tbuckley/cabot-search huggingface dataset:
Abstract 16502: Non-Healthcare Data is Now Healthcare’s Biggest Information Asset - an Analysis of Geographic Social Determinant Data and Its Relationship to Hypertension
Authors: Ross Goglia, Khan Siddiqui
Journal: Circulation (2018)

Two of the biggest healthcare topics in 2018 have been 1) social determinants of health (SDOH) and 2) the new AHA blood pressure guidelines, which places many more Americans in the high BP category...
GENE-05. ATRX IN-FRAME FUSION NEUROBLASTOMA IS SENSITIVE TO EZH2 INHIBITION VIA MODULATION OF NEURONAL GENE SIGNATURES
Authors: Zulekha Qadeer, David Valle-Garcia, Dan Hasson, Aroa Soriano, Anqi Ma, Lyra Griffiths, Maged Zeineldin, Zhen Sun, Luz Jubierre, Dan Filipescu, Asif Chowdhury, Orla Deevy, Xiang Chen, David Finkelstein, Armita Bahrami, David Meni, Elizabeth Stewart, Sara Federico, Soledad Gallego, Fumiko Dekio, Mary Fowkes, John Maris, William Weiss, Stephen Roberts, Nai-Kong Cheung, Jian Jin, Miguel Segura, Michael Dyer, Emily Bernstein
Journal: Neuro-Oncology (2019)

Mutations and structural alterations of the SWI/SNF-like chromatin remodeler ATRX (Alpha Thalassemia/Mental Retardation, X-linked) have been reported at high frequency in a number of adult and pediatric tumors. However, the consequences of ATRX mutations in cancer and their impact on the epigenome remain ill defined. Particularly intriguing are the large N-terminal deletions of ATRX in neuroblastoma that generate in-frame fusion (IFF) proteins devoid of key chromatin interaction domains, while retaining the SWI/SNF-like helicase domain. We hereby demonstrate that ATRX IFF proteins have distinct genomic distribution compared to wild type (WT) ATRX and are absent from H3K9me3-enriched chromatin, yet bound to active promoters. We find REST (RE-1 Silencing Transcription Factor) as one such ATRX IFF target that is activated and promotes silencing of neuronal differentiation genes. Notably, we uncover that ATRX IFF cells display exquisite sensitivity to EZH2 inhibitors (EZH2i) in vitro and in vivo, due in part to derepression of neurogenesis genes, including a subset of REST targets. Examination of the epigenomic landscape of neuroblastoma tumor specimens harboring ATRX IFFs reveals that H3K27me3 occupies a subset of neurogenesis genes that are transcriptionally silenced and sensitive to EZH2i in our cell-based assays. In summary, this study demonstrates that ATRX structural alterations are not loss-of-function as predicted, and supports EZH2i as a key therapeutic strategy for ATRX IFF neuroblastoma.
SYSTEMIC AND LOCAL OSTEOCLASTOGENIC POTENTIAL OF MONONUCLEAR CELLS IN PATIENTS WITH RHEUMATOID ARTHRITIS AND SPONDYLOARTHRITIS
Authors: Zrinka Jajić, Marina Ikić, Nataša Kovačić, Elvira Lazić, Frane Grubišić, Hrvoje Mitrović, Ana Marušić, Danka Grčević
Journal: Annals of the Rheumatic Diseases (2010)
Randomized Double-Blind Phase II Study of Regorafenib in Patients With Metastatic Osteosarcoma
Authors: Lara E. Davis, Vanessa Bolejack, Christopher W. Ryan, Kristen N. Ganjoo, Elizabeth T. Loggers, Sant Chawla, Mark Agulnik, Michael B. Livingston, Damon Reed, Vicky Keedy, Daniel Rushing, Scott Okuno, Denise K. Reinke, Richard F. Riedel, Steven Attia, Leo Mascarenhas, Robert G. Maki
Journal: Journal of Clinical Oncology (2019)

PURPOSE SARC024 is a phase II clinical trial of the multikinase inhibitor regorafenib in specific sarcoma subtypes, including advanced osteosarcoma. We hypothesized that regorafenib would improve progression-free survival (PFS) in patients with sarcoma and report the results of the osteosarcoma cohort. PATIENTS AND METHODS This trial enrolled patients with progressive metastatic osteosarcoma with measurable disease by RECIST who had received at least one prior line of therapy. Patients were randomly assigned at a ratio of one to one to regorafenib or placebo. Crossover was allowed at time of disease progression. PFS was the primary end point of the study, which was powered to detect a difference of at least 3 months in median PFS. RESULTS Forty-two patients from 12 centers were enrolled between September 2014 and May 2018. Median age was 37 years (range, 18 to 76 years). Patients had received an average of 2.3 prior therapy regimens. Ten patients receiving placebo crossed over to active drug at time of progression. Study enrollment was stopped early, after a data safety monitoring committee review. Median PFS was significantly improved with regorafenib versus placebo: 3.6 months (95% CI, 2.0 to 7.6 months) versus 1.7 months (95% CI, 1.2 to 1.8 months), respectively (hazard ratio, 0.42; 95% CI, 0.21 to 0.85; P = .017). In the context of the crossover design, there was no statistically significant difference in overall survival. Fourteen (64%) of 22 patients initially randomly assigned to regorafenib experienced grade 3 to 4 events attributed to treatment, including one grade 4 colonic perforation. CONCLUSION The study met its primary end point, demonstrating activity of regorafenib in patients with progressive metastatic osteosarcoma. No new safety signals were observed. Regorafenib should be considered a treatment option for patients with relapsed metastatic osteosarcoma.
Front-Line Ibrutinib Therapy for Chronic Lymphocytic Leukemia (CLL) in the Real World: Responses, Toxicity, Outcomes and Subsequent Therapies
Authors: Anthony R. Mato, John N. Allan, John M. Pagel, Danielle M. Brander, Brian T. Hill, Bruce D. Cheson, Richard R. Furman, Nicole Lamanna, Constantine S. Tam, Ryan Jacobs, Frederick Lansigan, Paul M. Barr, Mazyar Shadman, Alan P Skarbnik, Douglas F. Beach, Jeffrey J. Pu, Alison R. Sehgal, Allison M. Winter, Clive S Zent, Hande H. Tuncer, Arun K Singavi, Stephen J. Schuster, Peter V. Pickens, Nirav N Shah, Annalynn Williams, Christina Howlett, Hanna Weissbrot, Naveed Ali, Bhavisha Patel, Krista Isaac, Joanna Rhodes, Mitchell E. Hughes, Sirin Khajavian, Elizabeth T Chatburn, Andrea Sitlinger, Eve Tranchito, Erica Bharat Bhavsar, Neil Bailey, Timothy F. Burns, Melissa Yacur, Mansi Malhotra, Sasanka Handunnetti, Kaitlin Kennard, Chadi Nabhan, Chaitra S. Ujjani
Journal: Blood (2017)
Case 13-2019: A 54-Year-Old Man with Alcohol Withdrawal and Altered Mental Status
Authors: Andrew Z. Fenves, Amirkasra Mojtahed, Mladen Nisavic, Lucas R. Massoth
Journal: New England Journal of Medicine (2019)

A 54-year-old man was admitted to the hospital for alcohol withdrawal. On the fifth day, after resolution of withdrawal symptoms, he was found to be delirious, lethargic, and minimally responsive. Laboratory evaluation was notable for anion-gap metabolic acidosis. Additional diagnostic test results were received.
US doctors’ group sues over faecal contamination of chicken
Authors: Owen Dyer
Journal: BMJ (2019)

The Physicians Committee for Responsible Medicine, which represents 12 000 doctors in the United States, is suing the US Department of Agriculture (USDA), claiming that the government is disregarding concerns about faecal contamination in poultry.1

The lawsuit would require the government to prohibit the sale of raw meat contaminated with faeces and to have the term “wholesome” taken off inspection labels.

“USDA misleads consumers every time inspectors slap a ‘wholesome’ label on contaminated food,” said Deborah Dubow Press, the group’s general counsel. “Consumers should be horrified to know …
US hospitals predict wave of dismissals over undisclosed China links
Authors: Owen Dyer
Journal: BMJ (2019)

One of the US’s best known hospitals, MD Anderson Cancer Center in Houston, Texas, is dismissing three Chinese American scientists after the National Institutes of Health singled them out by name in complaints, alleging that their NIH grant applications had concealed extensive links to Chinese institutions and that they posed a threat to US funded intellectual property.

The dismissals may herald others across the US, indicate recent warnings from the NIH director, Francis Collins, who told a Senate hearing earlier this month that his agency had sent similar letters to “more than 55” institutions. These followed an open letter sent last August to more than 10 000 institutions warning them that “foreign entities have mounted systematic programs to influence NIH researchers and peer reviewers.”1

The NIH sent five letters to MD Anderson, each naming a principal investigator in research funded by the NIH and listing alleged violations of grant application guidelines. The hospital provided the letters to The BMJ . The scientists’ names are redacted, as are those of allegedly affiliated universities and companies in China, but three of the researchers are described as grantees of China’s Thousand Talents programme, which aims to attract foreign trained scientists to China. …
High Yield of RNA Sequencing for Targetable Kinase Fusions in Lung Adenocarcinomas with No Mitogenic Driver Alteration Detected by DNA Sequencing and Low Tumor Mutation Burden
Authors: Ryma Benayed, Michael Offin, Kerry Mullaney, Purvil Sukhadia, Kelly Rios, Patrice Desmeules, Ryan Ptashkin, Helen Won, Jason Chang, Darragh Halpenny, Alison M. Schram, Charles M. Rudin, David M. Hyman, Maria E. Arcila, Michael F. Berger, Ahmet Zehir, Mark G. Kris, Alexander Drilon, Marc Ladanyi
Journal: Clinical Cancer Research (2019)

Targeted next-generation sequencing of DNA has become more widely used in the management of patients with lung adenocarcinoma; however, no clear mitogenic driver alteration is found in some cases. We evaluated the incremental benefit of targeted RNA sequencing (RNAseq) in the identification of gene fusions and MET exon 14 (METex14) alterations in DNA sequencing (DNAseq) driver-negative lung cancers.Lung cancers driver negative by MSK-IMPACT underwent further analysis using a custom RNAseq panel (MSK-Fusion). Tumor mutation burden (TMB) was assessed as a potential prioritization criterion for targeted RNAseq.As part of prospective clinical genomic testing, we profiled 2,522 lung adenocarcinomas using MSK-IMPACT, which identified 195 (7.7%) fusions and 119 (4.7%) METex14 alterations. Among 275 driver-negative cases with available tissue, 254 (92%) had sufficient material for RNAseq. A previously undetected alteration was identified in 14% (36/254) of cases, 33 of which were actionable (27 in-frame fusions, 6 METex14). Of these 33 patients, 10 then received matched targeted therapy, which achieved clinical benefit in 8 (80%). In the 32% (81/254) of DNAseq driver-negative cases with low TMB [0-5 mutations/Megabase (mut/Mb)], 25 (31%) were positive for previously undetected gene fusions on RNAseq, whereas, in 151 cases with TMB >5 mut/Mb, only 7% were positive for fusions (P < 0.0001).Targeted RNAseq assays should be used in all cases that appear driver negative by DNAseq assays to ensure comprehensive detection of actionable gene rearrangements. Furthermore, we observed a significant enrichment for fusions in DNAseq driver-negative samples with low TMB, supporting the prioritization of such cases for additional RNAseq.See related commentary by Davies and Aisner, p. 4586.
Low plasma vitamin D is associated with adverse colorectal cancer survival after surgical resection, independent of systemic inflammatory response
Authors: P G Vaughan-Shaw, L Zgaga, L Y Ooi, E Theodoratou, M Timofeeva, V Svinti, M Walker, F O’Sullivan, A Ewing, S Johnston, F V N Din, H Campbell, S M Farrington, M G Dunlop
Journal: Gut (2019)

Objective We assessed the effect of surgical resection of colorectal cancer (CRC) on perioperative plasma vitamin D (25OHD) and C-reactive protein (CRP) level. We investigated the relationship between circulating vitamin D level and CRC survival. Design We sequentially sampled 92 patients undergoing CRC resection, and measured plasma 25OHD and CRP. For survival analyses, we assayed 25OHD and CRP in two temporally distinct CRC patient cohorts (n=2006, n=2100) and investigated the association between survival outcome, circulating vitamin D and systemic inflammatory response. Results Serial sampling revealed a postoperative fall (mean 17.3 nmol/L; p=3.6e-9) in plasma 25OHD (nadir days 1–2). CRP peaked 3–5 days postoperatively (143.1 mg/L; p=1.4e-12), yet the postoperative fall in 25OHD was independent of CRP. In cohort analyses, 25OHD was lower in the 12 months following operation (mean=48.8 nmol/L) than preoperatively (54.8 nmol/L; p=1.2e-5) recovering after 24 months (52.2 nmol/L; p=0.002). Survival analysis in American Joint Committee on Cancer stages I–III demonstrated associations between 25OHD tertile and CRC mortality (HR=0.69; 95% CI 0.46 to 0.91) and all-cause mortality (HR=0.68; 95% CI 0.50 to 0.85), and was independent of CRP. We observed interaction effects between plasma 25OHD and rs11568820 genotype (functional VDR polymorphism) with a strong protective effect of higher 25OHD only in patients with GG genotype (HR=0.51; 95% CI 0.21 to 0.81). We developed an online tool for predicted survival ( https://apps.igmm.ed.ac.uk/mortalityCalculator/ ) that incorporates 25OHD with clinically useful predictive performance (area under the curve 0.77). Conclusions CRC surgery induces a fall in circulating 25OHD. Plasma 25OHD level is a prognostic biomarker with low 25OHD associated with poorer survival, particularly in those with rs11568820 GG genotype. A randomised trial of vitamin D supplementation after CRC surgery has compelling rationale.
Bleeding incidence and risk factors among cancer patients treated with anticoagulation
Authors: Dana E. Angelini, Tomas Radivoyevitch, Keith R. McCrae, Alok A. Khorana
Journal: American Journal of Hematology (2019)

Compared to age-matched controls, cancer patients have increased risk of bleeding when treated with anticoagulation. However, there are little data regarding bleeding as it relates to anticoagulant choice and other risk factors. We evaluated the six-month incidence of bleeding among patients treated with anticoagulation who had bleeding risk factors. Data were obtained from Explorys (IBM Watson, Inc.), which pools data from multiple US healthcare organizations. Cohorts of patients were created to compare bleeding events between cancer and non-cancer patients treated with anticoagulation within six months of starting anticoagulation. Potential bleeding risk factors such as cancer type, metastatic disease, obesity, chronic kidney disease stage III or higher, and platelet count were evaluated. We compared ratios of numbers of patients in specific cohorts using chi-squared tests with continuity correction. The cohort comprised 3 283 140 cancer patients, of whom 435 140 (13.3%) received anticoagulation within six months of their cancer diagnosis. Bleeding incidence was higher in cancer vs non-cancer patients across all anticoagulants studied: warfarin 20.2% vs 12.6%, rivaroxaban 16.7% vs 12.1%, LMWH 13.2% vs 9.7%, and apixaban 14.5% vs 9.3%, P < .001 for all comparisons. Among all anticoagulants except warfarin, we found increased bleeding incidence in cancer patients with metastatic disease, gastrointestinal primary, CKD ≥ stage III, and platelets <100,000 × 109 /L. Bleeding incidence was higher in cancer patients regardless of the anticoagulant used. Patients with gastrointestinal malignancies had a higher incidence of bleeding compared to other tumors across all anticoagulants. Other factors associated with increased risk of bleeding included metastatic disease, chronic kidney disease, and thrombocytopenia.
Synergistic effect of immune checkpoint blockade and anti-angiogenesis in cancer treatment
Authors: Ming Yi, Dechao Jiao, Shuang Qin, Qian Chu, Kongming Wu, Anping Li
Journal: Molecular Cancer (2019)

Immune checkpoint inhibitor (ICI) activates host's anti-tumor immune response by blocking negative regulatory immune signals. A series of clinical trials showed that ICI could effectively induce tumor regression in a subset of advanced cancer patients. In clinical practice, a main concerning for choosing ICI is the low response rate. Even though multiple predictive biomarkers such as PD-L1 expression, mismatch-repair deficiency, and status of tumor infiltrating lymphocytes have been adopted for patient selection, frequent resistance to ICI monotherapy has not been completely resolved. However, some recent studies indicated that ICI resistance could be alleviated by combination therapy with anti-angiogenesis treatment. Actually, anti-angiogenesis therapy not only prunes blood vessel which is essential to cancer growth and metastasis, but also reprograms the tumor immune microenvironment. Preclinical studies demonstrated that the efficacy of combination therapy of ICI and anti-angiogenesis was superior to monotherapy. In mice model, combination therapy could effectively increase the ratio of anti-tumor/pro-tumor immune cell and decrease the expression of multiple immune checkpoints more than PD-1. Based on exciting results from preclinical studies, many clinical trials were deployed to investigate the synergistic effect of the combination therapy and acquired promising outcome. This review summarized the latest understanding of ICI combined anti-angiogenesis therapy and highlighted the advances of relevant clinical trials.
Effect of ultra-short-term treatment of patients with iron deficiency or anaemia undergoing cardiac surgery: a prospective randomised trial
Authors: Donat R Spahn, Felix Schoenrath, Gabriela H Spahn, Burkhardt Seifert, Philipp Stein, Oliver M Theusinger, Alexander Kaserer, Inga Hegemann, Axel Hofmann, Francesco Maisano, Volkmar Falk
Journal: The Lancet (2019)
Unusual gastric lesion in an iron-deficient patient
Authors: Kathleen Bryce, Mark Hawthorne, Iain Ewing
Journal: Gut (2019)

A 23-year-old woman presented with abdominal pain and iron-deficiency anaemia. She had recently used a non-steroidal anti-inflammatory for flu-like illness and had been taking oral iron supplementation for the last month.

She was referred for upper GI endoscopy and the endoscopic image is shown in figure 1. The area of abnormality was biopsied, and the histology slide is shown in figure 2.

What is the abnormality shown in the …
LGG-16. PREDICTORS OF OUTCOME IN BRAF-V600E PEDIATRIC GLIOMAS TREATED WITH BRAF INHIBITORS: A REPORT FROM THE PLGG TASKFORCE
Authors: Liana Nobre, Michal Zapotocky, Scott Ryall, Ana Guerreiro Stucklin, Julie Bennett, Lorena Baroni, David Sumerauer, Josef Zamecnik, Lenka Krskova, Adela Misove, Zdenek Pavelka, Jaroslav Sterba, Ofelia Cruz, Andres Morales La Madrid, Palma Solano, Eduardo Quiroga-Cantero, Adela Canete, Julia Balaguer Guill, Maria Luisa Garre, Samatha Mascelli, Valentina Iurilli, Peter Hauser, Didier Frappaz, Cecile Faure Conter, Jordan Hansford, Nisreen Amayiri, Helena Morse, Magnus Sabel, Anne Grete Bechensteen, Jack Su, Murali Chintagumpala, Matthias Karajannis, Gurcharanjeet Kaur, Jonathan Finlay, Diana Osorio, Scott Coven, David Eisenstat, Bev Wilson, Frank Van Landeghem, Helen Toledano, Sonika Dahiya, Karen Gauvain, Sarah Leary, Theodore Nicolaides, Elisabeth Finch, Sabine Mueller, Jean Mulcahy Levy, Nicholas Foreman, David Ellison, Alvaro Lassaletta, Valerie Larouche, Naureen Mushtaq, Till Milde, Cornelis Vantilburg, Olaf Witt, Duarte Salgado, Inga Harting, Miriam Bornhorst, Roger Packer, Mariana Fernandes, Sarah Injac, Abhi Bavle, Daniel Alderete, Vijay Ramaswamy, Michael Taylor, Peter Dirks, Tara McKeown, Ute Bartels, Eric Bouffet, Cynthia Hawkins, Uri Tabori
Journal: Neuro-Oncology (2019)

The BRAF-V600E mutation is found in 15–20% of pediatric low grade gliomas (PLGG) and result in worse outcome and higher risk of transformation to high grade gliomas (PHGG). Although ongoing trials are assessing the role of BRAF inhibitors (BRAFi) in these children, data are still limited. We aimed to report overall response rates and predictors of outcome in childhood BRAF-V600E gliomas. We collected clinical, imaging and molecular information of patients treated with BRAFi outside trials from centers participating in the PLGG taskforce. Response was calculated by RANO criteria and follow up data were collected for all patients. Sixty-six patients were treated with BRAFi (55 PLGG and 11 PHGG); median follow-up time was 1.5 years (0.1-5y). In PLGG, objective response (tumor reduction of >25%) was observed in 77% compared to 15% in a cohort treated with conventional chemotherapy (pCDKN2A deletion was not associated with lack of response, while specific enhancing patterns correlated strongly with response to BRAFi. Two-year PFS for the BRAF-V600E PLGG was 74% vs 47% for BRAFi vs chemotherapy, respectively (p=0.02). Our data reveal rapid, dramatic and sustained response of BRAF-V600E PLGG to BRAFi. These are in contrast to BRAF-V600E PHGG and non-enhancing PLGG. Additional molecular analyses are being performed to identify poor responders and emerging mechanisms of resistance in these tumors.
Abstract 17490: Cerebral Near Infrared Resonance Spectroscopy Insensitively Detects Critically Low Venous Oxyhemoglobin Saturation Following Stage 1 Palliation for Hypoplastic Left Heart Syndrome
Authors: Erin Rescoe, Xiaoqi Tang, John N Kheir
Journal: Circulation (2016)

Background: Venous oxyhemoglobin saturation (SvO2) is considered a gold standard in assessing the adequacy of tissue oxygen delivery (DO2); SvO2 <40% often represents compromised DO2. Regional oxyg...
Effect of low-level BCR-ABL1 kinase domain mutations identified by next-generation sequencing in patients with chronic myeloid leukaemia: a population-based study
Authors: Aytug Kizilors, Elena Crisà, Nicholas Lea, Roberto Passera, Syed Mian, Jamal Anwar, Steve Best, Franck E Nicolini, Robin Ireland, Maadh Aldouri, Christopher Pocock, Tim Corbett, Richard Gale, Emily Bart-Smith, Simon Weston-Smith, Clare Wykes, Austin Kulasekararaj, Sophie Jackson, Patrick Harrington, Donal McLornan, Kavita Raj, Antonio Pagliuca, Ghulam J Mufti, Hugues de Lavallade
Journal: The Lancet Haematology (2019)
THER-06. PROTEASOME INHIBITION IN PRIMARY MEDULLOBLASTOMA CELL CULTURE AND PATIENT-DERIVED XENOGRAFT MODELS: A POTENTIAL THERAPEUTIC IMPLICATION
Authors: Ashley S Plant, Michelle Pulley, Kaijun Di, Carey Goldsmith, Jody Pathare, Michael Muhonen, William G Loudon, Joffre Olaya, Daniela Bota
Journal: Neuro-Oncology (2019)

Recent research has shown a role of proteasome ubiquitination in medulloblastoma tumorigenesis and proteasome inhibition as a possible therapeutic target. In medulloblastoma primary cell culture and in a Patched1 haploinsufficiency medulloblastoma mice model, bortezomib, a proteasome inhibitor, has been shown to limit tumor growth via induction of apoptosis and inhibition of cell proliferation. However, its clinical utility is limited by its inability to cross the blood brain barrier and association with peripheral neuropathy. Marizomib, a more lipophilic proteasome inhibitor, has been shown to cross the blood brain barrier in preclinical studies and is being used in Phase III studies for adult glioblastoma in combination with radiation and temozolomide. Here, we evaluated dose dependent cell killing of marizomib in two group 3, myc-amplified medulloblastoma cell cultures. IC50’s were determined and were consistent with and slightly lower than that seen in adult glioblastoma cell cultures. We suggest marizomib warrants further investigation as a potential therapeutic target for recurrent medulloblastoma. Future studies will include determination of IC50’s for marizomib in cell lines for all medulloblastoma molecular subgroups and primary cell cultures as well as in vitro testing with patient-derived xenograft models.