bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mdm2 Loss of Heterozygosity Cooperates with Mutant p53 in Acute Myeloid Leukemia
Authors: Pourebrahim Rasoul , Montoya Rafael Heinz , Alaniz Zoe , Ostermann Lauren B , Luong Hung Alex , Khoury Joseph D. , Andreeff Michael 
Published: February 2021

TP53 mutations are observed in 5 to10% of de novo AML cases with dismal disease prognosis and response to therapy. We found that MDM2 loss of heterozygosity (MDM2 LOH) in AML was always concomitant with TP53 missense mutations (log2 odds ratio&gt;3, p&lt;.001), and not TP53 deletions or truncations whereas in lymphomas, MDM2 LOH and TP53 mutations were mutually exclusive. To understand the functional association of MDM2 LOH and TP53 mutation in AML, we generated a conditional somatic Trp53 mutant AML mouse by combining a Trp53R172H mutation with Mdm2 haploinsufficiency in hematopoietic cells using Vav-cre transgenic mice combined with RosamTmG (mTmG) allele as tracing reporter. The conditional mutant Trp53 allele used in this study harbored a R172H mutation downstream of a wildtype Trp53 cDNA flanked by loxP sites (Trp53wm-R172H) so that the expression of the wildtype Trp53 was preserved before the recombination. Mouse cohorts were generated to harbor one Trp53wm-R172H allele and a Trp53fl or were homozygous for the floxed Trp53 allele (Trp53fl/fl). The expression of Cre in hematopoietic stem cells resulted in heterozygous deletion of Mdm2 and conversion of WT Trp53 to Trp53R172, which corresponds to TP53R175H, one of the most frequent mutations in AML. Mice with somatic Trp53 mutation died due to lymphoma, however, Mdm2 haploinsufficient mice combined with Trp53 mutation succumbed to AML. The disease was immunophenotypically and histologically characterized as AML based on the bone marrow histopathology and expression of Cd11b and Ly6A on the surface of leukemic cells. Immunohistopathology of bone marrow and spleen of MdmLOH p53Mut showed a highly proliferative AML characterized by strong nuclear expression of Ki67 and mutant p53 in the bone marrow of mice. Together, our data identifies Mdm2 LOH to be essential for malignant transformation of p53 mutant myeloid lineage leading to AML development.

Disclosures
Andreeff: Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Amgen: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees.
COVID-19 and Hematologic Malignancies: Single Institution Analysis
Authors: Anusim Nwabundo , Smalley Melanie , Zimmer Markie Sue , Lang Doyle , Jindal Vishal , Ahaneku Hycienth O , Gupta Ruby , Franklin Candace , Jaiyesimi Ishmael 
Published: February 2021

Introduction
COVID-19 in patients with hematologic malignancies are poorly characterized. Theoretically, it is believed that patients with malignancies having a significant chance of succumbing to COVID-19 due to the immunosuppression from the disease and myelosuppression from the cancer therapy compared to their counterparts without malignancies. However, there is scant evidence to support this claim. Here we analyze the outcomes of patients with hematologic malignancies and COVID-19.
Methods
This is a retrospective review of all patients with hematologic malignancies with confirmed COVID-19 admitted to any one of the Beaumont hospitals in Michigan between March 1st,2020 and July 1st ,2020. Data regarding the demographics, cancer diagnosis and management, covid-19 management and outcomes were abstracted.
Results
A total of 32 patients with hematologic malignancies were identified. Of these 32 patients, five patients also had solid malignancies. Median age was 70.5 years (22-91 years) with patients being predominantly female 18 (56 %) and Caucasians 16 (50%). Median BMI was 26.5 kg/m2 (15-79 kg/m2).
The most prevalent hematologic malignancies were Chronic/Small Lymphocytic lymphoma 7(25%) and Multiple Myeloma 6(19%). The median length of stay in the hospital was 9 days (2-61days).
Twelve patients were on active therapy prior to COVID-19 diagnosis. Therapies administered include radiation, surgery, anti-CD30 antibody drug conjugate, immunomodulatory agents, proteasome inhibitors, Bruton tyrosine kinase inhibitors, steroids and chemotherapy. These agents were held at the time of diagnosis of COVID-19
Twenty two patients (69%) patients received a combination of hydroxychloroquine and azithromycin which were standard of care at that time. A total of 31 (97%) patients were on anticoagulation of which 14 (45%) were on therapeutic doses while 17 (55%) were on prophylactic dose.
Four (13%) of the patients were admitted in the ICU. A total of 6 deaths were reported and the median age was 83 years (66-91 years). Four deaths were attributed to COVID-19. Two non-COVID-19 deaths were as a result of aspiration pneumonia and hospital acquired pneumonia. Only one patient with COVID-19 received treatment for malignancy (surgical cytoreduction) but succumbed to COVID-19 four days later. All patients who died received a combination of hydroxychloroquine and azithromycin.
Conclusion
Our study, though limited by sample size, shows that about a third of patients received treatment for their hematologic malignancies around the time of COVID-19 diagnosis and only one death was reported. Patients are currently being advised to participate in clinical trials to better evaluate outcomes while on treatment for hematologic malignancies.

Disclosures
No relevant conflicts of interest to declare.
Therapeutic Cancer Vaccination Targeting Shared Tumor Associated Antigens in Combination with Azacitidine for High Risk Myelodysplastic Syndrome - a Phase I Clinical Trial
Authors: Holmberg-Thydén Staffan , Dufva Inge Høgh , Ortved Gang Anne , Fredslund Breinholt Marie , Schejbel Lone , Andersen Mette Klarskov , Kadivar Mohammad , Svane Inge Marie , Grønbæk Kirsten , Reker Hadrup Sine , El Fassi Daniel 
Published: February 2021

Background: Standard care for patients with high risk myelodysplastic syndrome (MDS) is hypomethylating agents, such as azacitidine (AZA). AZA can induce expression of silenced genes, including methylated tumor associated antigens. Such tumor associated antigens may be recognized by T cells, and therefore exploited for immunotherapeutic targeting. To our knowledge, this is the first clinical study that combine hypomethylating agents with a multi-peptide therapeutic cancer vaccine in a hematological malignancy.
Method: In this open label phase 1 trial (ClinicalTrials.gov NCT02750995), we combine AZA with a peptide vaccine targeting antigens encoded from NY-ESO-1, MAGE-A3, PRAME and WT-1, which have previously been demonstrated to be upregulated by AZA treatment. Four long synthetic peptides containing previously described class I and class II epitopes for a variety HLA types was emulsified in Incomplete Freund's Adjuvant for subcutaneous injection. Patients were included following verified treatment response to six courses of AZA monotherapy.
Result: Five patients were included in the study and treated with the vaccine. The combination therapy showed only few adverse events during the study period, whereof none classified as serious. There was one instance of grade 4 toxicity; a case of neutrophil count decrease, requiring administration of prophylactic antibiotics, and two instances of grade 3 toxicity; platelet count decrease and neutrophil count decrease. No vaccine-specific immune response could be detected using intracellular cytokine staining or ELISpot assays, however changes in the phenotypic composition of immune cells and their expression of stimulatory and inhibitory markers were identified in individual patients. All patients progressed to AML with a mean time to progression from inclusion (TTP) of 4.9 months (range 2.8 to 7.6). Survival was 17 months (range 10.9 to 30.6) from MDS diagnosis. Sequencing of bone marrow showed clonal evolution of malignant cells, as well as appearance of novel mutations.
Conclusion: The patients progressed to AML with an average time of only five months after initiating the combination therapy. This may be unrelated to the experimental treatment, but the trial was terminated early as there was no sign of clinical benefit or immunological response.
Figure 1. (a) Trial design. All participants received six courses of AZA prior to inclusion and were evaluated with bone marrow biopsy for treatment response. Vaccination was given together with the next three courses of AZA. (b) Vaccine composition. Synthetic long peptides from NY-ESO-1, PRAME, MAGE-A3 and WT-1 were emulsified in adjuvant Montanide ISA 51.
Figure 1

Disclosures
No relevant conflicts of interest to declare.
Outcomes in Patients with Hematological Malignancies Receiving Anti-CD20 Therapy in the Setting of COVID-19 Infection
Authors: Lopez Carlos A , Chitty David , Chi Jeffrey , Saif Wasif , Goldberg Bradley 
Published: February 2021

Objective: The global COVID-19 pandemic has posed a major challenge for patients with hematological malignancies undergoing treatment. For patients with acute leukemia and aggressive lymphomas, delaying curative chemotherapy treatments has historically been associated with adverse outcomes. In the absence of any quality prospective data, expert recommendation has been to treat when possible. Though earlier studies have reported that cancer patients are at an increased risk for mortality due to COVID-19 when compared to the general population, questions remain unanswered as to how specific agents used to treat malignancies affect the natural history of COVID-19. In particular, the effect of anti-CD20 therapy in patients with lymphoid malignancies remains unexplored in patients who contract COVID-19 during their treatment.
Methods: We conducted a retrospective chart review of patients at our New York-based institution to identify any COVID-19 positive patients that required inpatient treatment for their lymphoid malignancy from December 31st, 2019 to July 31st, 2020. Only patients that had received anti-CD20 therapy (rituximab or obinutuzumab) were included in this study. COVID-19 positivity was determined via a positive PCR-based test (either nasopharyngeal swab or bronchoalveolar lavage).
Results: A total of 13 patients were identified, with primary hematological diagnoses including DLBCL (6), ALL (1), MALT lymphoma (1), follicular lymphoma (2), and chronic lymphocytic leukemia (1). The COVID-19 related mortality rate in this cohort was 46% (6), with the remainder recovering from COVID-19. Of the 7 patients who survived, 2 patients had persistently positive COVID-19 PCR-based testing after clinical recovery, 2 failed to develop detectable IgG anti-COVID-19 antibodies, 1 had not had antibody testing, and 2 had detectable antibodies. Of the 2 patients that developed antibodies after recovery, 1 had undetectable anti-COVID-19 IgG levels 55 days later on subsequent testing.
Conclusions: Patients who are hospitalized with lymphoid malignancies and are requiring anti-CD20 therapy seem to be at increased risk of COVID-19-related mortality. Furthermore, anti-CD20 therapy appears to adversely impact the development of IgG antibodies and appears to be associated with delayed clearance of the virus on PCR-based testing.

Disclosures
Saif: Lexicon: Research Funding; Yivia: Research Funding; NGM Bio.: Research Funding; Nouscom: Research Funding; ITA Group: Other: Teaching Engagement, Travel Compesation; UpToDate: Patents & Royalties: Royalties; Merck Sharp & Dohme Corporation: Honoraria; Incyte: Research Funding.
Pegfilgrastim Versus Filgrastim in the Supportive Care of Heavily Pretreated Multiple Myeloma in Treatment with Pomalidomide-Dexamethasone
Authors: Cerchione Claudio , Catalano Lucio , Nappi Davide , Pareto Anna Emanuele , Musuraca Gerardo , Lucchesi Alessandro , Pane Fabrizio , Martinelli Giovanni 
Published: February 2021

Background
Pegfilgrastim is a pegylated long-acting recombinant form of G-CSF that extends the half-life and allows for once-per-cycle dosing, requiring less frequent dosing than nonpegylated G-CSF.
Aims
The objective of this study was to compare the efficacy and safety of pegfilgrastim in patients affected by heavily pretreated MM, treated with pomalidomide-dexamethasone, in order to determine whether a single subcutaneous injection of pegfilgrastim is as effective as daily injections of standard filgrastim, in terms of haematological toxicity, febrile neutropenic episodes, antibiotic usage and hospedalization duration.
Methods
57 patients (31 M and 26 F) were enrolled, median age at diagnosis 69 years (r. 52-84), and median age at start of treatment 76 years (r.56-90) treated with several lines of treatments (median 7, r. 2-12), every refractory to all the drugs previously received, received Pomalidomide-Dexamethasone (P 4 mg for 21 days, D 40 mg days 1,8,15,22, pegfilgrastim day +8) every 28 days, until progression.
Results
Since first course, received in domestic setting, with a very good compliance, patients performed blood counts once weekly and received, from day +8 to day +19, prophylactic oral chinolonic antibiotics and anti-fungal drugs. During neutropenia after first cycle, Filgrastim (5 μgr/kg/day for 3 days) was given if neutrophils count was &lt;1500 x 10^9 cells/L. Median number of filgrastim administrations was 4.6 (r. 3-6); nadir neutropenia was registered after a median of 10.4 days (r. 7-14); median of nadir neutrophil count was 1.13 x 10^9 cells/L (r.0.3 - 1.5), with maximum duration of 14 days. From the second course, all patients switched to prophylaxis with pegfilgrastim (6 mg), injected subcutaneously with a single administration on day +3 independently from the neutrophil count at that time. During pegfilgrastim, neutropenia was never longer than 8 days, with a consequent reduction of neutropenia-related infections. Median nadir neutrophil count, evaluated for every patients for at least three courses of therapy (r. 3-6) registered at day +11, was 1.28 (r.0.9-2.2). Only 4 patients needed a supplement of 3 administrations of filgrastim. Pegfilgrastim was well tolerated in all patients: main side effects in our patients were mild fever and bone pain (21.2%).
Conclusions
In patients affected by heavily pretreated MM treated with pomalidomide-dexamethasone, pegfilgrastim seems to reduce the incidence of severe neutropenia and infections and may increase the possibility to maintain the scheduled time of treatment.

Disclosures
Lucchesi: Novartis: Honoraria; Incyte: Honoraria; Pfizer: Honoraria.
Validating a Novel Framework to Classify Inpatient Hematology Consultation Requests
Authors: Patell Rushad , Forbath Natalia , Dodge Laura , Carney Brian J. , Cool Josephine , Persaud Brian , Ricotta Daniel N , Hale Andrew J , Freed Jason A 
Published: February 2021

Background:
Consistent classification of consult requests may lead to more productive, efficient, and collegial conversations about patient care, which can facilitate improved work satisfaction and an enhanced learning environment. We propose an organizing framework of 7 specific consultation types: ideal, obligatory, procedural, S.O.S., confirmatory, inappropriate, and curbside. We aimed to obtain validity evidence for this rubric to consistently classify consultation requests in an academic setting.
Methods:
A random sample of 100 de-identified hematology oncology consultation requests made through the online consult portal from a single academic center were selected and independently coded as 1 of the 7 consultation types by 3 hematologists and 3 hospitalists. Perfect (same consult assignment by all coders) and partial (same consult assignment by &gt;4/6 coders) concordance was calculated. Perfect and partial (&gt;2/3 coders) inter-rater concordance based on consult subtypes and provider specialty was also calculated. To assess if length of consult request has an impact on the classification of consult, the length of the request was compared across concordant, partially concordant, and discordant requests.
Results:
Of the 100 consults, perfect concordance was 57%, and partial concordance was 92% (Figure 1). Perfect concordance was 69% amongst hematologists and 78% amongst hospitalists. In cases without perfect concordance (n=43), hematologists agreed with each other 76% of the time, while hospitalists agreed with each other 81% of the time. Of the consults that at least 4 coders classified in the same way, hospitalists were more likely than hematologists to have perfect concordance for ideal consults (89% vs. 66%, respectively; P=0.001) but less likely to have perfect concordance for S.O.S consults (56% vs. 100%, respectively; P=0.003). Hematologists were twice more likely than hospitalists to classify a consult request as S.O.S (26.7% vs. 12.3%, P&lt;0.001), while a greater proportion of hospitalists classified consults as ideal (74% vs. 61%, P=0.007). There was no significant difference in the word count of requests that were perfectly concordant (68+35), partially concordant (65+51), or discordant (39+22) (P=0.18).
Conclusion:
Hematology oncology consult requests can be classified into a novel rubric of 7 specific subtypes. Overall, partial concordance between primary providers and consultants was high, and perfect concordance was moderate. Hematologists were more likely to classify consult requests as S.O.S (without specific questions) than primary providers. Opportunities exist to utilize the rubric to improve communication between health care providers and to improve the medical education of trainees.

Disclosures
No relevant conflicts of interest to declare.
A zebrafish model of granulin deficiency reveals essential roles in myeloid cell differentiation
Authors: Campbell Clyde A. , Fursova Oksana , Cheng Xiaoyi , Snella Elizabeth , McCune Abbigail , Li Liangdao , Solchenberger Barbara , Schmid Bettina , Sahoo Debashis , Morton Mark , Traver David , Espín-Palazón Raquel 
Published: February 2021

AbstractGranulin is a pleiotropic protein involved in inflammation, wound healing, neurodegenerative disease, and tumorigenesis. These roles in human health have prompted research efforts to use granulin to treat rheumatoid arthritis and frontotemporal dementia and to enhance wound healing. But how granulin contributes to each of these diverse biological functions remains largely unknown. Here, we have uncovered a new role for granulin during myeloid cell differentiation. We have taken advantage of the tissue-specific segregation of the zebrafish granulin paralogues to assess the functional role of granulin in hematopoiesis without perturbing other tissues. By using our zebrafish model of granulin deficiency, we revealed that during normal and emergency myelopoiesis, myeloid progenitors are unable to terminally differentiate into neutrophils and macrophages in the absence of granulin a (grna), failing to express the myeloid-specific genes cebpa, rgs2, lyz, mpx, mpeg1, mfap4, and apoeb. Functionally, macrophages fail to recruit to the wound, resulting in abnormal healing. Our CUT&RUN experiments identify Pu.1, which together with Irf8, positively regulates grna expression. In vivo imaging and RNA sequencing experiments show that grna inhibits the expression of gata1, leading to the repression of the erythroid program. Importantly, we demonstrated functional conservation between the mammalian granulin and the zebrafish ortholog grna. Our findings uncover a previously unrecognized role for granulin during myeloid cell differentiation, which opens a new field of study that can potentially have an impact on different aspects of human health and expand the therapeutic options for treating myeloid disorders such as neutropenia or myeloid leukemia.
PML-controlled responses in severe congenital neutropenia withELANE-misfolding mutations
Authors: Olofsen Patricia A. , Bosch Dennis A. , Roovers Onno , van Strien Paulina M. H. , de Looper Hans W. J. , Hoogenboezem Remco M. , Barnhoorn Sander , Mastroberardino Pier G. , Ghazvini Mehrnaz , van der Velden Vincent H. J. , Bindels Eric M. J. , de Pater Emma M. , Touw Ivo P. 
Published: February 2021

AbstractMutations in ELANE cause severe congenital neutropenia (SCN), but how they affect neutrophil production and contribute to leukemia predisposition is unknown. Neutropenia is alleviated by CSF3 (granulocyte colony-stimulating factor) therapy in most cases, but dose requirements vary between patients. Here, we show that CD34+CD45+ hematopoietic progenitor cells (HPCs) derived from induced pluripotent stem cell lines from patients with SCN that have mutations in ELANE (n = 2) or HAX1 (n = 1) display elevated levels of reactive oxygen species (ROS) relative to normal iPSC-derived HPCs. In patients with ELANE mutations causing misfolding of the neutrophil elastase (NE) protein, HPCs contained elevated numbers of promyelocyte leukemia protein nuclear bodies, a hallmark of acute oxidative stress. This was confirmed in primary bone marrow cells from 3 additional patients with ELANE-mutant SCN. Apart from responding to elevated ROS levels, PML controlled the metabolic state of these ELANE-mutant HPCs as well as the expression of ELANE, suggestive of a feed-forward mechanism of disease development. Both PML deletion and correction of the ELANE mutation restored CSF3 responses of these ELANE-mutant HPCs. These findings suggest that PML plays a crucial role in the disease course of ELANE-SCN characterized by NE misfolding, with potential implications for CSF3 therapy.
Influence of height on endothelial maintenance activity: a narrative review
Authors: Shimizu Yuji , Maeda Takahiro 
Published: February 2021

AbstractRecent studies have revealed an inverse association between height and cardiovascular disease. However, the background mechanism of this association has not yet been clarified. Height has also been reported to be positively associated with cancer. Therefore, well-known cardiovascular risk factors, such as increased oxidative stress and chronic inflammation, are not the best explanations for this inverse association because these risk factors are also related to cancer. However, impaired blood flow is the main pathological problem in cardiovascular disease, while glowing feeding vessels (angiogenesis) are the main characteristic of cancer pathologies. Therefore, endothelial maintenance activity, especially for the productivity of hematopoietic stem cells such as CD34-positive cells, could be associated with the height of an individual because this cell contributes not only to the progression of atherosclerosis but also to the development of angiogenesis. In addition, recent studies have also revealed a close connection between bone marrow activity and endothelial maintenance; bone marrow-derived hematopoietic stem cells contribute towards endothelial maintenance. Since the absolute volume of bone marrow is positively associated with height, height could influence endothelial maintenance activity. Based on these hypotheses, we performed several studies. The aim of this review is not only to discuss the association between height and bone marrow activity, but also to describe the potential mechanism underlying endothelial maintenance. In addition, this review also aims to explain some of the reasons that implicate hypertension as a major risk factor for stroke among the Japanese population. The review also aims to clarify the anthropological reasons behind the high risk of atherosclerosis progression in Japanese individuals with acquired genetic characteristics.