Clinical outcomes in patients with Philadelphia chromosome-positive leukemia treated with ponatinib in routine clinical practice-data from a Belgian registry.

Data on clinical use of ponatinib are limited. This prospective registry aimed to evaluate outcomes of ponatinib treatment in routine practice over 3 years (2016-2019) in Belgium (NCT03678454). Patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) were treated with ponatinib per current label. Fifty patients (33 CML and 17 Ph+ ALL) were enrolled. Fifty-five percent of CML and 29% of Ph+ ALL patients had received ≥3 prior tyrosine kinase inhibitors (TKIs). Reasons for starting ponatinib were intolerance (40%), relapse or refractoriness (28%) to previous TKIs, progression (16%), or T315I mutation (16%). Median follow-up was 15 months for CML and 4.5 months for Ph+ ALL patients. Best response was a major molecular response in 58% of CML and 41% of Ph+ ALL patients. Of 20 patients who started ponatinib due to intolerance to previous TKIs, 9 (64%) CML and 4 (67%) Ph+ ALL achieved a major molecular response. Three-year estimates of overall survival were 85.3% and 85.6%, respectively, in CML and Ph+ ALL patients; estimated progression-free survival was 81.6% and 48.9%. Adverse reactions were reported in 34 patients (68%); rash (26%) and dry skin (10%) were most common. Reported cardiovascular adverse reactions included vascular stenosis (3), arterial hypertension (2), chest pain (1), palpitations (1), and vascular occlusion (1). This Belgian registry confirms results from the PACE clinical trial and supports routine ponatinib use in CML and Ph+ ALL patients who are resistant or intolerant to previous TKIs or with the T315I mutation.

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).

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.

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

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

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 × 109 /L [33.3%], and platelet > 400 × 109 /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.

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

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.

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.

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.

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

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.

Acute autonomic dysregulation due to HHV-6 encephalitis in an immunocompromised patient: a case report and literature review.

Human herpesvirus-6 (HHV-6), in particularly HHV-6B, can reactivate in immunocompromised patients. Especially after stem cell transplantation, reactivation of HHV-6 can cause complications, such as limbic encephalitis. We present a case of a 61-year-old man with B-cell non-Hodgkin lymphoma. He presented with subacute lethargy, confusion and hyperhidrosis. Following this, we will give a short review of the literature considering clinical and technical features as well as treatment options.

The Dynamics of Nucleotide Variants in the Progression from Low-Intermediate Myeloma Precursor Conditions to Multiple Myeloma: Studying Serial Samples with a Targeted Sequencing Approach.

Multiple myeloma (MM), or Kahler's disease, is an incurable plasma cell (PC) cancer in the bone marrow (BM). This malignancy is preceded by one or more asymptomatic precursor conditions, monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering multiple myeloma (SMM). The molecular mechanisms and exact cause of this progression are still not completely understood. In this study, the mutational profile underlying the progression from low-intermediate risk myeloma precursor conditions to MM was studied in serial BM smears. A custom capture-based sequencing platform was developed, including 81 myeloma-related genes. The clonal evolution of single nucleotide variants and short insertions and deletions was studied in serial BM smears from 21 progressed precursor patients with a median time of progression of six years. From the 21 patients, four patients had no variation in one of the 81 studied genes. Interestingly, in 16 of the 17 other patients, at least one variant present in MM was also detected in its precursor BM, even years before progression. Here, the variants were present in the pre-stage at a median of 62 months before progression to MM. Studying these paired BM samples contributes to the knowledge of the evolutionary genetic landscape and provides additional insight into the mutational behavior of mutant clones over time throughout progression.

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.

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.

Adjunctive Volasertib in Patients With Acute Myeloid Leukemia not Eligible for Standard Induction Therapy: A Randomized, Phase 3 Trial.

In this phase 3 trial, older patients with acute myeloid leukemia ineligible for intensive chemotherapy were randomized 2:1 to receive the polo-like kinase inhibitor, volasertib (V; 350 mg intravenous on days 1 and 15 in 4-wk cycles), combined with low-dose cytarabine (LDAC; 20 mg subcutaneous, twice daily, days 1-10; n = 444), or LDAC plus placebo (P; n = 222). Primary endpoint was objective response rate (ORR); key secondary endpoint was overall survival (OS). Primary ORR analysis at recruitment completion included patients randomized ≥5 months beforehand; ORR was 25.2% for V+LDAC and 16.8% for P+LDAC (n = 371; odds ratio 1.66 [95% confidence interval (CI), 0.95-2.89]; P = 0.071). At final analysis (≥574 OS events), median OS was 5.6 months for V+LDAC and 6.5 months for P+LDAC (n = 666; hazard ratio 0.97 [95% CI, 0.8-1.2]; P = 0.757). The most common adverse events (AEs) were infections/infestations (grouped term; V+LDAC, 81.3%; P+LDAC, 63.5%) and febrile neutropenia (V+LDAC, 60.4%; P+LDAC, 29.3%). Fatal AEs occurred in 31.2% with V+LDAC versus 18.0% with P+LDAC, most commonly infections/infestations (V+LDAC, 17.1%; P+LDAC, 6.3%). Lack of OS benefit with V+LDAC versus P+LDAC may reflect increased early mortality with V+LDAC from myelosuppression and infections.

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

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.

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.

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.

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

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.

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.

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.

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

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.

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

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.

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

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.

Bone marrow cell transfer in acute myocardial infarction.

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.