Publications by authors named "Koen Theunissen"

33 Publications

Recombinant Zoster Vaccine Significantly Reduces the Impact on Quality of Life Caused by Herpes Zoster in Adult Autologous Hematopoietic Stem Cell Transplant Recipients: A Randomized Placebo-Controlled Trial (ZOE-HSCT).

Biol Blood Marrow Transplant 2019 12 5;25(12):2474-2481. Epub 2019 Aug 5.

Royal Melbourne Hospital, Melbourne, Victoria, Australia.

Herpes zoster (HZ) can have a substantial impact on quality of life (QoL). The vaccine efficacy (VE) of a recombinant zoster vaccine (RZV) was 68.2% (95% confidence interval [CI], 55.6% to 77.5%) in a phase 3 study in adult autologous hematopoietic stem cell transplant (HSCT) recipients (NCT01610414). Herein, we report the impact of RZV on patients' QoL. Autologous HSCT recipients were randomized 1:1 to receive 2 doses of RZV or placebo, given 1 to 2 months apart. QoL was measured by the Short Form Survey-36 and Euro-QoL-5 Dimension at baseline, 1 month, and 1 year postdose 2 and during suspected HZ episodes with the Zoster Brief Pain Inventory (ZBPI). The RZV impact on ZBPI burden of illness and burden of interference scores was estimated. The 2 scores were calculated from the area under the curve (days 0 to 182) of the ZBPI worst pain and ZBPI activities of daily living scores, respectively, assuming a score of 0 for patients not having a confirmed HZ episode. The ZBPI maximum worst pain score was significantly lower in the RZV than placebo group (mean: 5.8 versus 7.1, P = .011). Consequently, the VE estimates for HZ burden of illness (82.5%; 95% CI, 73.6 to 91.4) and burden of interference (82.8%; 95% CI, 73.3 to 92.3) were higher than the HZ VE estimate (ie, 68.2%). RZV showed significantly better QoL scores than placebo 1 week following rash onset among patients with confirmed HZ. In addition to reducing the risk of HZ and its complications, RZV significantly reduced the impact of HZ on patients' QoL in those who developed breakthrough disease.
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http://dx.doi.org/10.1016/j.bbmt.2019.07.036DOI Listing
December 2019

Interruption or Discontinuation of Tyrosine Kinase Inhibitor Treatment in Chronic Myeloid Leukaemia: A Retrospective Cohort Study (SPARKLE) in Belgium.

Acta Haematol 2019 4;142(4):197-207. Epub 2019 Jun 4.

Novartis Pharma NV/SA, Vilvoorde, Belgium.

Objectives: To assess interruptions/discontinuations of tyrosine kinase inhibitor (TKI) treatment in Belgian patients with chronic myeloid leukaemia (CML).

Methods: This retrospective study included patients with TKI interruptions/discontinuations of ≥4 continuous weeks (no clinical trial context) between May 2013 and May 2016. Data collection took place between October 2016 and February 2017.

Results: All 60 participants (69 interruptions/discontinuations) had chronic-phase CML and 75% had at least a major molecular response (≥MMR) at interruption/discontinuation. Most interruptions/discontinuations occurred while on imatinib (36/69; 49%) and dasatinib (20/69; 29%). Most interruptions/discontinuations occurred due to side effects/intolerance (46/69; 67%); other reasons included a wish to conceive (6/69; 9%) and attempts to achieve treatment-free remission (TFR) (6/69; 9%). Interruptions due to side effects occurred later for imatinib- or dasatinib-treated patients than for those on nilotinib or ponatinib. Treatment was re-initiated in 62% (43/69) of cases. Most interruptions caused by side effects/intolerance were followed by treatment changes. All 4 patients with ≥MR 4.5 at interruption/discontinuation and ≥11-month follow-up who had not restarted treatment maintained the response.

Conclusion: Although TKIs are used for long-term CML treatment, physicians sometimes recommend interruptions/discontinuations. In this study, interruptions/discontinuations were mainly caused by side effects or intolerance, rather than TFR attempts.
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http://dx.doi.org/10.1159/000499329DOI Listing
March 2020

Providing both autologous and allogeneic hematopoietic stem cell transplants (HSCT) may have a stronger impact on the outcome of autologous HSCT in adult patients than activity levels or implementation of JACIE at Belgian transplant centres.

Bone Marrow Transplant 2019 09 29;54(9):1434-1442. Epub 2019 Jan 29.

CHU de Liège, Liège, Belgium.

While performance since the introduction of the JACIE quality management system has been shown to be improved for allogeneic hematopoietic stem cell transplants (HSCT), impact on autologous-HSCT remains unclear in Europe. Our study on 2697 autologous-HSCT performed in adults in 17 Belgian centres (2007-2013) aims at comparing the adjusted 1 and 3-yr survival between the different centres & investigating the impact of 3 centre-related factors on performance (time between JACIE accreditation achievement by the centre and the considered transplant, centre activity volume and type of HSCT performed by centres: exclusively autologous vs both autologous & allogeneic). We showed a relatively homogeneous performance between Belgian centres before national completeness of JACIE implementation. The 3 centre-related factors had a significant impact on the 1-yr survival, while activity volume and type of HSCT impacted the 3-yr survival of autologous-HSCT patients in univariable analyses. Only activity volume (impact on 1-yr survival only) and type of HSCT (impact on 1 and 3-yr survivals) remained significant in multivariable analysis. This is explained by the strong relationship between these 3 variables. An extended transplantation experience, i.e., performing both auto & allo-HSCT, appears to be a newly informative quality indicator potentially conveying a multitude of underlying complex factors.
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http://dx.doi.org/10.1038/s41409-019-0458-8DOI Listing
September 2019

A Belgian consensus protocol for autologous hematopoietic stem cell transplantation in multiple sclerosis.

Acta Neurol Belg 2018 Jun 13;118(2):161-168. Epub 2018 Mar 13.

Department of Hematology, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Belgium.

Multiple sclerosis is considered to be an immune mediated inflammatory disorder of the central nervous system. It mainly affects young, socioeconomic active patients. Although our armamentarium for this disease has significantly evolved in recent years some patients remain refractory to conventional therapies. In these cases, autologous hematopoietic stem cell transplantation can be considered as a therapeutic option. Decreasing morbidity, mortality, and increasing patient awareness have led to rising inquiry by our patients about this treatment option. With the aim of a standardized protocol and data registration, a Belgian working party on stem cell therapy in multiple sclerosis was established. In this paper, we report the consensus protocol of this working party on autologous hematopoietic stem cell transplantation in multiple sclerosis.
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http://dx.doi.org/10.1007/s13760-018-0905-0DOI Listing
June 2018

Disease and treatment characteristics of polycythemia vera patients in Belgium: Results from a scientific survey.

Eur J Haematol 2018 Apr 7;100(4):361-366. Epub 2018 Feb 7.

Novartis Pharma NV/SA, Vilvoorde, Belgium.

Objective: The current survey aimed to gather predefined disease parameters and treatment strategies to characterize the polycythemia vera (PV) patient population in Belgium.

Methods: Cross-sectional data from PV patients, seen at least once between May 2014 and May 2015 at 10 sites in Belgium, were collected in aggregated form and analyzed descriptively and quantitatively.

Results: Data from 343 PV patients were collected. Of these, 174 (50.7%) were male and 256 (74.6%) were ≥60 years of age. Ninety-two (26.8%) had a prior history of thrombotic events. Considerable proportions of patients had increased hematological parameters (hematocrit > 45% [31.2%], leukocytes > 10 × 10 /L [33.3%], and platelet > 400 × 10 /L [38.2%]). Most patients had non-palpable spleen (284, 87.7%) and no phlebotomies during the past 6 months (197, 57.4%). Low-dose aspirin was given as thrombosis prophylaxis in 249 (72.6%) patients, while 232 (67.6%) received hydroxyurea (HU) as cytoreductive treatment. Forty-one patients (12.0%) were reported as resistant and/or intolerant to HU. Seventeen patients (5.0%) received ruxolitinib in the context of clinical trials.

Conclusion: This survey provides better insight into the characteristics of Belgian PV patients and currently used treatment strategies. It shows that 232 (67.6%) PV patients continue to receive HU despite being potentially HU-resistant.
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http://dx.doi.org/10.1111/ejh.13022DOI Listing
April 2018

Posaconazole plasma exposure correlated to intestinal mucositis in allogeneic stem cell transplant patients.

Eur J Clin Pharmacol 2016 Aug 11;72(8):953-63. Epub 2016 Apr 11.

Clinical Pharmacology and Pharmacotherapy, Department of Pharmaceutical and Pharmacological Sciences, University Hospitals Leuven, Leuven, Belgium.

Purpose: Low posaconazole plasma concentrations (PPCs) are frequently encountered in allogeneic hematopoietic stem cell transplant (HSCT) patients, due to variable gastrointestinal absorption. In this study, the impact of intestinal mucositis on posaconazole exposure is investigated.

Patients And Methods: A prospective pharmacokinetic study was performed including allogeneic HSCT patients receiving posaconazole prophylaxis with the oral suspension or tablets. Steady state PPCs were determined using high-performance liquid chromatography-fluorescence detection at the day of transplantation (=day 0), day +7, and +14. Citrulline was measured using liquid chromatography-tandem mass spectrometry to evaluate severity of mucositis, at baseline (day -7 or -6), and at day 0, +7 and +14. Additionally, citrulline plasma concentrations and steady state trough PPCs were determined in hematological patients without HSCT or mucositis.

Results: Thirty-four HSCT patients received posaconazole oral suspension together with 25 cL of Coca Cola, 6 HSCT patients received posaconazole tablets and 33 hematological patients not receiving HSCT received posaconazole oral suspension. The median (interquartile range) average PPC was 0.26 mg/L (0.17-0.43), 0.67 mg/L (0.27-1.38), and 1.08 mg/L (0.96-1.38), with suspension in HSCT patients, suspension in hematological patients and tablets in HSCT patients, respectively. A higher trough PPC was encountered with the oral suspension when citrulline plasma concentrations were above 10 μmol/L compared to values below 10 μmol/L (p < 0.001), whereas for tablets, average PPCs remained high with citrulline plasma concentrations below or above 10 μmol/L (p = 0.64).

Conclusion: Posaconazole tablets should be preferred to suspension in HSCT patients immediately after transplantation to prevent insufficient plasma exposure due to intestinal mucositis.
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http://dx.doi.org/10.1007/s00228-016-2057-6DOI Listing
August 2016

The use of erythropoiesis-stimulating agents with ruxolitinib in patients with myelofibrosis in COMFORT-II: an open-label, phase 3 study assessing efficacy and safety of ruxolitinib versus best available therapy in the treatment of myelofibrosis.

Exp Hematol Oncol 2015 15;4:26. Epub 2015 Sep 15.

University of Leipzig, Leipzig, Germany.

Background: Anemia is considered a negative prognostic risk factor for survival in patients with myelofibrosis. Most patients with myelofibrosis are anemic, and 35-54 % present with anemia at diagnosis. Ruxolitinib, a potent inhibitor of Janus kinase (JAK) 1 and JAK2, was associated with an overall survival benefit and improvements in splenomegaly and patient-reported outcomes in patients with myelofibrosis in the two phase 3 COMFORT studies. Consistent with the ruxolitinib mechanism of action, anemia was a frequently reported adverse event. In clinical practice, anemia is sometimes managed with erythropoiesis-stimulating agents (ESAs). This post hoc analysis evaluated the safety and efficacy of concomitant ruxolitinib and ESA administration in patients enrolled in COMFORT-II, an open-label, phase 3 study comparing the efficacy and safety of ruxolitinib with best available therapy for treatment of myelofibrosis. Patients were randomized (2:1) to receive ruxolitinib 15 or 20 mg twice daily or best available therapy. Spleen volume was assessed by magnetic resonance imaging or computed tomography scan.

Results: Thirteen of 146 ruxolitinib-treated patients had concomitant ESA administration (+ESA). The median exposure to ruxolitinib was 114 weeks in the +ESA group and 111 weeks in the overall ruxolitinib arm; the median ruxolitinib dose intensity was 33 mg/day for each group. Six weeks before the first ESA administration, 10 of the 13 patients had grade 3/4 hemoglobin abnormalities. These had improved to grade 2 in 7 of the 13 patients by 6 weeks after the first ESA administration. The rate of packed red blood cell transfusions per month within 12 weeks before and after first ESA administration remained the same in 1 patient, decreased in 2 patients, and increased in 3 patients; 7 patients remained transfusion independent. Reductions in splenomegaly were observed in 69 % of evaluable patients (9/13) following first ESA administration.

Conclusions: Concomitant use of an ESA with ruxolitinib was well tolerated and did not affect the efficacy of ruxolitinib. Further investigations evaluating the effects of ESAs to alleviate anemia in ruxolitinib-treated patients are warranted (ClinicalTrials.gov identifier, NCT00934544; July 6, 2009).
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http://dx.doi.org/10.1186/s40164-015-0021-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4570722PMC
September 2015

Non-myeloablative allogeneic hematopoietic cell transplantation following fludarabine plus 2 Gy TBI or ATG plus 8 Gy TLI: a phase II randomized study from the Belgian Hematological Society.

J Hematol Oncol 2015 Feb 6;8. Epub 2015 Feb 6.

Department of Hematology, University of Liège, and CHU of Liège, Sart-Tilman, 4000, Liège, Belgium.

Background: Few studies thus far have compared head-to-head different non-myelooablative conditioning regimens for allogeneic hematopoietic cell transplantation (allo-HCT).

Methods: Here, we report the results of a phase II multicenter randomized study comparing non-myeloablative allo-HCT from HLA-identical siblings (n = 54) or from 10/10 HLA-matched unrelated donors (n = 40) with either fludarabine plus 2 Gy total body irradiation (Flu-TBI arm; n = 49) or 8 Gy TLI + anti-thymocyte globulin (TLI-ATG arm; n = 45) conditioning.

Results: The 180-day cumulative incidences of grade II-IV acute GVHD (primary endpoint) were 12.2% versus 8.9% in Flu-TBI and TLI-ATG patients, respectively (P = 0.5). Two-year cumulative incidences of moderate/severe chronic GVHD were 40.8% versus 17.8% in Flu-TBI and TLI-ATG patients, respectively (P = 0.017). Five Flu-TBI patients and 10 TLI-ATG patients received pre-emptive DLI for low donor chimerism levels, while 1 Flu-TBI patient and 5 TLI-ATG patients (including 2 patients given prior pre-emptive DLIs) received a second HCT for poor graft function, graft rejection, or disease progression. Four-year cumulative incidences of relapse/progression were 22% and 50% in Flu-TBI and TLI-ATG patients, respectively (P = 0.017). Four-year cumulative incidences of nonrelapse mortality were 24% and 13% in Flu-TBI and TLI-ATG patients, respectively (P = 0.5). Finally, 4-year overall (OS) and progression-free survivals (PFS) were 53% and 54%, respectively, in the Flu-TBI arm, versus 54% (P = 0.9) and 37% (P = 0.12), respectively, in the TLI-ATG arm.

Conclusions: In comparison to patients included in the Flu-TBI arm, patients included in the TLI-ATG arm had lower incidence of chronic GVHD, higher incidence of relapse and similar OS.

Trial Registration: The study was registered on ClinicalTrial.gov ( NCT00603954 ) and EUDRACT (2010-024297-19) .
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http://dx.doi.org/10.1186/s13045-014-0098-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4332717PMC
February 2015

Adequate iron chelation therapy for at least six months improves survival in transfusion-dependent patients with lower risk myelodysplastic syndromes.

Leuk Res 2014 May 14;38(5):557-63. Epub 2014 Feb 14.

Centre Hospitalier de Jolimont, Jolimont, Belgium; Institut Jules Bordet, Bruxelles, Belgium.

Background: Most patients with myelodysplastic syndromes (MDS) require transfusions at the risk of iron overload and associated organ damage, and death. Emerging evidence indicates that iron chelation therapy (ICT) could reduce mortality and improve survival in transfusion-dependent MDS patients, especially those classified as International Prognostic Scoring System (IPSS) Low or Intermediate-1 (Low/Int-1).

Methods: Follow-up of a retrospective study. Sample included 127 Low/Int-1 MDS patients from 28 centers in Belgium. Statistical analysis stratified by duration (≥6 versus <6 months) and quality of chelation (adequate versus weak).

Results: Crude chelation rate was 63% but 88% among patients with serum ferritin ≥1000 μg/L. Of the 80 chelated patients, 70% were chelated adequately mainly with deferasirox (26%) or deferasirox following deferoxamine (39%). Mortality was 70% among non-chelated, 40% among chelated, 32% among patients chelated ≥6 m, and 30% among patients chelated adequately; with a trend toward reduced cardiac mortality in chelated patients. Overall, median overall survival (OS) was 10.2 years for chelated and 3.1 years for non-chelated patients (p<0.001). For patients chelated ≥6 m or patients classified as adequately chelated, median OS was 10.5 years. Mortality increased as a function of average monthly transfusion intensity (HR=1.08, p=0.04) but was lower in patients receiving adequate chelation or chelation ≥6 m (HR=0.24, p<0.001).

Conclusion: Six or more months of adequate ICT is associated with markedly better overall survival. This suggests a possible survival benefit of ICT in transfusion-dependent patients with lower-risk MDS.
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http://dx.doi.org/10.1016/j.leukres.2014.02.003DOI Listing
May 2014

Response to rituximab-based therapy and risk factor analysis in Epstein Barr Virus-related lymphoproliferative disorder after hematopoietic stem cell transplant in children and adults: a study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation.

Clin Infect Dis 2013 Sep 13;57(6):794-802. Epub 2013 Jun 13.

Department of Pediatric Hematology and Oncology, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.

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.
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http://dx.doi.org/10.1093/cid/cit391DOI Listing
September 2013

Non-hodgkin lymphoma after treatment with extended dosing temozolomide and radiotherapy for a glioblastoma: a case report.

Case Rep Oncol 2013 Jan 19;6(1):45-9. Epub 2013 Jan 19.

Department of Medical Oncology, University of Hasselt, Diepenbeek, Belgium.

Temozolomide (TMZ) is an alkylating agent, used for the treatment of high-grade gliomas. This case report describes the development of a non-Hodgkin lymphoma in a patient treated with extended-dose temozolomide and radiotherapy. In addition to the possible mutagenic effect of temozolomide - as described for all alkylating agents - there might have been an immunosuppressive effect of TMZ. The pathological appearance of the lymphoma as well as the presence of a grade 3 lymphopenia early in treatment supports this hypothesis. As the use of TMZ increases, the awareness that TMZ may induce secondary malignancies should increase as well.
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http://dx.doi.org/10.1159/000346614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3573799PMC
January 2013

Detection of galactomannan in bronchoalveolar lavage fluid samples of patients at risk for invasive pulmonary aspergillosis: analytical and clinical validity.

J Clin Microbiol 2012 Apr 1;50(4):1258-63. Epub 2012 Feb 1.

Department of Hematology, Acute Leukemia and Stem Cell Transplantation Unit, Universitaire Ziekenhuizen Leuven, Campus Gasthuisberg, Catholic University of Leuven, Leuven, Belgium.

Invasive pulmonary aspergillosis (IPA) is frequent and often fatal in immunosuppressed patients. Timely diagnosis of IPA improves survival but is difficult to make. We examined the analytical and clinical validity of galactomannan (GM) testing of bronchoalveolar lavage (BAL) fluid in diagnosing IPA in a mixed population by retrospectively reviewing records of 251 consecutive at-risk patients for whom BAL fluid GM testing was ordered. The performance of the enzyme immunoassay was evaluated by using a range of index cutoffs to define positivity. Three samples were associated with proven IPA, 56 were associated with probable IPA, 63 were associated with possible invasive fungal disease (IFD), and 129 were associated with no IFD. Using a BAL fluid GM index of ≥0.8 (optimal optical density [OD] index cutoff identified by a receiver operating characteristic curve), the sensitivity in diagnosing proven and probable IPA was 86.4%, and the specificity was 90.7%. At this cutoff, positive and negative predictive values were 81% and 93.6%, respectively. However, an OD index value of ≥3.0 corresponded to a 100% specificity, thus ruling the disease in, irrespective of the pretest probability. Conversely, an OD index cutoff of <0.5 corresponded to a high sensitivity, virtually always ruling the disease out. For all values in between, the posttest probability of IPA depends largely on the prevalence of disease in the at-risk population and the likelihood ratio of the OD index value. Detection of GM in BAL fluid samples of patients at risk of IPA has an excellent diagnostic accuracy provided results are interpreted in parallel with clinico-radiological findings and pretest probabilities.
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http://dx.doi.org/10.1128/JCM.06423-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3318563PMC
April 2012

Progressive improvement in cutaneous and extracutaneous chronic graft-versus-host disease after a 24-week course of extracorporeal photopheresis--results of a crossover randomized study.

Biol Blood Marrow Transplant 2011 Dec 11;17(12):1775-82. Epub 2011 May 11.

Medical University of Vienna, Departments of Internal Medicine I and Dermatology, Vienna, Austria.

In a prior multicenter randomized controlled trial, we found that a 12-week course of extracorporeal photopheresis (ECP) plus standard immunosuppressive therapy resulted in several beneficial outcomes in patients with corticosteroid-refractory/intolerant/dependent chronic graft-versus-host disease (GVHD). Here, we report the results of an open-label crossover ECP study in 29 eligible participants randomized initially to the standard of care non-ECP (control) arm. Eligible for the crossover ECP study were control arm patients who either (1) had progression of cutaneous chronic GVHD (cGVHD), defined as >25% worsening from baseline as measured by the percent change in the total skin score (TSS) at any time, or (2) had less than 15% improvement in the TSS, or had a ≤25% reduction in corticosteroid dose at week 12 of the initial study. ECP was administered 3 times during week 1, then twice weekly until week 12, followed by 2 treatments monthly until week 24. The median age of the study cohort was 43 (20-67) years and 90% had extensive cGVHD. The median months from onset of cGVHD to start of ECP were 26 (range: 4-79). Twenty-five of 29 patients (86%) completed the 24-week course of ECP. Complete or partial skin response at week 24 was noted in 9 patients (31%). The median percent of decrease in TSS from baseline to weeks 12 and 24 was -7.9 and -25.8, respectively. In 4 (17%) and 8 (33%) patients, a ≥50% reduction in corticosteroid dose at weeks 12 and 24 was observed. Extracutaneous cGVHD response was highest in oral mucosa with 70% complete and partial resolution after week 24. In conclusion, progressive improvement in cutaneous and extracutaneous cGVHD was observed after a 24-week course of ECP in patients who previously had no clinical improvement or exhibited worsening of cGVHD while receiving standard immunosuppressive therapy alone in a randomized study. These results confirm previous findings and support the notion that prolonged ECP appears to be necessary for optimal therapeutic effects in corticosteroid-refractory cGVHD patients.
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http://dx.doi.org/10.1016/j.bbmt.2011.05.004DOI Listing
December 2011

Myeloablative conditioning predisposes patients for Toxoplasma gondii reactivation after allogeneic stem cell transplantation.

Clin Infect Dis 2010 Apr;50(8):1127-34

Hematology Department, University Hospitals Leuven, 3000 Leuven, Belgium.

Background: Toxoplasmosis is an often fatal opportunistic infection following allogeneic hematopoietic stem cell transplantation and is largely due to deferred diagnosis. In addition, breakthrough infections occur during prophylaxis with trimethoprim-sulfamethoxazole.

Methods: From November 2001 onwards, we routinely monitored all stem cell transplant recipients who were seropositive for Toxoplasma gondii and/or who received a transplant from a donor who was seropositive for T. gondii reactivation by polymerase chain reaction of peripheral blood samples. The aim of this study was to evaluate the incidence of and the risk factors for Toxoplasma reactivation in this population not receiving specific prophylaxis. We also studied the feasibility of a preemptive treatment approach based on this routine monitoring.

Results: We report a toxoplasmosis incidence of 8.7% (18 of 208 patients). Twelve patients (5.8%) had a T. gondii infection at diagnosis; 6 patients (2.9%) had Toxoplasma disease, including cerebral toxoplasmosis (n = 5) and cardiopulmonary toxoplasmosis (n = 1). We identified myeloablative conditioning and conditioning with high-dose total body irradiation (10-12 Gy) as risk factors for T. gondii reactivation, whereas patients with a seropositive donor were less likely to experience reactivation. Patients with T. gondii disease had a significantly higher number of transcripts in blood than did patients with a T. gondii infection. Finally, with a strategy of routine monitoring and preemptive treatment with clindamycin-pyrimethamine, we only had 3 Toxoplasma-related deaths among our patients, which is a much lower rate than that reported in the literature.

Conclusions: Systematic monitoring with polymerase chain reaction is a good means to detect T. gondii reactivation and could reduce T. gondii-related mortality among hematopoietic stem cell transplant recipients.
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http://dx.doi.org/10.1086/651266DOI Listing
April 2010

Bronchoalveolar lavage fluid galactomannan for the diagnosis of invasive pulmonary aspergillosis in patients with hematologic diseases.

Clin Infect Dis 2009 Dec;49(11):1688-93

Department of Hematology, Medical Intensive Care Unit, University Hospital Gasthuisberg, Leuven, Belgium

Background: Prompt diagnosis of invasive pulmonary aspergillosis (IPA) remains a challenge. Galactomannan (GM) detection in bronchoalveolar lavage (BAL) fluid by the Platelia enzyme immunoassay aims to further improve upon the test's utility by applying it directly to specimens from the target organ.

Methods: A retrospective analysis of the Platelia assay was performed on BAL samples from 99 evaluable high-risk hematology patients, including 58 with proven or probable IPA.

Results: BAL GM demonstrated an improved sensitivity profile (91.3% with an optical density [OD] index cutoff of >or=1.0) in comparison with culture and microscopy (50% and 53.3%, respectively). The diagnostic accuracy as given by the area under the receiver operating characteristic curve was 0.93 (95% confidence interval, 0.88-0.99); further decreasing the OD index cutoff to 0.5 compromised specificity more than it improved sensitivity. Estimates of the positive and negative predictive value of the Platelia assay on BAL samples (OD index, >or=1.0) were 76% and 96%, respectively. The mean BAL GM OD index was not different in neutropenic versus nonneutropenic case patients (3.9 and 4.5, respectively; P = .3); however, a trend toward decreased sensitivity in patients receiving mold-active prophylaxis was noted.

Conclusion: BAL GM is a valuable adjunctive diagnostic tool to other conventional microbiologic and radiologic studies.
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http://dx.doi.org/10.1086/647935DOI Listing
December 2009

Membrane-anchored uPAR regulates the proliferation, marrow pool size, engraftment, and mobilization of mouse hematopoietic stem/progenitor cells.

J Clin Invest 2009 Apr 9;119(4):1008-18. Epub 2009 Mar 9.

VIB--Vesalius Research Center, Katholieke Universiteit Leuven, Leuven, Belgium.

The mechanisms of BM hematopoietic stem/progenitor cell (HSPC) adhesion, engraftment, and mobilization remain incompletely identified. Here, using WT and transgenic mice, we have shown that membrane-anchored plasminogen activator, urokinase receptor (MuPAR) marks a subset of HSPCs and promotes the preservation of the size of this pool of cells in the BM. Loss or inhibition of MuPAR increased HSPC proliferation and impaired their homing, engraftment, and adhesion to the BM microenvironment. During mobilization, MuPAR was inactivated by plasmin via proteolytic cleavage. Cell-autonomous loss of the gene encoding MuPAR also impaired long-term engraftment and multilineage repopulation in primary and secondary recipient mice. These findings identify MuPAR and plasmin as regulators of the proliferation, marrow pool size, homing, engraftment, and mobilization of HSPCs and possibly also of HSCs.
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http://dx.doi.org/10.1172/JCI36010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662545PMC
April 2009

Galactomannan serves as a surrogate endpoint for outcome of pulmonary invasive aspergillosis in neutropenic hematology patients.

Cancer 2009 Jan;115(2):355-62

Department of Hematology, University Hospital Gasthuisberg, Leuven, Belgium.

Background: A noninvasive, objective, reproducible, and quantitative Aspergillus-specific surrogate marker is needed for a more accurate assessment of the outcome of invasive aspergillosis (IA) in patients with a hematologic disorder. The quantitative serum galactomannan index (GMI) assay seems to fulfill the requirements of surrogacy for outcome evaluation.

Methods: Kappa statistics were used to determine the strength of correlation between GMI outcome and clinical outcome (survival or death), autopsy data, and response outcome of IA in 70 adults with prolonged neutropenia. All patients underwent serial GMI monitoring until discharge or death.

Results: The overall correlation between GMI and clinical outcome was good at 6 weeks (kappa=0.5882; 95% confidence interval [95% CI], 0.4023-0.7741) and was excellent at 12 weeks (kappa=0.8857; 95% CI, 0.7766-0.9948). Concordance with autopsy findings was perfect (kappa=1). At 6 weeks, the correlation between GMI and response outcome (favorable or unfavorable) was excellent (kappa=0.7523; 95% CI, 0.5803-0.9243). Survival was significantly better in patients who became GMI-negative (P<.0001).

Conclusions: In neutropenic patients with seropositive IA, serum galactomannan index outcome strongly correlates with survival, autopsy findings, and response outcome. This finding may have implications for patient management and for clinical trial design.
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http://dx.doi.org/10.1002/cncr.24022DOI Listing
January 2009

Improved regional function after autologous bone marrow-derived stem cell transfer in patients with acute myocardial infarction: a randomized, double-blind strain rate imaging study.

Eur Heart J 2009 Mar 23;30(6):662-70. Epub 2008 Dec 23.

Department of Cardiology, Gasthuisberg University Hospital, University of Leuven, 49 Herestraat, B-3000 Leuven, Belgium.

Aims: To investigate whether intracoronary transfer of bone marrow progenitor cells (BMPCs) early after reperfusion of an acute myocardial infarction improves regional myocardial function in a randomized double-blind, placebo-controlled strain rate imaging study.

Methods And Results: Regional myocardial deformation was measured using velocity-derived strain rate imaging in 67 STEMI patients randomized 1:1 to intracoronary infusion of BMPC (n = 33) or placebo (n = 34). Myocardial segments were grouped into infarct (n = 232), border (n = 250), and remote (n = 526) based on MRI-delayed enhancement and the perfusion territory of the infarct-related vessel. Four months after revascularization and progenitor cell/placebo transfer, regional myocardial deformation (rate) improved significantly more in the infarct segments of BMPC patients (treatment effect on end-systolic strain: -3.7 +/- 1.0%, P = 0.0003; peak-systolic strain rate: -0.20 +/- 0.07 s(-1), P = 0.0035). These findings were confirmed by a significantly greater improvement of longitudinal mitral valve ring displacement in the infarct walls of BMPC patients (treatment effect: 0.93 mm, P = 0.034).

Conclusion: Intracoronary infusion of BMPC early after reperfusion of a STEMI improves recuperation of regional myocardial function at 4 months' follow-up. Quantitative assessment of regional systolic function might be more sensitive than global LV ejection fraction for the evaluation of BMPC therapy after STEMI.
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http://dx.doi.org/10.1093/eurheartj/ehn532DOI Listing
March 2009

Early diagnosis and preemptive therapy of pulmonary mold infections in high-risk patients.

Curr Infect Dis Rep 2008 Nov;10(6):459-65

University Hospital Gasthuisberg, Department of Hematology, Acute Leukemia and Stem Cell Transplantation Unit, Herestraat 49, B-3000 Leuven, Belgium.

The management of pulmonary mold infections in at-risk patients is hampered by the difficulty in diagnosing these infections. Therefore, most practitioners rely on universal prophylaxis and on the early empirical use of antifungals, especially in neutropenic cancer patients and stem cell transplant recipients. However, a strategy of preemptive or diagnostic-driven antifungal therapy is being explored based on advances in imaging techniques and in fungal antigen detection methods. This article highlights the controversies surrounding the prevention and the early treatment of invasive mold infections in high-risk patients.
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http://dx.doi.org/10.1007/s11908-008-0075-yDOI Listing
November 2008

Optimization of the cutoff value for the Aspergillus double-sandwich enzyme immunoassay.

Clin Infect Dis 2007 May 4;44(10):1329-36. Epub 2007 Apr 4.

Department of Hematology, Universitaire Ziekenhuizen, Catholic University Leuven, Leuven, Belgium.

Background: Many health care centers worldwide use the Platelia Aspergillus enzyme immunoassay (PA-EIA; Bio-Rad Laboratories) for diagnosis of invasive aspergillosis (IA). A cutoff optical density (OD) index of 1.5 was originally recommended by the manufacturer, but in practice, most institutions use lower cutoff values. Moreover, a cutoff OD index of 0.5 was recently approved in the United States. In the present study, we set out to optimize the cutoff level by performing a retrospective analysis of PA-EIA values for samples that had been obtained prospectively from adult patients at risk for IA at 2 European health care centers.

Methods: In total, 239 treatment episodes were included of which there were 19 episodes of proven IA and 19 episodes of probable IA. Per-episode and per-test analyses and receiver operating characteristic curves were used to determine the optimal cutoff value.

Results: In the per-episode analysis, lowering the cutoff OD index for positivity from 1.5 to 0.5 increased the overall sensitivity by 21% (from 76.3% to 97.4%) but decreased the overall specificity by 7% (from 97.5% to 90.5%). Requiring 2 consecutive samples with an OD index > or = 0.5 resulted in the highest test accuracy, with an improved positive predictive value. At a cutoff OD index of 0.5, the antigen test result was positive during the week before conventional diagnosis in 65% of cases and during the week of diagnosis in 79.5% of cases.

Conclusions: A cutoff OD index of 0.5--identical to the approved cutoff in the United States--improves the overall performance of the PA-EIA for adult hematology patients.
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http://dx.doi.org/10.1086/514349DOI Listing
May 2007

Advances in the serological diagnosis of invasive Aspergillus infections in patients with haematological disorders.

Mycoses 2007 ;50 Suppl 1:2-17

Department of Haematology, Universitaire Ziekenhuizen Leuven, Catholic University, Leuven, Belgium.

A reliable diagnosis of invasive aspergillosis in patients with haematological malignancies is seldom achieved antemortem. Conventional laboratory diagnostic methods are insensitive and time-consuming, resulting in late diagnosis and treatment and contributing to unacceptably high mortality. As a result, routine antifungal prophylaxis and early empirical treatment have been recommended. However, overtreatment associated with these strategies results in increased toxicity and cost. The use of sensitive and rapid non-culture-based diagnostic assays, such as detection of Aspergillus antigens (galactomannan, beta-D-glucan) or detection of genomic DNA sequences may allow a shift in emphasis from empirical to pre-emptive therapy, especially when substantiated by suggestive radiological findings. These new tools may be used to confirm a presumed diagnosis of invasive aspergillosis, or, when used to screen high-risk patients, may identify an infection at the early stage of disease. The excellent negative predictive value of these assays should convince clinicians to withhold antifungal therapy in persistently febrile neutropenic patients with no other signs of fungal infection. On the other hand, consecutive positive results in a high-risk population should at least trigger a complete diagnostic work-up. This review will focus on the diagnostic utility as well as on the pitfalls of serial screening for the presence of circulating fungal antigens in haematology patients.
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http://dx.doi.org/10.1111/j.1439-0507.2007.01375.xDOI Listing
July 2007

Preemptive antifungal therapy: still a way to go.

Curr Opin Infect Dis 2006 Dec;19(6):551-6

Department of Hematology, Acute Leukemia and Stem Cell Transplantation Unit, University Hospital Gasthuisberg, Leuven, Belgium.

Purpose Of Review: Early treatment of invasive mold infections improves the outcome. Therapy is often delayed, however, because available diagnostic tools such as culture, microscopy and conventional radiology lack sensitivity; consequently, empirical initiation of antifungal therapy has been advocated, particularly for patients with prolonged unexplained neutropenic fever.

Recent Findings: Much recent progress has been made in the development and evaluation of nonculture-based assays, including the detection of the fungal antigens galactomannan and beta-D-glucan and the detection of fungal DNA by polymerase chain reaction techniques. These new tools should aid the rapid, early diagnosis of invasive fungal disease, especially when used as screening tools in conjunction with sensitive imaging techniques.

Summary: The review will consider these recent developments with the purpose of introducing the concept of preemptive antifungal therapy.
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http://dx.doi.org/10.1097/QCO.0b013e3280106854DOI Listing
December 2006

Defining a case of invasive aspergillosis by serum galactomannan.

Med Mycol 2006 Sep;44(Supplement_1):S173-S178

Department of Haematology, University Hospital Gasthuisberg, Leuven, Belgium.

The timely diagnosis of invasive aspergillosis (IA) remains difficult. In recent years, increased experience has been gained with the Platelia™ Aspergillus enzyme immunoassay. However, the excellent sensitivity and high positive predictive value that has been reported in earlier studies cannot consistently be reproduced in some of the more recent studies. As expected, this stems from major methodological and clinical heterogeneities between studies. This article reviews these between-study heterogeneities and concludes that the detection of serum galactomannan can be used to define a case of IA in a well-defined population of at-risk patients.
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http://dx.doi.org/10.1080/13693780600835732DOI Listing
September 2006

Impact of the intensity of the pretransplantation conditioning regimen in patients with prior invasive aspergillosis undergoing allogeneic hematopoietic stem cell transplantation: A retrospective survey of the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation.

Blood 2006 Nov 23;108(9):2928-36. Epub 2006 May 23.

Hematology Department of Sant Pau Hospital, Autonomous University of Barcelona, Spain.

In this retrospective study, we analyzed the outcomes of 129 patients who underwent an allogeneic hematopoietic stem cell transplantation (allo-HSCT) and had a history of probable or proven invasive aspergillosis (IA), of whom 57 (44%) received a reduced-intensity conditioning (RIC). Overall, 27 patients with IA progressed after the allo-HSCT (cumulative incidence [CumInc] at 2 years, 22%). The variables that increased the 2-year CumInc of IA progression were (1) longer duration of neutropenia after transplantation; (2) advanced status of the underlying disease; and (3) less than 6 weeks from start of systemic anti-Aspergillus therapy and the allo-HSCT. In addition, (4) conventional myeloablative conditioning increased the risk of progression early after transplantation (before day 30) only, while 3 variables increased the risk beyond day 30 were (5) cytomegalovirus disease; (6) bone marrow or cord blood as source of stem cells; and (7) grades II to IV acute graft-versus-host disease (GVHD). A risk model for progression was generated, defined as low (0-1 risk factors, 6% incidence), intermediate (2-3 risk factors, 27% incidence), or high risk (> or = 3 risk factors, 72% incidence [P < .001]). These findings may help in the interpretation and design of future studies on secondary prophylaxis of IA after an allo-HSCT.
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http://dx.doi.org/10.1182/blood-2006-03-008706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895522PMC
November 2006

Bone marrow cell transfer in acute myocardial infarction.

Nat Clin Pract Cardiovasc Med 2006 Mar;3 Suppl 1:S69-72

Coronary Care Unit, Department of Cardiology, Gasthuisberg University Hospital, University of Leuven, Belgium.

Permanent loss of cardiomyocytes after ischemic injury often initiates the development of heart failure and adversely affects clinical outcome. The concept of progenitor-cell transfer for enhancing cardiac repair has raised new therapeutic prospects. Promising results have been reported in early studies in rodents, using various modalities of progenitor-cell transfer in the dysfunctional heart, although underlying mechanisms remain ill defined. Despite ongoing controversies over whether or not stem cells can autonomously adapt cardiomyocyte-like behavior after genetic reprogramming or whether they merely fuse with native host cardiomyocytes, early-phase clinical trials have shown a reassuring safety profile and suggest a functional benefit. However, identification of the intrinsic value of stem cell transfer in patients after myocardial infarction will require carefully designed randomized, placebo-controlled, blinded studies. While these are becoming available, a number of critical questions about the choice of progenitor-cell type, dosage regimen, and timing of administration need to be considered, and end points for future clinical trials need to be chosen carefully. There is great enthusiasm for this novel treatment paradigm in patients with ischemic cardiomyopathy, but only carefully conducted clinical trials paralleled by preclinical studies in relevant animal models will ultimately identify the best conditions and indications for cell transfer.
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http://dx.doi.org/10.1038/ncpcardio0440DOI Listing
March 2006

Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial.

Lancet 2006 Jan;367(9505):113-21

Department of Cardiology, Gasthuisberg University Hospital, University of Leuven, Leuven, Belgium.

Background: The benefit of reperfusion therapies for ST-elevation acute myocardial infarction (STEMI) is limited by post-infarction left-ventricular (LV) dysfunction. Our aim was to investigate the effect of autologous bone marrow-derived stem cell (BMSC) transfer in the infarct-related artery on LV function and structure.

Methods: We did a randomised, double-blind, placebo-controlled study in 67 patients from whom we harvested bone marrow 1 day after successful percutaneous coronary intervention for STEMI. We assigned patients optimum medical treatment and infusion of placebo (n=34) or BMSC (n=33). Our primary endpoint was the increase in LV ejection fraction and our secondary endpoints were change in infarct size and regional LV function at 4 months' follow-up, all assessed by MRI. We assessed changes in myocardial perfusion and oxidative metabolism with serial 1-[11C]acetate PET. Analyses were per protocol. This study is registered with , number NCT00264316.

Findings: Mean global LV ejection fraction 4 days after percutaneous coronary intervention was 46.9% (SD 8.2) in controls and 48.5% (7.2) in BMSC patients, and increased after 4 months to 49.1% (10.7) and 51.8% (8.8; OR for treatment effect 1.036, 95% CI 0.961-1.118, p=0.36). Compared with placebo infusion, BMSC transfer was associated with a significant reduction in myocardial infarct size (BMSC treatment effect 28%, p=0.036) and a better recovery of regional systolic function. Myocardial perfusion and metabolism increased similarly in both groups. We noted no complications associated with BMSC transfer and all but one patient in the BMSC group completed the 4 months' follow-up.

Interpretation: Intracoronary transfer of autologous bone marrow cells within 24 h of optimum reperfusion therapy does not augment recovery of global LV function after myocardial infarction, but could favourably affect infarct remodelling.
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http://dx.doi.org/10.1016/S0140-6736(05)67861-0DOI Listing
January 2006

Galactomannan and computed tomography-based preemptive antifungal therapy in neutropenic patients at high risk for invasive fungal infection: a prospective feasibility study.

Clin Infect Dis 2005 Nov 29;41(9):1242-50. Epub 2005 Sep 29.

Department of Hematology, University Hospital Gasthuisberg, Leuven, Belgium.

Background: Empirical antifungal therapy is the standard treatment for persistent or relapsing antibiotic-resistant neutropenic fever. However, overtreatment resulting in increased toxicity and treatment-related cost is a major shortcoming of such therapy. We assessed the feasibility of a "preemptive" approach based on the incorporation of sensitive, noninvasive diagnostic tests for consecutive high-risk neutropenic patients who had received fluconazole prophylaxis while avoiding empirical therapy.

Methods: A total of 136 treatment episodes for persons who were at risk of acquiring invasive fungal infection (IFI) were screened for the presence of galactomannan with an enzyme immunoassay. A diagnostic evaluation, which included thoracic computed tomography scanning (HRCT) and bronchoscopy with lavage, was performed on the basis of well-defined clinical, radiological, and microbiological criteria. Only seropositive patients and patients with a positive microbiological test result plus supportive radiological findings received liposomal amphotericin B.

Results: Neutropenic fever developed in 117 episodes, of which at least 41 episodes (35%) satisfied existing criteria for empirical antifungal therapy. However, our protocol-driven preemptive approach reduced the rate of antifungal use for these episodes from 35% to 7.7% (a 78% reduction) and led to the early initiation of antifungal therapy in 10 episodes (7.3%) that were clinically not suspected of being IFI. No undetected cases of invasive aspergillosis were identified; 1 case of zygomycosis was missed. Breakthrough candidemia was diagnosed by conventional culture techniques and was treated successfully. With use of a preemptive approach, the 12-week survival rate for patients with IFI was 63.6% (it was 63.1% for those with invasive aspergillosis).

Conclusion: Preemptive therapy based on enzyme immunoassay and HRCT reduced the exposure to expensive and potentially toxic drugs and offered effective antifungal control, but it failed to detect non-Aspergillus IFI.
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http://dx.doi.org/10.1086/496927DOI Listing
November 2005

Fatal pulmonary infection in a leukaemic patient caused by Hormographiella aspergillata.

J Med Microbiol 2005 Jul;54(Pt 7):685-688

Immunology and Microbiology1, Hematology2, Internal Medicine3 and Pathology5, University Hospital Leuven, Herestraat 49, 3000 Leuven, Belgium 4Laboratory for Microbiology, MCH, Maria Theresiastraat 63A, 3000 Leuven, Belgium.

A case of autopsy-proven fungal pneumonia in a relapsed leukaemia patient is reported. The fungus Hormographiella aspergillata was cultured from two bronchoalveolar fluid samples and identified through morphological examination and ITS2 sequence analysis. In addition, galactomannan was detected in eight consecutive serum samples, which suggested a co-infection with Aspergillus species. The patient was treated with caspofungin.
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http://dx.doi.org/10.1099/jmm.0.46016-0DOI Listing
July 2005

A multifactorial analysis of umbilical cord blood, adult bone marrow and mobilized peripheral blood progenitors using the improved ML-IC assay.

Exp Hematol 2005 Feb;33(2):165-72

Stem Cell Biology Program, Department of Medicine and Cancer Center, University of Minnesota Medical School, Minneapolis, Minn., USA.

Objective: Assays that can evaluate the potential of individual human hematopoietic stem cells (HSC) are still lacking. We previously developed the myeloid-lymphoid initiating cell (ML-IC) assay that enumerates single CD34(+) cells that generate long-term culture-initiating (LTC-IC) and NK-initiating (NK-IC) daughter cells, or single primitive progenitors with multilineage potential. When transplanted in vivo, umbilical cord blood (UCB) has greater repopulating ability than bone marrow (BM) or mobilized peripheral blood (MPB). Whether the greater in vivo repopulating ability is due to an increased frequency of HSC in UCB and generative potential of UCB, BM, and MPB CD34(+) cells is not known.

Materials And Methods: Single UCB, BM, and MPB CD34(+)CD38(-)Lin(-) or CD34(+)CD38(-)CD33(-) cells were plated in ML-IC assay and after 2 to 4 weeks, progeny was evaluated for frequency and generative potential of ML-IC. We also tested whether the ML-IC assay could be used to define if increased numbers of primitive progenitors generated by different cytokines in expansion cultures are mediated by recruitment of quiescent cells or by increasing their generative potential.

Results: The frequency of ML-IC in BM, UCB, and MPB was similar, but the generative potential of UCB ML-IC was significantly higher. Substitution of Flt3-L, SCF, and IL-7 with Flt3-L and thrombopoietin significantly increased the generative potential of ML-IC, whereas Flt3-L, SCF, and hyper-IL-6 increased both ML-IC frequency and generative potential.

Conclusion: The ML-IC assay demonstrates that the greater repopulating ability of UCB is due to the higher generative ability of HSC in UCB. Furthermore, the ML-IC assay can discriminate between cytokine-mediated expansion of hematopoietic progenitors by enhancing generation of immature daughter cells or by recruiting otherwise quiescent cells.
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http://dx.doi.org/10.1016/j.exphem.2004.10.016DOI Listing
February 2005

Early detection of Toxoplasma infection by molecular monitoring of Toxoplasma gondii in peripheral blood samples after allogeneic stem cell transplantation.

Clin Infect Dis 2005 Jan 7;40(1):67-78. Epub 2004 Dec 7.

Division of Clinical Hematology, Hospital de la Sant Creu i Sant Pau, Barcelona, Spain.

Background: Isolated case reports have shown that recipients of allogeneic hematopoietic stem cell transplants (HSCTs) who develop toxoplasmosis may have circulating Toxoplasma gondii DNA in peripheral blood before the onset of clinical symptoms.

Methods: We prospectively studied 106 T. gondii-seropositive adult recipients of HSCTs for the incidence of reactivation of toxoplasmosis in the first 6 months after transplantation. Toxoplasmosis infection (TI) was defined by a positive result of polymerase chain reaction (PCR) of peripheral blood specimens, whereas toxoplasmosis disease (TD) was defined as an invasive infection.

Results: The incidence of TI was 16% (95% confidence interval [CI], 8%-21%), whereas the incidence of TD was 6% (95% CI, 1%-10%). In the 16 patients with TI, the incidence of disease was 38%, whereas it was 0% in patients without TI (P<.0001). In most patients, the onset of TD or treatment for TI was preceded by an increase in the parasite load in peripheral blood samples, as determined by quantitative PCR.

Conclusions: Toxoplasmosis occurs more commonly after HSCT than has previously been suggested, and routine PCR testing of peripheral blood specimens may be an appropriate tool for guiding preemptive therapy in patients at very high risk of developing invasive disease.
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http://dx.doi.org/10.1086/426447DOI Listing
January 2005