tbuckley/cabot-search huggingface dataset:
Role of immunotherapy in Ewing sarcoma
Authors: Erin Morales, Michael Olson, Fiorella Iglesias, Saurabh Dahiya, Tim Luetkens, Djordje Atanackovic
Journal: Journal for ImmunoTherapy of Cancer (2020)

Ewing sarcoma (ES) is thought to arise from mesenchymal stem cells and is the second most common bone sarcoma in pediatric patients and young adults. Given the dismal overall outcomes and very intensive therapies used, there is an urgent need to explore and develop alternative treatment modalities including immunotherapies. In this article, we provide an overview of ES biology, features of ES tumor microenvironment (TME) and review various tumor-associated antigens that can be targeted with immune-based approaches including cancer vaccines, monoclonal antibodies, T cell receptor-transduced T cells, and chimeric antigen receptor T cells. We highlight key reasons for the limited efficacy of various immunotherapeutic approaches for the treatment of ES to date. These factors include absence of human leukocyte antigen class I molecules from the tumor tissue, lack of an ideal surface antigen, and immunosuppressive TME due to the presence of myeloid-derived suppressor cells, F2 fibrocytes, and M2-like macrophages. Lastly, we offer insights into strategies for novel therapeutics development in ES. These strategies include the development of gene-modified T cell receptor T cells against cancer–testis antigen such as XAGE-1, surface target discovery through detailed profiling of ES surface proteome, and combinatorial approaches. In summary, we provide state-of-the-art science in ES tumor immunology and immunotherapy, with rationale and recommendations for future therapeutics development.
Part 1 Results of a Dose-Finding Study of Belantamab Mafodotin in Combination with Pomalidomide and Dexamethasone for the Treatment of Relapsed/Refractory Multiple Myeloma (RRMM)
Authors: Suzanne Trudel, Arleigh McCurdy, Heather J. Sutherland, Martha L Louzada, Christopher P. Venner, Hira S Mian, Rami Kotb, Ibraheem Othman, Fernando Camacho, Engin Gul, Donna E. Reece, Darrell J White, Molei Fu
Journal: Blood (2021)
TMOD-30. IDENTIFYING NEW DRIVERS OF GROUP 3 MEDULLOBLASTOMA
Authors: Meher Beigi Masihi, Catherine Lee, Alexandra Garancher, Grace Furnari, Robert Wechsler-Reya
Journal: Neuro-Oncology (2020)

Abstract Medulloblastoma (MB) is the most common malignant childhood brain tumor. MB can be divided into four major subgroups – WNT, Sonic hedgehog (SHH), Group 3 (G3-MB), and Group 4 (G4-MB) – that exhibit distinct genetic alterations, gene expression profiles, and clinical outcomes. Patients with G3-MB have the worst prognosis, and a deeper understanding of this form of the disease is critical for development of new therapies. Most G3-MBs express high levels of the MYC oncogene, suggesting that MYC plays an important role in tumorigenesis. However, MYC overexpression is not sufficient to drive tumor formation. To identify genes that cooperate with MYC to promote development of G3-MB, we performed an in vivo mutagenesis screen using mice expressing the Sleeping Beauty (SB) transposon. Cerebellar stem cells isolated from transposon/transposase-expressing transgenic mice were infected with viruses encoding Myc, and these cells were transplanted into the cerebellum of adult hosts. Tumors that arose were subjected to DNA and RNA sequencing to identify candidate genes, and these genes were subjected to functional analysis to determine whether they could cooperate with Myc to drive G3-MB. These studies identified the transcription factor Ras-responsive element binding protein 1 (Rreb1) as a potent Myc-cooperating gene. Tumors driven by Myc and Rreb1 (MR tumors) resemble G3-MB at a histological and molecular level. Moreover, RREB1 is overexpressed in human G3-MB, and knockdown of RREB1 expression impairs growth of G3-MB cell lines and patient-derived xenografts. Ongoing studies are aimed at identifying the molecular mechanisms by which Rreb1 contributes to tumor growth. Our studies demonstrate an important role for RREB1 in G3-MB, and provide a new model that can be used to identify therapeutic targets and develop more effective and less toxic therapies for this devastating pediatric brain tumor.
Kinetic Changes of Plasma Renin Concentrations Predict Acute Kidney Injury in Cardiac Surgery Patients
Authors: Mira Küllmar, Khaschayar Saadat-Gilani, Raphael Weiss, Christina Massoth, Anas Lagan, Manuel Núñez Cortés, Joachim Gerss, Lakhmir S. Chawla, Danilo Fliser, Melanie Meersch, Alexander Zarbock
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: The renin–angiotensin–aldosterone system is a major pathway in regulating blood pressure, glomerular filtration, and fluid homeostasis. During inflammatory diseases, generation of angiotensin II might be disturbed, leading to increased renin concentrations. Cardiac surgery and the use of cardiopulmonary bypass both induce inflammatory response and cardiovascular instability, which can contribute to acute kidney injury (AKI).Objectives: To investigate whether renin concentrations are associated with hypotension and AKI.Methods: This is a single-center, prospective, observational study among patients undergoing cardiac surgery.Measurements and Main Results: The primary endpoint was the occurrence of AKI within 72 hours after cardiac surgery. A total of 197 patients were available for the primary analysis. The median renin serum concentration was 40.2 μU/ml (quartile 1 [Q1]–Q3, 9.3–144.4) at baseline and 51.3 μU/ml (Q1–Q3, 19.1–167.0) 4 hours after cardiac surgery, whereas the difference between postoperation and preoperation concentrations (Δ-renin) was 3.7 μU/ml (Q1–Q3, −22.7 to 50.9). Patients with an elevated Δ-renin developed an AKI significantly more often (43% vs. 12.2%; P < 0.001). High Δ-renin after cardiac surgery was associated with a significantly lower mean arterial pressure, longer time on vasopressors, and longer length of ICU and hospital stay. The area under the curve (AUC) of Δ-renin for the prediction of AKI (AUC, 0.817; 95% confidence interval, 0.747–0.887) was significantly greater compared with the AUC of the postoperative renin concentrations (AUC, 0.702; 95% CI, 0.610–0.793; P = 0.007).Conclusions: Elevated renin concentrations were associated with cardiovascular instability and increased AKI after cardiac surgery. Elevated renin concentrations could be used to identify high-risk patients for cardiovascular instability and AKI who would benefit from timely intervention that could improve their outcomes.
9P Circulating tumour cells (CTCs) count and PD-L1 expression in untreated extensive small cell lung cancer patients treated in the REACTION trial, a phase II study of etoposide and cis/carboplatin with or without pembrolizumab (NCT02580994)
Authors: J. Menis, P. Bironzo, G. Radj, L. Greillier, I. Monnet, L. Livi, R. Young, C. Decroisette, N. Cloarec, G. Robinet, R. Schott, R. Califano, F. De Marinis, M. Mauer, A. Pochesci, M. Silva, C. Caramella, A-M. Dingemans, C. Dive, B. Besse
Journal: Annals of Oncology (2020)
NIMG-62. AMPHETAMINE-ASSOCIATED CNS VASCULITIS MASQUERADING AS TUMOUR
Authors: Akhil Shivaprasad, Muhammad Qasim, Lauren Langford, Gregory Fuller, Adel K El-Naggar, Ashwin Vishwanathan, Ivo Tremont-Lukats, Nazanin Majd
Journal: Neuro-Oncology (2020)

Abstract Amphetamine-associated CNS vasculitis is controversial. There are few reports but none as a tumor mimic to our knowledge. We describe a pathology-proven, amphetamine-associated CNS vasculitis resembling a tumor. A 41-year-old man presented with six weeks of progressive confusion and left-sided weakness. CT head reported a right thalamic mass with vasogenic edema. Laboratory tests were unremarkable except for cannabinoids and amphetamine in urine. MRI brain showed enhancement in right frontotemporal lobe, basal ganglia, and thalamus concerning for glioblastoma multiforme. After high-dose IV dexamethasone, an initial biopsy showed reactive gliosis, perivascular lymphocytic cuffing by CD3+, rare CD20+ cells and no infection. He continued to decline. MRI 22 days after admission showed increased T2/FLAIR hyperintensity, multifocal areas of enhancement, microhemorrhages, and ischemia. High-grade glioma, lymphoma and infectious encephalitis remained on differentials. Treatment included broad-spectrum antibiotics and acyclovir. Biopsy on 23rd day showed reactive gliosis with parenchymal macrophage infiltration and perivascular cuffing with mixed inflammatory infiltrates. CSF: slightly elevated WBCs (8/µL), elevated protein (139mg/dL), normal glucose, and no infection. MRI whole spine and CT body were unremarkable. The patient was transferred to MDACC 5.5 weeks after initial presentation. He was alert with expressive aphasia, right gaze preference, left hemiplegia, and right hemiparesis. He underwent a right anterior temporal lobectomy. Pathology showed extensive cortical laminar and white matter necrosis with macrophage infiltration and microglial activation. In areas of the preserved cortex, vasculocentric lymphocytic aggregates were present and reticulin staining showed lymphocytic infiltration of the vascular walls. Immunophenotyping (CD3, CD20) showed an almost pure T-cell population. The predominance of intramural T-lymphocytes reflected a vasculitic process. The final diagnosis was cerebral vasculitis with subacute infarction. The patient died six days later. The autopsy findings were identical to the previous resection without evidence of systemic inflammation.
GCT-48. OUTCOME OF CNS MALIGNANT NON-GERMINOMATOUS GERM CELL TUMORS (GCT) WITH AFP &amp;gt; 1000 ng/ml AT DIAGNOSIS TREATED ACCORDING TO SIOP CNS GCT 96
Authors: Gabriele Calaminus, Didier Frappaz, Rolf-Dieter Kortmann, Thankamma Ajithkumar, Torsten Pietsch, Alexandre Vasiljevic, Umberto Ricardi, Cecile Faure-Conter, Beate Timmermann, Claire Alapetite, Matthew J Murray, Maria Luisa Garre, James C Nicholson
Journal: Neuro-Oncology (2020)

Abstract Analysis of CNS MMGCT with AFP &amp;gt;1000 ng/ml (serum and/or CSF) at diagnosis, treated on trial in SIOP-CNS-GCT-96, revealed an inferior prognosis (32% 5-year progression-free survival) compared with AFP &amp;lt;1000 ng/ml (76%). As this patient group is small, to evaluate a bigger cohort, we revisited all patients treated according to SIOP-CNS-GCT-96, who were registered in the database until July 2015. Between October 1996 and July 2015, 373 patients with CNS MMGCT were registered. 48 patients (13%) presented with an AFP &amp;gt;1000 ng/ml at diagnosis. 41 patients were evaluable with a median observation time of 2.4 years; 6/41 received chemotherapy alone. Primary site, histological components (if available), metastatic status and outcome were evaluated. Primary site was pineal in 29/41, suprasellar in 6/41, bifocal 1/41 and other in 5/41 patients. 10/41 patients were metastatic at diagnosis. Four to five courses of standard PEI and radiotherapy (RT) or 2 standard and two intensified PEI (as for SIOP CNS GCT II) were administered in 32 patients. Two received less then 4x PEI and RT, 6 patients &amp;lt;6 years were treated with PEI (either standard or intensified) alone. 16/34 patients with PEI and RT are alive in CR; 2/6 patients without RT survived. Overall, 18/40 (45%) survived. 10–15% of CNS MGGCT are high-risk patients by diagnostic AFP, with the pineal as the main tumour site. Outcome of &amp;lt;50% survival is unsatisfactory. Further research, international cooperation and common data analysis is needed to identify additional risk factors and develop alternative treatment strategies.
IMMU-39. TIM-3 APTAMER IN COMBINATION WITH RADIOTHERAPY RESULTS IN ENHANCED SURVIVAL IN DIPG MODELS
Authors: Naiara Martinez-Velez, Marc Garcia-Moure, Montserrat Puigdelloses, Virginia Laspidea, Iker Ausejo, Luis Isaac Ramos, Oren J Becher, Fernando Pastor, Marta M Alonso
Journal: Neuro-Oncology (2020)

Abstract Pediatric diffuse midline gliomas-H3-K27M-mutant are aggressive brain tumours that arise during childhood. Despite new advances in genomic knowledge and the significant number of clinical trial testing new targeted therapies, patient outcome is still insufficient. Cancer immunotherapy is opening new therapeutic options representing a hope for this orphan disease. Aptamers are single-stranded nucleic acid ligands design to achieve a remarkable affinity and specificity to their targets, comparable to antibodies. TIM-3, is a potential immune checkpoint target, typically involved in T-cell exhaustion. Recent studies showed that TIM-3 is also expressed in tumour and glial cells and it plays an important role in brain tumour responses mediated by myeloid cells. In this work, we examined the anti-tumour effect of an aptamer against TIM-3 alone or in combination with radiotherapy. Of importance, we tested TIM-3 aptamer in a murine glioma and DIPG model, where we not observed any toxicity. TIM-3 administration increased overall survival but was unable to control the disease. Of importance, TIM-3 combination with radiotherapy improved the overall survival of treated mice when compared with single treatments leading to 50% of long-term survivors. TIM-3 aptamer administration increase T-infiltration in the tumour site compared to non-treated or library control. Mechanistic studies performed on day 16 showed an increase in CD8 effector cells, a decrease in T-regulators Foxp3+ cells and an increase in IFN-gamma expression suggesting the triggering of an antitumor-immune response. Rechallenge experiments demonstrated immune memory in the long-term responders that led to reject tumour re-implantation, confirming that TIM-3 aptamer treatment in combination with RT elicits specific antitumor immunity in mouse glioma models. These results suggest that immuno-therapies approaches in combination with radiotherapy would be worth exploring in the treatment of deadly DMG-H3K27-Mutant tumours.
Abstract 10592: Laboratory-based Intermountain Risk Score Compared to The Charlson and Elixhauser Comorbidity Indices for Mortality Prediction
Authors: Benjamin D Horne, Gregory L Snow, Allison Butler, Emily L Wilson, Susan Rea, Sarah Majercik, Jeffrey L Anderson, Joseph Bledsoe
Journal: Circulation (2019)

Introduction: The Charlson and Elixhauser comorbidity indices predict mortality for clinical, administrative, and research applications. The Intermountain Mortality Risk Scores (IMRS) are laborator...
Depression After Myocardial Infarction: Unraveling the Mystery of Poor Cardiovascular Prognosis and Role of Beta-Blocker Therapy⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Roland von Känel, Stefan Begré
Journal: Journal of the American College of Cardiology (2006)
NIMG-50. INITIAL EXPERIENCE: DETECTION OF ABERRANT HYPERPOLARIZED [1-13C]PYRUVATE METABOLISM IN PATIENTS WITH GBM PRIOR TO RESECTION
Authors: Adam Autry, Jeremy Gordon, Marisa LaFontaine, Hsin-Yu Chen, Javier Villanueva-Meyer, Susan Chang, Jennifer Clarke, Duan Xu, Janine Lupo, Peder Larson, Daniel Vigneron, Yan Li
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Detecting radiological response or resistance to treatment in patients with GBM is difficult with conventional MRI. In response to this challenge, hyperpolarized carbon-13 (HP-13C) MRI techniques were developed to probe real-time [1-13C]pyruvate metabolism. METHODS Dynamic HP-13C MRI was acquired pre-operatively from 6 patientswith recurrent GBM following intravenous injection of HP [1-13C]pyruvate. Five were confirmed with tumor progression and one had treatment effects without progression. Frequency-selective echo-planar imaging (8 slices, 3s temporal resolution, 3.38 cm3 spatial resolution, 60s acquisition) captured [1-13C]pyruvate metabolism to [1-13C]lactate and [1-13C]bicarbonate in the brain. Proton imaging included 3-D FLAIR, T1-weighted post-Gd IRSPGR, and spectroscopy. Carbon-13 voxels with non-enhancing lesion (NEL) or contrast-enhancing lesion (CEL) were identified for subsequent analysis. Temporally-summed HP-13C metabolite data within the CEL and NEL were evaluated using the pyruvate-to-lactate ratio; a modified ratio that takes into account vascular contributions of pyruvate; and parameter percentile ranks over the entire brain. Proton spectroscopy data were processed to obtain choline-to-NAA index (CNI) maps, which provide z-scores of relative tissue abnormality. RESULTS All of the anatomic lesions displayed abnormal CNI with maximum values of 3.22-6.35. The 5 patients with CEL lesions demonstrated 87th– 98thpercentile levels of pyruvate in the brain; and 95th-100thpercentile levels of lactate in 4 progressed patients and 60thpercentile in the patient presenting with treatment effects. For the patient with an exclusively non-enhancing lesion, percentile levels of pyruvate and lactate were 66thand 88thin the brain, respectively. The mean+/-SD percentile of the lactate-to-pyruvate and modified ratios were 75+/-22, 86+/-23 and 60+/-3, 71+/-12 in the progressed and non-progressed patients, respectively. CONCLUSION These data importantly demonstrate aberrant [1-13C]pyruvate metabolism in patients with GBM in both contrast-enhancing and non-enhancing lesions. Ongoing studies will further characterize the utility of HP imaging markers.
Survival Impact of Anti-GD2 Antibody Response in a Phase II Ganglioside Vaccine Trial Among Patients With High-Risk Neuroblastoma With Prior Disease Progression
Authors: Irene Y. Cheung, Nai-Kong V. Cheung, Shakeel Modak, Audrey Mauguen, Yi Feng, Ellen Basu, Stephen S. Roberts, Govind Ragupathi, Brian H. Kushner
Journal: Journal of Clinical Oncology (2020)

Anti-GD2 monoclonal antibody (mAb) has proven efficacy in high-risk neuroblastoma (HR-NB). A small phase I GD2/GD3 vaccine trial (n = 15) described long-term survival and a favorable safety profile among patients with a history of disease progression (PD). The kinetics of mounting antibody response to vaccine and its prognostic impact on survival are now investigated in a phase II study (ClinicalTrials.gov identifier: NCT00911560).One hundred two patients with HR-NB who achieved remission after salvage therapies were enrolled in this trial. They received seven subcutaneous injections of GD2/GD3 vaccine spanning 1 year plus oral β-glucan starting at week 6 after the third dose of vaccine. Serum anti-vaccine antibody titers were quantified by enzyme-linked immunosorbent assay. Single nucleotide polymorphisms (SNPs) were determined by quantitative polymerase chain reaction. Kaplan-Meier and landmark Cox Regression models were used for survival estimates.Patients had a history of one (63%), two (21%), or three to six (16%) episodes of PD. 82% of them progressed following anti-GD2 mAb (m3F8/dinutuximab/naxitamab) therapy. Vaccine-related toxicities were self-limited injection-associated local reactions and fever without any > grade 3 toxicities. The progression-free survival (PFS) was 32% ± 6%, and the overall survival (OS) was 71% ± 7% at 5 years. Serum anti-GD2 (immunoglobulin G1 [IgG1] and IgM) and anti-GD3 (IgG1) titers showed notable increases following the initiation of β-glucan at week 6. There was an association between IgG1 titer and SNP rs3901533 of dectin-1, the β-glucan receptor. Multivariable analyses showed that anti-GD2-IgG1 titer ≥ 150 ng/mL by week 8 was associated with favorable PFS and OS, while having prior episodes of PD and the time from last PD to vaccine were associated with PFS.GD2/GD3 vaccine plus β-glucan elicited robust antibody responses in patients with HR-NB with prior PD. Higher anti-GD2-IgG1 titer was associated with improved survival.
Early Treatment and <i>IL1RN</i> Single‐Nucleotide Polymorphisms Affect Response to Anakinra in Systemic Juvenile Idiopathic Arthritis
Authors: Manuela Pardeo, Marianna Nicoletta Rossi, Denise Pires Marafon, Emanuela Sacco, Claudia Bracaglia, Chiara Passarelli, Ivan Caiello, Giulia Marucci, Antonella Insalaco, Chiara Perrone, Anna Tulone, Giusi Prencipe, Fabrizio De Benedetti
Journal: Arthritis & Rheumatology (2020)

Objective To evaluate the impact of early treatment and IL1RN genetic variants on the response to anakinra in systemic juvenile idiopathic arthritis (JIA). Methods Response to anakinra was defined as achievement of clinically inactive disease (CID) at 6 months without glucocorticoid treatment. Demographic, clinical, and laboratory characteristics of 56 patients were evaluated in univariate and multivariate analyses as predictors of response to treatment. Six single‐nucleotide polymorphisms (SNPs) in the IL1RN gene, previously demonstrated to be associated with a poor response to anakinra, were genotyped by quantitative polymerase chain reaction (qPCR) or Sanger sequencing. Haplotype mapping was performed with Haploview software. IL1RN messenger RNA (mRNA) expression in whole blood from patients, prior to anakinra treatment initiation, was assessed by qPCR. Results After 6 months of anakinra treatment, 73.2% of patients met the criteria for CID without receiving glucocorticoids. In the univariate analysis, the variable most strongly related to the response was disease duration from onset to initiation of anakinra treatment, with an optimal cutoff at 3 months (area under the curve 84.1%). Patients who started anakinra treatment ≥3 months after disease onset had an 8‐fold higher risk of nonresponse at 6 months of treatment. We confirmed that the 6 IL1RN SNPs were inherited as a common haplotype. We found that homozygosity for ≥1 high‐expression SNP correlated with higher IL1RN mRNA levels and was associated with a 6‐fold higher risk of nonresponse, independent of disease duration. Conclusion Our findings on patients with systemic JIA confirm the important role of early interleukin‐1 inhibition and suggest that genetic IL1RN variants predict nonresponse to therapy with anakinra.
Downregulation of PA28α induces proteasome remodeling and results in resistance to proteasome inhibitors in multiple myeloma
Authors: Yanyan Gu, Benjamin G. Barwick, Mala Shanmugam, Craig C. Hofmeister, Jonathan Kaufman, Ajay Nooka, Vikas Gupta, Madhav Dhodapkar, Lawrence H. Boise, Sagar Lonial
Journal: Blood Cancer Journal (2020)

Abstract Protein homeostasis is critical for maintaining eukaryotic cell function as well as responses to intrinsic and extrinsic stress. The proteasome is a major portion of the proteolytic machinery in mammalian cells and plays an important role in protein homeostasis. Multiple myeloma (MM) is a plasma cell malignancy with high production of immunoglobulins and is especially sensitive to treatments that impact protein catabolism. Therapeutic agents such as proteasome inhibitors have demonstrated significant benefit for myeloma patients in all treatment phases. Here, we demonstrate that the 11S proteasome activator PA28α is upregulated in MM cells and is key for myeloma cell growth and proliferation. PA28α also regulates MM cell sensitivity to proteasome inhibitors. Downregulation of PA28α inhibits both proteasomal load and activity, resulting in a change in protein homeostasis less dependent on the proteasome and leads to cell resistance to proteasome inhibitors. Thus, our findings suggest an important role of PA28α in MM biology, and also provides a new approach for targeting the ubiquitin-proteasome system and ultimately sensitivity to proteasome inhibitors.