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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.
Assuntos
Proteína HMGA1a , Sarcoma , Trabectedina , Trabectedina/farmacologia , Humanos , Sarcoma/tratamento farmacológico , Sarcoma/patologia , Sarcoma/genética , Sarcoma/metabolismo , Proteína HMGA1a/metabolismo , Proteína HMGA1a/genética , Animais , Linhagem Celular Tumoral , Camundongos , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Prognóstico , Feminino , Leiomiossarcoma/tratamento farmacológico , Leiomiossarcoma/patologia , Leiomiossarcoma/genética , Leiomiossarcoma/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Desmoid tumors are rare, benign, but locally aggressive fibromatoses that pose significant therapeutic challenges, particularly when located in the head and neck region. This report details the case of an extensive cervical desmoid tumor dependent on the levator scapulae muscle and involving the vertebral artery managed through surgical resection and intraoperative navigation. A 45-year-old male presented with a slowly growing cervical mass. Imaging revealed an 83x68x40 mm mass in the right lateral paravertebral space, dependent on the levator scapulae muscle and involving the vertebral artery. Biopsy confirmed a low-grade fusocellular myofibroblastic neoplasm consistent with a desmoid tumor. Given the poor prognosis associated with the symptomatic mass, surgical resection was performed using Brainlab intraoperative navigation (Brainlab, Munich, Germany). The procedure was successful, with preservation of vital structures and no evidence of recurrence postoperatively. Desmoid tumors in the head and neck region, though rare, require precise diagnostic and therapeutic approaches due to their aggressive nature and proximity to critical anatomical structures. The use of intraoperative navigation, in this case, facilitated accurate tumor resection, minimizing damage to surrounding tissues. Pathological analysis revealed a CTNNB1 gene mutation, specifically the S45P variant, which is associated with an increased risk of recurrence. This case highlights the importance of a multidisciplinary approach, incorporating advanced surgical techniques and genetic analysis, in the management of complex desmoid tumors. Intraoperative navigation proved invaluable in achieving successful surgical outcomes, underscoring its potential utility in similar cases. Continued follow-up is essential, given the potential for recurrence associated with desmoid tumors.
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Extraskeletal myxoid chondrosarcoma (EMC) is a rare malignant soft tissue tumor of unpredictable clinical behavior. The morphological spectrum of EMC based on histology alone can be difficult. There is no precise immunohistochemical (IHC) profile that together with the clinical parameters is able to predict the clinical outcome. We studied 31 cases confirmed as EMC. Clinical and follow-up data were recorded. Histopathological, molecular, and IHC studies were performed. Association among histopathological parameters was assessed using a chi-square test to determine homogeneity or linear trend for ordinal variables. The Kaplan-Meier proportional risk test (log rank) was used to study the impact of the histological, IHC, and molecular factors on progression-free survival (PFS) and disease-specific survival (DSS). Most EMCs showed a typical architectural pattern. Only a few cases presented an atypical histology (higher cellularity and solid pattern). IHC positivity (focal or diffuse) was present for CDK4 (100%), STAT-6 (90%), CD117 (84%), HNK-1 (81%), SATB2 (68%), and S-100 (58%). Synaptophysin and INSM1 were expressed in 22.6% and 38.7% of cases respectively. The EWSR1::NR4A3 rearrangement was found in 19 cases and 7 tumors presented the TAF15::NR4A3 fusion. Positive surgical margins together with atypical histology and expression of p53 and Ki67 correlated with worse clinical prognosis. EMCs express several IHC markers which are also seen in other soft tissue sarcomas. The molecular detection of NR4A3 rearrangement supports the differential diagnosis. Positive surgical margins together with atypical histology and positive expression of p53 and Ki-67 seem to predict a poor clinical outcome with worse prognosis, increased rate of recurrence, metastasis, and poor overall survival.
Assuntos
Condrossarcoma , Sarcoma , Neoplasias de Tecidos Moles , Humanos , Antígeno Ki-67/metabolismo , Proteína Supressora de Tumor p53/genética , Prognóstico , Margens de Excisão , Condrossarcoma/genética , Sarcoma/patologia , Proteínas Repressoras/metabolismoRESUMO
Soft tissue sarcomas (STS) are an uncommon and biologically heterogeneous group of tumors arising from mesenchymal cells. The incidence is estimated at five cases per 100,000 people per year. Retroperitoneal sarcomas (RPS) account for 10-15% of all STS, and their management depends on their anatomical characteristics and histotype. Due to their very low incidence, it is recommended that RPS be treated in reference centers and evaluated by an experienced multidisciplinary team (MDT). In Spain, the Spanish Group for Research in Sarcomas (GEIS) brings together experts from various specialties to promote research on sarcomas and improve treatment results. This paper summarizes the GEIS recommendations for the diagnosis, treatment, and follow-up of patients with RPS.
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Uterine sarcomas are rare and heterogeneous malignancies accounting for 1% to 3% of all gynaecological tumours. There are many histological subtypes recognised, including leiomyosarcomas, endometrial stromal sarcoma, and uterine carcinosarcoma, although the latest has been recently discarded in this group. Despite its low incidence, these types of cancer currently entail multiple challenges, either in diagnostics or clinical management, with a poor prognosis associated. The present work aimed to complete a comparative analysis of the different histological subtypes based on the clinicopathological characteristics of our population, the therapeutic characteristics, and associated prognosis in 161 patients treated in our centre during the period between 1985 and 2020. Moreover, a systematic review grouped a total of 2211 patients with a diagnosis of uterine sarcoma from 19 articles published in 16 countries from 2002 to 2021 was performed, all with retrospective analyses. Our results showed that apart from uterine carcinosarcoma, leiomyosarcoma is the most frequent subtype of uterine sarcoma, with unique clinical, demographic, and survival parameters. To our knowledge, this is the first systematic review conducted in this field and, thus, it shows the difficulties of collecting a significant number of patients per year, a valid reason why multicentre or national registries are recommended to allow a more exhaustive analysis of this pathology.
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Predictive biomarkers of trabectedin represent an unmet need in advanced soft-tissue sarcomas (STS). DNA damage repair (DDR) genes, involved in homologous recombination or nucleotide excision repair, had been previously described as biomarkers of trabectedin resistance or sensitivity, respectively. The majority of these studies only focused on specific factors (ERCC1, ERCC5, and BRCA1) and did not evaluate several other DDR-related genes that could have a relevant role for trabectedin efficacy. In this retrospective translational study, 118 genes involved in DDR were evaluated to determine, by transcriptomics, a predictive gene signature of trabectedin efficacy. A six-gene predictive signature of trabectedin efficacy was built in a series of 139 tumor samples from patients with advanced STS. Patients in the high-risk gene signature group showed a significantly worse progression-free survival compared with patients in the low-risk group (2.1 vs 6.0 months, respectively). Differential gene expression analysis defined new potential predictive biomarkers of trabectedin sensitivity (PARP3 and CCNH) or resistance (DNAJB11 and PARP1). Our study identified a new gene signature that significantly predicts patients with higher probability to respond to treatment with trabectedin. Targeting some genes of this signature emerges as a potential strategy to enhance trabectedin efficacy.
Assuntos
Sarcoma , Tetra-Hidroisoquinolinas , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Dano ao DNA , Reparo do DNA/genética , Dioxóis/efeitos adversos , Humanos , Estudos Retrospectivos , Sarcoma/tratamento farmacológico , Sarcoma/genética , Tetra-Hidroisoquinolinas/efeitos adversos , Trabectedina/uso terapêuticoRESUMO
BACKGROUND: Li-Fraumeni syndrome (LFS) is an autosomal dominant hereditary disease. It is associated with the loss of function of the p53 protein and an increased risk of malignant tumor development at early age. The most frequently detected tumors include breast cancer, sarcomas, leukemia, brain tumors, and adrenocortical carcinomas. While sarcomas account for only 1% of solid tumors, they are more frequently detected in these families. CASE PRESENTATION: We report a simultaneous diagnosis of hepatic perivascular epithelioid cell tumor (PEComa), a very rare subtype of sarcoma, in two siblings with a LFS. CONCLUSIONS: The simultaneous diagnosis of PEComa in two siblings presented in this case allowed us to review the frequency of PEComa in this genetic syndrome previously reported, which was very little. Despite its rarity, PEComa must be considered in the differential diagnosis of new-onset liver lesions in patients who were previously diagnosed with LFS.