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British Journal of Pharmacology Jan 2022Osteosarcoma is one of the most common primary tumours of the bone, with a 5-year survival rate of less than 20% after the development of metastases. Osteosarcoma is... (Review)
Review
Osteosarcoma is one of the most common primary tumours of the bone, with a 5-year survival rate of less than 20% after the development of metastases. Osteosarcoma is highly predisposed in Paget's disease of the bone, and both have common characteristic skeletal features due to rapid bone remodelling. Osteosarcoma prognosis is location dependent, which further emphasizes the likely contribution of the bone microenvironment in its pathogenesis. Mechanobiology describes the processes involved when mechanical cues from the changing physical microenvironment of the bone are transduced to biological pathways through mechanosensitive cellular components. Mechanobiology-driven therapies have been used to curb tumour progression by direct alteration of the physical microenvironment or inhibition of metastasis-associated mechanosensitive proteins. This review emphasizes the contribution of mechanobiology to the progression of osteosarcoma and sheds light on current mechanobiology-based therapies and potential new targets for improving disease management. Additionally, the many different 3D models currently used to study osteosarcoma mechanobiology are summarized.
Topics: Biophysics; Bone Neoplasms; Humans; Osteitis Deformans; Osteosarcoma; Tumor Microenvironment
PubMed: 34679192
DOI: 10.1111/bph.15713 -
F1000Research 2018Chondrosarcomas constitute a heterogeneous group of primary bone cancers characterized by hyaline cartilaginous neoplastic tissue. They are the second most common... (Review)
Review
Chondrosarcomas constitute a heterogeneous group of primary bone cancers characterized by hyaline cartilaginous neoplastic tissue. They are the second most common primary bone malignancy. The vast majority of chondrosarcomas are conventional chondrosarcomas, and most conventional chondrosarcomas are low- to intermediate-grade tumors (grade 1 or 2) which have indolent clinical behavior and low metastatic potential. Recurrence augurs a poor prognosis, as conventional chondrosarcomas are both radiation and chemotherapy resistant. Recent discoveries in the biology, genetics, and epigenetics of conventional chondrosarcomas have significantly advanced our understanding of the pathobiology of these tumors and offer insight into potential therapeutic targets.
Topics: Bone Neoplasms; Chondrosarcoma; Epigenesis, Genetic; Humans; Prognosis; Therapeutics
PubMed: 30519452
DOI: 10.12688/f1000research.15953.1 -
Frontiers in Immunology 2019Immunotherapy is often perceived as a relatively recent advance. In reality, however, one should be looking for the beginnings of cancer immunotherapy under different... (Review)
Review
Immunotherapy is often perceived as a relatively recent advance. In reality, however, one should be looking for the beginnings of cancer immunotherapy under different names as far as in the Antiquity. The first scientific attempts to modulate patients' immune systems to cure cancer can be attributed to two German physicians, Fehleisen and Busch, who independently noticed significant tumor regression after erysipelas infection. The next significant advances came from William Bradley Coley who is known today as the Father of Immunotherapy. It was Coley who first attempted to harness the immune system for treating bone cancer in 1891. His achievements were largely unnoticed for over fifty years, and several seminal discoveries in the field of Immunology, such as the existence of T cells and their crucial role in immunity in 1967, stepped up the research toward cancer immunotherapy known today. The following paper tracks cancer immunotherapy from its known beginnings up until recent events, including the 2018 Nobel Prize award to James Allison and Tasuku Honjo for their meticulous work on checkpoint molecules as potential therapeutic targets. That work has led to the successful development of new checkpoint inhibitors, CAR T-cells and oncolytic viruses and the pace of such advances brings the highest hope for the future of cancer treatment.
Topics: Bone Neoplasms; History, 19th Century; History, 20th Century; History, 21st Century; Humans; Immunotherapy
PubMed: 31921205
DOI: 10.3389/fimmu.2019.02965 -
International Journal of Molecular... Sep 2020Osteosarcoma is the most common primary malignant bone tumour in children and adolescents. Due to micrometastatic spread, radical surgery alone rarely results in cure.... (Review)
Review
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.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Disease-Free Survival; Drug Resistance, Neoplasm; Humans; Osteosarcoma; Survival Rate
PubMed: 32961800
DOI: 10.3390/ijms21186885 -
Current Osteoporosis Reports Oct 2021For solid tumours such as breast and prostate cancer, and haematological malignancies such as myeloma, bone represents a supportive home, where the cellular crosstalk is... (Review)
Review
PURPOSE OF REVIEW
For solid tumours such as breast and prostate cancer, and haematological malignancies such as myeloma, bone represents a supportive home, where the cellular crosstalk is known to underlie both tumour growth and survival, and the development of the associated bone disease. The importance of metabolic reprogramming is becoming increasingly recognised, particularly within cancer biology, enabling tumours to adapt to changing environments and pressures. This review will discuss our current understanding of metabolic requirements and adaptations within the tumour-bone microenvironment.
RECENT FINDINGS
The bone provides a unique metabolic microenvironment, home to highly energy-intensive processes such as bone resorption and bone formation, both of which are dysregulated in the presence of cancer. Approaches such as metabolomics demonstrate metabolic plasticity in patients with advanced disease. Metabolic crosstalk between tumour cells and surrounding stroma supports disease pathogenesis. There is increasing evidence for a key role for metabolic reprogramming within the tumour-bone microenvironment to drive disease progression. As such, understanding these metabolic adaptations should reveal new therapeutic targets and approaches.
Topics: Bone Neoplasms; Glycolysis; Humans; Tumor Microenvironment
PubMed: 34319488
DOI: 10.1007/s11914-021-00695-7 -
European Journal of Cancer (Oxford,... Mar 2019High-grade osteosarcoma is a primary malignant bone tumour mainly affecting children and young adults. The European and American Osteosarcoma Study (EURAMOS)-1 is a... (Randomized Controlled Trial)
Randomized Controlled Trial
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.
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Cisplatin; Cohort Studies; Doxorubicin; Female; Follow-Up Studies; Humans; Male; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Prognosis; Survival Rate
PubMed: 30685685
DOI: 10.1016/j.ejca.2018.11.027 -
The American Journal of Surgical... Apr 2018ACTB-GLI1 fusions have been reported as the pathognomonic genetic abnormality defining an unusual subset of actin-positive, perivascular myoid tumors, known as...
A Distinct Malignant Epithelioid Neoplasm With GLI1 Gene Rearrangements, Frequent S100 Protein Expression, and Metastatic Potential: Expanding the Spectrum of Pathologic Entities With ACTB/MALAT1/PTCH1-GLI1 Fusions.
ACTB-GLI1 fusions have been reported as the pathognomonic genetic abnormality defining an unusual subset of actin-positive, perivascular myoid tumors, known as "pericytoma with the t(7;12) translocation." In addition, GLI1 oncogenic activation through a related MALAT1-GLI1 gene fusion has been recently reported in 2 unrelated gastric tumors, namely plexiform fibromyxoma and gastroblastoma. Triggered by unexpected targeted RNA-sequencing results detecting GLI1-related fusions in a group of malignant neoplasms with round to epithelioid morphology, and frequently strong S100 protein immunoreactivity, we investigated their clinicopathologic features in relation to other known pathologic entities sharing similar genetics. On the basis of a combined approach of targeted RNA sequencing and fluorescence in situ hybridization screening, we identified 6 cases with GLI1 gene fusions, including 4 fused to ACTB, 1 with MALAT1 and 1 with PTCH1 gene. Patients had a mean age of 36 years at diagnosis (range, 16 to 79 y) and slight female predilection all except 1 tumor originated in the soft tissue. Microscopically, the tumors had a monomorphic epithelioid phenotype arranged in a distinctive nested or cord-like architecture, separated by thin septae and delicate capillary network. All except 2 cases were strongly positive for S100 protein, whereas being negative for SOX10, SMA, and EMA. Only 1 tumor showed focal cytokeratin positivity in rare cells. Although the tumors showed some resemblance to pericytic/glomus tumors or myoepithelial tumors, the immunoprofile was not supportive of either lineage. Moreover, in contrast to the benign course of so-called pericytoma with t(7;12), 3 patients in this series developed metastatic disease to either lymph nodes or lung. In fact the only patient with lung metastases showed a novel PTCH1-GLI1 gene fusion. It remains to be determined whether these tumors represent a clinically and immunohistologically distinct subset of pericytoma, or an altogether novel soft tissue sarcoma. Our findings open new opportunities for targeted therapy, as tumors with GLI1 oncogenic activation, and subsequent PTCH1 overexpression, might be sensitive to sonic hedgehog pathway inhibitors.
Topics: Actins; Adolescent; Adult; Aged; Biomarkers, Tumor; Biopsy; Bone Neoplasms; Epithelioid Cells; Female; Gene Fusion; Gene Rearrangement; Genetic Predisposition to Disease; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Male; Middle Aged; Neoplasm Metastasis; Patched-1 Receptor; Phenotype; RNA, Long Noncoding; S100 Proteins; Soft Tissue Neoplasms; Young Adult; Zinc Finger Protein GLI1
PubMed: 29309307
DOI: 10.1097/PAS.0000000000001010 -
Archives of Pathology & Laboratory... Jun 2017Chondroblastoma is a rare primary bone tumor of young people that typically arises in the ends of the long bones. Radiologic investigations show a small, circumscribed,... (Review)
Review
Chondroblastoma is a rare primary bone tumor of young people that typically arises in the ends of the long bones. Radiologic investigations show a small, circumscribed, lytic lesion. The tumor is characterized histologically by the proliferation of chondroblasts along with areas of mature cartilage, giant cells, and occasionally, secondary aneurysmal bone cyst formation. Chondroblastoma, however, may also present with atypical features, such as prominent hemosiderin deposition, numerous giant cells, or the presence of a large aneurysmal bone cyst component. Malignant entities such as clear cell chondrosarcoma and chondroblastic osteosarcoma must also be considered. Recently, immunohistochemical stains such as DOG1 and SOX9 have been described in chondroblastoma, and K36M mutations in either the H3F3A or H3F3B genes have also been identified. While generally regarded as a benign entity, chondroblastoma manifests an intermediate type of behavior, given its ability to recur locally, and rarely, metastasize.
Topics: Amino Acid Substitution; Anoctamin-1; Bone Neoplasms; Bone and Bones; Chloride Channels; Chondroblastoma; Chondrosarcoma; Diagnosis, Differential; Histones; Humans; Mutation; Neoplasm Proteins; Neoplasm Recurrence, Local; Osteosarcoma; SOX9 Transcription Factor
PubMed: 28557595
DOI: 10.5858/arpa.2016-0281-RS -
Journal of Nuclear Medicine : Official... Jun 2023Osteosarcoma is the most common type of primary malignant bone tumor. F-FDG PET/CT is useful for staging, detecting recurrence, monitoring response to neoadjuvant... (Review)
Review
Osteosarcoma is the most common type of primary malignant bone tumor. F-FDG PET/CT is useful for staging, detecting recurrence, monitoring response to neoadjuvant chemotherapy, and predicting prognosis. Here, we review the clinical aspects of osteosarcoma management and assess the role of F-FDG PET/CT, in particular with regard to pediatric and young adult patients.
Topics: Young Adult; Humans; Child; Positron Emission Tomography Computed Tomography; Fluorodeoxyglucose F18; Bone Neoplasms; Positron-Emission Tomography; Osteosarcoma; Radiopharmaceuticals; Neoplasm Staging
PubMed: 37201958
DOI: 10.2967/jnumed.123.265592 -
International Journal of Molecular... Jan 2023Primary bone tumors (PBTs) represent a huge variety of rare malignancies that originate in the skeletal system [...].
Primary bone tumors (PBTs) represent a huge variety of rare malignancies that originate in the skeletal system [...].
Topics: Humans; Translational Research, Biomedical; Bone Neoplasms
PubMed: 36768270
DOI: 10.3390/ijms24031946