HMGA1 regulates trabectedin sensitivity in advanced soft-tissue sarcoma (STS): A Spanish Group for Research on Sarcomas (GEIS) study.

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.

Updated Review and Clinical Recommendations for the Diagnosis and Treatment of Patients with Retroperitoneal Sarcoma by the Spanish Sarcoma Research Group (GEIS).

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.

Extraskeletal myxoid chondrosarcoma: p53 and Ki-67 offer prognostic value for clinical outcome - an immunohistochemical and molecular analysis of 31 cases.

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.

Retrospective Analysis of Patients with Gynaecological Uterine Sarcomas in a Tertiary Hospital.

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.

A DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedin.

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.

Simultaneous diagnosis of liver PEComa in a family with known Li-Fraumeni syndrome: a case report.

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.

Cistoadenocarcinoma mucinoso retroperitoneal: presentación de un caso / Retroperitoneal mucinous cystadenocarcinoma: a case report

Antecedentes: Los cistoadenocarcinomas mucinososretroperitoneales primarios son neoplasias muy poco frecuentes.Hay 34 casos descritos en la literatura inglesa y continúasiendo controvertida su patogénesis. Métodos: Presentamosel caso de una mujer de 47 años con una lesión quísticaasintomática de 8 cm de longitud diagnosticada dequiste cortical renal, en otro centro. En revisiones posterioresla lesión alcanza 23 cm de diámetro. Es remitida al Hospitalde Móstoles donde se realiza un TAC que es informadocomo quiste mesotelial o linfangioma retroperitoneal. Losniveles de alfa-fetoproteína estaban dentro de la normalidad.Se realiza su resección quirúrgica. El Servicio de AnatomíaPatológica recibe una tumoración quística unilocular, quepesa 4.300 gramos y mide 24 × 18 × 15 cm, cuyos cortes histológicosmuestran un epitelio mucosecretor con áreas sólidaspapilares y focos infiltrativos pobremente diferenciados.Seis meses después de la cirugía no hay evidencia de recidivaneoplásica. Resultados y conclusiones: Los cistoadenocarcinomasmucinosos retroperitoneales primarios presentanun curso clínico agresivo, cuyo tratamiento de elección esquirúrgico y en ocasiones quimioterápico. Respecto a supatogenia existen diversas teorías: unas postulan su origen entejido ovárico heterotópico, otras en un teratoma retroperitonealo duplicación intestinal. La hipótesis mas aceptadaactualmente es el desarrollo a partir de metaplasia mucinosadel mesotelio celómico. Es importante tener presente al cistoadenocarcinomamucinoso retroperitoneal en el diagnósticodiferencial de otros tumores quísticos retroperitoneales(AU)

Introduction: Retroperitoneal mucinous cystadenocarcinomais extremely rare, with only 34 cases published todate. The pathogenesis of this tumour remains controversial.Materials and methods: This case report presents a 47 yearold woman who was being investigated for a renal cyst. An8cm retroperitoneal cystic mass was seen initially but, onsubsequent examination, it had increased to 23 cm in diameter.A CT scan rendered a diagnosis of mesothelial cystor retroperitoneal lymphangioma. á-fetoprotein levels werenormal. The tumour was surgically excised. Macroscopicallyit was a 24 × 18 × 15 cm, unilocular, cystic tumourwith solid areas. Microscopically, it was seen to be lined bymucinous epithelial cells with poorly differentiated areas. 6months post-operatively, she is alive and well and withoutevidence of recurrence. Results and conclusions: Retroperitonealmucinous cystadenocarcinoma has an aggressiveclinical course, and surgical excision is the treatment ofchoice, followed by chemotherapy on some occasions. Thereare various hypotheses for the pathogenesis of thistumour, including an origin from heterotopic ovarian tissue,retroperitoneal teratoma or intestinal duplication. However,the most widely accepted theory is that of coelomic metaplasia.Although rare, these tumours should be included inthe differential diagnosis of retroperitoneal cystic tumours(AU)