tbuckley/cabot-search huggingface dataset:
Prospective study evaluating the effect of impaired tamoxifen metabolisation on efficacy in breast cancer patients receiving tamoxifen in the neo-adjuvant or metastatic setting.
Authors: Anneleen Lintermans, Kathleen Van Asten, Lynn Jongen, Chantal Blomme, Diether Lambrechts, Ben Van Calster, An Poppe, Hans Wildiers, Anne-Sophie Dieudonné, Jan Decloedt, Patrick Berteloot, Didier Verhoeven, Markus Joerger, Peter Vuylsteke, Wim Wynendaele, Ignace Vergote, Henk-jan Guchelaar, Vincent O. Dezentje, Robert Paridaens, Patrick Neven
Journal: Journal of Clinical Oncology (2016)

523 Background: Tamoxifen is commonly used to treat estrogen receptor (ER)-positive breast cancers, though the response to tamoxifen and its adverse event profile have a high degree of inter-individual variability. This might be attributable to the highly polymorphic CYP450 enzymes converting tamoxifen to more active metabolites and the patient’s genotype which modulates plasma levels. The clinical relevance of subtherapeutic endoxifen levels on clinical outcome, however, is controversial for a lack of data from prospective clinical studies. Methods: Postmenopausal women with ER-positive breast cancer starting tamoxifen as neo-adjuvant or first line metastatic treatment were included. The association between objective response rate (ORR) and steady state endoxifen levels was assessed. This was also evaluated for clinical benefit (CB) and progression-free survival (PFS). Tamoxifen and metabolite levels were assessed using high-performance liquid chromatography-tandem mass spectrometry. Additionally, we assessed the impact of 33 pharmacogenetic variants in CYP450 by Sequenom MassARRAY on endoxifen levels. Results: 247 patients were included in the analysis. Although endoxifen concentrations showed large variability (0.7 – 35.1 µg/l), ORR to tamoxifen was high at 45% and 83% of patients experienced CB. Endoxifen levels were not associated with ORR (p=0.56). Additionally, no clear association between endoxifen levels and both CB (p=0.12) and PFS (p=0.10) was found. 12 SNPS in CYP450 exhibited a minor allele frequency > 0.05 and were included in the analysis. CYP2D6*4 and *41 explained 13% (95% CI, 6-21%) of variability in endoxifen levels. Conclusions: Results from this first prospective clinical trail do not suggest therapeutic monitoring of endoxifen to be of clinical value in postmenopausal women treated with tamoxifen for breast cancer in the neoadjuvant or advanced setting. Furthermore, SNPs in CYP2D6 accounted for only a small fraction of the high variability of endoxifen plasma concentrations and cannot be recommended to guide individual dosing of tamoxifen at present. Clinical trial information: NCT00965939.
Simplified and original Wells rules plus age-adjusted D-dimer test were useful for ruling out suspected PE
Authors: Alex Gallus
Journal: Annals of Internal Medicine (2017)

Source Citation van Es N, Kraaijpoel N, Klok FA, et al. The original and simplified Wells rules and age-adjusted D-dimer testing to rule out pulmonary embolism: an individual patient data meta-analysis. J Thromb Haemost. 2017;15:678-84. 28106338
A phase II trial of temozolomide (TMZ) 1 week on/1 week off as initial treatment for high risk low grade oligodendroglial tumors: An AINO (Italian Association for Neuro-Oncology) study.
Authors: Roberta Ruda, Alessia Pellerino, Federica Franchino, Andrea Pace, Carmine Maria Carapella, Cristina Dealis, Manuela Caroli, Marina Faedi, Chiara Bomprezzi, Riccardo Soffietti
Journal: Journal of Clinical Oncology (2017)

2026 Background: The efficacy of dose-dense temozolomide (TMZ, 1 week on/1 week off ) in grade II gliomas is not well known and could depend on the molecular subtype. Methods: Between 2006 and 2010 a single arm phase II study on 60 patients with grade II oligodendroglial tumors was performed. Inclusion criteria were as follows: 1) age ≥ 18 years; 2) KPS ≥ 70; 3) biopsy-proven grade II oligodendroglioma or oligoastrocytoma ; 4) a measurable residual tumor after surgery. The primary endpoint was tumor response on MRI according to RANO criteria, while the secondary endpoints were progression-free survival (PFS), overall survival (OS), and seizure control. Most patients (65%) had seizures. Molecular factors (IDH 1-2 mutations, 1p19q codeletion, MGMT methylation) were available in 49/60 patients (81.7%). The median number of cycles was 11 (2-18). Median follow up was 64 months (7-112). Results: Response rate was PR in 21/60 (35%) patients, minor PR (mPR) in 14/60 (23%), SD in 21/60 (35%) and PD in 4/60 (7%). Most patients achieved the best tumor response within 6 months after the start of TMZ. Among patients with mPR and PR, 15/49 (30.6%) were IDH1-2 mutated with a PFS of 71.4% at 36 months and 28.6% at 60 months with a median value of 46 months while 11/49 (22.4%) were IDH 1-2 wild-type with a PFS of 45.8% at 36 months and 25% at 60 months with a median value of 34 months. OS was 90.5% at 36 months and 66.7% at 60 months with a median value of 76 months in the IDH1-2 mutated/1p19q codeleted subgroup, while OS was 66.7% at 36 months and 50% at 60 months with a median value of 60 months in the IDH1-2 wild-type subgroup. Responses were higher in MGMT methylated patients. Seizure improvement was achieved in 29/34 patients (85%): 17/33 (52%) patients at 12 months and 18/29 (62.1%) at 24 months were seizure-free. Time to maximal seizure response was earlier than that observed on MRI (3 vs 6 months). Conclusions: Dose-dense TMZ has shown a significant activity in terms of tumor and seizure control, especially in IDH1-2 mutated/1p19q codeleted patients. Seizure reduction could represent an early indicator of response to chemotherapy and maybe predict the duration of response. Clinical trial information: 2007-000386-38.
Final report of a phase I study of 2-hydroxyoleic acid (2OHOA) a novel sphingomyelin synthase activator in patients (pt) with advanced solid tumors (AST) including recurrent high grade gliomas (rHGG).
Authors: Analia Azaro, Elizabeth R. Plummer, Ander Urruticoechea, Jordi Rodon, Noor R Md Haris, Gareth Veal, Antoine Perier, Vicenc Tur, Pablo V. Escriba, Xavier Busquets, Joan Alberti, Elisabet Sicart, Dearbhaile Collins, Ricardo Fernandez, Evelyne Bettenhaussen, Edwin Klumper, Juanita Suzanne Lopez
Journal: Journal of Clinical Oncology (2017)

2554 Background: 2OHOA is an orally bioavailable, first-in-class synthetic hydroxylated fatty acid, that activates SGMS1 and modulates the lipid content of cancer cell membranes. This regulates the localization of key signaling proteins, including Ras and PKC at the plasma membrane, leading to inactivation of Ras/MAPK, PI3K/Akt and PKC/cyclin/CDK signaling pathways. A dose escalation (DE) and partial expansion cohorts (EC) results of the phase 1 study have previously been reported. We now present the final results of the study. Methods: 2OHOA was evaluated in a 3+3 DE design (7 cohorts from 500mg/d to 16000mg/d) and 2 EC at 4000mg TID in 21 days cycles. PK profiles were determined after single dose (fasted [D-7] or fed [D1]) and multiple doses (fed [D21]) during DE phase and only on D1 throughout EC.Safety assessments were based on CTCAEv4.Tumor response was measured by RECIST and RANO every 6 weeks. Results: Overall 54 pt (DE: 32 pt; 21AST/11rHGG; EC: 22 pt; 12 AST/10 rHGG) were treated (median age 60, range 19-78 years). During the EC the most common treatment related G1-G2 toxicities were diarrhea (n = 13;11pt),nausea (n = 7;6pt), ALT increase (n = 6;4pt), pruritus in throat (4pt), fatigue (4pt) and vomiting (3pt). No G3-G4 toxicities or DLTs were reported confirming the MTD from the DE at 4g TID. Food intake did not alter oral 2OHOA bioavailability. Steady state was already achieved at D8. Power model showed dose proportionality in terms of AUC and Cmax, after single and multiple BID dosing. Average t1/2 ranged from1-2h to 8-12h with delayed Tmax and longer half-lives at higher doses. One glioblastoma (GBM) pt had sustained partial response ( &gt; 2,5 years) and 4rHGG pt (3 GBM) achieved stable disease for at least 6 months. They had previously received 2 lines of treatment without bevacizumab. Tumor markers were measured and will be presented. Conclusions: 2OHOA is well tolerated at the P2RD of 4000mg TID PO daily. The preliminary antitumor activity including a sustained PR in heavy pretreated rHGG pt warrants further investigation in a Ph2 study Clinical trial information: NCT01792310.
Women informed to screen depending on measures of risk (WISDOM): A RCT of personalized vs. annual screening for breast cancer.
Authors: Sarah Rosenberg-Wohl, Martin Eklund, Jeffrey Tice, Elad Ziv, Celia Kaplan, Laura Van't Veer, Andrea LaCroix, Lisa Madlensky, Arash Naeim, Neil Wenger, Alexander D. Borowsky, Joshua Fenton, Hoda Anton-Culver, Michael Hogarth, Thomas Cink, Susie Brain, Diane Heditsian, Vivian Lee, Allison S Fiscalini, Laura Esserman
Journal: Journal of Clinical Oncology (2016)

TPS1594 Background: Currently in the United States, the majority of women are recommended to undergo annual mammographic screening for breast cancer starting at age 40, regardless of personal risk. The United States is the only country where annual screening starting at age 40 is standard practice, yet the US breast cancer mortality rate is not lower than that of comparable Western European countries. The Wisdom Study (Women Informed to Screen Depending on Measures of Risk) is an innovative, risk-based screening (RBS) paradigm that employs a comprehensive risk prediction model incorporating established and recently validated high-impact breast cancer risk factors, including mutations in high-to-moderate risk genes (i.e. BRCA 1/2), common genetic variants (SNPs), mammographic density and co-morbidities. Methods: The risk-based screening strategy uses the Breast Cancer Surveillance Consortium (BCSC) model’s 5-year risk and polygenic risk score derived from 157 SNPs, in a Bayesian calculation to generate breast cancer risks that will inform personalized recommendations for the age to start and stop, frequency, and modality of screening. Women who are deemed at elevated risk for aggressive tumors are recommended to undergo more frequent screening, while those deemed at low risk are recommended to have less frequent screening. All recommendations are within the USPSTF guidelines. We are recruiting 100,000 women between the ages of 40 and 74 without a prior diagnosis of breast cancer or DCIS. Women learn about the Wisdom Study, its purpose, and the importance of randomization through our custom-designed web-based portal (Salesforce). Patients are asked if they are willing to be randomized to RBS vs. annual screening. Those who choose not to be randomized can join the observational cohort and select RBS or annual screening. Women consent via DocuSign. Women in the RBS cohort are sent a genetic testing kit that uses saliva to screen for gene mutations in 9 high-to-moderate risk genes and 157 SNPs that have a validated association with breast cancer risk in Caucasian, African American, Asian, and Latino populations. The pilot is open as of Oct 2015 and the full trial opens April 2016. Clinical trial information: NCT02620852.
Pan-cancer panel testing in individuals with abnormal immunohistochemistry (IHC) staining of the mismatch-repair (MMR) genes.
Authors: Shujuan Pan, Hannah C Cox, Krystal Brown, Jamie Willmott, Heidi Gorringe, Erin Mundt, Eric Thomas Rosenthal, Karla Bowles, Bradford Coffee, Debora Mancini-Dinardo
Journal: Journal of Clinical Oncology (2017)

e13014 Background: IHC staining of the MMR genes is often used to screen for Lynch syndrome (LS) in patients with newly diagnosed colorectal cancer (CRC) and endometrial cancer (EC). Genetic testing of MMR genes guided by IHC has historically been used to confirm a diagnosis of LS. Given the known genetic heterogeneity of LS-related cancers, we assessed the extent to which IHC results reliably predicted findings with pan-cancer panel testing. Methods: We analyzed results from pan-cancer panel testing of 750 individuals with abnormal IHC results from 2013-2016. The panel included the MMR genes and other genes associated with CRC and/or other cancers. All clinical data, including IHC results, were obtained from provider-completed test request forms. Results: CRC (66.0%) was the most common cancer among tested individuals with abnormal IHC results, followed by EC (35.1%). 236 pathogenic variants (PVs) were identified in 228 (30.4%) individuals, 8 of whom carried two distinct mutations. Overall, 191 (80.9%) PVs occurred in MMR genes that were concordant with IHC results. The remaining 45 (19.1%) PVs were not predicted by IHC results, and included two PVs in MMR genes ( MSH6 PV with MLH1/PMS1 absent in IHC, MSH2 PV with PMS2 absent in IHC). The majority of PVs that were not predicted by IHC results occurred in non-MMR genes associated with CRC and EC (n=27, 60.0%; see Table). Conclusions: In this cohort, PVs were identified in 30% of individuals with abnormal IHC who were tested with a pan-cancer panel. Nearly 20% of PVs occurred in non-MMR genes that would be missed by MMR gene-specific testing based on IHC results. Collectively, this suggests pan-cancer panel testing may increase diagnostic yield among individuals with abnormal IHC. [Table: see text]
Parkinson’s Disease Genes VPS35 and EIF4G1 Interact Genetically and Converge on α-Synuclein
Authors: Nripesh Dhungel, Simona Eleuteri, Ling-bo Li, Nicholas J. Kramer, Justin W. Chartron, Brian Spencer, Kori Kosberg, Jerel Adam Fields, Klodjan Stafa, Anthony Adame, Hilal Lashuel, Judith Frydman, Kang Shen, Eliezer Masliah, Aaron D. Gitler
Journal: Neuron (2015)
Abstract 13647: Comparison of the HEART and TIMI Risk Scores for Suspected Acute Coronary Syndrome in the Emergency Department
Authors: Benjamin Sun, Amber Laurie
Journal: Circulation (2015)

Introduction: The emergency department (ED) evaluation for suspected acute coronary syndrome (ACS) is common, costly, and challenging. Risk scores may facilitate clinical care and screening for research studies. The Thrombolysis in Myocardial Infarction (TIMI) score is perhaps the best known example, but the HEART score demonstrates promise specifically in ED settings. Hypothesis: We tested the null hypothesis that the TIMI and HEART risk scores have equivalent test characteristics in the ED evaluation of suspected ACS. Methods: We analyzed data from the Internet Tracking Registry of Acute Coronary Syndromes (i*trACS) from 9 EDs on patients with suspected ACS, 1999-2001. We excluded patients with an ED diagnosis of ACS, or without sufficient data to calculate TIMI and HEART scores. The primary outcome was 30-day major adverse cardiovascular events (MACE), including all-cause death, acute myocardial infarction, and urgent revascularization. We describe test characteristics of the TIMI and HEART risk scores. Results: The study cohort included 8,255 patients with 508 (6.2%) 30-day MACE. Receiver operating curve analysis favored HEART (c-statistic: 0.75, 95%CI 0.73-0.77) over TIMI (c-statistic: 0.68, 95%CI 0.66-0.70). A HEART score &gt;3 (negative predictive value[NPV] 0.98, 95%CI 0.98-0.99; positive predictive value [PPV] 0.10, 95%CI 0.09-0.11) demonstrates equivalent or superior NPV/PPV compared to TIMI&gt;0 (NPV 0.98, 95%CI;0.97-0.98; PPV 0.08, 95%CI 0.07-0.08) and TIMI&gt;1 (NPV 0.96, 95%CI 0.96-0.97; PPV 0.1, 95%CI 0.09-0.11). Conclusions: The HEART score is more accurate than TIMI and specifically outperforms TIMI at “low-risk” thresholds.
Platelets Express Activated P2Y <sub>12</sub> Receptor in Patients With Diabetes Mellitus
Authors: Liang Hu, Lin Chang, Yan Zhang, Lili Zhai, Shenghui Zhang, Zhiyong Qi, Hongmei Yan, Yan Yan, Xinping Luo, Si Zhang, Yiping Wang, Satya P. Kunapuli, Hongying Ye, Zhongren Ding
Journal: Circulation (2017)

Background: Platelets from patients with diabetes mellitus are hyperactive. Hyperactivated platelets may contribute to cardiovascular complications and inadequate responses to antiplatelet agents in the setting of diabetes mellitus. However, the underlying mechanism of hyperactivated platelets is not completely understood. Methods: We measured P2Y 12 expression on platelets from patients with type 2 diabetes mellitus and on platelets from rats with diabetes mellitus. We also assayed platelet P2Y 12 activation by measuring cAMP and VASP phosphorylation. The antiplatelet and antithrombotic effects of AR-C78511 and cangrelor were compared in rats. Finally, we explored the role of the nuclear factor-κB pathway in regulating P2Y 12 receptor expression in megakaryocytes. Results Platelet P2Y 12 levels are 4-fold higher in patients with type 2 diabetes mellitus compared with healthy subjects. P2Y 12 expression correlates with ADP-induced platelet aggregation (r=0.89, P &lt;0.01). P2Y 12 in platelets from patients with diabetes mellitus is constitutively activated. Although both AR-C78511, a potent P2Y 12 inverse agonist, and cangrelor have similar antiplatelet efficacy on platelets from healthy subjects, AR-C78511 exhibits more powerful antiplatelet effects on diabetic platelets than cangrelor (aggregation ratio 36±3% versus 49±5%, respectively, P &lt;0.05). Using a FeCl 3 -injury mesenteric arteriole thrombosis model in rats and an arteriovenous shunt thrombosis model in rats, we found that the inverse agonist AR-C78511 has greater antithrombotic effects on GK rats with diabetes mellitus than cangrelor (thrombus weight 4.9±0.3 mg versus 8.3±0.4 mg, respectively, P &lt;0.01). We also found that a pathway involving high glucose-reactive oxygen species-nuclear factor-κB increases platelet P2Y 12 receptor expression in diabetes mellitus. Conclusions Platelet P2Y 12 receptor expression is significantly increased and the receptor is constitutively activated in patients with type 2 diabetes mellitus, which contributes to platelet hyperactivity and limits antiplatelet drug efficacy in type 2 diabetes mellitus.
Spectrochemical analysis highlights similarities in adenocarcinomas irrespective of primary tissue origins.
Authors: Danielle Bury, Guy Faust, Maria Paraskevaidi, Timothy P Dawson, Francis L. Martin
Journal: Journal of Clinical Oncology (2017)

e13551 Background: Identification of primary tissue origin of brain metastases can be histopathologically challenging. Initial diagnosis of malignancy can be provided on intraoperative tissue smears; however, it requires formal histopathological examination along with immunohistochemistry to reach a final diagnosis. On occasion this will still fail to determine primary origin. This study aims to demonstrate if Raman spectroscopy is able to determine primary tissue origin of brain metastasis of three common primary tumours. Methods: Formalin fixed paraffin embedded tissue from twenty brain metastasis comprising colorectal adenocarcinomas ( n= 7), lung adenocarcinomas ( n= 7) and melanomas ( n= 6) were obtained from the Brain Tumour NorthWest tissue bank. Sections (10-μm thick) were placed onto glass slides covered in aluminium foil and de-waxed prior to spectral acquisition. 25 spectra per section were collected at random, using a 785 nm laser at 1200 g mm -1 grating with an acquisition time of 30 sec. Computational analysis within a MatLab environment was then conducted. Results: Following PCA-LDC analysis, classification accuracy of the three groups was; colorectal adenocarcinoma 71.3%, lung adenocarcinoma 71% and melanoma 70%. A one-way ANOVA showed statistically significant differences between the three groups, p = 0.0014. On combining adenocarcinoma groups accuracy increased to 87.8%, whilst melanoma fell to 68.9%. A student’s t-test confirmed statistical significance between the two groups, p &lt; 0.0001. Conclusions: Raman spectroscopy can classify different tumours by type, though sensitivity and specificity is diminished if used to classify primary tissue origin of adenocarcinomas. Therefore for clinical use, such new tools may aid the clinician to determine tumour type intra-operatively but classic histopathology is still required for tissue origin confirmation. Such technologies may provide a useful adjunct to more conventional approaches; for instance, decreasing the number of immunohistochemical stains required to determine tissue origin. These results also suggest strong similarities between adenocarcinomas of different primary origins.
Efficacy of a Weight Loss Intervention for African American Breast Cancer Survivors
Authors: Melinda Stolley, Patricia Sheean, Ben Gerber, Claudia Arroyo, Linda Schiffer, Anjishnu Banerjee, Alexis Visotcky, Giamila Fantuzzi, Desmona Strahan, Lauren Matthews, Roxanne Dakers, Cynthia Carridine-Andrews, Katya Seligman, Sparkle Springfield, Angela Odoms-Young, Susan Hong, Kent Hoskins, Virginia Kaklamani, Lisa Sharp
Journal: Journal of Clinical Oncology (2017)

Purpose African American women with breast cancer have higher cancer-specific and overall mortality rates. Obesity is common among African American women and contributes to breast cancer progression and numerous chronic conditions. Weight loss interventions among breast cancer survivors positively affect weight, behavior, biomarkers, and psychosocial outcomes, yet few target African Americans. This article examines the effects of Moving Forward, a weight loss intervention for African American breast cancer survivors (AABCS) on weight, body composition, and behavior. Patients and Methods Early-stage (I-III) AABCS were randomly assigned to a 6-month interventionist-guided (n = 125) or self-guided (n = 121) weight loss program supporting behavioral changes to promote a 5% weight loss. Anthropometric, body composition, and behavioral data were collected at baseline, postintervention (6 months), and follow-up (12 months). Descriptive statistics and mixed models analyses assessed differences between groups over time. Results Mean (± standard deviation) age, and body mass index were 57.5 (± 10.1) years and 36.1 (± 6.2) kg/m
NO DIFFERENCE IN MUSCLE INJURY RATES DURING PROFESSIONAL FOOTBALL MATCHES PRECEDED BY THREE TO FIVE DAYS OF RECOVERY
Authors: Håkan Bengtsson, Jan Ekstrand, Markus Waldén, Martin Hägglund
Journal: British Journal of Sports Medicine (2017)

Background There are conflicting results concerning associations between match congestion and injury rates in professional football. Objective To analyze associations between short term match congestion and injury rates in professional football and to study the influence of long term match congestion on such associations. Design Prospective cohort study. Setting Male professional football. Participants 122 743 individual match exposures for 2 625 players. Assessment of Risk Factors Short term match congestion was defined as the number of days recovery between two match exposures. Long term match congestion was defined as the total match exposure in 30 days preceding a match. Injury rates during individual player match exposures were compared depending on short term match congestion (≤3, 4, 5, 6, and 7 to 10 recovery days). To analyse the influence of players' long term match congestion all match observations were grouped into tertiles (long term match congestion ≤5.0, 5.0 to 7.5 and ≥7.5 hours respectively) and analysed separately. Main Outcome Measurements Muscle injury rates. Results There was no difference in muscle injury rates in matches preceded by four (OR 1.03, 95% CI 0.90 to 1.19) or five (OR 1.03, 95% CI 0.85 to 1.25) days recovery compared with the reference group three or less. However, muscle injury rates were lower in matches preceded by six (OR 0.80, 95% CI 0.65 to 0.97) or seven to ten days of recovery (OR 0.81, 95% CI 0.70 to 0.93) compared with three or less. The same patterns persisted in all long term match congestion tertiles. Conclusions While no protective effect was seen after four or five days recovery compared to three or less days muscle injury rates were lower after six or more days recovery between matches.