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1.
Ann Oncol ; 31(3): 422-429, 2020 03.
Article in English | MEDLINE | ID: mdl-32067684

ABSTRACT

BACKGROUND: Long-term survival of high-risk neuroblastoma patients is still below 50% despite intensive multimodal treatment. This trial aimed to address whether the addition of two topotecan-containing chemotherapy courses compared to standard induction therapy improves event-free survival (EFS) of these patients. PATIENTS AND METHODS: An open-label, multicenter, prospective randomized controlled trial was carried out at 58 hospitals in Germany and Switzerland. Patients aged 1-21 years with stage 4 neuroblastoma and patients aged 6 months to 21 years with MYCN-amplified tumors were eligible. The primary endpoint was EFS. Patients were randomly assigned to standard induction therapy with six chemotherapy courses or to experimental induction chemotherapy starting with two additional courses of topotecan, cyclophosphamide, and etoposide followed by standard induction chemotherapy (eight courses in total). After induction chemotherapy, all patients received high-dose chemotherapy with autologous hematopoietic stem cell rescue and isotretinoin for consolidation. Radiotherapy was applied to patients with active tumors at the end of induction chemotherapy. RESULTS: Of 536 patients enrolled in the trial, 422 were randomly assigned to the control arm (n = 211) and the experimental arm (n = 211); the median follow-up time was 3.32 years (interquartile range 1.65-5.92). At data lock, the 3-year EFS of experimental and control patients was 34% and 32% [95% confidence Interval (CI) 28% to 40% and 26% to 38%; P = 0.258], respectively. Similarly, the 3-year overall survival of the patients did not differ [54% and 48% (95% CI 46% to 62% and 40% to 56%), respectively; P = 0.558]. The response to induction chemotherapy was not different between the arms. The median number of non-fatal toxicities per patient was higher in the experimental group while the median number of toxicities per chemotherapy course was not different. CONCLUSION: While the burden for the patients was increased by prolonging the induction chemotherapy and the toxicity, the addition of two topotecan-containing chemotherapy courses did not improve the EFS of high-risk neuroblastoma patients and thus cannot be recommended. CLINICAL TRIALS. GOV NUMBER: NCT number 03042429.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Induction Chemotherapy , Neuroblastoma , Adolescent , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Child , Child, Preschool , Disease-Free Survival , Germany , Humans , Infant , Neuroblastoma/drug therapy , Prospective Studies , Switzerland , Treatment Outcome , Young Adult
3.
Eur J Pediatr ; 174(5): 675-86, 2015 May.
Article in English | MEDLINE | ID: mdl-25804192

ABSTRACT

UNLABELLED: In a prospective multicentre study of bloodstream infection (BSI) from November 01, 2007 to July 31, 2010, seven paediatric cancer centres (PCC) from Germany and one from Switzerland included 770 paediatric cancer patients (58% males; median age 8.3 years, interquartile range (IQR) 3.8-14.8 years) comprising 153,193 individual days of surveillance (in- and outpatient days during intensive treatment). Broviac catheters were used in 63% of all patients and Ports in 20%. One hundred forty-two patients (18%; 95% CI 16 to 21%) experienced at least one BSI (179 BSIs in total; bacteraemia 70%, bacterial sepsis 27%, candidaemia 2%). In 57%, the BSI occurred in inpatients, in 79% after conventional chemotherapy. Only 56 % of the patients showed neutropenia at BSI onset. Eventually, patients with acute lymphoblastic leukaemia (ALL) or acute myeloblastic leukaemia (AML), relapsed malignancy and patients with a Broviac faced an increased risk of BSI in the multivariate analysis. Relapsed malignancy (16%) was an independent risk factor for all BSI and for Gram-positive BSI. CONCLUSION: This study confirms relapsed malignancy as an independent risk factor for BSIs in paediatric cancer patients. On a unit level, data on BSIs in this high-risk population derived from prospective surveillance are not only mandatory to decide on empiric antimicrobial treatment but also beneficial in planning and evaluating preventive bundles. WHAT IS KNOWN: • Paediatric cancer patients face an increased risk of nosocomial bloodstream infections (BSIs). • In most cases, these BSIs are associated with the use of a long-term central venous catheter (Broviac, Port), severe and prolonged immunosuppression (e.g. neutropenia) and other chemotherapy-induced alterations of host defence mechanisms (e.g. mucositis). What is New: • This study is the first multicentre study confirming relapsed malignancy as an independent risk factor for BSIs in paediatric cancer patients. • It describes the epidemiology of nosocomial BSI in paediatric cancer patients mainly outside the stem cell transplantation setting during conventional intensive therapy and argues for prospective surveillance programmes to target and evaluate preventive bundle interventions.


Subject(s)
Bacteremia/epidemiology , Candidemia/epidemiology , Cross Infection/epidemiology , Leukemia, Myeloid, Acute/epidemiology , Neoplasm Recurrence, Local , Precursor Cell Lymphoblastic Leukemia-Lymphoma/epidemiology , Bacteremia/microbiology , Blood-Borne Pathogens , Cancer Care Facilities/statistics & numerical data , Candidemia/microbiology , Catheter-Related Infections/epidemiology , Catheter-Related Infections/microbiology , Child , Cross Infection/microbiology , Female , Hospitals, Pediatric/statistics & numerical data , Humans , Leukemia, Myeloid, Acute/blood , Leukemia, Myeloid, Acute/microbiology , Male , Precursor Cell Lymphoblastic Leukemia-Lymphoma/blood , Precursor Cell Lymphoblastic Leukemia-Lymphoma/microbiology , Prospective Studies , Risk Factors
4.
Klin Padiatr ; 226(6-7): 332-7, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25062112

ABSTRACT

BACKGROUND: TEL-AML the most common genetic alteration in childhood precursor B acute lymphoblastic leukemia (BCP-ALL) is associated with a favorable prognosis. PATIENTS AND METHOD: We studied the expression of nerve growth factor/tumor necrosis factor receptor (NGFR/TNFR)/ligand family members on 108 primary BCP-ALL samples by flow cytometry and compared both their baseline expression and CD40-induced modulation on TEL-AML positive and negative leukemia samples. RESULTS: Our findings demonstrate that TEL-AML positive patients exhibit a significantly higher percentage of CD40, CD27 and p75NTR positive blasts at diagnosis. This might well contribute to the improved relapse-free survival of these patients assessed in Kaplan Meier analysis as CD27 and p75NTR directly mediate apoptotic signals. Furthermore CD40 ligation enhances antigen presenting and T cell stimulatory capacity via significant up regulation of CD70 while adequate response to physiological maturation signals as indicated by concomitant down regulation of CD27 is retained in TEL-AML positive leukemia. CONCLUSION: These data provide novel insights in immunological control mechanisms preserved in this leukemia subtype and suggest that not only treatment with chemicals such as HDAC inhibitors but also retained in vivo response to CD40 ligation contributes to improved immune surveillance in these patients which may add to a superior relapse-free survival observed particularly in the presence of other risk factors.


Subject(s)
CD27 Ligand/genetics , CD40 Antigens/genetics , Core Binding Factor Alpha 2 Subunit/genetics , Oncogene Proteins, Fusion/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Up-Regulation/genetics , Adolescent , Child , Child, Preschool , Female , Flow Cytometry , Humans , Infant , Male , Nerve Tissue Proteins/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/immunology , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/mortality , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Prognosis , Receptors, Nerve Growth Factor/genetics , Receptors, Tumor Necrosis Factor/genetics , Survival Rate , T-Lymphocytes/immunology , T-Lymphocytes/pathology , Tumor Cells, Cultured/immunology , Tumor Cells, Cultured/pathology , Tumor Necrosis Factor Receptor Superfamily, Member 7/genetics
5.
Klin Padiatr ; 223(6): 335-40, 2011 Nov.
Article in English | MEDLINE | ID: mdl-22012602

ABSTRACT

BACKGROUND: Preventive approaches (including those related to care of long term central venous catheters, CVADs) and the incidence of bloodstream infections (BSI) in 2 German university affiliated paediatric oncology units. PATIENTS AND METHODS: Non-interventional prospective observational study using the Oncoped surveillance module. Center A included 85 patients in 31 months and Center B 84 patients in 21 months. The populations did not differ in terms of age, gender, malignancy and disease status (first illness vs. relapse). Center A used ports (46 %) and 2 different Broviac catheters (54 %), in Center B nearly all patients with a CVAD had Broviacs (96 %). 30 BSI (24 patients) were diagnosed in Centre A and 28 BSI (22 patients) in Center B. Patients with relapsed malignancy experienced more BSI (51.4 % vs. 20.9 %; p = 0.001). Incidence rates were significantly lower in Center A (3.47 vs. 7.93 BSI/1000 CVAD days; p = 0.037). Poisson regression analysis revealed a significant lower incidence density (BSI/100 inpatient days) for all BSI in Center A (RR 0.47 CI95 0.27-0.81, p = 0.006). Overall, 52 % of all pathogens detected in blood cultures in Center A were Gram-positive (57 % in Center B) and 48 % Gram-negative (43 in Center B). One ALL patient without a CVAD died due to overwhelming sepsis caused by an ESBL-producing E. cloacae isolate. CONCLUSION: Paediatric cancer treatment centers differ substantially in regard to management of CVADs and in other preventive strategies. The most important use of local surveillance data is longitudinal internal assessment in close cooperation with microbiology and hospital hygiene experts.


Subject(s)
Bacteremia/mortality , Bacteremia/prevention & control , Catheterization, Central Venous/adverse effects , Neoplasms/immunology , Opportunistic Infections/prevention & control , Sepsis/mortality , Sepsis/prevention & control , Adolescent , Bacteremia/immunology , Cancer Care Facilities , Catheterization, Central Venous/instrumentation , Child , Child, Preschool , Cooperative Behavior , Cross-Sectional Studies , Female , Hospitals, University , Humans , Interdisciplinary Communication , Longitudinal Studies , Male , Neoplasms/complications , Opportunistic Infections/immunology , Opportunistic Infections/mortality , Population Surveillance , Prospective Studies , Risk Factors , Sepsis/immunology
6.
Leukemia ; 25(4): 648-54, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21242993

ABSTRACT

Human multipotent mesenchymal stromal cells (MSCs) exhibit multilineage differentiation potential, support hematopoiesis, and inhibit proliferation and effector function of various immune cells. On the basis of these properties, MSC are currently under clinical investigation in a range of therapeutic applications including tissue repair and immune-mediated disorders such as graft-versus-host-disease refractory to pharmacological immunosuppression. Although initial clinical results appear promising, there are significant concerns that application of MSC might inadvertently suppress antimicrobial immunity with an increased risk of infection. We demonstrate here that on stimulation with inflammatory cytokines human MSC exhibit broad-spectrum antimicrobial effector function directed against a range of clinically relevant bacteria, protozoal parasites and viruses. Moreover, we identify the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) as the underlying molecular mechanism. We furthermore delineate significant differences between human and murine MSC in that murine MSC fail to express IDO and inhibit bacterial growth. Conversely, only murine but not human MSC express inducible nitric oxide synthase on cytokine stimulation thus challenging the validity of murine in vivo models for the preclinical evaluation of human MSC. Collectively, our data identify human MSC as a cellular immunosuppressant that concurrently exhibits potent antimicrobial effector function thus encouraging their further evaluation in clinical trials.


Subject(s)
Anti-Bacterial Agents/metabolism , Bacteria/growth & development , Cytomegalovirus/growth & development , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Mesenchymal Stem Cells/physiology , Multipotent Stem Cells/physiology , Stromal Cells/physiology , Toxoplasma/growth & development , Animals , Antiviral Agents/pharmacology , Bacteria/drug effects , Cells, Cultured , Cytokines/immunology , Cytokines/metabolism , Cytomegalovirus/drug effects , Cytomegalovirus Infections/immunology , Cytomegalovirus Infections/metabolism , Cytomegalovirus Infections/virology , Humans , Immune Tolerance , Immunosuppression Therapy , Interferon-gamma/pharmacology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Nitric Oxide Synthase Type II/metabolism , Toxoplasma/drug effects , Toxoplasmosis/immunology , Toxoplasmosis/metabolism , Toxoplasmosis/parasitology
7.
Pediatr Transplant ; 15(4): E80-6, 2011 Jun.
Article in English | MEDLINE | ID: mdl-20214747

ABSTRACT

MHC class II deficiency is a rare and fatal form of primary combined immunodeficiency caused by a lack of T-cell-dependent humoral and cellular immune response to foreign antigens, which can only be cured by allogenic stem cell transplantation. In the literature search, we identified 68 cases of HSCT in MHC class II deficiency in the last 14 yr. Pre- and post-transplant MHC class II deficiency is complicated by overwhelming viral infections, a high incidence of GvHD, and graft failure with a poor overall survival rate below 50%. We report an eight-month-old boy presenting with severe respiratory infections and chronic diarrhea, whose sister died at the age of four yr from septicemia. MHC II deficiency was caused by an RFXANK-mutation and treated successfully by 4/6 mismatched unrelated CBT after a myeloablative conditioning regimen based on anti-thymocyte globulin, busulfane, fludarabine, and cyclophosphamide. At present, our patient is well with full immune reconstitution 3(4/12) yr after CBT. CB may represent an alternative source of stem cells for children with MHC class II deficiency without a suitable donor.


Subject(s)
Fetal Blood/transplantation , Hematopoietic Stem Cell Transplantation/methods , Histocompatibility Antigens Class II/immunology , Immunologic Deficiency Syndromes/surgery , Follow-Up Studies , Graft Survival , Histocompatibility Antigens Class II/genetics , Histocompatibility Testing , Humans , Immunologic Deficiency Syndromes/diagnosis , Infant , Male , Risk Assessment , Severity of Illness Index , Transplantation Conditioning/methods , Transplantation, Homologous , Treatment Outcome
8.
Biol Blood Marrow Transplant ; 16(10): 1428-35, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20399877

ABSTRACT

Major advances in the monitoring and treatment of viral infections after hematopoietic stem cell transplantation (HSCT) have been achieved over the last decade. The appropriate extent of viral monitoring and antiviral therapy remains controversial, and reports in pediatric patients receiving allogeneic unmanipulated hematopoietic stem cells (HSCs) are sparse. A total of 40 pediatric patients who underwent HSCT with either peripheral blood stem cells (PBSCs, n = 30) or bone marrow (BM; n = 10) were prospectively monitored every week for viral DNAemia (VDNA) by simultaneous detection of cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV6), human adenovirus (ADV), and polyoma BK virus (BKV) using real-time TaqMan polymerase chain reaction (PCR). All patients received prophylactic acyclovir and preemptive ganciclovir (GCV) when 500 copies/microg DNA (EBV/HHV6) or >1 copy/microg DNA (CMV) were detected on 2 consecutive measurements. VDNA occurred in 25 of 40 recipients (CMV, 11/40 patients [28%]; EBV, 19/40 [48%]; HHV6, 2/40 [5%]; ADV/BKV, 1/40) and was found exclusively after neutrophil engraftment and in most cases up to day +100. Recurrent VDNA (P = .028) and (readily treatable) viral disease (P = .003) were observed predominantly in patients suffering from nonmalignant diseases, a cohort characterized by delayed lymphocyte engraftment. VDNA occurred more frequently in HLA-mismatched HSCT and in the 24 of 40 patients receiving antithymocyte globulin (ATG). The incidence of EBV, but not that of CMV, was increased in the ATG group. Yet, in these patients, viral loads of both EBV and CMV were higher, but with prompt initiation of preemptive GCV, no posttransplantation lymphoproliferative disorder or other life-threatening morbidities occurred. HHV6 was typically detected at low viral loads (<10(2) copies/microg DNA), with only 5% of HSC recipients fulfilling our HHV6 criteria for triggering GCV treatment. In multivariate analysis, ATG treatment, HLA mismatch, recipient CMV seropositivity, and stem cell source, but not severe acute graft-versus-host disease were identified as independent risk factors for VDNA. This comprehensive viral monitoring program with defined thresholds for initiation of preemptive GCV effectively prevents the development of critical viral disease, even in high-risk patients receiving ATG.


Subject(s)
Hematopoietic Stem Cell Transplantation , Postoperative Complications/epidemiology , Virus Diseases/epidemiology , Adenoviridae Infections/diagnosis , Adenoviridae Infections/drug therapy , Adenoviridae Infections/epidemiology , Adenoviridae Infections/prevention & control , Adolescent , Antilymphocyte Serum , Antiviral Agents/administration & dosage , Antiviral Agents/therapeutic use , BK Virus/isolation & purification , Bone Marrow Transplantation/statistics & numerical data , Child , Child, Preschool , DNA, Viral/blood , Female , Ganciclovir/therapeutic use , Graft vs Host Disease/complications , Hematologic Neoplasms/surgery , Hematopoietic Stem Cell Transplantation/statistics & numerical data , Herpesviridae Infections/diagnosis , Herpesviridae Infections/drug therapy , Herpesviridae Infections/epidemiology , Herpesviridae Infections/prevention & control , Humans , Infant , Male , Peripheral Blood Stem Cell Transplantation/statistics & numerical data , Polyomavirus Infections/diagnosis , Polyomavirus Infections/drug therapy , Polyomavirus Infections/epidemiology , Polyomavirus Infections/prevention & control , Postoperative Complications/diagnosis , Postoperative Complications/drug therapy , Postoperative Complications/prevention & control , Premedication , Prospective Studies , Transplantation, Homologous , Viremia/diagnosis , Viremia/epidemiology , Virus Diseases/diagnosis , Virus Diseases/drug therapy , Virus Diseases/prevention & control , Young Adult
9.
Klin Padiatr ; 221(6): 351-7, 2009.
Article in English | MEDLINE | ID: mdl-19890786

ABSTRACT

PURPOSE: Stem cell transplantation (SCT) can definitely cure chronic myeloid leukemia (CML), a rare disease in childhood. We prospectively evaluated the results of early SCT in pediatric CML after standardized pretreatment with hydroxyurea+/-interferon. PATIENTS AND METHODS: Between 1995 and 2004, 200 children (median age: 12.4 years) were enrolled and stratified: given the availability of an HLA-matched related donor (MRD), SCT was scheduled within 6 months and otherwise from an unrelated donor (UD) within 12 months following diagnosis. RESULTS: 176 patients underwent SCT; from MRD within median 4 months and from UD within median 11 months after diagnosis. At SCT, 158 patients were in chronic phase (CP1 or CP2), 9 patients were in accelerated phase and 9 patients were in blast crisis (BC). The conditioning regimen - total body irradiation or busulfan - exerted no different impact on overall survival (OS). Probability of OS at 5 years was 87+/-11% if grafted from a sibling (n=41), 52+/-9% from matched UD (MUD, n=71), and 45+/-16% from mismatched donors (MMD, n=55), respectively. A trend for better OS in CP1 was observed if SCT was performed within 6 months (n=49; 74+/-9%), compared to 7-12 months (n=52; 62+/-15%), and >12 months (n=43; 62+/-17%) after diagnosis, respectively (p=0.157). Probability of relapse at 5 years was 20+/-12%. Transplant-related mortality and graft-versus-host disease mainly contributed to the inferior outcome in UD and HLA-mismatched SCT. CONCLUSION: These data from the first prospective trial on CML restricted to children and adolescents might be considered for decision making when balancing the risks of SCT against the increasing use of imatinib as upfront treatment for CML.


Subject(s)
Hematopoietic Stem Cell Transplantation , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Adolescent , Antineoplastic Agents/therapeutic use , Benzamides , Bone Marrow Purging , Child , Disease-Free Survival , Female , Graft vs Host Disease/mortality , Humans , Imatinib Mesylate , Kaplan-Meier Estimate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/mortality , Male , Piperazines/therapeutic use , Prospective Studies , Pyrimidines/therapeutic use , Transplantation Conditioning/methods , Transplantation, Homologous
10.
Klin Padiatr ; 220(6): 353-7, 2008.
Article in English | MEDLINE | ID: mdl-18949670

ABSTRACT

BACKGROUND: There is a subgroup of pediatric patients with an immature immunophenotype of proB-ALL that still poses a therapeutic challenge, even if the overall prognosis in B cell precursor acute lymphoblasic leukemia (BCP-ALL) is very good. Due to impaired treatment response these patients are prone to suffer relapse and are thus by definition stratified into the clinically defined high risk group receiving intensified chemotherapy. Besides response to chemotherapy long term prognosis is also influenced by immunological control mechanisms. Thus, high expression of the TNF receptor CD40 has been shown to prevent particularly late relapse in BCP-ALL suggesting a pivotal role of this regulatory molecule for maintenance of the remission status. PATIENTS AND METHODS: We therefore determined the baseline expression and CD40-mediated modulation of TNF receptor and costimulatory molecules in 5 patients with proB-ALL, 8 with preB-ALL and 22 with c-ALL performing FACS analysis. We particularly compared the TNF receptor status on proB-ALL blasts to the expression on more mature preB- and c-ALL blasts. RESULTS: Here, we demonstrate for the first time a significantly lower baseline expression and CD40-induced modulation capacity of TNF receptor and costimulatory molecules in pediatric proB-ALL compared to more mature precursor B-ALL blasts. CONCLUSION: The lower expression and defective capacity of proB-ALL blasts to respond to CD40 ligand stimulation might resemble the immature feature of these blasts and besides increased chemoresistance contribute to the impaired prognosis of these patients due to escape from apoptosis and immunological control mechanisms.


Subject(s)
Blast Crisis/immunology , CD40 Antigens/genetics , Gene Expression Regulation, Leukemic/genetics , Gene Expression Regulation, Leukemic/immunology , Immunophenotyping , Leukemia, Prolymphocytic, B-Cell/immunology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/immunology , Receptors, Tumor Necrosis Factor/immunology , Adolescent , B7-1 Antigen , B7-2 Antigen/genetics , B7-2 Antigen/immunology , CD40 Antigens/immunology , Child , Child, Preschool , Fas Ligand Protein/immunology , Female , Humans , Infant , Male , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/immunology , Prognosis , Up-Regulation/immunology
11.
Klin Padiatr ; 220(3): 147-52, 2008.
Article in English | MEDLINE | ID: mdl-18478486

ABSTRACT

Hematopoietic stem cell transplantation is the only permanent treatment for the hematological manifestations in Fanconi anemia (FA). As FA patients have a dramatically increased intrinsic propensity to develop malignancies later in life and the genotoxic stress afflicted during conditioning advances the manifestation age especially of squamous cell carcinomas, choosing an optimally suited treatment regimen appears critical for long-term, tumor-free survival after stem cell transplantation. Here, we report our experiences in 6 consecutive FA patients transplanted with HLA-matched sibling donors where we combined an established pre-transplantation treatment consisting of thoraco-abdominal irradiation (TAI), cyclophosphamide (CYC) and cyclosporine A graft-versus-host prophylaxis with antibody-mediated IN VIVO T-cell depletion strategies after infusion of the graft. This approach has ensured sustained engraftment with long-term survival and an excellent post transplant performance status without any evidence of secondary malignancies in all six patients after a median follow-up of more than 10 years.


Subject(s)
Bone Marrow Purging/methods , Fanconi Anemia/therapy , Graft vs Host Disease/prevention & control , Hematopoietic Stem Cell Transplantation/methods , Lymphocyte Depletion/methods , T-Lymphocytes/immunology , Child , Child, Preschool , Combined Modality Therapy , Cyclophosphamide/therapeutic use , Disease-Free Survival , Fanconi Anemia/immunology , Fanconi Anemia/mortality , Female , Follow-Up Studies , Graft vs Host Disease/immunology , Humans , Immunosuppressive Agents/therapeutic use , Lymphatic Irradiation/methods , Male , Transplantation, Isogeneic
12.
Bone Marrow Transplant ; 41(3): 253-9, 2008 Feb.
Article in English | MEDLINE | ID: mdl-17982498

ABSTRACT

Neurological complications are a relevant cause of morbidity and mortality after haematopoietic stem cell transplantation (SCT). We retrospectively analysed neurological complications of 165 paediatric patients who underwent SCT between 1996 and 2003. In all, 111 (67%) transplantations were allogeneic and 54 (33%) transplantations were autologous. Post-SCT neurological complications were seen in 24% of patients. They were seen in six children after autologous SCT and in 11 and 23 cases after allogeneic-related and -unrelated SCT. Neurological symptoms occurred between day +22 and +912 after transplantation and were classified into two groups. The first group (n=21) offered non-repetitive symptoms lasting less than 24 h without any cerebral imaging and cerebrospinal fluid(CSF) abnormalities. The second group (n=19) was characterized by progressive neurological symptoms, pathological MRI findings and/or abnormal results in CSF. Those with a progressive clinical course resulted from infections (n=10), drug toxicity (n=5), cerebrovascular events (n=2) and the central nervous system (CNS) relapse of the underlying disease (n=2). In particular, cerebral aspergillosis and toxoplasmosis after allogeneic unrelated SCT are a major challenge and are associated with a high mortality. In conclusion, our data suggest that patients presenting with progressive neurological symptoms after SCT require prompt diagnostic procedures and initiation in antimicrobial therapy in case of any findings suggestive of CNS infection.


Subject(s)
Hematopoietic Stem Cell Transplantation/adverse effects , Meningitis/etiology , Neoplasm Recurrence, Local , Neurotoxicity Syndromes/etiology , Seizures/etiology , Adolescent , Adult , Child , Child, Preschool , Cohort Studies , Female , Hospitals, Pediatric , Humans , Infant , Male , Meningitis/diagnosis , Meningitis/therapy , Neoplasm Recurrence, Local/complications , Neurotoxicity Syndromes/diagnosis , Neurotoxicity Syndromes/therapy , Retrospective Studies , Seizures/diagnosis , Seizures/therapy , Survival Analysis
13.
Klin Padiatr ; 219(6): 318-22, 2007.
Article in English | MEDLINE | ID: mdl-18050041

ABSTRACT

In nine patients (pts) with soft tissue sarcoma refractory to conventional therapy (incomplete response or relapse) intensified chemotherapy was administered combining 0.75 mg/m (2) topotecan, 100 mg/m (2) etoposide, 100 mg/m (2) carboplatin and 200 mg/m (2) cyclophosphamide on day 1-5 (TECC). To avoid prolonged intervals between the serial TECC courses autologous hematopoietic stem cell supports (median 1.0 x 10(6) CD34+ cells per kg body weight (bw), range 0.5-2.8 x 10(6) CD34+ cells/kg bw, SD 0.6 x 10(6) CD34+ cells/kg bw) were given on day 7. All pts received granulocyte colony stimulating factor (GCSF) from day 8 in addition. All together 39 TECC courses (minimum 2 courses, maximum 6 courses per pt) were administered, with a median interval of 32 (range 21-52) days until recovery. Leukopenia (<1000/microl) occurred 9 days (range 3-13 days; SD 2.4 days) after end of chemotherapy and persisted for 9 (range 3-15 days; SD 3 days) days. In 31/39 TECC courses readmission to hospital was required for supportive therapy mainly due to neutropenic fever. In this period pts received 0.83 (range 0-1) red blood cell units and 2.35 (range 1-4) platelet units. C-reactive protein in neutropenic pts as an indicator for infection after TECC chemotherapy was detectable after 36 of 39 chemotherapy courses leading to further supportive therapy (median 10.4 mg/dl, range 1.1-28.3 mg/dl; SD 6.67 mg/dl). Duration of total inpatient treatment per TECC course including supportive therapy was in median 13.5 days (range 7-53 days; SD 4.3 days). Only two children had a prolonged infection (77 and 100 days). Clinical and objective tumor responses, defined as complete remission, very good partial response and partial response were observed in 9/9 pts at eight weeks after the last TECC course and were maintained at six months in 7/9 pts. Median time to progression and median overall survival time after TECC chemotherapy were 20.3 months and 25.2 months, respectively. These data provide evidence that in very high risk pts refractory to standard high risk therapy, a combination of TECC chemotherapy and stem cell support is feasible in pts with incomplete remission respectively relapsed STS pts and demonstrates promising antineoplastic activity. Therefore, this regimen warrants further investigation in prospective trials.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Hematopoietic Stem Cell Transplantation , Sarcoma/therapy , Adolescent , Adult , Carboplatin/administration & dosage , Child , Child, Preschool , Cyclophosphamide/administration & dosage , Etoposide/administration & dosage , Feasibility Studies , Female , Follow-Up Studies , Humans , Infant , Magnetic Resonance Imaging , Male , Neoplasm, Residual/surgery , Remission Induction , Sarcoma/diagnosis , Sarcoma/drug therapy , Time Factors , Topotecan/administration & dosage , Transplantation, Autologous , Treatment Outcome
14.
Bone Marrow Transplant ; 40(10): 945-9, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17768387

ABSTRACT

We report a retrospective analysis of 11 children with Down syndrome (DS) treated by SCT in eight German/Austrian SCT centres. Indications for transplantation were acute lymphoblastic leukaemia (N=8) and acute myeloid leukaemia (N=3). A reduced intensity conditioning (RIC) containing 2 Gy TBI was given to two patients, another five received a myeloablative regimen with 12 Gy TBI. Treosulphan or busulphan was used in the remaining four children. Four of eleven (36%) patients are alive. All of them were treated with a myeloablative regimen. One of the four surviving children relapsed 9 months after SCT and is currently receiving palliative outpatient treatment. The main cause of death was relapse (5/11). Two children died of regimen-related toxicity (RRT), one from severe exfoliative dermatitis and multiorgan failure after a treosulphan-containing regimen, the other from GvHD-related infections after RIC. Acute GvHD of the skin was observed in 10 of 10 evaluable patients, and chronic GvHD in 4 of 8. Our data show that DS patients can tolerate commonly used, fully myeloablative preparative regimens. The major cause of death is relapse rather than RRT resulting in an event-free survival of 18% and over all survival of 36%.


Subject(s)
Down Syndrome/complications , Hematopoietic Stem Cell Transplantation/adverse effects , Leukemia, Myeloid, Acute/therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Adolescent , Child , Child, Preschool , Female , Graft vs Host Disease/prevention & control , Humans , Male , Recurrence , Retrospective Studies , Transplantation Conditioning/adverse effects , Treatment Failure
15.
Pediatr Hematol Oncol ; 24(5): 343-54, 2007.
Article in English | MEDLINE | ID: mdl-17613879

ABSTRACT

Children with cancer have an overall chance of survival of 70-80%. Despite significant advances in supportive care during the last years, infections remain a major cause of therapy-associated morbidity and death. Between January and December 2000, oncology patients (ONC) treated on a pediatric oncology ward after chemotherapy (n = 109), loco-regional thermochemotherapy (n = 13), or hematopoietic stem cell (HSCT) transplantation (n = 35) suffered a total of 249 febrile infectious complications (HSCT 40/ONC 209). These episodes were analyzed retrospectively and compared with 125 ONC patients with 133 febrile infections in 1980/81. The relative incidence of fever of unknown origin (FUO) decreased from 1980/81 to 2000 (p <.001). The frequency of bloodstream infections (BSI) in febrile episodes was comparable in both periods with 37% (50/135) in 1980 and 29% (72/249) in 2000. In both periods, gram-positive bacteria were the most frequent organisms, whereas gram-negative organisms were detected in approximately 20% of BSI. In 1980/81 microbiologically (MDI) or clinically documented infections (CDI) were not detected, whereas in 2000 27% of all infectious were MDI/CDI. During the last 20 years, improved diagnostic tools have resulted in an increased detection rate of infectious agents causing febrile episodes in pediatric cancer patients. The comparison of the two observation periods did not reveal a change in the microbiologic spectrum. Despite the fact that in 2000 more patients were treated with intensified chemotherapy because of relapse, infection-related mortality was unchanged compared to 1980/81. This observation may indicate a sufficient preemptive antibacterial therapy followed by better diagnostic tools and goal-oriented treatment.


Subject(s)
Infections/etiology , Neoplasms/complications , Antineoplastic Agents/adverse effects , Child , Fever , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Incidence , Infections/diagnosis , Infections/epidemiology , Infections/microbiology , Neoplasms/epidemiology , Neoplasms/therapy , Retrospective Studies , Sepsis
16.
Klin Padiatr ; 219(3): 127-33, 2007.
Article in English | MEDLINE | ID: mdl-17525905

ABSTRACT

BACKGROUND: Survivin, a member of the inhibitor of apoptosis protein (IAP) family is transiently expressed at low levels during normal hematopoesis but profoundly overexpressed in adult leukemia potentially contributing to leukemogenesis due to deregulated apoptosis and defective cell cycle control. Alternative splicing results in four different mRNA variants survivin, survivin2B, survivin-DeltaExon3 and survivin-3B, with distinct cellular localization patterns and anti-apoptotic potential. Due to co-localization of survivin and survivin-2B in the cytoplasm survivin-2B may permit interactive fine-tuning of survivin actions and moreover play an attenuating role in its anti-apoptotic function. Lack of survivin-2B is associated with disease progression of malignomas suggesting a differential role of these isoforms in tumorigenesis. PATIENTS AND METHODS: We therefore determined the expression of the functional survivin splice variants performing RT- and real-time PCR in a purely pediatric cohort of 20 patients suffering from precursor B-ALL (BCP-ALL). RESULTS: Here, we demonstrate for the first time in pediatric patients with precursor B-ALL an association between lower survivin-2B expression and affiliation to the high risk group. CONCLUSION: The idea that survivin-2B may act as natural antagonist of survivin could potentially be used in novel approaches of anti-cancer treatment by influencing the proportional expression of the different splice variants.


Subject(s)
Apoptosis/genetics , Genetic Variation/genetics , Microtubule-Associated Proteins/genetics , Neoplasm Proteins/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Protein Isoforms/genetics , Child , Cohort Studies , Coumarins , Gene Expression Regulation, Leukemic , Humans , Inhibitor of Apoptosis Proteins , Leukocyte Count , Polymerase Chain Reaction , Prognosis , RNA, Messenger/genetics , Retrospective Studies , Reverse Transcriptase Polymerase Chain Reaction , Risk Factors , Survivin
17.
J Cancer Res Clin Oncol ; 133(3): 199-209, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17053889

ABSTRACT

PURPOSE: Although gene transfer with retroviral vectors has shown distinct clinical success in defined settings, efficient genetic manipulation of hematopoietic progenitor cells remains a challenge. To address this issue we have evaluated different transduction protocols and retroviral constructs in the non-obese diabetes (NOD)/severe combined immunodeficiency disease (SCID) xenograft model. METHODS: An extended transduction protocol requiring 144 h of in vitro manipulation was compared to a more conventional protocol requiring 96 h only. RESULT: While pretransplantation analysis of cells transduced with a retroviral vector, expressing the enhanced green fluorescent protein (EGFP) marker gene, demonstrated significantly higher overall transduction rates for the extended protocol (33.6 +/- 2.3 vs. 22.1 +/- 3.8%), EGFP expression in CD34+ cells before transplantation (4.0 +/- 0.9 vs. 11.6 +/- 2.5%), engraftment of human cells in NOD/SCID bone marrow 4 weeks after transplantation (4.5 +/- 1.7 vs. 36.5 +/- 9.4%) and EGFP expression in these cells (0 +/- 0 vs. 11.3 +/- 2.8%) were significantly impaired. When the 96 h protocol was used in combination with the spleen focus forming virus (SFFV)/murine embryonic stem cell (MESV) hybrid vector SFbeta11-EGFP, high transduction rates for CD45+ (41.0 +/- 5.3%) and CD34+ (38.5 +/- 3.7%) cells prior to transplantation, as well as efficient human cell engraftment in NOD/SCID mice 4 weeks after transplantation (32.4 +/- 3.5%), was detected. Transgene expression was observed in B-lymphoid (15.9 +/- 2.0%), myeloid (36.5 +/- 3.5%) and CD34+ cells (10.1 +/- 1.5%). CONCLUSION: Our data show that CD34+ cells maintained in cytokines for multiple days may differentiate and loose their capacity to contribute to the haematological reconstitution of NOD/SCID mice. In addition, the SFFV/MESV hybrid vector SFbeta11-EGFP allows efficient transduction of and gene expression in haematopoietic progenitor cells.


Subject(s)
Cord Blood Stem Cell Transplantation , Gene Transfer Techniques , Graft Survival/genetics , Green Fluorescent Proteins/biosynthesis , Hematopoietic Stem Cells/cytology , Severe Combined Immunodeficiency/therapy , Animals , Antigens, CD34/biosynthesis , DNA Primers/chemistry , Feasibility Studies , Genetic Therapy/methods , Genetic Vectors , Humans , Leukocyte Common Antigens/biosynthesis , Mice , Mice, Inbred NOD , Mice, SCID , Severe Combined Immunodeficiency/immunology , Spleen Focus-Forming Viruses/genetics , Transduction, Genetic
18.
Klin Padiatr ; 218(6): 355-65, 2006.
Article in English | MEDLINE | ID: mdl-17080339

ABSTRACT

Immunotherapy of childhood malignancies has a magic aura of promising an easy way to cure. It is not only the public, but also the medical community, which has caused this hope. Therefore, it was worthwhile to bring together a panel of experts working in the field of immunotherapy in order to discuss ongoing projects, and to show hopes and disappointments. The result was a fascinating symposium sponsored by The Kind Philipp Leukemia Foundation (Mönchengladbach, Germany). The symposium took place in the Reissensburg near Ulm (Germany) which gives the ideal location for such an event.


Subject(s)
Immunotherapy , Neoplasms/therapy , Age Factors , Animals , Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Cancer Vaccines/administration & dosage , Cell Line, Tumor , Child , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Cytokines/therapeutic use , Disease Models, Animal , Feasibility Studies , Genetic Therapy , Graft vs Leukemia Effect , Hematopoietic Stem Cell Transplantation , Humans , Immunologic Factors/therapeutic use , Immunotherapy, Adoptive , Killer Cells, Natural/immunology , Leukemia/therapy , Mice , Peripheral Blood Stem Cell Transplantation , T-Lymphocytes/immunology , Transplantation, Homologous
19.
Haematologica ; 91(5 Suppl): ECR07, 2006 May.
Article in English | MEDLINE | ID: mdl-16709515

ABSTRACT

Isolated renal relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT) in children with acute lymphoblastic leukemia (ALL) is a rare condition. Generally, in ALL, the sites most frequently affected by extramedullary relapse are the central nervous system (CNS) and the testicles. Here we report on three young boys with relapsed B-precursor ALL, who underwent alloHSCT from HLA-identical siblings and suffered a histopathologically proven isolated unilateral renal relapse (two patients) or a combined renal and testicular relapse (one patient) 6, 10 and 12 months post alloHSCT. In all patients at the time of relapse bone marrow showed complete remission with complete donor hematopoiesis. They all received total body irradiation with partial shielding of the kidneys as part of their conditioning therapy, such that renal shielding could be an explanation for the observed accumulation of renal relapses. Moreover, during the past few years so called immune privilege has been postulated for frequent relapse sites such as the CNS, the testicles and the anterior chamber of the eye. Impaired accessability of these organs by cytotoxic T-cells (CTLs) with a reduced graft-versus-leukemia (GvL) effect after alloHSCT is based on a number of different molecular and cellular mechanisms. Similar mechanisms have been shown to be effective in the tubulointerstitial space of the kidney, rendering the kidney a potentially immune privileged site. Due to these observations we advocate sufficient treatment of the kidneys during conditioning therapy.


Subject(s)
Hematopoietic Stem Cell Transplantation , Kidney/pathology , Leukemic Infiltration , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Child , Child, Preschool , Combined Modality Therapy , Dendritic Cells/transplantation , Disease Progression , Etoposide/therapeutic use , Fatal Outcome , Humans , Immunotherapy , Kidney/radiation effects , Leukocyte Transfusion , Magnetic Resonance Imaging , Male , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/immunology , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/surgery , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/immunology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/radiotherapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/surgery , Radiation Protection , Recurrence , Salvage Therapy , Tomography, X-Ray Computed , Transplantation Conditioning/adverse effects , Transplantation, Homologous , Whole-Body Irradiation/adverse effects
20.
J Hosp Infect ; 62(1): 80-8, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16242206

ABSTRACT

The aim of this prospective study was to analyse the incidence of nosocomial infections (NIs) during neutropenia after haematopoietic stem cell transplantation (HSCT) in paediatric and adult patients. Diagnosis of NI followed the modified surveillance protocol of the German National Reference Centre for Surveillance of NIs. During the 24-month study period, 38 and 39 transplantations were performed in paediatric and adult patients, respectively. Eighty percent and 92% of the paediatric and adult patients, respectively, underwent allogenic HSCT. In total, 1156 neutropenic days were documented. The incidence of NI during neutropenia in all recorded cases was 38.9 NI per 1000 days, without significant difference between the groups. No difference was found in the incidence rates of pneumonia, while there was a trend towards a higher incidence of bloodstream infection in adult patients. Significantly more episodes of fever of unknown origin were found in paediatric than adult patients. Pathogens were isolated in 19 of 45 cases of NI. Of the clinically documented infections, Gram-positive organisms were isolated in 79%, Gram-negative organisms were isolated in 16% and fungi were isolated in 5%. Surveillance of NI is an effective instrument to control the quality of health care. It should focus on device-associated infections or specific high-risk targets such as nosocomial pneumonia.


Subject(s)
Bone Marrow Transplantation/adverse effects , Cross Infection/epidemiology , Neutropenia/complications , Peripheral Blood Stem Cell Transplantation/adverse effects , Population Surveillance , Adolescent , Adult , Child , Child, Preschool , Cross Infection/microbiology , Humans , Incidence , Infant , Middle Aged , Prospective Studies
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