Somatic mutations acquired in healthy tissues as we age are major determinants of cancer risk. Whether variants confer a fitness advantage or rise to detectable frequencies by chance remains largely unknown. Blood sequencing data from ~50,000 individuals reveal how mutation, genetic drift, and fitness shape the genetic diversity of healthy blood (clonal hematopoiesis). We show that positive selection, not drift, is the major force shaping clonal hematopoiesis, provide bounds on the number of hematopoietic stem cells, and quantify the fitness advantages of key pathogenic variants, at single-nucleotide resolution, as well as the distribution of fitness effects (fitness landscape) within commonly mutated driver genes. These data are consistent with clonal hematopoiesis being driven by a continuing risk of mutations and clonal expansions that become increasingly detectable with age.

https://science.sciencemag.org/content/sci/367/6485/1449.full.pdf

The evolutionary dynamics and fitness landscape of clonal hematopoiesis

Editor's Choice - European Society for Vascular Surgery (ESVS) 2021 Clinical Practice Guidelines on the Management of Venous Thrombosis.

Germ line variants predispose to both JAK2 V617F clonal hematopoiesis and myeloproliferative neoplasms

In recent years the evidence is increasing that chronic inflammation may be an important driving force for clonal evolution and disease progression in the Philadelphia-negative myeloproliferative neoplasms (MPNs), essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). Abnormal expression and activity of a number of proinflammatory cytokines are associated with MPNs, in particular MF, in which immune dysregulation is pronounced as evidenced by dysregulation of several immune and inflammation genes. In addition, chronic inflammation has been suggested to contribute to the development of premature atherosclerosis and may drive the development of other cancers in MPNs, both nonhematologic and hematologic. The MPN population has a substantial inflammation-mediated comorbidity burden. This review describes the evidence for considering the MPNs as inflammatory diseases, A Human Inflammation Model of Cancer Development, and the role of cytokines in disease initiation and progression. The consequences of this model are discussed, including the increased risk of second cancers and other inflammation-mediated diseases, emphasizing the urgent need for rethinking our therapeutic approach. Early intervention with interferon-alpha2, which as monotherapy has been shown to be able to induce minimal residual disease, in combination with potent anti-inflammatory agents such as JAK-inhibitors is foreseen as the most promising new treatment modality in the years to come.

https://downloads.hindawi.com/journals/mi/2015/102476.pdf

MPNs as Inflammatory Diseases: The Evidence, Consequences, and Perspectives

Myeloproliferative neoplasm stem cells.

Summary

The JAK2 V617F somatic mutation is present in the majority of patients with myeloproliferative cancer (polycythaemia vera, essential thrombocytosis, and primary myelofibrosis). However, the diagnostic value of the JAK2 V617F somatic mutation for myeloproliferative cancer in the general population is unknown. We examined this question in 49 488 individuals from the Copenhagen General Population Study. We also examined the association between JAK2 V617F somatic mutation, rs10974944 germline genotype, haematological phenotype, any cancer, haematological cancer, myeloproliferative cancer, ischaemic heart disease, and venous thromboembolism. The JAK2 V617F somatic mutation was present in 0·1% (n = 68), increasing across rs10974944 germline genotypes (P-trend = 0·001). JAK2 V617F somatic mutation positives versus negatives had higher erythrocyte (P = 2 × 10−5), thrombocyte (P = 2 × 10−16), and leucocyte (P = 4 × 10−9) counts, and had 2·7-/2·5-fold risk of cancer (prevalent/incident), 44-/28-fold risk of haematological cancer, 221-/97-fold risk of myeloproliferative cancer, 2·2-/1·2-fold risk of ischaemic heart disease, and 3·1-/1·0-fold risk of venous thromboembolism. By combining conventional haematological parameters with a test for the JAK2 V617F somatic mutation, myelo;?>proliferative cancer could be identified or ruled out with a sensitivity of 47–100% and a specificity of 98–100%. In conclusion, in the general population the JAK2 V617F somatic mutation has a high diagnostic value for myeloproliferative cancer when combined with conventional haematological parameters.

Diagnostic value of JAK2 V617F somatic mutation for myeloproliferative cancer in 49 488 individuals from the general population.

Clinical significance of the JAK2V617F mutation in patients with a myeloproliferative neoplasm has been the target of intensive research in recent years. However, there is considerably uncertainty about prognosis in JAK2V617F positive individuals without overt signs of myeloproliferative disease. In this study, we tested the hypothesis that increased JAK2V617F somatic mutation burden is associated with myeloproliferative neoplasm progression rate in the general population. Among 49,488 individuals from the Copenhagen General Population Study, 63 (0.1%) tested positive for the JAK2V617F mutation in the time period 2003-2008. Of these, 48 were available for re-examination in 2012. Level of JAK2V617F mutation burden was associated with myeloproliferative neoplasm progression rate, consistent with a biological continuum of increasing JAK2V617F mutation burden across increasing severity of myeloproliferative neoplasm from no disease (n=8 at re-examination) through essential thrombocythemia (n=20) and polycythemia vera (n=13) to primary myelofibrosis (n=7). Among those diagnosed with a myeloproliferative neoplasm only at re-examination in 2012, in the preceding years JAK2V617F mutation burden increased by 0.55% per year, erythrocyte volume fraction increased by 1.19% per year, and erythrocyte mean corpuscular volume increased by 1.25% per year, while there was no change in platelet count or erythropoietin levels. Furthermore, we established a JAK2V617F mutation burden cut-off point of 2% indicative of disease versus no disease; however, individuals with a mutation burden below 2% may suffer from a latent form of myeloproliferative disease revealed by a slightly larger spleen and/or slightly higher lactic acid dehydrogenase concentration compared to controls. Of all 63 JAK2V617F positive individuals, 48 were eventually diagnosed with a myeloproliferative neoplasm.

JAK2V617F somatic mutation in the general population: myeloproliferative neoplasm development and progression rate.

The effect of flexible assertive community treatment in Denmark: a quasi-experimental controlled study.

Introduction: Flexible Assertive Community Treatment (FACT) is a model of integrated care aiming to increase continuity of care for individuals with severe mental illness. FACT teams have been implemented in many countries by merging Assertive Community Treatment (ACT) and standard care from Community Mental Health teams (CMHTs). However, there has been little research on how practitioners experienced the fusion of these teams. Aim: This study explores how former ACT and CMHT practitioners perceived the implementation of FACT. Method: Perceptions of the FACT model, implementation strategies and adaptations of the model were investigated through 17 semi-structured interviews with FACT practitioners. Results: Perceived positive contributions of FACT included the recognition that FACT addressed a service gap for a group of patients who could benefit from increased support and improved integration of outpatient and hospital care. Perceived disadvantages of FACT included the experience that FACT drew away resources from ACT patients with the highest psychiatric needs. The findings also describe barriers to implementation, such as lack of perceived benefit of FACT, the maintenance of traditional work culture and insufficient organisational capacity. These challenges required the negotiation of local implementation strategies and adaptations. Conclusion: FACT increases access to intensive care for a broader group of patients with severe mental illness. However, findings from this study also suggest that the increased caseload in FACT compared with ACT and a changed mindset may not reflect the needs of the smaller group of patients who find it difficult to engage with mental health care services.

/pdf/a-qualitative-study-on-the-implementation-of-flexible-aclawx2zos.pdf

A Qualitative Study on the Implementation of Flexible Assertive Community Treatment - an Integrated Community-based Treatment Model for Patients with Severe Mental Illness.

Camilla Munch Nielsen

Papers

Diagnostic value of JAK2 V617F somatic mutation for myeloproliferative cancer in 49 488 individuals from the general population.

JAK2V617F somatic mutation in the general population: myeloproliferative neoplasm development and progression rate.

The effect of flexible assertive community treatment in Denmark: a quasi-experimental controlled study.

A Qualitative Study on the Implementation of Flexible Assertive Community Treatment - an Integrated Community-based Treatment Model for Patients with Severe Mental Illness.