Anaplastic oligodendroglioma are chemotherapy-sensitive tumors. We now present the long-term follow-up findings of a randomized phase III study on the addition of six cycles of procarbazine, ...lomustine, and vincristine (PCV) chemotherapy to radiotherapy (RT).
Adult patients with newly diagnosed anaplastic oligodendroglial tumors were randomly assigned to either 59.4 Gy of RT or the same RT followed by six cycles of adjuvant PCV. An exploratory analysis of the correlation between 1p/19q status and survival was part of the study. Retrospectively, the methylation status of the methyl-guanine methyl transferase gene promoter and the mutational status of the isocitrate dehydrogenase (IDH) gene were determined. The primary end points were overall survival (OS) and progression-free survival based on intent-to-treat analysis.
A total of 368 patients were enrolled. With a median follow-up of 140 months, OS in the RT/PCV arm was significantly longer (42.3 v 30.6 months in the RT arm, hazard ratio HR, 0.75; 95% CI, 0.60 to 0.95). In the 80 patients with a 1p/19q codeletion, OS was increased, with a trend toward more benefit from adjuvant PCV (OS not reached in the RT/PCV group v 112 months in the RT group; HR, 0.56; 95% CI, 0.31 to 1.03). IDH mutational status was also of prognostic significance.
The addition of six cycles of PCV after 59.4 Gy of RT increases both OS and PFS in anaplastic oligodendroglial tumors. 1p/19q-codeleted tumors derive more benefit from adjuvant PCV compared with non-1p/19q-deleted tumors.
The N=52Ga83β decay was studied at ALTO. The radioactive 83Ga beam was produced through the ISOL photofission technique and collected on a movable tape for the measurement of γ-ray emission following ...β decay. While β-delayed neutron emission has been measured to be 56–85% of the decay path, in this experiment an unexpected high-energy 5–9 MeV γ-ray yield of 16(4)% was observed, coming from states several MeVs above the neutron separation threshold. This result is compared with cutting-edge QRPA calculations, which show that when neutrons deeply bound in the core of the nucleus decay into protons via a Gamow–Teller transition, they give rise to a dipolar oscillation of nuclear matter in the nucleus. This leads to large electromagnetic transition probabilities which can compete with neutron emission, thus affecting the β-decay path. This process is enhanced by an excess of neutrons on the nuclear surface and may thus be a common feature for very neutron-rich isotopes, challenging the present understanding of decay properties of exotic nuclei.
The level structure of the neutron-rich 77Cu nucleus is investigated through β-delayed γ-ray spectroscopy at the Radioactive Isotope Beam Factory of the RIKEN Nishina Center. Ions of 77Ni are ...produced by in-flight fission, separated and identified in the BigRIPS fragment separator, and implanted in the WAS3ABi silicon detector array, surrounded by Ge cluster detectors of the EURICA array. A large number of excited states in 77Cu are identified for the first time by correlating γ rays with the β decay of 77Ni, and a level scheme is constructed by utilizing their coincidence relationships. The good agreement between large-scale Monte Carlo shell model calculations and experimental results allows for the evaluation of the single-particle structure near 78Ni and suggests a single-particle nature for both the 5/2−1 and 3/2−1 states in 77Cu, leading to doubly magic 78Ni.
Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As ...medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy.
Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic ...stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication.
Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models.
Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 chr11, chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas.
Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials.
The level structures of 70Co and 70Ni, populated from the β decay of 70Fe, have been investigated using β-delayed γ-ray spectroscopy following in-flight fission of a 238U beam. The experimental ...results are compared to Monte-Carlo Shell-Model calculations including the pf+g9/2+d5/2 orbitals. The strong population of a (1+) state at 274 keV in 70Co is at variance with the expected excitation energy of ∼1 MeV from near spherical single-particle estimates. This observation indicates a dominance of prolate-deformed intruder configurations in the low-lying levels, which coexist with the normal near spherical states. It is shown that the β decay of the neutron-rich A=70 isobars from the new island of inversion to the Z=28 closed-shell regime progresses in accordance with a newly reported type of shell evolution, the so-called Type II, which involves many particle-hole excitations across energy gaps.
Abstract Background The prognosis of patients with anaplastic oligodendrogliomas (AOD) and oligoastrocytomas (AOA) is variable. Biomarkers might be helpful to identify more homogeneous disease ...subtypes and improve therapeutic index. The aim of this study is to develop new clinical, pathological and molecular prognostic models for locally diagnosed anaplastic gliomas with oligodendroglial features (AOD or AOA). Methods Data from 368 patients with AOD or AOA recruited in The European Organisation for Research and Treatment of Cancer (EORTC) trial 26951 on adjuvant PCV (Procarbazine, CCNU, Vincristine) chemotherapy in anaplastic oligodendroglial tumours were used to develop multifactor models to predict progression free survival (PFS) and overall survival (OS). Different models were compared by their percentage of explained variation (PEV). Prognostic calculators were derived from these new models. Results Treatment (for PFS only), younger age, confirmed absence of residual tumour on imaging, frontal location, good World Health Organisation (WHO) performance status, absence of endothelial abnormalities and/or necrosis, 1p/19q codeletion and Isocitrate dehydrogenase 1 (IDH1) mutation were independent factors that predicted better PFS and OS. Conclusions We identified important prognostic factors for AOD and AOA and showed that molecular markers added a major contribution to clinical and pathological factors in explaining PFS and OS. With a positive predictive value of 92% for PFS and 94% for OS, our models allow physicians to precisely identify high risk patients and aid in making therapeutic decisions.
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK), which is transiently expressed during development of the central and peripheral nervous system. ALK has been recently identified ...as a major neuroblastoma predisposition gene and activating mutations have also been identified in a subset of sporadic neuroblastoma tumors. Two hot spots of ALK mutations have been observed at positions F1174 and R1275. Here, we studied stably transfected cell lines expressing wild-type or F1174L- or R1275Q-mutated ALK in parallel with a neuroblastoma cell line (CLB-GE) in which the allele mutated at position F1174 is amplified. We observed that the mutated ALK variants were essentially intracellular and were largely retained in the reticulum/Golgi compartments. This localization was corroborated by a defect of N-linked glycosylation. Although the mutated receptors exhibited a constitutive activation, the minor pool of receptor addressed to the plasma membrane was much more tyrosine phosphorylated than the intracellular pool. The use of antagonist monoclonal antibodies suggested that the constitutive activity of the mutated receptors did not require the dimerization of the receptor, whereas adequate dimerization triggered by agonist monoclonal antibodies increased this activity. Finally, kinase inactivation of the mutated receptors restored maturation and cell-surface localization. Our results show that constitutive activation of ALK results in its impaired maturation and intracellular retention. Furthermore, they provide a rationale for the potential use of kinase inhibitors and antibodies in ALK-dependent tumors.
Nuclei in the vicinity of 78Ni are important benchmarks for nuclear structure, which can reveal changes in the shell structure far from stability. Spectroscopy of the odd-odd isotope 78Cu was ...performed for the first time in an experiment with the EURICA setup at the Radioactive Isotope Beam Factory at RIKEN Nishina Center. Excited states in the neutron-rich isotope were populated following the β decay of 78Ni produced by in-flight fission and separated by the BigRIPS separator. A level scheme based on the analysis of γ−γ coincidences is presented. Tentative spin and parity assignments were made when possible based on the β-decay feeding intensities and γ-decay properties of the excited states. Time correlations between β and γ decay show clear indications of an isomeric state with a half-life of 3.8(4) ms. Large-scale Monte Carlo shell-model calculations were performed using the A3DA-m interaction and a valence space comprising the full fp shell and the 1g9/2 and 2d5/2 orbitals for both protons and neutrons. The comparison of the experimental results with the shell-model calculations allows interpreting the excited states in terms of spin multiplets arising from the proton-neutron interaction. The results provide further insight into the evolution of the proton single-particle orbitals as a function of neutron number, and quantitative information about the proton-neutron interaction outside the doubly magic 78Ni core.
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