tbuckley/cabot-search huggingface dataset:
Dasatinib Plus Intensive Chemotherapy in Children, Adolescents, and Young Adults With Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia: Results of Children’s Oncology Group Trial AALL0622
Authors: William B. Slayton, Kirk R. Schultz, John A. Kairalla, Meenakshi Devidas, Xinlei Mi, Michael A. Pulsipher, Bill H. Chang, Charles Mullighan, Ilaria Iacobucci, Lewis B. Silverman, Michael J. Borowitz, Andrew J. Carroll, Nyla A. Heerema, Julie M. Gastier-Foster, Brent L. Wood, Sherri L. Mizrahy, Thomas Merchant, Valerie I. Brown, Lance Sieger, Marilyn J. Siegel, Elizabeth A. Raetz, Naomi J. Winick, Mignon L. Loh, William L. Carroll, Stephen P. Hunger
Journal: Journal of Clinical Oncology (2018)

Purpose Addition of imatinib to intensive chemotherapy improved survival for children and young adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. Compared with imatinib, dasatinib has increased potency, CNS penetration, and activity against imatinib-resistant clones. Patients and Methods Children's Oncology Group (COG) trial AALL0622 (Bristol Myers Squibb trial CA180-204) tested safety and feasibility of adding dasatinib to intensive chemotherapy starting at induction day 15 in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia age 1 to 30 years. Allogeneic hematopoietic stem-cell transplantation (HSCT) was recommended for patients at high risk based on slow response and for those with a matched family donor regardless of response after at least 11 weeks of therapy. Patients at standard risk based on rapid response received chemotherapy plus dasatinib for an additional 120 weeks. Patients with overt CNS leukemia received cranial irradiation. Results Sixty eligible patients were enrolled. Five-year overall (OS) and event-free survival rates (± standard deviations [SD]) were 86% ± 5% and 60% ± 7% overall, 87% ± 5% and 61% ± 7% for standard-risk patients (n = 48; 19% underwent HSCT), and 89% ± 13% and 67% ± 19% for high-risk patients (n = 9; 89% underwent HSCT), respectively. Five-year cumulative incidence (± SD) of CNS relapse was 15% ± 6%. Outcomes (± SDs) were similar to those in COG AALL0031, which used the same chemotherapy with continuous imatinib: 5-year OS of 81% ± 6% versus 86% ± 5% ( P = .63) and 5-year disease-free survival of 68% ± 7% versus 60% ± 7% ( P = 0.31) for AALL0031 versus AALL0622, respectively. IKZF1 deletions, present in 56% of tested patients, were associated with significantly inferior OS and event-free survival overall and in standard-risk patients. Conclusion Dasatinib was well tolerated with chemotherapy and provided outcomes similar to those with imatinib in COG AALL0031, where all patients received cranial irradiation. Our results support limiting HSCT to slow responders and suggest a potential role for transplantation in rapid responders with IKZF1 deletions.
Patients with Obesity Caused by Melanocortin-4 Receptor Mutations Can Be Treated with a Glucagon-like Peptide-1 Receptor Agonist
Authors: Eva W. Iepsen, Jinyi Zhang, Henrik S. Thomsen, Elizaveta L. Hansen, Mette Hollensted, Sten Madsbad, Torben Hansen, Jens J. Holst, Jens-Christian Holm, Signe S. Torekov
Journal: Cell Metabolism (2018)
The mucus bundles responsible for airway cleaning are retained in cystic fibrosis and by cholinergic stimulation
Authors: Anna Ermund, Lauren N. Meiss, Brendan Dolan, Andrea Bähr, Nikolai Klymiuk, Gunnar C. Hansson
Journal: European Respiratory Journal (2018)

The beneficial effect of anticholinergic therapy for chronic lung diseases such as chronic obstructive pulmonary disease (COPD) is well documented, although cholinergic stimulation paradoxically inhibits liquid absorption, increases ciliary beat frequency and increases airway surface liquid transport. Using pig tracheobronchial explants, we quantified basal mucus transport before as well as after incubation with the clinically used antimuscarinic compound ipratropium bromide (Atrovent) and stimulation with acetylcholine. As expected, surface liquid transport was increased by acetylcholine and carbachol. In contrast, the mucus bundles secreted from the submucosal glands normally transported on the cilia were stopped from moving by acetylcholine, an effect inhibited by ipratropium bromide. Interestingly, in pigs lacking a functional cystic fibrosis (CF) transmembrane conductance regulator (CFTR) channel, the mucus bundles were almost immobile. As in wild-type pigs, CF surface liquid transport increased after carbachol stimulation. The stagnant CF mucus bundles were trapped on the tracheal surface attached to the surface goblet cells. Pseudomonas aeruginosa bacteria were moved by the mucus bundles in wild-type but not CF pigs. Acetylcholine thus uncouples airway surface liquid transport from transport of the surface mucus bundles as the bundles are dynamically inhibited by acetylcholine and the CFTR channel, explaining initiation of CF and COPD, and opening novel therapeutic windows.
Long noncoding RNA DANCR, working as a competitive endogenous RNA, promotes ROCK1-mediated proliferation and metastasis via decoying of miR-335-5p and miR-1972 in osteosarcoma
Authors: Yong Wang, Xiandong Zeng, Ningning Wang, Wei Zhao, Xi Zhang, Songling Teng, Yueyan Zhang, Zhi Lu
Journal: Molecular Cancer (2018)

Accumulating evidences indicate that non-coding RNAs (ncRNAs) including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) acting as crucial regulators in osteosarcoma (OS). Previously, we reported that Rho associated coiled-coil containing protein kinase 1 (ROCK1), a metastatic-related gene was negatively regulated by microRNA-335-5p (miR-335-5p) and work as an oncogene in osteosarcoma. Whether any long non-coding RNAs participate in the upstream of miR-335-5p/ROCK1 axial remains unclear. Expression of differentiation antagonizing non-protein coding RNA (DANCR) and miR-335-5p/miR-1972 in osteosarcoma tissues were determined by a qRT-PCR assay and an ISH assay. Osteosarcoma cells' proliferation and migration/invasion ability changes were measured by a CCK-8/EDU assay and a transwell assay respectively. ROCK1 expression changes were checked by a qRT-PCR assay and a western blot assay. Targeted binding effects between miR-335-5p/miR-1972 and ROCK1 or DANCR were verified by a dual luciferase reporter assay and a RIP assay. In vivo experiments including a nude formation assay as well as a CT scan were applied to detect tumor growth and metastasis changes in animal level. In the present study, an elevated DNACR was found in osteosarcoma tissue specimens and in osteosarcoma cell lines, and the elevated DNACR was closely correlated with poor prognosis in clinical patients. Functional experiments illustrated that a depression of DANCR suppressed ROCK1-mediated proliferation and metastasis in osteosarcoma cells. The results of western blot assays and qRT-PCR assays revealed that DANCR regulated ROCK1 via crosstalk with miR-335-5p and miR-1972. Further cellular behavioral experiments demonstrated that DNACR promoted ROCK1-meidated proliferation and metastasis through decoying both miR-335-5p and miR-1972. Finally, the outcomes of in vivo animal models showed that DANCR promoted tumor growth and lung metastasis of osteosarcoma. LncRNA DANCR work as an oncogene and promoted ROCK1-mediated proliferation and metastasis through acting as a competing endogenous RNA (ceRNA) in osteosarcoma.
Signatures of mutational processes and response to neoadjuvant chemotherapy in breast cancer: A genome-based investigation in the neoadjuvant GeparSepto trial.
Authors: Carsten Denkert, Michael Untch, Stephen Charles Benz, Karsten Weber, Justin Golovato, Jan Budczies, Valentina Nekljudova, Elmar Stickeler, Rahul Parulkar, Andreas Schneeweiss, Christian Jackisch, J Zachary Sanborn, Bettina Conrad, Hermann Wiebringhaus, Jens Bodo Huober, Kerstin Rhiem, Patrick Soon-Shiong, Peter A. Fasching, Shahrooz Rabizadeh, Sibylle Loibl
Journal: Journal of Clinical Oncology (2018)

574 Background: Different mutational processes act over the evolutionary history of a malignant tumor, driven by e.g. abnormal DNA editing, mutagens or age-related DNA alterations. Many of these processes generate defined combinations of mutation types, which have been described as mutational signatures. The clinical relevance of mutational signatures has not been studied to a great extent. We investigate the hypothesis that the individual patterns of mutational signatures determine the clinical behavior of breast cancer (BC) , in particular response to neoadjuvant chemotherapy. Methods: In the GeparSepto study (NCT01583426) women with primary invasive BC were randomized to either nab-paclitaxel or solvent-based paclitaxel followed by EC. Pretherapeutic FFPE core biopsies of HER2-neg BC were used for whole genome/exome sequencing (n = 405). Mutational signatures were identified as described by Alexandrov et al. (Cell Rep. 3, 2013). Results: 24 of the the 30 mutational signatures were present in at least 10% of the 405 tumors , the most predominant were Sig1 (age-related, 94.8%), Sig13 (APOBEC-related, 87.7%), Sig6 (MMR-def.-related, 69.9%), Sig3 (BRCA-related, 61.5%), Sig28 (60.7%), and Sig16 (60.2%). The signatures 3, 4, 11, 13, 17, 21, and 24 were increased and signatures 10, 16, 28, and 29 decreased in TNBC compared to luminal BC. A significant correlation with the number of stromal tumor-infiltrating lymphocytes was observed for signatures 3, 4, 13, 23, and 24, an association with increased Ki67 was observed for Sig 3, 4, 6, 11, 12, 13, 16, 23, and 24. Tumors with signatures 3, 11 and 13 had a significantly increased response rate to neoadjuvant chemotherapy, this was also observed in the subgroups of TNBC (sign 11) and luminal BC (sign 3, 9, 13). Conclusions: Whole-exome sequencing in breast cancer FFPE core biopsies from clinical cohorts can be used to identify mutational signatures. The pattern of these signatures, in particular the presence of BRCA-related (Sig3) and APOBEC-related (Sig13) reflect the clinical behavior of breast cancer and might be used to identify tumors with an increased response rate to neoadjuvant chemotherapy.
Whole-exome sequencing and immune profiling of early-stage lung adenocarcinoma with fully annotated clinical follow-up
Authors: H. Kadara, M. Choi, J. Zhang, E.R. Parra, J. Rodriguez-Canales, S.G. Gaffney, Z. Zhao, C. Behrens, J. Fujimoto, C. Chow, Y. Yoo, N. Kalhor, C. Moran, D. Rimm, S. Swisher, D.L. Gibbons, J. Heymach, E. Kaftan, J.P. Townsend, T.J. Lynch, J. Schlessinger, J. Lee, R.P. Lifton, I.I. Wistuba, R.S. Herbst
Journal: Annals of Oncology (2017)

Ann Oncol 2017; 28(1): 75–82 (doi:) This paper has been corrected to update two author affiliations. Y. Yoo’s affiliation was corrected from 3 to 9, and R. P. Lifton’s first affiliation was corrected from 2 to 3. Whole-exome sequencing and immune profiling of early-stage lung adenocarcinoma with fully annotated clinical follow-upAnnals of OncologyVol. 28Issue 1PreviewLung adenocarcinomas (LUADs) lead to the majority of deaths attributable to lung cancer. We performed whole-exome sequencing (WES) and immune profiling analyses of a unique set of clinically annotated early-stage LUADs to better understand the pathogenesis of this disease and identify clinically relevant molecular markers. Full-Text PDF Open Archive
Tobacco Product Use Among Middle and High School Students — United States, 2011–2017
Authors: Teresa W. Wang, Andrea Gentzke, Saida Sharapova, Karen A. Cullen, Bridget K. Ambrose, Ahmed Jamal
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

Tobacco use is the leading cause of preventable disease and death in the United States, and nearly all tobacco use begins during youth and young adulthood (1,2). CDC and the Food and Drug Administration (FDA) analyzed data from the 2011-2017 National Youth Tobacco Surveys (NYTS)* to determine patterns of current (past 30-day) use of seven tobacco product types among U.S. middle school (grades 6-8) and high school (grades 9-12) students and estimate use nationwide. Among high school students, current use of any tobacco product decreased from 24.2% (estimated 3.69 million users) in 2011 to 19.6% (2.95 million) in 2017. Among middle school students, current use of any tobacco product decreased from 7.5% (0.87 million) in 2011 to 5.6% (0.67 million) in 2017. In 2017, electronic cigarettes (e-cigarettes) were the most commonly used tobacco product among high (11.7%; 1.73 million) and middle (3.3%; 0.39 million) school students. During 2016-2017, decreases in current use of hookah and pipe tobacco occurred among high school students, while decreases in current use of any tobacco product, e-cigarettes, and hookah occurred among middle school students. Current use of any combustible tobacco product, ≥2 tobacco products, cigarettes, cigars, smokeless tobacco, and bidis did not change among middle or high school students during 2016-2017. Comprehensive and sustained strategies can help prevent and reduce the use of all forms of tobacco products among U.S. youths (1,2).
AIPAC (Active Immunotherapy PAClitaxel): A randomized, double blind, placebo controlled, multinational phase IIb trial evaluating the efficacy of eftilagimod alpha (a soluble LAG-3 fusion protein) in combination with paclitaxel in hormone receptor positive metastatic breast cancer.
Authors: Luc Dirix, A. Jager, Frederik Marme, Etienne Brain, Anne Caroline Armstrong, Sergiusz Nawrocki, Frederic Triebel
Journal: Journal of Clinical Oncology (2018)

TPS1109 Background: Eftilagimod alpha (efti, previously IMP321) is a recombinant LAG-3Ig fusion protein that binds to MHC class II and mediates antigen-presenting cell (APC) activation followed by CD8 T-cell activation. The activation of the dendritic cell network with efti injected s.c. the day after chemotherapy at a time when these APC are loaded with tumor antigens may lead to stronger anti-tumor CD8 T cell responses. AIPAC (Active Immunotherapy PAClitaxel; NCT02614833) is a Phase IIb trial in hormone receptor-positive stage IV metastatic breast carcinoma patients receiving eftilagimod alpha (efti; also named IMP321) or placebo as adjunctive to weekly paclitaxel as a first-line chemotherapy. The safety run-in stage (stage 1) has been completed in 2016 and the randomized part (stage 2) is recruiting. Methods: This clinical trial is a placebo-controlled, double-blind, 1:1 randomized Phase IIb study aiming to enroll 226 patients at multiple centers across 7 different European countries. Patients with metastatic receptor positive breast adenocarcinoma receiving first line chemotherapy with weekly paclitaxel and with measurable disease according to RECIST 1.1 are enrolled. Patient eligible to Her2/neu targeted therapy are excluded from the trial. In the first treatment phase, paclitaxel (80 mg/m² IV at D1, D8, D15 plus efti (30 mg) or placebo at D2, D16 (i.e. injected SC the day after paclitaxel, every two weeks) will be administered for 6 cycles (1 cycle = 4 weeks). This is followed by a maintenance phase in which stable or responding patients will receive efti or placebo for up to additional 52 weeks (12 injections). The primary endpoint is progression-free survival. Secondary endpoints include overall survival, tumor response according to RECIST 1.1., time to and duration of response, duration of stable disease and quality of life. Clinical trial information: NCT02614833.
Anesthesia Care Handovers and Risk of Adverse Outcomes
Authors: Vikas N. O'Reilly-Shah, Grant C. Lynde, Craig S. Jabaley
Journal: JAMA (2018)

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The humanistic burden of advanced non-small cell lung cancer: What are the key drivers of caregiver burden?
Authors: Robert Wood, Gavin Taylor-Stokes, Fiona Smith, Oana Christina Chirita, Carlos Chaib Torralba
Journal: Journal of Clinical Oncology (2018)

149 Background: Advanced Non-Small Cell Lung Cancer (aNSCLC) impacts the lives of patients and their caregivers. This analysis aimed to provide insight into the clinical, patient and caregiver factors associated with increased caregiver burden. Methods: Data from a cross-sectional study of aNSCLC patients and informal (unpaid) caregivers in France, Germany and Italy, were collected from May 2015 to June 2016, consisting of a chart review and patient and caregiver surveys. Caregiver burden was assessed using the Zarit Burden Interview (ZBI), measured on a 0-88 scale. An ordinary least square regression model was constructed to assess clinical, patient and caregiver factors associated with ZBI. Measured at time of survey completion, covariates included: country, patient age, sex, body mass index, stage of NSCLC, Eastern Cooperative Oncology Group Performance Status (ECOG-PS), disease duration, smoking status, presence of brain metastases, histology, comorbidities, chemotherapy treatment, caregiver age and sex, and the number of formal (paid) and informal caregiver hours provided per week by additional caregivers. A significance level of 0.05 was used. Results: 331 caregivers were analysed. Mean (SD) caregiver age was 53.8 years (12.4), 239 (72.2%) were female. Caregivers provided a mean (SD) of 17.8 (23.4) hours of care per week. Mean (SD) formal / informal caregiver hours provided by other caregivers was 3.9 (13.3) / 3.9 (12.0). Many caregivers did not receive support from additional formal (75.5%) or informal (68.6%) caregivers. Mean (SD) ZBI score was 31.3 (14.8). Significant independent predictors of ZBI were patient’s ECOG-PS and number of additional informal caregiver hours provided. ZBI scores for caregivers of patients with an ECOG-PS of 3-4 were 7.68 units higher compared to those with an ECOG-PS of 0-2 (p = 0.006). Also, ZBI scores increased by 0.16 units per hour of informal caregiver provided by additional caregivers (p = 0.008). Conclusions: The key drivers of caregiver burden found in the study reinforce the need to develop supportive and personalised interventions to maintain patient performance status by delaying progression, and reduce informal caregiver hours supporting the patient.
Finding the middle ground in bile duct injury: the evolving role of biliary rendezvous
Authors: Mouen Khashab, Manuel Perez-Miranda
Journal: Endoscopy (2018)

See also: Percutaneous-endoscopic rendezvous procedure for the management of bile duct injuries after cholecystectomy: short- and long-term outcomes Endoscopy eFirstDOI: 10.1055/s-0043-123935
Cerebral Embolus From Aortic Valve Fragment
Authors: Saeed A. Alqahtani, Itshac Itsik Ben-Dor, Ai-Hsi Liu
Journal: JAMA Neurology (2018)

This case report describes an African American woman in her early 80s with a history of severe aortic stenosis who underwent elective transcatheter aortic valve replacement using a bioprosthetic valve with balloon valvuloplasty.
Determinants of high tumor mutational burden (TMB) and mutational signatures in breast cancer.
Authors: Romualdo Barroso-Sousa, Esha Jain, Dewey Kim, Ann H. Partridge, Ofir Cohen, Nikhil Wagle
Journal: Journal of Clinical Oncology (2018)

1010 Background: High TMB correlates with high neoantigen burden, and this is thought to be predictive of response to immunotherapy. The aim of this work is to evaluate frequency, mutational patterns, and genomic profile of hypermutated breast cancer. Methods: We used sequencing data from publically available on cbioportal.org, including TCGA, France 2016, MSK-IMPACT, MBCProject, AACR-GENIE, and ongoing studies at our institute (The Center for Cancer Precision Medicine Metastatic Breast Cancer Study; The Young Women's Breast Cancer Study) to evaluate mutational load across breast cancers. Samples were classified as having high TMB if they had > 10 mutations (mut) per megabase (MB). Results: We included 3689 samples for the analysis. The median TMB was 1.55 mut/MB. TMB significantly varied according to histology (ductal > lobular, p= 4.6x10-13), tumor subtype (HR-/ HER2+ > TNBC > HR+/HER2+ > HR+/HER2-, p < 0.05), staging (metastatic > primary, p= 2.2x10-16) and site of metastasis (higher soft tissue, and lowest lung, p < 0.05). We found a total of 70 (~2%) hypermutated tumors (62.8% metastatic vs 37.2% primary samples). Mutational signature analysis of the hypermutated samples showed the presence of dominant APOBEC (77.1%), homologous recombination (HR; 2.9%), defective DNA mismatch repair (MMR; 18.6%), and POLE hypermutation (1.4%) signatures. Median TMB was higher for samples with POLE and HR signature, followed by those with MMR and APOBEC (93.1, 38.7, 14.6 and 12.4 mut/MB, respectively). Among hypermutated tumors, 8 samples had somatic mutation in the POLE gene, but only the case with POLE signature high had a characterized POLE driver mutation. In addition, 80% of hypermutated tumors with APOBEC signature had PIK3CA mutations versus 31% of hypermutated tumors with other signatures (p = 0.0005). Conclusions: TMB is correlated with clinical parameters including histology, receptor subtype and site of metastasis. Different mutational signatures are present in this population, including POLE, defective DNA MMR, HR and APOBEC. The potential role of these different signatures in predicting benefit to immunotherapy in hypermutated breast cancers is unclear, and warrants further investigation.