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Clinical Sarcoma Research 2016A chronic inflammatory cell infiltrate is commonly seen in response to primary malignant tumours of bone. This is known to contain tumour-associated macrophages (TAMs)...
BACKGROUND
A chronic inflammatory cell infiltrate is commonly seen in response to primary malignant tumours of bone. This is known to contain tumour-associated macrophages (TAMs) and lymphocytes; dendritic cells (DCs) and mast cells (MCs) have also been identified but whether these and other inflammatory cells are seen commonly in specific types of bone sarcoma is uncertain.
METHODS
In this study we determined the nature of the inflammatory cell infiltrate in 56 primary bone sarcomas. Immunohistochemistry using monoclonal antibodies was employed to assess semiquantitatively CD45+ leukocyte infiltration and the extent of the DC, MC, TAM and T and B lymphocyte infiltrate.
RESULTS
The extent of the inflammatory infiltrate in individual sarcomas was very variable. A moderate or heavy leukocyte infiltrate was more commonly seen in conventional high-grade osteosarcoma, undifferentiated pleomorphic sarcoma and giant cell tumour of bone (GCTB) than in Ewing sarcoma, chordoma and chondrosarcoma. CD14+/CD68+ TAMs and CD3+ T lymphocytes were the major components of the inflammatory cell response but (DC-SIGN/CD11c+) DCs were also commonly noted when there was a significant TAM and T lymphocyte infiltrate. MCs were identified mainly at the periphery of sarcomas, including the osteolytic tumour-bone interface.
DISCUSSION
Our findings indicate that, although variable, some malignant bone tumours (e.g. osteosarcoma, GCTB) are more commonly associated with a pronounced inflammatory cell infiltrate than others (e.g. chondrosarcoma. Ewing sarcoma); the infiltrate is composed mainly of TAMs but includes a significant DC, T lymphocyte and MC infiltrate.
CONCLUSION
Tumours that contain a heavy inflammatory cell response, which includes DCs, TAMs and T lymphocytes, may be more amenable to immunomodulatory therapy. MCs are present mainly at the tumour edge and are likely to contribute to osteolysis and tumour invasion.
PubMed: 27482375
DOI: 10.1186/s13569-016-0053-3 -
Expert Opinion on Pharmacotherapy Oct 2013Mastocytosis is a disorder characterized by abnormal mast cell (MC) accumulation in skin and internal organs such as bone marrow. The disease follows a benign course in... (Review)
Review
INTRODUCTION
Mastocytosis is a disorder characterized by abnormal mast cell (MC) accumulation in skin and internal organs such as bone marrow. The disease follows a benign course in most patients with cutaneous and indolent systemic mastocytosis (SM); however, advanced variants associated with decreased life expectancy also exist. Pharmacotherapy of mastocytosis is aimed at the control of symptoms caused by MC mediator release, treatment of comorbidities and cytoreductive therapies in advanced variants.
AREAS COVERED
This article will cover the general treatment principles of anti-MC mediator and cytoreductive therapies of mastocytosis. The literature discussed was retrieved with PubMed using the search terms 'treatment of mastocytosis,' 'mastocytosis antimediator therapy' and looking for important cross-references.
EXPERT OPINION
Pharmacotherapy of mastocytosis should be individualized for each patient considering the category of disease, reduction of risk of anaphylaxis, constitutional symptoms and comorbidities including osteoporosis. Cytoreductive therapies are generally reserved for patients with aggressive mastocytosis (ASM), MC leukemia (MCL) and MC sarcoma (MCS); however, some patients with indolent disease and recurrent anaphylactic episodes not responsive to antimediator therapies may also be considered for cytoreduction on a case-by-case basis.
Topics: Humans; Immunologic Factors; Mastocytosis; Protein Kinase Inhibitors
PubMed: 24044484
DOI: 10.1517/14656566.2013.824424 -
Frontiers in Immunology 2023Hypermethylated in Cancer 1 (HIC1) was originally confirmed as a tumor suppressor and has been found to be hypermethylated in human cancers. Although growing evidence...
BACKGROUND
Hypermethylated in Cancer 1 (HIC1) was originally confirmed as a tumor suppressor and has been found to be hypermethylated in human cancers. Although growing evidence has supported the critical roles of HIC1 in cancer initiation and development, its roles in tumor immune microenvironment and immunotherapy are still unclear, and no comprehensive pan-cancer analysis of HIC1 has been conducted.
METHODS
HIC1 expression in pan-cancer, and differential HIC1 expression between tumor and normal samples were investigated. Immunohistochemistry (IHC) was employed to validate HIC1 expression in different cancers by our clinical cohorts, including lung cancer, sarcoma (SARC), breast cancer, and kidney renal clear cell carcinoma (KIRC). The prognostic value of HIC1 was illustrated by Kaplan-Meier curves and univariate Cox analysis, followed by the genetic alteration analysis of HIC1 in pan-cancer. Gene Set Enrichment Analysis (GSEA) was conducted to illustrate the signaling pathways and biological functions of HIC1. The correlations between HIC1 and tumor mutation burden (TMB), microsatellite instability (MSI), and the immunotherapy efficacy of PD-1/PD-L1 inhibitors were analyzed by Spearman correlation analysis. Drug sensitivity analysis of HIC1 was performed by extracting data from the CellMiner™ database.
RESULTS
HIC1 expression was abnormally expressed in most cancers, and remarkable associations between HIC1 expression and prognostic outcomes of patients in pan-cancer were detected. HIC1 was significantly correlated with T cells, macrophages, and mast cell infiltration in different cancers. Moreover, GSEA revealed that HIC1 was significantly involved in immune-related biological functions and signaling pathways. There was a close relationship of HIC1 with TMB and MSI in different cancers. Furthermore, the most exciting finding was that HIC1 expression was significantly correlated with the response to PD-1/PD-L1 inhibitors in cancer treatment. We also found that HIC1 was significantly correlated with the sensitivity of several anti-cancer drugs, such as axitinib, batracylin, and nelarabine. Finally, our clinical cohorts further validated the expression pattern of HIC1 in cancers.
CONCLUSIONS
Our investigation provided an integrative understanding of the clinicopathological significance and functional roles of HIC1 in pan-cancer. Our findings suggested that HIC1 can function as a potential biomarker for predicting the prognosis, immunotherapy efficacy, and drug sensitivity with immunological activity in cancers.
Topics: Humans; Ferroptosis; Immune Checkpoint Inhibitors; Programmed Cell Death 1 Receptor; Prognosis; Carcinoma, Renal Cell; Kidney Neoplasms; Tumor Microenvironment; Kruppel-Like Transcription Factors
PubMed: 37388742
DOI: 10.3389/fimmu.2023.1182030 -
Pathobiology : Journal of... 2020Most cases of mastocytosis are indolent, usually cutaneous mastocytosis or indolent systemic mastocytosis (SM). Aggressive mast cell (MC) diseases are very rare and... (Review)
Review
Most cases of mastocytosis are indolent, usually cutaneous mastocytosis or indolent systemic mastocytosis (SM). Aggressive mast cell (MC) diseases are very rare and often fatal. They can develop de novo or due to progression of indolent forms and can present in different ways; either as MC sarcoma or as advanced SM which includes aggressive SM, MC leukemia, and SM with an associated hematological neoplasm. This review will describe these different aggressive forms of mastocytosis, illustrated by cases submitted to the workshop of the 18th Meeting of the European Association for Haematopathology, Basel 2016, organized by the European Bone Marrow Working Group. In addition, the diagnostic criteria for identifying myelomastocytic leukemia, an aggressive myeloid neoplasm with partial MC differentiation that falls short of the criteria for SM, and disease progression in patients with established mastocytosis are discussed.
Topics: Bone Marrow; Congresses as Topic; Diagnosis, Differential; Disease Progression; Europe; Humans; Leukemia, Mast-Cell; Mastocytosis; Mastocytosis, Systemic; Myeloproliferative Disorders
PubMed: 31802761
DOI: 10.1159/000504099 -
Cellular and Molecular Life Sciences :... Aug 2012Cell adhesion molecule 1 (CADM1), expressed by human lung mast cells (HLMCs), mediates their adhesion to airway smooth muscle (ASM), and contributes to ASM-dependent... (Comparative Study)
Comparative Study
Cell adhesion molecule 1 (CADM1), expressed by human lung mast cells (HLMCs), mediates their adhesion to airway smooth muscle (ASM), and contributes to ASM-dependent HLMC proliferation and survival. CADM1 is expressed in alternatively spliced isoforms, but those present in HLMCs and their function are not known. We cloned three functional and one cryptic non-functional isoform with alternative splicing between exons 7/11 and 1/2, respectively, from HLMCs and human MC lines (HMC-1 and LAD2). Differentiated HLMCs and LAD2 cells expressed the functional isoform SP4 containing exons 7/8/11 (~80% of clones), as well as SP1 (exons 7/8/9/11) and a novel SP6 (exons 7/8/9/10/11). In contrast, immature HMC-1 cells expressed only functional SP4. SP4 overexpression in HMC-1 cells and HLMCs augmented homotypic adhesion to a greater extent than SP1 in various conditions. In contrast, CADM1 downregulation abolished homotypic adhesion, indicating that CADM1 is the sole receptor mediating mast cell aggregation. CADM1-mediated adhesion was enhanced by the presence of cell survival factors. SP1 overexpression in HMC-1 cells compromised survival compared to SP4 overexpression or control. CADM1 downregulation resulted in reduced viability and decreased expression of the pro-survival protein Mcl-1(L), but not Blc-2 or Bcl-X(L), and increased caspase-3/7 activity in both HMC-1 cells and HLMCs. This coincided with decreased basal Kit levels in HLMCs. In summary, human MCs express multiple CADM1 isoforms which exhibit differential regulation of survival and homotypic adhesion. The most highly expressed SP4 isoform is likely to contribute to MC aggregation and longevity in mastocytosis, and augment the pathophysiology of allergic diseases.
Topics: Blotting, Western; Cell Adhesion; Cell Adhesion Molecule-1; Cell Adhesion Molecules; Cell Aggregation; Cell Survival; Cells, Cultured; Humans; Immunoglobulins; Leukemia, Mast-Cell; Lung; Mast Cells; Mast-Cell Sarcoma; Protein Isoforms; RNA, Messenger; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction
PubMed: 22438059
DOI: 10.1007/s00018-012-0948-y -
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 Canadian Veterinary Journal = La... Sep 2017Mast cell tumors (MCTs) are commonly encountered in dogs and have been reported in cutaneous, conjunctival, oral mucosal, and gastrointestinal locations, but not in an...
Mast cell tumors (MCTs) are commonly encountered in dogs and have been reported in cutaneous, conjunctival, oral mucosal, and gastrointestinal locations, but not in an intramuscular location. Medical records at 2 referral centers in the UK were examined to find cases of MCTs in this location. Seven dogs were identified as having an intramuscular MCT by a combination of fine-needle aspirate cytology and computed tomography or ultrasound. None of the dogs had evidence of local lymph node metastasis. Six dogs had no evidence of distant metastasis and surgery was carried out as the primary treatment option. Three of those dogs also had adjunctive chemotherapy due to a high Ki67 value or high mitotic index. All 6 dogs that had had surgery were alive at follow-up with a minimum elapsed time of 7 months. One dog had a course of chemotherapy due to the location, size, and evidence of biological activity of the tumor and died 23 days afterwards. The prognosis of intramuscular mast cell tumors appears to be favorable in most cases.
Topics: Animals; Dog Diseases; Dogs; Mast-Cell Sarcoma; Neoplasm Staging; Prognosis
PubMed: 28878416
DOI: No ID Found -
Cureus Dec 2023KIT gene mutations in Ewing sarcomas are rare; however, they are much more frequent in other neoplasms, namely mastocytosis. We describe a case of an adult male with a...
KIT gene mutations in Ewing sarcomas are rare; however, they are much more frequent in other neoplasms, namely mastocytosis. We describe a case of an adult male with a one-year duration of recurrent episodes of pain, swelling, and redness on the proximal phalanx of the third finger of his right hand. A core biopsy suggested a possible mastocytosis. After four years of recurrent episodes and worsening symptoms, an incisional biopsy revealed an Ewing sarcoma with a KIT gene mutation (M541L, on exon 10). KIT gene mutations with gain-of-function were identified in 2.6% of Ewing sarcomas. In this case, the detection of a KIT mutation in an Ewing sarcoma developed at the site of previous mast cell proliferation raises the hypothesis of a possible sarcomatous evolution of the original lesion. To the best of our knowledge, similar cases are not described in the current literature. This is also the first report describing the KIT M541L mutation (exon 10) in Ewing sarcoma.
PubMed: 38222235
DOI: 10.7759/cureus.50537 -
BMC Cancer Jan 2023Mastocytosis is a very rare disorder and is divided into three prognostically distinct variants by World Health Organization: Cutaneous mastocytosis (CM), systemic...
Mastocytosis is a very rare disorder and is divided into three prognostically distinct variants by World Health Organization: Cutaneous mastocytosis (CM), systemic mastocytosis (SM), and mast cell sarcoma or localized mast cell (MC) tumors. The wide range of complaints may cause patients to consult various clinics, with resulting mis- or underdiagnosis. Therefore, cooperation between different subspecialties is of paramount importance. In this article, we have compiled 104 adult mastocytosis cases diagnosed and followed in our Hematology and other clinics. 86 (82.7%) of 104 patients had systemic mastocytosis. Osteoporosis, disease-related complications, and secondary malignancies are important topics in this group. We know that indolent form has great survival. But smoldering or aggressive mastocytosis has a poor prognosis. CM and indolent SM have a significantly better prognosis compared to aggressive SM (p < 0.001). We found that the presence of more than 25% of mast cells in the bone marrow, the presence of concomitant marrow dysplasia, and the presence of disease-related complications affect survival (p < 0.001). In addition to the WHO classification, the IPSM scoring system is indicative of the prognosis in this rare disease.
Topics: Adult; Humans; Mastocytosis, Systemic; Mastocytosis; Mast Cells; Bone Marrow; Prognosis; Myeloproliferative Disorders
PubMed: 36694141
DOI: 10.1186/s12885-022-10498-3 -
Journal of Veterinary Internal Medicine 2006The Patnaik histologic grading system is commonly used to predict the behavior of cutaneous mast cell tumors (MCTs) in dogs, but it is less useful for grade 2 MCTs...
The Patnaik histologic grading system is commonly used to predict the behavior of cutaneous mast cell tumors (MCTs) in dogs, but it is less useful for grade 2 MCTs because they exhibit considerable variation in biological behavior. In this retrospective study, immunohistochemical staining for Ki-67, proliferating cell nuclear antigen (PCNA), and survivin and a standardized argyrophilic staining of nucleolar organizer regions (AgNOR) protocol were performed on 121 archived paraffin-embedded specimens of canine cutaneous MCTs, for which clinical follow-up data were available. Cox regression models indicated that the Ki-67 score (hazard ratio, 1.92; P < .001) and mean AgNOR score (hazard ratio, 2.57; P < .001) were significantly associated with Patnaik grade and survival time. A binary Ki-67 variable (cutoff point Ki-67 score = 1.8) was a significant predictor of survival for dogs with grade 2 MCTs. The estimated 1-, 2-, and 3-year survival probabilities for dogs with grade 2 MCTs and Ki-67 scores less than 1.8 were 0.92, 0.86, and 0.77, respectively (SEs, 0.08, 0.14, and 0.23, respectively; median not estimable). The corresponding survival probabilities for dogs with grade 2 MCTs and Ki-67 scores higher than 1.8 were 0.43, 0.21, and 0.21, respectively (SEs, 0.19, 0.18, and 0.18, respectively; median survival time, 395 days). No significant association was identified between survival and survivin score or PCNA score. This study shows that both mean AgNOR score and Ki-67 score are prognostic markers for canine MCTs. The Ki-67 score can be used to divide Patnaik grade 2 MCTs into 2 groups with markedly different expected survival times.
Topics: Animals; Antigens, Nuclear; Apoptosis; Biomarkers; Cell Proliferation; Dog Diseases; Dogs; Gene Expression Regulation, Neoplastic; Inhibitor of Apoptosis Proteins; Mast-Cell Sarcoma; Neoplasm Proteins; Nuclear Proteins; Prognosis; Proliferating Cell Nuclear Antigen
PubMed: 16496935
DOI: 10.1892/0891-6640(2006)20[151:cmctco]2.0.co;2