Osteosarcoma

In the paper

“Using these genomic aberrations to infer the evolution of the tumours, loss of TP53 and RB1 likely occurs early in the transformation process (with TP53 inactivation required to propagate abnormal genomes 39,40,41 ), followed by rapid accumulation of driver lesions such as MYC amplification, PTEN loss 42 and deletion of ATRX”

What the sources say

• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [39] Overholtzer, M. et al. The presence of p53 mutations in human osteosarcomas correlates with high levels of genomic instability. Proc. Natl Acad. Sci. USA 100, 11547–11552 (2003). One of the first studies to show that p53 mutations correlate with high levels of genomic instability in osteosarcomas. sourceExperimental — accuracy not yet measured
• Not checked yetcites [40] Eischen, C. M. Genome stability requires p53. Cold Spring Harb. Perspect. Med. 6, a026096 (2016). source
• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [41] Hanel, W. & Moll, U. M. Links between mutant p53 and genomic instability. J. Cell. Biochem. 113, 433–439 (2012). sourceExperimental — accuracy not yet measured
• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [42] Gerstung, M. et al. The evolutionary history of 2,658 cancers. Nature 578, 122–128 (2020). sourceExperimental — accuracy not yet measured

In the paper

“This work-up recommendation reveals lung metastases in 15-20% of patients, and occasionally identifies tumours within other bones or, very rarely, lesions at other sites.”

What the sources say

• Not checked yetcites [107] Meyer, J. S. et al. Imaging guidelines for children with Ewing sarcoma and osteosarcoma: a report from the Children’s Oncology Group Bone Tumor Committee. Pediatr. Blood Cancer 51, 163–170 (2008). source

In the paper

“In these trials, MTKIs were effective in reducing PFS, becoming the mainstay of treatments for patients with relapsed disease.”

What the sources say

• Not checked yetcites [12] Mirabello, L. et al. Frequency of pathogenic germline variants in cancer-susceptibility genes in patients with osteosarcoma. JAMA Oncol. 6, 724–734 (2020). This study demonstrates a high frequency of potentially pathogenic germline mutations in patients with osteosarcoma, supporting the role of germline genetic testing. source
• Not checked yetcites [159] Boddu, P. et al. Treated secondary acute myeloid leukemia: a distinct high-risk subset of AML with adverse prognosis. Blood Adv. 1, 1312–1323 (2017). source
• Not checked yetcites [160] Armstrong, G. T. et al. Late mortality among 5-year survivors of childhood cancer: a summary from the childhood cancer survivor study. J. Clin. Oncol. 27, 2328–2338 (2009). source

In the paper

“Osteosarcoma is the most common primary malignant tumour of the bone.”

What the sources say

• Not checked yetcites [1] Mirabello, L., Troisi, R. J. & Savage, S. A. Osteosarcoma incidence and survival rates from 1973 to 2004: data from the surveillance, epidemiology, and end results program. Cancer 115, 1531–1543 (2009). source

In the paper

“Osteosarcoma incidence is bimodal, peaking at 18 and 60 years of age”

What the sources say

• Not checked yetcites [1] Mirabello, L., Troisi, R. J. & Savage, S. A. Osteosarcoma incidence and survival rates from 1973 to 2004: data from the surveillance, epidemiology, and end results program. Cancer 115, 1531–1543 (2009). source

In the paper

“Osteosarcoma is defined histologically as a tumour of osteoid-producing cells, which often exist within an admixture of adipogenic, muscle, spindle, fibroblastic and chondroblastic cells 3 .”

What the sources say

• Not checked yetcites [3] Klein, M. J. & Siegal, G. P. Osteosarcoma: anatomic and histologic variants. Am. J. Clin. Pathol. 125, 555–581 (2006). source

In the paper

“with an incidence in children and adolescents of ~3-4.5 cases per million population per year 10 .”

What the sources say

• Not checked yetcites [10] Mirabello, L., Troisi, R. J. & Savage, S. A. International osteosarcoma incidence patterns in children and adolescents, middle ages and elderly persons. Int. J. Cancer 125, 229–234 (2009). source

In the paper

“Health disparities do not seem to have a major effect on survival outcomes but data are limited 17 .”

What the sources say

• Not checked yetcites [17] Ilcisin, L. A. S. et al. Poverty, race, ethnicity, and survival among U.S. children with non-metastatic osteosarcoma treated on EURAMOS-1: a report from the Children’s Oncology Group. J. Clin. Oncol. 40, 10004 (2022). source

In the paper

“It is particularly uncommon in young children <10 years of age in whom the genetic aetiology may be different to that in adolescents 12 .”

What the sources say

• Not checked yetcites [12] Mirabello, L. et al. Frequency of pathogenic germline variants in cancer-susceptibility genes in patients with osteosarcoma. JAMA Oncol. 6, 724–734 (2020). This study demonstrates a high frequency of potentially pathogenic germline mutations in patients with osteosarcoma, supporting the role of germline genetic testing. source

In the paper

“In addition, polygenic interactions may explain the association between tall stature and risk of osteosarcoma 24 .”

What the sources say

• Not checked yetcites [24] Mirabello, L. et al. Height at diagnosis and birth-weight as risk factors for osteosarcoma. Cancer Causes Control 22, 899–908 (2011). source

In the paper

“This genomic complexity has long been interpreted as a sign of chromosomal instability but emerging data suggest that the mechanisms triggering complexity are active early in the process of malignant transformation 35,37 .”

What the sources say

• Not checked yetcites [35] Sayles, L. C. et al. Genome-informed targeted therapy for osteosarcoma. Cancer Discov. 9, 46–63 (2019). A study that defines potentially actionable molecular subtypes of osteosarcoma. source
• Not checked yetcites [37] Rajan, S. et al. Remarkably stable copy-number profiles in osteosarcoma revealed using single-cell DNA sequencing. Preprint at bioRxiv https://doi.org/10.1101/2021.08.30.458268 (2021). source

In the paper

“These rearrangements give rise to genome-wide copy number alterations, usually dominated by copy number loss, including of PTEN and CDKN2A/B, but with recurrent amplifications of MYC, VEGFA and CCNE1 (ref.35 ).”

What the sources say

• Not checked yetcites [35] Sayles, L. C. et al. Genome-informed targeted therapy for osteosarcoma. Cancer Discov. 9, 46–63 (2019). A study that defines potentially actionable molecular subtypes of osteosarcoma. source

In the paper

“The genomic landscape of osteosarcoma tumours is usually dominated by widespread structural rearrangements, suggesting that several different mutational mechanisms, including chromothripsis, chromoplexy, kataegis and other structure-altering mechanisms, are involved 32,33,34 .”

What the sources say

• Not checked yetcites [32] Cortés-Ciriano, I. et al. Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing. Nat. Genet. 52, 331–341 (2020). source
• Not checked yetcites [33] Chen, X. et al. Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma. Cell Rep. 7, 104–112 (2014). The majority of TP53 loss in osteosarcoma occurs through intron 1 rearrangements or deletions rather than through point mutations. source
• Not checked yetcites [34] Perry, J. A. et al. Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma. Proc. Natl Acad. Sci. USA 111, E5564–E5573 (2014). source

In the paper

“Radiotherapy-associated osteosarcomas tend to occur within the radiation field following a long latency period of >10 years and are more frequent in patients with cancer predisposition syndromes such as Li-Fraumeni syndrome or hereditary retinoblastoma 25 .”

What the sources say

• Not checked yetcites [25] Tucker, M. A. et al. Bone sarcomas linked to radiotherapy and chemotherapy in children. N. Engl. J. Med. 317, 588–593 (1987). source

In the paper

“it is estimated that malignant transformation to osteosarcoma occurs in ~1% of patients with Paget disease 26 .”

What the sources say

• Not checked yetcites [26] Cundy, T. Paget’s disease of bone. Metabolism 80, 5–14 (2018). source

In the paper

“Osteosarcoma tumours often show signs of whole-genome duplication, which probably occurs in response to stresses imposed by pervasive copy number losses 36 .”

What the sources say

• Not checked yetcites [36] Wu, C. C. et al. Immuno-genomic landscape of osteosarcoma. Nat. Commun. 11, 1008 (2020). Molecular profiling of samples from patients with osteosarcoma characterizes immune subsets, including immune enrichment among older patients. source

In the paper

“The age-adjusted incidence rate was 1.9 per million for those aged 0-9 years, 6.7 per million for those aged 10-24 years, 1.9 per million for those aged 25-59 years and 2 per million for those aged ≥60 years.”

What the sources say

• Not checked yetcites [16] Cole, S., Gianferante, D. M., Zhu, B. & Mirabello, L. Osteosarcoma: a surveillance, epidemiology, and end results program‐based analysis from 1975 to 2017. Cancer 128, 2107–2118 (2022). source

In the paper

“Osteosarcoma is slightly more common in males, with an average male-to-female ratio of 1.4:1 (ref.15 ).”

What the sources say

• Not checked yetcites [15] Brown, H. K., Schiavone, K., Gouin, F., Heymann, M.-F. & Heymann, D. Biology of bone sarcomas and new therapeutic developments. Calcif. Tissue Int. 102, 174–195 (2018). source

In the paper

“In the USA, osteosarcoma accounts for <1% of all new cancer diagnoses with ~1,000 new cases diagnosed per year, half of these cases occurring in children and adolescents 1 .”

What the sources say

• Not checked yetcites [1] Mirabello, L., Troisi, R. J. & Savage, S. A. Osteosarcoma incidence and survival rates from 1973 to 2004: data from the surveillance, epidemiology, and end results program. Cancer 115, 1531–1543 (2009). source

In the paper

“The incidence rise and peak in adolescents up to the age of 24 years are often attributed to the hormonal changes that occur during puberty with an earlier peak in girls than in boys 13 .”

What the sources say

• Not checked yetcites [13] Glass, A. G. & Fraumeni, J. F. Jr. Epidemiology of bone cancer in children. J. Natl Cancer Inst. 44, 187–199 (1970).

In the paper

“Epidemiological observations support this interpretation as tumours were found to arise most frequently within the metaphyses of long bones in children, adolescents and young adults during times of peak linear growth, suggesting that the bone-producing and cartilage-producing cells that proliferate rapidly during those growth spurts are those susceptible to the transformation giving rise to osteos”

What the sources say

• Not checked yetcites [29] Jones, K. B. Osteosarcomagenesis: modeling cancer initiation in the mouse. Sarcoma 2011, 694136 (2011). source
• Not checked yetcites [30] Mutsaers, A. J. & Walkley, C. R. Cells of origin in osteosarcoma: mesenchymal stem cells or osteoblast committed cells? Bone 62, 56–63 (2014). source

In the paper

“Whether these benign bone tumours trigger a transformation based on the accumulation of genetic and epigenetic events or the creation of an environment permissive to malignant transformation remains unclear 28 .”

What the sources say

• Not checked yetcites [28] Picci, P. et al. Late sarcoma development after curettage and bone grafting of benign bone tumors. Eur. J. Radiol. 77, 19–25 (2011). source

In the paper

“in patients with metastatic disease, event-free survival outcomes remain poor at less than 30%.”

In the paper

“Notably, the incidence of osteosarcoma in children and adolescents has increased from the 1970s to the 2000s but has declined in adults >60 years of age.”

What the sources say

• Not checked yetcites [16] Cole, S., Gianferante, D. M., Zhu, B. & Mirabello, L. Osteosarcoma: a surveillance, epidemiology, and end results program‐based analysis from 1975 to 2017. Cancer 128, 2107–2118 (2022). source

In the paper

“Particularly in older adults, osteosarcomas may also arise in the setting of Paget disease of bone and other bone disorders, suggesting a role of abnormal bone turnover in osteosarcoma pathogenesis 26 .”

What the sources say

• Not checked yetcites [26] Cundy, T. Paget’s disease of bone. Metabolism 80, 5–14 (2018). source

In the paper

“The frequency of germline mutations in patients with osteosarcoma ranges from 18% to 28% and these mutations are more common in younger patients 12,18 .”

What the sources say

• Not checked yetcites [12] Mirabello, L. et al. Frequency of pathogenic germline variants in cancer-susceptibility genes in patients with osteosarcoma. JAMA Oncol. 6, 724–734 (2020). This study demonstrates a high frequency of potentially pathogenic germline mutations in patients with osteosarcoma, supporting the role of germline genetic testing. source
• Not checked yetcites [18] Zhang, J. et al. Germline mutations in predisposition genes in pediatric cancer. N. Engl. J. Med. 373, 2336–2346 (2015). source

In the paper

“Osteosarcoma incidence has a bimodal age distribution with a primary peak in adolescents and young adults and a second, smaller peak in the seventh and eighth decade of life 1”

What the sources say

• Not checked yetcites [1] Mirabello, L., Troisi, R. J. & Savage, S. A. Osteosarcoma incidence and survival rates from 1973 to 2004: data from the surveillance, epidemiology, and end results program. Cancer 115, 1531–1543 (2009). source

In the paper

“Patients with retinoblastoma and Rothmund-Thomson syndrome might present with osteosarcoma in their teens, and osteosarcoma associated with Werner syndrome or Li-Fraumeni syndrome presents in middle age 22,23 .”

What the sources say

• Not checked yetcites [22] Hameed, M. & Mandelker, D. Tumor syndromes predisposing to osteosarcoma. Adv. Anat. Pathol. 25, 217–222 (2018). source
• Not checked yetcites [23] Calvert, G. T. et al. At-risk populations for osteosarcoma: the syndromes and beyond. Sarcoma 2012, 152382 (2012). source

In the paper

“A major caveat is that each of these alterations only applies to a very limited number of patients, making clinical trials of these subgroups challenging, and many more common alterations are not associated with targetable therapies.”

In the paper

“Osteosarcoma development can be described by the conjunction of multiple factors: oncogenic events that initiate malignant transformation, a progressive increase of genetic aberrations with the increasing proliferation rate of cells committed towards the osteoblast lineage during bone growth 44 , and involvement of a permissive microenvironment, which is a prerequisite for the growth of cancer”

What the sources say

• Not checked yetcites [44] Kovac, M. et al. Exome sequencing of osteosarcoma reveals mutation signatures reminiscent of BRCA deficiency. Nat. Commun. 6, 8940 (2015). source

In the paper

“deletion of ATRX, which seems to activate alternative lengthening of telomeres and is associated with decreased survival 36,43 .”

What the sources say

• Not checked yetcites [36] Wu, C. C. et al. Immuno-genomic landscape of osteosarcoma. Nat. Commun. 11, 1008 (2020). Molecular profiling of samples from patients with osteosarcoma characterizes immune subsets, including immune enrichment among older patients. source
• Not checked yetcites [43] Lawlor, R. T. et al. Alternative lengthening of telomeres (ALT) influences survival in soft tissue sarcomas: a systematic review with meta-analysis. BMC Cancer 19, 232 (2019). source

In the paper

“Osteosarcoma cells educate these MSCs by secreting TGFβ-containing extracellular vesicles 60 , triggering MSC IL-6 release and activating a STAT3-mediated tumour progression programme that drives the formation of metastatic foci within the lung 61 .”

What the sources say

• Not checked yetcites [60] Baglio, S. R. et al. Blocking tumor-educated MSC paracrine activity halts osteosarcoma progression. Clin. Cancer Res. 23, 3721–3733 (2017). source
• Not checked yetcites [61] Tu, B., Du, L., Fan, Q. M., Tang, Z. & Tang, T. T. STAT3 activation by IL-6 from mesenchymal stem cells promotes the proliferation and metastasis of osteosarcoma. Cancer Lett. 325, 80–88 (2012). source

In the paper

“The single most frequently altered gene is the tumour suppressor TP53, which is lost in >90% of osteosarcoma tumours, with the majority lost through intron 1 rearrangements or deletions rather than through point mutations 33,36,38 .”

What the sources say

• Not checked yetcites [33] Chen, X. et al. Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma. Cell Rep. 7, 104–112 (2014). The majority of TP53 loss in osteosarcoma occurs through intron 1 rearrangements or deletions rather than through point mutations. source
• Not checked yetcites [36] Wu, C. C. et al. Immuno-genomic landscape of osteosarcoma. Nat. Commun. 11, 1008 (2020). Molecular profiling of samples from patients with osteosarcoma characterizes immune subsets, including immune enrichment among older patients. source
• Not checked yetcites [38] Behjati, S. et al. Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma. Nat. Commun. 8, 15936 (2017). source

In the paper

“The dialogue between osteosarcoma cells and their microenvironment is crucial for tumour growth at the bone site and is associated with direct interaction among mesenchymal, vascular and immune cells (depending on cell differentiation level) 45 , the interaction of cells with soluble factors such as chemokines and cytokines 46 , and the interaction of cells with extracellular vesicles 47 .”

What the sources say

• Not checked yetcites [45] Tellez-Gabriel, M. et al. Analysis of gap junctional intercellular communications using a dielectrophoresis-based microchip. Eur. J. Cell Biol. 96, 110–118 (2017). source
• Not checked yetcites [46] Bénédicte Brounais, L.-R. & Frédéric, L. In Bone Cancer 221–239, Ch. 18 (Academic Press, 2022).
• Not checked yetcites [47] Lan, M. et al. Extracellular vesicles-mediated signaling in the osteosarcoma microenvironment: roles and potential therapeutic targets. J. Bone Oncol. 12, 101–104 (2018). source

In the paper

“This seed and soil phenomenon is driven by a microenvironment that modulates osteosarcoma cell behaviour and facilitates proliferation, quiescence, invasion, migration, and drug resistance 15,51,52,53 and contributes to their intrinsic heterogeneity 54,55 .”

What the sources say

• Not checked yetcites [15] Brown, H. K., Schiavone, K., Gouin, F., Heymann, M.-F. & Heymann, D. Biology of bone sarcomas and new therapeutic developments. Calcif. Tissue Int. 102, 174–195 (2018). source
• Not checked yetcites [51] Heymann, M.-F., Lézot, F. & Heymann, D. The contribution of immune infiltrates and the local microenvironment in the pathogenesis of osteosarcoma. Cell. Immunol. https://doi.org/10.1016/j.cellimm.2017.10.011 (2017). source
• Not checked yetcites [52] Brown, H. K., Tellez-Gabriel, M. & Heymann, D. Cancer stem cells in osteosarcoma. Cancer Lett. 386, 189–195 (2017). source
• Not checked yetcites [53] Grunewald, T. G. et al. Sarcoma treatment in the era of molecular medicine. EMBO Mol. Med. 12, e11131 (2020). source
• Not checked yetcites [54] Zhou, Y. et al. Single-cell RNA landscape of intratumoral heterogeneity and immunosuppressive microenvironment in advanced osteosarcoma. Nat. Commun. 11, 6322 (2020). source
• Not checked yetcites [55] Guo, J. et al. Single-cell profiling of tumor microenvironment heterogeneity in osteosarcoma identifies a highly invasive subcluster for predicting prognosis. Front. Oncol. 12, 732862 (2022). source

In the paper

“large-scale sequencing has identified only moderate levels of point mutations with few recurrently mutated genes 33,34,36,38 .”

What the sources say

• Not checked yetcites [33] Chen, X. et al. Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma. Cell Rep. 7, 104–112 (2014). The majority of TP53 loss in osteosarcoma occurs through intron 1 rearrangements or deletions rather than through point mutations. source
• Not checked yetcites [34] Perry, J. A. et al. Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma. Proc. Natl Acad. Sci. USA 111, E5564–E5573 (2014). source
• Not checked yetcites [36] Wu, C. C. et al. Immuno-genomic landscape of osteosarcoma. Nat. Commun. 11, 1008 (2020). Molecular profiling of samples from patients with osteosarcoma characterizes immune subsets, including immune enrichment among older patients. source
• Not checked yetcites [38] Behjati, S. et al. Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma. Nat. Commun. 8, 15936 (2017). source

In the paper

“However, the overall role of osteoclasts in osteosarcoma development remains unclear as they seem to hold a pro-tumorigenic role in early-stage disease 48 but an opposite role in later-stage disease 49 .”

What the sources say

• Not checked yetcites [48] Cackowski, F. C. et al. Osteoclasts are important for bone angiogenesis. Blood 115, 140–149 (2010). source
• Not checked yetcites [49] Endo-Munoz, L., Evdokiou, A. & Saunders, N. A. The role of osteoclasts and tumour-associated macrophages in osteosarcoma metastasis. Biochim. Biophys. Acta 1826, 434–442 (2012).

In the paper

“The most likely order of events for osteosarcoma evolution is loss of TP53 and RB1 as early events, of which TP53 loss is likely the initiator of genomic instability 39,40,41 followed by whole-genome doubling, gain of 8q (CMYC) and loss of 10q (PTEN) 42 .”

What the sources say

• Not checked yetcites [39] Overholtzer, M. et al. The presence of p53 mutations in human osteosarcomas correlates with high levels of genomic instability. Proc. Natl Acad. Sci. USA 100, 11547–11552 (2003). One of the first studies to show that p53 mutations correlate with high levels of genomic instability in osteosarcomas. source
• Not checked yetcites [40] Eischen, C. M. Genome stability requires p53. Cold Spring Harb. Perspect. Med. 6, a026096 (2016). source
• Not checked yetcites [41] Hanel, W. & Moll, U. M. Links between mutant p53 and genomic instability. J. Cell. Biochem. 113, 433–439 (2012). source
• Not checked yetcites [42] Gerstung, M. et al. The evolutionary history of 2,658 cancers. Nature 578, 122–128 (2020). source

In the paper

“The cytoskeletal linker ezrin provides a scaffold for PI3K-AKT signalling and facilitates survival through the stresses that disseminated tumour cells first encounter within the lung 72,73,74 .”

What the sources say

• Not checked yetcites [72] Khanna, C. et al. The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis. Nat. Med. 10, 182–186 (2004). source
• Not checked yetcites [73] Bulut, G. et al. Small molecule inhibitors of ezrin inhibit the invasive phenotype of osteosarcoma cells. Oncogene 31, 269–281 (2012). source
• Not checked yetcites [74] Ren, L. et al. Dysregulation of Ezrin phosphorylation prevents metastasis and alters cellular metabolism in osteosarcoma. Cancer Res. 72, 1001–1012 (2012). source

In the paper

“Mesenchymal stem cells (MSCs) have been implicated in osteosarcoma metastasis and therapeutic resistance 57,58,59 .”

What the sources say

• Not checked yetcites [57] Stamatopoulos, A. et al. Mesenchymal stromal cells for bone sarcoma treatment: roadmap to clinical practice. J. Bone Oncol. 16, 100231 (2019). source
• Not checked yetcites [58] Perrot, P. et al. Safety concern between autologous fat graft, mesenchymal stem cell and osteosarcoma recurrence. PLoS ONE 5, e10999 (2010). source
• Not checked yetcites [59] Cortini, M., Avnet, S. & Baldini, N. Mesenchymal stroma: role in osteosarcoma progression. Cancer Lett. 405, 90–99 (2017). source

In the paper

“Skeletal imaging with PET or technetium bone scans is important to identify covert bony disease 107 .”

What the sources say

• Not checked yetcites [107] Meyer, J. S. et al. Imaging guidelines for children with Ewing sarcoma and osteosarcoma: a report from the Children’s Oncology Group Bone Tumor Committee. Pediatr. Blood Cancer 51, 163–170 (2008). source

In the paper

“Staging is guided primarily by the Musculoskeletal Tumour Society (MSTS) staging system for sarcomas 108 , which defines tumours as being either low or high grade, confined to an anatomic compartment or violating anatomic barriers, and localized or metastatic.”

What the sources say

• Not checked yetcites [108] Wolf, R. E. & Enneking, W. F. The staging and surgery of musculoskeletal neoplasms. Orthop. Clin. North. Am. 27, 473–481 (1996). source

In the paper

“The response to neoadjuvant chemotherapy, assessed in the definitive resection specimen, has clear prognostic value and has been used in previous clinical trials to stratify patients into good responders and poor responders; however, intensification of treatment did not improve outcomes in the poor responder group 114 .”

What the sources say

• Not checked yetcites [114] Marina, N. M. et al. Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial. Lancet Oncol. 17, 1396–1408 (2016). An international randomized clinical trial fails to show benefit of addition of I/E to MAP chemotherapy in the primary treatment of osteosarcoma. source

In the paper

“The loss of structural integrity due to tumour-related osteolysis puts patients at risk for pathological fractures, which occur in ~10% of patients and can complicate initial management 102 .”

What the sources say

• Not checked yetcites [102] Zhou, Y. et al. The effect of pathological fractures on the prognosis of patients with osteosarcoma: a meta-analysis of 14 studies. Oncotarget 8, 73037–73049 (2017). source

In the paper

“Indeed, IGF1 receptor amplifications occur in up to 14% of patients with osteosarcoma 38 , which seems to drive activation of the PI3K-AKT-mTOR pathway through the MAPK pathway 98 .”

What the sources say

• Not checked yetcites [38] Behjati, S. et al. Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma. Nat. Commun. 8, 15936 (2017). source
• Not checked yetcites [98] Li, Y. S., Liu, Q., He, H. B. & Luo, W. The possible role of insulin-like growth factor-1 in osteosarcoma. Curr. Probl. Cancer 43, 228–235 (2019). source

In the paper

“Copy number amplifications of potentially targetable genes seemed to predict sensitivity to specific agents 35 ; however, subsequent work has shown that the picture is much more complicated 9 .”

What the sources say

• Not checked yetcites [35] Sayles, L. C. et al. Genome-informed targeted therapy for osteosarcoma. Cancer Discov. 9, 46–63 (2019). A study that defines potentially actionable molecular subtypes of osteosarcoma. source
• Not checked yetcites [9] Gill, J. & Gorlick, R. Advancing therapy for osteosarcoma. Nat. Rev. Clin. Oncol. 18, 609–624 (2021). source

In the paper

“The promising preclinical successes seen with CDK12 inhibitors 92 and drugs that block protein elongation 93 may not be surprising as osteosarcoma cells depend on massive levels of protein production.”

What the sources say

• Not checked yetcites [92] Bayles, I. et al. Ex vivo screen identifies CDK12 as a metastatic vulnerability in osteosarcoma. J. Clin. Invest. 129, 4377–4392 (2019). source
• Not checked yetcites [93] Chang, L.-S. et al. Targeting protein translation by rocaglamide and didesmethylrocaglamide to treat MPNST and other sarcomas. Mol. Cancer Ther. 19, 731–741 (2020). source

In the paper

“Patients experiencing fractures have higher rates of lung metastasis, both at presentation and subsequent to treatment 102 .”

What the sources say

• Not checked yetcites [102] Zhou, Y. et al. The effect of pathological fractures on the prognosis of patients with osteosarcoma: a meta-analysis of 14 studies. Oncotarget 8, 73037–73049 (2017). source

In the paper

“Most patients present with high-grade lesions that have both bony and soft tissue components, making the presence or absence of metastasis the primary risk-stratifying feature at diagnosis.”

In the paper

“For core needle biopsies, adequate sampling of the tissue has to be ensured as osteosarcoma lesions can be quite heterogeneous and diagnostic features (such as malignant osteoid) can vary from sample to sample.”

In the paper

“In 2008, guidelines from the Children's Oncology Group were published 107 , and are still widely accepted, advocating PET imaging with accompanying whole-body CT or whole-body MRI, with isotope bone scans if these modalities are not available.”

What the sources say

• Not checked yetcites [107] Meyer, J. S. et al. Imaging guidelines for children with Ewing sarcoma and osteosarcoma: a report from the Children’s Oncology Group Bone Tumor Committee. Pediatr. Blood Cancer 51, 163–170 (2008). source

In the paper

“There has been a long-standing interest in immune-based therapies centred on the activity of mifamurtide in osteosarcoma in phase II and subsequently on a randomized phase III trial conducted by the Children's Oncology Group 81 .”

What the sources say

• Not checked yetcites [81] Meyers, P. A. et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival — a report from the Children’s Oncology Group. J. Clin. Oncol. 26, 633–638 (2008). source

In the paper

“A small number of patients present with localized, lower-grade parosteal and periosteal lesions 109,110 .”

What the sources say

• Not checked yetcites [109] Sheth, D. S. et al. Conventional and dedifferentiated parosteal osteosarcoma. Diagnosis, treatment, and outcome. Cancer 78, 2136–2145 (1996). source
• Not checked yetcites [110] Grimer, R. J. et al. Periosteal osteosarcoma — a European review of outcome. Eur. J. Cancer 41, 2806–2811 (2005). source

In the paper

“Patients who present with lung metastasis have the worst prognosis, with 3-year survival rates of <30% 113 .”

What the sources say

• Not checked yetcites [113] Aljubran, A. H., Griffin, A., Pintilie, M. & Blackstein, M. Osteosarcoma in adolescents and adults: survival analysis with and without lung metastases. Ann. Oncol. 20, 1136–1141 (2009). source

In the paper

“The genomic complexity of osteosarcoma might suggest sensitivity to immune modulators such as immune-checkpoint inhibitors (ICIs) but the overall mutational burden within most osteosarcomas is markedly less than that associated with responses to immune-checkpoint inhibition in other adult tumours 83 .”

What the sources say

• Not checked yetcites [83] Gröbner, S. N. et al. The landscape of genomic alterations across childhood cancers. Nature 555, 321–327 (2018). source

In the paper

“Fine-needle aspirates are usually inadequate for a definitive diagnosis of osteosarcoma due to the lack of sufficient histological context and the resulting difficulty to assess tumour grade, and are therefore not recommended.”

In the paper

“The definition of good responder and poor responder to chemotherapy varies depending on the study.”

What the sources say

• Not checked yetcites [115] Rosen, G., Murphy, M. L., Huvos, A. G., Gutierrez, M. & Marcove, R. C. Chemotherapy, en bloc resection, and prosthetic bone replacement in the treatment of osteogenic sarcoma. Cancer 37, 1–11 (1976). source
• Not checked yetcites [116] Rosen, G. et al. Preoperative chemotherapy for osteogenic sarcoma: selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy. Cancer 49, 1221–1230 (1982). source

In the paper

“All patients presenting with newly diagnosed disease should undergo CT imaging of the chest, which has the highest efficiency in identifying lung nodules (Fig. 6g).”

In the paper

“The workup for the presenting symptoms usually includes plain-film radiographs, potentially revealing large lesions that are causing destruction of normal trabecular bone with poorly defined margins 103”

What the sources say

• Not checked yetcites [103] Papagelopoulos, P. J. et al. Current concepts in the evaluation and treatment of osteosarcoma. Orthopedics 23, 858–867 (2000). source

In the paper

“Local recurrence rates for extremity osteosarcoma are low and generally less than 5%, suggesting that, in most cases, complete resection is achieved.”

In the paper

“This applies to both patients with localized disease and those with primary metastatic osteosarcoma, provided complete surgical removal of all known metastatic deposits has been achieved.”

In the paper

“Some studies suggested that the histological subtype of osteosarcoma can influence the degree of necrosis, with chondroblastic and telangiectatic subtypes having less necrosis but those differences have not translated into improvement in survival 1,118 .”

What the sources say

• Not checked yetcites [1] Mirabello, L., Troisi, R. J. & Savage, S. A. Osteosarcoma incidence and survival rates from 1973 to 2004: data from the surveillance, epidemiology, and end results program. Cancer 115, 1531–1543 (2009). source
• Not checked yetcites [118] Bacci, G. et al. Neoadjuvant chemotherapy for high-grade central osteosarcoma of the extremity. Cancer 97, 3068–3075 (2003). source

In the paper

“No specific blood-based biomarkers or routine imaging for screening and early detection of osteosarcoma exist.”

In the paper

“Low-grade lesions, including low-grade central lesions, are treated by local surgical control only.”

In the paper

“Molecular features that identify patients at higher risk include RB1 loss, MYC amplification and VEGFA amplification, among others.”

In the paper

“However, considerable chemotherapy-related toxic effects were observed; neutropenia and other haematological adverse effects were most frequent.”

What the sources say

• Not checked yetcites [133] Ferrari, S. et al. EURO-B.O.S.S.: a European study on chemotherapy in bone-sarcoma patients aged over 40: Outcome in primary high-grade osteosarcoma. Tumori 104, 30–36 (2018). source

In the paper

“Identification of individuals at risk enables adherence to clinical practice guidelines and early identification and risk reduction for osteosarcoma as well as other cancers 120 .”

What the sources say

• Not checked yetcites [120] Villani, A. et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. Lancet Oncol. 17, 1295–1305 (2016). source

In the paper

“Limb salvage is feasible for most patients with extremity tumours via reconstruction using an endoprosthetic implant, or allogeneic or autologous bone graft.”

In the paper

“The most efficacious regimens employ at least three of these drugs, yet adding a fourth agent may not lead to further benefits 128 .”

What the sources say

• Not checked yetcites [128] Anninga, J. K. et al. Chemotherapeutic adjuvant treatment for osteosarcoma: where do we stand? Eur. J. Cancer 47, 2431–2445 (2011). source

In the paper

“Given that therapy changes based on necrosis grading have not been shown to modify survival outcomes, the use of necrosis grading has declined.”

In the paper

“In addition, patients with unresectable primary or metastatic disease at diagnosis and those with disease relapse have extremely poor outcomes 2,126 .”

What the sources say

• Not checked yetcites [2] Bielack, S. S. et al. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J. Clin. Oncol. 20, 776–790 (2002). A study that affirms tumour site and size, primary metastases, response to chemotherapy, and surgical remission as independent prognostic factors in patients with osteosarcoma. source
• Not checked yetcites [126] Kempf-Bielack, B. et al. Osteosarcoma relapse after combined modality therapy: an analysis of unselected patients in the Cooperative Osteosarcoma Study Group (COSS). J. Clin. Oncol. 23, 559–568 (2005). source

In the paper

“The improvement in prognosis seems linear with increasing necrosis, with some studies setting the cut-off point between good and poor between grades 2 and 3, whereas others have set it between grades 3 and 4.”

What the sources say

• Not checked yetcites [117] Bishop, M. W. et al. Assessing the prognostic significance of histologic response in osteosarcoma: a comparison of outcomes on CCG-782 and INT0133 — a report from the Children’s Oncology Group Bone Tumor Committee. Pediatr. Blood Cancer 63, 1737–1743 (2016). This study validates the prognostic significance of pathological treatment response in osteosarcoma following neoadjuvant chemotherapy. source

In the paper

“Intermediate-grade lesions, including periosteal lesions and most osteosarcomas that affect the jaw, similarly need local control, which is also typically surgery.”

In the paper

“Minimally invasive and non-invasive growing implants enable limb-salvage reconstruction as well as future limb-length equality for patients with skeletal immaturity 135 .”

What the sources say

• Not checked yetcites [135] Ruggieri, P. et al. Outcome of expandable prostheses in children. J. Pediatr. Orthop. 33, 244–253 (2013). source

In the paper

“Otherwise, intralesional or marginal resections increase local recurrence rate, which is associated with reduced overall survival 2,134 .”

What the sources say

• Not checked yetcites [2] Bielack, S. S. et al. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J. Clin. Oncol. 20, 776–790 (2002). A study that affirms tumour site and size, primary metastases, response to chemotherapy, and surgical remission as independent prognostic factors in patients with osteosarcoma. source
• Not checked yetcites [134] Picci, P. et al. Relationship of chemotherapy-induced necrosis and surgical margins to local recurrence in osteosarcoma. J. Clin. Oncol. 12, 2699–2705 (1994). source

In the paper

“Guidelines for patients and families with Li-Fraumeni syndrome include annual whole-body MRI to screen for multiple possible malignancies, including sarcomas, and maintaining a high index of suspicion for rare cancers 122 .”

What the sources say

• Not checked yetcites [122] Kratz, C. P. et al. Cancer screening recommendations for individuals with Li-Fraumeni syndrome. Clin. Cancer Res. 23, e38–e45 (2017). source

In the paper

“Osteosarcomas in other craniofacial locations can be high grade, and are treated with chemotherapy and local control in such case.”

In the paper

“Intensive blood and imaging-based surveillance in patients with pathogenic germline TP53 variants has been shown to be feasible, resulting in the detection of solid tumours at an earlier stage and associated with improved long-term survival, although these findings were not specific to osteosarcoma 120 .”

What the sources say

• Not checked yetcites [120] Villani, A. et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. Lancet Oncol. 17, 1295–1305 (2016). source

In the paper

“There is no standard-of-care systemic therapy for patients >40 years of age with a poor outcome and few clinical trials to inform practice 132 .”

What the sources say

• Not checked yetcites [132] Grimer, R. J. et al. Osteosarcoma over the age of forty. Eur. J. Cancer 39, 157–163 (2003). source

In the paper

“Here, the number of metastases and completeness of excision seem to affect outcomes 6 .”

What the sources say

• Not checked yetcites [6] Kager, L. et al. Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols. J. Clin. Oncol. 21, 2011–2018 (2003). source

In the paper

“Progress was only made with the introduction of systemic chemotherapy, which was soon administered neoadjuvantly 127 .”

What the sources say

• Not checked yetcites [127] Jaffe, N., Puri, A. & Gelderblom, H. Osteosarcoma: evolution of treatment paradigms. Sarcoma 2013, 203531 (2013). source

In the paper

“Surgery is also an important local control modality for metastatic sites, with long-term survival improving with the resection of lung metastases.”

In the paper

“Retrospective analysis of the European Musculoskeletal Oncology Society of patients over 40 years did demonstrate that adult patients may benefit from aggressive treatment with surgery and chemotherapy, with outcomes possibly being related to decreased chemotherapy administered to some of the elderly patients 132 .”

What the sources say

• Not checked yetcites [132] Grimer, R. J. et al. Osteosarcoma over the age of forty. Eur. J. Cancer 39, 157–163 (2003). source

In the paper

“The dosage of chemotherapy given before surgery shifts the degree of necrosis but it does not change the prognostic value of necrosis grading nor influence survival 119 .”

What the sources say

• Not checked yetcites [119] Meyers, P. A. et al. Intensification of preoperative chemotherapy for osteogenic sarcoma: results of the Memorial Sloan-Kettering (T12) protocol. J. Clin. Oncol. 16, 2452–2458 (1998). source

In the paper

“For intermediate-grade osteosarcomas, the role of chemotherapy is controversial and certainly not associated with the same risk-to-benefit relationship as high-grade osteosarcomas.”

In the paper

“For example, necrosis grading had four levels but each level was only defined descriptively 115,116 and percentages were added later to facilitate comparison 116 .”

What the sources say

• Not checked yetcites [115] Rosen, G., Murphy, M. L., Huvos, A. G., Gutierrez, M. & Marcove, R. C. Chemotherapy, en bloc resection, and prosthetic bone replacement in the treatment of osteogenic sarcoma. Cancer 37, 1–11 (1976). source
• Not checked yetcites [116] Rosen, G. et al. Preoperative chemotherapy for osteogenic sarcoma: selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy. Cancer 49, 1221–1230 (1982). source

In the paper

“Treatment for anthracycline-induced heart failure is similar to that of heart failure from any cause 164 .”

What the sources say

• Not checked yetcites [164] Armenian, S. H. et al. Recommendations for cardiomyopathy surveillance for survivors of childhood cancer: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Lancet Oncol. 16, e123–e136 (2015). source

In the paper

“Ablative surgery (amputation) may be associated with poor joint function but usually involves fewer episodes of revision surgery than limb salvage.”

In the paper

“Osteosarcoma recurs most often in the lung followed by bone at a site distant to the primary tumour.”

In the paper

“The cumulative anthracycline dose is a major risk factor for severe cardiomyopathy development but young age at treatment, female sex, peak drug exposure and additional stress to the heart have also been implicated 161,162,163 .”

What the sources say

• Not checked yetcites [161] Mancilla, T. R., Iskra, B. & Aune, G. J. Doxorubicin-induced cardiomyopathy in children. Compr. Physiol. 9, 905–931 (2019). source
• Not checked yetcites [162] Bhagat, A. & Kleinerman, E. S. Anthracycline-induced cardiotoxicity: causes, mechanisms, and prevention. Adv. Exp. Med. Biol. 1257, 181–192 (2020). source
• Not checked yetcites [163] Rawat, P. S., Jaiswal, A., Khurana, A., Bhatti, J. S. & Navik, U. Doxorubicin-induced cardiotoxicity: an update on the molecular mechanism and novel therapeutic strategies for effective management. Biomed. Pharmacother. 139, 111708 (2021). source

In the paper

“The regimens include high-dose ifosfamide with or without etoposide and gemcitabine and docetaxel.”

What the sources say

• Not checked yetcites [104] Strauss, S. J. et al. Bone sarcomas: ESMO-EURACAN-GENTURIS-ERN PaedCan Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann. Oncol. 32, 1520–1536 (2021). source
• Not checked yetcites [141] NCCN. Treatment by cancer type. NCCN https://www.nccn.org/guidelines/category_1 (2022).

In the paper

“Among all paediatric patients with cancer, those with osteosarcoma carry one of the highest rates of genetic cancer predisposition (10-20%) 12 ; Li-Fraumeni syndrome is the most prominent but hereditary retinoblastoma, helicase-associated cancers and others also contribute 157 .”

What the sources say

• Not checked yetcites [157] Kratz, C. P. et al. Predisposition to cancer in children and adolescents. Lancet Child Adolesc. Health 5, 142–154 (2021). source

In the paper

“Anthracycline-induced, severe cardiomyopathy is another common, potentially fatal late effect of chemotherapy, with ~2% of non-relapse-related deaths among childhood cancer survivors attributed to cardiomyopathy or heart failure 160 .”

What the sources say

• Not checked yetcites [160] Armstrong, G. T. et al. Late mortality among 5-year survivors of childhood cancer: a summary from the childhood cancer survivor study. J. Clin. Oncol. 27, 2328–2338 (2009). source

In the paper

“Trials combining ICIs with other anticancer therapies, such as MTKIs, and trials of other immune activation approaches, such as antibody combinations and cellular therapy, in individuals with osteosarcoma are in early stages 9 .”

What the sources say

• Not checked yetcites [9] Gill, J. & Gorlick, R. Advancing therapy for osteosarcoma. Nat. Rev. Clin. Oncol. 18, 609–624 (2021). source