tbuckley/cabot-search huggingface dataset:
HSR19-107: Nivolumab for Newly Diagnosed Classical Hodgkin Lymphoma: Patient-Reported Outcomes From CheckMate 205 Cohort D
Authors: Radhakrishnan Ramchandren, Stephen M. Ansell, Philippe Armand, Andreas Engert, Fiona Taylor, Kim Cocks, Clara Chen, Bryan Bennett, Alejandro Moreno-Koehler, Adam Roeder, Anne Sumbul, Mariana Sacchi, David Cella
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: Patients (pts) with classical Hodgkin lymphoma (cHL) frequently experience reduced health-related quality of life (HRQoL) (Oerlemans et al, Ann Hematol 2011). Nivolumab, a fully human IgG4 anti-programmed death-1 (PD-1) immune checkpoint inhibitor monoclonal antibody, demonstrated efficacy and clinically meaningful improvement in pt-reported outcomes (PROs) in pts with relapsed/refractory cHL in cohorts A, B, and C of CheckMate 205 (NCT02181738) (Armand et al, J Clin Oncol 2018; Engert et al, ASH 2017). Nivolumab monotherapy followed by nivolumab + doxorubicin, vinblastine and dacarbazine (N-AVD) demonstrated an objective response rate of 84% in newly diagnosed cHL (cohort D of CheckMate 205; Ramchandren et al, EHA 2018). We present PROs in CheckMate 205 cohort D. Methods: Pts ≥18 years of age with untreated, advanced-stage cHL, with ECOG performance status (PS) of 0–1 received 4 doses of nivolumab monotherapy (240 mg IV Q2W) followed by N-AVD for 6 cycles (12 doses). Pts then entered the follow-up (FU) period. PROs were an exploratory endpoint, assessed using the EuroQol 5 Dimensions-3 level (EQ-5D-3L) and associated visual analog scale (EQ-VAS) in all treated pts who had both a baseline (monotherapy cycle 1) and post-baseline assessment. EQ-VAS ranges from 0–100, with higher scores indicating better HRQoL. In EQ-5D-3L, pts can report no, some, or extreme problems in each of 5 dimensions (mobility, self-care, activity, pain, and anxiety). Results: 51 pts were treated. At baseline, median age was 37 years, 63% were male, 59% had ECOG PS of 0. 49 pts (96%) completed baseline EQ-VAS. Mean EQ-VAS scores exceeded the mean baseline score at the end of monotherapy, after 2 combination cycles, at the end of therapy, and during follow-up (Table 1). The proportion of pts reporting some or extreme problems in EQ-5D-3L was numerically lower than or similar to baseline after monotherapy for all dimensions, but was numerically higher than baseline (dimensions of mobility and activity) after 2 combination cycles, and remained close to or numerically below baseline during follow-up (dimensions of self-care, activity, pain, and anxiety). Conclusions: Pt-reported HRQoL, as assessed by observed mean EQ-VAS scores, did not deteriorate from baseline during treatment with nivolumab followed by N-AVD. Proportions of pts reporting problems in individual EQ-5D-3L dimensions were generally similar to baseline during treatment and follow-up.
Peak Inspiratory Flow Rate: An Emerging Biomarker in Chronic Obstructive Pulmonary Disease
Authors: Donald A. Mahler
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

and 2015.Significant racial and sex differences in asthma-related mortality continue to exist, with mortality being highest among African American women and lowest among non-Hispanic white men.The decrease in asthma-related mortality was consistent in both sexes and in all race groups, with the largest decrease in patients older than 65 years.This decline in asthma-related mortality may be related to overall improvements in the diagnosis and management of asthma.However, research specifically focused on asthma in the elderly is still limited.Older adults, in general, are more likely to have higher rates of severe asthma and asthma-related hospitalization and mortality (3, 9).Yet the prevalence of asthma in adults older than 65 years remains relatively low compared with that of younger adults, which is reported to be between 4.5% and 12.7% (10).Lower prevalence in this age group is probably related to the underdiagnosis or misdiagnosis, often as chronic obstructive pulmonary disease, of asthma in older adults (11).There is also evidence that asthma in this population is phenotypically different than asthma in younger patients.Furthermore, treatment failure risk increases with age (2), placing older patients with asthma at higher risk for severe uncontrolled asthma.Although asthma mortality has dropped by 43% since 1999, older age, female sex, and African American race continue to be associated with higher risk for asthma-related mortality.This reflects the overall complexity of the disease and the interaction of different factors that contribute to disease control.With a greater risk for severe asthma, this group of patients would benefit from targeted interventions geared toward optimizing asthma therapy and improving access to care.In general, with the world population aging, it will become increasingly important to have research focused on the pathophysiology, diagnosis, and management of asthma in older populations.In summary, asthma-related mortality has declined in all age groups older than 15 years in the United States from 1999 to 2015.Although this decline was seen in both sexes and all races, asthma mortality continues to be higher in women compared with men, African American women in particular.Our findings suggest that improvements in the diagnosis and management of asthma have led to declines in asthma-related mortality.Following these trends in asthma mortality can help to direct focus toward at-risk populations who might benefit the most from targeted interventions.
Influenza A(H3N2) virus exhibiting reduced susceptibility to baloxavir due to a polymerase acidic subunit I38T substitution detected from a hospitalised child without prior baloxavir treatment, Japan, January 2019
Authors: Emi Takashita, Chiharu Kawakami, Rie Ogawa, Hiroko Morita, Seiichiro Fujisaki, Masayuki Shirakura, Hideka Miura, Kazuya Nakamura, Noriko Kishida, Tomoko Kuwahara, Akira Ota, Hayato Togashi, Ayako Saito, Keiko Mitamura, Takashi Abe, Masataka Ichikawa, Masahiko Yamazaki, Shinji Watanabe, Takato Odagiri
Journal: Eurosurveillance (2019)

In January 2019, two influenza A(H3N2) viruses carrying an I38T substitution in the polymerase acidic subunit (PA), which confers reduced susceptibility to baloxavir, were detected from epidemiologically unrelated hospitalised children in Japan. The viruses exhibited reduced susceptibility to baloxavir but were susceptible to neuraminidase inhibitors. Only one of the two children had been treated with baloxavir. An epidemiological analysis suggests possible transmission of the PA I38T mutant A(H3N2) virus among humans.
Current Treatment Landscape of Nasopharyngeal Carcinoma and Potential Trials Evaluating the Value of Immunotherapy
Authors: Quynh Thu Le, A Dimitrios Colevas, Brian O’Sullivan, Anne W M Lee, Nancy Lee, Brigette Ma, Lillian L Siu, John Waldron, Chwee-Ming Lim, Nadeem Riaz, Jean Lynn, Shakun Malik
Journal: JNCI Journal of the National Cancer Institute (2019)

Nasopharyngeal carcinoma (NPC) is a type of head and neck cancer with a distinctive regional and racial prevalence. It is associated with Epstein-Barr virus infection and has a high propensity for regional and distant metastases, while it is very sensitive to radiation and chemotherapy. A common feature of Epstein-Barr virus-positive NPC is the dense infiltration of lymphocytes in the tumor stroma and positive programmed death-ligand 1 expression in tumor cells, making it an attractive target for immunotherapy, especially immune checkpoint inhibitors. As new immunotherapeutic agents are being rapidly adopted in many cancers, including head and neck cancer, the National Cancer Institute sponsored a clinical trial planning meeting to identify opportunities for developing phase II and III trials testing immunotherapy in different stages of NPC. The meeting started with the summary of the biology of the disease, current standards of care, and evidence of immunotherapy in this cancer. Three subcommittees were tasked to develop clinical trials: loco regionally advanced, nonmetastatic NPC; widely metastatic NPC; and either local recurrence after initial treatment or presenting with oligometastatic disease. This article summarizes the proceedings of this clinical trial planning meeting and provides a road map for future trials incorporating immune checkpoint inhibitors for therapeutic management of NPC. This road map, though specific for NPC, may also be applicable to other virally driven cancers that have similar ability to evade the host's immune system.
A novel in vitro model of simulated twice a day iron supplementation for assessment of iron uptake and cellular damage
Authors: Hans Christian Winkler, Lea Maria von Moos, Julian Kornprobst, Mirjam Schneider, Florentine M Hilty, Monika Hilbe, Myrtha Arnold, Nathalie Ziegler, Diogo Sales Mato, Elisabeth M Schraner, Peter Wick, Barbara Bathke, Shana J Sturla, Ioannis Trantakis, Hubertus Hochrein, Wolfgang Langhans, Mark Suter, Hanspeter Naegeli, Michael B Zimmermann
Journal: American Journal of Hematology (2017)
Chronic Airway Diseases Early Stratification (CADSET): a new ERS Clinical Research Collaboration
Authors: Alvar Agusti, Rosa Faner, Gavin Donaldson, Elise Heuvelin, Robab Breyer-Kohansal, Erik Melén, Anke H. Maitland-van der Zee, Jørgen Vestbo, James P. Allinson, Lowie E.G.W. Vanfleteren, Maarten van den Berge, Ian M. Adcock, Lies Lahousse, Guy Brusselle, Jadwiga A. Wedzicha
Journal: European Respiratory Journal (2019)

A recent editorial in the European Respiratory Journal highlighted the strategic importance of the Clinical Research Collaborations (CRCs) launched in 2013 by the European Respiratory Society (ERS) [1]. These have the aim of 1) promoting the exchange of research ideas among clinicians and affiliated scientists in Europe and/or globally; 2) building an infrastructure for prospective clinical research; 3) securing additional funding through national and European Union funding streams; and 4) facilitating the planning, implementation, evaluation and publication of clinical and translational studies at pan-European level and beyond. So far, there are currently 17 ongoing CRCs that cover eight major respiratory disease domains (airway diseases, interstitial lung diseases, pulmonary vascular diseases, sleep and breathing disorders, respiratory critical care, paediatric respiratory diseases, respiratory infections and thoracic oncology), all of them linked to one or more ERS assemblies [2–12]. The ERS launches a new Clinical Research Collaboration (CADSET) to study the determinants and implications of different lung function trajectories through life <http://ow.ly/nf4E30nGsJG> We are grateful for the support from the ERS office in Lausanne, Switzerland, in logistics and organisation of CADSET.
Long-Term Effects of Oral Eliglustat on Skeletal Manifestations of Gaucher Disease Type 1: Results from Four Completed Clinical Trials
Authors: Pramod K. Mistry, Joel Charrow, Timothy Cox, Elena Lukina, Theodore Marinakis, Meredith C. Foster, Sebastiaan J.M. Gaemers, Judith Peterschmitt
Journal: Blood (2018)
β blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial
Authors: Càndid Villanueva, Agustín Albillos, Joan Genescà, Joan C Garcia-Pagan, José L Calleja, Carles Aracil, Rafael Bañares, Rosa M Morillas, María Poca, Beatriz Peñas, Salvador Augustin, Juan G Abraldes, Edilmar Alvarado, Ferran Torres, Jaume Bosch
Journal: The Lancet (2019)
YIA19-002: Axl-RTK Inhibition Modulates T Cell Functions and Synergizes With Chimeric Antigen Receptor T Cell Therapy in B Cell Malignancies
Authors: Saad S. Kenderian, Reona Sakemura, Nan Yang, Michelle Cox, Sutapa Sinha, Michael Hansen, Kendall Schick, Cynthia Forsman, Justin Boysen, Wei Ding, Sameer Parikh, Neil Kay
Journal: Journal of the National Comprehensive Cancer Network (2019)

Despite the remarkable outcomes of CD19-directed chimeric antigen receptor T (CART19) cell therapy in B-cell malignancies, the durable responses in diffuse large B-cell lymphoma are less than 40%, and strategies to enhance this response are desperately needed. Inhibition of AXL RTK with TP0903, a high-affinity AXL inhibitor has been found to induce robust apoptosis of malignant B cells. Here, we aimed to examine the role of AXL RTK inhibition with TP0903 on T-cell function in B-cell malignancies. First, we investigated the influence of TP0903 on CART19 cell phenotype and functions. Here, we used 41BB costimulated, lentiviral-transduced CART cells. AXL inhibition led to polarization of CART cells into a Th1 phenotype when T cells were stimulated with the CD19+ mantle cell lymphoma (MCL) cell line Jeko or with leukemic B cells isolated from patients with chronic lymphocytic leukemia (CLL), in the presence of TP0903 (Fig 1A). Exposure of activated CART cells to TP0903 also resulted in significant downregulation of inhibitory receptors on activated CART cells (Fig 1B), a reduction of conical cytokines known to be associated with the development of cytokine release syndrome (CRS) (Fig 1C). To investigate the effect of AXL RTK inhibition of CART cells with TP0903 in vivo, we established MCL xenografts through the injection of 1.0x106 of Jeko into NSG mice. A week later, mice were treated with either vehicle alone, TP0903 (20 mg/kg/day) alone, 0.5x10 6 of CART19 alone, or TP0903 (20mg/kg/day)+0.5x10 6 of CART19. Three weeks after the treatment, mice were rechallenged with 1.0x10 6 of Jeko. Mice treated with CART19 and TP0903 rejected the tumor challenge while mice previously treated with CART19 alone redeveloped MCL, suggesting that AXL inhibition enhanced CART cell persistence (Fig 1D). Finally, we validated our preclinical findings in correlative analyses of phase 1 clinical trial of TP0903 in patients with solid tumors (NCT02729298). Similar to our findings, there was a significant reduction in Tregs, reduction of inhibitory receptors and polarization to a Th1 phenotype. These findings will be further investigated in a planned phase 1 clinical trial of TP0903 in relapsed/refractory CLL (NCT03572634) In summary, we demonstrated for the first time that AXL inhibition polarizes T cells into a Th1 phenotype, downregulates inhibitory receptors, and synergizes with CART cells in B-cell malignancies. These findings encourage further study of TP0903 as an enhancer of T-cell immunotherapies.
Tuberculosis in the European Union/European Economic Area: much progress, still many challenges
Authors: Jean-Paul Guthmann, Walter Haas
Journal: Eurosurveillance (2019)

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Impaired human hematopoiesis due to a cryptic intronic <i>GATA1</i> splicing mutation
Authors: Nour J. Abdulhay, Claudia Fiorini, Jeffrey M. Verboon, Leif S. Ludwig, Jacob C. Ulirsch, Barbara Zieger, Caleb A. Lareau, Xiaoli Mi, Anindita Roy, Esther A. Obeng, Miriam Erlacher, Namrata Gupta, Stacey B. Gabriel, Benjamin L. Ebert, Charlotte M. Niemeyer, Rami N. Khoriaty, Philip Ancliff, Hanna T. Gazda, Marcin W. Wlodarski, Vijay G. Sankaran
Journal: The Journal of Experimental Medicine (2019)

Studies of allelic variation underlying genetic blood disorders have provided important insights into human hematopoiesis. Most often, the identified pathogenic mutations result in loss-of-function or missense changes. However, assessing the pathogenicity of noncoding variants can be challenging. Here, we characterize two unrelated patients with a distinct presentation of dyserythropoietic anemia and other impairments in hematopoiesis associated with an intronic mutation in GATA1 that is 24 nucleotides upstream of the canonical splice acceptor site. Functional studies demonstrate that this single-nucleotide alteration leads to reduced canonical splicing and increased use of an alternative splice acceptor site that causes a partial intron retention event. The resultant altered GATA1 contains a five-amino acid insertion at the C-terminus of the C-terminal zinc finger and has no observable activity. Collectively, our results demonstrate how altered splicing of GATA1, which reduces levels of the normal form of this master transcription factor, can result in distinct changes in human hematopoiesis.
HSR19-104: Patterns of Providers’ Mammogram Referrals for Asymptomatic Breast Cancer Survivors
Authors: Guadalupe R. Palos, Katherine Gilmore, Patricia Chapman, Weiqi Bi, Paula Lewis-Patterson, Alma Maria Rodriguez
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: NCCN Guidelines recommend annual mammography for surveillance in asymptomatic women diagnosed with breast cancer. There is limited evidence to support which type of mammogram—screening or diagnostic—should be ordered for asymptomatic breast cancer survivors. Our objective was to assess the referral patterns for mammograms in 2 breast clinics: survivorship (SC) and oncology (OC). Methods: A retrospective analysis of institutional databases was conducted to identify a convenience sample of women with limited invasive breast cancer who were (1) alive 5 years post-treatment and (2) seen at a SC or OC visit scheduled from January 1 to December 31, 2015. The primary outcome was women who received a diagnostic or screening mammogram during the 2015 calendar year. Demographic, clinical, and mammogram characteristics were also analyzed. Simple descriptive statistics were used to aggregate and compare data. Chi-square analysis tested for statistical significance. Results: A convenience sample of 354 cases was identified. Of those, 247 met the eligibility criteria for this analysis, SC=147 and OC=100. In this cohort, the mean age of diagnosis was 50.42 (±11.12), the majority were white (74.1%), and most received a diagnostic mammogram (64.4%). A greater proportion of diagnostic mammograms were ordered for women seen in OC (40.1%) vs SC (24. 3%). This finding was statistically significant (P=.00). Overall, 91.9 % of the mammogram results were negative and with a low proportion of “positive” (2.0%) or “need for additional imaging testing” (6.1%) reported. Recurrence rates in this cohort were also found to be low (1.6%). Conclusions: In this cohort, we found a difference in the type of mammogram ordered by providers in dedicated survivorship or medical oncology clinics. Our findings suggest that despite the greater use of diagnostic mammograms among this cohort of long-term breast cancer survivors, the overall proportion of positive findings, further imaging tests, or recurrence rates was low. It is concerning that many asymptomatic breast cancer survivors continue to receive a diagnostic mammogram as part of their surveillance visit. Further studies are needed to identify the emotional, financial, and physical toxicities associated with diagnostic mammograms.
Beneficial associations of low and large doses of leisure time physical activity with all-cause, cardiovascular disease and cancer mortality: a national cohort study of 88,140 US adults
Authors: Min Zhao, Sreenivas P Veeranki, Shengxu Li, Lyn M Steffen, Bo Xi
Journal: British Journal of Sports Medicine (2019)

Background Evidence on the role of very low or very high volumes of leisure time physical activity (PA) on the risk of all-cause and cause-specific mortality is limited. We aimed to examine the associations of different levels of leisure time PA with the risk of all-cause, cardiovascular disease (CVD) and cancer-specific mortality. Methods Data were from 12 waves of the National Health Interview Surveys (1997–2008) linked to the National Death Index records through 31 December 2011. A total of 88 140 eligible participants aged 40–85 years were included. Results Compared with inactive individuals, those performing 10–59 min/week of PA had 18% lower risk of all-cause mortality (hazard ratio (HR): 0.82, 95% confidence interval (CI): 0.72–0.95). Those who reported 1–2 times (150–299 min/week) the recommended level of leisure time PA had 31% (HR: 0.69, 95%CI: 0.63–0.75) reduced risk of all-cause mortality. Importantly, the continued benefits were observed among those performing leisure time PA 10 or more times (≥1500 min/week) the recommended minimum level (HR: 0.54, 95% CI: 0.45–0.64). For 10–59, 150–299 and ≥1500 min/week of PA, the corresponding HRs (95% CIs) for CVD-specific mortality were 0.88 (0.67–1.17), 0.63 (0.52–0.78) and 0.67 (0.45–0.99), respectively: for cancer-specific mortality were 0.86 (0.66–1.11), 0.76 (0.64–0.89) and 0.53 (0.39–0.73), respectively. In addition, there was a larger reduction in all-cause and cause-specific mortality for vigorous vs. moderate intensity PA. Conclusions We found that beneficial association between leisure time PA and mortality starts from a low dose. Doing more vigorous exercise could lead to additional health benefits.
Nano-Structural Effects on Gene Transfection: Large, Botryoid-Shaped Nanoparticles Enhance DNA Delivery via Macropinocytosis and Effective Dissociation
Authors: Wenyuan Zhang, Xuejia Kang, Bo Yuan, Huiyuan Wang, Tao Zhang, Mingjie Shi, Zening Zheng, Yuanheng Zhang, Chengyuan Peng, Xiaoming Fan, Huaiyu Yang, Youqing Shen, Yongzhuo Huang
Journal: Theranostics (2019)

Effective delivery is the primary barrier against the clinical translation of gene therapy. Yet there remains too much unknown in the gene delivery mechanisms, even for the most investigated polymeric carrier (i.e., PEI). As a consequence, the conflicting results have been often seen in the literature due to the large variability in the experimental conditions and operations. Therefore, some key parameters should be identified and thus strictly controlled in the formulation process. Methods: The effect of the formulation processing parameters (e.g., concentration or mixture volume) and the resulting nanostructure properties on gene transfection have been rarely investigated. Two types of the PEI/DNA nanoparticles (NPs) were prepared in the same manner with the same dose but at different concentrations. The microstructure of the NPs and the transfection mechanisms were investigated through various microscopic methods. The therapeutic efficacy of the NPs was demonstrated in the cervical subcutaneous xenograft and peritoneal metastasis mouse models. Results: The high-concentration process (i.e., small reaction-volume) for mixture resulted in the large-sized PEI/DNA NPs that had a higher efficiency of gene transfection, compared to the small counterpart that was prepared at a low concentration. The microstructural experiments showed that the prepared small NPs were firmly condensed, whereas the large NPs were bulky and botryoid-shaped. The large NPs entered the tumor cells via the macropinocytosis pathway, and then efficiently dissociated in the cytoplasm and released DNA, thus promoting the intranuclear delivery. The enhanced in vivo therapeutic efficacy of the large NPs was demonstrated, indicating the promise for local-regional administration. Conclusion: This work provides better understanding of the effect of formulation process on nano-structural properties and gene transfection, laying a theoretical basis for rational design of the experimental process.