Page 556 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

534 PART IV Specific Malignancies in the Small Animal Patient

between good and poor responders involved oxidative phos- Recently, the putative role of monocyte and macrophage regu-
phorylation, bone development, PKA signaling, cell adhesion, latory roles in dogs with OSA were evaluated in an attempt to
understand how monocyte phenotype and chemotactic func-
106
cytoskeletal remodeling, and immune response.
VetBooks.ir files were derived from 32 primary OSA tumors derived from two tion might be perturbed in dogs with OSA. 197 In 18 dogs with
In a similar expression profiling study, prognostic gene pro-
OSA, the cell surface expression of multiple chemokine recep-
groups of dogs based upon ST. 191 Dogs surviving for less than 6 tors, in particular CCR2 and CXCR2, were downregulated in
months or more than 6 months were categorized as either poor peripheral blood monocytes, potentially leading to reduced direc-
or good responders respectively. Gene profiling identified 51 tional migration and extravasation. Additionally, the monocytes
gene transcripts to be differentially expressed. Within the poor from dogs with OSA were functionally impaired as exhibited by
responder group, genes uniformly overexpressed were associated decreased chemotaxis ex vivo. These findings could explain why
with biologic pathways involved in proliferation, drug resistance, dogs with OSA may have elevations in circulating monocytes as
and metastases. In addition to identifying differentially expressed well as provide potential mechanisms by which OSA cells might
genes and associated pathways between dogs categorized as good evade the innate immune system through the induction of mono-
and poor responders, the findings from the study further substan- cyte chemotactic dysfunction.
tiated the molecular pathway similarities shared between humans
and dogs, including Wnt, integrin, and chemokine/cytokine Another study characterized the immune microenvironment
signaling. of canine primary OSA through the association of macrophage
+
+
Lastly, a highly influential study was conducted that leveraged (CD204 ) and lymphocyte infiltrates (both effector CD3 and
the more homogeneous genetic background of dogs diagnosed regulatory Foxp3 T-cells) within the primary tumor with DFI
with OSA to detect underlying and conserved gene expression and ST in 30 dogs treated with amputation and carboplatin
patterns previously undetectable in historic canine and human therapy. 198 Although the extent and phenotype of primary
gene microarray analysis. 192 By differential gene expression pro- tumoral lymphocyte infiltrates did not influence outcomes, the
filing of early passage immortalized OSA cell lines derived from surface area of macrophage infiltration did have an effect on
primary tumors, the investigators were able to identify gene signa- outcomes. Dogs with more than 4.7% surface area infiltrate with
+
tures associated with G2/M transition and DNA damage check- CD204 macrophages experienced a significantly longer DFI.
point, as well as microenvironment interactions, which permitted These findings suggest that tumor-infiltrating macrophages may
the unbiased segregation of OSA samples into distinct molecular contribute to inhibiting localized OSA metastatic progression.
subclassifications and predicted outcome. Most significantly, the
same genetic signatures identified in dogs also allowed for prog- Therapy Directed at the Primary Tumor
nostic molecular classification of human OSA, powerfully under-
scoring the scientific merit derived from comparative oncologic Surgery
studies. Table 25.1 provides an overview of surgical options for primary
Perturbations of the immune system are common among can- bone tumors based on anatomic site.
cer patients, and regulatory T cells (Tregs) and myeloid-derived
suppressor cells have the capacity to attenuate effective antitumor Amputation
immune responses with the potential to negatively affect progno- Amputation of the affected limb is the standard local treatment
sis. Tregs have been characterized in healthy and cancer-bearing for canine appendicular OSA. Even large and giant breed dogs will
dogs, 193–195 with some studies demonstrating that dogs with OSA usually function well after limb amputation, and most owners are
have increases in the percentage and absolute counts of circulat- pleased with mobility and quality of life of their pets after surgery;
ing Tregs. 196 The clinical significance of Tregs on OSA progno- 88% of dogs have the same or near same quality of life after amputa-
sis has recently been characterized in a study of 12 dogs treated tion, and 73% of dogs return to their preamputation activity levels
with amputation and systemic chemotherapy. 196 Dogs with high after surgery. 199,200 Most dogs will readily compensate and, although
(higher than the mean) versus low (lower than the mean) per- the osteoarthritis may progress more rapidly in the three-legged dog,
centages of Tregs identified in blood or tumor tissue did not have this rarely results in a clinical problem. Physical therapy and reha-
differences in DFI or ST; however, high or low CD8/Treg ratio in bilitation is an important adjunct to postamputation recovery and
the blood was associated with clinical outcomes as dogs with low should be considered as part of the routine postoperative care for
CD8/Treg ratios had a significantly shorter ST than dogs with amputation patients. Severe preexisting orthopedic or neurologic
high CD8/Treg ratios. conditions may cause poor results in some cases and careful pre-
In addition to Tregs and their potential prognostic value in OSA, operative examination is important. Complete forequarter ampu-
one study has demonstrated that routine hemogram parameters— tation is recommended for thoracic limb tumors and coxofemoral
specifically lymphocyte and monocyte counts—can also predict disarticulation (amputation) for pelvic limb lesions. This level of
clinical outcomes in dogs with OSA. 163 In 69 dogs treated with amputation assures complete removal of the local tumor and also
amputation and systemic chemotherapy, baseline lymphocyte and results in a more cosmetic and functional outcome. For proximal
monocyte counts were associated with DFI. Shorter DFIs were femoral tumors, complete amputation and en bloc acetabulectomy
observed in dogs initially presenting with relative lymphocytosis is recommended to obtain proximal soft tissue margins (Fig. 25.5).
(≥1000 cell/uL) and relative monocytosis (≥400 cell/uL), and
these original conclusions were further substantiated by a second Limb Salvage
population of OSA dogs treated in an identical manner. Mechanis- Although most dogs function well with amputation, there are
tically, it was hypothesized that the association of relative monocy- some dogs for which LSS would be preferred over amputation,
tosis and reduced DFI could be the presence of myeloid-derived such as dogs with severe preexisting orthopedic or neurologic dis-
suppressor cells, a population of cells characterized by their ability ease or dogs whose owners absolutely will not permit amputation.
to suppress antitumor immune responses. Until relatively recently, only a few reports of LSS in dogs, with