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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Hemangiosarcoma , Humanos , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/metabolismo , Neoplasias de los Conductos Biliares/cirugía , Neoplasias de los Conductos Biliares/genética , Conductos Biliares Intrahepáticos/patología , Colangiocarcinoma/patología , Colangiocarcinoma/metabolismo , Colangiocarcinoma/cirugía , Colangiocarcinoma/genética , Resultado Fatal , Hemangiosarcoma/patología , Hemangiosarcoma/metabolismo , Hemangiosarcoma/cirugía , Hemangiosarcoma/genética , Queratina-7/metabolismo , Mutación , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Thyroid angiosarcoma (TAS) is an aggressive vascular tumor, accounting for 20 % of thyroid mesenchymal neoplasms and affecting elderly patients with frequent extra-thyroidal local extension and distant spread. It usually arises in the context of a long-standing goiter with higher incidence in iodine-deficient Alpine districts of Italy, Austria and Switzerland. Nevertheless, a relevant proportion of cases have been documented in iodine sufficient areas, being unrelated to goitrogen etiology and possibly associated with other risk factors. Histological features consist of large epithelioid cells with severe pleomorphism, arranged in a solid growth pattern with formation of vascular spaces, and set in a fibrotic stroma admixed with hemosiderin deposits and necrosis. Immunohistochemistry reveals positive staining for CD31, ERG and factor VIII, frequently accompanied by cytokeratin expression. Such findings may raise concern for the diagnosis of angiomatoid anaplastic carcinoma, which can be ruled out by the absence of thyroidal differentiation markers (including PAX8 and TTF-1). Cytological findings are rather non-specific and fine needle aspiration frequently yields inconclusive results. The genetic background of angiosarcoma is dominated by the impairment of genes deeply involved in angiogenesis, proliferation and survival (including MYC, KDR, FLT4, PTPRB and PLCG1) along with the dysregulation of crucial pathways like PIK3CA/AKT/mTOR and MAP kinase, with a relevant impact on possible novel therapeutic strategies. However, little is known about the molecular features of TAS and more investigations are needed to improve the characterization of this entity.
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Hemangiosarcoma , Neoplasias de la Tiroides , Humanos , Hemangiosarcoma/patología , Hemangiosarcoma/genética , Hemangiosarcoma/diagnóstico , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/diagnóstico , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genéticaRESUMEN
BACKGROUND Epithelioid angiosarcoma arising in a schwannoma is an exceedingly rare and aggressive malignancy, with less than 25 cases reported in the English-language literature. Histopathologically, it combines the spindle cell characteristics of schwannomas with the epithelioid, vascular nature of angiosarcomas. The presence of SMARCB1 frameshift loss-of-function (LOF) mutations impairs gene function, contributing to various aggressive cancers. CASE REPORT A 58-year-old man presented with slow-growing masses on the back and arm. Ultrasound and MRI findings were suspicious for nerve sheath tumor. He underwent surgical resection and biopsy, with results revealing SOX10-positive, S100-positive, CD31-positive, excisional margins-positive characteristics of high-grade epithelioid angiosarcoma arising in a schwannoma. A PET scan suggested metastasis to intrathoracic lymph nodes. Tempus molecular profiling showed SMARCB1 frameshift LOF. He was treated with weekly paclitaxel and tazemetostat, with slight improvement in pain; however, he developed symptomatic disease progression. Due to extensive metastatic disease precluding surgical resection, palliative radiation was added to the systemic treatment regimen. After several cycles of treatments with worsening symptoms, he decided to enter hospice care. CONCLUSIONS Presentation of high-grade angiosarcoma arising in schwannoma can be non-specific, posing a diagnostic challenge. Histopathology and immunohistochemistry are essential in the diagnosis and may be characterized by the presence of SMARCB1 frameshift LOF as a prognostic biomarker. Surgical resection with negative margins is the cornerstone of treatment supplemented by chemotherapy and radiotherapy. Patients should be monitored closely for recurrence or metastasis.
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Hemangiosarcoma , Neurilemoma , Proteína SMARCB1 , Humanos , Masculino , Neurilemoma/patología , Neurilemoma/genética , Persona de Mediana Edad , Hemangiosarcoma/genética , Hemangiosarcoma/patología , Hemangiosarcoma/terapia , Proteína SMARCB1/genética , Mutación del Sistema de Lectura , MutaciónRESUMEN
Angiosarcoma is a rare and aggressive soft tissue sarcoma with a poor prognosis and limited treatment options. The role of interleukin-13 (IL-13) and its receptors in angiosarcoma pathogenesis has been largely unknown. We first reanalyzed transcriptomic data from a published angiosarcoma cohort and found IL13RA2 mRNA elevated in angiosarcoma versus normal tissue. In addition, high IL13RA2 expression was significantly associated with increased nonsynonymous mutations. We next detected high IL-13 receptor α2 (IL-13Rα2) expression in angiosarcoma cell lines and patient samples compared to other cell types and benign vascular tumors. Moreover, histological analysis showed the presence of IL-13 in the angiosarcoma microenvironment. Functional studies using angiosarcoma cell lines, MO-LAS-B cells, revealed the promoting effect of IL-13 on cell proliferation. The effect was inhibited by siRNA-mediated knockdown of IL13RA2 or neutralizing antibodies against IL-13, suggesting the impact of IL-13/IL-13Rα2 axis in the angiosarcoma proliferation. In addition, IL-13 stimulation increased mRNA levels of IL13RA2 and VEGFA, suggesting an underlying positive feedback mechanism, which was attenuated by a STAT6 inhibitor. These findings highlight the importance of the IL-13/IL-13Rα2 axis in angiosarcoma progression and its potential as a novel therapeutic target for this challenging malignancy.
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Hemangiosarcoma , Subunidad alfa2 del Receptor de Interleucina-13 , Interleucina-13 , Humanos , Hemangiosarcoma/patología , Hemangiosarcoma/genética , Hemangiosarcoma/metabolismo , Proliferación Celular , Subunidad alfa2 del Receptor de Interleucina-13/genética , Subunidad alfa2 del Receptor de Interleucina-13/metabolismo , Interleucina-13/metabolismo , Interleucina-13/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Transducción de Señal , Microambiente TumoralRESUMEN
Background: Intimal sarcoma (IS) and angiosarcoma (AS), two rare yet highly aggressive vascular mesenchymal malignancies, present significant therapeutic challenges due to their scarcity, which underscoring the urgent need to investigate genetic alterations and tumor microenvironment (TME) features for novel therapeutic development. Methods: We performed integrated analysis of whole-exome sequencing (WES)/1021-gene panel sequencing, RNA sequencing, and immunohistochemistry (IHC) data from 31 IS and 35 AS patients to identify potential precision therapy. Results: Genomic profiling revealed 522 and 518 single nucleotide variants (SNVs) in the IS and AS cohorts, respectively. TP53 mutations predominated in AS versus IS (15/35 vs 2/31, p < 0.001). Conversely, IS exhibited significantly more copy number variants (CNVs), particularly involving the KDR/KIT/PDGFRA locus (chromosome 4) and the CDK4/MDM2 locus (chromosome 12) (p < 0.001). Strikingly, 25/31 (81%) IS patients harbored CDK4 copy number gains or CDKN2A/B losses, compared to only 2/35 (6%) AS patients (p < 0.001). TME analysis revealed no significant inter-group differences overall; however, pulmonary artery IS specimens demonstrated substantial immune infiltration. Notably, reduced CD3+ T-cell density correlated with shorter survival (p =0.029). PD-L1 expression analysis (≥1% cutoff) showed positivity in 6/8 evaluable patients, including 3 with >50% tumor cell staining. Two IS patients receiving postoperative Sintilimab (PD-1 inhibitor) experienced prolonged survival (overall survival: 14+ and 56+ months, respectively). Conclusions: This study characterizes the distinct mutation landscape yet similar immune microenvironment of rare IS and AS. Given the frequent cell cycle dysregulation and the observed PD-L1 expression in a subset of patients, CDK4/6 inhibitors and PD-1/PD-L1 inhibitors warrant further clinical investigation for these patients.
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Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Hemangiosarcoma , Inmunoterapia , Inhibidores de Proteínas Quinasas , Sarcoma , Humanos , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/genética , Femenino , Masculino , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Sarcoma/genética , Sarcoma/tratamiento farmacológico , Sarcoma/inmunología , Persona de Mediana Edad , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Anciano , Hemangiosarcoma/genética , Hemangiosarcoma/tratamiento farmacológico , Hemangiosarcoma/inmunología , Variaciones en el Número de Copia de ADN , Secuenciación del Exoma , Inmunoterapia/métodos , Adulto , Inhibidores de Proteínas Quinasas/uso terapéutico , Mutación , Biomarcadores de Tumor/genética , Anciano de 80 o más Años , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , MultiómicaRESUMEN
PURPOSE: Angiosarcomas (AS) are rare vascular sarcomas. Secondary AS (sAS) arise from DNA-damaging factors such as radiotherapy and UV radiation (UV-AS) or due to chronic lymphedema. The prognosis for advanced AS is poor, with limited treatment options. Immune checkpoint inhibition is not approved for AS, but high intratumoral T-cell density and frequent mutations in sAS may support efficacy. PATIENTS AND METHODS: This prospective, single-arm, multicenter phase II trial assessed the efficacy and safety of cemiplimab (350 mg, intravenously every 3 weeks) in patients with locally advanced or metastatic sAS using a Simon's two-stage design. The primary outcome was the best overall response rate within 24 weeks of treatment. Secondary outcomes included time to response, duration of response, progression-free survival, overall survival, and predictive biomarkers for treatment response. RESULTS: Eighteen patients (12 with AS from radiotherapy, 3 with UV-AS, and 3 with AS due to chronic lymphedema) were treated with cemiplimab. The best overall response rate was 27.8% (4 partial responses, 1 complete response), with a time to response of 2.6 months and a duration of response of 6.9 months. The median progression-free survival was 3.7 months, and the median overall survival was 13.1 months. Grade ≥3 immune-related adverse events occurred in 33.3% of patients. High tumor mutational burden was observed in three patients with UV-AS, two of whom showed a response. High intratumoral CD3+ (P = 0.019), CD4 (P = 0.046), CD8+ (P = 0.026), and FoxP3+ (P = 0.026) T-cell densities; low platelet-to-lymphocyte ratio (P = 0.026); and Colidextribacter abundance were associated with response. CONCLUSIONS: Cemiplimab shows promising effectivity in sAS and warrants further investigation. Promising predictive blood and tissue biomarkers were identified, indicating potential for improved patient selection.
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Anticuerpos Monoclonales Humanizados , Antineoplásicos Inmunológicos , Biomarcadores de Tumor , Hemangiosarcoma , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Biomarcadores de Tumor/genética , Adulto , Hemangiosarcoma/tratamiento farmacológico , Hemangiosarcoma/patología , Hemangiosarcoma/mortalidad , Hemangiosarcoma/etiología , Hemangiosarcoma/genética , Estudios Prospectivos , Pronóstico , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/administración & dosificación , Anciano de 80 o más AñosRESUMEN
PURPOSE: Bone angiosarcoma (B-AS) is an exceedingly rare and aggressive vascular neoplasm, with limited therapeutic options and poor outcomes. Unlike the more prevalent clinical subsets (breast, head and neck), the pathogenesis of B-AS remains poorly defined, with no targeted therapeutic strategies available. Moreover, the often delays in diagnosis, either radiographically or pathologically, as well as the common multifocal presentation, further impact the feasibility of surgical management, contributing to lower survival rates. In this study, we investigated the clinicopathologic and molecular characteristics of B-AS to better define prognostic factors influencing outcomes. PATIENTS AND METHODS: This retrospective study analyzed 22 cases of B-AS managed at a single tertiary cancer center from 1998 to 2024. Clinical and pathologic data were extracted through chart reviews and re-assessment of radiology and histology. Molecular characterization was performed in a subset using targeted next-generation sequencing (NGS). RESULTS: The cohort included 14 males and eight females (median age: 64.5 years), with tumors mostly involving femur, pelvis, and spine. Twelve (55%) patients presented with disease limited to the bone, either solitary or multifocal, while 10 (45%) patients presented in addition with extraskeletal metastases at diagnosis. The skeletal distribution included six (27%) solitary bone lesions, with the remaining 16 being multifocal (four contiguous, twelve disseminated). A surgical procedure for the bone lesions was performed in 73% of cases, varying from intralesional curetting to limb amputation. Half of the patients received radiation, and 73% chemotherapy. By molecular profiling, all tumors showed a low tumor mutational burden (TMB), with the most frequent alterations being KDR mutations and MYC amplifications. Age and chemotherapy were significantly associated with improved overall survival (OS) (p < 0.005); however, the 3-year OS was only 30%. CONCLUSION: Despite the multidisciplinary approach and orthopedic oncology expertise from a tertiary cancer center, the prognosis for B-AS remains poor. Although limited in number, the molecular profiling revealed overlapping genomic alterations with other clinical subsets of AS, having the potential for individualized patient management.
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Neoplasias Óseas , Hemangiosarcoma , Humanos , Hemangiosarcoma/genética , Hemangiosarcoma/patología , Hemangiosarcoma/terapia , Masculino , Femenino , Persona de Mediana Edad , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Neoplasias Óseas/terapia , Anciano , Estudios Retrospectivos , Adulto , Anciano de 80 o más Años , Pronóstico , Secuenciación de Nucleótidos de Alto Rendimiento , Mutación , Biomarcadores de Tumor/genéticaRESUMEN
Cutaneous angiosarcoma is a rare aggressive malignancy with poor prognosis. Due to its rarity, high-level evidence from randomized controlled trials is limited, and treatment strategies have historically been adapted from other sarcomas. These guidelines aim to provide updated recommendations based on newly available evidence to standardize clinical practice in Japan. The 2024 revision was conducted under the Japanese Dermatological Association's commission, incorporating expert reviews and public comments. Given the lack of an established staging system, recommendations were formulated through systematic literature reviews and a structured consensus process. Five clinical questions were addressed, covering first-line chemoradiotherapy (CRT), management of residual lesions post-CRT, second-line treatment options, the role of pembrolizumab in tumor mutational burden-high cases, and treatment strategies for nonhead-and-neck angiosarcomas. Key recommendations include weakly recommending CRT for large (≥ 5 cm) nonmetastatic tumors, preferring drug modification over excision for residual lesions after CRT, and equally considering docetaxel, pazopanib, or eribulin for paclitaxel-resistant cases. Pembrolizumab was weakly recommended for tumor mutational burden-high cases. For radiation-associated angiosarcoma, surgical treatment was favored over CRT, while Stewart-Treves syndrome cases were treated similarly to head-and-neck angiosarcoma. Future directions emphasize the need for multicenter registry studies and prospective trials to refine treatment strategies. As advances in genomic medicine and immunotherapy evolve, guideline updates will be essential to ensure optimal patient care.
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Dermatología , Hemangiosarcoma , Neoplasias Cutáneas , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Quimioradioterapia/normas , Quimioradioterapia/métodos , Dermatología/normas , Hemangiosarcoma/terapia , Hemangiosarcoma/patología , Hemangiosarcoma/diagnóstico , Hemangiosarcoma/genética , Japón , Neoplasias Cutáneas/terapia , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/diagnóstico , Sociedades Médicas/normasRESUMEN
BACKGROUND: Angiosarcoma is a rare and aggressive malignancy with limited treatment options. This phase II, multicenter, open-label, single-arm study (AngioCheck) evaluated the efficacy and safety of nivolumab in patients with cutaneous angiosarcoma previously treated with taxane-based chemotherapy. METHODS: Eligible patients had histologically confirmed cutaneous angiosarcoma, prior treatment with docetaxel or paclitaxel, and at least one measurable lesion. Patients received nivolumab 480â¯mg every four weeks. The primary endpoint was the centrally reviewed overall response rate (ORR). Secondary endpoints included investigator-assessed ORR, overall survival (OS), and progression-free survival (PFS). An exploratory biomarker analysis was conducted to assess tumor mutational burden (TMB). RESULTS: Twenty-three patients were enrolled across 11 institutions in Japan. The investigator-assessed ORR was 21.7â¯% (5 patients with partial response [PR], while the centrally reviewed ORR was 13.0â¯% (3 PR; 90â¯% CI: 3.7-30.4), which did not meet the predefined success threshold. The median OS was 259 days (90â¯% CI: 188.0-387.0), and the median PFS was 59 days (90â¯% CI: 57-112). TMB analysis was performed in 16 patients: among TMB-high patients (nâ¯=â¯7), there were 0 PR and 3 stable disease (SD); among non-TMB-high patients (nâ¯=â¯9), 2 PR and 1â¯SD were observed. Although the TMB-high group had a numerically higher disease control rate (PR + SD; 42.9â¯% vs. 33.3â¯%), no significant association between TMB status and treatment response was found. CONCLUSIONS: Nivolumab monotherapy did not achieve the predefined response rate in this cohort of pretreated cutaneous angiosarcoma patients. No correlation between TMB-high status and objective response was identified. Further investigations are needed to explore predictive biomarkers and combination strategies to improve therapeutic efficacy.
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Antineoplásicos Inmunológicos , Hemangiosarcoma , Nivolumab , Neoplasias Cutáneas , Humanos , Nivolumab/uso terapéutico , Nivolumab/efectos adversos , Hemangiosarcoma/tratamiento farmacológico , Hemangiosarcoma/patología , Hemangiosarcoma/genética , Hemangiosarcoma/mortalidad , Masculino , Femenino , Anciano , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/mortalidad , Persona de Mediana Edad , Anciano de 80 o más Años , Adulto , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: Angiosarcoma, a rare and highly aggressive malignancy originating from vascular endothelial cells, is characterized by its rapid progression, high invasiveness, and poor prognosis. Due to the limited understanding of its tumor microenvironment (TME) and the absence of effective treatments, further research is essential to elucidate its pathogenic mechanisms and improve therapeutic strategies. OBJECTIVE: This study aims to characterize the cellular heterogeneity and unique TME of primary breast angiosarcoma using single-cell RNA sequencing (scRNA-seq), to identify potential therapeutic targets and improve clinical outcomes. METHODS: Tumor samples were obtained from a patient with bilateral primary breast angiosarcoma and two patients with invasive breast cancer. Single-cell RNA sequencing (scRNA-seq) was conducted to capture the transcriptomic profiles of individual cells within the tumor samples. Following stringent quality control, a total of 31,771 cells were analyzed using comprehensive bioinformatics approaches. Cell populations were identified and classified into distinct cell types, and differential gene expression analysis was performed to explore key signaling pathways. Functional enrichment analysis was used to identify pathways related to tumor progression and immune evasion. Additionally, cell-cell communication networks were mapped to understand interactions within the TME, with a focus on pathways that may serve as therapeutic targets. RESULTS: The scRNA-seq analysis revealed significant differences in the distribution of perivascular cells, fibroblasts, T cells, endothelial cells, and myeloid cells in breast angiosarcoma compared to invasive breast cancer. Key pathways enriched in angiosarcoma samples included growth factor binding, platelet-derived growth factor binding, and ribosome biogenesis, with abnormal expression of several ribosomal proteins. Notably, genes such as FAT4, KDR, FN1, and KIT were highly expressed in angiosarcoma endothelial cells, correlating with poor prognosis. Cell communication analysis highlighted the CXCL12-CXCR4 axis as a crucial mediator of the TME in angiosarcoma. CONCLUSION: This study provides critical insights into the TME of primary breast angiosarcoma, highlighting potential molecular targets and pathways for therapeutic intervention. These findings may inform the development of more effective treatment strategies for this rare and challenging tumor type.
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Biomarcadores de Tumor , Neoplasias de la Mama , Hemangiosarcoma , Análisis de la Célula Individual , Microambiente Tumoral , Humanos , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Hemangiosarcoma/genética , Hemangiosarcoma/patología , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Análisis de la Célula Individual/métodos , Regulación Neoplásica de la Expresión Génica , Biomarcadores de Tumor/genética , Perfilación de la Expresión Génica , Transcriptoma , Análisis de Secuencia de ARN , Pronóstico , Transducción de Señal , Comunicación CelularRESUMEN
Cutaneous angiosarcoma (CAS) is a life-threatening neoplasm with a 5-year survival rate of under 40% in advanced cases. As available treatments for CAS are limited, novel therapeutics must be explored. To identify potential therapeutic candidates, we conducted a drug screening analysis using an angiosarcoma cell line, HAMON. Cancer-related gene analysis revealed alterations in FGFR4, MYCN, CDKN2A, NF1, TP53, KDM6A, ATRX, MSH6, ATM, and NOTCH1 in HAMON cells. Screening of 4681 FDA-approved drugs identified four candidate compounds, with the proteasome inhibitor bortezomib selected for further study. ATP and MTT assays revealed bortezomib to be the most effective candidate against HAMON cells. Clonogenic assays revealed fewer HAMON cell colonies in the range of 1-10 nM bortezomib. DNA-content fluorescence-activated cell sorting analysis revealed a notable increase in the sub-G0/G1 phases, suggesting cell death without cell cycle arrest. Annexin V-propidium iodide staining revealed a significant increase in the percentage of early and late apoptotic cells in the bortezomib group. Mechanistically, bortezomib induced activation of NF-κB and endoplasmic reticulum stress signaling. The administration of bortezomib to immunocompromised mice implanted with HAMON cells induced apoptosis of tumor cells. This study identified the proteasome inhibitor bortezomib as a potential candidate for angiosarcoma in vitro and in vivo.
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Antineoplásicos , Bortezomib , Hemangiosarcoma , Inhibidores de Proteasoma , Neoplasias Cutáneas , Hemangiosarcoma/tratamiento farmacológico , Hemangiosarcoma/patología , Hemangiosarcoma/genética , Humanos , Animales , Bortezomib/farmacología , Ratones , Inhibidores de Proteasoma/farmacología , Línea Celular Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Apoptosis/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Estados Unidos , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/genética , Antineoplásicos/farmacologíaRESUMEN
Splenic hemangiosarcoma (HSA) is a common canine tumor with histology and genetics analogous to human angiosarcoma (AS), a rare and aggressive malignancy arising from vascular cells. To assess biomarkers and inform therapeutics options, spontaneously arising HSAs were systematically profiled for genetic mutations prior to long-term assessment of patient response to chemotherapy and/or targeted therapy. We leveraged the real-world clinical-genomic data of dogs from the FidoCure® platform, a next-generation sequencing (NGS) screen of cancer loci. For all dogs, regardless of therapeutic approach, PTEN and P53 mutations were overall predictors of poor outcome, while NRAS mutation predicted better outcome. However, P53, PIK3CA, ATRX and NRAS predicted a better response to therapies that specifically included a targeted drug. Analyzing gene-drug interactions, we found tumors with P53 mutation were highly responsive to HDAC or MTOR inhibition, while tumors with PIK3CA mutation only predicted response to MTOR inhibition. For veterinarians, this real-world evidence bridges an important translational gap for targeted therapies, demonstrating a comparable or better outcome compared to standard adjuvant chemotherapy alone and an even further enhancement of survival with combined targeted therapy and chemotherapy. The investigation also uncovered a relationship between specific therapeutic interventions and outcomes when particular gene mutations were present, suggesting they could serve as biomarkers. Since canine HSA is a likely correlate for human AS, the study highlights the benefit of canine HSA as a model to inform precision medicine for AS, a rare human malignancy.
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Biomarcadores de Tumor , Enfermedades de los Perros , Hemangiosarcoma , Neoplasias del Bazo , Perros , Animales , Hemangiosarcoma/genética , Hemangiosarcoma/veterinaria , Hemangiosarcoma/tratamiento farmacológico , Biomarcadores de Tumor/genética , Enfermedades de los Perros/genética , Enfermedades de los Perros/tratamiento farmacológico , Mutación , Secuenciación de Nucleótidos de Alto Rendimiento , Genómica , Neoplasias del Bazo/genética , Neoplasias del Bazo/tratamiento farmacológico , Neoplasias del Bazo/veterinaria , Proteína p53 Supresora de Tumor/genética , Resultado del Tratamiento , Femenino , MasculinoRESUMEN
Cutaneous angiosarcoma is a rare and highly aggressive skin malignancy. The aim of this study is to explore the alteration of serum-derived extracellular vesicle (EV) in angiosarcoma patients and to evaluate its clinical utility as a novel circulating biomarker. In a microarray analysis to examine the differential expression of specific EV-associated microRNAs in sera between cutaneous angiosarcoma patients and healthy controls, 73 microRNAs with significant upregulation and 100 microRNAs with significant downregulation, respectively, were identified in patients with angio-sarcoma. Among them, quantitative PCR confirmed that miR-184, miR-3925-5p, miR-3926, and miR-5703 were upregulated in sera of cutaneous angiosarcoma patients compared with those of healthy controls and melanoma patients. Additionally, these 4 microRNAs were expressed more highly in angiosarcoma cell lines compared with normal human endothelial cell lines and were prone to elevate along with disease progression. Furthermore, a gene analysis predicted that the target gene set of microRNAs might affect the regulation of TP53 via the epigenetic regulation of MECP2. Taken together, these 4 extracellular vesicle-associated microRNAs in circulation serve as a promising liquid biomarker to identify angiosarcoma patients and trace disease progression.
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Biomarcadores de Tumor , MicroARN Circulante , Vesículas Extracelulares , Hemangiosarcoma , MicroARNs , Neoplasias Cutáneas , Humanos , Hemangiosarcoma/sangre , Hemangiosarcoma/genética , Hemangiosarcoma/patología , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/genética , Vesículas Extracelulares/patología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/sangre , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , MicroARNs/sangre , MicroARNs/genética , Femenino , Estudios de Casos y Controles , Masculino , Persona de Mediana Edad , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Anciano , Valor Predictivo de las Pruebas , MicroARN Circulante/sangre , MicroARN Circulante/genética , Adulto , Perfilación de la Expresión Génica/métodosRESUMEN
As multiple imaging modalities cannot reliably diagnose cardiac tumors, the molecular approach offers alternative ways to detect rare ones. One such molecular approach is CRISPR-based diagnostics (CRISPR-Dx). CRISPR-Dx enables visual readout, portable diagnostics, and rapid and multiplex detection of nucleic acids such as microRNA (miRNA). Dysregulation of miRNA expressions has been associated with cardiac tumors such as atrial myxoma and angiosarcoma. Diverse CRISPR-Dx systems have been developed to detect miRNA in recent years. These CRISPR-Dx systems are generally classified into four classes, depending on the Cas proteins used (Cas9, Cas12, Cas13, or Cas12f). CRISPR/Cas systems are integrated with various isothermal amplifications to detect low-abundance miRNAs. Amplification-free CRISPR-Dx systems have also been recently developed to detect miRNA directly. Herein, we critically discuss the advances, pitfalls, and future perspectives for these CRISPR-Dx systems in detecting miRNA, focusing on the diagnosis and prognosis of cardiac tumors.
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Sistemas CRISPR-Cas , Neoplasias Cardíacas , MicroARNs , Humanos , MicroARNs/genética , Neoplasias Cardíacas/genética , Neoplasias Cardíacas/diagnóstico , Sistemas CRISPR-Cas/genética , Mixoma/genética , Mixoma/diagnóstico , Hemangiosarcoma/genética , Hemangiosarcoma/diagnóstico , Biomarcadores de Tumor/genéticaRESUMEN
PURPOSE: Cardiac angiosarcoma is a rare, aggressive malignancy with limited treatment options. Both sporadic and familial cases occur, with recent links to germline POT1 mutations. The genomic landscape of this disease is poorly understood. EXPERIMENTAL DESIGN: We conducted comprehensive genomic profiling of cardiac angiosarcoma to assess the burden of germline predisposition and identify other recurrent genomic alterations of clinical significance. RESULTS: Six patients were female, and four were male. The median age at presentation was 40 years (range, 21-69 years). All cases with available follow-up exhibited an aggressive clinical course (6/8 patients died of disease). KDR alterations, including novel structural variants, were found in 9/11 cases at a rate significantly higher than that in noncardiac angiosarcomas. POT1 mutations were present in 45.5% of cardiac angiosarcoma cases. In three of five POT1-mutant cases, the germline status was confirmed through testing of normal tissue, and in one additional case, the germline status was inferred with high probability through allele frequency analysis. Additionally, we identified novel recurrent MED12 exon 2 mutations in POT1 wild-type cardiac angiosarcoma, suggesting an alternative path to cardiac angiosarcoma oncogenesis. CONCLUSIONS: Cardiac angiosarcoma demonstrates a unique genetic profile, distinct from noncardiac angiosarcoma. This study highlights the role of germline POT1 burden on cardiac angiosarcoma development and demonstrates recurrent MED12 alterations for the first time. The reported KDR variants provide a potential avenue for the treatment of this aggressive disease. Given the prevalence of germline POT1 mutations reported in this study, germline genetic testing should be considered in patients diagnosed with cardiac angiosarcoma.
Asunto(s)
Mutación de Línea Germinal , Neoplasias Cardíacas , Hemangiosarcoma , Proteínas de Unión a Telómeros , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Humanos , Hemangiosarcoma/genética , Hemangiosarcoma/patología , Femenino , Masculino , Adulto , Persona de Mediana Edad , Anciano , Neoplasias Cardíacas/genética , Neoplasias Cardíacas/patología , Proteínas de Unión a Telómeros/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Complejo Shelterina , Adulto Joven , Predisposición Genética a la Enfermedad , Genómica/métodosRESUMEN
BACKGROUND: Primary cardiac angiosarcoma (PCAS) is a rare and aggressive heart tumour with limited treatment options and a poor prognosis. Understanding cellular heterogeneity and tumour microenvironment (TME) is crucial for the development of effective therapies. Here, we investigated the intratumoural heterogeneity and TME diversity of PCAS using single-cell RNA sequencing (scRNA-seq). METHODS: We performed scRNA-seq analysis on tumour samples from four patients with PCAS, supplemented with multicolour immunohistochemistry for identification. We used scRNA-seq data from five normal cardiac tissue samples downloaded from public databases for comparative analyses. Bioinformatic analyses, including Cell Ranger, Seurat, Monocle2, hdWGCNA, SCENIC and NicheNet, were utilized to identify distinct cell populations, transcriptional patterns, and co-regulating gene modules. RESULTS: Our analysis revealed significant intratumoural heterogeneity in PCAS driven by diverse biological processes such as protein synthesis, degradation, and RIG-I signalling inhibition. The SCENIC analysis identified three primary transcription factors' clusters (CEBPB, MYC and TAL1). T-cell subset analysis showed exhausted antigen-specific T-cells, complicating the efficacy of immune checkpoint blockade. Furthermore, we observed suppressive macrophages (SPP1+ and OLR1+) and reduced mitochondrial gene MT-RNR2 (MTRNR2L12) expression in TME-infiltrating cells, indicating impaired mitochondrial function. CONCLUSION: This study elucidates the complex cellular landscape and immune microenvironment of PCAS, highlighting potential molecular targets for the development of novel therapies. These findings underscore the importance of a multifaceted therapeutic approach for addressing the challenges posed by PCAS's heterogeneity and immune evasion. KEY POINTS: Insights into the heterogeneity and transcriptional patterns of sarcoma cells may explain the challenges in treating primary cardiac angiosarcoma (PCAS) using the current therapeutic modalities. Characterization of the immune microenvironment revealed significant immunosuppression mediated by specific myeloid cell populations (SPP1+ and OLR1+ macrophages). Identification of mitochondrial dysfunction in immune cells within the PCAS microenvironment, particularly the notable downregulation of the MTRNR2L12 protein, suggests a new avenue for therapeutic targeting.
Asunto(s)
Neoplasias Cardíacas , Hemangiosarcoma , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Microambiente Tumoral , Humanos , Hemangiosarcoma/genética , Hemangiosarcoma/patología , Microambiente Tumoral/genética , Neoplasias Cardíacas/genética , Neoplasias Cardíacas/patología , Análisis de la Célula Individual/métodos , Análisis de Secuencia de ARN/métodos , Masculino , Femenino , Persona de Mediana EdadRESUMEN
Angiosarcoma (AS) is a malignant vascular neoplasm comprising neoplastic endothelial cells accounting for 1%-4% of soft tissue sarcomas. While lymphedema-associated and post-irradiation ASs are almost always driven by a high-level amplification of MYC (8q24), sporadic ASs, including those of breast parenchymal origin, typically lack MYC amplification. Here, we report a case of sporadic breast MYC-amplified AS in a 19-year-old female with no history of lymphedema or irradiation, who was referred to our hospital for an enlarging right breast mass. After needle biopsy, the patient underwent right mastectomy and axillary lymphadenectomy. Microscopically, atypical endothelial cells proliferated and formed well-defined or slit-like vascular channels that invaded and dissected the breast parenchymal fat, ducts, and lobules. In a limited area, the tumor cells showed solid sheet-like proliferation with increased mitotic figures of 40 per 2 mm2 with a small area of necrosis. Immunohistochemical analysis revealed strong positivity for c-Myc. Fluorescence in situ hybridization (FISH) with MYC break-apart probes showed a high-level 5' single signal amplification. The patient was disease-free 16 months post-surgery. Nanopore sequencing successfully detected not only a high-level amplification of the 8q24 region, including MYC, but also multiple structural variants of the 8q24 region. In-depth analysis revealed extrachromosomal circular DNA amplification including the MYC protein-coding region and upstream region but not the downstream region. We also performed methylation classification using nanopore-based methylation data to successfully categorize the tumor as AS. This case report highlights the potential utility of nanopore sequencing in the diagnosis of sarcomas.
Asunto(s)
Neoplasias de la Mama , Amplificación de Genes , Hemangiosarcoma , Secuenciación de Nanoporos , Humanos , Femenino , Hemangiosarcoma/genética , Hemangiosarcoma/patología , Secuenciación de Nanoporos/métodos , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , ADN Circular/genética , Proteínas Proto-Oncogénicas c-myc/genética , Adulto JovenRESUMEN
There is an emerging group of distinct vascular neoplasms with NFATC1/2 fusions, involving bones and soft tissues and often displaying focal epithelioid morphology, variable atypia of endothelial cells, predominantly vasoformative and in some cases focal solid growth. Although they may show aggressive local growth and may recur locally, malignant behaviour has not been documented. We present a case of a 35-year-old woman with multiple vascular neoplasms with a EWSR1::NFATC2 fusion involving the lungs, multiple bones (vertebra, femurs, tibia, pelvis) and probably the liver. The bone lesions were locally aggressive and recurred after surgical treatment. Nine years after the first manifestation, there was progression to an epithelioid angiosarcoma. The patient died 3 months after the diagnosis of epithelioid angiosarcoma with massive lung and liver involvement(metastases). In addition to the EWSR1::NFATC2 fusion, an activating PIK3CA gene mutation was identified in the angiosarcoma but not in the previously diagnosed bone tumours. To the best of our knowledge, this is the first documentation of malignant progression of a vascular neoplasm with NFATC1/2 fusion as well as visceral (lung) involvement.
Asunto(s)
Progresión de la Enfermedad , Hemangiosarcoma , Factores de Transcripción NFATC , Proteína EWS de Unión a ARN , Humanos , Femenino , Adulto , Hemangiosarcoma/genética , Hemangiosarcoma/patología , Factores de Transcripción NFATC/genética , Proteína EWS de Unión a ARN/genética , Resultado Fatal , Neoplasias Vasculares/genética , Neoplasias Vasculares/patología , Proteínas de Fusión Oncogénica/genética , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Fusión Génica , Mutación , Fosfatidilinositol 3-Quinasa Clase IRESUMEN
Angiosarcomas, clinically aggressive cancers of endothelial origin, are a rare subtype of soft-tissue sarcomas characterized by resistance to chemotherapy and dismal prognosis. In this study, we aim to identify the transcriptomic biomarkers of chemoresistance in angiosarcoma. We examined 72 cases of Asian angiosarcomas, including 35 cases treated with palliative chemotherapy, integrating information from NanoString gene expression profiling, whole transcriptome profiling (RNA-seq), immunohistochemistry, cell line assays, and clinicopathological data. In the chemoresistant cohort (defined as stable disease or progression), we observed the significant overexpression of genes, including SPP1 (log2foldchange 3.49, adj. p = 0.0112), CXCL13, CD48, and CLEC5A, accompanied by the significant enrichment of myeloid compartment and cytokine and chemokine signaling pathways, as well as neutrophils and macrophages. RNA-seq data revealed higher SPP1 expression (p = 0.0008) in tumor tissues over adjacent normal compartments. Immunohistochemistry showed a significant moderate positive correlation between SPP1 protein and gene expression (r = 0.7016; p < 0.00110), while higher SPP1 protein expression correlated with lower chemotherapeutic sensitivity in patient-derived angiosarcoma cell lines MOLAS and ISOHAS. In addition, SPP1 mRNA overexpression positively correlated with epithelioid histology (p = 0.007), higher tumor grade (p = 0.0023), non-head and neck location (p = 0.0576), and poorer overall survival outcomes (HR 1.84, 95% CI 1.07-3.18, p = 0.0288). There was no association with tumor mutational burden, tumor inflammation signature, the presence of human herpesvirus-7, ultraviolet exposure signature, and metastatic state at diagnosis. In conclusion, SPP1 overexpression may be a biomarker of chemoresistance and poor prognosis in angiosarcoma. Further investigation is needed to uncover the precise roles and underlying mechanisms of SPP1.
Asunto(s)
Resistencia a Antineoplásicos , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Hemangiosarcoma , Transcriptoma , Humanos , Hemangiosarcoma/genética , Hemangiosarcoma/patología , Hemangiosarcoma/tratamiento farmacológico , Hemangiosarcoma/metabolismo , Resistencia a Antineoplásicos/genética , Perfilación de la Expresión Génica/métodos , Femenino , Masculino , Persona de Mediana Edad , Línea Celular Tumoral , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Anciano , Pronóstico , AdultoRESUMEN
Angiosarcomas of the kidney and adrenal gland are rare, highly aggressive vascular neoplasms. Their genomic profile has not been systematically studied to date. We report the clinicopathologic and molecular features of six angiosarcomas centered in the kidney/adrenal gland. All patients were male adults, ranging from 58 to 77 years of age. Tumor sizes ranged from 2.5 to 22.5 cm. Half of the cases demonstrated hot spot mutations in the KDR gene, while one-third demonstrated mutations in the PIK3CA gene; both of these gene alterations being previously described, preferentially in breast angiosarcomas. In addition, two cases each demonstrated BRIP1 gene amplification, CTNNB1 and ETV6 mutations, which have not been previously reported in angiosarcoma. Notably, molecular studies were critical in establishing the correct diagnoses in three cases: one was an epithelioid angiosarcoma originally misdiagnosed as metastatic adenocarcinoma to the adrenal gland, the second was a vasoformative angiosarcoma that mimicked hemangioma, and the third was a collision tumor between a high-grade angiosarcoma and a chromophobe renal cell carcinoma which was originally diagnosed as a sarcomatoid renal cell carcinoma. In summary, angiosarcomas of the kidney and adrenal gland have a high frequency of recurrent genetic alterations, some of them being shared with other angiosarcoma subtypes, while other appear to be novel. In particular, activating hot spot KDR and PIK3CA mutations represent potential therapeutic targets for these highly aggressive cancers.