tbuckley/cabot-search huggingface dataset:
Anticancer applications of allosteric inhibitors of proteasome.
Authors: Pawel A. Osmulski, Jodie Cropper, Matt Giletto, Corey Jones, Caleb Killer, Shoulei Jiang, Jetze Tepe, Bandana Chatterjee, Tim Huang, Maria E Gaczynska
Journal: Journal of Clinical Oncology (2017)

e23066 Background: Proteasome as a hub protease of the ubiquitin proteasome pathway is an established anticancer drug target. Several drugs that inhibit proteasome are currently used to successfully treat aggressive blood cancers. These drugs are based on their competition with protein substrates of proteasome. However, efficacy of these drugs toward solid cancers is inadequate. Besides, the side effects and developing drug resistance are increasingly hampering the therapy. Therefore, there is an unmet challenge to develop new types of proteasome targeting compounds that are efficient against solid cancers and utilize other mechanisms to stop proteasome. Here we present a compound with a novel molecular mechanism, potentially bypassing limitations of the available drugs. Methods: We rationally designed and synthesized a series of small molecule “B” compounds, derivatives of a binding domain of seco-rapamycin that noncompetitively interfere with peptidase activities of proteasome. We tested effects of the compounds in vitro on purified proteasome, in cellulo with selected cancer cell lines and in a xenograft mouse model of prostate cancer. Results: We found that compound B1 binds to the catalytic core of proteasome far from the catalytic sites, destabilizes assembly of the 26S proteasome responsible for digest of polyUb substrates and allosterically inhibits its proteolytic activities. Molecularly, B1 impedes the gating mechanism responsible for substrate uptake as found with AFM. Tryptophan fluorescence indicates that B1 changes proteasome fold and the binding mode of competitive inhibitors. B1 substantially decreases viability of selected cancer cell lines and shifts their mechanical phenotype toward noncancerous status. B1 synergizes with bortezomib decreasing the IC50 5-10 fold. In a xenograft hormone resistant prostate cancer model, B1 treatment leads to shrinkage of the tumor size, decreases enumeration of aggressive, EpCAM+ CTCs and shifts the macrophage profile toward predator M1 type. Conclusions: B1 compounds constitute a new class of noncompetitive allosteric inhibitors of proteasome that could be useful to develop to treat aggressive prostate cancers alone or in synergy with competitive inhibitors.
Multicentric randomized phase II trial of gamma knife surgery (GKS) versus image-guided, intensity-modulated radiation therapy (IG-IMRT) in patients with sacrococcygeal chordoma.
Authors: Shun Lu, Jin Yi Lang, Weidong Wang, Mei Feng, Bingwen Zou, Xinhao Peng
Journal: Journal of Clinical Oncology (2017)

11033 Background: Chordoma is a rare slow-growing neoplasm arisen from cellular remnants of the notochord. About 30% occur in the sacrococcygeal region. Surgical resection is recommended treatment. Due to the high recurrence rate, adjuvant radiation therapy was suggested to receive as an effective method to improve local control rates. Methods: Thirty eight patients were pathologically diagnosed as non-metastatic sacrococcygeal chordoma from Aug. 2003 to May. 2015 were recruited retrospectively to analysis. All patients received surgical resection after diagnosed. Initial surgery included subtotal resection (24% of patients), and gross total resection (76% of patients). Among these patients, 25 patients treated with adjuvant IG-IMRT, while 13 patients treated GKS after surgical resection. The median follow-up was 40 months (range, 6–151 month) for all patients, The PTV of IG-IMRT group received total doses were 60 Gy (range, 56-74Gy), delivered with 2-2.2 Gy/fraction, while GKS group underwent a total of 6-8 sessions treatment. Results: For the IG-IMRT group and the GKS group, the 5-year overall survival and local control rates were 87.5% and 67.7%, respectively. And 5-year local control rates were 35% and 22.2%, respectively. In total, 18 patients progressed locally: 11 were in the IG-IMRT group and 7 in the GKS group. In comparison with GKS group, the IG-IMRT group has a better overall recurrence-free survival (p = 0.03), the significance remained after adjusted for surgery results, age and gender. Moreover, there is no significant difference of overall survival was found between these two groups. Conclusions: We report favorable local control and adverse event rates following IG-IMRT, and suggested IG-IMRT is the first choice of adjuvant radiation therapy for sacrococcygeal chordoma treatment.
Oral Rehydration Solution—An Essential Therapy for Childhood Gastroenteritis—Reply
Authors: Eric R. Coon, Ricardo A. Quinonez, Alan R. Schroeder
Journal: JAMA Pediatrics (2018)

In Reply We thank Guarino et al for highlighting the fact that acute gastroenteritis is a devastating disease in developing countries and that treatment with oral rehydration solution made from clean drinking water, salt, and sugar is life saving and inexpensive.
Elevated preoperative peripheral blood neutrophil-to-lymphocyte ratio to predict clinical outcome in patients with localized soft tissue sarcoma.
Authors: Jason Yongsheng Chan, Zewen Zhang, Winston Chew, Grace Fangmin Tan, Chloe Liwen Lim, Lingyue Zhou, Wei Lin Goh, Sathiyamoorthy Selvarajan, Kesavan Sittampalam, Francis Chin, Jonathan Yi Hui Teh, Mann Hong Tan, Khee Chee Soo, Melissa Teo, Farid Mohamad, Richard Hong Hui Quek
Journal: Journal of Clinical Oncology (2017)

11049 Background: Recent studies suggest that markers of systemic inflammation such as blood neutrophil-to-lymphocyte ratio (NLR) may be prognostic for various cancers, though its clinical utility has not been widely accepted. This study aims to investigate its clinical relevance in patients (pts) with soft tissue sarcoma (STS). Methods: Five hundred and twenty-nine pts with localized STS who had available pre-operative blood counts at the time of diagnosis were retrospectively examined. An optimal cutoff for high NLR ( &gt; 2.5) in predicting overall survival (OS) and relapse-free survival (RFS) in pts who underwent curative surgery (n = 473) was determined using receiver operating curve analyses. Cutoffs for platelet-lymphocyte ratios (PLR, &gt; 180) and lymphocyte-monocyte ratios (LMR, &lt; 3.6) were similarly obtained. Survival analysis was performed using the Kaplan-Meier method and multivariate Cox proportional models. Median follow-up was 40 months. Results: A high NLR was present in 311 (58.8%) pts, which was significantly associated with tumor grade ( p&lt; 0.0001), depth ( p= 0.003) and size &gt; 5 cm ( p= 0.0242), but not with age at diagnosis, sex or ethnicity. High NLR was associated with both worse OS (HR 1.78; 95%CI 1.28-2.47; p= 0.0005) and RFS (HR 1.54; 95%CI 1.17-2.03; p= 0.0019), as were age at diagnosis, tumor grade, size, PLR and LMR. In multivariate models adjusted for clinicopathological predictors of survival, only NLR, in addition to tumor grade and size, were independently associated with worse OS (HR 1.52; 95%CI 1.09-2.11; p= 0.0131) and RFS (HR 1.42; 95%CI 1.08-1.85; p= 0.0114). Analysis of survival according to American Joint Committee on Cancer (AJCC) stages subdivided as NLR-high and NLR-low revealed a significant worse prognosis for NLR-high subgroups ( p&lt; 0.0001), with a 2.2-fold and 1.5-fold higher risk of death within stages II (HR 2.20; 95%CI 1.20-4.01; p= 0.0103) and III (HR 1.55; 95%CI 1.01-2.37; p= 0.0459), respectively. Conclusions: High NLR is an independent marker of poor prognosis among pts with localized STS. Inclusion of NLR as a classifier into the AJCC staging of STS may improve estimation of survival.
Getting consistent results from comparative analysis of RNA_Seq data from single patients.
Authors: Holly Beale, Ellen Kephart, Lauren Sanders, Jacob Pfeil, Isabel Bjork, Sofie R. Salama, David Haussler, Olena Morozova
Journal: Journal of Clinical Oncology (2018)

e24194 Background: The Treehouse Childhood Cancer Initiative uses RNA-Seq to measure gene expression in tumors from kids with relapses to identify potentially druggable, activated pathways. RNA-Seq results are more consistent among samples that are more deeply sequenced, and measurements of highly expressed genes are more consistent than others. Methods: Data from eight deeply sequenced tumors (
A clinico-biological Risk Assessment Model for VTE in ambulatory patients with lung adenocarcinoma on chemotherapy issued from the ROADMAP study.
Authors: Grigoris Gerotziafas, Ilias Evmorfiadis, Paraskevi Boura, Patrick Van Dreden, Andriani Charpidou, Aurelie Rousseau, Annette K Larsen, Konstantinos N. Syrigos, Rabiatou Sangare, Ioannis Gkiozos, Ismail Elalamy
Journal: Journal of Clinical Oncology (2016)

e23271 Background: In ambulatory patients with advanced or metastatic stage of lung adenocarcinoma (LA) the risk of VTE increases during chemotherapy. but individual risk factors cannot identify patients at risk. The available RAM are not applicable in patients already on chemotherapy. The prospective longitudinal non interventional study ROADMAP was designed to elaborate a RAM for VTE specific for ambulatory patients with LA on chemotherapy. Methods: Patients with LA on chemotherapy were included and followed up at 3, 6 and 12 months. Documented symptomatic VTE was the end-point of the study. Blood samples were collected at inclusion and assessed for thrombin generation (TG) and procoagulant phospholipids (PPL-ct). Assays and reagents were from Diagnostic Stago (France). Multivariate analysis was performed and the RAM was developed using the logistic regression. Sensitivity, specificity and the predictive value of the RAM were calculated. The ROC Curve was plotted. Results: The study included 150 patients (mean age 65 years, 73% male). The LA diagnosis was done within 6 months before inclusion in 70% of them and 90% had advanced or metastatic disease at inclusion. In 85% of patients the ECOG performance status was < 3. In one year follow up 12 symptomatic VTE episodes occured (8%), 75% of which occurred within the 3 months from inclusion. The RAM includes the following variables: Recent hospitalisation, Time since diagnosis of the cancer, Mean Rate Index of TG and PPL-ct. The ROC analysis gave a AUC value of 0.84. The sensitivity of the RAM was 89% and the specificiy was 70%. The postive predictive value is 16% and the negative predictive value is 98% Conclusions: The new RAM for VTE is specific for ambulatory patients with LA on chemotherapy and can relibly predict VTE using simple clinical variables and biomarkers of hypercoagulability. This RAM can be used by physitians for the identification of ambulatory lung cancer patients eligible for thromboprophylaxis.
A phase I trial assessing oral S-1 combined with fixed doses of irinotecan in advanced gastrointestinal malignancies (aGM) in 1<sup>st</sup>- or 2<sup>nd</sup>-line treatment.
Authors: Emmanuelle Samalin, Antoine Italiano, Simon Thezenas, Thibault Mazard, Eric Assenat, Sophie Cousin, Antoine Adenis, Sylvain Poujol, Isabelle Solassol, Patrick Chalbos, Fabienne Portales, Marc Ychou
Journal: Journal of Clinical Oncology (2018)

e16189 Background: S-1, an oral fluoropyrimidine, combined with Irinotecan (IRI) or Oxaliplatin (OX) (biweekly schedule) was assessed in Asian populations with acceptable safety profile and efficacy. This phase I trial aimed to evaluate the safety of S-1 in combination with IRI (SIRI) then with IRI and OX (SIRINOX) in patients with aGM. We present here the results of the SIRI step. Methods: Eligible patients had aGM not previously exposed to IRI and/or OX. A 3+3 dose-escalation study with 4 S-1 dose-levels (25, 30, 35 and 40mg/m2, twice/day from day 1 to day 8) combined with IRI 90 min IV 180mg/m2 fixed-dose, every 2 weeks, was performed for SIRI. The primary objectives were to identify the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of SIRI. Secondary objectives included response rate (RR), progression-free (PFS) and overall (OS) survival. Results: 14 patients were enrolled. Patients characteristics were: median age, 63 (37-85), 10/14 female; all patients were PS 0 (57%) and 1 (43%). Tumor types were: 10 biliary tract and 2 gastric adenocarcinomas, and 1 esophageal and 1 anal squamous cell carcinomas. Median number of cycles was 5 (1-19). Grade ≥ 3 adverse events (AEs) (Table) and deaths occurred in 7 (50%) and 2 (14%) patients (levels 3 and 4), respectively. Three dose-limiting toxicities were reported in levels 3 (n = 1) and 4 (n = 2). The DMT was reached at level 4 (40mg/m²). The RP2D was set at 35 mg/m². 1 out of 11 patients evaluable for efficacy achieved a tumor response (RR = 7%, 95%CI: 2-34), and 5/11 patients had a stable disease. Median OS and PFS were 5.2 [95%CI: 2.8–not reached] and 2 [95%CI: 1.2-5.2] months, respectively. Treatment is still ongoing (30 cycles) in one patient with stable biliary tract cancer. Conclusions: MTD and RP2D of this SIRI combination were 40mg/m² and 35 mg/m², respectively. The SIRINOX step was planned but the study was prematurely stopped for funding reasons. Clinical trial information: NCT02387138. Acknowledgements This study was supported by Nordic Pharma. Grade ≥ 3 AEs related to treatment 25mg/m2 n = 3 30mg/m2 n = 3 35mg/m2 n = 6 40mg/m2 n = 2 Diarrhea 0 0 1 1 Neutropenia 2 0 1 0 Asthenia 1 0 1 1 Others 0 1 1 1
TCT-277 Safety and feasibility of Trans Catheter interruption of ruptured sinus of Valsalva aneurysm (RSOVA) using the Coccoon Duct Occluder (CDO): immediate results and mid-term follow-up
Authors: Santosh Sinha, Vinay Krishna, Ramesh Thakur, Chandra Varma, Mahmodula Razi, Puneet Aggarwal, Mohammad Asif, Kumar Himanshu
Journal: Journal of the American College of Cardiology (2018)
Novel, sensitive simplex and multiplex assays for KRAS and NRAS mutation detection.
Authors: Samantha Epistolio, Majbritt Hauge Kyneb, Michael Boergesen, Mariann Guldmann-Christensen, Kirsten Voogd, Stephen Hamilton-Dutoit, Christina Andersen, Alice Riva, Luca Mazzucchelli, Tine Yde Wolff, Jan Lorenzen, Ulf Bech Christensen, Cristiana Sessa, Milo Frattini
Journal: Journal of Clinical Oncology (2016)

e23269 Background: Activating KRAS/NRAS mutations in colorectal cancer (CRC) predict resistance to anti Epidermal Growth Factor Receptor targeted therapies. To improve the molecular characterization of CRC, we developed novel simplex and multiplex real-time PCR based assays (SensiScreen) for KRAS/NRAS analysis, and compared them with Direct Sequencing (DS), Mutant-Enriched PCR (ME-PCR), TheraScreen and Cobas. Methods: SensiScreen assays (PentaBase) comprise SuPrimers (DNA primers with increased specificity), BaseBlockers (suppressing amplification of wild-type genes) and HydrolEasy probes (hydrolysis probe with increased S/N ratio and sensitivity). Sensitivity studies on plasmids and extracted cell line DNA were performed. Three cohorts were analyzed for KRAS exon 2 mutations: Cohort 1 (n = 100), SensiScreen was compared with DS and ME-PCR; Cohort 2 (n = 79), with DS and TheraScreen; and Cohort 3 (n = 307), with Cobas. KRAS exons 3/4 and NRAS exons 2/3/4 were tested by DS and SensiScreen on 156 patients. Results: Our sensitivity studies gave superimposable results for both simplex and multiplex assays. DS had a limit of detection of 10%, ME-PCR of 0.1% and SensiScreen of ≤ 0.1%. Patients with mutations found in KRAS exon 2 were: Cohort 1: 33 (33%) by DS, 43 (43%) by ME-PCR and 45 (45%) by SensiScreen. Cohort 2: 17 (21%) by DS, 19 (24%) by TheraScreen and 19 (24%) by SensiScreen. Cohort 3: 84 (27%) by Cobas and 88 (29%) by SensiScreen. In KRAS exons 3/4-NRAS exons 2/3, DS identified mutations in 6 (3.8%), 4 (2.6%), 1 (0.6%) and 2 (1.3%) cases respectively, whereas SensiScreen detected mutations in 8 (5.1%), 8 (5.1%), 4 (2.6) and 8 (5.1%) cases respectively. No NRAS exon 4 mutations were detected. Simplex and multiplex assays identified the same mutations. Conclusions: SensiScreen simplex and multiplex assays are novel, rapid, easy-to-use and highly sensitive methodologies enabling better identification of KRAS/NRAS mutations in CRC than currently used methodologies. The multiplex version analyzes 44 mutations of 6 exons with only 11 reactions.
Does treatment-related toxicity affect quality of life in patients with metastatic colorectal cancer? A systematic review.
Authors: Claudia Schuurhuizen, Annemarie Braamse, Inge Konings, Joost Dekker, Henk M.W. Verheul
Journal: Journal of Clinical Oncology (2016)

e18106 Title: Does treatment-related toxicity affect quality of life in patients with metastatic colorectal cancer? A systematic reviewBackground: New systemic treatment regimens in patients with metastatic colorectal cancer (mCRC) have significantly improved overall survival and prognosis. These new treatment regimens are often accompanied by increased treatment-related toxicity. As one of the goals of new treatments is to maintain patients’ quality of life (QOL), we systematically reviewed how treatment-related toxicity in recent RCTs in patients with mCRC receiving systemic treatment relates to global QOL. Methods: Phase III RCTs comparing systemic non-curative treatments in patients with mCRC and published between 2004-2015 were considered. Studies were evaluated on the basis of global QOL scores, treatment-related toxicity (assessed by scoring relevant adverse events) and primary outcomes. Results: A total of 30 studies were identified (n = 19863). No difference in global QOL outcomes between treatment arms was shown in 25 studies (83,3%). In the experimental arms, increased treatment-related toxicity was reported in 19 studies (63,3%). Increased treatment-related toxicity was mostly accompanied by a neutral global QOL outcome. In ten out of eleven studies with a better primary outcome, no improvement in global QOL was seen. Conclusions: We here report that evaluation of the global QOL of patients with mCRC included in RCTs with palliative systemic treatment was similar despite consistently increased treatment-related toxicity of the experimental compared to the standard treatment arms. These combined findings make us question the validity of the currently used measurements of QOL and/or toxicity in RCTs. At present, QOL data do not seem to achieve their original potential in facilitating informed treatment decisions and providing information to better understand the effectiveness of novel therapies.
<i>CCL5</i> expression and tumor infiltrating immune cells in triple negative breast cancer.
Authors: Jhajaira Araujo, Andrea C. Gomez, Roberto Salgado, Justin M. Balko, Alfredo Aguilar, Franco Doimi, Zaida Morante, Henry Gomez, Joseph A. Pinto
Journal: Journal of Clinical Oncology (2017)

11553 Background: CCL5 is a chemo-attractant of regulatory T cells, promoting tumor immune avoidance and related to a poor outcome in several malignancies; however, in triple negative breast cancer (TNBC), it is related to a better outcome. Our aim was to evaluate the correlation between CCL5 and tumor infiltrating immune cells and their prognosis value. Methods: We evaluated 72 TNBC patients with residual disease after neoadjuvant chemotherapy with matched data of tumor infiltrating lymphocytes (TILs) count and CCL5 expression (profiled with NanoString). CCL5 expression levels were log2 transformed and median centered. Correlation between TILs (log2 transformed) and CCL5 was evaluated with the Spearman’s rank test. Cox PH model was used to investigate the effect of CCL5 (median as cutoff) and TILs ( &lt; 20% and ≥20%) in distant-recurrence free survival. We used the CIBERSORT platform to evaluate the immune cells composition according to the expression of CCL5 (higher vs. lower or equal than median) in 3 independent TNBC datasets (GSE25066, GSE58812 and GSE76124). Results: There was a significant correlation between TILs and residual tumor size (P = 0.017) and CCL5 (ρ = 0.347, P = 0.003). In univariate analysis, TILs (HR = 0.276, 95%IC: 0.128-0.593; P = 0.001) and CCL5 (HR = 0.401; 95%CI: 0.206-0.781; P = 0.007) were both associated with outcome. In a multivariate analysis with CCL5 expression and TILs count, TILs was the only significant marker with a P = 0.008 (HR = 0.336; 95%CI: 0.150-0.753), in contrast to CCL5 (HR = 0.573; 95%CI: 0.285-1.154; P = 0.124). CIBERSORT analysis suggested that high CCL5 expression is associated with recruitment of CD8 cells (13% v 6%, P &lt; 0.001; 6% v 1%, P &lt; 0.001 and 12% v 8%, P = 0.003), activated CD4 memory T cells (4% vs. 2%, P &lt; 0.001; 5% vs. 0%, P &lt; 0.001; 3% vs. 0%, P &lt; 0.001) and Macrophages M1 (9% vs. 7%, P = 0.022; 13% vs. 8%, P = 0.005; 11% vs. 5%, P &lt; 0.001) in GSE25066, GSE58812 and GSE76124 datasets, respectively. Conclusions: TILs was the stronger and more significant prognostic immunological marker, even than CCL5 expression. High CCL5 expression was associated with enrichment of CD8 cells, activated CD4 memory T cells and Macrophages M1. Role of these cells in TNBC should be explored more deeply.
Y-90 radioembolization comparative outcomes between solid tumor malignancies: A single institution experience.
Authors: Joshua Harris, Prashanti Atluri, Neha Desouza, Jason Hoffman, Abie Eweka
Journal: Journal of Clinical Oncology (2017)

e15704 Background: Transcatheter arterial radioembolization with Y90 is a locoregional therapy for unresectable hepatic malignancy with a more favorable side effect profile compared to trans-arterial chemoembolization. Increasingly, TARE is being utilized in multiple tumor types, for patients with primary hepatic malignancy or metastatic disease that is either liver-dominant or liver-only in distribution. Methods: This single-institution, retrospective study included all patients with hepatic malignancy treated with TARE from May 2012 to June 2016. Primary diagnoses included colon, breast, HCC, carcinoid, pancreatic or gastric cancer. Response was determined according to RECIST 1.1 criteria, based on each patient's followup cross-sectional imaging. 67 doses were administered to 44 patients. The mean dose administered was 25.27 mCi. The primary endpoint was response to therapy. The secondary endpoint was time to progression, in the liver. Results: Initial post-treatment cross-sectional imaging was obtained at an average of 13.9 (± 3.55 weeks, 95% CI) weeks on all patients, with 68% of patients demonstrating partial response, 29% stable disease and 3% of patients with progression. Median imaging follow-up was 6.86 months (± 1.5 months, 95% CI). Over that time period, 16% of patients developed recurrent or disease progression in previously treated lesions. In these patients, the median time to liver progression was 66 weeks. Conclusions: TARE is an effective and durable means of attaining control of disease in the liver. Patients with HCC demonstrated the highest response rate overall. This data adds to the building body of evidence supporting the use of TARE, and is unique as it comparatively assesses TARE response rates in various hepatic malignancies. [Table: see text]
Abstract 12255: Differential Expression of miRNAs in BAG3-mutation Carriers With Dilated Cardiomyopathy
Authors: Carlos Zaragoza, Marta Saura, David de Gonzalo, Ignacio Hernandez, Javier Diez, Alipio Mangas, Jose-Luis Zamorano, Rocio Toro
Journal: Circulation (2017)

Introduction: A new familial dilated cardiomyopathy (DCM) was found related to mutations in the antiapoptotic BAG3 gene. MicroRNAs (miRNAs) are short non-coding RNAs playing significant roles in ca...