Therapeutic implications of improved molecular diagnostics for rare CNS-embryonal tumor entities: results of an international, retrospective study

International audienceAbstract BACKGROUND Only few data are available on treatment-associated behavior of distinct rare CNS-embryonal tumor entities previously treated as “CNS-primitive neuroectodermal tumors” (CNS-PNET). Respective data on specific entities, including CNS neuroblastoma, FOXR2 activated (CNS NB-FOXR2), and embryonal tumor with multi-layered rosettes (ETMR) are needed for development of differentiated treatment strategies. METHODS Within this retrospective, international study, tumor samples of clinically well-annotated patients with the original diagnosis of CNS-PNET were analyzed using DNA methylation arrays (n=307). Additional cases (n=66) with DNA methylation pattern of CNS NB-FOXR2 were included irrespective of initial histological diagnosis. Pooled clinical data (n=292) were descriptively analyzed. RESULTS DNA methylation profiling of “CNS-PNET” classified 58(19%) cases as ETMR, 57(19%) as HGG, 36(12%) as CNS NB-FOXR2, and 89(29%) cases were classified into 18 other entities. Sixty-seven (22%) cases did not show DNA methylation patterns similar to established CNS tumor reference classes. Best treatment results were achieved for CNS NB-FOXR2 patients (5-year PFS: 63%±7%, OS: 85%±5%, n=63), with 35/42 progression-free survivors after upfront craniospinal irradiation (CSI) and chemotherapy. The worst outcome was seen for ETMR and HGG patients with 5-year PFS of 18%±6% and 22%±7%, and 5-year OS of 24%±6% and 25%±7%, respectively. CONCLUSION The historically reported poor outcome of CNS-PNET patients becomes highly variable when tumors are molecularly classified based on DNA methylation profiling. Patients with CNS NB-FOXR2 responded well to current treatments and a standard-risk-CSI based regimen may be prospectively evaluated. The poor outcome of ETMR across applied treatment strategies substantiates the necessity for evaluation of novel treatments

Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors

We recently reported that atypical teratoid rhabdoid tumors (ATRTs) comprise at least two transcriptional subtypes with different clinical outcomes; however, the mechanisms underlying therapeutic heterogeneity remained unclear. In this study, we analyzed 191 primary ATRTs and 10 ATRT cell lines to define the genomic and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets. We found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, we discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype

Psychotherapieforschung

These guidelines address the diagnosis and management of atherosclerotic, aneurysmal, and thromboembolic peripheral arterial diseases (PADs). The clinical manifestations of PAD are a major cause of acute and chronic illness, are associated with decrements in functional capacity and quality of life, cause limb amputation, and increase the risk of death. Whereas the term “peripheral arterial disease” encompasses a large series of disorders that affect arterial beds exclusive of the coronary arteries, this writing committee chose to limit the scope of the work of this document to include the disorders of the abdominal aorta, renal and mesenteric arteries, and lower extremity arteries. The purposes of the full guidelines are to (a) aid in the recognition, diagnosis, and treatment of PAD of the aorta and lower extremities, addressing its prevalence, impact on quality of life, cardiovascular ischemic risk, and risk of critical limb ischemia (CLI); (b) aid in the recognition, diagnosis, and treatment of renal and visceral arterial diseases; and (c) improve the detection and treatment of abdominal and branch artery aneurysms. Clinical management guidelines for other arterial beds (e.g., the thoracic aorta, carotid and vertebral arteries, and upper-extremity arteries) have been excluded from the current guidelines to focus on the infradiaphragmatic arterial system and in recognition of the robust evidence base that exists for the aortic, visceral, and lower extremity arteries