Myelofibrosis

The World Health Organization (WHO) classification defines myelofibrosis (MF) to comprise of the three principal subtypes, primary myelofibrosis, post-polycythaemia vera myelofibrosis, and post-essential thrombocythaemia. Each subtype appears to exhibit a similar pathogenesis, clinical presentation, evolution, and treatment. The critical driver mutations involved in the pathogenesis are be JAK2, MPL, or CALR; mutations in the splicing machinery genes, the epigenome, transcription factors, and dysregulation in the haematopoietic stem cell niche also play pathogenetic roles. Myelofibrosis is a progressive disease, often evolves from a precursor disease state without any clinical symptoms and few laboratory anomalies, to more advanced stages with substantial symptom-burden. Janus kinase (JAK) inhibitors, such as ruxolitinib, afford significant symptomatic benefit, but no major impact on the JAK2 allelic burden, and many patients are offered a risk-adapted approach.

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Differences in Clinical and Molecular Characteristics and Outcome in Prefibrotic and Overt Primary Myelofibrosis According to 2016 WHO Criteria. a Study on 639 Patients of the Agimm Group

Blood ◽

10.1182/blood.v128.22.943.943 ◽

2016 ◽

Vol 128 (22) ◽

pp. 943-943

Author(s):

Paola Guglielmelli ◽

Giada Rotunno ◽

Annalisa Pacilli ◽

Elisa Rumi ◽

Vittorio Rosti ◽

...

Keyword(s):

Reference Group ◽

Primary Myelofibrosis ◽

World Health ◽

Driver Mutations ◽

Molecular Characteristics ◽

Risk Category ◽

Type I ◽

Who Criteria ◽

Health Organization

Abstract The revised 2016 World Health Organization (WHO) classification of myeloid neoplasms dictated distinct criteria for prefibrotic (prePMF) and overt primary myelofibrosis (PMF), based on bone marrow (BM) morphology, including fibrosis grade (G)<1 in prePMF and G2-3 in PMF, and presence of leukoerythroblastosis in PMF. AIM: to describe the characteristics and outcome of patients (pts) with a diagnosis of prePMF versus PMF according to the 2016 WHO criteria. METHODS. We used a database of ca 800 pts collected in 5 Italian tertiary centers of the AGIMM project. Pts annotated with diagnosis of pre/early PMF and PMF were identified, and BM biopsies were re-classified according to current criteria. A total of 639 pts with full information were retrieved; all were annotated for both driver mutations (JAK2V617F, MPLW515x, CALR) and High Molecular Risk mutations (HMR; Vannucchi et al, Leukemia 2013;1861), including ASXL1, EZH2, SRSF2, IDH1/2. RESULTS. Of the 639 pts, 274 (42.8%) were re-classified as prePMF and 365 (57.2%) as PMF. After a median follow-up (FU) of 3.6y, 212 pts (33.2%) had died, 23% prePMF vs 40.8% PMF (P<.0001); 69 pts (10.8%) transformed to leukemia (AL), 8.0% vs 12.9% in prePMF vs PMF (P= .033). At diagnosis, compared to PMF, prePMF pts were enriched in females (57.2% vs 42.9%, P=.01), were younger (59.4 vs 64.7y; P<.001) and with less >65y old individuals (36.1% vs 46.8%, P= .004), had higher Hb (12.7 vs 10.7g/dL; P<.0001) and fewer anemic subjects (Hb<10g/dL:14.2% vs 38.4%; P<.0001), showed higher platelet (plt) count (453 vs 247x109/L; P<.0001) and fewer thrombocytopenic subjects (<100x109/L; 8.0% vs 18.1%; P<.0001); blasts >1% were found in 12.0% vs 26.3% (P<.0001), while leukocyte count and % of pts with >25x109/L were similar. Abnormal karyotype in 18.5% prePMF vs 38.6% PMF (n=317; P<.0001). Constitutional symptoms were reported in 20.8% prePMF vs 34.3% PMF (P<.0001), palpable splenomegaly in 64.2% vs 83.1% (P<.0001), spleen >10cm in 10.5% vs 24.1% (P<.0001). Major thrombosis occurred in 15.5% of prePMF vs 9.0% PMF (P=.02). According to IPSS, 74.2% and 25.8% of prePMF pts were in the lower and higher risk categories, respectively, vs 50.8% and 49.2% of PMF (P<.0001). At the latest FU, most prePMF pts maintained a lower risk category (65.8%) according to DIPSS unlike PMF with 69.3% being categorized as higher risk (P<.0001). The proportion of patients with JAK2V617F (and their median allele burden), MPLW515x and CALR (type I and type II) mutations was similar in prePMF and PMF; triple-negative (TN) pts were slightly more frequent in PMF (14%) than prePMF (9.9%; P=.041). Conversely, 24.8% of prePMF pts vs 41.1% PMF were HMR (P<.0001), the frequent mutated genes were ASXL1 and EZH2; >2 HMR mutations, that are prognostically negative (Guglielmelli et al, Leukemia 2014; 28), were found in 11.8% of PMF pts vs 4.7% prePMF (P<.0001). Median survival (OS) was 17.6y in prePMF vs 7.2y in PMF (P<.0001). OS was accurately predicted by IPSS in both prePMF and PMF. Using CALR type 1 mutation as the reference group, CALR type 2, JAK2/MPL mutations and triple negativity were negative predictors. HMR status was prognostically significant for OS in both prePMF (HR1.8, 95%CI 1.1-3.0, P=.03) and PMF (HR 2.5; 1.8-3.4, P<.0001) as it was >2 HMR mutations (HR 9.3, 4.5-19.0 and 3.4,2.1-5.3, respectively; P<.0001). CONCLUSIONS. This analysis of pts with contemporary diagnosis of prePMF and PMF disclosed important clinical, hematologic and molecular differences between the two, and indirectly suggested that they might represent a phenotypic continuum where increased grade of fibrosis associates with worsening of disease manifestations and outcome. Disclosures Vannucchi: Novartis: Consultancy, Research Funding, Speakers Bureau; Baxalta: Speakers Bureau; Shire: Speakers Bureau.

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Update from the latest WHO classification of MPNs: a user’s manual

Hematology ◽

10.1182/asheducation-2016.1.534 ◽

2016 ◽

Vol 2016 (1) ◽

pp. 534-542 ◽

Cited By ~ 12

Author(s):

Francesco Passamonti ◽

Margherita Maffioli

Keyword(s):

Diagnostic Criteria ◽

Who Classification ◽

Triple Negative ◽

Myeloproliferative Neoplasms ◽

Primary Myelofibrosis ◽

World Health ◽

Driver Mutations ◽

Health Organization

Abstract The 2016 multiparameter World Health Organization (WHO) classification for Philadelphia-negative myeloproliferative neoplasms (MPNs) integrates clinical features, morphology, and genetic data to diagnose polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The main novelties are: (1) the reduction of the hemoglobin (Hb) level threshold to diagnose PV, now established at 16.5 g/dL for men and 16 g/dL for women (based on the identification of MPN patients with PV-consistent bone marrow [BM] features and a Hb level lower than that established in the 2008 WHO classification for PV); (2) the recognition of prefibrotic/early PMF, distinguishable from ET on the basis of BM morphology, an entity having a higher tendency to develop overt myelofibrosis or acute leukemia, and characterized by inferior survival; (3) the central role of BM morphology in the diagnosis of ET, prefibrotic/early PMF, PMF, and PV with borderline Hb values; megakaryocyte number and morphology (typical in ET, atypical in both PMF forms) accompanied by a new distinction of reticulin fibrosis grade in PMF (grade 1 in prefibrotic/early PMF and grade 2-3 in PMF) constitute diagnostic criteria; and (4) the inclusion of all mutually exclusive MPN driver mutations (JAK2, CALR, and MPL) as major diagnostic criteria in ET and PMF; 10% to 15% of these patients are triple negative, and in these cases the search for an additional clonal marker (eg, mutations in ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, and SF3B1) is warranted.

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Organization of restrictive quarantine measures to prevent especially dangerous infections

Spravočnik vrača obŝej praktiki (Journal of Family Medicine) ◽

10.33920/med-10-2005-01 ◽

2020 ◽

pp. 6-11

Author(s):

Petr Ilyin

Keyword(s):

Infectious Diseases ◽

Clinical Symptoms ◽

International Health ◽

World Health ◽

The World ◽

History Of ◽

Entire History ◽

Health Organization ◽

Former Ussr ◽

Health Regulations

Especially dangerous infections (EDIs) belong to the conditionally labelled group of infectious diseases that pose an exceptional epidemic threat. They are highly contagious, rapidly spreading and capable of affecting wide sections of the population in the shortest possible time, they are characterized by the severity of clinical symptoms and high mortality rates. At the present stage, the term "especially dangerous infections" is used only in the territory of the countries of the former USSR, all over the world this concept is defined as "infectious diseases that pose an extreme threat to public health on an international scale." Over the entire history of human development, more people have died as a result of epidemics and pandemics than in all wars combined. The list of especially dangerous infections and measures to prevent their spread were fixed in the International Health Regulations (IHR), adopted at the 22nd session of the WHO's World Health Assembly on July 26, 1969. In 1970, at the 23rd session of the WHO's Assembly, typhus and relapsing fever were excluded from the list of quarantine infections. As amended in 1981, the list included only three diseases represented by plague, cholera and anthrax. However, now annual additions of new infections endemic to different parts of the earth to this list take place. To date, the World Health Organization (WHO) has already included more than 100 diseases in the list of especially dangerous infections.

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Genetic Abnormalities, Clonal Evolution, and Cancer Stem Cells of Brain Tumors

Medical Sciences ◽

10.3390/medsci6040085 ◽

2018 ◽

Vol 6 (4) ◽

pp. 85 ◽

Cited By ~ 5

Author(s):

Ugo Testa ◽

Germana Castelli ◽

Elvira Pelosi

Keyword(s):

Brain Tumors ◽

Clonal Evolution ◽

Pediatric Brain Tumors ◽

Genetic Alterations ◽

World Health ◽

Driver Mutations ◽

Low Grade ◽

High Grade ◽

Genetic Profiling ◽

Health Organization

Brain tumors are highly heterogeneous and have been classified by the World Health Organization in various histological and molecular subtypes. Gliomas have been classified as ranging from low-grade astrocytomas and oligodendrogliomas to high-grade astrocytomas or glioblastomas. These tumors are characterized by a peculiar pattern of genetic alterations. Pediatric high-grade gliomas are histologically indistinguishable from adult glioblastomas, but they are considered distinct from adult glioblastomas because they possess a different spectrum of driver mutations (genes encoding histones H3.3 and H3.1). Medulloblastomas, the most frequent pediatric brain tumors, are considered to be of embryonic derivation and are currently subdivided into distinct subgroups depending on histological features and genetic profiling. There is emerging evidence that brain tumors are maintained by a special neural or glial stem cell-like population that self-renews and gives rise to differentiated progeny. In many instances, the prognosis of the majority of brain tumors remains negative and there is hope that the new acquisition of information on the molecular and cellular bases of these tumors will be translated in the development of new, more active treatments.

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Analysis of Separability of COVID-19 and Pneumonia in Chest X-ray Images by Means of Convolutional Neural Networks

Proceedings ◽

10.3390/proceedings2020054031 ◽

2020 ◽

Vol 54 (1) ◽

pp. 31

Author(s):

Joaquim de Moura ◽

Lucía Ramos ◽

Plácido L. Vidal ◽

Jorge Novo ◽

Marcos Ortega

Keyword(s):

Neural Networks ◽

Convolutional Neural Networks ◽

Clinical Symptoms ◽

Early Stage ◽

World Health ◽

Complete Analysis ◽

Screening Process ◽

X Ray ◽

Chest X Ray ◽

Health Organization

The new coronavirus (COVID-19) is a disease that is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). On 11 March 2020, the coronavirus outbreak has been labelled a global pandemic by the World Health Organization. In this context, chest X-ray imaging has become a remarkably powerful tool for the identification of patients with COVID-19 infections at an early stage when clinical symptoms may be unspecific or sparse. In this work, we propose a complete analysis of separability of COVID-19 and pneumonia in chest X-ray images by means of Convolutional Neural Networks. Satisfactory results were obtained that demonstrated the suitability of the proposed system, improving the efficiency of the medical screening process in the healthcare systems.

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Haematopathology of classic myeloproliferative neoplasms

Oxford Specialist Handbook: Myeloproliferative Neoplasms ◽

10.1093/med/9780198744214.003.0004 ◽

2020 ◽

pp. 45-62

Author(s):

Hans Michael Kvasnicka ◽

Jürgen Thiele

Keyword(s):

Continuous Improvement ◽

Who Classification ◽

Myeloproliferative Neoplasms ◽

Primary Myelofibrosis ◽

World Health ◽

Polycythaemia Vera ◽

The World ◽

Health Organization ◽

Diagnostic Importance

The classification of the World Health Organization (WHO) continues to advocate the diagnostic importance of bone marrow (BM) morphology in the diagnostic workup of myeloproliferative neoplasms (MPN). In this regard, distinctive histological BM patterns characterize specific subtypes of MPN and are the key to a meaningful clinical and molecular-defined risk stratification of patients. In this regard, the morphological denominator includes a characteristic megakaryocytic proliferation along with variable changes in the granulopoiesis and erythropoiesis. Importantly, diagnosis of MPN requires absence of relevant dysgranulopoiesis or dyserythropoiesis. In terms of clinical practice, the concept of precursor stages provides the possibility of an early intervention by appropriate therapeutic regimens that might prevent fatal complications like thrombosis and haemorrhage, especially in early stages of polycythaemia vera or in primary myelofibrosis. However, the WHO classification is not aimed to capture all biological true cases of MPN or guarantee a complete diagnostic specificity and thus might be in need of continuous improvement following clinical experience.

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STAT5 is Expressed in CD34+/CD38− Stem Cells and Serves as a Potential Molecular Target in Ph-Negative Myeloproliferative Neoplasms

Cancers ◽

10.3390/cancers12041021 ◽

2020 ◽

Vol 12 (4) ◽

pp. 1021 ◽

Cited By ~ 3

Author(s):

Emir Hadzijusufovic ◽

Alexandra Keller ◽

Daniela Berger ◽

Georg Greiner ◽

Bettina Wingelhofer ◽

...

Keyword(s):

Stem Cells ◽

Myeloproliferative Neoplasms ◽

Jak2 V617f ◽

Primary Myelofibrosis ◽

Janus Kinase ◽

Signaling Cascades ◽

Nuclear Compartment ◽

Downstream Signaling ◽

Direct Targeting ◽

Calr Mutations

Janus kinase 2 (JAK2) and signal transducer and activator of transcription-5 (STAT5) play a key role in the pathogenesis of myeloproliferative neoplasms (MPN). In most patients, JAK2 V617F or CALR mutations are found and lead to activation of various downstream signaling cascades and molecules, including STAT5. We examined the presence and distribution of phosphorylated (p) STAT5 in neoplastic cells in patients with MPN, including polycythemia vera (PV, n = 10), essential thrombocythemia (ET, n = 15) and primary myelofibrosis (PMF, n = 9), and in the JAK2 V617F-positive cell lines HEL and SET-2. As assessed by immunohistochemistry, MPN cells displayed pSTAT5 in all patients examined. Phosphorylated STAT5 was also detected in putative CD34+/CD38− MPN stem cells (MPN-SC) by flow cytometry. Immunostaining experiments and Western blotting demonstrated pSTAT5 expression in both the cytoplasmic and nuclear compartment of MPN cells. Confirming previous studies, we also found that JAK2-targeting drugs counteract the expression of pSTAT5 and growth in HEL and SET-2 cells. Growth-inhibition of MPN cells was also induced by the STAT5-targeting drugs piceatannol, pimozide, AC-3-019 and AC-4-130. Together, we show that CD34+/CD38− MPN-SC express pSTAT5 and that pSTAT5 is expressed in the nuclear and cytoplasmic compartment of MPN cells. Whether direct targeting of pSTAT5 in MPN-SC is efficacious in MPN patients remains unknown.

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Screening diabetes mellitus patients for pulmonary tuberculosis: a multisite study in Indonesia, Peru, Romania and South Africa

Transactions of the Royal Society of Tropical Medicine and Hygiene ◽

10.1093/trstmh/traa100 ◽

2020 ◽

Author(s):

Bachti Alisjahbana ◽

Susan M McAllister ◽

Cesar Ugarte-Gil ◽

Nicolae Mircea Panduru ◽

Katharina Ronacher ◽

...

Keyword(s):

Diabetes Mellitus ◽

South Africa ◽

Clinical Symptoms ◽

Economic Status ◽

World Health ◽

Diagnostic Tools ◽

Sputum Smear ◽

Tb Treatment ◽

Chest X Ray ◽

Health Organization

Abstract Background Diabetes mellitus (DM) patients are three times more likely to develop tuberculosis (TB) than the general population. Active TB screening in people with DM is part of a bidirectional approach. The aim of this study was to conduct pragmatic active TB screening among DM patients in four countries to inform policy. Methods DM patients were recruited in Indonesia (n=809), Peru (n=600), Romania (n=603) and South Africa (n=51). TB cases were diagnosed using an algorithm including clinical symptoms and chest X-ray. Presumptive TB patients were examined with sputum smear and culture. Results A total of 171 (8.3%) individuals reported ever having had TB (South Africa, 26%; Indonesia, 12%; Peru, 7%; Romania, 4%), 15 of whom were already on TB treatment. Overall, 14 (0.73% [95% confidence interval 0.40 to 1.23]) TB cases were identified from screening. Poor glucose control, smoking, lower body mass index, education and socio-economic status were associated with newly diagnosed/current TB. Thirteen of the 14 TB cases diagnosed from this screening would have been found using a symptom-based approach. Conclusions These data support the World Health Organization recommendation for routine symptom-based screening for TB in known DM patients in high TB-burden countries. DM patients with any symptoms consistent with TB should be investigated and diagnostic tools should be easily accessible.

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