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Copyright of Monatsschrift Kinderheilkunde is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Monatsschrift Kinderheilkunde is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Der Diabetologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Purpose: Preclinical data indicate there is strong synergism of action against Ewing sarcoma in sequential treatment with trabectedin followed by irinotecan and it appears to be related to a selective blockade of the transcription factor EWS-FLI1. This combination was evaluated in Ewing sarcoma patient who was progressing with standard therapies. Methods: Trabectedin was given as a 24-h iv infusion on day 1 at the dose of 1 mg/sqm, and irinotecan 75 mg/sqm on day 2 and then on days 2 and 4, every 3 weeks from the seventh course. Results: The therapy was well tolerated with transient hematological toxicity and transaminitis and induced stabilization of the disease lasting for 11 courses, with clinical improvement and marked reduction of the need for opioids. However, shortly before the 12th course, sudden death occurred, possibly due to cerebral stroke, presumably not related to the drug treatment. Conclusions: The encouraging clinical benefit observed with the combination and its good tolerability deserves further investigation in Ewing sarcoma. [ABSTRACT FROM AUTHOR]

Copyright of Monatsschrift Kinderheilkunde is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: The development of a successful immunotherapy is hampered by an ineffective T-cell repertoire against tumour antigens and the inability of the patient's immune system to overcome tolerance-inducing mechanisms. Here, we test the specific recognition and lytical potential of allo-restricted CD8(+) T cells against Ewing tumour (ET) associated antigens Enhancer of Zeste, Drosophila Homolog 2 (EZH2), and Chondromodulin-I (CHM1) identified through previous microarray analysis.Methods: Following repetitive CHM1(319) (VIMPCSWWV) and EZH2(666) (YMCSFLFNL) peptide-driven stimulations with HLA-A 0201(+) dendritic cells (DC), allo-restricted HLA-A 0201(-) CD8(+) T cells were stained with HLA-A 0201/peptide multimers, sorted and expanded by limiting dilution.Results: Expanded T cells specifically recognised peptide-pulsed target cells or antigen-transfected cells in the context of HLA-A 0201 and killed HLA-A 0201(+) ET lines expressing the antigen while HLA-A 0201(-) ET lines were not affected. Furthermore, adoptively transferred T cells caused significant ET growth delay in Rag2(-/-)γ(C)(-/-) mice. Within this context, we identified the CHM1(319) peptide as a new candidate target antigen for ET immunotherapy.Conclusion: These results clearly identify the ET-derived antigens, EZH2(666) and CHM1(319), as suitable targets for protective allo-restricted human CD8(+) T-cell responses against non-immunogenic ET and may benefit new therapeutic strategies in ET patients treated with allogeneic stem cell transplantation. [ABSTRACT FROM AUTHOR]

Copyright of Monatsschrift Kinderheilkunde is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

We examined the role of total body magnetic resonance imaging (TB-MRI)-governed involved compartment irradiation (ICI) and high-dose chemotherapy (HDC), followed by stem cell rescue (SCR) in patients with high-risk Ewing tumors (ETs) with multiple primary bone metastases (high-risk ET-MBM). Eleven patients with high-risk ET-MBM receiving initial assessment of involved bones by TB-MRI were registered from 1995 to 2000 (group A). In all, 6 patients out of 11 had additional lung disease at initial diagnosis; all had multifocal bone disease with more than three bones involved. After systemic induction with etoposide, vincristine, adriamycin (doxorubicin), ifosfamide, and actinomycin D (EVAIA) or VAIA chemotherapy, ICI of all sites positive by TB-MRI was administered, followed by HDC and SCR. A second group matched for observation period and consisting of 26 patients with more than three involved bones at diagnosis was treated with the European Intergroup Cooperative Ewing Sarcoma Study-92 (EICESS-92) protocol (group B). These patients did not receive TB-MRI and consequently did not receive TB-MRI-governed ICI, or HDC and SCR. Survival in group A vs group B was 45 vs 8% at 5 years and 27 vs 8% at 10 years after diagnosis (log rank and Breslow: P<0.005). We conclude that TB-MRI-governed ICI followed by HDC and SCR in ET-MBM is feasible and warrants further evaluation in prospective studies. [ABSTRACT FROM AUTHOR]

Copyright of Monatsschrift Kinderheilkunde is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Monatsschrift Kinderheilkunde is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Granulocyte-macrophage (GM-CSF) and granulocyte colony-stimulating factors (G-CSF) are equally effective hematopoietic growth factors in terms of their potential to shorten the period of neutropenia following high-dose chemotherapy or to mobilize hematopoietic stem cells. Thus the choice between the two preparations must be based on a comparison of adverse effects. Both GM-CSF and G-CSF have been implicated in disturbances of the hemostatic system, resulting in both hemorrhagic and thrombotic complications. We therefore studied the effects of GM-CSF and G-CSF therapy on hemostasis both ex vivo and clinically. In a prospective, non-randomized study 34 patients who were treated with a myeloablative regimen according to the hyper-ME+/-C protocol and stem cell or bone marrow transplantation received posttransplantation hematopoietic support with GM-CSF (n=15) or G-CSF (n=19). The patients were monitored for alterations in plasmatic coagulation parameters and clinical evidence of hemorrhagic or thrombotic events. GM-CSF, but not G-CSF, induced a significant, albeit usually mild activation of the coagulation cascade. We observed an increased frequency of veno-occlusive disease in the GM-CSF group (3/15 vs. 1/19 on G-CSF, n.s.). Other thrombotic events were rare. At the same time, hemorrhage was both more common and more severe in GM-CSF treated patients than in those on G-CSF (macroscopic hemorrhage 11/15 vs. 10/19, III hemorrhage 7/15 vs. 1/19 on GM-CSF or G-CSF, respectively). In conclusion, unlike G-CSF, if given after hyper-ME chemotherapy plus stem cell or bone marrow transplantation, at the dosage used here GM-CSF induced an activation of the coagulation system and was associated with an increased risk of hemostasis associated treatment complications. [ABSTRACT FROM AUTHOR]

Copyright of Strahlentherapie und Onkologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Monatsschrift Kinderheilkunde is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

In childhood, aplastic anemia is a rare disease of unknown etiology. Besides toxic effects, also an infectious or an autoimmune origin are discussed. We report on an 8-year-old boy with very severe aplastic anemia (VSAA) who developed pancreatitis together with panniculitis. Initially, active cytomegalovirus (CMV) infection was thought to be possibly contributive. Ganciclovir was tried resulting in clearance of CMV, but VSAA persisted. Two months after the onset of VSAA, oligosymptomatic pancreatitis was observed together with the onset of severe febrile panniculitis, occurring with multiple painful enlarged subcutaneous infiltrates of up to 7 cm in diameter. Treatment according to the Severe Aplastic Anemia-94 (SAA-94) protocol consisting of glucocorticoids, cyclosporin A (CsA), anti-thymocyte globulin and granulocyte colony-stimulating factor was instituted. Since this treatment did not lead to remission after day 110, escalation of the CsA dose up to 8 mg/kg body weight was tried. This regimen resulted in complete recovery of panniculitis and symptoms of pancreatitis. Incomplete hematological remission was reached and, to date, the patient has not required transfusions for 6 months. Because this boy suffered simultaneously from three rare disorders, which all responded to intense immunosuppression, this observation may underline common autoimmune mechanisms of these distinct diseases. [ABSTRACT FROM AUTHOR]

Unlabelled: Of a total of 117 bone marrow transplant (BMT) recipients in the period from August 1988 to November 1995, 9 (7.7%) developed haemorrhagic cystitis. This condition was characterized in all nine patients by late onset (day +24 to +50 post-BMT), long duration (1 to 7 weeks), and the excretion of BK virus in the urine, as confirmed by electron microscopy, DNA hybridization and PCR analysis. Adenovirus was not involved. The serological assessment of BK virus-specific IgM and IgG pre- and post-BMT is consistent with viral reactivation in all patients, although a primary infection cannot be absolutely excluded in a single patient. A significant correlation between the use of high-dose busulphan (16 mg/kg) in the preparative regimen and development of haemorrhagic cystitis (P = 0. 0003) was evident. The severe course of the disease in two patients resulted in bladder tamponade; bleeding could not be inhibited with coagulation and laser treatment. Deterioration was prevented by bladder irrigation via a suprapubic catheter. Remission occurred spontaneously in all patients.Conclusion: BK virus induced haemorrhagic cystitis in a paediatric bone marrow transplantation recipients is characterized by late onset, long duration, viral reactivation and correlates to high-dose busulphan. Severe bleeding could not be influenced by surgical intervention. [ABSTRACT FROM AUTHOR]

During T cell selection in the thymic cortex more than 90% of the thymocytes are eliminated by apoptosis. Based on this biology, we propose to define blasts of T cell acute lymphoblastic leukemia (ALL) with the phenotype of cortical thymocytes (CD1+ and/or CD4+ 8+) as selection-related (SR) and all other T-ALL immunophenotypes as non-selection-related (NSR). The COALL cooperative treatment studies for childhood ALL offer a tool to study the outcome in T-ALL subgroups as children with T-ALL are allocated uniformly to the high risk arm of the protocol. In the COALL-85, -89 and -92 protocols, 39/83 cases presented as SR and 44/83 cases as NSR. Five-year event-free survival of SR phenotype is significantly better compared to the NSR group (0.87 +/- 0.06 vs 0.66 +/- 0.07, log rank test, P = 0.01). T-ALL with SR phenotype is a distinct subgroup of leukemia with excellent prognosis under a high risk treatment protocol. [ABSTRACT FROM AUTHOR]

Unlabelled: Risk factors for venous thrombosis in adults are the prothrombin (PT) G20210A, the factor (F) V G1691A mutations and hereditary deficiencies of protein C, protein S and antithrombin. However, data are limited on the relevance of these risk factors for thrombosis in children and adolescents. We therefore investigated 119 patients aged 0-18 with spontaneous venous thrombosis and controls (n = 100) for the presence of the factor V G1691A mutation and the prothrombin G20210A variant with respect to thrombotic onset and thrombosis location. The following frequencies (patients vs. controls), odds ratios (OR), 95%-confidence intervals (CI) and p-values were found: FV G1691A, 19.3% vs. 5%, OR/CI 4.55/1.66-12.5, p = 0.0038 and prothrombin G20210A, 8.4% vs. 3%, OR/CI 2.96/0.8-11, p = 0.17. A combination of the FV G1691A mutation with the PT G20210A variant was found in 3 children (2.5% of cases) but only once in the controls. With a median (range) age of 2 years (0-17), carriers of the FV mutation were significantly younger compared with patients carrying the PT variant (16 years: 0-18, p < 0.001). Vascular accidents in carriers of the FV mutation occurred in deep veins of the leg (n = 11), cerebral veins (n = 4), renal veins (n = 3) and portal veins (n = 2). Patients with the PT mutation showed spontaneous thrombosis in the majority of cases in the deep veins of the leg (n = 5) and in the central nervous system (n = 2). Combined defects were found in a neonate with renal venous thrombosis and in two adolescents with deep vein thrombosis.Conclusion: Data presented here suggest that the heterozygous FV mutation is the most commonly found prothrombotic risk factor responsible for spontaneous thrombosis during infancy and early childhood. In contrast, the PT G20210A variant is likely to be more important during puberty and adolescence. [ABSTRACT FROM AUTHOR]

Copyright of Strahlentherapie und Onkologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Strahlentherapie und Onkologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

IL-10 plays an important role in the control of immune reactions during systemic infection. Here, IL-10 serum levels were investigated in patients after BMT. The IL-10 levels correlated with the clinical course of the patients and with serum levels of C-reactive protein (CRP) and neopterin (NP). A total of 26 patients with AML (7), ALL (12), CML (2), NHL (3) and multifocal Ewing’s sarcoma (2) had received autologous (10) or allogeneic (16) BMT from related (9) or unrelated donors (7). Routine serum samples were obtained prior to BMT and at days 46 and 100 after BMT. However, in patients with severe complications additional samples were drawn at individual points in time. Prior to BMT, IL-10 serum levels were not detectable in 24/24 patients. Post-BMT, 11 patients developed elevated IL-10 levels, of these eight died of complications (DOC), whereas only one of 15 patients with undetectable IL-10 died of complications, indicating that high IL-10 levels were significantly correlated with severe life-threatening complications (χ2, P < 0.01). to determine the pathomechanism and role of the increased il-10 levels, they were correlated to the respective np and crp serum concentrations. crp and np concentrations were found significantly elevated in patients with detectable il-10, indicating a severe acute phase reaction associated with macrophage activation. in conclusion, high il-10 serum levels in patients after bmt were significantly associated with fatal outcome. since il-10 is a strong suppressor of t cell immunity, high il-10 production in patients with severe complications such as septic shock or gvhd >grade II after BMT might lead to functional immunodeficiency contributing to the poor prognosis of these patients. [ABSTRACT FROM AUTHOR]

In Germany allotransplantation of bone marrow or peripheral blood stem cells is presently performed by 34 different teams operating more or less independently. Thus, strategies of immunogenetic donor search, use of the various tissue typing techniques and policy on acceptable HLA mismatches in related and unrelated settings may vary considerably from one transplant centre to another. This paper summarises the results of the first German consensus meeting on immunogenetic donor search for bone marrow/peripheral blood stem cell grafting. The main goal of the participating transplant physicians and immunogeneticists was to define national standards for the above issues. [ABSTRACT FROM AUTHOR]

Incubation of CML marrow in long-term culture (LTC) conditions may result in selection of normal (Ph-) LTC-initiating cells (LTC-IC) as early as 10 days, and in production of Ph- clonogenic cells and mature end cells within 5 weeks. This was the rationale for using marrow cells from 10-day-old LTC to autograft nine chronic phase CML patients, ineligible for HLA-matched sibling donor transplant, and who were selected on the basis of a pre-transplant screening LTC test. Of the transplanted patients three died; two of graft failure and one of therapy-related toxicity with 97% Ph- cells 16 months following the autograft. The reconstituting haemopoietic cells in the seven engrafted patients were 100% Ph- in four,  90% Ph- in two and 71% Ph- in the seventh, with a duration of complete cytogenetic response of 6–12 months. Three patients reverted to chronic phase and 100% Ph+ haemopoiesis 27–36 months post-autograft. The other three patients remain in continuous haematological remission with 22% Ph- cells in one and complete cytogenetic remission in the other two 3–4 years post-autograft. IFN therapy was generally introduced on the first evidence of recurrence of Ph+ cells or of cytogenetic deterioration. Further strategies to modulate immune surveillance in vivo may improve the outcome of cultured marrow autografts which give an initial and rather prolonged bias towards Ph- haemopoiesis. [ABSTRACT FROM AUTHOR]

Ex vivo production of interleukin 10 (IL-10) and interferon-γ (IFN-γ) was investigated in patients with (n = 5) or without (n = 5) chronic graft-versus-host disease (cGVHD) after allogeneic BMT. Patients were matched for time after transplantation and type of transplant. Anti-CD3-induced IL-10 production in MNCs isolated from patients with cGVHD (range/median: 26–650 pg/106 MNC; 400 pg/106 MNC) was significantly reduced compared to patients without cGVHD (646–2662 pg/106 MNC; 1314 pg/106 MNC; P < 0.05) or healthy controls (679–6361 pg/106 MNC; 3054 pg/106 MNC, P < 0.01). In vitro inhibition of IL-10 by an anti-IL-10 monoclonal antibody enhanced the release of IFN-γ by anti-CD3-stimulated MNCs from 354 ± 34 pg/106 MNCs to 899 ± 61 pg/106 MNCs. Thus, low IL-10 production may cause high IFN- γ release. In anti-CD3-activated MNCs obtained from patients with cGVHD IFN- γ production was significantly increased (324–3331 pg/106 MNC; 1849 pg/106 MNC) compared to healthy donors (127–900 pg/106 MNC; 305 pg/106 MNC P < 0.01). in addition, median ifn-γ release by anti-CD3-activated MNCs obtained from patients without cGVHD (464 pg/106 MNC) was about five-fold lower than in patients with cGVHD. In contrast to cytokine production, the differential leukocyte count (percentages of monocytes, T cells and CD4/CD8 ratio) was essentially the same both in patients with or without cGVHD. Thus, a different activation of Th-1 and Th-2 cells by anti-CD3 may be responsible for the deviant cytokine productions in patients with cGVHD. In conclusion, we observed significantly decreased IL-10 production in patients with cGVHD and an increased median IFN-γ secretion, which may contribute to the altered cytokine production after allogeneic BMT leading to cGVHD. Thus,... [ABSTRACT FROM AUTHOR]

Patients with primary metastatic or recurrent rhabdomyosarcoma (RMS) have a very poor prognosis. Since high-dose chemotherapy (HDC) ± TBI was thought to improve survival, many centers performed this therapy using different types of hematopoietic rescue (auto BM or PBSC, allo BM). This is a retrospective, multicenter analysis of the results of treatment in 36 patients with primary metastatic or relapsed RMS who were given HDC ± TBI and hematopoietic rescue between 1986 and 1994. The median age was 6 years (<1–22 years). primary therapy was given according to either one of the cooperative german soft tissue sarcoma studies cws-81, -86, -91 or the european study for stage iv malignant mesenchymal tumors in childhood. there were 22 alveolar rms, 13 embryonal rms and one undifferentiated sarcoma. the indication for hdc was primary metastatic disease (27 patients) or a relapse of a primary localized tumor (nine patients). thirty-two patients were in 1st or 2nd cr when given hdc and four in vgpr. the median time from last event to hdc was 44 weeks (21–110). hdc consisted of fractionated melphalan ((4 × 30–45 mg/m2), VP16 40–60 mg/kg, carboplatin 3 × 400–500 mg/m2) in 26 patients, 10 of whom received additional FTBI. Seven patients were treated with melphalan alone or in combination with carboplatin. Two patients received cyclophosphamide/busulphan with TLI (total lymphoid irradiation) and one cyclophosphamide with FTBI. Thirty-one patients were given autologous BM or PBSC as hematopoietic rescue and five allogeneic bone marrow from HLA-identical siblings. Fourteen patients received GM-CSF or G-CSF after hematopoietic stem cell transfusion (HSCT). Ten patients received adjuvant IL-2. There was one toxic HDC-related death. Nine patients are alive and free of disease with a median observation time of 57 months (32–108). The median time from HDC to relapse was 4 months (1–17). The... [ABSTRACT FROM AUTHOR]

Multiple transplant-related complications (MTRC) represent a severe condition after bone marrow transplantation (BMT) and are supposed to reflect systemic endothelial damage. Soluble thrombomodulin (sTM) and plasminogen activator inhibitor type-1 (PAI-1) were investigated as markers of endothelial dysfunction in 35 patients after autologous or allogeneic BMT and compared with the occurrence of the typical complications sepsis, veno-occlusive disease of the liver (VOD), graft-versus-host disease (GVHD), and capillary leakage syndrome (CLS). PAI-1 was assessed by an assay of functional activity and sTM by antigenic determination. In patients who had undergone allogeneic BMT and had no transplant-related complications (TRC), PAI-1 peaked on day +14 (20±5 units/ml), and sTM doubled in comparison to the starting range, to 60–80 ng/ml between days +14 and +49. In contrast, PAI-1 and sTM were unchanged following autologous BMT. PAI-1 was increased in sepsis, CLS, and VOD to 39–49 units/ml ( p<0.05, compared with patients without TRC), and in GVHD to 16–47 units/ml (not significant). Soluble TM increased to 63–309 ng/ml in patients with sepsis, VOD, or CLS ( p<0.05, compared with patients without TRC) and to 79–224 ng/ml in GVHD (not significant). The increase of sTM and PAI-1 was also positively correlated to the number of complications, so that in patients with three complications PAI-1 was increased 2.8-fold and sTM 3.5-fold over patients with no complications at all. We conclude that endothelial dysfunction is a feature of VOD, sepsis, CLS, and to lesser extent of GVHD and is worse in patients with multiple complications. [ABSTRACT FROM AUTHOR]

The prognosis of patients with severe capillary leakage syndrome (CLS) after bone marrow transplantation (BMT) is dismal despite aggressive use of intensive care therapy. Because the activated classical pathway of complement and relatively low levels of C1 esterase inhibitor (C1 INH) acitivity are known features in these patients, we evaluated the efficacy of a therapy using purified, human C1 INH concentrate. Severe CLS was defined as increase in body weight by more than 3% within 24 h combined with generalized edema, impaired hemodynamic system (tachycardia and/or decreased blood pressure), and non-responsiveness to furosemide. Of 142 patients, 22 developed severe CLS. The first seven patients whom we diagnosed with this complication were assessed as control patients. Fifteen patients with severe CLS were treated with C1 INH concentrate using a cumulative dose of 180 units/kg body wt. (initial dose: 60 units/kg, followed by two doses at 30 units/kg and four doses at 15 units/kg, every 12 h). The survival rate of patients with CLS was 57% at 1 year after BMT in the C1 INH treatment group, compared with 14% in the control group ( p=0.008). Eight of 15 treated patients are alive at a median of 9 months (range: 4–55) after BMT. The plasma levels of the complement activation parameters C4d and C5a were 3±1.1 mg/dl (mean±S.D.) and 0.3±0.1 μg/l, respectively, prior to BMT, increasing to 8.2±2.1 mg/dl and 1.3±0.4 μg/l, respectively, at diagnosis of CLS. After infusion of C1 INH concentrate the plasma levels of C5a and C4d normalized. The activity of C1 INH rose to 139±10% of normal human plasma NHP pool (mean±S.D.) after infusion. The CH50 values were not significantly altered. The fluid status normalized within 11 days in 14 of 15 treated patients. The results of this study suggest that therapy with C1 INH concentrate improves the prognosis of patients with CLS after BMT. This has to be confirmed in a randomized, controlled trial. [ABSTRACT FROM AUTHOR]

Age, hematopoietic growth factors, cyclosporin A, mode of bone marrow transplantation (BMT) (autologous, allogeneic-related, unrelated), and underlying disease were assessed as potential risk factors for capillary leakage syndrome (CLS) in 96 patients after BMT. CLS was defined as unexplained weight gain of > 3% within 24 h and nonresponsiveness to furosemide. CLS occurred in 9/21 patients after unrelated compared with 2/33 after allogeneic-related BMT (p = 0.0017) for hematopoietic disorders (n = 54) and in 6/7 patients after allogeneic-related compared with 3/35 after autologous BMT (p = 0.001) for solid tumors (n = 42). Hematopoietic growth factors and cyclosporin A were no significant risk factors on their own. We conclude that unrelated BMTs or high-intensity conditioning regimens used in combination with allogeneic-related BMT are the main risk factors for CLS. [ABSTRACT FROM AUTHOR]

Infusions of recombinant human tumor necrosis-alpha plus recombinant human interferon-gamma (rhTNF alpha/rhIFN gamma) were assessed in two patients with Ewing's sarcoma. We analyzed platelet count, coagulation and the terminal complement complex (TCC). During cycles with continuous rhTNF alpha-infusions we found a rapid, marked decrease of platelet count (minus 90% of initial values) and a simultaneous increase of TCC (plus 84% of initial values) at day 4. At days 5-7 a spontaneous increase of platelet count and decrease of TCC were visible. Short-term infusion led to a milder, continuous decrease of platelet counts and to a moderate, progressive increase of TCC at days 5-7. Bleeding occurred only as petechia and mild hemoglobinuria. There was no effect related to the dosage of rhTNF alpha or rhIFN gamma. Relevant differences were seen only in the variable time courses of rhTNF alpha application. Ex vivo analysis of one patient's platelets showed no cytokine-related effect on induced aggregation according to Born. Additionally, we analyzed in vitro effects of the cytokines on platelet count, platelet aggregation, and the assembly of TCC in platelet membranes. No effects were found after incubation of platelet-rich plasma (PRP) with 1000 pg/ml rhTNF alpha and/or 50 pg/ml rhIFN gamma. Fluid-phase and membrane-bound TCC did not change after incubation of PRP with cytokines. A slightly time-dependent increase of TCC without alteration of platelet count and platelet function did not agree with the assumption of a direct injury to platelets. We assume a cytokine-mediated role of the endothelium in platelet loss. [ABSTRACT FROM AUTHOR]

Vascular-leak syndrome (VLS) is a common complication in the first 3 weeks after bone marrow transplantation (BMT). The patients present with weight gain, generalized edema, ascites, pericardial or pleural effusions, tachycardia, arterial hypotonia, and/or pre-renal failure. The aim of our study was to investigate the role of the complement system in VLS. The protein concentrations of C3 and C4 were studied by immunodiffusion, and total hemolytic complement activity was studied by assessment of CH50. C1 esterase inhibitor (C1 Inh), the major inhibitor of the classical pathway of complement, was assessed by a functional test. Activation of complement was assessed by C4d (a C4 activation product). Twelve patients were followed prospectively from start of conditioning therapy to day +21 after bone marrow transplantation. Eight of 12 patients did not develop VLS. These patients had an increase of C3 between day +9 and day +13 (range: 1.3- to 1.5-fold, median: 1.4-fold), C4 (range: 1.3- to 1.9-fold, median: 1.4-fold), CH50 (range: 1.3- to 1.6-fold, median: 1.4-fold), and C1 Inh (range: 1.2- to 1.5-fold, median: 1.3-fold). Four of 12 patients developed VLS. C1 Inh activity was decreased to 0.60- to 0.80-fold. This decrease began 2-6 days prior to clinical diagnosis of VLS (n = 3), or at onset of VLS (n = 1). Patients with VLS showed elevated C4d concentrations (up to 2.4 mg/dl, upper normal threshold value: 0.9 mg/dl). Patients with VLS reveal an activated state of the complement system which is accompanied by a reduced activity of C1 Inh. Insufficient control of complement activation may contribute to VLS in patients after BMT. [ABSTRACT FROM AUTHOR]

One consistent feature of the Ewing's tumour family is the presence of a balanced translocation involving band q12 and band q24 of chromosome 22 and chromosome 11. Recent cloning of the chromosome breakpoint regions of t(11;22)(q24;q12) Ewing's sarcoma translocation has revealed that the breakpoints were localized within the Ewing's sarcoma gene (EWS gene) on chromosome 22 and the Fli-1 gene on chromosome 11. Molecular genetic techniques can thus be applied to the detection of the t(11;22) translocation in Ewing's tumours. By reverse transcription and polymerase chain reaction technique (RT-PCR) 11 Ewing's tumour derived cell lines, 12 primary Ewing's tumours, and 11 tumours after treatment were analysed for the occurence of the t(11;22) translocation. Furthermore, blood and bone marrow samples from 5 patients were available for RT-PCR. In 78% of the cell lines and 91% of the primary Ewing's tumours the t(11;22) translocation was detectable by RT-PCR. In bone marrow samples from a Ewing's sarcoma patient presenting in relapse tumour cells were detected by molecular genetic analysis. Our results indicate that molecular genetic detection of the t(11;22) translocation is valuable in the differential diagnosis of small round cell tumours and will provide important information for the staging and prognosis of Ewing's tumour. [ABSTRACT FROM AUTHOR]

Neisseria meningitidis infection may present as meningitis or as severe, fulminant sepsis. In order to classify individual patients early according to the expected course of the disease, we developed a score named Neisseria sepsis index [NESI]. The NESI was defined using the parameters heart rate, mean arterial blood pressure, base excess and presence of acute subcutaneous bleeding and/or skin necroses (minimal value [= no evidence for sepsis] NESI 0; maximum value [= most severe sepsis] NESI 8). Seventeen patients with documented, systemic N. meningitidis infection were prospectively assessed for the terminal complement complex (TCC), serum tumour necrosis factor alpha (TNF alpha) levels (as laboratory parameters for severity of sepsis) and NESI score. The evaluation was immediately performed when the patients were admitted to the hospital. The 17 patients showed the following distribution of data: NESI 0 (n = 4), NESI 1 (n = 6), NESI 2 (n = 0), NESI 3 (n = 1), NESI 4 (n = 2), NESI 5 (n = 2), NESI 6 (n = 0), NESI 7 (n = 1), NESI 8 (n = 1). Mortality was 4/17 patients, all had NESI > or = 5. TCC values ranged from 647-6461 ng/ml (normal range: 130-360 ng/ml); and was not correlated to NESI. TNF alpha values ranged from 10-910 pg/ml and were correlated to NESI (r2 = 0.71, n = 17, P < 0.001). In patients with fatal outcome, TNF alpha was 600 +/- 160 pg/ml (mean +/- SEM) and in surviving patients 130 +/- 50 pg/ml (mean +/- SEM). TNF alpha was increased in 15/17 patients when compared to normal controls (< 27 pg/ml). CONCLUSION. The NESI is based on few clinical, objective data, that are available in every hospital. NESI appears to offer an instrument: (1) for making decisions in regard to appropriate monitoring and treatment of vital organ function; and (2) for assessing the quality of care for this life-threatening infection. [ABSTRACT FROM AUTHOR]

Three human cell lines derived from Ewing's sarcoma (RM-82, VH-64, and WE-68) were investigated to establish the influence of recombinant human interferon γ (rhIFNγ) and tumour necrosis factor α (rhTNFα) on cell proliferation and survival and to characterize IFNγ and TNFα receptor expression. Incorporation of [H]thymidine into cells was inhibited by rhIFNγ after 24 h of incubation. Half-maximal inhibition was observed with 10-80 U/ml rhIFNγ. A maximal effect (50%-70% inhibition of cell proliferation) was achieved by treatment of cells with 250 U/ml rhIFNγ. The influence of rhTNFα on proliferation was found to differ among cell lines and varied with the concentration and the duration of exposure of cells to this cytokine. In WE-68 and VH-64 cells [H]thymidine incorporation was not affected by rhTNFα up to 2000 U/ml after 96 h of incubation, where-as in RM-82 cells the incorporation was inhibited by 35% after 48 h of incubation with 100 U/ml rhTNFα. However, all cell lines showed a synergistic antiproliferative response to the combination of rhIFNγ and rhTNFα after 24 h of incubation. The human recombinant cytokines interleukin(IL)-1α, IL-1β, IL-2, IL-3, IL-4, IL-6 and granulocyte/macrophagecolony-stimulating factor, tested alone and in combination with rhIFNγ and rhTNFα, had no influence on cell proliferation. Binding studies in the cell lines withI-rhIFNγ revealed a dissociation constant ( K) of 160-306 p M and approximately 8000-13500 receptors/cell. Binding experiments withI-rhTNFα indicated 430-1250 receptors/cell with K ranging from 13 p M to 162 p M. These data indicate that, among various cytokines, only IFN and TNFα are capable of potently reducing Ewing's sarcoma cell growth in vitro. Our data suggest that IFN alone or in combination with TNFα may be useful in the design of novel strategies in Ewing's sarcoma therapy. [ABSTRACT FROM AUTHOR]

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This case report shows reversible brain MRI changes probably associated with acyclovir toxicity. So far, neuroimaging in acyclovir toxicity had been negative or uninformative. A 12-year-old girl developed focal secondary generalizing epileptic fits following 4 weeks of prophylactic administration of acyclovir (3 × 10 mg/kg body weight/day i.v.) on day +22 after allogeneic peripheral blood stem cell transplantation for CML. Infective causes were excluded. Brain MRI demonstrated multiple gadolinium-enhancing areas with impairment of the blood–brain barrier in cortical and subcortical regions. Clinical symptoms and neuroimaging pathology resolved completely within 9 days of acyclovir withdrawal. [ABSTRACT FROM AUTHOR]

The combination of piperacillin with tazobactam (PIP/TAZ) extends the activity of piperacillin against gram-positive, gram-negative, and anaerobic bacteria. The broad-spectrum of this formulation, together with its low degree of organ toxicity observed in adults, makes PIP/TAZ a tempting choice for children with radio-/chemotherapy-induced neutropenia. However, the use of PIP/TAZ is not yet approved for children under 12 years of age. The tolerability of PIP/TAZ was assessed in 19 children and adolescents between 2 and 18 years of age who developed a fever during aplasia after high dose radio-/chemotherapy and autologous stem cell transplantation (HD-SCT) for primary multifocal or relapsed solid tumours. Treatment with PIP/TAZ was initiated on average 3 days after HD-SCT, and the treatment was continued for approximately 10 days. Both clinical observation and laboratory studies showed no relevant alterations that would have been attributable to PIP/TAZ treatment. These results indicate that PIP/TAZ appears to be well tolerated in children during the acute phase of HD-SCT. [ABSTRACT FROM AUTHOR]

A patient with glycogen storage disease (GSD) type Ib, neutrophenia, chronic inflammatory bowel disease and recurrent abscesses was treated with recombinant human granulocyte-macrophage colony stimulating factor (GM-CSF). GM-CSF (and also granulocyte colony stimulating factor) therapy markedly increased the neutrophil counts and reduced the frequency of infections and inflammation. We conclude that myeloid growth factors are effective for the treatment and prevention of acute infections and chronic inflammatory complications in patients with GSD Ib. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor about allogeneic stem cell transplantation in post transplant lymphoproliferative disease.

Reports on an unrelated cord blood transplantation in an infant with severe multisystem Langerhans cell hystiocytosis (LCH) and its clinical outcome, engraftment and culture of monocyte-derived dendritic cells. Characterization of LCH and its symptoms in children younger than 2 years; Details of umbilical cord blood transplantation and engraftment of donor hematopoiesis in an infant patient; Complications of post-transplant clinical course and treatment with stem cell transplantation; Evidence from the data for the concept of treating LCH with hematopoietic stem cell transplantation with related or unrelated donors.

Presents a medical case of a boy with Fanconi anemia associated with oesophageal and anal atresia. Implantation of a Hickman-Broviae catheter; Occurence of a grade IV anaphylactic reaction; Findings before and after bone marrow transplantation.