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Background: Feline injection site fibrosarcoma is an aggressive and infiltrative tumour arising in the background of chronic inflammation. The aim of this study was to evaluate the expression of metallothionein (I-II) in feline injection site fibrosarcomas and to assess its possible relationships with Ki67 index, inflammation score and tumour grade. The study included 40 feline fibrosarcomas, located in the common injection sites (i.e., interscapular area, thigh, flank), constituting archival diagnostic specimens collected between 2019-2020. Tumours were graded histologically according to the newly proposed soft-tissue sarcoma grading system in cats. Immunohistochemistry was performed to evaluate the expression of Ki67 and metallothionein in tumour cells., Results: The cytoplasmic and sometimes nuclear expression of metallothionein was observed in all tumours grade I, 66.67% of tumours grade II and 55% of tumours grade III. The expression of metallothionein was negatively correlated with tumour grade and inflammation score, while the Ki67 index was positively correlated with tumour grade, inflammation score and necrosis score., Conclusion: The downregulation of MT expression in feline injection site fibrosarcomas seems to be connected with an increase in the inflammatory infiltration, hence tumour progression. This is the first study describing metallothionein expression in feline injection site fibrosarcomas., (© 2023. The Author(s).)

Background: fFeline injection-site sarcomas (FISSs) are mesenchymal tumors that can occur in cats after injections of different medical agents and are easily prone to recurrence., Aim: The aims of this study were to report treatment outcomes for cats with feline injection-site sarcomas (FISSs) treated with both bleomycin and cisplatin, per adjuvant electrochemotherapy (ECT) protocol., Methods: The medical records of cats with a diagnosis of FISS that were treated with ECT using both bleomycin and cisplatin were retrospectively evaluated. A total of 27 cats were available for statistical evaluation of their response. The cats received intravenous 20 mg/m2 bleomycin, and the tumor bed and margins were infiltrated with cisplatin at the dose of 0.5 mg/cm2. Then, the trains of permeabilizing biphasic electric pulses lasting 50 + 50 µseconds each were delivered in bursts of 1,300 V/cm using caliper electrodes under sedation. A second session was performed 2 weeks later., Results: Side effects were limited to local inflammation in three cats. Three cats developed local tumor recurrence at days 180, 180, and 545 after surgery, two cats developed recurrence and metastases at 100 and 505 days after surgery, and two cats experienced distant metastases. A median time to recurrence could not be calculated as over 80% of the study population remained disease free or were censored due to death from other causes. Mean survival time was 985 days, and median cumulative survival for all cases was 1,000 days., Conclusion: When compared to historical controls, the results of this study demonstrate the superior rates of tumor-free survival and disease-free interval. This adjuvant therapy could be a useful addition to the current options for FISS in consideration of its efficacy, limited toxicity, and ease of administration.

Local recurrence (LR) is the major concern in the treatment of feline injection-site sarcoma (FISS). Pretreatment leukocyte counts and ratios have been reported as diagnostic and/or prognostic markers in human and canine oncology. The aim of this retrospective study was to explore the prognostic impact on LR and overall survival time (OST) of pretreatment neutrophil-to-lymphocyte ratio (NLR), white blood cell count (WBCC), neutrophil count (NC) and lymphocyte count (LC) in cats with surgically excised FISS. Eighty-two cats with histologically confirmed FISS at first presentation, without distant metastases, and with available pretreatment haematological analyses were retrospectively enrolled. The correlation of NLR, WBCC, NC, LC with tumour variables and patient variables was explored. NLR was correlated with tumour size (P = .004), histological pattern of tumour growth (P = .024) and histotype (P = .029), while WBCC and NC were associated with ulceration (P = .007, P = .011) and pattern of growth (P = .028, P = .004). No significant relationships emerged between LC and any of the considered variables. The impact of NLR, WBCC, NC, LC on LR and OST was then estimated in univariate and multivariate analysis. In univariate analysis, NLR, WBCC and NC were significant prognostic factors for both LR and OST. NLR, WBCC and NC remained prognostic in multivariate analysis for LR but not for OST. When NLR, WBCC and NC were jointly analysed, WBCC was the marker with the greater impact on LR. Preoperative NLR, WBCC and NC may aid in identifying cats at higher risk of LR., (© 2019 John Wiley & Sons Ltd.)

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., (© 2019 American College of Veterinary Radiology.)

Background: Chronic inflammation has been implicated in sarcomagenesis. Among various factors, activation of nuclear factor-kappa B (NF-κB) signaling pathway has been documented being able to target genes associated with tumor progression and up-regulate the expression of tumor-promoting cytokines and survival genes in several human solid tumors. Feline injection sites sarcomas (FISS) are malignant entities derived from the mesenchymal origin. The disease has been considered to be associated with vaccine adjuvant, aluminum, which serves as a stimulus continuously inducing overzealous inflammatory and immunologic reactions. To understand the contribution of NF-κB in FISS, detection of activated NF-κB in paraffin-embedded specimens, in vitro establishment of primary cells derived from FISS, and evaluation of the effects of the NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), on primary tumor cells were conducted., Results: In this study, nuclear expression of NF-κB p65 was detected in 83.3% of FISS cases and not correlated with tumor grading, sex, and age. Primary cells derived from FISS in three cats exhibiting same immunohistochemical characteristics as their original tumor were successfully established. The NF-κB inhibitor, DHMEQ, was able to prevent nuclear translocation of NF-κB p65, inhibit cell proliferation, migration, and colonization in dosage-dependent manners, and induce cell apoptosis in these primary FISS cells., Conclusions: High expression rate of nuclear NF-κB p65 in FISS cases and dose-dependent inhibitory effects on the growth of FISS primary cells treated with NF-κB inhibitor suggested that NF-κB might be a potential molecular therapeutic target for FISS.

Feline injection site sarcoma (FISS) is a mesenchymal neoplasm with highly malignant characteristics. These tumours originate in anatomical sites where there has been previous parenteral administration of medicinal substances or implantation of medical devices. The aim of this study was to investigate the epidemiological and pathological features associated with FISS in the southern region of Brazil. The database of the Department of Veterinary Pathology of the Federal University of Rio Grande do Sul was searched for excisional and incisional biopsy samples compatible with FISS submitted between 2007 and 2017. Biopsy reports were reviewed and epidemiological information, including breed, age and sex of affected cats, as well as gross findings including anatomical location and size of the tumour and the presence of tissue invasion, were extracted. Eighty-nine samples were selected based on the established criteria. Most animals were of undefined breed and were female cats with a median age of 10 years. Grossly, 84.8% of the tumours were >2 cm in diameter. Regarding anatomical location, 34.9% of the tumours were located in the subcutaneous tissue of the thoracic wall, 29.2% in the flank, 21.3% in the interscapular region and 14.6% in the limbs. Histologically, the tumours originated in the subcutaneous tissue and were diagnosed as malignant mesenchymal neoplasms. Most were compatible with fibrosarcomas, but variants with features of pleomorphic sarcoma or chondrosarcoma were recognized. All tumours exhibited areas of necrosis and peripheral inflammatory infiltrate, composed predominantly of lymphocytes, plasma cells and macrophages. The results of this study suggest the need for dissemination of information on FISS epidemiology and guidelines for management of this tumour to veterinarians in the region., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The use of vaccines including aluminum (Al)-based adjuvants is widespread among small ruminants and other animals. They are associated with the appearance of transient injection site nodules corresponding to granulomas. This study aims to characterize the morphology of these granulomas, to understand the role of the Al adjuvant in their genesis, and to establish the presence of the metal in regional lymph nodes. A total of 84 male neutered lambs were selected and divided into 3 treatment groups of 28 animals each: (1) vaccine (containing Al-based adjuvant), (2) adjuvant-only, and (3) control. A total of 19 subcutaneous injections were performed in a time frame of 15 months. Granulomas and regional lymph nodes were evaluated by clinicopathological means. All of the vaccine and 92.3% of the adjuvant-only lambs presented injection-site granulomas; the granulomas were more numerous in the group administered the vaccine. Bacterial culture in granulomas was always negative. Histologically, granulomas in the vaccine group presented a higher degree of severity. Al was specifically identified by lumogallion staining in granulomas and lymph nodes. Al median content was significantly higher ( P < .001) in the lymph nodes of the vaccine group (82.65 μg/g) compared with both adjuvant-only (2.53 μg/g) and control groups (0.96 μg/g). Scanning transmission electron microscopy demonstrated aggregates of Al within macrophages in vaccine and adjuvant-only groups. In these two groups, Al-based adjuvants induce persistent, sterile, subcutaneous granulomas with macrophage-driven translocation of Al to regional lymph nodes. Local translocation of Al may induce further accumulation in distant tissues and be related to the appearance of systemic signs.

Background: Feline injection-site sarcoma (FISS), an aggressive iatrogenic subcutaneous malignancy, is challenging to manage clinically and little is known about the molecular basis of its pathogenesis. Tumor transcriptome profiling has proved valuable for gaining insights into the molecular basis of cancers and for identifying new therapeutic targets. Here, we report the first study of the FISS transcriptome and the first cross-species comparison of the FISS transcriptome with those of anatomically similar soft-tissue sarcomas in dogs and humans., Methods: Using high-throughput short-read paired-end sequencing, we comparatively profiled FISS tumors vs. normal tissue samples as well as cultured FISS-derived cell lines vs. skin-derived fibroblasts. We analyzed the mRNA-seq data to compare cancer/normal gene expression level, identify biological processes and molecular pathways that are associated with the pathogenesis of FISS, and identify multimegabase genomic regions of potential somatic copy number alteration (SCNA) in FISS. We additionally conducted cross-species analyses to compare the transcriptome of FISS to those of soft-tissue sarcomas in dogs and humans, at the level of cancer/normal gene expression ratios., Results: We found: (1) substantial differential expression biases in feline orthologs of human oncogenes and tumor suppressor genes suggesting conserved functions in FISS; (2) a genomic region with recurrent SCNA in human sarcomas that is syntenic to a feline genomic region of probable SCNA in FISS; and (3) significant overlap of the pattern of transcriptional alterations in FISS with the patterns of transcriptional alterations in soft-tissue sarcomas in humans and in dogs. We demonstrated that a protein, BarH-like homeobox 1 (BARX1), has increased expression in FISS cells at the protein level. We identified 11 drugs and four target proteins as potential new therapies for FISS, and validated that one of them (GSK-1059615) inhibits growth of FISS-derived cells in vitro., Conclusions: (1) Window-based analysis of mRNA-seq data can uncover SCNAs. (2) The transcriptome of FISS-derived cells is highly consistent with that of FISS tumors. (3) FISS is highly similar to soft-tissue sarcomas in dogs and humans, at the level of gene expression. This work underscores the potential utility of comparative oncology in improving understanding and treatment of FISS.

Objectives: Feline injection site sarcoma (FISS) is a rapid growing locally aggressive tumor with a low metastatic rate. Its histologic features are clearly defined, but there are few studies regarding its immunohistochemical characteristics. The present study investigated the immunohistochemical characteristics of 21 cases of FISS., Methods: FISSs from 12 male and nine female cats, 20 mixed-breed and one Siamese, were included in the study. After histopathological diagnosis, additional histologic sections were immunostained for vimentin, cytokeratin, desmin, S100 protein, viral feline leukemia virus (FeLV) particles, cyclooxygenase 2 (COX-2) and c-KIT. Positive and negative controls were adopted accordingly. Immunostainings were classified as positive or negative according to the number of positive cells from a total of 1000 cells per tumor section., Results: Histopathologic diagnosis of the tumors revealed 18 (85.7%) fibrosarcomas and three (14.3%) other sarcomas; four fibrosarcomas (22.2%) were grade III, five (27.8%) were grade II and nine (50.0%) were grade I. Two sarcomas were grade III and one was grade II. Seventeen (81%) tumors were negative for desmin. All samples were positive for vimentin. Twenty tumors (95.2%) were positive for S-100 protein. Positivity for c-KIT was observed in four (19%) samples; COX-2 was positive in 13 (61.9%) and FeLV viral particles were positive in nine (42.9%) FISSs., Conclusions and Relevance: Immunohistochemical findings of FISSs revealed positive immunostainings for desmin, vimentin, S-100 protein, c-KIT, COX-2 and FeLV viral particles.

Background: Bone marrow-derived mesenchymal stem cells (BM-MSCs) are frequently used in the treatment of musculoskeletal injuries. Fully characterised cells that are readily available for use is optimum. Allogenic BM-MSCs can satisfy the need for rapid treatment, however, their safety has been questioned., Objectives: Objectives were to characterise BM-MSCs from an adult donor horse, in vitro, and to identify and describe adverse reactions that occurred following their injection into other horses. We hypothesised that BM-MSCs capable of proliferation, differentiation and lacking MHC II from one donor could be implanted into another individual without significant adverse reactions and the frequency of adverse reactions in clinical cases would be similar to that previously reported for autologous BM-MSCs., Study Design: Retrospective clinical study., Methods: BM-MSCs were proliferated and characterised from one donor and cryopreserved for clinical use. Medical records for horses injected with allogenic BM-MSCs from this donor at a single hospital were used. After routine lameness exam, lesions were identified using diagnostic ultrasound or MRI. Post injection reaction was defined as increased pain, swelling, or heat at or near injection site, or increased lameness. Treatments required for each reaction were noted., Results: BM-MSCs proliferated and underwent differentiation. Cells were found to be negative for MHC-II (<2%) and were viable after cryopreservation and shipping. Ten of 230 (4.35%) injections were noted to be associated with an adverse reaction. Adverse reactions occurred in synovial structures (n = 3) and in soft tissues (n = 7)., Main Limitations: This investigation could underestimate the number and severity of reactions. Mild reactions, such as synovitis, may have been missed. Also, anti-inflammatory drugs could overshadow mild reactions, making them less likely to be detected., Conclusions: Fully characterised allogenic BM-MSCs originating from a single donor horse can be administered to horses with soft tissue injuries with a low rate of adverse reaction. The Summary is available in Portuguese - see Supporting Information., (© 2018 EVJ Ltd.)

Feline injection site sarcomas (FISSs) are mesenchymal neoplasms that develop at the sites of delivery of vaccines or other injectable products. Vaccine adjuvants can trigger an intense and persistent inflammatory response that may lead to neoplastic transformation. The proinflammatory role of cyclo-oxygenase (COX)-2 is well known and its overexpression has prognostic value in multiple neoplastic processes. One hundred and seventeen FISSs were evaluated for the degree of inflammation and anaplasia. Immunohistochemistry was used to determine the expression of COX-2 in these sarcomas. There was a significant association between the degree of inflammation and the expression of COX-2 by neoplastic cells. COX-2 expression was lower in tumours with higher degrees of anaplasia. These findings may be useful in predicting the sensitivity of FISSs to treatment with COX-2 inhibitors. The potential therapeutic use of such agents could then be restricted to tumours with lower degrees of anaplasia., (Copyright © 2018. Published by Elsevier Ltd.)

Feline injection site sarcomas (FISS) were first described in the early 1990s. Despite extensive research, the pathogenesis of these tumours has not been elucidated conclusively. Their appearance and the marked increase in their incidence has been mainly connected to the injection of vaccines, and it is assumed that a chronic inflammatory reaction at the injection site triggers subsequent malignant transformation. The role of alum-based adjuvants has been discussed, but is controversial. The present study of the Swiss Feline Cancer Registry (SFCR) with data from 2009 to 2014 revealed a marked decrease of the incidence of fibrosarcomas compared with the previous observation period. Notably, this drop occurred after a non-adjuvanted feline leukaemia virus vaccine was introduced in Switzerland in 2007. This observation, together with the previous findings of the SFCR, further supports the notion that alum-adjuvanted vaccines are involved in the genesis of FISS and that non-adjuvanted vaccines might be safer for cats., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objectives Owing to its highly infiltrative growth, feline injection-site sarcoma (FISS) carries a significant risk of local tumour recurrence. Parameters of possible prognostic significance (eg, tumour size and location, resection of de novo vs recurrent tumours, and achievement of tumour-free surgical margins) were examined with regard to their influence on recurrence rate (RR), disease-free interval (DFI) and survival time (ST). Methods This was a retrospective analysis of cats with FISSs located on the chest or abdominal wall or the interscapular region treated in a single institution using a standardised radical resection technique with 3 cm lateral margins and full-thickness body wall resection (tumours over chest/abdominal wall) or a minimum of two fascial planes (interscapular tumours). Results Median postoperative DFI and ST of 131 cats with FISSs was 21 and 24 months, respectively. Patients operated on for recurrent tumours were significantly more likely to die from tumour-related reasons compared with patients with de novo tumours ( P <0.001). RR and DFI in the different tumour locations were comparable ( P = 0.544 and P = 0.17, respectively). Local tumour recurrence occurred in 38.1% of the cats. Cats operated on for tumour recurrences had a significantly higher chance of another recurrence (RR 55.5% vs 33.3%; P = 0.005). Completeness of excision was determined by taking tumour bed biopsies. Tumour bed biopsies that did not contain tumour cells were associated with a significantly lower RR compared with those with tumour cells (30.5% vs 76.2%). Conclusions and relevance Depending on prognostic factors such as surgery for primary vs recurrent tumour, tumour-free resection margins and tumour location, the RR in FISS ranges from 33-55%, despite curative intent radical surgery. This study may help in identifying patients at risk for recurrence.

Recently published guidelines have made specific vaccine recommendations purported to potentially reduce the incidence of feline injection-site sarcomas (FISS). These recommendations have largely been based on experimental models of inflammation under different vaccine formulations. In none of these studies did sarcomas occur. It is scientifically untenable to address FISS risk based on propensity of vaccines to elicit differential inflammatory responses if none of those responses led to sarcoma development. Although the recommendations may ultimately be found to be prescient and valid, it will take considerable additional research before this can happen. Until then, such guidelines must be regarded with skepticism., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To determine the in vitro chemosensitivity of feline injection site-associated sarcoma (FISAS) cells to carboplatin concentrations generated by elution of carboplatin-impregnated calcium sulfate hemihydrate (CI-CSH) beads., Study Design: In vitro study., Sample: Five immortalized cell lines from histologically confirmed, primary FISASs., Methods: For each cell line, one 96-well microplate was used for each time point (24, 48, 72 hours). In each microplate, 3 wells were seeded with ∼7.5 × 10 3 cells per well for every carboplatin treatment added, ranging from 5 to 450 µM. Microculture plates were incubated for 24, 48, or 72 hours. Drug efficacy was assessed via a bioreductive fluorometric assay. For apoptosis analysis, 3 wells were seeded with ∼5 × 10 4 cells per well for every carboplatin treatment added, ranging from 5 to 450 µM. Flow cytometry was performed and the relative percentages of viable, apoptotic, and late apoptotic/necrotic cells were reported. All experiments were run in triplicates., Results: Carboplatin exerted dose-dependent and time-dependent effects on FISAS cell viability. The IC 50 values were within the range of carboplatin concentrations eluted from CI-CSH beads., Conclusion: Elution of carboplatin from CI-CSH beads generate concentrations sufficient to result in 50% growth inhibition of FISAS cells in vitro. Local tumor control might be achieved by implantation of CI-CSH beads immediately following radical or marginal excision of the primary tumor or by implantation without tumor resection., (© 2017 The American College of Veterinary Surgeons.)

Feline injection-site sarcomas (FISS) are malignant skin tumours of mesenchymal origin, the treatment of which is a challenge for veterinary surgeons. The role of surgery, radiotherapy and chemotherapy in FISS treatment has been studied, and a correlation between "clean" surgical margins and disease-free survival has been shown. In addition, clean surgical margins are one of the most important factors for achieving a low recurrence rate. The most effective method of FISS treatment includes combining radical surgery with pre- or postoperative radiotherapy. Chemotherapy may be used as a palliative method of treatment or may be considered an adjunctive therapy for surgery and radiotherapy. In cats with FISS without metastasis, the use of immunostimulant treatment with Oncept IL-2, intended as a complementary immunotherapy in association with surgery and brachytherapy, may also be considered to reduce the risk of relapse and increase the time to relapse. Additionally, this review focuses on recent advances in FISS treatment, including the use of novel compounds, such as doxorubicin conjugated to glutathione-stabilized gold nanoparticles, liposomal doxorubicin or tyrosine kinase inhibitors.