•An evidence based approach to prognostication for canine cutaneous mast cell tumors can improve clinical decision making.•Prognostic features including staging, grading, margin evaluation, and ...evaluation of molecular markers are reviewed.•Algorithms for choosing local and systemic therapy are provided based on current understanding of prognostic features.
In view of the varied biologic behavior and the costs of treatment for canine cutaneous mast cell tumors, development of appropriate treatment plans for individual affected dogs can be difficult, but decisions regarding treatment should be made using a systematic, evidence-based approach. This manuscript reviews the current state of diagnostics and prognostication of canine cutaneous mast cell tumors, and suggests a combined approach based on clinical and pathologic assessment for decision making regarding treatment choices. The current state of histologic grading, evaluation of proliferation indices, evaluation of mutations in the c-kit gene and KIT expression, evaluation of excision and clinical staging are examined. On the basis of the current understanding of prognostication and treatment response, algorithms for selection of local and systemic therapy are presented.
A red ruffed lemur (Varecia rubra) from a zoo in Louisiana, USA, was euthanized for worsening paresis. Brain and spinal cord histology identified eosinophilic meningoencephalomyelitis with ...intralesional adult Angiostrongylus sp. nematodes. PCR and sequencing confirmed A. cantonensis infection, indicating this parasite constitutes an emerging zoonosis in the southeastern United States.
Feline oral squamous cell carcinoma (FOSCC) is an aggressive malignancy with invasive and metastatic behavior. It is poorly responsive to chemotherapy and radiation. Neoplastic epithelial-mesenchymal ...transition (EMT) portends highly malignant behavior and enhances resistance to therapy. In transitioning to a more malignant phenotype, carcinoma stem cells undergo transformation mediated by expression of proteins, endowing them with mesenchymal properties advantageous to cell survival. The goal of the current study was to identify proteins associated with EMT in FOSCC. This study documents protein expression patterns in 10 FOSCC biopsies and 3 FOSCC cell lines (SCCF1, SCCF2, SCCF3), compatible with an EMT phenotype. As markers of EMT, P-cadherin, N-cadherin, vimentin, nuclear transcription factors Twist and Snail, hypoxia inducible factor 1α (HIF-1α), programmed death ligand 1, and vascular endothelial growth factor D, as well as E-cadherin, were examined using immunohistochemistry, Western blot, and enzyme-linked immunosorbent assay. P-cadherin, Twist, HIF-1α, and programmed death ligand 1 were commonly expressed in biopsies and cell lines. N-cadherin, classically associated with EMT, was not highly expressed, and E-cadherin was coexpressed along with proteins characteristic of EMT in all specimens. Production of vascular endothelial growth factor A by cell lines, a process regulated by HIF-1α expression, was suppressed by the small-molecule inhibitor dasatinib. These data are consistent with EMT in FOSCC and shed light on cellular changes that could contribute to the aggressive behavior of FOSCC.
The prognostic significance of internal tandem duplication (ITD) mutations in exons 8 and 11 of c-kit has been well-described for canine cutaneous mast cell tumors (MCTs), but c-kit mutations have ...rarely been reported in subcutaneous MCTs. The objective of this study was to identify the prevalence of ITD mutations in exons 8 and 11 of c-kit in canine subcutaneous MCTs and to investigate its association with histologic grade, KIT pattern, and proliferation markers. ITD mutations in exons 8 and 11 of c-kit, mitotic count, Ki67 index, AgNOR number, Ki67xAgNOR score, KIT pattern, and histologic grade (two-tier system) were retrospectively recorded for 216 dogs with subcutaneous MCTs. ITD mutations in exons 8 and 11 of c-kit were detected in 23 (10.6%) and 12 (5.56%) subcutaneous MCTs, respectively. Exon 11 mutations were significantly associated with Kiupel high grade (p < 0.001) and increased mitotic count (p < 0.001) compared to subcutaneous MCTs with no mutations in exons 8 or 11 (p = 0.002) or subcutaneous MCTs with a mutation in exon 8 (p = 0.001). There was no significant association of either c-kit mutation with KIT patterns or proliferation activity. This study identified a higher prevalence of ITD mutations in exons 8 and 11 of c-kit in subcutaneous MCTs than previously reported. Like their cutaneous counterpart, subcutaneous MCTs with exon 11 mutations were more likely to be histologically high grade and have a higher mitotic count, whereas such associations were not observed in subcutaneous MCTs with exon 8 mutations.
Here, we describe the synthesis, characterization and in vitro and in vivo performance of a series of tantalum oxide (TaO
) based nanoparticles (NPs) for computed tomography (CT). Five distinct ...versions of 9-12 nm diameter silane coated TaO
nanocrystals (NCs) were fabricated by a sol-gel method with varying degrees of hydrophilicity and with or without fluorescence, with the highest reported Ta content to date (78%). Highly hydrophilic NCs were left bare and were evaluated in vivo in mice for micro-CT of full body vasculature, where following intravenous injection, TaO
NCs demonstrate high vascular CT contrast, circulation in blood for ∼3 h, and eventual accumulation in RES organs; and following injection locally in the mammary gland, where the full ductal tree structure can be clearly delineated. Partially hydrophilic NCs were encapsulated within mesoporous silica nanoparticles (MSNPs; TaO
@MSNPs) and hydrophobic NCs were encapsulated within poly(lactic-co-glycolic acid) (PLGA; TaO
@PLGA) NPs, serving as potential CT-imagable drug delivery vehicles. Bolus intramuscular injections of TaO
@PLGA NPs and TaO
@MSNPs to mimic the accumulation of NPs at a tumor site produce high signal enhancement in mice. In vitro studies on bare NCs and formulated NPs demonstrate high cytocompatibility and low dissolution of TaO
. This work solidifies that TaO
-based NPs are versatile contrast agents for CT.
During the 2019 Eastern equine encephalitis virus (EEEV) outbreak in Michigan, two 2-month old Mexican wolf pups experienced neurologic signs, lymphohistiocytic neutrophilic meningoencephalitis with ...neuronal necrosis and neuronophagia, and acute death. We identified EEEV by reverse transcription real-time PCR and in situ hybridization. Vector mosquitoes were trapped at the zoo.
Primary colorectal follicular lymphomas are rare indolent lymphoid neoplasms in humans that have not been reported in dogs. We describe 3 cases of primary colorectal follicular lymphoma in dogs with ...histologic and immunohistochemical features similar to their human counterpart. Initial clinical signs in all dogs included tenesmus, hematochezia, and a palpable rectal mass. Two dogs were castrated males and 1 an intact female, between 9 months and 2 years of age, and of varied breeds. All 3 cases of colorectal follicular lymphoma were characterized by proliferation of follicular germinal centers with no polarity or mantle zone and were composed of centrocytes admixed with fewer centroblasts. By immunohistochemistry, lymphoid cells expressed CD20, BCL2, and BCL6 and lacked expression of CD3, CD5, and cyclin D1. Polymerase chain reaction for rearrangements of the immunoglobulin heavy chain confirmed a monoclonal population in all cases. In 2 of the 3 cases, a solitary nodular colorectal mass was excised and appeared curative; however, the third case had multiple colorectal masses and the animal developed multicentric lymphoma. This case series immunohistochemically characterizes and distinguishes colorectal follicular lymphoma from atypical lymphoid hyperplasia.
Excessive rates of demand lipolysis in the adipose tissue (AT) during periods of negative energy balance (NEB) are associated with increased susceptibility to disease and limited lactation ...performance. Lipolysis induces a remodeling process within AT that is characterized by an inflammatory response, cellular proliferation, and changes in the extracellular matrix (ECMT). The adipose tissue macrophage (ATM) is a key component of the inflammatory response. Infiltration of ATM-forming cellular aggregates was demonstrated in transition cows, suggesting that ATM trafficking and phenotype changes may be associated with disease. However, it is currently unknown if ATM infiltration occurs in dairy cows only during NEB states related to the transition period or also during NEB-induced lipolysis at other stages of lactation. The objective of this study was to evaluate changes in ATM trafficking and inflammatory phenotypes, and the expression of genetic markers of AT remodeling in healthy late-lactation cows during feed restriction-induced NEB. After a 14-d (d −14 to d −1) preliminary period, Holstein cows were randomly assigned to 1 of 2 feeding protocols, ad libitum (AL) or feed restriction (FR), for 4 d (d 1–4). Caloric intake was reduced in FR to achieve a targeted energy balance of −15 Mcal/d of net energy for lactation. Omental and subcutaneous AT samples were collected laparoscopically to harvest stromal vascular fraction (SVF) cells on d −3 and 4. The FR induced a NEB of −14.1±0.62 Mcal/d of net energy for lactation, whereas AL cows remained in positive energy balance (3.2±0.66 Mcal/d of NEL). The FR triggered a lipolytic response reflected in increased plasma nonesterified fatty acids (0.65±0.05 mEq/L on d 4), enhanced phosphorylation of hormone sensitive lipase, and reduced adipocyte diameter. Flow cytometry and immunohistochemistry analysis revealed that on d 4, FR cows had increased numbers of CD172a+, an ATM (M1 and M2) surface marker, cells in SVF that were localized in aggregates. However, FR did not alter the number of SVF cells expressing M1 markers (CD14 and CD11c) or M2 markers (CD11b and CD163). This finding contrasts with the predominately M1 phenotype observed previously in ATM from clinically diseased cows. No changes were observed in the expression of ECMT-related or cell proliferation markers. In summary, an acute 4-d lipolytic stimulus in late-lactation dairy cows led to ATM infiltration with minimal changes in inflammatory phenotype and no changes in ECMT. These results underscore that physiological changes related to parturition, the onset of lactation, extended periods of lipolysis, or a combination of these can induce intense AT remodeling with enhanced ATM inflammatory phenotype expression that may impair the metabolic function of AT in transition dairy cattle.
Sex differences in hepatocellular carcinoma (HCC) development are regulated by sex and non-sex chromosomes, sex hormones, and environmental factors. We previously reported that Ncoa5+/− mice develop ...HCC in a male-biased manner. Here we show that NCOA5 expression is reduced in male patient HCCs while the expression of an NCOA5-interacting tumor suppressor, TIP30, is lower in female HCCs. Tip30 heterozygous deletion does not change HCC incidence in Ncoa5+/− male mice but dramatically increases HCC incidence in Ncoa5+/− female mice, accompanied by hepatic hyperpolarization-activated cyclic nucleotide-gated cation channel 3 (HCN3) overexpression. HCN3 overexpression cooperates with MYC to promote mouse HCC development, whereas Hcn3 knockout preferentially hinders HCC development in female mice. Furthermore, HCN3 amplification and overexpression occur in human HCCs and correlate with a poorer prognosis of patients in a female-biased manner. Our results suggest that TIP30 and NCOA5 protect against female liver oncogenesis and that HCN3 is a female-biased HCC driver.
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•Tip30 heterozygous deletion increases HCC rate in Ncoa5+/− mice in a female-biased manner•HCN3 is preferentially upregulated in the liver of dual Tip30 and Ncoa5 mutant female mice•HCN3 has female-biased oncogenic activities to promote HCC development•HCN3 overexpression correlates with poor prognosis of HCC patients with a female bias
Zhang et al. report a female-biased mechanism underlying hepatocellular carcinoma (HCC) development that is regulated by transcription coregulators NCOA5 and TIP30. The ion channel HCN3 is identified as a female-biased HCC driver.
Gastrointestinal stromal tumors (GISTs) are common mesenchymal neoplasms in the gastrointestinal tract of humans and dogs. Little is known about the pathogenesis of these tumors. This study evaluated ...the role of c-KIT in canine GISTs; specifically, we investigated activating mutations in exons 8, 9, 11, 13, and 17 of c-KIT and exons 12, 14, and 18 of platelet-derived growth factor receptor, alpha polypeptide (PDGFRA), all of which have been implicated in human GISTs.
Seventeen canine GISTs all confirmed to be positive for KIT immunostaining were studied. Exons 8, 9, 11, 13 and 17 of c-KIT and exons 12, 14, and 18 of PDGFRA, were amplified from DNA isolated from formalin-fixed paraffin-embedded samples.
Of these seventeen cases, six amplicons of exon 11 of c-KIT showed aberrant bands on gel electrophoresis. Sequencing of these amplicons revealed heterozygous in-frame deletions in six cases. The mutations include two different but overlapping six base pair deletions. Exons 8, 9, 13, and 17 of c-KIT and exons 12, 14, and 18 of PDGFRA had no abnormalities detected by electrophoresis and sequencing did not reveal any mutations, other than synonymous single nucleotide polymorphisms (SNPs) found in exon 11 of c-KIT and exons 12 and 14 of PDGFRA.
The deletion mutations detected in canine GISTs are similar to those previously found in the juxtamembrane domain of c-KIT in canine cutaneous mast cell tumors in our laboratory as well as to those reported in human GISTs. Interestingly, none of the other c-KIT or PDGFRA exons showed any abnormalities in our cases. This finding underlines the critical importance of c-KIT in the pathophysiology of canine GISTs. The expression of KIT and the identification of these activating mutations in c-KIT implicate KIT in the pathogenesis of these tumors. Our results indicate that mutations in c-KIT may be of prognostic significance and that targeting KIT may be a rational approach to treatment of these malignant tumors. This study further demonstrates that spontaneously occurring canine GISTs share molecular features with human GISTs and are an appropriate model for human GISTs.
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