tbuckley/cabot-search huggingface dataset:
Vzhe-039, a Novel Structurally-Enhanced Allosteric Hemoglobin Effector Inhibits Sickling of SS Erythrocytes In Vitro, and Exhibits Improved Pharmacologic Properties In Vivo
Authors: Martin K. Safo, Guoyan Xu, Mohini Ghatge, Qiukan Chen, Carla Casu, David Tanya, Yan Zhang, Jurgen Venitz, Osheiza Abdulmalik
Journal: Blood (2016)
PATH-53. IMMUNOLOGICAL PROFILING OF MUTATIONAL AND TRANSCRIPTIONAL SUBGROUPS IN PEDIATRIC AND ADULT HIGH-GRADE GLIOMAS
Authors: Michael Bockmary, Frederick Klauschen, Cecile Maire, Stefan Rutkowski, Manfred Westphal, Katrin Lamszus, Ulrich Schüller, Malte Mohme
Journal: Neuro-Oncology (2019)

Abstract Immunological treatment strategies, including checkpoint inhibition, are currently under investigation for high-grade gliomas, but their success is limited. Hence, it is crucial to determine immunological pathways that can be targeted and to identify subgroups of patients likely to benefit from immunotherapies. Previous studies are still limited by comparably small sample sizes and there is only few data about specific immunological mechanisms in pediatric high-grade glioma. We gathered published gene expression data from 1135 adult and pediatric high-grade gliomas and applied a machine learning technique to determine their mutational (K27, G34, IDHmut, IDHwt) and transcriptional subtype. Subsequently, immune cell infiltration and functional immune pathway signatures were evaluated in correlation to histological diagnosis, age, transcriptional and mutational subtype. T-SNE analysis and unsupervised hierarchical clustering was applied to detect subgroup-specific immune microenvironments across all high-grade glioma subtypes. Four distinct microenvironmental phenotypes of immune cell infiltration were identified, which can be stratified into vascular, monocytic/stromal, monocytic/T-cell and APC/NK/T-cell dominant immune clusters. Immune cell infiltration correlated strongly with transcriptional and mutational subtypes but was independent of age and histological diagnosis (p&lt; 0.01). H3F3A mutated tumors had significantly fewer tumor infiltrating lymphocytes and macrophages. By including functional pathways and correlating the expression of immunostimulatory and inhibitory receptor/ligand interactions, we were able to define the immunological microenvironment and to identify possible immunological subtypes associated with poor prognosis as well as subtypes that might be especially amenable to checkpoint inhibition. In addition, comparisons of overall survival with the immunological microenvironment and specifically with immune checkpoint molecules revealed diverse correlations within the transcriptional and mutational subgroups. In conclusion, we shat that mutational and transcriptional subgroups of pediatric and adult high-grade gliomas are characterized by distinct immunological tumor microenvironments. Our analysis demonstrates the immunological heterogeneity within this entity and emphasizes an immune specific stratification of subgroups for upcoming immunotherapy trials.
Dual Targeting of ALDH1 and ALDH3: A Promising Therapeutic Approach in Acute Myeloid Leukemia
Authors: Mileidys Perez-Alea, Julien Colle, Muhube Yazir, Céline Baier, Yasmine Labiad, Isabelle Arnoux, Geoffroy Venton, Guillaume Guillaume, Ismail Ceylan, Regis T. Costello
Journal: Blood (2019)
An Alternative to Sodium Polystyrene Sulfonate and Patiromer for the Treatment of Hyperkalemia
Authors: Ian Sabir
Journal: JAMA Internal Medicine (2019)

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Sequential Therapy with Cyclophosphamide, Bortezomib and Dexamethasone Followed By Autologous Stem Cell Transplant Is Safe and Highly Effective in AL Amyloidosis
Authors: Marco Basset, Paolo Milani, Andrea Foli, Mario Nuvolone, Jessica Ripepi, Margherita Bozzola, Giampaolo Merlini, Giovanni Palladini
Journal: Blood (2019)
RARE-01. NATIONWIDE TRENDS IN MANAGEMENT OF ADULT MYXOPAPILLARY EPENDYMOMA
Authors: Daphne Baracena, Patrick Kelly, Arpine Khudanyan, Claire Turina, Jerry Jaboin, Shearwood McClelland III
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION Myxopapillary ependymomas (MPE) are WHO Grade I ependymomas that occur in the spine and have an annual incidence of 0.05–0.08 per 100,000 people. Maximal, safe surgical resection is the recommended first line therapy. Due to the rarity of the disease there is a relatively poor understanding of the use of radiotherapy (RT) in the management of disease. METHODS Using the National Cancer Database (NCDB), we analyzed the patterns and impact of RT on spinal MPE in adults diagnosed between 2002 and 2016. RESULTS Of 753 qualifying cases, the majority of patients underwent resection (n = 617, 81.9%). A relatively small portion received RT (n = 103, 13.3%) with most receiving RT after surgical resection (n = 98, 95.1%). The likelihood of patients to undergo resection and RT was significantly associated with patient age at diagnosis (p = 0.002), tumor size (p &lt; 0.001), and race (p = 0.017). Chemotherapy was not widely utilized (only 0.27% of patients). DISCUSSION Although practice patterns can be highlighted from this 15-year analysis, given the high survival in this disease entity, progression-free survival (PFS) is an important outcome not available from this database. As expected, surgery is the primary means to manage adult MPE. For spinal MPE, it is understood that gross total resection (GTR) should be attempted whenever possible as GTR has been associated with improved PFS in several studies. RT and chemotherapy are used infrequently. In univariate analyses, RT was employed more often for larger tumor sizes, Latino/Hispanic ethnicity, and younger age at diagnosis. The impact of RT on overall survival is indeterminate given the 1.6% death rate in the cohort. Analyses of the impact of RT on PFS in a larger database would be beneficial for determining an algorithm for post-operative and definitive radiotherapy in this disease entity.
PDTM-06. DISULFIRAM-COPPER PROLONGS SURVIVAL AND REDUCES STEM-CELLNESS IN PEDIATRIC GROUP 3 MEDULLOBLASTOMA THROUGH NUCLEAR SEQUESTRATION OF NPL4
Authors: Riccardo Serra, Tianna Zhao, Joshua Casaos, Noah Leviton Gorelick, Antonella Mangraviti, Alessandro Olivi, Henry Brem, Eric Jackson, Betty Tyler
Journal: Neuro-Oncology (2019)

Abstract Medulloblastoma (MB), an aggressive pediatric brain malignancy, is commonly classified into four subtypes. Although survival has improved remarkably, Group 3 and Shh-driven tumors still experience high rates of recurrent and metastatic disease. Disulfiram (DSF), a safe and inexpensive drug, has shown an antitumor effect when administered with copper (Cu++) against other brain malignancies, and its repurposing to MB could benefit current standards of treatment. ONS76 (Shh-driven Tp53 wild-type), UW228 (Shh-driven Tp53-mutated), D425med and D341med (Group 3) lines were treated with DSF-Cu++and tested with viability, proliferation and clonogenic assays. Flow cytometry (FACS) with AnnexinV-PI, Ki67, PI/RNAse for necrosis and cell cycle, and CD133 and Aldefluor for cell-stemness were carried out. MB lines were tested with western blotting (WB) and immunofluorescence (IF) for NPL4(Nuclear protein localization protein 4 homolog), AIF (apoptosis-inducing factor), cleaved-PARP(Poly-ADP-ribose-polymerase), H2AX and other molecular targets. In vivo safety (n=8) and efficacy studies (n=16) were carried out on Nu/Nu athymic mice implanted intracranially (IC) with D425med cells, along with Hematoxylin/Eosin and immunohistochemistry analyses on brain samples. DSF-Cu++showed remarkable cytotoxic and anti-proliferative activity against all MB lines. In particular, NPL4, a protein involved in the ubiquitin signaling, appears to be the primary DSF target, as previously shown in other malignancies. Apoptosis quickly follows the Heat-Shock Response, as confirmed by FACS, WB and IF, and cell-stemness is decreased significantly by nanomolar doses of DSF-Cu++(p=0.002). Oral administration of DSF-Cu++was proven safe at doses of 100 mg/kg and significantly prolonged survival in IC xenografts (median 28.5 days; p=0.02) compared to controls (median 24 days). DSF, a compound used in the treatment of chronic alcoholism, has recently shown a remarkable effect in a number of malignancies when co-administered with Cu++. We provide proof of its potential as a chemotherapeutic for pediatric MB, and describe its molecular mechanism of action.
Inhibition of Mcl-1 Enhances the Efficacy of Tyrosine Kinase Inhibition in FLT3 Mutated AML and Synergizes with Venetoclax Targeting AML Stem Cells
Authors: Bing Z Carter, Wenjing Tao, Po Yee Mak, Qi Zhang, Xiangmeng Wang, Vinitha Mary Kuruvilla, Carli Stewart, Vivian Ruvolo, Venkata Lokesh Battula, Marina Y Konopleva, Sean Caenepeel, Jude Canon, Paul Hughes, PK Morrow, Michael Andreeff
Journal: Blood (2019)
Optimized CT Attenuation and SUV Prediction Thresholds for Differentiating Enostoses From Untreated and Treated Metastases on Attenuation-Corrected 18F-FDG PET/CT
Authors: Harrison T. Lee, Daniel A. Pryma, Ronnie Sebro
Journal: Clinical Nuclear Medicine (2019)

Purpose The objective of this study was to evaluate the accuracy of using CT attenuation and SUVs to differentiate enostoses from untreated and treated osteoblastic metastases on the attenuation-correction CT component of 18 F-FDG PET/CTs. Methods We retrospectively reviewed 18 F-FDG PET/CT studies of 117 patients (169 lesions), of which 65 had imaging of enostoses, and 52 had imaging showing the transition of lesions from untreated to treated osteoblastic metastases. We measured the mean CT attenuations and the SUVmax and SUVmean of each lesion. Receiver operating characteristic curve analyses were used to evaluate the accuracy of each metric in distinguishing enostoses from untreated and treated osteoblastic metastases. Results For differentiating enostoses from untreated osteoblastic metastases, mean CT attenuation achieved an area under the receiver operating characteristic curve (AUC) of 90.8%, with an optimized threshold of 795 HU. SUVmax achieved an AUC of 94.9%, with an optimized threshold of 2.2. For differentiating enostoses from treated osteoblastic metastases, the AUCs for every metric decreased, with mean CT attenuation being the best at 82.7%. A joint predictive model combining both CT attenuation and SUV increased the AUC to 88.3%, and performance was significantly better than SUVmax or SUVmean alone ( P = 0.029 and P = 0.049, respectively). Conclusions CT attenuation and SUV can reliably distinguish between enostoses and metastases on 18 F-FDG PET/CT. However, the accuracy of these metrics decreases when used to differentiate enostoses from treated metastases. A joint prediction model combining CT attenuation with SUV can improve accuracy.
Primary Results from the Phase 3 Tourmaline-AL1 Trial of Ixazomib-Dexamethasone Versus Physician's Choice of Therapy in Patients (Pts) with Relapsed/Refractory Primary Systemic AL Amyloidosis (RRAL)
Authors: Angela Dispenzieri, Eftathios Kastritis, Ashutosh D Wechalekar, Stefan O. Schönland, Kihyun Kim, Vaishali Sanchorawala, Heather J Landau, Fiona Kwok, Kenshi Suzuki, Raymond L Comenzo, Deborah Berg, Guohui Liu, Douglas V. Faller, Giampaolo Merlini
Journal: Blood (2019)
ROS‐Mediated Apoptosis and Anticancer Effect Achieved by Artesunate and Auxiliary Fe(II) Released from Ferriferous Oxide‐Containing Recombinant Apoferritin
Authors: Peng Ji, Haiqin Huang, Shirui Yuan, Le Wang, Siqi Wang, Yiwei Chen, Na Feng, Hanitrarimalala Veroniaina, Ziheng Wu, Zhenghong Wu, Xiaole Qi
Journal: Advanced Healthcare Materials (2019)

Abstract Reactive oxygen species (ROS)‐mediated apoptosis is considered a crucial therapeutic mechanisms for artesunate (AS). As an Fe(II)‐dependent drug, the anticancer effect of AS is often limited due to insufficient Fe(II) concentration in targeted cells. To overcome this problem, a recombinant apoferritin nanocarrier containing ferriferous oxide (M‐HFn) is constructed to produce auxiliary exogenous Fe(II) when delivering AS to cancer cells. Here, the newly fabricated AS‐loaded M‐HFn nanoparticles (M‐HFn@AS NPs) can significantly improve the tumor‐specific targeting and intracellular uptake efficiency of AS in human cervical carcinoma cells. After being captured in the acidic cavity of endosomes, M‐HFn@AS NPs can simultaneously release Fe(II) and allow AS to activate satisfactory ROS‐mediated apoptosis. Furthermore, in vivo studies demonstrate that M‐HFn@AS NPs can selectively accumulate in tumors to efficiently inhibit tumor growth. Thus, M‐HFn@AS NPs are a promising system to enhance the therapeutic effect of Fe(II)‐dependent drugs.
Hematologic Malignancies Exhibit Selective Vulnerability to Inhibition of De Novo Pyrimidine Biosynthesis By AG-636, a Novel Inhibitor of Dihydroorotate Dehydrogenase in Phase 1 Clinical Trials
Authors: Danielle Ulanet, Victor Chubukov, John Coco, Gabrielle McDonald, Mya Steadman, Rohini Narayanaswamy, Sebastien Ronseaux, Sung Choe, Tabea Erdmann, Kevin Truskowski, Kavitha Nellore, Siva Sanjeeva Rao, Hosahalli Subramanya, Georg Lenz, Michael Cooper, Josh Murtie, Kevin Marks
Journal: Blood (2019)
P1.20 S-allyl Cysteine Induces Cytotoxic Effects on Human NSCLC Cell Lines
Authors: M. Orozco-Morales, N. Hernandez-Pedro, P. Barrios-Bernal, O. Arrieta, L.M. Ruiz-Godoy, A. Santamaría, A.L. Colín-González
Journal: Journal of Thoracic Oncology (2019)
Phase II Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability–High/Mismatch Repair–Deficient Metastatic Colorectal Cancer: KEYNOTE-164
Authors: Dung T. Le, Tae Won Kim, Eric Van Cutsem, Ravit Geva, Dirk Jäger, Hiroki Hara, Matthew Burge, Bert O’Neil, Petr Kavan, Takayuki Yoshino, Rosine Guimbaud, Hiroya Taniguchi, Elena Elez, Salah-Eddin Al-Batran, Patrick M. Boland, Todd Crocenzi, Chloe E. Atreya, Yi Cui, Tong Dai, Patricia Marinello, Luis A. Diaz Jr, Thierry André
Journal: Journal of Clinical Oncology (2019)

KEYNOTE-164 (NCT02460198) evaluated the antitumor activity of pembrolizumab in previously treated, metastatic, microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) colorectal cancer (CRC).This phase II open-label study involved 128 centers worldwide. Eligible patients were age ≥ 18 years and had metastatic MSI-H/dMMR CRC treated with ≥ 2 prior lines of standard therapy, including fluoropyrimidine, oxaliplatin, and irinotecan with or without anti-vascular endothelial growth factor/epidermal growth factor receptor monoclonal antibody (cohort A) or ≥ 1 prior line of therapy (cohort B). MSI-H/dMMR status was assessed locally. Patients received pembrolizumab 200 mg every 3 weeks for up to 2 years until progression, unacceptable toxicity, or withdrawal. The primary end point was objective response rate by RECIST version 1.1 by independent central review. Secondary end points were duration of response, progression-free survival (PFS), overall survival, safety, and tolerability.A total of 124 patients with MSI-H/dMMR CRC (61 in cohort A, 63 in cohort B) enrolled. At data cutoff, median follow-up was 31.3 months (range, 0.2-35.6 months) for cohort A and 24.2 months (range, 0.1-27.1 months) for cohort B. Objective response rate was 33% (95% CI, 21% to 46%) and 33% (95% CI, 22% to 46%), respectively, with median duration of response not reached in either cohort. Median PFS was 2.3 months (95% CI, 2.1 to 8.1 months) and 4.1 months (95% CI, 2.1 to 18.9 months). Median overall survival was 31.4 months (95% CI, 21.4 months to not reached) and not reached (95% CI, 19.2 months to not reached). Treatment-related grade 3-4 adverse events occurred in 10 patients (16%) in cohort A and 8 (13%) in cohort B, with the most common occurring in ≥ 2 patients being pancreatitis, fatigue, increased alanine aminotransferase, and increased lipase (2 patients each; 3%) in cohort A.Pembrolizumab is effective with a manageable safety profile in patients with MSI-H/dMMR CRC.
INNV-12. OUTCOMES IN A REAL-WORLD PRACTICE FOR PATIENTS WITH PRIMARY GLIOBLASTOMA: IMPACT OF A SPECIALIZED NEURO-ONCOLOGY CANCER CARE PROGRAM
Authors: Nilanjana Banerji, Meghan Hultman, Megan Tipps, Minda Liu, Patricia Bruns, John Trusheim
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION Standard care for newly diagnosed glioblastoma consists of maximal surgical resection followed by radiotherapy with concurrent and adjuvant temozolomide. Prognosis for glioblastoma still remains poor, with a reported median survival of 14.6 months. Published data indicate that optimal outcomes in this population require involvement of an experienced team providing multidisciplinary care. We report here the outcomes in a real-world setting for glioblastoma patients treated at a specialized neuro-oncology cancer care program. PATIENTS AND METHODS Data from fifty consecutive patients with primary glioblastoma pursuing care at the Givens Brain tumor Center were analyzed. Coordinated medical care was provided by dedicated neuro-oncology and surgical clinicians, supplemented by care from nurse coordinators, social workers, care guides, genetic counselors, and other specialties. Demographic, pathologic, and clinical information was abstracted from electronic medical records. RESULTS Median patient age was 58 (range, 23–80) years and 26% were ≥65 years of age. Gross total resection was achieved in 91.5% patients, with 56% of resections performed in the Institution’s iMRI suite. A majority of patients received radiation and chemotherapy. In accordance with cancer program guidelines, 48% of the cases were presented at multidisciplinary tumor conferences. A LifeCourse™ care guide was utilized by 30% of the patients. Bevacizumab was used as second-line therapy with/without carboplatin in 63.2% patients. Optune treatment was administered to 27 patients. Additionally, eligible patients enrolled in clinical trials both at primary and recurrent stages. Median progression-free survival (PFS) and overall survival (OS) was 9.1 (range, 2.2–30.5) months and 19.4 (range, 4.6–31.8) months, respectively. End-of-life hospice care was elected by 48% patients. CONCLUSION PFS and OS in this real-world settings were comparable to outcomes noted in controlled clinical trials. These results indicate that efficient, quality care may be achieved with a multidisciplinary treatment approach, producing exceptional survival rates in patients with glioblastoma.
Comparative Outcomes of Relapsed Follicular Lymphoma Patients Treated with Novel Agents: A Multi-Center Analysis
Authors: Allison M. Winter, Wei Wei, Emily C. Ayers, Daniel J. Landsburg, Saba Raya, Brad S. Kahl, Andrew Rogers, Kami J. Maddocks, Mohammad Khan, Adam S. Kittai, Alexey Danilov, Chaitra S. Ujjani, Ryan C. Lynch, Loretta J. Nastoupil, Melody R. Becnel, Luke Zurbriggen, Vaishalee P. Kenkre, Sheenu Sheela, Nilanjan Ghosh, Boyu Hu, Deborah M. Stephens, Amy Ayers, Jonathon B. Cohen, Brian T. Hill
Journal: Blood (2019)
Genetics of Monosomy 7 and Del(7q) in MDS Informs Potential Therapeutic Targets
Authors: Cassandra M Kerr, Vera Adema, Wencke Walter, Stephan Hutter, Christina A. Snider, Yasunobu Nagata, Manja Meggendorfer, Claudia Haferlach, Valeria Visconte, Mikkael A. Sekeres, Thomas Laframboise, Torsten Haferlach, Jaroslaw P. Maciejewski
Journal: Blood (2019)
Flow-Cytometry Based Detection of Any Minimal Residual Disease (FC-MRD) in Children with T-Acute Lymphoblastic Leukemias (T-ALL) Is a Powerful Indicator of Outcome
Authors: Prashant Tembhare, Gaurav Narula, Gaurav Chatterjee, Twinkle Khanka, Mahima Sanyal, Sitaram Ghogale, Nikhil Patkar, Nilesh Deshpande, Yajamanam Badrinath, Sumeet Gujral, Shripad Banavali, Papagudi Ganesan Subramanian
Journal: Blood (2019)
DDIS-31. A NOVEL BRAIN-PERMEANT CHEMOTHERAPEUTIC AGENT FOR THE TREATMENT OF BREAST CANCER LEPTOMENINGEAL METASTASIS
Authors: Jiaojiao Deng, Sophia Chernikova, Wolf-Nicolas Fischer, Kerry Koller, Bernd Jandeleit, Gordon Ringold, Melanie Hayden Gephart
Journal: Neuro-Oncology (2019)

Abstract Leptomeningeal metastasis (LM), a spread of cancer to the cerebrospinal fluid and meninges, is universally and rapidly fatal due to poor detection and no effective treatment. Breast cancers account for a majority of LMs from solid tumors, with triple-negative breast cancers (TNBCs) having the highest propensity to metastasize to LM. The treatment of LM is challenged by poor drug penetration into CNS and high neurotoxicity. Therefore, there is an urgent need for new modalities and targeted therapies able to overcome the limitations of current treatment options. Quadriga has discovered a novel, brain-permeant chemotherapeutic agent that is currently in development as a potential treatment for glioblastoma (GBM). Recently, we have demonstrated dose-dependent in vitro and in vivo anti-tumor activity with various breast cancer cell lines including the human TNBC cell line MDA-MB-231. To evaluate the in vivo antitumor activity of the compound on LM, we used the mouse model of LM based on the internal carotid injection of luciferase-expressing MDA-MB-231-BR3 cells. Once the bioluminescence signal intensity from the metastatic spread reached (0.2 - 0.5) x 106photons/sec, mice were dosed i.v. (8 mg/kg once a week for nine weeks) or i.p. (4 or 8 mg/kg twice a week for nine weeks). Tumor growth was monitored by bioluminescence. The compound was well tolerated and caused a significant delay in metastatic growth resulting in significant extension of survival. Tumors regressed completely in ~ 28 % of treated animals in the i.p. group. Given that current treatments for LM are palliative with only few studies reporting a survival benefit, Quadriga’s new agent could be effective as a therapeutic for both primary and metastatic brain tumors such as LM. REF: https://onlinelibrary.wiley.com/doi/full/10.1002/pro6.43