tbuckley/cabot-search huggingface dataset:
Baseline Blood Eosinophils and Reduction of Asthma Exacerbations By Omalizumab in Children with Moderate-to-Severe Allergic Asthma
Authors: Stanley J. Szefler, Thomas B. Casale, Karin Rosén, Benjamin L. Trzaskoma, Tmirah Haselkorn, Benjamin Ortiz, William Busse
Journal: Journal of Allergy and Clinical Immunology (2017)
Retinoic acid and TGF-β signalling cooperate to overcome MYCN-induced retinoid resistance
Authors: David J. Duffy, Aleksandar Krstic, Melinda Halasz, Thomas Schwarzl, Anja Konietzny, Kristiina Iljin, Desmond G. Higgins, Walter Kolch
Journal: Genome Medicine (2017)

Retinoid therapy is widely employed in clinical oncology to differentiate malignant cells into their more benign counterparts. However, certain high-risk cohorts, such as patients with MYCN-amplified neuroblastoma, are innately resistant to retinoid therapy. Therefore, we employed a precision medicine approach to globally profile the retinoid signalling response and to determine how an excess of cellular MYCN antagonises these signalling events to prevent differentiation and confer resistance. We applied RNA sequencing (RNA-seq) and interaction proteomics coupled with network-based systems level analysis to identify targetable vulnerabilities of MYCN-mediated retinoid resistance. We altered MYCN expression levels in a MYCN-inducible neuroblastoma cell line to facilitate or block retinoic acid (RA)-mediated neuronal differentiation. The relevance of differentially expressed genes and transcriptional regulators for neuroblastoma outcome were then confirmed using existing patient microarray datasets. We determined the signalling networks through which RA mediates neuroblastoma differentiation and the inhibitory perturbations to these networks upon MYCN overexpression. We revealed opposing regulation of RA and MYCN on a number of differentiation-relevant genes, including LMO4, CYP26A1, ASCL1, RET, FZD7 and DKK1. Furthermore, we revealed a broad network of transcriptional regulators involved in regulating retinoid responsiveness, such as Neurotrophin, PI3K, Wnt and MAPK, and epigenetic signalling. Of these regulators, we functionally confirmed that MYCN-driven inhibition of transforming growth factor beta (TGF-β) signalling is a vulnerable node of the MYCN network and that multiple levels of cross-talk exist between MYCN and TGF-β. Co-targeting of the retinoic acid and TGF-β pathways, through RA and kartogenin (KGN; a TGF-β signalling activating small molecule) combination treatment, induced the loss of viability of MYCN-amplified retinoid-resistant neuroblastoma cells. Our approach provides a powerful precision oncology tool for identifying the driving signalling networks for malignancies not primarily driven by somatic mutations, such as paediatric cancers. By applying global omics approaches to the signalling networks regulating neuroblastoma differentiation and stemness, we have determined the pathways involved in the MYCN-mediated retinoid resistance, with TGF-β signalling being a key regulator. These findings revealed a number of combination treatments likely to improve clinical response to retinoid therapy, including co-treatment with retinoids and KGN, which may prove valuable in the treatment of high-risk MYCN-amplified neuroblastoma.
Polydom Is an Extracellular Matrix Protein Involved in Lymphatic Vessel Remodeling
Authors: Nanami Morooka, Sugiko Futaki, Ryoko Sato-Nishiuchi, Masafumi Nishino, Yuta Totani, Chisei Shimono, Itsuko Nakano, Hiroyuki Nakajima, Naoki Mochizuki, Kiyotoshi Sekiguchi
Journal: Circulation Research (2017)

Lymphatic vasculature constitutes a second vascular system essential for immune surveillance and tissue fluid homeostasis. Maturation of the hierarchical vascular structure, with a highly branched network of capillaries and ducts, is crucial for its function. Environmental cues mediate the remodeling process, but the mechanism that underlies this process is largely unknown.Polydom (also called Svep1) is an extracellular matrix protein identified as a high-affinity ligand for integrin α9β1. However, its physiological function is unclear. Here, we investigated the role of Polydom in lymphatic development.We generated Polydom-deficient mice. Polydom-/- mice showed severe edema and died immediately after birth because of respiratory failure. We found that although a primitive lymphatic plexus was formed, it failed to undergo remodeling in Polydom-/- embryos, including sprouting of new capillaries and formation of collecting lymphatic vessels. Impaired lymphatic development was also observed after knockdown/knockout of polydom in zebrafish. Polydom was deposited around lymphatic vessels, but secreted from surrounding mesenchymal cells. Expression of Foxc2 (forkhead box protein c2), a transcription factor involved in lymphatic remodeling, was decreased in Polydom-/- mice. Polydom bound to the lymphangiogenic factor Ang-2 (angiopoietin-2), which was found to upregulate Foxc2 expression in cultured lymphatic endothelial cells. Expressions of Tie1/Tie2 receptors for angiopoietins were also decreased in Polydom-/- mice.Polydom affects remodeling of lymphatic vessels in both mouse and zebrafish. Polydom deposited around lymphatic vessels seems to ensure Foxc2 upregulation in lymphatic endothelial cells, possibly via the Ang-2 and Tie1/Tie2 receptor system.
Grade 2–4 Acute Graft-Versus-Host Disease and Extensive Chronic Graft-Versus-Host Disease Are Associated with Significantly Decreased Survival Following Reduced Intensity Allogeneic Stem Cell Transplantation.
Authors: Geoffrey W. Chan, Andreas K. Klein, Kellie A. Sprague, Kenneth B. Miller, Francine M. Foss
Journal: Blood (2004)
Omalizumab Efficacy in Severe Asthma without Allergenic Sensitization
Authors: Blanca De Vega Sánchez, Vicente Roig Figueroa, Agueda Herrero Pérez, Enrique Macías Fernández, Angela Peñaloza GonzÃ°lez, Juarros Martínez Santiago, Vielba Dueñas David, Ramos Cancelo Isabel
Journal: Journal of Allergy and Clinical Immunology (2017)
Aromatase inhibitors and the risk of contralateral breast cancer in <i>BRCA</i> mutation carriers.
Authors: Maryam Nemati Shafaee, Angelica M. Gutierrez-Barrera, Heather Y. Lin, Banu Arun
Journal: Journal of Clinical Oncology (2015)

3 Background: Contralateral breast cancer (CBC) risk in BRCA1 &amp; 2 mutations is up to 64%. Patients (pts) with estrogen receptor positive (ER+) breast cancer (BC) are offered tamoxifen (TAM) or Aromase inhibitors (AI) adjuvantly. Reports suggest that TAM may reduce the risk of CBC in BRCA mutation; however there is no such data on the effect of AIs. Here, we evaluate the effect of TAM and AI as potential CBC risk reducers in a cohort of women with known BRCA status. Methods: 1043 BC pts receiving genetic counseling and BRCA testing were included. 13 had metastasis, 168 had a variant BRCA, and 50 had synchronous BC, and were excluded. Of the 812 remaining pts, 153 had a deleterious BRCA 1 or 2 mutations. Pts were followed from the diagnosis of BC until CBC, death, or last follow-up. The study had IRB approval. Univariate analyses were performed to test the significance of each variable in relation to BRCA status using chi-square tests for categorical variables and t tests for continuous variables. Results: The median age at diagnosis of BC was 42.3 years (range: 21-84). Median follow up was 8.6 years. 86% (700) had ER+ tumors, 80% were diagnosed with T1-2, and 81% had N0-N1. 76% (622) received TAM, and 37% (304) received AI. A total of 68 (8.7%) CBCs occurred of which 14% (21/153) occurred in BRCA carriers vs 7% (47/659) in BRCA non-carriers. Multivariate analyses indicated that BRCA status and AI use were significantly associated with CBC. Specifically, compared with BRCA negative, pts with BRCA1+ or BRCA2+ had larger hazard of developing CBC, Hazard Ratio (HR) (95% confidence interval (CI)) = 2.49 (1.21, 5.10), p = 0.013 for BRCA1+ vs Negative. HR (95%CI) = 1.97 (1.05, 3.73), p = 0.036 for BRCA2+ vs Negative. Compared to pts who did not receive AI, those who received AI had smaller hazard of developing CBC, HR (95%CI) = 0.42 (0.22, 0.81), p = 0.01. The interaction between AI and BRCA status was not significant (p = 0.4), hence all pts benefited from AI use in terms of CBC risk reduction. TAM use did not show significant effect on the risk of CBC in univariate and multivariate analyses (p &gt; 0.13). Conclusions: This is the first report showing that AIs can reduce risk of CBC in women with BC who have a BRCA mutation. This finding should be validated in larger independent cohorts.
A Phase 1 first-in-human study of MEDI0680, an anti-PD-1 monoclonal antibody (mAb) in adult patients (pts) with advanced tumors
Authors: A. Naing, S. Goel, B. Curti, A. Weise, J.P. Eder, S. Marshall, C. Morehouse, X. Li, J.J. Karakunnel, J. Infante
Journal: Annals of Oncology (2016)
Chromatin State Shaping the Gene Expression Profiling in the Inducible Differentiation of Promyelocytic Leukemia Cells
Authors: Chunhua Song, Lisa Chung, Xiaokang Pan, Li Zhanjun, Yali Ding, Mansi Sachdev, Sunil Muthusami, Chandrika S. Gowda, Zheng Ge, Sadie Steffens, Bi-Hua Tan, Christina Kendziorski, Michael Newton, Sinisa Dovat
Journal: Blood (2014)
Combination immunotherapy: a road map
Authors: Patrick A. Ott, F. Stephen Hodi, Howard L. Kaufman, Jon M. Wigginton, Jedd D. Wolchok
Journal: Journal for ImmunoTherapy of Cancer (2017)

Cancer immunotherapy and in particular monoclonal antibodies blocking the inhibitory programed cell death 1 pathway (PD-1/PD-L1) have made a significant impact on the treatment of cancer patients in recent years. However, despite the remarkable clinical efficacy of these agents in a number of malignancies, it has become clear that they are not sufficiently active for many patients. Initial evidence, for example with combined inhibition of PD-1 and CTLA-4 in melanoma and non-small cell lung cancer (NSCLC), has highlighted the potential to further enhance the clinical benefits of monotherapies by combining agents with synergistic mechanisms of action. In order to address the current progress and consider challenges associated with these novel approaches, the Society for Immunotherapy of Cancer (SITC) convened a Combination Immunotherapy Task Force. This Task Force was charged with identifying and prioritizing the most promising prospects for combinatorial approaches as well as addressing the challenges associated with developing these strategies. As a result of the extensive clinical benefit and tolerable side effects demonstrated with agents inhibiting the PD-1 pathway, an overview of current evidence to support its promising potential for use as a backbone in combination strategies is presented. In addition, key issues in the development of these strategies including preclinical modeling, patient safety and toxicity considerations, clinical trial design, and endpoints are also discussed. Overall, the goal of this manuscript is to provide a summary of the current status and potential challenges associated with the development and clinical implementation of these strategies.
Measuring impact of survivorship care plans on head and neck cancer patients.
Authors: Bridgett Ann Harr, Joanna Bodmann, Shlomo A. Koyfman, Tobenna Igweonu Nwizu, Nikhil Purushottam Joshi, Denise I. Ives, Melissa L Rahe, Jean F Hamker, David J. Adelstein
Journal: Journal of Clinical Oncology (2016)

73 Background: At our institution, patients who have completed treatment for a locoregionally confined head and neck cancer are followed in a multidisciplinary head and neck survivorship clinic initiated by the administration of a formal, patient specific survivorship care plan (SCP). We sought to assess the impact of these SCP visits on patient understanding of their disease, its treatment, and potential late effects and follow up plans. Methods: An IRB approved survey was administered by an uninvolved third party, to an unselected sequential series of head and neck cancer survivorship patients at the time of a regularly scheduled follow up visit. The survey focused on the knowledge recalled from the SCP, and whether this changed over time. We analyzed two cohorts of patients, based on whether the SCP had been given to them within the last 18 months or not. Results: Preliminary results from the first 20 patients surveyed are presented. These patients received their SCP 3-27 months before being surveyed. Primary tumor sites included oropharynx (16) and larynx (4) and most patients had been treated with intensity modulated radiation therapy (19) and concurrent cisplatin (11). Conclusions: Although patients’ recall about receiving a formal SCP appeared to diminish over time, the information provided by this SCP plan and subsequent survivorship visits was retained. Whether this reflected the SCP itself, or the reinforcement of continued close follow up survivorship visits cannot be determined, but merits further investigation. [Table: see text]
Prevention of Venous Thromboembolism after Acute Ischemic Stroke with Enoxaparin Versus Unfractionated Heparin and the Impact of Stroke Severity.
Authors: David G. Sherman, Gregory W. Albers, Christopher Bladin, Min Chen, Cesare Fieschi, Alberto A. Gabbai, Carlos S. Kase, William O’Riordan, Graham F. Pineo
Journal: Blood (2006)
Comprehensive molecular and immunological analysis to assess the tumor immune contexture in stage II and III colorectal cancer
Authors: K. Silina, U. Petrausch, F. Posch, S. Leibl, A. Mündlein, H. Moch, A. Siebenhüner, R. Stupp, J. Riedl, B.C. Pestalozzi, P. Schraml, A. Gerger, T. Winder
Journal: Annals of Oncology (2016)
NIMG-76. MIDBRAIN GLIOMAS: A LARGE SERIES THAT IDENTIFIES FEATURES CORRESPONDING WITH OUTCOME
Authors: Devorah Segal, Harini Rao, Cheddhi Thomas, Benjamin Cohen, Matija Snuderl, Matthias Karajannis, Jeffrey Allen
Journal: Neuro-Oncology (2016)

Midbrain gliomas are a group of slow-growing, low-grade tumors that arise from the tectum and/or tegmentum. Clinical symptoms at diagnosis are usually due to aqueductal compression resulting in non-communicating hydrocephalus and managed by an endoscopic third ventriculostomy. In the majority of patients, diagnosis is based on imaging characteristics, and only a subset undergo biopsy or resection. As a result, little is known about the histopathological and molecular genetic spectrum of midbrain gliomas. We reviewed a series of 58 consecutive patients (age range birth-52 years) with midbrain gliomas treated at our institution over more than 30 years. Anatomically, these tumors appear to fall into two distinct radiographic categories: limited to the tectum and/or the periaqueductal gray matter of the tegmentum (Group A) and diffuse tumors that include the tectum and infiltrate the pons and/or thalamus (Group B). Twenty-one of our patients (Group A – 6, Group B – 12, unknown -- 3) had biopsies or surgical resection, and tissue was available for histologic and molecular analyses including methylation profiling and BRAF mutation analysis. Most tumors with available tissue, regardless of radiographic group, were found to be low-grade gliomas, primarily pilocytic astrocytomas (13 pilocytic astrocytomas, 7 other low grade gliomas). Most of our patients had a benign clinical course, with 10% requiring no treatment, and 34% receiving only endoscopic third ventriculostomy or ventriculoperitoneal shunt. Radiographic group was significantly associated with likelihood to progress and with progression-free survival, with only 12.5% of Group A tumors progressing but 46.4% of Group B tumors progressing (p=0.008). In addition, progression –free survival was significantly longer in Group A patients. Overall, survival in our cohort was 100% over more than 30 years, reinforcing that these are treatable tumors with generally excellent outcomes.
Cyclophosphamide and Prednisone Induction Effectively Decreased the Incidence of Engraftment Syndrome In Patients with POEMS Syndrome Who Undergo Stem Cell Transplantation.
Authors: Victor H Jimenez-Zepeda, Donna E. Reece, Suzanne Trudel, Christine Chen, Ahmed M. Rabea, Vishal Kukreti
Journal: Blood (2010)
Diagnostic and Disease Management Algorithms for Gaucher Disease: A Guide for Haematologists
Authors: Pramod K Mistry, Maria Domenica Cappellini, Elena Lukina, Hayri Özsan, Sara Mach Pascual, Hanna Rosenbaum, Maria Helena Solano, Zachary Simon Spigelman, Jesús Villarrubia, Nora Patricia Watman, Gero Massenkeil
Journal: Blood (2008)
Protection of CML Progenitors from Bcr-Abl Tyrosine Kinase Inhibitor Mediated Apoptosis by the Bone Marrow Stromal Microenvironment.
Authors: Bin Zhang, Heiko Konig, Tinisha Mcdonald, Tessa L. Holyoake, Dario Campana, Ravi Bhatia
Journal: Blood (2007)
The MEK1/2 Inhibitor AZD6244 (ARRY-142886) Downregulates Constitutive and Adhesion-Induced c-MAF Oncogene Expression and Its Downstream Targets in Human Multiple Myeloma.
Authors: Yu-Tzu Tai, Giovanni Tonon, Xian-Feng Li, Matthew Rumizen, Weihua Song, Aileen Morrison, Peter Burger, Nikhil C. Munshi, Kenneth C. Anderson
Journal: Blood (2006)
First-in-human, first-in-class, phase I study of a human monoclonal antibody CNTO 888 to the CC-chemokine ligand 2 (CCL2/MCP-1) in patients with solid tumors
Authors: S. K. Sandhu, P. C. Fong, S. Frentzas, A. Patnaik, K. Papadopoulos, B. Tromp, T. Puchalski, B. Berns, A. W. Tolcher, J. S. De-Bono
Journal: Journal of Clinical Oncology (2009)

e13500 Background: The chemokine CCL2 promotes angiogenesis, tumor proliferation, migration and metastasis through PI3K and NFkB signaling. CNTO 888 is a human IgG1κ monoclonal antibody with high binding affinity for CCL2 and documented preclinical antitumor activity. Methods: Patients were administered a 90 minute infusion of CNTO 888 on day 1, day 28 and subsequently on a q14 schedule. Exploratory PD assessments include diffusion contrast enhanced CT, circulating tumor and endothelial cells, free and bound CCL2 levels, bone markers and paired tumor biopsies. Results: 21 patients in cohorts of 3–6 patients received repeated CNTO 888 infusions at 5 dose levels (0.3mg/kg, 1mg/kg, 3mg/kg, 10mg/kg, 15 mg/kg). A further 23 patients are currently being evaluated in 2 expansion cohorts; 10mg/kg (n=12) and 15mg/kg (n=11). No dose limiting toxicities were seen up to 15 mg/kg q14. Preliminary pharmacokinetic (PK) data for doses ≤ 10 mg/kg showed linear kinetics with a bi-exponential decline and a t1/2 of 4.4 - 8.7 days. The 10 mg/kg dose level resulted in steady-state minimum concentrations above that needed to inhibit chemotaxis and calcium mobilization in preclinical studies. Dose-dependent increase in bound CCL2 levels of &gt; 1000-fold seen following treatment, supports target modulation. 2 patients demonstrated stable disease (SD) &gt; 6 months at 15mg/kg CNTO 888 (ocular melanoma and neuroendocrine tumor). Another patient at 0.3mg/kg CNTO 888 with ovarian cancer had 50% CA125 decline and SD for 10 months. Conclusions: CNTO 888 is well tolerated with no DLTs when administered up to 15mg/kg q14. Preliminary evidence of antitumor activity is reported. [Table: see text]
QLIF-08. AN INVESTIGATION OF BRAIN-TUMOR RELATED EPILEPSY IN THE GliomaSE CONSORTIUM
Authors: Paula Warren, Burt Nabors, Noah Peeri, Zachary Thompson, Reid Thompson, Sajeel Chowdhary, Jeffrey J. Olson, Renato LaRocca, Carrie Rozmeski, Peter Forsyth, Kathleen Egan
Journal: Neuro-Oncology (2016)

Seizures are a significant symptom of primary brain tumors. The aim of this study is to examine the occurrence and timing of seizures in an adult glioma population. The analysis was based on 195 patients with a diagnosis of primary glioma consecutively enrolled in a clinic-based case-control study (‘GliomaSE’) at Moffitt Cancer Center in Tampa, FL (n=123) or the University of Alabama at Birmingham (n=72) between 2007 and 2011. Patient (age and gender) and tumor (glioma subtype, tumor hemisphere, and lobe) data was available for all subjects. Tumor-related seizure was determined based on a review of medical records and classified according to seizure status (ever or never) and timing of onset (at presentation or later in the disease course). Independent associations with seizure status were evaluated using multivariate logistic regression. Seizure at presentation (SAP) was reported in 98 (50%) patients and was reported as occurring later in the disease course in 25 (13%) patients. When compared to no record of seizure (n=72 patients; 37%), SAP was associated with age less than 50 years (26% versus 44%; p=0.024), non-GBM subtype (28% versus 44%; p=0.037), and left hemisphere location (43% versus 59%; p=0.044). In multivariate analyses, suggestive though nonsignificant independent associations with SAP were found for age less than 50 years (odds ratio (OR): 1.79); non-GBM subtype (OR: 1.78); location in temporal lobe (OR: 1.61); and location in the left hemisphere (OR: 1.87). All results were similar when considering seizure onset occurring before or after diagnosis. Our findings for SAP occurring more frequently in the non-GBM subtype and in temporal lobe tumors are in keeping with previous findings in the literature. The unexpected finding that younger age associates with SAP, even when controlling for tumor subtype, warrants further study.
P13.11 Outcome evaluation of oligometastatic patients with single, large brain metastases treated with gross total resection (GTR) followed by hypofractionated stereotactic radiosurgery (HSRS) on the tumor bed
Authors: P. Navarria, F. Pessina, A. Ascolese, L. Cozzi, S. Tomatis, M. Riva, L. Bello, E. Clerici, F. Lobefalo, M. Scorsetti
Journal: Neuro-Oncology (2016)

AbstractIntroduction:In case of large brain metastases (BMs), treatment option include whole-brain-radiation-therapy (WBRT), surgery, single dose radiosurgery (SRS) or Hypofractionated stereotactic radiosurgery (HSRS). None of these, when given as a single modality are able to obtain and adequate local control rate. Therefore a combined approach, if feasible, is recommended. The aim of this study was to evaluate the benefit of a combined treatment, gross total resection (GTR) followed by adjuvant hypofractionated-stereotactic-radiosurgery (HSRS) on the tumor bed, in oligometastatic patients with single, large BMs.Methods and Materials:From January 2011 to March 2015, 69 patients with single, large BMs, controlled primary tumor and extracranial disease were treated. All patients underwent gross total resection (GTR) followed by HSRS on the tumor bed with a total dose of 30 Gy in 3 daily fractions. Clinical outcome was evaluated by neurological examination and MRI 2 months after RT and then every 3 months. Local progression was defined as radiographic increase of the enhancing abnormality in the treated brain volume and brain distant progression (BDP) as the presence of new brain metastases or leptomeningeal enhancement outside the treated brain volume. Surgical morbidity and radiation-therapy toxicity, local control (LC), brain distant progression (BDP), and overall survival (OS) were evaluated.Results:The median preoperative volume and maximum diameter of BMS was 18.45 cm3 (range 4.06–64.23 cm3) and 3.6 cm (range 2.1–5.4 cm); the median clinical target volume (CTV) was 29 cm3 (range 4.06–203.10 cm3) and the median planning target volume (PTV) was 55.19 cm3 (range 17.18–282.90 cm3). The median follow-up was 24 months (range 4–33 months). The 1-and 2-year LC in site of treatment was 100%; the median, 1-and 2-year BDP was 11.9 months, 19.6% and 33 %; the median, 1-and 2-year OS was 24 months (range 4–33 months), 91.3% and 73%. No severe postoperative morbidity or radiation toxicity occurred in our series.Conclusions:Multimodal approach, surgery followed by HSRS, can be an effective treatment option for selected patients with single, large brain metastases from different solid tumors.Keywords: brain metastases, surgical resection, hypofractionated-stereotactic-radiosurgery
Results of Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia of the FAB M0 Subtype in First Complete Remission: A Survey of the Acute Leukemia Working Party of the European Bone Marrow Transplant Group (EBMT).
Authors: Andree-Laure Herr, Myriam Labopin, Rosy Reiffers, Donald Bunjes, Didier Blaise, Bernard Hurtenstein, Norbert C. Gorin, Eliane Gluckman, Vanderson Rocha
Journal: Blood (2004)