tbuckley/cabot-search huggingface dataset:
QOLP-04. THE EVOLVING ROLE OF COMPLEMENTARY CANNABIS THERAPY IN GLIOBLASTOMA TREATMENT
Authors: Nicholas Blondin
Journal: Neuro-Oncology (2018)

Evidence suggests a therapeutic role for cannabinoids, including cannabidiol (CBD) and tetrahydrocannabinol (THC), to treat glioblastoma (GBM) in cell cultures and animal models. It is unknown if cannabinoids can effectively treat GBM in human patients. We define therapeutic treatment as ingesting a cannabis oil concentrate of at least 50 mg of cannabinoid per day, for at least one month, while also receiving standard-of-care treatments. In Part 1 of our analysis, two time periods were defined. During Time Period 1 (TP1, 9/1/2014–6/1/2017), 12 GBM patients registered for CT MMP. During Time Period 2 (TP2, 6/1/2017-6/1/2018), 11 GBM patients registered for CT MMP. Data includes patient age, gender, ethnicity, tumor characteristics, cannabis treatment strategy (low use, palliative, or therapeutic), when the patient initiated cannabis relative to the diagnosis date, and overall survival (OS). In Part 2, we evaluated OS at 1 and 2 years in patients who used therapeutic cannabis, compared to those who had low or palliative use. During TP1, 6 patients used therapeutic cannabis. 5 patients are still alive (median of 25.4 months from diagnosis). 7 patients were male, with median age of 53 (range 17–74). During TP2, 9 patients used therapeutic cannabis. 6 patients are still alive (median of 8.8 months from diagnosis). 9 patients were female, with median age of 65 (range 50–78). Among the 23 patients who registered for CT MMP, therapeutic cannabis use was associated with increased OS at 1 year (80% vs 74%, p=0.03), and increased OS at 2 years (73% vs 65%, p=0.002) compared to low or palliative use. Therapeutic cannabis therapy was well tolerated, with no significant adverse events. CONCLUSIONS: Therapeutic cannabis therapy can be integrated into standard-of-care treatments for GBM. Our data suggest that there may be a survival benefit. Further research studies of cannabis are warranted.
STEM-06. A DRAFT SINGLE-CELL ATLAS OF HUMAN GLIOBLASTOMA REVEALS SPATIAL AND DIFFERENTIATION GRADIENTS OF STEM-LIKE CELLS
Authors: Soeren Mueller, Aparna Bhaduri, Elizabeth DiLullo, Garima Yagnik, Daniel Lim, Manish Aghi, Arnold Kriegstein, Aaron Diaz
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) stem-like cells (GSCs) expressing markers of the proneural (e.g. OLIG2, DLL3) and mesenchymal (e.g. CHI3L1(YKL-40), CD44) GBM molecular-subtypes have been described. However, it is unknown if these two GSC types are sufficient to generate the spectrum of cellular heterogeneity observed in GBM. The spatial localization and niche interactions of GSCs have not been fully elucidated. We perform single-cell RNA-sequencing (scRNA-seq) and matched exome sequencing of human GBMs from a cohort of 21 patients, profiling over 40,000 cells. We combine in silico lineage tracing and meta-analysis of public data to identify recurrent cellular hierarchies of GSCs and their progeny. We map GBM cells to tumor-anatomical structures using reference atlases. We perform immunofluorescence staining and automated image analysis on a cohort of 300 human GBMs using markers of GSC lineage and phenotype to visualize and quantify niche interactions. Proneural GSCs (pGSCs) upregulate markers of cell-cycle progression and PDGF signaling compared to mesenchymal GSCs (mGSCs). By contrast, most mGSCs have a quiescent phenotype, but overexpress cytokines responsible for the chemotaxis of myeloid-derived suppressor cells (e.g. CSF1, CCL2, PTGS2). We find cycling mGSCs enriched in the perivascular space and quiescent mGSCs enriched in hypoxic regions, pGSCs are enriched in the tumor’s invasive edge. Increased mGSC content, but not increased pGSC content correlates with significantly inferior survival in TCGA data. All clonal expressed-mutations in our biopsies are found in the GSC populations, with a greater representation of mutations in mGSCs. We conclude that varying proportions of mGSCs and pGSCs, their progeny and stromal/immune cells are sufficient to explain the genetic and phenotypic heterogeneity observed in GBM. Moreover, pGSCs and mGSCs aggregate in distinct tumor compartments, display different rates of proliferation and distinct niche interactions. Intratumor heterogeneity is a barrier to targeted therapeutics. This study sheds light on the heterogeneity of GSCs in vivo.
Membrane cholesterol and substrate stiffness co-ordinate to induce the remodelling of the cytoskeleton and the alteration in the biomechanics of vascular smooth muscle cells
Authors: Hanna J Sanyour, Na Li, Alex P Rickel, Josh D Childs, Courtney N Kinser, Zhongkui Hong
Journal: Cardiovascular Research (2018)

Aims Cholesterol not only deposits in foam cells at the atherosclerotic plaque, but also plays an important role as a regulator of cell migration in atherogenesis. In addition, the progression of atherosclerosis leads to arterial wall stiffening, and thus altering the micromechanical environment of vascular smooth muscle cells (VSMCs) in vivo. Our studies aim to test the hypothesis that membrane cholesterol and substrate stiffness co-ordinate to regulate VSMCs biomechanics, and thus potentially regulate VSMCs migration and atherosclerotic plaque formation. Methods and results Methyl-β-cyclodextrin was used to manipulate membrane cholesterol content in VSMCs isolated from the descending thoracic aorta of male Sprague-Dawley rats and cultured on Type I collagen-coated polyacrylamide gel substrates with varying stiffness. Atomic force microscopy (AFM) was used to determine VSMCs stiffness and integrin-fibronectin (FN) adhesion. The alignment of submembranous actin filaments was visualized with AFM and confocal microscopy. The constriction force of rat aorta was measured ex vivo using a multi-wire myograph system. Our results demonstrated that cholesterol-depletion and substrate-softening induced a significant decrease in VSMCs stiffness and adhesion to FN, as well as cytoskeletal disorganization. In addition, the contractile force of rat aorta was reduced upon cholesterol-depletion. Cholesterol-enrichment resulted in an increase in stiffness, adhesion to FN, cytoskeletal organization of VSMCs compared with the cholesterol-depleted cells, and enhanced contractile force of rat aortas compared with the cholesterol-depleted vessel rings. Conclusion Cell membrane cholesterol and substrate stiffness synergistically affect VSMCs elastic modulus (E-modulus) by regulating the organization of the actin cytoskeleton. Except for the 3.5 kPa gel substrate, cholesterol-depletion decreased VSMCs-FN adhesion force, adhesion loading rate, cytoskeletal orientation, and E-modulus compared with the control VSMCs. Conversely, cholesterol-enrichment significantly increased cytoskeleton orientation, stiffness, and VSMCs-FN cell adhesion force compared with both control and cholesterol-depleted VSMCs on a soft substrate.
New RCP code of conduct aims to challenge #MeToo behaviours
Authors: Jacqui Wise
Journal: BMJ (2018)

The Royal College of Physicians has published a new code of conduct to make explicit the behaviours that are expected from members and fellows in an effort to tackle matters raised by movements such as #MeToo.

The 10 point code says doctors should treat others with respect and consideration and recognise and value diversity and individual differences. It says doctors should recognise they hold a position of authority and be mindful of the impact of their behaviour on patients, junior staff, and other healthcare professionals. It is particularly aimed …
Endoscopic ultrasound-guided hepaticogastrostomy combined with novel uncovered metal stent
Authors: Takeshi Ogura, Nobu Nishioka, Akira Miyano, Rieko Kamiyama, Kazuhide Higuchi
Journal: Endoscopy (2018)

Endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) has been developed as an alternative method for biliary drainage after failed endoscopic retrograde cholangiopancreatography (ERCP) [1]. EUS-HGS may be indicated for patients with advanced disease stages [2] [3]. However, following recent developments in chemotherapy, such as FOLFIRINOX (folinic acid + fluorouracil + irinotecan + oxaliplatin) [4], longer survival may be obtained; therefore, longer stent patency is clearly required.
Longer procoagulant phospholipid-dependent clotting time, lower endogenous thrombin potential and higher tissue factor pathway inhibitor concentrations are associated with increased VTE occurrence in patients with newly diagnosed multiple myeloma: results of the prospective ROADMAP-MM-CAT study
Authors: Despina Fotiou, Theodoros N. Sergentanis, Loula Papageorgiou, Kimon Stamatelopoulos, Maria Gavriatopoulou, Efstathios Kastritis, Theodora Psaltopoulou, Stella Salta, Patrick Van Dreden, Rabiatou Sangare, Annette K. Larsen, Evangelos Terpos, Ismail Elalamy, Meletios A. Dimopoulos, Grigoris T. Gerotziafas
Journal: Blood Cancer Journal (2018)

Venous thromboembolism (VTE) is a common complication in newly diagnosed symptomatic multiple myeloma (NDMM) patients. We explored cellular and plasma hypercoagulability in NDMM patients to identify relevant biomarkers that can be used in combination with clinical factors in the development of a risk assessment model (RAM) for VTE. Untreated patients (n = 144) with NDMM were prospectively enrolled, baseline biomarkers prior to anti-myeloma treatment and thromboprophylaxis initiation were obtained. These were compared against values in a group of healthy individuals with similar age and sex distribution. The primary study end point was symptomatic VTE occurrence. At 12-month follow-up cumulative VTE rate was 10.4%. NDMM patients showed biological signs of cellular and plasma hypercoagulability and endothelial cell activation. Procoagulant phospholipid clotting time (Procoagulant-PPL) was shorter, P-selectin levels lower and thrombin generation attenuated overall compared to healthy subjects. Longer Procoag-PPL®, lower endogenous thrombin potential (ETP), and higher levels of tissue factor pathway inhibitor (TFPI) were associated with VTE occurrence. Multivariate analysis showed that Procoag-PPL® and ETP were independent risk factors for VTE. We conclude that Procoag-PPL® and ETP can be prospectively incorporated into a RAM for VTE in MM in combination with clinical and disease risk factors.
Mineralocorticoid Receptor Antagonism Treatment for All Patients With ST-Segment Myocardial Infarction?
Authors: Robin A. P. Weir
Journal: JAMA Internal Medicine (2018)

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Abstract 12373: Differences in Predictive Ability of HAS-BLED and HEMORR2HAGES in Patients With Atrial Fibrillation According to Age
Authors: Laurent Fauchier, Adeline Samson, Gwendoline Chaize, Anne-Françoise Gaudin, Alexandre Vainchtock, Cécile Bailly, François-Emery Cotté
Journal: Circulation (2014)

Introduction/Hypothesis: In stroke prevention of patients with atrial fibrillation (AF), major bleeding is the main concern which can impact decision for thromboembolic prophylaxis, especially amon...
Abstract 15538: Heart Rate Reserve in Fontan and Pulmonary Hypertension Patients: Chronotropic Incompetence or Chronotropic Protection?
Authors: Guido Claessen, André La Gerche, Alexander Van De Bruaene, Mathias Claeys, Jan Bogaert, Piet Claus, Werner Budts, Marion Delcroix, Hein Heidbuchel, Marc Gewillig
Journal: Circulation (2016)

Introduction: Patients with pulmonary hypertension or a Fontan circulation are said to have an impaired heart rate (HR) response to exercise. However, it is yet to be determined whether the impaired HR response in these patients is a primary disorder of chronotropic responsiveness or a consequence of changes in cardiac load. Hypothesis: We hypothesized that patients with chronic thromboembolic pulmonary hypertension (CTEPH) or a Fontan circulation would have a normal HR response relative to exercise intensity, but an attenuated maximal HR due to decreased systemic ventricular filling. Methods: 40 subjects (20 controls, 10 CTEPH and 10 Fontan) underwent cardiac magnetic resonance imaging with simultaneous invasive pressure recording during supine bicycle exercise to near maximal exertion. Adjusted HR reserve (HRR) was determined as the change from rest to peak exercise HR divided by the difference of age-predicted maximal heart rate (220 - age) and resting HR. Results: Adjusted HHR was lower in Fontan and ...
GENE-18. DIVERGENT CLONAL EVOLUTION OF MELANOMA BRAIN METASTASES DURING TREATMENT WITH IMMUNOTHERAPY
Authors: Christopher Alvarez-Breckenridge, Benjamin Izar, Jackson Stocking, Matt Lastrapes, Naema Nayyar, Corey Gill, Mia Bertalan, Alexander Kaplan, Devin McCabe, Douglas Johnson, Craig Horbinski, Rasheed Zakaria, Farshad Nassiri, Gelareh Zadeh, David Fisher, Maria Martinez-Lage, Mario Suva, Ryan Sullivan, Daniel Cahill, Scott Carter, Priscilla Brastianos
Journal: Neuro-Oncology (2018)

Reversal of immune cell exhaustion through immune checkpoint blockade (ICB) has become a first-line approach for patients with metastatic melanoma due to success in controlling extracranial tumors. However, patients frequently experience discordant responses, with extracranial response and intracranial progression. We hypothesize that ICB exerts selective pressure leading to the clonal evolution of treatment resistant clones that ultimately culminate in disease progression. We collected a cohort of 97 patients, encompassing 312 pre- and post-immunotherapy melanoma tumors, for whole exome sequencing (WES) and included primary, extracranial, or intracranial samples. Each tumor was analyzed for somatic mutations, copy number alterations, neoantigen profile, and patient specific phylogenetic trees were constructed encompassing a tumor’s genetic subclones. Heterogeneity of the tumor microenvironment was evaluated using high multiplicity single-cell immunofluorescent staining (CycIF). Single cell sequencing was performed on fresh tissue from 4 pre-treatment and 14 post-immunotherapy melanoma brain metastases using the Smart-Seq2 protocol. WES of pre- and post-immunotherapy tumors yielded distinct patterns of clonal evolution and immunoediting within brain metastases compared to their extracranial counterparts, including mutations in B2M. In paired pre- and post-immunotherapy samples, CycIF demonstrated decreased in CD8 infiltration and increased CD45RO, FOXP3, and PD-L1 staining suggesting less cytotoxic, terminally differentiated T cells in resistant tumors. Single cell sequencing analysis of 3,974 tumor and immune cells demonstrated patient-specific tumor clustering and gene expression profiles mediating resistance to ICB. In conclusion, we document, for the first time, evidence of ongoing branched evolution during immunotherapy in brain metastases with divergence compared to systemic sites of disease. Next-generation sequencing provides novel insights into clonal evolution mediating discordant responses of intra- and extracranial sites and immunosuppressive features of the intracranial tumor microenvironment. Targeting these mechanisms of resistance provide potential therapeutic avenues for patients with progressive intracranial disease.
CMET-14. DISTANT BRAIN FAILURE FOLLOWING STEREOTACTIC RADIOSURGERY FOR BRAIN METASTASES FROM NON-SMALL CELL LUNG CANCER
Authors: Andrew Keller, Sean All, Hanisha Patel, Steven Nguyen, Luke Pearson, Naren Ramakrishna
Journal: Neuro-Oncology (2018)

We examined distant brain failure rates and underlying prognostic factors among patients treated with SRS for brain metastases from NSCLC. We performed an IRB-approved retrospective study of 178 NSCLC patients treated with Linear Accelerator-based stereotactic radiosurgery (SRS) for 526 brain metastases. Median time to distant brain failure (DBF) was defined as time from initial SRS to MRI revealing a new lesion. Kaplan Meier and Cox proportional hazards model were used for statistical evaluation. All but 10 patients were classified by histology, with the majority (76%) classified as adenocarcinoma. 116 patients (65%) had uncontrolled extracranial disease. 22 patients (12%) received previous WBRT and 15 patients (8%) received concurrent WBRT. 6 patients were ALK positive and 63 were ALK-negative. 26 patients were EGFR positive and 64 were EGFR negative. The median time to development of 1 brain metastasis was 8 months, with 22 patients (12%) only developing 1 additional brain metastasis and 89 patients (50%) developing greater than 1 additional brain metastasis. Median time to development of 2–4 brain metastases was 12 months, with 39 patients (22%) developing only 2–4 additional brain metastases and 50 patients (28%) developing greater than 4 additional brain metastases. Median time to development of greater than 4 additional brain metastases was 26 months. Median time to leptomeningeal disease (LMD) was 62 months, with 21 patients (12%) developing LMD. On univariate analysis, adenocarcinoma histology (p=0.031), EGFR mutation negative or unknown (p=0.042), and controlled extracranial disease (p=0.011) were positive prognostic factors for time to development of 1 additional brain metastasis. We report the incidence of distant brain failure among lung cancer patients treated with SRS. Our study revealed that the probability of distant brain failure is increased for those with EGFR mutation, active extracranial disease, or non-adenocarcinoma histology.
ACTR-48. FEASIBILITY OF DISCONTINUATION OF ADJUVANT TEMOZOLOMIDE AFTER 12 CYCLES REMAINING WITHOUT PROGRESSION FOR PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Motoo Nagane, Keiichi Kobayashi, Kuniaki Saito, Saki Shimizu, Shinya Suematsu, Satoshi Kume, Yuma Okamura, Yoshiaki Shiokawa
Journal: Neuro-Oncology (2018)

Standard of care for newly diagnosed glioblastoma (GBM) has been chemoradiotherapy with concomitant and adjuvant temozolomide (TMZ) (Stupp regimen). Optimal number of adjuvant TMZ cycles, however, has not been well established yet, although the pivotal trial used 6 cycles. In routine practice, up to 24 cycles have been frequently given, while many recent trials have adopted 12 cycles without solid evidence. Here we investigated outcome of and prognostic factors associated with discontinuation of adjuvant TMZ after 12 cycles without progression. Ninety six patients treated with Stupp regimen since May 2007 to March 2017 in our institution were retrospectively analyzed. Overall survival (OS) and progression-free survival (PFS) were evaluated with Kaplan-Meier method and statistical significance was determined by logrank test. There were 20 patients (21%, med age 57 yo; med KPS 70; female 12) identified who completed 12 adjuvant TMZ cycles without progression. Nine patients discontinued adjuvant TMZ (Group A), while 11 continued beyond 12 cycles (Group B). Median PFS (mPFS) and median OS (mOS) were 40.6 m and 53.7 m, respectively. mPFS after 12 cycles of adjuvant TMZ (mPFS-TMZ12) for all 20 patients, Group A, and B were 26.8 m, 96.2 m, and 26.8 m (p=0.379 for latter 2), respectively. mOS after 12 cycles of adjuvant TMZ (mOS-TMZ12) were 40 m, not reached, and 27.2 m (p=0.080), respectively. Factors significantly associated with better PFS were young age, female, higher KPS, debulking resection, and no residual enhancing disease (NRD) at TMZ12, and were female, debulking resection, and NRD at TMZ12 with OS. A minor subset of GBM patients could continue adjuvant TMZ for 12 cycles without progression and benefited for better survival. In this cohort of patients, discontinuation of adjuvant TMZ after 12 cycles may not compromise their outcome, especially in those with no residual disease.
Diagnostic vs Management Reasoning—Reply
Authors: David A. Cook, Jonathan Sherbino, Steven J. Durning
Journal: JAMA (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Innate immune crosstalk in asthmatic airways: Innate lymphoid cells coordinate polarization of lung macrophages
Authors: Jihyun Kim, Yuna Chang, Boram Bae, Kyoung-Hee Sohn, Sang-Heon Cho, Doo Hyun Chung, Hye Ryun Kang, Hye Young Kim
Journal: Journal of Allergy and Clinical Immunology (2018)