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Adult-onset urticaria pigmentosa/mastocytosis in the skin almost always persists throughout life. The prevalence of systemic mastocytosis in such patients is not precisely known. Bone marrow biopsies from 59 patients with mastocytosis in the skin and all available skin biopsies (n=27) were subjected to a meticulous cytological, histological, immunohistochemical, and molecular analysis for the presence of WHO-defined diagnostic criteria for systemic mastocytosis: compact mast cell infiltrates (major criterion); atypical mast cell morphology, KIT D816V, abnormal expression of CD25 by mast cells, and serum tryptase levels >20 ng/ml (minor criteria). Systemic mastocytosis is diagnosed when the major diagnostic criterion plus one minor criterion or at least three minor criteria are fulfilled. Systemic mastocytosis was confirmed in 57 patients (97%) by the diagnosis of compact mast cell infiltrates plus at least one minor diagnostic criterion (n=42, 71%) or at least three minor diagnostic criteria (n=15, 25%). In two patients, only two minor diagnostic criteria were detectable, insufficient for the diagnosis of systemic mastocytosis. By the use of highly sensitive molecular methods, including the analysis of microdissected mast cells, KIT D816V was found in all 58 bone marrow biopsies investigated for it but only in 74% (20/27) of the skin biopsies. It is important to state that even in cases with insufficient diagnostic criteria for systemic mastocytosis, KIT D816V-positive mast cells were detected in the bone marrow. This study demonstrates, for the first time, that almost all patients with adult-onset mastocytosis in the skin, in fact, have systemic mastocytosis with cutaneous involvement.

Canine/feline (sub-)cutaneous tumors, which include lipomas, mastocytomas and soft tissue sarcomas, introduce diagnostic challenges due to inherent tissue heterogeneity, accompanied by diverse clinical pathogenesis. Current study integrates conventional imaging techniques optical (white light and autofluorescence) as well as high frequency ultrasound imaging to train machine learning classifiers: linear discriminant analysis, support vector machine and random forest. Study resulted in ~ 100% classification efficiency between benign lipoma and combined mastocytoma and sarcoma tissues for all the classifiers. For the differentiation between mastocytoma and sarcoma tumors, both support vector machine and random forest outperformed conventional linear discriminant analysis classifier. Support vector machine displayed the highest classification efficiency for bimodal groups: (i) ultrasound + fluorescence and (ii) ultrasound + white light as well as (iii) fluorescence + white light. However, it failed for trimodal ultrasound + optics combination, indicating possible upper limit for imaging mode addition. The multimodal effect was obtained using both statistically significant set of features as well as optimal set of features, determined using sequential feature addition. Resulting classification efficiency for combined ultrasound + fluorescence approach was > 85% and even higher for ultrasound + white light or ultrasound + optics multimodal approaches reaching ~ 95%. In the classification of mastocytoma and sarcoma, support vector machine classifier was able to detect significant ( p  < 0.05) multimodal effect for bimodal groups of: (i) fluorescence + white light, (ii) ultrasound + fluorescence and (iii) ultrasound + white light. On the contrary, random forest demonstrated relevant increment only for the combination of fluorescence and white light. Inferior features of ultrasound or fluorescence have been evaluated to be competitive with the features of highly-efficient white light as they were automatically selected during the process of feature optimization. In addition, another phenomenon of manifestation of multimodality has been observed: in multimodal groups, ultrasound features tended to substitute the features of white light, not just simply be added to them. Multimodal approach was determined to be highly-required for the classification of heterogeneous mastocytoma and sarcoma tumors, which display more similar morphological characteristics. However, when differentiating very distinct lipomas from mastocytomas or sarcomas, the multimodal approach was not a requisite.

Prophylactic vaccination is one of the fundamental elements of health policy. Poland has a universal vaccination programme, which is systematically modified depending on the changing epidemiological situation of infectious diseases, as well as current medical knowledge, which has its implications in legislation. Mastocytosis is a haematopoietic neoplasm occurring in children, usually with a benign course, limited to the skin and resolving before adolescence. However, the implementation of the general prophylactic vaccination programme in children with mastocytosis raises many concerns among doctors and parents. Vaccinations are among the exogenous agents that may cause mast cell activation and release of biologically active substances, resulting in the exacerbation of mastocytosis symptoms and an increased risk of anaphylaxis. However, the incidence of adverse effects of vaccinations in children with different forms of mastocytosis is in fact comparable to or only slightly higher than in the general population, and vaccine-related events are usually mild and local. Unfortunately, there is a lack of understanding regarding vaccinations in children with mastocytosis both among general practitioners and parents. The aims of this paper are to outline the current state of knowledge on the safety of vaccinations in this group of patients, to promote knowledge related to vaccination in patients with mastocytosis, and to emphasise that mastocytosis is not a contraindication to vaccination.

Within the “One Health, One Medicine” and comparative oncology paradigms, algal extracts have attracted attention, containing natural compounds (NCs) with biological activities, including anti-cancer properties. To characterize the biological effects of a Sphaerococcus coronopifolius extract (SCE), two canine mastocytoma and two normal cell lines were used. After a preliminary screening of three algal extracts, SCE cytotoxicity was measured using Alamar Blue, Sulforhodamine B, and Neutral Red Uptake assays. After assessing the selectivity versus tumor cells and its chemical characterization, SCE mechanisms of action were investigated using RNA-seq, quantitative PCR, flow cytometry and immunoblotting approaches. SCE showed an IC50 comprised between 25 and 35 μg/mL in tumor cell lines, but it also affected normal ones (selectivity index < 2.0). RNA-seq and flow cytometry revealed that SCE negatively affected cell cycle and mevalonate pathway in tumor cells. Additional flow cytometry and immunoblotting investigations suggested a concentration- and time-dependent pro-apoptotic effect of SCE and DNA damage events. In conclusion, SCE demonstrated promising anti-cancer activity in mastocytoma cell lines by targeting the mevalonate pathway, arresting the cell cycle, and inducing apoptosis and DNA damage. Furthermore, the results presented here reinforce the idea that NCs may be promising candidates in comparative anti-cancer chemotherapy.

Study advances current diagnostic efficiency of canine/feline (sub-)cutaneous tumors using machine learning and multimodal imaging data. White light (WL), fluorescence (FL) and ultrasound (US) imaging were combined into hybrid approaches to differentiate between malignant mastocytomas, soft tissue sarcomas and benign lipomas. Support Vector Machine and Ensemble classifiers were optimized via sequential feature selection. US radio-frequency signals were quantitatively analyzed to derive the colormaps of six US estimates, corresponding to spectral and temporal domains of the acoustic field. This resulted in the quantification of 72 morphological features for US; as well as 24 and 12 - for WL and FL data, respectively. Resulting classification efficiency for mastocytoma and sarcoma using US data was >75%; US+FL − 75-80%; US+WL − 85-90% and US+OPTICS − 90-95%. ∼100% classification efficiency was achieved for the differentiation between benign and malignant tumors even using single WL feature for Ensemble classifier. US features, resulting in inferior classification efficiency, were competitive to superior optical, as they were selected during optimization to be added to or replace optical counterparts. Additional tissue differentiation was performed on z-stacks of US colormaps, obtained using 3D arrays of US radio-frequency signals. This resulted in ∼70% differentiation efficiency for mastocytoma and sarcoma as well as >95% for benign and malignant tissues. The obtained additional metric of classification efficiency provides complementary diagnostic support, which for Support Vector Machine can be expressed as: 90.3 ± 1.9% (US+WL)×71.2 ± 0.6% (US Depth Profile ). This hybrid criterion adds robustness to diagnostic model and may be very beneficial to characterize heterogeneous tissues.

This study introduces Raman imaging technique for diagnosing skin cancer in veterinary oncology patients (dogs and cats). Initially, Raman spectral bands (with specificity to certain molecular structures and functional groups) were identified in formalin-fixed samples of mast cell tumors and soft tissue sarcomas, obtained through routine veterinary biopsy submissions. Then, a custom-built Raman macro-imaging system featuring an intensified CCD camera (iXon Ultra 888, Andor, UK), tunable narrow-band Semrock (USA) optical filter compartment was used to map the spectral features at 1437 cm −1 and 1655 cm −1 in ex vivo tissue. This approach enabled wide-field (cm 2 ), rapid (within seconds), and safe (< 400 mW/cm 2 ) imaging conditions, supporting accurate diagnosis of tissue state. The findings indicate that machine learning classifiers - particularly support vector machine (SVM) and decision tree (DT) - effectively distinguished between soft tissue sarcoma, mastocytoma and benign tissues using Raman spectral band imaging data. Additionally, combining Raman macro-imaging with residual near-infrared (NIR) autofluorescence as a bimodal imaging technique enhanced diagnostic performance, reaching 85 - 95% in accuracy, sensitivity, specificity, and precision - even with a single spectral band (1437 cm −1 or 1655 cm −1 ). In conclusion, the proposed bi-modal imaging is a pioneering method for veterinary oncology science, offering to improve the diagnostic accuracy of malignant tumors.

Mast cell tumours (MCTs) are common neoplasms in dogs and are usually regarded as potentially malignant. Several studies have attempted to identify biomarkers to better predict biological behaviours for this tumour. The aim of this study was to identify pathways connected to clinical and histopathological malignancies, shorter survival times, and poor prognoses associated with MCTs. We performed genome-wide gene expression analyses on tissues obtained from 15 dogs with single MCTs, and identified two distinct tumour subtypes-high-risk and low-risk-associated with differences in histological grades, survival times, Ki67 indices, and occurrence of death due the disease. Comparative analyses of RNA sequence profiles revealed 71 genes that were differentially expressed between high- and low-risk MCTs. In addition to these analyses, we also examined gene co-expression networks to explore the biological functions of the identified genes. The network construction revealed 63 gene modules, of which 4 were significantly associated with the more aggressive tumour group. Two of the gene modules positively correlated with high-risk MCTs were also associated with cell proliferation and extracellular matrix-related terms. At the top of the extracellular matrix module category, genes with functions directly related to those of cancer-associated fibroblasts (CAFs) were identified. Immunohistochemical analyses also revealed a greater number of CAFs in high-risk MCTs. This study provides a method for the molecular characterisation of canine MCTs into two distinct subtypes. Our data indicate that proliferation pathways are significantly involved in malignant tumour behaviours, which are known to be relevant for the induction and maintenance of MCTs. Finally, animals presenting high-risk MCTs overexpress genes associated with the extracellular matrix that can be robustly linked to CAF functions. We suggest that CAFs in the MCT stroma contribute to cancer progression.

Immunotherapy is a promising alternative treatment for canine mast cell tumour (MCT). However, evasion of immune recognition by downregulating major histocompatibility complex (MHC) molecules might decline treatment efficiency. Enhancing MHC expression through interferon-gamma (IFN-γ) is crucial for effective immunotherapy. In-house and reference canine MCT cell lines derived from different tissue origins were used. The impacts of IFN-γ treatment on cell viability, expression levels of MHC molecules, as well as cell apoptosis were evaluated through the MTT assay, RT-qPCR and flow cytometry. The results revealed that IFN-γ treatment significantly influenced the viability of canine MCT cell lines, with varying responses observed among different cell lines. Notably, IFN-γ treatment increased the expression of MHC I and MHC II, potentially enhancing immune recognition and MCT cell clearance. Flow cytometry analysis in PBMCs-mediated cytotoxicity assays showed no significant differences in overall apoptosis between IFN-γ treated and untreated canine MCT cell lines across various target-to-effector ratios. However, a trend towards higher percentages of late and total apoptotic cells was observed in the IFN-γ treated C18 and CMMC cell lines, but not in the VIMC and CoMS cell lines. These results indicate a variable response to IFN-γ treatment among different canine MCT cell lines. In summary, our study suggests IFN-γ's potential therapeutic role in enhancing immune recognition and clearance of MCT cells by upregulating MHC expression and possibly promoting apoptosis, despite variable responses across different cell lines. Further investigations are necessary to elucidate the underlying mechanisms and evaluate IFN-γ's efficacy in in vivo models.

4-1BB is a major costimulatory receptor that promotes the survival and expansion of activated T cells. Administration of agonistic anti-4-1BB Abs has been previously shown to enhance tumor immunity in mice. Abs are cell-based products posing significant cost, manufacturing, and regulatory challenges. Aptamers are oligonucleotide-based ligands that exhibit specificity and avidity comparable to, or exceeding, that of Abs. To date, various aptamers have been shown to inhibit the function of their cognate target. Here, we have described the development of an aptamer that binds 4-1BB expressed on the surface of activated mouse T cells and shown that multivalent configurations of the aptamer costimulated T cell activation in vitro and mediated tumor rejection in mice. Because aptamers can be chemically synthesized, manufacturing and the regulatory approval process should be substantially simpler and less costly than for Abs. Agonistic aptamers could therefore represent a superior alternative to Abs for the therapeutic manipulation of the immune system.

Mast cell tumours (MCTs) are common malignant neoplasms in dogs, for which prognosis and therapeutic decisions are based on histological features and proliferation markers. Autophagy is a cellular catabolic process responsible for degrading cytoplasmic components to maintain homeostasis, alterations in which are frequently linked to tumour growth and progression. This study was conducted to investigate the occurrence of autophagy in canine MCTs and to verify its value as a prognostic indicator for dogs with the disease. Beclin-1 and LC3B expressions were investigated using immunohistochemistry, and autophagy was ultrastructurally characterised. The autophagic phenomenon was successfully visualised in neoplastic mast cells under transmission electron and immunoelectron microscopy. MCTs from dogs that died due to the disease showed higher positivity for Beclin-1 and dogs with MCTs presenting a LC3B granular immunohistochemical pattern had a significantly shorter post-surgical survival. The occurrence of autophagy is an indicator of poor prognosis. Future studies are needed to elucidate the specific mechanisms and open new opportunities to treatments targeting this cancer cell advantage.