Chemotherapy for a secondary malignancy nearly restores complete chimerism in an SCID-patient after HSCT.

For patients with inborn errors of immunity (IEI) and other inborn diseases, mixed donor chimerism is a well-accepted outcome of hematopoietic stem cell transplantation (HSCT). Cytoreductive chemotherapy for a secondary malignancy is a potential challenge for the stability of the graft function after HSCT. We report on a boy with X-SCID who developed Ewing sarcoma ten years after HSCT which was successfully treated with cytoreductive chemotherapy, surgery and local radiation. Surprisingly, this treatment had a positive impact on mixed chimerism with an increase of donor-cell proportions from 40% for neutrophils and 75% for non-T-mononuclear cells (MNCs) to >90% for both. T-cell counts remained stable with 100% of donor origin. This is -to our knowledge- the first report on the impact of cytoreductive chemotherapy on post-HSCT mixed chimerism and provides an important first impression for future patients.

A partial human LCK defect causes a T cell immunodeficiency with intestinal inflammation.

Lymphocyte-specific protein tyrosine kinase (LCK) is essential for T cell antigen receptor (TCR)-mediated signal transduction. Here, we report two siblings homozygous for a novel LCK variant (c.1318C>T; P440S) characterized by T cell lymphopenia with skewed memory phenotype, infant-onset recurrent infections, failure to thrive, and protracted diarrhea. The patients' T cells show residual TCR signal transduction and proliferation following anti-CD3/CD28 and phytohemagglutinin (PHA) stimulation. We demonstrate in mouse models that complete (Lck-/-) versus partial (LckP440S/P440S) loss-of-function LCK causes disease with differing phenotypes. While both Lck-/- and LckP440S/P440S mice exhibit arrested thymic T cell development and profound T cell lymphopenia, only LckP440S/P440S mice show residual T cell proliferation, cytokine production, and intestinal inflammation. Furthermore, the intestinal disease in the LckP440S/P440S mice is prevented by CD4+ T cell depletion or regulatory T cell transfer. These findings demonstrate that P440S LCK spares sufficient T cell function to allow the maturation of some conventional T cells but not regulatory T cells-leading to intestinal inflammation.

Immune-epithelial cell cross-talk enhances antiviral responsiveness to SARS-CoV-2 in children.

The risk of developing severe COVID-19 rises dramatically with age. Schoolchildren are significantly less likely than older people to die from SARS-CoV-2 infection, but the molecular mechanisms underlying this age-dependence are unknown. In primary infections, innate immunity is critical due to the lack of immune memory. Children, in particular, have a significantly stronger interferon response due to a primed state of their airway epithelium. In single-cell transcriptomes of nasal turbinates, we find increased frequencies of immune cells and stronger cytokine-mediated interactions with epithelial cells, resulting in increased epithelial expression of viral sensors (RIG-I, MDA5) via IRF1. In vitro, adolescent peripheral blood mononuclear cells produce more cytokines, priming A549 cells for stronger interferon responses to SARS-CoV-2. Taken together, our findings suggest that increased numbers of immune cells in the airways of children and enhanced cytokine-based interactions with epithelial cells tune the setpoint of the epithelial antiviral system. Our findings shed light on the molecular basis of children's remarkable resistance to COVID-19 and may suggest a novel concept for immunoprophylactic treatments.

Long-term haematological response and maintained immunological function after laparoscopic subtotal splenectomy in patients with hereditary spherocytosis.

INTRODUCTION: Subtotal or total splenectomy are recommended in severe and should be considered in intermediate forms of hereditary spherocytosis (HS). Data on laparoscopic subtotal splenectomy (LSTS) in HS patients are sparse. METHODS: Thirty three patients with HS (median age 10.7 years (yrs), range 1.8-15.5) underwent LSTS. Baseline and follow-up investigation included haematological parameters, microscopic analysis of pitted erythrocytes (pitE), and B-cell subpopulations assessed by flow cytometry. Results were compared to those of non-splenectomised HS patients, HS patients after total splenectomy (TS), and healthy individuals. RESULTS: After LSTS, haemoglobin levels were normalised in all patients. During median long-term follow-up of 3.9 yrs (range 1.1-14.9), only four patients presented mild anaemia. Despite re-growing of the remnant spleen none of the patients required a second surgical intervention. As compared to TS, PitE in LSTS patients were significantly lower and indicated normal to only moderately decreased spleen function. Relative but not absolute IgM memory B-cell counts were reduced in both LSTS and TS patients. CONCLUSIONS: LSTS is effective for the treatment of patients with HS. A small remnant spleen is sufficient to provide adequate phagocytic function and to induce a pool of IgM memory B-cells.

Complement and platelets: prothrombotic cell activation requires membrane attack complex-induced release of danger signals.

Complement activation in the diseases paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) results in cytolysis and fatal thrombotic events, which are largely refractory to anticoagulation and/or antiplatelet therapy. Anticomplement therapy, however, efficiently prevents thrombotic events in PNH and aHUS, but the underlying mechanisms remain unresolved. We show that complement-mediated hemolysis in whole blood induces platelet activation similarly to activation by adenosine 5'-diphosphate (ADP). Blockage of C3 or C5 abolished platelet activation. We found that human platelets failed to respond functionally to the anaphylatoxins C3a and C5a. Instead, complement activation did lead to prothrombotic cell activation in the whole blood when membrane attack complex (MAC)-mediated cytolysis occurred. Consequently, we demonstrate that ADP receptor antagonists efficiently inhibited platelet activation, although full complement activation, which causes hemolysis, occurred. By using an established model of mismatched erythrocyte transfusions in rats, we crossvalidated these findings in vivo using the complement inhibitor OmCI and cobra venom factor. Consumptive complement activation in this animal model only led to a thrombotic phenotype when MAC-mediated cytolysis occurred. In conclusion, complement activation only induces substantial prothrombotic cell activation if terminal pathway activation culminates in MAC-mediated release of intracellular ADP. These results explain why anticomplement therapy efficiently prevents thromboembolisms without interfering negatively with hemostasis.

Arterial events in cancer patients treated with apixaban for venous thrombosis.

INTRODUCTION: In a recent interventional study of cancer patients with newly diagnosed venous thrombosis (VT), we found a high risk of arterial thrombotic events (AT) during treatment with therapeutic doses of apixaban. METHODS: Total 298 cancer patients with VT received apixaban as treatment and secondary prophylaxis for up to 36 months. AT was registered as a serious adverse event, and this is a post hoc analysis of risk factors for AT. Clinical risk factors and concomitant medication were assessed through odds ratios (OR) with 95 % confidence interval using multivariate logistic regression. Biomarkers were assessed by non-parametric testing. RESULTS: AT occurred in 16/298 patients (5.4 %, 95 % confidence interval (CI) 3.1-8.6 %). Median leucocyte count at baseline was higher in patients with AT compared with patients without AT (11 vs. 6.8·109/L, p < 0.01). Clinical factors associated with AT were pancreatic cancer (OR 13.7, 95 % CI 4.3-43.1), ovarian cancer (OR 19.3, 95 % CI 2.3-164.4), BMI <25 percentile (OR 3.1, 95 % CI 1.1-8.8) and previous VT (OR 4.4, 95 % CI 1.4-13.7). Pancreatic cancer had a cumulative incidence of AT of 36 % compared with 0.8 % for all other cancers at 6 months (p < 0.01). Non-steroidal anti-inflammatory drugs (OR 4.9, 95 % CI 1.0-26) and antiplatelet treatment (OR 3.8, 95 % CI 1.2-12.2) were associated with AT. CONCLUSION: In cancer patients with apixaban treated VT, pancreatic cancer was strongly associated with AT. In addition, ovarian cancer, BMI < 25 percentile, previous VT, antiplatelet treatment, non-steroidal anti-inflammatory drug use and high leucocyte count at baseline were associated with AT. The CAP study is registered with the unique identifier NCT02581176 in ClinicalTrials.gov.

[Factor Xa inhibitors in the prevention and treatment of venous thromboembolism in cancer patients]. / Faktor Xa-hemmere til forebygging og behandling av venøs tromboembolisme ved kreft.

Venous thromboembolism is a common complication of cancer. The prevalence varies according to cancer type and increases proportionally with the stage of cancer. In the past 15-20 years, low molecular weight heparin has been recommended as the first-line treatment. New international guidelines now allow for use of direct factor Xa inhibitors both as prophylaxis and treatment for venous thromboembolism. Prophylaxis should as a general rule only be initiated in patients with moderate to high risk. Bleeding risk assessment is important before starting anticoagulation. Both thrombosis and bleeding risk can change and should therefore be assessed on an ongoing basis. In this clinical review, use of anticoagulation therapy in cancer patients is discussed with particular emphasis on the use of direct factor Xa inhibitors.

Novel mutation and expanding phenotype in IRF2BP2 deficiency.

OBJECTIVES: Inborn errors of immunity manifest with susceptibility to infection but may also present with immune dysregulation only. According to the European Society for Immunodeficiencies Registry about 50% of inborn errors of immunity are classified as common variable immunodeficiencies (CVID). In only few CVID patients are monogenic causes identified. IFN regulatory factor-2 binding protein 2 (IRF2BP2) is one of 20 known genes associated with CVID phenotypes and has only been reported in two families so far. We report another IRF2BP2-deficient patient with a novel pathogenic variant and phenotype and characterize impaired B cell function and immune dysregulation. METHODS: We performed trio whole-exome sequencing, determined B cell subpopulations and intracellular calcium mobilization upon B cell receptor crosslinking in B cells. T cell subpopulations, T cell proliferation and a type I IFN signature were measured. Colonoscopy and gastroduodenoscopy including histopathology were performed. RESULTS: The 33-year-old male presented with recurrent respiratory infections since childhood, colitis and RA beginning at age 25 years. We identified a novel de novo nonsense IRF2BP2 variant c.1618C>T; p.(Q540*). IgG deficiency was detected as consequence of a severe B cell differentiation defect. This was confirmed by impaired plasmablast formation upon stimulation with CpG. No serum autoantibodies were detected. Intracellular cytokine production in CD4+ T cells and CTLA4 expression on FOXP3+ Tregs were impaired. Type I IFN signature was elevated. CONCLUSION: The identified loss-of-function variant in IRF2BP2 severely impairs B cell development and T cell homeostasis, and may be associated with colitis and RA. Our results provide further evidence for association of IRF2BP2 with CVID and contribute to the understanding of the underlying pathomechanisms.

Cadmium exposure in adults across Europe: Results from the HBM4EU Aligned Studies survey 2014-2020.

The objectives of the study were to estimate the current exposure to cadmium (Cd) in Europe, potential differences between the countries and geographic regions, determinants of exposure and to derive European exposure levels. The basis for this work was provided by the European Human Biomonitoring Initiative (HBM4EU) which established a framework for alignment of national or regional HBM studies. For the purpose of Cd exposure assessment, studies from 9 European countries (Iceland, Denmark, Poland, Czech Republic, Croatia, Portugal, Germany, France, Luxembourg) were included and urine of 20-39 years old adults sampled in the years 2014-2021 (n = 2510). The measurements in urine were quality assured by the HBM4EU quality assurance/quality control scheme, study participants' questionnaire data were post-harmonized. Spatially resolved external data, namely Cd concentrations in soil, agricultural areas, phosphate fertilizer application, traffic density and point source Cd release were collected for the respective statistical territorial unit (NUTS). There were no distinct geographic patterns observed in Cd levels in urine, although the data revealed some differences between the specific study sites. The levels of exposure were otherwise similar between two time periods within the last decade (DEMOCOPHES - 2011-2012 vs. HBM4EU Aligned Studies, 2014-2020). The age-dependent alert values for Cd in urine were exceeded by 16% of the study participants. Exceedances in the different studies and locations ranged from 1.4% up to 42%. The studies with largest extent of exceedance were from France and Poland. Association analysis with individual food consumption data available from participants' questionnaires showed an important contribution of vegetarian diet to the overall exposure, with 35% higher levels in vegetarians as opposed to non-vegetarians. For comparison, increase in Cd levels due to smoking was 25%. Using NUTS2-level external data, positive associations between HBM data and percentage of cropland and consumption of Cd-containing mineral phosphate fertilizer were revealed, which indicates a significant contribution of mineral phosphate fertilizers to human Cd exposure through diet. In addition to diet, traffic and point source release were identified as significant sources of exposure in the study population. The findings of the study support the recommendation by EFSA to reduce Cd exposure as also the estimated mean dietary exposure of adults in the EU is close or slightly exceeding the tolerable weekly intake. It also indicates that regulations are not protecting the population sufficiently.

Hyper-IgE and Carcinoma in CADINS Disease.

Background: Atopic dermatitis (AD) affects up to 25% of children and 10% of adults in Western countries. When severe or recurrent infections and exceedingly elevated serum IgE levels occur in AD patients, an inborn error of immunity (IEI) may be suspected. The International Union of Immunological Societies classification lists variants in different genes responsible for so-called Hyper-IgE syndromes. Diagnosing an underlying IEI may influence treatment strategies. Methods: Clinical and diagnostic workup of family members are presented including a detailed immunological description and histology of the carcinoma. Functional testing of the novel variant in CARD11 underlying 'CARD11-associated atopy with dominant interference of NF-kB signaling' (CADINS) was performed. Results: We report on an 18-year-old patient with a long-standing history of infections, accompanied by hypogammaglobulinemia, intermittent agranulocytosis, atopy, eosinophilia and colitis. The working diagnosis of common variable immunodeficiency was revised when a novel heterozygous CARD11 variant [c.223C>T; p.(Arg75Trp)] was identified. Functional studies confirmed this variant to have a dominant negative (DN) effect, as previously described in patients with CADINS. Five other family members were affected by severe atopy associated with the above variant, but not hypogammaglobulinemia. Malignancies occurred in two generations: an HPV-positive squamous cell carcinoma and a cutaneous T-cell lymphoma. So far, one patient is under treatment with dupilumab, which has shown marked benefit in controlling severe eczema. Conclusion: The phenotypic spectrum associated with heterozygous CARD11 DN mutations is broad. Partial T-cell deficiency, diminished IFN-γ cytokine and increased IL-4 production, were identified as disease-causing mechanisms. Malignant disease associated with germline CARD11 DN variants has only been reported sporadically. HPV vaccination in teenage years, and cytology screening analogous with routine cervical swabs may be recommended. Treatment with dupilumab, a monoclonal antibody blocking interleukin-4- and interleukin-13 signaling, may be of benefit in controlling severe and extended AD for some patients as reported for STAT3 loss-of-function.

Low dose apixaban as secondary prophylaxis of venous thromboembolism in cancer patients - 30 months follow-up.

BACKGROUND: There are no data on the effect of low-dose anticoagulation as secondary prophylaxis for venous thromboembolism (VTE) in cancer patients. We assessed the efficacy and safety of low-dose apixaban for 30 months, after initial 6 months of full-dose treatment. METHODS: We included 298 patients with cancer and any type of VTE in a single arm interventional clinical trial. All patients were treated with full-dose apixaban (5 mg twice daily) for 6 months. Total 196 patients with active cancer after 6 months treatment continued with apixaban 2.5 mg twice daily for another 30 months. The main endpoints were recurrent VTE, major bleeding and clinically relevant non-major bleeding. RESULTS: During the 30 months of treatment with low-dose apixaban 14 (7.6%; 95% confidence interval (CI) 4.0%-11.7%) patients experienced recurrent VTE, six (3.1%; 95% CI 1.1%-6.5%) experienced major bleeding and 16 (8.1%, 95% CI: 4.7%-12.8%) experienced clinically relevant non-major bleeding. The incidence rate per person month of recurrent VTE was 0.8% (95% CI 0.41-1.6) at 2-6 months with full-dose apixaban, and 1.0% (95% CI 0.5-1.9) at 7-12 months with low-dose apixaban. The incidence rate of major bleeding was 1.1% (95% CI 0.6-2.0) at 2-6 months, and 0.3% (95% CI 0.1-1.0) at 7-12 months. Between 12 and 36 months the incidence rate of recurrent VTE and major bleedings remained low. CONCLUSION: Dose reduction of apixaban to 2.5 mg twice daily seems safe after 6 months of full-dose treatment. After 12 months the incidence rate of recurrent VTE and major bleeding remained low.

Biomarkers of DNA Damage Response Enable Flow Cytometry-Based Diagnostic to Identify Inborn DNA Repair Defects in Primary Immunodeficiencies.

DNA damage is a constant event in every cell caused by exogenous factors such as ultraviolet and ionizing radiation (UVR/IR) and intercalating drugs, or endogenous metabolic and replicative stress. Proteins of the DNA damage response (DDR) network sense DNA lesions and induce cell cycle arrest, DNA repair, and apoptosis. Genetic defects of DDR or DNA repair proteins can be associated with immunodeficiency, bone marrow failure syndromes, and cancer susceptibility. Although various diagnostic tools are available to evaluate DNA damage, their quality to identify DNA repair deficiencies differs enormously and depends on affected pathways. In this study, we investigated the DDR biomarkers γH2AX (Ser139), p-ATM (Ser1981), and p-CHK2 (Thr68) using flow cytometry on peripheral blood cells obtained from patients with combined immunodeficiencies due to non-homologous end-joining (NHEJ) defects and ataxia telangiectasia (AT) in response to low-dose IR. Significantly reduced induction of all three markers was observed in AT patients compared to controls. However, delayed downregulation of γH2AX was found in patients with NHEJ defects. In contrast to previous reports of DDR in cellular models, these biomarkers were not sensitive enough to identify ARTEMIS deficiency with sufficient reliability. In summary, DDR biomarkers are suitable for diagnosing NHEJ defects and AT, which can be useful in neonates with abnormal TREC levels (T cell receptor excision circles) identified by newborn screening. We conclude that DDR biomarkers have benefits and some limitations depending on the underlying DNA repair deficiency.

Endovascular versus surgical treatment of cranial dural arteriovenous fistulas: a single-center 8-year experience.

BACKGROUND: Cranial dural arteriovenous fistulas (dAVFs) are rare lesions managed mainly with endovascular treatment (EVT) and/or surgery. We hypothesize that there may be subtypes of dAVFs responding better to a specific treatment modality in terms of successful obliteration and cessation of symptoms and/or risks. METHODS: All dAVFs treated during 2011-2018 at our hospital were analyzed retrospectively. Presenting symptoms, radiological variables, treatment modality, complications, and residual symptoms were related to dAVF type using the original Djindjian classification. RESULTS: We treated 112 dAVFs in 107 patients (71, 66% males). They presented with hemorrhage (n = 23; 21%), non-hemorrhagic symptoms (n = 75; 70%), or were discovered incidentally (n = 9; 8%). There were 25 (22%) type I, 29 (26%) type II, 26 (23%) type III, and 32 (29%) type IV fistulas. EVT was the primary treatment modality in 72/112 (64%) dAVFs whereas 40/112 (36%) underwent primary surgery with angiographic obliteration rates of 60% and 90%, respectively. Using a secondary treatment modality in 23 dAVFs, we obtained a final obliteration rate of 93%, including all type III/IV and 26/27 (96%) type II dAVFs. Except for headache, residual symptoms were rare and minor. Permanent neurological complications consisted of five cranial nerve deficits. CONCLUSIONS: We recommend EVT as first treatment modality in types I, II, and in non-hemorrhagic type III/IV dAVFs. We recommend surgery as first treatment choice in acute hemorrhagic dAVFs and as secondary choice in type III/IV dAVFs not successfully occluded by EVT. Combining the two modalities provides obliteration in 9/10 dAVF cases at a low procedural risk.

A woman in her seventies with acute onset of blindness. / En kvinne i 70-årene med akutt blindhet.

BACKGROUND: Dural arteriovenous fistulae are among the most common causes of pulsatile tinnitus. Selective angiography can be necessary for a definitive diagnosis, but in rare cases has been reported to cause sudden cortical blindness. CASE PRESENTATION: We present a woman in her seventies for whom cerebral angiography revealed a dural arteriovenous fistula. Two hours after the angiography she experienced sudden bilateral blindness. A local cause of sudden visual loss was excluded by clinical examination, cerebral bleeding was excluded by CT scan, vascular spasms and occlusions were excluded by CT angiography and acute infarction over the bilateral parieto-occipital cortex was excluded by MRI. The CT scan did, however, show contrast enhancement in the visual cortex from the contrast given during the previously performed cerebral angiography. The patient's vision spontaneously recovered within six days after the angiography, with no residual neurological deficits in her subsequent clinical follow up. Surgery was later performed on her dural arteriovenous fistula, which successfully treated the pulsatile tinnitus. INTERPRETATION: Transient cortical blindness is a rare but dramatic complication after cerebral angiography, thought to be caused by the transient neurotoxic effects of iodine-containing contrast agents. When other causes of sudden blindness are excluded, the patient can be reassured about the excellent prognosis for this condition.

Differential DNA Damage Response of Peripheral Blood Lymphocyte Populations.

DNA damage occurs constantly in every cell triggered by endogenous processes of replication and metabolism, and external influences such as ionizing radiation and intercalating chemicals. Large sets of proteins are involved in sensing, stabilizing and repairing this damage including control of cell cycle and proliferation. Some of these factors are phosphorylated upon activation and can be used as biomarkers of DNA damage response (DDR) by flow and mass cytometry. Differential survival rates of lymphocyte subsets in response to DNA damage are well established, characterizing NK cells as most resistant and B cells as most sensitive to DNA damage. We investigated DDR to low dose gamma radiation (2Gy) in peripheral blood lymphocytes of 26 healthy donors and 3 patients with ataxia telangiectasia (AT) using mass cytometry. γH2AX, p-CHK2, p-ATM and p53 were analyzed as specific DDR biomarkers for functional readouts of DNA repair efficiency in combination with cell cycle and T, B and NK cell populations characterized by 20 surface markers. We identified significant differences in DDR among lymphocyte populations in healthy individuals. Whereas CD56+CD16+ NK cells showed a strong γH2AX response to low dose ionizing radiation, a reduced response rate could be observed in CD19+CD20+ B cells that was associated with reduced survival. Interestingly, γH2AX induction level correlated inversely with ATM-dependent p-CHK2 and p53 responses. Differential DDR could be further noticed in naïve compared to memory T and B cell subsets, characterized by reduced γH2AX, but increased p53 induction in naïve T cells. In contrast, DDR was abrogated in all lymphocyte populations of AT patients. Our results demonstrate differential DDR capacities in lymphocyte subsets that depend on maturation and correlate inversely with DNA damage-related survival. Importantly, DDR analysis of peripheral blood cells for diagnostic purposes should be stratified to lymphocyte subsets.

Successful hematopoietic stem cell transplantation in a 4-1BB deficient patient with EBV-induced lymphoproliferation.

Complete remission from recurrent EBV-positive lymphoma is not mandatory before HSCT to achieve long-term cure in a patient suffering from a recently described immunodeficiency affecting the T-cell coactivation molecule 4-1BB.

Matched Family Donor Lymphocyte Infusions as First Cellular Therapy for Patients with Severe Primary T Cell Deficiencies.

Patients with primary immunodeficiencies caused by severe defects in T cell immunity are at risk of acquiring life-threatening infections. Cellular therapies are necessary to establish normal T cell function and to allow for long-term survival. This is most commonly achieved by hematopoietic stem cell transplantation (HSCT), but the outcome of this procedure is impaired if active infections are present at the time of HSCT. Donor lymphocyte infusions (DLIs) are a well-established therapeutic strategy following HSCT to treat viral infections, improve donor cell engraftment, or achieve graft-versus-leukemia activity in malignant disease. Here we present a cohort of 6 patients with primary T cell deficiencies who received transfusions of unselected mature donor lymphocytes prior and not directly related to allogeneic HSCT. DLIs obtained from the peripheral blood of HLA-identical (10/10) family donors were transfused without prior conditioning to treat or prevent life-threatening infections. All patients are alive with a follow-up of 0.5 to 16.5 years after the initial T cell administration. Additional cellular therapies were administered in 5 of 6 patients at 0.8 to 15 months after the first DLI. Mild cutaneous graft-versus-host disease (GVHD, stage ≤2) was observed in 3 of 6 patients and resolved spontaneously. We provide evidence that unselected HLA-identical DLIs can effectively prevent or contribute to overcome infections with a limited risk for GVHD in T cell deficient patients. The T cell system established by this readily available source can provide T cell function for years and can serve as a bridge to additional cellular therapies or, in specific conditions, as definite treatment.

Thrombosis and bleedings in a cohort of cancer patients treated with apixaban for venous thromboembolism.

INTRODUCTION: The direct oral anti-coagulants (DOAC) edoxaban and rivaroxaban are suggested treatment alternatives for cancer-associated venous thromboembolism (VTE) together with low molecular-weight heparins. New studies indicate that the DOAC apixaban also is an option for cancer-associated VTE. The current study assessed recurrent VTE, arterial thrombosis, bleedings and adverse events in a cohort of apixaban treated cancer patients with VTE. MATERIALS AND METHODS: Single-arm, interventional study of apixaban as treatment of cancer-associated VTE. Inclusion criteria were cancer with objectively verified VTE. Patients received apixaban 10 mg bid for seven days, then 5 mg bid for six months. Primary efficacy and safety outcomes were recurrent VTE and bleeding respectively. This trial is registered with ClinicalTrials.gov identifier NCT02581176. RESULTS: We recruited 298 cancer patients with VTE. During six months treatment, recurrent VTE or death related to VTE occurred in 12 patients (4.0%, 95% confidence interval (CI) 2.1-6.9%). Major bleeding occurred in 16 patients (5.4%, 95% CI 2.8-7.9), most frequently gastrointestinal bleeding. There were no overrepresentation of major bleedings among patients with gastrointestinal cancer (7/126, 5.5%, 95% CI 2.3-11%). Twenty-six patients experienced one or more clinically relevant non-major bleedings (8.9%, 95% CI 5.5-12%). Twelve patients had arterial thrombosis (4.0%, 95% CI 2.1-6.9%), of which the majority were strokes in patients with pancreatic cancer. Death occurred in 35 patients (12%, 95% CI 8.3-16%). CONCLUSION: The frequency of recurrent VTE and major bleedings are in line with other studies on apixaban in cancer-associated VTE. Arterial thrombosis was a frequent serious adverse event.