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Contains fulltext : 126184.pdf (Publisher’s version ) (Closed access) Timing of treatment for invasive fungal disease (IFD) is critical for making appropriate clinical decisions. Historically, many centres have treated at-risk patients prior to disease detection to try to prevent fungal colonization or in response to antibiotic-resistant fever. Many studies have indicated that a diagnostic-driven approach, using radiological tests and biomarkers to guide treatment decisions, may be a more clinically relevant and cost-effective approach. The Invasive Fungal Infections Cooperative Group of the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) defined host clinical and mycological criteria for proven, probable and possible classes of IFD, to aid diagnosis. However, some patients at risk of IFD do not meet EORTC/MSG criteria and have been termed Groups B (patients with persistent unexplained febrile neutropenia) and C (patients with non-definitive signs of IFD) in a study by Maertens et al. (Haematologica 2012; 97: 325-7). Consequently, we considered the most appropriate triggers (clinical or radiological signs or biomarkers) for treatment of all patient groups, especially the unclassified B and C groups, based on our clinical experience. For Group C patients, additional diagnostic testing is recommended before a decision to treat, including repeat galactomannan tests, radiological scans and analysis of bronchoalveolar lavage fluid. Triggers for stopping antifungal treatment were considered to include resolution of all clinical signs and symptoms. For Group B patients, it was concluded that better definition of risk factors predisposing patients to fungal infection and the use of more sensitive diagnostic tests are required to aid treatment decisions and improve clinical outcomes. 01 november 2013

Item does not contain fulltext Recombinant activated factor VII (rFVIIa) and plasma-derived factor VII (pdFVII) are used to prevent bleedings in severe FVII deficient patients, despite their short half-lifes. It is suggested that FVII levels of 15-20IU/dL are sufficient to maintain hemostasis. We analyzed the pharmacodynamic effects of FVII substitution therapy in the Nijmegen Hemostasis Assay (NHA) that simultaneously measures thrombin and plasmin generation. Ten severe FVII deficient patients were treated with 20mug/kg rFVIIa or 25IU/kg pdFVII in a cross-over design. Thrombin generation lag-time (TG-LT) was identified as an effect-response parameter. Pharmacodynamic analysis using a maximum effect model showed 50% reduction of the TG-LT effect at ~2IU/dL FVII activity for both rFVIIa and pdFVII. The FVII activity to obtain TG-LT comparable to the upper limit of normal range in healthy controls (4min) was given by the effective concentration (ECnormal), showing sufficient hemostasis at 3-4IU/dL FVII activity. No association was seen between FVII activity and other thrombin or plasmin generation parameters as measured by NHA. In conclusion, 3-4IU/dL FVII activity seems sufficient to maintain hemostasis in patients with severe FVII deficiency during prophylaxis. These data may suggest a potential value for measurement of TG-LT in the monitoring of FVII(a) therapy.

Item does not contain fulltext In the last decade, there have been some favourable developments in the management of invasive fungal diseases, including definitions, diagnosis and drugs for treatment. This has led to a gradual awareness that caring for patients at risk need not solely rely on an empirical therapy approach but that a degree of individualisation is possible, provided certain prerequisites are met. 01 juli 2013

Background The treatment-related burden for patients undergoing hematopoietic stem cell transplantation (HSCT) may be relieved by physical exercises. Purpose The purpose of this study was to summarize and analyze the evidence provided by randomized controlled trials (RCTs) on physical exercise interventions among patients with cancer undergoing HSCT. Data Sources PubMed, CINAHL, EMBASE, the Cochrane Library, and PEDro were searched for relevant RCTs up to October 1, 2011. Study Selection Two reviewers screened articles on inclusion criteria and indentified relevant RCTs. Data Extraction Two authors assessed the selected articles for risk of bias. Data extraction was performed by 1 reviewer. Meta-analyses were undertaken to estimate the outcomes quality of life (QOL), psychological well-being and distress, and fatigue. Data Synthesis Eleven studies were included, with study populations consisting of recipients undergoing either an allogeneic or autologous HSCT (n=734). Four studies had low risk of bias. The exercise interventions were performed before, during, and after hospitalization for the HSCT. Different exercise programs on endurance, resistance and/or activities of daily living training, progressive relaxation, and stretching were used. Meta-analyses showed that exercise during hospitalization led to a higher QOL (weighted mean difference=8.72, 95% confidence interval=3.13, 14.31) and less fatigue (standardized mean difference=0.53, 95% confidence interval=0.16, 0.91) in patients with an allogeneic HSCT at the moment of discharge from the hospital. No marked effects were found for psychological well-being and distress. Individual study results suggested significant positive effects on QOL, fatigue, psychological well-being and distress, and physical functioning. Limitations Prevalent shortcomings in the included studies were the heterogeneity among studies and the lack of blinding of participants, personnel, and outcome assessment. Conclusions The results suggest that recipients of HSCT may benefit from physical exercise.

Contains fulltext : 117669.pdf (Publisher’s version ) (Open Access) The efficacy of voriconazole is potentially compromised by considerable pharmacokinetic variability. There are increasing insights into voriconazole concentrations that are safe and effective for treatment of invasive fungal infections. Therapeutic drug monitoring is increasingly advocated. Software to aid in the individualization of dosing would be an extremely useful clinical tool. We developed software to enable the individualization of voriconazole dosing to attain predefined serum concentration targets. The process of individualized voriconazole therapy was based on concepts of Bayesian stochastic adaptive control. Multiple-model dosage design with feedback control was used to calculate dosages that achieved desired concentration targets with maximum precision. The performance of the software program was assessed using the data from 10 recipients of an allogeneic hematopoietic stem cell transplant (HSCT) receiving intravenous (i.v.) voriconazole. The program was able to model the plasma concentrations with a high level of precision, despite the wide range of concentration trajectories and interindividual pharmacokinetic variability. The voriconazole concentrations predicted after the last dosages were largely concordant with those actually measured. Simulations provided an illustration of the way in which the software can be used to adjust dosages of patients falling outside desired concentration targets. This software appears to be an extremely useful tool to further optimize voriconazole therapy and aid in therapeutic drug monitoring. Further prospective studies are now required to define the utility of the controller in daily clinical practice.

Contains fulltext : 117729.pdf (Publisher’s version ) (Open Access) To evaluate the relevance of directing antigen-specific CD4(+) T helper cells as part of effective anticancer immunotherapy, we investigated the immunologic and clinical responses to vaccination with dendritic cells (DC) pulsed with either MHC class I (MHC-I)-restricted epitopes alone or both MHC class I and II (MHC-I/II)-restricted epitopes. We enrolled 33 stage III and IV HLA-A*02:01-positive patients with melanoma in this study, of whom 29 were evaluable for immunologic response. Patients received intranodal vaccinations with cytokine-matured DCs loaded with keyhole limpet hemocyanin and MHC-I alone or MHC-I/II-restricted tumor-associated antigens (TAA) of tyrosinase and gp100, depending on their HLA-DR4 status. In 4 of 15 patients vaccinated with MHC-I/II-loaded DCs and 1 of 14 patients vaccinated with MHC-I-loaded DCs, we detected TAA-specific CD8(+) T cells with maintained IFN-gamma production in skin test infiltrating lymphocyte (SKIL) cultures and circulating TAA-specific CD8(+) T cells. If TAA-specific CD4(+) T-cell responses were detected in SKIL cultures, it coincided with TAA-specific CD8(+) T-cell responses. In 3 of 13 patients tested, we detected TAA-specific CD4(+)CD25(+)FoxP3(-) T cells with high proliferative capacity and IFN-gamma production, indicating that these were not regulatory T cells. Vaccination with MHC-I/II-loaded DCs resulted in improved clinical outcome compared with matched control patients treated with dacarbazine (DTIC), median overall survival of 15.0 versus 8.3 months (P = 0.089), and median progression-free survival of 5.0 versus 2.8 months (P = 0.0089). In conclusion, coactivating TAA-specific CD4(+) T-helper cells with DCs pulsed with both MHC class I and II-restricted epitopes augments TAA-specific CD8(+) T-cell responses, contributing to improved clinical responses. Cancer Res; 73(1); 19-29. (c)2012 AACR.

This study was aimed to investigate whether any association could be found between the presence of an inflamed and infected periodontium (e.g., gingivitis and periodontitis) and the development of bacteremia during neutropenia following allogeneic hematopoietic stem cell transplantation (HSCT). Eighteen patients underwent a periodontal examination before HSCT. Patients were classified as periodontally healthy [all periodontal pocket depths (PPD) a parts per thousand currency signaEuro parts per thousand 4 mm and bleeding on probing (BOP) a parts per thousand currency signaEuro parts per thousand 10 %) or as having gingivitis/periodontitis (PPD a parts per thousand yenaEuro parts per thousand 4 mm and BOP > 10 %]. Oral mucositis (OM) was scored using the daily mucositis score. Blood cultures were taken at least twice weekly. Five patients were periodontally healthy, while 13 patients had gingivitis or periodontitis. Twelve patients (67 %) developed bacteremia during neutropenia, of which 11 patients (61 %) had one or more episodes of bacteremia due to coagulase-negative staphylococci (CONS, most often Staphylococcus epidermidis) or to oral viridans streptococci (OVS), or both. Patients with gingivitis/periodontitis more often had bacteremia than those with a healthy periodontium (p = 0.047), and BOP was associated with bacteremia (p = 0.049). All patients developed ulcerative OM, but its severity and duration were not associated with bacteremia. OM duration and the length of stay in the hospital were strongly correlated (R = 0.835, p a parts per thousand currency signaEuro parts per thousand 0.001). This study indicates that periodontal infections may contribute to the risk of developing OVS and CONS bacteremia during neutropenia following HSCT. While our results point to the importance of periodontal evaluation and management before HSCT, further studies on periodontal contribution to systemic infectious complications are warranted

Item does not contain fulltext OBJECTIVES: The underlying mechanism for amphotericin B-induced acute kidney injury (AKI) remains poorly understood and may be immunologically mediated. We assessed whether the development of nephrotoxicity is linked to a distinct cytokine profile in patients receiving amphotericin B deoxycholate (AmBD). PATIENTS AND METHODS: In 58 patients who received AmBD, circulating serum interleukin (IL)-6, IL-8 and IL-10 were measured at baseline, week 1 and week 2 of antifungal treatment and correlated to the development of renal impairment. The Cox proportional hazards model approach was adopted for analysis. RESULTS: The P value was 0.026 for the overall effect of IL-6 on time to development of AKI. An increasing or non-receding IL-6 trend by week 1 of AmBD treatment (followed by a decreasing or non-receding IL-6 trend from week 1 to week 2) correlated with an increased likelihood of nephrotoxicity [hazard ratio (HR) 6.93, P value 0.005 and HR 3.46, P value 0.035, respectively]. Similarly, persistently increasing IL-8 levels were linked to a 3.84-fold increased likelihood of AKI. CONCLUSIONS: In patients receiving AmBD, persistence of an elevated pro-inflammatory cytokine milieu is associated with a predisposition to drug-related kidney injury.

Background: High von Willebrand factor (VWF) levels are an established risk factor for arterial thrombosis, including coronary heart disease and ischemic stroke. It has been hypothesized that von Willebrand disease (VWD) patients are protected against arterial thrombosis; however, this has never been confirmed in clinical studies. Objectives: To investigate the prevalence of arterial thrombosis in VWD patients relative to the general population. Patients/Methods: We included 635 adult patients with VWF levels ≤ 30 U dL-1, aged 16-85 years, from the nationwide cross-sectional 'Willebrand in the Netherlands' (WiN) study and compared the prevalence of arterial thrombosis with two reference populations from the general Dutch population adjusted for age and sex as standardized morbidity ratios (SMRs). Results: Twenty-nine arterial thrombotic events occurred in 21 patients (3.3%). Five patients suffered an acute myocardial infarction and three an ischemic stroke. Unstable angina pectoris was recorded 12 times, transient ischemic attack nine. The prevalence of all arterial thrombotic events combined (acute myocardial infarction, ischemic stroke and coronary heart disease) was 39% and 63% lower than in the two reference populations. The prevalence of cardiovascular disease in VWD was lower than in the general population, SMR 0.60 (95% CI, 0.32-0.98) for coronary heart disease and SMR 0.40 (95% CI, 0.13-0.83) for acute myocardial infarction. For ischemic stroke the prevalence was 35-67% lower compared with two reference populations, SMR 0.65 (95% CI, 0.12-1.59) and 0.33 (95% CI, 0.06-0.80), respectively. Conclusions: This is the first study showing that VWD patients have a reduced prevalence of arterial thrombosis and provides important insights into the role of VWF in the pathogenesis of arterial thrombosis. © 2013 International Society on Thrombosis and Haemostasis.

Item does not contain fulltext The mortality associated with post-transplant lymphoproliferative disorder (PTLD) induced by EBV infection can be reduced by monitoring EBV by polymerase-chain-reaction and rituximab given pre-emptively. We performed a retrospective analysis of the risk factors for the occurrence of EBV infection/disease and EBV-related mortality among 273 consecutive recipients of a T-cell-depleted allo-SCT during two periods: (a) before the implementation of a comprehensive protocol (2006-2008) and (b) afterwards (2009-2011). EBV infection was detected in 61 (22%) cases, and 28 cases were considered to have had EBV disease. Treatment with antithymocyte globulin was the most important risk factor (odds ratio (OR) 2.4; 95% confidence interval (CI) 1.3-4.2, P=0.001). After implementation of the protocol, in patients experiencing EBV infection, pre-emptive therapy was started more often and sooner (median 3 vs 6 days, P=0.002). Moreover, there were fewer cases of monomorphic PTLD (4/33 (12%) vs 11/28 (39%), P=0.01), and the EBV-related mortality was lower for patients experiencing EBV infection (2/33 (6%) vs 8/28 (29%), OR 0.2; 95% CI 0.05-0.9, P=0.03). The EBV protocol proved feasible and resulted in faster initiation of pre-emptive therapy, the diagnosis in an earlier stage of EBV disease, and decreased EBV-related mortality.Bone Marrow Transplantation advance online publication, 10 June 2013; doi:10.1038/bmt.2013.84.

Neutralizing antibodies (inhibitors) toward factor VIII form a severe complication in nonsevere hemophilia A, profoundly aggravating the bleeding pattern. Identification of high-risk patients is hampered by lack of data that take exposure days to therapeutic factor VIII concentrates into account. In the INSIGHT study, we analyzed the association between F8 mutation and inhibitor development in patients with nonsevere hemophilia A (factor VIII 2-40 IU/dL). This analysis included 1112 non-severe hemophilia A patients from 14 centers in Europe and Australia that had genotyped at least 70% of their patients. Inhibitor risk was calculated as Kaplan-Meier incidence with cumulative number of exposure days as the time variable. During 44 800 exposure days (median, 24 exposure days per patient; interquartile range [IQR], 7-90), 59 of the 1112 patients developed an inhibitor; cumulative incidence of 5.3% (95% confidence interval [CI], 4.0-6.6) after a median of 28 exposure days (IQR, 12-71). The inhibitor risk at 50 exposure days was 6.7% (95% CI, 4.5-8.9) and at 100 exposure days the risk further increased to 13.3% (95% CI, 9.6-17.0). Among a total of 214 different F8 missense mutations 19 were associated with inhibitor development. These results emphasize the importance of F8 genotyping in nonsevere hemophilia A. ( Blood . 2013; 122(11):1954-1962) © 2013 by The American Society of Hematology.

Item does not contain fulltext The prevalence of obesity in patients with haemophilia (PWH) is increasing. We investigated the effect of obesity on bleeding frequency and clotting factor concentrate (CFC) usage in PWH and assessed whether prothrombotic changes observed in obesity differ between controls and PWH. Number of bleeds and CFC usage were compared between obese (N = 51) and non-obese (N = 46) haemophilia A patients. Markers of haemostasis and fibrinolysis were compared between PWH, and gender-, age- and body mass index (BMI)-matched non-haemophilic controls (N = 91). Median number of bleeds/patient-month was comparable between obese and non-obese patients with severe haemophilia (P = 0.791). Obese patients with severe haemophilia used 1.4 times more CFC/patient-month than non-obese patients (P = 0.036). When adjusting for weight this difference disappeared (P = 0.451). von Willebrand factor plasma concentration (VWF:Ag), factor VIII activity and endogenous thrombin potential were higher in obese than in non-obese controls. Obesity did not influence these markers in PWH. Plasminogen activator inhibitor type 1 levels were higher in obese vs. non-obese PWH (P < 0.001), whereas levels were comparable between PWH and controls (P = 0.912). Plasmin-alpha2-antiplasmin complex (PAP) levels appeared to be lower in obese vs. non-obese subjects, both within controls (P = 0.011) and PWH (P = 0.008). However, in PWH, PAP levels were higher than in controls (P < 0.001). Obesity is associated with an increase in net CFC usage in PWH, but has no effect on bleeding frequency. In addition, obesity attenuates hyperfibrinolysis in PWH. Future research investigating whether obese PWH need CFC treatment dosed on weight or whether a lower dosage would suffice to prevent and treat bleedings is needed. 01 september 2013

Clin Microbiol Infect 2012; 18 (Suppl. 7): 918 Abstract As the mortality associated with invasive Candida infections remains high, it is important to make optimal use of available diagnostic tools to initiate antifungal therapy as early as possible and to select the most appropriate antifungal drug. A panel of experts of the European Fungal Infection Study Group (EFISG) of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) undertook a data review and compiled guidelines for the clinical utility and accuracy of different diagnostic tests and procedures for detection of Candida infections. Recommendations about the microbiological investigation and detection of candidaemia, invasive candidiasis, chronic disseminated candidiasis, and oropharyngeal, oesophageal, and vaginal candidiasis were included. In addition, remarks about antifungal susceptibility testing and therapeutic drug monitoring were made.

Item does not contain fulltext INTRODUCTION: Flow cytometry allows the analysis of multiple antigens in a single tube at a single cell level. We present a rapid and sensitive two tube flow cytometric protocol for the detection of multiple platelet antigens and activation markers gated on a pure platelet population. MATERIALS AND METHODS: The presence of platelet specific antigens was analyzed in citrated whole blood of normal platelets and from patients diagnosed with platelet abnormalities. Quiescent platelets as well as stimulated platelets were analyzed using a gating strategy based on ubiquitously expressed platelet membrane markers. A ubiquitously expressed platelet marker was combined with antibodies against the activated alpha2b-beta3 (PAC-1), Lysosomal Activated Membrane Protein (CD63) and P-selectin (CD62P). RESULTS: We were able to detect the platelet antigens CD36, CD41, CD42a, CD42b and CD61 in one single tube. Our approach allowed the single tube determination of PAC-1, CD63 and CD62P after activation of platelets by thrombin, collagen, ADP and PAR-1, and determination of platelet abnormalities. CONCLUSIONS: Our two tube multi-parameter screening protocol is suited for the analysis of platelet antigens expressed on quiescent and activated platelets and allows the detection of aberrancies as found in blood of patients with thrombocytopathy such as Glanzmann Thrombasthenia, storage pool disease with diminished granule content and patients treated with clopidogrel and acetylsalicylic acid. 01 juli 2012

The monitoring and prediction of treatment responses to invasive aspergillosis (IA) are difficult. We determined whether serum galactomannan index (GMI) trends early in the course of disease may be useful in predicting eventual clinical outcomes. For the subjects recruited into the multicenter Global Aspergillosis Study, serial GMIs were measured at baseline and at weeks 1, 2, and 4 following antifungal treatment. Clinical response and survival at 12 weeks were the outcome measures. GMI trends were analyzed by using the generalized estimation equation approach. GMI cutoffs were evaluated by using receiver-operating curve analyses incorporating pre- and posttest probabilities. Of the 202 study patients diagnosed with IA, 71 (35.1%) had a baseline GMI of ≥0.5. Week 1 GMI was significantly lower for the eventual responders to treatment at week 12 than for the nonresponders (GMIs of 0.62 ± 0.12 and 1.15 ± 0.22, respectively; P = 0.035). A GMI reduction of >35% between baseline and week 1 predicted a probability of a satisfactory clinical response. For IA patients with pretreatment GMIs of n = 131; 64.9%), GMI ought to remain low during treatment, and a rising absolute GMI to >0.5 at week 2 despite antifungal treatment heralded a poor clinical outcome. Here, every 0.1-unit increase in the GMI between baseline and week 2 increased the likelihood of an unsatisfactory clinical response by 21.6% ( P = 0.018). In summary, clinical outcomes may be anticipated by charting early GMI trends during the first 2 weeks of antifungal therapy. These findings have significant implications for the management of IA.

Item does not contain fulltext Haematopoietic stem cell transplantation (SCT) is an expensive lifesaving procedure, which is increasingly performed in patients with haematological diseases. Developments in the protocol for SCT have resulted in cost estimates that require updating. We aimed to calculate actual costs for SCT and to identify major cost drivers by means of a daily practice cost study. We randomly selected 191 patients, treated at three university hospitals, who underwent an autologous (auto) SCT or allogeneic (allo) SCT in 2007, 2008 or 2009. Allo-SCT included sibling donors, matched unrelated donors (MUD) and umbilical cord blood (UCB). Resource use was collected from the hospital registration systems and medical files. The total costs included selection and harvesting of stem cells, transplantation and 1-year follow-up. The average costs per patient were 45,670 for auto-SCT and 101,919 for sibling allo-SCT. The costs of transplantations from unrelated donors were much higher: 171,478 for allo-SCT-MUD and 254,689 for allo-SCT-UCB. Hospital inpatient days together with laboratory and other activities were the main cost drivers across all types of SCT. Besides, donor search costs were a large cost component in allo-SCT-sib (18 %) and allo-SCT-MUD (12 %). Real-world costs were above routine reimbursement and appropriate financing is necessary to guarantee the continuation of SCT. The costs calculated in this study provide reliable up-to-date input for cost-effectiveness studies and budget revision. 01 december 2012

Item does not contain fulltext PURPOSE: Between 30 and 50% of febrile neutropenic episodes are accounted for by infection. C-reactive protein (CRP) is a nonspecific parameter for infection and inflammation but might be employed as a trigger for diagnosis. The aim of the study was to evaluate whether (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT can be used to detect inflammatory foci in neutropenic patients with elevated CRP and whether it helps to direct treatment. METHODS: Twenty-eight consecutive patients with neutropenia as a result of intensive chemotherapy for haematological malignancies or myeloablative therapy for haematopoietic stem cell transplantation were prospectively included. (18)F-FDG PET/CT was added to the regular diagnostic workup once the CRP level rose above 50 mg/l. RESULTS: Pathological FDG uptake was found in 26 of 28 cases despite peripheral neutrophil counts less than 0.1 x 10(-9)/l in 26 patients: in the digestive tract in 18 cases, around the tract of the central venous catheter (CVC) in 9 and in the lungs in 7 cases. FDG uptake in the CVC tract was associated with coagulase-negative staphylococcal bacteraemia (p < 0.001) and deep venous thrombosis (p = 0.002). The number of patients having Streptococcus mitis bacteraemia appeared to be higher in patients with grade 3 oesophageal FDG uptake (p = 0.08). Pulmonary FDG uptake was associated with the presence of invasive fungal disease (p = 0.04). CONCLUSION: (18)F-FDG PET/CT scanning during chemotherapy-induced febrile neutropenia and increased CRP is able to detect localized foci of infection and inflammation despite the absence of circulating neutrophils. Besides its potential role in detecting CVC-related infection during febrile neutropenia, the high negative predictive value of (18)F-FDG PET/CT is important for avoiding unnecessary diagnostic tests and therapy. 01 januari 2012

Mortality due to ischemic heart disease is lower in hemophilia patients when compared to the general male population. As coagulation plays a role in the inflammatory pathways involved in atherogenesis, we investigated whether the clotting factor deficiency protects hemophilia patients from developing atherosclerosis. Coronary artery calcification (CAC), a measure of the extent of atherosclerosis and assessed with multi detector-row computed tomography, was compared between men with and without hemophilia. Patients (n = 42) with severe or moderate hemophilia A (mean age 65.1 ± 5.1 years) were included. The comparison population consisted of 613 non-hemophilic males (mean age 66.6 ± 4.5 years) from the Rotterdam Study, a Dutch population-based follow-up study. None of the study subjects were HIV infected or had a history of cardiovascular disease (CVD). CAC was quantified according to the standardized and internationally accepted Agatston score. Linear regression was used to investigate the association between hemophilia and, because of its skewed distribution, the natural log transformed Agatston score. We did not observe a difference in Agatston score between men with and without hemophilia in either univariate (mean difference ln [Agatston score + 1] and 95% CI: 0.186 [-0.566 to 0.938]) or multivariate (0.571 [-0.164 to 1.307]) analyses adjusted for age, BMI, hypercholesterolemia and hypertension. Severe calcification (Agatston score > 400) was found in 24.4% of the hemophilia patients and in 23.7% of the non-hemophilic males (P = 0.743). This study shows that the extent of coronary artery atherosclerosis is comparable between men with and without hemophilia. Ischemic CVD is an increasing problem in aging hemophilia patients and treatment is complex due to the delicate equilibrium between bleeding and thrombosis. Results from this study underline the importance of screening and treating atherosclerosis risk factors to minimize the risk of CVD in hemophilia patients. Disclosure of Interest: A. Tuinenburg received a CSL Behring Prof Heimburger Award in 2010 to perform this study.

Purpose: Electroporation of dendritic cells (DC) with mRNA encoding tumor-associated antigens (TAA) has multiple advantages compared to peptide loading. We investigated the immunologic and clinical responses to vaccination with mRNA-electroporated DC in stage III and IV melanoma patients. Experimental design: Twenty-six stage III HLA*02:01 melanoma patients scheduled for radical lymph node dissection (stage III) and 19 melanoma patients with irresectable locoregional or distant metastatic disease (referred to as stage IV) were included. Monocyte-derived DC, electroporated with mRNA encoding gp100 and tyrosinase, were pulsed with keyhole limpet hemocyanin and administered intranodally. TAA-specific T-cell responses were monitored in blood and skin-test infiltrating lymphocyte (SKIL) cultures. Results: Comparable numbers of vaccine-induced CD8+ and/or CD4+ TAA-specific T-cell responses were detected in SKIL cultures; 17/26 stage III patients and 11/19 stage IV patients. Strikingly, in this population, TAA-specific CD8+ T cells that recognize multiple epitopes and produce elevated levels of IFNγ upon antigenic challenge in vitro, were significantly more often observed in stage III patients; 15/17 versus 3/11 stage IV patients, P = 0.0033. In stage IV patients, one mixed and one partial response were documented. The presence or absence of IFNγ-producing TAA-specific CD8+ T cells in stage IV patients was associated with marked difference in median overall survival of 24.1 months versus 11.0 months, respectively. Conclusion: Vaccination with mRNA-electroporated DC induces a broad repertoire of IFNγ producing TAA-specific CD8+ and CD4+ T-cell responses, particularly in stage III melanoma patients. Clin Cancer Res; 18(19); 5460–70. ©2012 AACR.

Item does not contain fulltext Graft-versus-host disease (GVHD) and fungal infections are frequent complications after allogeneic hematopoietic stem cell transplantation (HSCT). Single nucleotide polymorphisms (SNPs) in genes of the immune system can influence the inflammatory cascade and T cell-driven alloimmune reactions after HSCT, and thus increasing the incidence of GVHD and infectious complications. Here, we investigated the effect of SNPs in IL-23R and CCR6 on posttransplantation outcome in 161 recipients of partially T cell-depleted HSCT. Remarkably, IL-23R SNPs were not associated with clinical outcome, but we found that disparities in the CCR6 tagSNP rs2301436 and SNP rs3093023 are independently associated with the occurrence of chronic GVHD (cGVHD) and invasive fungal disease. In multivariate analysis, patients receiving a transplant from a homozygous rs2301436 G allele donor showed less cGVHD (odds ratio [OR]: 0.16; P = .002), as was the case for a homozygous donor rs3093023 G allele (OR: 0.24; P = .005). In parallel, the GG genotype at rs2301436 in donors was associated with a higher incidence of invasive fungal disease at day 100 after HSCT (OR: 3.59; P = .008). This study shows that CCR6 SNPs can be used to predict clinical outcome, and that polymorphisms in the CCR6 gene may influence T cell-mediated immune reactions after HSCT.

As culture-based methods for the diagnosis of invasive fungal diseases (IFD) in leukemia and hematopoietic SCT patients have limited performance, non-culture methods are increasingly being used. The third European Conference on Infections in Leukemia (ECIL-3) meeting aimed at establishing evidence-based recommendations for the use of biological tests in adult patients, based on the grading system of the Infectious Diseases Society of America. The following biomarkers were investigated as screening tests: galactomannan (GM) for invasive aspergillosis (IA); β-glucan (BG) for invasive candidiasis (IC) and IA; Cryptococcus Ag for cryptococcosis; mannan (Mn) Ag/anti-mannan (A-Mn) Ab for IC, and PCR for IA. Testing for GM, Cryptococcus Ag and BG are included in the revised EORTC/MSG (European Organization for Research and Treatment of Cancer/Mycoses Study Group) consensus definitions for IFD. Strong evidence supports the use of GM in serum (A II), and Cryptococcus Ag in serum and cerebrospinal fluid (CSF) (A II). Evidence is moderate for BG detection in serum (B II), and the combined Mn/A-Mn testing in serum for hepatosplenic candidiasis (B III) and candidemia (C II). No recommendations were formulated for the use of PCR owing to a lack of standardization and clinical validation. Clinical utility of these markers for the early management of IFD should be further assessed in prospective randomized interventional studies.

The role of plerixafor in optimizing peripheral blood stem cell mobilization for autologous stem cell transplantation

Item does not contain fulltext The performance of the new Platelia Candida Antigen Plus (Ag Plus) and Antibody Plus (Ab Plus) assays (Biorad Laboratories, France) was evaluated using a collection of serum samples obtained from 21 patients with microbiologically proven invasive candidiasis and 30 control patients who were being treated with myeloablative chemotherapy, and the data compared with that obtained with the earlier version of the Platelia Candida assays (Ag and Ab), and 1,3-ss-D-glucan (BG) detection systems. The sensitivity of the Ag Plus and Ab Plus assays in the per patient analysis ranged from 55-70% and from 30-64% for patients with less than 15 days of neutropenia and more than 15 days of neutropenia, respectively. Sensitivity and time to detection of these new assays was not significantly better than of the conventional Platelia Candida tests. However, the specificity of the Ag-Plus assay was reduced by approximately 50% as compared to the Ag assay. Logistic regression analysis showed that this was probably due to the fact that circulating mannan was also being detected by the Ag Plus assay in patients with superficial candidiasis. Further studies are needed to confirm our results and to determine the place of the Platelia Ag Plus and Ab Plus assays in the management of haematology patients at risk for Candida infections.

Item does not contain fulltext PURPOSE OF REVIEW: Single-nucleotide polymorphisms (SNPs) appear to influence the risk of invasive mould disease (IMD) in immunocompromised patients. This raises the question of whether genetic risk prediction can be used to alter clinical practice. This review focuses on the current status of genetic association studies regarding invasive fungal disease among hematology patients, with an emphasis on IMD. RECENT FINDINGS: Many studies have shown that SNPs in genes encoding cytokines, chemokines, and their receptors can increase the risk for IMD. Greater emphasis has recently been placed on SNPs in pattern-recognition receptors, including Toll-like receptor 4 (TLR4) and dectin-1. An association has been found between SNPs in TLR4 and dectin-1 and invasive aspergillosis, which has been strengthened by biological evidence from in-vitro and in-vivo studies that showed a loss of function in the presence of the SNP. Nevertheless, despite improving our understanding of host antifungal defenses in immunocompromised hosts, clinical applicability is still a long way off. Current genetic associations need further validation, as virtually all studies suffer methodological limitations such as small sample size, heterogeneity of cohorts, selection bias, ill defined outcome measure, and statistical flaws, mainly the lack of adjustments for multiple comparisons. SUMMARY: Genetic variations in immune genes are associated with the risk for IMD among hematology patients although inconsistencies are frequently reported. The next step will be to select consistent SNPs and test them for their value in assessing risk in larger, better designed multicenter studies that will necessitate collaboration of multiple institutions in national or international consortia.

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Invasive fungal diseases, especially those caused by molds, show many similarities with lymphomas and other hema tologic cancers. Indeed, unequivocal proof for the pres ence of these life-threatening diseases relies on histopatho logical evidence or on the demonstration of malignant cells or fungi by microscopic examination or culture. In general, if left untreated, these diseases will disseminate and prove fatal. Before adequate treatment is started, a staging workup in search of metastatic lesions needs to be performed, usually involving (but not limited to) whole body computed tomog raphy (CT) scanning, with or without positron emission tomography, and a thorough examination of sanctuary sites. In addition, prognostic scores are constructed at baseline and immunophenotypic profiles, cytogenetic, molecular or sero logic markers are identified. The latter may have prognostic value or later serve as surrogate markers for detecting residual disease or for guiding further therapy. First-line therapy typically consists of a single drug or combination of drugs, includ ing the use of monoclonal antibodies or immunomodulatory drugs. Moreover, successful first-line therapy is frequently followed by maintenance therapy for several months, with or without adjunctive radiotherapy or surgery. In case of refrac tory disease or relapse, salvage treatment is started using drugs with different modes of action. Finally, the crude mor tality rate of invasive fungal disease is not that different from the mortality rate of most malignant blood disorders, being around 40%. However, assessing the role of the underlying malignant disease or of invasive fungal disease remains difficult, especially when a postmortem examination is not car ried out. Despite the obvious similarities, clinicians seem to accept different thresholds for initiating diagnostic workups and for starting treatment. Virtually no hemato-oncologist would consider starting antineoplastic chemotherapy, immunother apy or radiotherapy to prevent the development of malignant disease in a population at risk, or to ‘treat’ a strong clinical suspicion that the patient may have malignant disease, even if their decision is based on a marker in the absence of histopathological evidence. However, a large majority of these physicians are apparently willing to start expensive broad-spectrum antifungal agents for these exact indications, irrespective of the immediate and long-term consequences, be they in terms of cost, the development of resistance or tox icity. This liberal approach developed in the early 1980s and was fueled by the lack of reliable non-invasive diagnostic tools, a reluctance to look for tissue-based evidence in cytopenic patients, and the impression that early treatment would result in better outcome. Over the last few decades, four basic strategies have been developed and investigated in clinical studies to deal with invasive fungal disease, particularly in neutropenic patients. As far as invasive mold disease is concerned, it is possible to delineate various patterns that are encountered in the neu tropenic population (Table 1) based on radiological signs and clinical symptoms that might be consistent with invasive fun gal disease, and on mycology results, with a view to assessing whether or not they are consistent with infection, disease or both. Each pattern is evaluated for its compatibility with infection and disease, and whether or not it meets the current EORTC/MSG definitions. 1 Management options are also assigned to each pattern. The diagnosis is predicated from a CT scan, and also by testing for evidence of infection directly by culture, and indirectly by testing for galactomannan, though PCR and beta-d-glucan might be included as well. Categories from A through to E each progress along an axis of certainty of diagnosis of invasive fungal disease. Whilst category A represents no invasive fungal disease at all, cate gory E represents proven invasive fungal disease according to current EORTC/MSG definitions. Categories B, C and D rep resent the spectrum in between these two extremes. Category A is made up of patients who might be considered suitable candidates for prophylaxis, 2

van der Velden, W J F M Donnelly, J P Blijlevens, N M A Comment Letter United States Biol Blood Marrow Transplant. 2011 Oct;17(10):1421-3. Epub 2011 Apr 27.

Contains fulltext : 127295.pdf (Publisher’s version ) (Closed access) Abstract BACKGROUND: This study was designed to determine whether delivering neo-adjuvant chemotherapy at a higher dose in a shorter period of time improves outcome of breast cancer patients. PATIENTS AND METHODS: Women with newly diagnosed breast cancer were randomly assigned to neoadjuvant chemotherapy of four cycles of doxorubicin and cyclophosphamide followed by four cycles of docetaxel (AC 60/600 - T 100mg/m(2)) or six cycles of TAC (75/50/500mg/m(2)) every 3 weeks. The primary endpoint was the pathologic complete response (pCR) rate, defined as no invasive tumour present in the breast. RESULTS: In total, 201 patients were included. Baseline characteristics were well balanced. AC-T resulted in pCR in 21% and TAC in 16% of patients (odds ratio 1.44 (95% confidence interval (CI) 0.67-3.10). AC-T without primary granulocyte-colony stimulating factor (G-CSF) prophylaxis was associated with more febrile neutropenia compared to TAC with primary G-CSF prophylaxis (23% versus 9%), and with more grade 3/4 sensory neuropathy (5% versus 0%). CONCLUSIONS: With a higher cumulative dose for the concurrent arm, no differences were observed between the two treatment arms with respect to pCR rate. The differential toxicity profile could partly be explained by different use of primary G-CSF prophylaxis. Copyright © 2013 Elsevier Ltd. All rights reserved. KEYWORDS: Breast cancer, Cyclophosphamide, Docetaxel, Doxorubicin, Neoadjuvant chemotherapy

Item does not contain fulltext Allogeneic stem cell transplantation (allo-SCT) can induce remission in patients with hematologic malignancies due to graft-versus-tumor (GVT) responses. This immune-mediated antitumor effect is often accompanied by detrimental graft-versus-host disease (GVHD), however. Both GVT and GVHD are mediated by minor histocompatibility antigen (MiHA)-specific T cells recognizing peptide products from polymorphic genes that differ between recipient and donor. In this study, we evaluated whether mismatches in a panel of 17 MiHAs are associated with clinical outcome after partially T cell-depleted allo-SCT. Comprehensive statistical analysis revealed that DNA mismatches for one or more autosomal-encoded MiHAs was associated with increased relapse-free survival in recipients of sibling transplants (P = .04), particularly in those with multiple myeloma (P = .02). Moreover, mismatches for the ubiquitous Y chromosome-derived MiHAs resulted in a higher incidence of acute GVHD grade III-IV (P = .004), whereas autosomal MiHA mismatches, ubiquitous or restricted to hematopoietic cells, were not associated with severe GVHD. Finally, we found considerable differences among MiHAs in their capability of inducing in vivo T cell responses using dual-color tetramer analysis of peripheral blood samples collected after allo-SCT. Importantly, detection of MiHA-specific T cell responses was associated with improved relapse-free survival in recipients of sibling transplants (P = .01). Our findings provide a rationale for further boosting GVT immunity toward autosomal MiHAs with a hematopoietic restriction to improve outcomes after HLA-matched allo-SCT.

Item does not contain fulltext Gastrointestinal (GI) mucositis is a common side effect of intense chemotherapy to prepare patients for hematopoietic SCT. Measuring intestinal damage objectively remains difficult, and clinicians often rely on albumin levels as an indicator of GI mucositis, but citrulline might be a more specific marker, which has in the past been shown to correlate with clinical signs of GI mucositis. We evaluated the courses of albumin and citrulline following different conditioning regimens for SCT and studied their relatedness to the subsequent inflammatory response using C-reactive protein. Patterns of albumin and citrulline differed significantly between myeloablative and non-myeloablative conditioning regimens. After myeloablative regimens, decreasing citrulline levels preceded the occurrence of inflammation unlike albumin levels, which decreased thereafter. Albumin levels were greatly influenced by inflammation, confirming it to be a 'negative acute-phase protein', whereas citrulline levels were not. Citrulline appeared to be a better biomarker of GI mucositis than albumin. Measuring citrulline might prove useful in clinical decision making, in identifying GI mucositis, and it would also be of interest to see how it compares with other biomarkers in the setting of acute GI GVHD. 01 juli 2013

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Contains fulltext : 119153.pdf (Publisher’s version ) (Open Access) Vaccination against cancer by using dendritic cells has for more than a decade been based on dendritic cells generated ex vivo from monocytes or CD34(+) progenitors. Here, we report on the first clinical study of therapeutic vaccination against cancer using naturally occurring plasmacytoid dendritic cells (pDC). Fifteen patients with metastatic melanoma received intranodal injections of pDCs activated and loaded with tumor antigen-associated peptides ex vivo. In vivo imaging showed that administered pDCs migrated and distributed over multiple lymph nodes. Several patients mounted antivaccine CD4(+) and CD8(+) T-cell responses. Despite the limited number of administered pDCs, an IFN signature was observed after each vaccination. These results indicate that vaccination with naturally occurring pDC is feasible with minimal toxicity and that in patients with metastatic melanoma, it induces favorable immune responses. Cancer Res; 73(3); 1063-75. (c)2012 AACR.

Item does not contain fulltext BACKGROUND: Considerable progress has been made in our understanding of the biological basis for cancer therapy-induced mucosal barrier injury (mucositis). The last formal review of the subject by MASCC/ISOO was published in 2007; consequently, an update is timely. METHODS: Panel members reviewed the biomedical literature on mucositis pathobiology published between January 2005 and December 2011. RESULTS: Recent research has provided data on the contribution of tissue structure changes, inflammation and microbiome changes to the development of mucositis. Additional research has focused on targeted therapy-induced toxicity, toxicity clustering and the investigation of genetic polymorphisms in toxicity prediction. This review paper summarizes the recent evidence on these aspects of mucositis pathobiology. CONCLUSION: The ultimate goal of mucositis researchers is to identify the most appropriate targets for therapeutic interventions and to be able to predict toxicity risk and personalize interventions to genetically suitable patients. Continuing research efforts are needed to further our understanding of mucositis pathobiology and the pharmacogenomics of toxicity. 01 juli 2013

Item does not contain fulltext BACKGROUND: The objective of this analysis was to investigate prognostic factors that influence the outcome of Epstein-Barr virus (EBV)-related posttransplant lymphoproliferative disorder (PTLD) after a rituximab-based treatment in the allogeneic hematopoietic stem cell transplant (HSCT) setting. METHODS: A total of 4466 allogeneic HSCTs performed between 1999 and 2011 in 19 European Group for Blood and Marrow Transplantation centers were retrospectively analyzed for PTLD, either biopsy-proven or probable disease. RESULTS: One hundred forty-four cases of PTLD were identified, indicating an overall EBV-related PTLD frequency of 3.22%, ranging from 1.16% for matched-family donor, 2.86% for mismatched family donor, 3.97% in matched unrelated donors, and 11.24% in mismatched unrelated donor recipients. In total, 69.4% patients survived PTLD. Multivariable analysis showed that a poor response of PTLD to rituximab was associated with an age >/=30 years, involvement of extralymphoid tissue, acute GVHD, and a lack of reduction of immunosuppression upon PTLD diagnosis. In the prognostic model, the PTLD mortality increased with the increasing number of factors: 0-1, 2, or 3 factors being associated with mortality of 7%, 37%, and 72%, respectively (P < .0001). Immunosuppression tapering was associated with a lower PTLD mortality (16% vs 39%), and a decrease of EBV DNAemia in peripheral blood during therapy was predictive of better survival. CONCLUSIONS: More than two-thirds of patients with EBV-related PTLD survived after rituximab-based treatment. Reduction of immunosuppression was associated with improved outcome, whereas older age, extranodal disease, and acute graft-vs-host disease predicted poor outcome. 01 september 2013

Item does not contain fulltext A role for gut bacteria in the pathogenesis of graft-versus-host disease (GVHD) has been firmly established; however, the role of Candida spp, which form part of the mycobiome, remains unknown. In a homogenous group of patients who underwent allogeneic stem cell transplantation (SCT), we found a significant impact of Candida colonization on the occurrence of acute GVHD. Patients colonized with Candida spp developed significantly more grade II-IV acute GVHD compared with noncolonized patients (50% vs 32%; P = .03), as well as more gastrointestinal (GI)-GVHD (33% vs 19%; P = .05). Colonization with Candida spp was more frequent in patients bearing the loss-of-function polymorphism Y238X, which results in dectin-1 dysfunction, compared with patients with the wild-type allele (73% vs 31%; P = .002). There was no direct effect of dectin-1 dysfunction on acute GVHD, although it did influence the occurrence of GVHD indirectly through Candida colonization. The exact mechanism of GVHD induction by Candida spp colonization of the mucosa is unknown, but the link might prove to be the induction of Th 17/IL-23 responses through activation of pattern recognition receptors by fungal motifs, including beta-d-glucan and mannans. These data indicate a role for the mycobiome in the pathogenesis of GVHD and suggest that altering the mycobiome by antifungal drugs can help ameliorate GI-GVHD. In addition, given that the genetic constitution of patients affects susceptibility to both Candida colonization and GVHD, whether identifying gene polymorphisms will facilitate personalized treatment of SCT recipients remains to be determined.

Twelve laboratories evaluated candidate material for an Aspergillus DNA calibrator. The DNA material was quantified using limiting-dilution analysis; the mean concentration was determined to be 1.73 × 10 10 units/ml. The calibrator can be used to standardize aspergillosis diagnostic assays which detect and/or quantify nucleic acid.

Dear Editor, In April 2009, a 19-year-old male presented with progressive pain on his left upper arm. A MRI scan of the arm showed a large tumor of the distal left humerus (Fig. 1a). Because an osteosarcoma was suspected, a biopsy was performed. After the biopsy, the patient presented with a fracture of his arm as a result of minor trauma. This fracture was managed conservatively with an upper arm cast. The biopsy revealed necrotic bone fragments with an infiltration of myeloblasts admixed with immature eosinophils; hence, the diagnosis of a myeloid sarcoma (MS) was established. Besides the pain in his arm, the patient had no complaints, especially no fever, night sweats, weight loss, hemorrhage, or anemia. On physical examination, neither lymphadenopathy and hepatosplenomegaly nor neurological signs were noticed. His peripheral blood counts were normal. A PET scan did not show any other bone lesion. On histological examination, the MS consisted of myelo/monoblasts with expression of lysozyme, partly weak myeloid peroxidase (MPO), and focally CD34 and CD117. A bone marrow aspirate was performed to exclude acute myeloid leukemia (AML). Morphology of the bone marrow did not support a diagnosis of AML or chronic myeloid leukemia (CML), although with flow cytometric immunophenotyping (IPT), a small population (2 %) of aberrant myeloblasts expressing CD15, CD34, and CD117 were found. Intriguingly, cytogenetic analysis of the bone marrow aspirate showed a Philadelphia chromosome (t(9;22)(q34;q11.2)) in 2 of 13 analyzed cells. Subsequent fluorescence in situ hybridization on the tumor biopsy showed that the blasts harbored the BCR-ABL fusion gene (Fig. 1b). PCR performed on peripheral blood and bone marrow showed BCR-ABL levels of 3.3×10 and 1.5×10 copies/ml, respectively. Because of the bad prognosis, the patient was treated with intensive chemotherapy followed by allogeneic stem cell transplantation (SCT) with peripheral blood stem cells from a matched unrelated donor. The therapy was complemented with local radiotherapy of his left arm. During his treatment, the left arm recovered swiftly, and at the time of SCT, he was no longer depending on the cast. Now 2 years after SCT, he is still in remission with an undetectable BCR-ABL level. MS is a rare disease that is reported in 2.5–9.0 % of patients with AML. It can occur concomitantly, following or, rarely, antedating the onset of systemic AML [1]. MS can also occur in the presence of other hematological diseases such as myelodysplastic syndrome and myeloproliferative neoplasia, including CML [2]. Certain known cytogenetic abnormalities, in particular t(8;21), have been associated with a higher incidence of MS [1, 2]. However, the presence of a Philadelphia chromosome t(9;22) is extremely rare and virtually no reports exist on cases in AML with the remainder almost exclusively occurring during CML blast crisis [2]. The phenotype of MS is mostly monoblastic or myelomonocytic, often expressing CD34, CD68, CD99, CD117, MPO, and TdT [2]. In our patient, the MS had this common L. F. J. van Groningen (*) :W. J. F. M. van der Velden Department of Hematology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, the Netherlands e-mail: l.vangroningen@aig.umcn.nl

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Item does not contain fulltext This randomized-controlled trial studied the efficacy of palifermin in a chemotherapy-only, high-dose Melphalan (HDM) transplant setting, to reduce oral mucositis (OM) and its sequelae measured by patient-reported outcomes (PRO) and medical resource use. Palifermin, relative to placebo was given either pre-/post-HDM or pre-HDM in patients with multiple myeloma (MM) undergoing auto-SCT at 39 European centers. Oral cavity assessment (WHO) and PRO questionnaires (oral mucositis daily questionnaire (OMDQ) and EQ 5D) were used in 281 patients (mean age 56, +/-s.d.=8 years). 57 patients received placebo. One hundred and fifteen subjects were randomized to pre-/post-HDM receiving palifermin on 3 consecutive days before HDM and after auto-SCT and 109 patients were randomized to pre-HDM, receiving palifermin (60 mug/kg/day) i.v. for 3 consecutive days before HDM. There was no statistically significant difference in maximum OM severity. Severe OM occurred in 37% (placebo), 38% (pre-/post-HDM) and 24% (pre-HDM) of patients. No significant difference was observed with respect to PRO assessments or medical resource use, but more infections and fever during neutropenia were reported in pre-/post-HDM vs placebo (for example, 51 and 26%). To conclude, palifermin was unable to reduce OM or OM-related patient's burden in MM transplant patients. 01 juli 2013

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Item does not contain fulltext On behalf of the lymphoma and multiple myeloma working parties of the Dutch/Belgian Haemato-Oncology Foundation for Adults in The Netherlands (HOVON), we present a guideline for diagnosis and management of Waldenstrom's macroglobulinemia (WM). Considering the indolent behaviour and heterogeneous clinical presentation of WM, it is crucial to determine the right indications for treatment, as well as to individualise therapeutic options. There are significant differences from the approach to multiple myeloma or the treatment of other indolent non-Hodkgin lymphomas, and these results cannot always be extrapolated. There is a lack of large clinical trials due to the low incidence of WM. Based on the available data, we provide a practical diagnostic classification, as well as recommendations for first-line therapy and options for treating relapsed disease. Some typical clinical features of WM, such as autoimmune phenomena and 'IgM flare' after rituximab treatment, are highlighted. A more elaborate version of this guideline was published in the 'Nederlands Tijdschrift voor Hematologie' (Dutch Journal for Hematology) September 2012. 01 maart 2013

Clin Microbiol Infect 2012; 18 (Suppl. 7): 6877 Abstract Mucosal candidiasis is frequent in immunocompromised HIV-infected highly active antiretroviral (HAART) naive patients or those who have failed therapy. Mucosal candidiasis is a marker of progressive immune deficiency. Because of the frequently marked and prompt immune reconstitution induced by HAART, there is no recommendation for primary antifungal prophylaxis of mucosal candidiasis in the HIV setting in Europe, although it has been evidenced as effective in the pre-HAART era. Fluconazole remains the first line of therapy for both oropharyngeal candidiasis and oesophageal candidiasis and should be preferred to itraconazole oral solution (or capsules when not available) due to fewer side effects. For patients who still present with fluconazole-refractory mucosal candidiasis, oral treatment with any other azole should be preferred based on precise Candida species identification and susceptibility testing results in addition to the optimization of HAART when feasible. For vaginal candidiasis, topical therapy is preferred.

Item does not contain fulltext PURPOSE: The aim of this study was to review the available literature and define clinical practice guidelines for the use of agents for the prevention and treatment of gastrointestinal mucositis. METHODS: A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. Based on the evidence level, one of the following three guideline determinations was possible: recommendation, suggestion, and no guideline possible. RESULTS: A total of 251 clinical studies across 29 interventions were examined. Panel members were able to make one new evidence-based negative recommendation; two new evidence-based suggestions, and one evidence-based change from previous guidelines. Firstly, the panel recommends against the use of misoprostol suppositories for the prevention of acute radiation-induced proctitis. Secondly, the panel suggests probiotic treatment containing Lactobacillus spp., may be beneficial for prevention of chemotherapy and radiotherapy-induced diarrhea in patients with malignancies of the pelvic region. Thirdly, the panel suggests the use of hyperbaric oxygen as an effective means in treating radiation-induced proctitis. Finally, new evidence has emerged which is in conflict with our previous guideline surrounding the use of systemic glutamine, meaning that the panel is unable to form a guideline. No guideline was possible for any other agent, due to inadequate and/or conflicting evidence. CONCLUSIONS: This updated review of the literature has allowed new recommendations and suggestions for clinical practice to be reached. This highlights the importance of regular updates. 01 januari 2013

Item does not contain fulltext The aim of this study was to calculate the costs of the current initial treatment of acute myeloid leukemia. Resource use was collected for 202 patients who started with intensive chemotherapy in 2008 or 2009. The costs of the first induction course were significantly higher than the costs of the second induction course. Allogeneic transplantation from a matched unrelated donor was significantly more expensive than the other consolidation treatments. In-hospital stay was the major cost driver in the treatment of AML. Research regarding possibilities of achieving the same or better health outcome with lower costs is warranted. 01 maart 2013

and CD45RO CD28 T-lymphocyte sub-sets, 5 days after autologous stem cell transplantation (aSCT), predicted a lower risk of fever and infec-tion during neutropenia. Similarly, lower cell counts were observed in patients suffering from oral mucositis (OM) compared with those without OM. The authors concluded that measuring absolute lympho-cyte counts and lymphocyte subsets following aSCT could be used to predict the occurrence of fever and infections. Moreover, they suggested a protective role for lymphocytes with regard to infections during neu-tropenia as well as mucositis. We believe, however, that their conclusions are premature and that their observations were most likely confounded by the presence of conditioning-induced mucositis that results in infl ammation, fever and bacteremia. Firstly, the authors concluded that there was no relationship between mucositis and neu-tropenic fever or infection in their study cohort. This is at odds with several reports that show a strong rela-tionship between oral and intestinal mucositis and fever and infection (2 – 5). The relatively small study group possibly explains the lack of this relationship in the current study. Also, the manner of scoring of mucositis could have contributed, as, although the World Health Organization (WHO) OM score is a good clinical score, this scale is limited and not sen-sitive enough to detect the changes that correspond with infl ammation. Scales incorporating infl amma-tory mucosal changes, and biomarkers such as cit-rulline, are probably better because they correspond strongly with tissue damage-related infl ammation (5,6). We believe that, with the use of more sensitive tools, the difference in mucositis severity between the patient group with and without fever might have been signifi cant, as opposed to the mere trend observed by Schmidmaier

Blennow and Mattsson1 recently concluded in a reply to Meije et al.2 that standardization of Aspergillus PCR diagnosis is needed. We agree with this, which is why we set up a Working Group of the International Society of Human and Animal Mycology, known as the European Aspergillus PCR initiative (EAPCRI) (http://www.eapcri.eu). This group has forged ahead, developing the necessary framework for establishing standards.3

Contains fulltext : 110506.pdf (Publisher’s version ) (Closed access) Background Hodgkin Lymphoma (HL) is highly curable when treated accurately. The challenge is to cure patients with the minimal risk of long-term complications. For that, optimal initial diagnostics are required to determine the optimal treatment plan. We offer non-academic hospitals in our Regional Comprehensive Cancer Centre network a centralised review of all diagnostic procedures from patients with newly diagnosed HL. We report our experience on concordances and discrepancies between local findings and central review results. Patients and methods A haematologist and radiation oncologist at the Hodgkin Radboud University Nijmegen Medical Centre outpatient clinic examined all patients with newly diagnosed HL between February 2006 and May 2010. In a multidisciplinary lymphoma conference, diagnostic information is reviewed and treatment advice formulated. Discordant findings in pathology, staging and therapy were recorded as 'minor', no therapeutic consequences or 'major', adapted therapy advice. Results Altogether, 125 patients were included. Pathology review showed 86% concordance, with 4% major discordance, mainly nodular lymphocyte predominant sub-type. Revision of initial staging was concordant in 77%; however 15% major discordance of which most were upstaged. This resulted in 19% treatment adaption. Conclusion Our findings highlight the discrepancies in interpretation of diagnostic tests. We advocate centralised review process for all newly diagnosed patients with HL.

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Item does not contain fulltext Patients with von Willebrand disease (VWD), the most common inherited bleeding disorder, display large variation in bleeding tendency, which is not completely related to VWF levels. The cause of variability in clinical expression is largely unknown. The effect of plasma fibrinolytic capacity on bleeding tendency in VWD patients has not been investigated. We hypothesized that enhanced fibrinolysis may result in a more severe bleeding phenotype. Therefore, we measured the fibrinolytic potential in patients with moderate or severe VWD to investigate the contribution of fibrinolysis to the bleeding tendency. Fibrinolytic potential was measured as plasma clot lysis time (CLT) with and without addition of potato carboxypeptidase inhibitor (PCI) in 638 patients with moderate or severe VWD who participated in a nationwide multicentre cross-sectional study. Bleeding severity was measured using the Bleeding Score (BS).The CLTs were significantly longer, indicative of hypofibrinolysis, in men compared to women with VWD [106.2 (IQR 95.7-118.1) vs. 101.9 (IQR 92.8-114.0) min]. The CLTs prolonged with increasing age. No association was found between VWF or FVIII levels and CLT, or between VWF or FVIII levels and CLT(+PCI) . No association was observed for BS in a model with 10log-transformed CLT, adjusted for age, gender, VWF:Act and FVIII [b = 6.5 (95%CI -0.3 to 13.4)]. Our study showed that the plasma fibrinolytic potential does not influence bleeding tendency in VWD patients and therefore does not explain the variability in bleeding phenotype in VWD. 01 mei 2012

The EORTC Infectious Disease Group (IDG) and its forerunners, the International Antimicrobial Therapy Cooperative Group (IATCG) and the Invasive Fungal Infection Group (IFIG), have helped drive and develop clinical practice in the management of bacterial and fungal infectious diseases. Besides undertaking seminal studies, the group in its various forms has played a key role in understanding the nature and management of the infectious complications that arise during the treatment of cancer, particularly hematological malignancies. The IATCG was also instrumental in setting the stage for large randomized controlled trials to address therapies for dealing with infections that developed during neutropenia. The three most important achievements of the group were in finding a rational basis for managing bacterial and fungal infections, the establishment of disease definitions, and the development of the guidelines. © 2012 European Organisation for Research and Treatment of Cancer., SCOPUS: ar.j, info:eu-repo/semantics/published