tbuckley/cabot-search huggingface dataset:
Building a specialty accountable care organization (ACO) for cancer: Using cost groupers in breast cancer (BC) and malignant hematology (MH).
Authors: Janene Culumber, Brian Kiss, Hugo Francisco Fernandez, Karen Wartenberg, Lisa DeMaria, Riti Shimkhada, John W. Peabody
Journal: Journal of Clinical Oncology (2013)

253 Background: New payment models, such as accountable care organizations (ACOs), bundled payments and global budgets will shift some financial risk from payers to providers. The first step in creating a cancer ACO will be to partner with payers to understand aggregate costs over time. Methods: Moffitt Cancer Center (MCC) is partnering with Florida Blue in (BCBS of FL) in developing a specialty ACO strategy for cancer. As an initial step, we created an analytical framework to group and estimate the total costs of cancer care for newly diagnosed breast cancer (BC) and malignant hematology (MH) patients. We used HIPPA-compliant Florida Blue claims billings from 2010-2012 to capture all episodes of care within each calendar year. BC and MH patients were attributed to MCC if they had at least 3 annual visits. Claims from attributed patients were grouped into 7 categories. We calculated the annual costs and the costs by category to generate a Per Member Per Year (PMPY) cost and determine the stability and/or trends in these costs. Results: The PMPY data for the three years (2010, 2011, 2012) were stable over time. Important trends, however, were noted: outpatient (OP) costs, which include infusion chemotherapy, rose similarly (16 and 13%, respectively), inpatient (IP) costs for BC increased 10%, compared to an 8% decrease in IP cost for MH over the 3 years. Physician costs remained stable, consistent with other reports. Conclusions: Moving away from volume-based reimbursement requires building partnerships between payers and providers. We created disease-based cost groupers for two cancer conditions as a first step. Cost trends were stable over time. These findings will give payers and partners confidence to explore ways to improve quality and reducing cost as they consider new arrangements such as a specialty ACO. [Table: see text]
Comparison of Cyclosporine A and Mycophenolate Mofetil vs Cyclosporine A and Methotrexate in Reduced Intensity Conditioning HLA Sibling Allogeneic Stem Cell Transplantation. A Case-Match Single-Center Experience.
Authors: Jose L. Piñana, David Valcárcel, Rodrigo Martino, Rocio Parody, Anna Sureda, Javier Briones, Julio Delgado, Blanca Snchez, Salut Brunet, Jorge Sierra
Journal: Blood (2007)
The Efficacy and Long-Term Outcomes of ASCT in POEMS Syndrome: A Multicenter Retrospective Study in Japan
Authors: Chika Kawajiri, Emiko Sakaida, Chikako Ohwada, Toshihiro Miyamoto, Taichi Azuma, Jun Taguchi, Takehiko Mori, Yuichi Hasegawa, Tadakazu Kondo, Toshiaki Yujiri, Makoto Yoshimitsu, Mitsuru Tsudo, Toshihiko Iwasaki, Akio Shigematsu, Ritsuro Suzuki, Yoshiko Atsuta, Makoto Hirokawa, Hisashi Sakamaki, Chiaki Nakaseko
Journal: Blood (2014)
Novel lncRNA T-UCR as a potential downstream driver of the Wnt/β-catenin pathway in hepatobiliary carcinogenesis
Authors: Maite G Fernández-Barrena, Maria J Perugorria, Jesus M Banales
Journal: Gut (2016)

Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the most frequent primary liver tumours and their incidence is increasing worldwide. HCC commonly originates from chronic necroinflammation of liver parenchyma that promotes the malignant transformation of proliferating hepatocytes, whereas CCA arises from neoplastic biliary transformation. These types of cancer are frequently diagnosed in advanced stages compromising the limited therapeutic options mainly based on surgery. The molecular and cellular heterogeneity of these tumours, together with their rich tumour microenvironment, contribute to drug resistance and malignant recurrence. This clinical scenario results in poor prognosis.1 ,2 

In the last years, intense efforts are being made to ascertain the molecular mechanisms involved in the pathogenesis of both types of cancer in order to find new effective therapeutic options. Understanding liver cancer biology, elucidation of fundamental molecular pathways and determination of genetic and epigenetic abnormalities (ie, DNA methylation, histone modifications and non-coding RNA dysregulation) have strongly emerged as key elements to accomplish this goal. With this vision, in this issue of Gut , Carotenuto et al 3 have identified the ultraconserved long non-coding RNA (lncRNA) uc.158− as a cancer-specific mediator of Wnt/β-catenin pathway in both HCC and CCA. The Wnt/β-catenin signalling pathway is essential in liver pathophysiology regulating cell differentiation, proliferation and survival, among others. Whereas this pathway plays a pivotal role during liver embryogenesis, its impaired and/or excessive activation may promote the development and progression of different cancers, including hepatobiliary tumours. In HCC, ∼50% …
Double-blind, placebo-controlled, multicentric randomized phase IIb neoadjuvant study of letrozole-lapatinib in postmenopausal HER2-negative, hormone receptor-positive operable breast cancer.
Authors: P. F. Conte, V. Guarneri, D. G. Generali, A. Bottini, L. Bazzola, F. Piacentini, F. Artioli, K. Cagossi, G. Bisagni, M. Bagnalasta, E. Tagliafico, E. Barbieri, L. Cavanna, A. Ravaioli, R. D'Amico, R. Vicini, A. Frassoldati
Journal: Journal of Clinical Oncology (2011)

550 Background: The crosstalk between the ER pathway and erbB receptor family is emerging as a mechanism of resistance to hormonal therapy. The combination of lapatinib-letrozole might prevent or delay the development of endocrine resistance. On these premises we have designed a multicentric phase IIb randomized, double-blind, placebo controlled study to evaluate the clinical and biological effects of combined letrozole+lapatinib/placebo as neoadjuvant therapy in previously untreated ER+ve/HER2-ve breast cancer patients. Primary aim is the percentage of breast clinical response, as measured by ultrasonography (US). Secondary aims include pathologic response, percentage of breast conserving surgery, modulation of Ki67 and HER2/EGFR pathways, and gene expression analysis. Methods: After diagnostic core biopsy, patients were randomized to letrozole 2.5 mg continuous daily dosing (CDD) + lapatinib 1500mg CDD or to letrozole- placebo, given for 24 weeks before surgery. Results: As of October 2010, the planned accrual has been completed. Ninety-two postmenopausal women have been randomized. Patient characteristics were as follows: median age 68 yrs (range 48-89 yrs); stage at diagnosis: IIA 49%; IIB 41%, IIIA 10%. Median ER expression 95% (range 30-100%); median PgR expression 68% (range 0-100%). At diagnosis, mean US tumor size was 3 cm (range 1.2-8 cm). Seventy-one patients are evaluable so far. The ORR (PR + CR) by US at the completion of therapy was 61%; SD was observed in 27% of the patients. Four patients experienced PD. Five patients prematurely discontinued therapy due to toxicity (n=1), consent withdrawal (n=3) or lost to follow up (n=1). No change in mean LVEF was observed at the 3- and 6-month evaluations. The data will be unblinded by April 2011. Conclusions: Preliminary blinded results suggest that the combination of letrozole+lapatinib/placebo is associated with clear tumor downstaging. Final unblinded results per treatment arm, including pathologic response, clinical response by centralized review and biomarker analyses will be presented at the meeting.
Evidence for Autostimulatory Mechanisms in Chronic Lymphocytic Leukemia.
Authors: Martin Trepel, Fabian Muller, Mareike Frick, Janina Rahlff, Claudia Wehr, Frederic Simon, Bernd Leistler, Hendrik Veelken, Roland H. Mertelsmann, Mascha Binder
Journal: Blood (2012)
Cytotoxic Exposure to Both Hematopoietic Stem and Progenitor Cells and the Bone Marrow Niche Cooperate to Promote Leukemogenesis in a Mouse Model of Therapy-Related Myeloid Neoplasms with a Del(5q)
Authors: Angela Stoddart, Jianghong Wang, Chunmei Hu, Anthony A. Fernald, Elizabeth M. Davis, Jason X. Cheng, Michelle M. Le Beau
Journal: Blood (2015)
Targeting the ATR/CHK1 Axis with PARP Inhibition Results in Tumor Regression in <i>BRCA</i>-Mutant Ovarian Cancer Models
Authors: Hyoung Kim, Erin George, Ryan L. Ragland, Stavros Rafail, Rugang Zhang, Clemens Krepler, Mark A. Morgan, Meenhard Herlyn, Eric J. Brown, Fiona Simpkins
Journal: Clinical Cancer Research (2016)

Abstract Purpose: PARP inhibition (PARPi) has modest clinical activity in recurrent BRCA-mutant (BRCAMUT) high-grade serous ovarian cancers (HGSOC). We hypothesized that PARPi increases dependence on ATR/CHK1 such that combination PARPi with ATR/CHK1 blockade results in increased cell death and tumor regression. Experimental Design: Effects of PARPi (olaparib), CHK1 inhibition (CHK1i;MK8776), or ATR inhibition (ATRi;AZD6738) alone or in combination on survival, colony formation, cell cycle, genome instability, and apoptosis were evaluated in BRCA1/2MUT HGSOC cells. Tumor growth in vivo was evaluated using a BRCA2MUT patient-derived xenograft (PDX) model. Results: PARPi monotherapy resulted in a decrease in BRCAMUT cell survival, colony formation and suppressed but did not eliminate tumor growth at the maximum tolerated dose (MTD) in a BRCA2MUT PDX. PARPi treatment increased pATR and pCHK1, indicating activation of the ATR–CHK1 fork protection pathway is relied upon for genome stability under PARPi. Indeed, combination of ATRi or CHK1i with PARPi synergistically decreased survival and colony formation compared with single-agent treatments in BRCAMUT cells. Notably, PARPi led to G2 phase accumulation, and the addition of ATRi or CHK1i released cells from G2 causing premature mitotic entry with increased chromosomal aberrations and apoptosis. Moreover, the combinations of PARPi with ATRi or CHK1i were synergistic in causing tumor suppression in a BRCA2MUT PDX with the PARPi–ATRi combination inducing tumor regression and in most cases, complete remission. Conclusions: PARPi causes increased reliance on ATR/CHK1 for genome stability, and combination PARPi with ATR/CHK1i is more effective than PARPi alone in reducing tumor burden in BRCAMUT models. Clin Cancer Res; 23(12); 3097–108. ©2016 AACR.
A Novel Road Map for Blood Lineage Commitment and Development: Identification of a Lympho-Myeloid Stem/Progenitor Cell Lacking Erythro-Megakaryocytic Potential.
Authors: Liping Yang, Jörgen Aolfsson, Robert Månsson, David Bryder, Ole-Johan Borge, Lina Thoren, Ewa Sitnicka, Yutaka Sasaki, Mikael Sigvardsson, Sten Eirik W. Jacobsen
Journal: Blood (2004)
Abstract 1191: The RNA binding protein, HuR, regulates pancreatic cancer cell metabolism
Authors: Fernando F. Blanco, Mahsa Zarei, Jonathan R. Brody, Laszlo G. Boros, Jordan M. Winter
Journal: Cancer Research (2015)

Abstract Introduction: Few proteins have been found to be master-regulators of pancreatic ductal adenocarcinoma (PDA) cell metabolism (e.g., LKB1, KRAS). We recently demonstrated that the regulatory RNA binding protein, HuR, binds to numerous metabolic mRNA transcripts and regulates their expression. Additionally, HuR silencing with small interfering RNAs(siRNAs) inhibited growth of PDA cells in vitro under glucose deprivation. Herein, we manipulated HuR expression levels in PDA cells and performed isotope tracer fate association studies to better understand HuR's role in metabolic reprogramming. Methods: We used 13C-labeled nutrients to map carbon flux in BxPC3 pancreatic cancer cells that were either transiently transfected with siRNA oligos against HuR (siHuR) or scrambled control (siCTRL). Cells were incubated with standard DMEM or mild glucose deprivation (5 mM glucose) for 48 hours, and media were supplemented with [1,2-13C2]-D-glucose or [U-13C5]-L-glutamine tracers for the final 24 hours. A total of 24 samples were snap frozen and prepared for GC-MS isotopomer analysis (3 replicates X 2 different siRNA oligos X 2 isotope tracers X 2 glucose concentrations). Transfection experiments were validated for reduced HuR expression (&amp;gt;70% reduction) and reduced protein expression of at least one metabolic and established HuR target (e.g., IDH1) by immunoblot. Results: HuR silencing directly impaired fatty acid (Table, line 1-3), ribose (line 5) and glycogen synthesis (line 6). Reductive carboxylation of glutamine-derived isocitrate was impaired and futile carbon exchange fluxes were prevalent (not shown). Conclusions: HuR enhances metabolic efficiency in PDA cells by directly regulating multiple metabolic pathways. Ongoing microarray studies will highlight which metabolic transcripts are post-transcriptionally regulated by HuR, resulting in the observed phenotype. Altered metabolites due to HuR silencing in PDA cells ([1,2-13C2]-D-glucose tracer)PathwayMetabolitesiHuR 25mM glucosesiHuR 5 mM glucoseCorrelation1Myristate (C:14) Intracell13C enrichment70.271.01.02Myristate (C:14) intracellFNS (direct)56.060.41.03Oleate (C:18-1) IntracellIndirect synthes-m187.689.51.04Glutam extracell [C2-C5]13C-m1 (m/z198)97.497.91.05RNA-ribose Intracell [C1-C4]13C-m3(m/z242)99.399.10.9846Glucose intracell [C3-C6]Peak area, Glycog-gluc74.180.10.983 Citation Format: Fernando F. Blanco, Mahsa Zarei, Jonathan R. Brody, Laszlo G. Boros, Jordan M. Winter. The RNA binding protein, HuR, regulates pancreatic cancer cell metabolism. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1191. doi:10.1158/1538-7445.AM2015-1191
329. Identifying Pharmacological Enhancers of Adenoviral Vector Replication and Transgene Expression
Authors: Briti Saha, Jean-Simon Diallo, Robin J. Parks
Journal: Molecular Therapy (2015)

Adenovirus (Ad) vectors are currently the most commonly used vehicle for therapeutic gene delivery in human gene therapy, and oncolytic Ad-based gene therapy has shown promise in several types of cancer. We are interested in identifying compounds that enhance or inhibit Ad gene expression and replication.We have designed a novel Ad vector containing the RFP gene within the late transcription unit. Thus, the level of RFP expression correlates to the extent of virus replication. We have also validated a high-throughput system for screening small molecules using this vector. The anticancer chemotherapy drug vorinostat was initially expected to increase gene expression from the vector since it is a pan-histone deacetylase inhibitor (HDACI), and HDACIs have been shown to increase Ad transgene expression. However, our assays show that vorinostat significantly delays the onset of vector replication and transgene expression, and that these effects may be specific to the inhibition of class I HDACs. We are currently working on elucidating the mechanism by determining the role of specific class I HDACs and the downstream effects of HDAC-activity loss. Consequences of HDAC inhibition on vector replication and transgene expression will also be studied in vivo. In the future, we will use our Ad construct to screen small-molecule libraries and identify novel enhancers of these processes.
Two Novel Activating Germline Mutations of the C-RAF Proto-Oncogene Predisposing to Solid Tumors and Therapy-Related Acute Myeloid Leukemia.
Authors: Armin Zebisch, Philipp B. Staber, Katja Fischereder, Claudia Bodner, Karin Hiden, Werner Linkesch, Holger W. Auner, Werner Emberger, Christian Windpassinger, Michael G. Schimek, Gerald Hoefler, Jakob Troppmair, Heinz Sill
Journal: Blood (2004)
Trispecific Killer Engagers (TriKEs) that contain IL-15 to make NK cells antigen specific and to sustain their persistence and expansion
Authors: Jeffrey S. Miller, Martin Felice, Ron McElmurry, Valerie McCullar, Xianzheng Zhou, Jakub Tolar, Joerg Uwe Schmohl, Angela Panoskaltsis-Mortari, Bin Zhang, Elizabeth Taras, Michael R. Verneris, Sarah Cooley, Daniel J. Weisdorf, Bruce R. Blazar, Dan Vallera
Journal: Blood (2015)
Reply to H.J.A. Adams et al and E. Laffon et al
Authors: Michel Meignan, Anne Ségolène Cottereau, Annibale Versari, Loïc Chartier, Jehan Dupuis, Sami Boussetta, Ilaria Grassi, René-Olivier Casasnovas, Corinne Haioun, Hervé Tilly, Vittoria Tarantino, Julien Dubreuil, Massimo Federico, Gilles Salles, Stefano Luminari, Judith Trotman
Journal: Journal of Clinical Oncology (2017)
Abstract 228: A novel device to perform rapid high-throughput in vivo drug sensitivity testing and identify optimal drug therapy for personalized cancer treatment
Authors: Oliver Jonas
Journal: Cancer Research (2015)

Abstract We have developed an implantable device that can perform drug sensitivity testing of a large number of anti-cancer agents inside the living tumor. This device contains reservoirs that release microdoses of single agents or drug combinations into distinct spatial regions of the tumor in local concentrations that are representative of concentrations achieved during systemic drug treatment. Local efficacy and drug concentration profile are evaluated for each drug or combination on the device, and the local efficacy was confirmed to be an excellent predictor of systemic efficacy across multiple drugs and tumor models. Currently up to 16 individual drugs or combinations can be assessed independently, without systemic drug exposure, through minimally invasive biopsy of a small region of a single tumor. Moreover, this assay takes into consideration physiologic effects that contribute to drug response by allowing drugs to interact with the living tumor in its native microenvironment. Because these effects are crucial to predicting drug response we envision that these devices will help identify optimal drug therapy before systemic treatment is initiated and could significantly extend drug response prediction beyond the predictive biomarkers used today. These devices may also potentially be used in clinical drug development to safely gather efficacy data on new compounds before pharmacological optimization. Note: This abstract was not presented at the meeting. Citation Format: Oliver Jonas. A novel device to perform rapid high-throughput in vivo drug sensitivity testing and identify optimal drug therapy for personalized cancer treatment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 228. doi:10.1158/1538-7445.AM2015-228
Final efficacy and updated safety results of the randomized phase III BEATRICE trial evaluating adjuvant bevacizumab-containing therapy in triple-negative early breast cancer
Authors: R. Bell, J. Brown, M. Parmar, M. Toi, T. Suter, G.G. Steger, X. Pivot, J. Mackey, C. Jackisch, R. Dent, P. Hall, N. Xu, L. Morales, L. Provencher, R. Hegg, L. Vanlemmens, A. Kirsch, A. Schneeweiss, N. Masuda, F. Overkamp, D. Cameron
Journal: Annals of Oncology (2016)
Surrogate End Points for Overall Survival in Loco-Regionally Advanced Nasopharyngeal Carcinoma: An Individual Patient Data Meta-analysis
Authors: Federico Rotolo, Jean-Pierre Pignon, Jean Bourhis, Sophie Marguet, Julie Leclercq, Wai Tong Ng, Jun Ma, Anthony T. C. Chan, Pei-Yu Huang, Guopei Zhu, Daniel T. T. Chua, Yong Chen, Hai-Qiang Mai, Dora L. W. Kwong, Yoke Lim Soong, James Moon, Yuk Tung, Kwan-Hwa Chi, George Fountzilas, Li Zhang, Edwin Pun Hui, Anne W. M. Lee, Pierre Blanchard, Stefan Michiels
Journal: JNCI Journal of the National Cancer Institute (2016)

Background: Our objective was to evaluate progression-free survival (PFS) and distant metastasis–free survival (DMFS) as surrogate end points for overall survival (OS) in randomized trials of chemotherapy in loco-regionally advanced nasopharyngeal carcinomas (NPCs). Methods: Individual patient data were obtained from 19 trials of the updated Meta-Analysis of Chemotherapy in Nasopharyngeal Carcinoma (MAC-NPC) plus one additional trial (total = 5144 patients). Surrogacy was evaluated at the individual level using a rank correlation coefficient ρ and at the trial level using a correlation coefficient R2 between treatment effects on the surrogate end point and OS. A sensitivity analysis was performed with two-year PFS/DMFS and five-year OS. Results: PFS was strongly correlated with OS at the individual level (ρ = 0.93, 95% confidence interval [CI] = 0.93 to 0.94) and at the trial level (R2 = 0.95, 95% CI = 0.47 to 1.00). For DMFS, too, the individual-level correlation with OS was strong (ρ = 0.98, 95% CI = 0.98 to 0.98); at trial level, the correlation was high but the regression adjusted for measurement error could not be computed (unadjusted R2 = 0.96, 95% CI = 0.94 to 0.99). In the sensitivity analysis, two-year PFS was highly correlated with five-year OS at the individual level (ρ = 0.89, 95% CI = 0.88 to 0.90) and at the trial level (R2 = 0.85, 95% CI = 0.46 to 1.00); two-year DMFS was highly correlated with five-year OS at the individual level (ρ = 0.95, 95% CI = 0.94 to 0.95) and at the trial level (R2 = 0.78, 95% CI = 0.33 to 1.00). Conclusions: PFS and DMFS are valid surrogate end points for OS to assess treatment effect of chemotherapy in loco-regionally advanced NPC, while PFS can be measured earlier.