tbuckley/cabot-search huggingface dataset:
A rationale and model for tobacco and nicotine assessment during cancer treatment.
Authors: G. W. Warren, S. M. Arnold, J. Valentino, M. Randall, M. R. Kudrimoti
Journal: Journal of Clinical Oncology (2010)

e12034 Background: Tobacco use during cancer treatment is associated with poor clinical outcomes, but accurate tobacco and nicotine use (TNU) assessments are limited in cancer treatment populations. To address the interactions between TNU and clinical cancer treatment, an efficient model of assessment requires development. Methods: A longitudinal cohort of head and neck squamous cell carcinoma patients treated with definitive radiotherapy (RT) or chemoradiotherapy (CRT) are being enrolled in an Institutional Review Board approved protocol to evaluate the relationship between TNU and treatment outcome, recurrence, and survival using entry and weekly self-reported (SR) assessments in combination with objective serum cotinine (SC) measurements (a quantifiable marker of TNU). Results: A thorough background review is presented demonstrating that TNU promotes tumor growth and decreases therapeutic response in clinical and/or preclinical models. At interim analysis, 50 patients are enrolled and SC assessments are complete for 37 patients. Though 32% report TNU at study entry, SC confirms that 41% have TNU at some time during RT or CRT and 22% continued TNU in the last week of RT or CRT. There is significant variability in SC concentrations within individual patients over the course of RT or CRT. Even with patient knowledge of SC assessments, SR assessments did not identify 20% of SC positive patients. In 30% of patients reporting tobacco use at study entry, 55% planned to continue tobacco use during RT or CRT. Patients reported that family and friends (not doctors) were the primary social support for cessation. Conclusions: There is significant individual SC variability during RT or CRT and specific TNU patterns are not well characterized with single SR or SC entry assessments. This model demonstrates an inexpensive mechanism of monitoring TNU during cancer treatment and should be incorporated into the design and analysis of clinical trials. No significant financial relationships to disclose.
Translational Breast Cancer Research Consortium (TBCRC) 022: A Phase II Trial of Neratinib for Patients With Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer and Brain Metastases
Authors: Rachel A. Freedman, Rebecca S. Gelman, Jeffrey S. Wefel, Michelle E. Melisko, Kenneth R. Hess, Roisin M. Connolly, Catherine H. Van Poznak, Polly A. Niravath, Shannon L. Puhalla, Nuhad Ibrahim, Kimberly L. Blackwell, Beverly Moy, Christina Herold, Minetta C. Liu, Alarice Lowe, Nathalie Y.R. Agar, Nicole Ryabin, Sarah Farooq, Elizabeth Lawler, Mothaffar F. Rimawi, Ian E. Krop, Antonio C. Wolff, Eric P. Winer, Nancy U. Lin
Journal: Journal of Clinical Oncology (2016)

Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer in the CNS are limited. Neratinib is an irreversible inhibitor of erbB1, HER2, and erbB4, with promising activity in HER2-positive breast cancer; however, its activity in the CNS is unknown. We evaluated the efficacy of treatment with neratinib in patients with HER2-positive breast cancer brain metastases in a multicenter, phase II open-label trial.Eligible patients were those with HER2-positive brain metastases (≥ 1 cm in longest dimension) who experienced progression in the CNS after one or more line of CNS-directed therapy, such as whole-brain radiotherapy, stereotactic radiosurgery, and/or surgical resection. Patients received neratinib 240 mg orally once per day, and tumors were assessed every two cycles. The primary endpoint was composite CNS objective response rate (ORR), requiring all of the following: ≥ 50% reduction in volumetric sum of target CNS lesions and no progression of non-target lesions, new lesions, escalating corticosteroids, progressive neurologic signs/symptoms, or non-CNS progression--the threshold for success was five of 40 responders.Forty patients were enrolled between February 2012 and June 2013; 78% of patients had previous whole-brain radiotherapy. Three women achieved a partial response (CNS objective response rate, 8%; 95% CI, 2% to 22%). The median number of cycles received was two (range, one to seven cycles), with a median progression-free survival of 1.9 months. Five women received six or more cycles. The most common grade ≥ 3 event was diarrhea (occurring in 21% of patients taking prespecified loperamide prophylaxis and 28% of those without prophylaxis). Patients in the study experienced a decreased quality of life over time.Although neratinib had low activity and did not meet our threshold for success, 12.5% of patients received six or more cycles. Studies combining neratinib with chemotherapy in patients with CNS disease are ongoing.
Abstract 9642: An Image Based Evaluation of Dynamic Heart Function Following Different Cardiopulmonary Bypass Techniques, Using New High-Resolution 4D Echocardiography
Authors: Priyanka Vachhani, Rohini Deb, Shahryar Ashraf, Kaavya Mandi, Kevin Truong, Lydia Tam, Vivian Chen, Jiahui Zhang, Cole Streiff, Meihua Zhu, Stephen Langley, Muhammad Ashraf, David J Sahn
Journal: Circulation (2013)

Background: In this study, we evaluated the impact of different cardiopulmonary bypass methods on dynamic heart function. Methods: We studied 12 open-chest piglets (3-5kg). Body temperature, oxygen saturation, blood gases and vital signs were continually monitored. Baseline 4D full volume image loops were acquired from the heart surface with a 4Z1c matrix transducer on a Siemens SC 2000 ultrasound system at frame rate &gt; 30 VPS. Five piglets were subjected to cross-circulation cardiopulmonary bypass for 2 hours using an adult matched donor. Seven piglets were subjected to conventional bypass for the same duration, 3 with matched blood at body temperature (normothermic) and 4 with matched hypothermic blood. After 2 hours of bypass, normal circulation was restored, 4D images acquired after stabilization and images were analyzed offline using VMM motion analysis software from Siemens. Results: In piglets with cross-circulation, average peak apical and basal rotation was slightly increased (0.25-0.95°) and average peak strain (both circumferential and longitudinal) values were diminished in all segments (2.25-4.15%, p=0.039). Piglets with normothermic cardiopulmonary bypass showed similar mechanical changes in LV strain and rotation (p=0.017). Piglets with hypothermic bypass, however, showed a greater increase in LV rotation (1.25-1.75°) and greater depression of strain values (4.25-6.15%). Conclusion: New 4D echo is feasible to monitor dynamic heart function after cardiopulmonary bypass.
Abstract 19111: Multipotent Mesp1 Progenitors Contribute to a Population of Cardiac Fibroblasts During Development and After Injury
Authors: Sara Ranjbarvaziri, Shah R Ali, Mahmood Talkhabi, Ali Subat, Peng Zhao, Reza Ardehali
Journal: Circulation (2013)

Mesp1 is considered as a master regulator for cardiovascular development. It has previously been shown that progenitor cells expressing Mesp1 contribute to the cardiovascular lineage, including cardiomyocytes, endothelial and vascular smooth muscle cells. To date, no direct link between progenitor cells expressing Mesp1 and cardiac fibroblasts has been reported. We hypothesized that cardiovascular progenitors expressing Mesp1 during early development also give rise to the cardiac mesenchyme. We performed lineage tracing experiments to identify the precursors of cardiac fibroblasts. We generated Mesp1Cre mT/mG mice, in which Mesp1-derived progenies are indelibly labeled GFP. We used fluorescent activated cell sorting (FACS) to isolate fibroblasts using Thy1 as an inclusive surface marker for fibroblasts and excluding hematopoietic markers (CD45, Ter119), macrophages (Cd11b) and endothelial cells (CD31). Our results showed that the majority of cardiac fibroblasts (&gt; 75%) are derived from Mesp1-expressing cells. Cardiac fibroblasts (derived from Mesp1-expressing and Mesp1-nonexpressing cells) were cultured in vitro and positive for fibroblast markers after 3 passages with a dose dependent response to TGFβ treatment. Immunostaining of the adult heart tissue sections also showed presence of fibroblasts derived from both Mesp1 and non-Mesp1 progenitors. In order to determine whether these cells respond differentially to cardiac fibrosis, we performed transaortic constriction and sham surgery on the transgenic mice. Our data shows that the relative proportion of Mesp1-derived fibroblasts remains the same despite proliferation after pressure overload, suggesting that fibroblast division upon injury is not restricted to certain developmentally restricted fibroblast populations. In summary, we provide evidence that cardiac fibroblasts may share a common embryonic origin with the cardiovascular lineages.
Advantages Cryopreserved Lymphocytes for Sequential Evaluation of Human Immune Competence. II. Mixed Lymphocyte Cultures and of Mononuclear Cell Subpopulations
Authors: H F Sears, S C Tondreau, S A Rosenberg
Journal: JNCI Journal of the National Cancer Institute (1978)

Peripheral blood lymphocytes were obtained from normal volunteer donors over a 2-week period. One-way or two-way mixed lymphocyte reactions, percentages of T-cells and B-cells, and percentages of monocytes were quantitated on both fresh and cryopreserved lymphocytes. These comparisons revealed that the measurement of mixed leukocyte reactions, fractions of E-rosettes and EA rosettes, and the fraction of esterase-staining cells were not altered by cryopreservation and storage at -196 degrees C up to 1 year. Cryopreserved reference lymphocytes provided a stable standard for use as stimulating cells in mixed lymphocyte cultures and could be irradiated or treated with mitomycin C prior to being frozen, without alteration of their function as stimulator cells. Cryopreserved cells thus appeared to be utilizable in the sequential measurement of the immune competence of humans.
CD40 pathway activation status and germinal B-cell identity are predictive of response to anti-CD40 (SGN-40) in preclinical NHL models
Authors: Lily Shi, Bart Burington, Thomas Januario, Jeffrey Lau, Shang-Fan Yu, Allen Ebens, David Dornan
Journal: Clinical Cancer Research (2008)

B33  Anti-CD40 (SGN-40) is a humanized IgG1 monoclonal antibody that binds to CD40, mediates effector cell functions (ADCC/ADCP), and activates downstream signaling pathways. SGN-40 has shown activity in a phase I single agent multi-dose trial in non Hodgkin’s lymphoma, with greatest activity in diffuse large B-cell lymphoma (overall response rate of 21%, or 3/14 pts) (Advani et al. 2008, ICML). Previous in vitro studies of the mechanism of activity implicated important components of the GCB phenotype, such as bcl-6 (Lewis et al. 2007, ASH). However, the mechanism of action of SGN-40 remains imprecisely characterized. In order to elucidate the mechanism of action and to identify candidate predictive markers for SGN-40 activity in an unbiased fashion, we assessed the ability of SGN-40 to induce cell-cycle arrest and apoptosis across a panel of 31 non-Hodgkin’s lymphoma cell lines and utilized molecular profiling for correlation with activity. These data identified the baseline level of CD40 signaling as an important predictor of SGN-40 sensitivity. Cell lines that were sensitive to SGN-40 had minimal activation of the CD40 pathway in the absence of SGN-40 whereas the cell lines that were resistant to SGN-40 treatment displayed constitutive activation of the CD40 pathway. Thus, SGN-40 appears to mediate apoptosis through activation of CD40 signaling in quiescent cells. In addition to these findings, we observed that SGN-40 activity was strikingly enriched in the Germinal Center B-Cell (GCB) subclass of DLBCL cell lines in contrast to the Activated B-Cell (ABC) subclass. With a view of generating a clinically feasible assay from FFPE tissue, we developed a 14-gene signature by Stepwise Linear Modeling utilizing genes from the CD40 pathway activation and GCB gene sets; the classifier gave >96% accuracy (30/31) on the ‘training’ set of cell lines and 75% (3/4) accuracy on a ‘test’ set of xenografts. We also extensively characterized the mechanism of action of SGN-40 by using SGN-40-stimulation of cell lines that are sensitive and resistant, as well as normal B-cells, and identified specific genes within each class by microarray and Western blot analyses that may explain their resultant drug sensitivity phenotype. Overall, our data provides unique insights into SGN-40 mechanisms of action, provides a testable hypothesis of the clinical mechanism of action, and potentially a diagnostic test to identify patients more likely to benefit from SGN-40. Efforts are currently underway to test the clinical relevance of these findings.
Effectiveness of neoadjuvant chemotherapy including bevacizumab in patients with resectable colorectal cancer liver metastases
Authors: B. Gruenberger, W. Scheithauer, D. Tamandl, C. Zielinski, J. Schueller, T. Gruenberger
Journal: Journal of Clinical Oncology (2007)

4060 Background: Chemotherapy including bevacizumab has become the new standard in the first line treatment of patients with metastatic colorectal cancer (mCRC). Response to chemotherapy has been assessed as major prognostic factor for RFS in resectable mCRC patients, but safety concerns have been raised. We conducted a phase II trial to evaluate the safety of neoadjuvant chemotherapy including bevacizumab (Bev). Methods: Patients with resectable mCRC received six cycles (3 months) of neoadjuvant XELOX (capecitabine 3,500mg/m 2 /day days 1–7 plus oxaliplatin 85mg/m 2 day 1) with bevacizumab (5mg/kg) every 2 weeks. The sixth cycle did not include Bev resulting in a gap of 5 weeks between last Bev and surgery. Primary end points were feasibility of neoadjuvant treatment with this regimen and response rate; secondary end points were feasibility of curative liver resection and perioperative morbidity of the surgical procedure. Results: 54 patients (32 male, 22 female) with a median age of 61 years (SD ± 10.6) were included. The median number of preoperative cycles was 6 (SD ± 2). Grade 3/4 side effects were PNP in 13%, H&amp;F in 3%, diarrhea in 38%, anaemia in 3% and neutropenia in 12% of our patients. Thromboembolic events occurred in 4 patients (7%), hypertension grade III in 2 (4%) and perforation in 1 (2%) patients. A dose reduction of chemotherapy was required in 43%. There were no treatment related deaths. The overall objective response rate for all 54 patients was 74% (40 patients) including 11% pCR. 11 additional patients (20%) had stable disease and only 3 (6%) progressed. Potential curative surgery was performed in all but 5 patients (91%). 2 patients were not resected due to PD, 2 because of pulmonary embolism during chemotherapy and 1 patient because of positive hilar lymph nodes. Conclusions: These data provide evidence that neoadjuvant chemotherapy including bevacizumab can be safely administered in patients with resectable mCRC. A high response rate and a disease control rate of 94% suggest that XELOX + Bev is an effective regimen in this treatment setting. No significant financial relationships to disclose.
Final efficacy results for bevacizumab plus standard first-line chemotherapies in patients with metastatic colorectal cancer: First BEAT
Authors: S. R. Berry, E. Van Cutsem, A. Kretzschmar, M. Michael, F. Rivera, M. DiBartolomeo, M. A. Mazier, N. Andre, D. Cunningham
Journal: Journal of Clinical Oncology (2008)

4025 Background: Bevacizumab (BEV) significantly extends overall (OS) and/or progression-free survival (PFS) when combined with standard first-line chemotherapy (CT) regimens in patients (pts) with metastatic colorectal cancer (mCRC). First BEAT is an international prospective observational study evaluating the safety and efficacy profile of BEV when combined with a variety of CT regimens in a general pt population with mCRC Methods: Eligible pts were treated with first-line CT (physician’s choice) plus BEV 5mg/kg q2w (5- fluorouracil [5-FU]-based CT) or 7.5mg/kg q3w (capecitabine [cap]-based CT) until disease progression. Disease progression was assessed by investigators. Main trial endpoints included safety, PFS and OS. Results: 1,965 pts were enrolled across 41 countries between June 2004 and February 2006, of which 1,914 were evaluable by 2 August 2007 (male 58%; median age 59 years, 33% ≥65 years; ECOG PS 0/1 65%/34%). Most commonly used CT regimens in combination with BEV included FOLFOX (29%), FOLFIRI (26%), XELOX (18%) and 5-FU/cap monotherapy (15%). Median follow-up was 21.4 months; 60-day mortality was 2.5%; 52% pts were treated until progression. Grade 3–5 adverse events or SAEs of special interest included bleeding (3.2%), gastrointestinal perforation (1.8%), arterial thromboembolism (1.3%), hypertension (5.1%), proteinuria (1.0%) and wound-healing complications (1.0%). Overall median PFS was 10.8 months (95% CI: 10.4–11.3, based on 1,396 events) Updated analyses based on the final data cut off (November 2007), including first report of median OS, will be presented at the meeting. Conclusions: In this large community-based study, the safety and efficacy of first-line BEV with the most common chemotherapy regimens for mCRC in daily clinical practice is consistent with that observed in randomized phase III clinical trials. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Roche Roche Hoffmann-La Roche AG Roche Roche Roche Roche
IgG Glycome in Colorectal Cancer
Authors: Frano Vučković, Evropi Theodoratou, Kujtim Thaçi, Maria Timofeeva, Aleksandar Vojta, Jerko Štambuk, Maja Pučić-Baković, Pauline M. Rudd, Lovorka Đerek, Dražen Servis, Annika Wennerström, Susan M. Farrington, Markus Perola, Yurii Aulchenko, Malcolm G. Dunlop, Harry Campbell, Gordan Lauc
Journal: Clinical Cancer Research (2016)

Alternative glycosylation has significant structural and functional consequences on IgG and consequently also on cancer immunosurveillance. Because of technological limitations, the effects of highly heritable individual variations and the differences in the dynamics of changes in IgG glycosylation on colorectal cancer were never investigated before.
Abstract 13283: Cardioprotective Role of Hydrogen Peroxide and Erythropoietin during Acute Coronary Occlusion in Canine Native Coronary Collateral Microcirculation in Vivo
Authors: Toyotaka Yada, Hiroaki Shimokawa, Osamu Hiramatsu, Minoru Satoh, Naoki Kashihara, Aya Takaki, Masami Goto, Hiroshi Nakamaoto, Yasuo Ogasawara, Fumihiko Kajiya
Journal: Circulation (2010)

Background:  We have previously demonstrated that endothelium-derived hydrogen peroxide (H 2 O 2 ) is an endothelium-derived hyperpolarizing factor and plays a crucial regulatory role in canine coronary microcirculation in vivo. However, the role of endogenous H 2 O 2  in coronary collateral vasodilatation during myocardial ischemia before and after erythropoietin (EPO) remains to be examined. We thus examined whether endogenous H 2 O 2  is involved in vasodilatation of native collateral microvessels during ischemia before and after EPO in vivo.   Methods:  Canine subepicardial native collateral small arteries (CSA ≥100 μm) and arterioles (CA  2 O 2  into water and oxygen, 1000 U/ml, 10 min), (iv) EPO+L-NMMA (NO synthase inhibitor, 2 μmol/min for 20 min ic), (v) EPO+L-NMMA+catalase, (vi) EPO+L-NMMA+apamin+charybdotoxin [K Ca  channels blockers; apamin 1 μmol/min and charybdotoxin (CTX) 100 nmol/min, for 20 min ic] and (vii) EPO+wortmannin (an inhibitor of PI3 kinase, 1.5 μg/kg/min for 30 min ic).   Results:  Myocardial ischemia caused significant vasodilatation in CA (19±3%) but not in CSA (2±1%) under control conditions. After EPO, the vasodilatation was significantly increased in both-sized arteries (CA 27±5%, CSA 8±2%) compared with control, and was significantly decreased by catalase in CA (13±2%). The enhancing effect of EPO was decreased by L-NMMA (−1±1%) but not by catalase (8±1%) in CSA and the inhibitory effect was more pronounced after L-NMMA+catalase (CA 9±2%, CSA -3±2%), L-NMMA+apamin+CTX (CA 7±2%, CSA −3±1%) or wortmannin (CA 7±2%, CSA −3±1%) in both-sized arteries. EPO ameliorated ischemia-induced impairment of myocardial Akt phosphorylation, which was abolished by L-NMMA+catalase or wortmannin. EPO also ameliorated oxidative stress and myocardial injury compared with control, as assessed by plasma 8-hydroxydeoxyguanosine and troponin-T in the coronary sinus, respectively.   Conclusions:  EPO enhances H 2 O 2 -mediated dilatation of canine coronary collateral arterioles during myocardial ischemia in vivo.
Altered Expression and Activity of Topoisomerases During All-Trans Retinoic Acid-Induced Differentiation of HL-60 Cells
Authors: Masako Aoyama, Dale R. Grabowski, Richard J. Isaacs, Kim A. Krivacic, Lisa A. Rybicki, Ronald M. Bukowski, Mahrukh K. Ganapathi, Ian D. Hickson, Ram Ganapathi
Journal: Blood (1998)
Acupuncture for Menopausal Hot Flashes
Authors: Carolyn Ee, Charlie Xue, Patty Chondros, Stephen P. Myers, Simon D. French, Helena Teede, Marie Pirotta
Journal: Annals of Internal Medicine (2016)

Background: Hot flashes (HFs) affect up to 75% of menopausal women and pose a considerable health and financial burden. Evidence of acupuncture efficacy as an HF treatment is conflicting. Objective: To assess the efficacy of Chinese medicine acupuncture against sham acupuncture for menopausal HFs. Design: Stratified, blind (participants, outcome assessors, and investigators, but not treating acupuncturists), parallel, randomized, sham-controlled trial with equal allocation. (Australia New Zealand Clinical Trials Registry: ACTRN12611000393954) Setting: Community in Australia. Participants: Women older than 40 years in the late menopausal transition or postmenopause with at least 7 moderate HFs daily, meeting criteria for Chinese medicine diagnosis of kidney yin deficiency. Interventions: 10 treatments over 8 weeks of either standardized Chinese medicine needle acupuncture designed to treat kidney yin deficiency or noninsertive sham acupuncture. Measurements: The primary outcome was HF score at the end of treatment. Secondary outcomes included quality of life, anxiety, depression, and adverse events. Participants were assessed at 4 weeks, the end of treatment, and then 3 and 6 months after the end of treatment. Intention-to-treat analysis was conducted with linear mixed-effects models. Results: 327 women were randomly assigned to acupuncture (n = 163) or sham acupuncture (n = 164). At the end of treatment, 16% of participants in the acupuncture group and 13% in the sham group were lost to follow-up. Mean HF scores at the end of treatment were 15.36 in the acupuncture group and 15.04 in the sham group (mean difference, 0.33 [95% CI, −1.87 to 2.52]; P = 0.77). No serious adverse events were reported. Limitation: Participants were predominantly Caucasian and did not have breast cancer or surgical menopause. Conclusion: Chinese medicine acupuncture was not superior to noninsertive sham acupuncture for women with moderately severe menopausal HFs. Primary Funding Source: National Health and Medical Research Council.