tbuckley/cabot-search huggingface dataset:
CytoBas: Precision component‐resolved diagnostics for allergy using flow cytometric staining of basophils with recombinant allergen tetramers
Authors: Craig I. McKenzie, Nirupama Varese, Pei M. Aui, Bruce D. Wines, Philip Mark Hogarth, Francis Thien, Mark Hew, Jennifer M. Rolland, Robyn E. O’Hehir, Menno C. van Zelm
Journal: Allergy (2021)

Diagnostic tests for allergy rely on detecting allergen-specific IgE. Component-resolved diagnostics incorporate multiple defined allergen components to improve the quality of diagnosis and patient care.To develop a new approach for determining sensitization to specific allergen components that utilizes fluorescent protein tetramers for direct staining of IgE on blood basophils by flow cytometry.Recombinant forms of Lol p 1 and Lol p 5 proteins from ryegrass pollen (RGP) and Api m 1 from honeybee venom (BV) were produced, biotinylated, and tetramerized with streptavidin-fluorochrome conjugates. Blood samples from 50 RGP-allergic, 41 BV-allergic, and 26 controls were incubated with fluorescent protein tetramers for flow cytometric evaluation of basophil allergen binding and activation.Allergen tetramers bound to and activated basophils from relevant allergic patients but not controls. Direct fluorescence staining of Api m 1 and Lol p 1 tetramers had greater positive predictive values than basophil activation for BV and RGP allergy, respectively, as defined with receiver operator characteristics (ROC) curves. Staining intensities of allergen tetramers correlated with allergen-specific IgE levels in serum. Inclusion of multiple allergens coupled with distinct fluorochromes in a single-tube assay enabled rapid detection of sensitization to both Lol p 1 and Lol p 5 in RGP-allergic patients and discriminated between controls, BV-allergic, and RGP-allergic patients.Our novel flow cytometric assay, termed CytoBas, enables rapid and reliable detection of clinically relevant allergic sensitization. The intensity of fluorescent allergen tetramer staining of basophils has a high positive predictive value for disease, and the assay can be multiplexed for a component-resolved and differential diagnostic test for allergy.
Updated Overall Survival in a Randomized Study Comparing Dacomitinib with Gefitinib as First-Line Treatment in Patients with Advanced Non-Small-Cell Lung Cancer and EGFR-Activating Mutations
Authors: Tony S. Mok, Ying Cheng, Xiangdong Zhou, Ki Hyeong Lee, Kazuhiko Nakagawa, Seiji Niho, Alka Chawla, Rafael Rosell, Jesus Corral, Maria Rita Migliorino, Adam Pluzanski, Kay Noonan, Yiyun Tang, Malaika Pastel, Keith D. Wilner, Yi-Long Wu
Journal: Drugs (2020)

ARCHER 1050, an ongoing, randomized, open-label, phase III trial of dacomitinib versus gefitinib in newly diagnosed patients with advanced non-small-cell lung cancer (NSCLC) and an EGFR-activating mutation, reported significant improvement in overall survival (OS) with dacomitinib. This paper reports an updated OS analysis of ARCHER 1050 after an extended follow-up. In this multinational, multicenter trial, adults (aged ≥ 18 years or ≥ 20 years in Japan and Korea) with newly diagnosed NSCLC and EGFR mutation (exon 19 deletion or exon 21 L858R substitution), and no history of central nervous system metastases, were randomized 1:1 to receive dacomitinib 45 mg/day (n = 227) or gefitinib 250 mg/day (n = 225). Randomization was stratified by race and EGFR mutation type. An ad hoc updated analysis of OS was conducted at the protocol-defined cut-off of 48 months from first dosing of the last enrolled patient (13 May 2019). After a median follow-up of 47.9 months, 133 (58.6%) patients had died in the dacomitinib arm and 152 (67.6%) in the gefitinib arm. The hazard ratio (HR) for OS was 0.748 (95% CI 0.591–0.947; two-sided P = 0.0155); median OS was 34.1 months with dacomitinib versus 27.0 months with gefitinib. The HR for OS in patients with dose reduction(s) in the dacomitinib arm (n = 154) compared with all patients in the gefitinib arm was 0.554 (95% CI 0.420–0.730); median OS was 42.5 months for patients with dose reduction(s) in the dacomitinib arm. The most common adverse events were diarrhea (87.7%), paronychia (61.7%), dermatitis acneiform (49.3%), and stomatitis (43.6%) with dacomitinib, and diarrhea (55.8%) and alanine aminotransferase increased (40.2%) with gefitinib. The OS benefit from first-line treatment with dacomitinib versus gefitinib was maintained after extended follow-up in patients with advanced NSCLC with EGFR-activating mutations. NCT01774721 (registered 24 January 2013).
MODL-24. AN ORGANOTYPIC CHUNK CULTURE TECHNIQUE TO STUDY DISEASE MECHANISM AND DEVELOP TARGETED THERAPEUTICS FOR PEDIATRIC ADAMANTINOMATOUS CRANIOPHARYNGIOMA
Authors: Trinka Vijmasi, Eric Prince, Astrid Hengartner, Susan Staulcup, Andrea Griesinger, Andrew Donson, Ahmed Gilani, Nicholas Foreman, Todd Hankinson
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Advances in the treatment of Adamantinomatous Craniopharyngioma (ACP) face challenges with translation to clinical study due to the absence of robust culture models of the disease. We developed a technique for culturing human ACP tissue in an organotypic chunk culture format that retains the tumor microenvironment for a duration sufficient to evaluate potential targeted therapeutics. METHODS Intraoperatively collected tumor tissue from pediatric ACP was cut into volumes of approximately 3 mm3 and rested over a semi-permeable insert placed in the wells of a 6-well plate. Specimens were cultured in (1) Control media, media containing (2) Tocilizumab, (3) Trametinib, and (4) combination of Tocilizumab and Trametinib, for 24 and 96 hours. Specimens were harvested for paraffin embedding, protein and gene expression assays. Supernatants were collected to assay secreted components. Paraffin embedded specimens were sectioned and stained for H&amp;E, Pan-CK, Beta-Catenin, cleaved Caspase-3, Ki-67, and Phospho-ERK. RESULTS H&amp;E staining revealed characteristic histologic features of ACP with epithelial cells with palisading nuclei, wet keratin and ghost cells. Tumor sections were markedly positive for epithelial cell markers, Pan-CK and Beta-Catenin. Ki-67 and cleaved Caspase-3 were restricted to a small fraction of cells, indicating low index of proliferation and apoptosis under the culture conditions. The response to drug treatments shall be determined using gene expression assays and evaluation of the secreted components. CONCLUSION The organotypic chunk culture technique appears to maintain the viability and integrity of ACP tumors for several days and may serve as an appropriate model for pre-clinical studies to develop targeted therapeutics for pediatric ACP.
A Patient in Their 40s With Intermittent Hemoptysis
Authors: Susana Ortega-Silva, Grecia Iveth Maryelis Raymundo-Martínez, Hugo Rodríguez-Zanella
Journal: JAMA Cardiology (2020)

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Metastatic colorectal cancer cells maintain the TGFβ program and use TGFBI to fuel angiogenesis
Authors: Barbara Chiavarina, Brunella Costanza, Roberto Ronca, Arnaud Blomme, Sara Rezzola, Paola Chiodelli, Ambre Giguelay, Guillame Belthier, Gilles Doumont, Gaetan Van Simaeys, Simon Lacroix, Takehiko Yokobori, Bilguun Erkhem-Ochir, Patrick Balaguer, Vincent Cavailles, Eric Fabbrizio, Emmanuel Di Valentin, Stephanie Gofflot, Olivier Detry, Guy Jerusalem, Serge Goldman, Philippe Delvenne, Akeila Bellahcène, Julie Pannequin, Vincent Castronovo, Andrei Turtoi
Journal: Theranostics (2020)

Colorectal cancer (CRC) cells are traditionally considered unresponsive to TGFβ due to mutations in the receptors and/or downstream signaling molecules. TGFβ influences CRC cells only indirectly via stromal cells, such as cancer-associated fibroblasts. However, CRC cell ability to directly respond to TGFβ currently remains unexplored. This represents a missed opportunity for diagnostic and therapeutic interventions. Methods: We examined whether cancer cells from primary CRC and liver metastases respond to TGFβ by inducing TGFβ-induced protein ig-h3 (TGFBI) expression, and the contribution of canonical and non-canonical TGFβ signaling pathways to this effect. We then investigated in vitro and in vivo TGFBI impact on metastasis formation and angiogenesis. Using patient serum samples and an orthotopic mouse model of CRC liver metastases we assessed the diagnostic/tumor targeting value of novel antibodies against TGFBI. Results: Metastatic CRC cells, such as circulating tumor cells, directly respond to TGFβ. These cells were characterized by the absence of TGFβ receptor mutations and the frequent presence of p53 mutations. The pro-tumorigenic program orchestrated by TGFβ in CRC cells was mediated through TGFBI, the expression of which was positively regulated by non-canonical TGFβ signaling cascades. TGFBI inhibition was sufficient to significantly reduce liver metastasis formation in vivo. Moreover, TGFBI pro-tumorigenic function was linked to its ability to stimulate angiogenesis. TGFBI levels were higher in serum samples from untreated patients with CRC than in patients who were receiving chemotherapy. A radiolabeled anti-TGFBI antibody selectively targeted metastatic lesions in vivo, underscoring its diagnostic and therapeutic potential. Conclusions: TGFβ signaling in CRC cells directly contributes to their metastatic potential and stromal cell-independence. Proteins downstream of activated TGFβ, such as TGFBI, represent novel diagnostic and therapeutic targets for more specific anti-metastatic therapies.
PATH-07. QUALITY ASSURANCE IN CEREBROSPINAL FLUID CYTOLOGY ASSESSMENT FOR MEDULLOBLASTOMA STAGING LEADS TO POTENTIAL IMPROVED RISK-GROUP ASSESSMENT IN THE PROSPECTIVE MULTICENTER HIT-2000 TRIAL
Authors: Christian Hagel, Veronika Sloman, Martin Mynarek, Katharina Petrasch, Denise Obrecht, Frank Deinlein, Renate Schmid, André O von Bueren, Carsten Friedrich, B Ole Juhnke, Nicolas U Gerber, Robert Kwiecien, Hermann Girschick, Alexandra Höller, Antonia Zapf, Katja von Hoff, Stefan Rutkowski
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Cerebrospinal fluid (CSF) dissemination of medulloblastoma (M1 stage) is a high-risk prognostic factor. However, because diagnostic criteria for M1 staging are missing we specified process-related and cytomorphological parameters influencing the predictive value of the CSF status. PATIENTS AND METHODS CSF samples and cytology reports from 405 medulloblastoma patients of the prospective multicenter trial HIT-2000 were reviewed and related to 5-year progression free survival (5y-PFS). RESULTS Tumor cells were detected in 237/1073 CSF cytospins. M1-patients and M2/3 patients with radiologically detected metastases showed a worse 5y-PFS than M0 patients (54% and 52% vs. 76%; p=0.01 and p&amp;lt;0.001). Lumbar sampling was more sensitive than ventricular sampling. M0 diagnosed specimens containing &amp;gt;50% lytic cells and/or less than 10 nucleated cells showed a decreased 5y-PFS (61%). Further investigation of cytological parameters revealed a poor outcome for cases harboring &amp;gt; 3 tumor cell clusters and individual tumor cells (5y-PFS 33%) vs. cases with ≥ 2 individual tumor cells but no clusters (5y-PFS 61%). In bi-variable Cox-regression, ≥ 2 vs. 0 or 1 tumor cells were associated with a Hazard Ratio (HR) of 0.52 (95%-Confidence Interval (CI): 0.12, 2.30; p=0.39), whereas &amp;gt; 3 vs. no tumor cell clusters were associated with a HR of 8.94 (95%-CI: 1.66, 48.22; p=0.01). CONCLUSIONS CSF staging in medulloblastoma should comprise lumbar specimens with &amp;lt;50% lytic cells and a minimum of 10 nucleated cells. The predictive value of CSF cytology in M1 cases may predominantly depend on tumor cell clusters. The latter finding needs to be confirmed in prospective trials.
MBRS-56. RE-EVALUATION OF LEPTOMENINGEAL METASTASIS IN MEDULLOBLASTOMA WITH MAGNETIC RESONANCE IMAGING, RELATED SYMPTOMS AND CEREBROSPINAL FLUID METABOLOMIC PROFILES
Authors: Ji Hye Im, Byong Chul Yoo, Jun Hwa Lee, Kyung-Hee Kim, Jong Heon Kim, Hyeon Jin Park, Meerim Park, Ji Woong Kwon, Sang Hoon Shin, Heon Yoo, Seung Ah Choi, Jae Yeol Yang, Ji Hoon Phi, Seung-Ki Kim, Ho-Shin Gwak
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Diagnosis of leptomeningeal metastasis (LM) in medulloblastoma is made by positive findings in either MRI or CSF cytology. We studied if CSF metabolomics profile can differentiate the discordant results between MRI and CSF cytology and reflect the sampling time related to treatment. MATERIALS AND METHODS We prospectively collected 83 CSF samples from 45 medulloblastoma patients. A total of 6,527 low-mass ions (LMIs) were detected using liquid chromatography tandem mass spectrometry (LC-MS/MS). Discriminative low-mass ions (LMIs) between four different MRI and cytology results groups were evaluated and representative LMIs were identified. RESULTS CSF cytology and MRI finding were both positive for LM in 8 samples and both negative for 47 samples. Tests were cytology (-) and MRI (+) in 20 samples, whereas cytology (+) and MRI (-) status were in the remaining 8 samples. The diagnostic accuracy by area under the curve (AUC) was 0.722 for cytology and 0.888 for MRI each. Based on the exclusiveness of LMI between groups, we verified 27 discriminative LMIs in MRI (+)/ cytology (+), 9 LMIs in MRI (+)/ cytology (-), and 12 LMIs in MRI (-) and cytology (+) group, separately. Metabolic pathways involved in MRI (+)/ cytology (+) group were linoleic acid, phenylalanine, TCA cycle, retinol, arginine-ornithine, nicotinate-nicotinamide, etc. Low-mass-ion discriminant equation (LOME), which could differentiate both different MRI and cytology results and the sampling time or presence of LM-related symptoms was found. CONCLUSION Non-targeted MSanalysis CSF metabolite in medulloblastomas revealed significantly different profiles, and these results suggest LMI profiles might have a higher sensitivity for LM diagnosis than either MRI or cytology.
Steatosis and Diastolic Dysfunction: The Skinny on Myocardial Fat⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Jason B. Lindsey, Steven P. Marso
Journal: Journal of the American College of Cardiology (2008)
SURG-43. APPLICATIONS AND RESTRICTION OF 980NM DIODE LASER FOR BRAIN TUMOR MICROSURGERY - A PIONEER CASE SERIES AND A CRITICAL REVIEW
Authors: Aline Campos Paiva, João Luiz Vitorino Araujo, Renan Lovato, Márcio Krambek, José Esteves Veiga
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Quality of life is essential for oncological patients. There are several tools that help surgery become more precise with less morbidity. Diode laser can cut and coagulate through thermal effect being helpful during surgery. It is a precise and useful technology that improves outcomes in neurooncology. OBJECTIVES To describe a pioneer case series of oncological use of diode laser and main applications of several types of laser in neurooncology. METHODS Detailed description of a pioneer case series of oncological patients that undergone to neurosurgical laser assisted procedures. An interventional longitudinal prospective study was conducted. Patients that had as mainly hypothesis the diagnosis of glioma or meningioma were selected. Also it was performed an extensive literature review about lasers in neurosurgery with special focus in diode laser. RESULTS There was not any paper describing the use of diode laser in neurooncology. The 980nm diode laser was used in 15 patients. The device had an easy handling. Decreased intra-operative time for hemostasis, lesser blood loss requiring less blood transfusion was observed. No post-operative complications occurred. CONCLUSIONS Diode laser is a useful tool for brain tumor surgery especially concerning hemostasis, providing decreased blood loss with lesser intra-operative duration. Surgical site coagulation is more effective causing less damage to adjacent structures specially in gliomas near eloquent regions. We consider this technique as a suitable adjuvant therapy for brain tumor surgeries providing an excellent hemostasis and helping cutting and vaporize lesion. This device makes surgery safer and decrease oncological morbidity.
EXTH-37. TARGETING EPIGENETIC VULNERABILITIES IDENTIFIED FROM A CRISPR SCREEN IN H3.3K27M DIPG
Authors: Eshini Panditharatna, Neekesh Dharia, Deyao Li, Alexander Beck, McKenzie Shaw, Li Jiang, Maria Trissal, Ilon Liu, Caleb Lareau, Jamie Anastas, Michael Quezada, Olivia Hack, Hafsa Mire, William Jerome, Guillaume Kugener, David Root, Francisca Vazquez, Lingling Dai, Tingjian Wang, Nathan Mathewson, Yang Shi, Kimberly Stegmaier, Michelle Monje, Todd Golub, Jun Qi, Mariella Filbin
Journal: Neuro-Oncology (2020)

Abstract Children diagnosed with diffuse intrinsic pontine glioma (DIPG), a type of high grade glioma in the brainstem, currently have a dismal 5-year overall survival of only 2%. The majority of DIPG patients harbor a K27M mutation in histone 3.3 encoding genes (H3.3K27M). To understand if the aberrant epigenetic landscape induced by H3.3K27M provides an opportunity for novel targeted therapies, we conducted the first CRISPR/Cas9 screen using a focused library of 1,350 epigenetic regulatory and cancer related genes in six H3.3K27M DIPG patient-derived primary neurosphere cell lines. We identified gene dependencies in chromatin regulators, polycomb repressive complexes 1 and 2 (PRC1 and PRC2), histone demethylases, acetyltransferases and deacetylators as novel tumor cell dependencies in DIPG. We hypothesized that targeting dysregulated functions of chromatin regulators by genetically deleting and chemically targeting these epigenetically induced vulnerabilities, we could ameliorate, or even reverse the downstream oncogenic effects of the aberrant epigenetic landscape of DIPG. In our secondary CRISPR nanoscreen, we first used six single guide RNAs (sgRNA) to knockout each gene using CRISPR/Cas9 ribonucleoprotein nucleofections, followed by use of three best sgRNAs combined with homology directed repair templates. Compared to lentiviral delivery, nucleofection is a rapid method, with reduced off-target toxicity, suitable for single gene knockouts in DIPG neurospheres. Secondary CRISPR validations confirmed dependencies in BMI1, CBX4, KDM1A, EZH2, EED, SUZ12, HDAC2, and EP300. Next, we conducted a chemical screen using 20 inhibitors and degraders to target the aberrant activity of HDAC, KDM1A, P300/CBP, PRC1 and PRC2. We identified eight chemical compounds that were effective in H3.3K27M DIPG neurosphere cell lines at low drug concentrations. Among these, an inhibitor and degrader targeting P300/CBP activity indicates a novel strategy of epigenetic therapy in DIPG. Through our combinatorial testing, we will identify a synergistic combination of epigenetic therapy for treating children diagnosed with H3.3K27M DIPG.
CTIM-03. PHASE II STUDY OF REGORAFENIB IN BEVACIZUMAB REFRACTORY RECURRENT GLIOBLASTOMA
Authors: Yasmeen Rauf, Cathy Schilero, David Peereboom, Manmeet Ahluwalia
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Most patients with glioblastoma (GBM) receive bevacizumab as part of their treatment. There is no good therapeutic option after bevacizumab failure. Regorafenib has potent preclinical antitumor activity and long-lasting anti-angiogenic activity as measured by dynamic contrast enhanced (DCE) – magnetic resonance imaging (MRI). Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment. METHODS Patients with progression of GBM after treatment with Bevacizumab will be eligible for the study. Oral administration of Regorafenib at 160 mg once daily will be administered for 3 weeks on /1 week off. Weekly dose escalation of regorafenib from 80 mg to 160 mg/day will be employed as per the Redos strategy. Patients start the treatment 80 mg/day in week 1, with weekly dose escalation to 120 mg in week 2, then 160 mg week in 3 if no significant drug-related toxicities are observed. They will be continued on treatment with Regorafenib 160 md /day till tumor progression or toxicity. They will get MRI brain every 4 weeks during the study. RESULTS Primary endpoint is median Overall survival. Secondary endpoints include progression free survival at 6 months and the median time to progression and objective response rate using the modified RANO criteria. The overall safety and tolerability of regorafenib by CTCAE version 5.0. will also be reported. CONCLUSION This is an ongoing clinical trial.
Broken Promises — How Medicare Part D Has Failed to Deliver Savings to Older Adults
Authors: Stacie B. Dusetzina, Benyam Muluneh, Nancy L. Keating, Haiden A. Huskamp
Journal: New England Journal of Medicine (2020)

For expensive specialty drugs, it's unclear how quickly substantial price competition among generics manufacturers can be achieved. Even if generic specialty drugs have far lower list prices than brand-name versions, savings may not accrue to Medicare beneficiaries.
IMG-08. UNUSUAL IMAGING FINDINGS IN TWO CASES OF PAEDIATRIC LOW GRADE GLIOMA
Authors: Vickyanne Carruthers, Kathryn Siddle, Gail Halliday, Simon Bailey, Rebecca Hill
Journal: Neuro-Oncology (2020)

Abstract Low grade gliomas (LGG), including pilocytic astrocytoma (PCA), are the commonest paediatric brain tumours and their behaviour is well understood, typically following a benign course. BRAF fusion is common, particularly in PCA of the cerebellum and optic pathway. Here we present two patients whose LGG behaved in an unusual fashion. The first patient who was treated 6 years previously on LGG2 with vincristine and carboplatin for a tectal plate lesion was identified on routine imaging to have local tumour progression and underwent completion staging. This showed a new enhancing soft tissue abnormality within the spinal cord at the level of L2. Due to radiological dubiety both lesions were biopsied for histological and molecular analysis, confirming LGG of the tectal plate and finding the spinal lesion to be a myxopapillary ependymoma. The second patient presented with acute hydrocephalus following a 2 year history of neurocognitive impairments. He was found to have a large, complex tumour centred in and expanding the bodies of both lateral ventricles with significant mass effect. Radiologically this was most in keeping with a central neurocytoma but histological analysis confirmed it to be a PCA with KIAA1549-BRAF fusion. The first case demonstrates the utility of molecular analysis in confirming two distinct tumour types in one patient, in a situation where metastasis would not be expected and would significantly alter treatment and prognosis. The second is an example of how imaging can be misleading in a KIAA1549-BRAF fused PCA presenting as an intraventricular mass.