tbuckley/cabot-search huggingface dataset:
Clinical significance of ERβ mRNA expression in ERα-negative and triple-negative breast cancers.
Authors: Young Choi Kim, Hadong Kim, Tae-Hoon Kim
Journal: Journal of Clinical Oncology (2013)

545 Background: Previously at the 2012 ASCO meeting, we reported significant ERβ mRNA expression in ERα-negative (ERα-) and triple negative breast cancers (TNBC). In this study, we analyzed its clinical outcome and correlation with other clinical parameters. Methods: A total of 141 cases consisted of 69 ERα- BC including 41 TNBC and 72 ERα+ BC were obtained from patients aged 29 to 97 years old between 2003 and 2010. Treatments included surgery, hormone, chemo- or radiotherapy, or any combinations. The follow-up period ranged from 1 to 132 months. ERβ mRNA was analyzed from formalin-fixed tumor tissues by RT-PCR. ERα, PR, Her-2, Ki-67, AIB-1, NFk/p65, p-c-jun, Ki-67, TIF-2, SRC-1, CK5/6 and p53 were tested by immunohistochemistry. The correlation was deemed significant if p value less than 0.05 from Chi-square. Overall survival (SVR) was defined from the date of diagnosis to last follow-up or death attributed to BC and was analyzed by the Kaplan-Meier curves and Wilcoxon rank sum. Results: Single or combination of ERβ isoform(s) was highly expressed in both ERα- and TNBC and ERβ2 was the most frequent (48.8%) and ERβ5, the least (30.2%). In contrast, ERβ5 was the most frequent in ERα+BC. Presence of all or any ERβ isoform was associated with significantly higher SVR in all cases, and in TNBC (ERβ total, Wilcoxon p = 0.0177, ERβ2, p= 0.0329), and also with negative LN (p&lt; 0.0001). ERβ2 and ERβ5 were expressed in 63.2% and 30 %, respectively, in 20 patients died in 1 to 60 months. Over expression of AIB-1, NF-kB/p65 and TIF-2 was associated with ERβ1 and ERβ2 (p&lt;0.05). Ki-67 + cells were mostly ERβ + BC than ERα+. ERα mRNA expression was up-regulated, and ERβ,down- regulated, with the ERα: ERβ+ ratio of 3-1000:1. There was no association between ERβ expression and the stage, age, tumor size, and postmenopausal status. Conclusions: Specific ERβ isoform appears to be a significant discriminating factor for SVR and negative node. ERβ2 is the predominant isoform in ERα- but ERβ5 in ERα+BC, suggesting a distinct role of ERβ isoform in ERα- and ERα+BC. ERβ isoform may be a selective therapeutic target in this cohort. ERβ+/ Ki-67+cells appear to be a sub-population of BC arising from basal-myoepithelial cells in this cohort.
Mammostrat as an immunohistochemical multigene assay for prediction of early relapse risk in the TEAM pathology study.
Authors: John M. S. Bartlett, Kenneth J. Bloom, Tammy Robson, Thomas J. Lawton, Cornelis J. H. Van De Velde, Douglas T. Ross, Robert S. Seitz, Rodney A. Beck, Annette Hasenburg, Dirk Guenter Kieback, Hein Putter, Christos Markopoulos, Luc Yves Dirix, Caroline M. Seynaeve, Daniel Rea
Journal: Journal of Clinical Oncology (2012)

516 Background: Some postmenopausal patients with hormone sensitive early breast cancer remain at high risk of relapse despite endocrine therapy, and might benefit additionally from adjuvant chemotherapy. The challenge is to prospectively identify such patients. The Mammostrat test uses five immunohistochemical markers to stratify patients regarding recurrence risk, and may inform treatment decisions. We tested the efficacy of this panel in the TEAM trial. Methods: Pathology blocks from 4598 TEAM patients were collected and TMAs constructed. The cohort was 47% node positive and 36% were also treated with adjuvant chemotherapy. Triplicate 0.6mm 2 TMA cores were stained and positivity for p53, HTF9C, CEACAM5, NDRG1, SLC7A5 assessed. Cases were assigned a Mammostrat risk score, and distant relapse free (DRFS) and disease free survival (DFS) analysed. Results: In multivariate regression analyses, corrected for conventional clinicopathological markers, Mammostrat provided significant additional information on DRFS after endocrine therapy in ER positive node negative patients (N=1226) not receiving chemotherapy (p=0.004). Further analyses in all patients not exposed to chemotherapy, irrespective of nodal status (N=2559) and in the entire cohort (N=3837) showed Mammostrat scores provide additional information on DRFS in these groups (p=0.001 and p&lt;0.0001 respectively; multivariate analyses). No differences were seen between the two endocrine treatment regimens. Conclusions: The Mammostrat score predicts DRFS for both exemestane and tamoxifen-exemestane treated patients irrespective of nodal status and chemotherapy. The ability of this test to provide additional outcome data following treatment provides further evidence for its’ utility in risk stratification of ER positive postmenopausal breast cancer patients.
Gene scoring model to predict recurrence in low- and intermediate-risk uterine endometrial cancer: Establishment of uterine print.
Authors: Tatsuyuki Chiyoda, Yoichi M Ito, Fumio Kataoka, Wataru Yamagami, Hiroyuki Nomura, Hiroshi Tsuda, Hideo Tanaka, Masashi Takano, Sadako Nishimura, Yoko Iguchi, Shiho Hashimoto, Tomoko Yoshihama, Nobuyuki Susumu, Daisuke Aoki
Journal: Journal of Clinical Oncology (2013)

5590 Background: Endometrial cancers (ECs) classified as low-, intermediate-, and high-risk, based on clinical and pathological features (CPF: Lurain, 2007) associated with 5%, 15%, and 25% risk of recurrence, respectively. The need for adjuvant chemotherapy in intermediate-risk patients is controversial. We examined whether gene expression profiling can more accurately predict the prognosis of ECs, excluding the CPF-based high-risk group. Methods: Tumor specimens were obtained from 136 ECs including 14 recurrences, excluding high-risk cases. Gene expression profiles were achieved using a custom array consisting of 85 genes associated with EC recurrence and 20 internal controls that were previously screened. We established the gene scoring model (GSM) for recurrence by the logistic regression model in randomly selected 68 ECs including 7 recurrences, and evaluated the accuracy of GSM in other 68 ECs including 7 recurrences. This process was repeated 100 times. We calculated the mean accuracy of GSM and compared it with the accuracy of CPF. We also compared GSM and CPF with respect to progression-free survival (PFS) by use of the log-rank test. Results: Median age of all cases was 58 (29-86) years, and stage, histologic grade, and risk classification based on CPF were as follows: (I, 107; II, 15; III, 14), (G1, 69; G2, 57; G3, 10), and (low, 67; intermediate, 69). The median follow-up period was 1830 (1626-3444) days. The GSM was established based on the expression of 4 genes (PRCC, SPC25, PXDN, and LBXCOR1) and 10 internal controls. The area under the receiver operating characteristic curve of GSM to predict recurrence was 0.87 in 68 test cases. Based on the CPF, 68 cases were classified as 30 low-risk and 38 intermediate-risk, and the sensitivity and specificity of CPF was 86% and 48% each in the 68 test cases. When sensitivity of GSM was fixed at 86%, specificity of 67% was achieved, and 68 cases were classified as 42 risk (-) and 26 risk (+). PFS was significantly related with GSM (p = 0.006); however, it was not related with CPF (p = 0.09). Conclusions: GSM can predict the prognosis of ECs (low- and intermediate-risk) more precisely than CPF.
Dietary Fat and Its Relation to Heart Attacks and Strokes
Journal: JAMA (1961)

CURRENT available knowledge is sufficient to warrant a general statement regarding the relation of diet to the possible prevention of atherosclerosis (Appendix I). A heart attack, also called coronary thrombosis or myocardial infarction, or just plain "coronary," is almost always caused by atherosclerosis (arteriosclerosis or hardening of the arteries). Stroke, or apoplexy, is often caused by the same condition. The problem of preventing or retarding these diseases is, then, one of preventing or retarding atherosclerosis. <h3>How Does Atherosclerosis Develop?—</h3> Athero-Atherosclerosis is a complex disease of the arteries. It is known that a number of factors influence or are related to its development. Among these factors are a high content in the blood of a type of fat called cholesterol, elevation of blood pressure above normal, presence of diabetes, obesity, and a habit of excessive cigarette smoking. Age, sex, and heredity are also important. <h3>What Types of Research Relate Diet to</h3>
Response prediction by MALDI-TOF-MS serum peptide profiling of combination treatment with sorafenib and erlotinib in patients with non-small cell lung cancer.
Authors: Maria Rovithi, Joline S. Lind, Thang V Pham, Jaco C Knol, Henk M.W. Verheul, Egbert F Smit, Connie R. Jimenez
Journal: Journal of Clinical Oncology (2012)

e18094 Background: Mass spectrometry can be used to generate diagnostic peptide peak profiles "signatures" of serum samples 1 . Peak profiles can be used to compare different sera and correlate samples (i.e., patient groups) with clinical data to assist in diagnosis, monitoring, and/or prediction. Indeed, in recent studies, we and other researchers have successfully combined serum peptide profiling by mass spectrometry (MS) with bioinformatics and have established distinctive serum polypeptide MS patterns that correlate with cancer types and clinically relevant outcomes 2 . We performed serum peptide profiling of patients with advanced stage non-small cell lung cancer (NSCLC) treated with erlotinib and sorafenib in a previously reported clinical trial at baseline, after one week of treatment, and after three weeks of treatment, to establish treatment efficacy signatures. Methods: Using automated magnetic C18 bead-assisted serum peptide capture coupled to matrix-assisted laser desorption/ ionization time of flight mass spectrometry (MALDI-TOF MS), serum peptide profiling 1 of 50 NSCLC patients was conducted and peptide mass profiles (spectra) obtained. Data analyses of pretreatment serum peptide profiles, as well as dynamic changes in peptide abundance during treatment, were performed to establish support-vector machine-based algorithms that can predict treatment efficacy. Results: A 13 ion-peptide signature could discriminate with a sensitivity of 93% and specificity of 71% a training group of patients with short progression free survival (n=14) and long progression free survival (n=14). The signature shows discriminative power for the remaining non-overlapping set of 22 patients, as well as for the complete dataset of 50 patients. Pattern analysis of overall responses and toxicity is ongoing. Conclusions: Serum peptidome profiling using MALDI-TOF-MS coupled to pattern diagnostics may provide biomarkers predictive of response to targeted treatment in patients with NSCLC, thus enabling pretreatment selection of appropriate subgroups.
The Elderly Project By the Fondazione Italiana Linfomi (FIL): A Prospective Multidimensional Assessment of Elderly Patients with Diffuse Large B-Cell Lymphoma
Authors: Francesco Merli, Stefano Luminari, Alessandra Tucci, Federica Cavallo, Caterina Mammi, Luigi Rigacci, Erica Finolezzi, Giuseppina Cabras, Alberto Fabbri, Vittorio Ruggero Zilioli, Dario Marino, Annalisa Chiappella, Monica Balzarotti, Annalisa Arcari, Guido Gini, Flavia Salvi, Stefan Hohaus, Monica Tani, Roberto Sartori, Maria Christina Cox, Luigi Marcheselli, Michele Spina
Journal: Blood (2016)
Do patient-reported symptoms predict for emergency department visits? A population-based analysis.
Authors: Lisa Catherine Barbera, Clare Atzema, Rinku Sutradhar, Hsien Seow, Doris Howell, Amna Husain, Jonathan Sussman, Craig Earle, Ying Liu, Deborah Jane Dudgeon
Journal: Journal of Clinical Oncology (2012)

6039 Background: Since 2007 in Ontario, Canada, the Edmonton Symptom Assessment System (ESAS) has been routinely used to assess symptoms in cancer patients in both ambulatory and home-care settings. The purpose of this study was to determine the relationship between individual patient symptoms, and their severity, with the likelihood of an emergency department (ED) visit. Methods: The cohort includes all cancer patients in Ontario who completed an ESAS assessment between January 2007 and March 2009. We linked multiple provincial health databases to describe the cohort and determine if an ED visit occurred within 7 days of the patient’s first ESAS. Multivariate logistic regression was used to determine the association between symptom scores (absent: score 0; mild: 1-3; moderate: 4-7; severe: 8-10) and the likelihood of an ED visit. Results: The cohort included 45,118 unique patients whose first assessment contributes to the study. 3.8% (n=1732) had an ED visit. The patients with ED visits were more likely to be men, to have lung or gastro-intestinal cancer, to have had recent radio or chemotherapy, and to have a shorter survival. The proportion of patients with ED visits increased from 2% to 10-12% as individual symptom scores increased from 0 to 10. Anxiety and depression were not associated with ED visits in the model, regardless of severity. Pain, nausea, drowsiness, appetite and shortness of breath with moderate or severe scores were associated with ED visits. Tiredness and wellbeing were the only symptoms to show a significant association for mild, moderate and severe scores. A well being score of 7-10 (reference score=0) had the highest odds ratio of 1.8 (95% CI 1.4-2.3). Conclusions: Worsening symptoms clearly contribute to ED visits. While specific symptoms like pain are obvious targets for management in the outpatient setting, constitutional symptoms like wellbeing or fatigue are associated with even higher odds. Though difficult to manage, such symptoms also warrant detailed assessment in order to optimize patient outcomes.
Genome-wide association study of glioma subtypes identifies specific differences in genetic susceptibility to glioblastoma and non-glioblastoma tumors
Authors: Beatrice S Melin, Jill S Barnholtz-Sloan, Margaret R Wrensch, Christoffer Johansen, Dora Il'yasova, Ben Kinnersley, Quinn T Ostrom, Karim Labreche, Yanwen Chen, Georgina Armstrong, Yanhong Liu, Jeanette E Eckel-Passow, Paul A Decker, Marianne Labussière, Ahmed Idbaih, Khe Hoang-Xuan, Anna-Luisa Di Stefano, Karima Mokhtari, Jean-Yves Delattre, Peter Broderick, Pilar Galan, Konstantinos Gousias, Johannes Schramm, Minouk J Schoemaker, Sarah J Fleming, Stefan Herms, Stefanie Heilmann, Markus M Nöthen, Heinz-Erich Wichmann, Stefan Schreiber, Anthony Swerdlow, Mark Lathrop, Matthias Simon, Marc Sanson, Ulrika Andersson, Preetha Rajaraman, Stephen Chanock, Martha Linet, Zhaoming Wang, Meredith Yeager, John K Wiencke, Helen Hansen, Lucie McCoy, Terri Rice, Matthew L Kosel, Hugues Sicotte, Christopher I Amos, Jonine L Bernstein, Faith Davis, Dan Lachance, Ching Lau, Ryan T Merrell, Joellen Shildkraut, Francis Ali-Osman, Siegal Sadetzki, Michael Scheurer, Sanjay Shete, Rose K Lai, Elizabeth B Claus, Sara H Olson, Robert B Jenkins, Richard S Houlston, Melissa L Bondy
Journal: Nature Genetics (2017)
Phase 1 study of dabrafenib in pediatric patients (pts) with relapsed or refractory <i>BRAF</i> V600E high- and low-grade gliomas (HGG, LGG), Langerhans cell histiocytosis (LCH), and other solid tumors (OST).
Authors: Mark W. Kieran, Darren R Hargrave, Kenneth J. Cohen, Isabelle Aerts, Ira J. Dunkel, Trent Ryan Hummel, Irene Jimenez, Andrew DJ Pearson, Christine A. Pratilas, James Whitlock, Eric Bouffet, Wei-Ping Violet Shen, Alberto Broniscer, Anne-Isabelle Bertozzi, Joan L Sandberg, Allison M. Florance, Benjamin B. Suttle, Pat Haney, Mark W. Russo, Birgit Geoerger
Journal: Journal of Clinical Oncology (2015)

10004 Background: Dabrafenib is an orally available, selective ATP-competitive inhibitor of BRAF V600E kinase, approved in unresectable or metastatic melanoma pts with the V600E mutation. This international study was designed to determine the recommended phase 2 dose (RP2D) in pts < 18yrs based on maximum tolerated dose, or systemic exposure similar to that seen in adult pts (AUC, 4000–5500 ng*h/mL), whichever came first. Methods: Dabrafenib was given orally twice daily, beginning at 3.0mg/kg/day. Toxicity, pharmacokinetics, and response were assessed by disease-appropriate criteria at each dose for pts > 12yrs and ≤ 12yrs. Doses of 3.0, 3.75, 4.5, and 5.25mg/kg/day were assessed by a rolling six design. When a dose level was filled and under assessment, additional pts could join the previous dose level deemed tolerable. Results: Enrollment for phase 1 completed at 27 pts, 15 male, median age 9yrs (range 1–17), with HGG n = 8, LGG n = 15, LCH n = 2, and OST n = 2. One pt had a dose-limiting toxicity (DLT) of grade 3 maculopapular rash (MR) at 4.5mg/kg/day, but is on study ≈9mths after restarting dabrafenib at 3.75mg/kg/day. Serious adverse events judged related to dabrafenib included MR (1 pt); hypotension, disseminated intravascular coagulation, fever (1 pt, outside DLT period); and arthralgia (1 pt). Duration on study ranged from 9wks to 19mo (ongoing); 20 pts remain on treatment. The RP2D for pts > 12yrs is 4.5mg/kg/day (median AUC 5285) and 5.25mg/kg/day (median AUC 4384) for ≤ 12yrs. Investigator-assessed best radiographic responses included 3 complete response (CR), 3 partial response (PR) and 2 progressive disease (PD) in HGG; 8 PR, 6 stable disease (SD) and 1 PD in LGG; 2 CR in LCH; 1 SD and 1 PD in OST (source data verification ongoing). Conclusions: The RP2D of dabrafenib for children > 12yrs and for those ≤ 12 was determined based on the target AUC when taken twice daily. The drug was well-tolerated with manageable toxicity. A high proportion of pts demonstrated radiographic responses in this phase 1 trial in different BRAF V600E-positive tumors. The disease stratified phase 2 component of the study is underway (NCT01677741). Clinical trial information: NCT01677741.
Incidence of venous thromboembolic events (VTE) in multiple myeloma patients receiving lenalidomide (LEN) with and without dexamethasone (DEX).
Authors: Nancy A. Brandenburg, Tyler Knight, Kathryn P. Anastassopoulos, Neil Minton, Robert D. Knight
Journal: Journal of Clinical Oncology (2012)

e18559 Background: LEN showed significant efficacy and was generally well tolerated when combined with DEX in two randomized, double-blind, pivotal phase 3 registration trials in relapsed or refractory multiple myeloma (MM). VTEs have been associated with LEN and DEX combination (LEN+DEX) regimens in patients (pts) who may have other risk factors for VTE. Fewer VTEs have been reported among pts receiving low dose DEX. This study examined the incidence of first VTE and associated risk factors among MM pts receiving LEN and LEN+DEX. Methods: An exploratory, retrospective, claims-based study of pts diagnosed with MM and receiving LEN from Jan 2006 – June 2008 was performed using OptumInsight’s Invision Data Mart Multiplan database. Pts receiving additional MM chemotherapies were excluded. DEX dose level was defined over the first four 28-day cycles of LEN as: low (≤160 mg), medium (&gt;160 mg to &lt;480 mg), or high (≥ 480 mg). Cumulative incidence of first VTE (deep vein thrombosis or pulmonary embolism) within 120 days of initiating LEN treatment was calculated from Kaplan-Meier curves. Risk factors for VTE were examined using hazard ratios (HRs) from a Cox model that included demographics, prior MM therapy, comorbid conditions, DEX dose, and prophylactic use of anti-thrombotics. Results: 643 LEN-treated MM pts were identified (mean age 60 years, 60% male, 13.5% with prior VTE). Cumulative incidence of first VTE at 120 days from first LEN dose was 6.1% overall (95% CI 4.4-8.3%) and 7.2% (5.1-10.2%) in LEN+DEX. VTE risk for LEN without DEX (n=190; 66 with other steroids) was 3.4% (1.5-7.5%). VTE risk by DEX dose level was 5.9% (3.6-9.7%) for low DEX (n=286), 7.5% (3.6-15.1%) for medium DEX (n=99), and 12.3% (6.3-23.1%) for high DEX (n=66). Significant risk factors for VTE were prior VTE (HR=3.9; p&lt;0.001), recent surgery (HR=2.1; p=0.047), renal failure (HR=2.2; p=0.023), and high dose DEX (HR=2.3; p=0.045). Conclusions: Incommunity-based MM pts treated with LEN+DEX, VTE risk increases with the dose of DEX. The exact mechanism by which DEX intensity impacts VTE is not clear. In addition to high dose DEX, other known VTE risk factors were observed.
First-in-human phase 1 study of the novel indoleamine-2,3-dioxygenase (IDO) inhibitor NLG-919.
Authors: Samir Khleif, David Munn, Asha Nyak-Kapoor, Mario R. Mautino, Eugene Kennedy, Nicholas N. Vahanian, Charles J. Link
Journal: Journal of Clinical Oncology (2014)

TPS3121 Background: IDO is an enzyme that catalyzes the initial and rate limiting step in the conversion of tryptophan to kynurenine. Tryptophan depletion enhances the number and function of the Treg (suppressive) arm of the immune system and inhibits the effector T cell (stimulatory) arm. In addition, it has been shown that kynurenine metabolites may augment the suppressive effects on inflammation and immune responses. The main function of IDO is the regulation of acquired local and peripheral immune tolerance in normal and pathological conditions. In cancer, IDO can either be expressed directly by the tumor cells themselves, or induced indirectly in host antigen presenting cells by the tumor. In these settings, IDO mediates an acquired immune tolerance towards tumors, allowing tumors to thwart immune responses by the host. Therefore, IDO is an attractive target in therapeutic interventions aimed at restoring the immune response towards the tumor. NLG-919 inhibits the enzymatic activity of IDO. Agents that inhibit the IDO pathway have been shown to act synergistically with each other as well as with chemotherapy and other checkpoint inhibitors such as anti-CTLA-4, anti-PD-1, and anti-PD-L1. We believe current SOC treatments that incorporate single or multiple IDO pathway inhibitors in combination with other checkpoint inhibitors may add significant benefit to an active immunotherapy regimen. Methods: This study is a Phase 1, dose escalation study of NLG-919 for patients with advanced solid tumor malignancies. Eligible patients have pathologically confirmed relapsed or refractory solid tumors for which no approved therapy exists. Up to 36 patients will be enrolled and the dose of NLG-919 will be escalated according to a standard 3+3 design. NLG-919 will be administered orally twice daily for the first 21 days of repeating 28 day cycles. Patients may receive drug until disease progression. Endpoints include safety, toxicity, and determination of a MTD or MBED that can be taken forward into phase 2 studies. Furthermore, additional immunological, pharmacokinetic, and pharmacodynamics tests are also planned. Clinical trial information: NCT02048709.