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EJHaem Feb 2024
PubMed: 38406540
DOI: 10.1002/jha2.860 -
Annals of Hematology Dec 2023To date, no therapeutic strategy has been shown to be effective in reducing the risk of polycythemia vera (PV) transforming into myelofibrosis or leukemia, and the main...
To date, no therapeutic strategy has been shown to be effective in reducing the risk of polycythemia vera (PV) transforming into myelofibrosis or leukemia, and the main goal of current treatment is to prevent thrombotic events. Recent studies have shown that higher levels of inflammation are associated with an increased risk of thrombosis in PV patients, while the correlation between inflammation and abnormal lipid metabolism with the risk of thrombosis in PV has not been reported. In this retrospective study, 148 patients with newly diagnosed PV who visited the Affiliated Hospitals of Nanchang University from January 2013 to June 2023 were categorized into low-risk group and high-risk group according to the risk of thrombosis, and were subsequently divided into thrombosis non-progression group and progression group. The differences of novel inflammatory markers PHR, NHR, MHR, LHR, and SIRI in each group were analyzed and compared with healthy adults who underwent physical examination in the hospitals during the same period. The results showed that PHR, NHR, MHR, and SIRI levels were significantly higher in the PV group than in the control group (P < 0.001), while HDL-C levels were considerably lower (1.09 vs. 1.31, P < 0.001). Comparisons within the groups of PV patients revealed that PHR, MHR, NHR, NLR, and SIRI levels were significantly higher in the high-risk group for thrombosis than in the low-risk group (P < 0.01); the thrombosis PHR, NHR, NLR, and SIRI levels were higher in the group with progression of thrombosis than in the group without progression of thrombosis (P < 0.05), while HDL-C levels were significantly lower (1.02 vs. 1.12, P < 0.001). The results of the ROC curve analysis showed that NHR (AUC = 0.791), HDL-C (AUC = 0.691), PHR (AUC = 0.668), NLR(AUC = 0.658), and SIRI (AUC = 0.638) had high diagnostic efficacy for identifying PV patients with thrombosis progression. Multivariate analysis showed that NHR, NLR, MHR, and LHR were independent risk factors for PV patients with thrombosis progression (P < 0.05). Kaplan-Meier survival curves showed that NHR ≥ 5.82 × 10/mmol, NLR ≥ 6.295, PHR ≥ 280.4 × 10/mmol, MHR ≥ 0.295 × 10/mmol, LHR ≥ 1.41 × 10/mmol, and SIRI ≥ 1.53 × 10/L were risk factors for PFS in PV patients. The study demonstrates for the first time that novel inflammatory markers PHR, NHR, MHR, LHR, and SIRI may be used as new predictors for PV patients with thrombosis progression. NHR has the highest value in predicting thrombosis in PV patients and is superior to NLR which was reported previously.
Topics: Adult; Humans; Polycythemia Vera; Retrospective Studies; Lipid Metabolism; Thrombosis; Inflammation
PubMed: 37907800
DOI: 10.1007/s00277-023-05518-6 -
Microbiology Spectrum Sep 2023Essential thrombocythemia (ET) is part of the Philadelphia chromosome-negative myeloproliferative neoplasms. It is characterized by an increased risk of thromboembolic...
Essential thrombocythemia (ET) is part of the Philadelphia chromosome-negative myeloproliferative neoplasms. It is characterized by an increased risk of thromboembolic events and also to a certain degree hypermetabolic symptoms. The gut microbiota is an important initiator of hematopoiesis and regulation of the immune system, but in patients with ET, where inflammation is a hallmark of the disease, it is vastly unexplored. In this study, we compared the gut microbiota via amplicon-based 16S rRNA gene sequencing of the V3-V4 region in 54 patients with ET according to mutation status Janus-kinase 2 ()-positive vs -negative patients with ET, and in 42 healthy controls (HCs). Gut microbiota richness was higher in patients with ET (median-observed richness, 283.5; range, 75-535) compared with HCs (median-observed richness, 191.5; range, 111-300; < 0.001). Patients with ET had a different overall bacterial composition (beta diversity) than HCs (analysis of similarities [ANOSIM]; = 0.063, = 0.004). Patients with ET had a significantly lower relative abundance of taxa within the phylum compared with HCs (51% vs 59%, = 0.03), and within that phylum, patients with ET also had a lower relative abundance of the genus (8% vs 15%, < 0.001), an important immunoregulative bacterium. The microbiota signatures were more pronounced in patients harboring the mutation, and highly similar to patients with polycythemia vera as previously described. These findings suggest that patients with ET may have an altered immune regulation; however, whether this dysregulation is induced in part by, or is itself inducing, an altered gut microbiota remains to be investigated. IMPORTANCE Essential thrombocythemia (ET) is a cancer characterized by thrombocyte overproduction. Inflammation has been shown to be vital in both the initiation and progression of other myeloproliferative neoplasms, and it is well known that the gut microbiota is important in the regulation of our immune system. However, the gut microbiota of patients with ET remains uninvestigated. In this study, we characterized the gut microbiota of patients with ET compared with healthy controls and thereby provide new insights into the field. We show that the gut microbiota of patients with ET differs significantly from that of healthy controls and the patients with ET have a lower relative abundance of important immunoregulative bacteria. Furthermore, we demonstrate that patients with -positive ET have pronounced gut microbiota signatures compared with -negative patients. Thereby confirming the importance of the underlying mutation, the immune response as well as the composition of the microbiota.
PubMed: 37695126
DOI: 10.1128/spectrum.00662-23 -
Cancers Jul 2023Myelofibrosis (MF) is a heterogeneous disease regarding its mutational landscape, clinical presentation, and outcomes. The aim of our work is to evaluate the genomic...
Clinical Characteristics and Outcomes of Patients with Primary and Secondary Myelofibrosis According to the Genomic Classification Using Targeted Next-Generation Sequencing.
Myelofibrosis (MF) is a heterogeneous disease regarding its mutational landscape, clinical presentation, and outcomes. The aim of our work is to evaluate the genomic classification of MF considering whether it is primary or secondary. One-hundred seventy-five patients, 81 with primary MF (PMF) and 94 with secondary MF (SMF) were hierarchically allocated into eight molecular groups. We found that disruption/aneuploidy ( = 16, 9%) was more frequent (12% versus 6%) and showed higher allele burden (57% versus 15%, = 0.01) in SMF than in PMF, and was associated with shorter survival (median 3.5 years). Mutations in chromatin/spliceosome genes ( = 72, 41%) represented the most frequent genomic group in PMF. Homozygous mutation ( = 40, 23%) was enriched with old patients with SMF after long-standing polycythemia vera, whereas MF with heterozygous mutation ( = 22, 13%) was similarly distributed among PMF and SMF. MF with mutation ( = 19, 11%) predominated in post-essential thrombocythemia MF. The remaining genomic groups were infrequent. disruption, chromatin/spliceosome mutation, and homozygous mutation were associated with significantly shorter survival and higher risk of progression. In conclusion, genomic classification reveals different pathogenic pathways between PMF and SMF and provides relevant information regarding disease phenotype and outcomes.
PubMed: 37568719
DOI: 10.3390/cancers15153904 -
Photodiagnosis and Photodynamic Therapy Feb 2024To evaluate the choroidal thickness and retrobulbar hemodynamic parameters in polycythemia vera (PV) patients in comparison with healthy individuals, and to investigate... (Review)
Review
BACKGROUND
To evaluate the choroidal thickness and retrobulbar hemodynamic parameters in polycythemia vera (PV) patients in comparison with healthy individuals, and to investigate the relationship of these values with blood hematocrit levels.
METHODS
This prospective study included the 35 eyes of 35 PV patients and the 30 eyes of 30 healthy individuals. Choroidal thickness was measured at the subfoveal area and at 500 µm intervals nasal and temporal to the fovea up to a distance of 1500 µm. Color Doppler ultrasonography (CDU) was used to evaluate the retrobulbar vessels. Complete blood count values were recorded.
RESULTS
Choroidal thickness was found to be significantly lower in the PV group than in the control group at the subfoveal, nasal 500, and temporal 500 and 1000 µm measurement points (p = 0.01, p = 0.011, p = 0.04, p = 0.045, respectively). The central retinal artery (CRA) peak systolic velocity (PSV) and end diastolic velocity (EDV) values and the ophthalmic artery (OA) PSV value were significantly lower in the PV group than in the control group (p < 0.001, p < 0.001, p = 0.019, respectively). No significant difference was present between the groups in terms of CRA and OA resistive index (RI) and pulsatile index (PI) values (p = 0.388, p = 0.564, p = 0.897, p = 0.693, respectively). A negative correlation was found between the blood hematocrit levels and the subfoveal, nasal 500 µm, and temporal 500 µm choroidal thickness measurements and the CRA PSV and EDV and the OA PSV values.
CONCLUSIONS
PV may cause microvascular changes and lead to ocular vascular complications by affecting the choroidal and retrobulbar blood flow.
Topics: Humans; Prospective Studies; Polycythemia Vera; Blood Flow Velocity; Photochemotherapy; Photosensitizing Agents; Hemodynamics; Choroid
PubMed: 38246214
DOI: 10.1016/j.pdpdt.2024.103985 -
Internal Medicine (Tokyo, Japan) Nov 2023Objective Testing for the Janus activating kinase 2 (JAK2) V617F mutation is important for diagnosing and treating myeloproliferative neoplasms (MPNs). Recently, urine...
Objective Testing for the Janus activating kinase 2 (JAK2) V617F mutation is important for diagnosing and treating myeloproliferative neoplasms (MPNs). Recently, urine cell-free DNA (ucfDNA) was reported to be useful for detecting tumor-specific gene mutations in several solid tumors. However, its utility in detecting such mutations in hematological malignancies has not yet been assessed. In this study, we assessed whether or not the JAK2 V617F mutation could be detected in ucfDNA and whether or not its positivity rate in ucfDNA was associated with the JAK2 V617F allele ratio of peripheral blood cells in patients with MPN. Methods The JAK2 V617F allele ratio of genomic DNA from peripheral blood cells was determined using quantitative polymerase chain reaction (qPCR) or droplet digital PCR (ddPCR). ucfDNA was subjected to ddPCR. The correlation between the JAK2 V617F mutation positivity rates of blood-derived DNA and those of ucfDNA was assessed. Materials Twelve patients with polycythemia vera and 12 patients with essential thrombocythemia were enrolled. Ethylenediaminetetraacetic acid-treated peripheral blood (100 mL) and 15-30 mL of fresh urine were used. Results The JAK2 V617F mutation was detected in the ucfDNA from all 20 JAK2 V617F mutation-positive patients. In addition, the JAK2 V617F mutation positivity rate of ucfDNA was correlated with the JAK2 V617Fs allele ratio of blood-derived DNA, including in both estimated glomerular filtration rate (eGFR) groups (patients with an eGFR ≥50 or <50 mL/min/1.73 m). Conclusion Our results indicate that ucfDNA is a valuable tool for diagnosing and monitoring MPN. Given these findings, other disease-specific gene mutations in hematological malignancies may also be detectable in ucfDNA.
PubMed: 38008450
DOI: 10.2169/internalmedicine.2837-23 -
Frontiers in Oncology 2023Myeloproliferative neoplasms (MPNs) are classified into Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) and Ph-negative MPNs. translocation is the... (Review)
Review
Myeloproliferative neoplasms (MPNs) are classified into Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) and Ph-negative MPNs. translocation is the key genetic event of CML, whereas mutations are molecular aberrations of Ph-negative MPNs. Despite initially considered mutually exclusive genetic aberrations, the co-occurrence of and has been reported in a limited number of cases. The two genetic alterations may be identified either at the same time or aberration may be detected in patients with a previous CML treated with tyrosine kinase inhibitors or, finally, translocation occurs in patients with a history of -positive MPN. This combination of genomic alterations is potentially confounding with clinical manifestations often misinterpreted either as disease progression or drug resistance, therefore leading to inappropriate patient's treatment. Our systematic review aims to improve hematologist and pathologist knowledge on this rare subset of patients. Starting from the presentation of two additional cases from our routine daily practice, we focus mainly on clinical, laboratory, and bone marrow histological findings, which may represent useful clues of and co-occurrence. The interaction between and clones during the disease course as well as therapy and outcome are presented.
PubMed: 38282677
DOI: 10.3389/fonc.2023.1329298 -
Haematologica Nov 2023Hereditary erythrocytosis is a rare hematologic disorder characterized by an excess of red blood cell production. Here we describe a European collaborative study...
Hereditary erythrocytosis is a rare hematologic disorder characterized by an excess of red blood cell production. Here we describe a European collaborative study involving a collection of 2,160 patients with erythrocytosis sequenced in ten different laboratories. We focused our study on the EGLN1 gene and identified 39 germline missense variants including one gene deletion in 47 probands. EGLN1 encodes the PHD2 prolyl 4-hydroxylase, a major inhibitor of hypoxia-inducible factor. We performed a comprehensive study to evaluate the causal role of the identified PHD2 variants: (i) in silico studies of localization, conservation, and deleterious effects; (ii) analysis of hematologic parameters of carriers identified in the UK Biobank; (iii) functional studies of the protein activity and stability; and (iv) a comprehensive study of PHD2 splicing. Altogether, these studies allowed the classification of 16 pathogenic or likely pathogenic mutants in a total of 48 patients and relatives. The in silico studies extended to the variants described in the literature showed that a minority of PHD2 variants can be classified as pathogenic (36/96), without any differences from the variants of unknown significance regarding the severity of the developed disease (hematologic parameters and complications). Here, we demonstrated the great value of federating laboratories working on such rare disorders in order to implement the criteria required for genetic classification, a strategy that should be extended to all hereditary hematologic diseases.
Topics: Humans; Polycythemia; Hypoxia-Inducible Factor-Proline Dioxygenases; Germ-Line Mutation; Base Sequence
PubMed: 37317877
DOI: 10.3324/haematol.2023.282913 -
ELife Apr 2024High-altitude polycythemia (HAPC) affects individuals living at high altitudes, characterized by increased red blood cells (RBCs) production in response to hypoxic...
High-altitude polycythemia (HAPC) affects individuals living at high altitudes, characterized by increased red blood cells (RBCs) production in response to hypoxic conditions. The exact mechanisms behind HAPC are not fully understood. We utilized a mouse model exposed to hypobaric hypoxia (HH), replicating the environmental conditions experienced at 6000 m above sea level, coupled with in vitro analysis of primary splenic macrophages under 1% O to investigate these mechanisms. Our findings indicate that HH significantly boosts erythropoiesis, leading to erythrocytosis and splenic changes, including initial contraction to splenomegaly over 14 days. A notable decrease in red pulp macrophages (RPMs) in the spleen, essential for RBCs processing, was observed, correlating with increased iron release and signs of ferroptosis. Prolonged exposure to hypoxia further exacerbated these effects, mirrored in human peripheral blood mononuclear cells. Single-cell sequencing showed a marked reduction in macrophage populations, affecting the spleen's ability to clear RBCs and contributing to splenomegaly. Our findings suggest splenic ferroptosis contributes to decreased RPMs, affecting erythrophagocytosis and potentially fostering continuous RBCs production in HAPC. These insights could guide the development of targeted therapies for HAPC, emphasizing the importance of splenic macrophages in disease pathology.
Topics: Animals; Mice; Humans; Spleen; Altitude Sickness; Splenomegaly; Ferroptosis; Leukocytes, Mononuclear; Macrophages; Hypoxia
PubMed: 38629942
DOI: 10.7554/eLife.87496 -
The Journal of Veterinary Medical... Apr 2024Here we report a case series of two dogs diagnosed as renal interstitial cell tumor (RICT) accompanied by elevated serum erythropoietin level and marked polycythemia....
Here we report a case series of two dogs diagnosed as renal interstitial cell tumor (RICT) accompanied by elevated serum erythropoietin level and marked polycythemia. RICT is a rare tumor in dogs, originating from renal interstitial cells. While several renal tumors such as renal lymphoma, adenocarcinoma, carcinoma, sarcoma, fibrosarcoma and nephroblastoma may cause polycythemia, polycythemia caused by RICT has never been reported in dogs. The tumors in both dogs were solitary and lied within cortex or cortico-medullary junction. Histopathology revealed spindle-shaped cells suggesting mesenchymal origin, with no mitotic figures suggesting that the tumors in both dogs were benign. Following surgical removal of the affected kidney, serum erythropoietin level and polycythemia normalized in both dogs.
Topics: Male; Dogs; Animals; Polycythemia; Leydig Cell Tumor; Erythropoietin; Dog Diseases; Kidney Neoplasms
PubMed: 38383003
DOI: 10.1292/jvms.23-0413