bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract PO-022: Impact of COVID-19 pandemic on new patient and consult visits at 20 hematology/oncology practices in the ASCO PracticeNET learning network
Authors: Bourbeau Brian , Guharoy Mou , Garrett-Mayer Elizabeth , Grubbs Stephen , Unger Paul , McAneny Barbara , Schilsky Richard L.
Published: December 2020

Introduction: During March 2020, as the emergence of COVID-19 began to influence medical and social behaviors in the United States, oncology practices reported a disruption in normal referral and patient management patterns. Participants and staff of ASCO's PracticeNET learning network sought to explore and quantify the impact of this disruption through an analysis of patient activity at multiple hematology/oncology practices.

Methods: 20 practices submitted their billing data for analysis; practices were located in 14 states and ranged in size from 2 to 29 hematologists/oncologists. From this dataset we analyzed a total of 11,453 new patient and consult visits (Current Procedural Terminology codes 99201-99205, 99241-99245, 99251-99255, and 99341-99345) performed by hematologists/oncologists from February 9 to April 18, 2020. The number of visits performed from February 9 to March 14, 2020 was compared to visits performed from March 15 to April 18, 2020. A principal diagnosis was assigned to each visit following usual coding and billing practices.

Results: From February 9 to March 14, practices performed an average of 70.1 (median 55.5) new patient and consult visits per week. From March 15 to April 19, practices performed an average of 44.5 new patient and consult visits per week. The average decrease in visits among practices was 35% (95% confidence interval (CI): -42%, -29%). The decline in visits per practice ranged from -61% to -13%. New patient and consult visits for solid neoplasms decreased by an average of 22% (95% CI: -31%, -13%), visits for blood neoplasms decreased by an average of 36% (95% CI: -25%, -47%), and visits for benign hematology and circulatory disorders decreased by an average of 44% (95% CI: -53%, -34%).

Conclusions: Oncology practices experienced a decline in new patient and consult visits, first observed in the week of March 15. New patient and consult visits for blood neoplasms, benign hematology, and circulatory disorders experienced a greater decline than visits for solid neoplasms. The decrease in activity could be the result of prioritization of resources or changes in patient behavior in seeking care. Further study is necessary to quantify the impact of these findings on patient access and outcomes and to monitor recovery efforts.

Citation Format: Brian Bourbeau, Mou Guharoy, Elizabeth Garrett-Mayer, Stephen Grubbs, Paul Unger, Barbara McAneny, Richard L. Schilsky. Impact of COVID-19 pandemic on new patient and consult visits at 20 hematology/oncology practices in the ASCO PracticeNET learning network [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr PO-022.
Abstract PO-076: Training and information during COVID-19 pandemic: The masterpiece in young oncologists
Authors: Ranallo Nicoletta , Bastianelli Lucia , Merloni Filippo , Cantini Luca , Ricci Giulia , Ballatore Zelmira , Berardi Rossana
Published: December 2020

Background: The COVID-19 pandemic was a health emergency that required a rapid response by the Italian National Health System. Health care professionals needed to be properly trained and informed about their patients' procedures and proper management. During an emergency, the information must be exhaustive, clear, and timely to allow correct diagnostic and therapeutic continuity. It is also important that all health workers are promptly and homogeneously trained to guarantee the best treatment path even during the pandemic. Our survey aimed to investigate the level of information and training of health workers in oncology during the pandemic and, in particular, the difference in perception between operators under and over 35 years of age.

Materials and Methods: An on-line multiple-choice survey was submitted to oncology health workers during the pandemic, investigating individual perception of resources, information, and staff training management by hospital centers. No open questions were included.

Results: A total of 383 health workers replied to the survey (116 under 35 years versus 267 over 35 years). In the under-35 group, a total of 65% declared they had been timely and sufficiently informed to understand the extent of the problem compared to 50% of those over 35 (P=0.007). About 80% of young professionals were adequately informed and two thirds (63%) were informed about procedures/recommendations to be followed during the pandemic. However, in professionals over 35, only 56% declared they had the right information and over 65% did not feel adequately trained (P= <0.01). Furthermore, 44% of those over 35 felt not sufficiently prepared for the management of the cancer patient during an epidemic compared to only 28% of those under 35 (P=0.015).

Conclusion: The survey showed a different perception of information and training of health care professionals based on the age group. This could be determined by a different degree of task and responsibility but also by the greater and faster readiness of the younger operators to acquire new information and to draw on a renewed ability to face an emergency by reorganizing themselves quickly and actively.

Citation Format: Nicoletta Ranallo, Lucia Bastianelli, Filippo Merloni, Luca Cantini, Giulia Ricci, Zelmira Ballatore, Rossana Berardi. Training and information during COVID-19 pandemic: The masterpiece in young oncologists [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr PO-076.
Abstract PO-083: Prostate cancer and COVID-19: Impact of hormonal therapy on severe outcomes
Authors: Tawagi Karine , Burton Jeff , Maslov Diana , Lunski Michael , Matrana Marc , Johnson Daniel
Published: December 2020

Background: Early reports on cancer patients infected with COVID-19 have suggested a high risk of hospitalization and death compared to the general population. Limited data are available on outcomes in specific cancer types. We aim to identify whether hormonal treatment impacts severe outcomes (rate of hospitalization, ICU admission, intubation, and death) in prostate cancer patients.

Methods: We conducted a multicenter study in the state of Louisiana, throughout the Ochsner Health System, in both tertiary and nontertiary centers. Patients must carry a diagnosis of prostate cancer and have a completed SARS-CoV-2 test between March 1st and April 30th, 2020. Chi-squared and Fisher’s exact tests were performed to compare the proportion of patients experiencing severe outcomes between treatment groups.

Results: As of April 30, 2020, a total of 56 patients with prostate cancer who had a positive SARS-COV-2 test were identified. Median age 69, median BMI 28.8, 78.6% (n=44) black, 58.9% (n=33) current/former smokers, HTN, DM2, and CKD were the most common comorbidities, and 12.5% (n=7) of patients had stage IV disease. Of these patients, 26.8% (n=15) were on hormonal treatment (received within 90 days of COVID+ test). In terms of severe outcomes, 58.9% (n=33) of patients required hospitalization, 17.9% (n=10) required ICU admission with 14.3% (n=8) patients requiring intubation, and 23.2% (n=13) of patients died. There was no statistical difference in rate of severe outcomes (rate of hospitalization, ICU admission, intubation, and death) among prostate cancer patients receiving hormonal therapy vs. those receiving no hormonal therapy.

Conclusion: With an ongoing global pandemic of COVID-19, it is important to identify characteristics leading to increased risk of severe events in cohorts of cancer patients. This small cohort does not identify hormonal therapy as a risk factor for increased rate of severe outcomes in patients with prostate cancer. Further analyses describing impact of specific hormonal regimens on risk of hospitalization and death will be completed by time of presentation.

Citation Format: Karine Tawagi, Jeff Burton, Diana Maslov, Michael Lunski, Marc Matrana, Daniel Johnson. Prostate cancer and COVID-19: Impact of hormonal therapy on severe outcomes [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr PO-083.
Abstract IA03: Optimizing immunostimulatory antibodies for cancer immunotherapy
Authors: Yu Xiaojie , White Anne , Glennie Martin , Tews Ivo , Fisher Hayden , Orr Chris , French Ruth , Beers Stephen , Al'Shamkhani Aymen , Dadas Osman , Roghanian Ali , Willoughby Jane , Cragg Mark S.
Published: December 2020

Agonistic antibodies directed to immunostimulatory receptors are a currently untapped source for immunotherapy. Whereas checkpoint blockers have translated into the clinic, the rules for agonistic antibodies have been more difficult to discern and these reagents await further optimization. Here we discuss the salient properties of monoclonal antibodies (mAb) required to strongly agonize these receptors and discuss potential strategies for the future. We show that immunostimulatory mAb (ISA) can agonize key stimulatory receptors on the cell surface—many of which are from the TNFR family—and highlight the importance of isotype. Using CD40 mAb as a paradigm, we show that receptor clustering is key for ISA responses—probably mimicking ligand. This clustering can be achieved via Fc gamma receptor (FcgR) engagement or independently with the hIgG2(B) isotype. For CD40 this is highly epitope dependent, showing that epitope, isotype, and domain location all interact to drive mAb agonism. Finally, we show that isotype engineering can overcome “weak” epitopes. This can be completely independent of FcgR interaction in the case of hIgG2B, which may be of use in humans where the FcgR profile within the tumor microenvironment may vary.

Citation Format: Xiaojie Yu, Anne White, Martin Glennie, Ivo Tews, Hayden Fisher, Chris Orr, Ruth French, Stephen Beers, Aymen Al'Shamkhani, Osman Dadas, Ali Roghanian, Jane Willoughby, Mark S. Cragg. Optimizing immunostimulatory antibodies for cancer immunotherapy [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr IA03.
Abstract IA11: AYA lymphomas: Bridging the divide
Authors: Kelly Kara
Published: December 2020

Lymphomas account for approximately 20-25% of annual cancer diagnoses in the adolescent and young adult (AYA) population, defined as ages 15–39 years. Despite continued improvements in lymphoma outcomes, AYAs have not exhibited survival gains to the same extent as other age groups. At present, this survival gap is a manifestation of many compounding factors including a lack of sufficient understanding of the tumor biology or the optimal therapeutic approaches, as well as delays in diagnosis, the supportive care needs, long-term toxicity risk, developmental stage of the AYA, and socioeconomic factors. There is no established standard of care for AYA lymphomas, and there is significant divergence in treatment approaches between medical and pediatric oncology.

Data on the heterogeneity of lymphoid malignancies in the AYA population as compared with younger pediatric and older adult groups will be reviewed. The highest proportion (35-70%) of lymphoid malignancies are due to Hodgkin lymphoma and lymphoblastic leukemia/lymphoma, followed by diffuse large B-cell lymphoma (10%-20%). Sex, race, and ethnic differences in the AYA lymphomas are also observed. These findings suggest that AYA lymphomas are biologically distinct from those present in the pediatric and adult populations. Factors that may contribute to the observed age-based variation in disease include evolution of the immune system with age, changes in the impact of genetic susceptibility, and viral and/or environmental exposures.

There is a marked difference between the pediatric and adult approaches for AYA lymphomas. The example of AYA Hodgkin lymphoma will be reviewed. The pediatric backbone chemotherapy regimen has been doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC), whereas the adult regimen has been doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Radiation therapy is incorporated more often in pediatric high-risk regimens and adult low-risk approaches. Because disease biology does not conform to an 18-year-old cutoff, which of these approaches is most appropriate for AYAs has not been established. Treatment approach is not standard and is often driven by the experience of the physician. Recent progress in developing collaborative clinical trials through the North American National Clinical Trials Network will be reviewed.

Citation Format: Kara Kelly. AYA lymphomas: Bridging the divide [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr IA11.
Abstract IA25: CREBBP: Not all mutations are created equal
Authors: Green Michael R.
Published: December 2020

Follicular lymphoma (FL) and the EZB/C3 subtype of diffuse large B-cell lymphoma (DLBCL) are characterized by frequent mutations of chromatin-modifying genes, including KMT2D, CREBBP, and EZH2. Genomic analysis of serial biopsies from FL patients has allowed the reconstruction of evolutionary phylogenies and highlighted CREBBP mutations as occurring predominantly as early events in disease evolution and residing within common progenitor cells that seed relapse. Patient tumor cells with CREBBP mutations have significantly reduced MHC class II expression and perturbed T-cell responses to tumor, suggesting a role for CREBBP mutations in driving immune evasion. Knock-out and knock-down studies of Crebbp confirmed its tumor-suppressor function in animal models, but uncovered some differences compared to the phenotypes observed in association with CREBBP mutations in primary tumors. Mutations of CREBBP most often encode missense amino acid substitutions within the catalytic lysine acetyltransferase (KAT) domain rather than nonsense/frameshift variants that result in a loss of protein expression. Here I will discuss recently published and unpublished data regarding the function of CREBBP mutations in B-cell lymphoma, functional differences between classes of mutations (KAT domain missense vs. nonsense/frameshift) and between different mutational hotspots within the KAT domain. Furthermore, I will discuss how these functional insights provide a rationale for targeted therapeutic strategies in B-cell lymphoma.

Citation Format: Michael R. Green. CREBBP: Not all mutations are created equal [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr IA25.
Abstract PO-12: Activity of ASTX660, a small-molecule IAP antagonist, reveals a novel, immune-based therapeutic approach in T-cell lymphoma
Authors: Jueliger Simone , Ferrari Nicola , Ward George , Munck Joanne , Smyth Tomoko , Davis Matthew , Gewinner Christina , Ferraldeschi Roberta , Lyons John , Sims Martin
Published: December 2020

Introduction: ASTX660 is a potent, non-peptidomimetic antagonist of the cellular and X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP), which is currently being tested in a first-in-human phase I-II study in patients with advanced solid tumors and lymphomas (NCT02503423). IAP antagonists are known regulators of cell death and have been reported to modulate immune responses (1). Herein, we describe the profile of ASTX660 in preclinical models with a specific focus on ASTX660's ability to harness a particular form of regulated cell death in T-cell lymphoma that directs an effective immune response and leads to sustained tumor regressions.

Methods: ASTX660 was profiled across a panel of T-cell lymphoma lines, assessing apoptosis, necroptosis, and immunogenic cell death (ICD). ASTX660 was tested in vitro with or without caspase-8/RIPK1 inhibitors to demonstrate mechanism of action. Target engagement along with induction of apoptosis, necroptosis, and ICD markers were analyzed by Western blotting and flow cytometry. Murine tumor models in immunocompetent and immunocompromised mice were utilized to evaluate the efficacy of ASTX660 in the presence or absence of an adaptive immune response.

Results: ASTX660 antagonized IAPs in cell lines, as indicated by a decrease in cIAP1 protein levels. In certain murine T-cell lymphoma cell lines, ASTX660 treatment was associated with an increase in cell death and release of biomarkers of ICD. Use of caspase and RIPK1 inhibitors indicated the cell death was via necroptosis. In a syngeneic model of T-cell lymphoma, administration of ASTX660 resulted in complete and sustained tumor regressions which were not seen in mice deficient in T and B cells. Mice cured of T-cell lymphoma by ASTX660 were resistant to a second inoculation of the same lymphoma.

Conclusion: These data add to the description of ASTX660's mode of action and our ongoing understanding of the preliminary clinical efficacy in T-cell lymphoma (2). We describe a new role for ASTX660 as an immunomodulatory molecule with potential to deliver a novel immune-based therapeutic approach in T-cell lymphoma.

References: 1. Michie J et al. Cells 2020;9(1). 2. Hollebecque A et al. 2019 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.

Citation Format: Simone Jueliger, Nicola Ferrari, George Ward, Joanne Munck, Tomoko Smyth, Matthew Davis, Christina Gewinner, Roberta Ferraldeschi, John Lyons, Martin Sims. Activity of ASTX660, a small-molecule IAP antagonist, reveals a novel, immune-based therapeutic approach in T-cell lymphoma [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-12.
Abstract PO-36: Functional bypass of cell cycle entry checkpoints by MYC T58A mutation in germinal center-derived lymphomas
Authors: Lee Jongkuen , Dominguez-Sola David
Published: December 2020

Somatic missense mutations targeting MYC's coding sequence are found in >50% of Burkitt lymphomas and in a small fraction of diffuse large B-cell lymphomas. These mutations typically arise in translocated MYC alleles and cluster at specific protein residues, particularly Threonine 58 (T58). Previous studies in non-B cell models suggested that MYC mutations enhance oncogenic properties by escaping MYC-induced apoptosis. However, the functional impact of these mutations on the biology of germinal center (GC) B cells, where these mutations arise, has never been investigated. In GC B cells, MYC expression is induced by positive selection signals during cognate interactions with T follicular helper cells, concurrent with activation of PI3K and mTOR signaling. PI3K and mTOR are activated upon CD40 and B-cell receptor co-engagement and are critically required for positive selection and clonal expansion of GC B cells. Using newly generated MYC T58A knock-in mouse models, we found that MYC T58A mutation allows B cells to bypass a cell cycle entry checkpoint dependent on PI3K and mTOR activities. Exposure of wild-type (WT) B cells to rapamycin or, less markedly, to PI3K inhibitors, prevented the proliferation upon CD40 and IL4 stimulation ex vivo (a cytokine combination mimicking T-cell help) whereas MYC T58A mutant B cells divided multiple times and maintained adequate rates of active biosynthesis. Similarly, administration of rapamycin to immunized WT mice collapsed formed GCs while MYC T58A GCs maintained normal size and proliferation rates in vivo. These phenotypes were in part explained by the effects of PI3K/mTOR signaling on GSK3-beta, a kinase that normally phosphorylates MYC T58 to control protein turnover. Differences in metabolic and gene expression profiles between MYC WT and T58A cells offered additional insights into the mechanisms by which this mutation bypasses PI3K/mTOR checkpoint. Finally, we found that GC B cell-specific overexpression of MYC T58A, resulted in abnormally enlarged GCs upon immunization, a phenotype common to lymphoma models. Altogether, these results indicate that MYC somatic mutations confer competitive advantages to B cells by bypassing a strict requirement for upstream signals during cell cycle entry, which may support the clonal expansion of MYC mutant B cells during GC responses. These results have important translational implications, particularly given the increasing interest in the potential use of PI3K and/or mTOR inhibitors in the treatment of lymphomas.

Citation Format: Jongkuen Lee, David Dominguez-Sola. Functional bypass of cell cycle entry checkpoints by MYC T58A mutation in germinal center-derived lymphomas [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-36.
Abstract PO-54: Mechanistic consequences of histone-deacetylase inhibition towards sensitizing PD1 blockade-resistant B-cell lymphomas
Authors: Wang Xiaoguang , Waschke Brittany C. , Woolaver Rachel A. , Chen Zhangguo , Zhang Gan , Piscopio Anthony D. , Liu Xuedong , Wang Jing H.
Published: December 2020

PD1 blockade is effective in a subset of B-cell lymphoma patients (e.g., classical Hodgkin lymphomas); however, most patients do not respond to anti-PD1 therapy. To overcome PD1 resistance, we employ a newly developed isoform-selective histone-deacetylase-inhibitor (HDACi) (OKI-179) and a novel mouse mature B-cell lymphoma, G1XP lymphoma, that resembles immunosuppressive features of human B-cell lymphomas including downregulation of major histocompatibility complex (MHC) class I and II, exhaustion of CD8 and CD4 tumor-infiltrating lymphocytes (TILs), and PD1-blockade resistance. Using multiple lymphoma models, we show that combined treatment of OKI-179/anti-PD1 significantly inhibited growth of B-cell lymphomas refractory to PD1 blockade; furthermore, sensitivity to single or combined treatment required tumor-derived MHC class I, and positively correlated to MHC class II level. We conclude that OKI-179 sensitizes lymphomas to PD1 blockade by enhancing tumor immunogenicity. Additionally, we found that different HDACi exhibited distinct effects on tumors and T cells, yet the same HDACi could differentially affect HLA expression on different human B-cell lymphomas. Thus, our study highlights the importance of immunologic effects of HDACi on antitumor responses and suggests that optimal treatment efficacy requires personalized design and rational combination based on prognostic biomarkers (e.g., MHCs) and unique profiles of HDACi.

Citation Format: Xiaoguang Wang, Brittany C. Waschke, Rachel A. Woolaver, Zhangguo Chen, Gan Zhang, Anthony D. Piscopio, Xuedong Liu, Jing H. Wang. Mechanistic consequences of histone-deacetylase inhibition towards sensitizing PD1 blockade-resistant B-cell lymphomas [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-54.
Plasma Magnesium Concentrations and Risk of Incident Cancer in Adults with Hypertension: A Nested Case-Control Study
Authors: Lin Tengfei , Bi Chonglei , Song Yun , Guo Huiyuan , Liu Lishun , Zhou Ziyi , Wang Binyan , Tang Genfu , Liu Chengzhang , Yang Yan , Ling Wenhua , Yang Jingang , Cui Yimin , Zhang Chengguo , Li Gang , Li Jiaang , Li Jianping , Zhang Yan , Huo Yong , Wang Xiaobin , Zhang Hao , Qin Xianhui , Xu Xiping
Published: December 2020

Objective: The association between plasma magnesium and risk of incident cancer remains inconclusive in previous studies. We aimed to investigate the prospective relationship of baseline plasma magnesium concentrations with the risk of incident cancer and to examine possible effect modifiers. Methods: A nested case-control study with 228 incident cancer cases and 228 matched controls was conducted using data from the China Stroke Primary Prevention Trial (CSPPT), a randomized, double-blind, controlled trial, conducted from May 2008 to August 2013. Study outcomes included incident cancer and its subtypes. Results: When plasma magnesium concentrations were assessed as quartiles, a significantly higher incident risk of total cancer was found in participants in quartile 1 (<0.76 mmol/L; odds ratio [OR] = 2.70; 95% CI: 1.33–5.49) and quartile 4 (≥0.89 mmol/L; OR = 2.05; 95% CI: 1.12–3.76), compared with those in quartile 3 (0.83 to <0.89 mmol/L). In cancer site-specific analyses, similar trends were found for gastrointestinal cancer, esophageal cancer, gastric cancer, breast cancer, lung cancer, and other cancers. Furthermore, none of the variables, including age, sex, current smoking status, current alcohol intake, BMI, systolic blood pressure, and total cholesterol levels at baseline significantly modified the association between plasma magnesium and cancer risk. Conclusions: Both low and high plasma magnesium concentrations were significantly associated with an increased incident risk of cancer, compared with the reference concentrations of 0.83 to <0.89 mmol/L among hypertensive adults.
The Role of Nrf2 in D-Galactose-Induced Cardiac Aging in Mice: Involvement of Oxidative Stress
Authors: Yang Xilan , Jia Jian , Ding Ling , Yu Zhen , Qu Chen
Published: December 2020

Introduction: Cardiac aging is the major risk factor for advanced heart disease, which is the leading cause of death in developed countries, accounting for >30% of deaths worldwide. Objective: To discover the detailed mechanism of cardiac aging and develop an effective therapeutic candidate drug to treat or delay cardiac aging. Methods: We used D-galactose to induce cardiac aging in Nrf2+/+ and Nrf2–/– mice, and then treated these mice with vehicle or the Nrf2 activator, CDDO-imidazolide (CDDO-Im). Results and Conclusions: D-galactose injection significantly induced cardiac aging, cell apoptosis, and oxidative stress in Nrf2+/+ mice, all of which were further exacerbated in Nrf2–/– mice. CDDO-Im treatment can effectively weaken oxidative stress and enhance the activities of antioxidant enzymes, but CDDO-Im lost its antioxidative effect in the Nrf2–/– mice. Nrf2 activator CDDO-Im could therefore effectively protect against D-galactose-induced cardiac aging by inhibiting oxidative stress, suggesting that CDDO-Im might be a potential and promising therapeutic candidate drug to treat cardiac aging.
Antigen Expression Varies Significantly between Molecular Subgroups of Acute Myeloid Leukemia Patients: Clinical Applicability Is Hampered by Establishment of Relevant Cutoffs
Authors: Herborg Laura Laine , Nederby Line , Brøndum Rasmus Froberg , Hansen Maria , Hokland Peter , Roug Anne Stidsholt
Published: December 2020

Introduction: In this single-center study of 268 acute myeloid leukemia (AML) patients, we have tested if a subset of 4 routinely employed immunophenotypic stem cell-associated markers correlated with the presence of recurrently mutated genes and if the markers were predictive for mutational status. Methods: Immunophenotypic data from 268 diagnostic AML samples obtained in 2009–2018 were analyzed retrospectively for the antigens CD34, CD117, CD123, and CLEC12A. Correlation between immunophenotypes and mutations was analyzed by Fischer’s exact test. Clinical applicability of the markers for predicting mutational status was evaluated by receiver operating characteristics analyses, where an area under the curve (AUC) of at least 0.85 was accepted as clinically relevant. Results: For a number of genes, the antigen expression differed significantly between mutated and wild-type gene expression. Despite low AUCs, CD123 and CLEC12A correlated with FLT3+NPM1− and FLT3+NPM1+. Three subsets met the AUC requirements (CD34+, CD34+CD117+, and CD34−CD117+) for predicting FLT3−NPM1+ or FLT3+NPM1+. Conclusion: The value of immunophenotypes as surrogate markers for mutational status in AML seems limited when employing CD123 and CLEC12A in combination with CD34 and CD117. Defining relevant cutoffs for given markers is challenging and hampered by variation between laboratories and patient groups.
Clinical and Inflammatory Features of Exacerbation-Prone Asthma: A Cross-Sectional Study Using Multidimensional Assessment
Authors: Feng Min , Zhang Xin , Wu Wen Wen , Chen Zhi Hong , Oliver Brian G. , McDonald Vanessa M. , Zhang Hong Ping , Xie Min , Qin Ling , Zhang Jie , Wang Lei , Li Wei Min , Wang Gang , Gibson Peter G.
Published: December 2020

Background: Reducing asthma exacerbations is a major target of current clinical guidelines, but identifying features of exacerbation-prone asthma (EPA) using multidimensional assessment (MDA) is lacking. Objective: To systemically explore the clinical and inflammatory features of adults with EPA in a Chinese population. Methods: We designed a cross-sectional study using the Severe Asthma Web-based Database from the Australasian Severe Asthma Network (ASAN). Eligible Chinese adults with asthma (n = 546) were assessed using MDA. We stratified patients based on exacerbation frequency: none, few (1 or 2), and exacerbation prone (≥3). Univariate and multivariable negative binomial regression analyses were performed to investigate features associated with the frequency of exacerbations. Results: Of 546 participants, 61.9% had no exacerbations (n = 338), 29.6% had few exacerbations (n = 162), and 8.4% were exacerbation prone (n = 46) within the preceding year. EPA patients were characterized by elevated blood and sputum eosinophils but less atopy, with more controller therapies but worse asthma control and quality of life (all p < 0.05). In multivariable models, blood and sputum eosinophils (adjusted rate ratio = 2.23, 95% confidence interval = [1.26, 3.84] and 1.67 [1.27, 2.21], respectively), FEV1 (0.90 [0.84, 0.96]), bronchodilator responsiveness (1.16 [1.05, 1.27]), COPD (2.22 [1.41, 3.51]), bronchiectasis (2.87 [1.69, 4.89]), anxiety (2.56 [1.10, 5.95]), and depression (1.94 [1.20, 3.13]) were found. Further, upper respiratory tract infection (1.83 [1.32, 2.54]) and food allergy (1.67 [1.23, 2.25]) were at high risk of asthma symptom triggers. Conclusion: EPA is a clinically recognizable phenotype associated with several recognizable traits that could be addressed by targeted treatment.
Prognostic Impact of Peripheral Blood T-Cell Subsets at the Time of Diagnosis on Survival in Patients with Diffuse Large B-Cell Lymphoma
Authors: Shin Ho-Jin , Kim Do-Young , Chung JooSeop , Shin Kyung-Hwa , Lee Hyungi
Published: December 2020

Introduction: The effects of lymphocyte subtypes, including helper (Th), natural killer (NK), and regulatory (Treg) cells, and other T-cell subtypes on treatment outcomes in diffuse large B-cell lymphoma (DLBCL) patients are not clearly established. Methods: Among 151 consecutive patients diagnosed with DLBCL, we collected peripheral blood samples at diagnosis from 91 patients who received at least 1 cycle of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab) chemotherapy and analyzed lymphocyte subsets by flow cytometry. Results: DLBCL patients had a higher proportion of CD4+CD25+ Treg (p < 0.001) and lower absolute lymphocyte count than those of healthy controls. Lymphopenia at diagnosis was associated with advanced-stage disease (p = 0.001), a high-intermediate/high-risk International Prognostic Index (IPI) (p < 0.001), and older age (p = 0.060). High-intermediate/high-risk IPI, high proportion of CD3+CD4+ Th cells, and extranodal site ≥2 correlated with unfavorable prognostic factors for survival. High proportion of Th cells was associated with fewer cytotoxic T cells and NK cells at the time of diagnosis. Conclusion: This study showed an association between circulating lymphocyte subsets including Th cells, Tregs, and NK cells and clinical outcomes in DLBCL; however, further confirmation is needed via prospective trials.
Outcome of Patients Admitted to Intensive Care Units due to Influenza-Related Severe Acute Respiratory Illness in 2017–2018 Flu Season: A Multicenter Study from Turkey
Authors: Ortac Ersoy Ebru , Er Berrin , Ciftci Fatma , Gulleroglu Aykan , Suner Kezban , Arpinar Burcu , Aygencel Gulbin , Bacakoglu Feza , Akpinar Serdar , Comert Bilgin , Sungurtekin Hulya , Altıntas Defne , Rollas Kazim , Turan Sema , Topeli Arzu
Published: December 2020

Background: Influenza can cause severe acute respiratory illness (SARI), which occurs as local outbreaks or seasonal epidemics with high intensive care unit (ICU) admission and mortality rates. Mortality is mainly due to SARI. Objective: The aim of this study was to evaluate the outcome of patients admitted to ICU due to influenza-related SARI in 2017–2018 flu season in Turkey. Methods: A retrospective multicenter study was conducted in 13 ICUs with a total of 216 beds from 6 cities in Turkey. All adult patients (over 18 years) admitted to the ICUs in 2017–2018 flu season (between September 1, 2017, and April 30, 2018) because of SARI and with a positive nasopharyngeal swab for influenza were included in the study. Results: A total of 123 cases were included in the study. The mean age of patients was 64.5 ± 17.5 years, and 66 (53.7%) patients were older than 65 years. The ICU mortality was 33.9%, and hospital mortality was 35.6%. Invasive mechanical ventilation (IMV), acute kidney injury (AKI), hematologic malignancy, and >65 years of age were the factors affecting mortality in influenza. Conclusion: SARI due to influenza carries a high mortality rate, and IMV, AKI, presence of hematologic malignancy, and older age are independent risk factors for mortality.
The Effectiveness of an Active Learning Program in Promoting a Healthy Lifestyle among Older Adults with Low Health Literacy: A Randomized Controlled Trial
Authors: Uemura Kazuki , Yamada Minoru , Okamoto Hiroshi
Published: December 2020

Background: Older adults often have a greater need for health information and health care services because access to these helps them manage their health and the chronic conditions of aging. Therefore, low health literacy bears a special significance for the population of older adults. Objectives: The aim of this study was to examine the effects of an active learning program on health literacy, lifestyle behaviors, physical function, and mental health among community-dwelling older adults with low health literacy. Methods: This single-blind, randomized controlled trial involved 60 participants aged ≥65 years with a low health literacy who were randomly assigned to an intervention (n = 30) or control (n = 30) group. Across 24 weeks, the intervention group attended weekly 90-min active learning program sessions, which involved exploratory learning, group work, and the self-planning of behavior changes that promote a healthy lifestyle. The control group attended a 90-min class, which was taught in accordance with the didactic teaching method. For both groups, the programs focused on the role of exercise, diet/nutrition, and cognitive activity for promoting health among older adults. The outcome measures were administered at baseline and week 24. Comprehensive health literacy (i.e., primary outcome) was assessed using the Health Literacy Scale-14. Lifestyle factors (i.e., physical activity, dietary variety, life-space mobility, and social network size), physical function, and depressive symptoms were measured. We used a linear mixed model to estimate the intervention effects in accordance with the intention-to-treat approach. Results: When compared to the control group, the intervention group demonstrated a significant improvement in communicative health literacy, step count, engagement in moderate-to-vigorous physical activity, dietary variety, life-space mobility, social network size, grip strength, gait speed, and depressive symptoms. Conclusions: The active learning program can promote a healthy lifestyle and prevent functional decline among older adults who lack the confidence to engage in health communication.
Vedolizumab-Induced Liver Injury
Authors: Mascarenhas Saraiva Miguel , Ribeiro Tiago , Dias Emanuel , Lopes Joanne Lopes , Cardoso Hélder , Macedo Guilherme
Published: December 2020

Drug-induced liver injury is an important cause of acute liver injury. Immunomodulatory therapies, such as vedolizumab (VDZ), are being increasingly used for the treatment of several diseases, most importantly inflammatory bowel disease. Several studies have demonstrated the safety of this substance. To date, only one post-marketing study has reported a case of hepatotoxicity attributable to VDZ. The authors present the case of a 41-year-old woman followed at the gastroenterology outpatient clinic for ulcerative colitis (UC) and autoimmune hepatitis (AIH). This patient was being treated with low-dose glucocorticoids for AIH (prednisolone 10 mg), with adequate disease control. Additionally, she was being treated with oral salicylates (mesalamine 3 g/day) and oral budesonide (9 mg/day) for her UC. For uncontrolled UC, she was started on VDZ. Two weeks after the first infusion of VDZ, the patient developed a clinical and analytical phenotype compatible with acute hepatitis. Diagnostic workup for causes of hepatocellular liver injury retrieved no results. A liver biopsy corroborated the diagnosis of toxic hepatitis overlapping chronic liver disease. VDZ was withdrawn and the patient experienced complete recovery of liver tests over the following weeks. In this case report, we present the first post-marketing case of hepatocellular liver injury in probable relation to VDZ.
Unusual Case of Posterior Fossa Extradural Hematoma in a Child: Review of the Literature
Authors: Caruso Gerardo , Fiore Patrizia , Gorgoglione Maria Luisa , Ricciardo Giuseppe , Caffo Maria
Published: December 2020

Introduction: Posterior fossa extradural hematoma (PFEH) is a rare pathology often due to nuchal region trauma. In children, PFEH causes rapid decline of the neurological status also for brain stem compression. Early brain computed tomography (CT) scan is necessary suspicious for PFEH. Most patients need surgical evacuation. Case Presentation: In this article, we present a 5-year-old patient arrived for meningitis that came out in favor of PFEH after an accurate history record. Discussion/Conclusion: Accurate anamnestic records, especially in pediatric patients, prevent from misleading clinic and neurological presentation. Brain CT scan is an indispensable diagnostic tool in order to promptly recognize and treat PFEH considering that rapid cognitive impairment of patients raises the risk of mortality and morbidity.
Evaluating the Outcomes of a Hospital-to-Community Model of Integrated Care for Dementia
Authors: Ha Ngoc Huong Lien , Yap Lin Kiat Philip , Nicholas Sean Olivia , Chan Ivana , Wee Shiou Liang
Published: December 2020

Introduction: Living with dementia is challenging for persons with dementia (PWDs) and their families. Although multi-component intervention, underscored by the ethos of person-centred care, has been shown to maintain quality of life (QOL) in PWDs and caregivers, a lack of service integration can hinder effectiveness. Methods: CARITAS, an integrated care initiative provided through a hospital-community care partnership, endeavours to provide person-centred dementia care through ambulatory clinic consults, case management, patient and caregiver engagement, and support. We evaluated CARITAS’ clinical outcomes and cost-effectiveness with a naturalistic cross-sectional within-subject design. We assessed patients’ function, QOL, and behavioural problems post-intervention. We estimated CARITAS’ cost-effectiveness from a patient’s perspective, benchmarking it against other dementia treatments and Singapore’s Gross Domestic Product (GDP) per capita. Results: CARITAS care significantly improved health utility (p < 0.001), reduced caregiver burden (p < 0.001), and improved PWDs’ behavioural problems (p < 0.001) related to “memory” (p < 0.001), “disruption” (p = 0.017), and “depression” (p < 0.001). CARITAS’ benefits (dRMBPC = 0.357, dEQ5D index = 0.328, dZBI = 0.361) were comparable to those of other pharmacological and non-pharmacological interventions for dementia. CARITAS costs SG$133,056.69 per quality-adjusted life years gain, yielding an incremental cost-effectiveness ratio of 1.31 and 1.49 against the cost of donepezil in patients with mild Alz­heimer’s disease and Singapore’s GDP per capita in 2019, respectively, falling within the cost-effectiveness threshold of 1.0–3.0. Discussion: CARITAS integrated dementia care is a cost-effective intervention that showed promising outcomes for PWDs and their caregivers.
Arqueologia, comunidade, ancestralidade e outros assuntos para pensar a identidade quilombola
Authors: Almeida Fabio Guaraldo , Pedroso Michelle Borges , Campos Sílvio
Published: December 2020

O mote da IV Semana Internacional de Arqueologia Discentes MAE/USP girou entorno da pluralização de debates a partir de perspectivas que enfatizassem a preocupação com contextos sociais e culturais marginalizados pelas sociedades, pelos estudos, pelas instituições etc. A periferia se tornou centro e as discussões foram construídas a partir de problemas de sujeitos e contextos esquecidos e apagados. Assim, enfatizamos a importância de falar sobre os que estão às margens, mas mais ainda sobre a importância de deixar que eles mesmos falassem e de criar possibilidades para que suas vozes sejam ouvidas. A mesa "Arqueologias Quilombolas" promoveu o debate entre diferentes perspectivas e a presença de Silvio Campos, junto às demais pesquisadoras, confirma a urgência de repensarmos nossas estruturas universitárias hierárquicas. Nós precisamos promover e valorizar outras formas de produção de conhecimento e perceber que sempre temos muito a ensinar, mas temos muito mais a aprender com os outros. Silvio nos ensinou sobre sua comunidade a partir de suas narrativas, saberes e vivências. Depois de sua participação na mesa conversamos um pouco mais com ele sobre sua vida, sua comunidade e a Arqueologia. A entrevista que se segue apresenta alguns dos pontos por nós discutidos.
Heterogeneity of T Cells in Atherosclerosis Defined by Single-Cell RNA-Sequencing and Cytometry by Time of Flight
Authors: Winkels Holger , Wolf Dennis
Published: December 2020

The infiltration and accumulation of pro- and anti-inflammatory leukocytes within the intimal layer of the arterial wall is a hallmark of developing and progressing atherosclerosis. While traditionally perceived as macrophage- and foam cell-dominated disease, it is now established that atherosclerosis is a partial autoimmune disease that involves the recognition of peptides from ApoB (apolipoprotein B), the core protein of LDL (low-density lipoprotein) cholesterol particles, by CD4
+
T-helper cells and autoantibodies against LDL and ApoB. Autoimmunity in the atherosclerotic plaque has long been understood as a pathogenic T-helper type-1 driven response with proinflammatory cytokine secretion. Recent developments in high-parametric cell immunophenotyping by mass cytometry, single-cell RNA-sequencing, and in tools exploring antigen-specificity have established the existence of several unforeseen layers of T-cell diversity with mixed T
H
1 and T regulatory cells transcriptional programs and unpredicted fates. These findings suggest that pathogenic ApoB-reactive T cells evolve from atheroprotective and immunosuppressive CD4
+
T regulatory cells that lose their protective properties over time. Here, we discuss T-cell heterogeneity in atherosclerosis with a focus on plasticity, antigen-specificity, exhaustion, maturation, tissue residency, and its potential use in clinical prediction.
Circulating Markers of Neutrophil Extracellular Traps Are of Prognostic Value in Patients With COVID-19
Authors: Ng Henry , Havervall Sebastian , Rosell Axel , Aguilera Katherina , Parv Kristel , von Meijenfeldt Fien A. , Lisman Ton , Mackman Nigel , Thålin Charlotte , Phillipson Mia
Published: December 2020

Objective:

The full spectrum of coronavirus disease 2019 (COVID-19) infection ranges from asymptomatic to acute respiratory distress syndrome, characterized by hyperinflammation and thrombotic microangiopathy. The pathogenic mechanisms are poorly understood, but emerging evidence suggest that excessive neutrophil extracellular trap (NET) formation plays a key role in COVID-19 disease progression. Here, we evaluate if circulating markers of NETs are associated with COVID-19 disease severity and clinical outcome, as well as to markers of inflammation and in vivo coagulation and fibrinolysis.

Approach and Results:

One hundred six patients with COVID-19 with moderate to severe disease were enrolled shortly after hospital admission and followed for 4 months. Acute and convalescent plasma samples as well as plasma samples from 30 healthy individuals were assessed for markers of NET formation: citrullinated histone H3, cell-free DNA, NE (neutrophil elastase). We found that all plasma levels of NET markers were elevated in patients with COVID-19 relative to healthy controls, that they were associated with respiratory support requirement and short-term mortality, and declined to those found in healthy individuals 4 months post-infection. The levels of the NET markers also correlated with white blood cells, neutrophils, inflammatory cytokines, and C-reactive protein, as well as to markers of in vivo coagulation, fibrinolysis, and endothelial damage.

Conclusions:

Our findings suggest a role of NETs in COVID-19 disease progression, implicating their contribution to an immunothrombotic state. Further, we observed an association between circulating markers of NET formation and clinical outcome, demonstrating a potential role of NET markers in clinical decision-making, as well as for NETs as targets for novel therapeutic interventions in COVID-19.
NADPH Oxidases Are Required for Full Platelet Activation In Vitro and Thrombosis In Vivo but Dispensable for Plasma Coagulation and Hemostasis
Authors: Vara Dina , Mailer Reiner K. , Tarafdar Anuradha , Wolska Nina , Heestermans Marco , Konrath Sandra , Spaeth Manuela , Renné Thomas , Schröder Katrin , Pula Giordano
Published: December 2020

Objective:

Using 3KO (triple NOX [NADPH oxidase] knockout) mice (ie, NOX1
−/−
/NOX2
−/−
/NOX4
−/−
), we aimed to clarify the role of this family of enzymes in the regulation of platelets in vitro and hemostasis in vivo.

Approach and Results:

3KO mice displayed significantly reduced platelet superoxide radical generation, which was associated with impaired platelet aggregation, adhesion, and thrombus formation in response to the key agonists collagen and thrombin. A comparison with single-gene knockouts suggested that the phenotype of 3KO platelets is the combination of the effects of the genetic deletion of NOX1 and NOX2, while NOX4 does not show any significant function in platelet regulation. 3KO platelets displayed significantly higher levels of cGMP—a negative platelet regulator that activates PKG (protein kinase G). The inhibition of PKG substantially but only partially rescued the defective phenotype of 3KO platelets, which are responsive to both collagen and thrombin in the presence of the PKG inhibitors KT5823 or Rp-8-pCPT-cGMPs, but not in the presence of the NOS (NO synthase) inhibitor L-NG-monomethyl arginine. In vivo, triple NOX deficiency protected against ferric chloride–driven carotid artery thrombosis and experimental pulmonary embolism, while hemostasis tested in a tail-tip transection assay was not affected. Procoagulatory activity of platelets (ie, phosphatidylserine surface exposure) and the coagulation cascade in platelet-free plasma were normal.

Conclusions:

This study indicates that inhibiting NOXs has strong antithrombotic effects partially caused by increased intracellular cGMP but spares hemostasis. NOXs are, therefore, pharmacotherapeutic targets to develop new antithrombotic drugs without bleeding side effects.