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1.
Haematologica ; 108(7): 1768-1781, 2023 Jul 01.
Article in English | MEDLINE | ID: mdl-36519325

ABSTRACT

The BCL-2 inhibitor venetoclax has revolutionized the treatment of acute myeloid leukemia (AML) in patients not benefiting from intensive chemotherapy. Nevertheless, treatment failure remains a challenge, and predictive markers are needed, particularly for relapsed or refractory AML. Ex vivo drug sensitivity testing may correlate with outcomes, but its prospective predictive value remains unexplored. Here we report the results of the first stage of the prospective phase II VenEx trial evaluating the utility and predictiveness of venetoclax sensitivity testing using different cell culture conditions and cell viability assays in patients receiving venetoclax-azacitidine. Participants with de novo AML ineligible for intensive chemotherapy, relapsed or refractory AML, or secondary AML were included. The primary endpoint was the treatment response in participants showing ex vivo sensitivity and the key secondary endpoints were the correlation of sensitivity with responses and survival. Venetoclax sensitivity testing was successful in 38/39 participants. Experimental conditions significantly influenced the predictive accuracy. Blast-specific venetoclax sensitivity measured in conditioned medium most accurately correlated with treatment outcomes; 88% of sensitive participants achieved a treatment response. The median survival was significantly longer for participants who were ex vivo-sensitive to venetoclax (14.6 months for venetoclax-sensitive patients vs. 3.5 for venetoclax-insensitive patients, P<0.001). This analysis illustrates the feasibility of integrating drug-response profiling into clinical practice and demonstrates excellent predictivity. This trial is registered with ClinicalTrials.gov identifier: NCT04267081.


Subject(s)
Antineoplastic Agents , Leukemia, Myeloid, Acute , Humans , Prospective Studies , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/drug therapy , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use
2.
Front Immunol ; 13: 819929, 2022.
Article in English | MEDLINE | ID: mdl-36466816

ABSTRACT

Krüppel-like factor 2 (KLF2) is a transcription factor with significant roles in development, maturation, differentiation, and proliferation of several cell types. In immune cells, KLF2 regulates maturation and trafficking of lymphocytes and monocytes. KLF2 participates in regulation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Although pulmonary arterial hypertension (PAH) related to KLF2 genetic variant has been suggested, genetic role of KLF2 associated with immune dysregulation has not been described. We identified a family whose members suffered from lymphopenia, autoimmunity, and malignancy. Whole exome sequencing revealed a KLF2 p.(Glu318Argfs*87) mutation disrupting the highly conserved zinc finger domain. We show a reduced amount of KLF2 protein, defective nuclear localization and altered protein-protein interactome. The phenotypically variable positive cases presented with B and T cell lymphopenia and abnormalities in B and T cell maturation including low naive T cell counts and low CD27+IgD-IgM- switched memory B cells. KLF2 target gene (CD62L) expression was affected. Although the percentage of (CD25+FOXP3+, CD25+CD127-) regulatory T cells (Treg) was high, the naive Treg cells (CD45RA+) were absent. Serum IgG1 levels were low and findings in one case were consistent with common variable immunodeficiency (CVID). Transcription of NF-κß pathway genes and p65/RelA phosphorylation were not significantly affected. Inflammasome activity, transcription of genes related with JAK/STAT pathway and interferon signature were also comparable to controls. Evidence of PAH was not found. In conclusion, KLF2 variant may be associated with familial immune dysregulation. Although the KLF2 deficient family members in our study suffered from lymphopenia, autoimmunity or malignancy, additional study cohorts are required to confirm our observations.


Subject(s)
Lymphopenia , Premature Birth , Female , Humans , Janus Kinases , STAT Transcription Factors , Signal Transduction , Zinc Fingers , Kruppel-Like Transcription Factors/genetics , Zinc
4.
Cancer Cell ; 38(3): 380-399.e13, 2020 09 14.
Article in English | MEDLINE | ID: mdl-32649887

ABSTRACT

Understanding factors that shape the immune landscape across hematological malignancies is essential for immunotherapy development. We integrated over 8,000 transcriptomes and 2,000 samples with multilevel genomics of hematological cancers to investigate how immunological features are linked to cancer subtypes, genetic and epigenetic alterations, and patient survival, and validated key findings experimentally. Infiltration of cytotoxic lymphocytes was associated with TP53 and myelodysplasia-related changes in acute myeloid leukemia, and activated B cell-like phenotype and interferon-γ response in lymphoma. CIITA methylation regulating antigen presentation, cancer type-specific immune checkpoints, such as VISTA in myeloid malignancies, and variation in cancer antigen expression further contributed to immune heterogeneity and predicted survival. Our study provides a resource linking immunology with cancer subtypes and genomics in hematological malignancies.


Subject(s)
Gene Expression Profiling/methods , Gene Expression Regulation, Neoplastic , Leukemia, Myeloid/genetics , Lymphoma, Large B-Cell, Diffuse/genetics , Acute Disease , Epigenesis, Genetic , Genomics/methods , HLA Antigens/genetics , Humans , Immunotherapy/methods , Leukemia, Myeloid/immunology , Leukemia, Myeloid/therapy , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Lymphoma, Large B-Cell, Diffuse/immunology , Lymphoma, Large B-Cell, Diffuse/therapy , Multiple Myeloma/genetics , Multiple Myeloma/immunology , Multiple Myeloma/therapy , Mutation , Tumor Suppressor Protein p53/genetics
5.
Am J Gastroenterol ; 114(4): 648-655, 2019 04.
Article in English | MEDLINE | ID: mdl-30747770

ABSTRACT

OBJECTIVES: Common variable immunodeficiency (CVID) is associated with a spectrum of autoimmune complications. We studied the prevalence of gastrointestinal (GI) manifestations and infections in patients with CVID. METHODS: Complete clinical data of 132 Finnish patients with CVID (106 probable and 26 possible CVID) followed up between 2007 and 2016 were collected to a structured database. Data on endoscopies, histology, and laboratory studies were retrieved from patient files. RESULTS: Most common referral indications were diarrhea and/or weight loss (47%-67%). Patients with probable CVID had higher fecal calprotectin and α1-antitrypsin and lower blood vitamin B12 than patients with possible CVID. Gastroscopy and colonoscopy were done to 71 (67%) and 63 (59%) patients with probable CVID, respectively. Endoscopies showed that 15% of them had chronic active gastritis and 17% atrophic gastritis and 3% had gastric adenocarcinoma. A celiac sprue-like condition was found in 7 patients (10%), of whom 3 responded to a gluten-free diet. Colonoscopies demonstrated unspecific colitis (14%), ulcerative colitis (8%), microscopic colitis (10%), and Crohn's disease (2%). Colonic polyps were noted in 30% of patients, and 3% had lower GI malignancies. Thirty-five patients with CVID had bacterial or parasitic gastroenteritis; chronic norovirus was detected in 4 patients with probable CVID. Patients with GI inflammation had higher levels of fecal calprotectin and blood CD8 T lymphocytes but lower counts of CD19CD27 memory B cells and/or CD19 B cells. Immunophenotype with low B-cell counts was associated with higher fecal calprotectin levels. DISCUSSION: Patients with CVID had a high prevalence of GI manifestations and infections of the GI tract. GI inflammation was associated with a distinct immunophenotype and elevated fecal calprotectin.


Subject(s)
Common Variable Immunodeficiency/complications , Gastrointestinal Diseases/etiology , Gastrointestinal Diseases/immunology , Biomarkers/metabolism , Female , Finland/epidemiology , Gastrointestinal Diseases/epidemiology , Humans , Immunophenotyping , Male , Middle Aged , Prevalence
6.
Bone Marrow Transplant ; 54(7): 1022-1028, 2019 07.
Article in English | MEDLINE | ID: mdl-30361500

ABSTRACT

Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). This study evaluated clinical and morphological practices of TA-TMA diagnosis in EBMT centers. Two questionnaires, one for transplant physician and one for morphologist, and also a set of electronic blood slides from 10 patients with TA-TMA and 10 control patients with various erythrocyte abnormalities, were implemented for evaluation. Seventeen EBMT centers participated in the study. Regarding criteria used for TA-TMA diagnosis, centers reported as follows: 41% of centers used the International Working Group (IWG) criteria, 41% used "overall TA-TMA" criteria and 18% used physician's decision. The threshold of schistocytes to establish TA-TMA diagnosis in the participating centers was significantly associated with morphological results of test cases evaluations (p = 0.002). The mean number of schistocytes reported from blood slide analyses were 4.3 ± 4.5% for TA-TMA cases (range 0-19.6%, coefficient of variation (CV) 0.7) and 1.3 ± 1.6% for control cases (range 0-8.3%, CV 0.8). Half of the centers reported schistocyte levels below 4% for 7/10 TA-TMA cases. The intracenter variability was low, indicating differences in the institutional practices of morphological evaluation. In conclusion, the survey identified the need for the standardization of TA-TMA morphological diagnosis.


Subject(s)
Graft vs Host Disease , Hematologic Diseases , Hematopoietic Stem Cell Transplantation , Hospitals, Special , Thrombotic Microangiopathies , Adolescent , Adult , Female , Graft vs Host Disease/blood , Graft vs Host Disease/diagnosis , Graft vs Host Disease/etiology , Hematologic Diseases/blood , Hematologic Diseases/diagnosis , Hematologic Diseases/therapy , Humans , Male , Practice Guidelines as Topic , Thrombotic Microangiopathies/blood , Thrombotic Microangiopathies/diagnosis , Thrombotic Microangiopathies/etiology , Young Adult
7.
Transfusion ; 58(6): 1372-1376, 2018 06.
Article in English | MEDLINE | ID: mdl-29492974

ABSTRACT

BACKGROUND: Blood transfusion through the intraosseous route is gaining popularity in emergency medicine. Pretransfusion peripheral blood (PB) samples are usually not available in these patients, leading to discrepancies in blood group typing and a possible delay in transferring to group-specific blood products. The aim of this study was to assess the feasibility of ABO and D typing and red blood cell alloantibody screening in marrow (BM) samples. STUDY DESIGN AND METHODS: Direct and reverse ABO typing, D typing, and a two-cell alloantibody screen were performed in EDTA-anticoagulated BM samples with standard manual column agglutination techniques. EDTA-anticoagulated PB samples were used as controls. RESULTS: The mean age of the study subjects (n = 71) was 47 years (range, 1-82 years). All ABO groups and both D+ and D- types were represented. In all subjects, concordant results were observed for all analyses in BM and PB samples. In 15 (21%) of the samples, a discrepancy of one reaction strength step (1+) was observed in at least one of the analyses (Cohen's weighted κ = 0.993); this did not affect interpretation of the results. CONCLUSION: Blood group typing and alloantibody screening are feasible in BM samples, providing proof-of-concept that intraosseous samples for blood group serologic analyses can be collected from emergency patients before intraosseous blood transfusion. This will enable a timely transfer to group-specific blood products and enable conservation of the valuable universal-donor blood products.


Subject(s)
Blood Grouping and Crossmatching/methods , Blood Transfusion/methods , Bone Marrow/immunology , Infusions, Intraosseous , Isoantibodies/analysis , ABO Blood-Group System , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Emergency Medical Services , Humans , Infant , Middle Aged , Rh-Hr Blood-Group System , Young Adult
8.
Front Immunol ; 8: 1190, 2017.
Article in English | MEDLINE | ID: mdl-29033928

ABSTRACT

BACKGROUND: Common variable immunodeficiency (CVID) is the most common primary immunodeficiency. Prevalence varies greatly between countries and studies. Most diagnostic criteria include hypogammaglobulinemia and impaired vaccine response. AIM: To evaluate the minimum prevalence as well as the clinical and immunological phenotypes of CVID in Southern Finland. METHODS: We performed a cross-sectional study to assess all adult CVID patients followed up in three hospital districts in Southern and South-Eastern Finland between April 2007 and August 2015. CVID diagnosis was based, with a minor modification, on the ESID/PAGID criteria for primary CVID. Antipolysaccharide responses to Pneumovax® were defined as impaired only if 50% or more of the serotypes did not reach a level of 0.35 µg/mL after vaccination. We further characterized the patients' B cell phenotypes and complications associated with CVID. RESULTS: In total, 9 patients were excluded due to potential secondary causes before diagnosis. ESID/PAGID criteria were met by 132 patients (males 52%), of whom, 106 had "probable" and 26 "possible CVID." Based on the population statistics in the three hospital districts, the minimum adult prevalence per 100,000 inhabitants in Finland for all CVID ("probable CVID," respectively) patients was 6.9 (5.5). In the highest prevalence district (Helsinki and Uusimaa), the prevalence was 7.7 (6.1). CVID patients suffer from frequent complications. Ten patients died during follow-up. Of probable CVID patients, 73% had more than one clinical phenotype. Intriguingly, gradual B cell loss from peripheral blood during follow-up was seen in as many as 16% of "probable CVID" patients. Patients with possible CVID displayed somewhat milder clinical and laboratory phenotypes than probable CVID patients. We also confirm that large granular lymphocyte lymphoproliferation is a CVID-associated complication. CONCLUSION: The prevalence of CVID in Finland appears the highest recorded, likely reflecting the genetic isolation and potential founder effects in the Finnish population. Studies to discover potential gene variants responsible for the high prevalence in Finland thus seem warranted. Increased awareness of CVID among physicians would likely lead to earlier diagnosis and improved quality of care.

9.
Br J Haematol ; 174(4): 600-9, 2016 Aug.
Article in English | MEDLINE | ID: mdl-27072379

ABSTRACT

Early response after induction is a prognostic factor for disease outcome in childhood acute myeloid leukaemia (AML). Residual disease (RD) detection by multiparameter flow cytometry (MFC) was performed at day 15 and before consolidation therapy in 101 patients enrolled in the Nordic Society of Paediatric Haemato-Oncology AML 2004 study. A multicentre laboratory approach to RD analysis was used. Event-free survival (EFS) and overall survival (OS) was significantly different in patients with and without RD at both time points, using a 0·1% RD cut-off level. RD-negative and -positive patients after first induction showed a 5-year EFS of 65 ± 7% and 22 ± 7%, respectively (P < 0·001) and an OS of 77 ± 6% (P = 0·025) and 51 ± 8%. RD-negative and -positive patients at start of consolidation therapy had a 5-year EFS of 57 ± 7% and 11 ± 7%, respectively (P < 0·001) and an OS of 78 ± 6% and 28 ± 11%) (P < 0·001). In multivariate analysis only RD was significantly correlated with survival. RD before consolidation therapy was the strongest independent prognostic factor for EFS [hazard ratio (HR):5·0; 95% confidence interval (CI):1·9-13·3] and OS (HR:7·0; 95%CI:2·0-24·5). In conclusion, RD before consolidation therapy identifies patients at high risk of relapse in need of intensified treatment. In addition, RD detection can be performed in a multicentre setting and can be implemented in future trials.


Subject(s)
Flow Cytometry/methods , Leukemia, Myeloid, Acute/mortality , Neoplasm, Residual/diagnosis , Adolescent , Child , Child, Preschool , Disease-Free Survival , Female , Humans , Infant , Infant, Newborn , Male , Neoplasm, Residual/mortality , Prognosis , Remission Induction , Risk , Survival Analysis , Time Factors
10.
Pediatr Blood Cancer ; 62(3): 522-8, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25417898

ABSTRACT

BACKGROUND: Increasing evidence suggests that early and rapid lymphocyte recovery following allogeneic hematopoietic stem cell transplantation (HSCT) is associated with better survival. PROCEDURE: We retrospectively analyzed very early lymphocyte subset counts following transplantation from our 5-year pediatric allogeneic HSCT material to find clinically relevant associations with post transplant outcome, and the major complication of HSCT, acute graft-versus-host disease (aGVHD). We analyzed HSCTs performed due to acute leukemias and lymphomas from matched unrelated donors (MUD, n = 33), unrelated cord blood (UCB, n = 9) and matched sibling donors (MSD, n = 17). RESULTS: Patients with grafts from MUDs and grade II-IV aGVHD) had higher (median 2.1 compared to 0.3, P<0.0001) and earlier (at day +18 post transplant vs. day +25, P = 0.004) first measurable CD4(+) /CD8(+) T cell ratio, compared to patients with no or grade I aGVHD, respectively. At day +32 after HSCT patients with MUDs and significant aGVHD had higher levels of both CD4(+) and CD8(+) T cell subsets. Low (below median 120/µL) versus high natural killer (NK) cell counts at day +32 were associated with 3-year event-free survival of 27.4 +/- 9.0% versus 82.4 +/- 6.4% (P < 0.0001), cumulative transplant-related mortality of 44.7 +/- 12.2% versus 3.0 +/- 3.0% (P < 0.001) and cumulative relapse incidence of 50.4 +/- 12.2% versus 15.0 +/- 6.2% (P = 0.019), respectively. CONCLUSIONS: We conclude that early lymphocyte subset counts following allogeneic HSCT have an association with aGVHD and post transplant outcome.


Subject(s)
Graft vs Host Disease/immunology , Graft vs Host Disease/mortality , Hematopoietic Stem Cell Transplantation , Killer Cells, Natural/immunology , Acute Disease , Allografts , CD4 Lymphocyte Count , Child , Child, Preschool , Disease-Free Survival , Female , Follow-Up Studies , Graft vs Host Disease/blood , Graft vs Host Disease/pathology , Humans , Infant , Leukemia/blood , Leukemia/immunology , Leukemia/mortality , Leukemia/pathology , Leukemia/therapy , Lymphoma/blood , Lymphoma/immunology , Lymphoma/mortality , Lymphoma/therapy , Male , Retrospective Studies , Survival Rate
11.
Blood ; 125(4): 639-48, 2015 Jan 22.
Article in English | MEDLINE | ID: mdl-25349174

ABSTRACT

The signal transducer and activator of transcription (STAT) family of transcription factors orchestrate hematopoietic cell differentiation. Recently, mutations in STAT1, STAT5B, and STAT3 have been linked to development of immunodysregulation polyendocrinopathy enteropathy X-linked-like syndrome. Here, we immunologically characterized 3 patients with de novo activating mutations in the DNA binding or dimerization domains of STAT3 (p.K392R, p.M394T, and p.K658N, respectively). The patients displayed multiorgan autoimmunity, lymphoproliferation, and delayed-onset mycobacterial disease. Immunologically, we noted hypogammaglobulinemia with terminal B-cell maturation arrest, dendritic cell deficiency, peripheral eosinopenia, increased double-negative (CD4(-)CD8(-)) T cells, and decreased natural killer, T helper 17, and regulatory T-cell numbers. Notably, the patient harboring the K392R mutation developed T-cell large granular lymphocytic leukemia at age 14 years. Our results broaden the spectrum of phenotypes caused by activating STAT3 mutations, highlight the role of STAT3 in the development and differentiation of multiple immune cell lineages, and strengthen the link between the STAT family of transcription factors and autoimmunity.


Subject(s)
Agammaglobulinemia , Autoimmune Diseases , Genetic Diseases, Inborn , Leukemia, Large Granular Lymphocytic , Mutation, Missense , Mycobacterium Infections , STAT3 Transcription Factor , Adolescent , Adult , Agammaglobulinemia/genetics , Agammaglobulinemia/immunology , Agammaglobulinemia/pathology , Amino Acid Substitution , Autoimmune Diseases/genetics , Autoimmune Diseases/immunology , Autoimmune Diseases/pathology , B-Lymphocytes/immunology , B-Lymphocytes/pathology , Cell Differentiation/genetics , Cell Differentiation/immunology , Dendritic Cells/immunology , Dendritic Cells/pathology , Female , Genetic Diseases, Inborn/genetics , Genetic Diseases, Inborn/immunology , Genetic Diseases, Inborn/pathology , Humans , Killer Cells, Natural/immunology , Killer Cells, Natural/pathology , Leukemia, Large Granular Lymphocytic/genetics , Leukemia, Large Granular Lymphocytic/immunology , Leukemia, Large Granular Lymphocytic/pathology , Mycobacterium Infections/genetics , Mycobacterium Infections/immunology , Mycobacterium Infections/pathology , Protein Structure, Tertiary , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/immunology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/pathology , Th17 Cells/immunology , Th17 Cells/pathology
12.
Duodecim ; 130(3): 269-77, 2014.
Article in Finnish | MEDLINE | ID: mdl-24660387

ABSTRACT

A previously healthy 40-year-old man developed febrile episodes of unknown origin, articular symptoms, venous occlusion of the lower limb and transient elevation of hepatic enzymes, and cutaneous symptoms. Computed tomography scanning revealed enlarged lymph nodes, but no sample was collected. In addition to microcytic anemia, a high serum ferritin level and an increased IL-2 receptor value in serum were found. Drug therapy against tuberculosis and borreliosis was started, but febrile episodes continued and in a few days the patient developed multiorgan dysfunction. Hemophagocytic lymphohistiocytosis associated with T-cell lymphoma was revealed as the underlying condition.


Subject(s)
Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphoma, T-Cell/diagnosis , Adult , Diagnosis, Differential , Ferritins/blood , Fever of Unknown Origin , Humans , Liver Function Tests , Lymphedema , Male , Receptors, Interleukin-2/blood , Tomography, X-Ray Computed
14.
Scand J Clin Lab Invest ; 73(6): 494-502, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23837874

ABSTRACT

Peripheral blood mononuclear cells of Crohn's disease (CD) patients with the common 1007fs mutation of the caspase recruitment domain-containing 15/nucleotide-binding oligomerization domain-containing 2 (CARD15/NOD2) gene show impaired nuclear factor kappa B (NF-κB) activation in response to muramyl dipeptide (MDP), as determined by Western blotting. We applied phospho-specific flow cytometry to examine NF-κB and p38 activation in whole blood monocytes of 16 CD patients with or without the 1007fs and previously described rare mutations of the CARD15 gene, and healthy reference subjects. Aliquots of whole blood were supplemented with MDP (0-1000 ng/mL), incubated for 10-40 min and processed for flow cytometry. Bacterial lipopolysaccharide (LPS) was used as a positive control agonist. We found that NF-κB and p38 phosphorylation induced by MDP was not detectable in monocytes of patients homozygous for the CARD15 1007fs mutation, while those induced by LPS were normal. We also determined MDP-induced NF-κB phosphorylation levels in nuclear extracts of mononuclear cells separated from blood using enzyme-linked immunosorbent assay (ELISA), and observed that the levels decreased in a 1007fs mutation-dose dependent manner. We conclude that phospho-specific whole blood flow cytometry provides a means to study phosphorylation of NF-κB and p38 in clinical samples and can be applied to screening of CD patients homozygous for the CARD15 1007fs mutation.


Subject(s)
Acetylmuramyl-Alanyl-Isoglutamine/blood , Crohn Disease/blood , Leukocytes, Mononuclear/metabolism , Adult , Aged , Case-Control Studies , Crohn Disease/diagnosis , Crohn Disease/genetics , Female , Flow Cytometry , Humans , Male , Middle Aged , Mutation, Missense , NF-kappa B/blood , Nod2 Signaling Adaptor Protein/genetics , Phosphoproteins/blood , Phosphorylation , Protein Processing, Post-Translational , Signal Transduction , p38 Mitogen-Activated Protein Kinases/blood
15.
Pancreatology ; 13(2): 118-24, 2013.
Article in English | MEDLINE | ID: mdl-23561969

ABSTRACT

BACKGROUND/OBJECTIVES: Circulating polymorphonuclear leukocytes (PMNLs) may contribute to development of organ dysfunction in acute pancreatitis (AP). We outlined aberrations in PMNL signaling profiles in patients with AP complicated by organ dysfunction and immune suppression. METHODS: Study comprised 13 patients treated at intensive care unit due to severe AP complicated by vital organ dysfunction. Mean proportion (SEM) of HLA-DR-positive monocytes was 55.0% (4.1%). 13 healthy volunteers served as reference subjects. Phosphorylation of PMNL NFκB, p38, ERK1/2 and STAT3, -5 and -6 was determined using whole blood flow cytometry. Transmigration of PMNLs was studied using endothelial EA-HY cell monolayer. RESULTS: Proportions of NFκB phosphorylation-positive PMNLs were lower in the patients' than in reference subjects' blood samples supplemented with tumor necrosis factor. p38 phosphorylation was normal while ERK1/2 phosphorylation was decreased. STAT3 was constitutively activated in five patients. Proportion of patients' pSTAT6-positive cells was normal while fluorescence intensity was decreased. STAT5 phosphorylation was normal. Transmigration of patients' PMNLs was increased. CONCLUSIONS: In patients with AP complicated by organ dysfunction proportion of pNFκB-positive PMNLs is decreased. This impairs patients' defense mechanisms against infection. Despite immune suppression, PMNL transmigration was increased and p38 phosphorylation capacity was not depressed, which may contribute to end organ inflammation and dysfunction.


Subject(s)
Neutrophils/physiology , Pancreatitis/complications , Pancreatitis/pathology , Signal Transduction/physiology , Adult , Aged , Extracellular Signal-Regulated MAP Kinases/genetics , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , Humans , Male , Middle Aged , NF-kappa B/genetics , NF-kappa B/metabolism , Phosphorylation , STAT Transcription Factors/genetics , STAT Transcription Factors/metabolism , p38 Mitogen-Activated Protein Kinases/genetics , p38 Mitogen-Activated Protein Kinases/metabolism
16.
Pediatr Res ; 73(4 Pt 1): 469-75, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23269117

ABSTRACT

BACKGROUND: As a protective response to an inflammatory stimulus, the antigen-presenting molecules (human leukocyte antigen-DR (HLA-DR)) on monocytes are downregulated. If severe, the response may lead to immunodepression or immunoparalysis, associated with an increased rate of morbidity and mortality in adults. In very low birth weight (VLBW) infants, birth and intensive care present major immunological challenges. METHODS: We measured monocyte HLA-DR expression by flow cytometry and determined 13 plasma cytokines in 56 VLBW infants (gestational age (GA): 23.7-31.8 wk) and 25 controls (GA: 34.1-41.4 wk). RESULTS: HLA-DR expression decreased postnatally both in VLBW and in control infants. In VLBW infants, GA and respiratory distress syndrome (RDS) both showed associations with HLA-DR nadir on day 3, when 45% of them met the criteria of immunodepression. HLA-DR expression was lower in those infants subsequently developing infection (74 vs. 49% (day 3) and 85 vs. 68% (day 7); both P = 0.002). Interleukin (IL)-6 on day 1 was a predictor of the HLA-DR nadir. CONCLUSION: VLBW infants are in a state of immunodepression postnatally. This immunodepression correlated with GA and was a predisposing factor for late infections. The downregulation of HLA-DR during RDS probably indicates an RDS-induced antigen load on the immune system.


Subject(s)
HLA-DR Antigens/blood , Immune Tolerance , Infant, Extremely Premature/immunology , Infant, Premature/immunology , Infant, Very Low Birth Weight/immunology , Monocytes/immunology , Biomarkers/blood , Case-Control Studies , Down-Regulation , Female , Flow Cytometry , Gestational Age , Humans , Infant, Extremely Premature/blood , Infant, Newborn , Infant, Premature/blood , Infant, Very Low Birth Weight/blood , Inflammation Mediators/blood , Intensive Care Units, Neonatal , Interleukin-6/blood , Male , Opportunistic Infections/blood , Opportunistic Infections/immunology , Prospective Studies , Respiratory Distress Syndrome, Newborn/blood , Respiratory Distress Syndrome, Newborn/immunology , Risk Factors , Time Factors
17.
Acta Paediatr ; 101(8): e373-7, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22537137

ABSTRACT

AIMS: Loss of specific immunity follows allogeneic haematopoietic stem cell transplantation (HSCT) in the majority of cases. Responses to (re)vaccinations can be used as indicators of a functional immunological recovery. METHODS: Twenty-three paediatric recipients of HSCT were enrolled in a single centre setting and responses to scheduled immunizations analysed. RESULTS: Immunity to vaccine-preventable diseases was impaired post HSCT, but (re)vaccinations induced protective responses in 59-100%, depending on the vaccine, regardless of prior graft-versus-host disease (GVHD) history. CONCLUSION: Despite the marked impact of moderate to severe chronic prior GVHD on both the qualitative and quantitative T-cell recovery post allogenic HSCT, most paediatric recipients of allogeneic stem cell grafts appear to attain protective antibody levels after immunization.


Subject(s)
Hematopoietic Stem Cell Transplantation , Postoperative Care , Transplantation Immunology , Vaccination , Vaccines/immunology , Adolescent , Antibodies, Bacterial/blood , Antibodies, Viral/blood , Child , Child, Preschool , Diphtheria Toxin/immunology , Flow Cytometry , Graft vs Host Disease/immunology , Haemophilus influenzae type b/immunology , Humans , Measles virus/immunology , Poliovirus/immunology , Prospective Studies , Streptococcus pneumoniae/immunology , Tetanus Toxin/immunology , Young Adult
18.
Leuk Lymphoma ; 53(10): 1920-8, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22397313

ABSTRACT

There is no consensus on treatment strategies for elderly patients with mantle cell lymphoma (MCL). In this prospective phase II study we investigated whether the poor outcome could be improved, with reasonable toxicity, by prolonging the immunochemotherapy. Ten cycles of alternating cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP)/cytarabine (AraC) with eight doses of rituximab (R) were given as induction. The potential synergism of intermediate-dose AraC and fludarabine was tested in cycles 6-8. Induction was followed by bimonthly rituximab maintenance for 2 years. The median age of the 60 included patients was 74 years, and the Mantle Cell Lymphoma International Prognostic Index (MIPI) was intermediate or high risk in 98% of the patients. The overall response rate was 95% (complete response/complete response unconfirmed 87%). The response of 11 patients improved with cycles 6-8 (R-fludarabine-AraC). Progression-free survival was 70% and overall survival 72% at 4 years, respectively. Treatment related mortality was 2%. Severe infections were rare, with only one grade 4 infection. More dose reductions were needed during fludarabine-containing courses as compared to R-AraC. In 20 patients a transient grade 4 neutropenia without severe infections was recorded during maintenance. In conclusion, elderly patients with MCL can be treated relatively intensively with acceptable toxicity.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma, Mantle-Cell/drug therapy , Aged , Aged, 80 and over , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Antibodies, Monoclonal, Murine-Derived/adverse effects , Antibodies, Monoclonal, Murine-Derived/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cyclophosphamide/adverse effects , Cyclophosphamide/therapeutic use , Cytarabine/administration & dosage , Doxorubicin/adverse effects , Doxorubicin/therapeutic use , Female , Humans , Induction Chemotherapy , Lymphoma, Mantle-Cell/mortality , Maintenance Chemotherapy , Male , Prednisone/adverse effects , Prednisone/therapeutic use , Rituximab , Treatment Outcome , Vidarabine/administration & dosage , Vidarabine/analogs & derivatives , Vincristine/adverse effects , Vincristine/therapeutic use
19.
Acta Paediatr ; 101(4): 403-9, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22107344

ABSTRACT

AIM: In preterm infants, inflammation and intra-alveolar fibrin formation characterize respiratory distress syndrome (RDS). Tissue factor (TF) is a link between inflammation and coagulation pathways. We investigated the relationship between TF and cytokines in preterm infants to gain information of the role of TF in the inflammatory response. METHODS: We measured TF in plasma and in tracheal aspirates and analysed TF on monocytes by flow cytometry and 13 cytokines from plasma, in 56 preterm infants (birthweight 600-1500 g) during their first week. RESULTS: Plasma TF increased and peaked on day 3 and correlated with both RDS and inversely with paO2/FIO2. On day 1, TF in tracheal aspirates was 10-fold higher than in plasma and correlated with plasma TF (4888 vs. 506 pg/mL, R = 0.692, p = 0.013, n = 12). Of main pro-inflammatory cytokines, plasma TF correlated post-natally with IL-8 and IL-6 but not with IL-1 or TNF-α. CONCLUSIONS: Respiratory morbidity associates with high TF in lungs and plasma. In sick newborn infants, upregulation of TF may be mediated by IL-6 and IL-8. High TF and pro-inflammatory cytokines may together participate in the pathogenesis of pulmonary and extrapulmonary injury in preterm infants through pro-inflammatory mechanisms.


Subject(s)
Bronchopulmonary Dysplasia/metabolism , Lung/metabolism , Plasma/chemistry , Respiratory Distress Syndrome, Newborn/metabolism , Thromboplastin/analysis , Bronchopulmonary Dysplasia/epidemiology , Cytokines/blood , Female , Humans , Infant, Newborn , Infant, Premature , Inflammation , Male , Morbidity , Respiratory Distress Syndrome, Newborn/epidemiology , Thromboplastin/metabolism
20.
Neonatology ; 100(3): 241-7, 2011.
Article in English | MEDLINE | ID: mdl-21701213

ABSTRACT

BACKGROUND: Preeclampsia and preterm labor often underlie preterm birth, and are associated with maternal inflammation. In preterm infants, respiratory distress syndrome (RDS) and mechanical ventilation are associated with systemic inflammation. OBJECTIVE: We aimed to study whether early-onset preeclampsia or preterm labor modulate the systemic inflammation affecting preterm infants with RDS. METHODS: We recruited mechanically ventilated infants with gestational ages <32 weeks; 11 infants were born after early-onset preeclampsia and 25 after preterm labor. Blood was drawn during postnatal days 1-7, and the mean values of days 1-2, 3-4 and 5-6 were used. Phagocyte CD11b expression was analyzed with flow cytometry, and plasma C-reactive protein (CRP) concentrations with immunoturbidimetry. RESULTS: As compared with infants born after preterm labor, infants born after early-onset preeclampsia had higher CD11b expression on days 1-6 on both neutrophils and monocytes. In addition, infants born after early-onset preeclampsia had higher CRP concentrations on days 2-6 (all p < 0.05). CONCLUSIONS: As compared with infants born after preterm labor to mothers without preeclampsia, infants born after early-onset preeclampsia presented with a stronger postnatal systemic inflammatory reaction. Antenatal exposure to preeclampsia may induce fetal leukocyte priming and regulation of inflammation, and thereby modify postnatal inflammatory reactions and morbidity.


Subject(s)
Infant, Premature , Inflammation/diagnosis , Obstetric Labor, Premature/diagnosis , Pre-Eclampsia/diagnosis , Premature Birth/diagnosis , Respiration, Artificial/adverse effects , Adult , Birth Weight , C-Reactive Protein/analysis , CD11b Antigen/metabolism , Female , Fetal Diseases , Gestational Age , Humans , Infant, Newborn , Inflammation/etiology , Inflammation/metabolism , Leukocyte Count , Monocytes/metabolism , Neutrophils/metabolism , Obstetric Labor, Premature/physiopathology , Phagocytes/metabolism , Pre-Eclampsia/physiopathology , Pregnancy , Premature Birth/physiopathology , Respiratory Distress Syndrome, Newborn/etiology
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