tbuckley/cabot-search huggingface dataset:
PATH-16. COMPREHENSIVE GENOMIC PROFILING ACCURATELY DETERMINES 1p19q CODELETION STATUS IN GLIOMAS
Authors: Radwa Sharaf, Dean C Pavlick, Garrett M Frampton, Maureen Cooper, Jacqueline Jenkins, Brian Alexander, Timothy Cloughesy, William Yong, Linda Liau, Phioanh Nghiemphu, Matthew Ji, Albert Lai, Lee A Albacker, Shakti H Ramkissoon
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Genomic profiling of gliomas is vital to ensure diagnostic accuracy, inform prognosis, and identify therapeutic options for primary and recurrent tumors. The integration of genomic biomarkers into brain tumor classification has improved the diagnostic accuracy and led to the development of molecularly stratified clinical trials. DESIGN Comprehensive genomic profiling (CGP) was performed on FFPE material from 310 (162 FoundationOne® and 148 FoundationOne® CDx) samples of brain tumors with available 1p19q FISH results, initially diagnosed by submitting institutions based on histology. Via CGP, we analyzed tumors in up to 395 cancer-associated genes (including IDH1/2) and predicted 1p19q codeletion using a custom research-use only algorithm. Progression-free (PFS) and overall survival (OS) were determined for 519 patients based on computationally predicted 1p19q codeletion status. RESULTS For all samples, regardless of their IDH1/2 mutation status, concordance between 1p19q status based on FISH and our algorithm was 97.1%, (301/310), with a positive predictive value (PPV) of 100% (133/133) and sensitivity of 93.7% (133/142). All discordant samples were called as positive for codeletion by FISH and negative by our CGP-based algorithm. Discordant samples were either IDH1/2 wild-type (2) or IDH1/2, ATRX, and TP53 altered (7), consistent with the genomic profile of diffuse astrocytomas. For IDH1/2-mutated samples, concordance was 96.7% (238/246). In the clinical outcomes dataset, median PFS was 35 months for the codeletion group compared to 13 months for the non-codeletion group (hazard ratio (HR): 0.60; 95% CI: 0.40-0.88; p=0.009). Similarly, median OS was 160 and 34 months respectively for codeleted versus intact (HR: 0.46; 95% CI: 0.28-0.76; p=0.002). CONCLUSIONS 1p19q codeletion status derived from CGP is highly concordant with FISH results suggesting that CGP-derived 1p19q codeletion status may be a reliable substitute for traditional FISH testing. Patients with CGP-derived 1p19q codeletion showed increased PFS and OS compared to non-codeleted counterparts.
CBIO-09. INTRATUMORAL HETEROGENEITY OF DIELECTRIC PROPERTIES IN GLIOBLASTOMA
Authors: Martin Proescholdt, Amer Haj, Christian Doenitz, Nils Ole Schmidt, Zeev Bomzon
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Recently, tumor treating fields (TTFields) were established for the treatment of newly diagnosed glioblastoma (GBM). One of the most crucial parameters defining the treatment efficacy of TTFields is the electric field intensity, which depends on the dielectric properties of the tumor tissue. In this study we determined the dielectric properties of GBM by analyzing resected tissue following a fast acquisition protocol. To account for the intratumoral heterogeneity, different regions of the tumor were analyzed separately. METHODS A cohort of 38 patients with newly diagnosed GBM were analyzed. Tissue probes were acquired from the vital tumor area and perinecrotic compartment. The tissue was measured immediately to avoid artifacts. A fragment was dissected from each tissue sample and was placed into a cylindrical cell with a known diameter. The impedance was recorded at frequencies 20Hz-1MHz using a software specifically developed for this study, which controls the LCR meter. The measured impedance was translated into dielectric properties of the sample (conductivity and relative permittivity) based on the parallel plate model, the recorded complex impedance and the geometry of the samples. Each tissue probe was fixed, and stained with H&amp;E to visualize cellularity, luxol fast blue to analyze the myelinated fiber content and against factor VIII related antigen to assess tumor vascularity. RESULTS We found significant differences between the conductivity and permittivity of tissue samples from each individual tumor (mean conductivity [S/m]: 0.302; range: 0.607 – 0.100; mean permittivity [Farad/m]: 3519.8; range: 11182.5 – 135.7). Consistently, the perinecrotic areas displayed lower conductivity values compared to the solid tumor compartments. Histological analysis revealed significantly higher cellularity and lower myelinated fiber content in tissue samples with high conductivity and permittivity. CONCLUSION The dielectric properties of GBM show a high intratumoral heterogeneity which correlate to the extent of cellularity and myelin fiber content within the tissue.
GCT-06. DIAGNOSIS OF A RARE CASE OF RECURRENT GERM CELL TUMOR BY CSF PLACENTAL ALKALINE PHOSPHATASE PRESENTING WITH DIFFUSE INTRAAXIAL ABNORMALITY IN THE LOWER BRAINSTEM
Authors: Hiroki Yamada, Tomohiro Abiko, Hirokazu Fujiwara, Kazunari Yoshida, Hikaru Sasaki
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Germ cell tumors in the central nervous system (CNS) typically arise either at suprasellar and/or pineal region, and occasionally at basal ganglia. We report a case of diagnostically challenging, recurrent germ cell tumor presented with diffuse intraaxial abnormality in and across the lower brainstem, which was diagnosed by the elevated placental alkaline phosphatase (PLAP) level in cerebrospinal fluid (CSF). CASE DESCRIPTION: A 28-year-old man had been treated by chemoradiotherapy at the previous hospital for bifocal suprasellar and pineal lesions with the provisional diagnosis of germinoma without histological confirmation. Three years later, he presented with progressive weakness of bilateral extremities for weeks. Magnetic resonance imaging showed a diffuse, bilaterally symmetric high intensity lesion on T2-weighted image with slight contrast enhancement across the ventral side of the medulla oblongata to the upper cervical spinal cord. Serum and CSF hCG, hCG-β, and AFP were all negative. Since the image findings were atypical for recurrent germ cell tumor, some kind of myelitis was initially suspected. Therefore, steroid pulse therapy was administered. However, the patient’s symptom was still gradually progressing. Then, the CSF PLAP turned out to be positive, indicating the recurrence of germinoma. Accordingly, platinum-based chemotherapy was administered, and the imaging findings, patient’s symptoms, and CSF PLAP began to improve. The patient is to be treated with radiotherapy following chemotherapy. CONCLUSION We report a rare case of CNS germ cell tumor that presented with diffuse intraaxial lesion in the lower brainstem in which examination of CSF PLAP was extremely useful.
Mitochondria Are Transferred from Non-Malignant Stroma Cells to Malignant Plasma Cells, Via Tunnelling Nanotubules in a CD38 Dependent Mechanism, a Process That Promotes Myeloma Proliferation
Authors: Christopher Marlein, Rachel Piddock, Lyubov Zaitseva, Martin Auger, Kristian Bowles, Stuart Rushworth
Journal: Blood (2017)
NFB-01. FUNCTIONAL CHARACTERIZATION OF ATRX LOSS IN NF1-ASSOCIATED GLIOMA AND MPNST
Authors: Ming Yuan, Karlyne Reilly, Christine Pratilas, Christopher Heaphy, Fausto Rodriguez
Journal: Neuro-Oncology (2020)

Abstract To identify the biologic relevance of ATRX loss in NF1-associated gliomagenesis, we studied the effects of Atrx loss using four previously characterized Nf1+/-Trp53+/- murine glioma lines. Lines 130G#3 and 158D#8 (corresponding to grade IV and III gliomas, respectively) displayed preserved ATRX protein expression compared to NIH-3T3 cells. We studied the effects of Atrx knockdown in these two lines in the presence and absence of the TERT inhibitor, BIRBR1532. Using a telomere-specific FISH assay, we identified increased signal intensity after Atrx knockdown, only in the presence of the TERT inhibitor. These features are reminiscent of ALT, although there were no significant alterations in cell growth. Next, we studied the effect of ATRX loss in MPNST lines ST88-14, NF90-8, STS-26T. These cell lines all expressed ATRX and DAXX. However, STS-26T contained a TERT promoter mutation and ST88-14 had a known SNP in the TERT promoter, while NF90-8 had no alterations. ATRX siRNA knockdown showed no significant effects in cell proliferation or apoptosis. However, ATRX knockdown resulted in rare ultra-bright foci, indicative of ALT. Next, we studied the in vitro effect of the ATR inhibitor VE-821 in MPNST cell lines. Only NF90-8 (lacking TERT alterations) demonstrated a decrease in growth after ATRX knockdown and VE-821 treatment. However, ATRX knockdown alone did not affect sensitivity to carboplatin. Our findings further support a role for ATRX loss with subsequent ALT activation in a biologic subset of NF1-associated malignancies, thereby opening an opportunity for therapeutic targeting of these aggressive tumors using specific classes of drugs.
Complement controls the immune synapse and tumors control complement
Authors: Alan Herbert
Journal: Journal for ImmunoTherapy of Cancer (2020)

The synapses between immune cells and their targets are 150 Å wide. They regulate immune cell responses (IRs) to cognate antigens. Here, I outline a potential mechanism for self-nonself discrimination based on the C3d and iC3b proteolytic fragments of complement protein C3. The proposed C3 checkpoint works through complement receptor 3 (CR3), which binds both C3d and iC3b. The CR3 conformations involved differ; the bent, cis-acting CR3 engages C3d, activating the immune cell expressing CR3; the extended, transacting CR3 conformer binds iC3b on another cell, inhibiting IRs. The CR3 complexes formed with iC3b and C3d vary greatly in size. Only bound C3d is small enough to fit within the synapse. It stimulates IRs by countering the inhibitory signals that iC3b generates at the synapse edge. The competition between C3d and iC3b dynamically determines whether or not an immune cell activates. Host cells use regulators of complement activation (RCA) to coat themselves with iC3b, silencing IRs against self by preventing synapse formation. Tumors exploit this process by overexpressing C3 and RCA to masquerade as ‘super-self’, with iC3b masking neoantigens. Enhancing synapse formation by specifically labeling cancer cells as nonself with targeted C3d therapeutics offers a new strategy for boosting tumor-specific immunity.
Anaerobic Respiration of NOX1-Derived Hydrogen Peroxide Licenses Bacterial Growth at the Colonic Surface
Authors: Brittany M. Miller, Megan J. Liou, Lillian F. Zhang, Henry Nguyen, Yael Litvak, Eva-Magdalena Schorr, Kyung Ku Jang, Connor R. Tiffany, Brian P. Butler, Andreas J. Bäumler
Journal: Cell Host & Microbe (2020)
Myeloproliferative neoplasms and pregnancy: Overview and practice recommendations
Authors: Naseema Gangat, Ayalew Tefferi
Journal: American Journal of Hematology (2020)

Pregnancy in the context of myeloproliferative neoplasms (MPN) poses unique fetal and maternal challenges. Current literature in this regard mostly involves essential thrombocythemia (ET) and less so polycythemia vera (PV) or myelofibrosis. In ET, live birth rate is estimated at 70% with first trimester fetal loss (˜ 30%) as the major complication. Risk of pregnancy-associated complications is higher in PV, thus mandating a more aggressive treatment approach. Herein, we appraise the relevant literature, share our own experience and propose management recommendations. Aspirin therapy may offer protection against fetal loss; however the additive benefit of systemic anticoagulation or cytoreductive therapy, in the absence of high risk disease, is unclear. We recommend cytoreductive therapy in the form of interferon alpha in all high risk and select low-risk ET and PV patients with history of recurrent fetal loss, prominent splenomegaly or suboptimal hematocrit control with phlebotomy. In addition, all women with PV should maintain strict hematocrit control <45% with the aid of phlebotomy. Systemic anticoagulation with low molecular weight heparin is advised in patients with history of venous thrombosis. Further clarification awaits prospective clinical trials that implement risk adapted therapeutic interventions.
NIMG-57. ASSOCIATION OF RADIOMICS BASED TUMOR SHAPE IRREGULARITY MEASURES AND GAMMA KNIFE DOSE PLANNING INDICES IN VESTIBULAR SCHWANNOMAS
Authors: Esra Sümer, Ece Tek, Meriç Şengöz, M Necmettiin Pamir, Alp Dinçer, Alpay Özcan, *Koray Özduman, *Esin Öztürk-Işık
Journal: Neuro-Oncology (2020)

Abstract Gamma knife radiosurgery (GKRS) delivers an unevenly distributed radiation dose to a tumor, with a sharp falloff outside the target. Although the dose inhomogeneity within a tumor is strongly influenced by its shape, routine GKRS dose planning does not account for it. We hypothesized that shape irregularity measures were correlated with treatment planning indices, and might provide insight during treatment planning. The aims of this study were to quantify the shape irregularity measures in vestibular schwannomas, estimate their correlations with core radiosurgical planning measures, and define the most predictive shape feature for dose effectiveness. METHODS: Four dose plan indices, which were the selectivity index (SI), gradient index (GI), efficiency index (EI), and Paddick’s conformity index (PCI) were estimated from the GKRS plans of 234 vestibular schwannomas. All dose plans were prepared using Gamma Plan 10.0 and above and all treatments were delivered using a perfexion/ICON platform. Three-dimensional (3D) tumor models were rendered using 3D Slicer Software from segmented T1-weighted MR images. Sixteen irregularity measures were calculated for each tumor using Radiomics in MATLAB. Spearman correlation coefficients (r) were computed to find associations of the dose plan indices with the irregularity descriptors. The most predictive shape feature for dose efficiency was identified using the least absolute shrinkage and selection operator (Lasso). RESULTS: The shape irregularity measures were negatively correlated with SI, EI, and PCI, and positively correlated with GI. Volumetric index of sphericity (VioS) had the highest correlations with SI (r = 0.63, p= 3.27E-23), GI (r= -0.58, p= 1.10E-19), EI (r = 0.69, p= 0.00), and PCI(r= 0.68, p = 6.73E-28), and Lasso feature selection identified VioS as the most important feature for predicting all dose plan indices. CONCLUSION: VioS provides a numerical quantification of tumor shape irregularity, and it is highly correlated with the GKRS dose planning indices. *indicates co-senior authors
NCMP-27. THE USE OF INTRAVENOUS IMMUNOGLOBULIN (IVIG) DURING SEVERE NEUROTOXICITY AMONG THE RECIPIENTS OF CHIMERIC ANTIGEN RECEPTOR T-CELLS (CAR-T) THERAPY
Authors: Sepideh Mokhtari, Justin Asquith, Christina Bachmeier, Rawan Faramand, Youngchul Kim, Edwin Peguero, Solmaz Sahebjam, Michael Jain, Michael Vogelbaum, Marco Davila, Peter Forsyth, Frederick Locke, Lazaryan Aleksandr
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Severe Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS) occurs in ~ 30% of Diffuse Large B Cell Lymphoma (DLBCL) patients treated with CAR-T cell therapy. The current treatment for severe ICANS is glucocorticoids, and this may be combined with tocilizumab for concurrent cytokine release syndrome. Even with these treatments, neurotoxicity can persist. It is essential, therefore, to find additional treatments to more effectively reverse CAR-T neurotoxicity. OBJECTIVE We summarize our institutional experience using IVIG to treat severe or refractory ICANS after glucocorticoids alone. METHOD This is a single center retrospective cohort study of neurologic and oncologic outcomes among patients who received axicabtagene ciloleucel (axi-cel) for DLBCL or its variants from May 2015 to February 2019. We identified those patients who developed severe ICANS subsequently treated with glucocorticoids alone (n = 10) or glucocorticoids plus IVIG (n = 9). RESULTS The median age of all 19 patients was 63 (range 47-75, and 68% were males). All IVIG recipients received glucocorticoids prior to IVIG administration. There was no significant difference in time to resolution (TTR) of severe ICANS between both groups (median 3 vs. 3 days, Log-rank p = 0.331). However, we found that all IVIG recipients had experienced either escalation of their neurotoxicity grade or persistent severe neurotoxicity after initiation of steroids (p = 0.001). Moreover, IVIG recipients had worse ECOG performance status prior to axi-cel therapy (p = 0.03). CONCLUSION Although we found no difference in TTR of severe ICANS with addition of IVIG to glucocorticoids, our analysis suggests that the addition of IVIG blunted the effects of steroid-refractory neurotoxicity. Patients who received IVIG had worsening ICANS despite administration of steroids and therefore might have benefited from the earlier addition of IVIG. Controlled studies may clarify the potential efficacy of IVIG in severe neurotoxicity after CAR-T therapy.
NIMG-10. A RETROSPECTIVE ANALYSIS OF SURVIVAL FOLLOWING TREATMENT WITH BEVACIZUMAB IN GLIOBLASTOMA PATIENTS WITH RADIOGRAPHICALLY-CONFIRMED SUBEPENDYMAL OR LEPTOMENINGEAL SPREAD OF DISEASE
Authors: Shama Farooq, Onur Yildirim, Robert Young, Jamie Tisnado, Alexandra Miller
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE We performed a retrospective analysis examining subependymal disease (SED) and leptomeningeal disease (LMD) in bevacizumab treated IDH-wildtype glioblastoma (GBM) patients to assess potential differences in survival. BACKGROUND GBMs are highly infiltrative and often invade the subependymal and leptomeningeal space making them challenging to treat. At recurrence, patients are commonly treated with bevacizumab, which leads to decreased tumor size and swelling. Patients have improved PFS, but there is no benefit in OS. This may reflect infiltrative disease progression--a hallmark of late-stage disease. We hypothesized patients with CSF spread manifested by SED and LMD may have worse outcomes after bevacizumab than patients with non-disseminated disease. METHODS We retrospectively reviewed charts of all IDH-wildtype GBM patients who received bevacizumab in 2016. MRI scans were reviewed by experienced neuro-radiologists to characterize patients into radiographically defined groups (“0” = no LMD/no SED; “1”= no SED/LMD contact; “2”= no SED/LMD dissemination, and “3’= LMD present). Survival from initiation of bevacizumab to death for each group was compared to group “0” (with no SED/LMD). Survival outcomes were analyzed via t-tests. RESULTS We evaluated 87 IDH-WT GBM patients. Radiographically, patients were grouped-- “0”= 16 (18%), “1”= 33 (38%), “2”= 20 (23%), and “3”= 18 (21%). There was no difference between group “0” and any radiographically defined subgroups. Median survival for group “0”= 187 days; group “1”= 219 days; group “2”= 217 days; group “3”= 169 days. CONCLUSION Contrary to our hypothesis, there was no significant difference in survival from the initiation of bevacizumab in patients with SED or LMD. This may be related to the fact that these patients also typically have a high burden of parenchymal disease. Further work is necessary to test this hypothesis in a larger cohort.
THU0179 Magnetic resonance imaging of the hand in early rheumatoid arthritis
Authors: I Ertenli, D Altınok, S Kiraz, Y Karadeniz, MA Oztürk, S Apras, M Çalgüneri
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> This study is planned as a prospective investigation of the accuracy of magnetic resonance imaging for the demonstration of early-stage rheumatoid arthritis findings of both hands, with the goal of differentiating magnetic resonance imaging and plain film findings of the patients having early -stage rheumatoid arthritis. <h3>Methods</h3> Ten patients who met American Rheumatism Association criteria for rheumatoid arthritis and symptoms of less than one year duration were accepted for the study. After full clinical assessment, laboratory tests and radiographs of the hands were undertaken, magnetic resonance imaging was performed on a 1.5 tesla imager using an extremity coil using SE T1, TSE T2, fat suppressed T2, flash 2d 3DGRE and postcontrast fat suppressed T1 weighted sequences. <h3>Results</h3> 6 of 10 patients had periarticular osteoporosis on plain radiography. All of the 10 patients had subcondral erosions, 8 patients had effusion in proximal interphalangeal joints, 8 had synovial hypertrophy, 7 had tendonitis, 5 had tendon erosions and tears and 2 had ulnar collateral ligament ruptures. <h3>Conclusion</h3> Magnetic resonance imaging not only allows direct visualisation of the inflammatory soft tissue, but also its effect on the bone, cartilage, tendons and ligaments. Magnetic resonance imaging, due to its superior soft-tissue contrast and tomographic changes is more sensitive to than plain radiography in demonstrating the changes due to rheumatoid arthritis. This may contribute to more accurate diagnosis in early-stage rheumatoid arthritis patients and allow an earlier decision to start proper medication and defining progression or remission of the disease.
Quality management of ovarian cancer serum profiles using functionalizied magnetic beads, AnchorChipTM technology, MALDI-TOF MS and, MALDI-TOF/TOF MS
Authors: Sau-Mei Leung, Samuel C. Mok
Journal: Cancer Research (2004)

5225  Proteomics fingerprinting using mass spectrometry (MS) to discover multivariate cancer biomarkers from biological fluids has become increasingly important in elucidating the disease mechanism as well as developing diagnostic assays. Matrix Assisted Laser Desorption Ionization-Time Of Flight (MALDI-TOF) MS is a powerful tool for the analysis of such complex samples because of its sample throughtput and ability to couple with different off-line sample fractionation techniques. However, in order to generate reliable and reproducible proteomics fingerprint, stringent quality controls are required in all the experimental steps from sample collection, sample fractionation, MALDI target preparation, instrumentation, and pattern recognition analysis. All these steps affect whether the resulting spectrum has well defined, resolved, and reproducible peaks with good signal-to-noise ratio for comparison. The goal of this study was to understand where are the variabilities during the profiling experiments and how to manage and reduce them in order to generate high quality proteomics fingerprints. We used serum and other biological samples from ovarian cancer as an example. We profiled serum samples by using functionalized magnetic beads that could enrich a specific subset of serum proteins and peptides based on their absorption to the beads. This step was then followed by elution, transferring onto AnchorChip™ target and analyzing in either a MALDI-TOF or a MALDI-TOF/TOF MS equipped with automated data acquisition. The resulting spectra were visualized and analyzed by ClinProTools™ software for pattern recognition. Our results showed that magnetic beads were able to fractionate human serum samples and other biological fluids and reproducible profiles could be obtained. In addition, the AnchorChip technology provided high sensitivity in MS detection by concentrating the matrix/fractionated serum samples to a 600um spot. For sample storage, we borrowed the concept from cryogenic preservation of cultured cells and established seed stocks and working stocks so that samples used for quality controls could last for at least 4 to 5 years to avoid frequent freezing and thawing of samples. We also showed that proper data acquistion parameters, for example, method settings, laser energy, matrix blaster shots, and the number of shots, also dramatically affected the quality of the spectrum. The results of this study suggest that good quality control of each experimental step during profiling experiment and good understanding of what causes these variations will result in better profiling data, in turn, more reliable proteomic fingerprints.