Necrotising soft tissue infections. / Nekrotiserende bløtdelsinfeksjoner.

Necrotising soft tissue infections can affect the skin, subcutaneous tissue, superficial fascia, deep fascia and musculature. The infections are severe, they spread quickly and can result in extensive tissue loss. Although rare, morbidity and mortality rates are high. Early clinical identification is crucial for the outcome, and rapid infection control through surgery and targeted antibiotic treatment is needed to save lives. Few prospective clinical trials have been conducted for the treatment of this type of infection. Specific challenges include rapid identification of the condition and the uncertain efficacy of the various treatment options. In this clinical review article, we describe clinical characteristics, diagnostics and treatment.

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.

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.

Scoring systems for early detection of sepsis on the ward. / Skåringsverktøy for tidlig oppdagelse av sepsis på sengepost.

BACKGROUND: Sepsis is one of the most common causes of death in Norwegian hospitals. The condition is often overlooked with treatment being delayed. Scoring systems to detect patients with sepsis have mostly been studied in emergency departments and more rarely on wards. The objective of this study was to investigate the ability of various clinical scoring systems to identify sepsis in patients on wards. MATERIAL AND METHOD: The ability of the scoring systems SIRS (Systemic Inflammatory Response Syndrome), qSOFA (quick Sequential Organ Failure Assessment) and NEWS2 (National Early Warning Score 2) to identify patients with sepsis was compared in a study of adult patients with clinically suspected severe infection on wards at Haukeland University Hospital in the period March-December 2019. The diagnosis of sepsis was made based on an increase in SOFA (Sequential Organ Failure Assessment) score of 2 or more in the first 24 hours after inclusion. RESULTS: 89 patients with suspected new onset of severe infection were identified. Sepsis was diagnosed in 55 of these patients. SIRS had a sensitivity of 82 % and a specificity of 6 % in diagnosing sepsis, qSOFA had a sensitivity of 20 % and a specificity of 97 %, while NEWS2 with a threshold of an aggregate score ≥ 5 and/or 3 in a single parameter had a sensitivity of 96 % and a specificity of 59 %. Oxygen saturation with a threshold of 95 % was the most sensitive measurement for sepsis. INTERPRETATION: NEWS2 was better suited than qSOFA and SIRS for early detection of sepsis on wards.

Clinical Characteristics and Histopathology in Suspected Necrotizing Soft Tissue Infections.

Background: Necrotizing soft tissue infections (NSTIs) are severe diseases with high morbidity and mortality. The diagnosis is challenging. Several guidelines recommend tissue biopsies as an adjunct diagnostic in routine management, but neither biopsy sampling nor classification is standardized or validated. We studied the quality of tissue biopsy examination as part of routine diagnostics in NSTIs. Methods: This was a retrospective cohort study of adult patients undergoing surgery due to suspected NSTIs in which tissue biopsy was taken as part of routine management. Clinical data were reviewed. The biopsies were evaluated according to a proposed histopathologic classification system and independently assessed by 2 pathologists. Interrater reliability and diagnostic accuracy were determined. Results: Tissue biopsies from 75 patients were examined, 55 NSTIs and 20 non-NSTIs cases. The cohorts were similar in clinical characteristics. Interrater reliability for histopathologic staging was moderate (0.53) and fair (0.37) for diagnosis. The sensitivity of histologic diagnosis was 75% and the specificity 80%. The positive predictive value was 91% and the negative predictive value 53%. Necrotizing Infection Clinical Composite Endpoint (NICCE) success was associated with a more severe histological stage, achieved by 42% and 71% of the cases in stage 1 and 2, respectively (P = .046). Conclusions: Our findings suggest that tissue biopsies have low clinical accuracy. The interrater reliability among experienced pathologists is only fair to moderate. A histopathologically more severe stage was associated with favorable outcome. These findings discourage the use of histopathologic evaluation as part of contemporary management of patients with suspected NSTI.

Concomitant Hemophagocytic Lymphohistiocytosis and Cytomegalovirus Disease: A Case Based Systemic Review.

Background: Hemophagocytic lymphohistiocytosis (HLH) is an immune mediated life-threatening condition. It is driven by an overactivation of the immune system and causes inflammatory tissue damage potentially leading to organ failure and death. Primary HLH is caused by genetic mutations, while secondary HLH is triggered by external factors. Viral infections are a well-known cause of secondary HLH. Cytomegalovirus (CMV) is a virus in the herpes family known to cause HLH in rare cases. Methods: We report a recent case of CMV-induced HLH, followed by a systematic review of described cases of this rare disease entity, through a structured search in the medical database PubMed. All articles were assessed on a predetermined set of inclusion criteria. Results: A total of 74 patients (age > 18 years) with CMV-related HLH were identified, 29 men, 42 women, and three patients with unspecified gender. Median age was 37.5 years (range 18-80). Sixty-six patients (88%) had one or more comorbid conditions and 22 patients (30%) had inflammatory bowel disease (IBD), the most frequent comorbidity. Forty patients (54%) received some form of immunomodulating treatment prior to HLH development. The general treatment approach was in general dual, consisting of antiviral treatment and specific immunomodulating HLH treatment approaches. Treatment outcome was at 77% survival, while 23% had fatal outcome. Conclusion: The findings highlight the importance of early diagnostic work up and treatment intervention. Ability to recognize the characteristic clinical traits and perform specific HLH diagnostic workup are key factors to ensure targeted diagnostic work and treatment intervention for this patient group.

MicroRNA serum profiles and chronic graft-versus-host disease.

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.

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.

COVID-19 myocarditis and postinfection Bell's palsy.

Here we present the case of a 37-year-old previously healthy man who developed fever, headache and a unilateral, painful neck swelling while working offshore. He had no known contact with anyone with COVID-19; however, due to the ongoing pandemic, a nasopharyngeal swab was performed, which was positive for the virus. After transfer to hospital for assessment his condition rapidly deteriorated, requiring admission to intensive care for COVID-19 myocarditis. One week after discharge he re-presented with unilateral facial nerve palsy. Our case highlights an atypical presentation of COVID-19 and the multifaceted clinical course of this still poorly understood disease.

Febrile Neutropenia in Acute Leukemia. Epidemiology, Etiology, Pathophysiology and Treatment.

Acute leukemias are a group of aggressive malignant diseases associated with a high degree of morbidity and mortality. An important cause of both the latter is infectious complications. Patients with acute leukemia are highly susceptible to infectious diseases due to factors related to the disease itself, factors attributed to treatment, and specific individual risk factors in each patient. Patients with chemotherapy-induced neutropenia are at particularly high risk, and microbiological agents include viral, bacterial, and fungal agents. The etiology is often unknown in infectious complications, although adequate patient evaluation and sampling have diagnostic, prognostic and treatment-related consequences. Bacterial infections include a wide range of potential microbes, both Gram-negative and Gram-positive species, while fungal infections include both mold and yeast. A recurring problem is increasing resistance to antimicrobial agents, and in particular, this applies to extended-spectrum beta-lactamase resistance (ESBL), Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE) and even carbapenemase-producing Enterobacteriaceae (CPE). International guidelines for the treatment of sepsis in leukemia patients include the use of broad-spectrum Pseudomonas-acting antibiotics. However, one should implant the knowledge of local microbiological epidemiology and resistance conditions in treatment decisions. In this review, we discuss infectious diseases in acute leukemia with a major focus on febrile neutropenia and sepsis, and we problematize the diagnostic, prognostic, and therapeutic aspects of infectious complications in this patient group. Meticulously and thorough clinical and radiological examination combined with adequate microbiology samples are cornerstones of the examination. Diagnostic and prognostic evaluation includes patient review according to the multinational association for supportive care in cancer (MASCC) and sequential organ failure assessment (SOFA) scoring system. Antimicrobial treatments for important etiological agents are presented. The main challenge for reducing the spread of resistant microbes is to avoid unnecessary antibiotic treatment, but without giving to narrow treatment to the febrile neutropenic patient that reduce the prognosis.

Inflammatory Mediator Profiles Differ in Sepsis Patients With and Without Bacteremia.

Systemic levels of cytokines are altered during infection and sepsis. This prospective observational study aimed to investigate whether plasma levels of multiple inflammatory mediators differed between sepsis patients with and those without bacteremia during the initial phase of hospitalization. A total of 80 sepsis patients with proven bacterial infection and no immunosuppression were included in the study. Plasma samples were collected within 24 h of hospitalization, and Luminex® analysis was performed on 35 mediators: 16 cytokines, six growth factors, four adhesion molecules, and nine matrix metalloproteases (MMPs)/tissue inhibitors of metalloproteinases (TIMPs). Forty-two patients (52.5%) and 38 (47.5%) patients showed positive and negative blood cultures, respectively. There were significant differences in plasma levels of six soluble mediators between the two "bacteremia" and "non-bacteremia" groups, using Mann-Whitney U test (p < 0.0014): tumor necrosis factor alpha (TNFα), CCL4, E-selectin, vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), and TIMP-1. Ten soluble mediators also significantly differed in plasma levels between the two groups, with p-values ranging between 0.05 and 0.0014: interleukin (IL)-1ra, IL-10, CCL2, CCL5, CXCL8, CXCL11, hepatocyte growth factor, MMP-8, TIMP-2, and TIMP-4. VCAM-1 showed the most robust results using univariate and multivariate logistic regression. Using unsupervised hierarchical clustering, we found that TNFα, CCL4, E-selectin, VCAM-1, ICAM-1, and TIMP-1 could be used to discriminate between patients with and those without bacteremia. Patients with bacteremia were mainly clustered in two separate groups (two upper clusters, 41/42, 98%), with higher levels of the mediators. One (2%) patient with bacteremia was clustered in the lower cluster, which compromised most of the patients without bacteremia (23/38, 61%) (χ2 test, p < 0.0001). Our study showed that analysis of the plasma inflammatory mediator profile could represent a potential strategy for early identification of patients with bacteremia.

Patients with Treatment-Requiring Chronic Graft versus Host Disease after Allogeneic Stem Cell Transplantation Have Altered Metabolic Profiles due to the Disease and Immunosuppressive Therapy: Potential Implication for Biomarkers.

Chronic graft versus host disease (cGVHD) is a common long-term complication after allogeneic hematopoietic stem cell transplantation. The objective of our study was to compare the metabolic profiles for allotransplant recipients and thereby identify metabolic characteristics of patients with treatment-requiring cGVHD. The study included 51 consecutive patients (29 men and 22 women; median age: 44 years, range: 15-66 years) transplanted with peripheral blood stem cells derived from human leukocyte antigen-matched family donors. All serum samples investigated by global metabolomic profiling were collected approximately 1 year posttransplant (median 358 days). Thirty-one of the 51 patients (61%) had cGVHD 1 year posttransplant. The affected organs were (number of patients) liver/bile duct (23), eyes (15), gastrointestinal tract (14), skin (13), mouth (10), lungs (3), and urogenital tract (1). We compared the metabolic profile for patients with and without cGVHD, and a Random Forrest Classification Analysis then resulted in 75% accuracy in differentiating the two groups. The 30 top-ranked metabolites from this comparison included increased levels of bile acids, several metabolites from the cytokine-responsive kynurenine pathway for tryptophan degradation, pro-inflammatory lipid metabolites, phenylalanine and tyrosine metabolites derived from the gut microbial flora, and metabolites reflecting increased oxidative stress. However, nine of these 30 top-ranked metabolites were probably altered due to cyclosporine or steroid treatment, and we therefore did a hierarchical clustering analysis including all 51 patients but only based on the other 21 cGVHD-specific metabolites. This analysis identified three patient subsets: one cluster included mainly patients without cGVHD and had generally low metabolite levels; another cluster included mainly patients with cGVHD (most patients with at least three affected organs) and high metabolite levels, and the last intermediate group including cGVHD patients with limited organ involvement. We conclude that allotransplant recipients with cGVHD have an altered metabolic profile caused both by the disease and its immunosuppressive treatment.

Coordination of Metabolism and Virulence Factors Expression of Extraintestinal Pathogenic Escherichia coli Purified from Blood Cultures of Patients with Sepsis.

One of the trademarks of extraintestinal pathogenic Escherichia coli is adaptation of metabolism and basic physiology to diverse host sites. However, little is known how this common human pathogen adapts to permit survival and growth in blood. We used label-free quantitative proteomics to characterize five E. coli strains purified from clinical blood cultures associated with sepsis and urinary tract infections. Further comparison of proteome profiles of the clinical strains and a reference uropathogenic E. coli strain 536 cultivated in blood culture and on two different solid media distinguished cellular features altered in response to the pathogenically relevant condition. The analysis covered nearly 60% of the strains predicted proteomes, and included quantitative description based on label-free intensity scores for 90% of the detected proteins. Statistical comparison of anaerobic and aerobic blood cultures revealed 32 differentially expressed proteins (1.5% of the shared proteins), mostly associated with acquisition and utilization of metal ions critical for anaerobic or aerobic respiration. Analysis of variance identified significantly altered amounts of 47 proteins shared by the strains (2.7%), including proteins involved in vitamin B6 metabolism and virulence. Although the proteomes derived from blood cultures were fairly similar for the investigated strains, quantitative proteomic comparison to the growth on solid media identified 200 proteins with substantially changed levels (11% of the shared proteins). Blood culture was characterized by up-regulation of anaerobic fermentative metabolism and multiple virulence traits, including cell motility and iron acquisition. In a response to the growth on solid media there were increased levels of proteins functional in aerobic respiration, catabolism of medium-specific carbon sources and protection against oxidative and osmotic stresses. These results demonstrate on the expressed proteome level that expression of extraintestinal virulence factors and overall cellular metabolism closely reflects specific growth conditions. Data are available via ProteomeXchange with identifier PXD002912.

Altered plasma levels of cytokines, soluble adhesion molecules and matrix metalloproteases in venous thrombosis.

BACKGROUND/AIM: Recent studies have emphasized the importance of the inflammatory response mediated by monocyte and neutrophil activation in deep venous thrombosis (DVT); we therefore investigated whether this response was reflected in the plasma profile of inflammatory mediators in patients with suspected DVT. METHODS: We included a group of 169 consecutive patients admitted to hospital from the primary health care service with suspected lower limb DVT. Plasma levels of 43 mediators were examined for a cohort of 89 consecutive patients and 20 healthy controls by Luminex multiplex analyses, i.e. 13 interleukins, 3 immunomodulatory cytokines, 8 chemokines, 8 growth factors, 3 adhesion molecules and 8 matrix metalloproteases. Selected mediators were analyzed for a second cohort of 80 consecutive patients. RESULTS: Thirty-five of 169 (21%) of referred patients were diagnosed with DVT. Only P-selectin (p<0.0001), vascular cell adhesion protein 1 (VCAM-1, p=0.0009), matrix metalloprotease 8 (MMP-8, p=0.0151) and hepatocyte growth factor (HGF, p=0.0415) differed significantly when comparing patients with and without DVT. When comparing DVT patients with healthy controls we observed significant differences for several mediators, where P-selectin (p=0.0009), VCAM-1 (p<0.0001), all the MMPs (all p<0.0014) and HGF (p<0.0001) showed the strongest significant differences. Unsupervised hierarchical clustering analyses based on biomarkers showing differences between patients with and without DVT could be used to identify patient subsets that differed significantly in DVT frequency. CONCLUSION: Plasma biomarker profiling of selected soluble mediators can be used to identify subsets among patients with suspected lower limb thrombosis that differ significantly in their frequencies of DVT.

Systemic levels of the endothelium-derived soluble adhesion molecules endocan and E-selectin in patients with suspected deep vein thrombosis.

The initial evaluation of patients with suspected deep vein thrombosis includes the use of biomarkers reflecting activation of the coagulation system. However, the thromboembolic process and neighboring inflammatory responses also affect endothelial cells, and endothelial cell markers may therefore be altered by the disease. In the present population-based single-center study, we investigated the plasma levels of the endothelium-specific biomarkers soluble E-selectin and endocan in a consecutive and unselected group of 120 patients admitted to hospital for suspected deep vein thrombosis. Blood samples were collected when patients arrived at the hospital. DVT patients showed evidence for an acute phase reaction with increased serum C-reactive protein levels, but this was similar to many other patients admitted with suspected but not verified thrombosis. Plasma endocan and E-selectin levels did not differ between patients with thrombosis, healthy controls and the patients without verified thrombosis (i.e. patients with other causes of their symptoms, including various inflammatory and non-inflammatory conditions). However, the combined use of endothelial biomarkers, C-reactive protein and D-dimer could be used to identify patient subsets with different frequencies of venous thrombosis. Thus, analysis of plasma biomarker profiles including endothelial cell markers may be helpful in the initial evaluation of patients with deep vein thrombosis.

Stem cell mobilization and harvesting by leukapheresis alters systemic cytokine levels in patients with multiple myeloma.

BACKGROUND AIMS: Stem cell mobilization and harvesting by peripheral blood leukapheresis in patients with myeloma can alter plasma levels of certain cytokines. In the present study, we investigated the effects of these interventions on a larger group of cytokines. METHODS: Plasma cytokine levels were determined in 15 patients with myeloma who were undergoing peripheral blood stem cell harvesting, and we compared the patients with healthy donors who were undergoing platelet apheresis. RESULTS: Several cytokines showed altered levels in patients with myeloma when examined after chemotherapy plus granulocyte colony-stimulating factor-induced stem cell mobilization. The most striking effect was increased levels of several CCL (CCL2/3/4) and CXCL (CXCL5/8/10/11) chemokines as well as increased thrombopoietin, interleukin 1 receptor antagonist, interleukin-4, granulocyte colony-stimulating factor and hepatocyte growth factor. Stem cell harvesting by apheresis altered the plasma levels of several mediators (CD40 ligand, interleukin 1 receptor antagonist, CCL5 and CXCL5/8/10/11). Apheresis in patients with myeloma had divergent effects on these chemokine levels, although they were all still significantly higher than for healthy individuals. Thrombapheresis in healthy individuals had only minor effects on plasma cytokine levels. Stem cell graft supernatants showed high levels of several cytokines, especially CCL and CXCL chemokines. Analyses of chemokine profiles in pre-apheresis plasma and graft supernatants suggested that such profiling can be used to detect prognostically relevant differences between patients. CONCLUSIONS: Our results demonstrate that patients with myeloma have an altered cytokine network during stem cell mobilization, and the network is further altered during stem cell harvesting by leukapheresis. These treatment- or procedure-induced alterations involve several mediators known to affect myeloma cell proliferation, migration and survival.

Targeted anti-leukemic therapy as disease-stabilizing treatment for acute myeloid leukemia relapse after allogeneic stem cell transplantation: Will it be possible to combine these strategies with retransplantation or donor lymphocyte infusions?

Allogeneic stem cell transplantation is commonly used in the treatment of high-risk acute myeloid leukemia (AML). This intensive treatment has a high early transplant-related mortality, and an additional significant cause of death in these patients is later AML relapse. Retransplantation can be considered for a minority of patients, but only 10-20% of selected patients then achieve long-term survival. Donor lymphocyte infusion (DLI) has an antileukemic effect, but the effect of this treatment usually lasts for only 3-4 months. A possible strategy to improve the prognosis could be to combine antileukemic T-cell therapy (i.e. DLI) with AML-targeting therapy. Several aspects have to be considered for such approaches: (i) the therapy should have immunomodulatory rather than immunosuppressive effects; (ii) the regimen should have a low hematological toxicity to preserve residual normal bone marrow function; and (iii) the treatment should have a documented antileukemic effect. DLI elicit both graft versus host and graft versus leukemia effects, and could be added to pharmacological treatment. Epigenetic targeting should be considered in these patients because both demethylating agents as well as the histone deacetylase inhibitors have documented antileukemic effects and have a relatively low hematological toxicity. Other drugs to consider are thalidomide, lenalidomide, antiangiogenic agents, tyrosine kinase inhibitors and heat shock protein 90 inhibitors, which all have both antileukemic and immunomodulatory effects. Relatively few clinical studies are available for patients with this high-risk disease. The designs of future clinical trials have to carefully consider the antileukemic and immunomodulatory effects together with the risk of especially hematological toxicity.