tbuckley/cabot-search huggingface dataset:
Diverse evolutionary dynamics in glioblastoma inference by multi-region and single-cell sequencing.
Authors: Kui Wu, Weiqing Wan, Yong Hou, Fuqiang Li, Guibo Li, Liqin Xu, Xulian Shi, Michael Dean, Liwei Zhang
Journal: Journal of Clinical Oncology (2016)

11580 Background: Glioblastoma (GBM) is a common intracranial tumor and the most malignant form of brain cancer in adults and results in a high global mortality. GBM displays mutational complexity but the exact evolutionary process is poorly understood. This remarkable inter and intra-tumoral heterogeneity and genetic complexity limits further improvements in clinical applications for this disease. Methods: We applied multi-region sampling to sequence the whole genome of 448 single cells, to assess mutational diversity and gain insight into tumor evolutionary dynamics in two primary GBMs, one harboring an EGFR amplification and the other was wild-type at EGFR locus. Results: The EGFR-amplified case had initial driver mutations in the TP53 and PTEN and subclonal mutations in KIT and ERCC4. Identification of founder and subclonal copy number variants indicates gradually clonal differentiation not only involves point mutations but also copy number alterations. Single cell analysis identified complex aberrations in extrachromosomally amplified PDGFRA, by deleting exon 9 together with exon 8 or exon 10, to select for more oncogenic clones. In contrast the non EGFR-amplified GBM displays a punctuated evolutionary pattern, characterized by chromosomal deletions and evidence of chromothripsis. Conclusions: We characterized the evolutionary dynamics in both GBM tumors by pinpointing alteration events in distinct cell populations. Our findings thus demonstrate diverse cancer evolutionary models contribute to tumor heterogeneity in GBM and provide implications for improving diagnosis and therapeutic treatment for this lethal disease.
As-needed budesonide–formoterol better controlled mild asthma vs terbutaline, but maintenance budesonide was better
Authors: Matthew B. Stanbrook
Journal: Annals of Internal Medicine (2018)

ACP Journal Club18 September 2018As-needed budesonide–formoterol better controlled mild asthma vs terbutaline, but maintenance budesonide was betterMatthew B. Stanbrook, MD, PhDMatthew B. Stanbrook, MD, PhDToronto Western Hospital, University of Toronto, Toronto, Ontario, Canada (M.B.S.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJC-2018-169-6-031 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationO’Byrne PM, FitzGerald JM, Bateman ED, et al. Inhaled combined budesonide–formoterol as needed in mild asthma. N Engl J Med. 2018;378:1865-76. https://pubmed.ncbi.nlm.nih.gov/29768149Clinical Impact RatingsGIM/FP/GP: Allerg & Immunol: Pulmonology: References1 Sobieraj DM, Weeda ER, Nguyen E, et al. Association of inhaled corticosteroids and long-acting β-agonists as controller and quick relief therapy with exacerbations and symptom control in persistent asthma: a systematic review and meta-analysis. JAMA 2018;319:1485-96. [PMID: 29554195] Google Scholar2 Global Initiative for Asthma. Global strategy for asthma management and prevention, 2018. http://ginasthma.org/2018-gina-report-global-strategy-for-asthma-management-and-prevention/ (accessed 9 Jul 2018). Google Scholar3 Horne R. Compliance, adherence and concordance: implications for asthma treatment. Chest. 2006;130(1 Suppl):65S-72S. [PMID: 16840369] Google Scholar Author, Article, and Disclosure InformationAffiliations: Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada (M.B.S.)This article was published at Annals.org on 4 September 2018. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoAs-needed budesonide–formoterol was noninferior to maintenance budesonide for exacerbations in mild asthma Matthew B. Stanbrook As-needed budesonide–formoterol was noninferior to maintenance budesonide for exacerbations in mild asthma Matthew B. Stanbrook Metrics 18 September 2018Volume 169, Issue 6Page: JC31KeywordsAdverse eventsAsthmaClinical trialsHazard ratioHealth careInflammationMedical risk factorsOdds ratioPatientsPulmonary medicine ePublished: 18 September 2018 Issue Published: 18 September 2018 Copyright & PermissionsCopyright © 2018 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Phase II study of panitumumab, 5-fluorouracil, mitomycin-c and radiotherapy treatment in patients with non-metastatic squamous cell carcinoma of the anal canal: safety and efficacy results (VITAL study)—GEMCAD 09-02.
Authors: Jaime Feliu, Rocio Garcia-Carbonero, Jaume Capdevila, Inmaculada Guasch, Vicente Alonso, Carlos López-López, Pilar Garcia Alfonso, Carmen Castañon Lopez, Isabel Sevilla, Joan Maurel
Journal: Journal of Clinical Oncology (2018)

3566 Background: More than 80% of squamous cell carcinoma of the anal canal (SCCAC) express epidermal growth factor receptor protein (EGFR). VITAL was a phase II, multicentre, single arm study, which aimed to evaluate efficacy and safety of the addition of panitumumab (Pmab) to fluorouracil (5-FU), mitomycin C (M) and radiotherapy (RT) standard treatment in patients with SCCAC (NCT01285778). Methods: Treatment naïve patients ≥ 18 years old, with SCCAC (Stage T2-T4, any N, M0 defined by MRI) with ≤ 2 ECOG performance status, received Pmab (6 mg/kg, day 1 and q2w during 8 weeks), 5-FU (1000 mg/m2/day; IV infusion, days 1-4 and 29-32) and M (10mg/m2, days 1 and 29) plus RT 45 Gy (1.8 Gy/fraction) to the primary tumour and mesorectal, iliac and inguinal lymph nodes, plus boost dose of 10-15 Gy to primary tumour and affected lymph nodes. The primary objective was disease free survival (DFS) at 3 years (anticipated DFS: 73.7% ± 12%) estimated by Kaplan-Meier. Multivariable analysis of efficacy variables adjusting for key baseline covariates will be presented. Results: A total of 58 patients (31 women; median age: 59 years; ECOG performance status: 0 [41%] / 1 [57%] / 2 [2%]; TNM II [29%] / IIIA [21%] / IIIB [47%]/ non-evaluable [NE] [4%]) were evaluated. The 3-year DFS rate was 61.1% (95%CI 47.1 - 72.4). The median follow-up was 45 months. The 3-year overall survival rate and progression free survival rate were 78.4% (95%CI 65.1-87.1) and 57.5% (95%CI 43.6 - 69.2) respectively. Eighteen patients (31.0%) had a colostomy within the first 2 years post-treatment. Grade 3-4 toxicities were experienced by 53 (91%) patients. Radiation skin injury (19%), diarrhoea (10%), neutropenia (9%) and leukopenia (19%) were the most common ( > 10%) grade 3-4 adverse events associated with Pmab. There were no toxic deaths. Potential predictive efficacy and safety biomarkers are currently being assessed. Conclusions: The overall 3-year DFS rate does not reach the anticipated level for the main objective of the study. The multivariable analysis will determine if any subgroup of patients may benefit from this treatment scheme. Financed by Amgen S.A. Clinical trial information: NCT01285778.
A cross-sectional view of radiation dose fractionation schemes used for treating painful bone metastases (PBM) within Veterans Health Administration’s Radiation Oncology Centers.
Authors: George Anthony Dawson, Ignat Glushko, Kevin Greener, Michael Philip Hagan
Journal: Journal of Clinical Oncology (2016)

10110 Background: The use of single fraction (SF) radiotherapy in the treatment of PBM in the United States is now gaining clinical acceptance, especially at large institutional levels. In this cross-sectional report, we report the varying dose fractionation schemes used to treat PBM by VHA Radiation Oncology (RO) Centers. Methods: An electronic request was sent to 38 active VHA RO centers asking them to provide the radiation dose fractionation scheme used in the 10 most recently treated PBM - using (International Classification of Diseases (ICD) 198.5 - secondary malignancy of bone / bone marrow). Data collection: 03/01/2015 to 03/16/2015. Dosing schemes analyzed by fraction number: single (1-2), HPF (3-7) and MF (8-12). We recorded variations within the new 5 VHA regions: 1 to 5, and with the 18 (1 to 23) Veterans Integrated Service Networks (VISN) within them. All are oriented East to West. Results: We collected a total of 395 events for PBM treatment interventions - 375 were evaluable. Of the 375 cases, SF was used in 69 (18%); HPF (3-7) used in 75 (19%); MF (8 to 12) used in 190 (50%). The most commonly used dose scheme: MF - 300cGy x10 – 166(44%) of 375. HPF - 400cGy x5 - 67(17%) of 375. SF - 800cGy x1 – 62(16%) of 375. For a summary of most common dose schemes, see the Table. Conclusions: This report highlights support for ASTRO’s 2013 CHOOSING WISELY Campaign, and the willingness to use SF and HPF radiotherapy for PBM, within the VHA, though it reflected regional variations. Multiple Fractions Hypofractionated Single Fraction 300cGy x 10 400cGy x 5 800cGy x 1 Highest Regional Usage 62% (Region 4) 30% (Region 5) 30% (Region 5) Lowest Regional Usage 37% (Region 5) 13% (Region 4) 14% (Region 2) Highest VISN Usage 78% (VISN 1) 45% (VISNs 4 & 12) 80% (VISN 20) Lowest VISN Usage 0% (VISN 20) 0% (VISNs 5 & 22) 0% (VISNs 1 & 23)
P01.094 Hypofractionnated Stereotactic Radiation Therapy and Durvalumab combination in recurrent Glioblastoma (GBM): Results of the phase I part of the phase I/II STERIMGLI trial
Authors: D Larrieu-Ciron, G Peyraga, D Pouessel, A Mervoyer, B Cabarrou, J Attal, M Robert, P Olivier, M Mounier, E Cohen-Jonathan Moyal
Journal: Neuro-Oncology (2018)

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. Survival data in GBM are correlated with systematic local relapse, whose management is not standardized. Several treatments can be discussed in recurrent GBM, including re-irradiation. Hypofractionated Stereotactic Radiation Therapy (hFSRT) has shown efficacy and safety in recurrent GBM (PFS from 3.4 to 5 months), but needs improvement. Pre-clinical studies have assessed the combination of hFSRT with anti-PD-1 antibody in newly diagnosed GBM with significant efficacy. We hypothesized that the combination of a checkpoint inhibitor with high-dose RT can improve survival for patients with recurrent GBM. Thus, we performed a national, multicenter, open-label phase I/II trial to assess the combination of hFSRT with anti-PD-L1 Durvalumab (Durva) for unifocal recurrent GBM (size ≤ 35 mm). We present the results of the bi-centric phase I. A standard 3 + 3 dose-escalation design was performed. Patients were treated by hFSRT in 3 fractions (8 Gy per fraction at 80% isodose, for a total dose of 24 Gy) on Day 1, 3 and 5. Durva infusion 1500 mg first dose (Level 1) or 750 mg (Level -1) started on the last day of hFSRT (Day 5). Then, 1500 mg Durva were delivered every 4 weeks until relapse (for a maximum of 12 months). The combination was defined as safe if 1 patient or less among 6 present a dose-limiting toxicity (DLT) within the first 4 weeks after RT. Secondary objectives included intracranial PFS and OS. Brain MRI, Quality of Life and Neuro-Cognition Tests were performed before RT and then every 8 weeks until relapse. All of the 6 patients included at the Level 1 completed the hFSRT course. Four patients presented adverse effects (any grade). Only 1 presented a DLT (immune related grade 3 vestibular neuritis), with a distant response observed (Durva efficacy or abscopal effect). No DLT related to hSFRT or combination of Durva and hFSRT was reported. Neither serious adverse event nor immune-related adverse event of special interest was reported during DLT period. Complete results (intracranial PFS, OS) are currently being analysed. The combination of hFSRT (24 Gy, 3x8 Gy on Day 1, 3, and 5) with Durvalumab (1500 mg) on the third fraction of hFSRT (Day 5) and then every 4 weeks for recurrent GBM is well tolerated. Complete phase I results will be presented. Multicentric phase II study is ongoing.
Cancer drug assessment: What is driving high clinical added value in France?
Authors: Judith Fernandez, Mathilde Grande, Bachir Dahmani, Sorin Stanel, Margaret Galbraith, Nicolas Albin, Chantal Belorgey, Loic Guillevin, Anne d'Andon
Journal: Journal of Clinical Oncology (2017)

6526 Background: Concerns about the increase of cancer drug prices emphasized the need to base pricing decisions on clinical added value (CAV). In France, the CAV assessment is done by the National Authority for Health (HAS) on a 5-point scale based on clinical data. The magnitude of the CAV is partly used by the economic committee for healthcare products to determine drugs prices: a major to moderate CAV leads to the highest prices. Recognizing the importance of presenting clear statements, we analyzed which criteria are taking into account for CAV appraisal. Methods: A retrospective and descriptive study analysis of all new hematology/oncology cancer indications assessed by HAS between 2010 and 2015 has been conducted. For each appraisal, information regarding the level of evidence and clinical effect has been collected. Results: 78 new cancer indications (58 drugs) have been assessed: 20 had a major to moderate CAV (25%), 32 a minor CAV (41%) and 26 no CAV (33%). The percentage of major to moderate CAV was higher when a comparative pivotal trial was conducted (25%, 16/62 vs. 20%, 4/16). Among the 62 comparative trials, 58 had a superiority design (94%) supporting a major to moderate CAV in 27% (16/58) of the cases. Overall survival (OS) was measured in 91% of the pivotal trials (n = 71) and in 24% (n = 19) as a primary outcome. A higher proportion of major to moderate CAV were observed in trials using OS as a primary endpoint (31%, 6/19) than progression free survival (PFS) (23%, 9/39) or response rate (25%, 5/20).When a major to moderate CAV was obtained, a median absolute gain of 4 and 8 months for OS and PFS respectively were observed. All non-inferiority or non-conclusive designs led to no or minor CAV whatever the quantity of clinical effect. Conclusions: CAV is assessed in a two-step process where clinical effect is taken into account when level of evidence is appropriate. Consequently, there is not a unique profile of outcomes supporting a major to moderate CAV but a combination of several key elements such as study design, primary endpoint, and statistical significance. HAS appraisals remain multi-factorial, and medical need add a nuance to HAS expectations in terms of level of evidence.
Early rebiopsy to identify mechanisms and biomarkers of tumor cell survival following epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy.
Authors: Caroline Elizabeth McCoach, Dan Merrick, Dara L. Aisner, Paul A. Bunn, D. Ross Camidge, Dexiang Gao, Kimi Kondo, Robert Charles Doebele
Journal: Journal of Clinical Oncology (2017)

TPS9100 Background: Significant advances in the clinical outcomes of lung cancer patients have been achieved in part due to the identification of targetable driver mutations. The success of targeting oncogenic drivers with TKIs has allowed for improvements in response rates, progression free survival and overall survival. Despite these improvements, patients ultimately relapse. Acquired resistance has been evaluated in post-progression tumor samples and is caused by a variety of mechanisms including secondary resistance mutations, gene copy number gains, gene amplification, or bypass pathway activation. Residual tumor burden with surviving cancer cells are the origin of the ultimate tumor progression. Studies analyzing signaling pathways and other markers of these tumor cells or microenvironmental cells in tumor samples before clinical resistance develops are needed to determine how best to target this compartment. Methods: Eligible patients will have a new diagnosis of advanced NSCLC with an EGFR TKI sensitizing mutation. Additional inclusion criteria include ECOG 0-2, a tumor measurable by RECIST 1.1 and at least 2cm in one dimension, and tumor site that is accessible and safe to biopsy. Patients will undergo a pretreatment target lesion biopsy, begin treatment with an EGFR TKI then receive a second biopsy of the same target lesion after two weeks of therapy. Our primary objective is to identify differences between pretreatment and early treatment tumor samples. To do this we will be using a combination of RNA seq, multiplex protein expression analysis and proximity ligation assays. Secondary objectives include identification of predictive markers that can be used to determine which tumors will undergo epithelial to mesenchymal transition or activate other survival pathways and determination of the success rate and adverse event rate of repeat biopsy. Patients are currently being enrolled at a single academic institution however, additional clinical site openings are pending. Our goal enrollment for this study is 47 patients to achieve 20 paired biopsy samples. We will present updated enrollment and demographic information. Clinical trial information: NCT03042221.
TCT-771 Temporal Trends in Risk Profiles of Patients Receiving Percutaneous Coronary Intervention and Coronary Artery Bypass Grafting: Insights from the Washington State Clinical Outcomes Assessment Program (COAP)
Authors: Akash Kataruka, Charles Maynard, Kathleen Kearney, Sean Bell, James McCabe, Jacob Doll, Ravi Hira
Journal: Journal of the American College of Cardiology (2018)
A phase 1 multicenter, open-label, dose-escalation and dose-expansion study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity, and antitumor activity of MEDI7247 in patients with select relapsed/refractory hematologic malignancies.
Authors: Amir Tahmasb Fathi, William Bruce Donnellan, Roger M. Lyons, Michael B. Maris, Tae Min Kim, Won Seog Kim, Gary J. Schiller, Camille N. Abboud, Martha Lucia Arellano, Elizabeth H. Cull, Karen W. L. Yee, Danielle Michelle Townsley, Fujun Wang, John G. Bothos, Nai-Shun Yao, Gilles A. Salles
Journal: Journal of Clinical Oncology (2018)

TPS2603 Background: Survival outcomes in patients with relapsed/refractory multiple myeloma (MM), acute myeloid leukemia (AML), or diffuse large B-cell lymphoma (DLBCL) remains poor, and there is a high unmet need for new therapeutic options in these patient populations. MEDI7247 is a first-in-class antibody-drug conjugate consisting of an anti–Na+-dependent alanine-serine-cysteine transporter 2 (ASCT2) monoclonal antibody, site-specifically conjugated to highly cytotoxic DNA cross-linking pyrrolobenzodiazepine (PBD) dimers (drug-to-antibody ratio of close to 2) via a protease-cleavable linker. ASCT2 is overexpressed in a broad range of solid tumors and hematologic malignancies (e.g. MM, AML, and DLBCL), and has low expression in normal tissues. MEDI7247 has demonstrated potent and specific in vitro and in vivo antitumor activity in a variety of preclinical models with varying levels of ASCT2 expression. Methods: This is a first-in-human, phase 1, multicenter, open-label, dose-escalation and dose-expansion study in patients with selected hematologic malignancies (MM, AML, and DLBCL) who have relapsed after, or are refractory to prior standard therapy, and for whom there is no standard salvage regimen available (NCT03106428). The primary objectives are to assess safety and tolerability, describe dose-limiting toxicities, and determine the maximum tolerated dose or a recommended dose of MEDI7247. The secondary objectives are to evaluate the antitumor activity (best overall response, objective response rate, time to response, duration of response, progression-free survival, and overall survival as defined in the relevant response criteria), pharmacokinetics, and immunogenicity of MEDI7247. Recruitment is ongoing for this study; as of February 6, 2018, 19 patients have been enrolled (AML, n = 11; DLBCL, n = 6; MM, n = 2) with a target enrollment of up to 228 patients. Clinical trial information: NCT03106428.
THU0369 Creation of a weighted slicc sle classification criteria and comparison with proposed eular/acr sle classification criteria
Authors: M. Petri, D.W. Goldman, L.S. Magder
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> In previous validation work, the SLICC 2012 SLE classification criteria were more sensitive than the revised ACR-11 criteria, while both criteria had similar agreement with physician diagnoses. Both of these classification rules count each SLE manifestation equally. <h3>Objectives</h3> Our objective was to derive and test a classification rule which differentially weights the variable used in the SLICC classification rule. We also compared this rule to a recently proposed EULAR/ACR classification rule that also uses a weighted approach. <h3>Methods</h3> The physician-rated patient scenarios used to develop the 2012 SLICC classification criteria were re-employed to devise a weighted classification rule. A multiple linear regression model was constructed with the 2012 SLICC criteria variables as predictors and the binary outcome (physician classification of SLE) as the outcome. To generate the weights for each criteria, we then multiplied each criteria’s coefficient by 100 and rounded to the nearest integer. The ‘Direct Coombs’ criteria (coefficient &lt;1) was deleted for simplicity. The weights for the remaining manifestations were: acute cutaneous,26 chronic cutaneous,12 oral ulcers,<sup><sup>16</sup></sup> arthritis,<sup><sup>9</sup></sup> serositis,<sup><sup>16</sup></sup> renal without biopsy,<sup><sup>9</sup></sup> neurologic,<sup><sup>9</sup></sup> hemolytic anaemia,<sup><sup>1</sup></sup> leukopenia or lymphopenia,<sup><sup>14</sup></sup> thrombocytopenia,<sup><sup>15</sup></sup> alopecia,<sup><sup>9</sup></sup> ANA,<sup><sup>17</sup></sup> anti-dsDNA,<sup><sup>19</sup></sup> anti-Sm,<sup><sup>16</sup></sup> antiphospholipid antibodies,<sup><sup>8</sup></sup> low complement.<sup><sup>11</sup></sup> A cutoff for classification was chosen as the score that maximised overall agreement (i.e., the sum of sensitivity and specificity) of the new weighted criteria with physician diagnosis. Patients with lupus nephritis or the new weighted classification rule of 56 or more with at least one clinical component and one immunologic component were classified as SLE. We evaluated the performance of this revised SLICC criteria, on an independent set of patient scenarios, and compared this to the performance of the older revised ACR criteria, the previous <sup><sup>SLICC 2012</sup></sup> criteria, and the newly proposed EULAR/ACR criteria. <h3>Results</h3> Table 1 shows the performance of the four classification rules. There was no statistically significant difference (at the 0.05-level) between any pair of rules with respect to overall agreement with the physician diagnosis. <h3>Conclusions</h3> The two newly derived weighted classification rules did not perform better than the existing list-based rules in terms of over-all agreement. Given that the list-based rules are easy to calculate, they may be preferred in most clinical settings. <h3>Disclosure of Interest</h3> None declared
TCT-302 A simple CHA2DS2-VASc derived score for assessing long-term prognosis in STEMI patients (cardioCHUS STEMI registry)
Authors: Alfredo Redondo Diéguez, Ana Belen Cid Alvarez, Fernando Gómez Peña, Alejandro Avila Carrillo, Diego Lopez Otero, Ramiro Trillo
Journal: Journal of the American College of Cardiology (2018)