tbuckley/cabot-search huggingface dataset:
Annals Graphic Medicine - Paused
Authors: Emily Steinberg
Journal: Annals of Internal Medicine (2018)

Web Exclusives6 November 2018Annals Graphic Medicine - PausedFREEEmily Steinberg, MFAEmily Steinberg, MFAPennsylvania State University, Wyncote, Pennsylvania (E.S.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G18-0004 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Editors' Note: This Graphic Medicine was published previously in: Steinberg E. Paused. Cleaver Magazine. Intro by Squier S. Issue 22, 6 June 2018. Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: Pennsylvania State University, Wyncote, Pennsylvania (E.S.)Disclosures: The author has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G18-0004.Author/Illustrator Information: Emily Steinberg is a painter and graphic novelist whose published works include a graphic memoir, short comics, and visual narratives. She teaches painting, drawing, graphic novel, and the History of Comics at Penn State Abington. More of her work may be seen at emilysteinberg.com.Author Contributions: Conception and design: E. Steinberg.Final approval of the article: E. Steinberg. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 6 November 2018Volume 169, Issue 9Page: W33-W39KeywordsConflicts of interestDisclosure ePublished: 6 November 2018 Issue Published: 6 November 2018 Copyright & PermissionsCopyright © 2018 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
QOLP-17. REVIEW AND META-ANALYSIS OF NAUSEA AND VOMITING TRIALS FOR MALIGNANT GLIOMAS
Authors: Mary Affronti, Dina Randazzo, Sarah Woodring, Frances McSherry, Patrick Healy, James Herndon, Mallika Weant, Elizabeth Miller, Eric Lipp, Henry Friedman, Katherine Peters
Journal: Neuro-Oncology (2018)

effects (weight gain, fatigue, pain, vision changes) contributing to dissatisfaction throughout the disease trajectory.Specific changes in appearance (hair loss, indentation on head, skin dryness) were also problematic factors affecting adjustment and coping.An ascribed negative outlook (9%) (self-conscious, feeling ashamed or vulnerable) magnified awareness of longterm permanent changes, but some (8%) described the implementation of a positive outlook (using exercise and hope) allowing for acceptance of these changes.CONCLUSION: These findings offer insight from the patients perspective on identified physical, mental and treatment-related factors regarding body image concerns and the scope of issues faced by PBT patients.Understanding patient concerns allows for a multidimensional approach in management of key areas with the goal of improving overall quality of life.
Abstract 13702: Immediate Widespread Administration of Intracoronary Allogeneic Cardiosphere-Derived Cells (CDCs) is More Efficacious Than Delayed Treatment of Myocardial Infarction (MI)
Authors: Gen Suzuki, Brian Weil, Rebeccah F Young, James A Fallavollita, John M Canty
Journal: Circulation (2017)

Introduction: Although CDCs improve myocardial function, the relative benefits of immediate vs delayed treatment on remote zone remodeling and function following acute MI have not been established....
PRC2 loss induces chemoresistance by repressing apoptosis in T cell acute lymphoblastic leukemia
Authors: Ingrid M. Ariës, Kimberly Bodaar, Salmaan A. Karim, Triona Ni Chonghaile, Laura Hinze, Melissa A. Burns, Maren Pfirrmann, James Degar, Jack T. Landrigan, Sebastian Balbach, Sofie Peirs, Björn Menten, Randi Isenhart, Kristen E. Stevenson, Donna S. Neuberg, Meenakshi Devidas, Mignon L. Loh, Stephen P. Hunger, David T. Teachey, Karen R. Rabin, Stuart S. Winter, Kimberly P. Dunsmore, Brent L. Wood, Lewis B. Silverman, Stephen E. Sallan, Pieter Van Vlierberghe, Stuart H. Orkin, Birgit Knoechel, Anthony G. Letai, Alejandro Gutierrez
Journal: The Journal of Experimental Medicine (2018)

The tendency of mitochondria to undergo or resist BCL2-controlled apoptosis (so-called mitochondrial priming) is a powerful predictor of response to cytotoxic chemotherapy. Fully exploiting this finding will require unraveling the molecular genetics underlying phenotypic variability in mitochondrial priming. Here, we report that mitochondrial apoptosis resistance in T cell acute lymphoblastic leukemia (T-ALL) is mediated by inactivation of polycomb repressive complex 2 (PRC2). In T-ALL clinical specimens, loss-of-function mutations of PRC2 core components (
NCMP-22. TREATMENT-RELATED ADVERSE EFFECTS IN PATIENTS WITH MALIGNANT GLIOMA: ESTABLISHMENT OF KEY FEATURES FOR PSEUDOPROGRESSION AND TREATMENT-INDUCED NECROSIS.
Authors: Sebastian Winter, Eugene Vaios, Alona Muzikansky, Marc R. Bussière, Helen Shih, Maria Martinez-Lage, Franziska Loebel, Peter Vajkoczy, Jorg Dietrich
Journal: Neuro-Oncology (2018)

Pseudoprogression (PP) and treatment-induced necrosis (TN) are insufficiently characterized, clinically challenging conditions. Since both entities radiographically mimic recurrent disease, patients frequently require surgical interventions to guide management. We aimed to characterize the clinical and radiographic features of PP and TN that may facilitate non-invasive differentiation from recurrent disease. Patients with malignant glioma and a diagnosis of either PP (appearance <6 months post-radiotherapy [RT] completion) or TN (appearance >6 months post-RT) were retrospectively identified and compared using clinical-radiographic and histopathological data. Each imaging event/lesion diagnosed as PP or TN was evaluated as a region of interest (ROI) by T1+C weighted MRI and correlated to the respective RT dose distribution. Cumulatively, PP (n=27) and TN (n=37) groups comprised 137 individual radiographic ROIs (n=62 biopsy-proven, n=75 radiographic diagnosis). Most patients received concurrent and sequential chemotherapy. Gender and KPS did not differ significantly between groups. Patients with PP had mostly glioblastomas (81 vs 40%; p<0.002), fewer IDH1 mutations (p<0.006), a greater incidence of recurrence (p=0.03) and a shorter median overall survival (3.25 years vs. not reached (62% survival estimate at 24.5 years); p<0.0001). PP lesions occurred earlier (median onset post-RT: 1 vs. 11 months; p<0.00001), mostly during anti-neoplastic treatment (85 vs 32%; p<0.0005), and necessitated more steroid-based interventions (p<0.04). TN lesions often initially appeared periventricularly (n=22/37; 60%), were more numerous (median: 2 vs. 1 ROIs; p=0.01), and contained fewer malignant elements upon biopsy (p=0.008). While distance from the tumor resection cavity (RC) varied considerably for TN lesions (median: 21.5mm; range: 078mm), PP predominantly developed at the RC as a non-nodular, ring-like enhancing structure (p<0.0001). CONCLUSIONS: PP and TN appear to occur in clinically distinct patient populations and differ significantly in spatio-temporal radiographic pattern and histopathology. Increased familiarity with their unique features will improve patient management and may avoid unnecessary surgical procedures.
CADD-13. COMBINED INHIBITION OF NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE (NAMPT) AND POLY (ADP-RIBOSE) POLYMERASE (PARP) IMPAIRS GLIOBLASTOMA CELL GROWTH
Authors: Lee Hwang, Yu-Ting Su, Michael Vogelbaum, Mark Gilbert, Jing Wu
Journal: Neuro-Oncology (2018)

Glioblastoma is aggressive with poor prognosis. Nicotinamide phosphoribosyltransferase (NAMPT) is essential to maintain nicotinamide adenine dinucleotide metabolism during rapid proliferation and regulates poly (ADP-ribose) polymerase (PARP), which is crucial for DNA repair. Targeting both NAMPT and PARP may represent a treatment strategy in glioblastoma. We hypothesize that the combined inhibition of NAMPT and PARP can induce synergistic cell death in tumor, while sparing significant cytotoxicity in normal astrocytes. NAMPT expression was determined in a group of six human glioblastoma cell lines and normal human astrocytes (NHA) by Western blotting. To analyze the cytotoxic effects of the treatments in tumor and normal cells, U251 and NHA cells were selected to receive FK866 (NAMPT inhibitor), Olaparib (PARP inhibitor), or both drugs for 72 hours prior to the cell viability test. Various levels of NAMPT expression were demonstrated in a group of glioblastoma cell lines and NHA, where U251 showed the strongest expression. We demonstrated a significant decrease of cell viability in U251 cells that were treated with FK866 in a dose-dependent manner. A 32% reduction of cell viability was demonstrated at a dose as low as 10 nM. However, a 28% reduction of cell viability was found in NHA at the EC50 concentration for U251 cells. When tumor cells were treated with a combination of FK866 and Olaparib at their EC50 concentrations (28nM and 406nM), 72% and 50% reductions of cell viability occurred in tumor cells and NHA, respectively. The combined treatment with FK866 and Olaparib enhances cytotoxicity in glioblastoma cells compared to the single-agent therapy, representing a promising therapeutic strategy. However, the toxic effects on NHA are concerning and warrant further investigations to determine a precise therapeutic window in preclinical models before the treatment is considered for clinical trials.
Abstract 12030: The Process of Left Atrial Appendage Dysfunction Evaluated by 3D Transesophageal Echocardiography
Authors: Fujimaki Haruka, Yoshiyuki Hama, Tai Sekine, Yoshihide Fujimoto, Masashi Yamamoto, Toshihide Himi
Journal: Circulation (2015)

Introduction: Left atrial appendage (LAA) dysfunction progressively evolves in atrial fibrillation (AF) patients. LAA transesophageal echocardiographic (TEE) parameters can predict thrombotic tendencies and AF treatment outcomes. However, the process of LAA dysfunction remains to be elucidated. Methods: Eighty-four persistent AF patients (64men, age 68±10) that underwent TEE were enrolled. We obtained three-dimensional full-volume LAA data from these patients and reconstructed two-dimensional LAA cross sectional images at the orifice and mid-portion level of the LAA. The maximum and minimum cross-sectional LAA areas were measured at each position and the area change ratio at the orifice (ACR-O) and mid-portion (ACR-M) were calculated. We defined low contractility as a decreasing area change ratio (ACR) of &lt;30% at each position and evaluated the associations between the ACR-O, ACR-M, and continuous AF duration. Results: The patients were categorized into three groups based on the ACR-O and ACR-M: those that maintained both ACR-Os and ACR-Ms (n=48, Group 1), those with reduced ACR-Os and maintained ACR-Ms (n=17, Group 2), and those with both reduced ACR-Os and ACR-Ms (n=19, Group 3). There were no patients with maintained ACR-Os and reduced ACR-Ms. The mean continuous AF durations of each group were 29±42, 54±40, and 88±87 months, respectively. In Group 3, the LAA emptying flow velocity was significantly decreased compared to that in Group 1 and Group 2 (38±19, 31±14, 22±11,cm/s) and LAA thrombi were detected more frequently (0%, 12%, 58%). Conclusions: This study suggested that LAA dysfunction occurred from the orifice and progressed toward the mid-portion. When LAA dysfunction extended over the mid-portion, the LAA flow velocity decreased and LAA thrombi were detected more frequently. Even though anticoagulant drugs were administrated in all patients, 58% of patients had thrombi in Group 3. These patients should be considered for additional therapeutic approaches.
MNGI-01. SURGICAL RESECTION AND ORBITAL RECONSTRUCTION IN SPHENO-ORBITAL MENINGIOMAS
Authors: Churl-Su Kwon, Omar Al-Awar
Journal: Neuro-Oncology (2018)

To describe surgical technique and outcomes of surgical resection of intracranial, intra-orbital and intra-osseous disease in spheno-orbital meningiomas (SOMs) with periorbital and bony orbit reconstruction. We performed a single institution retrospective review of consecutive cases between 2005 and 2016. Meningioma pathology records of 1007 patients revealed 125 sphenoid meningiomas of which 32 patients met eligibility criteria for SOMs. Clinical findings, radiographic features, operative technique, outcomes and follow-up data are presented. Of the 32 patients 20 met inclusion criteria. Mean follow-up duration was 69 months. The mean age of patients was 55 (range 32–82) with a female predominance (16F:4M). 4 (20%) had vascular involvement and 12 (60%) cavernous sinus infiltration. 9 (45%) tumors extended medially to the foramen rotundum and ovale. 8 (40%) patients did not require a bony orbital reconstruction, 11 (55%) had a split calvarial bone graft and 1 (5%) patient had a temporalis muscle graft. In 19 (95%) patients, pericranium was used for reconstruction of the peri-orbita and dura. 8 (40%) patients had complete clearance of their orbital disease. All patients presented with proptosis and in the majority this was corrected. 17 (85%) patients had WHO grade I disease with the other 3 (15%) WHO grade II disease. Of the 13 patients who had visual impairment, 9 patients had improved vision postoperatively, including 3 patients whose vision returned to normal. The management of SOM remains challenging for both resection and reconstruction. The goals of surgery entail recovery of compromised CN function and long-term tumor control. A multidisciplinary approach allows for safe resection with improvement in cosmesis. The benefits of orbital reconstruction are: structural, cosmetic, and provide landmarks for postoperative imaging.
EXTH-80. IMPAIRED PARP1 DNA REPAIR DEFINES CHEMO-SENSITIVITY IN IDH1-MUTATED CELL
Authors: Yanxin Lu, Yang Liu, Mark Gilbert, Jing Wu, Chunzhang Yang
Journal: Neuro-Oncology (2018)

Mutations in isocitrate dehydrogenase (IDH1/2) are the most prevalent genetic deficiency in lower grade gliomas. IDH-mutated in glioma exhibits better clinical outcomes with longer patient survival, as well as greater sensitivity to chemotherapy. In the present study, we explored the molecular mechanisms that determine the chemo-sensitivity in IDH1-mutated cells, and seek a potential therapeutic strategy by targeting PARP/BER DNA repair pathway. We investigated transcriptomic profiles from 530 WHO grade II/III glioma based on their IDH1/2 mutation status. We established IDH1-mutated cells and investigated the alterations in nicotinamide adenine dinucleotide (NAD+), Poly (ADP-ribose) polymerase (PARP)-associated DNA repair and DNA damage in these cells in response to temozolomide (TMZ). Moreover, we evaluated the PARP inhibitor olaparib and its synergistic effect on TMZ-associated cytotoxicity. Our results showed that the IDH1-mutated cells are more vulnerable to genotoxic agent, which recapitulate the disease phenotype in IDH1-mutated glioma. TMZ treatment resulted in an over 20-fold increase of cell death in IDH1-mutated cells compared with wild type counterpart. IDH1-mutated cells exhibited an over 1.3-fold DNA damage and a 1.42-fold increase in cellular apoptosis with TMZ treatment. Mechanistically, IDH1-mutated cells exhibited compromised NAD+ metabolism, as well as concomitant PARP/BER DNA repair pathway. IDH1-mutated cells produced 83.8% less poly (ADP-ribose) polymer (pADPR), an important substrate for PARP-associated DNA repair, during TMZ treatment. This suggests that their incompetence to maintain genomic integrity was due to decreased availability of NAD+. Targeting the PARP-associated DNA repair pathway using olaparib, an FDA-approved PARP inhibitor, remarkably potentiated TMZ-induced cytotoxic effects by 2.16-fold in IDH1-mutated cells. Our findings demonstrate that metabolic defects in IDH1-mutated cells affect PARP-associated DNA repair pathway via NAD+ depletion, and therefore prompt the sensitivity to chemotherapies. Targeting PARP-associated DNA repair pathway suggests a novel therapeutic avenue for IDH1-mutated gliomas.
Surfactant Free Delivery of Docetaxel by Poly[(<i>R</i>)‐3‐hydroxybutyrate‐(<i>R</i>)‐3‐hydroxyhexanoate]‐Based Polymeric Micelles for Effective Melanoma Treatments
Authors: Zheng Luo, Lu Jiang, Chizhu Ding, Benhui Hu, Xian Jun Loh, Zibiao Li, Yun‐Long Wu
Journal: Advanced Healthcare Materials (2018)

Abstract Docetaxel (DTX) is a new semisynthetic chemical in the taxoid family and serves a wide spectrum of chemotherapeutics. Current commercial formulation of DTX is based on the addition of the nonionic surfactants (i.e., ethanol and Tween 80), which are reported to cause severe hemolysis, hypersensitivity reactions, or neurotoxic toxicity and greatly hinders patient tolerance or compliance. In this report, a novel low‐toxic, biodegradable, and amphiphilic poly[( R )‐3‐hydroxybutyrate‐( R )‐3‐hydroxyhexanoate] (PHBHx)‐based polyurethane (a copolymer made of hydrophobic PHBHx with biocompatible D ‐3‐hydroxybutyric acid as degradation product, thermosensitive polypropylene glycol (PPG), and hydrophilic polyethylene glycol (PEG) segments) with nanosized micelle formation ability to encapsulate DTX, as a surfactant free formulation, is reported. Interestingly, this DTX‐loaded poly(PHBHx/PEG/PPG urethane) micelle formulation with &gt;90% drug loading efficiency shows significantly improved DTX solubility in aqueous medium, reduced hemolysis for better blood compatibility, and increased drug uptake in A375 melanoma cells, which provides the possibility of systematic delivery of DTX. As a proof‐of‐concept, an A375 melanoma xenograft mouse model is established to verify the therapeutic effect of this DTX‐loaded poly(PHBHx/PEG/PPG urethane) micelle formulation, indicating the promising application of PHBHx‐based polymeric nanosized micelle as a surfactant free formulation of chemotherapeutics which might greatly be beneficial for controllable delivery of pharmaceutics and cancer therapy.
NCMP-05. RITUXIMAB AS INITIAL THERAPY FOR THE REVERSAL OF MYASTHENIA GRAVIS NEUROTOXICITY CAUSED BY IPILIMUMAB/NIVOLUMAB
Authors: Neha Verma, Muhammed Jaffer, Edwin Peguero, Sepideh Mokhtari
Journal: Neuro-Oncology (2018)

In patients with melanoma treated with immune checkpoint inhibitors (ICIs), neurological toxicities developed in 1% treated with Ipilimumab and 3% after Nivolumab. This rises to 14% when co-administered. Patients treated with ICIs are susceptible to Myasthenia Gravis like syndrome. There are several case reports that demonstrate the benefits of rituximab in both acetylcholine receptor (AChR) and muscle specific kinase (MuSK) antibody-positive MG patients. This study demonstrates the benefit of Rituximab in early goal therapy. OBSERVATION: A 70 year old female with scalp dermal spindle cell melanoma participating in a clinical trial with Nivolumab versus Ipilimumab/Nivolumab presented with diplopia. She suffered from shortness of breath and intermittent bilateral eye ptosis. Her ophthalmologic symptoms started following cycle one of therapy. Her ophthalmologist and allergist felt she had allergies. Her symptoms worsened with generalized muscle weakness and horizontal diplopia. One year later, her neurologist diagnosed her with Myasthenia Gravis. She did not receive treatment and had difficulty contacting her neurologist. She saw her pulmonologist for worsening dyspnea and her pulmonary function test showed a decreased negative inspiratory force (NIF) < 20 cm H2O. She declined admission and was treated with Mestinon 60 mg q4hr and prednisone 90 mg. Her NIF and FVC did not improve and she was given IVIG for 5 days. Her PFTs had only slightly improved. She received 1 dose of Rituximab at 375 mg/m2 and her FVC improved to >2.5 L. She was discharged on prednisone 40 mg daily and Mestinon 60 mg TID. Three days after Rituximab she was completely asymptomatic. DISCUSSION: Our case study shows a patient treated with immune checkpoint inhibitors developed Myasthenia gravis like syndrome and was successfully treated with Rituximab. Our study shows the importance of Rituximab as initial therapy for the reversal of MG like syndrome caused by Ipilimumab/Nivolumab.
Proposals for revised IWG 2018 hematological response criteria in patients with MDS included in clinical trials
Authors: U. Platzbecker, P. Fenaux, L. Adès, A. Giagounidis, V. Santini, A. A. van de Loosdrecht, D. Bowen, T. de Witte, G. Garcia-Manero, E. Hellström-Lindberg, U. Germing, R. Stauder, L. Malcovati, Mikkael A. Sekeres, David P. Steensma, S. Gloaguen
Journal: Blood (2018)
STEM-28. TISSUE FACTOR PROMOTES THE GLIOMA STEM CELL PHENOTYPE, AND IS SUPPRESSED BY MUTANT IDH1
Authors: Dusten Unruh, Snezana Mirkov, Brian Wray, Jonathan Lamano, Denise M Scholtens, Jann N Sarkaria, C David James, Craig Horbinski
Journal: Neuro-Oncology (2018)

Isocitrate dehydrogenase 1 mutant (IDH1mut) gliomas have global genomic hypermethylation, are less aggressive than IDH1 wild-type (IDH1wt) gliomas, and generally grow poorly in vitro and in vivo. Yet little data exist that connect specific hypermethylation targets to this unique phenotype. We previously reported that the gene encoding Tissue Factor (TF), F3, which promotes both thrombosis and malignant behavior, is among the most hypermethylated and downregulated genes in IDH1mut gliomas. In multiple IDH1wt and IDH1mut patient-derived glioma cell lines, F3 was hypermethylated in IDH1mut cells compared to IDH1wt cells, with reduced TF protein expression. A demethylating agent, decitabine, increased F3 transcription in IDH1mut glioma cells, but not in IDH1wt cells. TF knockdown greatly reduced proliferation, colony formation, glioma stem cell (GSC) marker expression, and xenograft growth of IDH1wt/EGFRvIIIamp GBM6 cells and IDH1wt/EGFRamp GBM12 cells, but not of NF1-mutant GBM43 cells. Conversely, TF induction enhanced the proliferation and colony formation of IDH1mut GBM164 and TB09 cells, especially GBM164. TF also increased the in vivo “take rate” of intracranial GBM164 xenografts from 0% to 100%, but did not enable TB09 xenograft growth. TF activated receptor tyrosine kinases (RTKs) in GBM6, GBM12, and GBM164, but RTK expression was very low in GBM43 and TB09. Transcriptomic profiling showed that only two genes were downregulated after TF knockdown in GBM6 and GBM12, and also upregulated after TF induction in GBM164: PROM1, encoding CD133, and CTNND2, encoding δ-catenin. Neither gene was affected by TF manipulation in GBM43 or TB09. High F3 mRNA correlated with enrichment of GSC markers, and worse outcome, in TCGA gliomas. These data suggest that: (i) TF promotes a GSC phenotype through RTKs; (ii) CD133 and δ-catenin may be critical effectors of TF-induced GSC behavior; (iii) TF methylation reduces IDH1mut glioma malignancy; (iv) TF is an attractive, novel therapeutic target in IDH1wt gliomas.