Osteosarcomas are aggressive bone tumours with a high degree of genetic heterogeneity, which has historically complicated driver gene discovery. Here we sequence exomes of 31 tumours and decipher their evolutionary landscape by inferring clonality of the individual mutation events. Exome findings are interpreted in the context of mutation and SNP array data from a replication set of 92 tumours. We identify 14 genes as the main drivers, of which some were formerly unknown in the context of osteosarcoma. None of the drivers is clearly responsible for the majority of tumours and even TP53 mutations are frequently mapped into subclones. However, >80% of osteosarcomas exhibit a specific combination of single-base substitutions, LOH, or large-scale genome instability signatures characteristic of BRCA1/2-deficient tumours. Our findings imply that multiple oncogenic pathways drive chromosomal instability during osteosarcoma evolution and result in the acquisition of BRCA-like traits, which could be therapeutically exploited.

PurposeEURAMOS-1, an international randomized controlled trial, investigated maintenance therapy with pegylated interferon alfa-2b (IFN-α-2b) in patients whose osteosarcoma showed good histologic response (good response) to induction chemotherapy.Patients and MethodsAt diagnosis, patients age ≤ 40 years with resectable high-grade osteosarcoma were registered. Eligibility after surgery for good response random assignment included ≥ two cycles of preoperative MAP (methotrexate, doxorubicin, and cisplatin), macroscopically complete surgery of primary tumor, < 10% viable tumor, and no disease progression. These patients were randomly assigned to four additional cycles MAP with or without IFN-α-2b (0.5 to 1.0 μg/kg per week subcutaneously, after chemotherapy until 2 years postregistration). Outcome measures were event-free survival (EFS; primary) and overall survival and toxicity (secondary).ResultsGood response was reported in 1,041 of 2,260 registered patients; 716 consented to random assignment (MAP, n = 359; MAP plus IFN-α-2b, n = 357), with baseline characteristics balanced by arm. A total of 271 of 357 started IFN-α-2b; 105 stopped early, and 38 continued to receive treatment at data freeze. Refusal and toxicity were the main reasons for never starting IFN-α-2b and for stopping prematurely, respectively. Median IFN-α-2b duration, if started, was 67 weeks. A total of 133 of 268 patients who started IFN-α-2b and provided toxicity information reported grade ≥ 3 toxicity during IFN-α-2b treatment. With median follow-up of 44 months, 3-year EFS for all 716 randomly assigned patients was 76% (95% CI, 72% to 79%); 174 EFS events were reported (MAP, n = 93; MAP plus IFN-α-2b, n = 81). Hazard ratio was 0.83 (95% CI, 0.61 to 1.12; P = .214) from an adjusted Cox model.ConclusionAt the preplanned analysis time, MAP plus IFN-α-2b was not statistically different from MAP alone. A considerable proportion of patients never started IFN-α-2b or stopped prematurely. Long-term follow-up for events and survival continues.

Chordomas are rare, malignant bone tumors of the skull-base and axial skeleton. Until recently, there was no consensus among experts regarding appropriate clinical management of chordoma, resulting in inconsistent care and suboptimal outcomes for many patients. To address this shortcoming, the European Society of Medical Oncology (ESMO) and the Chordoma Foundation, the global chordoma patient advocacy group, convened a multi-disciplinary group of chordoma specialists to define by consensus evidence-based best practices for the optimal approach to chordoma. In January 2015, the first recommendations of this group were published, covering the management of primary and metastatic chordomas. Additional evidence and further discussion were needed to develop recommendations about the management of local-regional failures. Thus, ESMO and CF convened a second consensus group meeting in November 2015 to address the treatment of locally relapsed chordoma. This meeting involved over 60 specialists from Europe, the United States and Japan with expertise in treatment of patients with chordoma. The consensus achieved during that meeting is the subject of the present publication and complements the recommendations of the first position paper.

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BACKGROUND The objective of this study was to evaluate noninvasive magnetic resonance (MR) thermography for the monitoring of regional hyperthermia (RHT) in patients with soft tissue sarcomas of the lower extremities and pelvis. METHODS Noninvasive MR monitoring during RHT was performed in 9 patients who had high‐risk soft tissue sarcomas of the lower extremities or pelvis during neoadjuvant chemotherapy plus RHT in the scope of the European Organization for Research and Treatment of Cancer 62961/European Society for Hyperthermic Oncology RHT‐95 study. Anatomic and temperature‐sensitive data sets were acquired every 10 minutes before and during RHT (using gradient‐echo‐sequences with variable echo times). MR temperature distributions were derived from the phase differences by using the proton‐resonance frequency shift method. A phase convolution setting phase shifts to zero in the fat tissue was performed as a drift correction. The mean MR temperatures in the tumor and muscles and the index temperatures (e.g., T90, which covers 90% of the target volume) and thermal doses were determined and compared with pathohistologic responses and direct temperature measurements if available. RESULTS Thirty of 72 MR‐thermography data sets (>40% of heat sessions) were evaluable. A significant correlation was observed between pathohistologic response (defined as a necrosis rate ≥90%) and standardized thermal parameters, such as thermal dose cumulative equivalent minutes at 43°C to 90% of the target volume (T90) (P = .050), mean T90 (P = .048), or T50 (P = .050). The correlation of 13 conventional temperature measurements performed in selected patients and sessions invasively in the tumor or noninvasively in rectum and bladder revealed an excellent correlation with MR temperatures (R2 = .96). CONCLUSIONS Noninvasive MR thermography of soft tissue sarcoma was feasible and suitable for validating the quality of heating during RHT. Cancer 2006. © 2006 American Cancer Society.

Purpose: To determine if diffusion-weighted imaging (DWI) can be used as a surrogate marker of tumor response to anticancer therapy in patients with soft-tissue sarcomas. Materials and Methods:Magnetic resonance imaging (MRI) including echo-planar DWI sequences was performed prospectively in 23 consecutive patients with soft-tissue sarcomas before and after initiation of regional or systemic chemotherapy. The mean interval between initial and follow-up MRI was 56.9 Ϯ 23.2 days. Tumor volumes were determined by manual segmentation of tumor borders on contrast-enhanced T1-weighted images. The apparent diffusion coefficient (ADC) was calculated from corresponding sections of ADC maps on initial and follow-up DWI. Subsequently, changes in tumor volumes and ADC were correlated using the Pearson correlation coefficient.Results: A high degree of correlation was found when changes in tumor volumes and ADC values were compared (r ϭ Ϫ0.925, P Ͻ 0.0001), regardless of the effectiveness of anticancer therapy expressed as changes of tumor volume.Conclusion: DWI can be used as a supplement to morphologic imaging for the evaluation of tumor response to anticancer therapy in patients with soft-tissue sarcomas. As cellular changes are expected to precede morphologic changes in treated tumors, DWI performed at an early stage of fractionated therapy may provide unique prognostic information of its effectiveness.

Background: Local recurrence (LR) in osteosarcoma is associated with very poor prognosis. We sought to evaluate which factors correlate with LR in patients who achieved complete surgical remission with adequate margins. Patients and methods:We analyzed 1355 patients with previously untreated high-grade central osteosarcoma of the extremities, the shoulder and the pelvis registered in neoadjuvant Cooperative Osteosarcoma Study Group trials between 1986 and 2005. Seventy-six patients developed LR.Results: Median follow-up was 5.56 years. No participation in a study, pelvic tumor site, limb-sparing surgery, soft tissue infiltration beyond the periosteum, poor response to neoadjuvant chemotherapy, failure to complete the planned chemotherapy protocol and biopsy at a center other than the one performing the tumor resection were significantly associated with a higher LR rate. No differences were found for varying surgical margin widths. Surgical treatment at centers with small patient volume and additional surgery in the primary tumor area, other than biopsy and tumor resection, were significantly associated with a higher rate of ablative surgery.Conclusions: Patient enrollment in clinical trials and performing the biopsy at experienced institutions capable of undertaking the tumor resection without compromising the oncological and functional outcome should be pursued in the future.

Purpose To investigate the eligibility of diffusion‐weighted imaging (DWI) for the evaluation of tumor cellularity in patients with soft‐tissue sarcomas. Materials and Methods Thirty consecutive patients with a total of 31 histologically‐proven soft‐tissue sarcomas prospectively underwent magnetic resonance imaging (MRI) including DWI with echo‐planar imaging (EPI) technique immediately before open biopsy (N = 1) or tumor resection (N = 30). Fourteen patients had no previous anticancer treatment, 16 had received neoadjuvant therapy. Tumor cellularity as determined from histological sections was compared with minimum apparent diffusion coefficient (ADC). Results Tumor cellularity correlated well with minimum ADC in a linear fashion, with a Pearson correlation coefficient of –0.88 (95% confidence interval [CI]: –0.75 to –0.96). This relationship was not influenced by prior anticancer treatment. There was only a tendency toward lower ADC in tumor with higher grading but no significant dependency (P = 0.08). Conclusion DWI has proven useful for the assessment of tumor cellularity in soft‐tissue sarcomas. In result, DWI may be used as a powerful noninvasive tool to monitor responses of cytotoxic treatment as reflected by changes in tumor cellularity. J. Magn. Reson. Imaging 2009. © 2009 Wiley‐Liss, Inc.