Tumor necrosis factor and lymphotoxin-alpha genetic polymorphisms and risk of relapse in childhood B-cell precursor acute lymphoblastic leukemia: a case-control study of patients treated with BFM therapy

BACKGROUND: Circulating levels of tumor necrosis factor (TNF) and lymphotoxin-α (LT-α) have been associated with outcome in solid and hematologic malignancies. Within the TNF gene and the LT-α gene, polymorphisms have been identified at nucleotide positions -308 and +252, respectively. The variant alleles for TNF are designated TNF1 and TNF2, the ones for LT-α LT-α (10.5 kb) and LT-α (5.5 kb). Of interest, TNF2 and LT-α (5.5 kb) were shown to be associated with higher TNF and LT-α plasma levels than their counterparts. In the present study, we investigated the associations of the above mentioned polymorphisms with risk of relapse in childhood acute lymphoblastic leukemia (ALL) treated according to Berlin-Frankfurt-Münster (BFM) protocols. METHODS: Matched case-control study of 64 relapsed and 64 successfully treated non-relapsed childhood B-cell precursor ALL patients of standard and intermediate risk for treatment failure. RESULTS: The odds ratio (OR) for the combined category of TNF1/TNF2 and TNF2/TNF2 genotypes in comparison to the TNF1/TNF1 genotype was 1.17 (95 % confidence interval (CI) = 0.53 - 2.56, P = 0.697). The ORs for the LT-α (10.5 kb/5.5 kb) and the LT-α (5.5 kb/5.5 kb) genotypes with reference to the LT-α (10.5 kb/10.5 kb) genotype were 2.17 (95 % CI = 0.84 - 5.58, P = 0.107) and 0.5 (95 % CI = 0.09 - 2.66, P = 0.418), respectively. CONCLUSIONS: Our results do not suggest a major role of the investigated genetic polymorphisms with regard to risk of relapse in standard- and intermediate-risk childhood B-cell precursor ALL treated according to BFM protocols

Qualität 2030

Qualität und Sicherheit dienen als Projektionsfläche für die unterschiedlichsten Problemstellungen im deutschen Gesundheitssystem. Tragfähige Zielvorstellungen als Basis für die Weiterentwicklung der Qualitätssicherung in Deutschland sind jedoch nicht in Sicht, Glaubwürdigkeit und Vertrauen in Instrumente und Begrifflichkeiten gehen verloren. Wir fahren fort, Menge statt Qualität zu finanzieren, sektorale Abschottung geht über Zusammenarbeit. Bei allen gesetzgeberischen Aktivitäten – ein grundlegender Reformansatz ist bislang nicht erkennbar. Hier setzt Qualität 2030 an und schlägt einen Ordnungsrahmen für das Gesundheitswesen vor, in dem Qualität und Patientensicherheit die steuernden Faktoren sind. Es wird klar formuliert, welche grundlegenden Reformansätze erforderlich sind, welche Interventionen (z.B. Pay for Performance) notwendig sind und wie diese – ohne negative Begleiteffekte – in das System eingeführt werden können. Qualität 2030 steht zudem für einen realistischen Zeitrahmen zur Umsetzung dieses Paradigmenwechsels; das Werk ist Argumentations- und Arbeitsgrundlage für die notwendigen Reformen

ROMANTIC RECULTIVATING OF SELF AND ENVIRONMENT

My project discusses the important philosophical role that interacting with nature (as opposed to having limited access to nature preserves and the like) plays in the life of an individual. As such I discuss the biological implications for experiences of real (as contrasted with simulated) nature and, in so doing, also discuss the connection of biology to philosophy. I go on to discuss the sociological and psychological ramifications of this interactive relationship through notions such as love and community and their ties to philosophy. I then close with a discussion of the necessity of artistic expression and how those endeavors can be manifested or realized in and through experience with natural environments

Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and susceptibility to pediatric acute lymphoblastic leukemia in a German study population

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) has a major impact on the regulation of the folic acid pathway due to conversion of 5,10-methylenetetrahydrofolate (methylene-THF) to 5-methyl-THF. Two common polymorphisms (677C>T and 1298A>C) in the gene coding for MTHFR have been shown to reduce MTHFR enzyme activity and were associated with the susceptibility to different disorders, including vascular disease, neural tube defects and lymphoid malignancies. Studies on the role of these polymorphisms in the susceptibility to acute lymphoblastic leukemia (ALL) led to discrepant results. METHODS: We retrospectively evaluated the association of the MTHFR 677C>T and 1298A>C polymorphisms with pediatric ALL by genotyping a study sample of 443 ALL patients consecutively enrolled onto the German multicenter trial ALL-BFM 2000 and 379 healthy controls. We calculated odds ratios of MTHFR genotypes based on the MTHFR 677C>T and 1298A>C polymorphisms to examine if one or both of these polymorphisms are associated with pediatric ALL. RESULTS: No significant associations between specific MTHFR variants or combinations of variants and risk of ALL were observed neither in the total patient group nor in analyses stratified by gender, age at diagnosis, DNA index, immunophenotype, or TEL/AML1 rearrangement. CONCLUSION: Our findings suggest that the MTHFR 677C>T and 1298A>C gene variants do not have a major influence on the susceptibility to pediatric ALL in the German population

Methotrexate-associated toxicity in children with Down syndrome and acute lymphoblastic leukemia during consolidation therapy with high dose methotrexate according to ALL-BFM treatment regimen

Children with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) often suffer from severe toxicities during treatment, especially with high-dose methotrexate (HD-MTX). Systematic data on methotrexate (MTX) toxicity in these patients are rare. We analyzed seven MTX-associated toxicities during consolidation therapy in 103 DS- and 1,109 non-DS-patients (NDS) with ALL (NDS-ALL) enrolled in ALL-Berlin-Frankfurt-Münster (ALL-BFM) trials between 1995-2016 and 1995-2007, respectively. Patients received four courses MTX (5 g/m2 each) plus intrathecal MTX and 6-mercaptopurine (6-MP). From 2004 onwards, a dose of 0.5 g/m2 in the first MTX course has been recommended for DS-patients. DS-patients showed higher rates of grade 3/4 toxicities after the first course with 5 g/m2 MTX compared to NDS-patients (grade 3/4 toxicities 62 in 45 DS-patients vs 516 in 1,089 NDS-patients, P<0.001). The dose reduction (0.5 g/m2) in DS-patients has reduced toxicity (39 in 51 patients, P<0.001) without increasing the relapse risk (reduced dose, 5-year cumulative relapse incidence = 0.09±0.04 vs high dose, 0.10±0.05, P=0.51). MTX dose escalation to 1.0 g/m2 for DS-patients who tolerated 0.5 g/m2 (n= 28 of 51 patients) did not result in an increased rate of grade 3/4 toxicities after the second course (P=0.285). Differences in MTX plasma levels at 42 and 48 hours after the start of the first methotrexate infusion did not explain higher toxicity rates in DS-patients treated with 0.5 g/m2 compared to NDS-patients treated with 5 g/m2 Within the DS cohort a higher MTX plasma level was associated with increased toxicity. In conclusion, dose reduction in the first MTX course reduced severe toxicities without increasing the risk of relapse. (ClinicalTrials.gov identifier: NTC00430118, NCT01117441)

MAP3K7 is recurrently deleted in pediatric T-lymphoblastic leukemia and affects cell proliferation independently of NF-κB

Background: Deletions of 6q15–16.1 are recurrently found in pediatric T-cell acute lymphoblastic leukemia (T-ALL). This chromosomal region includes the mitogen-activated protein kinase kinase kinase 7 (MAP3K7) gene which has a crucial role in innate immune signaling and was observed to be functionally and prognostically relevant in different cancer entities. Therefore, we correlated the presence of MAP3K7 deletions with clinical parameters in a cohort of 327 pediatric T-ALL patients and investigated the function of MAP3K7 in the T-ALL cell lines CCRF-CEM, Jurkat and MOLT-4. Methods: MAP3K7 deletions were detected by multiplex ligation-dependent probe amplification (MLPA). T-ALL cell lines were transduced with adeno-associated virus (AAV) vectors expressing anti-MAP3K7 shRNA or a non-silencing shRNA together with a GFP reporter. Transduction efficiency was measured by flow cytometry and depletion efficiency by RT-PCR and Western blots. Induction of apoptosis was measured by flow cytometry after staining with PE-conjugated Annexin V. In order to assess the contribution of NF-κB signaling to the effects of MAP3K7 depletion, cells were treated with TNF-α and cell lysates analyzed for components of the NF-κB pathway by Western blotting and for expression of the NF-κB target genes BCL2, CMYC, FAS, PTEN and TNF-α by RT-PCR. Results: MAP3K7 is deleted in approximately 10% and point-mutated in approximately 1% of children with T-ALL. In 32 of 33 leukemias the deletion of MAP3K7 also included the adjacent CASP8AP2 gene. MAP3K7 deletions were associated with the occurrence of SIL-TAL1 fusions and a mature immunophenotype, but not with response to treatment and outcome. Depletion of MAP3K7 expression in T-ALL cell lines by shRNAs slowed down proliferation and induced apoptosis, but neither changed protein levels of components of NF-κB signaling nor NF-κB target gene expression after stimulation with TNF-α. Conclusions: This study revealed that the recurrent deletion of MAP3K7/CASP8AP2 is associated with SIL-TAL1 fusions and a mature immunophenotype, but not with response to treatment and risk of relapse. Homozygous deletions of MAP3K7 were not observed, and efficient depletion of MAP3K7 interfered with viability of T-ALL cells, indicating that a residual expression of MAP3K7 is indispensable for T-lymphoblasts

MAP3K7 is recurrently deleted in pediatric T-lymphoblastic leukemia and affects cell proliferation independently of NF-κB

Background: Deletions of 6q15–16.1 are recurrently found in pediatric T-cell acute lymphoblastic leukemia (T-ALL). This chromosomal region includes the mitogen-activated protein kinase kinase kinase 7 (MAP3K7) gene which has a crucial role in innate immune signaling and was observed to be functionally and prognostically relevant in different cancer entities. Therefore, we correlated the presence of MAP3K7 deletions with clinical parameters in a cohort of 327 pediatric T-ALL patients and investigated the function of MAP3K7 in the T-ALL cell lines CCRF-CEM, Jurkat and MOLT-4. Methods: MAP3K7 deletions were detected by multiplex ligation-dependent probe amplification (MLPA). T-ALL cell lines were transduced with adeno-associated virus (AAV) vectors expressing anti-MAP3K7 shRNA or a non-silencing shRNA together with a GFP reporter. Transduction efficiency was measured by flow cytometry and depletion efficiency by RT-PCR and Western blots. Induction of apoptosis was measured by flow cytometry after staining with PE-conjugated Annexin V. In order to assess the contribution of NF-κB signaling to the effects of MAP3K7 depletion, cells were treated with TNF-α and cell lysates analyzed for components of the NF-κB pathway by Western blotting and for expression of the NF-κB target genes BCL2, CMYC, FAS, PTEN and TNF-α by RT-PCR. Results: MAP3K7 is deleted in approximately 10% and point-mutated in approximately 1% of children with T-ALL. In 32 of 33 leukemias the deletion of MAP3K7 also included the adjacent CASP8AP2 gene. MAP3K7 deletions were associated with the occurrence of SIL-TAL1 fusions and a mature immunophenotype, but not with response to treatment and outcome. Depletion of MAP3K7 expression in T-ALL cell lines by shRNAs slowed down proliferation and induced apoptosis, but neither changed protein levels of components of NF-κB signaling nor NF-κB target gene expression after stimulation with TNF-α. Conclusions: This study revealed that the recurrent deletion of MAP3K7/CASP8AP2 is associated with SIL-TAL1 fusions and a mature immunophenotype, but not with response to treatment and risk of relapse. Homozygous deletions of MAP3K7 were not observed, and efficient depletion of MAP3K7 interfered with viability of T-ALL cells, indicating that a residual expression of MAP3K7 is indispensable for T-lymphoblasts