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Background High-grade osteosarcoma is a primary malignant bone tumour mainly affecting children and young adults. The European and American Osteosarcoma Study (EURAMOS)-1 is a collaboration of four study groups aiming to improve outcomes of this rare disease by facilitating randomised controlled trials. Methods Patients eligible for EURAMOS-1 were aged ≤40 years with M0 or M1 skeletal high-grade osteosarcoma in which case complete surgical resection at all sites was deemed to be possible. A three-drug combination with methotrexate, doxorubicin and cisplatin was defined as standard chemotherapy, and between April 2005 and June 2011, 2260 patients were registered. We report survival outcomes and prognostic factors in the full cohort of registered patients. Results For all registered patients at a median follow-up of 54 months (interquartile range: 38–73) from biopsy, 3-year and 5-year event-free survival were 59% (95% confidence interval [CI]: 57–61%) and 54% (95% CI: 52–56%), respectively. Multivariate analyses showed that the most adverse factors at diagnosis were pulmonary metastases (hazard ratio [HR] = 2.34, 95% CI: 1.95–2.81), non-pulmonary metastases (HR = 1.94, 95% CI: 1.38–2.73) or an axial skeleton tumour site (HR = 1.53, 95% CI: 1.10–2.13). The histological subtypes telangiectatic (HR = 0.52, 95% CI: 0.33–0.80) and unspecified conventional (HR = 0.67, 95% CI: 0.52–0.88) were associated with a favourable prognosis compared with chondroblastic subtype. The 3-year and 5-year overall survival from biopsy were 79% (95% CI: 77–81%) and 71% (95% CI: 68–73%), respectively. For patients with localised disease at presentation and in complete remission after surgery, having a poor histological response was associated with worse outcome after surgery (HR = 2.13, 95% CI: 1.76–2.58). In radically operated patients, there was no good evidence that axial tumour site was associated with worse outcome. Conclusions In conclusion, data from >2000 patients registered to EURAMOS-1 demonstrated survival rates in concordance with institution- or group-level osteosarcoma trials. Further efforts are required to drive improvements for patients who can be identified to be at higher risk of adverse outcome. This trial reaffirms known prognostic factors, and owing to the large numbers of patients registered, it sheds light on some additional factors to consider.

An operative approach with wide or marginal margins improves local control and OS. If the surgical margin is intralesional or excision is impossible, additional radiotherapy has a positive influence on prognosis.

BEV+IRI resulted in a superior PFS-6 rate and median PFS compared with TMZ. However, BEV+IRI did not improve OS, potentially because of the high crossover rate. BEV+IRI did not alter QOL compared with TMZ.

Chordomas are tumors that arise at vertebral bodies and the base of the skull. Although rare in incidence, they are deadly owing to slow growth and a lack of effective therapeutic options. In this study, we addressed the need for chordoma cell systems that can be used to identify therapeutic targets and empower testing of candidate pharmacologic drugs. Eight human chordoma cell lines that we established exhibited cytology, genomics, mRNA, and protein profiles that were characteristic of primary chordomas. Candidate responder profiles were identified through an immunohistochemical analysis of a chordoma tissue bank of 43 patients. Genomic, mRNA, and protein expression analyses confirmed that the new cell systems were highly representative of chordoma tissues. Notably, all cells exhibited a loss of CDKN2A and p16, resulting in universal activation of the CDK4/6 and Rb pathways. Therefore, we investigated the CDK4/6 pathway and responses to the CDK4/6-specific inhibitor palbociclib. In the newly validated system, palbociclib treatment efficiently inhibited tumor cell growth in vitro and a drug responder versus nonresponder molecular signature was defined on the basis of immunohistochemical expression of CDK4/6/pRb (S780). Overall, our work offers a valuable new tool for chordoma studies including the development of novel biomarkers and molecular targeting strategies. Cancer Res; 75(18); 3823-31. Ó2015 AACR.

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Abstract:Background: Medulloblastoma in adult patients is rare, with 0.6 cases per million. Prognosis depends on clinical factors and medulloblastoma entity. No prospective data on the feasibility of radio-chemotherapy exist. The German Neuro-Oncology Working Group (NOA) performed a prospective descriptive multicenter single-arm Phase II trial to evaluate feasibility and toxicity of radio-polychemotherapy. Methods: The NOA-07 trial combined cranio-spinal irradiation with vincristine, followed by eight cycles of cisplatin, lomustine and vincristine. Adverse events, imaging and progression patterns, histological and genetic markers, health-related quality of life (HRQoL) and cognition were evaluated. Primary endpoint was the rate of toxicityrelated treatment terminations after four chemotherapy cycles, and the toxicity profile. The feasibility goal was reached if at least 45% of patients received at least 4 cycles of maintenance chemotherapy. Results: Thirty patients were evaluable. Each 50% percent showed classic and desmoplastic-nodular histology. Sixty-seven percent were classified into the sonic hedgehog (SHH) subgroup without TP53 alterations, 13% in wingless (WNT), and 17% in Non-WNT/Non-SHH. Four cycles of chemotherapy were feasible in the majority (n=21; 70.0%). Hematological side effects and polyneuropathy were prevalent toxicities. During the active treatment period, HRQoL and verbal fluency improved significantly. The 3-year event-free survival rate (EFS) was 66.6% at the time of databank lock. Conclusions: Radio-polychemotherapy did lead to considerable toxicity and a high amount of dose reductions throughout the first four chemotherapy cycles that may affect efficacy. Thus, we propose frequent patient surveillance using this regimen.Modifications of the regimen may increase feasibility of radio-polychemotherapy of adult patients with medulloblastoma. Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation N-O-D-17-00180R1Dear Prof. Wen, many thanks for the opportunity to, for the second time, re-submit our above mentioned manuscript to NeuroOncology with major revisions.Below, you will find our point-to-point answer to all reviewer comments. Please be aware that there are two open questions where we will need the feedback of the acting editor and the reviewer, respectively.We declare that our manuscript, or any part of it, has not been previously published or submitted concurrently to any other journal, and that all co-authors have read and approved the revised version of the manuscript. We further declare that we agree to pay for full color reproduction.We hope that the revisions will now qualify the manuscript for publication in Neuro-Oncology. We will however be happy to address further questions, if indicated. . This hypothesis results in an exploratory and descriptive feasibility design, focusing on the rate of toxicity-related treatment terminations after 4 cycles of adjuvant chemotherapy. The statistical approach of this study therefore did not contain a formal H0/...

• MRI texture analysis may assist in differentiating low-grade chondrosarcoma from enchondroma. • Kurtosis in the contrast-enhanced T1w has the highest power of discrimination. • Tools provide insight into tumour characterisation as a non-invasive imaging biomarker.