tbuckley/cabot-search huggingface dataset:
Analytical and clinical validation of a novel in-house deep-sequencing method for minimal residual disease monitoring in a phase II trial for multiple myeloma
Authors: J Martinez-Lopez, B Sanchez-Vega, S Barrio, I Cuenca, Y Ruiz-Heredia, R Alonso, I Rapado, C Marin, M-T Cedena, B Paiva, N Puig, M-V Mateos, R Ayala, M-T Hernández, C Jimenez, L Rosiñol, R Martínez, A-I Teruel, N Gutiérrez, M-L Martin-Ramos, A Oriol, J Bargay, J Bladé, J San-Miguel, R Garcia-Sanz, J-J Lahuerta
Journal: Leukemia (2017)

support for the investigation of the contribution of altered ribosomal biogenesis to an oncogenic differentiation block.
SNP-Array-Based Karyotyping Has Impact on Cytogenetic Diagnosis and Prognosis of Non-Core Binding Factor Primary and Secondary AML.
Authors: Ramon V. Tiu, Lukasz P. Gondek, Andrew J. Dunbar, Mikkael A. Sekeres, Matt E. Kalaycio, Michael A. McDevitt, Jaroslaw P. Maciejewski
Journal: Blood (2007)
Durable Remission with Salvage Autotransplants in Patients with Multiple Myeloma.
Authors: Nina Shah, Khawaja Fraz Ahmed, Sofia Qureshi, Jatin Shah, Robert Z Orlowski, Donna M Weber, Chitra Hosing, Uday Popat, Amin Alousi, Richard E Champlin, Sergio Giralt, Muzaffar Qazilbash
Journal: Blood (2009)
Role of Megakaryocytes in Breast Cancer Metastasis to Bone
Authors: Walter Jackson, Donna M. Sosnoski, Sara E. Ohanessian, Paige Chandler, Adam Mobley, Kacey D. Meisel, Andrea M. Mastro
Journal: Cancer Research (2017)

Little is known about how megakaryocytes may affect metastasis beyond serving as a source of platelets. In this study, we explored the functional implications of megakaryocyte accumulation in the femurs of mice after injection of metastatic or non-metastatic breast cancer cells in 4T1.2 BALB/cJ and MDA-MB-231 nude mouse models. At bone metastatic sites, but not primary growth sites, tumor growth was associated with increased megakaryopoiesis in both model systems. In the orthotopic BALB/cJ model, extramedullary hematopoiesis occurred in the spleen, resulting in a four-fold increase in megakaryocytes. In support of the hypothesis that reducing megakaryocytes may reduce metastasis, we found that thrombopoietin-deficient mice exhibited a 90% relative decrease in megakaryocytes, yet they developed more aggressive metastasis than wild-type hosts. In human clinical specimens, we observed an increase in megakaryocytes in the bone marrow of 6/8 patients with metastatic breast cancer compared with age- and gender-matched controls. Taken together, our results suggested that an increase in megakaryocytes occurring in response to metastatic cells entering the bone marrow confers some measure of protection against metastasis, challenging present views on the role of megakaryocytes in this setting. Cancer Res; 77(8); 1942-54. ©2017 AACR.
MPTH-49. IS GANGLIOGLIOMA A CNS TUMOR WITH ARRESTED DEVELOPMENT?
Authors: David Eisenstat, Frank van Landeghem
Journal: Neuro-Oncology (2016)

Gangliogliomas (GG) are low grade neuroepithelial tumours of the central nervous system (CNS) comprised of neoplastic glial and neuronal cells. There are no animal models or cell lines to study. Microarray data of a panel of low grade gliomas including GG revealed overexpression of the DLX2 homeobox gene required for tangential interneuronal migration and differentiation in the embryonic forebrain. We hypothesized that DLX2 regulates neural versus glial cell fate decisions in CNS progenitors and that GG are arrested in development. DLX2 expression was examined along with glial fibrillary acidic protein (GFAP; glial marker) and synaptophysin and/or NeuN (neuronal markers) expression in a cohort of GG tumours using immunohistochemistry and dual immunofluorescence labelling of formalin fixed paraffin embedded (FFPE) tissue sections. BRAF mutational status was also assessed. In our discovery cohort (Genoa), 10/30 samples (33%) expressed DLX2. In our validation cohort (Edmonton), 22/36 (61%) expressed nuclear DLX2 and 12/22 DLX2+ cases had BRAF mutations (55%; 11 V600E, 1 V600G). 12/18 cases with BRAF mutations were DLX2+ (67%). One heavily pre-treated child with progressive cervicomedullary GG has had a very good partial response to BRAF inhibitor therapy. All 22 DLX2+ tumours co-expressed GFAP (100%) and 21/22 (95%) also expressed synaptophysin or NeuN. Our results support GG as neurodevelopmental tumours arising from bipotential CNS progenitors that are arrested at the neural-glial cell fate “decision” point. Biological or differentiation-based treatments could be considered +/- BRAF inhibitors for those GG with/without the V600E mutation, respectively.
XPO1 in B cell hematological malignancies: from recurrent somatic mutations to targeted therapy
Authors: Vincent Camus, Hadjer Miloudi, Antoine Taly, Brigitte Sola, Fabrice Jardin
Journal: Journal of Hematology & Oncology (2017)

Many recent publications highlight the large role of the pivotal eukaryotic nuclear export protein exportin-1 (XPO1) in the oncogenesis of several malignancies, and there is emerging evidence that XPO1 inhibition is a key target against cancer. The clinical validation of the pharmacological inhibition of XPO1 was recently achieved with the development of the selective inhibitor of nuclear export compounds, displaying an interesting anti-tumor activity in patients with massive pre-treated hematological malignancies. Recent reports have shown molecular alterations in the gene encoding XPO1 and showed a mutation hotspot (E571K) in the following two hematological malignancies with similar phenotypes and natural histories: primary mediastinal diffuse large B cell lymphoma and classical Hodgkin's lymphoma. Emerging evidence suggests that the mutant XPO1 E571K plays a role in carcinogenesis, and this variant is quantifiable in tumor and plasma cell-free DNA of patients using highly sensitive molecular biology techniques, such as digital PCR and next-generation sequencing. Therefore, it was proposed that the XPO1 E571K variant may serve as a minimal residual disease tool in this setting. To clarify and summarize the recent findings on the role of XPO1 in B cell hematological malignancies, we conducted a literature search to present the major publications establishing the landscape of XPO1 molecular alterations, their impact on the XPO1 protein, their interest as biomarkers, and investigations into the development of new XPO1-targeted therapies in B cell hematological malignancies.
Liposomal Cytarabine (Depocyte®) for the Treatment of Meningeal or CNS Disease in Acute Leukemias (AL) and Non-Hodgkin Lymphomas (NHL): A Single Centre Experience.
Authors: Andrea Camera, Giuseppe Cerciello, Fabiana Perna, Ciro R. Rinaldi, Elefanti Michele, Silvia Ferrari, Bruno Rotoli
Journal: Blood (2006)
Galectin‐9: Diverse roles in hepatic immune homeostasis and inflammation
Authors: Lucy Golden‐Mason, Hugo R. Rosen
Journal: Hepatology (2017)

Glycan-binding proteins, which include galectins, are involved at all stages of immunity and inflammation, from initiation through resolution. Galectin-9 (Gal-9) is highly expressed in the liver and has a wide variety of biological functions in innate and adaptive immunity that are instrumental in the maintenance of hepatic homeostasis. In the setting of viral hepatitis, increased expression of Gal-9 drives the expansion of regulatory T cells and contraction of effector T cells, thereby favoring viral persistence. The dichotomous nature of Gal-9 is evident in hepatocellular carcinoma, where loss of expression in hepatocytes promotes tumor growth and metastasis, whereas overexpression by Kupffer cells and endothelial cells inhibits the antitumor immune response. In nonalcoholic fatty liver disease, Gal-9 is involved indirectly in the expansion of protective natural killer T-cell populations. In ischemic liver injury, hepatocyte-derived Gal-9 is both diagnostic and cytoprotective. In drug-induced acute liver failure, plasma levels correlate with outcome. Here, we offer a synthesis of recent and emerging findings on Gal-9 in the regulation of hepatic inflammation. Ongoing studies are warranted to better elucidate the pathophysiology of hepatic immune-mediated diseases and to develop new therapeutic interventions using glycan-binding proteins. (Hepatology 2017;66:271-279).
EXTH-19. A COMBINATION OF PALBOCICLIB AND RADIOTHERAPY IMPROVES SURVIVAL IN GLIOBLASTOMA
Authors: Kerrie McDonald, Swapna Joshi, Mustafa Khasraw
Journal: Neuro-Oncology (2016)

New treatments are urgently needed for patients diagnosed with MGMT unmethylated glioblastoma. Palbociclib (Pfizer) is a CDK4/6 inhibitor. The aim of this study was to assess efficacy of palbociclib as a monotherapy and in combination with radiotherapy on glioblastoma patient derived cell lines (PDCLs) and xenografts that were MGMT unmethylated and RB1 proficient. A panel of 6 PDCLs were treated with different concentrations of palbociclib alone, and with radiotherapy (4Gy). We assessed the effect of treatment using clonogenic assays (the ability to form tumor colonies). We also measured expression of RB1, CDK4, CDK6, H2AX and cleaved-PARP (a measure of apoptosis). The PDCL, RN1 was intracranially injected into the brains of Nod Skid gamma mice and treated in vivo with palbociclib (75mg/kg; gavage) and Radiotherapy (4Gy). Palbociclib alone was effective in inhibition of tumor cell proliferation in all 6 PDCLs with concentrations ranging from 11uM to 22uM. We found significant synergy when palbociclib was administered with radiotherapy. Protein expression levels of RB1, CDK4 and CDK6 were significantly inhibited with the combination treatment and H2AX and cleaved PARP were induced. In vivo, significantly longer survival was observed in mice treated with the combination of palbociclib and radiotherapy. The median survival was 100.5 days (combination treatment) compared to 93 days (control); 83 days (radiotherapy only) and 92 days (Palbociclib only) (p value=0.0488). The combination of palbociclib and radiotherapy significantly improves overall survival in our xenografts models. In mice, the combination is safe and crosses the blood brain barrier. A phase I/II clinical trial for glioblastoma patients with MGMT unmethylated and RB1 proficient tumors is currently in development.
TMOD-23. DEVELOPMENT AND APPLICATION OF A NOVEL MODEL OF HUMAN LUNG-TO- BRAIN METASTASIS TO IDENTIFY GENETIC REGULATORS OF BRAIN METASTASIS INITIATING CELLS
Authors: Mohini Singh, Chitra Venugopal, Tomas Tokar, Kevin Brown, Nicole McFarlane, David Bakhshinyan, Parvez Vora, Maleeha Qazi, Sujeivan Mahendram, Thushyant Vijaykumar, Branavan Manoranjan, Amy Tong, Kathrin Durrer, Naresh Murty, Robin Hallet, John Hassell, David Kaplan, Jean-Claude Cutz, Igor Jurisica, Jason Moffat, Sheila Singh
Journal: Neuro-Oncology (2016)

Brain Metastases (BM) are the most common type of cerebral tumor in adult, occurring at a rate 10 times greater than that of primary brain cancers. The inherent abilities of a primary tumor cell capable of initiating a BM resembles that of a cancer stem cell (CSCs). We hypothesize that a subgroup of CSCs, termed brain metastasis-initiating cells (BMICs), are responsible for the initiation of BM and are identifiable by an exclusive subset of genes that regulate self-renewal and metastasis. Despite the prevalence and lethality of BM, there is no clinically relevant model that fully reflects metastasis in patients. We recently generated a novel human-mouse xenotransplantation model of BM that allows for interrogation of each phase of the metastatic process from lung to brain, through injection of human patient-derived BMICs into immunocompromised mice. Comprehensive interrogation of human BM using RNA interference screens with subsequent validation in our model identified SPOCK1 and TWIST2 as novel regulators of brain metastasis-initiating cell (BMIC) self-renewal and migration to the brain, respectively. A prospective cohort of primary lung cancer specimens showed SPOCK1 and TWIST2 over-expressed only in patients who ultimately developed BM. Protein-protein interaction network mapping identified novel BMIC regulatory genes with significant prognostic value in lung cancer patients. Specifically, the most significant connector between SPOCK1 and TWIST2, INHBA, a TGF-β ligand found mutated in lung adenocarcinoma, showed reduced expression in BMICs with knockdown of SPOCK1, defining a novel pathway between INHBA, SPOCK1 and TWIST2 and implicating the involvement of the TGF-β signaling pathway in BM development. Our development of a novel preclinical model of BM, through which we have identified several novel BMIC regulators, present potential therapeutic targets that could aid in blockage of the metastatic process, and transform a uniformly fatal systemic disease into a locally controlled and eminently more treatable one.
Establishment of primary human esophageal xenografts: Rationale for selection and cancer model.
Authors: L. Dodbiba, J. Teichman, A. Ramjaun, M. Li, B. Sun, Z. Chen, D. J. Renouf, M. S. Tsao, L. Ailles, G. Liu
Journal: Journal of Clinical Oncology (2011)

45 Background: New animal models of esophageal cancer are required to accelerate research into novel treatment strategies. Mouse xenografts used in pre-clinical drug testing are typically derived from cell lines, but several esophageal cancer cell lines have been contaminated (PMID 20075370). Xenografts implanted from surgically resected human tumors are a potentially viable model, and may better recapitulate the characteristics of the original tumor. We describe the feasibility of such an approach. Methods: 2-10 mm esophageal carcinoma fragments obtained from resected patient tumors were implanted directly into NOD/SCID mice. Tumors that grew beyond 1.5 cm in diameter were passaged serially. Pathologic properties were assessed from passage to passage. Potential clinicopathological predictors of engraftment were evaluated. Results: Of the 63 patients with tumors used for implantation, 67% were male; median age 66 (range 31-89); 31% node negative disease; 69% node positive disease; 12% metastatic; 55% received neoadjuvant therapy; 12% had prior Barrett's esophagus; 46% had pre-existing heartburn; 88% were distal esophageal/GE junction cancers. Engraftment occurred in 14/43 (33%) adeno-, 1/14 (7%) squamous, and 1/1 adenosquamous carcinomas (p=0.05; 5 others were rare tumors e.g. granular or small cell). Engraftment occurred in 6/31 well/moderately vs 7/18 poorly differentiated tumors (p=0.08). Because we amended our implantation procedures, we compared engraftment rates pre- (7/39; 18%) and post-amendment (8/23; 35%; p=0.13). The primary architecture of the xenografted tissue remained similar pathologically for up to 5+ passages. None of the following variables predicted for engraftment (p&gt;0.20 each comparison): cancer location, age, gender, history of heartburn, pre-operative therapy, presence of Barrett's esophagus, disease stage, or recurrence of primary cancer. Conclusions: Creation of esophageal cancer xenografts from primary human resected specimens is feasible. Adenocarcinomas, higher tumor grade, and newer implantation strategies were associated with improved engraftment. We are treating these models with chemotherapy to discover new pharmacogenomic predictive biomarkers. No significant financial relationships to disclose.
Development of a predictive radiomics signature for response to immune checkpoint inhibitors (ICIs) in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (RM-SCCHN)
Authors: A. Prawira, P. Dufort, J. Halankar, D.M. Paravasthu, A. Hansen, A. Spreafico, A.R. Abdul Razak, E. Chen, R.W. Jang, U. Metser, L.L. Siu
Journal: Annals of Oncology (2016)
Characterization of ferroptosis in murine models of hemochromatosis
Authors: Hao Wang, Peng An, Enjun Xie, Qian Wu, Xuexian Fang, Hong Gao, Zhuzhen Zhang, Yuzhu Li, Xudong Wang, Jiaying Zhang, Guoli Li, Lei Yang, Wei Liu, Junxia Min, Fudi Wang
Journal: Hepatology (2017)

Ferroptosis is a recently identified iron‐dependent form of nonapoptotic cell death implicated in brain, kidney, and heart pathology. However, the biological roles of iron and iron metabolism in ferroptosis remain poorly understood. Here, we studied the functional role of iron and iron metabolism in the pathogenesis of ferroptosis. We found that ferric citrate potently induces ferroptosis in murine primary hepatocytes and bone marrow–derived macrophages. Next, we screened for ferroptosis in mice fed a high‐iron diet and in mouse models of hereditary hemochromatosis with iron overload. We found that ferroptosis occurred in mice fed a high‐iron diet and in two knockout mouse lines that develop severe iron overload ( Hjv–/– and Smad4Alb/Alb mice) but not in a third line that develops only mild iron overload ( Hfe –/– mice). Moreover, we found that iron overload–induced liver damage was rescued by the ferroptosis inhibitor ferrostatin‐1. To identify the genes involved in iron‐induced ferroptosis, we performed microarray analyses of iron‐treated bone marrow–derived macrophages. Interestingly, solute carrier family 7, member 11 ( Slc7a11 ), a known ferroptosis‐related gene, was significantly up‐regulated in iron‐treated cells compared with untreated cells. However, genetically deleting Slc7a11 expression was not sufficient to induce ferroptosis in mice. Next, we studied iron‐treated hepatocytes and bone marrow–derived macrophages isolated from Slc7a11–/– mice fed a high‐iron diet. Conclusion: We found that iron treatment induced ferroptosis in Slc7a11–/– cells, indicating that deleting Slc7a11 facilitates the onset of ferroptosis specifically under high‐iron conditions; these results provide compelling evidence that iron plays a key role in triggering Slc7a11‐mediated ferroptosis and suggest that ferroptosis may be a promising target for treating hemochromatosis‐related tissue damage. (H epatology 2017;66:449–465).
MicroRNA Function in Human Hematopoiesis: Identification of Lineage- and Stage-Specific Expression Profiles, Pivotal Targets and Regulatory Circuitries.
Authors: Simona Chicarella, Nadia Felli, Manuela Ferracin, Elvira Pelosi, Ornella Morsilli, George Adrian Calin, Chang-Gong Liu, Massimo Negrini, Carlo Maria Croce, Cesare Peschle
Journal: Blood (2006)
EXTH-09. LOOKING FOR A CURE: DELTA-24-RDG AND RADIOTHERAPY FOR DIPG TREATMENT
Authors: Naiara Martínez-Vélez, Miguel Marigil Sanchez, Pablo Dominguez, Jose Javier Aristu, Juan Fueyo, Candelaria Gomez-manzano, Marie-Pierre Junier, Herve Chneiweiss, Elias El-harb, Ricardo Diez Valle, Sonia Tejada, Marta M Alonso
Journal: Neuro-Oncology (2016)

Diffuse Intrinsic Pontine Gliomas (DIPGs) represent the most frequent and the most aggressive tumor among brainstem gliomas in kids. Radiotherapy is the standard of care however, in a few months the tumor relapses. Despite advances in genetic knowledge of these tumors the outcome remains fatal. Delta-24-RGD is a safe adenovirus that is currently in clinical trial for adult gliomas with promising results. The main objective of this study is to evaluate the safety and the antitumor effect of Delta-24-RGD alone or combined with radiotherapy in DIPGs. Previously we showed that ­Delta-24-RGD displayed a potent antiglioma effect (IC50 ranging from 5 to 50 MOIs) in DIPG cell lines (n=4) that was mediated by an effective infection and replication. Delta-24-RGD effect is increased by radiotherapy inducing a synergistic e antitumor ffect (CI<1). Delta-24-RGD is able to infect and to replicate in radiated DIPG cells even at high doses (12Gy). Virus inhibited key proteins involved in DNA repair that play important roles in the resistance to radiotherapy such as Rad51 or the MNR complex. In vivo studies show that administration of Delta-24-RGD in orthotopic DIPG tumors no presented any toxicity. Efficacy studies of the virus alone or in combination with radiotherapy in nude mice are on-going. Our results showed that Delta-24-RGD exerts an effective antiglioma effect in vitro with no toxicity in vivo. This adenovirus is able to block the DNA damage repair machinery underscoring that combination with radiotherapy could provide a significant therapeutic advantage.
NCI Community Cancer Center Program (NCCCP): Disparities in time between cancer diagnosis and treatment initiation.
Authors: Stephanie Teixeira-Poit, Pamela Spain, Michael T. Halpern, Kathleen M. Castro, Irene Prabhu Das, Brenda A. Adjei, Steven Clauser
Journal: Journal of Clinical Oncology (2016)

279 Background: The National Cancer Institute Community Cancer Centers Program (NCCCP) was designed to improve care and reduce cancer disparities at community hospitals. This study examined the number of days between diagnosis and treatment for five National Quality Forum-endorsed cancer quality measures. Methods: A retrospective analysis of data from patients diagnosed and receiving breast or colon cancer treatment at 12 NCCCP sites was performed. We examined time to treatment for cancer quality measures, stratified by concordant and non-concordant patients. We compared patients diagnosed before (2006 – 2007) vs. during (2008-2013) the NCCCP period. Results: Concordant Cases. Time to treatment was significantly greater in the NCCCP vs. pre-NCCCP periods for three measures. Compared to pre-the NCCCP period, time to treatment in the NCCCP period was longer by 26 days for women with breast cancer receiving hormonal therapy (HT). Time to HT increased significantly among most patient and hospital subgroups (race, age, insurance, hospital size). Black, Medicaid, and/or uninsured patients generally had longer-than-average time to treatment for all measures when receiving guideline-concordant care. Non-Concordant Cases. Among women with breast cancer who received treatment outside the measure window, most eligible for multi-agent chemotherapy received treatment within one month after the cut-off. In contrast, a majority eligible for other cancer quality measures received treatment more than one after the cut-off. Among women who were non-concordant for HT, those with Medicare or private insurance were significantly more likely to begin HT within one month after the cut-off than were those with Medicaid. Conclusions: More than half of patients non-concordant on cancer quality measures received treatment more than one month after the treatment window. However, many were non-concordant because they were just outside the time window to be considered concordant (&lt; 30 days), particularly Medicaid patients. Rapid reporting of quality indicators could inform targeted efforts to improve care coordination and concordance rates, particularly among certain patient subgroups.
Assessment of the prognostic role of a 94-single nucleotide polymorphisms risk score in early breast cancer in the SIGNAL/PHARE prospective cohort: no correlation with clinico-pathological characteristics and outcomes
Authors: E. Curtit, X. Pivot, J. Henriques, S. Paget-Bailly, P. Fumoleau, M. Rios, H. Bonnefoi, P. Soulie, C. Jouannaud, H. Bourgeois, J.-Y. Pierga, I. Tennevet, V. Trillet-Lenoir, P. Kerbrat, T. Petit, T. Bachelot, J.-F. Deleuze, I. Pauporte, G. Romieu, D. Cox
Journal: Annals of Oncology (2016)
A Randomized 3-Arm Phase II Study to Determine the Most Promising Postgrafting Immunosuppression for Prevention of Acute Graft-Versus-Host Disease (GVHD) After Unrelated Donor Hematopoietic Cell Transplantation (HCT) Using Nonmyeloablative Conditioning for Patients with Hematologic Malignancies: A Multi-Center Trial.
Authors: Brenda M. Sandmaier, Michael Maris, Barry Storer, Lars Vindelov, Amelia Langston, James C. Wade, Wolfgang A. Bethge, Michael Pulsipher, Thoralf Lange, Thomas Chauncey, Finn Petersen, Kai Hübel, Ann Woolfrey, Mary E.D. Flowers, David G. Maloney, Rainer F. Storb
Journal: Blood (2009)
Initial Laboratory Findings Useful for Predicting the Diagnosis of Chronic ITP: Results of a Multicenter Prospective Study.
Authors: Masataka Kuwana, Yoshiyuki Kurata, Kingo Fujimura, Koji Fujisawa, Hideo Wada, Toshiro Nagasawa, Shosaku Nomura, Tetsuhito Kojima, Hideo Yagi, Yasuo Ikeda
Journal: Blood (2004)