Publications
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Tjønnfjord, Geir Erland; Osnes, Liv Toril N.; Spetalen, Signe; Haave, Ulla; Popperud, Trine Haug & Maniaol, Angelina H.
[Show all 17 contributors for this article]
(2026).
Anti‐MAG Polyneuropathy: Characterization of the Monoclonal Gammopathy and Clonal B‐Cell Population.
Journal of Immunology Research.
ISSN 2314-8861.
2026(1),
p. 1–9.
doi:
10.1155/jimr/1959235.
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Polyneuropathy due to antibodies to myelin‐associated glycoprotein (MAG) is a rare disease with an estimated prevalence of 1 per 100,000. Symptoms start in the sixth or seventh decade of life, presenting sensory polyneuropathy with sensory ataxia, paresthesia, mild motor deficit, and tremor of upper extremities. The neurophysiological features are compatible with length‐dependent demyelination. It is caused by monoclonal gammopathy of the IgM type produced by clonal B cells. In recent years the monoclonal anti‐CD20 antibody has become the preferred first‐line treatment, but with limited efficacy. We identified a cohort of 42 patients diagnosed with anti‐MAG polyneuropathy. Clinical data were collected retrospectively, and flow cytometry files and immune histochemistry slides were reassessed. We report that in most cases of anti‐MAG polyneuropathy, the monoclonal IgM is kappa‐restricted, the B‐cell population shows lymphoplasmacytic differentiation, MYD88 L265P mutation is a frequent finding, and the clonal B‐cell population includes plasma cells. These findings most likely explain the low efficacy of rituximab monotherapy. We found the burden of symptoms to be high among patients with anti‐MAG polyneuropathy as most of our patients had received intravenous immunoglobulin infusions and/or B‐cell‐directed treatment. We suggest that future treatment protocols for anti‐MAG polyneuropathy should incorporate plasma cell‐directed drugs. Furthermore, we found complement receptor 1 (CD35) to be down regulated on clonal B lymphocytes but not on normal B lymphocytes in these patients. We suggest that this may be a common feature of clonal B lymphocytes in chronic lymphoproliferative diseases.
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Nørgaard, Jakob Nordberg; Moore, Kari Lenita Falck; Slørdahl, Tobias Schmidt; Vik, Anders; Tvedt, Tor Henrik Andersson & Monsen, Heidi Berg
[Show all 7 contributors for this article]
(2026).
Høydosebehandling med autolog stamcellestøtte ved myelomatose i Norge 2008–20.
Tidsskrift for Den norske legeforening (Tidsskriftet).
ISSN 0029-2001.
146(5).
doi:
10.4045/tidsskr.25.0498.
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Bakgrunn og formål
Høydosebehandling med autolog stamcellestøtte (HMAS) er effektiv mot myelomatose. Hvilken type behandling som gis før og etter HMAS-behandlingen kan påvirke tid til tilbakefall og overlevelse. Formålet med denne studien var å sammenligne behandlingen gitt før og etter HMAS-behandling ved de fire sykehusene som tilbyr dette i Norge i perioden 2008–20.
Materiale og metode
Alle pasienter som fikk høydosebehandling med autolog stamcellestøtte som førstelinjebehandling for myelomatose i Norge i perioden 1.1.2008–31.12.2020, ble inkludert. Data om demografi, sykdom og behandling ble registrert. Pasientene ble fulgt til progresjon, død eller til studiens avslutning.
Resultater
Pasienter som mottok høydosebehandling med autolog stamcellestøtte ved St. Olavs hospital, fikk nesten utelukkende bortezomib-syklofosfamid-deksametason som induksjonsbehandling, mens bortezomib-lenalidomid-deksametason dominerte ved de tre andre HMAS-sentrene etter 2017. Vedlikeholdsbehandling ble gitt til 27 % av pasientene som mottok høydosebehandling med autolog stamcellestøtte i Oslo, mot 2–16 % ved de andre HMAS-sentrene. Median progresjonsfri overlevelse varierte mellom 29 og 38 måneder, og median totaloverlevelse var mellom 102 og 120 måneder på tvers av sentrene.
Fortolkning
Det var betydelige variasjoner i behandlingen før og etter høydosebehandling med autolog stamcellestøtte, spesielt etter 2017. Nasjonale retningslinjer åpnet for flere behandlingsvalg, noe som har medført ulik behandlingspraksis. De ulike behandlingsformene kan ha gitt utslag i forskjeller i progresjonsfri overlevelse og totaloverlevelse.
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Tvedt, Tor Henrik Andersson; Qvigstad, Christian; Nezvalova-Henriksen, Katerina; Bergland, Birgitte Strand; Bruserud, Øystein & Reikvam, Håkon
(2025).
Three-Month Posttransplant Lipidomic Profile Reflects Acute GVHD but Not Chronic GVHD Risk in Allogeneic Stem Cell Recipients.
European Journal of Haematology.
ISSN 0902-4441.
115(6),
p. 565–573.
doi:
10.1111/ejh.70011.
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Tsykunova, Galina; Holme, Pål Andre; Tran, Hoa Thi Tuyet; Frederiksen, Henrik; Tjønnfjord, Eirik & Munthe, Ludvig Andre
[Show all 16 contributors for this article]
(2025).
Safety and Efficacy of Daratumumab in Immune Thrombocytopenia.
Blood Advances.
ISSN 2473-9529.
10(1),
p. 143–154.
doi:
10.1182/bloodadvances.2025017279.
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Resistance to B-cell targeted therapies in immune thrombocytopenia (ITP) has been linked to persistence of autoantibody-producing CD38-positive long-lived plasma cells. CD38 antibody daratumumab has been proposed as a potential therapy for ITP. This multicenter, open-label, phase II study evaluated safety and efficacy of daratumumab in 21 previously treated ITP patients. Following a safety run-in, two dosing cohorts were included, receiving eight and ten subcutaneous injections of 1800 mg daratumumab weekly, respectively. Primary endpoints were safety and response (two consecutive platelet counts ≥50x109/L at week 12 for the safety run-in/Cohort 1, and at week 16 for Cohort 2). At baseline, median platelet count was 17x109/L, median number of prior therapies was four. Most treatment-emergent adverse events were transient grade 1-2, most commonly infections (38%).Two patients (4.7%) experienced grade 3 adverse events, one infusion-related reaction, and one SARS-CoV-2 infection with acute renal failure. Ten patients (48%) met the primary efficacy endpoint. Sustained response (two consecutive platelet counts ≥50x109/L at week 24) was achieved in eight patients (38%). Two patients relapsed after week 24. There was no difference in response or relapse rates between cohorts. Patient-reported quality of life measured by SF-36 improved in responding patients. Daratumumab decreased immunoglobulin levels in all patients, and substantially reduced CD38+ cells in peripheral blood and bone marrow. There was no significant difference in anti-platelet antibodies between responders and non-responders. This study confirms CD38 as an important target in ITP. NCT04703621; EudraCT 2019-004683-22.
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Nørgaard, Jakob Nordberg; Moore, Kari Lenita Falck; Slørdahl, Tobias Schmidt; Vik, Anders; Tvedt, Tor Henrik Anderson & Schjesvold, Fredrik
(2024).
VRD versus VCD as induction therapy before autologous stem cell transplantation in multiple myeloma: a nationwide population-based study.
Blood Cancer Journal.
14:60(1),
p. 1–4.
doi:
10.1038/s41408-024-01047-1.
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Induction therapy followed by autologous stem cell transplantation (ASCT) is standard of care for young and fit patients with newly diagnosed multiple myeloma (MM) [1]. Induction therapy has evolved from doublet to triplet to quadruplet regimens over the last decades. The most common triplet therapy is either Bortezomib-Cyclophosphamide-Dexamethasone (VCD), Bortezomib-Lenalidomide-Dexamethasone (VRD), or less frequently Bortezomib-Thalidomide-Dexamethasone (VTD). No large, randomized phase III study comparing the VCD and VRD regimens has been conducted and is unlikely to be done in the future. Retrospective studies and smaller prospective studies comparing VRD and VCD have produced mixed results [2,3,4,5,6,7].
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Aarstad, Helene Hersvik; Moe, Svein Erik Emblem; Lybak, Stein; Bruserud, Øystein; Tvedt, Tor Henrik Anderson & Aarstad, Hans Jørgen
(2024).
Plasma IL-1 and IL-6 Family Cytokines with Soluble Receptor Levels at Diagnosis in Head and Neck Squamous Cell Carcinoma: High Levels Predict Decreased Five-Year Disease-Specific and Overall Survival.
Cancers.
16(8).
doi:
10.3390/cancers16081484.
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Activation of the acute-phase cascade (APC) has been correlated with outcomes in various cancers, including head and neck squamous cell carcinoma (HNSCC). Primary drivers of the APC are the cytokines within the interleukin-6 (IL-6) and IL-1 families. Plasma levels of IL-6 family cytokines/soluble receptors (IL-6, IL-27, IL-31, OSM, CNTF, soluble (s-)gp130, s-IL-6Rα) and IL-1 family members (IL-1RA, s-IL-33Rα) were determined at diagnosis for 87 human papillomavirus (HPV)-negative (−) HNSCC patients. We then studied the 5-year Disease-Specific Survival (DSS) and Overall Survival (OS). Increased plasma levels of IL-6 (p < 0.001/p < 0.001) (DSS/OS), IL-31 (p = 0.044/p = 0.07), IL-1RA (p = 0.004/p = 0.035), soluble (s)-IL-6Rα p = 0.022/p = 0.035), and s-gp130 (p = 0.007/p = 0.003) at diagnosis were predictors of both OS and DSS from HPV(−) HNSCC patients. The cytokine DSS/OS predictions were associated with TNM stage and smoking history, whereas the soluble receptors IL-6Rα, gp130, and IL33Rα more uniquely predicted DSS/OS. Clinically, IL-6 levels above 2.5 pg/mL yielded 75% specificity and 70% sensitivity for DSS. In conclusion, high plasma levels of IL-6, IL-31, and IL-1RA, as well as the soluble receptors IL-6Rα, gp130, and IL33Rα, predicted clinical outcome. This shows their potential as candidates for both general therapy and immune therapy stratification, as well as being future platforms for the development of new immunotherapy.
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Fageräng, Beatrice Linnea Christina; Cyranka, Leon; Schjalm, Camilla; Ekholt, Karin; Larsen, Carina Sandem & Heinzelbecker, Julia
[Show all 14 contributors for this article]
(2024).
The function of the complement system remains fully intact throughout the course of allogeneic stem cell transplantation.
Frontiers in Immunology.
15.
doi:
10.3389/fimmu.2024.1422370.
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Introduction: Hematopoietic stem cell transplantation (HSCT) is associated with immune complications and endothelial dysfunction due to intricate donor-recipient interactions, conditioning regimens, and inflammatory responses. Methods: This study investigated the role of the complement system during HSCT and its interaction with the cytokine network. Seventeen acute myeloid leukemia patients undergoing HSCT were monitored, including blood sampling from the start of the conditioning regimen until four weeks post-transplant. Clinical follow-up was 200 days. Results: Total complement functional activity was measured by WIELISA and the degree of complement activation by ELISA measurement of sC5b-9. Cytokine release was measured using a 27-multiplex immuno-assay. At all time-points during HSCT complement functional activity remained comparable to healthy controls. Complement activation was continuously stable except for two patients demonstrating increased activation, consistent with severe endotheliopathy and infections. In vitro experiments with post-HSCT whole blood challenged with Escherichia coli, revealed a hyperinflammatory cytokine response with increased TNF, IL-1β, IL-6 and IL-8 formation. Complement C3 inhibition markedly reduced the cytokine response induced by Staphylococcus aureus, Aspergillus fumigatus, and cholesterol crystals. Discussion: In conclusion, HSCT patients generally retained a fully functional complement system, whereas activation occurred in patients with severe complications. The complement-cytokine interaction indicates the potential for new complement-targeting therapeutic strategies in HSCT.
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Chiang, Samuel C. C.; Covill, Laura E.; Tesi, Bianca; Campbell, Tessa M.; Schlums, Heinrich & Nejati-Zendegani, Jelve
[Show all 73 contributors for this article]
(2024).
Efficacy of T-cell assays for the diagnosis of primary defects in cytotoxic lymphocyte exocytosis.
Blood.
ISSN 0006-4971.
144(8),
p. 873–887.
doi:
10.1182/blood.2024024499.
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Primary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder associated with autosomal recessive variants in genes required for perforin-mediated lymphocyte cytotoxicity. A rapid diagnosis is crucial for successful treatment. Although defective cytotoxic T lymphocyte (CTL) function causes pathogenesis, quantification of natural killer (NK)–cell exocytosis triggered by K562 target cells currently represents a standard diagnostic procedure for primary HLH. We have prospectively evaluated different lymphocyte exocytosis assays in 213 patients referred for evaluation for suspected HLH and related hyperinflammatory syndromes. A total of 138 patients received a molecular diagnosis consistent with primary HLH. Assessment of Fc receptor–triggered NK-cell and T-cell receptor (TCR)–triggered CTL exocytosis displayed higher sensitivity and improved specificity for the diagnosis of primary HLH than routine K562 cell–based assays, with these assays combined providing a sensitivity of 100% and specificity of 98.3%. By comparison, NK-cell exocytosis after K562 target cell stimulation displayed a higher interindividual variability, in part explained by differences in NK-cell differentiation or large functional reductions after shipment. We thus recommend combined analysis of TCR-triggered CTL and Fc receptor–triggered NK-cell exocytosis for the diagnosis of patients with suspected familial HLH or atypical manifestations of congenital defects in lymphocyte exocytosis.
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Rørvik, Synne Dragesund; Torkildsen, Synne; Bruserud, Øystein & Tvedt, Tor Henrik Anderson
(2024).
Acute myeloid leukemia with rare recurring translocations—an overview of the entities included in the international consensus classification.
Annals of Hematology.
ISSN 0939-5555.
103(4),
p. 1103–1119.
doi:
10.1007/s00277-024-05680-5.
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Two different systems exist for subclassification of acute myeloid leukemia (AML); the World Health Organization (WHO) Classification and the International Consensus Classification (ICC) of myeloid malignancies. The two systems differ in their classification of AML defined by recurrent chromosomal abnormalities. One difference is that the ICC classification defines an AML subset that includes 12 different genetic abnormalities that occur in less than 4% of AML patients. These subtypes exhibit distinct clinical traits and are associated with treatment outcomes, but detailed description of these entities is not easily available and is not described in detail even in the ICC. We searched in the PubMed database to identify scientific publications describing AML patients with the recurrent chromosomal abnormalities/translocations included in this ICC defined patient subset. This patient subset includes AML with t(1;3)(p36.3;q21.3), t(3;5)(q25.3;q35.1), t(8;16)(p11.2;p13.3), t(1;22)(p13.3;q13.1), t(5;11)(q35.2;p15.4), t(11;12)(p15.4;p13.3) (involving NUP98), translocation involving NUP98 and other partner, t(7;12)(q36.3;p13.2), t(10;11)(p12.3;q14.2), t(16;21)(p11.2;q22.2), inv(16)(p13.3q24.3) and t(16;21)(q24.3;q22.1). In this updated review we describe the available information with regard to frequency, biological functions of the involved genes and the fusion proteins, morphology/immunophenotype, required diagnostic procedures, clinical characteristics (including age distribution) and prognostic impact for each of these 12 genetic abnormalities.
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Vo, Camilla Dao; Myhre, Anders Eivind; Abrahamsen, Ingerid Weum; Remberger, Mats; Mattsson, Jonas & Fløisand, Yngvar
[Show all 10 contributors for this article]
(2023).
Allogen stamcelletransplantasjon hos voksne 2015–21.
Tidsskrift for Den norske legeforening (Tidsskriftet).
ISSN 0029-2001.
143(4).
doi:
10.4045/tidsskr.22.0521.
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BAKGRUNN Allogen stamcelletransplantasjon er eneste kurative behandling for flere maligne og ikke-maligne blodsykdommer, og er assosiert med risiko for alvorlige komplikasjoner. De siste årene er det innført flere endringer med mål om å redusere behandlingsrelaterte komplikasjoner. Denne retrospektive studien gjennomgår kvalitetsindikatorer for pasienter som gjennomgikk transplantasjon i perioden 2015–21. MATERIALE OG METODE Studien inkluderte 589 voksne pasienter som ble behandlet med allogen stamcelletransplantasjon for første gang ved Oslo universitetssykehus fra mai 2015 til mai 2021. Tre toårsperioder er sammenliknet med deskriptive metoder. RESULTATER Fra 2015 til 2021 økte antall årlige førstegangstransplantasjoner fra 85 til 113. Ettårsoverlevelse økte fra 68 % i første toårsperiode til 74 % i andre periode og til 82 % i siste periode. Det var en reduksjon i både akutt og kronisk transplantat-mot-vert-sykdom, og andelen pasienter i live ett år etter transplantasjonen uten transplantat-mot-vert-sykdom eller residiv økte fra 42 % til 60 % i studieperioden. FORTOLKNING Siden 2015 er antall transplantasjoner økt samtidig som overlevelsen er forbedret og risikoen for komplikasjoner lavere.
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Tsykunova, Galina; Kristensen, Erle; Stray-Pedersen, Asbjørg; Bruserud, Øyvind; Sørensen, Ida Wiig & Bruserud, Øystein
[Show all 7 contributors for this article]
(2023).
Adult presentation of ornithine transcarbamylase deficiency: a possible cause of hyperammonemia after high-dose chemotherapy and stem cell transplantation.
Hematology.
ISSN 1024-5332.
28(1).
doi:
10.1080/16078454.2023.2265187.
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Hyperammonemia is a rare and often fatal complication following the conditioning therapy in autologous and allogeneic stem cell transplant recipients. It is characterized by anorexia, vomiting, lethargy and coma without any other apparent cause. The diagnosis is often delayed because symptoms can be subtle and ammonia is usually not included among the routine analyzes. Previous reports have not identified the molecular mechanisms behind hyperammonemia in stem cell transplant recipients. Urea cycle disorders (UCDs) are inborn errors of metabolism leading to hyperammonemia that usually presents in early childhood, whereas first presentation in adults is less common. Here we describe an adult woman with hyperammonemia following autologous stem cell transplantation for multiple myeloma. No apparent cause of hyperammonemia was identified, including portosystemic shunting, liver dysfunction or recent hyperammonemia-inducing chemotherapy. Hyperammonemia, normal blood glucose as well as anion gap and a previous history of two male newborns that died early after birth, prompted biochemical and genetic investigations for a UCD. A heterozygous variant in the X-linked gene encoding ornithine transcarbamylase (OTC) was identified and was regarded as a cause of UCD. The patient improved after treatment with nitrogen scavengers and high caloric intake according to a UCD protocol. This case report suggests that UCD should be considered as a possible cause of hyperammonemia following stem cell transplantation.
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Federico, Lorenzo; Tvedt, Tor Henrik Anderson; Gainullin, Murat; Osen, Julie Røkke; Chaban, Viktoriia & Lund, Kathrine Persgård
[Show all 19 contributors for this article]
(2023).
Robust spike-specific CD4<sup>+</sup> and CD8<sup>+</sup> T cell responses in SARS-CoV-2 vaccinated hematopoietic cell transplantation recipients: a prospective, cohort study.
Frontiers in Immunology.
14.
doi:
10.3389/fimmu.2023.1210899.
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Poor overall survival of hematopoietic stem cell transplantation (HSCT) recipients who developed COVID-19 underlies the importance of SARS-CoV-2 vaccination. Previous studies of vaccine efficacy have reported weak humoral responses but conflicting results on T cell immunity. Here, we have examined the relationship between humoral and T cell response in 48 HSCT recipients who received two doses of Moderna’s mRNA-1273 or Pfizer/BioNTech’s BNT162b2 vaccines. Nearly all HSCT patients had robust T cell immunity regardless of protective humoral responses, with 18/48 (37%, IQR 8.679-5601 BAU/mL) displaying protective IgG anti-receptor binding domain (RBD) levels (&gt;2000 BAU/mL). Flow cytometry analysis of activation induced markers (AIMs) revealed that 90% and 74% of HSCT patients showed reactivity towards immunodominant spike peptides in CD8 + and CD4 + T cells, respectively. The response rate increased to 90% for CD4 + T cells as well when we challenged the cells with a complete set of overlapping peptides spanning the entire spike protein. T cell response was detectable as early as 3 months after transplant, but only CD4 + T cell reactivity correlated with IgG anti-RBD level and time after transplantation. Boosting increased seroconversion rate, while only one patient developed COVID-19 requiring hospitalization. Our data suggest that HSCT recipients with poor serological responses were protected from severe COVID-19 by vaccine-induced T cell responses.
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Bartaula-Brevik, Sushma; Leitch, Calum; Valladares, Maria del Carmen Hernandez; Aasebø, Elise; Berven, Frode Steingrimsen & Selheim, Frode
[Show all 13 contributors for this article]
(2023).
Vacuolar ATPase Is a Possible Therapeutic Target in Acute Myeloid Leukemia: Focus on Patient Heterogeneity and Treatment Toxicity.
Journal of Clinical Medicine.
12(17).
doi:
10.3390/jcm12175546.
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Vacuolar ATPase (V-ATPase) is regarded as a possible target in cancer treatment. It is expressed in primary acute myeloid leukemia cells (AML), but the expression varies between patients and is highest for patients with a favorable prognosis after intensive chemotherapy. We therefore investigated the functional effects of two V-ATPase inhibitors (bafilomycin A1, concanamycin A) for primary AML cells derived from 80 consecutive patients. The V-ATPase inhibitors showed dose-dependent antiproliferative and proapoptotic effects that varied considerably between patients. A proteomic comparison of primary AML cells showing weak versus strong antiproliferative effects of V-ATPase inhibition showed a differential expression of proteins involved in intracellular transport/cytoskeleton functions, and an equivalent phosphoproteomic comparison showed a differential expression of proteins that regulate RNA processing/function together with increased activity of casein kinase 2. Patients with secondary AML, i.e., a heterogeneous subset with generally adverse prognosis and previous cytotoxic therapy, myeloproliferative neoplasia or myelodysplastic syndrome, were characterized by a strong antiproliferative effect of V-ATPase inhibition and also by a specific mRNA expression profile of V-ATPase interactome proteins. Furthermore, the V-ATPase inhibition altered the constitutive extracellular release of several soluble mediators (e.g., chemokines, interleukins, proteases, protease inhibitors), and increased mediator levels in the presence of AML-supporting bone marrow mesenchymal stem cells was then observed, especially for patients with secondary AML. Finally, animal studies suggested that the V-ATPase inhibitor bafilomycin had limited toxicity, even when combined with cytarabine. To conclude, V-ATPase inhibition has antileukemic effects in AML, but this effect varies between patients.
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Tislevoll, Benedicte Sjo; Hellesøy, Monica; Fagerholt, Oda Helen Eck; Gullaksen, Stein-Erik; Srivastava, Aashish & Birkeland, Even
[Show all 24 contributors for this article]
(2023).
Early response evaluation by single cell signaling profiling in acute myeloid leukemia.
Nature Communications.
14(1).
doi:
10.1038/s41467-022-35624-4.
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Aberrant pro-survival signaling is a hallmark of cancer cells, but the response to chemotherapy is poorly understood. In this study, we investigate the initial signaling response to standard induction chemotherapy in a cohort of 32 acute myeloid leukemia (AML) patients, using 36-dimensional mass cytometry. Through supervised and unsupervised machine learning approaches, we find that reduction of extracellular-signal-regulated kinase (ERK) 1/2 and p38 mitogen-activated protein kinase (MAPK) phosphorylation in the myeloid cell compartment 24 h post-chemotherapy is a significant predictor of patient 5-year overall survival in this cohort. Validation by RNA sequencing shows induction of MAPK target gene expression in patients with high phospho-ERK1/2 24 h post-chemotherapy, while proteomics confirm an increase of the p38 prime target MAPK activated protein kinase 2 (MAPKAPK2). In this study, we demonstrate that mass cytometry can be a valuable tool for early response evaluation in AML and elucidate the potential of functional signaling analyses in precision oncology diagnostics.
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Röth, Alexander; Broome, Catherine M.; Barcellini, Wilma; Jilma, Bernd; Hill, Quentin A. & Cella, David
[Show all 15 contributors for this article]
(2022).
Sutimlimab provides clinically meaningful improvements in patient-reported outcomes in patients with cold agglutinin disease: Results from the randomised, placebo-controlled, Phase 3 CADENZA study.
European Journal of Haematology.
ISSN 0902-4441.
doi:
10.1111/ejh.13903.
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Tvedt, Tor Henrik Anderson; Rose-John, Stefan; Tsykunova, Galina; Ahmed, Aymen B; Gedde-Dahl, Tobias & Ersvær, Elisabeth
[Show all 7 contributors for this article]
(2022).
IL-6 Responsiveness of CD4<sup>+</sup> and CD8<sup>+</sup> T Cells after Allogeneic Stem Cell Transplantation Differs between Patients and Is Associated with Previous Acute Graft versus Host Disease and Pretransplant Antithymocyte Globulin Therapy.
Journal of Clinical Medicine.
11(9).
doi:
10.3390/jcm11092530.
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Graft-versus-host disease (GVHD), one of the most common and serious complications after allogeneic stem cell transplantation, is mediated by allocative T cells. IL-6 mediates both pro- and anti-inflammatory effects and modulates T cell response through classical signaling and trans-signaling. We investigated the effects on the mTOR and JAK/STAT pathways after various types of IL-6 signaling for circulating T cells were derived from 31 allotransplant recipients 90 days post-transplant. Cells were stimulated with IL-6 alone, hyper-IL-6 (trans-signaling), IL-6+IL-6 receptor (IL-6R; classical + trans-signaling) and IL-6+IL-6R+soluble gp130-Fc (classical signaling), and flow cytometry was used to investigate the effects on phosphorylation of AKT (Thr308), mTOR (Ser2442), STAT3 (Ser727) and STAT3 (Tyr705). CD3+CD4+ and CD3+C8+ T cells responded to classical and trans IL-6 stimulation with increased STAT3 (Tyr705) phosphorylation; these responses were generally stronger for CD3+CD4+ cells. STAT3 (Tyr705) responses were stronger for patients with previous acute GVHD; CD3+CD4+ cells from GVHD patients showed an additional STAT3 (Ser727) response, whereas patients without acute GVHD showed additional mTOR (Ser2448) responses. Furthermore, treatment with antithymocyte globulin as a part of GVHD prophylaxis was associated with generally weaker STAT3 (Tyr705) responses and altered STAT3 (Ser727) responsiveness of CD3+CD4+ cells together with increased mTOR (Ser2448) responses for the CD3+CD8+ cells. Thus, early post-transplant CD3+CD4+ and CD3+ CD8+ T cell subsets differ in their IL-6 responsiveness; this responsiveness is modulated by antithymocyte globulin and differs between patients with and without previous acute GVHD. These observations suggest that allotransplant recipients will be heterogeneous with regard to the effects of post-transplant IL-6 targeting.
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Reikvam, Håkon; Vo, Anh Khoi; Johansen, Silje; Hemsing, Anette Lodvir; Solheim, Magne Haugland & Mosevoll, Knut Anders
[Show all 8 contributors for this article]
(2022).
MicroRNA serum profiles and chronic graft-versus-host disease.
Blood Advances.
ISSN 2473-9529.
6(18),
p. 5295–5306.
doi:
10.1182/bloodadvances.2021005930.
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Chronic graft-versus-host disease (cGVHD) is the most common long-term complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). During the last decade, the interest of micro RNAs (miRNAs) in the pathophysiological process of cGVHD has increased. The objectives of this study were to investigate a wide range of serum miRNAs in allografted patients and identify associations between miRNAs and cGVHD. The study included 79 allotransplanted adults, where serum samples were obtained 1 year after the allo-HSCT, and miRNA profiling analysis in serum was performed. Fifty of the 79 patients (63%) had signs of cGVHD at the 1-year post–allo-HSCT control. miRNA sequencing analysis revealed 1380 different miRNAs detected for at least 1 patient, whereas 233 miRNAs (17%) were detected in >70 patients. We identified 10 miRNAs that differed significantly between patients with and without cGVHD (P < .005; false discovery rate <0.1), and all of these miRNAs were detected for >75 of the patients. Furthermore, 5 distinct miRNAs, miR-365-3p, miR-148-3p, miR-122-5p, miR-378-3p, and miR-192-5p, were found to be particularly associated with cGVHD in our analysis and were validated by receiver operating characteristics analysis. Based on only 3 miRNAs, miR-365-3p, miR-148-3p, and miR-378-3p, we developed a miRNA signature that, by bioinformatic approaches and linear regression model, utterly improved our potential diagnostic biomarker model for cGVHD. We conclude that miRNAs are differently expressed among patients with and without cGVHD, although further and larger studies are needed to validate our present findings.
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Bruserud, Øystein; Tvedt, Tor Henrik Anderson; Ahmed, Aymen B; Vintermyr, Olav Karsten; Hervig, Tor Audun & Guttormsen, Anne Berit
[Show all 7 contributors for this article]
(2021).
Spontaneous Splenic Artery Rupture as the First Symptom of Systemic Amyloidosis.
Case Reports in Critical Care.
ISSN 2090-6420.
doi:
10.1155/2021/6676407.
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Spontaneous splenic rupture is a life-threatening condition leading to a rapidly progressing hypovolemic shock due to intra-abdominal blood loss, with a mortality rate of about 10%. Spontaneous splenic rupture can be caused by widely different disorders including acute and chronic infections, neoplastic disorders, and inflammatory noninfectious disorders. In this case report, we present a 67-year-old male patient with hemorrhagic shock caused by an acute bleeding from the splenic artery. The patient was massively transfused with blood products and fluids and underwent laparotomy for hemostatic control and clinical stabilization. Multiorgan involvement by amyloid light-chain amyloidosis (AL-amyloidosis) caused by plasma cell dyscrasia, specifically with infiltration of the spleen artery, was found to be the underlying cause of his life-threatening bleeding. Based on this case, we discuss the features of serious spleen bleeding, massive transfusion therapy in the intensive care setting, and AL-amyloidosis pathophysiology and treatment.
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Grønningsæter, Ida Sofie; Reikvam, Håkon; Aasebø, Elise; Bartaula-Brevik, Sushma; Hernandez‐valladares, Maria & Selheim, Frode
[Show all 10 contributors for this article]
(2021).
Effects of the autophagy‐inhibiting agent chloroquine on acute myeloid leukemia cells; characterization of patient heterogeneity.
Journal of Personalized Medicine.
11(8),
p. 1–23.
doi:
10.3390/jpm11080779.
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Autophagy is a highly conserved cellular degradation process that prevents cell damage and promotes cell survival, and clinical efforts have exploited autophagy inhibition as a therapeutic strategy in cancer. Chloroquine is a well-known antimalarial agent that inhibits late-stage autophagy. We evaluated the effects of chloroquine on cell viability and proliferation of acute myeloid leukemia acute myeloid leukemia (AML) cells derived from 81 AML patients. Our results show that chloroquine decreased AML cell viability and proliferation for the majority of patients. Furthermore, a subgroup of AML patients showed a greater susceptibility to chloroquine, and using hierarchical cluster analysis, we identified 99 genes upregulated in this patient subgroup, including several genes related to leukemogenesis. The combination of chloroquine with low-dose cytarabine had an additive inhibitory effect on AML cell proliferation. Finally, a minority of patients showed increased extracellular constitutive mediator release in the presence of chloroquine, which was associated with strong antiproliferative effects of chloroquine as well as cytarabine. We conclude that chloroquine has antileukemic activity and should be further explored as a therapeutic drug against AML in combination with other cytotoxic or metabolic drugs; however, due to the patient heterogeneity, chloroquine therapy will probably be effective only for selected patients.
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Tvedt, Tor Henrik Anderson; Vo, Anh Khoi; Bruserud, Øystein & Reikvam, Håkon
(2021).
Cytokine release syndrome in the immunotherapy of hematological malignancies: The biology behind and possible clinical consequences.
Journal of Clinical Medicine.
10(21).
doi:
10.3390/jcm10215190.
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Cytokine release syndrome (CRS) is an acute systemic inflammatory syndrome characterized by fever and multiple organ dysfunction associated with (i) chimeric antigen receptor (CAR)-T cell therapy, (ii) therapeutic antibodies, and (iii) haploidentical allogeneic stem cell transplantation (haplo-allo-HSCT). Severe CRS can be life-threatening in some cases and requires prompt management of those toxicities and is still a great challenge for physicians. The pathophysiology of CRS is still not fully understood, which also applies to the identifications of predictive biomarkers that can forecast these features in advance. However, a broad range of cytokines are involved in the dynamics of CRS. Treatment approaches include both broad spectrum of immunosuppressant, such as corticosteroids, as well as more specific inhibition of cytokine release. In the present manuscript we will try to review an update regarding pathophysiology, etiology, diagnostics, and therapeutic options for this serious complication.
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Aasebø, Elise; Brenner, Annette; Birkeland, Even; Tvedt, Tor Henrik Anderson; Selheim, Frode & Berven, Frode Steingrimsen
[Show all 7 contributors for this article]
(2021).
The constitutive extracellular protein release by acute myeloid leukemia cells—A proteomic study of patient heterogeneity and its modulation by mesenchymal stromal cells.
Cancers.
13(7).
doi:
10.3390/cancers13071509.
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Extracellular protein release is important both for the formation of extracellular matrix and for communication between cells. We investigated the extracellular protein release by in vitro cultured normal mesenchymal stem cells (MSCs) and by primary human acute myeloid leukemia (AML) cells derived from 40 consecutive patients. We observed quantifiable levels of 3082 proteins in our study; for the MSCs, we detected 1446 proteins, whereas the number of released proteins for the AML cells showed wide variation between patients (average number 1699, range 557–2380). The proteins were derived from various cellular compartments (e.g., cell membrane, nucleus, and cytoplasms), several organelles (e.g., cytoskeleton, endoplasmatic reticulum, Golgi apparatus, and mitochondria) and had various functions (e.g., extracellular matrix and exosomal proteins, cytokines, soluble adhesion molecules, protein synthesis, post-transcriptional modulation, RNA binding, and ribonuclear proteins). Thus, AML patients were very heterogeneous both regarding the number of proteins and the nature of their extracellularly released proteins. The protein release profiles of MSCs and primary AML cells show a considerable overlap, but a minority of the proteins are released only or mainly by the MSC, including several extracellular matrix molecules. Taken together, our observations suggest that the protein profile of the extracellular bone marrow microenvironment differs between AML patients, these differences are mainly caused by the protein release by the leukemic cells but this leukemia-associated heterogeneity of the overall extracellular protein profile is modulated by the constitutive protein release by normal MSCs.
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Bruserud, Øystein; Tsykunova, Galina; Hernandez-Valladares, Maria; Reikvam, Håkon & Tvedt, Tor Henrik Anderson
(2021).
Therapeutic use of valproic acid and all-trans retinoic acid in acute myeloid leukemia—literature review and discussion of possible use in relapse after allogeneic stem cell transplantation.
Pharmaceuticals.
14(5).
doi:
10.3390/ph14050423.
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Even though allogeneic stem cell transplantation is the most intensive treatment for acute myeloid leukemia (AML), chemo-resistant leukemia relapse is still one of the most common causes of death for these patients, as is transplant-related mortality, i.e., graft versus host disease, infections, and organ damage. These relapse patients are not always candidates for additional intensive therapy or re-transplantation, and many of them have decreased quality of life and shortened expected survival. The efficiency of azacitidine for treatment of posttransplant AML relapse has been documented in several clinical trials. Valproic acid is an antiepileptic fatty acid that exerts antileukemic activity through histone deacetylase inhibition. The combination of valproic acid and all-trans retinoic acid (ATRA) is well tolerated even by unfit or elderly AML patients, and low-toxicity chemotherapy (e.g., azacitidine) can be added to this combination. The triple combination of azacitidine, valproic acid, and ATRA may therefore represent a low-intensity and low-toxicity alternative for these patients. In the present review, we review and discuss the general experience with valproic acid/ATRA in AML therapy and we discuss its possible use in low-intensity/toxicity treatment of post-allotransplant AML relapse. Our discussion is further illustrated by four case reports where combined treatments with sequential azacitidine/hydroxyurea, valproic acid, and ATRA were used.
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Rundgren, Ida Marie; Ryningen, Anita; Tvedt, Tor Henrik Anderson; Bruserud, Øystein & Ersvær, Elisabeth
(2020).
Immunomodulatory drugs alter the metabolism and the extracellular release of soluble mediators by normal monocytes.
Molecules.
ISSN 1431-5157.
25:367(2),
p. 1–19.
doi:
10.3390/molecules25020367.
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Immunomodulatory drugs (IMiDs) are used in the treatment of hematological malignancies, especially multiple myeloma. IMiDs have direct anticancer effects but also indirect effects via cancer-supporting stromal cells. Monocytes are a stromal cell subset whose metabolism is modulated by the microenvironment, and they communicate with neighboring cells through extracellular release of soluble mediators. Toll-like receptor 4 (TLR4) is then a common regulator of monocyte metabolism and mediator release. Our aim was to investigate IMiD effects on these two monocyte functions. We compared effects of thalidomide, lenalidomide, and pomalidomide on in vitro cultured normal monocytes. Cells were cultured in medium alone or activated by lipopolysaccharide (LPS), a TLR4 agonist. Metabolism was analyzed by the Seahorse XF 96 cell analyzer. Mediator release was measured as culture supernatant levels. TLR4 was a regulator of both monocyte metabolism and mediator release. All three IMiDs altered monocyte metabolism especially when cells were cultured with LPS; this effect was strongest for lenalidomide that increased glycolysis. Monocytes showed a broad soluble mediator release profile. IMiDs decreased TLR4-induced mediator release; this effect was stronger for pomalidomide than for lenalidomide and especially thalidomide. To conclude, IMiDs can alter the metabolism and cell–cell communication of normal monocytes, and despite their common molecular target these effects differ among various IMiDs.
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Tvedt, Tor Henrik Anderson; Skaarud, Kristin Aneta Joan; Tjønnfjord, Geir Erland; Gedde-Dahl, Tobias; Iversen, Per Ole & Bruserud, Øystein
(2020).
The systemic metabolic profile early after allogeneic stem cell transplantation: Effects of adequate energy support administered through enteral feeding tube.
Biology of Blood and Marrow Transplantation.
ISSN 1083-8791.
26(2),
p. 380–391.
doi:
10.1016/j.bbmt.2019.10.005.
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Patients undergoing allogeneic stem cell transplantation usually require nutritional support. There is no consensus on whether enteral support through tube feeding should be preferred. A recent randomized study could not detect any difference between enteral and parenteral feeding with regard to post-transplant outcomes, whereas 2 retrospective studies described an association between enteral feeding and a favorable post-transplant outcome. We compared pre- and post-transplant plasma metabolomic profiles for 10 patients receiving mainly enteral nutritional support and 10 patients receiving mainly parenteral support. Samples were collected before conditioning and 3 weeks post-transplant; 824 metabolites were analyzed using mass spectrometry. The pretransplant metabolite profiles showed a significant overlap between the 2 groups. Post-transplant samples for both patient groups showed an increase of secondary bile acids and endocannabinoids, whereas reduced levels were seen for food preservatives, plasmalogens, and retinol metabolites. The main post-transplant differences between the groups were decreased levels of fatty acids and markers of mitochondrial activation in the control group, indicating that these patients had insufficient energy intake. A significant effect was also seen for heme/bilirubin metabolism for the parenteral support. To conclude, allotransplant recipients showed altered metabolic profiles early after transplantation; this was mainly due to the conditioning/transplantation/reconstitution, whereas the type of nutritional support had minor effects.
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Aarstad, Helene Hersvik; Gudbrandsdottir, Gigja; Hjelle, Karin; Bostad, Leif; Bruserud, Øystein & Tvedt, Tor Henrik Anderson
[Show all 7 contributors for this article]
(2020).
The biological context of c-reactive protein as a prognostic marker in renal cell carcinoma: Studies on the acute phase cytokine profile.
Cancers.
12(7),
p. 1–18.
doi:
10.3390/cancers12071961.
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High serum levels of the acute phase protein C-reactive protein (CRP) are associated with an adverse prognosis in renal cancer. The acute phase reaction is cytokine-driven and includes a wide range of inflammatory mediators. This overall profile of the response depends on the inducing event and can also differ between patients. We investigated an extended acute phase cytokine profile for 97 renal cancer patients. Initial studies showed that the serum CRP levels had an expected prognostic association together with tumor size, stage, nuclear grading, and Leibovich score. Interleukin (IL)6 family cytokines, IL1 subfamily mediators, and tumor necrosis factor (TNF)α can all be drivers of the acute phase response. Initial studies suggested that serum IL33Rα (the soluble IL33 receptor α chain) levels were also associated with prognosis, although the impact of IL33Rα is dependent on the overall cytokine profile, including seven IL6 family members (IL6, IL6Rα, gp130, IL27, IL31, CNTF, and OSM), two IL1 subfamily members (IL1RA and IL33Rα), and TNFα. We identified a patient subset characterized by particularly high levels of IL6, IL33Rα, and TNFα alongside an adverse prognosis. Thus, the acute phase cytokine reaction differs between renal cancer patients, and differences in the acute phase cytokine profile are associated with prognosis.
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Namakula, Rhoda; Bree, L Charlotte J de; Tvedt, Tor Henrik Anderson; Netea, Mihai G; Cose, Stephen & Hanevik, Kurt
(2020).
Monocytes from neonates and adults have a similar capacity to adapt their cytokine production after previous exposure to BCG and β-glucan.
PLOS ONE.
15(2).
doi:
10.1371/journal.pone.0229287.
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The Bacillus Calmette-Guérin (BCG) vaccine is administered at birth in tuberculosis (TB) endemic countries. BCG vaccination is also associated with protective non-specific effects against non-tuberculous infections. This seems at least in part mediated through induction of innate immune memory in myeloid cells, a process termed trained immunity. β-glucan, a component of the fungal cell wall from Candida albicans, induces a trained immunity phenotype in human monocytes with hyper-responsiveness against unrelated pathogens. We aimed to study the capacity of BCG and β-glucan to induce a similar phenotype by examining cytokine production in cord blood monocytes following re-stimulation. We used a well-known model of in vitro induction of trained immunity. Adherent mononuclear cells from neonates and adults, which consist mainly of monocytes, were stimulated in vitro with BCG or β-glucan for one day, after which the stimulus was washed away. Cells were rested for 5 days, then restimulated with LPS. Cytokine levels were measured using ELISA. Neonate and adult monocytes responded similarly in terms of cytokine production. BCG significantly increased IL-6 responses to LPS in both neonate and adult monocytes, while β-glucan induced increases of IL-6, IL-10 and TNF production capacity. The BCG and β-glucan induced increase in cytokine production, reminiscent of trained immunity, showed similar levelsin neonatal and adult monocytes. BCG mediated changes in cytokine production shows the feasibility of this in vitro assay for further studies regarding non-specific effects of vaccines.
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Tholin, Birgitte; Hauge, Marit Teigen; Aukrust, Pål; Fehrle, Lutz & Tvedt, Tor Henrik Anderson
(2020).
Hemophagocytic lymphohistiocytosis in a patient with COVID-19 treated with tocilizumab: a case report.
Journal of Medical Case Reports.
14:187,
p. 1–5.
doi:
10.1186/s13256-020-02503-9.
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Abstract Background The understanding of coronavirus disease 2019 (COVID-19) is rapidly evolving. Although it is primarily a respiratory illness, other manifestations, such as Guillain-Barré syndrome, immune thrombocytopenia, and immune-mediated thrombotic thrombocytopenic purpura, have been described. We present a case of a patient with hemophagocytic lymphohistiocytosis secondary to COVID-19 treated with tocilizumab with a marked biochemical improvement. Case presentation In this case report we present a Caucasian patient with COVID-19 who developed a marked elevation of inflammatory parameters with ferritin 36,023 μg/L, but also elevated C-reactive protein 334 mg/L and lactate dehydrogenase 1074 U/L, 1 week after admission to the intensive care unit. He met five of eight criteria for hemophagocytic lymphohistiocytosis, but he lacked the high fever and cytopenia seen in the majority of cases. He was treated with tocilizumab, a monoclonal antibody targeting the interleukin-6 receptor, and over the next days, a rapid decrease in ferritin and C-reactive protein levels was observed. However, his respiratory failure only improved gradually, and he was weaned off the respirator 11 days later. Conclusion COVID-19 may induce a hyperinflammatory clinical picture and in some cases develop into hemophagocytic lymphohistiocytosis. In our patient’s case, therapeutic interleukin-6 blockade abrogated signs of hyperinflammation but did not seem to improve pulmonary function. Measurement of ferritin and C-reactive protein, as well as quantification of interleukin-6 on indication, should be performed in patients with severe COVID-19. Specific treatment in such patients must also be contemplated, preferably in randomized controlled trials.
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Reikvam, Håkon; Tvedt, Tor Henrik Anderson; Johansen, Silje; setran, Hege Aase & Havre, Roald Flesland
(2020).
Surgical Treatment of Severe Bowel Obstruction as a Rare Complication Following Allogenic Hematopoietic Stem Cell Transplantation.
Transplantology.
ISSN 2673-3943.
1(2),
p. 102–110.
doi:
10.3390/transplantology1020010.
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Gastrointestinal graft-versus-host disease (GVHD) and cytomegalovirus (CMV) disease are common complications occurring after allogeneic hematopoietic stem cell transplantation (allo-HSCT), and contribute to a high degree of morbidity and mortality associated with allo-HSCT. Herein, we present a patient with severe intestinal GVHD complicated by recurring CMV enteritis, which overall resulted in severe terminal ileum stenosis. The patient underwent laparoscopic ileocecal resection that significantly reduced symptoms and possibly prevented the development of fulminant ileus. Surgical treatment is rarely used in the treatment of gastrointestinal GVHD; however, the current patient history illustrates that patients with inadequate symptom control and severe inflammatory bowel stenosis can be successfully managed with surgery. We also review published case reports on surgical treatment for severe gastrointestinal GVHD.
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Hagestande, Sofie; Kvam, Ann Kristin; Lothe, Inger Marie Bowitz; Gjelberg, Hilde K.; Bruserud, Øystein & Tvedt, Tor Henrik Anderson
(2020).
Aplastisk anemi.
Tidsskrift for Den norske legeforening (Tidsskriftet).
ISSN 0029-2001.
140(18),
p. 1–7.
doi:
10.4045/tidsskr.20.0139.
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Gudbrandsdottir, Gigja; Aarstad, Helene Hersvik; Bostad, Leif; Hjelle, Karin; Aarstad, Hans Jørgen & Bruserud, Øystein
[Show all 8 contributors for this article]
(2020).
Serum levels of the IL-6 family of cytokines predict prognosis in renal cell carcinoma (RCC).
Cancer Immunology and Immunotherapy.
ISSN 0340-7004.
70,
p. 1–12.
doi:
10.1007/s00262-020-02655-z.
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Purpose An improved understanding of RCC immunology should shed further light on RCC tumor biology. Our objective was to study to what extent serum levels of the IL-6 family of cytokines at diagnosis were relevant to survival. Methods A total of 118 consecutively patients with RCC, in which the tumor was surgically removed at Haukeland University Hospital during the period from 2007 to 2010, were included. The patients were followed-up for 10 years. The morning before surgery blood was sampled and serum frozen, with levels of IL-6, IL-27, IL-31, OSM, CNTF, IL-6Rα and gp130 determined. Results Among patients with the highest quartile of IL-6 (> 8 pg/ml) (n = 29), six of nine who had metastasis at diagnosis had such high IL-6 values. Among presumed radically treated patients, a high IL-6 and IL-27 strongly predicted recurrence. In particular, the predictions among patients with large (diameter > 7 cm) tumors were excellent regarding both IL-6 and IL-27 values. High gp130 serum levels predicted an overall survival (OS) among RCC patients with large tumors. Patients with a high IL-6 exhibited a strong expression of IL-6 in endothelial- and vascular smooth muscle cells. Moreover, the level of intra-tumoral CD3-positive cells predicted survival. Conclusions IL-6 and IL-27 seem to play a role in RCC biology. IL-6 enables the pinpointing of metastatic condition at diagnosis, as well as together with IL-27, the predicting of survival and recurrence. Endothelial cells and vascular smooth muscle cells are both suggested as important sources of IL-6.
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Berentsen, Sigbjørn; Barcellini, Wilma; D'Sa, Shirley; Randen, Ulla; Tvedt, Tor Henrik Anderson & Fattizzo, Bruno
[Show all 23 contributors for this article]
(2020).
Cold agglutinin disease revisited: a multinational, observational study of 232 patients.
Blood.
ISSN 0006-4971.
136(4),
p. 480–488.
doi:
10.1182/blood.2020005674.
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We retrospectively studied 232 patients with cold agglutinin disease (CAD) at 24 centers in 5 countries. In Norway and a northern region of Italy, the study was close to being population-based. For the first time, we demonstrate fourfold differences between cold and warmer climates regarding prevalence (20 vs 5 cases/million) and incidence (1.9 vs 0.48 cases/million per year). Mean baseline hemoglobin level was 9.3 g/dL, but 27% had hemoglobin <8 g/dL. Identification of typical features of CAD-associated lymphoproliferative disorder in the bone marrow was greatly increased by centralized biopsy assessment. CAD seems to be associated with a slightly increased risk of venous thrombosis. This work includes a follow-up study of therapies, focusing on the long-term outcomes of the rituximab plus bendamustine and rituximab plus fludarabine regimens. Rituximab plus bendamustine therapy resulted in responses in 35 (78%) of 45 patients; 24 (53%) achieved complete response. Interestingly, these rates were still higher than observed in the original (2017) prospective trial, and we also found a shift toward deeper responses with time. This is explained by the prolonged time to response seen in many patients, probably related to long-lived plasma cells. In patients responding to rituximab-bendamustine, median response duration was not reached after 88 months, and estimated 5-year sustained remission was 77%. The regimen appeared safe regarding late-occurring malignancies. Rituximab plus fludarabine therapy seems to carry a higher risk of long-term adverse effects.
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Trovik, Linn; Sandnes, Miriam; Blomberg, Bjørn; Holmaas, Gunhild; Ahmed, Aymen B. & Tvedt, Tor Henrik Anderson
[Show all 8 contributors for this article]
(2020).
Hemophagocytic lymphohistiocytosis and miliary tuberculosis in a previously healthy individual: a case report.
Journal of Medical Case Reports.
14:217,
p. 1–9.
doi:
10.1186/s13256-020-02555-x.
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Background Hemophagocytic lymphohistiocytosis (HLH) is a rare heterogenous genetic or acquired hyperinflammatory syndrome associated with a high degree of morbidity and mortality. HLH has clinical manifestations related to abnormal prolonged activation of T lymphocytes and macrophages with an excess of proinflammatory cytokines. The main causes of secondary HLH are malignancies and infectious diseases. Case presentation The patient was a 54-year-old man, originally from Eastern Africa, who had lived in Northern Europe for 30 years. Here we describe the clinical features, laboratory parameters, diagnostic workup, management and outcome data of a previously healthy 54-year-old man diagnosed with HLH secondary to tuberculosis. The patient was initially treated for a community-acquired pneumonia. He developed multiorgan failure with acute respiratory distress syndrome, hypertransaminasemia, and kidney and bone marrow dysfunction. The clinical course together with a simultaneous increase in serum ferritin raised the suspicion of HLH. The patient fulfilled seven out of eight diagnostic criteria for HLH. A thorough diagnostic workup with respect to HLH and a potential underlying disease was initiated. Cultivation of bronchoalveolar lavage fluid, stool and urine, and polymerase chain reaction of epithelioid cell granulomas in the bone marrow were all positive for Mycobacterium tuberculosis. He was treated for both HLH and tuberculosis, and he survived without any sequelae. Conclusions We present one of few published cases of a patient who survived HLH triggered by miliary tuberculosis. The current case illustrates the need for awareness of these two diagnoses, and the timely initiation of specific and supportive treatment to reduce mortality.
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Aarstad, Helene Hersvik; Moe, Svein Erik Emblem; Bruserud, Øystein; Lybak, Stein; Aarstad, Hans Jørgen & Tvedt, Tor Henrik Anderson
(2020).
The acute phase reaction and its prognostic impact in patients with head and neck squamous cell carcinoma: Single biomarkers including c-reactive protein versus biomarker profiles.
Biomedicines.
8:418(10),
p. 1–26.
doi:
10.3390/biomedicines8100418.
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C-reactive protein (CRP) has a prognostic impact in head and neck squamous cell carcinoma (HNSCC). However, the acute phase reaction involves many other proteins depending on its inducing events, including various cytokines that can function as reaction inducers. In the present study, we compared the pretreatment acute phase cytokine profile for 144 patients with potentially curative HNSCC. We investigated the systemic levels of interleukin (IL)6 family mediators (glycoprotein (gp130), IL6 receptor (R)α, IL6, IL27, IL31, oncostatin M (OSM), ciliary neurotrophic factor (CNTF)), IL1 subfamily members (IL1R antagonist (A), IL33Rα), and tumor necrosis factor (TNF)α. Patient subsets identified from this 10-mediator profile did not differ with regard to disease stage, human papilloma virus (HPV) status, CRP levels, or death cause. Increased CRP, IL6, and IL1RA levels were independent markers for HNSCC-related death in the whole patient population. Furthermore, gp130, IL6Rα, and IL31 were suggested to predict prognosis among tumor HPV-negative patients. Only IL6 predicted survival in HPV-positive patients. Finally, we did a clustering analysis of HPV-negative patients based on six acute phase mediators that showed significant or borderline association with prognosis in Kaplan–Meier analyses; three subsets could then be identified, and they differed in survival (p < 0.001). To conclude, (i) HPV-negative and HPV-positive HNSCC patients show similar variations of their systemic acute phase profiles; (ii) the prognostic impact of single mediators differs between these two patient subsets; and (iii) for HPV-negative patients, acute phase profiling identifies three patient subsets that differ significantly in survival.
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Bruserud, Øystein; Aarstad, Helene Hersvik & Tvedt, Tor Henrik Anderson
(2020).
Combined c-reactive protein and novel inflammatory parameters as a predictor in cancer—what can we learn from the hematological experience?
Cancers.
12(7),
p. 1–23.
doi:
10.3390/cancers12071966.
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Brattås, Marte Karen; Reikvam, Håkon; Tvedt, Tor Henrik Anderson & Bruserud, Øystein
(2019).
Precision medicine for TP53-mutated acute myeloid leukemia.
Expert Review of Precision Medicine and Drug Development.
4(5),
p. 263–274.
doi:
10.1080/23808993.2019.1644164.
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Reikvam, Håkon; Dalgaard, Jakob; Johansen, Silje; Tvedt, Tor Henrik Anderson & Bruserud, Øyvind
(2019).
Behandling av akutt myelogen leukemi hos eldre.
Tidsskrift for Den norske legeforening (Tidsskriftet).
ISSN 0029-2001.
139(8),
p. 1–6.
doi:
10.4045/tidsskr.18.0775.
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Berentsen, Sigbjørn; Hill, Anita; Hill, Quentin A.; Tvedt, Tor Henrik Anderson & Michel, Marc
(2019).
Novel insights into the treatment of complement-mediated hemolytic anemias.
Therapeutic Advances in Hematology (TAH).
ISSN 2040-6207.
doi:
10.1177/2040620719873321.
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Brattås, Marte Karen; Reikvam, Håkon; Tvedt, Tor Henrik Anderson & Bruserud, Øystein
(2019).
Dasatinib as an investigational drug for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia in adults.
Expert Opinion on Investigational Drugs.
ISSN 1354-3784.
28(5),
p. 411–420.
doi:
10.1080/13543784.2019.1597052.
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Brattås, Marte Karen; Reikvam, Håkon; Tvedt, Tor Henrik Anderson & Bruserud, Øystein
(2019).
Dasatinib is an investigational drug for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia in adults.
Expert Opinion on Investigational Drugs.
ISSN 1354-3784.
doi:
10.1080/13543784.2019.1597052.
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Tvedt, Tor Henrik Anderson; Hovland, Randi; Tsykunova, Galina; Ahmed, Aymen B; Gedde-Dahl, Thobias & Bruserud, Øyvind
(2018).
A pilot study of single nucleotide polymorphisms in the interleukin-6 receptor and their effects on pre- and post-transplant serum mediator level and outcome after allogeneic stem cell transplantation.
Clinical and Experimental Immunology.
ISSN 0009-9104.
193(1),
p. 130–141.
doi:
10.1111/cei.13124.
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Interleukin (IL)‐6 is an important regulator of immunity and inflammation in many diseases. Single nucleotide polymorphisms (SNPs) in the IL‐6 gene influence outcome after allogeneic stem cell transplantation (ASCT), but the possible importance of SNPs in the IL‐6 receptor has not been examined. We therefore investigated whether SNPs in the IL‐6R gene influenced biochemical characteristics and clinical outcomes after ASCT. We examined the IL‐6 promoter variant rs1800975 and the IL‐6R SNPs rs4453032, rs2228145, rs4129267, rs4845374, rs4329505, rs4845617, rs12083537, rs4845618, rs6698040 and rs4379670 in a 101 population‐based cohort of allotransplant recipients and their family donors. Patients being homozygous for the major alleles of the IL‐6R SNPs rs2228145 and rs4845618 showed high pretransplant CRP serum levels together with decreased sIL‐6R levels; the decreased IL‐6R levels persisted 6 months post‐transplant. In contrast, patients being homozygous for the minor allele of the IL‐6R SNP rs4379670 showed decreased pretransplant CRP levels. Furthermore, the IL‐6R rs4845618 donor genotype showed an association with severe acute graft‐versus‐host disease (GVHD), whereas the donor genotype of the IL‐6 SNP rs1800795 was associated with decreased survival 100 days post‐transplant. Finally, the recipient genotype of the IL‐6R SNP rs4329505 showed a strong association with 2‐years non‐relapse mortality, and this effect was also highly significant in multivariate analysis. IL‐6 and IL‐6R SNPs influence the clinical outcome after allogeneic stem cell transplantation.
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Bartaula-Brevik, Sushma; Brattås, Marte Karen; Tvedt, Tor Henrik Anderson; Reikvam, Håkon & Bruserud, Øystein
(2018).
Splenic tyrosine kinase (SYK) inhibitors and their possible use in acute myeloid leukemia.
Expert Opinion on Investigational Drugs.
ISSN 1354-3784.
27(4),
p. 377–387.
doi:
10.1080/13543784.2018.1459562.
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Nepstad, Ina; Hatfield, Kimberley Joanne; Tvedt, Tor Henrik Anderson; Reikvam, Håkon & Bruserud, Øystein
(2018).
Clonal heterogeneity reflected by pi3k-akt-mtor signaling in human acute myeloid leukemia cells and its association with adverse prognosis.
Cancers.
10:332(9),
p. 1–15.
doi:
10.3390/cancers10090332.
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Clonal heterogeneity detected by karyotyping is a biomarker associated with adverse prognosis in acute myeloid leukemia (AML). Constitutive activation of the phosphatidylinositol-3-kinase-Akt-mechanistic target of rapamycin (PI3K-Akt-mTOR) pathway is present in AML cells, and this pathway integrates signaling from several upstream receptors/mediators. We suggest that this pathway reflects biologically important clonal heterogeneity. We investigated constitutive PI3K-Akt-mTOR pathway activation in primary human AML cells derived from 114 patients, together with 18 pathway mediators. The cohort included patients with normal karyotype or single karyotype abnormalities and with an expected heterogeneity of molecular genetic abnormalities. Clonal heterogeneity reflected as pathway mediator heterogeneity was detected for 49 patients. Global gene expression profiles of AML cell populations with and without clonal heterogeneity differed with regard to expression of ectopic olfactory receptors (a subset of G-protein coupled receptors) and proteins involved in G-protein coupled receptor signaling. Finally, the presence of clonal heterogeneity was associated with adverse prognosis for patients receiving intensive antileukemic treatment. The clonal heterogeneity as reflected in the activation status of selected mediators in the PI3K-Akt-mTOR pathway was associated with a different gene expression profile and had an independent prognostic impact. Biological heterogeneity reflected in the intracellular signaling status should be further investigated as a prognostic biomarker in human AML.
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Tvedt, Tor Henrik Anderson; Melve, Guro Kristin; Tsykunova, Galina; Ahmed, Aymen B; Brenner, Annette & Bruserud, Øystein
(2018).
Immunological heterogeneity of healthy peripheral blood stem cell donors - Effects of granulocyte colony-stimulating factor on inflammatory responses.
International Journal of Molecular Sciences.
ISSN 1661-6596.
19:2886(10),
p. 1–16.
doi:
10.3390/ijms19102886.
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Interleukin-6 (IL-6) contributes to the development of immune-mediated complications after allogeneic stem cell transplantation. However, systemic IL-6 levels also increase during granulocyte colony-stimulating factor (G-CSF) mobilization of hematopoietic stem cells in healthy donors, but it is not known whether this mobilization alters systemic levels of other IL-6 family cytokines/receptors and whether such effects differ between donors. We examined how G-CSF administration influenced C-reactive protein (CRP) levels (85 donors) and serum levels of IL-6 family cytokines/receptors (20 donors). G-CSF increased CRP levels especially in elderly donors with high pretherapy levels, but these preharvesting levels did not influence clinical outcomes (nonrelapse mortality, graft versus host disease). The increased IL-6 levels during G-CSF therapy normalized within 24 h after treatment. G-CSF administration did not alter serum levels of other IL-6-familly mediators. Oncostatin M, but not IL-6, showed a significant correlation with CRP levels during G-CSF therapy. Clustering analysis of mediator levels during G-CSF administration identified two donor subsets mainly characterized by high oncostatin M and IL-6 levels, respectively. Finally, G-CSF could increase IL-6 release by in vitro cultured monocytes, fibroblasts, and mesenchymal stem cells. In summary, G-CSF seems to induce an acute phase reaction with increased systemic IL-6 levels in healthy stem cell donors.
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Tvedt, Tor Henrik Anderson; Ersvær, Elisabeth; Tveita, Anders & Bruserud, Øystein
(2017).
Interleukin-6 in allogeneic stem cell transplantation: Its possible importance for immunoregulation and as a therapeutic target.
Frontiers in Immunology.
8:667,
p. 1–15.
doi:
10.3389/fimmu.2017.00667.
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Allogeneic stem cell transplantation is associated with a high risk of treatment-related mortality mainly caused by infections and graft-versus-host disease (GVHD). GVHD is characterized by severe immune dysregulation and impaired regeneration of different tissues, i.e., epithelial barriers and the liver. The balance between pro- and anti-inflammatory cytokine influences the risk of GVHD. Interleukin-6 (IL-6) is a cytokine that previously has been associated with pro-inflammatory effects. However, more recent evidence from various autoimmune diseases (e.g., inflammatory bowel disease, rheumatoid arthritis) has shown that the IL-6 activity is more complex with important effects also on tissue homeostasis, regeneration, and metabolism. This review summarizes the current understanding of how pro-inflammatory IL-6 effects exerted during the peritransplant period shapes T-cell polarization with enhancement of Th17 differentiation and suppression of regulatory T cells, and in addition we also review and discuss the results from trials exploring non-selective IL-6 inhibition in prophylaxis and treatment of GVHD. Emerging evidence suggests that the molecular strategy for targeting of IL-6-initiated intracellular signaling is important for the effect on GVHD. It will therefore be important to further characterize the role of IL-6 in the pathogenesis of GVHD to clarify whether combined IL-6 inhibition of both trans- (i.e., binding of the soluble IL-6/IL-6 receptor complex to cell surface gp130) and cis-signaling (i.e., IL-6 ligation of the IL-6 receptor/gp130 complex) or selective inhibition of trans-signaling should be tried in the prophylaxis and/or treatment of GVHD in allotransplant patients.
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Tvedt, Tor Henrik Anderson; Nepstad, Ina & Bruserud, Øystein
(2017).
Antileukemic effects of midostaurin in acute myeloid leukemia?the possible importance of multikinase inhibition in leukemic as well as nonleukemic stromal cells.
Expert Opinion on Investigational Drugs.
ISSN 1354-3784.
26(3),
p. 343–355.
doi:
10.1080/13543784.2017.1275564.
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Brenner, Annette; Tvedt, Tor Henrik Anderson; Nepstad, Ina; Rye, Kristin Paulsen; Hagen, Karen Marie & Reikvam, Håkon
[Show all 7 contributors for this article]
(2017).
Patients with acute myeloid leukemia can be subclassified based on the constitutive cytokine release of the leukemic cells; the possible clinical relevance and the importance of cellular iron metabolism.
Expert opinion on therapeutic targets.
ISSN 1472-8222.
21(4),
p. 357–369.
doi:
10.1080/14728222.2017.1300255.
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Tvedt, Tor Henrik Anderson; Reikvam, Håkon & Bruserud, Øystein
(2016).
Nutrition in allogeneic stem cell transplantion - Clinical guidelines and immunobiological aspects.
Current Pharmaceutical Biotechnology.
ISSN 1389-2010.
17,
p. 92–104.
doi:
10.2174/138920101701151027163600.
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Brenner, Annette; Tvedt, Tor Henrik Anderson & Bruserud, Øystein
(2016).
The complexity of targeting PI3K-Akt-mTOR signalling in human acute myeloid leukaemia: The importance of leukemic cell heterogeneity, neighbouring mesenchymal stem cells and immunocompetent cells.
Molecules.
ISSN 1431-5157.
21:1512(11).
doi:
10.3390/molecules21111512.
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Therapeutic targeting of PI3K-Akt-mTOR is considered a possible strategy in human acute myeloid leukaemia (AML); the most important rationale being the proapoptotic and antiproliferative effects of direct PI3K/mTOR inhibition observed in experimental studies of human AML cells. However, AML is a heterogeneous disease and these effects caused by direct pathway inhibition in the leukemic cells are observed only for a subset of patients. Furthermore, the final effect of PI3K-Akt-mTOR inhibition is modulated by indirect effects, i.e., treatment effects on AML-supporting non-leukemic bone marrow cells. In this article we focus on the effects of this treatment on mesenchymal stem cells (MSCs) and monocytes/macrophages; both these cell types are parts of the haematopoietic stem cell niches in the bone marrow. MSCs have unique membrane molecule and constitutive cytokine release profiles, and mediate their support through bidirectional crosstalk involving both cell-cell contact and the local cytokine network. It is not known how various forms of PI3K-Akt-mTOR targeting alter the molecular mechanisms of this crosstalk. The effect on monocytes/macrophages is also difficult to predict and depends on the targeted molecule. Thus, further development of PI3K-Akt-mTOR targeting into a clinical strategy requires detailed molecular studies in well-characterized experimental models combined with careful clinical studies, to identify patient subsets that are likely to respond to this treatment.
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Mosevoll, Knut Anders; Lindås, Roald; Tvedt, Tor Henrik Anderson; Bruserud, Øystein & Reikvam, Håkon
(2015).
Altered plasma levels of cytokines, soluble adhesion molecules and matrix metalloproteases in venous thrombosis.
Thrombosis Research.
ISSN 0049-3848.
136(1),
p. 30–39.
doi:
10.1016/j.thromres.2015.04.002.
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Tvedt, Tor Henrik Anderson; Rye, Kristin Paulsen; Reikvam, Håkon; Brenner, Annette & Bruserud, Øystein
(2015).
The importance of sample collection when using single cytokine levels and systemic cytokine profiles as biomarkers - a comparative study of serum versus plasma samples.
Journal of Immunological Methods (JIM).
ISSN 0022-1759.
418,
p. 19–28.
doi:
10.1016/j.jim.2015.01.006.
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Lindås, Roald; Tvedt, Tor Henrik Anderson; Hatfield, Kimberley Joanne; Reikvam, Håkon & Bruserud, Øystein
(2014).
Preconditioning serum levels of endothelial cell-derived molecules and the risk of posttransplant complications in patients treated with allogeneic stem cell transplantation.
Journal of Transplantation.
ISSN 2090-0007.
p. 1–9.
doi:
10.1155/2014/404096.
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Endothelial cells are involved in the pathogenesis of acute graft-versus-host disease (GVHD) after allogeneic stem cell transplantation. These cells express several molecules that can be detected as biologically active soluble forms; serum levels of these molecules may thereby reflect the functional status of endothelial cells. Furthermore, acute GVHD is an inflammatory reaction and endothelial cells function as local regulators of inflammation. We therefore investigated whether differences in preconditioning/pretransplant serum levels of endothelium-expressed molecules (i.e., endocan, vascular cell adhesion molecule 1 (VCAM-1), and E-selectin) were associated with a risk of posttransplant GVHD. Our study should be regarded as a populationbased study of consecutive and thereby unselected patients (𝑛 = 56). Analysis of this pretreatment endothelium biomarker profile by unsupervised hierarchical clustering identified a subset of patients with increased early nonrelapse mortality. Furthermore, low endocan levels were significantly associated with acute GVHD in the liver and gastrointestinal tract, whereas high VCAM-1 levels were associated with acute GVHD in the skin only. Our study suggests that the preconditioning/pretransplant status of endothelial cells (possibly through altered trafficking of immunocompetent cells) is important for the risk and the organ involvement of later acute GVHD.
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Tvedt, Tor Henrik Anderson; Holme, Pål Andre & Bruserud, Øystein
(2014).
En mann i 80-årene med muskelstivhet og hudblødninger 1058.
Tidsskrift for Den norske legeforening (Tidsskriftet).
ISSN 0029-2001.
134(10),
p. 1058–1061.
doi:
10.4045/tidsskr.13.0817.
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Bruserud, Øystein; Tvedt, Tor Henrik Anderson; Quist-Paulsen, Petter; Ahmed, Aymen B; Gedde-Dahl, Thobias & Tjønnfjord, Geir Erland
[Show all 9 contributors for this article]
(2014).
Extracorporeal photopheresis (photochemotherapy) in the treatment of acute and chronic graft versus host disease: Immunological mechanisms and the results from clinical studies.
Cancer Immunology and Immunotherapy.
ISSN 0340-7004.
63(8),
p. 757–777.
doi:
10.1007/s00262-014-1578-z.
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Röth, Alexander; Barcellini, Wilma; Tvedt, Tor Henrik Anderson; Miyakawa, Yoshitaka; Kuter, David J. & Su, Jun
[Show all 11 contributors for this article]
(2024).
Correction to: Sutimlimab improves quality of life in patients with cold agglutinin disease: results of patient-reported outcomes from the CARDINAL study (Annals of Hematology, (2022), 101, 10, (2169-2177), 10.1007/s00277-022-04948-y).
Annals of Hematology.
ISSN 0939-5555.
doi:
10.1007/s00277-024-05709-9.
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Rørvik, Synne Dragesund; Abrahamsen, Ingerid Weum; Myhre, Anders Eivind; Vo, Camilla Dao; Meling, Eva Ødegaard & Bruserud, Øystein
[Show all 8 contributors for this article]
(2023).
Kronisk transplantat-mot-vertsykdom.
Tidsskrift for Den norske legeforening (Tidsskriftet).
ISSN 0029-2001.
143(4),
p. 337–341.
doi:
10.4045/tidsskr.22.0525.
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Kronisk transplantat-mot-vert-sykdom er en senkomplikasjon etter allogen stamcelletransplantasjon, og medfører kronisk inflammasjon og fibrose i forskjellige organer på grunn av feil regulering av donors immunceller. Sykdommen kan forekomme i alle organer, men sees hyppigst i hud, øyne, munnhule, gastrointestinaltraktus, genitalia, lunger, muskler, fascier og ledd. Kronisk transplantat-mot-vert-sykdom er assosiert med betydelig sykelighet og dødelighet, og behandling krever tett samarbeid mellom forskjellige deler av spesialisthelsetjenesten. Vi gir i denne artikkelen en klinisk oversikt over kronisk transplantat-mot-vert-sykdom basert på ikke-systematiske litteratursøk og egne kliniske erfaringer.
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Tislevoll, Benedicte Sjo; Hellesøy, Monica; Fagerholt, Oda Helen Eck; Gullaksen, Stein-Erik; Srivastava, Aashish & Birkeland, Even
[Show all 24 contributors for this article]
(2023).
Author Correction: Early response evaluation by single cell signaling profiling in acute myeloid leukemia (Nature Communications, (2023), 14, 1, (115), 10.1038/s41467-022-35624-4).
Nature Communications.
14(1).
doi:
10.1038/s41467-023-37488-8.
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Nome, Ragnhild Veline; Amundsen, Erik Koldberg; Tvedt, Tor Henrik Anderson; Fenstad, Mona H. & Øie, Erik
(2023).
Hvor ofte bør man gjenta blodprøver?
Tidsskrift for Den norske legeforening (Tidsskriftet).
ISSN 0029-2001.
143(1).
doi:
10.4045/tidsskr.22.0658.
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Tvedt, Tor Henrik Anderson; Steien, Egil; Øvrebø, Bente; Haaverstad, Rune; Hobbs, William & Wardęcki, Marek
[Show all 8 contributors for this article]
(2022).
Sutimlimab, an investigational C1s inhibitor, effectively prevents exacerbation of hemolytic anemia in a patient with cold agglutinin disease undergoing major surgery.
American Journal of Hematology.
ISSN 0361-8609.
97(2),
p. E51–E54.
doi:
10.1002/ajh.26409.
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Reikvam, Håkon; Dalgaard, Jakob; Johansen, Silje; Tvedt, Tor Henrik Anderson & Bruserud, Øystein
(2019).
Behandling av akutt myelogen leukemi hos eldre.
Tidsskrift for Den norske legeforening (Tidsskriftet).
ISSN 0029-2001.
doi:
10.4045/tidsskr.18.0775.
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Bruserud, Øystein; Melve, Guro Kristin; Gedde-Dahl, Thobias & Tvedt, Tor Henrik Anderson
(2018).
Immunological heterogeneity of healthy peripheral blood stem cell donors?preharvesting donor characteristics, additional heterogeneity induced by granulocyte colony-stimulating factor and possible importance for outcome after allotransplantation.
Expert Review of Hematology.
ISSN 1747-4086.
p. 1–3.
doi:
10.1080/17474086.2018.1511420.
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Nov. 27, 2025 3:39 PM
- Last modified
Nov. 27, 2025 3:39 PM
