FRACTION: protocol of a phase II study of Fedratinib and Nivolumab combination in patients with myelofibrosis and resistance or suboptimal response to JAK-inhibitor treatment of the German MPN study group (GSG-MPN).

Development of Janus-kinase (JAK) inhibitors has revolutionized the therapeutic landscape for patients with myeloproliferative neoplasia (MPN). Following approval of the first JAK1/2-inhibitor Ruxolitinib, symptoms of this inflammatory disease, characterized by splenomegaly, release of inflammatory cytokines and appearance of thrombosis, could be effectively reduced for the first time. However, JAK-inhibitor treatment is limited in several aspects: 1) duration of response: 3 years after initiation of therapy more than 50% of patients have discontinued JAK-inhibitor treatment due to lack of efficacy or resistance; 2) reduction of disease burden: while effective in reducing inflammation and constitutional symptoms, JAK-inhibitors fail to reduce the malignant clone in the majority of patients and therefore lack long-term efficacy. Early clinical trials for patients with myelofibrosis (MF) have tried to address these issues for patients with suboptimal response to Ruxolitinib therapy while combination therapies with Fedratinib are rare. Recent reports provided first evidence on how the JAK2-V617F mutated myeloid cells may influence T-cell responses. JAK2-V617F promoted the synthesis of PD-L1 in MPN cells leading to limited anti-neoplastic T-cell responses, metabolic changes in T-cells and eventually JAK2-V617F-driven immune-escape of MPN cells. These findings may facilitate the use of immunotherapeutic approaches for JAK-mutated clones. Immune checkpoints refer to a variety of inhibitory pathways that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. The FRACTION study is a single arm, open label Phase II trial investigating the combination of Fedratinib with the PD-1 inhibitor Nivolumab in patients with myelofibrosis and suboptimal or lack of response to JAK-inhibitor therapy. Over a 12 months period the trial assesses longer term outcomes, particularly the effects on clinical outcomes, such as induction of clinical remissions, quality of life and improvement of anemia. No prospective clinical trial data exist for combinations of JAK- and immune-checkpoint-inhibitors in the planned MF study population and this study will provide new findings that may contribute to advancing the treatment landscape for MF patients with suboptimal responses and limited alternatives.

Prediction of acute coronary syndrome in patients with myeloproliferative neoplasms.

Background: Patients with myeloproliferative neoplasms (MPN) are exposed to a higher risk of cardiovascular disease, especially cardiovascular calcification. The present research aimed to analyze the clinical features and coronary artery calcium score (CACS) in MPN patients, and construct an effective model to predict acute coronary syndrome (ACS) in MPN patients. Materials and methods: A total of 175 MPN patients and 175 controls were recruited from the First Affiliated Hospital of Ningbo University. Based on cardiovascular events, the MPN patients were divided into the ACS group and the non-ACS group. Multivariate Cox analysis was completed to explore ACS-related factors. Furthermore, ROC curves were plotted to assess the predictive effect of CACS combined with white blood cells (WBC) and platelet for ACS in MPN patients. Results: The MPN group exhibited a higher CACS than the control group (133 vs. 55, P < 0.001). A total of 16 patients developed ACS in 175 MPN patients. Compared with non-ACS groups, significant differences in age, diabetes, smoking history, WBC, percentage of neutrophil, percentage of lymphocyte, neutrophil count, hemoglobin, hematocrit, platelet, lactate dehydrogenase, ß 2-microglobulin, and JAK2V617F mutation were observed in the ACS groups. In addition, the CACS in the ACS group was also significantly higher than that in the non-ACS group (374.5 vs. 121, P < 0.001). The multivariable Cox regression analysis identified WBC, platelet, and CACS as independent risk factors for ACS in MPN patients. Finally, ROC curves indicated that WBC, platelet, and CACS have a high predictive value for ACS in MPN patients (AUC = 0.890). Conclusion: CACS combined with WBC and platelet might be a promising model for predicting ACS occurrence in MPN patients.

Myeloproliferative Neoplasms Transcriptome Reveals Pro-Inflammatory Signature and Enrichment in Peripheral Blood Monocyte-Related Genes.

Myeloproliferative neoplasms (MPN) are hematological diseases associated with genetic driver mutations in the JAK2, CALR, and MPL genes and exacerbated oncoinflammatory status. Analyzing public microarray data from polycythemia vera (n = 41), essential thrombocythemia (n = 21), and primary myelofibrosis (n = 9) patients' peripheral blood by in silico approaches, we found that pro-inflammatory and monocyte-related genes were differentially expressed in MPN patients' transcriptome. Genes related to cell activation, secretion of pro-inflammatory and pro-angiogenic mediators, activation of neutrophils and platelets, coagulation, and interferon pathway were upregulated in monocytes compared to controls. Together, our results suggest that molecular alterations in monocytes may contribute to oncoinflammation in MPN.

Regulation of STAT5 phosphorylation and interaction with SHP1 by lnc-AC004893, a long non-coding RNA overexpressed in myeloproliferative neoplasms.

OBJECTIVES: Constitutive activation of Janus kinase 2 (JAK2)/signal transducer and activator of transcription (STAT) signaling pathway is central to the pathogenesis of myeloproliferative neoplasms (MPNs). Long noncoding RNAs (lncRNAs) regulate diverse biological processes. However, the role of lncRNAs in MPN pathogenesis is not well studied. METHODS: The expression of lnc-AC004893 in MPN patients was measured by quantitative real-time PCR (qRT-PCR). Gene-specific short hairpin RNAs (shRNAs) were designed to inhibit the expression of lnc-AC004893, and western blot was performed to explore the role of lnc-AC004893 via regulating the JAK2/STAT5 signaling pathway. Furthermore, co-IP was performed to determine the binding ability of lnc-AC004893 and STAT5 protein. Finally, the BaF3-JAK2V617F-transplanted mouse model was used to assess the biological role of lnc-ac004893 in vivo. RESULTS: We report that lnc-AC004893, a poorly conserved pseudogene-209, is substantially upregulated in MPN cells compared with normal controls (NCs). Knockdown of lnc-AC004893 by specific shRNAs suppressed cell proliferation and decreased colony formation. Furthermore, the knockdown of lnc-AC004893 reduced the expression of p-STAT5 but not total STAT5 in HEL and murine IL-3-dependent Ba/F3 cells, which present constitutive and inducible activation of JAK2/STAT5 signaling. In addition, inhibition of murine lnc-ac004893 attenuated BaF3-JAK2V617F-transplanted phenotypes and extended the overall survival. Mechanistically, knockdown of lnc-AC004893 enhanced the binding ability of STAT5 and protein tyrosine phosphatase SHP1. Furthermore, knockdown of lnc-AC004893 decreased STAT5-lnc-AC004893 interaction but not SHP1-lnc-AC004893 interaction. CONCLUSION: Lnc-AC004893 regulates STAT5 phosphorylation by affecting the interaction of STAT5 and SHP1. Lnc-AC004893 might be a potential therapeutic target for MPN patients.

Atypical chronic myeloid leukemia found in a patient with eosinophilia for six years: a case report.

BACKGROUND: Atypical chronic myeloid leukemia (aCML) is a highly aggressive type of blood cancer that falls under the category of myelodysplastic/myeloproliferative neoplasms (MDS/MPN). In the fifth edition of the WHO classification of tumors, this category has been renamed MDS/MPN with neutrophilia. Although eosinophilia is commonly observed in blood cancers, it is rarely seen in aCML. CASE PRESENTATION: This study presents a case of aCML that was diagnosed six years after the patient developed eosinophilia. The patient had undergone tests to rule out other primary and secondary diseases, but the eosinophilia remained unexplained. Treatment with corticosteroids and hydroxyurea had proven ineffective. Six years later, the patient experienced an increase in white blood cells, primarily neutrophils. After ruling out other possible diagnoses, a combination of morphologic and molecular genetic findings led to the diagnosis of aCML. The patient responded well to treatment with azacitidine. CONCLUSIONS: This study summarizes the current state of aCML diagnosis and management and discusses the possible connection between eosinophilia and aCML.

Genetic alterations in myeloproliferative and myelodysplastic/myeloproliferative neoplasms - a practical guide to WHO-HAEM5.

Within the World Health Organization (WHO) classification of haematopoietic neoplasms, particularly its fifth version from 2022 (WHO-HAEM5), myeloid neoplasms are not only grouped into myeloproliferative (MPN) and myelodysplastic neoplasms (MDS). There is also a group of haematological disorders that share features of both categories termed myelodysplastic /myeloproliferative neoplasms (MDS/MPN). In this article, we aim to provide a comprehensive and practical guide to WHO-HAEM5 highlighting the genetic alterations that underlie MPN and MDS/MPN. This guide provides an overview of the overlapping commonalities among these entities, as well as their unique characteristics.

Impact of gender representativeness in online symptom survey and clinical trial participation among patients with myeloproliferative neoplasms.

Patients with myeloproliferative neoplasms (MPNs) face chronic symptom burden. Online symptom assessment studies allow for recruitment of large numbers of motivated patients, but patient self-selection can lead to sampling bias. This study evaluated how gender representativeness in MPN symptom surveys and trials impacted symptom score mean estimates, using data from 4825 survey respondents and 291 trial participants with MPNs. The survey data showed that men participated at a rate roughly 50% less than what would be expected based on prevalence, and women reported higher scores than men on average for six of 10 symptoms. Together, this led to potential over estimation in six of 10 symptom score means (ranging from 5.8% to 15.3% overestimated). The trial data showed less gender-based sampling bias compared to the survey data. Studies utilizing online symptom surveys should implement study design features to recruit more men, assess for gender participation imbalances, and provide weighted estimates where appropriate.

[Recommended diagnostics for pruritus affecting primary non-lesional skin]. / Empfohlene Diagnostik bei Pruritus auf primär unveränderter Haut.

BACKGROUND: Chronic pruritus affecting primary non-lesional skin (CPNL) manifests as a common symptom across a spectrum of diseases spanning various medical specialties. Given the diverse etiological factors involved, diagnosing the underlying condition poses a significant challenge. OBJECTIVES: To provide a comprehensive overview of clinical, laboratory, and imaging diagnostics for CPNL. MATERIALS AND METHODS: A thorough literature search on the diagnostics of chronic pruritus was conducted using PubMed with specific keywords "chronic pruritus AND non-lesional skin", "chronic itch AND non-lesional skin", "chronic pruritus AND diagnostics", "chronic itch AND diagnostics", "CKD-aP", "hepatic pruritus", "cholestatic pruritus", and "myeloproliferative neoplasms AND pruritus". RESULTS: A systematic diagnostic approach is recommended for patients with CPNL, guided by the prevalence of pruritus-associated diseases. Initial basic diagnostics facilitate a cost-effective and focused evaluation during the initial medical assessment. Information pertaining to underlying diseases can be further refined through specialized diagnostic procedures. CONCLUSIONS: CPNL often presents a diagnostic dilemma. Adopting a stepwise diagnostic strategy facilitates the identification of underlying etiologies, which is crucial for recognizing diseases and administering pruritus-specific pharmacotherapy.

Oral Decitabine/Cedazuridine Is an Effective Ambulatory Therapy for Patients With Myelofibrosis Refractory to JAK2 Inhibitor Therapy.

BACKGROUND: Outcomes are dismal for patients with myelofibrosis (MF) who are no longer responsive to JAK2 inhibitors (JAKi) and/or have increasing blast cell numbers. Although prior reports have suggested the benefits of intravenous decitabine (DAC) combined with ruxolitinib for patients with Myeloproliferative Neoplasm (MPN) accelerated/blast phase (AP/BP), decitabine-cedazuridine (DEC-C), an oral fixed-dose combination providing equivalent pharmacokinetic exposure, has not been evaluated in MF. METHODS: We conducted a retrospective analysis of 14 patients with high-risk MF refractory to ruxolitinib or MPN-AP (10-19% blasts) treated with DEC-C +/- JAKi at Mount Sinai Hospital from 2021 to 2024. RESULTS: The cohort was elderly (median age,76 years) and almost uniformly possessed high risk mutations with 13 of the 14 patients progressing on JAKi therapy. With a median follow-up of 9.4 months, the median overall survival (OS) was 29 months for the entire cohort. Median OS was 10.8 months for MPN-AP and was not reached for ruxolitinib refractory MF patients. All patients (n = 9) receiving > 4 cycles of DEC-C had clinical benefit exemplified by a reduction in blast cell numbers, spleen size, and lack of progression to MPN-BP (78%). Furthermore, 3/14 patients proceeded to allogeneic stem cell transplant. Myelosuppression was a common adverse event which was managed by reducing the number of days of administration of DEC-C from 5 to 3 per cycle. CONCLUSIONS: This report demonstrates the feasibility, tolerability, and clinical benefit of an exclusively ambulatory regimen for high-risk, elderly patients with advanced MF which warrants further evaluation in a prospective clinical trial.

Mathematical modelling of stem and progenitor cell dynamics during ruxolitinib treatment of patients with myeloproliferative neoplasms.

Introduction: The Philadelphia chromosome-negative myeloproliferative neoplasms are a group of slowly progressing haematological malignancies primarily characterised by an overproduction of myeloid blood cells. Patients are treated with various drugs, including the JAK1/2 inhibitor ruxolitinib. Mathematical modelling can help propose and test hypotheses of how the treatment works. Materials and methods: We present an extension of the Cancitis model, which describes the development of myeloproliferative neoplasms and their interactions with inflammation, that explicitly models progenitor cells and can account for treatment with ruxolitinib through effects on the malignant stem cell response to cytokine signalling and the death rate of malignant progenitor cells. The model has been fitted to individual patients' data for the JAK2 V617F variant allele frequency from the COMFORT-II and RESPONSE studies for patients who had substantial reductions (20 percentage points or 90% of the baseline value) in their JAK2 V617F variant allele frequency (n = 24 in total). Results: The model fits very well to the patient data with an average root mean square error of 0.0249 (2.49%) when allowing ruxolitinib treatment to affect both malignant stem and progenitor cells. This average root mean square error is much lower than if allowing ruxolitinib treatment to affect only malignant stem or only malignant progenitor cells (average root mean square errors of 0.138 (13.8%) and 0.0874 (8.74%), respectively). Discussion: Systematic simulation studies and fitting of the model to the patient data suggest that an initial reduction of the malignant cell burden followed by a monotonic increase can be recapitulated by the model assuming that ruxolitinib affects only the death rate of malignant progenitor cells. For patients exhibiting a long-term reduction of the malignant cells, the model predicts that ruxolitinib also affects stem cell parameters, such as the malignant stem cells' response to cytokine signalling.

Translation, Cultural Adaptation, and Validation into Romanian of the Myeloproliferative Neoplasm Symptom Assessment Form-Total Symptom Score (MPN-SAF TSS or MPN-10) Questionnaire.

Background: Patients with myeloproliferative neoplasms (MPNs) experience a high disease-related symptom burden. A specific instrument to evaluate quality of life (QoL), i.e., the MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS; MPN-10), was developed. We conducted the translation, cultural adaptation, and validation into Romanian of the MPN-10. Methods: We translated the MPN-10 and tested its psychometric properties. Results: We recruited 180 MPN patients: 66 polycythemia vera (36.67%), 61 essential thrombocythemia (33.89%), 51 primary and secondary myelofibrosis (SMF) (28.33%), and 2 MPN-unclassifiable (1.11%). The mean TSS was 19.51 ± 16.51 points. Fatigue, inactivity, and concentration problems were the most cumbersome symptoms. We detected scoring differences between MPN subtypes regarding weight loss (p < 0.001), fatigue (p = 0.006), early satiety (p = 0.007), night sweats (p = 0.047), pruritus (p = 0.05), and TSS (p = 0.021). There were strong positive associations between TSS and inactivity, fatigue, and concentration problems, and moderate negative correlations between QoL scores and all MPN-10 items. Cronbach's α internal consistency coefficient was 0.855. The Kaiser-Meyer-Olkin construct validity test result was 0.870 and the Bartlett Sphericity Test was significant (p < 0.001). Symptom scores were loaded into one single factor according to the exploratory factor analysis. Conclusions: The Romanian MPN-10 version displayed excellent psychometric properties and is a reliable instrument for assessing symptom burden and QoL in Romanian MPN patients.

Assessment of Total Antioxidant Capacity, 8-Hydroxy-2'-deoxy-guanosine, the Genetic Landscape, and Their Associations in BCR::ABL-1-Negative Chronic and Blast Phase Myeloproliferative Neoplasms.

Myeloproliferative neoplasms (MPNs), namely, polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are clonal stem cell disorders defined by an excessive production of functionally mature and terminally differentiated myeloid cells. MPNs can transform into secondary acute myeloid leukemia (sAML/blast phase MPN) and are linked to alterations in the redox balance, i.e., elevated concentrations of reactive oxygen species and markers of oxidative stress (OS), and changes in antioxidant systems. We evaluated OS in 117 chronic phase MPNs and 21 sAML cases versus controls by measuring total antioxidant capacity (TAC) and 8-hydroxy-2'-deoxy-guanosine (8-OHdG) concentrations. TAC was higher in MPNs than controls (p = 0.03), particularly in ET (p = 0.04) and PMF (p = 0.01). MPL W515L-positive MPNs had higher TAC than controls (p = 0.002) and triple-negative MPNs (p = 0.01). PMF patients who had treatment expressed lower TAC than therapy-free subjects (p = 0.03). 8-OHdG concentrations were similar between controls and MPNs, controls and sAML, and MPNs and sAML. We noted associations between TAC and MPNs (OR = 1.82; p = 0.05), i.e., ET (OR = 2.36; p = 0.03) and PMF (OR = 2.11; p = 0.03), but not sAML. 8-OHdG concentrations were not associated with MPNs (OR = 1.73; p = 0.62) or sAML (OR = 1.89; p = 0.49). In conclusion, we detected redox imbalances in MPNs based on disease subtype, driver mutations, and treatment history.

Prevalence and risk factors for hyperuricemia and hyperuricosuria in patients with hematologic malignancies.

Introduction: Hyperuricemia is a common complication of hematologic malignancies, and hyperuricosuria in this population has shown conflicting results. This study aimed to determine the prevalence of hyperuricemia and parameters associated with serum uric acid (SUA) and urine uric acid (UUA) in patients with lymphoma and myeloproliferative neoplasms (MPN). Methods: This cross-sectional study included adult patients with newly diagnosed lymphoma and MPN at the university-based hospital. Clinical characteristics were collected, and independent risk factors for hyperuricemia and hyperuricosuria were determined using multiple logistic regression. Results: One hundred and sixty-five patients were included with a median age of 55 years (45.5-64) and 51.5% were males. There were 91 patients (55.2%) with lymphoma and 74 cases (44.8%) of MPN. Overall, hyperuricemia was prevalent in 43.6% with a median SUA of 6.3 mg/dl (4.6-8) and hyperuricosuria was detected in 39.4% with a median 24-h UUA of 545 mg (365.4-991). Hyperuricemia was observed in patients with lymphoma and MPN in 20.9% and 71.6%, respectively, and hyperuricosuria in 15.4% and 68.9%, respectively. In lymphoma patients, estimated glomerular filtration rate (eGFR) <90 ml/min/1.73 m2 and serum lactate dehydrogenase (LDH) ≥ 250 U/L were associated with hyperuricemia with odds ratio (OR) 3.24, 95% confidence interval (CI) 1.95-11.07, p = 0.006 and OR 2.07, 95%CI 1.62-6.97, p = 0.039), and only elevated serum LDH was related to hyperuricosuria (OR 2.37, 95%CI 1.56-14.29, p = 0.036). In MPN patients, hemoglobin levels <10 g/dl and serum LDH ≥ 640 mg/dl were independent risk factors of hyperuricosuria (OR 1.88, 95%CI 1.42-8.39, p = 0.045 and OR 6.21, 95%CI 1.49-25.74, p = 0.012). Conclusion: Hyperuricemia in patients with hematologic malignancies was common, notably MPN, and parameters associated with hyperuricosuria were provided. In addition to the utilization of allopurinol in patients at high risk of tumor lysis syndrome, patients without hyperuricosuria may also be of significant interest.

[Relationship between DTA Mutations and Thromboembolism in Patients with Myeloproliferative Neoplasms].

OBJECTIVE: To analyze the DTA (DNMT3A, TET2, ASXL1) mutations in patients with myeloproliferative neoplasms (MPN), and preliminarily explore their correlation with thromboembolism. METHODS: Clinical characteristics of 62 patients diagnosed de novo MPN at Central Hospital Affiliated to Shandong First Medical University from September 2016 to September 2022 were retrospectively analyzed. Next-generation sequencing was used to detect 35 MPN-related genes, and the DTA mutations in MPN patients and their relationship with thromboembolic events were analyzed. RESULTS: 75.8% (47/62) of the patients presented pathogenic non-driver mutations, and the mean number of pathogenic non-driver mutations per patient was 1.08. Among them, the most frequently mutated non-driver genes were TET2 (38.7%, 24/62), DNMT3A (9.7%, 6/62) and ASXL1 (6.5%, 4/62). The presence of DTA gene mutations was 50% (31/62) in the total MPN patients, and mainly accompanied by driver mutations. The mutation rate of DTA in patients aged ≥60 years was significantly higher than that in patients <60 years old (P =0.039). The incidence of thromboembolism in patients with DTA mutation was 58.1% (18/31), which was significantly higher than that in patients without DTA mutation (19.4%, 6/31) (P =0.002). The TET2 gene mutation rate in MPN patients with thromboembolism was 66.7% (16/24), which was significantly higher than that in patients without thromboembolism (21.1%, 8/38) (P =0.00). CONCLUSION: Patients with MPN have a higher incidence of DTA mutations, which are mainly accompanied by driver gene mutations. The incidence of thromboembolism in MPN patients with DTA mutations is higher than that in patients without DTA mutations. Especially, the elderly (≥60 years) essential thrombocythemia(ET) and polycythemia vera(PV) patients with TET2 mutation should be vigilant for thromboembolic events.

The characteristics of CALR mutations in myeloproliferative neoplasms: a clinical experience from a tertiary care center in Qatar and a literature review.

BACKGROUND: Myeloproliferative neoplasms (MPNs) are hematological disorders characterized by abnormal production of myeloid cells due to genetic mutations. Since 2013, researchers have identified somatic mutations in the Calreticulin (CALR) gene, primarily insertions or deletions, in two Philadelphia chromosome-negative MPNs; essential thrombocytosis (ET) and primary myelofibrosis (PMF), and occasionally in chronic myelomonocytic leukemia (CMML). This study aims to identify the various types of CALR mutations and their impact on CALR-positive MPN patients' clinical manifestations and outcomes. METHODS: A single-center retrospective study was conducted. The data was collected from pre-existing records. The study was carried out on Philadelphia-negative MPN patients who were being followed up on at the NCCCR (National Center for Cancer Care and Research) to assess the clinical manifestation and outcome of disease treatment. All patients included, were followed in our center between January 1, 2008, and November 20, 2021. RESULTS: A total of 50 patients with CALR-positive MPN were reviewed with a median follow-up of three years (1-11). This cohort included 31 (62%) patients with ET, 10 (20%) patients with PMF, and 9 (18%) patients with prefibrotic myelofibrosis (pre-MF). The study involved 38 (76%) male and 12 (24%) female patients. There were 16 (32%) patients diagnosed before the age of 40, 24 (48%) patients diagnosed between the ages of 40 and 60; and 10 (20%) patients diagnosed after the age of 60. Molecular analysis showed 24 (48%) patients with CALR type 1, 21 (42%) patients with CALR type 2, and 5 (10%) patients with none Type 1, none Type 2 CALR mutations. Two patients have double mutations; 1(2%) with none Type 1, none Type 2 CALR and JAK2 mutations, and 1(2%) with CALR type 1 and MPL mutations. The thrombotic events were 3 (6%) venous thromboembolisms, 3 (6%) abdominal veins thromboses, 2 (4%) strokes, and 4 (8%) ischemic cardiac events. Only 4 (8%) patients progressed to Myelofibrosis and were carrying CALR 1 mutations, and 1 (2%) patient progressed to AML with CALR 2 mutation. CONCLUSION: The data shows a significant rise in CALR-positive MPN diagnoses in younger people, emphasizing the need for a better assessment tool to improve disease management and reduce complications.

The clinical significance of TAT, PIC, TM, and t-PAIC in vascular events of BCR/ABL-negative myeloproliferative neoplasms.

Predicting the likelihood vascular events in patients with BCR/ABL1-negative myeloproliferative neoplasms (MPN) is essential for the treatment of the disease. However, effective assessment methods are lacking. Thrombin-antithrombin complex (TAT), plasmin-α2- plasmininhibitor complex (PIC), thrombomodulin (TM), and tissue plasminogen activator-inhibitor complex (t-PAIC) are the new direct indicators for coagulation and fibrinolysis. The aim of this study was to investigate the changes of these four new indicators in thrombotic and hemorrhagic events in BCR/ABL1-negative MPN. The study cohort of 74 patients with BCR/ABL negative myeloproliferative disorders included essential thrombocythemia, polycythemia vera, and primary myelofibrosis (PMF). A panel of 4 biomarkers, including TAT, PIC, TM, and t-PAIC were determined using Sysmex HISCL5000 automated analyzers, whereas fibrin/fibrinogen degradation products (FDP), D-dimer and Antithrombin III (ATIII) were analyzed using Sysmex CS5100 coagulation analyzer. A total of 24 (32.4%) patients experienced thrombotic events and hemorrhagic events occurred in 8 patients (10.8%). Compared to patients without hemorrhagic-thrombotic events, patients with thrombotic events had higher fibrinogen (FIB) level, FDP level and lower ATIII activity, while patients with hemorrhagic events had lower white blood cell count and hemoglobin level, higher FDP level (P < 0.05). Patients with a JAK2V617F mutation were more likely to experience thrombotic events (P < 0.05). In addtion, patients with thrombotic events had higher TAT, PIC, TM, and t-PAIC levels than patients without hemorrhagic-thrombotic events (P < 0.05), whereas patients with hemorrhagic events had a lower median value in TAT and TM (no statistical difference, P > 0.05). Patients with higher TAT, TM and t-PAIC were more likely to experience thrombotic events (P < 0.05), and only TAT was positively correlated with thrombotic events (Spearman r =0.287, P = 0.019). TAT, PIC, TM, and t-PAIC combined with ATIII and FDP have a certain value for predicting thrombosis in patients with BCR/ABL1-negative MPN. These 6 parameters are worth further exploration as predictive factors and prognostic markers for early thrombotic events.

Advances in Molecular Understanding of Polycythemia Vera, Essential Thrombocythemia, and Primary Myelofibrosis: Towards Precision Medicine.

Myeloproliferative neoplasms (MPNs), including Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF), are characterized by the clonal proliferation of hematopoietic stem cells leading to an overproduction of hematopoietic cells. The last two decades have seen significant advances in our understanding of the molecular pathogenesis of these diseases, with the discovery of key mutations in the JAK2, CALR, and MPL genes being pivotal. This review provides a comprehensive update on the molecular landscape of PV, ET, and PMF, highlighting the diagnostic, prognostic, and therapeutic implications of these genetic findings. We delve into the challenges of diagnosing and treating patients with prognostic mutations, clonal evolution, and the impact of emerging technologies like next-generation sequencing and single-cell genomics on the field. The future of MPN management lies in leveraging these molecular insights to develop personalized treatment strategies, aiming for precision medicine that optimizes outcomes for patients. This article synthesizes current knowledge on molecular diagnostics in MPNs, underscoring the critical role of genetic profiling in enhancing patient care and pointing towards future research directions that promise to further refine our approach to these complex disorders.

Development of an Artificial-Intelligence-Based Tool for Automated Assessment of Cellularity in Bone Marrow Biopsies in Ph-Negative Myeloproliferative Neoplasms.

The cellularity assessment in bone marrow biopsies (BMBs) for the diagnosis of Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs) is a key diagnostic feature and is usually performed by the human eyes through an optical microscope with consequent inter-observer and intra-observer variability. Thus, the use of an automated tool may reduce variability, improving the uniformity of the evaluation. The aim of this work is to develop an accurate AI-based tool for the automated quantification of cellularity in BMB histology. A total of 55 BMB histological slides, diagnosed as Ph- MPN between January 2018 and June 2023 from the archives of the Pathology Unit of University "Luigi Vanvitelli" in Naples (Italy), were scanned on Ventana DP200 or Epredia P1000 and exported as whole-slide images (WSIs). Fifteen BMBs were randomly selected to obtain a training set of AI-based tools. An expert pathologist and a trained resident performed annotations of hematopoietic tissue and adipose tissue, and annotations were exported as .tiff images and .png labels with two colors (black for hematopoietic tissue and yellow for adipose tissue). Subsequently, we developed a semantic segmentation model for hematopoietic tissue and adipose tissue. The remaining 40 BMBs were used for model verification. The performance of our model was compared with an evaluation of the cellularity of five expert hematopathologists and three trainees; we obtained an optimal concordance between our model and the expert pathologists' evaluation, with poorer concordance for trainees. There were no significant differences in cellularity assessments between two different scanners.

Case Report and Literature Review of Acute Spontaneous Intraspinal Epidural Hematoma (SSEH) Secondary to Myeloproliferative Disease.

Background: Spontaneous spinal epidural hematoma (SSEH) presenting in the context of JAK2 V617F-positive myeloproliferative neoplasms is a rare condition, characterized by the compression of the spinal cord leading to various symptoms. The etiology, pathogenesis, and optimal treatment strategies for this condition remain undetermined. The occurrence of spontaneous spinal epidural hematoma (SSEH) in the context of JAK2 V617F-positive myeloproliferative neoplasms (MPNs) represents a rare manifestation. Magnetic Resonance Imaging (MRI) plays a crucial role in the definitive diagnosis of this condition. With a good understanding of the pathogenic characteristics and clinical presentations of this disease, a diagnosis can be reasonably made, even in the absence of MRI, based on physical examinations indicating the affected area. Once diagnosed, immediate surgery is recommended to attempt the restoration of spinal cord function. Postoperatively, the use of hydroxyurea has proven effective in disease control. Case Presentation: We report a case of a 65-year-old male patient who presented with progressive lumbar back pain and bilateral lower limb paralysis lasting for 36 hours. CT imaging revealed an intraspinal lesion at the L1-3 level, and genetic testing confirmed the presence of the JAK2V617F mutation. Following surgery, there was a significant recovery of sensory and motor function in the lower limbs. At one-year follow-up, the patient demonstrated good functional status, and blood tests indicated a platelet count within the normal range. Conclusion: The presented case adds to the existing literature on SSEH by highlighting the association with myeloproliferative neoplasms (MPNs), as evidenced by the JAK2V617F mutation. MPNs constitute a group of hematologic malignancies, and the association with SSEH is a rare occurrence. The exact interplay between MPNs and SSEH warrants further investigation, as the underlying mechanisms linking these conditions remain elusive. The case also underscores the importance of a multidisciplinary approach, involving hematologists and neurosurgeons, in the comprehensive management of such complex cases.