Treatment free remission (TFR) after second-generation tyrosine kinase inhibitors (2G-TKIs) treatment in chronic myeloid leukemia (CML): from feasibility to safety.

INTRODUCTION: Chronic myeloid leukemia (CML) prevalence is currently increasing due to the great efficacy of tyrosine kinase inhibitor (TKI) therapy. Discontinuation of treatment in the long-term, owing to avoid off-target side effects or treatment-free remission (TFR), has become an additional treatment goal in CML patients who achieved a deep molecular response (DMR). Second-generation TKIs (2 G-TKIs) have a significantly higher rate of DMR than imatinib. Hence, especially in young patients with a strategy of TFR, 2 G-TKIs are becoming the most frequently used TKIs and may increase TFR attempts in the future. AREAS COVERED: In this review, the main findings extrapolated from clinical trials and real-life evidence regarding 2 G-TKIs discontinuation were discussed, through broad research on Medline, Embase, and archives from EHA and ASH congresses. EXPERT OPINION: Overall, TFR rate after 2 G-TKIs is ranging from 40% to 60% for selected patients with sustained DMR and it can be considered a safe procedure, that have become, nowadays, a daily practice. However, many crucial aspects regarding treatment choices, timings, as well as predictive factors, patient communication, and optimal strategies need to be better clarified to improve successful TFR rate.

Physical Exercise in Kidney Renal Recipients: Where have We Come.

Background Kidney transplantation constitutes the most effective therapeutic option for patients suffering from end-stage renal disease but remains burdened by a high incidence of cardiovascular disease. To date, exercise is an important preventive strategy that has been underestimated; in kidney transplant patients exercise programs leads to an improvement in cardiorespiratory performance, muscle strength, arterial stiffness and patients' quality of life perception. Summary The nephrology and transplant community have moved from generic suggestions to specific indications regarding Frequency, Intensity, Time, Type, Volume, and Progression of physical exercise both in the pre- and post-transplant phase. The latest guidelines from the World Health Organization for patients with chronic conditions propose a combination of aerobic, muscle strengthening and multicomponent exercises (e.g. balance) to improve health. Based on recent evidence, a combined exercise program (aerobic and strength exercise) is largely proposed to kidney transplant recipients. Aerobic exercise should be performed at an intensity >60% of theoretical maximum heart rate or maximum oxygen uptake possibly every day, strength training should be performed at a >60% the estimate single Maximum Repetition, at least 2 times per week. Key Messages Physical exercise should be personalized in relation to the patient's baseline performance; increases must be progressive and gradual. Regular physical activity should also be recommended to patients awaiting for a transplant. Eventually, an organizational models based on a network of Nephrology Units, Transplant Centers, Sports Medicine Centers and fitness center or outdoor gym are essential elements for overcoming the logistical barriers for prescribing and carrying out regular physical activity.

The new neural pressure support (NPS) mode and the helmet: did we find the dynamic duo?

BACKGROUND: Noninvasive ventilation (NIV) is commonly used in clinical practice to reduce intubation times and enhance patient comfort. However, patient-ventilator interaction (PVI) during NIV, particularly with helmet interfaces, can be challenging due to factors such as dead space and compliance. Neurally adjusted ventilatory assist (NAVA) has shown promise in improving PVI during helmet NIV, but limitations remain. A new mode, neural pressure support (NPS), aims to address these limitations by providing synchronized and steep pressurization. This study aims to assess whether NPS per se improves PVI during helmet NIV compared to standard pressure support ventilation (PSV). METHODS: The study included adult patients requiring NIV with a helmet. Patients were randomized into two arms: one starting with NPS and the other with PSV; the initial ventilatory parameters were always set as established by the clinician on duty. Physiological parameters and arterial blood gas analysis were collected during ventilation trials. Expert adjustments to initial ventilator settings were recorded to investigate the impact of the expertise of the clinician as confounding variable. Primary aim was the synchrony time (Timesync), i.e., the time during which both the ventilator and the patient (based on the neural signal) are on the inspiratory phase. As secondary aim neural-ventilatory time index (NVTI) was also calculated as Timesync divided to the total neural inspiratory time, i.e., the ratio of the neural inspiratory time occupied by Timesync. RESULTS: Twenty-four patients were enrolled, with no study interruptions due to safety concerns. NPS demonstrated significantly longer Timesync (0.64 ± 0.03 s vs. 0.37 ± 0.03 s, p < 0.001) and shorter inspiratory delay (0.15 ± 0.01 s vs. 0.35 ± 0.01 s, p < 0.001) compared to PSV. NPS also showed better NVTI (78 ± 2% vs. 45 ± 2%, p < 0.001). Ventilator parameters were not significantly different between NPS and PSV, except for minor adjustments by the expert clinician. CONCLUSIONS: NPS improves PVI during helmet NIV, as evidenced by longer Timesync and better coupling compared to PSV. Expert adjustments to ventilator settings had minimal impact on PVI. These findings support the use of NPS in enhancing patient-ventilator synchronization and warrant further investigation into its clinical outcomes and applicability across different patient populations and interfaces. TRIAL REGISTRATION: This study was registered on www. CLINICALTRIALS: gov NCT06004206 Registry URL: https://clinicaltrials.gov/study/NCT06004206 on September 08, 2023.

Unwinding of a eukaryotic origin of replication visualized by cryo-EM.

To prevent detrimental chromosome re-replication, DNA loading of a double hexamer of the minichromosome maintenance (MCM) replicative helicase is temporally separated from DNA unwinding. Upon S-phase transition in yeast, DNA unwinding is achieved in two steps: limited opening of the double helix and topological separation of the two DNA strands. First, Cdc45, GINS and Polε engage MCM to assemble a double CMGE with two partially separated hexamers that nucleate DNA melting. In the second step, triggered by Mcm10, two CMGEs separate completely, eject the lagging-strand template and cross paths. To understand Mcm10 during helicase activation, we used biochemical reconstitution with cryogenic electron microscopy. We found that Mcm10 splits the double CMGE by engaging the N-terminal homo-dimerization face of MCM. To eject the lagging strand, DNA unwinding is started from the N-terminal side of MCM while the hexamer channel becomes too narrow to harbor duplex DNA.

Cascade reactions with two non-physiological partners for NAD(P)H regeneration via renewable hydrogen.

An attractive application of hydrogenases, combined with the availability of cheap and renewable hydrogen (i.e., from solar and wind powered electrolysis or from recycled wastes), is the production of high-value electron-rich intermediates such as reduced nicotinamide adenine dinucleotides. Here, the capability of a very robust and oxygen-resilient [FeFe]-hydrogenase (CbA5H) from Clostridium beijerinckii SM10, previously identified in our group, combined with a reductase (BMR) from Bacillus megaterium (now reclassified as Priestia megaterium) was tested. The system shows a good stability and it was demonstrated to reach up to 28 ± 2 nmol NADPH regenerated s-1 mg of hydrogenase-1 (i.e., 1.68 ± 0.12 U mg-1, TOF: 126 ± 9 min-1) and 0.46 ± 0.04 nmol NADH regenerated s-1 mg of hydrogenase-1 (i.e., 0.028 ± 0.002 U mg-1, TOF: 2.1 ± 0.2 min-1), meaning up to 74 mg of NADPH and 1.23 mg of NADH produced per hour by a system involving 1 mg of CbA5H. The TOF is comparable with similar systems based on hydrogen as regenerating molecule for NADPH, but the system is first of its kind as for the [FeFe]-hydrogenase and the non-physiological partners used. As a proof of concept a cascade reaction involving CbA5H, BMR and a mutant BVMO from Acinetobacter radioresistens able to oxidize indole is presented. The data show how the cascade can be exploited for indigo production and multiple reaction cycles can be sustained using the regenerated NADPH.

Laparoscopic Treatment of Perforated Peptic Ulcer: A Propensity Score-Matched Comparison of Interrupted Stitches Repair versus Knotless Barbed Suture.

Background: Peptic ulcers result from imbalanced acid production, and in recent decades, proton pump inhibitors have proven effective in treating them. However, perforated peptic ulcers (PPU) continue to occur with a persistent high mortality rate when not managed properly. The advantages of the laparoscopic approach have been widely acknowledged. Nevertheless, concerning certain technical aspects of this method, such as the best gastrorrhaphy technique, the consensus remains elusive. Consequently, the choice tends to rely on individual surgical experiences. Our study aimed to compare interrupted stitches versus running barbed suture for laparoscopic PPU repair. Methods: We conducted a retrospective study utilizing propensity score matching analysis on patients who underwent laparoscopic PPU repair. Patients were categorised into two groups: Interrupted Stitches Suture (IStiS) and Knotless Suture (KnotS). We then compared the clinical and pathological characteristics of patients in both groups. Results: A total of 265 patients underwent laparoscopic PPU repair: 198 patients with interrupted stitches technique and 67 with barbed knotless suture. Following propensity score matching, each group (IStiS and KnotS) comprised 56 patients. The analysis revealed that operative time did not differ between groups: 87.9 ± 39.7 vs. 92.8 ± 42.6 min (p = 0.537). Postoperative morbidity (24.0% vs. 32.7%, p = 0.331) and Clavien-Dindo III (10.7% vs. 5.4%, p = 0.489) were more frequently observed in the KnotS group, without any significant difference. In contrast, we found a slightly higher mortality rate in the IStiS group (10.7% vs. 7.1%, p = 0.742). Concerning leaks, no differences emerged between groups (3.6% vs. 5.4%, p = 1.000). Conclusions: Laparoscopic PPU repair with knotless barbed sutures is a non-inferior alternative to interrupted stitches repair. Nevertheless, further research such as randomised trials, with a standardised treatment protocol according to ulcer size, are required to identify the best gastrorraphy technique.

Long-term health-related quality of life and mental health in patients with immune thrombotic thrombocytopenic purpura.

Immune thrombotic thrombocytopenic purpura (iTTP) is a rare and potentially life-threatening disorder. Treatment advances have lowered morbidity rates, but past acute events can still cause long-term consequences, reducing health-related quality of life (HRQoL) and determining cognitive impairment, anxiety, and depression. We aimed to investigate these aspects and the role of caplacizumab and rituximab: 39 patients were evaluated using the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), the FACIT-Fatigue, the Hospital Anxiety and Depression Scale, and the Functional Assessment in Cancer Therapy-Cognitive Function questionnaires. The median age at study inclusion was 50 years (IQR 38-60), and the median follow-up from diagnosis was 97 months (IQR 14-182); 82% of patients were female, and 36% had one or more recurrences. Caplacizumab was administered in 16 patients (41%), as well as rituximab. ITTP patients reported lower physical and mental HRQoL scores than the general population. No differences in physical or mental domains were observed between patients treated or not with caplacizumab, while those who received rituximab reported lower scores in mental health. Neurological impairment at diagnosis correlated with worse fatigue. The majority of patients (72%) reported anxiety or depression (82%). ITTP had a significant impact on the long-term cognitive function, fatigue, depression, and anxiety levels of patients, with a negative effect on their HRQoL. Our findings underscore the need to pay special attention to patients' long-term physical and mental health, regardless of the medical treatments received.

Pharmacotherapeutic advances for chronic myelogenous leukemia: beyond tyrosine kinase inhibitors.

INTRODUCTION: Despite the notable success of tyrosine kinase inhibitors (TKIs) in treating chronic myeloid leukemia (CML), a subset of patients experiences resistance, or relapse after discontinuation. This challenge is attributed to the Ph+ leukemia stem cells (LSCs) pool not fully involved in the inhibition process due to the current therapeutic approach. AREAS COVERED: Current pharmacological advancements in CML therapy focus on targeting LSCs, intervening in self-renewal pathways, and exploiting biological vulnerabilities. Beyond BCR::ABL1 inhibition, innovative approaches include immunotherapy, epigenetic modulation, and interference with microenvironmental mechanisms. EXPERT OPINION: Diverse therapeutic strategies beyond TKIs are under investigation. Immunotherapy with interferon-α (IFN-α) shows some biological effects, although further research is needed for optimal application in enhancing discontinuation rates. Other compounds were able to mobilize Ph+ LSCs from the bone marrow niche (DPP-IV inhibitor vildagliptin or PAI-1 inhibitor TM5614) increasing the LSC clearance or target the CD26, a Ph+ specific surface receptor. It is noteworthy that the majority of these alternative strategies still incorporate TKIs. In conclusion, novel therapeutic perspectives are emerging for CML, holding the potential for substantial advancements in disease treatment.

Neutrophil to lymphocyte ratio in myelofibrosis patients treated with ruxolitinib may predict prognosis and rate of discontinuation.

BACKGROUND: Myelofibrosis (MF) is a clonal Philadelphia chromosome negative myeloproliferative neoplasm (Ph-MPN). MF is featured by an inflammatory condition that can also drive the progression of disease. Ruxolitinib (ruxo) is the-first-in-class Jak1/2 inhibitor approved for treatment of MF, proved to reduce spleen volume and decrease symptom burden. In various malignancies neutrophil-to-lymphocyte ratio (NLR) has been indicated as predictor of progression free survival (PFS) and overall survival (OS). NLR might reflect the balance between systemic inflammation and immunity and is emerging as a prognostic biomarker in several neoplasms, including the hematological ones. METHODS: We analyzed a cohort of 140 MF patients treated with ruxo to validate baseline NLR (as a continuous variable and as a cut-off 2) as predictor of OS and of ruxo treatment discontinuation. RESULTS: We found that both baseline NLR as a continuous variable [HR 0.8 (95% CI: 0.7-0.9) (p = .006)] and NLR (<2 vs. ≥2) [HR 3.4 (95% CI: 1.6-7.0) (p = .001)] were significantly associated with OS. Censoring for patients undergone allotransplant, baseline NLR <2 was predictive of an earlier ruxo any-other-cause discontinuation [HR 3.7 (95%CI 1.7-8.3) (p < .001)]. CONCLUSIONS: NLR before starting ruxo treatment may be used as a simple and early predictor of OS and earlier ruxo discontinuation in clinical practice.

Safety and Efficacy of TKIs in very Elderly Patients (≥75 Years) with Chronic Myeloid Leukemia.

BACKGROUND: While the outcomes of chronic phase chronic myeloid leukemia (CP-CML) patients aged over 65 years have been extensively evaluated in real-life experiences, limited data exist for the very elderly population (i.e., aged ≥ 75 years), especially for next-generation tyrosine kinase inhibitors (TKIs). In this retrospective study, we sought to evaluate the safety and efficacy of TKIs in this particular setting of patients. METHODS: We conducted a retrospective analysis of a multicenter cohort of 123 newly diagnosed CP-CML very elderly patients. RESULTS: The median age at diagnosis was 80 years (range: 75-96). In the first line, 86.1% of patients received imatinib, 7.1% dasatinib, 5.6% nilotinib, and 0.81% received bosutinib. A total of 31 patients (25.2%) switched to second-line therapy, nine patients to a third line, and one patient to a fourth line of therapy. Resistance to treatment was the primary reason for switching therapy in both the first (64.5%) and second lines (77.7%). At diagnosis, reduced doses were administered in 36.5% of patients, in 61.2% in the second line, and in all patients in subsequent lines of therapy. In the first-line setting, 71.9% of patients achieved an early molecular response (EMR, i.e., 3-month BCR::ABL1IS < 10%); at 6, 12, and 24 months, MR3 was reached by 35.7%, 55.7%, and 75.0% of patients, respectively, with 16.6%, 35.7%, and 51.7% achieving a deep molecular response (DMR) at the same time points. Treatment-free remission (TFR) was successfully attempted in 11 patients. During the follow-up period, adverse events (AEs) were observed in 78.8% of patients, including 22 cases of cardiovascular AEs. Toxicity grade ≥ 3 was more commonly observed in patients treated with standard doses of TKIs compared to reduced doses (p = 0.033). Overall, the median follow-up was 46.62 months (range: 1.8-206.2), and 43 patients died due to non-CML-related causes. Three patients died due to disease progression to advanced (n = 1) and blastic (n = 2) phases. The 5-year overall survival (OS) for the entire cohort was 71.9% (95% CI: 0.63-0.81), with no significant difference between the patients treated with standard doses of TKIs compared to those treated with reduced doses (p = 0.35). CONCLUSIONS: TKIs appear to be safe and effective even in very elderly CML patients, and dose optimization strategies yield satisfactory molecular responses for adequate disease control with an improved safety profile.

How to improve treatment-free remission eligibility in chronic myeloid leukaemia?

The achievement of treatment-free remission (TFR) has become a significant clinical end-point in the management of patients with chronic myeloid leukaemia (CML), providing an opportunity to discontinue therapy with tyrosine kinase inhibitors (TKIs) while maintaining deep molecular response (DMR). Early studies, such as the French STIM trial, have demonstrated that a portion of patients can maintain DMR after treatment cessation, with rates ranging from 40% to 50%, and most relapses occurring within the first 6 months. Key prognostic factors for successful TFR, including treatment duration, duration of DMR, risk scores, and transcript type, have been identified. Optimal patient selection for TFR remains a challenge, but recent research provides insights into potential strategies to increase TFR eligibility. Evidence suggests that early intervention switching to achieve optimal response, treatment combinations, proactive switch in the case of absence of DMR, dose-optimization and induction-maintenance approach can improve molecular responses and, consequently, enhance TFR eligibility. In this review, we report and discuss all the potential therapeutic strategies that may enhance eligibility for a first attempt at TFR, with a particular emphasis on potential future approaches.

Epicardial adipose tissue, pulmonary veins anatomy, and the P-wave/PR interval ratio in young patients with atrial fibrillation.

Background: Atrial fibrillation (AF) is uncommon in the youngest population. Epicardial adipose tissue (EAT) volume has been proposed as an independent AF risk factor. Objective: The aim of this retrospective study was to evaluate the impact of the EAT, the anatomy of the pulmonary veins (PVs), and electrocardiogram (ECG) features in these young patients with AF. Methods: Sixty-two patients divided in 2 groups, one with history of paroxysmal AF treated with ablation and the other, a control group, all younger than 30 years of age, were included. Computed tomography scans were performed in both groups to estimate the PVs anatomy and EAT volume. Twelve-lead ECGs were performed in all patients. Patients underwent follow-up in our outpatient clinic (35.9 ± 18.3 months). Results: In the AF group, the EAT volume around the left atrium was 22.25 ± 9.3 cm3 compared with 12.61 ± 3.37 cm3, showing a statistically significance difference (P = .003). Family history resulted to be another significant risk factor (P = .009). During follow-up, 67.7% of the patients treated were still free of events. The anatomy and morphology of the right-sided PVs seemed to play a more consistent role in the patients with AF recurrences (P = .04). The P/PR ratio, a new ECG index, seemed predict AF recurrences after ablation (P = .03). Conclusion: The abundance of EAT seems related to the risk of developing AF in young patients. The recurrence of AF is about 33% and does not seem related to the EAT volume, but rather to the anatomy of the PVs. A higher P/PR ratio might suggest recurrences.

The structural mechanism of dimeric DONSON in replicative helicase activation.

The MCM motor of the replicative helicase is loaded onto origin DNA as an inactive double hexamer before replication initiation. Recruitment of activators GINS and Cdc45 upon S-phase transition promotes the assembly of two active CMG helicases. Although work with yeast established the mechanism for origin activation, how CMG is formed in higher eukaryotes is poorly understood. Metazoan Downstream neighbor of Son (DONSON) has recently been shown to deliver GINS to MCM during CMG assembly. What impact this has on the MCM double hexamer is unknown. Here, we used cryoelectron microscopy (cryo-EM) on proteins isolated from replicating Xenopus egg extracts to identify a double CMG complex bridged by a DONSON dimer. We find that tethering elements mediating complex formation are essential for replication. DONSON reconfigures the MCM motors in the double CMG, and primordial dwarfism patients' mutations disrupting DONSON dimerization affect GINS and MCM engagement in human cells and DNA synthesis in Xenopus egg extracts.

Integration of a Smartphone HF-Dedicated App in the Remote Monitoring of Heart Failure Patients with Cardiac Implantable Electronic Devices: Patient Access, Acceptance, and Adherence to Use.

(200 w) Introduction. Remote monitoring (RM) of cardiac implantable electronic device (CIED) diagnostics helps to identify patients potentially at risk of worsening heart failure (HF). Additionally, knowledge of patient HF-related symptoms is crucial for decision making. Patient smartphone applications may represent an ideal option to remotely collect this information. PURPOSE: To assess real-world HF patient access, acceptance, and adherence to use of an HF-dedicated smartphone application (HF app). METHODS: In this study, 10 Italian hospitals administered a survey on smartphone/app use to HF patients with CIED. The subgroup who accepted it downloaded the HF app. Mean 1-year adherence of the HF app use was evaluated. RESULTS: A total of 495 patients (67 ± 13 years, 79% males, 26% NYHA III-IV) completed the survey, of which 84% had access to smartphones and 85% were willing to use the HF app. In total, 311/495 (63%) downloaded the HF app. Patients who downloaded the HF app were younger and had higher school qualification. Patients who were ≥60 years old had higher mean 1-year adherence (54.1%) than their younger counterparts (42.7%; p < 0.001). Hospitals with RM-dedicated staff had higher mean 1-year patient adherence (64.0% vs. 33.5%; p < 0.001). Adherence to HF app decreased from 63.3% (weeks_1-13) to 42.2% (weeks_40-52, p < 0.001). CONCLUSIONS: High access and acceptance of smartphones/apps by HF patients with CIED allow HF app use for RM of patient signs/symptoms. Younger patients with higher school qualifications are more likely to accept HF app; however, older patients have higher long-term adherence.

Effects of combined strength and endurance training on exercise capacity in kidney transplant cyclists and runners.

INTRODUCTION: After transplantation, engaging in regular physical activity (PA) or sport is recommended for health. Participation to competitive sports is increasingly common among kidney transplant recipients while little is known on how training affects the physical performance in transplanted athletes. AIM: The purpose of this case study was to assess the effects of a tailored training program on exercise parameters in kidney transplant cyclists (CKTRs) and runners (RKTRs). METHODS: Twelve male transplanted athletes were enrolled. The workload at aerobic and anaerobic thresholds, the submaximal aerobic power (V'O2 stage) and rate of perceived exertion (RPE) during an incremental cycling or running test, and the peak instantaneous force (PIF) during a countermovement jump were assessed at baseline (T0) and after 6 months of tailored training (T6) consisting in strength and aerobic exercises. Exercise adherence, blood lipid profile and renal function were also investigated. RESULTS: Eight CKTRs and 4 RKTRs completed the 6-month training period, with a significant increase of training volume (minutes/week). The exercise adherence was met by 90% in both groups. At T6, there were significant (p<0.05) improvements of maximum workload attained, the workload corresponding to the aerobic threshold and PIF, while workloads at anaerobic threshold, V'O2 stage and RPE were unchanged. Blood cholesterol significantly decreased (p<0.01), while the other blood parameters were unchanged. CONCLUSIONS: These findings indicate that the combined strength and endurance training is well tolerated and may improve exercise performance in this selected population of KTRs.

Health-Related Quality-of-Life Profile of Pediatric Patients with ß Thalassemia after Hematopoietic Stem Cell Transplantation.

Matched hematopoietic stem cell transplantation (HSCT) is a feasible and curative treatment in pediatric patients with beta thalassemia major (ß-TM). However, little data are available regarding patients and their parents' health-related quality of life (HRQoL) after the procedure. As such, we investigated the HRQoL of pediatric patients with ß-TM after HSCT compared to that of patients treated with blood transfusions and iron chelation. The health-related quality of life of 43 ß-TM pediatric patients and 43 parents were evaluated using the Pediatric Quality of Life Inventory (PedsQL). A total of 25 patients underwent HSCT: 15 from a sibling and 10 from an HLA-matched donor. The median follow-up time from HSCT was 5 years (range 1-13 years). The mean ages at the survey were 10.1 years (range 5-15) and 9.6 years (range 5-15) for transfused and transplanted patients, respectively. A significant reduction in HRQoL was reported in the group of transfused patients compared with that of patients transplanted in the following PedsQL domains: children's and parents' physical functions, Δ = -15.4, p = 0.009 and Δ = -11.3, p = 0.002, respectively; children's and parents' emotional functioning, Δ = -15.2, p = 0.026 and Δ = -15.2, p = 0.045, respectively; child's and parents' school functioning, Δ = -25, p = 0.005 and Δ = -22.5, p = 0.011, respectively; total child and parents scores, Δ = -14.5, p = 0.004 and Δ = -13.2, p = 0.005, respectively. The results of a multivariable analysis showed that the HSCT procedure was significantly associated with a higher total child PedsQL score (adjusted mean difference = 15.3, p = 0.001) and a higher total parent PedsQL score (adjusted mean difference = 14.1, p = 0.006). We found no significant difference in the HRQoL measured after sibling or unrelated human leukocyte antigen (HLA)-matched HSCT. Finally, a significant positive correlation across all the PedsQL domains was found between the scores reported by the children and those reported by their parents. In conclusion, our study shows that HSCT in pediatric patients with ß-TM is associated with a good overall HRQoL profile. This information further supports physicians when counseling patients and their parents before the HSCT procedure.

Renin-angiotensin inhibitors reduce thrombotic complications in Essential Thrombocythemia and Polycythemia Vera patients with arterial hypertension.

Essential Thrombocythemia (ET) and Polycythemia Vera (PV) are chronic myeloproliferative neoplasms (MPNs) characterized by thrombotic and hemorrhagic complications, leading to a high risk of disability and mortality. Although arterial hypertension was found to be the most significant modifiable cardiovascular (CV) risk factor in the general population, little is known about its role in MPNs as well as a possible role of renin-angiotensin system inhibitors (RASi) in comparison with other anti-hypertensive treatments. We investigated a large cohort of 404 MPN adult patients, 133 diagnosed with PV and 271 with ET. Over half of the patients (53.7%) reported hypertension at MPN diagnosis. The 15-year cumulative incidence of thrombotic-adverse events (TAEs) was significantly higher in patients with hypertension (66.8 ± 10.3% vs 38.5 ± 8.4%; HR = 1.83; 95%CI 1.08-3.1). Multivariate analysis showed that PV diagnosis and hypertension were independently associated with a higher risk of developing TAEs (HR = 3.5; 95%CI 1.928-6.451, p < 0.001 and HR = 1.8; 95%CI 0.983-3.550, p = 0.05, respectively). In multivariate analysis, the diagnosis of PV confirmed a significant predictive role in developing TAEs (HR = 4.4; 95%CI 1.92-10.09, p < 0.01), also considering only MPN patients with hypertension. In addition, we found that the use of RASi showed a protective effect from TAEs both in the whole cohort of MPN with hypertension (HR = 0.46; 95%CI 0.21-0.98, p = 0.04) and in the subgroup of thrombotic high-risk score patients (HR = 0.49; 95%CI 0.24-1.01, p = 0.04). In particular, patients with ET and a high risk of thrombosis seem to benefit most from RASi treatment (HR = 0.27; 95%CI 0.07-1.01, p = 0.03). Hypertension in MPN patients represents a significant risk factor for TAEs and should be adequately treated.

CCND2 mutations in atypical chronic myeloid leukemia: a report of two cases.

Atypical chronic myeloid leukemia (aCML) is a rare MDS/MPN disease characterized by the absence of BCR::ABL1 rearrangement and well known typical mutations associated with myeloproliferative disorders. Mutational landscape associated with this disease was recently described with frequent involvement of SETBP1 and ETNK1 mutations. CCND2 mutations have not been frequently detected in MPN or MDS/MPN patients. We describe two cases of aCML with two CCND2 mutations in 280 and 281 codons which rapidly develop progressive characteristics, and we reviewed the literature about this unfavorable association, suggesting a role as a new possible marker of aggressive disease.