Progression-dependent altered metabolism in osteosarcoma resulting in different nutrient source dependencies

Osteosarcoma (OS) is a primary malignant bone tumor and OS metastases are mostly found in the lung. The limited understanding of the biology of metastatic processes in OS limits the ability for effective treatment. Alterations to the metabolome and its transformation during metastasis aids the understanding of the mechanism and provides information on treatment and prognosis. The current study intended to identify metabolic alterations during OS progression by using a targeted gas chromatography mass spectrometry approach. Using a female OS cell line model, malignant and metastatic cells increased their energy metabolism compared to benign OS cells. The metastatic cell line showed a faster metabolic flux compared to the malignant cell line, leading to reduced metabolite pools. However, inhibiting both glycolysis and glutaminolysis resulted in a reduced proliferation. In contrast, malignant but non-metastatic OS cells showed a resistance to glycolytic inhibition but a strong dependency on glutamine as an energy source. Our in vivo metabolic approach hinted at a potential sex-dependent metabolic alteration in OS patients with lung metastases (LM), although this will require validation with larger sample sizes. In line with the in vitro results, we found that female LM patients showed a decreased central carbon metabolism compared to metastases from male patients

Loss-of-function uORF mutations in human malignancies

Ribosome profiling revealed widespread translational activity at upstream open reading frames (uORFs) and validated uORF-mediated translational control as a commonly repressive mechanism of gene expression. Translational activation of proto-oncogenes through loss-of-uORF mutations has been demonstrated, yet a systematic search for cancer-associated genetic alterations in uORFs is lacking. Here, we applied a PCR-based, multiplex identifier-tagged deep sequencing approach to screen 404 uORF translation initiation sites of 83 human tyrosine kinases and 49 other proto-oncogenes in 308 human malignancies. We identified loss-of-function uORF mutations in EPHB1 in two samples derived from breast and colon cancer, and in MAP2K6 in a sample of colon adenocarcinoma. Both mutations were associated with enhanced translation, suggesting that loss-of-uORF-mediated translational induction of the downstream main protein coding sequence may have contributed to carcinogenesis. Computational analysis of whole exome sequencing datasets of 464 colon adenocarcinomas subsequently revealed another 53 non-recurrent somatic mutations functionally deleting 22 uORF initiation and 31 uORF termination codons, respectively. These data provide evidence for somatic mutations affecting uORF initiation and termination codons in human cancer. The insufficient coverage of uORF regions in current whole exome sequencing datasets demands for future genome-wide analyses to ultimately define the contribution of uORF-mediated translational deregulation in oncogenesis

Effect of radiotherapy on local recurrence, distant metastasis and overall survival in 1200 extremity soft tissue sarcoma patients: retrospective analysis using IPTW-adjusted models

Background and purposeNeoadjuvant (NRTX) and adjuvant radiotherapy (ARTX) reduce local recurrence (LR) risk in extremity soft tissue sarcoma (eSTS), yet their impact on distant metastasis (DM) and overall survival (OS) is less well defined. This study aimed at analysing the influence of NRTX/ARTX on all three endpoints using a retrospective, multicentre eSTS cohort.Materials and methods1200 patients (mean age: 60.7 ± 16.8 years; 44.4 % females) were retrospectively included, treated with limb sparing surgery and curative intent for localised, high grade (G2/3) eSTS. 194 (16.2 %), 790 (65.8 %), and 216 (18.0 %) patients had received NRTX, ARTX and no RTX, respectively. For the resulting three groups (no RTX vs. NRTX, no RTX vs. ARTX, NRTX vs. ARTX) Fine&Gray models for LR and DM, and Cox-regression models for OS were calculated, with IPTW-modelling adjusting for imbalances between groups.ResultsIn the IPTW-adjusted analysis, NRTX was associated with lower LR-risk in comparison to no RTX (SHR [subhazard ratio]: 0.236; p = 0.003), whilst no impact on DM-risk (p = 0.576) or OS (p = 1.000) was found. IPTW-weighted analysis for no RTX vs. ARTX revealed a significant positive association between ARTX and lower LR-risk (SHR: 0.479, p = 0.003), but again no impact on DM-risk (p = 0.363) or OS (p = 0.534). IPTW-weighted model for NRTX vs. ARTX showed significantly lower LR-risk for NRTX (SHR for ARTX: 3.433; p = 0.003) but no difference regarding DM-risk (p = 1.000) or OS (p = 0.639).ConclusionNRTX and ARTX are associated with lower LR-risk, but do not seem to affect DM-risk or OS. NRTX may be favoured over ARTX as our results indicate better local control rates.Orthopaedics, Trauma Surgery and Rehabilitatio

Age-related differences of oncological outcomes in primary extremity soft tissue sarcoma: a multistate model including 6260 patients

Abstract Purpose: No studies extensively compared the young adults (YA, 18e39 years), middle-aged (40e69 year

Der Riesenzelltumor des Knochens : Eine Analyse von 87 Patienten [Giant cell tumor of bone. An evaluation of 87 patients]

Aim: Giant cell tumor (GCT) of bone is a very peculiar and interesting tumor due to of its biological behavior and the phenomenon of pulmonary metastases of a histologically benign tumor. We present the results of a retrospective study. Methods: Between 1965 and 2002 we treated 87 patients, 54 women and 33 men, for a GCT of bone. The average age of the patients was 28.2 (range 8 - 72) years. The median follow-up time was 91 months. 63 patients (72.4 %) were hospitalized with a primary tumor. Twelve of these patients (19 %) had a pathological fracture. 24 patients (27.6 %) presented with local recurrence. 7 tumors were malignant GCT of bone, 80 tumors were benign. According to the classification of Campanacci, 9 patients (10.3 %) were diagnosed in stage I, 42 (48.3 %) in stage II, and 36 (41.4 %) in stage III. Surgical procedures were intralesional curettage and packing with cement in 36 patients, and bone-grafting in 7. In 35 cases we performed a wide resection, and in nine an amputation. Results: Local recurrence was observed in 11 patients (12.6 %), all of them were benign GCT. Local recurrences were followed by an intralesional curettage and bone-grafting in three cases (42.8 %), packing with cement in seven (19.4 %). Three patients with local recurrence (27.3 %) also had synchronous pulmonary metastases. All patients diagnosed with benign GCT are still alive. 3 out of 7 patients with malignant GCT died from progression of metastatic disease. Conclusion: To reduce the risk of local recurrence and pulmonary metastases, we recommend an adjuvant therapy of GCT