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Germline SAMD9 and SAMD9L mutations (SAMD9/9Lmut) predispose to myelodysplastic syndromes (MDS) with propensity for somatic rescue. In this study, we investigated a clinically annotated pediatric MDS cohort (n = 669) to define the prevalence, genetic landscape, phenotype, therapy outcome and clonal architecture of SAMD9/9L syndromes. In consecutively diagnosed MDS, germline SAMD9/9Lmut accounted for 8% and were mutually exclusive with GATA2 mutations present in 7% of the cohort. Among SAMD9/9Lmut cases, refractory cytopenia was the most prevalent MDS subtype (90%); acquired monosomy 7 was present in 38%; constitutional abnormalities were noted in 57%; and immune dysfunction was present in 28%. The clinical outcome was independent of germline mutations. In total, 67 patients had 58 distinct germline SAMD9/9Lmut clustering to protein middle regions. Despite inconclusive in silico prediction, 94% of SAMD9/9Lmut suppressed HEK293 cell growth, and mutations expressed in CD34+ cells induced overt cell death. Furthermore, we found that 61% of SAMD9/9Lmut patients underwent somatic genetic rescue (SGR) resulting in clonal hematopoiesis, of which 95% was maladaptive (monosomy 7 ± cancer mutations), and 51% had adaptive nature (revertant UPD7q, somatic SAMD9/9Lmut). Finally, bone marrow single-cell DNA sequencing revealed multiple competing SGR events in individual patients. Our findings demonstrate that SGR is common in SAMD9/9Lmut MDS and exemplify the exceptional plasticity of hematopoiesis in children. This analysis of a large, clinically annotated cohort of individuals with predisposition to myelodysplastic syndromes reveals insights into the genetic determinants of disease progression and their relationship with clinical manifestations and therapy outcome.

Cell-free DNA profiling using patient blood is emerging as a non-invasive complementary technique for cancer genomic characterization. Since these liquid biopsies will soon be integrated into clinical trial protocols for pediatric cancer treatment, clinicians should be informed about potential applications and advantages but also weaknesses and potential pitfalls. Small retrospective studies comparing genetic alterations detected in liquid biopsies with tumor biopsies for pediatric solid tumor types are encouraging. Molecular detection of tumor markers in cell-free DNA could be used for earlier therapy response monitoring and residual disease detection as well as enabling detection of pathognomonic and therapeutically relevant genomic alterations. CONCLUSION: Existing analyses of liquid biopsies from children with solid tumors increasingly suggest a potential relevance for molecular diagnostics, prognostic assessment, and therapeutic decision-making. Gaps remain in the types of tumors studied and value of detection methods applied. Here we review the current stand of liquid biopsy studies for pediatric solid tumors with a dedicated focus on cell-free DNA analysis. There is legitimate hope that integrating fully validated liquid biopsy-based innovations into the standard of care will advance patient monitoring and personalized treatment of children battling solid cancers.

For localized, resectable neuroblastoma without MYCN amplification, surgery only is recommended even if incomplete. However, it is not known whether the genomic background of these tumors may influence outcome.

The need for the development of a specific quality management approach for built heritage is based on the complexity and specificity of historic buildings. The main aim of the research was therefore the development of a specific quality management approach for built heritage. The concepts that establish the approach were developed based on an understanding of the aim, the conservation principles and the challenges of heritage preservation. They are translated into an approach based on an analysis of existing quality management approaches in other fields. The scientific basis for the approach is acquired based on a thorough analysis of current practice and an exploratory study of two methods for quality improvement: knowledge enhancement and knowledge sharing. By establishing the analysis of current practice at three levels of detail, the obtained results identify a variety of approaches, problems, attitudes and technical issues. The research therefore gave a voice to different stakeholders and covered different types of interventions. The developed quality management approach is a participative approach that is founded on the establishment of continuous care, as well as the enhancement and sharing of knowledge. Its aim is the preservation of cultural significance. This is accomplished through a process of continuous care in which all stakeholders are equally involved. Technical knowledge, skills and knowledge on values and significance are essential for deciding on interventions and implementing them. Conservation quality therefore stems from the merging of three concepts: (1) continuous care, (2) the stakeholders, (3) knowledge. Regarding the management of historic structures, the analysis of maintenance practices in Flanders identifies the absence of a true preventive approach. Discrepancies in the significance of concepts such as maintenance, repair, conservation and renovation complicate the quality of maintenance activities. There is a limited implementation of true preventive actions, such as the cleaning of gutters, and professionals are not always involved for repair interventions. Monumentenwacht proves to be an important support for owners, thanks to their expertise and objective opinion. There is a potential to improve the management of built heritage by implementing the monitoring data into a system of reliability monitoring. The case study research on structural repair interventions demonstrates that professionals often implement a linear problem solving approach that does not include the controls-step of the ISCARSAH approach. The project-based involvement of engineers, sometimes even limited to part of the decision making process, complicates a true continuity in the continuous care for historic structures. The research therefore proposes the implementation of simple forms of structural monitoring by Monumentenwacht, in close collaboration with conservation engineers. The analysis of implemented mortar joint repair interventions individuates that knowledge is important for their correct implementation. However, professionals prefer to tackle the complex decision on a compatible mortar recipe based on their experience. Such attitudes impede a continuous knowledge enhancement on the compatibility of mortar joint repair interventions. Increased documentation of the characteristics of existing and newly implemented materials would facilitate the complex decision making. This requires the sharing of knowledge and experiences between different professionals. Furthermore, the skills, training and motivation of masons proved to be predominant for a correct implementation of mortar joint repair interventions. The quality of these interventions is therefore founded on the training and proudness of the masons. The second part of the dissertation focuses on an investigation into two methods for quality improvement: knowledge enhancement and knowledge sharing. Three exploratory investigations exemplify specific technical challenges that would benefit from knowledge enhancement through continuous care. Such knowledge enhancement could be achieved based on interdisciplinary knowledge sharing of advanced monitoring data. The exploratory study on knowledge sharing between the members of a building team advances the important interrelation between three inter-personal processes: (1) the establishment of trust, (2) the merging of cooperation through a shared understanding, (3) the creation of an on site operational community. status: published

BACKGROUND: Biology based treatment reduction, i.e. surgery alone also in case of not totally resected tumors, was advised in neuroblastoma patients with localized resectable disease without MYCN amplification. However, whether the genomic background of these tumors may influence outcome was unknown and therefore scrutinized in a meta-analysis comprising two prospective therapy studies and a ‘validation’ cohort. PATIENTS AND METHODS: Diagnostic samples were derived from 406 INSS stages 1/2A/2B tumors from three cohorts: LNESGI/II and COG. Genomic data were analyzed in two age groups (cut-off: 18 months) and quality controlled by the SIOPEN Biology Group. RESULTS: In both patient age groups stage 2 tumors led to similarly reduced event-free survival (5y-EFS: 83+3% versus 80+4%), but overall survival was only decreased in patients >18m (5y-OS: 97+1% versus 87+4%; p=0.001). In the latter age subgroup, only tumors with SCA led to relapses, with 11q loss as the strongest marker (5y-EFS: 40+15% versus 89+5%; p18m but not

Recently, two homologous genes, EXT1 and EXT2, with a putative tumor suppressor function have been described. Mutations in both genes are responsible for multiple exostosis syndrome (EXT), an autosomal dominant condition characterized by the presence of multiple osteochondromas, bony excrescences that sometimes undergo malignant transformation to chondrosarcoma. This family of EXT genes has been extended by the identification of an EXT-like (EXTL) gene showing a high degree of homology with the EXT genes. We report here a second EXT-like gene (EXTL2) which is homologous to the EXT and EXTL genes. EXTL2 consists of 5 exons encoding an ubiquitously expressed protein of 330 amino acids. In addition, a putative pseudogene, EXTL2P was also identified. The EXTL2 gene was assigned to chromosome 1p11-p12, whereas EXTL2P was mapped on chromosome 2q24-q31.

The gene coding for human beta-glucuronidase (GUSB) was mapped to 7q11.21 --> q11.22 by fluorescence in situ hybridization (FISH), thus clarifying the contradictory published localizations of this gene. Multiple unprocessed pseudogenes and pseudogene fragments for GUSB have been described. However, only two weak signals, one at chromosome band 5p13 and the other at 5q13, could be detected with FISH, suggesting considerable divergence between GUSB and its related sequences.