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T Klingebiel

Publications and source records attributed to T Klingebiel.

At least 19 recordsLinked to original sources
PubMed2007

Retrochorionic hematoma in congenital afibrinogenemia: resolution with fibrinogen concentrate infusions.

Without treatment, pregnancies in patients with congenital afibrinogenemia terminate in miscarriage at 5-6 weeks of gestation. Animal model studies have suggested that implantation site bleeding contributes to miscarriage in afibrinogenemia; however, retrochorionic hematoma in human congenital afibrinogenemia has not been previously observed. A patient with congenital afibrinogenemia receiving fibrinogen prophylaxis developed a retrochorionic hematoma in the first trimester. With continuous intensified fibrinogen concentrate replacement the hematoma resolved over 6 weeks, and the patient delivered a healthy infant. Median fibrinogen levels in the first trimester were 48 mg/dL and in second and third trimester 44 mg/dL. Median fibrinogen levels under 60 mg/dL may be adequate to maintain pregnancy in patients with congenital afibrinogenemia, although it is possible that higher levels might reduce the risk of hemorrhagic events.

Adult↗
PubMed2006

[Diagnostic difficulties in encephalitis and glioma].

BACKGROUND: Glial neoplasms can infiltrate the central nervous system extensively with relative preservation of the underlying neuronal architecture. The differential diagnosis between cerebral glioma and infective lesions can be very difficult to distinguish by MRI only. CASE REPORT: We report a 7 year old boy with recurrent vomiting, fever, weakness, abdominal pain and diarrhea. Besides an expressive speech disturbance the neurological examination showed no pathological findings. The sonography revealed discrete hepatomegaly and small pericardial effusion. MRI showed a diffuse mesencephalic and pontine swelling without contrast medium enhancement possibly pointing to an infective lesion. Microbiological, serological and metabolic investigations of blood and CSF were normal. After initial improvement associated with antibiotic, antiviral and dexamethasone treatment the process relapsed progessively. The 1H-MR-spectroscopy showed elevated cholin and decreased N-acetyl-aspartate levels suspicious for a proliferating process. Brain biopsy revealed anaplastic astrocytoma (WHO III). Despite of radiation and chemotherapy the tumordisease deteriorated and the patient died because of progressive brainstem infiltration one year later. CONCLUSION: This case report shows that cerebral glioma can mimick infective brain disease and that MR-spectroscopy is an important non-invasive tool in this differential diagnosis.

Aspartic Acid↗
PubMed2006

The MLL recombinome of acute leukemias.

Chromosomal rearrangements of the human MLL gene are a hallmark for aggressive (high-risk) pediatric, adult and therapy-associated acute leukemias. These patients need to be identified in order to subject these patients to appropriate therapy regimen. A recently developed long-distance inverse PCR method was applied to genomic DNA isolated from individual acute leukemia patients in order to identify chromosomal rearrangements of the human MLL gene. We present data of the molecular characterization of 414 samples obtained from 272 pediatric and 142 adult leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) was determined and several new TPGs were identified. The combined data of our study and published data revealed a total of 87 different MLL rearrangements of which 51 TPGs are now characterized at the molecular level. Interestingly, the four most frequently found TPGs (AF4, AF9, ENL and AF10) encode nuclear proteins that are part of a protein network involved in histone H3K79 methylation. Thus, translocations of the MLL gene, by itself coding for a histone H3K4 methyltransferase, are presumably not randomly chosen, rather functionally selected.

Acute Disease↗
PubMed2006

CD34(+)-selected stem cell boost for delayed or insufficient engraftment after allogeneic stem cell transplantation.

BACKGROUND: Poor graft function without rejection may occur after stem cell transplantation (SCT). CD34(+) stem cell boost (SCB) can restore marrow function but may induce or exacerbate GvHD. We therefore investigated the feasibility and efficacy of CD34(+)-selected SCB in some patients with poor graft function. We present the results for eight patients (median age 46 years) transplanted initially for myelofibrosis, acute leukemia, myeloma and NHL. Six patients had received HLA-matched and two mismatched grafts (PB, BM; n=5, 3). After a median of 128 days post-transplant, the median leukocyte and platelet counts were, respectively, 2.05/nL and 18/nL. None had achieved platelet counts >50/nL even though donor chimerism was >95% in seven recipients. METHODS: Positive selection of CD34(+) stem cells was performed on a CliniMACS device, observing GMP and achieving a median of 98.5% purity. The patients received a median of 1.7 x 10(6)/kg CD34(+) cells and 2.5 x 10(3)/kg CD3(+) T lymphocytes. RESULTS: Hemograms at days +30, +60 and +90, respectively, showed steadily increasing median leukocyte (2.55, 3.15 and 4.20/nL) and platelet (29, 39 and 95/nL) counts. After a median follow-up of 144 days, five patients remained alive. No patient had developed acute or chronic GvHD. One patient died of leukemic relapse and two others of systemic mycosis. DISCUSSION: These preliminary results point to the possibility of safely improving graft function using CD34(+) positively selected stem cells without necessarily increasing the incidence of GvHD in patients with poor graft function post-SCT. Experience with more patients and longer follow-up should clarify the optimal role for this procedure.

Adolescent↗
PubMed2006

Diagnostic approaches for immunocompromised paediatric patients with pulmonary infiltrates.

Pulmonary infiltrates in immunocompromised children often pose problems in terms of deciding on further diagnostic and therapeutic procedures, but few studies have evaluated the value of non-invasive and invasive diagnostic methods in paediatric populations. Both galactomannan ELISA and PCR protocols appear to be less useful in children than in adults. Invasive procedures, such as bronchoalveolar lavage or lung biopsy, can yield a pathohistological diagnosis and/or the isolation of a pathogen. Prospective studies in paediatric patients are needed urgently to assess the value of different diagnostic procedures and to define an effective and safe diagnostic strategy for the individual child.

Animals↗
PubMed2006

Quantification of chimerism within peripheral blood, bone marrow and purified leukocyte subsets: comparison of singleplex and multiplex PCR amplification of short tandem repeat (STR) loci.

OBJECTIVE AND METHODS: Chimerism analysis has become a routine diagnostic procedure after haematopoietic allogeneic stem cell transplantation for early detection of relapse of disease or graft failure. Whereas some centres developed individual in-house short tandem repeat (STR) systems, others prefer commercial multiplex PCR systems. However, little is known about inter-assay variation, which could have a significant impact on treatment decision. We therefore compared two commercial multiplex PCR kits with our in-house STR system using different sample sources, such as peripheral blood (PB), bone marrow (BM) and specific leukocyte subsets. RESULTS: Fifty samples of eighteen paediatric patients were analysed. For neither material, PB, BM and leukocyte subtypes, a significant difference between the STR systems tested was observed. Chimerism analyses of each single STR primer, which is component of both the in-house and the commercial STR system, did not reveal significant differences. CONCLUSION: Our analysis demonstrates that similar results can be obtained with both assays, even when using various sample sources. Further evaluation of different test systems will help to increase interlaboratory standardisation of chimerism analyses for early clinical intervention.

Adolescent↗
PubMed2005

How and when should we monitor chimerism after allogeneic stem cell transplantation?

SUMMARY: Chimerism analysis has become an important tool for the peri-transplant surveillance of engraftment. It offers the possibility to realize impending graft rejection and can serve as an indicator for the recurrence of the underlying malignant or nonmalignant disease. Most recently, these investigations have become the basis for treatment intervention, for example, to avoid graft rejection, to maintain engraftment and to treat imminent relapse by pre-emptive immunotherapy. This invited review focuses on the clinical implications of characterization of hematopoietic chimerism in stem cell transplantation.

Graft Survival↗
PubMed2005

Allogeneic haematopoietic stem cell transplantation in children with acute lymphoblastic leukaemia: the BFM/IBFM/EBMT concepts.

Children with high risk or relapsed acute lymphoblastic leukaemia (ALL) can benefit from allogeneic haematopoietic stem cell transplantation (SCT). To reduce transplantation-associated complications, the BFM study group, the IBFM study group and the PD-WP-EBMT initiated a prospective cooperative multicentre trail for paediatric ALL patients with an indication for allogeneic stem cell transplantation. Four-digit high-resolution HLA typing for all nonsibling donors, standardised GvHD prophylaxis and therapy, uniform conditioning regimen and minimum standards for supportive care should reduce not only treatment-related mortality but also ameliorate late effects for young patients. Furthermore, the prospective evaluation aims to assess the role of haematopoietic SCT in comparison to chemotherapy to enable valuable treatment recommendations for further decisions.

Child↗
PubMed2005

Late effects after stem cell transplantation (SCT) in children--growth and hormones.

Stem cell transplantation (SCT) has established itself as a very successful therapy in often otherwise unbeatable disorders. In a subset of children and adolescents there are, however, late effects, often as a combination of the underlying disorder, its primary treatment and subsequent SCT. In children and adolescents, disorders of growth and the endocrine system have been observed to occur frequently. The assurance of normal growth, puberty, fertility and thyroid function--including the prevention of secondary malignancies--is of utmost importance for the overall success of treatment and the maintenance of quality of life. This, however, requires a systematic and structured follow-up programme for patients after SCT. Patients and their families need to be made familiar with this concept early and physicians need to understand that such a system must be implemented as part of a comprehensive care.

Adolescent↗
PubMed2005

Hourly monitoring of circulating CD34+ cells to optimize timing of autologous apheresis in pediatric patients.

In order to increase the CD34+ cell yield in children undergoing autologous stem cell transplantation, the optimum time of apheresis after G-CSF administration has still to be found. We prospectively studied the mobilization of CD34+ cells and white blood cells in the peripheral blood (PB) of 20 pediatric patients before leukapheresis. The monitoring schedule covered 12 h, with blood samples taken before and at 2, 4, 5, 6, 7, 8, 10 and 12 h after G-CSF administration when 10 CD34+ cells/mul were reached. CD34+ cells were measured by flow cytometric analysis both in the single- and dual-platform setting. Two different patterns of mobilization (POM) emerged: 12 patients showed an increase in CD34+ cells in PB during the first 4 h after G-CSF (POM I), while eight patients had an initial decrease of CD34+ cells. However, all patients together showed a significant increase of CD34+ cells about 10 h after G-CSF administration. Further studies with more patients, using an enhanced monitoring schedule will be required to refine the results.

Adolescent↗
PubMed2005

Donor leukocyte infusion after hematopoietic stem cell transplantation in patients with juvenile myelomonocytic leukemia.

Juvenile myelomonocytic leukemia (JMML) is a clonal myeloproliferative disorder of early childhood. In all, 21 patients with JMML who received donor leukocyte infusion (DLI) after allogeneic hematopoietic stem cell transplantation (HSCT) for either mixed chimerism (MC, n=7) or relapse (n=14) were studied. Six patients had been transplanted from an HLA-matched sibling and 15 from other donors. Six of the 21 patients (MC: 3/7 patients; relapse: 3/14 patients) responded to DLI. Response rate was significantly higher in patients receiving a higher total T-cell dose (> or =1 x 10(7)/kg) and in patients with an abnormal karyotype. None of the six patients receiving DLI from a matched sibling responded. Response was observed in five of six patients who did and in one of 15 children who did not develop acute graft-versus-host disease following DLI (P=0.01). The overall outcome was poor even for the responders. Only one of the responders is alive in remission, two relapsed, and three died of complications. In conclusion, this study shows that some cases of JMML may be sensitive to DLI, this providing evidence for a graft-versus-leukemia effect in JMML. Infusion of a high number of T cells, strategies to reduce toxicity, and cytoreduction prior to DLI may improve the results.

Child↗
PubMed2005

Common genetic variants in the interleukin-6 and chitotriosidase genes are associated with the risk for serious infection in children undergoing therapy for acute myeloid leukemia.

Infectious complications represent a substantial cause of morbidity and mortality in children undergoing therapy for acute myeloid leukemia (AML). Since it has been shown that alterations in innate immune pathways contribute to the risk for serious infections, we analyzed well-characterized variants in innate immune genes (TNF, IL6, IL8, MPO, CHIT, FCGR2A, TLR2, and TLR4) to determine their possible contribution to infectious complications during therapy for pediatric AML. The study population consisted of 168 North European Caucasian children enrolled on the clinical trial AML-BFM 93. We found an association between Gram-negative bacterial infection and common, functional variants in two genes, IL6 and CHIT. The risk for infection was significantly higher in children with the G allele in the IL6 promoter at -174 bp (P=0.026) and in patients with the H allele of CHIT (P=0.033). The promoter variant in IL6 has been shown to increase expression while the H allele disrupts both function and circulating levels. Our data suggest that variant alleles of both IL6 and CHIT could influence susceptibility to infection with Gram-negative bacteria in children undergoing therapy for AML. Follow-up studies, namely replication association studies and in vitro investigation of these common polymorphisms, are warranted to confirm these observations.

Acute Disease↗
PubMed2004

Transplantation of highly purified peripheral-blood CD34+ progenitor cells from related and unrelated donors in children with nonmalignant diseases.

Transplantation of allogeneic stem cells is currently the only curative treatment for some nonmalignant pediatric diseases. We investigated whether transplantation of purified CD34(+) stem cells prevents acute and chronic GvHD and reduces transplant-related mortality. A total of 25 pediatric patients with nonmalignant diseases underwent allogeneic transplantation from 26 donors (matched related n=4, matched or partially matched unrelated n=14, mismatched related n=8). All grafts were purified peripheral-blood CD34(+) stem cells mobilized with G-CSF. Patients received a median of 12.9 x 10(6) CD34(+) progenitor cells with a median of 6.1 x 10(3) contaminating T-lymphocytes per kilogram of body weight. No post transplant immunosuppressive drugs were given for prophylaxis of GvHD. Engraftment was seen in 21 patients. Three patients engrafted after a second transplant and one patient failed to engraft. Two patients had autologous reconstitution 1.5 years post transplant and one of them was successfully retransplanted. No acute GvHD >grade II was seen, and only two patients developed limited, chronic GvHD. In all, 22 patients (88%) are alive with a median follow-up of 3.7 years. In total, 19 patients (76%) are free of disease or of progression. Transplantation of highly purified peripheral-blood CD34(+) stem cells is associated with low toxicity in patients with nonmalignant diseases.

Adolescent↗
PubMed2004

Clinical relevance of serial quantitative analysis of hematopoietic chimerism after allogeneic stem cell transplantation in children for severe aplastic anemia.

Allogeneic stem cell transplantation (allo-SCT) is a well-established treatment modality for children with severe aplastic anemia (SAA). Treatment failures are rare and mostly caused by graft rejection. Increasing mixed chimerism represents a stage at the very beginning of graft rejection, where immunological intervention might be an effective prophylactic approach. To substantiate this, we: (1) monitored peripheral blood cells from children with SAA after allo-SCT and performed pre-emptive immunotherapy in patients with increasing MC. In all, 23/34 courses of 32 children with SAA after allo-SCT showed a complete chimerism (CC) throughout and 10/34 developed different types of mixed chimerism (MC). Altogether, 4/10 with MC spontaneously developed decreasing MC, 2/10 courses persisted with low proportions of autologous cells below 30% (stable-MC), 4/10 developed increasing MC and one patient showed an autologous recovery. All patients with CC, decreasing MC or stable MC remained in continuous complete remission (CCR). In all, 2/4 patients with increasing MC developed graft rejection. Based on these observations, 2/4 new patients with increasing MC received low-dose DLIs prophylactically, and remained in CCR without any GVHD. These results substantiate that low-dose DLI in children with SAA and increasing MC can prevent graft rejection with a calculable risk to induce severe GVHD.

Adolescent↗
PubMed2004

Increasing mixed chimerism defines a high-risk group of childhood acute myelogenous leukemia patients after allogeneic stem cell transplantation where pre-emptive immunotherapy may be effective.

Children with leukemias and increasing mixed chimerism (increasing MC) after allogeneic stem cell transplantation have the highest risk to relapse. Early immunological intervention was found to be effective in these cases. To substantiate this on a defined group of pediatric acute myelogenous leukemia (AML) patients, we performed serial analysis of post transplant chimerism and pre-emptive immunotherapy in patients with increasing MC. In total, 81 children were monitored, 62 patients revealed complete chimerism (CC), low-level MC or decreasing MC. Increasing MC was detected in 19 cases. Despite early immunological intervention relapse was still significantly more frequent in patients with increasing MC (9/19) than in patients with CC, low-level or decreasing MC (8/62, P<0.005). The probability of 3-year event-free survival (EFS) was 52% for all patients (n=81), 59% for patients with CC, low-level MC, 60% for patients with decreasing MC (n=62), and 28% for patients with increasing MC (n=19, P<0.005). Patients with increasing MC who received early immunological intervention showed a significantly enhanced probability for event-free survival (pEFS 36%, n=15) compared to patients with increasing MC without intervention (pEFS 0%, n=4, P<0.05). These results prove that pediatric AML patients with increasing MC are at highest risk for relapse and that early immunological intervention can prevent relapse in these patients.

Adolescent↗
PubMed2004

Infectious complications in pediatric acute myeloid leukemia: analysis of the prospective multi-institutional clinical trial AML-BFM 93.

Infections still remain a major cause of therapy-associated morbidity and mortality in children with acute myeloid leukemia (AML). To improve supportive care measurements, detailed information on frequency and characteristic features of infectious complications is needed. We retrospectively analyzed the medical charts of 304 children, treated in 30 hospitals according to the multi-institutional clinical trial AML-BFM 93. Overall, 855 infectious complications occurred in 304 patients (fever without identifiable source (n=523; 61.2%), clinically (n=57; 6.7%) and microbiologically documented infections (n=275; 32.1%)). Neutropenia was present in 74.1% of the infectious episodes. In all, 20 patients died of infection-associated complications (15/276 (5.4%) patients without and 5/28 (17.9%) with Down syndrome), most of them during early induction therapy (n=11). Blood stream infections occurred in 228 episodes (Gram-positive (n=202) and Gram-negative (n=42) pathogens). Invasive fungal infection was probable or proven in 15 patients. In 113 out of the 855 infectious episodes (13.3%), pneumonia was radiologically diagnosed. Better strategies of supportive care might help to improve overall survival in children undergoing chemotherapy for AML. Therefore, children with AML should be treated in specialized pediatric centers, and there should be a very low threshold to readmit patients, in particular patients with pulmonary symptoms.

Acute Disease↗