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Laboratory Investigation; a Journal of... Mar 2024Recent studies have described several molecular subtypes and deregulation of immuno-oncologic signaling pathways in angiosarcoma. Interestingly, mast cells were enriched...
Recent studies have described several molecular subtypes and deregulation of immuno-oncologic signaling pathways in angiosarcoma. Interestingly, mast cells were enriched in subsets of angiosarcoma, although their significance remains unknown. In this study, we aim to verify this observation using immunohistochemistry (H scores) and NanoString transcriptomic profiling and explore the association between mast cells with clinical and biological features. In the study cohort (N = 60), H scores showed a significant moderate correlation with NanoString mast cell scores (r = 0.525; P < .001). Both H score and NanoString mast cell scores showed a significant positive correlation (P < .05) with head and neck location, nonepithelioid morphology, and lower tumor grade. Mast cell enrichment significantly correlated with higher NanoString regulatory T-cell scores (H score, r = 0.32; P = .01; NanoString mast cell score, r = 0.27; P = .04). NanoString mast cell scores positively correlated with signaling pathways relating to antigen presentation (r = 0.264; P = .0414) and negatively correlated with apoptosis (r = -0.366; P = .0040), DNA damage repair (r = -0.348; P = .0064), and cell proliferation (r = -0.542; P < .001). Interestingly, in the metastatic setting, patients with mast cell-enriched angiosarcoma showed poorer progression-free survival (median, 0.2 vs 0.4 years; hazard ratio = 3.05; P = .0489) along with a trend toward worse overall survival (median, 0.2 vs 0.6 years; hazard ratio, 2.86; P = .0574) compared with patients with mast cell-poor angiosarcoma. In conclusion, we demonstrated the presence of mast cells in human angiosarcoma and provided initial evidence of their potential clinical and biological significance. Future research will be required to elucidate their specific roles and mechanisms, which may uncover novel avenues for therapeutic intervention.
Topics: Humans; Hemangiosarcoma; Mast Cells; Signal Transduction; Apoptosis; Prognosis
PubMed: 38218317
DOI: 10.1016/j.labinv.2024.100323 -
European Journal of Medical Research Jan 2024The importance of protein tyrosine phosphatase non-receptor type 3 (PTPN3) in controlling multifaceted tumor cell behaviors throughout cancer development has received...
BACKGROUND
The importance of protein tyrosine phosphatase non-receptor type 3 (PTPN3) in controlling multifaceted tumor cell behaviors throughout cancer development has received widespread attention. Nevertheless, little is known about the biological roles of PTPN3 in drug sensitivity, immunotherapeutic effectiveness, tumor immune microenvironment, and cancer prognosis.
METHODS
The Cancer Genome Atlas (TCGA) database's RNAseq data were used to examine the expression of PTPN3 in 33 different cancer types. In addition, immunohistochemistry (IHC) was performed to validate the expression of PTPN3 across various cancer types within our clinical cohorts. The features of PTPN3 alterations were demonstrated throughout the cBioPortal database. This study focused on examining the prognostic and clinicopathological importance of PTPN3 through the acquisition of clinical data from the TCGA database. The investigation of PTPN3's probable role in the tumor immune microenvironment was demonstrated by the application of CIBERSORT, ESTIMATE algorithms, and the TISIDB database. Using Spearman's rank correlation coefficient, the relationships between PTPN3 expression and tumor mutation burden (TMB) and microsatellite instability (MSI) were evaluated. To further investigate the putative biological activities and downstream pathways of PTPN3 in various cancers in humans, Gene Set Enrichment Analysis (GSEA) was carried out. In addition, an examination was conducted to explore the associations between PTPN3 and the effectiveness of PD-1/PD-L1 inhibitors, utilizing data extracted from the GEO database.
RESULTS
PTPN3 was abnormally expressed in multiple cancer types and was also strictly associated with the prognosis of cancer patients. IHC was used to investigate and confirm the various expression levels of PTPN3 in various malignancies, including breast cancer, lung cancer, sarcoma, and kidney renal clear cell carcinoma in our clinical cohorts. There is a high correlation between the levels of PTPN3 expression in different cancers and infiltrating immune cells, including mast cells, B cells, regulatory T cells, CD8 + T cells, macrophages, and dendritic cells. Infiltrating immune cells, such as regulatory T cells, CD8 + T cells, macrophages, B cells, dendritic cells, and mast cells, are strongly correlated with PTPN3 expression levels in various tumors. The expression of PTPN3 exhibited a substantial correlation with many immune-related biomolecules and the expression of TMB and MSI in multiple types of cancer. In addition, PTPN3 has demonstrated promise in predicting the therapeutic benefits of PD-1/PD-L1 inhibitors and the susceptibility to anti-cancer medications in the treatment of clinical cancer.
CONCLUSIONS
Our findings highlight the importance of PTPN3 as a prognostic biomarker and predictor of immunotherapy success in various forms of cancer. Furthermore, PTPN3 appears to have an important role in modifying the tumor immune microenvironment, highlighting its potential as a promising biomarker for prognosis prediction, immunotherapeutic efficacy evaluation, and identification of immune-related characteristics in diverse cancer types.
Topics: Humans; Female; Immune Checkpoint Inhibitors; Programmed Cell Death 1 Receptor; Biomarkers; Breast Neoplasms; Carcinoma, Renal Cell; Kidney Neoplasms; Prognosis; Tumor Microenvironment; Protein Tyrosine Phosphatase, Non-Receptor Type 3
PubMed: 38173048
DOI: 10.1186/s40001-023-01587-5 -
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 -
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 -
Veterinary Pathology May 2024Disease monitoring of amphibian assurance populations is an important buffer against ongoing global extinctions. This study documents a high incidence of neoplasia in a...
Disease monitoring of amphibian assurance populations is an important buffer against ongoing global extinctions. This study documents a high incidence of neoplasia in a zoo-managed assurance population of Puerto Rican crested toads (; PRCTs). Over 5 years, neoplasia was diagnosed in 17/49 (35%) submitted adult PRCTs and was the cause of death or euthanasia in 13/17 (72%). Most toads were male (16/17; 94%) and 6 to 11-years-old (average 8.1 years). Notably, seven toads (41%) had multiple neoplasms. Of the 29 neoplasms identified, 17 (59%) were cutaneous or subcutaneous. The most common neoplasms included mast cell tumors (MCTs; 8/29; 28%), histiocytic sarcomas (6/29; 21%), lymphoma/leukemia (4/29; 14%), and squamous cell carcinomas (3/29; 10%). Distant metastases were documented in 6/8 (75%) toads with MCTs. Causes for neoplasia in this population were not determined though may include genetic or environmental factors. Continued investigations of managed endangered amphibians will help elucidate mechanisms of carcinogenesis.
Topics: Animals; Male; Female; Neoplasms; Animals, Zoo; Puerto Rico; Anura; Bufonidae; Endangered Species; Incidence
PubMed: 38018125
DOI: 10.1177/03009858231214029 -
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 -
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 -
Scientific Data Jul 2023The prognostic value of mitotic figures in tumor tissue is well-established for many tumor types and automating this task is of high research interest. However,...
The prognostic value of mitotic figures in tumor tissue is well-established for many tumor types and automating this task is of high research interest. However, especially deep learning-based methods face performance deterioration in the presence of domain shifts, which may arise from different tumor types, slide preparation and digitization devices. We introduce the MIDOG++ dataset, an extension of the MIDOG 2021 and 2022 challenge datasets. We provide region of interest images from 503 histological specimens of seven different tumor types with variable morphology with in total labels for 11,937 mitotic figures: breast carcinoma, lung carcinoma, lymphosarcoma, neuroendocrine tumor, cutaneous mast cell tumor, cutaneous melanoma, and (sub)cutaneous soft tissue sarcoma. The specimens were processed in several laboratories utilizing diverse scanners. We evaluated the extent of the domain shift by using state-of-the-art approaches, observing notable differences in single-domain training. In a leave-one-domain-out setting, generalizability improved considerably. This mitotic figure dataset is the first that incorporates a wide domain shift based on different tumor types, laboratories, whole slide image scanners, and species.
Topics: Humans; Algorithms; Prognosis; Mitosis; Neoplasms
PubMed: 37491536
DOI: 10.1038/s41597-023-02327-4 -
Veterinary Pathology Jan 2024Increased or constitutive activation of nuclear factor kappa B (NF-kB) is a feature of many chronic disease processes, including cancer. While NF-kB overactivation has...
Increased or constitutive activation of nuclear factor kappa B (NF-kB) is a feature of many chronic disease processes, including cancer. While NF-kB overactivation has been documented extensively in human oncology, there is a relative paucity of data documenting the same phenomenon in veterinary medicine. To assess NF-kB activity, antibodies to p65 and p100/p52, which are components of NF-kB heterodimers, were first validated for specificity and canine cross-reactivity via Western blot and labeling of immortalized cell pellets. Then, nuclear labeling for these antibodies was assessed via QuPath software in over 200 tumor tissue samples (10 hemangiosarcomas, 94 histiocytic sarcomas, 71 lymphomas, and 28 mast cell tumors) and compared to immunolabeling in appropriate normal tissue counterparts. Greater than 70% of spontaneous canine tumors evaluated in this study had more nuclear p65 and p100/p52 immunoreactivity than was observed in comparable normal cell populations. Specifically, 144/204 (70.58%) of tumors evaluated had positive p65 nuclear labeling and 179/195 (91.79%) had positive p100/p52 nuclear labeling. Surprisingly, greater nuclear p100/p52 reactivity was associated with a longer progression-free survival (PFS) and overall survival (OS) in canine lymphomas. These results provide support and preliminary data to investigate the role of NF-kB signaling in different types of canine cancer.
Topics: Animals; Dogs; Humans; NF-kappa B; Histiocytic Sarcoma; Hemangiosarcoma; Mast Cells; NF-kappa B p52 Subunit; Lymphoma; Dog Diseases
PubMed: 37357953
DOI: 10.1177/03009858231180484