212 research outputs found
DEFIBROTIDE FOR PROPHYLAXIS OF HEPATIC VENO-OCCLUSIVE DISEASE/SINUSOIDAL OBSTRUCTION SYNDROME IN PEDIATRIC HEMATOPOIETIC STEM CELL TRANSPLANTATION: SUBANALYSIS DATA FROM AN OPEN-LABEL, PHASE III, RANDOMIZED TRIAL.
No full textSub-analysis of risk groups from a randomized trial on the prophylactic use of defibrotid
Defibrotide for Prophylaxis of Hepatic Veno-Occlusive Disease in Pediatric Hematopoietic Stem Cell Transplantation: Subanalysis Data from an Open-Label, Phase III, Randomized Trial. Blood 2015; 126:4310
No full textDefibrotide for Prophylaxis of Hepatic Veno-Occlusive Disease in Pediatric Hematopoietic Stem Cell Transplantation: Subanalysis Data from an Open-Label, Phase III, Randomized Trial
Defibrotide for Prophylaxis of Hepatic Veno-Occlusive Disease in Pediatric Hematopoietic Stem Cell Transplantation: Subanalysis Data from an Open-Label, Phase III, Randomized Trial.
No full textSubgroups analysis of of patients from a randomized tria
DDX1 co-amplification confers collateral vulnerabilities in neuroblastoma
No full textDas Neuroblastom ist eines der häufigsten Tumoren im Kindesalter. Bei Hochrisko-Neuroblastomen weisen etwa 25 % der Patienten eine MYCN-Amplifikation auf. Die Behandlung dieser Patienten bleibt eine Herausforderung. Bei genauerer Betrachtung der amplifizierten Regionen umfasst diese große genomische Bereiche, die nicht nur MYCN, sondern auch Passagiergene und genregulatorische Elemente enthalten. Um MYCN-amplifizierte Neuroblastome zu behandeln, versuchten wir festzustellen, ob Co-Amplifikationen von Passagiergenen kollaterale therapeutische Vulnerabilitäten darstellen könnten. Durch die Analyse von Kopienzahl-Daten von 238 MYCN-amplifizierten Patienten identifizierten wir das DEAD-Box-Helicase-1 (DDX1)-Gen als ein Gen, welches häufig mit MYCN auf dem gleichen genomischen Fragment amplifiziert ist. Die Analyse eines CRISPR-Cas9-Funktionsverlust- Screens aus der Cancer Dependency Map, welche über 700 humanen Krebszelllinien beinhalten, zeigt, dass das Überleben von MYCN-amplifizierten Krebszellen mit DDX1-Co-Amplifikation von der gesteigerten Aktivität des mammalian target of rapamycin complex 1 (mTORC1) abhängt. Interaktionsproteomik identifizierte Dihydrolipoyl-S-Succinyltransferase (DLST), ein Bestandteil des Tricarboxylsäure (TCA)-Zyklusenzyms α-Ketoglutarat-Dehydrogenase (α-KGDH)-Komplexes, als Interaktionspartner von DDX1 in Mitochondrien. Lebendzell- Stoffwechselanalysen legten nahe, dass diese Interaktion die TCA-Aktivität beeinträchtigen und zu einer Anhäufung von α-Ketoglutarat (α-KG) führen kann, indem sie dessen Umwandlung in Succinyl-CoA stört. Die Anhäufung von α-KG verursacht metabolischen Stress und löst Zelltod aus, der durch eine gesteigerte mTORC1-Aktivität in Krebszellen kompensiert wird. Folglich führte die Störung der mTORC1-Funktion zu Zelltod, insbesondere in Zellen mit hoher DDX1-Kopienzahl. So kann die strukturell verknüpfte Co-Amplifikation eines Passagiergens (DDX1) und eines Onkogens (MYCN) auf dem gleichen Amplicon zu kollateralen Vulnerabilitäten bei Neuroblastomen führen.Neuroblastoma is one of the most common childhood tumors. In high-risk neuroblastoma, around 25% of patients harbor MYCN amplification. Treating neuroblastoma patients with MYCN amplification remains challenging. Taking a closer look at MYCN-amplified regions, DNA amplification encompasses large genomic regions harboring not only MYCN but also containing passenger genes and gene regulatory elements. To treat MYCN-amplified neuroblastoma, we sought to determine whether passenger co-amplifications can create collateral therapeutic vulnerabilities. By analyzing copy number data from 238 MYCN-amplified patients, we identified the DEAD-Box Helicase 1 (DDX1) gene to be frequently co-amplified with MYCN on the same genomic fragment. Analysis of CRISPR-Cas9 loss-of-function screens from the Cancer Dependency Map across over 700 human cancer cell lines revealed that the survival of MYCN-amplified cancer cells with DDX1 co-amplification depends on the enhanced activity of the mammalian target of rapamycin complex 1 (mTORC1). Interaction proteomics identified dihydrolipoamide S-succinyltransferase (DLST), a component of the tricarboxylic acid (TCA) cycle enzyme α-ketoglutarate dehydrogenase (α-KGDH) complex, as an interaction partner of DDX1 in mitochondria. Live-cell metabolomics suggested that this interaction can impair TCA activity and lead to the accumulation of α-ketoglutarate (α-KG) by interfering with its conversion to succinyl-CoA. Accumulation of α-KG, in turn, caused metabolic stress and triggered cell death, which was compensated for by enhanced mTORC1 activity in cancer cells. Consequently, disruption of mTORC1 function resulted in cell death, specifically in cells with an aberrantly high copy number of DDX1. Thus, structurally linked co-amplification of a passenger gene (DDX1) and an oncogene (MYCN) on the same amplicon can result in collateral vulnerabilities in neuroblastoma.
Irinotecan and temozolomide combined with dasatinib and rapamycin for patients with relapsed or refractory neuroblastoma: results of the prospective randomized RIST trial
No full textIrinotecan and temozolomide in combination with dasatinib and rapamycin versus irinotecan and temozolomide for patients with relapsed or refractory neuroblastoma (RIST-rNB-2011): a multicentre, open-label, randomised, controlled, phase 2 trial
No full texthttp://dx.doi.org/10.13039/501100005972 Stiftung Deutsche Krebshilf
The coming of age of the pediatric EBMT criteria
No full textAllogeneic stem cell transplantation (allo-SCT) offers a curative option in adult patients with acute lymphoblastic leukemia (ALL). Prognostic factors for survival after allo-SCT have not been sufficiently defined: pheno-/genotype, patients´ age, conditioning regimens and remission at allo-SCT are under discussion. We analyzed the outcome of 180 consecutive adult ALL-patients undergoing allo-SCT at our center between 1995 and 2018 to identify specific prognostic factors. In our cohort 19% were older than 55 years, 28% had Philadelphia-positive B-ALL, 24% T-ALL. 54% were transplanted in first complete remission (CR1), 13% in CR2 after salvage therapy, 31% reached no remission (8% within first-line, 23% within salvage therapy). In 66% conditioning contained total body irradiation (TBI). With a median follow-up of 10 years, we observed an overall survival of 33% at 10 years, and a progression free survival of 31%. The cumulative incidence of relapse was 41% at 10 years, the cumulative incidence of non-relapse mortality 28%. Acute graft-versus-host disease (GvHD) II°-IV° occurred in 31%, moderate/severe chronic GvHD in 27%. Survival was better in patients reaching CR before allo-SCT and in those receiving TBI. No difference between patients younger/older than 55 years and between different phenotypes was observed. Survival after allo-SCT improved considerably over the last decades
Targeted molecular therapy (modified RIST regimen) in relapsed high risk stage IV neuroblastoma: two cases report
No full textThe prognosis for children with recurrent or refractory neuroblastoma remains a significant clinical challenge, and currently there are no known curative salvage regimens. In this paper we investigated the effect of imatinib with rapamycin and the chemotherapeutic agents temozolomide and irinotecan. We treated two children with recurrent neuroblastoma with this so called RIST protocol. Both patients, off therapy for 15 and 31 months, respectively are well, and developing normally, without any complications. These findings suggest that a combination regimen of RIST may provide a therapeutic benefit with a favorable toxicity profile to a unfortunate subset of patients with neuroblastoma
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