tbuckley/cabot-search huggingface dataset:
S54 CPAP reduces exacerbations in tracheobronchomalacia
Authors: M Demirbag, G Tavernier, T Morris, K Hince, C Ustabasi, D Jones, S Fowler
Journal: Thorax (2016)

<h3>Overview</h3> Tracheobronchomalacia (TBM) is increasingly recognised as a significant diagnosis in patients diagnosed with “severe asthma”. Continuous Positive Airway Pressure (CPAP) is used as first line treatment to stent the airway in TBM patients in order to clear mucus and prevent irritation, inflammation and bacterial overgrowth thereby reducing the number of exacerbations experienced by patients. However, there is currently no published data which evaluates whether this intervention has an impact on outcomes in. This study describes a cohort of patients referred to a regional centre for severe asthma patients, who were subsequently diagnosed with TBM and analyses the impact of CPAP on exacerbations caused by TBM. <h3>Methods</h3> 20 TBM patients were identified at the North West Lung Centre in University Hospital South Manchester (UHSM) through clinics and department databases. Patient case notes and general practice medication prescriptions were used to obtain data on antibiotic and steroid prescriptions as well as hospital admissions (one year before and one after treatment). Exacerbations were analysed pre- and post-CPAP. Patient demographics were also recorded and compared to the cohort in the national severe asthma registry. <h3>Results</h3> TBM patients were found to have increased weight and BMI compared to the cohort described in the national severe asthma registry; weight 92.4 ± 28.8 in TBM compared to 81.2 ± 19.9 and BMI 35.5 ± 8.1 compared to 28.0. Analysis of CPAP data showed that with an average of 6 hours of CPAP daily at average pressures of 11 cm H<sub>2</sub>O significantly reduced the number of annual exacerbations experienced by over 50% for antibiotic and steroid prescriptions and significantly more for hospital admissions. Figure 1 shows the reduction in exacerbations in the year following the initiation of CPAP compared to the year before. <h3>Conclusions</h3> The severe asthma cohort with TBM are likely to have an increased weight and BMI. CPAP is an effective treatment option for TBM patients whilst awaiting the availability of more definitive surgical options and reduces antibiotic and steroid prescriptions as well as hospital admissions. It is recommended that all symptomatic TBM patients are considered for CPAP and monitored for exacerbations thereafter.
Phase II Study of Propylene Glycol-Free Melphalan (Evomela) Combined with Carmustine, Etoposide, and Cytarabine (BEAM) for Myeloablative Conditioning in Lymphoma Patients Undergoing Autologous Stem Cell Transplantation
Authors: Amanda F. Cashen, Kendall Gosch, Theresa Fletcher, Connie Ceriotti, Armin Ghobadi, Ravi Vij, Keith Stockerl-Goldstein, John F Dipersio, Camille N Abboud
Journal: Blood (2015)
PET-CT Has Major Diagnostic Value in the Evaluation of Smoldering Multiple Myeloma
Authors: Brittany L. Dykstra, Shaji Kumar, Angela Dispenzieri, Martha Q. Lacy, Francis Buadi, David Dingli, Prashant Kapoor, Wilson I Gonsalves, Morie A Gertz, S. Vincent Rajkumar
Journal: Blood (2014)
Activation of the c‐Jun N‐terminal kinase pathway aggravates proteotoxicity of hepatic mutant Z alpha1‐antitrypsin
Authors: Nunzia Pastore, Sergio Attanasio, Barbara Granese, Raffaele Castello, Jeffrey Teckman, Andrew A. Wilson, Andrea Ballabio, Nicola Brunetti‐Pierri
Journal: Hepatology (2017)

Alpha1-antitrypsin deficiency is a genetic disease that can affect both the lung and the liver. The vast majority of patients harbor a mutation in the serine protease inhibitor 1A (SERPINA1) gene leading to a single amino acid substitution that results in an unfolded protein that is prone to polymerization. Alpha1-antitrypsin defciency-related liver disease is therefore caused by a gain-of-function mechanism due to accumulation of the mutant Z alpha1-antitrypsin (ATZ) and is a key example of an disease mechanism induced by protein toxicity. Intracellular retention of ATZ triggers a complex injury cascade including apoptosis and other mechanisms, although several aspects of the disease pathogenesis are still unclear. We show that ATZ induces activation of c-Jun N-terminal kinase (JNK) and c-Jun and that genetic ablation of JNK1 or JNK2 decreased ATZ levels in vivo by reducing c-Jun-mediated SERPINA1 gene expression. JNK activation was confirmed in livers of patients homozygous for the Z allele, with severe liver disease requiring hepatic transplantation. Treatment of patient-derived induced pluripotent stem cell-hepatic cells with a JNK inhibitor reduced accumulation of ATZ.These data reveal that JNK is a key pathway in the disease pathogenesis and add new therapeutic entry points for liver disease caused by ATZ. (Hepatology 2017;65:1865-1874).
Cost of Joint Replacement Using Bundled Payment Models
Authors: Amol S. Navathe, Andrea B. Troxel, Joshua M. Liao, Nan Nan, Jingsan Zhu, Wenjun Zhong, Ezekiel J. Emanuel
Journal: JAMA Internal Medicine (2017)

Medicare launched the mandatory Comprehensive Care for Joint Replacement bundled payment model in 67 urban areas for approximately 800 hospitals following its experience in the voluntary Acute Care Episodes (ACE) and Bundled Payments for Care Improvement (BPCI) demonstration projects. Little information from ACE and BPCI exists to guide hospitals in redesigning care for mandatory joint replacement bundles.To analyze changes in quality, internal hospital costs, and postacute care (PAC) spending for lower extremity joint replacement bundled payment episodes encompassing hospitalization and 30 days of PAC.This observational study followed 3942 total patients with lower extremity joint replacement at Baptist Health System (BHS), which participated in ACE and BPCI.Lower extremity joint replacement surgery under bundled payment at BHS.Average Medicare payments per episode, readmissions, emergency department visits, prolonged length of stay, and hospital savings from changes in internal hospital costs and PAC spending.Overall, 3942 patients (mean [SD] age, 72.4 [8.4] years) from BHS were observed. Between July 2008 and June 2015, average Medicare episode expenditures declined 20.8%, from $26 785 to $21 208 (P < .001) for 3738 episodes of joint replacement without complications. It declined 13.8% from $38 537 to $33 216 (P = .61) for 204 episodes of joint replacement with complications. Readmissions and emergency department visits declined 1.4% (P = .14) and 0.9% (P = .98), respectively, while episodes with prolonged length of stay decreased 67.0% (P < .001). Patient illness severity remained stable. By 2015, 51.2% of overall hospital savings had come from internal cost reductions and 48.8% from PAC spending reductions. Reductions in implant costs, down on average $1920.68 (29%) per case, contributed the greatest proportion of hospital savings. Average PAC spending declined $2443.12 (27%) per case, largely from reductions in inpatient rehabilitation and skilled nursing facility spending but only when bundles included financial responsibility for PAC.During a period in which Medicare payments for joint replacement episodes increased by 5%, bundled payment for procedures at BHS was associated with substantial hospital savings and reduced Medicare payments. Decreases in PAC spending occurred only when it was included in the bundle.
P3.01-061 Prognostic Significance of Stem Cell-Related Marker Expression and Its Correlation with Histologic Subtypes in Lung Adenocarcinoma
Authors: Hyojin Kim, Eunhyang Park, Soo Young Park, Ping-Li Sun, Yan Jin, Ji Eun Kim, Sanghoon Jheon, Kwhanmien Kim, Choon Taek Lee, Jin-Haeng Chung
Journal: Journal of Thoracic Oncology (2017)
miRNA Profiling Predicts Survival and Identifies a Novel Putative Oncomir in Diffuse Large B-Cell Lymphoma Treated with Immunochemotherapy
Authors: Christoffer Hother, Ditte Reker, Konstantions Dimopoulos, Steen Knudsen, Thomas Jensen, Michael B. Møller, Peter De Nully Brown, Elisabeth Ralfkiaer, Kirsten Grønbæk
Journal: Blood (2012)
PUB145 The Aneuploidy of Inoculated Cell Culture of LLC under the Influence of N-Hydroxy-4-({[(E)-2phenylethenyl] Sulfonyl}Amino)Butanamide
Authors: Olena Dzhus, Liudmyla Garmanchuk, Viktoriia Nikulina, V. Orysyk, Yu. Zborovskiy, M. Vovk
Journal: Journal of Thoracic Oncology (2017)
P13 The rationale for setting up a dedicated pleural procedure list: benefits for patients and trusts
Authors: C Brockelsby, A Wells, P Deegan, W Kent, C Houghton, M Gautam
Journal: Thorax (2016)

<h3>Introduction and objectives</h3> Pleural disease contributes to a significant proportion of acute admissions and hospital bed-days. Traditionally, patients presenting with pleural effusion, were admitted for management, including patients with terminal disease. In May 2014, we designed one of the first dedicated pleural procedure lists regionally allowing patients to undergo procedures on a day-case basis. A dedicated pleural procedure room was established for a weekly session to accommodate a maximum of 5 pleural procedures. The list was consultant-delivered by a level 2 thoracic ultrasound-trained Consultant, with built in consultant cross-cover to prevent cancellation. An electronic referral system, pleural procedure patient pathway and WHO procedural checklist was designed to be completed for each case to maximise patient safety and efficiency. Dedicated nursing was provided to enhance patient experience and multi-professional development. The list provided weekly opportunity for education/training for those wishing to gain ultrasound certification and procedural competency-based assessment. This study looked at the impact of acute service redesign. <h3>Methods</h3> This was a review of a prospectively maintained database of a weekly pleural procedure list, from May 2014–May 2016. Comparison was made with data obtained from previous local audit, including LOS pre and post introduction of the new service. <h3>Results</h3> 398 patients were referred over 2 years; 178 outpatients, 200 inpatients. On average, 4 pleural procedures/ultrasound were performed per session. A total of 3738 bed days were saved, based on an average LOS of 22 days for patients previously admitted with pleural effusions, demonstrated by audit pre-2014. In 178 cases, due to the ambulatory nature of the introduced service, average LOS was reduced from 22 to 1 day. There have been no reported adverse events since set-up, and additional income has been generated by receiving a day-case best practice tariff (BPT), introduced in 2013/14. <h3>Conclusion</h3> Service innovation resulting in a dedicated hospital pleural procedure list has resulted in demonstrable benefits for patients in terms of LOS, patient safety and experience. Our set up has generated recurrent financial gains through bed day savings, created a regional hub for US training and confirmed the commendable merits of ambulatory care for patients requiring pleural procedures.
HDAC Inhibitor AR-42 Decreases CD44 Expression and Sensitizes Myeloma Cells to Lenalidomide
Authors: Hector Cordero-Nieves, Douglas W. Sborov, Alessandro Canella, Zhongfa Liu, Jessica Consiglio, Wenjun Ni, Emily Smith, Lara Rizzotto, Yvonne A Efebera, Don M. Benson, Luciano Cascione, Mo Xiaokui, John C. Byrd, Michael R. Grever, Craig C Hofmeister, Flavia Pichiorri
Journal: Blood (2014)
Aptamer-Targeted Attenuation of IL-2 Signaling in CD8 + T Cells Enhances Antitumor Immunity
Authors: Anugraha Rajagopalan, Alexey Berezhnoy, Brett Schrand, Yvonne Puplampu-Dove, Eli Gilboa
Journal: Molecular Therapy (2017)

Immune responses elicited against cancer using existing therapies such as vaccines or immune stimulatory antibodies are often not curative. One way to potentiate antitumor immunity is to enhance the long-term persistence of anti-tumor CD8+ T cells. Studies have shown that the persistence of activated CD8+ T cells is negatively impacted by the strength of interleukin 2 (IL-2) signaling. Here, we used small interfering RNAs (siRNAs) against CD25 (IL-2Rα) to attenuate IL-2 signaling in CD8+ T cells. The siRNAs were targeted to 4-1BB-expressing CD8+ T cells by conjugation to a 4-1BB-binding oligonucleotide aptamer. Systemic administration of the 4-1BB aptamer-CD25 siRNA conjugate downregulated CD25 mRNA only in 4-1BB-expressing CD8+ T cells promoting their differentiation into memory cells. Treatment with the 4-1BB aptamer-CD25 siRNA conjugates enhanced the antitumor response of a cellular vaccine or local radiation therapy. Indicative of the generality of this approach, 4-1BB aptamer-targeted delivery of an Axin-1 siRNA, a rate-limiting component of the β-catenin destruction complex, enhanced CD8+ T cell memory development and antitumor activity. These findings show that aptamer-targeted siRNA therapeutics can be used to modulate the function of circulating CD8+ T cells, skewing their development into long-lasting memory CD8+ T cells, and thereby potentiating antitumor immunity.
MA16.11 CNS Response to Osimertinib in Patients with T790M-Positive Advanced NSCLC: Pooled Data from Two Phase II Trials
Authors: Glenwood Goss, Chun-Ming Tsai, Frances Shepherd, Myung-Ju Ahn, Lyudmila Bazhenova, Lucio Crinò, Filippo De Marinis, Enriqueta Felip, Alessandro Morabito, Rachel Hodge, Mireille Cantarini, Tetsuya Mitsudomi, Pasi Jänne, James Chih-Hsin Yang
Journal: Journal of Thoracic Oncology (2017)
Retrospective Analysis of Infections In An Unselected Cohort of Patients with Multiple Myeloma Treated with Lenalidomide Combinations Therapies
Authors: Tommaso Caravita, Massimo Offidani, Silvia Gentili, Agostina Siniscalchi, Patrizia Caraffa, Vanessa Velotta, Paolo de Fabritiis, Pietro Leoni
Journal: Blood (2011)
Early Assessment of Minimal Residual Disease (MRD) by Qualitative PCR for NPM-ALK Identifies Patients At Very High Risk of Relapse in Anaplastic Large Cell Lymphoma
Authors: Christine Damm-Welk, Lara Mussolin, Marta Pillon, Martin Zimmermann, Alfred Reiter, Wilhelm Woessmann, Angelo Rosolen
Journal: Blood (2011)
Microenvironmental Up-Regulation of NF-kB Activity Via P65-Dependent and Independent Pathways in a Bioimaging Model of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia.
Authors: Hui-Jen Tsai, Seiichiro Kobayashi, Kiyoko Itoh, Takaomi Ishida, Kazuo Umezawa, Arinobu Tojo
Journal: Blood (2007)
Apoptosis Stimulating Protein of p53 (ASPP2) Heterozygous Mice Are Lymphoma-Prone and Display Attenuated Apoptosis and Cell Cycle Checkpoints
Authors: Kerstin Maria Kampa, Jared Acoba, Dexi Chen, Hun-Joo Lee, Kelly Beemer, Joel Gay, Zhyi Zhu, Emerson Padiernos, Marcus M Schittenhelm, Lothar Kanz, Christopher Corless, Charles Lopez
Journal: Blood (2008)
S83 Investigating the role of GCN2 in the pathogenesis of pulmonary hypertension
Authors: E Soon, A Crosby, M Southwood, S Moore, D Ron, S Marciniak, NW Morrell
Journal: Thorax (2016)

<h3>Background</h3> Mutations in the bone morphogenetic protein type II receptor (BMPR-II) underlie the majority (&gt;80%) of familial and up to 25% of ‘sporadic’ cases of idiopathic pulmonary arterial hypertension (PAH). Recently, homozygous recessive mutations in GCN2 (also known as EIF2AK4) were identified as causative in a rare cause of PAH, pulmonary veno-occlusive disease (PVOD) and pulmonary capillary haemangiomatosis (PCH). The mechanisms by which GCN2 deficiency contributes to the development of PAH remain unknown. GCN2 is a serine/threonine protein kinase, one of a family of 4 kinases that phosphorylate the α-subunit of the translation initiation factor eIF2α. Phosphorylation of eIF2α at serine 51 results in an inhibition of eIF2B (the eIF2 guanine nucleotide exchange factor), which ultimately leads to loss of eIF2α function. This results in inhibition of protein synthesis while enhancing the translation of a small number of mRNAs encoding proteins involved in the response to cellular stress. <h3>Methods</h3> We characterised the pulmonary vascular phenotype of the homozygous null <i>Gcn2</i> (<i>Gcn2−/−</i>) and wild-type controls at 6 months of age. This mouse was chosen because it mimics the homozygous loss-of-function genotype of patients with familial PVOD/PCH. In addition, we investigated the phenotype of <i>Gcn2−/−</i> mice crossed with <i>bmpr2</i>-deficient mice. In complementary <i>in vitro </i>studies, pulmonary artery smooth muscle cells (PASMCs) were extracted from patients with PVOD and idiopathic/heritable PAH and studied with wild-type controls. <h3>Findings</h3> The <i>Gcn2−/−</i> mouse displayed mild pulmonary hypertension. Mean right ventricular systolic pressure (RVSP) was 28.3 ± 1.2 mmHg in <i>Gcn2−/−</i> mice compared with 24.7 ± 1.1 mmHg in wild-type mice. <i>GCN2−/−</i> mice crossed with <i>bmpr2</i>-deficient mice demonstrated a further increase in RVSP (32.8 ± 4.1 mmHg). Exposure of human PASMCs derived from a PVOD patient, and patients with mutations in BMPR2, to L-histidinol, which increases the phosphorylation of eIF2α, resulted in proliferation of these cells but had no effect on control PASMCs. <h3>Conclusions</h3> GCN2 deficiency promotes the development of pulmonary hypertension in mice, an effect that is exaggerated by BMPR2 deficiency. Increased phosphorylation of eIF2α resulted in PASMC proliferation. Further elucidation of these mechanisms may reveal new treatments for this devastating disease.
Identification and characterization of mMesothelin epitopes following a combinatorial vaccine approach
Authors: ihid leao, Priya Ganesan, Daniel Laheru, Elizabeth Jaffee
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

4989 

Analysis of post-vaccination immune responses in a phase I clinical trial using whole cell pancreatic tumor vaccine engineered to secrete Granulocyte Macrophage-Colony stimulating factor (GM-CSF), identified mesothelin as a candidate antigen against which both T cell and antibody responses were directed in patients who remain disease-free. While the vaccine demonstrated the induction of immunity in a number of vaccinated patients, immune responses were not observed in the majority of treated patients. Tolerance caused by the inhibitory effects of regulatory-T cells could potentially explain this outcome.    In order to optimize the effect of a mesothelin directed vaccine, we’ve studied a murine mesothelin expressing pancreatic tumor model (PancO2) and assessed combinations of Treg depleting agents to explore the synergistic interaction between these treatment modalities. This combinatorial approach was capable of enhancing the efficacy of our GM-CSF secreting, mesothelin-expressing whole cell tumor vaccine. Mice treated with our vaccine plus Cyclophosphamide and anti-CD25 IL-2Ra monoclonal antibody (PC61) were able to develop anti-tumor immunity potent enough to eliminate established tumors. Mouse mesothelin 15-mer peptides overlapping by at least 9 amino acids were synthesized spanning the entire sequence of the mouse mesothelin protein and used to screen for CTL responses. The MHC class I restriction of the epitopes contained within these 15-mers was further studied through the generation of 8-mer and 9-mer peptides that overlapped by 7 and 8 amino acids respectively. We’ve identified activated CD8 T cell populations specific for two of the H2-Kb restricted epitopes in the immunized mice using dilutional IFN-gamma intracellular staining. In addition, antigen-specific killing function was detected for these epitopes using an in vivo CD8 T cell lysis assay. Finally, each epitope was compared for their ability to immunize mice against tumor challenge using peptide pulsed DCs. 80% of the mice immunized with dendritic cells pulsed with one of the H2-Kb mesothelin epitopes were protected against tumor challenge while in the control group (irrelevant peptide) only 20% of the animals were protected (p=0.0012). Taken together, our results demonstrated that a combinatorial approach based on depletion of Treg cells and provision of a whole cell GM-CSF vaccine is successful in generating mesothelin-specific CTLs that recognize specific MHC Class I restricted epitopes and is able to reject tumors in vivo. The understanding of the complete CD8 T cell repertoire in this model will be helpful in designing new methods for enhancing T cell based vaccines.    We are thankful for the support given by the Sol Gold Pancreatic Cancer Center, the Dana and Albert Broccoli Foundation, the Broad Foundation Grant, the GI Spore (P50CA62924) and NCDDG grants (U19CA113341).
P3.02c-006 EGFR and HER3 Inhibition - A Novel Therapy for Invasive Mucinous Non-Small Cell Lung Cancer Harboring an NRG1 Fusion Gene
Authors: Ji-Youn Han, Kun Young Lim, Jin Young Kim, Geon Kook Lee, Wolfgang Jacob, Maurizio Ceppi, Ian James, Max Hasman, Martin Weisser
Journal: Journal of Thoracic Oncology (2017)
What’s in an exome? Diversity of diagnostic and incidental findings revealed by clinical tumor and germline sequencing of 100 children with solid tumors.
Authors: D. Williams Parsons, Angshumoy Roy, Federico A. Monzon, Yaping Yang, Dolores H. López-Terrada, Murali M. Chintagumpala, Stacey L. Berg, Jed G Nuchtern, Susan G. Hilsenbeck, Tao Wang, Robin A. Kerstein, Sarah Scollon, Katie Bergstrom, Uma Ramamurthy, Jeff G. Reid, Donna M. Muzny, David A. Wheeler, Christine M. Eng, Richard A. Gibbs, Sharon E. Plon
Journal: Journal of Clinical Oncology (2014)

10012 Background: Whole exome sequencing (WES) can identify a wide spectrum of tumor and germline genetic findings. Before WES is incorporated into oncology practice, it is necessary to gain an understanding of the nature and frequency of these genetic results in cancer patients. Methods: The BASIC3 (Baylor Advancing Sequencing in Childhood Cancer Care) study investigates the clinical implementation of CLIA-certified WES for sequentially diagnosed children with CNS and non-CNS solid tumors. Blood and frozen tumor samples undergo WES, with the resulting germline and tumor reports deposited into the medical record and disclosed to families by their oncologist and a genetic counselor. Germline reports include: (1) deleterious mutations and variants of uncertain significance (VUS) in disease genes related to cancer or other patient phenotypes, (2) incidental medically-actionable mutations, (3) FDA-approved pharmacogenetic (PGX) variants, (4) mitochondrial (mtDNA) mutations, and (5) carrier status for recessive disorders if requested by parents. Results: Of the first 124 eligible families, 100 (81%) consented to participate. At least one somatic mutation of proven or potential clinical relevance was reported in 22/80 (28%) patients with tumor available (e.g. ALK, CTNNB1, BRAF, KRAS, KIT, TSC2). Diagnostic germline findings were found in 11 cases: 8 pathogenic mutations in dominant cancer susceptibility genes (TP53 x 2, MSH2, BRCA1, WT1, BRCA2, DICER1, VHL) and 3 mutations underlying non-oncologic diagnoses. There were 7 patients with medically-actionable incidental findings (2 in mtDNA). Nearly all patients harbored VUS in cancer genes (98%; median of 3) and PGX variants (89%; median of 1). Carrier mutations were reported in 76/89 (85%; median of 2) patients. Conclusions: Clinical tumor and germline WES revealed diagnostic and potentially actionable results in nearly 40% of pediatric solid tumor patients, including both cancer and non-cancer-related findings. Successful incorporation of genomic methods into the care of oncology patients will require preparation of clinicians to disclose and manage these diverse results. Supported by 1U01HG006485.
P3.03-026 Orotate Phosphoribosyltransferase is Overexpressed in Malignant Pleural Mesothelioma: Dramatically Responds One Case in High OPRT Expression
Authors: Yoichiro Hamamoto, Takeoka Shinjiro, Atsuto Mouri, Munehisa Fukusumi, Kazushige Wakuda, Tatsuya Ibe, Chie Honma, Yoshihito Arimoto, Kazuaki Yamada, Miyuki Wagatsuma, Akito Tashiro, Shingo Kamoshida, Mitsuhiro Kamimura
Journal: Journal of Thoracic Oncology (2017)