tbuckley/cabot-search huggingface dataset:
IgM anti-glycan antibodies in sera of colorectal cancer patients
Authors: A.A. Tikhonov, M. Chernichenko, V. Butvilovskaya, D. Sidorov, A. Rubina
Journal: Annals of Oncology (2018)

Background: Colorectal cancer (CRC) is diagnosed too late due to the almost asymptomatic course of the disease. Many issues of diagnosis, prognosis and predicting of the treatment efficiency have not yet been resolved. The search and validation of new reliable molecular markers of CRC are still relevant. The aim of this study is to analyze the levels of anti-glycan antibodies in the sera of CRC patients and healthy donors. Methods: Sera from 44 patients with CRC (15 with rectal cancer,16 with right-sided and 13 with left-sided colon cancer) and 53 healthy donors were analyzed using hydrogel glycan microarrays. Microarrays were manufactured according to the technology developed in EIMB RAS. Evaluation of expression levels of IgM antibodies to glycans was carried out using a fluorescent sandwich immunoassay. Statistical significance of the differences between groups was estimated according to the results of Kruskal-Wallis test. Results: The levels of IgM antibodies to the panel of immobilized glycans were measured in serum samples. It was shown that IgM antibody levels to 9 glycans - di-GalNAcβ, Manα1-4Manβ, 3'-sialyl-TF, 6-Su-6'-SiaLec, 3,6-SiaTn, SiaLea, Zymosan A, Zymosan, Lea - differed in healthy donors and in patients with rectal cancer (p < 0.01). Levels of IgM antibodies to di-GalNAcβ were found to be significantly different between patients with right-sided tumors and patients with rectal cancer, to 3,6-SiaTn - between patients with left-sided tumors and patients with rectal cancer, and to glycan Zymosan in all three groups of patients. The levels of IgM antibodies to the 5 glycans - 3'-sialyl-TF, 6-Su-6'-SiaLec, 3,6-SiaTn, Sia6H (type2) and Zymosan A - differed between healthy donors and CRC patients with moderately differentiated adenocarcinomas (p < 0.01). The level of IgM antibodies to glycan 3'-O-su-Lea was significantly different between patients with and without regional metastases (p < 0.01). Conclusions: Median IgM antibody levels to the number of glycans vary between groups of patients with different tumor locations and with different tumor grades. Significant difference for 3'-O-su-Lea IgM antibodies among CRC patients indicates its possible role as a marker of regional metastases. Legal entity responsible for the study: P. A. Hertsen Moscow Oncology Research Center - branch of FSBI NMRRC of the Ministry of Health of Russia, Moscow Russian Federation. Funding: Program of fundamental research for state academies for the period 2013 - 2020 (subprogram #0103-2014-003). Disclosure: All authors have declared no conflicts of interest.
Activation of protein phosphatase 1 by a selective phosphatase disrupting peptide reduces sarcoplasmic reticulum Ca<sup>2+</sup> leak in human heart failure
Authors: Thomas H. Fischer, Jörg Eiringhaus, Nataliya Dybkova, Alireza Saadatmand, Steffen Pabel, Silvio Weber, Yansong Wang, Maja Köhn, Theodor Tirilomis, Senka Ljubojevic, André Renner, Jan Gummert, Lars S. Maier, Gerd Hasenfuß, Ali El‐Armouche, Samuel Sossalla
Journal: European Journal of Heart Failure (2018)
TCT-221 Comparison of Transfemoral Transcatheter Aortic Valve Replacement Performed With a Simplified Protocol: “FAST-TAVR” Versus Standard Approach.
Authors: Grégoire Lefèvre, Arnaud Jégou, Grégoire Dambrin, Xavier Favereau, Fabien Picard
Journal: Journal of the American College of Cardiology (2018)
Progress in record numbers of approved therapies for gynecologic cancers: The lack of upfront approval for newly diagnosed cases.
Authors: Alisa Goldrich, Idoroenyi Usua Amanam, Amandeep Mann, Daniel Stuart Kapp, Bradley J. Monk, John K. Chan
Journal: Journal of Clinical Oncology (2018)

e14551 Background: To determine progress in FDA approved drugs for cancer therapies in over the past 12 years. Methods: Data from all approved oncologic or malignant hematologic indications were obtained from the FDA between 2006 and 2017. Results: Of 186 FDA approved oncologic New Drug and Biologic License Applications, 68% (n = 127) for solid and 32% (n = 59) liquid tumors. Based on the classes of drugs, 69 were small molecule, 67 monoclonal antibodies, 36 cytotoxics, 31 immunotherapies, 3 antibody drug conjugates, 5 hormones, 2 were others. 12% (n = 22) were for female cancers and 3% (n = 5) were for male cancers. To evaluate trends, we divided the study into three time periods based on the year of submission: 2006–2009, 2010–2013, and 2014–2017 and showed that the number of drugs approved increased from 44 (24%), 59 (32%), and 83 (45%) respectively. Drugs approved for female cancers increased from 6(27%), 7(32%), and 9(41%). Based on class of drug, there was an increase in small molecules (12 to 27 to 30) and monoclonal antibodies (12 to 11 to 17), immunotherapeutics (2 to 4 to 25) with corresponding decrease in chemotherapies (16 to 11 to 9) (p < 0.001). Over the three time periods, 2, 1, and 5 drugs were approved for gynecologic cancers; including 2 (topotecan and gemcitabine combination for cervix), 1 (liposomal doxorubicin generic for ovary), and 5 (bevacizumab for cervix, recurrent ovary, olaparib for recurrent and maintenance ovary, rucaparib for recurrent ovary, niraparib for maintenance ovary, and pembrolizumab for MSI positive uterine cancer). Although there is a significant increase in the new drug licenses with 8 new indications over the last 3 years, these approvals have been restricted to those with metastatic, recurrent, refractory, and biomarker only and after multiple failed lines of therapies. In fact, there were no approvals for gynecologic cancers in the upfront and setting, whereas 3 of 14 (21%) of breast cancer approvals were newly diagnosed disease. Conclusions: The FDA approval of new drugs and indications for gynecologic cancers have increased significantly over time; however, novel treatment are warranted for those with upfront and newly diagnosed cancers
Role of periodontal therapy in management of common complex systemic diseases and conditions: An update
Authors: Amarpreet Sabharwal, Isaac S. Gomes‐Filho, Elizabeth Stellrecht, Frank A. Scannapieco
Journal: Periodontology 2000 (2018)

The goal of this review is to summarize the results of randomized trials reported since 2010 that assessed the effect of periodontal interventions on at least one systemic outcome in human subjects of any age, gender or ethnicity. Oral outcome measures included gingivitis, pocket depth, clinical attachment loss and/or radiographic bone loss and oral hygiene indices. Studies were excluded if the trial was not completed or if treatment was not randomized. The results suggest that nonsurgical periodontal intervention provided to pregnant women is safe and improves periodontal status without preventing adverse pregnancy outcomes. Nonsurgical periodontal intervention was also found to provide modest improvement in glycemic control in individuals with type 2 diabetes mellitus and periodontitis. Also, improving oral care through mechanical or chemical control of dental-plaque biofilm formation can contribute to the prevention of respiratory infections in differing clinical settings, including hospitals and nursing homes, and in patients with chronic obstructive pulmonary disease. No clinical trials were reported that tested the effect of periodontal interventions on medical outcomes of atherosclerosis, cardiovascular diseases, stroke, rheumatoid arthritis, Alzheimer's disease, chronic kidney disease or malignant neoplasia.
Characteristics and outcomes of patients (pts) with metastatic KRAS mutant lung adenocarcinomas: Lung Cancer Mutation Consortium (LCMC) database.
Authors: Badi Edmond El Osta, Madhusmita Behera, Sungjin Kim, Lynne D Berry, Gabriel Sica, Rathi Narayana Pillai, Taofeek Kunle Owonikoko, Mark G. Kris, Bruce E. Johnson, David J. Kwiatkowski, Paul A. Bunn, Fadlo Raja Khuri, Suresh S. Ramalingam
Journal: Journal of Clinical Oncology (2017)

9021 Background: To better understand outcome heterogeneity in pts with KRAS mutant lung cancers, we analyzed the largest multi-institutional database of pts with metastatic KRAS mutant lung adenocarcinomas. Methods: We reviewed data of all pts who consented to LCMC between 2009-2015. Pts with known KRAS status were included in analyses. Mutation data along with co-mutations were obtained along with clinical outcomes. We evaluated baseline characteristics and association of KRAS data with overall survival (OS), calculated from date of distant metastasis to death, in a univariate and multivariable analyses. The median follow-up was 2.15 years (95% CI: 2.01-2.27). Results: 1655 (86%) of 1918 pts’ data were analyzed. Comparative characteristics are summarized in the Table. Among 450 (23%) pts with KRAS mutations: 58% female, 93% ever smokers, and median age 65 years. Main KRAS subtypes: G12C 39%, G12D and G12V were 18% each. Never smokers with KRAS mutation were more likely to have G12D subtypes (18%; p &lt; 0.001). Pts with KRAS mutation, the median OS was 1.96 years, with 2-year OS rate of 49%. Co-mutations (1-16) were checked in all KRAS mutant pts. Co-mutations were rare (14 pts; 3%). KRAS co-mutations were associated with improved OS in multivariable analyses (HR 0.35; 95% CI: 0.13-0.97; p = 0.04), but not KRAS main subtypes / codons. Co-mutation STK-11 in particular (17 of 92 pts; 18%) was associated with poor OS in univariate (HR 2.16; 95% CI: 1.03-4.54; p = 0.04) and multivariable analyses (HR 2.31; 95% CI: 1.18-5.50; p = 0.02). Pts with KRAS mutations had a trend towards a shorter survival (median OS 1.96 vs. 2.22 years; p = 0.08) and a decreased 2-year OS when compared to KRAS wildtype [49% (95% CI: 44-54%) vs. 55% (95% CI: 52-58%)], respectively. Conclusions: KRAS mutation is a significant predictor of worse survival outcomes in pts with metastatic lung adenocarcinomas. The presence of STK-11 co-mutation was associated with especially poor OS. [Table: see text]
Biomarkers associated with neurotoxicity in adult patients with relapsed or refractory B-ALL (R/R B-ALL) treated with CD19 CAR T cells.
Authors: Bianca Santomasso, Jae Hong Park, Isabelle Riviere, Elena Mead, Elizabeth Halton, Claudia Diamonte, Terence Purdon, Brigitte Senechal, Daniel Li, Michel Sadelain, Renier J. Brentjens
Journal: Journal of Clinical Oncology (2017)

3019 Background: CD19-specific chimeric antigen receptor (CAR) modified T cells produce high and durable anti-tumor activity, but can be associated with treatment-related toxicities including cytokine release syndrome (CRS) and neurotoxicity (NTX). NTX is poorly understood and it hasn't been clear where to focus further research. We report cerebrospinal fluid (CSF) data and neuroimaging characteristics of patients (pts) who developed severe NTX (sNTX) during our phase I clinical trial of CD19-specific 19-28z CAR T cells for adult pts with R/R B-ALL, which suggest new avenues for future research. Methods: 51 adult pts with R/R B-ALL were treated with 19-28z CAR T cells following conditioning chemotherapy at MSKCC. We analyzed the incidence and grade of NTX, CRS and correlative biomarkers in blood and CSF. Results: 21/51 treated pts developed sNTX (grade ≥3) complications such as encephalopathy, aphasia, depressed level of consciousness, myoclonus, and seizure. No pt developed grade 5 NTX and, in all but one case, neurologic symptoms fully resolved. We collected CSF by lumbar puncture and blood from 14 pts at the time of peak NTX. sNTX was correlated with pre-infusion disease burden (p = 0.013) and peak CAR T cell expansion in the blood (p = 0.0001), but we found no significant correlation between NTX grade and the CAR T cell concentration in the CSF during NTX. Instead CSF protein level was correlated with neurotoxicity grade (p = 0.0109). The cytokines IL6, IL8, IL10, IFNγ and GCSF were elevated in CSF over serum at the time of NTX and correlated with CSF protein levels (all p &lt; 0.005). These were distinct from serum cytokines significantly associated with sNTX at d3 of T cell infusion: GMCSF, IFNγ, IL15, IL5, IL10, and IL2 (all p &lt; 0.01). 4/21 patients developed a pattern of reversible MRI T2/FLAIR hyperintensity involving the bilateral thalami, dorsal pons, and medulla. Conclusions: NTX is predominantly reversible. MRI findings suggesting transient toxicity to deep grey structures and findings of a CSF-specific cytokine profile expand the hypotheses on the mechanism of NTX. Future studies will focus on determining the etiology of the CSF protein elevation and the distinct cytokine profile. Clinical trial information: NCT01044069.
Dose expansion cohort of a phase I trial of M6620 (formerly VX-970), a first-in-class ATR inhibitor, combined with gemcitabine (Gem) in patients (pts) with advanced non-small cell lung cancer (NSCLC).
Authors: Elizabeth Ruth Plummer, Natalie Cook, Hendrik-Tobias Arkenau, Jason M. Melear, Charles H. Redfern, Alexander I. Spira, Ki Y. Chung, Geoffrey Shapiro, Tufia C. Haddad, Suresh S. Ramalingam, Robert Wesolowski, Thomas Goddemeier, Martin H. Falk, Emma Dean
Journal: Journal of Clinical Oncology (2018)

e21048 Background: Ataxia telangiectasia and Rad3-related protein (ATR) is an essential regulator of the DNA damage response and is required for the survival of proliferating cells. DNA-damaging agents often induce replicative stress leading to activation and reliance on ATR. Thus, inhibition of ATR signalling is considered an attractive strategy to sensitize tumors to DNA-damaging chemotherapy. M6620 is a potent, selective inhibitor of ATR with preclinical anticancer activity in combination with DNA-damaging chemotherapy. Here, we report data for a dose expansion cohort of a phase I trial of M6620 combined with Gem in pts with advanced NSCLC (NCT02157792). Methods: Eligible pts had measurable (RECIST 1.1) advanced NSCLC and had received up to 2 lines of therapy, with one containing a platinum analog. Of 40 pts planned for enrollment, ≥20 had to have a TP53 mutation (TP53+), ≤10 ATM loss of expression (ATM–) (both alterations associated with sensitivity to ATR inhibitors in preclinical studies), and ≈10 neither TP53+ nor ATM–; status determined using fresh or archival tissue. Pts received Gem 1,000 mg/m2 on days 1 + 8 and M6620 210 mg/m2 on days 2 + 9 of each 21-day cycle. The primary endpoints were safety and overall response rate (ORR). Results: 33 pts received ≥1 dose of therapy and were included in the safety set (female, 18; median age, 62.0 years [range 36–76]; TP53+, 19; WHO PS 0/1, 9/23). 31/33 pts had a treatment-emergent adverse event (TEAE), with 19 (57.6%) having grade ≥3 TEAEs: fatigue (n = 6), neutropenia (4), anemia (3), thrombocytopenia (3), malaise (2), vomiting (2), ALT increase (2), AST increase (2), pneumonia (2), sepsis (2) (grade ≥3 TEAES occurring in ≥2 pts). Of the 24 pts who had received ≥1 dose of therapy and had baseline and on-treatment assessments, 3 pts had a PR (ORR 12.5%) and 18 pts had SD. Four pts had PR or SD for ≥6 months (clinical benefit rate 16.7%). Conclusions: The ATR inhibitor M6620 combined with Gem showed signs of activity in advanced NSCLC; tolerability was acceptable. Clinical trial information: NCT02157792.
Thirty-year analysis of randomized clinical trials in patients with acute myeloid leukemia.
Authors: Sagar Suresh Patel, Tomas Radivoyevitch, Aaron Thomas Gerds, Navneet S. Majhail, Hetty Carraway, Anjali S. Advani, Aziz Nazha, Jaroslaw P. Maciejewski, Matt E. Kalaycio, Mikkael A. Sekeres, Sudipto Mukherjee
Journal: Journal of Clinical Oncology (2016)

7032 Background: Population-based registries have reported improvements in overall survival (OS) for patients (pts) with acute myeloid leukemia (AML) receiving intensive chemotherapy (IC). In this study, we analyzed the contribution of experimental IC regimens to improved outcomes in AML pts over time. Methods: Cochrane Controlled Trials Register, Medline, Embase databases and conference abstracts were searched for adult AML trials from 1985 to 2015. Analyses were restricted to phase 3 RCTs using IC regimens; excluding acute promyelocytic leukemia. Complete response (CR), leukemia-free survival (LFS), and OS in the experimental arms (EAs) and control arms (CAs) were evaluated. Outcomes were stratified by age, younger or older based on whether > 65% of the pts in a study were < 60 or ≥ 60 years, respectively and by cytogenetic risk. Median OS of RCT pts was compared to 61000 pts from the Surveillance, Epidemiology, and End Results (SEER) registry. Results: 70 studies comprising 36429 AML pts were included. CR rates in EAs and CAs did not improve significantly in younger or older pts or in any cytogenetic risk groups over the study period. No significant change in LFS rates were observed over time in the EAs and CAs in both younger and older pts. Over 30 years, the median OS increased for younger pts in EAs at a rate of 29.52 days/yr (d/yr) (6.84-51.84; p = 0.012), but did not reach statistical significance for older pts (13.68 d/yr; 1.8-25.92; p = .03). For those in CAs, the corresponding rates for younger and older pts was 32.76 d/yr (8.64-56.88; p = 0.009) and 12.24 d/yr (2.88-27.93; p = .10), respectively. By comparison, the improvement in median OS over time in SEER cohort, was much less steep in both younger (18.36 d/yr; 30-212.4, p < .0001) and older pts (0.36 d/yr; 0.36-0.72, p = .003). Conclusions: Over the last 30 years, experimental therapies in AML have contributed minimally to improving OS, mostly in younger pts. No significant increment in LFS rates were observed in any age group, demonstrating a disappointing lack of clinical efficacy of EAs. Higher gains in OS for RCT pts in CA arms compared to SEER, indicates a divergence between controls and the general population, possibly due to increasing bias in the selection of controls for RCTs over time.
Management of patients with metastatic melanoma in the cancer immunotherapy era: A simulation-based assessment of medical oncologists.
Authors: Tara Herrmann, Douglas Blevins, Martin Warters
Journal: Journal of Clinical Oncology (2018)

e21512 Background: The past few years have seen a number of changes in standards of care for metastatic melanoma, challenging clinicians to integrate new treatment paradigms into practice. Methods: CME developed in the format of a virtual patient simulation (VPS) was made available via a website dedicated to continuous professional development. The VPS consisted of 2 cases presented in a platform that allowed oncologists to assess the patient and choose from an extensive database of diagnostic and treatment possibilities matching the scope and depth of practice. Clinical decisions made by participants were analyzed using a sophisticated decision engine, and instantaneous clinical guidance (CG) employing the current evidence-base and expert faculty recommendations was provided immediately after each decision. Oncologists were allowed a second chance at each decision point post-CG. Data were collected between 11/22/2016 and 1/29/2017. Results: 152 oncologists fulfilled the participation criteria for completing the simulation. Assessment of their practice prior to CG revealed: In a patient with newly diagnosed metastatic melanoma, 25% of oncologists did not order BRAF mutational testing. Moreover, only 31% ordered an appropriate cancer immunotherapy regimen. 10% of oncologists continued to order ipilimumab. In a patient with BRAF-mutated metastatic melanoma who has progressed on BRAF/MEK inhibitor combination, 22% did not discontinue the regimen. Almost 40% of oncologists prescribed a PD-1/CTLA-4 inhibitor regimen while 23% ordered a PD-1 inhibitor. Like in the previous case, 10% selected ipilimumab. Conclusions: Despite BRAF mutational testing being a critical element for selecting the most appropriate regimen for patients with metastatic melanoma, many oncologists fail to test. In addition, there appears to be confusion about how best to use the immune checkpoint inhibitors in this patient population. Our findings demonstrate a continued need to educate oncologists about how to select and prescribe the most appropriate regimen for a patient with metastatic melanoma.
Gastrointestinal (GI) cancer (CA) drugs approved by the US Food and Drug Administration (FDA): Clinical value and cost considerations.
Authors: Di Maria Jiang, Raymond Woo-Jun Jang, Kelvin K. Chan, Geoffrey Liu, Eitan Amir, Elena Elimova
Journal: Journal of Clinical Oncology (2018)

6619 Background: The mounting cost of CA drugs has presented significant financial toxicity to all stakeholders over recent years. We aimed to assess the clinical value and cost of GI CA drugs approved by the FDA. Methods: Approved GI CA drugs between 2006 and 2017 listed on fda.gov and their updated supporting data were identified. Clinical benefit was quantified by ASCO Value Framework v2 2016 (range < 180) and ESMO Magnitude of Clinical Benefit Scale (MCBS) v1.1 2017 (range 1-5). Higher scores indicate larger net benefit. Substantial benefit was defined as grade 4/5 by ESMO. For EGFR inhibitor outcomes, only patients with wild-type KRAS were assessed. Preliminary data presented on fda.gov were used if trial data is unpublished. Toxicity was omitted if unavailable. The Micromedex REDBOOK was used to estimate the total drug cost for each new agent, based on 2018 average wholesale prices for median treatment durations (or progression-free survival if unavailable). Results: Five monoclonal antibodies (Mab), 5 targeted therapies (TT), 1 recombinant fusion protein, 3 cytotoxic (CT) and 2 immunotherapy (IO) agents received approval for metastatic GI CA. Median ASCO scores/drug cost in USD per patient were 36/$65,310 (Mab), 38/$153,402 (TT), 55/$30,329 (CT) and 21/$78,864 (IO). Selected scores and drug costs are presented (Table). Only cetuximab for refractory colorectal CA (CRC) met the ESMO benefit threshold. pNET: pancreatic neuroendocrine tumor; HCC: hepatocellular carcinoma; PDAC: pancreatic ductal adenocarcinoma; MSI-H: microsatellite instability-high Conclusions: Although beneficial, most FDA-approved GI CA drugs met neither the ESMO definition of substantial improvement in benefit nor have a high ASCO value score, and incur considerable costs. CA Treatment Line Approved Drug ASCO value score ESMO MCBS Total Drug cost (USD) per patient CRC ≥3 Cetuximab 72 5 44,132 Panitumumab 2 1 23,939 pNET ≥1 Everolimus 1 2 153,402 Sunitinib 38 3 200,610 HCC 1 Sorafenib 46 2 110,050 2 Regorafenib 35 3 56,252 PDAC 1 Abraxane 62 1 38,171 2 Nal-irinotecan 55 2 26,182 MSI-H ≥2 Nivolumab 44 3 98,208 ≥3 Pembrolizumab 28 2 216,952