Peter Lang - Academia.edu (original) (raw)
Papers by Peter Lang
Frontiers in Immunology, 2013
In the last decade several therapeutic antibodies have been Federal Drug Administration (FDA) and... more In the last decade several therapeutic antibodies have been Federal Drug Administration (FDA) and European Medicines Agency (EMEA) approved. Although their mechanisms of action in vivo is not fully elucidated, antibody-dependent cellular cytotoxicity (ADCC) mediated by natural killer (NK) cells is presumed to be a key effector function. A substantial role of ADCC has been demonstrated in vitro and in mouse tumor models. However, a direct in vivo effect of ADCC in tumor reactivity in humans remains to be shown. Several studies revealed a predictive value of FcγRIIIa-V158F polymorphism in monoclonal antibody treatment, indicating a potential effect of ADCC on outcome for certain indications. Furthermore, the use of therapeutic antibodies after allogeneic hematopoietic stem cell transplantation is an interesting option. Studying the role of the FcγRIIIa-V158F polymorphism and the influence of Killer-cell Immunoglobuline-like Receptor (KIR) receptor ligand incompatibility on ADCC in this approach may contribute to future transplantation strategies. Despite the success of approved second-generation antibodies in the treatment of several malignancies, efforts are made to further augment ADCC in vivo by antibody engineering. Here, we review currently used therapeutic antibodies for which ADCC has been suggested as effector function.
British journal of haematology, 2018
Poor graft function (PGF) is a severe complication of haematopoietic stem cell transplantation (H... more Poor graft function (PGF) is a severe complication of haematopoietic stem cell transplantation (HSCT) and administration of donor stem cell boosts (SCBs) represents a therapeutic option. We report 50 paediatric patients with PGF who received 61 boosts with CD34+ selected peripheral blood stem cells (PBSC) after transplantation from matched unrelated (n = 25) or mismatched related (n = 25) donors. Within 8 weeks, a significant increase in median neutrophil counts (0·6 vs. 1·516 × 109 /l, P < 0·05) and a decrease in red blood cell and platelet transfusion requirement (median frequencies 1 and 7 vs. 0, P < 0·0001 and <0·001), were observed, and 78·8% of patients resolved one or two of their cytopenias. 36·5% had a complete haematological response. Median lymphocyte counts for CD3+ , CD3+ CD4+ , CD19+ and CD56+ increased 8·3-, 14·2-, 22.- and 1·6-fold. The rate of de novo acute graft-versus-host disease (GvHD) grade I-III was only 6% and resolved completely. No GvHD grade IV or...
Der Onkologe, 2011
ABSTRACT Im Rahmen aktueller Therapieoptimierungsstudien, die z.T. eine Hochdosischemotherapie mi... more ABSTRACT Im Rahmen aktueller Therapieoptimierungsstudien, die z.T. eine Hochdosischemotherapie mit autologem Stammzellsupport (autologe Stammzelltransplantation) einschließen, können pädiatrische Patienten mit soliden Tumoren häufig erfolgreich behandelt werden. Metastasierte Rezidive und bestimmte Höchstrisikogruppen hingegen können meist noch nicht kurativ angegangen werden. Eventuell könnten diese Patienten von einer allogenen Transplantation und dem damit verbundenen, immunologisch vermittelten Antitumoreffekt profitieren. Obwohl frühere, nicht randomisierte Vergleichsstudien mit stark limitierter Patientenzahl keinen Vorteil für die allogene Transplantation ergaben, existieren genügend experimentelle und klinische Hinweise auf einen Graft-versus-Tumor(GvT)-Effekt, um eine neuerliche Evaluation in aktuell laufenden pädiatrischen Studien mit deutlich reduzierter transplantationsassoziierter Toxizität zu rechtfertigen. Von der GPOH (Gesellschaft für pädiatrische Onkologie und Hämatologie) wird v.a. die Stammzelltransplantation von einem haploidentischen Familienspender mit nachfolgender Immuntherapie untersucht. High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation has been established for the treatment of several forms of pediatric tumors. However, patients with metastatic relapse or specific high risk groups still have a poor prognosis. It is an ongoing matter of debate if these patients may benefit from potential graft versus tumor (GvT) effects after allogenic stem cell transplantation. Although previous non-randomized retrospective studies with a limited number of patients were not able to show an advantage for allotransplants, there is clear experimental or clinical evidence for the existence of GvT effects. Moreover, since transplant-related toxicity has markedly improved in recent years, ongoing clinical trials have to re-evaluate the role of contemporary approaches for allotransplantation. German studies are focusing on immunological effects exerted by haploidentical family donors and on additional posttransplantation immunotherapy. SchlüsselwörterNK-Zellen–GvT-Effekt–Stammzelltransplantation–Solide Tumoren–Metastasen KeywordsNK cells–Graft versus tumor effect–Stem cell transplantation–Solid tumor–Neoplasm metastasis
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2014
Quantitative real-time PCR (qPCR) has been proposed as a highly sensitive method for monitoring h... more Quantitative real-time PCR (qPCR) has been proposed as a highly sensitive method for monitoring hematopoietic chimerism and may serve as a surrogate marker for the detection of minimal residual disease minimal residual disease in myelodysplastic syndrome (MDS), until specific methods of detection become available. Because a systematic comparison of the clinical utility of qPCR with the gold standard short tandem repeat (STR)-PCR has not been reported, we retrospectively measured chimerism by qPCR in 54 children transplanted for MDS in a previous study. Results obtained by STR-PCR in the initial study served as comparison. Because the detection limit of qPCR was sufficiently low to detect an autologous background, we defined the sample as mixed chimera if the proportion of recipient-derived cells exceeded .5%. The true positive rates were 100% versus 80% (qPCR versus STR-PCR, not significant), and mixed chimerism in most cases was detected earlier by qPCR than by STR-PCR (median, 31 ...
Journal of immunology (Baltimore, Md. : 1950), 2014
Graft-versus-host disease (GvHD) is a major cause of morbidity and mortality after allogeneic hem... more Graft-versus-host disease (GvHD) is a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. However, the pathophysiology of GvHD remains poorly understood. In this study, we analyzed the induction of Th17 cells by monocytes of patients with GvHD in vitro, demonstrating that monocytes isolated from patients with acute skin and intestinal GvHD stage I-IV and chronic GvHD induce significantly increased levels of Th17 cells compared with patients without GvHD. S100 proteins are known to act as innate amplifier of inflammation. We therefore investigated the presence of S100 proteins in the stool, serum, and bowel tissue of patients with GvHD and the influence of S100 proteins on the induction of Th17 cells. Elevated levels of S100 proteins could be detected in patients with acute GvHD, demonstrating the release of these phagocyte-specific proteins during GvHD. Furthermore, stimulation of monocytes with S100 proteins was found to promote Th17 developm...
Blood, Jan 18, 2014
Therapeutic natural killer (NK)-cell-mediated alloreactivity toward acute myeloid leukemia has la... more Therapeutic natural killer (NK)-cell-mediated alloreactivity toward acute myeloid leukemia has largely been attributed to mismatches between killer immunoglobulin-like receptors (KIRs) on NK cells and their ligands, HLA class I molecules, on target cells. While adult acute B-cell precursor leukemia (BCP-ALL) appears to be resistant to NK-cell-mediated lysis, recent data indicate that pediatric BCP-ALL might yet be a target of NK cells. In this study, we demonstrate in a donor-patient-specific NOD.Cg-Prkdc(scid) IL2rg(tmWjl)/Sz (NSG) xenotransplantation model that NK cells mediate considerable alloreactivity toward pediatric BCP-ALL in vivo. Notably, both adoptively transferred mature KIR(+) NK cells and immature KIR(-) NK cells arising early posttransplantation in humanized NSG mice exerted substantial antileukemic activity. Low-dose and long-term treatment of humanized NSG mice with the DNA-demethylating agent 5-aza-cytidine distinctly enhanced the antitumor response, interestingly...
Clinical science (London, England : 1979), 2015
Our previous studies in rats showed that incubation of monocytic dendritic cells (DCs) with the c... more Our previous studies in rats showed that incubation of monocytic dendritic cells (DCs) with the chemotherapeutic drug mitomycin C (MMC) renders the cells immunosuppressive. Donor-derived MMC-DCs injected into the recipient prior to transplantation prolonged heart allograft survival. Although the generation of DCs is labour-intensive and time-consuming, peripheral blood mononuclear cells (PBMCs) can be easily harvested. In the present study, we analyse under which conditions DCs can be replaced by PBMCs and examine their mode of action. When injected into rats, MMC-incubated donor PBMCs (MICs) strongly prolonged heart allograft survival. Removal of monocytes from PBMCs completely abrogated their suppressive effect, indicating that monocytes are the active cell population. Suppression of rejection was donor-specific. The injected MICs migrated into peripheral lymphoid organs and led to an increased number of regulatory T-cells (Tregs) expressing cluster of differentiation (CD) markers...
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 9, 2015
Although hematopoietic stem-cell transplantation is widely performed in children with high-risk a... more Although hematopoietic stem-cell transplantation is widely performed in children with high-risk acute lymphoblastic leukemia (ALL), the influence of donor types is poorly understood. Thus, transplantation outcomes were compared in the prospective multinational Berlin-Frankfurt-Muenster (BFM) study group trial: ALL-SCT-BFM 2003 (Allogeneic Stem Cell Transplantation in Children and Adolescents with Acute Lymphoblastic Leukemia). After conditioning with total-body irradiation and etoposide, 411 children with high-risk ALL received highly standardized stem-cell transplantations during the first or later remissions. Depending on donor availability, grafts originated from HLA-genoidentical siblings or from HLA-matched unrelated donors who were identified and matched by high-resolution allelic typing and were compatible in at least 9 of 10 HLA loci. Four-year event-free survival (± standard deviation [SD]) did not differ between patients with transplantations from unrelated or sibling dono...
der · M. Schumm · R. Hand gre tin ger · T. Klin ge bi el P. G. Schle gel · J. F. Beck · H. G. Sch... more der · M. Schumm · R. Hand gre tin ger · T. Klin ge bi el P. G. Schle gel · J. F. Beck · H. G. Scheel-Wal ter · D. Niet ham mer Uni ver si täts kin der kli nik, Eber hard-Karls-Uni ver si tät, Tü bin gen Be ar bei tung und Trans planta ti on hä ma to poe ti scher Stamm zel len Er geb nis se und kli ni scher Nut zen der Stammzellauf rei ni gung von al ter na ti ven Spen dern für die al lo ge ne Trans plan ta ti on im Kin desal ter Monatsschrift Kinderheilkd 2005 · 153:954-964 Die se Ar beit wur de un ter stützt durch die Deut sche For schungs ge mein schaft (SFB 510), die José-Car reras-Stif tung, die Rein hold-Beit lich-Stif tung, die Deut sche Krebs hil fe, die Wil helm-San der-Stif tung und das BMBF Tü bin gen Zusammenfassung · Abstract Monatsschrift Kinderheilkd 2005 · 153:954-964
Psychiatry research, Jan 30, 2014
The extent and time course of competition between a specific fear cue and task-related stimuli in... more The extent and time course of competition between a specific fear cue and task-related stimuli in early human visual cortex was investigated using electrophysiology. Steady-state visual evoked potentials (ssVEPs) were evoked using random-dot kinematograms that consisted of rapidly flickering (8.57 Hz) dots moving randomly, superimposed upon emotional or neutral distractor pictures. Participants were asked to detect intervals of coherently moving dots, ignoring the distractor pictures that varied in hedonic content. Women reporting high or low levels of snake fear were recruited from a large sample of healthy college students, and snake pictures served as fear-relevant distractors. The time-varying amplitude of the ssVEP evoked by the motion detection task showed significant reduction when viewing emotionally arousing, compared to neutral, distractors, replicating previous studies. For high-fear participants, snake distractors elicited a sustained attenuation of task evoked ssVEP amp...
Psychophysiology, 2015
Mental imagery is a fundamental cognitive process of interest to basic scientists and clinical re... more Mental imagery is a fundamental cognitive process of interest to basic scientists and clinical researchers. This study examined large-scale oscillatory brain activity in the alpha band (8-12 Hz) during language-driven mental imagery using dense-array EEG. Three experiments demonstrated relative increases in alpha amplitude: (1) during imagery prompted by words compared to fixation without imagery instruction, (2) during imagery of word content compared to imagery of geometric shapes, and (3) during imagery of emotionally evocative words compared to imagery of less emotionally arousing content. Alpha increases for semantically loaded imagery were observed in parieto-occipital regions, sustained throughout the imagery period. Findings imply that alpha oscillations index active memory and internal cognitive processing, reflecting neural communication in cortical networks representing motor, semantic, and perceptual aspects of the imagined scene.
Cytotherapy, 2015
Human mesenchymal stem or stromal cells (MSCs) represent a potential resource not only for regene... more Human mesenchymal stem or stromal cells (MSCs) represent a potential resource not only for regenerative medicine but also for immunomodulatory cell therapies. The application of different MSC culture protocols has significantly hampered the comparability of experimental and clinical data from different laboratories and has posed a major obstacle for multicenter clinical trials. Manufacturing of cell products for clinical application in the European Community must be conducted in compliance with Good Manufacturing Practice and requires a manufacturing license. In Germany, the Paul-Ehrlich-Institut as the Federal Authority for Vaccines and Biomedicines is critically involved in the approval process. This report summarizes a consensus meeting between researchers, clinicians and regulatory experts on standard quality requirements for MSC production. The strategy for quality control testing depends on the product's cell composition, the manufacturing process and the indication and ta...
Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions, 2014
Pediatric and Congenital Interventional Cardiology is the practice of catheter-based techniques t... more Pediatric and Congenital Interventional Cardiology is the practice of catheter-based techniques that improve cardiac physiology and circulation through the treatment of heart disease in children and adults with congenital or acquired heart defects. Over the last decade, and since last published training guidelines for pediatric cardiac catheterization and interventional cardiology were published in 2005 [1] the field of Pediatric and Congenital Cardiac Catheterization has evolved into a predominantly interventional discipline. As there is no sub-specialty certification for interventional cardiac catheterization in pediatrics, the Congenital Heart Disease Committee of the Society of Cardiovascular Angiography and Interventions has put together this consensus statement for advanced training in pediatric and congenital interventional cardiac catheterization. The statement puts forth recommendations for program infrastructure in terms of teaching, personnel, equipment, facilities, confe...
Blood, Jan 23, 2015
Hematopoietic stem cell transplantation (HSCT) has improved over the last decades. However, viral... more Hematopoietic stem cell transplantation (HSCT) has improved over the last decades. However, viral infections often remain refractory to pharmacologic treatment and require alternative treatment strategies such as immunotherapy. Adenovirus (AdV) is the predominant disease-causing pathogen in pediatric HSCT. In a clinical trial we analyzed safety and efficacy of ex vivo adoptive T-cell transfer (ACT) with hexon-specific T cells, predominantly of THELPER-1 phenotype, in thirty patients with AdV disease/viremia. ACT was feasible without acute toxicities or significant onset of graft-versus-host disease. ACT led to antiviral immunity in vivo up to 6 months with viral control, resulting in complete clearance of viremia in 86% of patients with antigen-specific T-cell responses. After a follow up of 6 months post ACT, overall survival was markedly increased in responders (mean: 122 days, 15 survivors) as compared to non-responders who all died shortly after ACT (mean: 24 days, no survivors)...
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 20, 2015
To elucidate the impact of minimal residual disease (MRD) after allogeneic transplantation, the A... more To elucidate the impact of minimal residual disease (MRD) after allogeneic transplantation, the Acute Lymphoblastic Leukemia Berlin-Frankfurt-Münster Stem Cell Transplantation Group (ALL-BFM-SCT) conducted a prospective clinical trial. In the ALL-BFM-SCT 2003 trial, MRD was assessed in the bone marrow at days +30, +60, +90, +180, and +365 after transplantation in 113 patients with relapsed disease. Standardized quantification of MRD was performed according to the guidelines of the Euro-MRD Group. All patients showed a 3-year probability of event-free survival (pEFS) of 55%. The cumulative incidence rates of relapse and treatment-related mortality were 32% and 12%, respectively. The pEFS was 60% for patients who received their transplantations in second complete remission, 50% for patients in ≥ third complete remission, and 0% for patients not in remission (P = .015). At all time points, the level of MRD was inversely correlated with event-free survival (EFS; P < .004) and positiv...
NeuroImage, 2011
Heightened perception of facial cues is at the core of many theories of social behavior and its d... more Heightened perception of facial cues is at the core of many theories of social behavior and its disorders. In the present study, we continuously measured electrocortical dynamics in human visual cortex, as evoked by happy, neutral, fearful, and angry faces. Thirty-seven participants endorsing high versus low generalized social anxiety (upper and lower tertiles of 2,104 screened undergraduates) viewed naturalistic faces flickering at 17.5 Hz to evoke steady-state visual evoked potentials (ssVEPs), recorded from 129 scalp electrodes. Electrophysiological data were evaluated in the time-frequency domain after linear source space projection using the minimum norm method. Source estimation indicated an early visual cortical origin of the face-evoked ssVEP, which showed sustained amplitude enhancement for emotional expressions specifically in individuals with pervasive social anxiety. Participants in the low symptom group showed no such sensitivity, and a correlational analysis across the entire sample revealed a strong relationship between self-reported interpersonal anxiety/avoidance and enhanced visual cortical response amplitude for emotional, versus neutral expressions. This pattern was maintained across the 3500 ms viewing epoch, suggesting that temporally sustained, heightened perceptual bias towards affective facial cues is associated with generalized social anxiety.
Klinische Pädiatrie, 2013
Viral infections after allogeneic stem cell transplantation (SCT) are an important cause of morbi... more Viral infections after allogeneic stem cell transplantation (SCT) are an important cause of morbidity and mortality as SCT can expose patients to a transient state of combined immunodeficieny. Most viral infections after SCT are caused by the endogenous reactivation of persistent pathogens such as adenovirus (ADV), cytomegalovirus (CMV), and Epstein-Barr-virus (EBV). The control of these infections will ultimately depend on the restoration of adequate T-cell immunity.
The Journal of Thoracic and Cardiovascular Surgery, 2000
We compared the Norwood stage I operation for hypoplastic left heart syndrome and other complex m... more We compared the Norwood stage I operation for hypoplastic left heart syndrome and other complex malformations with ductus-dependent systemic circulation. A retrospective study of 194 patients who underwent a Norwood stage I palliation between 1990 and 1998 was conducted. Malformations in 131 patients were classified as hypoplastic left heart syndrome, defined as aortic and mitral atresia or severe stenosis, normal segmental anatomy, intact ventricular septum, and hypoplasia of the left ventricle. Sixty three patients had other lesions: hypoplastic left ventricle with ventricular septal defect (n = 18), unbalanced complete atrioventricular canal (n = 9), complex double-outlet right ventricle (n = 14), double-inlet left ventricle (n = 11), tricuspid atresia with transposition of the great arteries (n = 6), and others (n = 5), including heterotaxia. Operative (>30 days) and 1-year survivals were lower for patients with hypoplastic left heart syndrome than for those with other lesions (63.4% vs 81%, P =.008, and 51.2% vs 71.4%, P =.02, respectively). The presence of a nonhypoplastic left ventricle (n = 27) was associated with higher operative and 1-year survivals (96.3% vs 64.7%, P =.002; 88.9% vs 52. 7%, P <.001). A restrictive atrial septal defect and prematurity tended to increase mortality across both groups. Cox proportional hazards regression indicated that a single right ventricle was the most important independent predictor of death (P <.001). Operative mortality for all patients undergoing the stage I procedure decreased from 38.5% (1990-1994) to 21.4% after 1994 (P =.02). The survival of patients with malformations other than hypoplastic left heart syndrome after the Norwood procedure is greater than for those with hypoplastic left heart syndrome. Staged palliation is valid surgical therapy in these patients, with good results in intermediate follow-up.
The Journal of Thoracic and Cardiovascular Surgery, 2001
Objective: Early primary repair of tetralogy of Fallot has been routinely performed at Children's... more Objective: Early primary repair of tetralogy of Fallot has been routinely performed at Children's Hospital, Boston, since 1972. We evaluated the long-term outcome of this treatment strategy including the influence of a transannular patch.
Frontiers in Immunology, 2013
In the last decade several therapeutic antibodies have been Federal Drug Administration (FDA) and... more In the last decade several therapeutic antibodies have been Federal Drug Administration (FDA) and European Medicines Agency (EMEA) approved. Although their mechanisms of action in vivo is not fully elucidated, antibody-dependent cellular cytotoxicity (ADCC) mediated by natural killer (NK) cells is presumed to be a key effector function. A substantial role of ADCC has been demonstrated in vitro and in mouse tumor models. However, a direct in vivo effect of ADCC in tumor reactivity in humans remains to be shown. Several studies revealed a predictive value of FcγRIIIa-V158F polymorphism in monoclonal antibody treatment, indicating a potential effect of ADCC on outcome for certain indications. Furthermore, the use of therapeutic antibodies after allogeneic hematopoietic stem cell transplantation is an interesting option. Studying the role of the FcγRIIIa-V158F polymorphism and the influence of Killer-cell Immunoglobuline-like Receptor (KIR) receptor ligand incompatibility on ADCC in this approach may contribute to future transplantation strategies. Despite the success of approved second-generation antibodies in the treatment of several malignancies, efforts are made to further augment ADCC in vivo by antibody engineering. Here, we review currently used therapeutic antibodies for which ADCC has been suggested as effector function.
British journal of haematology, 2018
Poor graft function (PGF) is a severe complication of haematopoietic stem cell transplantation (H... more Poor graft function (PGF) is a severe complication of haematopoietic stem cell transplantation (HSCT) and administration of donor stem cell boosts (SCBs) represents a therapeutic option. We report 50 paediatric patients with PGF who received 61 boosts with CD34+ selected peripheral blood stem cells (PBSC) after transplantation from matched unrelated (n = 25) or mismatched related (n = 25) donors. Within 8 weeks, a significant increase in median neutrophil counts (0·6 vs. 1·516 × 109 /l, P < 0·05) and a decrease in red blood cell and platelet transfusion requirement (median frequencies 1 and 7 vs. 0, P < 0·0001 and <0·001), were observed, and 78·8% of patients resolved one or two of their cytopenias. 36·5% had a complete haematological response. Median lymphocyte counts for CD3+ , CD3+ CD4+ , CD19+ and CD56+ increased 8·3-, 14·2-, 22.- and 1·6-fold. The rate of de novo acute graft-versus-host disease (GvHD) grade I-III was only 6% and resolved completely. No GvHD grade IV or...
Der Onkologe, 2011
ABSTRACT Im Rahmen aktueller Therapieoptimierungsstudien, die z.T. eine Hochdosischemotherapie mi... more ABSTRACT Im Rahmen aktueller Therapieoptimierungsstudien, die z.T. eine Hochdosischemotherapie mit autologem Stammzellsupport (autologe Stammzelltransplantation) einschließen, können pädiatrische Patienten mit soliden Tumoren häufig erfolgreich behandelt werden. Metastasierte Rezidive und bestimmte Höchstrisikogruppen hingegen können meist noch nicht kurativ angegangen werden. Eventuell könnten diese Patienten von einer allogenen Transplantation und dem damit verbundenen, immunologisch vermittelten Antitumoreffekt profitieren. Obwohl frühere, nicht randomisierte Vergleichsstudien mit stark limitierter Patientenzahl keinen Vorteil für die allogene Transplantation ergaben, existieren genügend experimentelle und klinische Hinweise auf einen Graft-versus-Tumor(GvT)-Effekt, um eine neuerliche Evaluation in aktuell laufenden pädiatrischen Studien mit deutlich reduzierter transplantationsassoziierter Toxizität zu rechtfertigen. Von der GPOH (Gesellschaft für pädiatrische Onkologie und Hämatologie) wird v.a. die Stammzelltransplantation von einem haploidentischen Familienspender mit nachfolgender Immuntherapie untersucht. High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation has been established for the treatment of several forms of pediatric tumors. However, patients with metastatic relapse or specific high risk groups still have a poor prognosis. It is an ongoing matter of debate if these patients may benefit from potential graft versus tumor (GvT) effects after allogenic stem cell transplantation. Although previous non-randomized retrospective studies with a limited number of patients were not able to show an advantage for allotransplants, there is clear experimental or clinical evidence for the existence of GvT effects. Moreover, since transplant-related toxicity has markedly improved in recent years, ongoing clinical trials have to re-evaluate the role of contemporary approaches for allotransplantation. German studies are focusing on immunological effects exerted by haploidentical family donors and on additional posttransplantation immunotherapy. SchlüsselwörterNK-Zellen–GvT-Effekt–Stammzelltransplantation–Solide Tumoren–Metastasen KeywordsNK cells–Graft versus tumor effect–Stem cell transplantation–Solid tumor–Neoplasm metastasis
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2014
Quantitative real-time PCR (qPCR) has been proposed as a highly sensitive method for monitoring h... more Quantitative real-time PCR (qPCR) has been proposed as a highly sensitive method for monitoring hematopoietic chimerism and may serve as a surrogate marker for the detection of minimal residual disease minimal residual disease in myelodysplastic syndrome (MDS), until specific methods of detection become available. Because a systematic comparison of the clinical utility of qPCR with the gold standard short tandem repeat (STR)-PCR has not been reported, we retrospectively measured chimerism by qPCR in 54 children transplanted for MDS in a previous study. Results obtained by STR-PCR in the initial study served as comparison. Because the detection limit of qPCR was sufficiently low to detect an autologous background, we defined the sample as mixed chimera if the proportion of recipient-derived cells exceeded .5%. The true positive rates were 100% versus 80% (qPCR versus STR-PCR, not significant), and mixed chimerism in most cases was detected earlier by qPCR than by STR-PCR (median, 31 ...
Journal of immunology (Baltimore, Md. : 1950), 2014
Graft-versus-host disease (GvHD) is a major cause of morbidity and mortality after allogeneic hem... more Graft-versus-host disease (GvHD) is a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. However, the pathophysiology of GvHD remains poorly understood. In this study, we analyzed the induction of Th17 cells by monocytes of patients with GvHD in vitro, demonstrating that monocytes isolated from patients with acute skin and intestinal GvHD stage I-IV and chronic GvHD induce significantly increased levels of Th17 cells compared with patients without GvHD. S100 proteins are known to act as innate amplifier of inflammation. We therefore investigated the presence of S100 proteins in the stool, serum, and bowel tissue of patients with GvHD and the influence of S100 proteins on the induction of Th17 cells. Elevated levels of S100 proteins could be detected in patients with acute GvHD, demonstrating the release of these phagocyte-specific proteins during GvHD. Furthermore, stimulation of monocytes with S100 proteins was found to promote Th17 developm...
Blood, Jan 18, 2014
Therapeutic natural killer (NK)-cell-mediated alloreactivity toward acute myeloid leukemia has la... more Therapeutic natural killer (NK)-cell-mediated alloreactivity toward acute myeloid leukemia has largely been attributed to mismatches between killer immunoglobulin-like receptors (KIRs) on NK cells and their ligands, HLA class I molecules, on target cells. While adult acute B-cell precursor leukemia (BCP-ALL) appears to be resistant to NK-cell-mediated lysis, recent data indicate that pediatric BCP-ALL might yet be a target of NK cells. In this study, we demonstrate in a donor-patient-specific NOD.Cg-Prkdc(scid) IL2rg(tmWjl)/Sz (NSG) xenotransplantation model that NK cells mediate considerable alloreactivity toward pediatric BCP-ALL in vivo. Notably, both adoptively transferred mature KIR(+) NK cells and immature KIR(-) NK cells arising early posttransplantation in humanized NSG mice exerted substantial antileukemic activity. Low-dose and long-term treatment of humanized NSG mice with the DNA-demethylating agent 5-aza-cytidine distinctly enhanced the antitumor response, interestingly...
Clinical science (London, England : 1979), 2015
Our previous studies in rats showed that incubation of monocytic dendritic cells (DCs) with the c... more Our previous studies in rats showed that incubation of monocytic dendritic cells (DCs) with the chemotherapeutic drug mitomycin C (MMC) renders the cells immunosuppressive. Donor-derived MMC-DCs injected into the recipient prior to transplantation prolonged heart allograft survival. Although the generation of DCs is labour-intensive and time-consuming, peripheral blood mononuclear cells (PBMCs) can be easily harvested. In the present study, we analyse under which conditions DCs can be replaced by PBMCs and examine their mode of action. When injected into rats, MMC-incubated donor PBMCs (MICs) strongly prolonged heart allograft survival. Removal of monocytes from PBMCs completely abrogated their suppressive effect, indicating that monocytes are the active cell population. Suppression of rejection was donor-specific. The injected MICs migrated into peripheral lymphoid organs and led to an increased number of regulatory T-cells (Tregs) expressing cluster of differentiation (CD) markers...
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 9, 2015
Although hematopoietic stem-cell transplantation is widely performed in children with high-risk a... more Although hematopoietic stem-cell transplantation is widely performed in children with high-risk acute lymphoblastic leukemia (ALL), the influence of donor types is poorly understood. Thus, transplantation outcomes were compared in the prospective multinational Berlin-Frankfurt-Muenster (BFM) study group trial: ALL-SCT-BFM 2003 (Allogeneic Stem Cell Transplantation in Children and Adolescents with Acute Lymphoblastic Leukemia). After conditioning with total-body irradiation and etoposide, 411 children with high-risk ALL received highly standardized stem-cell transplantations during the first or later remissions. Depending on donor availability, grafts originated from HLA-genoidentical siblings or from HLA-matched unrelated donors who were identified and matched by high-resolution allelic typing and were compatible in at least 9 of 10 HLA loci. Four-year event-free survival (± standard deviation [SD]) did not differ between patients with transplantations from unrelated or sibling dono...
der · M. Schumm · R. Hand gre tin ger · T. Klin ge bi el P. G. Schle gel · J. F. Beck · H. G. Sch... more der · M. Schumm · R. Hand gre tin ger · T. Klin ge bi el P. G. Schle gel · J. F. Beck · H. G. Scheel-Wal ter · D. Niet ham mer Uni ver si täts kin der kli nik, Eber hard-Karls-Uni ver si tät, Tü bin gen Be ar bei tung und Trans planta ti on hä ma to poe ti scher Stamm zel len Er geb nis se und kli ni scher Nut zen der Stammzellauf rei ni gung von al ter na ti ven Spen dern für die al lo ge ne Trans plan ta ti on im Kin desal ter Monatsschrift Kinderheilkd 2005 · 153:954-964 Die se Ar beit wur de un ter stützt durch die Deut sche For schungs ge mein schaft (SFB 510), die José-Car reras-Stif tung, die Rein hold-Beit lich-Stif tung, die Deut sche Krebs hil fe, die Wil helm-San der-Stif tung und das BMBF Tü bin gen Zusammenfassung · Abstract Monatsschrift Kinderheilkd 2005 · 153:954-964
Psychiatry research, Jan 30, 2014
The extent and time course of competition between a specific fear cue and task-related stimuli in... more The extent and time course of competition between a specific fear cue and task-related stimuli in early human visual cortex was investigated using electrophysiology. Steady-state visual evoked potentials (ssVEPs) were evoked using random-dot kinematograms that consisted of rapidly flickering (8.57 Hz) dots moving randomly, superimposed upon emotional or neutral distractor pictures. Participants were asked to detect intervals of coherently moving dots, ignoring the distractor pictures that varied in hedonic content. Women reporting high or low levels of snake fear were recruited from a large sample of healthy college students, and snake pictures served as fear-relevant distractors. The time-varying amplitude of the ssVEP evoked by the motion detection task showed significant reduction when viewing emotionally arousing, compared to neutral, distractors, replicating previous studies. For high-fear participants, snake distractors elicited a sustained attenuation of task evoked ssVEP amp...
Psychophysiology, 2015
Mental imagery is a fundamental cognitive process of interest to basic scientists and clinical re... more Mental imagery is a fundamental cognitive process of interest to basic scientists and clinical researchers. This study examined large-scale oscillatory brain activity in the alpha band (8-12 Hz) during language-driven mental imagery using dense-array EEG. Three experiments demonstrated relative increases in alpha amplitude: (1) during imagery prompted by words compared to fixation without imagery instruction, (2) during imagery of word content compared to imagery of geometric shapes, and (3) during imagery of emotionally evocative words compared to imagery of less emotionally arousing content. Alpha increases for semantically loaded imagery were observed in parieto-occipital regions, sustained throughout the imagery period. Findings imply that alpha oscillations index active memory and internal cognitive processing, reflecting neural communication in cortical networks representing motor, semantic, and perceptual aspects of the imagined scene.
Cytotherapy, 2015
Human mesenchymal stem or stromal cells (MSCs) represent a potential resource not only for regene... more Human mesenchymal stem or stromal cells (MSCs) represent a potential resource not only for regenerative medicine but also for immunomodulatory cell therapies. The application of different MSC culture protocols has significantly hampered the comparability of experimental and clinical data from different laboratories and has posed a major obstacle for multicenter clinical trials. Manufacturing of cell products for clinical application in the European Community must be conducted in compliance with Good Manufacturing Practice and requires a manufacturing license. In Germany, the Paul-Ehrlich-Institut as the Federal Authority for Vaccines and Biomedicines is critically involved in the approval process. This report summarizes a consensus meeting between researchers, clinicians and regulatory experts on standard quality requirements for MSC production. The strategy for quality control testing depends on the product's cell composition, the manufacturing process and the indication and ta...
Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions, 2014
Pediatric and Congenital Interventional Cardiology is the practice of catheter-based techniques t... more Pediatric and Congenital Interventional Cardiology is the practice of catheter-based techniques that improve cardiac physiology and circulation through the treatment of heart disease in children and adults with congenital or acquired heart defects. Over the last decade, and since last published training guidelines for pediatric cardiac catheterization and interventional cardiology were published in 2005 [1] the field of Pediatric and Congenital Cardiac Catheterization has evolved into a predominantly interventional discipline. As there is no sub-specialty certification for interventional cardiac catheterization in pediatrics, the Congenital Heart Disease Committee of the Society of Cardiovascular Angiography and Interventions has put together this consensus statement for advanced training in pediatric and congenital interventional cardiac catheterization. The statement puts forth recommendations for program infrastructure in terms of teaching, personnel, equipment, facilities, confe...
Blood, Jan 23, 2015
Hematopoietic stem cell transplantation (HSCT) has improved over the last decades. However, viral... more Hematopoietic stem cell transplantation (HSCT) has improved over the last decades. However, viral infections often remain refractory to pharmacologic treatment and require alternative treatment strategies such as immunotherapy. Adenovirus (AdV) is the predominant disease-causing pathogen in pediatric HSCT. In a clinical trial we analyzed safety and efficacy of ex vivo adoptive T-cell transfer (ACT) with hexon-specific T cells, predominantly of THELPER-1 phenotype, in thirty patients with AdV disease/viremia. ACT was feasible without acute toxicities or significant onset of graft-versus-host disease. ACT led to antiviral immunity in vivo up to 6 months with viral control, resulting in complete clearance of viremia in 86% of patients with antigen-specific T-cell responses. After a follow up of 6 months post ACT, overall survival was markedly increased in responders (mean: 122 days, 15 survivors) as compared to non-responders who all died shortly after ACT (mean: 24 days, no survivors)...
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 20, 2015
To elucidate the impact of minimal residual disease (MRD) after allogeneic transplantation, the A... more To elucidate the impact of minimal residual disease (MRD) after allogeneic transplantation, the Acute Lymphoblastic Leukemia Berlin-Frankfurt-Münster Stem Cell Transplantation Group (ALL-BFM-SCT) conducted a prospective clinical trial. In the ALL-BFM-SCT 2003 trial, MRD was assessed in the bone marrow at days +30, +60, +90, +180, and +365 after transplantation in 113 patients with relapsed disease. Standardized quantification of MRD was performed according to the guidelines of the Euro-MRD Group. All patients showed a 3-year probability of event-free survival (pEFS) of 55%. The cumulative incidence rates of relapse and treatment-related mortality were 32% and 12%, respectively. The pEFS was 60% for patients who received their transplantations in second complete remission, 50% for patients in ≥ third complete remission, and 0% for patients not in remission (P = .015). At all time points, the level of MRD was inversely correlated with event-free survival (EFS; P < .004) and positiv...
NeuroImage, 2011
Heightened perception of facial cues is at the core of many theories of social behavior and its d... more Heightened perception of facial cues is at the core of many theories of social behavior and its disorders. In the present study, we continuously measured electrocortical dynamics in human visual cortex, as evoked by happy, neutral, fearful, and angry faces. Thirty-seven participants endorsing high versus low generalized social anxiety (upper and lower tertiles of 2,104 screened undergraduates) viewed naturalistic faces flickering at 17.5 Hz to evoke steady-state visual evoked potentials (ssVEPs), recorded from 129 scalp electrodes. Electrophysiological data were evaluated in the time-frequency domain after linear source space projection using the minimum norm method. Source estimation indicated an early visual cortical origin of the face-evoked ssVEP, which showed sustained amplitude enhancement for emotional expressions specifically in individuals with pervasive social anxiety. Participants in the low symptom group showed no such sensitivity, and a correlational analysis across the entire sample revealed a strong relationship between self-reported interpersonal anxiety/avoidance and enhanced visual cortical response amplitude for emotional, versus neutral expressions. This pattern was maintained across the 3500 ms viewing epoch, suggesting that temporally sustained, heightened perceptual bias towards affective facial cues is associated with generalized social anxiety.
Klinische Pädiatrie, 2013
Viral infections after allogeneic stem cell transplantation (SCT) are an important cause of morbi... more Viral infections after allogeneic stem cell transplantation (SCT) are an important cause of morbidity and mortality as SCT can expose patients to a transient state of combined immunodeficieny. Most viral infections after SCT are caused by the endogenous reactivation of persistent pathogens such as adenovirus (ADV), cytomegalovirus (CMV), and Epstein-Barr-virus (EBV). The control of these infections will ultimately depend on the restoration of adequate T-cell immunity.
The Journal of Thoracic and Cardiovascular Surgery, 2000
We compared the Norwood stage I operation for hypoplastic left heart syndrome and other complex m... more We compared the Norwood stage I operation for hypoplastic left heart syndrome and other complex malformations with ductus-dependent systemic circulation. A retrospective study of 194 patients who underwent a Norwood stage I palliation between 1990 and 1998 was conducted. Malformations in 131 patients were classified as hypoplastic left heart syndrome, defined as aortic and mitral atresia or severe stenosis, normal segmental anatomy, intact ventricular septum, and hypoplasia of the left ventricle. Sixty three patients had other lesions: hypoplastic left ventricle with ventricular septal defect (n = 18), unbalanced complete atrioventricular canal (n = 9), complex double-outlet right ventricle (n = 14), double-inlet left ventricle (n = 11), tricuspid atresia with transposition of the great arteries (n = 6), and others (n = 5), including heterotaxia. Operative (>30 days) and 1-year survivals were lower for patients with hypoplastic left heart syndrome than for those with other lesions (63.4% vs 81%, P =.008, and 51.2% vs 71.4%, P =.02, respectively). The presence of a nonhypoplastic left ventricle (n = 27) was associated with higher operative and 1-year survivals (96.3% vs 64.7%, P =.002; 88.9% vs 52. 7%, P <.001). A restrictive atrial septal defect and prematurity tended to increase mortality across both groups. Cox proportional hazards regression indicated that a single right ventricle was the most important independent predictor of death (P <.001). Operative mortality for all patients undergoing the stage I procedure decreased from 38.5% (1990-1994) to 21.4% after 1994 (P =.02). The survival of patients with malformations other than hypoplastic left heart syndrome after the Norwood procedure is greater than for those with hypoplastic left heart syndrome. Staged palliation is valid surgical therapy in these patients, with good results in intermediate follow-up.
The Journal of Thoracic and Cardiovascular Surgery, 2001
Objective: Early primary repair of tetralogy of Fallot has been routinely performed at Children's... more Objective: Early primary repair of tetralogy of Fallot has been routinely performed at Children's Hospital, Boston, since 1972. We evaluated the long-term outcome of this treatment strategy including the influence of a transannular patch.