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Summary: CXCR4 cell surface expression is critical for the homing of T regulatory (Treg) cells to the bone marrow (BM). We hypothesize that CXCR4 enrichment on Tregs cell surface may abbreviate their transit time to reach BM. Umbilical cord-blood CD25+ Tregs underwent CXCR4 dual enrichment and ex vivo expansion using the CRANE process to generate CXCR4-enriched Tregs (TregCXCR4) cells, which showed a faster migration across the Transwell membrane toward CXCL12/stromal cell-derived factor 1α (SDF1α) at 15, 30, and 60 min, when compared to unmanipulated Tregcontrol cells (p

Interferons are cytokines with immunomodulatory properties and disease-modifying effects that have been used to treat myeloproliferative neoplasms (MPNs) for more than 35 years. The initial use of interferons was limited due to difficulties with administration and a significant toxicity profile. Many of these shortcomings were addressed by covalently binding polyethylene glycol to the interferon structure, which increases the stability, prolongs activity, and reduces immunogenicity of the molecule. In the current therapeutic landscape, pegylated interferons are recommended for use in the treatment of polycythemia vera, essential thrombocythemia, and primary myelofibrosis. We review recent efficacy, molecular response, and safety data for the two available pegylated interferons, peginterferon alfa-2a (Pegasys) and ropeginterferon alfa-2b-njft (BESREMi). The practical management of interferon-based therapies is discussed, along with our opinions on whether to and how to switch from hydroxyurea to one of these therapies. Key topics and questions related to use of interferons, such as their safety and tolerability, the significance of variant allele frequency, advantages of early treatment, and what the future of interferon therapy may look like, will be examined. Pegylated interferons represent an important therapeutic option for patients with MPNs; however, more research is still required to further refine interferon therapy.

Abstract Preclinically, enasidenib and azacitidine (ENA + AZA) synergistically enhance cell differentiation, and venetoclax (VEN), a small molecule Bcl2 inhibitor (i) is particularly effective in IDH2 mutated acute myeloid leukemia (IDH2 mut AML). This open label phase II trial enrolled patients (pts) with documented IDH2 mut AML. All patients received AZA 75 mg/m2/d x 7 d/cycle and ENA 100 mg QD continuously. Concomitant Bcl2i and FLT3i were allowed (NCT03683433).Twenty-six pts received ENA + AZA (median 68 years, range, 24–88); 7 newly diagnosed (ND) and 19 relapsed/refractory (R/R). In R/R AML patients, three had received prior ENA and none had received prior VEN. The composite complete remission rate (CRc) [complete remission (CR) or complete remission with incomplete hematologic recovery (CRi)] was 100% in ND AML, and 58% in R/R AML. Median OS was not reached in ND AML with median follow-up of 13.1 months (mo); Pts treated in first relapse had improved OS than those with ≥2 relapse (median OS not reached vs 5.2 mo; HR 0.24, 95% CI 0.07–0.79, p = 0.04). Two patients received ENA + AZA with a concomitant FLT3i, one responding ND AML patient and one nonresponding R/R AML patient. Seven R/R AML pts received ENA + AZA + VEN triplet, and with median follow up of 11.2 mo, median OS was not reached and 6-mo OS was 70%. The most frequent treatment-emergent adverse events include febrile neutropenia (23%). Adverse events of special interest included all-grade IDH differentiation syndrome (8%) and indirect hyperbilirubinemia (35%). ENA + AZA was a well-tolerated, and effective therapy for elderly pts with IDH2 mut ND AML as well as pts with R/R AML. The addition of VEN to ENA + AZA appears to improve outcomes in R/R IDH2 mut AML. Clinical trial registration information: https://clinicaltrials.gov/.NCT03683433

Abstract Background In terms of cardiovascular magnetic resonance are haematocrit values required for calculation of extracellular volume fraction (ECV). Previously published studies have hypothesized that haematocrit could be calculated from T1 blood pool relaxation time, however only native T1 relaxation time values have been used and the resulting formulae had been both in reciprocal and linear proportion. The aim of the study was to generate a synthetic haematocrit formula from only native relaxation time values first, calculate whether linear or reciprocal model is more precise in haematocrit estimation and then determine whether adding post-contrast values further improve its precision. Methods One hundred thirty-nine subjects underwent CMR examination. Haematocrit was measured using standard laboratory methods. Afterwards T1 relaxation times before and after the application of a contrast agent were measured and a statistical relationship between these values was calculated. Results Different linear and reciprocal models were created to estimate the value of synthetic haematocrit and ECV. The highest coefficient of determination was observed in the combined reciprocal model “− 0.047 + (779/ blood native) − (11.36/ blood post-contrast)”. Conclusions This study provides more evidence that assessing synthetic haematocrit and synthetic ECV is feasible and statistically most accurate model to use is reciprocal. Adding post-contrast values to the calculation was proved to improve the precision of the formula statistically significantly.

Abstract There is an unmet need to overcome nongenetic therapy-resistance to improve outcomes in AML, especially post-myeloproliferative neoplasm (MPN) secondary (s) AML. Studies presented describe effects of genetic knockout, degradation or small molecule targeted-inhibition of GFI1/LSD1 on active enhancers, altering gene-expressions and inducing differentiation and lethality in AML and (MPN) sAML cells. A protein domain-focused CRISPR screen in LSD1 (KDM1A) inhibitor (i) treated AML cells, identified BRD4, MOZ, HDAC3 and DOT1L among the codependencies. Our findings demonstrate that co-targeting LSD1 and one of these co-dependencies exerted synergistic in vitro lethality in AML and post-MPN sAML cells. Co-treatment with LSD1i and the JAKi ruxolitinib was also synergistically lethal against post-MPN sAML cells. LSD1i pre-treatment induced GFI1, PU.1 and CEBPα but depleted c-Myc, overcoming nongenetic resistance to ruxolitinib, or to BETi in post-MPN sAML cells. Co-treatment with LSD1i and BETi or ruxolitinib exerted superior in vivo efficacy against post-MPN sAML cells. These findings highlight LSD1i-based combinations that merit testing for clinical efficacy, especially to overcome nongenetic therapy-resistance in AML and post-MPN sAML.

Abstract Background Gigantic left atrium is defined in the current literature as an excessive dilatation of the left atrium above 65mm. Chronic mitral valve disease is associated with the development of thrombus in the left atrium in up to 19% of all cases of mitral insufficiency and appropriate treatment must be initiated to prevent thromboembolic events. In order to diagnose thrombi in the left atrium or left atrial appendage, various imaging methods may be used, including cardiac magnetic resonance. Case presentation The case report describes a 73-year-old male who developed recurrent sessile thrombus on the posterior wall of the gigantic left atrium. A large thrombus was first detected following mitral valve surgery despite effective vitamin K antagonist anticoagulation therapy. Echocardiography and cardiac magnetic resonance were used within the diagnostic procedure and to monitor the treatment outcomes. Cardiac magnetic resonance was shown to be beneficial as it provided a more precise description of the intra-atrial masses located on the posterior left atrial wall, and in such situations, is of greater benefit than standard echocardiography. This led to the surgical removal of the intra-atrial mass; nevertheless, it was quickly followed by the recurrence of the thrombus. The anticoagulant therapy was adjusted and fortified by the introduction of acetylsalicylic acid and sequentially clopidogrel, but this also did not resolve the thrombus formation. Finally, employing a combination of rivaroxaban and clopidogrel resulted in partial thrombus regression. Therefore, various pathophysiological aspects of thrombus formation and used anticoagulation strategies are discussed. Conclusions We describe a unique case of a recurrent thrombus located on the posterior wall of the gigantic left atrium. Cardiac magnetic resonance was shown to be beneficial in providing a more precise description of the intra-atrial masses located on the posterior left atrial wall as compared to standard echocardiographic examination. Development of a thrombus after mitral valve surgery despite effective anticoagulant therapy and its final resolution by introducing a combination of rivaroxaban and clopidogrel highlights the complex etiopathogenesis of thrombus formation. This supports the potential use of this combination in tailoring an individual personalized therapy for patients with recurrent atrial thrombi.

Approximately 20-50% patients with chronic phase chronic myeloid leukemia (CML-CP) treated with tyrosine kinase inhibitors (TKI) or with myelofibrosis (MF) treated with ruxolitinib develop grade ≥3 thrombocytopenia needing treatment interruptions and dose reductions. We conducted a non-randomized, phase II, single-arm study to determine the efficacy of eltrombopag for patients with CML or MF with persistent thrombocytopenia while on TKI or ruxolitinib. Eltrombopag was initiated at 50 mg/day, with dose escalation up to 300 mg daily allowed every 2 weeks. Twenty-one patients were enrolled (CML=15, MF=6); with a median age of 60 years (range, 31-97 years). The median platelet count was 44x109/L (range, 3-49x109/L) in CML and 62x109/L (range, 21-75x109/L) in MF. After a median of 18 months (range, 5-77 months), 12 of 15 patients with CML achieved complete platelet response. The median peak platelet count among responders was 154x109/L (range, 74-893x109/L). Among CML patients five could re-escalate the TKI dose and nine improved their response. None of the six patients with MF had a sustained response. Therapy was generally well tolerated. One patient discontinued therapy due to toxicity (elevated transaminases). One patient with CML developed significant thrombocytosis (>1,000x109/L). Another CML patient developed non occlusive deep venous thrombosis in the right upper extremity without thrombocytosis, and one MF patient had myocardial infarction. Eltrombopag may help improve platelet counts in CML patients receiving TKI with recurrent thrombocytopenia. Further studies are warranted (clinicaltrials gov. Identifier: NCT01428635).

Abstract Background Pegylated interferon alfa-2a (PEG-IFN-α-2a) is a potent immunomodulating agent capable of inducing high rate of hematologic and even complete molecular remission in patients with essential thrombocythemia (ET) and polycythemia vera (PV). We recently reported results of a phase 2 trial of PEG-IFN-α-2a in 83 patients with ET and PV after a median follow-up of 83 months. Here we report an analysis of bone marrow (BM) responses in these patients. Methods Among 83 patients, 58 (70%, PV 25, ET 31) had evaluable BM samples. BM responses and fibrosis grading were defined according to the International Working Group for Myeloproliferative Neoplasms Research and Treatment, and the European Consensus on grading of BM fibrosis, respectively. BM was assessed prior to enrollment, and every 6–24 months while on therapy in all patients, and after therapy discontinuation in some patients. Results The median age of analyzed 58 patients was 52 years, and 29% were males. After a median follow-up of 84 months, 32 patients are still on study. Hematologic (HR) and molecular responses (MR) were seen in 93 and 69% patients, respectively. Twenty-nine patients (50%) had a BM response, including 13 (22%) with a complete BM response (BM-CR). Moreover, 13 patients (22%) have experienced complete resolution of bone marrow reticulin fibrosis. Patients with BM response had higher duration of HR and MR, and lower discontinuation rate. Furthermore, patients with BM-CR had a higher probability of complete MR. The median duration of BM-CR was 30 months, and 9 patients have maintained their BM-CR (69%), including five who have maintained their response after discontinuation of therapy. Despite this observation, the pattern of HR, MR and BM response, their durability and interrelation was heterogeneous. Conclusions Our results show the ability of PEG-IFN-α-2a to induce complete BM responses in a subset of ET and PV patients, but its correlation with durable clinically relevant treatment benefit warrants further investigation. Trial registration This study is registered with ClinicalTrials.gov (NCT00452023), and is ongoing but not enrolling new patients.

Abstract Background Female carriers of dystrophin gene mutations (DMD-FC) were previously considered non-manifesting, but in recent decades, cardiomyopathy associated with muscular dystrophy and myocardial fibrosis has been described. Our study aimed to assess prospectively myocardial fibrosis in asymptomatic DMD-FC compared to a sex-matched control group (CG) with similar age distribution using native T1 mapping and extracellular volume (ECV) quantification by cardiovascular magnetic resonance (CMR) imaging. Materials and methods 38 DMD-FC with verified genetic mutation and 22 healthy volunteers were included. Using CMR, native T1 relaxation time and ECV quantification were determined in each group. Late gadolinium enhancement (LGE) was assessed in all cases. Results There were 38 DMD-FC (mean age 39.1 ± 8.8 years) and 22 healthy volunteers (mean age 39.9 ± 12.6 years) imagined by CMR. The mean global native T1 relaxation time was similar for DMD-FC and CG (1005.1 ± 26.3 ms vs. 1003.5 ± 25.0 ms; p-value = 0.81). Likewise, the mean global ECV value was also similar between the groups (27.92 ± 2.02% vs. 27.10 ± 2.89%; p-value = 0.20). The segmental analysis of mean ECV values according to the American Heart Association classification did not show any differences between DMD-FC and CG. There was a non-significant trend towards higher mean ECV values of DMD-FC in the inferior and inferolateral segments of the myocardium (p-value = 0.075 and 0.070 respectively). Conclusion There were no statistically significant differences in the mean global and segmental native T1 relaxation times and the mean global or segmental ECV values. There was a trend towards higher segmental mean ECV values of DMD-FC in the inferior and inferolateral walls of the myocardium.

In this prospective study involving 37 Duchenne muscular dystrophy (DMD) patients aged 8–18 years and older, we examined the impact of neurological and cardiac factors on quality of life (QoL). Our findings revealed a negative correlation between upper limb movement and overall mobility, self-service, and usual activities. Ambulatory and non-ambulatory DMD patients showed significant differences in mobility-related parameters. Cardiac evaluations demonstrated associations between mitral annular plane systolic excursion (MAPSE) and mobility-related aspects. The PEDSQL 3.0 neuromuscular model questionnaire further highlighted age-related and movement-related correlations with QoL. The loss of ambulatory status and reduced upper limb movement were negatively associated with QoL, while upper limb movement positively correlated with septal MAPSE. However, no significant associations were found between MAPSE and anxiety/depression. These findings underscore the multifaceted impact of DMD on QoL and emphasize the importance of considering both neurological and cardiac factors in comprehensive patient care.

Abstract Atrial fibrillation (AF) is an abnormal and irregular heartbeat caused by uncoordinated electrical impulses in the left atrium (LA), which could induce lasting changes in the heart tissue or could be a consequence of underlying cardiac disease. This study aimed to assess the left atrial phasic function and deformation in paroxysmal AF (PAF) patients—who had not received radiofrequency ablation and had no signs of permanent AF—using the cardiovascular magnetic resonance (CMR) feature-tracking (FT) technique. Fifty subjects (27 PAF patients and 23 controls) were included and examined with CMR. Their LA volume, LA function, LA longitudinal strain (LS) and LA strain rate were assessed in the LA reservoir, conduit, and contractile phases. PAF patients exhibited higher LA volumes than controls, while their LA emptying fraction and LA LS was significantly lower in all three phases. In contrast, the corresponding emptying volumes (total, passive and active) were similar in both groups. The LA volumetric rates from CMR-derived volume curves differed significantly in PAF patients vs controls in the reservoir and contractile phases. In contrast, the equivalent LV volumetric rates were similar. This study suggests that assessing the LA phasic function could offer insight into early LA impairments for PAF patients.

Abstract Rest pulmonary circulation parameters such as pulmonary transit time (PTT), heart rate corrected PTT (PTTc) and pulmonary transit beats (PTB) can be evaluated using several methods, including the first-pass perfusion from cardiovascular magnetic resonance. As previously published, up to 58% of patients after HTx have diastolic dysfunction detectable only in stress conditions. By using adenosine stress perfusion images, stress analogues of the mentioned parameters can be assessed. By dividing stress to rest biomarkers, potential new ratio parameters (PTT ratio and PTTc ratio) can be obtained. The objectives were to (1) provide more evidence about stress pulmonary circulation biomarkers, (2) present stress to rest ratio parameters, and (3) assess these biomarkers in patients with presumed diastolic dysfunction after heart transplant (HTx) and in childhood cancer survivors (CCS) without any signs of diastolic dysfunction. In this retrospective study, 48 patients after HTx, divided into subgroups based on echocardiographic signs of diastolic dysfunction (41 without, 7 with) and 39 CCS were enrolled. PTT was defined as the difference between the onset time of the signal intensity increase in the left and the right ventricle. PTT in rest conditions were without significant differences when comparing the CCS and HTx subgroup without diastolic dysfunction (4.96 ± 0.93 s vs. 5.51 ± 1.14 s, p = 0.063) or with diastolic dysfunction (4.96 ± 0.93 s vs. 6.04 ± 1.13 s, p = 0.13). However, in stress conditions, both PTT and PTTc were significantly lower in the CCS group than in the HTx subgroups, (PTT: 3.76 ± 0.78 s vs. 4.82 ± 1.03 s, p

Abstract Background Sarcoidosis is a systemic granulomatous disease affecting different organs including the heart. Myocardial strain analysis could potentially detect the early stages of cardiac dysfunction in sarcoidosis patients. The present study aims to assess the use of cardiac magnetic resonance (CMR) strain analysis using feature tracking (FT) in the detection of early cardiac involvement in asymptomatic patients with sarcoidosis. Methods One hundred and thirteen CMR studies of patients with sarcoidosis of the respiratory tract and/or extrapulmonary sarcoidosis without pre-existing known cardiovascular disease were included in the study and analysed using FT and compared to 22 age and gender-matched controls. Global longitudinal strain (GLS), global circumferential strain (GCS) and global radial strain (GRS) of the left ventricle (LV) were measured. Results The sarcoidosis patients did not significantly differ from the controls in basic demographic data and had normal global and regional systolic LV function—LV ejection fraction (EF) 66 ± 7% vs 65 ± 5% in the controls (p = NS). No statistically significant differences were found in all strain parameters between patients and controls: GLS (− 13.9 ± 3.1 vs. − 14.2 ± 2.5), GCS (− 23.4 ± 4.0 vs. − 22.2 ± 2.9) and GRS (53.4 ± 13.5 vs. 51.2 ± 13.6%) (p = NS). Conclusion Patients with sarcoidosis of the respiratory tract and/or extrapulmonary sarcoidosis had normal myocardial deformation measured by CMR-FT derived global strain

Abstract Background Duchenne muscular dystrophy (DMD) manifests in males mainly by skeletal muscle impairment, but also by cardiac dysfunction. The assessment of the early phases of cardiac involvement using echocardiography is often very difficult to perform in these patients. The aim of the study was to use cardiac magnetic resonance (CMR) strain analysis and mitral annular plane systolic excursion (MAPSE) in the detection of early left ventricular (LV) dysfunction in DMD patients. Methods and results In total, 51 male DMD patients and 18 matched controls were examined by CMR. MAPSE measurement and functional analysis using feature tracking (FT) were performed. Three groups of patients were evaluated: A/ patients with LGE and LV EF

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 51-year-old woman was diagnosed with essential thrombocythemia (ET) the previous year (April 2016) when she was incidentally found to have increased platelets (747 × 10 9 /L) during a yearly physical examination. Her past medical history was significant only for mild hypertension, which was well controlled with a low dose of a β-blocker. There was no history of thromboembolic events. A JAK2 V617F mutation was detected in her peripheral blood. A repeated platelet count 1 month later showed increased platelets of 871 × 10 9 /L and she began hydroxyurea. One year later, she presented to our clinic with a white cell count of 8.9 × 10 9 /L, hemoglobin 14 g/dL, and platelets 846 ×10 9 /L while receiving hydroxyurea 500 mg one day alternating with 1000 mg the next day and aspirin 81 mg once per day. The differential as well as other laboratory findings were within normal limits. She had chronic mild to moderate itching, but otherwise denied symptoms referable to ET. Her physical examination was notable for the absence of palpable hepatosplenomegaly. Bone marrow aspiration and biopsy revealed normocellular marrow with hyperplastic megakaryocytes in clusters, no reticulin fibrosis, and 2% blasts, compatible with ET. Molecular testing confirmed JAK2 V617F mutations at a variant allele frequency of 12% without any other mutations (81-gene panel), and her karyotype was diploid. She visited the clinic to discuss the next steps in her treatment.