Masitinib demonstrates anti-proliferative and pro-apoptotic activity in primary and metastatic feline injection-site sarcoma cells

Dysregulation of platelet-derived growth factor receptor (PDGFR) may play a role in feline injection-site sarcoma (ISS) cell growth and viability. Masitinib, a tyrosine kinase inhibitor approved for treatment of canine mast cell tumours, is highly selective for the PDGFR signalling pathway and may offer a new therapeutic approach for this disease. The in vitro effects of masitinib on growth, apoptosis and PDGFR signalling in two novel ISS cell lines were investigated. PDGFR expression was confirmed by Western blot in cell lines derived from a primary ISS tumour (JB) and a corresponding, histologically confirmed ISS lung metastasis (JBLM). Masitinib inhibited cell growth and PDGFR phosphorylation in both cell lines. Higher drug concentrations were required to inhibit growth than to modulate ligand-induced autophosphorylation of PDGFR. These in vitro data suggest that masitinib displays activity against both primary and metastatic ISS cell line and may aid in the clinical management of ISS.     

Masitinib mesylate does not enhance sensitivity to radiation in three feline injection-site sarcoma cell lines under normal growth conditions

Masitinib, a selective tyrosine kinase inhibitor, was investigated as a radiosensitizer in three primary feline injection-site sarcoma (ISS) cell lines. Sensitivity to masitinib was previously assessed via cell growth inhibition assays with mean IC₅₀ values of 5.5–8.6 μM. Clonogenic assays were performed to determine the effect of masitinib and radiation on cell survival. Single dose radiation (0–12 Gy) experiments were carried out under normal growth conditions in control ISS cells and in cells incubated with 1 or 6 μM masitinib for 72 h prior to irradiation. Radiation administered either alone or in combination with masitinib induced a dose-dependent reduction in clonogenic survival. Survival from the combined masitinib and radiation treatment was not significantly different from that of radiation alone. Results suggest that masitinib does not directly enhance ISS cell radiosensitivity under normal in vitro conditions, although this does not preclude the utility of further investigations to assess sensitization properties under altered conditions.     

DNA damage is a feature of feline injection‐site sarcoma

Feline injection‐site sarcoma (FISS) is commonly treated with surgery and radiation therapy. Despite aggressive therapy, FISS has a high recurrence rate. The true benefit of adjuvant chemotherapy is not known. DNA damage response mechanisms help protect against genomic instability but can also promote chemoresistance. In order to determine whether DNA damage is a feature of FISS, we evaluated tumour tissues with γH2AX immunohistochemistry. H2AX is phosphorylated to form γH2AX following DNA double strand breaks. Seventeen FISS specimens were evaluated prospectively. DNA damage ranged from 2.18 to33.7%, with a median of 16.2%. Significant differences were noted between cats (P < 0.0001). Mitotic index ranged from 0 to 57 with a median of 13 and did not correlate with γH2AX positivity (P = 0.2). Further studies are needed to determine if γH2AX expression may predict chemosensitivity and have independent value as a prognostic factor.     

Carcinosarcoma mimicking a feline injection‐site sarcoma in a cat

A 15‐year‐old spayed female domestic short‐haired cat with cutaneous/subcutaneous well‐circumscribed, alopecic mass approximately 25 × 30 mm in diameter, localized to the left shoulder region was brought to the veterinary surgery department. Despite the suggestive location and macroscopic appearance, feline injection‐site sarcoma was not suspected based on the cytologic examination of fine‐needle aspirates. The tumor was surgically resected, and tissue sections were evaluated microscopically. The tumor was found to be nonencapsulated with a distinct border between the neoplastic parenchyma and surrounding connective tissue. The neoplastic tissue consisted of 2 cell populations: elongated to spindle‐shaped cells arranged in bands and cords and malignant epithelial‐like cells. Both populations showed microscopic features of malignancy. Multinucleate giant cells with irregular cytoplasm were scattered among the neoplastic cells. The spindle‐shaped cells strongly expressed vimentin but did not express α‐smooth muscle actin (α‐SMA) or cytokeratin. Desmin was strongly expressed in about 0‐5% of cells. Epithelial‐like cells expressed cytokeratin, but not vimentin, desmin, or α‐SMA. Multinucleate giant cells expressed vimentin, but did not α‐SMA, desmin, or cytokeratin. Based on microscopic observations and IHC results, the final diagnosis was carcinosarcoma with histologic features compatible with feline injection‐site sarcoma, but without the clinical aggressiveness of this tumor.     

A case of feline pancreatitis

A 14-year-old, spayed female, domestic shorthair cat was referred to us with anorexia, pyrexia, and jaundice. Total bilirubin (TBIL) and feline trypsin-like immunoreactivity (fTLI) levels were remarkably high. Based on laparoscopic biopsy of the pancreas, the cat was diagnosed as having pancreatitis. As a result of treatment with a synthetic protease inhibitor and corticosteroid, the TBIL and fTLI values returned to normal and the clinical course was good.     

A case of feline sporotrichosis

We excised surgically a feline granulomatous lesion and performed histopathological, mycological and molecular examinations. As a result, it was diagnosed as sporotrichosis, which was the second recorded case of a cat so afflicted in Japan. After the operation, we recognized another nodule on the lymph node. Histopathological examination was therefore performed, but no fungi were detected. To prevent recurrence, the cat was administered a antimycotic drug, itraconazole. As a result, no recurrence was found. Excision of the lesion is the treatment of choice for feline sporotrichosis.     

The tyrosine kinase inhibitor toceranib in feline injection site sarcoma: efficacy and side effects

Because of their locally invasive growth and high recurrence rate despite of aggressive local therapy, treatment of feline sarcomas is challenging. The tyrosine kinase inhibitor (TKI) toceranib is currently licensed for the treatment of canine mast cell tumours. There are only few reports about TKI usage in cats. Previous studies indicated promising potential of TKI for the treatment of feline injection site sarcoma (FISS). In this prospective clinical trial, 18 cats with unresectable FISS were treated at a target dosage of 3.25 mg kg^?1 every other day to evaluate the clinical efficacy and toxicity of toceranib. There was no clinical response measurable. Adverse events were generally mild and temporary. Grade 3 or 4 adverse events developed infrequently and all resolved with drug holidays and dose reductions.     

A suspected case of feline dysautonomia

Abstract

Extract

Madam: — The purpose of this letter is to describe a case seen in our Levin Clinic which has many of the features characteristic of feline dysautonomia - the Key-Gaskell syndrome. Information on the history, clinical signs, pathology and treatment of the condition are given by Jones and Lee. ⁽⁴⁾ Jones, B.R. and Lee, E.A. 1985. Feline dysautonomia - the Key-Gaskell syndrome. N.Z. vet. J., 33: 58–58. [Taylor &; Francis Online], [Web of Science ®] , [Google Scholar](     

A case of feline primary hypoadrenocorticism

A 2-year-old entire female British Shorthair cat was referred to the University of Bristol for investigation of lethargy, weakness, constipation and hypothermia. Clinical examination revealed a profoundly weak, hypovolaemic and hypothermic cat. Serum biochemistry revealed hyponatraemia, hyperkalaemia and hyperphosphataemia and the urine was isosthenuric. Lack of response to exogenous adrenocorticotrophic hormone confirmed a diagnosis of hypoadrenocorticism. Treatment consisted initially of intravenous fluid therapy and subsequently a combination of fludrocortisone and prednisolone per os. At follow-up, 20 months after the initial diagnosis the cat remained stable and free of clinical signs.     

The use of immunohistochemistry and the polymerase chain reaction for detection of feline leukemia virus and feline sarcoma virus in six cases of feline ocular sarcoma

Ocular sarcoma was diagnosed by light microscopic examination in enucleated globes ( n  = 4), orbital tissue biopsy ( n  = 1) and ocular evisceration contents ( n  = 1) from six cats. To determine if feline leukemia virus (FeLV) or a replication-defective FeLV, feline sarcoma virus (FeSV), was present in these ocular sarcomas, immunohistochemistry (IHC) and polymerase chain reaction (PCR) for FeLV were utilized. Immunohistochemical staining for FeLV glycoprotein 70 (gp70) was performed on all six formalin-fixed, paraffin-embedded tumors using an avidin–biotin complex technique. DNA was extracted from each specimen and a 166 bp region of the FeLV long-terminal repeat (LTR) was amplified by PCR. All tumors were composed primarily of spindle cells; two neoplasms had PAS-positive basement membrane enveloping areas of spindle cells. All tumors involved the uvea and five of six tumors showed transcleral extension, one of which invaded the optic nerve. Immunohistochemical staining for FeLV gp 70 was negative. PCR to amplify a portion of the FeLV LTR was negative. Based on these findings of these limited number of cases, FeLV/FeSV may not play a role in the tumorigenesis of feline ocular sarcomas. However, additional tumors representing all morphological subtypes should be investigated for the presence of viral antigen and DNA. It is important to determine the etiology and pathogenesis of these malignant ocular sarcomas. If the cell of origin and pathogenesis involve ocular and lenticular injury, and FeLV/FeSV is not present, then the clinical management of cases of feline ocular trauma, uveitis and glaucoma may prevent the development of this tumor.     

In vitro efficacy of doxorubicin and etoposide against a feline injection site sarcoma cell line

Feline injection site sarcoma (ISS) is a locally invasive tumor, in which surgical treatment is frequently combined with radiation or chemotherapy to improve tumor control. The focus of this study was to evaluate the cytotoxic effects of doxorubicin or etoposide on a feline injection site sarcoma cell line (JB) and to assess the impact of combining these drugs on cell death and cell cycle. Both single agent and combination drug administration increased cell death and significantly reduced the number of viable cells. Cells in G0/G1 were significantly reduced while the G2/M fraction was significantly increased following treatment. Collectively, combining doxorubicin and etoposide at the lower EC yielded comparable results to the EC50 of either drug alone in degree of cytotoxicity, level of apoptosis, and % of cells in G2/M. The results of this study indicate that doxorubicin and etoposide alone and in combination differentially alter ISS cell viability and cycle.     

CT angiography and MRI imaging features do not predict the tumor type and grade of feline injection site sarcoma

Computed tomographic angiography (CTA) and magnetic resonance imaging (MRI) have been described as methods for preoperative surgical planning in cats with feline injection site sarcomas (FISS), however, few published studies have compared these modalities. The objective of this retrospective, secondary analysis study was to determine if imaging features of FISS on CTA and MRI are predictive of neoplastic peritumoral projections. Archived data from a previous prospective study were retrieved for 10 cats with FISS. All cats had been evaluated in a single anesthetic episode with MRI and dual phase CT (CTA) imaging followed by surgical removal. Histopathological grading and targeted histopathology of imaging‐identified peritumoral projections were performed. Two observers evaluated the CTA and MRI studies for FISS shape, margination, size, enhancement pattern, postcontrast uniformity, pre‐ and postcontrast margination, the number of muscles involved, mass mineralization, and bone lysis. Metal was present in the imaging field of three of 10 cats, resulting in one nondiagnostic MRI. Peritumoral projections were detected in all cats with both imaging modalities, and most were benign. At least one neoplastic peritumoral projection was detected in six cats using MRI, five cats using CTA, and three cats with both modalities. Higher grade FISS were larger than low grade using MRI, and FISS were larger using MRI. Other FISS imaging features using MRI and CTA were similar. Findings supported use of either MRI or CTA for detecting neoplastic peritumoral projections in cats with FISS. Authors recommend CTA for cats with known metallic objects in the scan field.     

Surgery alone versus surgery and doxorubicin for the treatment of feline injection-site sarcomas: a report on 69 cases

Sixty-nine cats were treated for injection-site sarcomas at the Veterinary Teaching Hospital of Grugliasco, Turin (Italy). The animals were divided into two subgroups: those subjected to four doxorubicin cycles combined with radical surgical excision 10 days after the second chemotherapy cycle (group A, 49 cats) or those treated with surgery alone (group B, 20 cats). Each cat was monitored for lung metastasis and local recurrence. In group A, 28 cats were alive at the end of the follow-up period. In this group, the recurrence rate was 40.8% while lung metastasis occurred in 12% of cats. In group B, eight animals were alive at the end of the follow-up period, while the rates of recurrence and metastasis were 35% and 10%. Neither the median disease-free interval nor the median overall survival was reached in either group. Moreover, there were no statistically significant differences between the two groups.