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1.
Cell ; 178(2): 346-360.e24, 2019 07 11.
Artículo en Inglés | MEDLINE | ID: mdl-31257026

RESUMEN

Neutrophils are a component of the tumor microenvironment and have been predominantly associated with cancer progression. Using a genetic approach complemented by adoptive transfer, we found that neutrophils are essential for resistance against primary 3-methylcholantrene-induced carcinogenesis. Neutrophils were essential for the activation of an interferon-γ-dependent pathway of immune resistance, associated with polarization of a subset of CD4- CD8- unconventional αß T cells (UTCαß). Bulk and single-cell RNA sequencing (scRNA-seq) analyses unveiled the innate-like features and diversity of UTCαß associated with neutrophil-dependent anti-sarcoma immunity. In selected human tumors, including undifferentiated pleomorphic sarcoma, CSF3R expression, a neutrophil signature and neutrophil infiltration were associated with a type 1 immune response and better clinical outcome. Thus, neutrophils driving UTCαß polarization and type 1 immunity are essential for resistance against murine sarcomas and selected human tumors.


Asunto(s)
Resistencia a la Enfermedad , Neoplasias/patología , Neutrófilos/inmunología , Sarcoma/patología , Linfocitos T/metabolismo , Animales , Cromonas/toxicidad , Resistencia a la Enfermedad/inmunología , Humanos , Inmunidad Innata , Interferón gamma/genética , Interferón gamma/metabolismo , Interleucina-12/genética , Interleucina-12/metabolismo , Estimación de Kaplan-Meier , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neoplasias/inmunología , Neoplasias/mortalidad , Infiltración Neutrófila , Neutrófilos/citología , Neutrófilos/metabolismo , Receptores del Factor Estimulante de Colonias/metabolismo , Sarcoma/inducido químicamente , Sarcoma/inmunología , Linfocitos T/citología , Linfocitos T/inmunología , Microambiente Tumoral
2.
Cell ; 171(4): 950-965.e28, 2017 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-29100075

RESUMEN

Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (TP53, ATRX, RB1) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types.


Asunto(s)
Sarcoma/genética , Adulto , Anciano , Anciano de 80 o más Años , Análisis por Conglomerados , Variaciones en el Número de Copia de ADN , Epigenómica , Genoma Humano , Estudio de Asociación del Genoma Completo , Humanos , Persona de Mediana Edad , Mutación , Sarcoma/diagnóstico , Sarcoma/patología , Adulto Joven
3.
CA Cancer J Clin ; 70(3): 200-229, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32275330

RESUMEN

Soft-tissue sarcomas (STS) are rare tumors that account for 1% of all adult malignancies, with over 100 different histologic subtypes occurring predominately in the trunk, extremity, and retroperitoneum. This low incidence is further complicated by their variable presentation, behavior, and long-term outcomes, which emphasize the importance of centralized care in specialized centers with a multidisciplinary team approach. In the last decade, there has been an effort to improve the quality of care for patients with STS based on anatomic site and histology, and multiple ongoing clinical trials are focusing on tailoring therapy to histologic subtype. This report summarizes the latest evidence guiding the histiotype-specific management of extremity/truncal and retroperitoneal STS with regard to surgery, radiation, and chemotherapy.


Asunto(s)
Medicina de Precisión/métodos , Sarcoma/patología , Neoplasias de los Tejidos Blandos/patología , Terapia Combinada/métodos , Humanos , Pronóstico , Sarcoma/terapia , Neoplasias de los Tejidos Blandos/terapia
4.
Nature ; 577(7791): 556-560, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31942077

RESUMEN

Soft-tissue sarcomas represent a heterogeneous group of cancer, with more than 50 histological subtypes1,2. The clinical presentation of patients with different subtypes is often atypical, and responses to therapies such as immune checkpoint blockade vary widely3,4. To explain this clinical variability, here we study gene expression profiles in 608 tumours across subtypes of soft-tissue sarcoma. We establish an immune-based classification on the basis of the composition of the tumour microenvironment and identify five distinct phenotypes: immune-low (A and B), immune-high (D and E), and highly vascularized (C) groups. In situ analysis of an independent validation cohort shows that class E was characterized by the presence of tertiary lymphoid structures that contain T cells and follicular dendritic cells and are particularly rich in B cells. B cells are the strongest prognostic factor even in the context of high or low CD8+ T cells and cytotoxic contents. The class-E group demonstrated improved survival and a high response rate to PD1 blockade with pembrolizumab in a phase 2 clinical trial. Together, this work confirms the immune subtypes in patients with soft-tissue sarcoma, and unravels the potential of B-cell-rich tertiary lymphoid structures to guide clinical decision-making and treatments, which could have broader applications in other diseases.


Asunto(s)
Linfocitos B/inmunología , Inmunoterapia , Sarcoma/tratamiento farmacológico , Sarcoma/inmunología , Estructuras Linfoides Terciarias/inmunología , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Linfocitos T CD8-positivos/inmunología , Estudios de Cohortes , Células Dendríticas Foliculares/inmunología , Humanos , Mutación , Fenotipo , Pronóstico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Reproducibilidad de los Resultados , Sarcoma/clasificación , Sarcoma/patología , Tasa de Supervivencia , Microambiente Tumoral
5.
J Pathol ; 264(3): 293-304, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-39258383

RESUMEN

Myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma (UPS) are two common and aggressive subtypes of soft tissue sarcoma. The aim of this study was to assess potential transcriptomic differences between MFS and UPS tumours and to evaluate the extent to which differences in gene expression profiles were associated with genomic and clinical features. The study included 162 patients with tumours diagnosed as MFS (N = 62) or UPS (N = 100). The patients had been diagnosed and treated at two Swedish sarcoma centres during a 30-year period. For gene expression profiling and gene fusion detection all tumours were analysed using RNA-sequencing and could be compared with data on clinical outcome (N = 155), global copy number profiles (N = 145), and gene mutations (N = 128). Gene expression profiling revealed three transcriptomic clusters (TCs) without any clear separation of MFS and UPS. One TC was associated with longer metastasis-free survival. These tumours had lower tumour mutation burden (TMB), were enriched for a copy number signature representative of focal LOH and chromosomal instability on a diploid background, and were relatively immune-depleted. MFS and UPS showed extensive genomic overlap, with whole genome doubling occurring more frequently among the latter. The results support the idea that MFS and UPS tumours have largely overlapping genomic and transcriptomic features, with UPS tumours showing more aggressive behaviour and more complex genomes. Independently of the tumour type, clinically relevant subgroups were revealed by gene expression analysis, and the finding of multiple genomic subgroups strongly suggest the existence of subgroups of relevance to treatment stratification. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.


Asunto(s)
Fibrosarcoma , Perfilación de la Expresión Génica , Mutación , Sarcoma , Transcriptoma , Humanos , Masculino , Fibrosarcoma/genética , Fibrosarcoma/patología , Femenino , Persona de Mediana Edad , Anciano , Perfilación de la Expresión Génica/métodos , Sarcoma/genética , Sarcoma/patología , Adulto , Anciano de 80 o más Años , Variaciones en el Número de Copia de ADN , Biomarcadores de Tumor/genética , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/patología , Regulación Neoplásica de la Expresión Génica , Genómica , Suecia
6.
J Pathol ; 264(2): 129-131, 2024 10.
Artículo en Inglés | MEDLINE | ID: mdl-39072755

RESUMEN

In a recent issue of The Journal of Pathology, Chen and colleagues established novel patient-derived ex vivo models of NTRK fusion-positive soft tissue sarcoma to characterize resistance mechanisms against targeted therapy with tyrosine kinase inhibitors. Prolonged exposure to escalating concentrations of the tyrosine kinase inhibitor, entrectinib, ultimately led to the occurrence of resistant clones that harbored an inactivating mutation in the NF2 gene, not previously described in this context, accompanied by increased PI3K/AKT/mTOR and Ras/Raf/MEK/ERK signaling. Finally, an inhibitor screen identified, among others, MEK and mTOR inhibitors as potential combination agents. © 2024 The Pathological Society of Great Britain and Ireland.


Asunto(s)
Resistencia a Antineoplásicos , Inhibidores de Proteínas Quinasas , Humanos , Resistencia a Antineoplásicos/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Neurofibromina 2/genética , Proteínas de Fusión Oncogénica/genética , Benzamidas/uso terapéutico , Benzamidas/farmacología , Receptor trkA/genética , Receptor trkA/metabolismo , Transducción de Señal/genética , Indazoles/uso terapéutico , Indazoles/farmacología , Mutación , Sarcoma/genética , Sarcoma/tratamiento farmacológico , Sarcoma/patología , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo
7.
J Pathol ; 263(2): 257-269, 2024 06.
Artículo en Inglés | MEDLINE | ID: mdl-38613194

RESUMEN

Genomic rearrangements of the neurotrophic receptor tyrosine kinase genes (NTRK1, NTRK2, and NTRK3) are the most common mechanism of oncogenic activation for this family of receptors, resulting in sustained cancer cell proliferation. Several targeted therapies have been approved for tumours harbouring NTRK fusions and a new generation of TRK inhibitors has already been developed due to acquired resistance. We established a patient-derived LMNA::NTRK1-rearranged soft-tissue sarcoma cell model ex vivo with an acquired resistance to targeted TRK inhibition. Molecular profiling of the resistant clones revealed an acquired NF2 loss of function mutation that was absent in the parental cell model. Parental cells showed continuous sensitivity to TRK-targeted treatment, whereas the resistant clones were insensitive. Furthermore, resistant clones showed upregulation of the MAPK and mTOR/AKT pathways in the gene expression based on RNA sequencing data and increased sensitivity to MEK and mTOR inhibitor therapy. Drug synergy was seen using trametinib and rapamycin in combination with entrectinib. Medium-throughput drug screening further identified small compounds as potential drug candidates to overcome resistance as monotherapy or in combination with entrectinib. In summary, we developed a comprehensive model of drug resistance in an LMNA::NTRK1-rearranged soft-tissue sarcoma and have broadened the understanding of acquired drug resistance to targeted TRK therapy. Furthermore, we identified drug combinations and small compounds to overcome acquired drug resistance and potentially guide patient care in a functional precision oncology setting. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.


Asunto(s)
Resistencia a Antineoplásicos , Reordenamiento Génico , Lamina Tipo A , Mutación , Neurofibromina 2 , Inhibidores de Proteínas Quinasas , Receptor trkA , Sarcoma , Humanos , Lamina Tipo A/genética , Lamina Tipo A/metabolismo , Resistencia a Antineoplásicos/genética , Receptor trkA/genética , Receptor trkA/antagonistas & inhibidores , Receptor trkA/metabolismo , Sarcoma/genética , Sarcoma/tratamiento farmacológico , Sarcoma/patología , Sarcoma/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Neurofibromina 2/genética , Neurofibromina 2/metabolismo , Piridonas/farmacología , Benzamidas/farmacología , Pirimidinonas/farmacología , Sirolimus/farmacología , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/patología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Transducción de Señal/efectos de los fármacos , Sinergismo Farmacológico , Indazoles
8.
Cell Mol Life Sci ; 81(1): 219, 2024 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-38758230

RESUMEN

HMGA1 is a structural epigenetic chromatin factor that has been associated with tumor progression and drug resistance. Here, we reported the prognostic/predictive value of HMGA1 for trabectedin in advanced soft-tissue sarcoma (STS) and the effect of inhibiting HMGA1 or the mTOR downstream pathway in trabectedin activity. The prognostic/predictive value of HMGA1 expression was assessed in a cohort of 301 STS patients at mRNA (n = 133) and protein level (n = 272), by HTG EdgeSeq transcriptomics and immunohistochemistry, respectively. The effect of HMGA1 silencing on trabectedin activity and gene expression profiling was measured in leiomyosarcoma cells. The effect of combining mTOR inhibitors with trabectedin was assessed on cell viability in vitro studies, whereas in vivo studies tested the activity of this combination. HMGA1 mRNA and protein expression were significantly associated with worse progression-free survival of trabectedin and worse overall survival in STS. HMGA1 silencing sensitized leiomyosarcoma cells for trabectedin treatment, reducing the spheroid area and increasing cell death. The downregulation of HGMA1 significantly decreased the enrichment of some specific gene sets, including the PI3K/AKT/mTOR pathway. The inhibition of mTOR, sensitized leiomyosarcoma cultures for trabectedin treatment, increasing cell death. In in vivo studies, the combination of rapamycin with trabectedin downregulated HMGA1 expression and stabilized tumor growth of 3-methylcholantrene-induced sarcoma-like models. HMGA1 is an adverse prognostic factor for trabectedin treatment in advanced STS. HMGA1 silencing increases trabectedin efficacy, in part by modulating the mTOR signaling pathway. Trabectedin plus mTOR inhibitors are active in preclinical models of sarcoma, downregulating HMGA1 expression levels and stabilizing tumor growth.


Asunto(s)
Proteína HMGA1a , Sarcoma , Trabectedina , Trabectedina/farmacología , Humanos , Sarcoma/tratamiento farmacológico , Sarcoma/patología , Sarcoma/genética , Sarcoma/metabolismo , Proteína HMGA1a/metabolismo , Proteína HMGA1a/genética , Animales , Línea Celular Tumoral , Ratones , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/uso terapéutico , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Pronóstico , Femenino , Leiomiosarcoma/tratamiento farmacológico , Leiomiosarcoma/patología , Leiomiosarcoma/genética , Leiomiosarcoma/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
9.
Genes Chromosomes Cancer ; 63(8): e23255, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39149945

RESUMEN

Near-haploidization, that is, loss of one copy of most chromosomes, is a relatively rare phenomenon in most tumors, but is enriched among certain soft tissue sarcomas, including undifferentiated pleomorphic sarcoma (UPS). Presumably, near-haploidization can arise through many mechanisms. This study aimed to identify gene rearrangements that could cause near-haploidization. We here present two UPS in which near-haploidization was an early event, identified through single nucleotide polymorphism (SNP) array analysis. One of the cases was studied further using whole genome and transcriptome sequencing, as well as cytogenetic and molecular cytogenetic methods. Both tumors had chromosomal rearrangements in the form of copy number shifts/structural variants affecting the SMC1A gene. These findings suggest that cohesin defects could contribute to mitotic errors resulting in massive loss of chromosomes. SMC1A encodes one of the components of the cohesin multiprotein complex, which is critical for proper alignment of the sister chromatids during S-phase and separation to opposite spindle poles. Further studies should explore the role of cohesin defects in near-haploidization in other sarcomas and to clarify its role in tumor development.


Asunto(s)
Proteínas de Ciclo Celular , Proteínas Cromosómicas no Histona , Sarcoma , Humanos , Proteínas Cromosómicas no Histona/genética , Proteínas de Ciclo Celular/genética , Sarcoma/genética , Sarcoma/patología , Haploidia , Polimorfismo de Nucleótido Simple , Masculino , Femenino , Cohesinas , Adulto , Persona de Mediana Edad
10.
Genes Chromosomes Cancer ; 63(6): e23251, 2024 06.
Artículo en Inglés | MEDLINE | ID: mdl-38884198

RESUMEN

Erythroid sarcoma (ES) is exceedingly rare in the pediatric population with only a handful of reports of de novo cases, mostly occurring in the central nervous system (CNS) or orbit. It is clinically and pathologically challenging and can masquerade as a nonhematopoietic small round blue cell tumor. Clinical presentation of ES without bone marrow involvement makes diagnosis particularly difficult. We describe a 22-month-old female with ES who presented with a 2-cm mass involving the left parotid region and CNS. The presence of crush/fixation artifact from the initial biopsy made definitive classification of this highly proliferative and malignant neoplasm challenging despite an extensive immunohistochemical workup. Molecular studies including RNA-sequencing revealed a NFIA::CBFA2T3 fusion. This fusion has been identified in several cases of de novo acute erythroid leukemia (AEL) and gene expression analysis comparing this case to other AELs revealed a similar transcriptional profile. Given the diagnostically challenging nature of this tumor, clinical RNA-sequencing was essential for establishing a diagnosis.


Asunto(s)
Factores de Transcripción NFI , Proteínas de Fusión Oncogénica , Proteínas Represoras , Sarcoma , Femenino , Humanos , Lactante , Factores de Transcripción NFI/genética , Proteínas de Fusión Oncogénica/genética , Sarcoma/genética , Sarcoma/patología , Sarcoma/diagnóstico
11.
Genes Chromosomes Cancer ; 63(1): e23196, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37702439

RESUMEN

The classification of many soft tissue tumors remains subjective due their rarity, significant overlap in microscopic features and often a non-specific immunohistochemical (IHC) profile. The application of molecular genetic tools, which leverage the underlying molecular pathogenesis of these neoplasms, have considerably improved the diagnostic abilities of pathologists and refined classification based on objective molecular markers. In this study, we describe the results of an international collaboration conducted over a 3-year period, assessing the added diagnostic value of applying molecular genetics to sarcoma expert pathologic review in a selected series of 84 uncommon, mostly unclassifiable mesenchymal tumors, 74 of which originated in soft tissues and 10 in bone. The case mix (71% historical, 29% contemporary) included mostly unusual and challenging soft tissue tumors, which remained unclassified even with the benefit of expert review and routine ancillary methods, including broad IHC panels and a limited number of commercially available fluorescence in situ hybridization (FISH) probes. All cases were further tested by FISH using a wide range of custom bacterial artificial chromosome probes covering most of known fusions in sarcomas, whereas targeted RNA sequencing was performed in 13 cases negative by FISH, for potential discovery of novel fusion genes. Tumor-defining molecular alterations were found in 48/84 tumors (57%). In 27 (32%) cases the tumor diagnosis was refined or revised by the additional molecular work-up, including five cases (6%), in which the updated diagnosis had clinical implications. Sarcoma classification is rapidly evolving due to an increased molecular characterization of these neoplasms, so unsurprisingly 17% of the tumors in this series harbored abnormalities only very recently described as defining novel molecularly defined soft tissue tumor subsets.


Asunto(s)
Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Hibridación Fluorescente in Situ/métodos , Sarcoma/diagnóstico , Sarcoma/genética , Sarcoma/patología , Neoplasias de los Tejidos Blandos/diagnóstico , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/patología , Biomarcadores de Tumor/genética , Análisis de Secuencia de ARN
12.
Genes Chromosomes Cancer ; 63(1): e23215, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38050902

RESUMEN

Undifferentiated sarcomas characterized by a primitive monomorphic round to spindle cell phenotype and often non-specific immunoprofile remain difficult to subclassify outside molecular analysis. The increased application of RNA sequencing in clinical practice led to significant advances and discoveries of novel gene fusions that furthered our understanding and refined classification of otherwise undifferentiated neoplasms. In this study, we report an undifferentiated round to spindle cell sarcoma arising in the femur of a 34-year-old female. The round to spindle tumor cells were arranged in short fascicles, with focal rosette formation, within a hyalinized stroma. The tumor immunoprofile included diffuse reactivity for CD99, SATB2, and TLE1 and patchy positivity for Cyclin D1, Keratin AE1/AE3, synaptophysin, and chromogranin. Other markers, such as EMA, SMA, desmin, S100, ERG, and WT1, were negative. Fluorescence in situ hybridization analysis for EWSR1 gene alterations showed a break-apart signal and targeted RNA sequencing revealed an EWSR1::SSX3 gene fusion. The patient received neoadjuvant chemotherapy followed by surgery and subsequently relapsed in less than a year with lung metastasis. Larger series are needed to determine if this fusion defines a novel subset of undifferentiated tumors or represents a genomic variant of already existing primitive round cell sarcoma categories, such as Ewing sarcoma or synovial sarcoma.


Asunto(s)
Sarcoma de Ewing , Sarcoma , Neoplasias de los Tejidos Blandos , Femenino , Humanos , Adulto , Hibridación Fluorescente in Situ , Sarcoma/genética , Sarcoma/patología , Sarcoma de Ewing/genética , Sarcoma de Ewing/patología , Factores de Transcripción/genética , Neoplasias de los Tejidos Blandos/genética , Fusión Génica , Biomarcadores de Tumor/genética , Proteínas de Fusión Oncogénica/genética , Proteína EWS de Unión a ARN/genética
13.
Genes Chromosomes Cancer ; 63(2): e23228, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-38380728

RESUMEN

An emerging group of spindle cell neoplasms harboring fusions involving NTRK or non-NTRK kinase genes often share characteristic S100 and/or CD34 expression; however, the diagnostic utility of immunohistochemical stains is not well established in this family owing to their lack of specificity. Recently, CD30 expression in spindle cell neoplasms with kinase gene fusions, such as NTRK, BRAF, RAF1, and RET, has been increasingly identified. We herein report a 10-year-old girl with high-grade spindle cell sarcoma of the neck. Prior to histopathological evaluation, flow cytometry (FCM) analysis and touch smear cytology of the tumor tissue revealed CD34+ and dimCD30+ spindle cell populations. Histopathologically, the case was characterized by monomorphic spindle-shaped cytomorphology with CD30, S100, and CD34 positivity and harbored close similarities with spindle cell neoplasms with NTRK or non-NTRK gene fusions. Subsequently, a comprehensive next-generation sequencing sarcoma panel identified a rare PLEKHH2::ALK fusion, and a diagnosis of ALK-rearranged spindle cell neoplasm was made. The patient showed significant tumor response to single-agent treatment with alectinib, an ALK-tyrosine kinase inhibitor. This case supports that CD30 is expressed in an ALK-rearranged mesenchymal neoplasm. The benefit of the early detection of CD30 expression by FCM for a prompt diagnosis and treatment is highlighted in the context of an aggressive clinical course. This case represents a learning experience regarding the need to the check the status of CD30 expression in these tumors and suggests the potential clinical benefits of CD30-targeted therapy.


Asunto(s)
Sarcoma , Neoplasias de los Tejidos Blandos , Femenino , Humanos , Niño , Inmunohistoquímica , Citometría de Flujo , Sarcoma/patología , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/patología , Fusión Génica , Proteínas Tirosina Quinasas Receptoras/genética , Biomarcadores de Tumor/genética
14.
Genes Chromosomes Cancer ; 63(6): e23249, 2024 06.
Artículo en Inglés | MEDLINE | ID: mdl-38884173

RESUMEN

The widespread use of advanced molecular techniques has led to the identification of several tumor types with PLAG1 gene fusions some of which also affect the skin and soft tissues. Herein, we present a 38-year-old female with a subcutaneous tumor affecting her forearm, which does not seem to fit into any currently recognized entity. It was a well-circumscribed tumor measuring 6 × 4,5 × 4 cm. It had a thick capsule composed of bland spindle cells forming palisades and Verocay body-like structures within a myxocollagenous background. Scattered calcifications were dispersed throughout the lesion. No cytological atypia, mitotic activity, or necrosis were present. Targeted NGS revealed a SOX10::PLAG1 fusion and fluorescent in situ hybridization confirmed the presence of PLAG1 gene rearrangement. The neoplastic cells showed a diffuse immunohistochemical expression of S100, SOX10, and PLAG1, as well as patchy desmin and CD34 positivity. The methylation profile of this tumor did not match any other entity covered by the DKFZ sarcoma classifier and apart from the gain of chromosome 12, the copy number profile was normal. The tumor was completely excised, and the patient has been free of disease for 4 years since the excision. While more cases are needed to confirm this tumor as a distinct entity, we propose a provisional name "SOX10::PLAG1-rearranged calcifying spindle cell tumor."


Asunto(s)
Proteínas de Unión al ADN , Proteínas de Fusión Oncogénica , Factores de Transcripción SOXE , Neoplasias de los Tejidos Blandos , Adulto , Femenino , Humanos , Calcinosis/genética , Calcinosis/patología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Sarcoma/genética , Sarcoma/patología , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/patología , Factores de Transcripción SOXE/genética , Factores de Transcripción SOXE/metabolismo
15.
Proteomics ; 24(12-13): e2300001, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38402423

RESUMEN

MALDI mass spectrometry imaging (MALDI imaging) uniquely advances cancer research, by measuring spatial distribution of endogenous and exogenous molecules directly from tissue sections. These molecular maps provide valuable insights into basic and translational cancer research, including tumor biology, tumor microenvironment, biomarker identification, drug treatment, and patient stratification. Despite its advantages, MALDI imaging is underutilized in studying rare cancers. Sarcomas, a group of malignant mesenchymal tumors, pose unique challenges in medical research due to their complex heterogeneity and low incidence, resulting in understudied subtypes with suboptimal management and outcomes. In this review, we explore the applicability of MALDI imaging in sarcoma research, showcasing its value in understanding this highly heterogeneous and challenging rare cancer. We summarize all MALDI imaging studies in sarcoma to date, highlight their impact on key research fields, including molecular signatures, cancer heterogeneity, and drug studies. We address specific challenges encountered when employing MALDI imaging for sarcomas, and propose solutions, such as using formalin-fixed paraffin-embedded tissues, and multiplexed experiments, and considerations for multi-site studies and digital data sharing practices. Through this review, we aim to spark collaboration between MALDI imaging researchers and clinical colleagues, to deploy the unique capabilities of MALDI imaging in the context of sarcoma.


Asunto(s)
Sarcoma , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Humanos , Sarcoma/diagnóstico por imagen , Sarcoma/patología , Biomarcadores de Tumor/análisis , Enfermedades Raras/diagnóstico por imagen , Enfermedades Raras/patología , Microambiente Tumoral
16.
Am J Physiol Cell Physiol ; 327(1): C34-C47, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38646787

RESUMEN

The dystrophin gene (Dmd) is recognized for its significance in Duchenne muscular dystrophy (DMD), a lethal and progressive skeletal muscle disease. Some patients with DMD and model mice with muscular dystrophy (mdx) spontaneously develop various types of tumors, among which rhabdomyosarcoma (RMS) is the most prominent. By contrast, spindle cell sarcoma (SCS) has rarely been reported in patients or mdx mice. In this study, we aimed to use metabolomics to better understand the rarity of SCS development in mdx mice. Gas chromatography-mass spectrometry was used to compare the metabolic profiles of spontaneously developed SCS and RMS tumors from mdx mice, and metabolite supplementation assays and silencing experiments were used to assess the effects of metabolic differences in SCS tumor-derived cells. The levels of 75 metabolites exhibited differences between RMS and SCS, 25 of which were significantly altered. Further characterization revealed downregulation of nonessential amino acids, including alanine, in SCS tumors. Alanine supplementation enhanced the growth, epithelial mesenchymal transition, and invasion of SCS cells. Reduction of intracellular alanine via knockdown of the alanine transporter Slc1a5 reduced the growth of SCS cells. Lower metabolite secretion and reduced proliferation of SCS tumors may explain the lower detection rate of SCS in mdx mice. Targeting of alanine depletion pathways may have potential as a novel treatment strategy.NEW & NOTEWORTHY To the best of our knowledge, SCS has rarely been identified in patients with DMD or mdx mice. We observed that RMS and SCS tumors that spontaneously developed from mdx mice with the same Dmd genetic background exhibited differences in metabolic secretion. We proposed that, in addition to dystrophin deficiency, the levels of secreted metabolites may play a role in the determination of tumor-type development in a Dmd-deficient background.


Asunto(s)
Ratones Endogámicos mdx , Rabdomiosarcoma , Sarcoma , Animales , Rabdomiosarcoma/metabolismo , Rabdomiosarcoma/patología , Rabdomiosarcoma/genética , Ratones , Sarcoma/metabolismo , Sarcoma/patología , Sarcoma/genética , Metabolómica/métodos , Línea Celular Tumoral , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Proliferación Celular , Masculino , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/patología , Distrofia Muscular de Duchenne/genética , Transición Epitelial-Mesenquimal , Sistema de Transporte de Aminoácidos ASC/metabolismo , Sistema de Transporte de Aminoácidos ASC/genética
17.
Mol Cancer ; 23(1): 37, 2024 02 19.
Artículo en Inglés | MEDLINE | ID: mdl-38374062

RESUMEN

Soft tissue sarcomas (STS) are diverse mesenchymal tumors with few therapeutic options in advanced stages. Trabectedin has global approval for treating STS patients resistant to anthracycline-based regimens. Recent pre-clinical data suggest that trabectedin's antitumor activity extends beyond tumor cells to influencing the tumor microenvironment (TME), especially affecting tumor-associated macrophages and their pro-tumoral functions. We present the phase I/II results evaluating a combination of metronomic trabectedin and low-dose cyclophosphamide on the TME in patients with advanced sarcomas. 50 patients participated: 20 in phase I and 30 in phase II. Changes in the TME were assessed in 28 patients using sequential tumor samples at baseline and day two of the cycle. Treatment notably decreased CD68 + CD163 + macrophages in biopsies from tumor lesions compared to pre-treatment samples in 9 of the 28 patients after 4 weeks. Baseline CD8 + T cell presence increased in 11 of these patients. In summary, up to 57% of patients exhibited a positive immunological response marked by reduced M2 macrophages or increased CD8 + T cells post-treatment. This positive shift in the TME correlated with improved clinical benefit and progression-free survival. This study offers the first prospective evidence of trabectedin's immunological effect in advanced STS patients, highlighting a relationship between TME modulation and patient outcomes.This study was registered with ClinicalTrial.gov, number NCT02406781.


Asunto(s)
Antineoplásicos Alquilantes , Sarcoma , Humanos , Trabectedina/uso terapéutico , Estudios Prospectivos , Antineoplásicos Alquilantes/uso terapéutico , Sarcoma/tratamiento farmacológico , Sarcoma/patología , Ciclofosfamida/uso terapéutico , Dioxoles , Microambiente Tumoral
18.
Mol Cancer ; 23(1): 172, 2024 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-39174949

RESUMEN

Exosomes mediate cell-to-cell crosstalk involving a variety of biomolecules through an intricate signaling network. In recent years, the pivotal role of exosomes and their non-coding RNAs cargo in the development and progression of several cancer types clearly emerged. In particular, tumor bulk and its microenvironment co-evolve through cellular communications where these nanosized extracellular vesicles are among the most relevant actors. Knowledge about the cellular, and molecular mechanisms involved in these communications will pave the way for novel exosome-based delivery of therapeutic RNAs as well as innovative prognostic/diagnostic tools. Despite the valuable therapeutic potential and clinical relevance of exosomes, their role on sarcoma has been vaguely reported because the rarity and high heterogeneity of this type of cancer. Here, we dissected the scientific literature to unravel the multifaceted role of exosomal non-coding RNAs as mediator of cell-to-cell communications in the sarcoma subtypes.


Asunto(s)
Comunicación Celular , Exosomas , ARN no Traducido , Sarcoma , Humanos , Exosomas/metabolismo , Exosomas/genética , Sarcoma/genética , Sarcoma/patología , Sarcoma/terapia , Sarcoma/metabolismo , ARN no Traducido/genética , Animales , Microambiente Tumoral/genética , Regulación Neoplásica de la Expresión Génica , Transducción de Señal , Biomarcadores de Tumor/genética , Investigación Biomédica Traslacional
19.
Cancer Sci ; 115(8): 2831-2838, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38763523

RESUMEN

Histological diagnosis of sarcomas (malignant bone and soft tissue tumors) is challenging due to their rarity, morphological diversity, and constantly evolving diagnostic criteria. In this study, we aimed to assess the concordance in histological diagnosis of bone and soft tissue tumors between referring hospitals and a tertiary sarcoma center and analyzed the clinical impact of the diagnostic alteration. We analyzed 628 consecutively accessioned specimens from 624 patients who visited a specialized sarcoma center for treatment. The diagnoses at referring hospitals and those at the sarcoma center were compared and classified into four categories: agreed, disagreed, specified, and de-specified. Of the 628 specimens, the diagnoses agreed in 403 (64.2%) specimens, whereas some changes were made in 225 (35.8%) specimens: disagreed in 153 (24.3%), specified in 52 (8.3%), and de-specified in 20 (3.2%) cases. The benign/intermediate/malignant judgment changed for 92 cases (14.6%). The diagnostic change resulted in patient management modification in 91 cases (14.5%), including surgical and medical treatment changes. The main inferred reason for the diagnostic discrepancies was a different interpretation of morphological findings of the tumor, which accounted for 48.9% of the cases. This was followed by the unavailability of specialized immunohistochemical antibodies and the unavailability of genetic analysis. In summary, our study clarified the actual clinical impact of diagnostic discrepancy in bone and soft tissue tumors. This may underscore the value of pathology consultation, facilitating access to specialized diagnostic tools, and continued education. These measures are expected to improve diagnostic precision and ultimately benefit patients.


Asunto(s)
Neoplasias Óseas , Derivación y Consulta , Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Neoplasias de los Tejidos Blandos/patología , Neoplasias de los Tejidos Blandos/diagnóstico , Sarcoma/patología , Sarcoma/diagnóstico , Masculino , Femenino , Neoplasias Óseas/patología , Neoplasias Óseas/diagnóstico , Persona de Mediana Edad , Adulto , Anciano , Adolescente , Adulto Joven , Niño , Anciano de 80 o más Años , Errores Diagnósticos , Centros de Atención Terciaria , Preescolar
20.
Cancer Sci ; 115(2): 575-588, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38115234

RESUMEN

Of the drugs used in second-line chemotherapy for soft tissue sarcoma (STS), trabectedin is effective for liposarcoma and leiomyosarcoma (L-sarcoma), eribulin for liposarcoma, and pazopanib for non-liposarcoma. The indications for these drugs in STS other than L-sarcoma have not been established. Here we explored the prognosis, mutation profiles, and drug-response factors in STS using real-world big data. Clinicogenomic data on 1761 patients with sarcoma who underwent FoundationOne CDx were obtained from a national database in Japan. Patients with TP53 and KDM2D mutations had a significantly shorter survival period of 253 (95% CI, 99-404) and 330 (95% CI, 20-552) days, respectively, than those without mutations. Non-supervised clustering based on mutation profiles generated 13 tumor clusters. The response rate (RR) to trabectedin was highest in an MDM2-amplification cluster (odds ratio [OR]: 2.2; p = 0.2). The RR was lowest for eribulin in an MDM2-amplification cluster (OR: 0.4; p = 0.03) and highest in a TERT-mutation cluster (OR: 3.0; p = 0.03). The RR was highest for pazopanib in a PIK3CA/PTEN-wild type cluster (OR: 2.1; p = 0.03). In particular, patients harboring mutations in genes regulating the PI3K/Akt/mTOR pathway had a lower RR than patients without mutations (OR: 0.3; p = 0.04). In STS, mutation profiles were more useful in predicting the drug response than histology. The present study demonstrated the potential of tailored therapy guided by mutation profiles established by comprehensive genomic profiling testing in optimizing second-line chemotherapy for STS. The findings of this study will hopefully contribute some valuable insights into enhancing STS treatment strategies and outcomes.


Asunto(s)
Furanos , Indazoles , Cetonas , Liposarcoma , Policétidos Poliéteres , Pirimidinas , Sarcoma , Sulfonamidas , Humanos , Trabectedina/uso terapéutico , Fosfatidilinositol 3-Quinasas , Sarcoma/tratamiento farmacológico , Sarcoma/genética , Sarcoma/patología , Liposarcoma/tratamiento farmacológico , Liposarcoma/genética , Genómica
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