Phase II study of irinotecan in combination with temozolomide (TEMIRI) in children with recurrent or refractory medulloblastoma: a joint ITCC and SIOPE brain tumor study

BackgroundThis multicenter phase II study investigated temozolomide + irinotecan (TEMIRI) treatment in children with relapsed or refractory medulloblastoma.MethodsPatients received temozolomide 100–125 mg/m2/day (days 1–5) and irinotecan 10 mg/m2/day (days 1–5 and 8–12) every 3 weeks. The primary endpoint was tumor response within the first 4 cycles confirmed ≥4 weeks and assessed by an external response review committee (ERRC). In a 2-stage Optimum Simon design, ≥6 responses in the first 15 evaluable patients were required within the first 4 cycles for continued enrollment; a total of 19 responses from the first 46 evaluable patients was considered successful.ResultsSixty-six patients were treated. Seven responses were recorded during stage 1 and 15 in the first 46 ERRC evaluated patients (2 complete responses and 13 partial responses). The objective response rate during the first 4 cycles was 32.6% (95% confidence interval [CI], 19.5%–48.0%). Median duration of response was 27.0 weeks (7.7–44.1 wk). In 63 patients evaluated by local investigators, the objective response rate was 33.3% (95% CI, 22.0%–46.3%), and 68.3% (95% CI, 55.3%–79.4%) experienced clinical benefit. Median survival was 16.7 months (95% CI, 13.3–19.8). The most common grade 3 treatment-related nonhematologic adverse event was diarrhea (7.6%). Grade 3/4 treatment-related hematologic adverse events included neutropenia (16.7%), thrombocytopenia (12.1%), anemia (9.1%), and lymphopenia (9%).ConclusionsThe planned study primary endpoint was not met. However, its tolerability makes TEMIRI a suitable candidate chemotherapy backbone for molecularly targeted agents in future trials in this setting

Effect of Alloying Additives and Casting Parameters on the Microstructure and Mechanical Properties of Silicon Bronzes

The studied silicon bronze (CuSi3Zn3Mn1) is characterised by good strength and corrosion resistance due to the alloying elements that are present in it (Si, Zn, Mn, Fe). This study analysed the casting process in green sand moulding, gravity die casting, and centrifugal casting with a horizontal axis of rotation. The influences of Ni and Zr alloying additives as well as the casting technology that was used were evaluated on the alloy’s microstructure and mechanical properties. The results of the conducted research are presented in the form of the influence of the technology (GS, GZ, GM) and the content of the introduced alloy additives on the mechanical parameters (UTS, A10, and Proof Stress, BHN). The analysis of the tests that were carried out made it possible to determine which of the studied casting technologies had the best mechanical properties. Microstructure of metal poured into metal mould was finer than that which was cast into moulding compound. Mechanical properties of castings made in moulding compound were lower than those that were cast into metal moulds. Increased nickel content affected the BHN parameter

Reduction in benefits of total flux expansion on divertor detachment due to parallel flows

The Super-X divertor (SXD) is an alternative divertor configuration leveraging total flux expansion at the outer strike point (OSP). Key features for the attractiveness of the SXD are facilitated detachment access and control, as predicted by the extended 2-point model (2PM). However, parallel flows are not consistently included in the 2PM. In this work, the 2PM is refined to overcome this limitation: the role of total flux expansion on the pressure balance is made explicit, by including the effect of parallel flows. In consequence, the effect of total flux expansion on detachment access and control is weakened, compared to predictions of the 2PM. This new model partially explains discrepancies between the 2PM and experiments performed on TCV, in ohmic L-mode scenarios, where in core density ramps in lower single-null (SN) configuration, the impact of the OSP major radius Rt on the CIII emission front movement in the divertor outer leg - used as a proxy for the plasma temperature - is substantially weaker than 2PM predictions; and in OSP sweeps in lower and upper SN configurations, with a constant core density, the peak parallel particle flux density at the OSP is almost independent of Rt, while the 2PM predicts a linear dependence. Finally, analytical and numerical modelling of parallel flows in the divertor is presented, to support the argument. It is shown that an increase in total flux expansion can favour supersonic flows at the OSP. Parallel flows are also shown to be relevant by analysing SOLPS-ITER simulations of TCV

A novel hydrogenic spectroscopic technique for inferring the role of plasma-molecule interaction on power and particle balance during detached conditions

Detachment, an important mechanism for reducing target heat deposition, is achieved through reductions in power, particle and momentum; which are induced through plasma-atom and plasma-molecule interactions. Experimental research in how those reactions precisely contribute to detachment is limited. Both plasma-atom as well as plasma-molecule interactions can result in excited hydrogen atoms which emit atomic line emission. In this work, we investigate a new Balmer Spectroscopy technique for Plasma-Molecule Interaction-BaSPMI. This first disentangles the Balmer line emission from the various plasma-atom and plasma-molecule interactions and secondly quantifies their contributions to particle (ionisation and recombination) and power balance (radiative power losses). Its performance is verified using synthetic diagnostic techniques of both attached and detached TCV and MAST-U SOLPS-ITER simulations. We find that H2 plasma chemistry involving H+2 and/or H− can substantially elevate the Hα emission during detachment, which we show is an important precursor for Molecular Activated Recombination. An example illustration analysis of the full BaSPMI technique shows that the hydrogenic line series, even Lyα as well as the medium-n Balmer lines, can be significantly influenced by plasma-molecule interactions by tens of percent. That has important implications for using atomic hydrogen spectroscopy for diagnosing divertor plasmas

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

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

Development of the SIOPE DIPG network, registry and imaging repository : a collaborative effort to optimize research into a rare and lethal disease

Diffuse intrinsic pontine glioma (DIPG) is a rare and deadly childhood malignancy. After 40 years of mostly single-center, often non-randomized trials with variable patient inclusions, there has been no improvement in survival. It is therefore time for international collaboration in DIPG research, to provide new hope for children, parents and medical professionals fighting DIPG. In a first step towards collaboration, in 2011, a network of biologists and clinicians working in the field of DIPG was established within the European Society for Paediatric Oncology (SIOPE) Brain Tumour Group: the SIOPE DIPG Network. By bringing together biomedical professionals and parents as patient representatives, several collaborative DIPG-related projects have been realized. With help from experts in the fields of information technology, and legal advisors, an international, web-based comprehensive database was developed, The SIOPE DIPG Registry and Imaging Repository, to centrally collect data of DIPG patients. As for April 2016, clinical data as well as MR-scans of 694 patients have been entered into the SIOPE DIPG Registry/Imaging Repository. The median progression free survival is 6.0 months (95% Confidence Interval (CI) 5.6-6.4 months) and the median overall survival is 11.0 months (95% CI 10.5-11.5 months). At two and five years post-diagnosis, 10 and 2% of patients are alive, respectively. The establishment of the SIOPE DIPG Network and SIOPE DIPG Registry means a paradigm shift towards collaborative research into DIPG. This is seen as an essential first step towards understanding the disease, improving care and (ultimately) cure for children with DIPG.Peer reviewe