tbuckley/cabot-search huggingface dataset:
Clinical activity of afatinib in a cohort of patients with lung adenocarcinoma harbouring uncommon <i>EGFR</i> mutations: A Spanish retrospective multicentre study.
Authors: Manuel Domine, Victor Diaz, Oscar Juan Vidal, Raquel Marse Fabregat, Paloma Martin, Jose Miguel Sanchez Torres, Silvia Muñoz, Georgia Anguera, Joaquim Bosch-Barrera, Luis Cabezon-Gutierrez, Silvia Catot, Yolanda Garcia, Inmaculada Ramos Garcia, Teresa Moran
Journal: Journal of Clinical Oncology (2018)

e21028 Background: U-EGFRm in exons 18-21 account for 12-15% of overall EGFR mutations in non-small cell lung cancer (NSCLC). Afatinib has shown activity against some u-EGFRm, especially G719X, L861Q, and S768I; although other u-EGFRm (Ins20, de novo T790M) have a lower likelihood of response. U-EGFRm have also been reported as co-mutations with other EGFRm (complex mutations). We examined the molecular and clinical characteristics and efficacy of afatinib in a cohort of p with advanced NSCLC carrying u-EGFRm in Spanish clinical practice. Methods: Medical records of 67 NSCLC p with u-EGFRm treated with afatinib between 2012 and 2017 at 23 Spanish institutions were reviewed. U-EGFRm were analysed as complex mutations (Group A), Ins20 (Group B), or single mutations (Group C). Efficacy data were evaluated in terms of tumour response and overall survival (OS). Results: Of the 67 p, 96% were Caucasian, all were adenocarcinoma, 46% were never smokers and 37% were former smokers, 79% were Stage IV at diagnosis, 79% had ECOG PS 0-1. Group A complex u-EGFRm consisted of double mutations of G719X+E709F, G719X+S768I, G719X+ L861Q, L858R+T790M, L858R+S768I, Del19+S768I, Del19+L747S, or R776C+L861Q. No differences in clinical characteristics were found between Group A (n = 20), Group B (n = 23), and Group C (n = 24). Afatinib was administered as 1st line therapy in 80% of p. Median time on therapy was 4.2 months (m) (range 2.0-12.9). Eighteen percent of p started afatinib at a reduced dose and 24% of p required a dose reduction. Response to afatinib was significantly higher in Group A and C (70% and 54%, respectively), compared with Group B (13%; pairwise comparison p < 0.001 and 0.013, respectively). Median OS for the entire cohort was 19.9 m (9.7-30.1). Hazard ratio for OS were 0.27 (95% CI 0.10-0-71, p = 0.009) and 0.40 (95% CI 0.17-0.95, p = 0.037) for Group A and C compared to Group B, respectively. Conclusions: In clinical practice, afatinib was active in u-EGFRm NSCLC , particularly in complex and single mutations. Further strategies are needed for p with ins20, a subgroup u-EGFRm with a lower clinical benefit with afatinib.
P26 MIR-101-3P CONTROLS <i>TRIB1</i> EXPRESSION IN HUMAN MACROPHAGES: A POTENTIAL TARGET IN ATHEROSCLEROTIC PLAQUES
Authors: C Niespolo, J S Viloria, O V Perez, H L Wilson, E Kiss-Toth
Journal: Cardiovascular Research (2018)

Background: Current research has demonstrated that monocyte/macrophages can coexist as diverse phenotypes which display an array of differing properties.The aim of this study is to robustly assess the ability of pro-and anti-inflammatory macrophages to polarise towards smooth muscle cell (SMC)-like and endothelial cell (EC)-like phenotypes.Methods and Results: Human peripheral blood mononuclear cells (PBMC) were differentiated into pro-or anti-inflammatory macrophages through seven days culture with granulocytemacrophage colony stimulating factors (GM-CSF) or M-CSF respectively.Utilising wellcharacterised SMC-related markers, pro-inflammatory macrophages demonstrated a significant upregulation of mRNA and/or protein expression of caldesmon (2-fold;p<0.05),calmodulin (2fold;p<0.05),smoothelin (3-fold;p<0.05),and vimentin (4-fold;p<0.05),compared to stimulated anti-inflammatory macrophages, all of which were further augmented upon three days PDGFBB and TGFb co-stimulation.Interestingly, employing well-characterised endothelial cell-related markers, three days stimulation of anti-inflammatory macrophages with FGF2 or VEGFA induced a significant up-regulation of mRNA and protein expression for CD31 (PECAM1) ($2.5fold;p<0.05) and VE-cadherin (4-fold;p<0.05),compared to stimulated pro-inflammatory macrophages.Despite no change/reduced in CDH5 (VE-cadherin) mRNA expression, protein expression was significantly increased upon VEGFA and FGF2 stimulation (3-fold and 7-fold respectively;p<0.05),suggesting a novel post-transcriptional regulatory mechanism.Conclusions: These findings imply that blood derived macrophages in culture can exhibit smooth muscle cell-and endothelial cell-like features, which are pre-dominant in pro-inflammatory macrophages, and accentuated by SMC or EC-related growth factors.As such, divergent macrophages as sites of vascular injury may harbour the potential to trans-differentiate into VSMC-like and EC-like cells to facilitate healing and stabilisation of vascular pathologies such as atherosclerotic plaques and aortic aneurysms.
Atypical negative ALK FISH accompanied by immunohistochemistry positivity harbored various ALK rearrangements in NSCLC patients and respond to targeted therapy.
Authors: Jianming Ying, Wenbin Li, Lei Guo, Li Junling, Ning Lu
Journal: Journal of Clinical Oncology (2016)

e20506 Background: Detection of ALK rearrangements in patients with non-small cell lung cancer (NSCLC) presents a significant technical challenge due to the existence of multiple translocation partners and break-points. Although fluorescence in situ hybridization (FISH) is the first FDA-approved method, there are some atypical negative FISH cases accompanied by immunohistochemistry (IHC) positivity and responded well to crizotinib treatment. Methods: 3128 NSCLCs were screened for ALK fusions through both FISH analysis and IHC assays with Ventana-D5F3 antibody. IHC results were scored with a binary scoring system. Fourteen cases with atypical negative FISH and positive IHC results were performed with targeted next-generation sequencing. Results: Among 3128 cases tested, 228 (7.3%) and 214 (6.8%) cases were ALK positive by IHC and FISH, respectively. Fourteen cases with atypical negative FISH all demonstrated IHC positivity. Two patients showed isolated 5’-side signal. Targeted next-generation sequencing analysis revealed two novel ALK partner genes, baculoviral inhibition of apoptosis protein repeat containing six (BIRC6) and Phosphatidylinositol Binding Clathrin Assembly Protein (PICALM). One patient showed isolated and attenuated 3’-red signal and demonstrated a novel translocation partner with CCAAT/Enhancer binding protein zeta (CEBPZ). Eight patients with fused signals and positive IHC demonstrated EML4-ALK fusions revealed by NGS and the relative abundance of fusion ranged from 7.26% to 37.8%. Besides, 3 patients with confirmed IHC positivity and negative FISH results did not exhibit any type of ALK fusions. Among them, 4 patients received crizotinib treatment and demonstrated partial responses at the end of follow-up. Conclusions: Our study showed that patients with atypical ALK FISH patterns, which are regarded as negative in the current criteria, could have positive results for IHC and also respond to ALK inhibitor therapy.
A Joint Statement from the European Association of Urology Renal Cell Cancer Guidelines Panel and the International Kidney Cancer Coalition: The Rejection of Ipilimumab and Nivolumab for Renal Cancer by the Committee for Medicinal Products for Human Use Does not Change Evidence-based Guideline Recommendations
Authors: Axel Bex, Laurence Albiges, Michael Staehler, Karim Bensalah, Rachel H. Giles, Saeed Dabestani, Fabian Hofmann, Milan Hora, Markus A. Kuczyk, Thomas B. Lam, Lorenzo Marconi, Axel S. Merseburger, Sergio Fernández-Pello, Rana Tahbaz, Yasmin Abu-Ghanem, Alessandro Volpe, Börje Ljungberg, Bernard Escudier, Thomas Powles
Journal: European Urology (2018)
Adoptive transfer of NK cells in combination with chemotherapy to improve outcomes of patients with locally advanced colon carcinoma.
Authors: Lingyu Li, Jiuwei Cui, Chang Wang, Yizhuo Wang, Chao Niu, Cheng Yao, Huimin Tian, Haofan Jin
Journal: Journal of Clinical Oncology (2017)

e15038 Background: The prognosis of advanced colon cancer (CC) patients remains disappointing, partly due to their greater proportion of CC-initiating cells (CICs), which is responsible for cancer drug-resistance and immune escape. Immunotherapies by harnessing the immune system to eliminate tumors have attracted broad attention. This study was to detect whether chemotherapy could enhance cytotoxicity of natural killer (NK) cells to CC cells (CCs), especially for CICs in vitro, and further evaluate the efficacy and safety of NK-cell therapy combined with chemotherapy in patients with local advanced CC. Methods: We observed that cytotoxicity of NK cells to CCs and CICs pretreated with 5-Fu or oxaliplatin. Then, an open-label pilot cohort study was conducted with local advanced CC patients who had received surgical excision. 60 patients elected to receive either NK-cell therapy combined with chemotherapy (NK-cell group, 27 patients) or pure chemotherapy (control group, 33 patients). Progression-free survival (PFS), overall survival (OS) and adverse effects were investigated. Results: Chemotherapy sensitized CCs and CICs to NK cell lysis through upregulation of their NK cell activating ligands and reducing inhibitory ligands. Poorly differentiated CCs were more susceptible to NK-cell than well-differentiated CCs, and CICs were more easily to be killed by NK cell than their differentiated CCs. In the cohort study, the 5-year PFS and OS rates in the NK-cell group were significantly higher than those in the control group (51.1% vs. 34.9%, p= 0.043; 73% vs. 51.3%, p= 0.038, respectively).Among patients with poorly differentiated carcinomas or low expression of HLA-1, median PFS in the NK-cell group vs. the control group was 23.5 vs. 11.5 months ( p= 0.047), and median OS was 30 vs. 15 months ( p= 0.043), respectively. No significant adverse reaction was found during NK-cell therapy. Conclusions: NK-cell therapy in combination with chemotherapy in locally advanced CC prevented recurrence and prolonged survival with acceptable adverse effects, especially for poorly differentiated carcinomas.
Abstract 13413: Silent Cerebral Ischemic Lesions After Atrial Fibrillation Ablation Among Oral Anticoagulants: Predictors of Diffusion-Weighted Imaging-Positive Lesions and Follow-up Study
Authors: Kohki Nakamura, Shigeto Naito, Kentaro Minami, Takehito Sasaki, Eri Goto, Yoshiaki Yamaguchi, Satoru Shimizu, Michiharu Senga, Toshiaki Yano, Yutaka Take, Koji Kumagai, Nobusada Funabashi, Yoshio Kobayashi, Shigeru Oshima
Journal: Circulation (2015)

Purpose: We aimed to identify the predictors of silent cerebral ischemic lesions (SCILs) detected on diffusion-weighted imaging (DWI) after catheter ablation of atrial fibrillation (AF) in patients with oral anticoagulants (OACs), and to determine whether postablation DWI-positive lesions develop into established cerebral infarcts or not on follow-up magnetic resonance imaging (MRI). Methods: This study prospectively included 183 consecutive AF patients (65±9 years; 133 males; paroxysmal/persistent/long-standing persistent AF [LSP-AF], 93/58/32) who received OAC therapy more than 3 weeks before an AF ablation and underwent MRI on the next day after the procedure. Warfarin (n=30; group W) was continued, while dabigatran (n=30; group D), rivaroxaban (n=62; group R), and apixaban (n=61; group A) were discontinued on the day of the procedure. Just after the femoral venous puncture during the procedure, a heparin bolus of 5000 units in group W and 10000 units in the others was given, followed by a continuous and additional bolus infusion of heparin to maintain an activated clotting time of 300-350 seconds. OAC therapy was continued for at least 3 months after the procedure in all patients. Results: A total of 38 lesions in 26 asymptomatic patients (14.1%) were detected on DWI. The incidence of SCILs was 10.0% in group W, 30.0% in group D, 8.1% in group R, and 14.8% in group A, respectively. The BNP level and percentage of patients with LSP-AF, dabigatran, and electrical cardioversion during the procedure were significantly higher in the patients with SCILs than in those without (all P&lt;0.05). In a multivariate logistic regression analysis, LSP-AF and the use of dabigatran were significant positive predictors of SCILs (odds ratios, 5.736 and 4.295; 95% confidence intervals, 2.163-15.212 and 1.541-11.966; P&lt;0.001 and 0.005). Of the 26 patients with SCILs, 8 with 11 lesions underwent follow-up MRI 161±54 days after the procedure. All 11 DWI-positive lesions disappeared and none resulted in subsequent infarcts on follow-up MRI. Conclusions: LSP-AF and dabigatran use were high risk factors for SCILs after AF ablation among the patients with OACs. However, no SCILs developed into chronic cerebral infarcts under continuous oral anticoagulation following the ablation.
Benign metastasizing leiomyoma (BML): A retrospective case series analysis of 8 patients (pts).
Authors: Vittoria Colia, Angelo Paolo Dei Tos, Elena Fumagalli, Rossella Bertulli, Domenica Lorusso, Francesco Raspagliesi, Carlo Morosi, Maria Luisa Carcangiu, Paolo Giovanni Casali, Roberta Sanfilippo
Journal: Journal of Clinical Oncology (2017)

e22525 Background: BML is a rare entity marked by the presence of lung lesions in women with a history of surgery for a benign leiomyoma of the uterus. Optimal treatment strategy for BML is poorly defined. We report on the activity of systemic therapy in a retrospective series of pts with BML. Methods: Cases diagnosed with BML from June 1993 to January 2017 at Istituto Nazionale Tumori, Milan, were reviewed. Results: Eight pts were identified, with a median age of 43 yrs. Estrogen and progesteron receptors were positive in all cases. All pts underwent surgery (3 hysterectomy, 2 myomectomy, 2 hysteroannessiectomy and 1 left ovariectomy) for suspected uterine leiomyoma (1 leg; 1 thigh); 2 pts had concomitant lung disease. 8 pts developed lung metastases and 2 had also limb metastases. 2 pts underwent lung metastasectomy, followed by watchful waiting with CT every 6 mos and were disease-free at their last follow up after 132 mos and 84 mos from diagnosis. 6 pts received systemic therapy for progressing advanced disease (1-6 lines). Among 6 pts treated, 2 were in fertility age and underwent ovary-sparing hysterectomy, receiving GnRH agonist with 1 PR lasting 96 mos and 1 SD lasting 38 mos; 2 pts received an aromatase inhibitor with 1 PR lasting 24 mos and 1 SD lasting 12 mos; 2 pts received oral estrogens with 1 PR lasting 39 mos and 1 SD lasting 2 mos; 1 pt received oral progestins with a PR lasting 12 mos; 3 patients received antracyclin +/- ifosfamide obtaining 2 PR after 3 cycles (cys) and 1 SD after 3 cys lasting 6 mos; 1 pt received high-dose ifosfamide with a PR after 5 cys; 1 pt received ifosfamide+dacarbazine obtaining a CR after 6 cys; 2 pts received gemcitabine with 1 PR after 3 cys and 1 SD after 2 cys lasting 6 mos; 1 pt received oral etoposide with a PR lasting 21 mos; 1 pt received sorafenib with a SD lasting 6 mos; 1 pt received everolimus with a PR lasting 57 mos. In this case, everolimus was discontinued due to lung toxicity. No pts progressed during treatment. At a median follow-up of 55 mos, 6 pts are alive, while 2 are dead of disease. Conclusions: In a series of 8 pts, we confirm the activity of hormonal treatment in BML. mTOR inihibitors or chemotherapy also show to be active.
Reprogramming of cell signaling in response to MEK inhibition in non-small cell cancer (NSCLC).
Authors: Yasir Elamin, Dianren Xia, Kathryn A. Gold, Lauren Averett Byers, You Hong Fan, Lixia Diao, Jing Wang, Uma Giri, Jayanthi Gudikote, Hai T. Tran, John Heymach
Journal: Journal of Clinical Oncology (2016)

e23222 Background: MEK inhibitors have limited success in cancer treatment because tumors circumvent their action. Here, we report broad proteomic analysis of NSCLC cell lines after treatment with the allosteric MEK1/2 inhibitor BAY86-9766. Methods: We treated 109 NSCLC cell lines with BAY86-9766. Proteomic analysis for total and phospho-proteins was performed by reverse phase protein array. Results: BAY86-9766 was effective at reducing pERK ( < 0.001) but this modulation was not significantly different between sensitive and resistant cell lines (P = 0.64). MEK inhibition induced expression and activation of receptor tyrosine kinases (RTK) including pEGFR, pHER2, pMET, pAXL, EGFR, VEGFR2, MET, KIT, IGF1R, and AXL (all < 0.001). This suggests a dominant negative feedback effect of the MAPK pathway on RTKs that is relieved upon MEK inhibition. MEK-ERK signaling is known to enhance stability of c-MYC. Moreover, c-MYC has been shown to be a negative regulator of RTKs transcription. Indeed, BAY86-9766 caused a decrease in c-MYC ( < 0.001) and phospho-c-MYC ( < 0.001) providing a potential explanation for the observed activation of RTKs in MEK-inhibitor treated NSCLC cells. The PI3K pathway was also activated in response to MEK inhibition with increased levels of pAKT(S473), pAKT(T308), AKT, and PI3K P110α as well as the AKT target GSK3β (all P < 0.02). In line with this, PTEN knockdown promoted MEKi resistance while overexpression increased MEKi sensitivity in vitro. MEK inhibition resulted in a dramatic increase in the expression of DNA damage response proteins; pATM(S1981), pATR(S428), pCHK1(s345), ATM, RAD50, RAD25, PARP, ERCC1, XRCC, BRCA1, MSH2, and KU80 (all P < 0.01). MEK inhibition led to decreased pLKB1(S428) ( < 0.001), increased total LKB1 ( < 0.001), pAMPKα(T172) (P = 0.017), and AMPKα ( < 0.001) indicating activation of LKB1-AMPK pathway in response to MEK inhibition. Conclusions: Our data uncovers a burst of signaling in several oncogenic pathways upon MEK inhibition. Taken together, this preclinical data help defining mechanisms of MEK inhibition resistance allowing rational design of combination therapies for NSCLC.
Effect of dexrazoxane on left ventricular function and treatment outcomes in patients with acute myeloid leukemia: A Children’s Oncology Group report.
Authors: Kelly D. Getz, Lillian Sung, Kasey Leger, Todd Allen Alonzo, Robert B Gerbing, Todd Michael Cooper, Edward Kolb, Alan S. Gamis, Bonnie Ky, Richard Aplenc
Journal: Journal of Clinical Oncology (2018)

10501 Background: Overall survival (OS) for pediatric acute myeloid leukemia (AML) has improved to > 65% due in part to the use of anthracycline (ATC)-containing chemotherapy regimens. ATC is also associated with increased cardiotoxicity risk. Cardioprotective agents such as dexrazoxane (DEX) may reduce cardiac injury during treatment. While data on the benefit of DEX are promising, studies in pediatric AML patients are limited. Given the very high ATC exposure in pediatric AML therapy, evaluating the utility of DEX in this population is critical. Methods: On Children’s Oncology Group trial AAML1031, DEX was administered at the discretion of treating physicians. DEX exposure was documented at each treatment course, and ejection fraction (EF) and shortening fraction (SF) values were recorded after each course and in follow up. Absolute change in EF from baseline (∆EF) was computed for each course. Early LVSD was defined as any EF < 50% or SF < 24% from the start of frontline therapy through the follow-up at one-year off-protocol. ∆EF at each course, occurrence of LVSD, and 3-year OS and disease free survival (DFS) were compared for DEX exposed and unexposed. Results: 1014 patients were included; 96 were DEX-exposed at each ATC course received and 918 were never exposed. Distributions of sex, age, race, initial white blood cell count, risk group, and treatment arm were similar for DEX exposed and unexposed. DEX exposed patients had smaller declines in EF than unexposed patients across courses (range of course-specific median ∆EF: 0 to -4.0 versus 0 to -6.4; all p < 0.05) and an overall lower risk for early LVSD (6.3% vs 19.2%, RR = 0.33, 95% CI: 0.15-0.72, p = 0.005). The effect of DEX on LVSD risk was particularly pronounced for female patients (RR = 0.16, 95% CI 0.05 – 0.65). DEX exposed patients had non-significantly higher 3-year OS (71.9% vs 63.0%, p = 0.093) and EFS (54.4% vs 44.2%, p = 0.070) compared to those unexposed. Conclusions: DEX is associated with smaller reductions in EF throughout pediatric AML therapy and a lower risk for early LVSD. Small numbers may have limited our ability to detect differences in OS and EFS. Longer follow-up is required to elucidate the sustained benefit of DEX.
A randomized trial of early endovenous ablation in venous ulceration: a critical appraisal
Authors: K.T. Weiß, F. Zeman, S. Schreml
Journal: British Journal of Dermatology (2018)

Aim Gohel et al. aimed to compare early endovenous ablation vs. deferred endovenous ablation of superficial venous reflux with regard to time to healing of venous leg ulcers, rate of healing at 24 weeks, recurrence rate, ulcer-free time and health-related quality of life. Setting and design This multicentre, parallel-group (ratio 1 : 1), randomized controlled trial was conducted in a vascular surgery department setting at 20 participating centres across the U.K. Study exposure A total of 450 patients with venous leg ulcers were randomly assigned to receive compression therapy and undergo early endovenous ablation of superficial venous reflux within 2 weeks after randomization (early-intervention group) or to receive compression therapy alone, with consideration of endovenous ablation deferred until after the ulcer was healed or until 6 months after randomization if the ulcer was unhealed (deferred-intervention group). Outcomes The primary outcome was the time to ulcer healing. Secondary outcomes were the rate of ulcer healing at 24 weeks, the rate of ulcer recurrence, the length of time free from ulcers (ulcer-free time) during the first year after randomization, and patient-reported health-related quality of life. Trial interventions Endovenous laser or radiofrequency ablation, ultrasound-guided foam sclerotherapy, or nonthermal, nontumescent methods of treatment (such as cyanoacrylate glue or mechanochemical ablation) were performed either alone or in combination. The treating clinical team determined the method and strategy of endovenous treatment. Results The time to ulcer healing was shorter in the early-intervention group than in the deferred-intervention group. Furthermore, more patients had healed ulcers with early intervention [hazard ratio for ulcer healing 1·38, 95% confidence interval (CI) 1·13–1·68; P = 0·001]. The median time to ulcer healing was 56 days (95% CI 49–66) in the early-intervention group and 82 days (95% CI 69–92) in the deferred-intervention group. The rate of ulcer healing at 24 weeks was 85·6% in the early-intervention group and 76·3% in the deferred-intervention group. The median ulcer-free time during the first year after trial enrolment was 306 days (interquartile range 240–328) in the early-intervention group and 278 days (interquartile range 175–324) in the deferred-intervention group (P = 0·002). The most common complications were pain and deep vein thrombosis (DVT) (early-intervention group: pain, six of 28; DVT, nine of 28; deferred-intervention group: pain, six of 24; DVT, three of 24). Conclusions Gohel et al. conclude that early endovenous ablation of superficial venous reflux results in faster healing of venous leg ulcers than deferred endovenous ablation. Patients assigned to the early-intervention group also had longer ulcer-free time during the first year after randomization.