Targeting Molecular Mechanisms Underlying Treatment Efficacy and Resistance in Osteosarcoma: A Review of Current and Future Strategies

Osteosarcoma is the most common primary malignant bone tumour in children and adolescents. Due to micrometastatic spread, radical surgery alone rarely results in cure. Introduction of combination chemotherapy in the 1970s, however, dramatically increased overall survival rates from 20% to approximately 70%. Unfortunately, large clinical trials aiming to intensify treatment in the past decades have failed to achieve higher cure rates. In this review, we revisit how the heterogenous nature of osteosarcoma as well as acquired and intrinsic resistance to chemotherapy can account for stagnation in therapy improvement. We summarise current osteosarcoma treatment strategies focusing on molecular determinants of treatment susceptibility and resistance. Understanding therapy susceptibility and resistance provides a basis for rational therapy betterment for both identifying patients that might be cured with less toxic interventions and targeting resistance mechanisms to sensitise resistant osteosarcoma to conventional therapies.

miR-106B-25 Cluster expression: a comparative human and canine osteosarcoma study

BackgroundOsteosarcoma (OS) is the most common primary malignant bone tumour in dogs and human beings, characterised by similar genetic and clinical features. With the aim to define similarities and differences in the biological aspects involved in OS progression, a comparative study was performed to create a model to improve patient outcome.MethodsFirst, the expression of microRNAs (miRNAs) belonging to the cluster miR-106b-25 (miR-106b, miR-25 and miR-93-5p) in human and canine OS tissue was compared.ResultsmiR-25 and miR-106b presented a variable expression not significantly different from the corresponding normal bone, while miR-93-5p expression was increased in all OS specimens, with higher levels in the canine subset compared with human. Accordingly, its target p21 presented a weaker and less homogeneous immunostaining distribution in the canine group. Given the high expression of miR-93-5p in all OS specimens, the functional response of human 143B and canine DAN OS cells to miRNA inhibition was evaluated. Although p21 expression increased after miR-93-5p inhibition both at mRNA and protein level, a more significant cell response in terms of proliferation and apoptosis was seen in canine OS cells.ConclusionsIn conclusion, canine OS tissue and cell line presented higher expression levels of miR-93-5p than human OS. In addition, the introduction of miR-93-5p inhibitor caused a cell response in 143B and DAN that differed for the more intense functional impact in the canine OS cell line.

Primary osteosarcoma of the skull in teenager

Osteosarcoma of the skull is a rare primary malignant bone tumour in children, representing 1–2% of all cranial tumours. We describe a case of a 17-year-old adolescent with chondroblastic osteosarcoma of the parietal-occipital bone and no distant metastases at presentation treated with neoadjuvant chemotherapy, surgery and, later, concurrent chemoradiotherapy. The patient suffered progressive disease and died 15 months after diagnosis. There are at least 15 paediatric cases of osteosarcoma of the skull described in the literature. Due to its rarity, there are no broad prospective studies on this entity, which has distinctive features when compared to other craniofacial tumours, carrying a worse prognosis. Complete surgical resection is needed for long-term survival, whereas chemotherapy and radiotherapy have still questionable indications.

Primary Leiomyosarcoma of Bone: Analysis of Prognosis

Leiomyosarcoma of bone is just one of the variants of spindle cell sarcoma of bone characterised by the expression of desmin and other markers indicating a significant element of smooth muscle in the tumour, without osteoid production we have investigated the management and outcome of this rare type of primary malignant bone tumour.Method. Retrospective review of data stored on a prospective database.Results. In a database of 3364 patients with primary malignant bone sarcomas, 31 patients were identified with a primary leiomyosarcoma of bone. There were 12 males and 19 females with a mean age of 46 and tumour size of 8 cm. The most common site was the distal femur followed by the proximal tibia. Treatment was with chemotherapy and surgical resection. Seven of the patients had metastases at diagnosis. Surgery was carried out in 28 patients, 8 having amputation and 20 limb salvage. Three patients developed local recurrence, but half developed metastases. All patient disease-specific survival was 57% at five years and 44% at 10 yrs but for those without metastases was 82% and 60%, respectively. The only prognostic factors were metastases at diagnosis.Conclusion. Leiomyosarcoma of bone is a very rare primary malignant bone tumour affecting a predominantly older population. Despite the high incidence of metastases, survival is better than for other bone sarcomas for those without metastases at diagnosis.