Combination therapy with ruxolitinib and pegylated interferon alfa-2a in newly diagnosed patients with polycythemia vera.

ABSTRACT: We report the 2-year end-of-study results from the phase 2 COMBI II clinical trial investigating the combination treatment of ruxolitinib and low-dose pegylated interferon alfa-2a in patients with newly diagnosed polycythemia vera (PV). The primary outcome was safety and key secondary endpoints were efficacy, based on hematologic parameters, quality-of-life measurements, and JAK2V617F variant allele frequency (VAF). We used the 2013 European LeukemiaNet and International Working Group-Myeloproliferative Neoplasms Research remission criteria. The remission criteria included remissions in symptoms, splenomegaly, peripheral blood counts, and bone marrow. We included 25 patients with PV with a median age of 70 years; 5 of those had prior thromboembolic events and 3 had computed tomography-verified splenomegaly. Two patients stopped both study drugs; 1 of these due to progression to post-PV myelofibrosis, the only one with a grade 3 infection. No events of herpes zoster infections were observed. None of the patients discontinued treatment due to psychiatric symptoms. The peripheral blood cell count remission rate was 92% at 24 months. Using the 2013 European LeukemiaNet and International Working Group-Myeloproliferative Neoplasms Research remission criteria, 14 (56%) achieved remission at 24 months; 3 (12%) achieved complete remission and 11 (44%) achieved partial remission. The following items from the Myeloproliferative Neoplasm Symptom Total Symptom Score were significantly reduced: abdominal discomfort, night sweats, itching, and bone pain. The median JAK2V617F VAF decreased from 47% (95% confidence interval [CI], 35-59) to 7% (95% CI, 3-15), and 60% of patients achieved molecular remission. In conclusion, combination treatment improved cell counts; bone marrow cellularity, and fibrosis; and decreased JAK2V617F VAF; with acceptable toxicity in patients with PV. The trial was registered at www.clinicaltrialsregister.eu as #EudraCT2018-004150-13.

The CALR mutations enhance the expression of the immunosuppressive proteins GARP and LAP on peripheral blood lymphocytes through increased binding of activated platelets.

Recently, an antibody which inhibits the glycoprotein A repetitions predominant (GARP)-mediated release of active transforming growth factor beta (TGFß) from the TGFß propeptide latency-associated peptide (LAP) showed preclinical activity in a murine model of the chronic myeloproliferative neoplasms (MPN). Consequently, we investigated the expression of the immunosuppressive molecules LAP and GARP on peripheral blood lymphocytes from 56 MPN patients and 11 healthy donors (HD). We found that lymphocytes from patients with MPN express higher levels of LAP and GARP with no strong differences found between the different MPN diagnoses. The impact of clinical parameters on the expression of LAP and GARP by lymphocytes showed that patients with calreticulin (CALR)mut MPN have increased expression compared with HD and patients with the Januskinase2 (JAK2) mutation. The fraction of lymphocytes bound to activated platelets (aPLT) strongly correlate to LAP and GARP expression suggesting that it is not the lymphocytes themselves but aPLT, which confer the increased expression of GARP and LAP on MPN patient lymphocytes. Notably, no differences in neither platelet counts nor anti-thrombotic therapy was identified between patients with JAK2- and CALRmut patients. Analysis of platelet gene expression failed to identify differences in expression of relevant genes between JAK2- and CALRmut patients.

Socioeconomic differences in discrepancies between expected and experienced discomfort from colonoscopy and colon capsule endoscopy.

Background: Social inequalities in colorectal cancer screening participation are evident. Barriers to screening participation include discomfort from diagnostic modalities. We aimed to describe the discomfort experienced from colonoscopy and colon capsule endoscopy (CCE) and investigate the discrepancy between expected and experienced discomfort stratified by socioeconomic status. Methods: A randomised controlled trial was conducted offering half of the colorectal cancer screening invitees the choice between CCE and colonoscopy after a positive faecal immunochemical test. This paper includes those who elected to undergo CCE. A positive CCE elicited referral for a therapeutic colonoscopy. Participants reported their discomfort from CCE and from any following colonoscopies in electronically distributed questionnaires. Discomfort was measured using visual analogue scales and compared between socioeconomic subgroups determined by educational level and income. Results: The experienced discomfort from CCE and colonoscopy differed significantly between educational levels but not income levels. The bowel preparation contributed the most to the experienced discomfort in both CCE and colonoscopy. The discrepancy between expected and experienced discomfort from colonoscopy increased with increasing educational and income levels. A similar trend was seen in CCE between educational levels but not income levels. Conclusions: None of the results indicated a higher discomfort in lower socioeconomic subgroups. Regardless of the investigation modality, the bowel preparation was the main contributor to experienced discomfort. The discrepancy between expected and experienced discomfort did not seem to be larger in lower socioeconomic subgroups, indicating that this is not a major barrier causing inequalities in screening uptake. This is the first study investigating individual discomfort discrepancy in both CCE and colonoscopy, while being able to stratify by socioeconomic status.

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.

COVID-19 severity in patients with chronic lymphocytic leukemia treated with venetoclax: a single-center observational cohort study.

Patients with chronic lymphocytic leukemia (CLL) are at high risk of developing severe COVID-19. The present study was undertaken to elucidate COVID-19 related morbidity and mortality in CLL patients treated with venetoclax. We present a single-center study of 108 patients with small lymphocytic lymphoma or CLL treated with venetoclax. Primary outcome was 30-day COVID-19 mortality. Secondary outcomes included COVID-19 severity and hospitalization rate. Forty-eight (44%) patients had PCR-verified SARS-COV-2 between March 2020 and January 2023. Thirty-six patients (75%) presented with asymptomatic/mild COVID-19 and 12 (25%) with severe/critical disease. The hospitalization rate was 46% with a 30-day mortality rate of only 4% and severe comorbidities as the primary cause of death. COVID-19 severity and mortality were similar before and during the Omicron era. High CIRS-scores (P < 0.02) and thrombocytopenia (P < 0.01) were more frequent in patients with severe/critical disease. In real-world data, most venetoclax treated patients presented with mild COVID-19. Hospitalization and mortality rates were low compared to data of general CLL populations. Our data indicate that venetoclax was a safe treatment option for CLL patients during the pandemic.

Neutrophil-to-lymphocyte ratio and all-cause mortality with and without myeloproliferative neoplasms-a Danish longitudinal study.

The neutrophil-to-lymphocyte ratio(NLR) is increased in chronic inflammation and myeloproliferative neoplasms (MPN). We hypothesize that NLR is associated with all-cause mortality and mortality by comorbidity burden in the general population and individuals with MPN. We included 835,430 individuals from The Danish General Suburban Population Study, general practitioners, and outpatient clinics. We investigated NLR on mortality stratified by prevalent and incident MPN, essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis (MF), comorbidity burden (CCI-score), and the Triple-A risk score using hazard ratio (HR) and 95% confidence interval (95%CI). NLR 1-1.9 was the reference level. During a median follow-up of 11.2 years, 197,802 deaths were recorded. All-cause mortality increased for a stepwise increasing NLR with a HR (95%CI) for NLR ≥ 6 of 2.06(2.03-2.09) for the whole population and 2.93(2.44-3.50) in prevalent MPN. ET, PV, and MF had a HR (95%CI) for NLR ≥ 2 of 2.14(1.71-2.69), 2.19(1.89-2.54), and 2.31(1.91-2.80). Results were similar for incident MPN. Mortality was higher for stepwise increasing NLR and CCI-score(pinteraction < 2×10-16), with a HR for NLR ≥ 6 of 2.23(2.17-2.29), 4.10(4.01-4.20), and 7.69(7.50-7.89), for CCI-score 0, 1-2, or ≥3. The Triple-A risk score demonstrated alignment with NLR. Increasing NLR and comorbidity burden were associated with lower survival in individuals without MPN but were even worse in prevalent and incident MPN, ET, PV, and MF.

JAK2V617F drives gut microbiota differences in patients with myeloproliferative neoplasms.

BACKGROUND: Essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (MF) are myeloproliferative neoplasms (MPN). Inflammation is involved in the initiation, progression, and symptomology of the diseases. The gut microbiota impacts the immune system, infection control, and steady-state hematopoiesis. METHODS: We analyzed the gut microbiota of 227 MPN patients and healthy controls (HCs) using next-generation sequencing. We expanded our previous results in PV and ET patients with additional PV, pre-MF, and MF patients which allowed us to compare MPN patients collectively, MPN sub-diagnoses, and MPN mutations (separately and combined) vs. HCs (N = 42) and compare within MPN sub-diagnoses and MPN mutation. RESULTS: MPN patients had a higher observed richness (median, 245 [range, 49-659]) compared with HCs (191.5 [range, 111-300; p = .003]) and a lower relative abundance of taxa within the Firmicutes phylum; for example, Faecalibacterium (6% vs. 14%, p < .001). The microbiota of CALR-positive patients (N = 30) resembled that of HCs more than that of patients with JAK2V617F (N = 177). In JAK2V617F-positive patients, only minor differences in the gut microbiota were observed between MPN sub-diagnoses, illustrating the importance of this mutation. CONCLUSION: The gut microbiota in MPN patients differs from HCs and is driven by JAK2V617F, whereas the gut microbiota in CALR patients resembles HCs more.

Proof of concept of triple COMBI therapy to prohibit MPN progression to AML.

Patients with accelerated or blast phase myeloproliferative neoplasms have a dismal prognosis. The report by de Castro et al. provides important information on the rationale and prospect for a novel therapeutic approach combining interferon-alpha2 with 5-azacytidine and a JAK1-2 inhibitor (ruxolitinib) to be explored in well-designed clinical trials. Commentary on: Castro et al. Ratio of stemness to interferon signalling as a biomarker and therapeutic target of myeloproliferative neoplasm progression to acute myeloid leukaemia. Br J Haematol 2024;204:206-220.

Carrot Juice Intake Affects the Cytokine and Chemokine Response in Human Blood after Ex Vivo Lipopolysaccharide-Induced Inflammation.

In vitro and animal studies have shown that carrot juice containing bioactive natural products, such as falcarinol (FaOH) and falcarindiol (FaDOH), can affect inflammation. The present study was designed to test whether oral intake of carrot juice containing the bioactive acetylenic oxylipins FaOH and FaDOH affects mediators of acute inflammation or the innate immune response in human blood. Carrot juice (500 mL) was administered orally to healthy volunteers, and blood samples were drawn before and 1 h after juice intake. Next, the blood samples were split in two, and one sample was stimulated ex vivo with lipopolysaccharide (LPS) and incubated at 37 °C for 24 h. The concentrations of 44 inflammatory cytokines and chemokines were examined using multiplex electrochemiluminescence analysis. In blood samples not stimulated with LPS, a significant increase in IL-15 was measured 1 h after carrot juice intake. Cytokines like IFN-É£, IL-12/IL-23(p40), IL-23, IL-17A, IL-17B, IL-17D, and IL-22 were significantly increased in LPS-stimulated blood samples after carrot juice intake. The upregulation of the immunostimulating cytokines belonging to the IL-23/IL-17 Th17 axis suggests that carrot juice intake could benefit diseases where inflammation plays a role, like in the early stages of diabetes or cancers.

Revisiting Circulating Extracellular Matrix Fragments as Disease Markers in Myelofibrosis and Related Neoplasms.

Philadelphia chromosome-negative chronic myeloproliferative neoplasms (MPNs) arise due to acquired somatic driver mutations in stem cells and develop over 10-30 years from the earliest cancer stages (essential thrombocythemia, polycythemia vera) towards the advanced myelofibrosis stage with bone marrow failure. The JAK2V617F mutation is the most prevalent driver mutation. Chronic inflammation is considered to be a major pathogenetic player, both as a trigger of MPN development and as a driver of disease progression. Chronic inflammation in MPNs is characterized by persistent connective tissue remodeling, which leads to organ dysfunction and ultimately, organ failure, due to excessive accumulation of extracellular matrix (ECM). Considering that MPNs are acquired clonal stem cell diseases developing in an inflammatory microenvironment in which the hematopoietic cell populations are progressively replaced by stromal proliferation-"a wound that never heals"-we herein aim to provide a comprehensive review of previous promising research in the field of circulating ECM fragments in the diagnosis, treatment and monitoring of MPNs. We address the rationales and highlight new perspectives for the use of circulating ECM protein fragments as biologically plausible, noninvasive disease markers in the management of MPNs.

Pronounced gut microbiota signatures in patients with JAK2V617F-positive essential thrombocythemia.

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 (JAK2V617F)-positive vs JAK2V617F-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; P < 0.001). Patients with ET had a different overall bacterial composition (beta diversity) than HCs (analysis of similarities [ANOSIM]; R = 0.063, P = 0.004). Patients with ET had a significantly lower relative abundance of taxa within the Firmicutes phylum compared with HCs (51% vs 59%, P = 0.03), and within that phylum, patients with ET also had a lower relative abundance of the genus Faecalibacterium (8% vs 15%, P < 0.001), an important immunoregulative bacterium. The microbiota signatures were more pronounced in patients harboring the JAK2V617F 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 JAK2V617F-positive ET have pronounced gut microbiota signatures compared with JAK2V617F-negative patients. Thereby confirming the importance of the underlying mutation, the immune response as well as the composition of the microbiota.

Whole blood transcriptional profiling reveals highly deregulated atherosclerosis genes in Philadelphia-chromosome negative myeloproliferative neoplasms.

BACKGROUND: The Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are associated with a huge comorbidity burden, including an increased risk of cardiovascular diseases. Recently, chronic inflammation has been suggested to be the driving force for clonal evolution and disease progression in MPN but also potentially having an impact upon the development of accelerated (premature) atherosclerosis. OBJECTIVES: Since chronic inflammation, atherosclerosis, and atherothrombosis are prevalent in MPNs and we have previously shown oxidative stress genes to be markedly upregulated in MPNs, we hypothesized that genes linked to development of atherosclerosis might be highly deregulated as well. METHODS: Using whole blood gene expression profiling in patients with essential thrombocythemia (ET; n = 19), polycythemia vera (PV; n = 41), or primary myelofibrosis (PMF; n = 9), we herein for the first time report aberrant expression of several atherosclerosis genes. RESULTS: Of 84 atherosclerosis genes, 45, 56, and 46 genes were deregulated in patients with ET, PV, or PMF, respectively. Furthermore, BCL2L1, MMP1, PDGFA, PTGS1, and THBS4 were progressively significantly upregulated and BCL2 progressively significantly downregulated from ET over PV to PMF (all FDR <0.05). CONCLUSIONS: We have for the first time shown massive deregulation of atherosclerosis genes in MPNs, likely reflecting the inflammatory state in MPNs in association with in vivo activation of leukocytes, platelets, and endothelial cells being deeply involved in the atherosclerotic process.

JAK2V617F mutation is highly prevalent in patients with ischemic stroke: a case-control study.

Ischemic stroke has a high recurrence rate despite treatment. This underlines the significance of investigating new possible cerebrovascular risk factors, such as the acquired gene mutation JAK2V617F found in 3.1% of the general population. We aimed to investigate the prevalence of the JAK2V617F mutation in a population with ischemic stroke compared with that in matched controls. We enrolled 538 consecutive Danish patients with ischemic stroke (mean age, 69.5 ± 10.9 years; 39.2% female) within 7 days of symptom onset. Using multiple-adjusted conditional logistic regression analysis, we compared the prevalence of JAK2V617F with that in age- and sex-matched controls free of ischemic cerebrovascular disease (ICVD) from the Danish General Suburban Population Study. DNA was analyzed for JAK2V617F mutation using sensitive droplet digital polymerase chain reaction in patients and controls. Of the 538 patients with ischemic stroke, 61 (11.3%) had JAK2V617F mutation. There were no differences in patient demographics or cerebrovascular comorbidities between the patients with and without mutations. Patients with ischemic stroke were more likely to have the JAK2V617F mutation than matched controls, in whom the JAK2V617F prevalence was 4.4% (odds ratio, 2.37; 95% confidence interval, 1.57-3.58; P < .001). A subanalysis stratified by smoking history revealed that the association was strongest in current smokers (odds ratio, 4.78; 95% confidence interval, 2.22-10.28; P < .001). Patients with ischemic stroke were 2.4 times more likely to have the JAK2V617F mutation than matched controls without ICVD when adjusting for other cerebrovascular risk factors. This finding supports JAK2V617F mutation as a novel cerebrovascular risk factor.

Socioeconomic differences in expected discomfort from colonoscopy and colon capsule endoscopy.

Individual income and educational level are associated with participation rates in colorectal cancer screening. We aimed to investigate the expected discomfort from the endoscopic diagnostic modalities of colonoscopy and colon capsule endoscopy in different socioeconomic groups as a potential barrier for participation. In a randomized clinical trial within the Danish colorectal cancer screening program, we distributed questionnaires to 2031 individuals between August 2020 and December 2022 to investigate the expected procedural and overall discomfort from investigations using visual analogue scales. Socioeconomic status was determined by household income and educational level. Multivariate continuous ordinal regressions were performed to estimate the odds of higher expected discomfort. The expected procedural and overall discomfort from both modalities were significantly higher with increasing educational levels and income, except for procedural discomfort from colon capsule endoscopy between income quartiles. The odds ratios for higher expected discomfort increased significantly with increasing educational level, whereas the differences between income groups were less substantial. Bowel preparation contributed most to expected discomfort in colon capsule endoscopy, whereas in colonoscopy, the procedure itself was the largest contributor. Individuals with prior experiences of colonoscopy reported significantly lower expected overall but not procedural discomfort from colonoscopy. The threshold for acceptable discomfort between subgroups is unknown, but the expected discomfort in colon capsule endoscopy and colonoscopy was higher in higher socioeconomic subgroups, suggesting that expected discomfort is not a significant contributor to the inequalities in screening uptake.

Projected future European power sector water usage across power scenarios and corresponding trends in water availability.

The current transition toward added renewables into the power mix is essential to mitigate climate change effects, but the energy transition has environmental impacts outside the scope of greenhouse gas emissions that also need attention. One such impact is the water-energy dependency nexus, where water dependencies are also seen for non-fossil technologies such as concentrated solar power (CSP), bioenergy and hydropower and mitigation technologies such as carbon capture and storage (CCS). In this light, the selection of power production technologies can potentially affect long-term water resource renewability and dry summer conditions, causing, e.g., power plant shutdowns. In this study, we employ an established and validated scheme of water consumption and withdrawal rates across energy conversion technologies at the European scale to project corresponding water usage rates towards 2050 for EU30 countries. We further use the entire range of global- and regional climate model ensembles for low-, medium- and high-emission scenarios to project trends and robustness estimates of freshwater resources and availability at the distributed level for corresponding countries and years towards 2100. The results show a high sensitivity of water usage rates to the implementation of energy technologies such as CSP and CCS, as well as the decommissioning rates of fossil technologies and some scenarios generally show unaltered or even vastly increasing water consumption and withdrawal rates. Further, the assumptions on using CCS technologies, an evolving field, show a high impact. The assessment of hydro-climatic projections showed some degree of overlaps between decreasing water availabilities and increasing power sector water usage, especially for one power production scenario with a high share of CCS implementation. Further, a vast climate model spread in water availability was seen for both yearly means and summer minima, emphasising the need to include extremes in water management, and the water availability was highly dependent on the emission scenario in some regions.

The utility of using Volunteered Geographic Information (VGI) for evaluating pluvial flood models.

Pluvial floods are increasingly threatening urban environments worldwide due to human-induced climate change. High-resolution, state-of-the-art pluvial flood models are urgently needed to inform climate change adaptation and disaster risk reduction measures but are generally not empirically tested because of the rarity of local high-intensity precipitation events and the lack of monitoring capabilities. Volunteered Geographic Information (VGI) collected by professionals, non-professionals and citizens and made available on the internet can be used to monitor the dynamic extent of a pluvial flood during and after an extreme rain event but is sometimes considered to be unreliable. In this paper, we explore the general utility of VGI to evaluate the performance of pluvial flood models and gain new insights to improve these models. As background for our research, we use the capital city of Budapest, which recently suffered three heavy rainfall events in just five years (2015, 2017 and 2020). For each pluvial flood event, we collected photographic evidence from different online media sources and estimated the associated water depths at various locations in the city from the image context. These were compared with the results of a 2D pluvial flood model that has been shown to provide comparable results to other state-of-the-art inundation models and is easily transferred to other urban areas due to its reliance on open data sources. We introduce a general methodology for comparing VGI with model data by probing different spatial resolutions. Our findings highlight untapped potential and fundamental challenges in using VGI for model evaluation. It is proposed that VGI may become an essential tool and improve the confidence in model-based risk assessments for climate change adaptation and disaster risk reduction.

Socioeconomic inequalities in interval colorectal cancer are explained by differences in faecal haemoglobin concentration and age: a register-based cohort study.

OBJECTIVE: To estimate the risk of interval colorectal cancer (CRC) in faecal immunochemical test (FIT) negative screening participants according to socioeconomic status. DESIGN: In this register-based study, first round FIT negative (<20 µg hb/g faeces) screening participants (biennial FIT, citizens aged 50-74) were followed to estimate interval CRC risk. Multivariate Cox proportional hazard regression models estimated HRs based on socioeconomic status defined by educational level and income. Models were adjusted for age, sex and FIT concentration. RESULTS: We identified 829 (0.7‰) interval CRC in 1 160 902 individuals. Interval CRC was more common in lower socioeconomic strata with 0.7‰ for medium-long higher education compared with 1.0‰ for elementary school and 0.4‰ in the highest income quartile compared with 1.2‰ in the lowest. These differences did not translate into significant differences in HR in the multivariate analysis, as they were explained by FIT concentration and age. HR for interval CRC was 7.09 (95% CI) for FIT concentrations 11.9-19.8 µg hb/g faeces, and 3.37 (95% CI) for FIT between 7.2 and 11.8 compared with those <7.2. The HR rose with increasing age ranging from 2.06 (95% CI 1.45 to 2.93) to 7.60 (95% CI 5.63 to 10.25) compared with those under 55 years. CONCLUSION: Interval CRC risk increased with decreasing income, heavily influenced by lower income individuals more often being older and having increased FIT concentrations. Individualising screening interval based on age and FIT result, may decrease interval CRC rates, reduce the social gradient and thereby increase the screening efficiency.

Case Report: First longitudinal study of a patient with CALR positive clonal hematopoiesis of indeterminate potential developing into pre-fibrotic myelofibrosis.

Initial diagnosis of overt myeloproliferative neoplasms (MPNs) represents the juncture during clonal evolution when symptoms or complications prompt an afflicted individual to seek medical attention. In 30-40% of the MPN subgroups essential thrombocythemia (ET) and myelofibrosis (MF), somatic mutations in the calreticulin gene (CALR) are drivers of the disease resulting in constitutive activation of the thrombopoietin receptor (MPL). In the current study, we describe a healthy CALR mutated individual during a 12 year follow-up from initial identification of CALR clonal hematopoiesis of indeterminate potential (CHIP) to the diagnosis of pre-MF. The pre-diagnostic exponential development dynamics of the malignant clone demonstrated close correlation with the platelet counts, neutrophil-to-lymphocyte (NLR) ratio, and inversely correlated to hemoglobin and erythrocyte counts. Backward extrapolation of the growth rate indicated the potential for discovery of the malignant clone many years prior to presentation of overt disease, opening a window of opportunity for early treatment intervention. We did not find any additional mutations associated with MPNs and the current case report provides novel information regarding the development of a driver mutation and the association with blood cell counts prior to clinical manifestation of symptoms suggesting that pre-diagnostic dynamics may supplement future diagnostic criteria for early diagnosis and intervention in MPN patients.