Publications by authors named "Emmanuel Gyan"

126 Publications

Low-Dose Pesticides Alter Primary Human Bone Marrow Mesenchymal Stem/Stromal Cells through ALDH2 Inhibition.

Cancers (Basel) 2021 Nov 14;13(22). Epub 2021 Nov 14.

Department of Biological Hematology, Tours University Hospital, 37000 Tours, France.

(1) Background: The impact of occupational exposure to high doses of pesticides on hematologic disorders is widely studied. Yet, lifelong exposure to low doses of pesticides, and more particularly their cocktail effect, although poorly known, could also participate to the development of such hematological diseases as myelodysplastic syndrome (MDS) in elderly patients. (2) Methods: In this study, a cocktail of seven pesticides frequently present in water and food (maneb, mancozeb, iprodione, imazalil, chlorpyrifos ethyl, diazinon and dimethoate), as determined by the European Food Safety Authority, were selected. Their in vitro effects at low-doses on primary BM-MSCs from healthy volunteers were examined. (3) Results: Exposure of normal BM-MSCs to pesticides for 21 days inhibited cell proliferation and promoted DNA damage and senescence. Concomitantly, these cells presented a decrease in aldehyde dehydrogenase 2 (ALDH2: mRNA, protein and enzymatic activity) and an increase in acetaldehyde levels. Pharmacological inhibition of ALDH2 with disulfiram recapitulated the alterations induced by exposure to low doses of pesticides. Moreover, BM-MSCs capacity to support primitive hematopoiesis was significantly altered. Similar biological abnormalities were found in primary BM-MSCs derived from MDS patients. (4) Conclusions: these results suggest that ALDH2 could participate in the pathophysiology of MDS in elderly people long exposed to low doses of pesticides.
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http://dx.doi.org/10.3390/cancers13225699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616329PMC
November 2021

The Influence of Underlying Disease on Rituximab Pharmacokinetics May be Explained by Target-Mediated Drug Disposition.

Clin Pharmacokinet 2021 Nov 13. Epub 2021 Nov 13.

Université de Tours, EA 4245 T2I, Tours, France.

Background And Objectives: Rituximab is an anti-CD20 monoclonal antibody approved in several diseases, including chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), rheumatoid arthritis (RA), and anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). The influence of underlying disease on rituximab pharmacokinetics has never been investigated for several cancer and non-cancer diseases simultaneously. This study aimed at assessing this influence using an integrated semi-mechanistic model accounting for target-mediated elimination of rituximab.

Methods: Rituximab concentration-time data from five studies previously published in patients with CLL, DLBCL, FL, RA, and AAV were described using a two-compartment model with irreversible binding of rituximab to its target antigen. Both underlying disease and target antigen measurements were assessed as covariates.

Results: Central volume of distribution was [95% confidence interval] 1.7-fold [1.6-1.9] higher in DLBCL than in RA, FL, and CLL, and it was 1.8-fold [1.6-2.1] higher in RA, FL, and CLL than in AAV. First-order elimination rate constants were 1.8-fold [1.7-2.0] and 1.3-fold [1.2-1.5] higher in RA, DLBCL, and FL than in CLL and AAV, respectively. Baseline latent antigen level (L) was 54-fold [30-94], 20-fold [11-36], and 29-fold [14-64] higher in CLL, DLBCL, and FL, respectively, than in RA and AAV. In lymphoma, L increased with baseline total metabolic tumor volume (p = 6.10). In CLL, the second-order target-mediated elimination rate constant (k) increased with baseline CD20 count on circulating B cells (CD20, p = 0.0081).

Conclusions: Our results show for the first time that rituximab pharmacokinetics is strongly influenced by underlying disease and disease activity. Notably, neoplasms are associated with higher antigen amounts that result in decreased exposure to rituximab compared to inflammatory diseases. Our model might be used to estimate unbound target amounts in upcoming studies.
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http://dx.doi.org/10.1007/s40262-021-01081-3DOI Listing
November 2021

Antibody Responses after a Third Dose of COVID-19 Vaccine in Kidney Transplant Recipients and Patients Treated for Chronic Lymphocytic Leukemia.

Vaccines (Basel) 2021 Sep 23;9(10). Epub 2021 Sep 23.

INSERM U1259, Université de Tours et CHRU de Tours, 37000 Tours, France.

The impact of a third dose of COVID-19 vaccine on antibody responses is unclear in immunocompromised patients. The objective of this retrospective study was to characterize antibody responses induced by a third dose of mRNA COVID-19 vaccine in 160 kidney transplant recipients and 20 patients treated for chronic lymphocytic leukemia (CLL). Prevalence of anti-spike IgG ≥ 7.1 and ≥ 30 BAU/mL after the third dose were 47% (75/160) and 39% (63/160) in kidney transplant recipients, and 57% (29/51) and 50% (10/20) in patients treated for CLL. Longitudinal follow-up identified a moderate increase in SARS-CoV-2 anti-spike IgG levels after a third dose of vaccine in kidney transplant recipients (0.19 vs. 5.28 BAU/mL, = 0.03) and in patients treated for CLL (0.63 vs. 10.7 BAU/mL, = 0.0002). This increase in IgG levels had a limited impact on prevalence of anti-spike IgG ≥ 30 BAU/mL in kidney transplant recipients (17%, 2/12 vs. 33%, 4/12, = 0.64) and in patients treated for CLL (5%, 1/20 vs. 45%, 9/20, = 0.008). These results highlight the need for vaccination of the general population and the importance of non-medical preventive measures to protect immunocompromised patients.
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http://dx.doi.org/10.3390/vaccines9101055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8539204PMC
September 2021

Validation of POD24 As a Robust Early Clinical Endpoint of Poor Survival in FL from 5,225 Patients on 13 Clinical Trials.

Blood 2021 Oct 6. Epub 2021 Oct 6.

University of Texas MD Anderson Cancer Center, Houston, Texas, United States.

Observational studies and standalone trials indicate that patients with follicular lymphoma (FL) who experience disease progression within 24 months of front-line chemoimmunotherapy (POD24), have poor outcomes. We performed a pooled analysis of 13 randomized clinical trials of FL patients in the pre- and post-rituximab era to identify clinical factors predicting POD24. Logistic regression models evaluated the association between clinical factors and POD24. Cox regression evaluated the association between POD24 as a time-dependent factor and subsequent overall survival (OS). A landmark analysis evaluated the association of POD24 on OS for the subset of patients who were alive at 24 months post trial registration. Patients without progression at 24 months at baseline had favorable performance status (PS), limited stage (I/II) disease, low FLIPI risk score, normal baseline hemoglobin, and normal baseline beta 2 microglobulin (B2M). In a multivariable logistic regression model, male gender (odds ratio (OR) = 1.30), PS >= 2 (OR = 1.63), B2M (>= 3mg/L) (OR = 1.43), and high FLIPI risk score (3 - 5) (OR = 3.14) were associated with increased risk of progression before 24 months. In the time-dependent Cox model and the 24 month landmark analysis, POD24 was associated with poor subsequent OS (hazard ratio (HR) = 4.85 and HR = 3.06, respectively). This is the largest pooled analysis using clinical trials data validating POD24 as a robust indicator of poor FL survival and identified clinical predictors of early death and progression that can aid in building comprehensive prognostic models incorporating clinical and molecular predictors of POD24.
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http://dx.doi.org/10.1182/blood.2020010263DOI Listing
October 2021

Megaloblastic anemia-related iron overload and erythroid regulators: a case report.

J Med Case Rep 2021 Sep 20;15(1):463. Epub 2021 Sep 20.

Department of Hematology and Cell Therapy, Tours University Hospital, 2 Boulevard Tonnellé, 37044, Tours Cedex, France.

Background: In ineffective erythropoiesis, hepcidin synthesis is suppressed by erythroid regulators, namely erythroferrone and growth differentiation factor-15. For the first time, the hypothesis that iron overload in megaloblastic anemia may be related to ineffective erythropoiesis is explored by describing the kinetics of hepcidin, erythroferrone, and growth differentiation factor-15 levels in a patient diagnosed with megaloblastic anemia associated with iron overload.

Case Presentation: An 81-year-old Caucasian male was admitted for fatigue. He had type-2 diabetes previously treated with metformin, ischemic cardiac insufficiency, and stage-3 chronic kidney disease. Vitiligo was observed on both hands. Biological tests revealed normocytic non-regenerative anemia associated with hemolysis, thrombocytopenia, and elevated sideremia, ferritin, and transferrin saturation levels. Megaloblastic anemia was confirmed with undetectable blood vitamin B12 and typical cytological findings like hyper-segmented neutrophils in blood and megaloblasts in bone marrow. The patient received vitamin B12 supplementation. At 3 months, biological parameters reached normal values. Hepcidin kinetics from diagnosis to 3 months inversely correlated with those of erythroferrone and growth differentiation factor-15.

Conclusions: This case suggests that iron-overload mechanisms of dyserythropoietic anemias may apply to megaloblastic anemias.
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http://dx.doi.org/10.1186/s13256-021-03065-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8451118PMC
September 2021

Infection in Patients with Suspected Thrombotic Microangiopathy Based on Clinical Presentation.

Clin J Am Soc Nephrol 2021 09;16(9):1355-1364

Service de Néphrologie-Hypertension, Dialyses, Transplantation Rénale, Néphrologie Pédiatrique, Hôpital Bretonneau et Hôpital Clocheville, Centre Hospitalier Universitaire (CHU) Tours, Tours, France et French Clinical Research Network Infrastructure-Cardiovascular and Renal Clinical Trialists, Tours, France

Background And Objectives: In contrast to shigatoxin-associated (STEC) causing hemolytic uremic syndrome, STEC-unrelated infections associated with thrombotic microangiopathy are less characterized.

Design, Setting, Participants, & Measurements: Our retrospective study in a four-hospital institution of 530 consecutive patients with adjudicated thrombotic microangiopathies during the 2009-2016 period studied STEC-unrelated infections' epidemiology and major outcomes (death, acute dialysis, and major cardiovascular events).

Results: STEC-unrelated infection was present in 145 of 530 (27%) patients, thrombotic microangiopathies without infection were present in 350 of 530 (66%) patients, and STEC causing hemolytic and uremic syndrome was present in 35 of 530 (7%) patients. They (versus thrombotic microangiopathy without infection) were associated with age >60 years (36% versus 18%), men (53% versus 27%), altered consciousness (32% versus 11%), mean BP <65 mm Hg (21% versus 4%), lower hemoglobin and platelet count, and AKI (72% versus 49%). They were associated with more than one pathogen in 36 of 145 (25%) patients (either isolated [14%] or combined [86%] to other causes of thrombotic microangiopathy); however, no significant clinical or biologic differences were noted between the two groups. They were more frequently due to bacteria (enterobacteria [41%], [11%], and [3%]) than viruses (Epstein-Barr [20%], cytomegalovirus [18%], influenza [3%], hepatitis C [1%], HIV [1%], and rotavirus [1%]). STEC-unrelated infections were independent risk factors for in-hospital death (odds ratio, 2.22; 95% confidence interval, 1.18 to 4.29), major cardiovascular event (odds ratio, 3.43; 95% confidence interval, 1.82 to 6.69), and acute dialysis (odds ratio, 3.48; 95% confidence interval, 1.78 to 7.03). Bacteria (versus other pathogens), and among bacteria, enterobacteria, presence of more than one bacteria, and without shigatoxin were risk factors for acute dialysis.

Conclusions: Infections are frequent thrombotic microangiopathy triggers or causes, and they are mostly unrelated to STEC. Infections convey a higher risk of death and major complications. The most frequent pathogens were enterobacteria, , Epstein-Barr virus, and cytomegalovirus.

Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_09_07_CJN17511120.mp3.
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http://dx.doi.org/10.2215/CJN.17511120DOI Listing
September 2021

Cerebral localization of chronic myelomonocytic leukemia: a case report.

J Med Case Rep 2021 Jul 25;15(1):368. Epub 2021 Jul 25.

Department of Hematology, Tours Hospital, Tours, France.

Background: Chronic myelomonocytic leukemia is a myelodysplastic/myeloproliferative neoplasm characterized by the infiltration of blood and bone marrow by immature monocytes. Cerebral localization of chronic myelomonocytic leukemia has never been described.

Case Presentation: We report the case of a Caucasian 59 year-old man with multiorgan chronic myelomonocytic leukemia infiltration, associated with uncommon brain involvement. There was no evidence of evolution to acute myeloid leukemia. The evidence of cerebral infiltration by chronic myelomonocytic leukemia was made after autopsy.

Conclusions: The fatal outcome of the patient raises the question of the potential benefit of early specific treatment, such as demethylating agents or intensive chemotherapy. Sharing such images of atypical and rapidly evolving chronic myelomonocytic leukemia and the disease history may help clinical decision-making in the future.
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http://dx.doi.org/10.1186/s13256-021-02947-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310603PMC
July 2021

Impact of High-Dose Methotrexate on the Outcome of Patients with Diffuse Large B-Cell Lymphoma and Skeletal Involvement.

Cancers (Basel) 2021 Jun 12;13(12). Epub 2021 Jun 12.

Maladies du Sang, CHU d'Angers, 49000 Angers, France.

Diffuse large B-cell lymphoma (DLBCL) with extra nodal skeletal involvement is rare. It is currently unclear whether these lymphomas should be treated in the same manner as those without skeletal involvement. We retrospectively analyzed the impact of combining high-dose methotrexate (HD-MTX) with an anthracycline-based regimen and rituximab as first-line treatment in a cohort of 93 patients with DLBCL and skeletal involvement with long follow-up. Fifty patients (54%) received upfront HD-MTX for prophylaxis of CNS recurrence (high IPI score and/or epidural involvement) or because of skeletal involvement. After adjusting for age, ECOG, high LDH levels, and type of skeletal involvement, HD-MTX was associated with an improved PFS and OS (HR: 0.2, 95% CI: 0.1-0.3, < 0.001 and HR: 0.1, 95% CI: 0.04-0.3, < 0.001, respectively). Patients who received HD-MTX had significantly better 5-year PFS and OS (77% vs. 39%, <0.001 and 83 vs. 58%, < 0.001). Radiotherapy was associated with an improved 5-year PFS (74 vs. 48%, = 0.02), whereas 5-year OS was not significantly different (79% vs. 66%, = 0.09). A landmark analysis showed that autologous stem cell transplantation was not associated with improved PFS or OS. The combination of high-dose methotrexate and an anthracycline-based immunochemotherapy is associated with an improved outcome in patients with DLBCL and skeletal involvement and should be confirmed in prospective trials.
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http://dx.doi.org/10.3390/cancers13122945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231126PMC
June 2021

Eltrombopag for myelodysplastic syndromes or chronic myelomonocytic leukaemia with no excess blasts and thrombocytopenia: a French multicentre retrospective real-life study.

Br J Haematol 2021 Jul 20;194(2):336-343. Epub 2021 Jun 20.

Service d'Hématologie Sénior, Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris (APHP), Université de Paris, Paris, France.

Despite a moderate prevalence in low-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML), thrombocytopenia remains a risk of severe bleeding and therapeutic options are still limited. There are only a few studies with eltrombopag (ELT), a thrombopoietin receptor agonist, in those patients. In this retrospective multicentre study, ELT was used in 50 patients with MDS and 11 with CMML, with no excess of marrow blasts and platelet counts of <50 × 10 /l in a 'real-life' situation. Platelet response occurred in 47 (77%) patients. The median (range) duration of response was 8 (0-69) months. None of the eight still responders who discontinued ELT had relapsed, at a median (range) of 16 (6-23) months after ELT discontinuation. Although 36% of the patients were anti-coagulated or anti-aggregated only 10% of patients had Grade ≥3 bleeding events. Thrombotic events were observed in six (10%) patients, who all but one had a medical history of arterial or venous thrombosis. Progression to acute myeloid leukaemia occurred in four (7%) patients. In this first 'real-life' study, ELT was effective and generally well tolerated in patients with MDS/CMML without excess blasts.
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http://dx.doi.org/10.1111/bjh.17539DOI Listing
July 2021

Intravenous high-dose methotrexate based systemic therapy in the treatment of isolated primary vitreoretinal lymphoma: An LOC network study.

Am J Hematol 2021 07 3;96(7):823-833. Epub 2021 May 3.

Ophthalmology, Centre Hospitalier Universitaire de Brest, Brest, France.

The treatment of primary vitreoretinal lymphoma (PVRL) remains controversial regarding the use of local, systemic, or combined treatments. The aim of this study was to analyze the efficacy and toxicity of intravenous high-dose methotrexate (IV HD-MTX) based systemic therapy in a uniformly treated population of PVRL patients. From a nationwide French database, we retrospectively selected 59 patients (median age: 70 years, median Karnofsky Performance Status: 90%) with isolated PVRL at diagnosis who received first-line treatment with HD-MTX between 2011 and 2018. 8/59 patients also received a local treatment. No deaths or premature discontinuations of MTX due to toxicity were reported. A complete response was obtained in 40/57 patients after chemotherapy. Before treatment, IL-10 was elevated in the aqueous humor (AH) or in the vitreous in 89% of patients. After treatment, AH IL-10 was undetectable in 87% of patients with a CR/uCR/PR and detectable in 92% of patients with PD/SD. After a median follow-up of 61 months, 42/59 (71%) patients had relapsed, including 29 isolated ocular relapses as the first relapse and a total of 22 brain relapses. The median overall survival, progression-free survival, ocular-free survival and brain-free survival were 75, 18, 29 and 73 months, respectively. IV HD-MTX based systemic therapy as a first-line treatment for isolated PVRL is feasible, with acceptable toxicity, even in an elderly population. This strategy seems efficient to prevent brain relapse with prolonged overall survival. However, the ocular relapse rate remains high. New approaches are needed to improve local control of this disease, and ocular assessment could be completed by monitoring AH IL-10.
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http://dx.doi.org/10.1002/ajh.26199DOI Listing
July 2021

Molecular classification and prognosis in younger adults with acute myeloid leukemia and intermediate-risk cytogenetics treated or not by gemtuzumab ozogamycin: Final results of the GOELAMS/FILO acute myeloid leukemia 2006-intermediate-risk trial.

Eur J Haematol 2021 Jul 18;107(1):111-121. Epub 2021 Apr 18.

Hématologie Clinique, Hôpital Cochin, AP-HP, Paris, France.

In this randomized phase 3 study, the FILO group tested whether the addition of 6 mg/m of gemtuzumab ozogamycin (GO) to standard chemotherapy could improve outcome of younger patients with de novo acute myeloid leukemia (AML) and intermediate-risk cytogenetics. GO arm was prematurely closed after 254 inclusions because of toxicity. A similar complete remission rate was observed in both arms. Neither event-free survival nor overall survival were improved by GO in younger AML patients (<60 years) ineligible for allogeneic stem-cell transplantation. (P = .086; P = .149, respectively). Using unsupervised hierarchical clustering based on mutational analysis of seven genes (NPM1, FLT3-ITD, CEBPA, DNMT3A, IDH1, IDH2, and ASXL1), six clusters of patients with significant different outcome were identified. Five clusters were based on FLT3-ITD, NPM1, and CEBPA mutations as well as epigenetic modifiers (DNMT3A, IDH1/2, ASXL1), whereas the last cluster, representing 25% of patients, had no mutation and intermediate risk. One cluster isolated FLT3-ITD mutations with higher allelic ratio and a very poor outcome. The addition of GO had no impact in these molecular clusters. Although not conclusive for GO impact in AML patients <60 years, this study provides a molecular classification that distinguishes six AML clusters influencing prognosis in younger AML patients with intermediate-risk cytogenetic.
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http://dx.doi.org/10.1111/ejh.13626DOI Listing
July 2021

Eosinophilic fasciitis (Shulman syndrome), a rare entity and diagnostic challenge, as a manifestation of severe chronic graft-versus-host disease: a case report.

J Med Case Rep 2021 Mar 15;15(1):135. Epub 2021 Mar 15.

Department of Hematology and Cell Therapy, University Hospital of Tours, 2 Boulevard Tonnellé, 37044, Tours Cedex 9, France.

Background: Shulman's disease, or eosinophilic fasciitis (EF), is a rare autoimmune disease, characterized by sclerodermic skin lesions with progressive induration and thickening of the soft tissues. Chronic graft-versus-host-disease (GVHD) presenting as EF is a very rare manifestation of cutaneous GVHD.

Case Presentation: We report an unusual case of EF in a 46-year-old Caucasian male patient who had received an allogenic hematopoietic stem cell transplantation in the context of relapsed/refractory multiple myeloma. The diagnosis was challenging, with the patient presenting hepatic dysfunction, normal eosinophils count, and incomplete clinical signs. Magnetic resonance imaging (MRI) and skin biopsy confirmed the diagnosis of EF. Early initiation of specific treatment with corticosteroids and prednisolone achieved complete response.

Conclusion: In practice, incomplete signs in this rare complication should lead to MRI as it is a major tool to guide decision-making based on the skin biopsy, allowing a rapid diagnosis and the initiation of treatment without delay.
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http://dx.doi.org/10.1186/s13256-021-02735-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958384PMC
March 2021

Oxaliplatin before autologous transplantation in combination with high-dose cytarabine and rituximab provides longer disease control than cisplatin or carboplatin in patients with mantle-cell lymphoma: results from the LyMA prospective trial.

Bone Marrow Transplant 2021 07 3;56(7):1700-1709. Epub 2021 Mar 3.

Department of Clinical Hematology, Nantes University Hospital, Nantes, France.

LyMA trial has demonstrated the benefit of rituximab maintenance after autologous stem cell transplantation (ASCT) in previously untreated mantle-cell lymphoma patients (MCL). Induction consisted of four courses of R-DHAP (rituximab, dexamethasone, high-dose cytarabine, and platinum derivative). The platinum derivative (PD) choice was free: R-DHA-cisplatin, R-DHA-carboplatin, or R-DHA-oxaliplatin. We investigated the prognostic impact of each PD. PFS and OS calculated from inclusion and investigated in an intention-to-treat (ITT) (= 298) and per-protocol analyses (PP) (n = 227). R-DHACis, R-DHACa, or R-DHAOx were used at first cycle in 184, 76, and 38 patients, respectively. Overall, 71 patients (59 in the R-DHACis) required a change in PD, mainly because of PD toxicity. In ITT-analysis, PFS in the R-DHACis and R-DHACa groups were similar (4-year PFS of 65%), while R-DHAOx had a better PFS (4-year PFS of 65% versus 86.5%, respectively, HR = 0.44, p = 0.02). The 4-year OS was 92% for R-DHAOx versus 75.9% for R-DHACis/DHACa (HR = 0.37, p = 0.03). Similar results were yielded in the PP analysis. Low MIPI and R-DHAOx were independent favorable prognostic markers for both PFS (HR = 0.44, p = 0.035) and OS (HR = 0.36, p = 0.045). In vitro and in silico analyses confirmed that oxaliplatin has an anti-MCL cytotoxic effect that differs from that of other PD. R-DHAOx before ASCT provides better outcome in transplantation eligible young MCL patients.
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http://dx.doi.org/10.1038/s41409-020-01198-2DOI Listing
July 2021

A randomized phase 3 trial of autologous vs allogeneic transplantation as part of first-line therapy in poor-risk peripheral T-NHL.

Blood 2021 05;137(19):2646-2656

Service d'Hematologie Clinique, Centre Hospitalier Universitaire, Hôpital Robert Debre, Reims, France.

First-line therapy for younger patients with peripheral T-cell non-Hodgkin lymphoma (T-NHL) consists of 6 courses of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with or without etoposide (CHOEP), consolidated by high-dose therapy and autologous stem cell transplantation (auto-SCT). We hypothesized that allogeneic stem cell transplantation (allo-SCT) could improve outcomes. 104 patients with peripheral T-cell non-Hodgkin lymphoma, except ALK+ anaplastic large cell lymphoma, 18 to 60 years, all stages, and all age adjusted International Prognostic Index scores, except 0 and stage I, were randomized to 4 cycles of CHOEP and 1 cycle of dexamethasone, cytosine-arabinoside, and platinum (DHAP) followed by high-dose therapy and auto-SCT or myeloablative conditioning and allo-SCT. The primary end point was event-free survival (EFS) at 3 years. After a median follow-up of 42 months, the 3-year EFS after allo-SCT was 43%, as compared with 38% after auto-SCT. Overall survival at 3 years was 57% vs 70% after allo- or auto-SCT, without significant differences between treatment arms. None of the 21 responding patients proceeding to allo-SCT relapsed, as opposed to 13 of 36 patients (36%) proceeding to auto-SCT. Eight of 26 patients (31%) and none of 41 patients died of transplant-related toxicity after allo- and auto-SCT, respectively. The strong graft-versus-lymphoma effect after allo-SCT was counterbalanced by transplant-related mortality. This trial is registered at www.clinicaltrials.gov as #NCT00984412.
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http://dx.doi.org/10.1182/blood.2020008825DOI Listing
May 2021

Automated Early Detection of Myelodysplastic Syndrome within the General Population Using the Research Parameters of Beckman-Coulter DxH 800 Hematology Analyzer.

Cancers (Basel) 2021 Jan 21;13(3). Epub 2021 Jan 21.

Department of Biological Hematology, Tours University Hospital, 37000 Tours, France.

The incidence of myelodysplastic syndrome increases with aging and the early diagnosis enables optimal care of these diseases. The DxH 800 hematology analyzer measures and calculates 126 cytological parameters, but only 23 are used for routine CBC assessment. The goal of this study was to use the 103 unexploited "research parameters" to develop an algorithm allowing for an early detection of subclinical MDS patients by triggering morphological analysis. Blood sample parameters from 101 MDS patients and 88 healthy volunteers were analyzed to identify the critical "research parameters" with: (i) the most significant differences between MDS patients and healthy volunteers, (ii) the best contributions to principal component analysis (PCA), first axis, and (iii) the best correlations with PCA, first two axes (cos > 0.6). Ten critical "research parameters" of white blood cells were identified, allowing for the calculation of an MDS-likelihood score (MDS-LS), based on logistic regression. Automatic calculation of the MDS-LS is easily implementable on the middleware system of the DxH 800 to generate a flag for blood smear review, and possibly early detection of MDS patients in the general population.
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http://dx.doi.org/10.3390/cancers13030389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865695PMC
January 2021

Long-term outcome of imatinib 400 mg compared to imatinib 600 mg or imatinib 400 mg daily in combination with cytarabine or pegylated interferon alpha 2a for chronic myeloid leukaemia: results from the French SPIRIT phase III randomised trial.

Leukemia 2021 08 22;35(8):2332-2345. Epub 2021 Jan 22.

Inserm CIC 1427, Université de Paris, Paris, France.

The STI571 prospective randomised trial (SPIRIT) French trial is a four-arm study comparing imatinib (IM) 400 mg versus IM 600 mg, IM 400 mg + cytarabine (AraC), and IM 400 mg + pegylated interferon alpha2a (PegIFN-α2a) for the front-line treatment of chronic-phase chronic myeloid leukaemia (CML). Long-term analyses included overall and progression-free survival, molecular responses to treatment, and severe adverse events. Starting in 2003, the trial included 787 evaluable patients. The median overall follow-up of the patients was 13.5 years (range 3 months to 16.7 years). Based on intention-to-treat analyses, at 15 years, overall and progression-free survival were similar across arms: 85%, 83%, 80%, and 82% and 84%, 87%, 79%, and 79% for the IM 400 mg (N = 223), IM 600 mg (N = 171), IM 400 mg + AraC (N = 172), and IM 400 mg + PegIFN-α2a (N = 221) arms, respectively. The rate of major molecular response at 12 months and deep molecular response (MR4) over time were significantly higher with the combination IM 400 mg + PegIFN-α2a than with IM 400 mg: p = 0.0001 and p = 0.0035, respectively. Progression to advanced phases and secondary malignancies were the most frequent causes of death. Toxicity was the main reason for stopping AraC or PegIFN-α2a treatment.
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http://dx.doi.org/10.1038/s41375-020-01117-wDOI Listing
August 2021

Occupational pesticide exposure increases risk of acute myeloid leukemia: a meta-analysis of case-control studies including 3,955 cases and 9,948 controls.

Sci Rep 2021 01 21;11(1):2007. Epub 2021 Jan 21.

Department of Biological Hematology, Tours University Hospital, Tours, France.

The impact of pesticides on health is a major public health concern. A higher risk to develop chronic lymphoid malignancies has been demonstrated to be associated with occupational pesticide exposure (OPE). By contrast, little is known of the impact of OPE on the occurrence of myeloid malignancies especially acute myeloid leukemia (AML). The purpose of this meta-analysis is to summarize data on the association between OPE and AML. A relevant dataset of case-control studies was extracted. Among 6784 references extracted, 14 were selected, representing 3,955 AML patients and 9,948 control subjects diagnosed between 1976 and 2010. An adverse association was found between OPE and AML (OR = 1.51; 95%CI: 1.10-2.08), not affected by sensitivity analyses. Funnel plot asymmetry suggested a publication bias underestimating OR. Stratified analysis showed the association to be driven by studies with: (1) monocentric AML patients and hospital-based control population, (2) Newcastle-Ottawa scale > 6 and the group of studies identified as with the lowest risk, (3) exposure assessment through peer-to-peer interview, (4) diagnosis in North America and Asia and after 1995, (5) restriction to de novo AML. Moreover, the association between OPE and AML was significant with insecticides. These findings broaden the spectrum of pesticide toxicity to myeloid malignancies.
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http://dx.doi.org/10.1038/s41598-021-81604-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820275PMC
January 2021

First-line treatment of double-hit and triple-hit lymphomas: Survival and tolerance data from a retrospective multicenter French study.

Am J Hematol 2021 03 29;96(3):302-311. Epub 2020 Dec 29.

Department of Hematology and Medical Oncology, Centre Léon Bérard, Lyon, France.

Historically, double or triple hit lymphoma (DHL and THL) have poor outcomes with conventional chemotherapy, but there is currently no guideline. We report the French experience in managing DHL and THL in first line using collective data on both survival and tolerance. All consecutive patients with newly diagnosis of large B-cell lymphoma with MYC, BCL2, and/or BCL6 rearrangements, as determined by FISH between January 2013 and April 2019 were included. Based on the eligibility criteria, 160 patients were selected among the 184 patients identified. With a median follow-up of 32 months, 2- and 4-year progression free survival (PFS) rates were 40% and 28% with R-CHOP compared with 57% and 52% with intensive chemotherapy (P = .063). There was no difference in overall survival (OS). For advanced stages, PFS was significantly longer with intensive chemotherapy than with R-CHOP (P = .029). There was no impact of autologous stem cell transplantation among patient in remission. For patients with central nervous system (CNS) involvement, the 2-year PFS and OS rate was 21% and 39%, vs 57% and 75% without CNS disease (P = .007 and P < .001). By multivariate analysis, elevated IPI score and CNS disease were strongly and independently associated with a poorer survival, whereas treatment was not significantly associated with OS. This is the largest series reporting the treatment of DHL and THL in Europe. The PFS was significantly longer with an intensive regimen for advanced stage, but no difference in OS, supporting the need for a prospective randomized trial.
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http://dx.doi.org/10.1002/ajh.26068DOI Listing
March 2021

Involvement of GPx-3 in the Reciprocal Control of Redox Metabolism in the Leukemic Niche.

Int J Mol Sci 2020 Nov 14;21(22). Epub 2020 Nov 14.

CNRS ERL 7001 LNOx "Leukemic Niche & Redox Metabolism", 37000 Tours, France.

The bone marrow (BM) microenvironment plays a crucial role in the development and progression of leukemia (AML). Intracellular reactive oxygen species (ROS) are involved in the regulation of the biology of leukemia-initiating cells, where the antioxidant enzyme GPx-3 could be involved as a determinant of cellular self-renewal. Little is known however about the role of the microenvironment in the control of the oxidative metabolism of AML cells. In the present study, a coculture model of BM mesenchymal stromal cells (MSCs) and AML cells (KG1a cell-line and primary BM blasts) was used to explore this metabolic pathway. MSC-contact, rather than culture with MSC-conditioned medium, decreases ROS levels and inhibits the Nrf-2 pathway through overexpression of GPx3 in AML cells. The decrease of ROS levels also inactivates p38MAPK and reduces the proliferation of AML cells. Conversely, contact with AML cells modifies MSCs in that they display an increased oxidative stress and Nrf-2 activation, together with a concomitant lowered expression of GPx-3. Altogether, these experiments suggest that a reciprocal control of oxidative metabolism is initiated by direct cell-cell contact between MSCs and AML cells. GPx-3 expression appears to play a crucial role in this cross-talk and could be involved in the regulation of leukemogenesis.
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http://dx.doi.org/10.3390/ijms21228584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696155PMC
November 2020

Horizontal meta-analysis identifies common deregulated genes across AML subgroups providing a robust prognostic signature.

Blood Adv 2020 10;4(20):5322-5335

Centre National de la Recherche Scientifique (CNRS) Equipe Recherche Labellisée (ERL) 7001-Leukemic Niche and Redox Metabolism (LNOx), Groupe Innovation et Ciblage Cellulaire (GICC) EA 7501, Université de Tours, Tours, France.

Advances in transcriptomics have improved our understanding of leukemic development and helped to enhance the stratification of patients. The tendency of transcriptomic studies to combine AML samples, regardless of cytogenetic abnormalities, could lead to bias in differential gene expression analysis because of the differential representation of AML subgroups. Hence, we performed a horizontal meta-analysis that integrated transcriptomic data on AML from multiple studies, to enrich the less frequent cytogenetic subgroups and to uncover common genes involved in the development of AML and response to therapy. A total of 28 Affymetrix microarray data sets containing 3940 AML samples were downloaded from the Gene Expression Omnibus database. After stringent quality control, transcriptomic data on 1534 samples from 11 data sets, covering 10 AML cytogenetically defined subgroups, were retained and merged with the data on 198 healthy bone marrow samples. Differentially expressed genes between each cytogenetic subgroup and normal samples were extracted, enabling the unbiased identification of 330 commonly deregulated genes (CODEGs), which showed enriched profiles of myeloid differentiation, leukemic stem cell status, and relapse. Most of these genes were downregulated, in accordance with DNA hypermethylation. CODEGs were then used to create a prognostic score based on the weighted sum of expression of 22 core genes (CODEG22). The score was validated with microarray data of 5 independent cohorts and by quantitative real time-polymerase chain reaction in a cohort of 142 samples. CODEG22-based stratification of patients, globally and into subpopulations of cytologically healthy and elderly individuals, may complement the European LeukemiaNet classification, for a more accurate prediction of AML outcomes.
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http://dx.doi.org/10.1182/bloodadvances.2020002042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594391PMC
October 2020

Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia.

Blood 2021 02;137(6):751-762

Notable Labs, Foster City, CA.

Approximately 50% of acute myeloid leukemia (AML) patients do not respond to induction therapy (primary induction failure [PIF]) or relapse after <6 months (early relapse [ER]). We have recently shown an association between an immune-infiltrated tumor microenvironment (TME) and resistance to cytarabine-based chemotherapy but responsiveness to flotetuzumab, a bispecific DART antibody-based molecule to CD3ε and CD123. This paper reports the results of a multicenter, open-label, phase 1/2 study of flotetuzumab in 88 adults with relapsed/refractory AML: 42 in a dose-finding segment and 46 at the recommended phase 2 dose (RP2D) of 500 ng/kg per day. The most frequent adverse events were infusion-related reactions (IRRs)/cytokine release syndrome (CRS), largely grade 1-2. Stepwise dosing during week 1, pretreatment dexamethasone, prompt use of tocilizumab, and temporary dose reductions/interruptions successfully prevented severe IRR/CRS. Clinical benefit accrued to PIF/ER patients showing an immune-infiltrated TME. Among 30 PIF/ER patients treated at the RP2D, the complete remission (CR)/CR with partial hematological recovery (CRh) rate was 26.7%, with an overall response rate (CR/CRh/CR with incomplete hematological recovery) of 30.0%. In PIF/ER patients who achieved CR/CRh, median overall survival was 10.2 months (range, 1.87-27.27), with 6- and 12-month survival rates of 75% (95% confidence interval [CI], 0.450-1.05) and 50% (95% CI, 0.154-0.846). Bone marrow transcriptomic analysis showed that a parsimonious 10-gene signature predicted CRs to flotetuzumab (area under the receiver operating characteristic curve = 0.904 vs 0.672 for the European LeukemiaNet classifier). Flotetuzumab represents an innovative experimental approach associated with acceptable safety and encouraging evidence of activity in PIF/ER patients. This trial was registered at www.clinicaltrials.gov as #NCT02152956.
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http://dx.doi.org/10.1182/blood.2020007732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885824PMC
February 2021

Retrospective review of end-of-life care in the last month of life in older patients with multiple myeloma: what collaboration between haematologists and palliative care teams?

BMJ Support Palliat Care 2020 Sep 4. Epub 2020 Sep 4.

Palliative Care Team, Regional University Hospital Centre Tours, Tours, Centre-Val de Loire, France

Objectives: Patients with haematological malignancies (HM) receive more aggressive treatments near the end-of-life (EOL) than patients with solid tumours. Palliative care (PC) needs are less widely acknowledged in patients with multiple myeloma (MM) than in other HM. The main objective of our study was to describe EOL care and PC referral in a population of older patients with MM.

Methods: We retrospectively included deceased inpatients and outpatients with an MM previously diagnosed at the age of 70 and over in two tertiary centres in France. We reported EOL characteristics regarding treatments considered to be aggressive-antimyeloma therapies, hospitalisations, blood product transfusions, intensive care units (ICUs) or emergency admissions-and PC referral.

Results: We included 119 patients. In their last month of life, 75 (63%) were hospitalised for fever, pain, asthenia, anaemia or bleeding, 49 (41%) were admitted in the emergency department and 12 (10%) in ICU, 76 (64%) still received antimyeloma therapy and 45 (38%) had at least two transfusions. Only 24 (20%) received PC intervention for pain, global care, family support, anxiety, social care or confusion. Median follow-up until death was 20 days.

Conclusions: Our study found a high rate of hospitalisations and antimyeloma therapies in the last month of life. The PC referral rate was low, often once specific treatments were stopped. Our results suggest the need for more effective collaboration between PC teams and haematologists in order to respond to the specific needs of these patients and to improve their quality of care at EOL.
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http://dx.doi.org/10.1136/bmjspcare-2020-002293DOI Listing
September 2020

Reactive oxygen species levels differentiate CD34 human progenitors based on CD38 expression.

Cytometry B Clin Cytom 2020 11 4;98(6):516-521. Epub 2020 Sep 4.

CNRS ERL7001 LNOx "Leukemic Niche & redox metabolism" and EA7501 GICC, Tours University, Tours, France.

Low reactive oxygen species (ROS) levels are well-established characteristics of mouse hematopoietic stem cells (HSCs). However, little is known about these levels in human HSCs. This study aimed at quantifying ROS levels in human CD34 CD38 and CD34 CD38 human progenitors from bone marrow, cord blood and cells mobilized for autologous HSC transplantation. A specifically devised multiparameter flow cytometry method was used to quantify ROS levels (H DCFDA staining) in sub-populations of primary cells. Results were confirmed by assessing gene expression level of the ROS scavenger GPX3, a key determinant of HSC self-renewal, in sorted CD34 CD38 and CD34 CD38 cells. CD34 CD38 cells from bone marrow and cord blood displayed significantly lower levels of ROS than CD34 CD38 cells and other leukocytes. Moreover, the correlation between ROS and GPX3 expression was verified in sorted CD34 CD38 and CD34 CD38 cells. These results confirm, in human, data previously reported in mice. Moreover, the flow cytometry assay we developed could allow for a more precise enumeration of repopulating primitive progenitors in the course of HSC transplantation.
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http://dx.doi.org/10.1002/cyto.b.21948DOI Listing
November 2020

High prevalence of clonal hematopoiesis in the blood and bone marrow of healthy volunteers.

Blood Adv 2020 08;4(15):3550-3557

Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, Paris, France.

Clonal hematopoiesis (CH) of indeterminate potential has been described in blood samples from large series of patients. Its prevalence and consequences are still not well understood because sequencing methods vary and because most studies were performed in cohorts comprising individuals with nonhematologic diseases. Here, we investigated the frequency of CH in 82 paired bone marrow and blood samples from carefully selected healthy adult volunteers. Forty-one genes known to be mutated in myeloid malignancies were sequenced with a 1% threshold of detection. In bone marrow samples, clones were found in almost 40% of healthy volunteers more than 50 years old. The most frequent mutations were found in DNMT3A and TET2, with 1 individual carrying 3 variants. Variant allele frequencies were highly concordant between blood and bone marrow samples. Blood parameters were normal except for those in 2 individuals: 1 had a mild macrocytosis and 1 had a mild thrombocytosis. Furthermore, no morphologic abnormalities or dysplasia were detected when bone marrow smears were carefully evaluated. Individuals with CH differed from others by age (62.8 vs 38.6 years; P < .0001) and platelet count (294 vs 241 ×109/L; P = .0208), the latter being no more significant when removing the 2 individuals who carried the JAK2 p.V617F mutation. These results confirm that CH is a very common condition in healthy adults over 50 years old. Consequently, the detection of driver myeloid mutations should be interpreted with caution in the absence of cytologic abnormalities in the blood and/or the bone marrow.
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http://dx.doi.org/10.1182/bloodadvances.2020001582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422125PMC
August 2020

Safety and efficacy of temsirolimus in combination with three different immuno-chemotherapy regimens in relapse and refractory mantle cell lymphoma, final results of the T phase IB trial of the LYSA.

Ann Hematol 2020 Aug 29;99(8):1771-1778. Epub 2020 Jun 29.

Department of Hematology, CHU de Nantes, University Hospital of Nantes, Nantes, France.

Mantle cell lymphoma has a dismal prognosis at relapse or in the refractory setting. Among therapies, mTor pathway targeting by temsirolimus has been the first strategy approved for relapse in Europe. While its efficacy in monotherapy has long been demonstrated, its use remains limited. In the T phase Ib clinical trial, we investigated the recommended dose of temsirolimus in association with R-CHOP (R-CHOP-T), or high-dose cytarabine plus rituximab (R-DHA-T), or fludarabine, cyclophosphamide plus rituximab (R-FC-T). From November 11, 2011 to February 26, 2015, forty-one patients were enrolled. Patients presented with high MIPI (47.5%) at relapse and a median number of treatments of 1 (1-3). Patients were treated by R-CHOP-T (n = 10), R-FC-T (n = 14), or R-DHA-T (n = 17) according to the choice of local investigators. The maximum tolerated dose (MTD) was 15 mg in the R-CHOP-T arm and has not been determined in other treatment arms because of toxicities. All patients experienced ≥ Grade 3 adverse events, mainly thrombocytopenia (76%). Twenty-six patients discontinued prematurely the treatment, mostly for toxicity (n = 12) and progression of the disease (n = 8). Of note, 6 patients of the R-DHA-T arm reached complete remission (35%). Temsirolimus with immuno-chemotherapy is associated with a high rate of toxicities. Determination of MTD could only be achieved for R-CHOP-T arm. Associations between temsirolimus and other targeted therapies may be warranted for R/R MCL patients.
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http://dx.doi.org/10.1007/s00277-020-04159-3DOI Listing
August 2020

Whole genome copy number analysis in search of new prognostic biomarkers in first line treatment of mantle cell lymphoma. A study by the LYSA group.

Hematol Oncol 2020 Oct 25;38(4):446-455. Epub 2020 Jun 25.

CRCINA, INSERM, CNRS, Université d'Angers, Université de Nantes, Nantes, France.

Mantle cell lymphoma (MCL) is a lymphoproliferative disorder characterized by the t(11;14)(q13;q32) CCND1/IGH translocation. This lymphoma is however extremely heterogeneous in terms of molecular alterations. Moreover, the course of the disease can vary greatly between indolent forms with slow progression and aggressive conditions rapidly pejorative. The identification of early markers allowing to predict individual patients outcome has however been unsuccessful so far. The LyMa trial treated homogeneously a cohort of young MCL patients. This appeared as a good opportunity to search for biomarkers of response to therapy. DNA extracted from diagnostic paraffin-embedded lymph node biopsies from 100 patients with newly diagnosed MCL, homogeneously treated in this prospective clinical trial, were investigated for copy number alterations and copy neutral loss of heterozygosity using the Oncoscan SNP-array scanning the whole genome. An independent confirmatory cohort was used to strengthen the possibly relevant anomalies observed. Here we describe the recurrent anomalies identified with this technique. Deletions of 17p(TP53) and 9p(CDKN2A) were more frequent in refractory or early relapsing patients (10%), but had no significant impact in univariate analysis on progression-free (PFS) or overall survival (OS). Regardless of the presence of TP53 or CDKN2A deletions, gains in 7p22 (8,5%) were associated with better PFS in univariate but not in multivariate analysis including MCL International Prognostic Index and treatment. Gains of 11q(CCDN1), suggesting gains of the CCND1/IGH fusion, were associated with worse OS and PFS in univariate and multivariate analyses. This worse prognosis impact was confirmed by FISH in an independent confirmatory cohort. This work, using a whole genome approach, confirms the broad genomic landscape of MCL and shows that gains of the CCND1/IGH fusion can be considered as a new prognostic structural variant. Genomic abnormalities of prognostic impact could be useful to strengthen or de-escalate treatment schedules or choosing targeted therapies or CART-cells.
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http://dx.doi.org/10.1002/hon.2750DOI Listing
October 2020
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