tbuckley/cabot-search huggingface dataset:
Androgen deprivation therapy and survival in patients with lung cancer.
Authors: Craig Henry Harlos, Marshall W. Pitz, Grace Musto
Journal: Journal of Clinical Oncology (2013)

1597 Background: The epidemiology of lung cancer differs between men and women. There exists significant evidence suggesting estrogens influence the pathophysiology of lung cancer, however the role of androgens remains unclear. This study was performed to determine if exposure to androgen deprivation therapy (ADT) has an effect on survival in male patients (pts) diagnosed with lung cancer. Methods: Using the population-based Manitoba Cancer Registry and Manitoba Health Administrative Databases, all pts diagnosed with lung cancer from January 1, 2004 to December 31, 2010 were identified. Information from the Drug Program Information Network (DPIN) and the Aria electronic record at CancerCare Manitoba were used to determine prescriptions filled for anti-androgens, 5-alpha reductase inhibitors and GnRH agonists as a measure of exposure (defined as having filled at least 2 prescriptions and/or bilateral orchiectomy). Multivariable analysis with Cox proportional hazards analysis was used to compare survival. Results: A total of 3018 men with lung cancer were identified between 2004 and 2010. Of these, 339 (10%) were identified as having used a form of ADT. The majority of pts received 5-alpha reductase inhibitors (85%), the most common being finasteride (80% of total). Multivariable analysis revealed that patients who received ADT prior to the diagnosis of lung cancer had no statistically significant difference in survival (HR: 0.97 p=0.69) compared to those who did not. Patients exposed to ADT after their diagnosis were found to have a significantly better survival than those not exposed (HR 0.36 p=0.0007). This effect was also seen in those who received ADT before and after diagnosis (HR 0.53 p&lt;0.0001). Conclusions: In male pts diagnosed with lung cancer, exposure to ADT is associated with significantly better survival when compared with no exposure. This effect is only seen when some or all of the exposure has occurred after the diagnosis of lung cancer. This study supports the hypothesis that the androgen pathway plays a role in lung cancer pathophysiology, and that androgen deprivation may improve prognosis
Abstract O.27: The Role Of CD40L And CD40 In The Pathogenesis Of Kawasaki Disease
Authors: Leon Parsaud, Parnian Arjmand, Trang T Duong, Rae S Yeung
Journal: Circulation (2015)

Kawasaki Disease (KD) is characterized by acute, systemic inflammation followed by a persistent immune response localized to the coronary arteries. Lactobacillus Casei Cell Wall Extract (LCWE) contains among its active ingredients a superantigen (SAg) that induces coronary arteritis in mice. LCWE induces massive immune activation followed by apoptosis or anergy. Previous work has shown that co-stimulatory signals can rescue a subset of SAg-reactive T-cells from apoptosis. CD40-CD40L (ligand) are members of the TNF superfamily which play a role in T-cell co-stimulation. Moreover, genome wide association studies have implicated CD40/CD40L as candidate genes in the pathogenesis of KD. We hypothesize that co-stimulation via the CD40 pathway regulates survival of SAg-reactive T-cells during disease development. Using thymidine proliferation assay and flow cytometry we show that activation of CD40 signaling via agonistic anti-CD40 antibody or recombinant soluble CD40L (rsCD40L) upregulates CD86 (ligand responsible for CD28 signaling) expression, reduces active-caspase-3 expression, indicating decreased cell death and promotes lymphocyte proliferation, Additionally, using CD28 deficient mice we show that lymphocytes do not proliferate in response to SAg plus CD40 stimulation indicating that CD28 is the intermediary that mediates the proliferative effects of CD40 activation. Furthermore, platelets, which are markedly elevated in KD, produce approximately 90% of the soluble CD40L in the circulation. We show that activated platelets (CD62P+) express CD40L and promotes cell survival as evidenced by enhanced lymphocyte proliferation. Likewise, the absence of CD40L negates the proliferative effects of platelet mediated proliferation. Lastly, to determine the role of CD40 stimulation on in vivo development of KD, LCWE was injected into B6 and CD40L deficient mice. We show that inflammation in the coronary arteries does not develop in the absence of CD40L. Therefore, CD40L plays a critical role in immune activation via upregulation of CD86 on antigen presenting cells leading to enhanced co-stimulation and T-cell survival.
Comparison of epigenetic aging in normal breast tissue from women with and without breast cancer.
Authors: Erin Wysong Hofstatter, Steven Horvath, Anees B. Chagpar, Vikram Wali, Veerle Bossuyt, Anna Maria Storniolo, Gauri Patwardhan, Marie-Kristin Von Wahlde, Lajos Pusztai
Journal: Journal of Clinical Oncology (2017)

1522 Background: Age is one of the most important risk factors for developing breast cancer. However, why increasing age is associated with increasing incidence of breast cancer remains poorly understood. We hypothesize that accumulated epigenetic alterations in the breast contribute to the development of breast cancer, and that such changes accumulate more rapidly in the breast during the lifetime of women who develop breast cancer as compared to their healthy peers. We therefore sought to identify an epigenetic pattern of accelerated breast tissue “aging” in women with breast cancer. Methods: Samples of normal breast tissue were collected from four cohorts of women: age &lt; 50 years with and without breast cancer, and age ≥50 years with and without breast cancer (BC). Samples were obtained from the Susan G. Komen Tissue Bank at IU Simon Cancer Center, reduction mammoplasties and adjuvant mastectomy specimens at Yale. The Illumina Human 450K BeadChip microarray was used to generate DNA methylation profiles. Data was analyzed using the “Epigenetic Clock”, a published biomarker of aging based on 353 specific CpGs in the human genome. Clinical data collected for each subject included: age, height, weight, ethnicity, medical and reproductive history, tobacco and alcohol use, family history of breast cancer, current medications, and tumor characteristics. Results: Normal breast tissue samples from 90 subjects were analyzed (age &lt; 50 with BC = 22, age &lt; 50 without BC = 30, age ≥50 with BC = 15, age ≥50 without BC = 23). Age range was 24-82 years and 18-82 years for cohorts with and without BC respectively. In the cohort with BC, 95% of tumors were estrogen receptor-positive. Overall, DNA methylation tissue age (DNAmAge) was strongly correlated with chronologic age (r = 0.88, p &lt; 0.001). However, normal breast tissue from women with breast cancer demonstrated significantly accelerated DNAmAge as compared to healthy peers (p &lt; 0.001). Conclusions: Normal breast tissue from women with breast cancer demonstrates evidence of an accelerated epigenetic "aging" process. DNAmAge of normal breast tissue may prove to be a useful tool in identifying those women at highest risk, and lend insight into novel mechanisms of breast cancer prevention.
The Multiple Myeloma Genome Project: Development of a Molecular Segmentation Strategy for the Clinical Classification of Multiple Myeloma
Authors: Brian A Walker, Mehmet K. Samur, Konstantinos Mavrommatis, Cody Ashby, Christopher P Wardell, Maria Ortiz, Fadi Towfic, Caleb K. Stein, Michael A Bauer, Michael Amatangelo, Giovanni Parmigiani, Zhinuan Yu, Matthew Trotter, Herve Avet-Loiseau, Graham H Jackson, Kenneth C. Anderson, Anjan Thakurta, Nikhil C. Munshi, Gareth J Morgan
Journal: Blood (2016)
RespondR signature to predict potential alternative therapies for taxane resistant triple-negative breast cancer patients.
Authors: Steven Allen Buechler, Yesim Gokmen-Polar, Sunil S. Badve
Journal: Journal of Clinical Oncology (2016)

1078 Background: There is a critical need to identify effective therapeutics for all triple-negative breast cancer (TNBC) patients. The 19-gene RespondR score significantly stratifies TNBC patients by likelihood of response to AT therapy. To identify potentially effective therapeutics for AT-insensitive TNBC patients; i.e., those with low RespondR score, we explore genomic and genetic data in The Cancer Genome Atlas (TCGA) dataset and response in a cisplatin-treated dataset. Methods: The RespondR score was calculated for TNBC patients in TCGA treated with a taxane (n = 84), and TNBC patients in GSE18864 treated with neoadjuvant cisplatin (n = 24). Results: Taxane-treated TNBC patients in TCGA with high RespondR score (RR-high, 46%) have significantly better 5-year relapse-free survival (0.92, 95%CI 0.82-1.0) than patients with low RespondR (RR-low) score (0.68, 95%CI 0.52-0.89). In these RR-low TCGA samples, relapse is significantly (p = 0.03) associated with loss of the gene PTEN (36% of the RR-low patients with PTEN loss relapse, while 12% of the samples without PTEN loss relapse). In RR-high, relapse is not associated with loss of PTEN (None of the RR-high group with PTEN loss relapse, while 10% of those without PTEN loss relapse). In addition, 31% of the RR-low relapse cases have loss of genes involved in DNA repair, e.g., XRCC4 and BRCA2, indicating possible sensitivity to platinum-based therapy. In the dataset GSE18864, 50% of the patients with low RespondR score achieve partial or complete pathological response to cisplatin treatment. Conclusions: The addition of other agents to AT treatment for patients with high RespondR score is unlikely to significantly improve survival over AT alone. Loss of PTEN is associated with higher incidence of recurrence specifically in patients with low RespondR scores. Patients with low RespondR score and PTEN loss could be ideal candidates for PARP1 or PI3K-AKT signaling inhibitors. DNA damaging agents may also significantly improve survival for low RespondR patients. RespondR provides vital information to TNBC patients and their physicians in the search for the most effective choice of chemotherapy.
Metronomic chemotherapy (mCHT) in HER2-ve advanced breast cancer (ABC) patients (pts): What has changed over the time? Preliminary results of the VICTOR-6 study.
Authors: Marina Elena Cazzaniga, Virginia Casadei, Katia Cagossi, Luigi Cavanna, Maria Concetta Cursano, Enrico Maria Romano De Conciliis, Vittorio Gebbia, Elisabetta Melegari, Benedetta Pellegrino, Graziella Pinotti, Rosalba Rossello, Salvatore Russo, Salvatore Ortu, Silvana Saracchini, Lucia Stocchi, Davide Toniolo, Giovanni Scognamiglio, Maria Rosaria Valerio, Anna Maria Vandone, Luca Clivio
Journal: Journal of Clinical Oncology (2017)

e12552 Background: mCHT is the minimum biologically effective dose of a chemotherapeutic agent, given at regular dosing regimen with no prolonged drug free interval, that leads to anti-tumor activity. Old regimens included Cyclophosphamide-Methotrexate (CM), whereas in the last years new regimens, such as Vinorelbine (VRL) and Capecitabine (CAPE)-based have been developed. Aim of this observational retrospective ongoing study is to describe the use of mCHT in ABC pts across 5 years and the clinical characteristics of the pts together with efficacy of old (CM-like) vs new (VRL/CAPE-based) metronomic regimens in terms of response and disease control. Methods: We retrospectively identified from clinical records those HER2-ve ABC pts who have received any kind of mCHT in the years 2011-2015, alone, or in combination with a non-metronomic drug. Standard statistical approaches were used for describing the sample characteristics. Logistic and non proportional hazard analysis were used to identify factors associated with response, and time to treatment failure and survival, respectively. This preliminary analysis focuses on Response Rate (RR) and Disease Control Rate (DCR). Results: From June 2011 to December 2015, 267 pts have been identified till now and 233 are fully evaluable. Median age at mCHT start was 67 years. 81% was HR+ and 33% had non-visceral metastatic disease. 22% of the pts received CM, 55% VRL-based and 23% mCAPE-based regimens. mCHT use increased over the time from 15.0% (2011) to 30% (2015). As 1 st -line treatment, CM was administered in 27% of compared with more than 48% of patients receiving CAPE/VRL-based regimens. Overall Response Rate (ORR) was 28% and Disease Control Rate (DCR) was 79%. Median duration of mCHT was 6.2 months. New generation metronomic regimens produced higher ORR in comparison to old ones (32% vs 13.5%), with similar duration of treatment (6.4 vs 5.4 months, respectively). Conclusions: The use of mCHT in the treatment of HER2-ve ABC pts has deeply changed across the last 5 years, being new generation regimens used in earlier lines of treatment, producing interesting results in terms of objective response and disease control.
Decreased Thymosin Beta 4 Expression Results in Poor Prognosis and Decreased Survival in Multiple Myeloma.
Authors: Jo Caers, Dirk Hose, Ine Kuipers, Tomas Jan Bos, Els Van Valckenborgh, Eline Menu, Elke De Bruyne, Hartmut Goldschmidt, Ben Van Camp, Bernard Klein, Karin Vanderkerken
Journal: Blood (2008)
Successful stem cell transplantation following orthotopic liver transplantation from the same haploidentical family donor in a girl with hemophagocytic lymphohistiocytosis
Authors: Susanne Matthes-Martin, Christina Peters, Alfred Königsrainer, Gerhard Fritsch, Thomas Lion, Andreas Heitger, Klaus Kapelari, Martina Kronberger, Felix Offner, Fritz Wrba, Raimund Margreiter, Helmut Gadner
Journal: Blood (2000)
Randomized Phase II Study Comparing Prophylactic Cranial Irradiation Alone to Prophylactic Cranial Irradiation and Consolidative Extracranial Irradiation for Extensive-Disease Small Cell Lung Cancer (ED SCLC): NRG Oncology RTOG 0937
Authors: Elizabeth M. Gore, Chen Hu, Alexander Y. Sun, Daniel F. Grimm, Suresh S. Ramalingam, Neal E. Dunlap, Kristin A. Higgins, Maria Werner-Wasik, Aaron M. Allen, Puneeth Iyengar, Gregory M.M. Videtic, Russell K. Hales, Ronald C. McGarry, James J. Urbanic, Anthony T. Pu, Candice A. Johnstone, Volker W. Stieber, Rebecca Paulus, Jeffrey D. Bradley
Journal: Journal of Thoracic Oncology (2017)
Systemic Exposure of Rituximab Increased By Ibrutinib: Pharmacokinetic Results from the Helios Trial
Authors: Paula Cramer, Fatih Demirkan, Graeme Fraser, Alexander Pristupa, Nancy L Bartlett, Marie-Sarah Dilhuydy, Javier Loscertales, Abraham Avigdor, Simon A. Rule, Olga Samoilova, Andre Goy, Siddhartha Ganguly, Italo Poggesi, Silvia Maria Lavezzi, Giuseppe De Nicolao, Jan de Jong, Martine Neyens, Mariya Salman, Angela Howes, Michelle Mahler
Journal: Blood (2016)
Plasma Dipeptidyl Peptidase-4 Activity, a Novel Biomarker or Even a Possible Therapeutic Target for Depression in Type 2 Diabetic Patients: Results from a Cross-Sectional Study in China
Authors: Tianpeng Zheng, Linyuan Qin, Bo Chen, Xueping Hu, Xiaoxi Zhang, Yihong Liu, Hongbo Liu, Shenghua Qin, Gang Li, Qinghua Li
Journal: Psychotherapy and Psychosomatics (2017)
Evolution of Cytochrome c Oxidase in Hypoxia Tolerant Sculpins (Cottidae, Actinopterygii)
Authors: Gigi Y. Lau, Milica Mandic, Jeffrey G. Richards
Journal: Molecular Biology and Evolution (2017)

Vertebrate hypoxia tolerance can emerge from modifications to the oxygen (O2) transport cascade, but whether there is adaptive variation to O2 binding at the terminus of this cascade, mitochondrial cytochrome c oxidase (COX), is not known. In order to address the hypothesis that hypoxia tolerance is associated with enhanced O2 binding by mitochondria we undertook a comparative analysis of COX O2 kinetics across species of intertidal sculpins (Cottidae, Actinopterygii) that vary in hypoxia tolerance. Our analysis revealed a significant relationship between hypoxia tolerance (critical O2 tension of O2 consumption rate; Pcrit), mitochondrial O2 binding affinity (O2 tension at which mitochondrial respiration was half maximal; P50), and COX O2-binding affinity (apparent Michaelis-Menten constant for O2 binding to COX; Km,app O2). The more hypoxia tolerant species had both a lower mitochondrial P50 and lower COX Km,app O2, facilitating the maintenance of mitochondrial function to a lower O2 tension than in hypoxia intolerant species. Additionally, hypoxia tolerant species had a lower overall COX Vmax but higher mitochondrial COX respiration rate when expressed relative to maximal electron transport system respiration rate. In silico analyses of the COX3 subunit postulated as the entry point for O2 into the COX protein catalytic core, points to variation in COX3 protein stability (estimated as free energy of unfolding) contributing to the variation in COX Km,app O2. We propose that interactions between COX3 and cardiolipin at four amino acid positions along the same alpha-helix forming the COX3 v-cleft represent likely determinants of interspecific differences in COX Km,app O2.
The changing utilization of neoadjuvant chemotherapy among different racial groups and its effect on mastectomy rates.
Authors: Tiffany Pinchinat, Hanan Abdulkareem, Xian Wu, Paul J. Christos, Rache M. Simmons, Himanshu Nagar, Tracy-Ann Moo
Journal: Journal of Clinical Oncology (2016)

1040 Background: Neoadjuvant chemotherapy (NAC) has been utilized to downstage disease and to allow breast conservation. There is limited data on the patterns of utilization of NAC among different racial groups. The purpose of this study is to explore NAC use over time among different racial groups and to examine its impact on final surgical procedure. Methods: Women with invasive breast cancer diagnosed between 2004 and 2013 were identified in the National Cancer Database. NAC use over time was determined for the following ethnic groups: non-Hispanic white, non-Hispanic black, Hispanic, and non-Hispanic Asian/Pacific islander. Similarly the use of breast conservation versus mastectomy was also evaluated over time for each racial group. The chi-square test for trend was used to assess the relationship between use of NAC/breast conservation and time, stratified by racial group. Results: Of 1,016,748 patients diagnosed with invasive breast cancer 84,773 received NAC. The rate of NAC utilization increased between 2006 to 2013, from 6.9% to 12% (p < 0.0001) overall. The greatest increase was seen in the non-Hispanic black population, 12% in 2006 to 17.5% in 2013. The majority of patients receiving NAC were stage 2 or 3 across all racial groups and remained consistent over time. Reported rate of pathologic complete response (pCR) increased from 3.5% in 2006 to 25% in 2013 (p < 0.0001); this was observed across all racial groups. From 2006 to 2013, the rate of mastectomy did not change, with approximately 65% of patients each year receiving mastectomy (p = 0.12). When examined by racial group, the proportions of patients receiving mastectomy also did not change over the study period. Conclusions: The use of NAC has doubled between 2006 and 2013, with the greatest increase in utilization seen in the non-Hispanic black population. There has been a concomitant increase in the rates of pCR observed across all racial groups. Despite the increased pCR, there was no change in the number of women having mastectomy over the study period when examined overall or based on racial group.
A phase II study of vandetanib in patients with non-small cell lung cancer harboring RET rearrangement.
Authors: Se-Hoon Lee, June-Koo Lee, Myung-Ju Ahn, Dong-Wan Kim, Jong-Mu Sun, Bhumsuk Keam, Tae Min Kim, Dae Seog Heo, Jin Seok Ahn, Yoon-La Choi, Hae-Sook Min, Yoon-Kyung Jeon, Keunchil Park
Journal: Journal of Clinical Oncology (2016)

9013 Background: Non-small cell lung cancer (NSCLC) with RET rearrangement is regarded as a unique entity in terms of pathogenesis. The purpose of this study is to investigate the efficacy and safety of vandetanib in patients with advanced NSCLC harboring RET gene rearrangement. Methods: This is a multi-institution, open-label, phase II trial (registered at clinicaltrials.gov with NCT01823068). The patients with advanced NSCLC with RET fusion confirmed by fluorescent in situ hybridization (FISH) were enrolled. They should have failed platinum-based chemotherapy, and had at least one measurable disease defined by RECIST 1.1. Performance status (PS) ECOG 0-2 was allowed. Results: Eighteen patients (12 males, 6 females) were enrolled between July 2013 and October 2015. Patients were aged 35 to 71 years (median, 55); ECOG PS 0/1/2 were 2/13/3. Four patients were previously treated with anti-angiogenic agents (three with bevacizumab and one with small molecule). In these patients treated with vandetanib 300 mg once daily, three patients (17%) had partial remission (confirmed, duration of 4.6+, 11.4, 16.7+ months) and another eight patients (44%, duration of 2.9, 3.6+, 4.6+, 4.7+, 5.4, 9.0, 9.6, 10.3+ months) had stable disease. Seven patients (39%) progressed without remission or stabilization. There were two grade 3 hypertension AEs, two QT prolongation AEs, one AST/ALT elevation, and no grade 4 AEs related to vandetanib. Dose reduction was done in four (22%) patients: two from QT prolongation, one from AST/ALT elevation, and one from hypertension. No treatment-related mortality was reported. Six (33%) patients died due to rapid tumor progression within 3 months of enrollment of the study. Conclusions: Vandetanib is moderately active in patients with NSCLC harboring RET rearrangement. Future investigation may be warranted to determine the intrinsic resistance mechanism to RET inhibitors. This research was conducted with support from AstraZeneca Korea Ltd. Clinical trial information: NCT01823068.
Longitudinal Analysis of Long-Term Safety and Efficacy of Recombinant Factor VIII Fc Fusion Protein (rFVIIFc) in Adults/Adolescents with Severe Hemophilia a
Authors: Barbara Konkle, K John Pasi, David J Perry, Johnny Mahlangu, Savita Rangarajan, Simon A Brown, Hideji Hanabusa, Ingrid Pabinger, Lynda M Cristiano, Elisa Tsao, Bent Winding, Desilu Glazebrook, Stefan Lethagen, Shannon Jackson
Journal: Blood (2016)
Mutant p53 as a therapeutic target for the treatment of triple-negative breast cancer: Prelinical investigation with the anti-p53 drug, APR-246.
Authors: Naoise C Synnott, Alyson M. Murray, Norma O'Donovan, John Crown, Michael J. Duffy
Journal: Journal of Clinical Oncology (2016)

1082 Background: Despite intensive efforts, a validated targeted therapy for triple-negative breast cancer (TNBC) remains elusive. One of the most frequent genetic alterations identified in TNBC is mutation in the p53 gene, which is found in > 80% of samples. The aim of this study was therefore to investigate the potential value of the mutant p53 reactivating compound, APR-246 for the treatment of TNBC. Methods: Cell viability was determined using the MTT assay. p53 protein levels were determined using Western blot and ELISA while both p63 and p73 levels were measured by Western blotting. Results: Based on a panel of 23 breast cancer cell lines, significantly lower IC50 values were found in p53 mutant compared to p53 wild-type cells (p= 0.014). Furthermore, a significant inverse correlation was found between IC50 values and p53 protein levels (p= 0.0001, r= -0.76). We also related response with levels of the p53 family members, p63 and p73. A significant inverse correlation was found between p63 protein levels and IC50 values (p= 0.01, r= -0.55). In contrast, no correlation was seen between p73 protein level and IC50 values. In an attempt to enhance response, APR-246 was combined with different cytotoxic agents. Both docetaxel and carboplatin showed an additive effect in combination with APR-246. However, this additive effect was cell line-dependent, i.e., docetaxel plus APR-246 was additive in MDA-MB-453 cells (CI = 0.92) cells but not in MDA-MB-468 cells (CI = 1.7), while carboplatin plus APR-246 was additive in MDA-MB-468 cells (CI = 0.94) but not in MDA-MB-453 cells (CI = 1.2). Conclusions: Based on our finding, either the mutational status of the p53 gene or p53 protein levels may be used to predict response to APR-246. Clinical trials investigating this agent should incorporate either or both of these measurements as potential predictive biomarkers.