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Judson. J Cancer Metastasis Treat 2021;7:28 https://dx.doi.org/10.20517/2394-4722.2021.110 Page 3 of 5

tumour cell survival and increased expression of β-catenin, a potential tumour suppressor in this disease.
Inhibition of GSK3β can induce apoptosis in osteosarcoma cells.

Other sarcomas in which GSK3β has been shown to play a potential role include rhabdomyosarcoma, again
possibly via the β-catenin pathway, synovial sarcoma, fibrosarcoma and undifferentiated pleomorphic
sarcoma. GSK3β may also be involved in tumour-induced suppression of the immune response as well as
being involved in doxorubicin-mediated cardiotoxicity, chemotherapy-associated neuropathy and impaired
tissue repair. Inhibitors of GSK3β have been demonstrated to have antitumour effects in vivo in
[12]
[13]
osteosarcoma synovial sarcoma and fibrosarcoma xenografts . To date there have been no clinical trials
of GSK3β inhibitors in sarcoma but these data would appear to justify such a study.
Another potential molecular target for sarcomas that involves the WNT pathway, but in this case the non-
canonical β-catenin independent pathway, is ROR2 (receptor tyrosine kinase-like orphan receptor 2). In the
[14]
paper by Tran et al. in this issue, they describe the ability of ROR2 to inhibit anoikis, and hence increase
the rate of pulmonary metastases in a mouse model of metastatic osteosarcoma, a process that involves
activation of AKT. It is suggested that AKT inhibitors currently in clinical development might play a role in
combatting the development of lung metastases in this disease. It is not clear whether this strategy would
have any utility against established micrometastases. Clinical trials investigating treatment to prevent the
development of metastases are hard to design. However, this pathway is worthy of further study and may
shed further light on the metastatic process in osteosarcoma.

[15]
The next two papers concern different aspects of orthopaedic oncology. The first, by Pacheco and Righi
from the Rizzoli Institute in Bologna, reviews malignant tumours of the bone surface. All sarcoma clinicians
will be familiar with the distinction between parosteal osteosarcoma and conventional high grade
osteosarcoma in terms of prognosis and need for intensive chemotherapy, in that the rare parosteal variant
has a good prognosis and does not require treatment with chemotherapy unless it differentiates, in which
case the prognosis is much worse. It is interesting to note that parosteal osteosarcoma is associated with
chromosomal amplification involving both the MDM2 and CDK4 genes, something it shares with well-
differentiated or dedifferentiated liposarcoma. They may be less familiar with periosteal osteosarcoma and
bone surface tumours of cartilaginous origins, such as secondary peripheral chondrosarcoma, which
originates in osteochondromas, and periosteal chondrosarcoma. All of these rare entities are very well
described, in terms of differential diagnosis, along with appropriate radiological and histological
illustrations, prognosis and management. The need for specialised multidisciplinary care is emphasised, as is
appropriate.

The paper by Pinnameni and Damron concerns reconstructive procedures for the proximal humerus in
[16]
the cancer setting. Techniques for reconstruction in the pelvis, including hip replacement, a common
procedure outside orthopaedic oncology, are well established. The proximal humerus represents a much
more difficult technical challenge not least because of the proximity of major nerves and blood vessels but
also the fact that stability of the glenohumeral joint is dependent on the surrounding muscles, which may
need to be sacrificed in a cancer operation. This paper deals with the indications for surgery, both primary
and secondary, the various techniques available, together with their pros and cons, both short term and long
term and recent developments in technology, including prosthetics. The paper concludes with the fact that
comparative studies are lacking to define the most appropriate reconstructive procedures, something that
only prospective clinical trials could achieve.