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The Veterinary Clinics of North... May 2024New knowledge and data can influence the treatment options of dogs and cats affected by neoplasms. Partial limb amputation with the use of a prosthesis is possible in... (Review)
Review
New knowledge and data can influence the treatment options of dogs and cats affected by neoplasms. Partial limb amputation with the use of a prosthesis is possible in dogs. Newer studies attempt to define better and understand the complications and limb function associated with this approach. Limb sparing is an alternative to amputation, and three-dimensional printing allows the manufacturing of personalized endoprostheses. Finally, the recommended approach for the excision of cutaneous mast cell tumors (MCTs) is with proportional margins. In dogs, grade shifting might have occurred when removing a recurrent MCT or soft tissue sarcoma.
Topics: Cats; Animals; Dogs; Skin Neoplasms; Surgical Oncology; Cat Diseases; Neoplasm Recurrence, Local; Dog Diseases; Treatment Outcome
PubMed: 38238221
DOI: 10.1016/j.cvsm.2023.12.010 -
Cancers Nov 2023Mast cell disorders range from benign proliferations to systemic diseases that cause anaphylaxis and other diverse symptoms to mast cell neoplasms with varied clinical... (Review)
Review
Mast cell disorders range from benign proliferations to systemic diseases that cause anaphylaxis and other diverse symptoms to mast cell neoplasms with varied clinical outcomes. Mastocytosis is the pathologic process of the accumulation of abnormal mast cells in different organs, mostly driven by mutations, and can present as cutaneous mastocytosis, systemic mastocytosis (SM), and mast cell sarcoma. The WHO 5th edition classification divides systemic mastocytosis into bone marrow mastocytosis, indolent systemic mastocytosis, smoldering systemic mastocytosis, aggressive systemic mastocytosis, systemic mastocytosis with an associated hematologic neoplasm, and mast cell leukemia. The new ICC classifies SM slightly differently. The diagnosis of SM requires the integration of bone marrow morphologic, immunophenotypic, and molecular findings, as well as clinical signs and symptoms. Moreover, understanding the wide range of clinical presentations for patients with mast cell disorders is necessary for accurate and timely diagnosis. This review provides an updated overview of mast cell disorders, with a special emphasis on SM, including the latest approaches to diagnosis, prognostic stratification, and management of this rare disease.
PubMed: 38067330
DOI: 10.3390/cancers15235626 -
British Journal of Haematology Feb 2024Mastocytosis constitutes the neoplastic proliferation of mast cells and is broadly classified into systemic mastocytosis (SM), cutaneous mastocytosis and mast cell... (Review)
Review
Mastocytosis constitutes the neoplastic proliferation of mast cells and is broadly classified into systemic mastocytosis (SM), cutaneous mastocytosis and mast cell sarcoma. SM is further partitioned into advanced (AdvSM) and non-advanced (SM-non-Adv) subcategories. AdvSM includes aggressive SM (ASM), SM with an associated haematological neoplasm (SM-AHN) and mast cell leukaemia (MCL). In 2022, two separate expert committees representing the 5th edition of the World Health Organization (WHO5) and the International Consensus (ICC) classification systems submitted revised classification criteria for SM, highlighted by the ICC-proposed incorporation of mast cell cytomorphology in the diagnostic criteria for MCL and myeloid-lineage restriction for the AHN component in SM-AHN. Recent developments in SM also include the introduction of KIT-targeting tyrosine kinase inhibitors (KITi), including midostaurin and avapritinib, both drugs have shown potent activity in reducing mast cell and mutant KIT burden and alleviating mast cell-associated organopathy and mediator symptoms; however, their overall impact on survival or superiority over pre-KITi era treatment options (e.g. cladribine) has not been studied in a controlled setting. In the current review, we provide a summary of recent changes in disease classification and an analysis of recent clinical trials and their impact on our current treatment approach in AdvSM.
Topics: Humans; Mastocytosis, Systemic; Mast Cells; Leukemia, Mast-Cell; Cladribine; Mastocytosis; Proto-Oncogene Proteins c-kit
PubMed: 38054381
DOI: 10.1111/bjh.19245 -
Journal of the American Veterinary... Nov 2023To determine the prevalence of splenic malignancy in cats undergoing splenectomy and to investigate possible factors associated with post-operative outcome.
OBJECTIVE
To determine the prevalence of splenic malignancy in cats undergoing splenectomy and to investigate possible factors associated with post-operative outcome.
ANIMALS
62 client-owned cats that underwent splenectomy.
METHODS
Medical records of 4 UK-based referral hospitals were searched and data reviewed retrospectively over 17 years. Factors associated with outcomes post-splenectomy were analyzed.
RESULTS
50 out of 62 cats (81%) were diagnosed with splenic neoplasia. Mast cell tumor ([MCT], 42%), hemangiosarcoma ([HSA], 40%), lymphoma and histiocytic sarcoma (6% each) were the most common tumor types. Fifteen cats (24%) presented with spontaneous hemoabdomen and were all diagnosed with splenic neoplasia. The diagnostic accuracy of cytology to detect splenic malignant lesions was 73% (100% for MCTs and 54% for mesenchymal tumors). Median survival time for cats with nonneoplastic splenic lesions was 715 days (IQR, 18 to 1,368) and 136 days for cats with splenic neoplasia (IQR, 35 to 348); median survival time was longer for cats with splenic MCT when compared to cats with HSA (348 vs 94 days; P < .001). Presence of metastatic disease and anemia (PCV < 24%) at diagnosis were associated with a poorer survival when considering all cats. Presence of anemia, a splenic mass on imaging or spontaneous hemoabdomen were associated with a diagnosis of HSA (P < .001).
CLINICAL RELEVANCE
Benign splenic lesions were uncommon in this cohort of cats. Spontaneous hemoabdomen should prompt the clinician to suspect neoplasia in cats with splenic disease. Anemia and evidence of metastasis at diagnosis were poor prognostic factors regardless of the final diagnosis.
Topics: Humans; Cats; Animals; Dogs; Splenectomy; Retrospective Studies; Prevalence; Splenic Neoplasms; Anemia; Hemoperitoneum; Dog Diseases; Hemangiosarcoma; Cat Diseases
PubMed: 37582488
DOI: 10.2460/javma.23.05.0258 -
PloS One 2024Ewing's sarcoma (ES) is the second most common bone and soft tissue malignancy in children and adolescents with a poor prognosis. The identification of genes with...
Ewing's sarcoma (ES) is the second most common bone and soft tissue malignancy in children and adolescents with a poor prognosis. The identification of genes with prognostic value may contribute to the prediction and treatment of this disease. The GSE17679, GSE68776, GSE63155, and GSE63156 datasets were downloaded from the Gene Expression Omnibus database and qualified. Prognostic value of differentially expressed genes (DEGs) between the normal and tumor groups and immune cell infiltration were explored by several algorithms. A prognostic model was established and validated. Finally, functional analyses of the DEGs were performed. Proline rich 11 (PRR11) and mast cell infiltration were noted as the key indicators for the prognosis of ES. Kaplan-Meier and scatter plots for the training and two validation sets showed that patients in the low-PRR11 expression group were associated with better outcomes than those in the high-PRR11 expression group. The concordance indices and calibration analyses of the prognostic model indicated good predictive accuracy in the training and validation sets. The area under the curve values obtained through the receiver operating characteristic analysis for 1-, 3-, 5-year prediction were ≥ 0.75 in the three cohorts, suggesting satisfactory sensitivity and specificity of the model. Decision curve analyses suggested that patients could benefit more from the model than the other strategies. Functional analyses suggested that DEGs were mainly clustered in the cell cycle pathway. PRR11 and mast cell infiltration are potential prognostic indicators in ES. PRR11 possibly affects the prognosis of patients with ES through the cell cycle pathway.
Topics: Adolescent; Child; Humans; Algorithms; Calibration; Prognosis; Sarcoma; Sarcoma, Ewing
PubMed: 38427643
DOI: 10.1371/journal.pone.0299720 -
Journal of the American Veterinary... Sep 2023To determine the incidence of histologic grade shift (alteration of grade relative to the original tumor) in recurrent canine soft tissue sarcoma (STS) and mast cell...
OBJECTIVE
To determine the incidence of histologic grade shift (alteration of grade relative to the original tumor) in recurrent canine soft tissue sarcoma (STS) and mast cell tumor (MCT), and to determine the level of agreement between blinded pathologist review and original histology interpretation of STS and MCT grades.
ANIMALS
15 dogs with recurrent cutaneous/subcutaneous STS and 5 dogs with recurrent cutaneous MCT. All included dogs underwent excision of both the primary and recurrent tumors and had tumor samples available for review.
PROCEDURES
The medical records and histology database from a single institution were reviewed, and data were recorded and analyzed. A single board-certified veterinary pathologist performed blinded evaluation of all excisional tumor samples, including both primary and recurrent disease, and these were evaluated independently and in conjunction with initial pathologic diagnoses.
RESULTS
Based on single pathologist review, 7 of 15 (46.7%) dogs with recurrent STS had grade shift characterized by a higher or lower recurrent tumor grade in 4 of 7 and 3 of 7 cases, respectively, and 1 of 5 dogs with recurrent MCT had grade shift characterized by an increased grade of the recurrent tumor. Variability in reported grade between original histology report and pathologist review occurred for 13 of 30 (43.3%) STS excisional biopsy samples and 0 of 10 MCT excisional biopsy samples.
CLINICAL RELEVANCE
Grade shift has been reported in multiple tumor types in people and has the potential to alter prognosis and treatment recommendations. This is the first study to document this phenomenon in dogs. Additional large-scale studies are needed to determine factors associated with grade shift as well as prognostic significance of grade shift for recurrent canine STS and MCT.
Topics: Animals; Dogs; Female; Male; Dog Diseases; Incidence; Recurrence; Retrospective Studies; Soft Tissue Neoplasms; Sarcoma
PubMed: 37257826
DOI: 10.2460/javma.23.01.0050 -
Clinical Cancer Research : An Official... Jun 2024To explore the cellular cross-talk of tumor-resident mast cells (MC) in controlling the activity of cancer-associated fibroblasts (CAF) to overcome tumor...
PURPOSE
To explore the cellular cross-talk of tumor-resident mast cells (MC) in controlling the activity of cancer-associated fibroblasts (CAF) to overcome tumor microenvironment (TME) abnormalities, enhancing the efficacy of immune-checkpoint inhibitors in sarcoma.
EXPERIMENTAL DESIGN
We used a coculture system followed by further validation in mouse models of fibrosarcoma and osteosarcoma with or without administration of the MC stabilizer and antihistamine ketotifen. To evaluate the contribution of ketotifen in sensitizing tumors to therapy, we performed combination studies with doxorubicin chemotherapy and anti-PD-L1 (B7-H1, clone 10F.9G2) treatment. We investigated the ability of ketotifen to modulate the TME in human sarcomas in the context of a repurposed phase II clinical trial.
RESULTS
Inhibition of MC activation with ketotifen successfully suppressed CAF proliferation and stiffness of the extracellular matrix accompanied by an increase in vessel perfusion in fibrosarcoma and osteosarcoma as indicated by ultrasound shear wave elastography imaging. The improved tissue oxygenation increased the efficacy of chemoimmunotherapy, supported by enhanced T-cell infiltration and acquisition of tumor antigen-specific memory. Importantly, the effect of ketotifen in reducing tumor stiffness was further validated in sarcoma patients, highlighting its translational potential.
CONCLUSIONS
Our study suggests the targeting of MCs with clinically administered drugs, such as antihistamines, as a promising approach to overcome resistance to immunotherapy in sarcomas.
Topics: Humans; Mice; Animals; Mast Cells; Tumor Microenvironment; Immune Checkpoint Inhibitors; B7-H1 Antigen; Sarcoma; Ketotifen; Cell Line, Tumor; T-Lymphocytes; Xenograft Model Antitumor Assays; Lymphocytes, Tumor-Infiltrating; Female; Cancer-Associated Fibroblasts; Doxorubicin; Osteosarcoma
PubMed: 38578281
DOI: 10.1158/1078-0432.CCR-24-0246 -
Heliyon Sep 2023The prognostic value of D-glucuronyl C5-epimerase ( and mast cell infiltration in Ewing sarcoma (ES) has not been well specified and highlighted, which may facilitate...
BACKGROUND
The prognostic value of D-glucuronyl C5-epimerase ( and mast cell infiltration in Ewing sarcoma (ES) has not been well specified and highlighted, which may facilitate survival prediction and treatment.
METHODS
Several qualified datasets were downloaded from the GEO website. Common differentially expressed genes between normal subjects and ES patients in GSE17679, GSE45544, and GSE68776 were identified and screened by multiple algorithms to find hub genes with prognostic value. The prognostic value of 64 infiltrating cells was also explored. A prognostic model was established and then validated with GSE63155 and GSE63156. Finally, functional analysis was performed.
RESULTS
and mast cell infiltration were screened as two indicators for a prognostic model. The Kaplan‒Meier analysis showed that patients in the low expression, mast cell infiltration and risk score groups had poorer outcomes than patients in the high expression, mast cell infiltration and risk score groups, both in the training and validation sets. Scatter plots and heatmaps also indicated the same results. The concordance indices and calibration analyses indicated a high prediction accuracy of the model in the training and validation sets. The time-dependent receiver operating characteristic analyses suggested high sensitivity and specificity of the model, with area under the curve values between 0.76 and 0.98. The decision curve analyses suggested a significantly higher net benefit by the model than the treat-all and treat-none strategies. Functional analyses suggested that glycosaminoglycan biosynthesis-heparan sulfate/heparin, the cell cycle and microRNAs in cancer were upregulated in ES patients.
CONCLUSIONS
and mast cell infiltration are potential prognostic indicators in ES. may affect the proliferation, angiogenesis and metastasis of ES by affecting the biosynthesis of heparan sulfate and heparin.
PubMed: 37662777
DOI: 10.1016/j.heliyon.2023.e19357 -
The Journal of Pharmacology and... Feb 2024This study provides a unique translational research opportunity to help both humans and dogs diagnosed with diseases that carry dismal prognoses in both species:...
This study provides a unique translational research opportunity to help both humans and dogs diagnosed with diseases that carry dismal prognoses in both species: histiocytic sarcoma (HS), hemangiosarcoma (HSA), and disseminated mastocytosis/mast cell tumor (MCT). Although exceedingly rare in humans, these so called "orphan diseases" are relatively more common in dogs. For these and other more commonplace cancers like lymphoma (Lym), dogs are an excellent translational model for human disease due to remarkably similar disease biology. In this study, assays were performed to assess the therapeutic potential of parthenolide (PTL), a known canonical nuclear factor kappa B (NF-B) signaling inhibitor with additional mechanisms of antineoplastic activity, including alteration of cellular reduction-oxidation balance. Canine cell lines and primary cells are sensitive to PTL and undergo dose-dependent apoptosis after exposure to drug. PTL exposure also leads to glutathione depletion, reactive oxygen species generation, and NF-B inhibition in canine cells. Standard-of-care therapeutics broadly synergize with PTL. In two canine HS cell lines, expression of NF-B pathway signaling partners is downregulated with PTL therapy. Preliminary data suggest that PTL inhibits NF-B activity of cells and extends survival time in a mouse model of disseminated canine HS. These data support further investigation of compounds that can antagonize canonical NF-B pathway signaling in these cancers and pave the way for clinical trials of PTL in affected dogs. As dogs are an excellent natural disease model for these cancers, these data will ultimately improve our understanding of their human disease counterparts and hopefully improve care for both species. SIGNIFICANCE STATEMENT: Disseminated neoplasms in human and canine cancers are challenging to treat, and novel therapeutic approaches are needed to improve outcomes. Parthenolide is a promising treatment for histiocytic sarcoma, hemangiosarcoma, and mast cell neoplasia.
Topics: Mice; Humans; Animals; Dogs; NF-kappa B; Cell Line, Tumor; Histiocytic Sarcoma; Hemangiosarcoma; Sesquiterpenes; Apoptosis
PubMed: 38135509
DOI: 10.1124/jpet.123.001851 -
Journal of the National Comprehensive... Jun 2024Mastocytosis is a heterogeneous group of disorders comprising cutaneous mastocytosis, systemic mastocytosis, and mast cell sarcoma. It is associated with a variety of...
Mastocytosis is a heterogeneous group of disorders comprising cutaneous mastocytosis, systemic mastocytosis, and mast cell sarcoma. It is associated with a variety of symptoms related to the release of mast cell mediators and mast cell tissue infiltration. Referral to specialized centers with expertise in the management of mastocytosis and multidisciplinary collaboration with subspecialists (eg, allergists for the management of anaphylaxis and drug hypersensitivities, anesthesiologists for invasive procedures or surgery, high-risk obstetrician for pregnancy) is recommended. The NCCN Guidelines for Systemic Mastocytosis provide evidence- and consensus-based recommendations for the diagnosis and comprehensive care of patients with systemic mastocytosis. The multidisciplinary panel of experts convenes at least once a year to review requested changes to the guidelines from both internal and external entities as well as to discuss data on existing and new therapies. These NCCN Guidelines Insights focus on some of the recent updates to the guidelines.
Topics: Humans; Mastocytosis, Systemic; Disease Management; Medical Oncology
PubMed: 38862005
DOI: 10.6004/jnccn.2024.0030