Publications by authors named "Maria Teresa Voso"

156 Publications

Increased Plasma Levels of lncRNAs , and Correlate with Negative Prognostic Factors in Myelofibrosis.

Cancers (Basel) 2021 Sep 22;13(19). Epub 2021 Sep 22.

Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Policlinico, 41124 Modena, Italy.

Long non-coding RNAs (lncRNAs) have been recently described as key mediators in the development of hematological malignancies. In the last years, circulating lncRNAs have been proposed as a new class of non-invasive biomarkers for cancer diagnosis and prognosis and to predict treatment response. The present study is aimed to investigate the potential of circulating lncRNAs as non-invasive prognostic biomarkers in myelofibrosis (MF), the most severe among Philadelphia-negative myeloproliferative neoplasms. We detected increased levels of seven circulating lncRNAs in plasma samples of MF patients ( = 143), compared to healthy controls ( = 65). Among these, high levels of , or correlate with detrimental clinical variables, such as high count of leukocytes and CD34+ cells, severe grade of bone marrow fibrosis and presence of splenomegaly. Strikingly, high plasma levels of = 0.0018) ( = 0.0008) or ( = 0.0348) are also associated with a poor overall-survival while high levels of correlate with a shorter leukemia-free-survival. Finally, multivariate analysis demonstrated that the plasma level of is an independent prognostic variable, suggesting that, if confirmed in future in an independent patients' cohort, it could be used for further studies to design an updated classification model for MF patients.
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http://dx.doi.org/10.3390/cancers13194744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507546PMC
September 2021

New insight into the catalytic -dependent and -independent roles of METTL3 in sustaining aberrant translation in chronic myeloid leukemia.

Cell Death Dis 2021 Sep 24;12(10):870. Epub 2021 Sep 24.

Department of Biology and Biotechnology 'Charles Darwin', Sapienza University of Rome, Rome, Italy.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by the presence of tyrosine kinase BCR-ABL1 fusion protein, which deregulate transcription and mRNA translation. Tyrosine kinase inhibitors (TKIs) are the first-choice treatment. However, resistance to TKIs remains a challenge to cure CML patients. Here, we reveal that the mA methyltransferase complex METTL3/METTL14 is upregulated in CML patients and that is required for proliferation of primary CML cells and CML cell lines sensitive and resistant to the TKI imatinib. We demonstrate that depletion of METTL3 strongly impairs global translation efficiency. In particular, our data show that METTL3 is crucial for the expression of genes involved in ribosome biogenesis and translation. Specifically, we found that METTL3 directly regulates the level of PES1 protein identified as an oncogene in several tumors. We propose a model in which nuclear METTL3/METTL14 methyltransferase complex modified nascent transcripts whose translation is enhanced by cytoplasmic localization of METTL3, independently from its catalytic activity. In conclusion, our results point to METTL3 as a novel relevant oncogene in CML and as a promising therapeutic target for TKI resistant CML.
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http://dx.doi.org/10.1038/s41419-021-04169-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463696PMC
September 2021

Long-Term Quality of Life of Acute Promyelocytic Leukemia Patients Treated with Arsenic Trioxide versus Chemotherapy.

Blood Adv 2021 Sep 16. Epub 2021 Sep 16.

"Sapienza" University, Roma, Italy.

The main objective of this study was to compare the long-term health-related quality of life of patients with acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) versus ATRA plus standard chemotherapy. Patients previously enrolled in the randomized controlled trial APL0406 were considered eligible for this follow-up study. The following patient-reported outcome measures were used: the EORTC QLQ-C30, the EORTC QLQ-CIPN20 and the SF-36. The prevalence of late comorbidities and health problems was also assessed. The clinical significance of differences was evaluated based on predefined thresholds. This study was registered at ClinicalTrials.gov (NCT03096496). One hundred sixty-one out of 232 potentially eligible patients were analyzed, of whom 83 were treated with ATRA-ATO and 78 were treated with ATRA-chemotherapy. The median time since diagnosis of the study sample was 8 years. The two largest clinically meaningful differences in the EORTC QLQ-C30 were observed for role functioning (Δ=8.4, 95% CI, 0.5 to 16.3) and dyspnea (Δ=-8.5, 95% CI, -16.4 to -0.7), favoring patients treated with ATRA-ATO. With regard to the SF-36 results, a clinically relevant better physical component score (Δ=4.6, 95% CI, 1.3 to 7.8) was observed in patients treated with ATRA-ATO, but this was not the case for the mental component score. The two groups showed similar profiles in the scores of the EORTC QLQ-CIPN20 scales and in the prevalence of late comorbidities. Overall, our findings suggest that the greater and more sustained antileukemic efficacy of ATRA-ATO is also associated with better long-term patient-reported outcomes than ATRA-chemotherapy.
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http://dx.doi.org/10.1182/bloodadvances.2021004649DOI Listing
September 2021

A Relapsing Meningeal Acute Myeloid Leukaemia FLT3-ITD+ Responding to Gilteritinib.

Chemotherapy 2021 24;66(4):134-138. Epub 2021 Aug 24.

Hematology, Polo Universitario Pontino, S.M. Goretti Hospital, Latina, Italy.

A patient with a therapy-related acute myeloid leukaemia (AML), NPM1mut, and FLT3-ITD+ was treated with induction and consolidation with CPX-351, obtaining a complete response (CR) but minimal residual disease persisted positive. Later, she complained progressive burning leg pain, weakening of the right hand and leg muscles, associated with absence of osteotendinous leg reflexes. Examination of cerebrospinal fluid (CSF) showed a meningeal relapse of AML. Moreover, a magnetic resonance imaging (MRI) showed 2 right meningeal implants of myeloid sarcoma and bone marrow revealed haematologic relapse of disease. She was treated with medicated lumbar punctures (LPs) followed by an FLA-Ida scheme, and she achieved a 2nd CR. Unfortunately, the patient developed hyperleucocytosis and reappearance of meningeal myeloid sarcoma at MRI. For this reason, a monotherapy with gilteritinib (an FLT3 inhibitor) was started: after 3 months of therapy, central nervous system (CNS)-disease shrunken and then faded, while AML in the bone marrow achieved only a partial response. This is the 1st report of a positive biological effect of gilteritinib on CNS (meningeal) myeloid sarcoma. There are no studies of gilteritinib concentration into CSF and penetration of gilteritinib into the blood-brain barrier should be further studied, given the paucity of drugs active on CNS relapse of AML. In patients receiving CPX-351 only, diagnostic LP should be considered after induction.
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http://dx.doi.org/10.1159/000518356DOI Listing
August 2021

Acute promyelocytic leukemia (APL) in very old patients: real-life behind protocols.

Acta Oncol 2021 Nov 30;60(11):1520-1526. Epub 2021 Aug 30.

Department of Translational and Precision Medicine, Sapienza University, Rome, Italy.

Background: Acute promyelocytic leukemia (APL) is uncommon among subjects aged ≥ 70 years and the better therapeutic strategy represents an unmet clinical need.

Materials And Methods: This prompted us to explore our real-life data on a retrospective cohort of 45 older APL patients (≥ 70 years) consecutively diagnosed at eight different hematologic institutions in Latium, Italy, from July 1991 to May 2019.

Results: Two patients (4.4%) died from early hemorrhagic complications before treatment could begin. Twenty-two patients (51.1%) (Group A) were enrolled or treated according to standard clinical protocols, while 21 (48.8%) (Group B) received an ATRA-based personalized approach due to poor performance status. Morphologic complete remission (CR) after induction therapy was achieved in 33 patients (76.7%) with 100% of patients in Group A and 52.3% in Group B ( < 0.001). Molecular CR was documented in 30 patients (69.7%) [20/22 (90.9%) in Group A and 10/21 (47.6%) in Group B ( = 0.002)]. Ten patients (23.2%) died during induction therapy, all in Group B. Five-year overall survival (OS) of the entire cohort was 46.1% (95% CI 28.2-64.0), with 72.6% (95% CI 42.9-100) in Group A vs. 27.2% (95% CI 7.5-46.9) in the Group B ( = 0.001).

Conclusions: The present analysis highlights that almost half of the patients received sub-optimal induction treatments and registered dismal outcomes demonstrating the importance of adopting standard therapies instead of modified or reduced personalized approaches also in the setting of frail older patients.
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http://dx.doi.org/10.1080/0284186X.2021.1971291DOI Listing
November 2021

Molecular landscape and prognostic impact of FLT3-ITD insertion site in acute myeloid leukemia: RATIFY study results.

Leukemia 2021 Jul 28. Epub 2021 Jul 28.

Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.

In acute myeloid leukemia (AML) internal tandem duplications of the FLT3 gene (FLT3-ITD) are associated with poor prognosis. Retrospectively, we investigated the prognostic and predictive impact of FLT3-ITD insertion site (IS) in 452 patients randomized within the RATIFY trial, which evaluated midostaurin additionally to intensive chemotherapy. Next-generation sequencing identified 908 ITDs, with 643 IS in the juxtamembrane domain (JMD) and 265 IS in the tyrosine kinase domain-1 (TKD1). According to IS, patients were categorized as JMDsole (n = 251, 55%), JMD and TKD1 (JMD/TKD1; n = 117, 26%), and TKD1sole (n = 84, 19%). While clinical variables did not differ among the 3 groups, NPM1 mutation was correlated with JMDsole (P = 0.028). Overall survival (OS) differed significantly, with estimated 4-year OS probabilities of 0.44, 0.50, and 0.30 for JMDsole, JMD/TKD1, and TKD1sole, respectively (P = 0.032). Multivariate (cause-specific) Cox models for OS and cumulative incidence of relapse using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable identified TKD1sole as unfavorable and HCT as favorable factors. In addition, Midostaurin exerted a significant benefit only for JMDsole. Our results confirm the distinct molecular heterogeneity of FLT3-ITD and the negative prognostic impact of TKD1 IS in AML that was not overcome by midostaurin.
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http://dx.doi.org/10.1038/s41375-021-01323-0DOI Listing
July 2021

Case Report: Very Late, Atypical Extra-Medullary Relapse in a Patient With Acute Promyelocytic Leukemia (APL) Rescued With a Transplant-Free Approach.

Front Oncol 2021 29;11:699886. Epub 2021 Jun 29.

Haematology Unit, St. Eugenio Hospital, Rome, Italy.

Relapses of acute promyelocytic leukemia (APL) beyond 7 years from the first molecular remission are exceptional, and it is unclear whether these relapses represent a new, therapy-related leukemia rather than a delayed relapse of the original leukemic clone. The increase extra-medullary relapses (ER) in the era of all-trans retinoic acid (ATRA) therapy suggests a potential correlation between ATRA therapy and ER, and several potential explanations have been proposed. The gold standard post-remission approach, particularly for patients in late relapse, has not yet been established. The benefit of a transplant approach has been questioned in this setting because continuing ATRA-arsenic trioxide (ATO) might be curative. Here we report on the case of an APL patient who relapsed 9 years after achieving her first molecular complete remission (mCR) and who showed an atypical isolated localization at nodal sites, including the into- and peri-parotid glands. Genomic breakpoint analysis detected the same bcr3 hybrid gene in DNA purified from bone marrow and lymph nodes, suggesting that the relapse was because of the reemergence of the initial clone. This case shows that APL, treated with ATRA and cytotoxic drugs, may still emerge in extra-medullary sites even after a very prolonged mCR and could be salvaged with an ATO-based protocol, not including a transplant approach.
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http://dx.doi.org/10.3389/fonc.2021.699886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276173PMC
June 2021

AMELIORATE: early intensification in -mutated acute myeloid leukemia based on peripheral blast clearance - MYNERVA-GIMEMA AML1919 trial.

Future Oncol 2021 Oct 13;17(29):3787-3796. Epub 2021 Jul 13.

SOD Ematologia, AOU Careggi, Firenze 50134, Italy.

AMELIORATE is a Phase III, randomized trial aiming to personalize treatment intensity in -mutated acute myeloid leukemia. The current study provides an early appraisal of chemosensitivity based on peripheral blasts clearance, as assessed by multiparameter flow cytometry, from baseline to day 4 of induction. This biomarker was previously demonstrated to predict complete remission achievement and measurable residual disease status. For patients experiencing low peripheral blast cells (i.e., ≤2.0 logs), two major adjustments of treatment as compared with current standard of care are envisioned in the experimental arm: the immediate switch to intensified induction with high-doses cytarabine (1500 mg/m b.i.d. on days 5-7 of induction); and the early allocation of the patient to high-risk disease category, to be further refined later based on postinduction measurable residual disease status.
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http://dx.doi.org/10.2217/fon-2021-0388DOI Listing
October 2021

Baseline T-lymphocyte subset absolute counts can predict both outcome and severity in SARS-CoV-2 infected patients: a single center study.

Sci Rep 2021 06 17;11(1):12762. Epub 2021 Jun 17.

Department of System Medicine, Tor Vergata University, Via Montpellier 1, 00133, Rome, Italy.

The aim of this study was to evaluate the role of baseline lymphocyte subset counts in predicting the outcome and severity of COVID-19 patients. Hospitalized patients confirmed to be infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) were included and classified according to in-hospital mortality (survivors/nonsurvivors) and the maximal oxygen support/ventilation supply required (nonsevere/severe). Demographics, clinical and laboratory data, and peripheral blood lymphocyte subsets were retrospectively analyzed. Overall, 160 patients were retrospectively included in the study. T-lymphocyte subset (total CD3+, CD3+ CD4+, CD3+ CD8+, CD3+ CD4+ CD8+ double positive [DP] and CD3+ CD4- CD8- double negative [DN]) absolute counts were decreased in nonsurvivors and in patients with severe disease compared to survivors and nonsevere patients (p < 0.001). Multivariable logistic regression analysis showed that absolute counts of CD3+ T-lymphocytes < 524 cells/µl, CD3+ CD4+ < 369 cells/µl, and the number of T-lymphocyte subsets below the cutoff (T-lymphocyte subset index [TLSI]) were independent predictors of in-hospital mortality. Baseline T-lymphocyte subset counts and TLSI were also predictive of disease severity (CD3+  < 733 cells/µl; CD3+ CD4+ < 426 cells/µl; CD3+ CD8+ < 262 cells/µl; CD3+ DP < 4.5 cells/µl; CD3+ DN < 18.5 cells/µl). The evaluation of peripheral T-lymphocyte absolute counts in the early stages of COVID-19 might represent a useful tool for identifying patients at increased risk of unfavorable outcomes.
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http://dx.doi.org/10.1038/s41598-021-90983-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211786PMC
June 2021

Mutational profile of ZBTB16-RARA-positive acute myeloid leukemia.

Cancer Med 2021 06 27;10(12):3839-3847. Epub 2021 May 27.

Department of Biomedicine and Prevention, University Tor Vergata Rome, Rome, Italy.

Background: The ZBTB16-RARA fusion gene, resulting from the reciprocal translocation between ZBTB16 on chromosome 11 and RARA genes on chromosome 17 [t(11;17)(q23;q21)], is rarely observed in acute myeloid leukemia (AML), and accounts for about 1% of retinoic acid receptor-α (RARA) rearrangements. AML with this rare translocation shows unusual bone marrow (BM) morphology, with intermediate aspects between acute promyelocytic leukemia (APL) and AML with maturation. Patients may have a high incidence of disseminated intravascular coagulation at diagnosis, are poorly responsive to all-trans retinoic acid (ATRA) and arsenic tryoxyde, and are reported to have an overall poor prognosis.

Aims: The mutational profile of ZBTB16-RARA rearranged AML has not been described so far.

Materials And Methods: We performed targeted next-generation sequencing of 24 myeloid genes in BM diagnostic samples from seven ZBTB16-RARA+AML, 103 non-RARA rearranged AML, and 46 APL. The seven ZBTB16-RARA-positive patients were then screened for additional mutations using whole exome sequencing (n = 3) or an extended cancer panel including 409 genes (n = 4).

Results: ZBTB16-RARA+AML showed an intermediate number of mutations per patient and involvement of different genes, as compared to APL and other AMLs. In particular, we found a high incidence of ARID1A mutations in ZBTB16-RARA+AML (five of seven cases, 71%). Mutations in ARID2 and SMARCA4, other tumor suppressor genes also belonging to SWI/SNF chromatin remodeling complexes, were also identified in one case (14%).

Discussion And Conclusion: Our data suggest the association of mutations of the ARID1A gene and of the other members of the SWI/SNF chromatin remodeling complexes with ZBTB16-RARA+AMLs, where they may support the peculiar disease phenotype.
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http://dx.doi.org/10.1002/cam4.3904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209618PMC
June 2021

Myeloid lncRNA LOUP mediates opposing regulatory effects of RUNX1 and RUNX1-ETO in t(8;21) AML.

Blood 2021 Oct;138(15):1331-1344

Harvard Medical School Initiative for RNA Medicine, Harvard Medical School, Boston, MA.

The mechanism underlying cell type-specific gene induction conferred by ubiquitous transcription factors as well as disruptions caused by their chimeric derivatives in leukemia is not well understood. Here, we investigate whether RNAs coordinate with transcription factors to drive myeloid gene transcription. In an integrated genome-wide approach surveying for gene loci exhibiting concurrent RNA and DNA interactions with the broadly expressed Runt-related transcription factor 1 (RUNX1), we identified the long noncoding RNA (lncRNA) originating from the upstream regulatory element of PU.1 (LOUP). This myeloid-specific and polyadenylated lncRNA induces myeloid differentiation and inhibits cell growth, acting as a transcriptional inducer of the myeloid master regulator PU.1. Mechanistically, LOUP recruits RUNX1 to both the PU.1 enhancer and the promoter, leading to the formation of an active chromatin loop. In t(8;21) acute myeloid leukemia (AML), wherein RUNX1 is fused to ETO, the resulting oncogenic fusion protein, RUNX1-ETO, limits chromatin accessibility at the LOUP locus, causing inhibition of LOUP and PU.1 expression. These findings highlight the important role of the interplay between cell-type-specific RNAs and transcription factors, as well as their oncogenic derivatives in modulating lineage-gene activation and raise the possibility that RNA regulators of transcription factors represent alternative targets for therapeutic development.
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http://dx.doi.org/10.1182/blood.2020007920DOI Listing
October 2021

What's new in the pathogenesis and treatment of therapy-related myeloid neoplasms.

Blood 2021 Sep;138(9):749-757

Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy; and.

Therapy-related myeloid neoplasms (t-MNs) include diseases onsetting in patients treated with chemo- and/or radiotherapy for a primary cancer, or an autoimmune disorder. Genomic variants, in particular, in familial cancer genes, may play a predisposing role. Recent advances in deep sequencing techniques have shed light on the pathogenesis of t-MNs, identifying clonal hematopoiesis of indeterminate potential (CHIP) as a frequent first step in the multihit model of t-MNs. CHIP is often detectable prior to any cytotoxic treatment, probably setting the fertile genomic background for secondary leukemogenesis. The evolution pattern toward t-MNs is then a complex process, shaped by the type of cancer therapy, the aging process, and the individual exposures, that favor additional hits, such as the acquisition of TP53 mutations and unfavorable karyotype abnormalities. The pathogenesis of t-MNs differs from MN associated with environmental exposure. Indeed, the genetic aberration patterns of MN developing in atomic bomb survivors show few mutations in classical DNA methylation genes, and a high prevalence of 11q and ATM alterations, together with TP53 mutations. Survival in t-MNs is poor. In addition to the biology of t-MNs, the patient's previous disease history and the remission status at t-MN diagnosis are significant factors contributing to unfavorable outcome. New drugs active in secondary leukemias include CPX-351, or venetoclax in combination with hypomethylating agents, monoclonal antibodies as magrolimab, or targeted drugs against pathogenic mutations. Allogeneic stem cell transplantation remains the best currently available therapeutic option with curative intent for fit patients with unfavorable genetic profiles.
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http://dx.doi.org/10.1182/blood.2021010764DOI Listing
September 2021

Poly(ADP-Ribose) Polymerase Inhibitors for Arsenic Trioxide-Resistant Acute Promyelocytic Leukemia: Synergistic In Vitro Antitumor Effects with Hypomethylating Agents or High-Dose Vitamin C.

J Pharmacol Exp Ther 2021 Jun 5;377(3):385-397. Epub 2021 Apr 5.

Pharmacology Section, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy (M.G., A.D.G., S.P.P., T.K., G.G., I.F.); Department of Physiology and Pharmacology "V. Erspamer," Sapienza University of Rome, Rome, Italy (M.G.); Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy (T.O., M.D., M.T.V.); Unit of Neuro-Oncohematology, Santa Lucia Foundation-IRCCS, Rome, Italy (T.O., M.T.V.); and IRCCS San Raffaele Pisana, Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy (F.C.)

Arsenic trioxide (ATO) is an anticancer agent used for the treatment ofacute promyelocytic leukemia (APL). However, 5%-10% of patients fail to respond or experience disease relapse. Based on poly(ADP-ribose) polymerase (PARP) 1 involvement in the processing of DNA demethylation, here we have tested the in vitro susceptibility of ATO-resistant clones (derived from the human APL cell line NB4) to PARP inhibitors (PARPi) in combination with hypomethylating agents (azacitidine and decitabine) or high-dose vitamin C (ascorbate), which induces 5-hydroxymethylcytosine (5hmC)-mediated DNA demethylation. ATO-sensitive and -resistant APL cell clones were generated and initially analyzed for their susceptibility to five clinically used PARPi (olaparib, niraparib, rucaparib, veliparib, and talazoparib). The obtained PARPi IC values were far below (olaparib and niraparib), within the range (talazoparib), or above (rucaparib and veliparib) the reported in patients, likely as a result of differences in the mechanisms of their cytotoxic activity. ATO-resistant APL cells were also susceptible to clinically relevant concentrations of azacitidine and decitabine and to high-dose ascorbate. Interestingly, the combination of these agents with olaparib, niraparib, or talazoparib resulted in synergistic antitumor activity. In combination with ascorbate, PARPi increased the ascorbate-mediated induction of 5hmC, which likely resulted in stalled DNA repair and cytotoxicity. Talazoparib was the most effective PARPi in synergizing with ascorbate, in accordance with its marked ability to trap PARP1 at damaged DNA. These findings suggest that ATO and PARPi have nonoverlapping resistance mechanisms and support further investigation on PARPi combination with hypomethylating agents or high-dose ascorbate for relapsed/ATO-refractory APL, especially in frail patients. SIGNIFICANCE STATEMENT: This study found that poly(ADP-ribose) inhibitors (PARPi) show activity as single agents against human acute promyelocytic leukemia cells resistant to arsenic trioxide at clinically relevant concentrations. Furthermore, PARPi enhance the in vitro efficacy of azacitidine, decitabine, and high-dose vitamin C, all agents that alter DNA methylation. In combination with vitamin C, PARPi increase the levels of 5-hydroxymethylcytosine, likely as a result of altered processing of the oxidized intermediates associated with DNA demethylation.
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http://dx.doi.org/10.1124/jpet.121.000537DOI Listing
June 2021

Use of Measurable Residual Disease to Evolve Transplant Policy in Acute Myeloid Leukemia: A 20-Year Monocentric Observation.

Cancers (Basel) 2021 Mar 3;13(5). Epub 2021 Mar 3.

Department of Biomedicine and Prevention, University Tor Vergata of Roma, 00133 Rome, Italy.

Measurable residual disease (MRD) is increasingly employed as a biomarker of quality of complete remission (CR) in intensively treated acute myeloid leukemia (AML) patients. We evaluated if a MRD-driven transplant policy improved outcome as compared to a policy solely relying on a familiar donor availability. High-risk patients (adverse karyotype, FLT3-ITD) received allogeneic hematopoietic cell transplant (alloHCT) whereas for intermediate and low risk ones (CBF-AML and NPM1-mutated), alloHCT or autologous SCT was delivered depending on the post-consolidation measurable residual disease (MRD) status, as assessed by flow cytometry. For comparison, we analyzed a matched historical cohort of patients in whom alloHCT was delivered based on the sole availability of a matched sibling donor. Ten-years overall and disease-free survival were longer in the MRD-driven cohort as compared to the historical cohort (47.7% vs. 28.7%, = 0.012 and 42.0% vs. 19.5%, = 0.0003). The favorable impact of this MRD-driven strategy was evident for the intermediate-risk category, particularly for MRD positive patients. In the low-risk category, the significantly lower CIR of the MRD-driven cohort did not translate into a survival advantage. In conclusion, a MRD-driven transplant allocation may play a better role than the one based on the simple donor availability. This approach determines a superior outcome of intermediate-risk patients whereat in low-risk ones a careful evaluation is needed for transplant allocation.
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http://dx.doi.org/10.3390/cancers13051083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959451PMC
March 2021

Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603/RATIFY trial.

Leukemia 2021 09 2;35(9):2539-2551. Epub 2021 Mar 2.

Novartis Pharma AG, Basel, Switzerland.

The prospective randomized, placebo-controlled CALGB 10603/RATIFY trial (Alliance) demonstrated a statistically significant overall survival benefit from the addition of midostaurin to standard frontline chemotherapy in a genotypically-defined subgroup of 717 patients with FLT3-mutant acute myeloid leukemia (AML). The risk of death was reduced by 22% on the midostaurin-containing arm. In this post hoc analysis, we analyzed the cumulative incidence of relapse (CIR) on this study and also evaluated the impact of 12 4-week cycles of maintenance therapy. CIR analyses treated relapses and AML deaths as events, deaths from other causes as competing risks, and survivors in remission were censored. CIR was improved on the midostaurin arm (HR = 0.71 (95% CI, 0.54-0.93); p = 0.01), both overall and within European LeukemiaNet 2017 risk classification subsets when post-transplant events were considered in the analysis as events. However, when transplantation was considered as a competing risk, there was overall no significant difference between the risks of relapse on the two randomized arms. Patients still in remission after consolidation with high-dose cytarabine entered the maintenance phase, continuing with either midostaurin or placebo. Analyses were inconclusive in quantifying the impact of the maintenance phase on the overall outcome. In summary, midostaurin reduces the CIR.
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http://dx.doi.org/10.1038/s41375-021-01179-4DOI Listing
September 2021

Targeting Lactate Metabolism by Inhibiting MCT1 or MCT4 Impairs Leukemic Cell Proliferation, Induces Two Different Related Death-Pathways and Increases Chemotherapeutic Sensitivity of Acute Myeloid Leukemia Cells.

Front Oncol 2020 5;10:621458. Epub 2021 Feb 5.

National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy.

Metabolism in acute myeloid leukemia (AML) cells is dependent primarily on oxidative phosphorylation. However, in order to sustain their high proliferation rate and metabolic demand, leukemic blasts use a number of metabolic strategies, including glycolytic metabolism. Understanding whether monocarboxylate transporters MCT1 and MCT4, which remove the excess of lactate produced by cancer cells, represent new hematological targets, and whether their respective inhibitors, AR-C155858 and syrosingopine, can be useful in leukemia therapy, may reveal a novel treatment strategy for patients with AML. We analyzed MCT1 and MCT4 expression and function in hematopoietic progenitor cells from healthy cord blood, in several leukemic cell lines and in primary leukemic blasts from patients with AML, and investigated the effects of AR-C155858 and syrosingopine, used alone or in combination with arabinosylcytosine, on leukemic cell proliferation. We found an inverse correlation between MCT1 and MCT4 expression levels in leukemic cells, and showed that MCT4 overexpression is associated with poor prognosis in AML patients. We also found that AR-C155858 and syrosingopine inhibit leukemic cell proliferation by activating two different cell-death related pathways, i.e., necrosis for AR-C155858 treatment and autophagy for syrosingopine, and showed that AR-C155858 and syrosingopine exert an anti-proliferative effect, additive to chemotherapy, by enhancing leukemic cells sensitivity to chemotherapeutic agents. Altogether, our study shows that inhibition of MCT1 or MCT4 impairs leukemic cell proliferation, suggesting that targeting lactate metabolism may be a new therapeutic strategy for AML, and points to MCT4 as a potential therapeutic target in AML patients and to syrosingopine as a new anti-proliferative drug and inducer of autophagy to be used in combination with conventional chemotherapeutic agents in AML treatment.
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http://dx.doi.org/10.3389/fonc.2020.621458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892602PMC
February 2021

From Clonal Hematopoiesis to Therapy-Related Myeloid Neoplasms: The Silent Way of Cancer Progression.

Biology (Basel) 2021 Feb 6;10(2). Epub 2021 Feb 6.

Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy.

Clonal hematopoiesis (CH) has been recognized as a predisposing factor for the development of myeloid malignancies. Its detection has been reported at different frequencies across studies, based on the type of genome scanning approach used and the population studied, but the latest insights recognize its virtual ubiquitous presence in older individuals. The discovery of CH in recent years paved the way for a shift in the paradigm of our understanding of the biology of therapy-related myeloid malignancies (t-MNs). Indeed, we moved from the concept of a treatment-induced lesion to a model where CH precedes the commencement of any cancer-related treatment in patients who subsequently develop a t-MN. Invariant patterns of genes seem to contribute to the arising of t-MN cases, with differences regarding the type of treatment received. Here, we review the principal studies concerning CH, the relationship with myeloid progression and the mechanisms of secondary t-MN development.
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http://dx.doi.org/10.3390/biology10020128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914896PMC
February 2021

Classification and Personalized Prognostic Assessment on the Basis of Clinical and Genomic Features in Myelodysplastic Syndromes.

J Clin Oncol 2021 04 4;39(11):1223-1233. Epub 2021 Feb 4.

Department of Physics and Astronomy, University of Bologna, Bologna, Italy.

Purpose: Recurrently mutated genes and chromosomal abnormalities have been identified in myelodysplastic syndromes (MDS). We aim to integrate these genomic features into disease classification and prognostication.

Methods: We retrospectively enrolled 2,043 patients. Using Bayesian networks and Dirichlet processes, we combined mutations in 47 genes with cytogenetic abnormalities to identify genetic associations and subgroups. Random-effects Cox proportional hazards multistate modeling was used for developing prognostic models. An independent validation on 318 cases was performed.

Results: We identify eight MDS groups (clusters) according to specific genomic features. In five groups, dominant genomic features include splicing gene mutations (, , and ) that occur early in disease history, determine specific phenotypes, and drive disease evolution. These groups display different prognosis (groups with mutations being associated with better survival). Specific co-mutation patterns account for clinical heterogeneity within - and -related MDS. MDS with complex karyotype and/or gene abnormalities and MDS with acute leukemia-like mutations show poorest prognosis. MDS with 5q deletion are clustered into two distinct groups according to the number of mutated genes and/or presence of mutations. By integrating 63 clinical and genomic variables, we define a novel prognostic model that generates personally tailored predictions of survival. The predicted and observed outcomes correlate well in internal cross-validation and in an independent external cohort. This model substantially improves predictive accuracy of currently available prognostic tools. We have created a Web portal that allows outcome predictions to be generated for user-defined constellations of genomic and clinical features.

Conclusion: Genomic landscape in MDS reveals distinct subgroups associated with specific clinical features and discrete patterns of evolution, providing a proof of concept for next-generation disease classification and prognosis.
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http://dx.doi.org/10.1200/JCO.20.01659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078359PMC
April 2021

Acute Promyelocytic Leukemia in Children: A Model of Precision Medicine and Chemotherapy-Free Therapy.

Int J Mol Sci 2021 Jan 11;22(2). Epub 2021 Jan 11.

Department of Pediatric Hemato-Oncology and Cell and Gene Therapy, Istituto di Ricovero e Cura a Carattere Scientifico Bambino Gesù Children's Hospital, 00165 Rome, Italy.

Acute promyelocytic leukemia (APL) represents a paradigm of precision medicine. Indeed, in the last decades, the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) completely revolutionized the therapeutic approach to this previously highly fatal disorder. This entirely chemotherapy-free treatment, which provided excellent survival rates, has been initially validated in adults and, recently, translated in the pediatric setting. This review summarizes currently available data on the use of ATRA and ATO combination in pediatric APL, providing a particular focus on peculiar issues and challenges, such as the occurrence of and death during induction (early death), as well as the advantage offered by the ATO/ATRA combination in sparing long-term .
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http://dx.doi.org/10.3390/ijms22020642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826974PMC
January 2021

Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells.

Cells 2020 11 5;9(11). Epub 2020 Nov 5.

Dipartimento di Scienze, Sezione di Scienze e Tecnologie Biomediche, Università Roma Tre, 00146 Roma, Italy.

Acute promyelocytic leukemia (APL) is a hematological disease characterized by a balanced reciprocal translocation that leads to the synthesis of the oncogenic fusion protein PML-RARα. APL is mainly managed by a differentiation therapy based on the administration of all- retinoic acid (ATRA) and arsenic trioxide (ATO). However, therapy resistance, differentiation syndrome, and relapses require the development of new low-toxicity therapies based on the induction of blasts differentiation. In keeping with this, we reasoned that a better understanding of the molecular mechanisms pivotal for ATRA-driven differentiation could definitely bolster the identification of new therapeutic strategies in APL patients. We thus performed an in-depth high-throughput transcriptional profile analysis and metabolic characterization of a well-established APL experimental model based on NB4 cells that represent an unevaluable tool to dissect the complex mechanism associated with ATRA-induced granulocytic differentiation. Pathway-reconstruction analysis using genome-wide transcriptional data has allowed us to identify the activation/inhibition of several cancer signaling pathways (e.g., inflammation, immune cell response, DNA repair, and cell proliferation) and master regulators (e.g., transcription factors, epigenetic regulators, and ligand-dependent nuclear receptors). Furthermore, we provide evidence of the regulation of a considerable set of metabolic genes involved in cancer metabolic reprogramming. Consistently, we found that ATRA treatment of NB4 cells drives the activation of aerobic glycolysis pathway and the reduction of OXPHOS-dependent ATP production. Overall, this study represents an important resource in understanding the molecular "portfolio" pivotal for APL differentiation, which can be explored for developing new therapeutic strategies.
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http://dx.doi.org/10.3390/cells9112423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716236PMC
November 2020

Terminal deoxynucleotidyl transferase (TdT) expression is associated with FLT3-ITD mutations in Acute Myeloid Leukemia.

Leuk Res 2020 12 15;99:106462. Epub 2020 Oct 15.

Department of Biomedicine and Prevention, University of Tor Vergata, Rome, Italy; Santa Lucia Foundation, I.R.C.C.S., Neuro-Oncohematology, Rome, Italy. Electronic address:

The terminal deoxynucleotidyl transferase (TdT) is a DNA polymerase expressed in acute myeloid leukemias (AMLs), where it may be involved in the generation of NPM1 and FLT3-ITD mutations. We studied the correlations between TdT expression and FLT3-ITD or NPM1 mutations in primary AML samples, and the impact on patients' survival. TdT expression was analyzed in 143 adult AML patients by flow cytometry as percentage of positivity and mean fluorescence intensity (MFI) on blasts. TdT was positive in 49 samples (34.2%), with a median of 48% TdT-positivity (range 7-98) and a median MFI of 2.70 (range 1.23-30.54). FLT3-ITD and NPM1 mutations were present in 24 (16.7%) and 34 (23.7%) cases, respectively. Median TdT expression on blasts was significantly higher in FLT3-ITD+, as compared with FLT3-ITD- AMLs (median 8% vs 0% respectively, p = 0.035). NPM1 mutational status, FLT3-ITD allelic ratio, karyotype, and ELN risk groups, did not correlate with TdT expression or MFI on blasts. TdT + patients had poorer survival as compared to TdT-, but this result was not confirmed by the multivariable analysis, where ELN risk stratification as well as age and type of treatment remained independent prognostic factors for OS. In summary, our results support the possible implication of TdT enzyme in the generation of FLT3-ITD mutations in AML.
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http://dx.doi.org/10.1016/j.leukres.2020.106462DOI Listing
December 2020

Acute Promyelocytic Leukemia After Radium-223 Exposure for Prostate Cancer in a Chemotherapy-Naïve Patient.

Nucl Med Mol Imaging 2020 Oct 9;54(5):256-260. Epub 2020 Jul 9.

Hematology, Polo Universitario Pontino, "Sapienza", Via A. Canova S.M. Goretti Hospital, Latina, Italy.

Ra-dichloride is a bone-seeking targeted alpha (α)-emitting approved for bone metastases in prostate cancer. Here, we report a case of therapy-related acute promyelocytic leukemia (t-APL) following administration of Ra, showing some evidence of a causative relationship. A patient with metastatic prostate cancer received therapy with Ra, with 6 injections of the radiopharmaceutical at a standard dose of 55 kBq/kg at 4-week intervals for a cumulative administered activity of 26.3 MBq. PET/CT with F-methylcholine repeated 1 month after the conclusion of Ra was negative. After 8 months, he developed pancytopenia and we made a diagnosis of therapy-related acute promyelocytic leukemia (t-APL). We then studied the genomic locations of the breakpoints in the PML and RARA genes, which were at nucleotide positions 1708-09 of PML intron 3, respectively, outside the previously reported Topo II-associated hotspot region. t-APL was cured with all-trans-retinoic acid (ATRA) and arsenic trioxide. The type of PML/RARA rearrangement we identified, in absence of other myelotoxic treatments, is suggestive of a possible direct causal relationship with exposure to Ra and warrants further investigations.
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http://dx.doi.org/10.1007/s13139-020-00652-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560650PMC
October 2020

Midostaurin in patients with acute myeloid leukemia and FLT3-TKD mutations: a subanalysis from the RATIFY trial.

Blood Adv 2020 10;4(19):4945-4954

Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus der TU Dresden, Dresden, Germany; and.

The results from the RATIFY trial (ClinicalTrials.gov: NCT00651261; CALGB 10603) showed that midostaurin combined with standard chemotherapy significantly improved outcomes in patients with FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML), compared with placebo. In this post hoc subgroup analysis from the trial, we evaluated the impact of midostaurin in 163 patients with FLT3-tyrosine kinase domain (TKD) mutations. At a median follow-up of 60.7 months (95% CI, 55.0-70.8), the 5-year event-free survival (EFS) rate was significantly higher in patients treated with midostaurin than in those treated with placebo (45.2% vs 30.1%; P = .044). A trend toward improved disease-free survival was also observed with midostaurin (67.3% vs 53.4%; P = .089), whereas overall survival (OS) was similar in the 2 groups. Patients with AML and NPM1mut/FLT3-TKDmut or core binding factor (CBF)-rearranged/FLT3-TKDmut genotypes had significantly prolonged OS with or without censoring at hematopoietic cell transplantation (HCT), compared with NPM1WT/CBF-negative AMLs. The multivariable model for OS and EFS adjusted for allogeneic HCT in first complete remission as a time-dependent covariable, revealed NPM1 mutations and CBF rearrangements as significant favorable factors. These data show that NPM1 mutations or CBF rearrangements identify favorable prognostic groups in patients with FLT3-TKD AMLs, independent of other factors, also in the context of midostaurin treatment.
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http://dx.doi.org/10.1182/bloodadvances.2020002904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556122PMC
October 2020

Characterization of FLT3-ITD acute myeloid leukemia: molecular profiling of leukemic precursor cells.

Blood Cancer J 2020 08 25;10(8):85. Epub 2020 Aug 25.

Department of Biomedicine and Prevention, University of Tor Vergata, Rome, Italy.

Acute myeloid leukemia (AML) with FLT3-ITD mutations (FLT3-ITD) remains a therapeutic challenge, with a still high relapse rate, despite targeted treatment with tyrosine kinase inhibitors. In this disease, the CD34/CD123/CD25/CD99+ leukemic precursor cells (LPCs) phenotype predicts for FLT3-ITD-positivity. The aim of this study was to characterize the distribution of FLT3-ITD mutation in different progenitor cell subsets to shed light on the subclonal architecture of FLT3-ITD AML. Using high-speed cell sorting, we sequentially purified LPCs and CD34+ progenitors in samples from patients with FLT3-ITD AML (n = 12). A higher FLT3-ITD load was observed within CD34/CD123/CD25/CD99+ LPCs, as compared to CD34+ progenitors (CD123+/-,CD25-,CD99low/-) (p = 0.0005) and mononuclear cells (MNCs) (p < 0.0001). This was associated with significantly increased CD99 mean fluorescence intensity in LPCs. Significantly higher FLT3-ITD burden was also observed in LPCs of AML patients with a small FLT3-ITD clones at diagnosis. On the contrary, the mutation burden of other myeloid genes was similar in MNCs, highly purified LPCs and/or CD34+ progenitors. Treatment with an anti-CD99 mAb was cytotoxic on LPCs in two patients, whereas there was no effect on CD34+ cells from healthy donors. Our study shows that FLT3-ITD mutations occur early in LPCs, which represent the leukemic reservoir. CD99 may represent a new therapeutic target in FLT3-ITD AML.
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http://dx.doi.org/10.1038/s41408-020-00352-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447750PMC
August 2020

Early intracranial haemorrhages in acute promyelocytic leukaemia: analysis of neuroradiological and clinico-biological parameters.

Br J Haematol 2021 04 10;193(1):129-132. Epub 2020 Aug 10.

Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.

Acute promyelocytic leukaemia (APL) represents a modern success of precision medicine. However, fatalities occurring within the first 30 days of induction treatment, in particular intracranial haemorrhage (ICH), remain the main causes of death. We studied the clinico-biological characteristics of 13 patients with APL who experienced ICH. Compared to 85 patients without this complication, patients with ICH were older and more frequently had high-risk APL. Moreover, positivity for the 'swirl' sign at neuroradiological imaging and hydrocephalus were predictors of a fatal outcome, together with lower fibrinogen, prolonged international normalized ratio (INR) and higher lactate dehydrogenase levels.
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http://dx.doi.org/10.1111/bjh.17018DOI Listing
April 2021

Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes.

Nat Med 2020 10 3;26(10):1549-1556. Epub 2020 Aug 3.

Department of Hematology, Democritus University of Thrace Medical School, Alexandroupolis, Greece.

Tumor protein p53 (TP53) is the most frequently mutated gene in cancer. In patients with myelodysplastic syndromes (MDS), TP53 mutations are associated with high-risk disease, rapid transformation to acute myeloid leukemia (AML), resistance to conventional therapies and dismal outcomes. Consistent with the tumor-suppressive role of TP53, patients harbor both mono- and biallelic mutations. However, the biological and clinical implications of TP53 allelic state have not been fully investigated in MDS or any other cancer type. We analyzed 3,324 patients with MDS for TP53 mutations and allelic imbalances and delineated two subsets of patients with distinct phenotypes and outcomes. One-third of TP53-mutated patients had monoallelic mutations whereas two-thirds had multiple hits (multi-hit) consistent with biallelic targeting. Established associations with complex karyotype, few co-occurring mutations, high-risk presentation and poor outcomes were specific to multi-hit patients only. TP53 multi-hit state predicted risk of death and leukemic transformation independently of the Revised International Prognostic Scoring System (IPSS-R). Surprisingly, monoallelic patients did not differ from TP53 wild-type patients in outcomes and response to therapy. This study shows that consideration of TP53 allelic state is critical for diagnostic and prognostic precision in MDS as well as in future correlative studies of treatment response.
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http://dx.doi.org/10.1038/s41591-020-1008-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381722PMC
October 2020

Essential Thrombocythemia and Acquired von Willebrand Syndrome: The Shadowlands between Thrombosis and Bleeding.

Cancers (Basel) 2020 Jun 30;12(7). Epub 2020 Jun 30.

Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44106, USA.

Over the past decade, new insights have emerged on the pathophysiology of essential thrombocythemia (ET), its clinical management, and associated thrombohemostatic disturbances. Here, we review the latest diagnostic and risk stratification modalities of ET and its therapeutics. Moreover, we discuss the clinical evidence-based benefits, deriving from major clinical trials, of using cytoreductive therapy and antiplatelet agents to lower the risk of fatal vascular events. Also, we focus on the condition of extreme thrombocytosis (>1000 × 10/L) and bleeding risk, the development and pathogenesis of acquired von Willebrand syndrome, and the clinical approach to this paradoxical scenario in ET.
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http://dx.doi.org/10.3390/cancers12071746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407619PMC
June 2020
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