosymbionts, and adaptation to plant defenses and phloem-sap-based diet. The ancestral nature of this duplication wave (106–227 Ma) and the lack of sufficiently conserved synteny make it difficult to conclude whether it originated from a whole-genome duplication event or, alternatively, from a burst of large-scale segmental duplications. Genome sequencing of other aphid species belonging to different Aphidomorpha and related lineages may clarify these findings.
Evaluation of the Role of Plerixafor in Peripheral Blood Progenitor Cell Mobilization and Collection in Autologous Donors with Multiple Myeloma and Non-Hodgkin Lymphoma
Authors: Isabelle Blais-Normandin, Philippe Nadeau, Linda Vallée, Rémy Angers, Manon Lescault, Nathalie Laflamme, Narcisse Singbo, Vincent Laroche
Journal: Blood (2019)
RDNA-06. TARGETING IDH1/2-MUTANT GLIOMAS WITH UNIQUE COMBINATIONS OF DNA REPAIR INHIBITORS
Authors: Amrita Sule, Ranjit Bindra
Journal: Neuro-Oncology (2019)

Abstract Mutations in the Isocitrate Dehydrogenase-1 and -2 (IDH1/2) genes occur in the vast majority of low-grade and secondary high-grade gliomas. These neomorphic mutations occur early on in gliomagenesis leading to the production of 2-Hydroxyglutarate (2HG). 2HG has been implicated in tumorigenesis via inhibiting α-ketoglutarate (αKG)-dependent dioxygenases. Our group recently demonstrated that the production of 2HG suppresses the high-fidelity homologous recombination (HR) DNA repair pathway, resulting in a state of “BRCAness”. We initially found that mutant IDH1/2-induced BRCAness confers exquisite sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors, a finding which now has been replicated by multiple independent laboratories. Although IDH1/2 mutations were first identified in gliomas and acute myeloid leukemia (AML) cells, multiple other tumor types have subsequently been shown to harbor these mutations. Current clinical trials are testing the efficacy of PARP inhibitors as a monotherapy, as well as in combination with other DNA repair inhibitors. Here, we demonstrate that novel combinations of DNA repair inhibitors can be utilized to synergistically target IDH1/2-mutant glioma cells. In particular, we demonstrate potent synergy with ATRi and PARPis, a finding which was validated in multiple structurally unique drugs within these classes. As this combination is active in BRCA1/2-mutant cancers, in particular after the emergence of PARPi resistance, these data suggest are consistent with an underlying HR defect in IDH1/2-mutant gliomas. These preclinical investigations will provide a blueprint for future clinical trials combining PARP and ATR inhibitors in the treatment of glioblastoma.
Disbalanced Erythroid Ferroportin Expression Contributes to Ineffective Erythroid Output in Anemia of Chronic Disease
Authors: Verena Petzer, Piotr Tymoszuk, Markus Seifert, Natascha Brigo, Philipp Grubwieser, Sylvia Berger, Richard Hilbe, Egon Demetz, Lara Valente de Souza, Günter Weiss, Dominik Wolf, Igor Theurl
Journal: Blood (2019)
The Trials (and Tribulations) of Complementary and Alternative Medicine in Oncology
Authors: Ethan B Ludmir, Amit Jethanandani, Walker Mainwaring, Austin B Miller, Timothy A Lin, Andres F Espinoza, Vivek Verma, Noam A VanderWalde, Aaron J Grossberg, B Ashleigh Guadagnolo, Albert C Koong, Reshma Jagsi, Charles R Thomas, C David Fuller
Journal: JNCI Journal of the National Cancer Institute (2019)

Two decades following the creation of the Office of Cancer Complementary and Alternative Medicine at the National Cancer Institute, the status of complementary and alternative medicine (CAM) research within oncology remains opaque. To better understand the landscape of CAM studies in oncology, we identified CAM-related phase III randomized controlled trials (RCTs) through ClinicalTrials.gov and compared these CAM trials to all non-CAM oncologic RCTs. Pearson χ2 testing was used to compare proportions across groups; all tests were two-sided. Comparing the 25 identified CAM RCTs with 739 non-CAM RCTs, CAM studies were more likely to be sponsored by a cooperative group (64.0% vs 28.6%, P < .001) and less likely to be industry funded (8.0% vs 76.5%, P < .001). CAM trials disproportionately excluded disease-related outcomes as endpoints (8.0% vs 84.6%, P < .001), were unsupported by prior early-phase data (55.0% vs 96.1%, P < .001), and did not meet the primary endpoint (8.7% vs 53.0%, P < .001). Given the observed relationship between encouraging pilot data and subsequent phase III trial success, we contend that future CAM RCTs may yield more promising findings if better supported by appropriately designed and well-characterized early-phase signals.
Quantitative Proteomic Analysis of Relapsed Multiple Myeloma Identifies CDK6 Upregulation As a Potential Targetable Resistance Mechanism for Lenalidomide
Authors: Yuen Lam Dora Ng, Stephan Bohl, Evelyn Ramberger, Oliver Popp, Imke Bauhuf, Anna Dolnik, Christian Steinebach, Michael Gütschow, Lars Bullinger, Philipp Mertins, Jan Kroenke
Journal: Blood (2019)
Evaluation of a Bifunctional Sirpα-CD123 Fusion Antibody for the Elimination of Acute Myeloid Leukemia Stem Cells
Authors: Siret Tahk, Saskia Schmitt, Christian Peter Augsberger, Binje Vick, Laia Pascual Ponce, Irmela Jeremias, Georg Wittmann, Nadja Fenn, Marion Subklewe, Karl-Peter Hopfner
Journal: Blood (2019)
Functional Consequences of TCAB1 Mutations in Dyskeratosis Congenita
Authors: Sushree Sangita Sahoo, Caitlin Roake, Liliana Rindle, Claudia Rössig, Markus Schmugge, Victor B Pastor, Brigitte Strahm, Marena R Niewisch, Gunda Ruzaike, Steven Artandi, Charlotte M Niemeyer, Melanie Börries, Hauke Busch, Marcin Wlodarski
Journal: Blood (2016)
ACTR-40. PHASE 2 SAFETY AND EFFICACY OF AR-67 (7-T-BUTYLDIMETHYLSILTYL-10-HYDROXYCAMPTOTHECIN) IN PATIENTS WITH RECURRENT GLIOBLASTOMA MULTIFORME (GBM) OR GLIOSARCOMA
Authors: Priya Kumthekar, Jeffrey Raizer, Robert Cavaliere, Craig Devoe, Randy Jensen, Volker Stieber, Tina Runk, Jai Grewal, Elise Brownell, Alex Zukiwski, Stefan Proniuk, Susanne Arnold, James Vredenburgh
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND AR-67 (formerly DB-67) is a novel 3rd generation camptothecin with improved safety and lipophilicity than current drugs in this class. Safety and efficacy of AR-67 were evaluated in a Phase 2 study in recurrent GBM/gliosarcoma in adult patients. METHODS AR-67 (7.5 mg/m2) was administered once daily by IV infusion for 5 consecutive days on a 21-day cycle. Cohort 1 patients (N=31/46 enrolled) had not received (or had not recently failed) bevacizumab. Cohort 2 patients (N=13/46 enrolled) had failed bevacizumab within 90 days before screening. Cohort assignments for 2/46 patients were undetermined. Tumor response was assessed ≥14d after every second cycle and before every third cycle using MRI. Primary endpoints were 6-month PFS (Cohort 1), and 2-month PFS (Cohort 2). RESULTS 45/46 patients received ≥ one dose of AR-67; one patient (Cohort 1) died prior to dosing. Efficacy: 6/30 (Cohort 1) and 2/13 (Cohort 2) treated patients achieved the primary endpoints of 6- and 2-month PFS, respectively. Across the study, PR was the best overall response in 3/45 treated patients, all in Cohort 1. SD was the best overall disease response in 7/45 treated patients (5 in Cohort 1 and 2 in Cohort2). Safety: AR-67 was well tolerated; 17 patients (38%) exhibited serious adverse events (SAEs) including headache and Grade 4/5 muscular weakness (2.2%). Most TEAEs were mild/moderate in intensity and Grade 1–3 intoxicity. Notably absent was Grade 4 diarrhea, a hallmark of other approved camptothecin chemotherapies. CONCLUSIONS AR-67 was well tolerated and exhibited a safety profile consistent with or better than currently approved camptothecins. 6/30 treated patients in Cohort 1 and 2/13 patients in Cohort 2 achieved the primary endpoints of 6- and 2-month PFS, respectively. PR was the best overall response in 3/45 treated patients and SD was the best overall response in 7/45 patients.
CMET-01. IMMUNE CHECKPOINT INHIBITORS FOR NON-SMALL CELL LUNG CANCER WITH BRAIN METASTASIS: THE ROLE OF GAMMA KNIFE RADIOSURGERY
Authors: Min Ho Lee, Kyung-Rae Cho, Jung-Il Lee
Journal: Neuro-Oncology (2019)

Abstract PURPOSE Immune checkpoint inhibitors (ICIs) are approved for the treatment of non-small cell lung cancer (NSCLC), but the safety and efficacy of the combined treatment with ICIs and gamma knife radiosurgery (GKS) remain undefined. METHODS We retrospectively reviewed the medical records of patients with brain metastases from NSCLC who were treated with ICIs between January 2015 and December 2017 at our institute. Of the 134 patients identified, 77 who were assessable for brain responses were categorized into three groups based on the medication administered and GKS: Group A, ICI alone; Group B, ICI with concurrent GKS within 14 days; and Group C, ICI with non-concurrent GKS. RESULTS The median follow-up duration after the diagnosis of brain metastases was 19.1 (range, 1–68.7) months. At the last follow-up, 48 patients (62.3%) died. The overall survival was shorter in Group A than in Groups B and C (P=0.001). There were no statistically significant differences in the intracranial disease progression-free survival (P=0.514), local progression-free survival (P=0.358), and complication rates among the three groups. Twelve patients presented with leptomeningeal seeding (LMS) during follow-up. There was a significant difference in the LMS-free duration from the time of administering ICIs (P=0.011) and the diagnosis of metastasis (P&lt; 0.001). CONCLUSION GKS in combination with ICI showed no favorable overall survival outcome in the treatment of brain metastasis from NSCLC. However, GKS with ICI did not increase the risk of complications. Furthermore, compared with ICI alone, GKS with ICI may be associated with a reduced incidence of LMS.
PRISM: A Platform Protocol for the Treatment of Relapsed/Refractory Aggressive Non-Hodgkin Lymphoma
Authors: Mark Roschewski, Raquel Izumi, Ahmed Hamdy, Manish R. Patel, Hendrik-Tobias Arkenau, Sven de Vos, Patrick M Reagan, Pier Luigi Zinzani, Andrew Davies, John M Pagel, Julie M Vose, Bojena Bitman, Graham Brock, Edwin Clark, Melanie M. Frigault, Joseph Ware, Buyue Yang, Wyndham Wilson, Louis Staudt, Ian W. Flinn
Journal: Blood (2019)
Switch from Every Two Weeks to Every Four Weeks Administration Schedule of AOP2014, an Innovative Pegylated Interferon Alpha, in Polycythemia Very Patients Allows Maintaining of Efficacy with Improved Toxicity Profile in Phase I/II Study
Authors: Heinz Gisslinger, Veronika Buxhofer-Ausch, Josef Thaler, Ernst Schloegl, Guenther A. Gastl, Dominik Wolf, Robert Kralovics, Bettina Gisslinger, Karin Strecker, Alexander Egle, Thomas Melchardt, Sonja Burgstaller, Ella Willenbacher, Michael Zoerer, Pavla Kadlecova, Oleh Zagrijtschuk, Christoph Klade, Richard Greil
Journal: Blood (2014)