Acute myeloid leukemia with rare recurring translocations-an overview of the entities included in the international consensus classification.

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.

Adult presentation of ornithine transcarbamylase deficiency: a possible cause of hyperammonemia after high-dose chemotherapy and stem cell transplantation.

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.

Vacuolar ATPase Is a Possible Therapeutic Target in Acute Myeloid Leukemia: Focus on Patient Heterogeneity and Treatment Toxicity.

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.

Casein Kinase 2 (CK2): A Possible Therapeutic Target in Acute Myeloid Leukemia.

The protein kinase CK2 (also known as casein kinase 2) is one of the main contributors to the human phosphoproteome. It is regarded as a possible therapeutic strategy in several malignant diseases, including acute myeloid leukemia (AML), which is an aggressive bone marrow malignancy. CK2 is an important regulator of intracellular signaling in AML cells, especially PI3K-Akt, Jak-Stat, NFκB, Wnt, and DNA repair signaling. High CK2 levels in AML cells at the first time of diagnosis are associated with decreased survival (i.e., increased risk of chemoresistant leukemia relapse) for patients receiving intensive and potentially curative antileukemic therapy. However, it is not known whether these high CK2 levels can be used as an independent prognostic biomarker because this has not been investigated in multivariate analyses. Several CK2 inhibitors have been developed, but CX-4945/silmitasertib is best characterized. This drug has antiproliferative and proapoptotic effects in primary human AML cells. The preliminary results from studies of silmitasertib in the treatment of other malignancies suggest that gastrointestinal and bone marrow toxicities are relatively common. However, clinical AML studies are not available. Taken together, the available experimental and clinical evidence suggests that the possible use of CK2 inhibition in the treatment of AML should be further investigated.

The Regulation of Neutrophil Migration in Patients with Sepsis: The Complexity of the Molecular Mechanisms and Their Modulation in Sepsis and the Heterogeneity of Sepsis Patients.

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Common causes include gram-negative and gram-positive bacteria as well as fungi. Neutrophils are among the first cells to arrive at an infection site where they function as important effector cells of the innate immune system and as regulators of the host immune response. The regulation of neutrophil migration is therefore important both for the infection-directed host response and for the development of organ dysfunctions in sepsis. Downregulation of CXCR4/CXCL12 stimulates neutrophil migration from the bone marrow. This is followed by transmigration/extravasation across the endothelial cell barrier at the infection site; this process is directed by adhesion molecules and various chemotactic gradients created by chemotactic cytokines, lipid mediators, bacterial peptides, and peptides from damaged cells. These mechanisms of neutrophil migration are modulated by sepsis, leading to reduced neutrophil migration and even reversed migration that contributes to distant organ failure. The sepsis-induced modulation seems to differ between neutrophil subsets. Furthermore, sepsis patients should be regarded as heterogeneous because neutrophil migration will possibly be further modulated by the infecting microorganisms, antimicrobial treatment, patient age/frailty/sex, other diseases (e.g., hematological malignancies and stem cell transplantation), and the metabolic status. The present review describes molecular mechanisms involved in the regulation of neutrophil migration; how these mechanisms are altered during sepsis; and how bacteria/fungi, antimicrobial treatment, and aging/frailty/comorbidity influence the regulation of neutrophil migration.

[Chronic graft-versus-host disease]. / Kronisk transplantat-mot-vert-sykdom.

Chronic graft-versus-host disease is a late complication of allogeneic stem cell transplantation and leads to chronic inflammation and fibrosis in various organs due to dysregulation of donor immune cells. The disease can occur in all organs, but is most frequently seen in the skin, eyes, oral cavity, gastrointestinal tract, genitalia, lungs, muscles, fascia and joints. Chronic graft-versus-host disease is associated with considerable morbidity and mortality, and treatment requires close collaboration between different parts of the specialist health services. This article provides a clinical review of chronic graft-versus-host disease based on a non-systematic literature search and the authors' own clinical experience.

Pretransplant systemic metabolic profiles in allogeneic hematopoietic stem cell transplant recipients - identification of patient subsets with increased transplant-related mortality.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is used in the treatment of high-risk acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS); however, the treatment has high risk of severe transplantation-related mortality (TRM). In this study, we examined pretransplantation serum samples derived from 92 consecutive allotransplant recipients with AML or MDS. Using nontargeted metabolomics, we identified 1274 metabolites including 968 of known identity (named biochemicals). We further investigated metabolites that differed significantly when comparing patients with and without early extensive fluid retention, pretransplantation inflammation (both being associated with increased risk of acute graft-versus-host disease [GVHD]/nonrelapse mortality) and development of systemic steroid-requiring acute GVHD (aGVHD). All three factors are associated with TRM and were also associated with significantly altered amino acid metabolism, although there was only a minor overlap between these three factors with regard to significantly altered individual metabolites. Furthermore, steroid-requiring aGVHD was especially associated with altered taurine/hypotaurine, tryptophan, biotin, and phenylacetate metabolism together with altered malate-aspartate shuttle and urea cycle regulation. In contrast, pretransplantation inflammation was associated with a weaker modulation of many different metabolic pathways, whereas extensive fluid retention was associated with a weaker modulation of taurine/hypotaurine metabolism. An unsupervised hierarchical cluster analysis based on the 13 most significantly identified metabolites associated with aGVHD identified a patient subset with high metabolite levels and increased frequencies of MDS/MDS-AML, steroid-requiring aGVHD and early TRM. On the other hand, a clustering analysis based on metabolites that were significantly altered for aGVHD, inflammation, and fluid retention comparison groups identified a patient subset with a highly significant association with TRM. Our study suggests that the systemic pretransplantation metabolic profiles can be used to identify patient subsets with an increased frequency of TRM.

Systemic Metabolomic Profiles in Adult Patients with Bacterial Sepsis: Characterization of Patient Heterogeneity at the Time of Diagnosis.

Sepsis is a dysregulated host response to infection that causes potentially life-threatening organ dysfunction. We investigated the serum metabolomic profile at hospital admission for patients with bacterial sepsis. The study included 60 patients; 35 patients fulfilled the most recent 2016 Sepsis-3 criteria whereas the remaining 25 patients only fulfilled the previous Sepsis-2 criteria and could therefore be classified as having systemic inflammatory response syndrome (SIRS). A total of 1011 identified metabolites were detected in our serum samples. Ninety-seven metabolites differed significantly when comparing Sepsis-3 and Sepsis-2/SIRS patients; 40 of these metabolites constituted a heterogeneous group of amino acid metabolites/peptides. When comparing patients with and without bacteremia, we identified 51 metabolites that differed significantly, including 16 lipid metabolites and 11 amino acid metabolites. Furthermore, 42 metabolites showed a highly significant association with the maximal total Sequential Organ Failure Assessment (SOFA )score during the course of the disease (i.e., Pearson's correlation test, p-value < 0.005, and correlation factor > 0.6); these top-ranked metabolites included 23 amino acid metabolites and a subset of pregnenolone/progestin metabolites. Unsupervised hierarchical clustering analyses based on all 42 top-ranked SOFA correlated metabolites or the subset of 23 top-ranked amino acid metabolites showed that most Sepsis-3 patients differed from Sepsis-2/SIRS patients in their systemic metabolic profile at the time of hospital admission. However, a minority of Sepsis-3 patients showed similarities with the Sepsis-2/SIRS metabolic profile even though several of them showed a high total SOFA score. To conclude, Sepsis-3 patients are heterogeneous with regard to their metabolic profile at the time of hospitalization.

High Mitochondrial Protein Expression as a Potential Predictor of Relapse Risk in Acute Myeloid Leukemia Patients with the Monocytic FAB Subtypes M4 and M5.

AML is a highly aggressive and heterogeneous form of hematological cancer. Proteomics-based stratification of patients into more refined subgroups may contribute to a more precise characterization of the patient-derived AML cells. Here, we reanalyzed liquid chromatography-tandem mass spectrometry (LC-MS/MS) generated proteomic and phosphoproteomic data from 26 FAB-M4/M5 patients. The patients achieved complete hematological remission after induction therapy. Twelve of them later developed chemoresistant relapse (RELAPSE), and 14 patients were relapse-free (REL_FREE) long-term survivors. We considered not only the RELAPSE and REL_FREE characteristics but also integrated the French-American-British (FAB) classification, along with considering the presence of nucleophosmin 1 (NPM1) mutation and cytogenetically normal AML. We found a significant number of differentially enriched proteins (911) and phosphoproteins (257) between the various FAB subtypes in RELAPSE patients. Patients with the myeloblastic M1/M2 subtype showed higher levels of RNA processing-related routes and lower levels of signaling related to terms like translation and degranulation when compared with the M4/M5 subtype. Moreover, we found that a high abundance of proteins associated with mitochondrial translation and oxidative phosphorylation, particularly observed in the RELAPSE M4/M5 NPM1 mutated subgroup, distinguishes relapsing from non-relapsing AML patient cells with the FAB subtype M4/M5. Thus, the discovery of subtype-specific biomarkers through proteomic profiling may complement the existing classification system for AML and potentially aid in selecting personalized treatment strategies for individual patients.

Pretransplant Systemic Lipidomic Profiles in Allogeneic Stem Cell Transplant Recipients.

Allogeneic stem cell transplantation is used in the treatment of high-risk hematological malignancies. However, this treatment is associated with severe treatment-related morbidity and mortality. The metabolic status of the recipient may be associated with the risk of development of transplant-associated complications such as graft-versus-host disease (GVHD). To better understand the impact of the lipidomic profile of transplant recipients on posttransplant complications, we evaluated the lipid signatures of patients with hematological disease using non-targeted lipidomics. In the present study, we studied pretransplant serum samples derived from 92 consecutive patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS). A total of 960 lipid biochemicals were identified, and the pretransplant lipidomic profiles differed significantly when comparing patients with and without the risk factors: (i) pretransplant inflammation, (ii) early fluid overload, and (iii) patients with and without later steroid-requiring acute GVHD. All three factors, but especially patients with pretransplant inflammation, were associated with decreased levels of several lipid metabolites. Based on the overall concentrations of various lipid subclasses, we identified a patient subset characterized by low lipid levels, increased frequency of MDS patients, signs of inflammation, decreased body mass index, and an increased risk of early non-relapse mortality. Metabolic targeting has been proposed as a possible therapeutic strategy in allotransplant recipients, and our present results suggest that the clinical consequences of therapeutic intervention (e.g., nutritional support) will also differ between patients and depend on the metabolic context.

IL-6 Responsiveness of CD4+ and CD8+ 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.

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.

Endocan in Acute Leukemia: Current Knowledge and Future Perspectives.

Endocan is a soluble dermatan sulfate proteoglycan expressed by endothelial cells and detected in serum/plasma. Its expression is increased in tumors/tumor vessels in several human malignancies, and high expression (high serum/plasma levels or tumor levels) has an adverse prognostic impact in several malignancies. The p14 endocan degradation product can also be detected in serum/plasma, but previous clinical studies as well as previously unpublished results presented in this review suggest that endocan and p14 endocan fragment levels reflect different biological characteristics, and the endocan levels seem to reflect the disease heterogeneity in acute leukemia better than the p14 fragment levels. Furthermore, decreased systemic endocan levels in previously immunocompetent sepsis patients are associated with later severe respiratory complications, but it is not known whether this is true also for immunocompromised acute leukemia patients. Finally, endocan is associated with increased early nonrelapse mortality in (acute leukemia) patients receiving allogeneic stem cell transplantation, and this adverse prognostic impact seems to be independent of the adverse impact of excessive fluid overload. Systemic endocan levels may also become important to predict cytokine release syndrome after immunotherapy/haploidentical transplantation, and in the long-term follow-up of acute leukemia survivors with regard to cardiovascular risk. Therapeutic targeting of endocan is now possible, and the possible role of endocan in acute leukemia should be further investigated to clarify whether the therapeutic strategy should also be considered.

Hematopoiesis, Inflammation and Aging-The Biological Background and Clinical Impact of Anemia and Increased C-Reactive Protein Levels on Elderly Individuals.

Anemia and systemic signs of inflammation are common in elderly individuals and are associated with decreased survival. The common biological context for these two states is then the hallmarks of aging, i.e., genomic instability, telomere shortening, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intercellular communication. Such aging-associated alterations of hematopoietic stem cells are probably caused by complex mechanisms and depend on both the aging of hematopoietic (stem) cells and on the supporting stromal cells. The function of inflammatory or immunocompetent cells is also altered by aging. The intracellular signaling initiated by soluble proinflammatory mediators (e.g., IL1, IL6 and TNFα) is altered during aging and contributes to the development of both the inhibition of erythropoiesis with anemia as well as to the development of the acute-phase reaction as a systemic sign of inflammation with increased CRP levels. Both anemia and increased CRP levels are associated with decreased overall survival and increased cardiovascular mortality. The handling of elderly patients with inflammation and/or anemia should in our opinion be individualized; all of them should have a limited evaluation with regard to the cause of the abnormalities, but the extent of additional and especially invasive diagnostic evaluation should be based on an overall clinical evaluation and the possible therapeutic consequences.

Toll-like Receptor 4, Osteoblasts and Leukemogenesis; the Lesson from Acute Myeloid Leukemia.

Toll-like receptor 4 (TLR4) is a pattern-recognizing receptor that can bind exogenous and endogenous ligands. It is expressed by acute myeloid leukemia (AML) cells, several bone marrow stromal cells, and nonleukemic cells involved in inflammation. TLR4 can bind a wide range of endogenous ligands that are present in the bone marrow microenvironment. Furthermore, the TLR4-expressing nonleukemic bone marrow cells include various mesenchymal cells, endothelial cells, differentiated myeloid cells, and inflammatory/immunocompetent cells. Osteoblasts are important stem cell supporting cells localized to the stem cell niches, and they support the proliferation and survival of primary AML cells. These supporting effects are mediated by the bidirectional crosstalk between AML cells and supportive osteoblasts through the local cytokine network. Finally, TLR4 is also important for the defense against complicating infections in neutropenic patients, and it seems to be involved in the regulation of inflammatory and immunological reactions in patients treated with allogeneic stem cell transplantation. Thus, TLR4 has direct effects on primary AML cells, and it has indirect effects on the leukemic cells through modulation of their supporting neighboring bone marrow stromal cells (i.e., modulation of stem cell niches, regulation of angiogenesis). Furthermore, in allotransplant recipients TLR4 can modulate inflammatory and potentially antileukemic immune reactivity. The use of TLR4 targeting as an antileukemic treatment will therefore depend both on the biology of the AML cells, the biological context of the AML cells, aging effects reflected both in the AML and the stromal cells and the additional antileukemic treatment combined with HSP90 inhibition.

Patients with Bacterial Sepsis Are Heterogeneous with Regard to Their Systemic Lipidomic Profiles.

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. In the present study, we investigated the systemic/serum lipidomic profile at the time of hospital admission for patients with bacterial sepsis. The study included 60 patients; 35 patients fulfilled the most recent 2016 Sepsis-3 criteria (referred to as Sepsis-3) whereas the remaining 25 patients had sepsis only according to the previous Sepsis-2 definition and could be classified as having Systemic Inflammatory Response Syndrome (SIRS). A total of 966 lipid metabolites were identified. Patients fulfilling the Sepsis-3 criteria differed from the Sepsis-2 patients with regard to only 15 lipid metabolites, and especially sphingolipids metabolism differed between these patient subsets. A total of only 43 metabolites differed between patients with and without bacteremia, including 12 lysophosphatidylcholines and 18 triacylglycerols (15 C18/C20 fatty acid metabolites decreased and three C14 myristate acid metabolites that were increased in bacteremia). Unsupervised hierarchical clustering analyses based on the identified sphingolipids, phosphatidylcholine and triacylglycerols showed that (i) the majority of Sepsis-3 patients differed from SIRS patients especially with regard to lysophosphatidylcholine levels; (ii) the minority of Sepsis-3 patients that clustered together with the majority of SIRS patients showed lower Sequential Organ Failure Assessment (SOFA) scores than the other Sepsis-3 patients; and (iii) the variation between the patients in the identified/altered sphingolipid and triacylglycerol metabolites further increased the heterogeneity of Sepsis-3 patients with regard to their systemic lipidomic profile at the time of diagnosis. To conclude, patients fulfilling the Sepsis-3 criteria differ with regard to their metabolic profile, and this variation depends on disease severity.

Necrotizing Bacterial Myositis as the Initial Presentation of Severe Aplastic Anaemia.

INTRODUCTION: Necrotizing soft tissue infections are rapidly progressing infections associated with severe inflammation and cytokine release. Early recognition and surgical intervention are key factors to secure survival. The current case presents a patient with multifocal necrotizing soft tissue infection as the initial presentation of severe aplastic anaemia. Case Presentation. A man in his fifties was admitted with septic shock with multiorgan failure and severe pancytopenia, after two days of malaise with high fever and right flank pain. The diagnosis streptococcal necrotizing myositis was significantly delayed due to atypical clinical findings. After initial surgical exploration, the decision was made to defer from surgical debridement due to extensive involvement of several muscle groups, grave pancytopenia, and suspected dismal prognosis. Surprisingly, the patient stabilized after antibiotics and intensive care treatment. Based on severe pancytopenia and hypocellular bone marrow, with no evidence of other bone marrow disorders, the patient was diagnosed with aplastic anaemia. Treatment for aplastic anaemia with antithymocyte globulin, cyclosporine, and eltrombopaq was started, and 2 months later, a partial haematological recovery was observed. The patient could be discharged from hospital without antibiotic treatment. CONCLUSIONS: This case illustrates the crucial role of a multidisciplinary approach on admission and further during the clinical course. Clinical improvement despite severe neutropenia and stabilization during immunosuppressive therapy suggest that immunological factors modulate clinical course in necrotizing soft tissue infections.

The association between cytokines and psychomotor speed in a spectrum of psychotic disorders: A longitudinal study.

BACKGROUND: In schizophrenia, impaired psychomotor speed is a common symptom predicting worse functional outcome. Inflammation causes changes in white matter integrity, which may lead to reduced psychomotor speed. Therefore, we wanted to investigate if peripheral inflammation assessed with cytokines affected performance on psychomotor speed in patients with a spectrum of psychotic disorders. METHODS: The current study is a prospective cohort study, including participants from a pragmatic, randomised controlled trial comparing three atypical antipsychotics in patients with a spectrum of psychotic disorders. For the purposes of this sub-study, we analysed drug treatment groups collectively. Psychomotor speed was assessed at baseline, and at weeks 6, 12, 26 and 52 of follow-up, using the neuropsychological tests trail making test (TMT) A and B, and symbol coding. Serum concentration of the following cytokines were measured: interleukin (IL)-ß, IL-2, IL-4, IL-6, IL-10, IL12 p70, IL-17a, interferon (IFN)-γ and tumor necrosis factor (TNF)-α. Blood samples were collected at baseline and after 1, 3, 6, 12, 26, 39 and 52 weeks. We analysed the effect of cytokines levels on psychomotor speed over time in linear mixed effects models. RESULTS: In our linear mixed effects models controlling for possible confounders, IFN-γ had a significant negative effect on TMT-A and symbol coding performance. None of the other tests for psychomotor speed were significantly associated with cytokines. Overall psychomotor speed performance increased significantly across the study period while cytokine levels remained stable. CONCLUSION: Our study indicates a negative association between IFN-γ and psychomotor speed, which might be of importance when understanding the mechanisms behind psychomotor deviations in psychotic disorders.

Cytokine Release Syndrome in the Immunotherapy of Hematological Malignancies: The Biology behind and Possible Clinical Consequences.

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.

Patient Heterogeneity in Acute Myeloid Leukemia: Leukemic Cell Communication by Release of Soluble Mediators and Its Effects on Mesenchymal Stem Cells.

Acute myeloid leukemia (AML) is an aggressive bone marrow malignancy, and non-leukemic stromal cells (including mesenchymal stem cells, MSCs) are involved in leukemogenesis and show AML-supporting effects. We investigated how constitutive extracellular mediator release by primary human AML cells alters proteomic profiles of normal bone marrow MSCs. An average of 6814 proteins (range 6493-6918 proteins) were quantified for 41 MSC cultures supplemented with AML-cell conditioned medium, whereas an average of 6715 proteins (range 6703-6722) were quantified for untreated control MSCs. The AML effect on global MSC proteomic profiles varied between patients. Hierarchical clustering analysis identified 10 patients (5/10 secondary AML) showing more extensive AML-effects on the MSC proteome, whereas the other 31 patients clustered together with the untreated control MSCs and showed less extensive AML-induced effects. These two patient subsets differed especially with regard to MSC levels of extracellular matrix and mitochondrial/metabolic regulatory proteins. Less than 10% of MSC proteins were significantly altered by the exposure to AML-conditioned media; 301 proteins could only be quantified after exposure to conditioned medium and 201 additional proteins were significantly altered compared with the levels in control samples (153 increased, 48 decreased). The AML-modulated MSC proteins formed several interacting networks mainly reflecting intracellular organellar structure/trafficking but also extracellular matrix/cytokine signaling, and a single small network reflecting altered DNA replication. Our results suggest that targeting of intracellular trafficking and/or intercellular communication is a possible therapeutic strategy in AML.