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Introduction: About 15% of people with a myeloproliferative neoplasm (MPN) are identified as MPN, unclassifiable using the 2016 WHO classification. Methods: We tested whether persons with platelet concentration ≥450 × 10E+9/L, bone marrow megakaryocyte morphology typical of prefibrotic/early myelofibrosis (pre-MF), and no minor criteria of pre-MF should be classified as a distinct MPN subtype, clonal megakaryocyte dysplasia with isolated thrombocytosis (CMD-IT). Results: 139 subjects meet these criteria who we compared with primary myelofibrosis (PMF) including 402 with pre-MF and 521 with overt myelofibrosis. CMD-IT subjects were more likely female and younger. They had lower frequencies of JAK2V617F compared with persons with PMF (55% vs. 70%; p < 0.001) and higher frequencies of CALR mutations (37% vs. 17%; p < 0.001). They also had lower frequency of variations associated with JAK2V617F susceptibility, JAK2 46/1 (35% vs. 47%; p = 0.021), and VEGFA rs3025039 (12% vs. 17%; p = 0.030). Subjects with CMD-IT had lower incidences of thrombotic events compared with those with pre-MF (9.7% vs. 26%; p < 0.001) and longer survival (median, not reached vs. 23 years; HR = 0.34 (0.10, 0.30); p < 0.001). Conclusion: Our data indicate CMD-IT is a distinct MPN subtype and should be included in the classification of myeloid neoplasms. [ABSTRACT FROM AUTHOR]

Introduction: In 1991, we reported 18 persons with a clinical-pathologic entity and termed atypical myeloproliferative disorder because they did not meet the contemporary diagnostic criteria for a myeloproliferative neoplasm. We sought to gain further knowledge on this disease entity. Methods: This retrospective cohort study included consecutive subjects registered in the database of the Center for the Study of Myelofibrosis in Pavia, Italy, from 1998 to 2020 (June), and diagnosed with atypical myeloproliferative disorder according to our adjudicated criteria. We studied clinical, histological, cytogenetic, and molecular covariates and risks of thrombosis, disease progression, and death. Data were compared with those of concurrent subjects with prefibrotic myelofibrosis. Results: Fifteen new subjects with atypical myeloproliferative disorder were identified. Seven were male. Median age was 50 years (IQR, 41–54 years). Thirteen were diagnosed with a synchronous symptomatic or incidentally detected thrombotic event. The bone marrow showed megakaryocyte hyperplasia with dysplasia. JAK2V617F was present in 10 subjects and CALR mutation in one. No other somatic mutations were identified in next generation sequencing. After a median follow-up of 101 months (IQR, 40–160 months), no subject had disease progression or blast transformation. Incidence of post-diagnosis or recurrent thrombosis was 3.9 events (95% confidence interval, 3.5–4.0) and 5.0 events (4.6–5.6) per 100 person-years. Features of subjects with atypical myeloproliferative disorder differed markedly from those of 546 subjects with prefibrotic myelofibrosis. Conclusion: Our data indicate that these 15 persons have a distinct myeloproliferative neoplasm. We propose naming this new disorder clonal megakaryocyte dysplasia with normal blood values. [ABSTRACT FROM AUTHOR]

Background: MYH9-related disease (MYH9-RD) is a rare autosomal dominant genetic syndrome characterized by congenital thrombocytopenia associated with the risk of developing progressive nephropathy, sensorineural deafness, and presenile cataract. During the collection of a large case-series of patients with MYH9-RD we noticed several cases with unexplained elevation of liver enzymes. Our aim was to evaluate if the alteration of liver tests is a feature of the MYH9-RD and to define its clinical significance. Methods and Findings: Data concerning liver tests, prospectively recorded in the Italian Registry for MYH9-RD, were collected and compared with those of three control populations: patients with autoimmune thrombocytopenia, patients with inherited thrombocytopenias other than MYH9-RD, and the participants to a large epidemiologic survey in an Italian geographic isolate. Thirty-eight of 75 evaluable MYH9-RD patients (50.7%) showed an elevation of ALT and/or AST, and 17 of 63 (27.0%) an increase of GGT. The increases ranged from 1.9±0.7 to 2.7±1.6 fold the upper normal limit. The prevalence of liver test alterations was significantly higher in MYH9-RD patients than in each of the control populations, with odds ratios ranging from 8.2 (95% CIs 2.2-44.8) to 24.7 (14.8-40.8). Clinical follow-up and more detailed liver studies of a subset of patients, including ultrasound liver scan, liver elastography and liver biopsy in one case, did not show any significant structural damage or evolution towards liver insufficiency. Conclusions: Elevation of liver enzymes is a frequent and previously unrecognized feature of the MYH9-RD syndrome; however, this defect does not appear to have poor prognostic value. [ABSTRACT FROM AUTHOR]

Purpose: In the WHO diagnostic classification, prefibrotic myelofibrosis (pre-MF) is included in the category of primary myelofibrosis (PMF). However, strong evidence for this position is lacking. Patients and Methods: We investigated whether pre-MF may be aligned along a clinical and biological continuum in 683 consecutive patients who received a WHO diagnosis of PMF. Results: As compared with PMF-fibrotic type, pre-MF (132 cases) showed female dominance, younger age, higher hemoglobin, higher platelet count, lower white blood cell count, smaller spleen index and higher incidence of splanchnic vein thrombosis. Female to male ratio and hemoglobin steadily decreased, while age increased from pre-MF to PMF- fibrotic type with early and to advanced bone marrow (BM) fibrosis. Likely, circulating CD34+ cells, LDH levels, and frequency of chromosomal abnormalities increased, while CXCR4 expression on CD34+ cells and serum cholesterol decreased along the continuum of BM fibrosis. Median survival of the entire cohort of PMF cases was 21 years. Ninety-eight, eighty-one and fiftysix percent of patients with pre-MF, PMF-fibrotic type with early and with advanced BM fibrosis, respectively, were alive at 10 years from diagnosis. Conclusion: Pre-MF is a presentation mode of PMF with a very indolent phenotype. The major consequences of this contention is a new clinical vision of PMF, and the need to improve prognosis prediction of the disease. [ABSTRACT FROM AUTHOR]

Increased mobilization of circulating endothelial progenitor cells may represent a new biological hallmark of myeloproliferative neoplasms. We measured circulating endothelial colony forming cells (ECFCs) in 106 patients with primary myelofibrosis, fibrotic stage, 49 with prefibrotic myelofibrosis, 59 with essential thrombocythemia or polycythemia vera, and 43 normal controls. Levels of ECFC frequency for patient's characteristics were estimated by using logistic regression in univariate and multivariate setting. The sensitivity, specificity, likelihood ratios, and positive predictive value of increased ECFC frequency were calculated for the significantly associated characteristics. Increased frequency of ECFCs resulted independently associated with history of splanchnic vein thrombosis (adjusted odds ratio = 6.61, 95% CI = 2.54-17.16), and a summary measure of non-active disease, i.e. hemoglobin of 13.8 g/dL or lower, white blood cells count of 7.8x109/L or lower, and platelet count of 4006109/L or lower (adjusted odds ratio = 4.43, 95% CI = 1.45-13.49) Thirteen patients with splanchnic vein thrombosis non associated with myeloproliferative neoplasms were recruited as controls. We excluded a causal role of splanchnic vein thrombosis in ECFCs increase, since no control had elevated ECFCs. We concluded that increased frequency of ECFCs represents the biological hallmark of a non-active myeloproliferative neoplasm with high risk of splanchnic vein thrombosis. The recognition of this disease category copes with the phenotypic mimicry of myeloproliferative neoplasms. Due to inherent performance limitations of ECFCs assay, there is an urgent need to arrive to an acceptable standardization of ECFC assessment. [ABSTRACT FROM AUTHOR]

Deposition of amyloid in the buttock is a rare complication of dialysis related amyloidosis (DRA), but this localization is even rarer in other types of amyloidoses. We report here the clinical, radiological, and biochemical features of a patient who incurred into this complication after 27 years of hemodialysis. Imaging of the amyloid deposition by magnetic resonance imaging (MRI) documents the amyloid infiltration in the muscles of the buttock region and highlights a peculiar feature of amyloid fibrils deposition in the subcutaneous fat. The amyloid deposition is confirmed by biochemical and microscopic analysis of fibrils extracted from a biopsy specimen. Review of literature and the features of this case lead to speculation that the peculiar involvement of the buttock region including muscles and subcutaneous fat in DRA might derive from the propagation of amyloid initially deposited in the hip joint. [ABSTRACT FROM AUTHOR]

Novel N-glycosylation sites are introduced by somatic mutation into the V genes of the majority of follicular lymphomas. Sites are positively selected and rare in normal memory B cells, indicating a potential role in tumour survival in the germinal centre (GC). The incidence of c. 40% in diffuse large B-cell lymphomas (DLBCL) parallels the known heterogenity of the disease. Immunodeficiency-related non-Hodgkin's lymphomas (NHL) include post-transplant lymphoproliferative disorders (PTLD) and acquired immunodeficiency syndrome-related NHL (AIDS-NHL). Most PTLD derive from B cells that carry mutated VH genes and that have completed the GC reaction. All AIDS-NHL carry mutated VH genes and variable features of GC or post-GC cells. To determine if N-glycosylation is a feature of immunodeficiency-related lymphomas, we analysed the VH genes of 19 PTLD and 36 AIDS-NHL. Novel sites were rare in PTLD (4/19), similar to memory B cells ( P = 0·15). AIDS-NHL, including DLBCL and Burkitt's lymphomas (BL), showed heterogeneity with 16 of 36 (44%) having novel sites. The findings indicate no selection of N-glycosylation sites in PTLD, consistent with post-GC features. The variable incidence of N-glycosylation sites in AIDS-NHL mirrors that in DLBCL and sporadic BL of immunocompetent hosts, supporting the known heterogeneity of these disorders, and possibly pointing to distinct routes of tumour development. [ABSTRACT FROM AUTHOR]