tbuckley/cabot-search huggingface dataset:
Risk of serious anemia with mTOR inhibitors in cancer patients: A meta-analysis of randomized controlled trials.
Authors: Anu Radha Neerukonda, Shiney Koshy, Shenhong Wu
Journal: Journal of Clinical Oncology (2014)

e13534 Background: Inhibitors of the mammalian target of rapamycin (mTOR) pathway including everolimus and temsirolimus are currently used for the treatment of several malignancies. Their application is limited by serious anemia, which may affect patients’ quality of life. This meta-analysis of RCTs was conducted to assess overall risk and risk factors of severe anemia in cancer patients treated with mTOR inhibitors. Methods: Databases from PubMed up to October 2013 were searched for relevant studies. Eligible studies included prospective randomized phase 2 and 3 clinical trials in which everolimus or temsirolimus was compared with controls in cancer patients. The data of anemia was extracted from the specific safety profile of each clinical trial. Overall incidence rates, relative risk (RR) and 95% confidence intervals (CI) were calculated using either random effects or fixed effects models. Results: A total of 3,586 patients (mTOR inhibitor: 1987, controls: 1599) with a variety of solid tumors from 7 RCTs were included in the analysis. The incidences of all-grade and high-grade anemia were 31.0% (95% CI: 10.9-62.2%) and 3.1% (95% CI: 1.0-9.4%) respectively. In comparison with controls, mTOR inhibitors significantly increased the risk for developing all-grade (RR: 2.41, 95% CI: 1.63-3.58, P<0.001) and high-grade anemia (RR: 1.90, 95% CI: 1.44-2.52, P<0.001). There was no significant difference between everolimus and temsirolimus in the increased risk of high-grade anemia (P=0.89). The increased risk of high-grade anemia was observed in patients with neuroendocrine tumor (RR: 13.48, 95% CI: 1.75-103.74; P=0.01) and renal cell carcinoma (RR: 1.95, 95% CI: 1.45-2.67; P<0.001), but not in breast cancer (RR: 1.11, 95% CI: 0.46-2.64; P=0.85). Conclusions: The use of mTOR inhibitors is associated with a significant increase in the risk of serious anemia in cancer patients.
Structural optimization and additional targets identification of antisense oligonucleotide G3139 encapsulated in a neutral cytidinyl-lipid combined with a cationic lipid in vitro and in vivo
Authors: Yuan Ma, Wenting Zhao, Yiding Li, Yufei Pan, Shuhe Wang, Yuejie Zhu, Lingxuan Kong, Zhu Guan, Jiancheng Wang, Lihe Zhang, Zhenjun Yang
Journal: Biomaterials (2019)
Pathway-based signature analysis of RNA-seq data to reveal new targetable avenues for metastatic castration-resistant prostate cancer (mCRPC) patients (pts): Preliminary results from the SU2C/PCF/AACR West Coast Prostate Cancer Dream Team (WCDT).
Authors: Adrian Bivol, Robert Baertsch, Artem Sokolov, Evan Paull, Yulia Newton, Theodore C. Goldstein, Adam Foye, Nader Pourmand, Jack Youngren, Rahul Parulkar, Asis Lopez, Ralph de Vere White, Joshi J. Alumkal, Alexandria Toschi, Tomasz M. Beer, Christopher P. Evans, Martin Edwin Gleave, Owen Witte, Eric Jay Small, Joshua M. Stuart
Journal: Journal of Clinical Oncology (2014)

11078 Background: The mechanisms of resistance to agents such as abiraterone or enzalutamide in pts with mCRPC are poorly understood, and progressive mCRPC has been challenging to biopsy and characterize on a molecular basis because of its bone tropism. As part of the WCDT project, which aims to identify genetic pathways underlying primary and acquired resistance to these agents, RNA-sequencing following laser capture microdissection of mCRPC biopsies was undertaken, along with a panel of 37 mutated cancer genes. Interpreting these data is challenging as few computational approaches exist that can leverage external data (e.g. TCGA) to shed light on pathways that drive cancer progression in an individual patient. Methods: RNA-seq and mutation data from mCRPC biopsies is interpreted by mapping onto a comprehensive pathway database connecting a tumor sample with genetic regulatory logic. Pathway mapping occurs either prior to inferring predictive signatures using the PARADIGM engine, or after differential gene expression analysis. Topological analysis reveals possible drug targets within the inferred networks. Results: 60 of 300 planned mCRPC pts have undergone a metastasis bx, RNA-seq data from 9 samples has been analyzed. PARADIGM-based signatures revealed expected neurotransmitter pathways discriminating neuroendocrine from non-NE samples. Gene expression-based signatures mapped onto pathways revealed RB1, Reelin, and VEGF signaling characteristic of liver metastases compared to mets from other tissues. Finally, gene expression-based signatures uncovered several pathways enriched in Abiraterone naive compared to resistant samples (FDR < 5%). Conclusions: Significant pathways can be inferred and potential drug targets identified on very small cohorts with this approach. Methods that harness existing datasets using pathway-guided descriptions may raise the interpretability of omics datasets collected in personalized medicine settings.
Impact of prior cancer on eligibility for lung cancer clinical trials.
Authors: David E. Gerber, Andrew L. Laccetti, Lei Xuan, Ethan Halm, Sandi Pruitt
Journal: Journal of Clinical Oncology (2014)

6566 Background: Fewer than 3% of adult oncology patients in the U.S. enroll onto clinical studies. Stringent eligibility criteria are a key factor limiting accrual. Among these, the assumption that a prior cancer diagnosis could interfere with study conduct or outcomes results in frequent exclusion of subjects with a prior cancer. We determined the prevalence and characteristics of prior cancer-related exclusion criteria in lung cancer clinical trials, and estimated their impact on study accrual. Methods: We reviewed lung cancer clinical trials sponsored or endorsed by the Eastern Oncology Cooperative Group, 1986-2013, for exclusion criteria related to a prior cancer diagnosis. We assessed the association between trial characteristics and prior cancer exclusion using chi-square analysis. We estimated prevalence of prior primary cancer diagnoses among lung cancer patients using Surveillance Epidemiology and End Results (SEER)-Medicare linked data. We applied these figures to trial accrual goals to estimate the percent and absolute number of patients excluded. Results: Fifty-one clinical trials were included. Trial accrual ranged 10-1500 patients (mean 290; total 14,785). Forty trials (78%) excluded patients with a prior cancer diagnosis as follows: any prior (16%), diagnosed within 5 years (39%), diagnosed within 2 or 3 years (7%), or active cancer (16%). Eighty-nine percent of trials with survival as a primary endpoint and 70% of trials with non-survival primary endpoints excluded patients with prior cancer (P=0.12). In SEER-Medicare data (N=210,509), rate of prior cancer diagnosis ranged 14-24% according to lung cancer stage and histology; 56% of prior cancers were diagnosed ≤5 years before the lung cancer diagnosis. Across trials, the estimated number and proportion of patients excluded due to prior cancer ranged from 0 to 207 (0-18%). Conclusions: A substantial proportion of patients are reflexively excluded from lung cancer clinical trials due to prior cancer. This inclusion criterion is applied widely across studies, including more than two-thirds of trials with non-survival endpoints. More research is needed to understand the basis and ramifications of this standard exclusion policy.
Hepatitis B Virus (HBV) Screening and Associated Outcomes in Malignant Hematology Patients Receiving Rituximab Therapy within the Rossy Cancer Network
Authors: Shen Li, Allaa Ali, Alexander Lawandi, Myriam Fernandez, Caroline Rousseau, Doneal Thomas, Sarit Assouline, Chantal Cassis, Todd Campbell Lee, Kelly L. Davison
Journal: Blood (2018)
Pathway correlates in ER-positive primary breast tumors with high-HOXB13 expression.
Authors: Catherine A. Schnabel, Yi Zhang
Journal: Journal of Clinical Oncology (2014)

e22063 Background: The HOXB13: IL17BR (H/I) gene expression ratio has been shown to predict benefit of extended adjuvant endocrine therapy in ER-positive (ER+) breast cancer, however, the underlying mechanistic basis of this predictive activity remains poorly understood. In this study, exploratory pathway analyses were conducted comparing ER+ breast tumors with high- vs low-HOXB13 expression using The Cancer Genome Atlas (TCGA) genomic dataset. Methods: Differential expression of mRNA (Agilent 244K array) and protein (MD Anderson reverse phase protein array) of ER+ breast tumors from the TCGA Data Portal were evaluated by t-tests based on bimodal HOXB13 expression (high vs low). Network models with altered activity were evaluated using Signaling Pathway Impact Analysis (SPIA) that provides a p-value capturing both gene-set enrichment and perturbation on a given pathway based on topology. HOXC13 was used as a negative control. Findings were independently validated using the Netherland Cancer Institute (NKI 295) breast cancer dataset. Results: TCGA gene expression data from 375 ER+ breast tumors were included. Of 17142 unique genes analyzed, 1331 genes showed differential expression between high (N=239) and low (N=136) HOXB13 tumors (p < 0.01). SPIA analyses of high HOXB13-expressing tumors using KEGG (Kyoto Encyclopedia of Genes and Genomes) showed the top ranking pathway alterations were mTOR (p=0.015), cell cycle (p=0.026), and DNA repair (p= 0.035). Independent analysis of 249 ER+ tumors from the NKI dataset showed consistent trend toward inhibition of the mTOR pathway. Suppression of the mTOR pathway was further evaluated through inspection of mTOR effector, 4EBP1. Both TCGA and NKI datasets showed a significantly higher gene expression of 4EBP1 (p = 0.026 and 0.002, respectively). In addition, TCGA data also showed higher protein expression of 4EBP1 (p = 0.083). Conclusions: This exploratory analysis revealed potential functional interaction between HOXB13 and the mTOR pathway, wherein high HOXB13 expression was associated with repressed mTOR signaling in these tumors. Further investigation of a role for HOXB13 in mTOR-ER regulatory cross-talk is warranted.
Highly sensitive and quantitative detection of EGFR T790M mutationin tumor samples by nanofluidic digital PCR.
Authors: Eiji Iwama, Koichi Takayama, Taishi Harada, Isamu Okamoto, Eishi Baba, Yoshinao Oda, Yoichi Nakanishi
Journal: Journal of Clinical Oncology (2014)

11091 Background: Although treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have a pronounced clinical benefit for patients with EGFR activating mutations, such patients inevitably develop drug resistances mainly due to the second mutation of T790M. In usual laboratory test, T790M emergence is reported qualitatively as presence or absence of the mutation. Methods: We evaluated the emergence of T790M with a highly sensitive and quantitative method, Nanofluidic Digital PCR. We compared digital PCR and Scorpion Amplification Refractory Mutation System (ARMS) in the sensitivity of detecting T790M. Digital PCR was used to calculate the ratio of T790M to the number of activating mutation alleles (T/A ratio) in 28 samples (15 pre- and 13 post-TKI treatment samples) obtained from 19 NSCLC with EGFRactivating mutations. We also calculated the ratio of double-stranded DNA (dsDNA) to DNA concentration (dsDNA/DNA ratio) to evaluate the quality of each sample DNA. Results: Digital PCR detected T790M more sensitively compared with ARMS (pre-TKI: 14 of 15 samples, 93.3% v 2 of 15 samples, 13.3%, p<0.001; and post-TKI: 13 of 13 samples, 100% v 4 of 13 samples, 30.8%, p<0.001). In 8 patients whose both samples (pre- and post-TKI) were available, T/A ratios in post-TKI samples was higher than that in pre-TKI samples (37.3% v 5.4%; p <0.01). Digital PCR could not detect T790M only in one formalin-fixed, paraffin-embedded tissue (FFPE) sample. The dsDNA/DNA ratios were low in FFPE samples compared with those in cryopreserved cells (0.96 v 0.07; p<0.001). The possible explanation is that DNA extracted from FFPE samples used in this study was so fragmented that T790M could not be detected by PCR. Conclusions: This study indicates that T790M is present in all tumor samples before EGFR-TKI treatment. It is possible to calculate the ratio of T790M allele in well-preserved samples by digital PCR. This method is useful to develop treatment strategy to overcome the resistance to EGFR-TKI treatment.
Role of Measurable Residual Disease (MRD) in Redefining Complete Response (CR) in Elderly Patients with Acute Myeloid Leukemia (AML): Results from the Pethema-Flugaza Phase III Clinical Trial
Authors: Bruno Paiva, David Martínez-Cuadron, Juan Miguel Miguel Bergua Burgues, Susana Vives, Jesús Lorenzo Algarra, Mar Tormo, Pilar Martínez-Sánchez, Josefina Serrano, Pilar Herrera, Fernando Ramos, Olga Salamero, Esperanza Lavilla, Cristina Gil, Jose Luiz Lopez Lorenzo, Maria-Belen Vidriales, Jorge Labrador, José F. Falantes, Maria Jose Sayas, Juana Merino, Ana Alfonso, Felipe Prosper, Jesus F San-Miguel, Miguel A. Sanz, Pau Montesinos
Journal: Blood (2018)
Recurrent PDGFRB mutations in unicentric Castleman disease
Authors: Zhaoming Li, Xuan Lan, Chaoping Li, Yanjie Zhang, Yingjun Wang, Weili Xue, Lisha Lu, Mengyuan Jin, Zhiyuan Zhou, Xinhua Wang, Ling Li, Lei Zhang, Xin Li, Xiaorui Fu, Zhenchang Sun, Jingjing Wu, Xudong Zhang, Hui Yu, Feifei Nan, Yu Chang, Jiaqin Yan, Xiaolong Wu, Guannan Wang, Dandan Zhang, Yuan Zhang, Ken H. Young, Mingzhi Zhang
Journal: Leukemia (2019)
Nivolumab versus nivolumab with ipilimumab versus trifluridine/tipiracil for metastatic microsatellite instability-high colorectal cancer: A modeling decision analysis.
Authors: Jacqueline N. Chu, Jin G. Choi, Sassan Ostvar, James A. Torchia, Kerry Lynn Reynolds, Justin F. Gainor, Daniel C. Chung, Jeffrey W. Clark, Chin Hur
Journal: Journal of Clinical Oncology (2018)

829 Background: Microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) patients who have failed chemotherapy have shown response to checkpoint blockade. We investigate optimal third-line treatment in MSI-H mCRC with regard to overall survival, quality of life years gained (QALYs), and cost-effectiveness. Methods: A Markov Model was created for a base case of a 57 year old man with MSI-H mCRC refractory to two lines of chemotherapy. Treatments compared were nivolumab, nivolumab with ipilimumab, and trifluridine/tipiracil. Patients could remain stable, progress to fourth-line chemotherapy or palliative care, experience drug toxicity, die from age/sex mortality, or die from cancer over their simulated lifetimes. Transitions between health states were based on the CheckMate 142 and RECOURSE trials. Outcomes were survival or unadjusted life years, QALYs, and incremental cost-effectiveness ratios (ICERs). The willingness to pay threshold was $100,000/QALY. Results: Nivolumab with ipilimumab was the most effective strategy as it yielded more unadjusted life-years (4.24) and QALYs (2.53) compared to nivolumab (3.95 LY, 2.33 QALYs) and trifluridine/tipiracil (0.74 LY, 0.07 QALYs). However, nivolumab with ipilimumab was not cost-effective compared to nivolumab and neither treatment strategy was cost-effective compared to trifluridine/tipiracil. Sensitivity analysis found nivolumab monotherapy could be cost-effective with decrease in drug cost to $2000/dose. Conclusions: Our modeling analysis finds that both single and dual checkpoint blockade yield significantly increased overall survival and QALYs for MSI-H mCRC compared to third-line chemotherapy, but were not cost-effective because of nivolumab cost. Decreases in drug pricing and/or duration of maintenance nivolumab could make nivolumab monotherapy cost-effective. [Table: see text]
Cardiac adenylyl cyclase overexpression precipitates and aggravates age-related myocardial dysfunction
Authors: Nathalie Mougenot, Delphine Mika, Gabor Czibik, Elizabeth Marcos, Shariq Abid, Amal Houssaini, Benjamin Vallin, Aziz Guellich, Hind Mehel, Daigo Sawaki, Grégoire Vandecasteele, Rodolphe Fischmeister, Roger J Hajjar, Jean-Luc Dubois-Randé, Isabelle Limon, Serge Adnot, Geneviève Derumeaux, Larissa Lipskaia
Journal: Cardiovascular Research (2018)

Increase of cardiac cAMP bioavailability and PKA activity through adenylyl-cyclase 8 (AC8) overexpression enhances contractile function in young transgenic mice (AC8TG). Ageing is associated with decline of cardiac contraction partly by the desensitization of β-adrenergic/cAMP signalling. Our objective was to evaluate cardiac cAMP signalling as age increases between 2 months and 12 months and to explore whether increasing the bioavailability of cAMP by overexpression of AC8 could prevent cardiac dysfunction related to age. Cardiac cAMP pathway and contractile function were evaluated in AC8TG and their non-transgenic littermates (NTG) at 2- and 12 months old. AC8TG demonstrated increased AC8, PDE1, 3B and 4D expression at both ages, resulting in increased phosphodiesterase and PKA activity, and increased phosphorylation of several PKA targets including sarco(endo)plasmic-reticulum-calcium-ATPase (SERCA2a) cofactor phospholamban (PLN) and GSK3α/β a main regulator of hypertrophic growth and ageing. Confocal immunofluorescence revealed that the major phospho-PKA substrates were co-localized with Z-line in 2-month-old NTG but with Z-line interspace in AC8TG, confirming the increase of PKA activity in the compartment of PLN/SERCA2a. In both 12-month-old NTG and AC8TG, PLN and GSK3α/β phosphorylation was increased together with main localization of phospho-PKA substrates in Z-line interspaces. Haemodynamics demonstrated an increased contractile function in 2- and 12-month-old AC8TG, but not in NTG. In contrast, echocardiography and tissue Doppler imaging (TDI) performed in conscious mice unmasked myocardial dysfunction with a decrease of systolic strain rate in both old AC8TG and NTG. In AC8TG TDI showed a reduced strain rate even in 2-month-old animals. Development of age-related cardiac dysfunction was accelerated in AC8TG, leading to heart failure (HF) and premature death. Histological analysis confirmed early cardiomyocyte hypertrophy and interstitial fibrosis in AC8TG when compared with NTG. Our data demonstrated an early and accelerated cardiac remodelling in AC8TG mice, leading to the development of HF and reduced lifespan. Age-related reorganization of cAMP/PKA signalling can accelerate cardiac ageing, partly through GSK3α/β phosphorylation.
Clinical significance of serum epithelial cell adhesion molecule (EPCAM) and vascular cell adhesion molecule-1 (VCAM-1) levels in lung cancer.
Authors: Senem Karabulut, Didem Tastekin, Rumeysa Ciftci, Makbule Tambas, Nergis Dagoglu, Murat Emin Guveli, Faruk Tas, Derya Duranyildiz, Adnan Aydiner
Journal: Journal of Clinical Oncology (2014)

e22192 Background: Cellular adhesion molecules might be good markers in some types of malignant tumors, provide useful information in diagnosis and prognosis. The objective of this study was to determine the clinical significance of the serum levels of epithelial cell adhesion molecule (EPCAM) and vascular cell adhesion molecule-1 (VCAM-1) in lung cancer patients. Methods: One hundred and thirty lung cancer patients were enrolled into this study. Serum EPCAM and VCAM-1 levels were determined by the solid-phase sandwich ELISA method. Age and sex matched 34 healthy controls were included in the analysis. Results: Median age was 58 years old, ranging from 35 to 80 years. The majority of the patients had NSCLC (83.8%) and stage IV disease (60.8%). The baseline serum VCAM-1 levels were significantly higher in patients than the control group (p=0.02) whereas there was no significant difference in the serum EPCAM levels between lung cancer patients and controls (p=0.16). Male patients had significantly higher serum VCAM-1 levels compared with female patients (p=0.04). The stage of disease and tumor histology were not correlated with the serum assays (p>0.05). The serum VCAM-1 levels were significantly elevated in chemotherapy unresponsive patients compared with responsive patients (p=0.02). Similar correlation was not found for the serum EPCAM levels (p=0.89). The serum VCAM-1 and EPCAM levels were found to be correlated to each other in lung cancer patients (rs= -0.152, p=0.05). The patients with elevated serum VCAM-1 levels had shorter survival than the ones with lower levels (1-year survival rates were 57.6% vs. 69.7%, respectively, p=0.04). However, serum EPCAM levels had no prognostic role in patients’ outcome (1-year survival rates were 62% vs. 65.1%, respectively, p=0.89). Conclusions: Contrary to serumEPCAM levels, serum VCAM-1 concentrations have diagnostic, predictive and prognostic role in patients with lung cancer.
Aplidine in patients with dedifferentiated liposarcomas: A French Sarcoma Group (FSG) study.
Authors: Antoine Italiano, Axel Le Cesne, Marina Pulido, Nicolas Penel, Sophie Piperno-Neumann, Christine Chevreau, Florence Duffaud, Olivier Mir, Binh Bui Nguyen
Journal: Journal of Clinical Oncology (2014)

10590 Background: Dedifferentiated liposarcomas (DDLPS) exhibit a strong activation of the JUN/JNK pathway which plays a crucial role in the dedifferentiation process. Aplidine is a novel anticancer drug requiring an activation of the JNK pathway to induce apoptosis in several tumors models. Methods: This was a multicentric single-arm phase 2 clinical trial based on two-stage Simon’s design which assessed safety and efficacy of aplidine in patients (pts) with advanced DDLPS. All pts had to have documented progressive disease (PD) as per RECIST 1.1 based on two imaging of less 3-months interval. Pts received aplidine 5 mg/m² every two weeks until PD or unacceptable toxicity. The primary endpoint was the 3-month non-PD rate according to RECIST. Based on the following hypotheses: 20% 3-month non-PD rate (H0), 40% acceptable 3-month non-PD rate (H1), 10% type I error rate, 90% power, a total of 37 assessable pts were necessary (17 for the first stage + 20 for the second stage). Following the inclusion of the first 17 pts, if ≥ four pts were progression-free at 3 months, the accrual was planned to continue. Accrual started in August 2012 and finished in May 2013 in six centers of the French Sarcoma Group. Results: As of May 27 2013, 24 pts (12 males, 12 females) were included in the study. Median age was 63 years (48-83). All the patients had at least one grade 1 or 2 adverse events (AE) possibly related to the drug whereas 11 pts (7.5%) had grade 3 or 4 AE. The most frequent adverse events were nausea, fatigue, anorexia and myalgia. The planned interim statistical analysis performed after central histological and radiological review showed that only one patient out of the first 17 evaluable patients had stable disease. Aplidine did not reach the primary endpoint to justify continuing accrual after the 1ststep of the study. Molecular analyses showed that JUN expression and amplification status were not correlated with outcome. Conclusions: The rapid accrual of this study demonstrates the feasibility of histology-specific research in sarcomas. Aplidine is not worth for further investigations in DDLPS. Clinical trial information: NCT01876043.
Myeloma-Induced Alterations of Glutamine Metabolism Impair Bone Microenvironment Niche in Multiple Myeloma Patients
Authors: Denise Toscani, Martina Chiu, Giuseppe Taurino, Emanuela Vicario, Valentina Marchica, Fabrizio Accardi, Anna Benedetta Dalla Palma, Paola Storti, Gaetano Donofrio, Franco Aversa, Ovidio Bussolati, Nicola Giuliani
Journal: Blood (2018)