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Synovial sarcoma (SS) is a rare soft-tissue tumor characterized by a monomorphic blue spindle cell histology and variable epithelial differentiation. Morphologically, SSs may be confused with other sarcomas. Systemic treatment is more effective for patients with high-risk SSs, patients with advanced disease, and younger patients. However, further studies are required to find new prognostic biomarkers. Herein, we describe the morphological, molecular, and clinical findings, using a wide immunohistochemical panel, of a series of SS cases. We studied 52 cases confirmed as SSs by morphological diagnosis and/or molecular studies. Clinical data (gender, age, tumor size, tumor location, resection margins, adjuvant treatment, recurrences, metastasis, and survival) were also retrieved for each patient. All the available H&E slides were examined by four pathologists. Three tissue microarrays (TMAs) were constructed for each of the tumors, and a wide immunohistochemical panel was performed. For time-to-event variables, survival analysis was performed using Kaplan-Meier curves and log-rank testing, or Cox regression. Statistical significance was considered at p < 0.05. The mean age of our patients was 40.33, and the median was 40.5 years. We found a predominance of males versus females (1.7:1). The most frequent morphological subtype was monophasic. TRPS1, SS18-SSX, and SSX-C-terminus were positive in 96% of cases. GLI1 expression was strong in six and focal (cytoplasmic) in twenty patients. Moreover, BCOR was expressed in more than half of SSs. Positive expression of both proteins, BCOR and GLI1, was correlated with a worse prognosis. Multivariate analysis was also performed, but only BCOR expression appeared to be significant. The combination of GLI1 and BCOR antibodies can be used to group SSs into three risk groups (low, intermediate, and high risk). We hypothesize that these findings could identify which patients would benefit from receiving adjuvant treatment and which would not. Moreover, these markers could represent therapeutic targets in advanced stages. However, further, larger series of SSs and molecular studies are necessary to corroborate our present findings.
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Biomarcadores de Tumor , Inmunohistoquímica , Proteínas Proto-Oncogénicas , Proteínas Represoras , Sarcoma Sinovial , Proteína con Dedos de Zinc GLI1 , Humanos , Sarcoma Sinovial/metabolismo , Sarcoma Sinovial/patología , Sarcoma Sinovial/genética , Masculino , Femenino , Proteínas Represoras/metabolismo , Proteínas Represoras/genética , Adulto , Persona de Mediana Edad , Pronóstico , Biomarcadores de Tumor/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteína con Dedos de Zinc GLI1/metabolismo , Proteína con Dedos de Zinc GLI1/genética , Anciano , Adulto Joven , Adolescente , Estimación de Kaplan-MeierRESUMEN
Herpes Simplex Virus type 1 (HSV-1) 1 is a neurotropic virus that has been associated with neurodegenerative disorders. The dysregulation of autophagy by HSV-1 has been proposed as a potential cause of neurodegeneration. While studies have extensively tackled the interaction between autophagy and HSV-1 in neurons, research in glial cells is currently limited. Our studies demonstrate that HSV-1 inhibits, but not completely blocks, the formation of autophagosomes in human oligodendroglioma- and astrocytoma- derived cell lines. These findings have been confirmed in murine oligodendrocyte precursor cells (OPCs). Finally, this study investigates the impact of autophagy on HSV-1 infection in glial cells. While the lack of basal autophagy in LC3B knockout glial cells does not have a significant effect on viral infection, cells without the autophagy-related protein ATG5 exhibit reduced viral production. The absence of ATG5 leads to a decrease in the transcription and replication of viral genes, as well as a delay in the initial stages of the formation of HSV-1 replication compartments. These findings indicate that while autophagy may not play a significant role in antiviral defense in glial cells, HSV-1 may be inhibiting autophagy to exploit non-canonical functions of certain components of the autophagic machinery, such as ATG5, to benefit its lifecycle.
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Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, with proto-oncogene, receptor tyrosine kinase (c-kit), or PDGFRα mutations detected in around 85% of cases. GISTs without c-kit or platelet-derived growth factor receptor alpha (PDGFRα) mutations are considered wild-type (WT), and their diverse molecular alterations and biological behaviors remain uncertain. They are usually not sensitive to tyrosine kinase inhibitors (TKIs). Recently, some molecular alterations, including neurotrophic tyrosine receptor kinase (NTRK) fusions, have been reported in very few cases of WT GISTs. This novel finding opens the window for the use of tropomyosin receptor kinase (TRK) inhibitor therapy in these subtypes of GIST. Herein, we report a new case of NTRK-fused WT high-risk GIST in a female patient with a large pelvic mass (large dimension of 20 cm). The tumor was removed, and the histopathology displayed spindle-predominant morphology with focal epithelioid areas, myxoid stromal tissue, and notable lymphoid infiltration with tertiary lymphoid structures. Ten mitoses were quantified in 50 high-power fields without nuclear pleomorphism. DOG1 showed strong and diffuse positivity, and CD117 showed moderate positivity. Succinate dehydrogenase subunit B (SDHB) was retained, Pan-TRK was focal positive (nuclear pattern), and the proliferation index Ki-67 was 7%. Next-generation sequencing (NGS) detected an ETV6::NTRK3 fusion, and this finding was confirmed by fluorescence in situ hybridization (FISH), which showed NTRK3 rearrangement. In addition, an RB1 mutation was found by NGS. The follow-up CT scan revealed peritoneal nodules suggestive of peritoneal dissemination, and Entrectinib (a TRK inhibitor) was administered. After 3 months of follow-up, a new CT scan showed a complete response. Based on our results and the cases from the literature, GISTs with NTRK fusions are very uncommon so far; hence, further screening studies, including more WT GIST cases, may increase the possibility of finding additional cases. The present case may offer new insights into the potential introduction of TRK inhibitors as treatments for GISTs with NTRK fusions. Additionally, the presence of abundant lymphoid infiltration in the present case may prompt further research into immunotherapy as a possible additional therapeutic option.
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Tumores del Estroma Gastrointestinal , Estructuras Linfoides Terciarias , Femenino , Humanos , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/genética , Hibridación Fluorescente in Situ , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Inmunoterapia , Proteínas Proto-Oncogénicas c-kit , Proteínas Tirosina Quinasas ReceptorasRESUMEN
Pseudorabies virus (PRV), a herpesvirus responsible for Aujeszky's disease, causes high mortality in swine populations. To develop effective and novel antiviral strategies, it is essential to understand the mechanism of entry used by PRV to infect its host. Viruses have different ways of entering host cells. Among others, they can use endocytosis, a fundamental cellular process by which substances from the external environment are internalized into the cell. This process is classified into clathrin-mediated endocytosis (CME) and clathrin-independent endocytosis (CIE), depending on the role of clathrin. Although the involvement of cholesterol-rich lipid rafts in the entry of PRV has already been described, the importance of other endocytic pathways involving clathrin remains unexplored to date. Here, we characterize the role of CME in PRV entry into the PK15 swine cell line. By using CME inhibitory drugs, we report a decrease in PRV infection when the CME pathway is blocked. We also perform the shRNA knockdown of the µ-subunit of the adaptor protein AP-2 (AP2M1), which plays an important role in the maturation of clathrin-coated vesicles, and the infection is greatly reduced when this subunit is knocked down. Furthermore, transmission electron microscopy images report PRV virions inside clathrin-coated vesicles. Overall, this study suggests for the first time that CME is a mechanism used by PRV to enter PK15 cells and provides valuable insights into its possible routes of entry.
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The chromosomal region 12q13-15 is rich in oncogenes and contains several genes involved in the pathogenesis of various mesenchymal neoplasms. Notable genes in this region include MDM2, CDK4, STAT6, DDIT3, and GLI1. Amplification of MDM2 and CDK4 genes can be detected in various mesenchymal and nonmesenchymal neoplasms. Therefore, gene amplification alone is not entirely specific for making a definitive diagnosis and requires the integration of clinical, radiological, morphological, and immunohistochemical findings. Neoplasms with GLI1 alterations may exhibit either GLI1 rearrangements or amplifications of this gene. Despite the diagnostic implications that the overlap of genetic alterations in neoplasms with changes in genes within the 12q13-15 region could create, the discovery of coamplifications of MDM2 with CDK4 and GLI1 offers new therapeutic targets in neoplasms with MDM2/CDK4 amplification. Lastly, it is worth noting that MDM2 or CDK4 amplification is not exclusive to mesenchymal neoplasms; this genetic alteration has also been observed in other epithelial neoplasms or melanomas. This suggests the potential use of MDM2 or CDK4 inhibitors in neoplasms where alterations in these genes do not aid the pathological diagnosis but may help identify potential therapeutic targets. In this review, we delve into the diagnosis and therapeutic implications of tumors with genetic alterations involving the chromosomal region 12q13-15, mainly MDM2, CDK4, and GLI1.
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Mesenchymal neoplasms with GLI1 alterations have recently been reported in several anatomic locations. Their morphology and immunohistochemistry (IHC) are nonspecific, making their recognition a true challenge. To assess the diagnostic value of GLI1 and p16 IHC for identifying GLI1-altered neoplasms, we evaluated 12 such neoplasms (6 GLI1-amplified and 6 with GLI1-fusions) using the GLI1 IHC. Additionally, we evaluated some of their morphological and molecular mimickers, including glomangiomas, Ewing sarcomas (ES), myxoid liposarcomas, and MDM2/CDK4-amplified sarcomas (well-differentiated liposarcoma/WDLPS, dedifferentiated liposarcoma/DDLPS, and intimal sarcoma). All successfully tested GLI1-altered tumors (11/11) demonstrated at least moderate/strong nuclear and/or cytoplasmic GLI1 IHC positivity. GLI1-amplified tumors exhibited a moderate/strong predominantly nuclear staining, compared to a moderate, patchy, and predominantly cytoplasmic GLI1 positivity in GLI1-fusion tumors. Among their mimics, GLI1 immunoreactivity, either cytoplasmic or nuclear, was observed in intimal sarcoma (3/3) and WDLPS/DDLPS (22/25). GLI1 IHC demonstrated 92% sensitivity and 90.8% specificity in diagnosing GLI1-altered neoplasms. Strong/moderate nuclear/cytoplasmic p16 immunoexpression was noted in all GLI1-amplified tumors compared to none of fused cases. Overall, the GLI1/p16 combination demonstrated a sensitivity and specificity of 100% and 93% for GLI1-amplified tumors. In conclusion, we confirm that GLI1 IHC represents a good, quick, and cheap helpful screening tool. The inclusion of p16 may aid in pre-screening for potential GLI1-amplified neoplasms and provide insights on which tumors warrant further molecular testing.
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The SOGUG-IMANOL trial was a phase 2, uncontrolled, Spanish multicenter study to assess the effect of maintenance treatment with olaparib on radiographic progression-free survival (PFS) in patients with metastatic castration-resistant prostate cancer (mCRPC) who achieved partial or complete response or disease stabilization on docetaxel treatment and had a documented germline/somatic mutation in any of the homologous recombination repair (HRR) genes. Patients received olaparib 300 mg orally twice daily. From the screened population (n = 134), 26 (19.4%) somatic mutations were found, and 14 patients were included in the study. The median radiographic PFS was 11.1 (95%CI, 5.7 to 16.5) months. The median PSA-PFS was 3.5 (95%CI, 1.0 to 6.0) months, and the median clinical PFS was 14.7 (95%CI, 1.8 to 27.5 months). Clinical benefit was observed in 12 patients (85.7%, 95%CI 67.4% to 100%), including two patients with partial response and 10 with stable disease. Six patients reported grade 3-5 adverse events: asthenia (n = 3), anemia (n = 2) and neutropenia (n = 1). In this setting, olaparib has been shown to be an efficacious maintenance treatment in terms of radiographic PFS and clinical benefit, becoming a therapeutic option for some patients harboring an HRR gene mutation and in scenarios where further investigation is needed.
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Primary rectal adenocarcinoma with extensive choriocarcinomatous differentiation is a rare neoplasm, with only sporadic cases reported worldwide. The prognosis is typically poor, and no standard therapy has been established for this tumor. We report a case of a 63-year-old woman who presented with lower abdominal and pelvic discomfort, as well as rectal bleeding. Endoscopy revealed a rectal tumor. She was diagnosed with primary rectal adenocarcinoma with extensive choriocarcinomatous differentiation, accompanied by liver metastasis and peritoneal carcinomatosis. The immunohistochemical profile demonstrated strong and diffuse positivity for keratin (AE1/AE3), beta-human chorionic gonadotropin (ß-HCG), p53, MYC, p16, and Ki-67. Molecular analysis indicated mutations in KRAS, TP53, and PI3KCA. Despite the tumor's profile, the serum ß-HCG level was not elevated. A chemotherapy regimen for metastatic colorectal adenocarcinoma was initiated, but there was a poor response, with rapid tumor progression. The patient survived for only 5 months postdiagnosis. We discuss the histopathological, immunohistochemical, and molecular findings, emphasizing their relevance to the differential diagnosis of neoplasms with choriocarcinomatous differentiation.
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Gastrointestinal stromal tumor (GIST) is the most common malignant neoplasm of mesenchymal origin. GIST spans a wide clinical spectrum that ranges from tumors with essentially no metastatic potential to malignant and life-threatening spread diseases. Gain-of-function mutations in KIT or PDGFRA receptor tyrosine kinases are the crucial drivers of most GISTs, responsible for tumor initiation and evolution throughout the entire course of the disease. The introduction of tyrosine kinase inhibitors targeting these receptors has substantially improved the outcomes in this formerly chemoresistant cancer. As of today, five agents hold regulatory approval for the treatment of GIST: imatinib, sunitinib, regorafenib, ripretinib, and avapritinib. This, in turn, represents a success for a rare neoplasm. During the past two decades, GIST has become a paradigmatic model in cancer for multidisciplinary work, given the disease-specific particularities regarding tumor biology and tumor evolution. Herein, we review currently available evidence for the management of GIST. This clinical practice guideline has been developed by a multidisciplinary expert panel (oncologist, pathologist, surgeon, molecular biologist, radiologist, and representative of patients' advocacy groups) from the Spanish Group for Sarcoma Research, and it is conceived to provide, from a critical perspective, the standard approach for diagnosis, treatment, and follow-up.
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BACKGROUND: Ovarian clear cell carcinomas (OCCCs) are rare, aggressive and chemoresistant tumors. Geographical and ethnic differences in the incidence of OCCC have been reported with a higher incidence in Asiatic countries. There is a paucity of information regarding OCCC in Latin America (LA) and other countries. METHODS: Here, we characterized two cohorts of 33 patients with OCCC from LA (24 from Brazil and 9 from Costa Rica) and a cohort of 27 patients from Spain. Genomic analysis was performed for 26 OCCC using the OncoScan platform. Tumors were classified according to their genomic landscapes into subgroups. Clinical parameters were related to the frequency of genomic aberrations. RESULTS: The median overall survival (OS) was not significantly different between the cohorts. Genomic landscapes were characterized by different homologous recombination deficiency (HRD) levels. No difference in the distribution of genomic landscapes profiles was detected between patients from the different cohorts. OCCCs with MYC-amplified tumors harboring a concomitant loss of a region in chromosome 13q12-q13 that includes the BRCA2 gene had the longest OS. In contrast, patients carrying a high number (> 30) of total copy number (CN) aberrations with no concomitant alterations in MYC and BRCA2 genes presented the shortest OS. Furthermore, amplification of the ASH1L gene was also associated with a shorter OS. Initial-stage OCCCs with early progression were characterized by gains in the JNK1 and MKL1 genes. CONCLUSIONS: Our results provide new data from understudied OCCC populations and reveal new potential markers for OCCCs.
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Adenocarcinoma de Células Claras , Carcinoma , Neoplasias Ováricas , Femenino , Humanos , Neoplasias Ováricas/patología , Genómica , Brasil , Adenocarcinoma de Células Claras/patologíaRESUMEN
Overexpression of the EPS15 Homology Domain containing 1 (EHD1) protein has been linked to tumorigenesis but whether its core function as a regulator of intracellular traffic of cell surface receptors plays a role in oncogenesis remains unknown. We establish that EHD1 is overexpressed in Ewing sarcoma (EWS), with high EHD1 mRNA expression specifying shorter patient survival. ShRNA-knockdown and CRISPR-knockout with mouse Ehd1 rescue established a requirement of EHD1 for tumorigenesis and metastasis. RTK antibody arrays identified IGF-1R as a target of EHD1 regulation in EWS. Mechanistically, we demonstrate a requirement of EHD1 for endocytic recycling and Golgi to plasma membrane traffic of IGF-1R to maintain its surface expression and downstream signaling. Conversely, EHD1 overexpression-dependent exaggerated oncogenic traits require IGF-1R expression and kinase activity. Our findings define the RTK traffic regulation as a proximal mechanism of EHD1 overexpression-dependent oncogenesis that impinges on IGF-1R in EWS, supporting the potential of IGF-1R and EHD1 co-targeting.
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Sarcoma de Ewing , Ratones , Animales , Sarcoma de Ewing/genética , Sarcoma de Ewing/metabolismo , Sarcoma de Ewing/patología , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Membrana Celular/metabolismo , Transducción de Señal/fisiología , Carcinogénesis/genética , Carcinogénesis/metabolismo , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismoRESUMEN
In this study, we identify USP1 as a transcriptional target of EWS::FLI1 and demonstrate the requisite function of USP1 in Ewing sarcoma (EWS) cell survival in response to endogenous replication stress. EWS::FLI1 oncogenic transcription factor drives most EWS, a pediatric bone cancer. EWS cells display elevated levels of R-loops and replication stress. The mechanism by which EWS cells override activation of apoptosis or cellular senescence in response to increased replication stress is not known. We show that USP1 is overexpressed in EWS and EWS::FLI1 regulates USP1 transcript levels. USP1 knockdown or inhibition arrests EWS cell growth and induces cell death by apoptosis. Mechanistically, USP1 regulates Survivin (BIRC5/API4) protein stability and the activation of caspase-9 and caspase-3/7 in response to endogenous replication stress. Notably, USP1 inhibition sensitizes cells to doxorubicin and etoposide treatment. Together, our study demonstrates that USP1 is regulated by EWS::FLI1, the USP1-Survivin axis promotes EWS cell survival, and USP1 inhibition sensitizes cells to standard of care chemotherapy. IMPLICATIONS: High USP1 and replication stress levels driven by EWS::FLI1 transcription factor in EWS are vulnerabilities that can be exploited to improve existing treatment avenues and overcome drug resistance.
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Sarcoma de Ewing , Humanos , Niño , Sarcoma de Ewing/metabolismo , Proteína Proto-Oncogénica c-fli-1/genética , Proteína Proto-Oncogénica c-fli-1/metabolismo , Survivin/genética , Survivin/metabolismo , Proteína EWS de Unión a ARN/genética , Proteína EWS de Unión a ARN/metabolismo , Línea Celular Tumoral , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Regulación Neoplásica de la Expresión Génica , Proteasas Ubiquitina-Específicas/metabolismoRESUMEN
Early stages are under-represented in studies on the molecular and immune features of high-grade serous ovarian carcinoma (HGSOC), and specific studies focused on early-stage HGSOC are required for a better prognostic stratification and to personalize chemotherapy. The aim of this study was to determine the prognostic significance of CD8+ and CD4+ tumor-infiltrating lymphocytes (TILs), tumoral cell PD-L1 expression, BRCA mutational status and tumor mutation burden (TMB) in early-stage HGSOC. A retrospective study was performed on stage I and II HGSOC from the Molecular Reclassification of Early Stages of Ovarian Cancer (RECLAMO) cohort from the Spanish Group of Ovarian Cancer Research (GEICO). Centralized histological typing was performed based on morphological and immunohistochemical features. Intraepithelial (i) and stromal (s) CD8+ and CD4+ T cells and PD-L1 were evaluated on tissue microarrays by immunohistochemistry. BRCA1 and BRCA2 mutation status and TMB were analyzed in tumor DNA using next-generation sequencing. The study included 124 tumors. High iCD8+ (>20 TILs/core), low/intermediate CD4+ (<20 TILs/core) and high CD8+/CD4+ ratio (>35/core) were associated with favorable outcomes. Tumor cell PD-L1 expression (TPS ≥ 1) was present in only 8% of tumors. In total, 11 (16%) and 6 (9%) out of 69 HGSOC tested carried pathogenic or likely pathogenic BRCA1 or BRCA2 mutations, respectively. Median TMB of 40 tumors analyzed was 5.04 mutations/Mb and only 6 tumors had 10 or more mutations/Mb. BRCA status and TMB were not associated with TILs or prognosis. When compared with studies on advanced HGSOC, our results suggested that prognostic variables differed according to stage and that more studies focused on early stages of HGSOC are needed to better stratify these tumors.
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Linfocitos Infiltrantes de Tumor , Neoplasias Ováricas , Humanos , Femenino , Pronóstico , Estudios Retrospectivos , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Neoplasias Ováricas/patología , MutaciónRESUMEN
The origin of tumors has been under discussion over the years. Different theories have been suggested to explain this phenomenon. Among them, the Cancer-Stem Cells model, is one of the most outstanding. In this study, we reported a case of a 72-year-old man who presented two histologically different tumors with a 7-years gap, a Penile Squamous Cell Carcinoma and a Pleomorphic Undifferentiated Sarcoma, that share some molecular features. Phonotypical differences were showed and confirmed at histological and IHC levels. Molecular analysis showed an HPV infection in the carcinoma. Additionally, sequencing results revealed common (CDKN2A and TERT) and exclusive (FBXW7 and TP53) genetic alterations in both tumors (Table 1). The possible germline origin of common mutations was discarded after negative germline testing. Here we describe, for the first time a clinical case of a possible origin of two histologically different tumors from a common ancestor based on molecular data. Even if different hypothesis appear as possible, the Cancer Stem Cell-based model appears as the most suitable.
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Genomic Instability (GI) is a transversal phenomenon shared by several tumor types that provide both prognostic and predictive information. In the context of high-grade serous ovarian cancer (HGSOC), response to DNA-damaging agents such as platinum-based and poly(ADP-ribose) polymerase inhibitors (PARPi) has been closely linked to deficiencies in the DNA repair machinery by homologous recombination repair (HRR) and GI. In this study, we have developed the Scarface score, an integrative algorithm based on genomic and transcriptomic data obtained from the NGS analysis of a prospective GEICO cohort of 190 formalin-fixed paraffin-embedded (FFPE) tumor samples from patients diagnosed with HGSOC with a median follow up of 31.03 months (5.87-159.27 months). In the first step, three single-source models, including the SNP-based model (accuracy = 0.8077), analyzing 8 SNPs distributed along the genome; the GI-based model (accuracy = 0.9038) interrogating 28 parameters of GI; and the HTG-based model (accuracy = 0.8077), evaluating the expression of 7 genes related with tumor biology; were proved to predict response. Then, an ensemble model called the Scarface score was found to predict response to DNA-damaging agents with an accuracy of 0.9615 and a kappa index of 0.9128 (p < 0.0001). The Scarface Score approaches the routine establishment of GI in the clinical setting, enabling its incorporation as a predictive and prognostic tool in the management of HGSOC.
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The emergent human coronavirus SARS-CoV-2 and its resistance to current drugs makes the need for new potent treatments for COVID-19 patients strongly necessary. Dextran sulfate (DS) polysaccharides have long demonstrated antiviral activity against different enveloped viruses in vitro. However, their poor bioavailability has led to their abandonment as antiviral candidates. Here, we report for the first time the broad-spectrum antiviral activity of a DS-based extrapolymeric substance produced by the lactic acid bacterium Leuconostoc mesenteroides B512F. Time of addition assays with SARS-CoV-2 pseudoviruses in in vitro models confirm the inhibitory activity of DSs in the early stages of viral infection (viral entry). In addition, this exopolysaccharide substance also reports broad-spectrum antiviral activity against several enveloped viruses such as SARS-CoV-2, HCoV229E, HSV-1, in in vitro models and in human lung tissue. The toxicity and antiviral capacity of DS from L. mesenteroides was tested in vivo in mouse models which are susceptible to SARS-CoV-2 infection. The described DS, administered by inhalation, a new route of administration for these types of polymers, shows strong inhibition of SARS-CoV-2 infection in vivo, significantly reducing animal mortality and morbidity at non-toxic doses. Therefore, we suggest that it may be considered as a potential candidate for antiviral therapy against SARS-CoV-2.
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Intimal sarcomas (IS) are rare malignant mesenchymal tumors arising in large blood vessels of the systemic and pulmonary circulation and also in the heart. They are morphologically similar to other spindle cell, poorly differentiated sarcomas. The prognosis is poor and depends mainly on surgical options. Three cases of IS were collected from two institutions. Clinical data were retrieved and histological study was performed. A wide immunohistochemical panel was analyzed. FISH of MDM2 gene was performed, and a molecular study with NGS was implemented in all cases. The mean age of our cases was 54 years. Histologically, the tumors presented a diffuse growth pattern with heterogeneous atypical epithelioid or spindle cells and extensive thrombosed areas. All cases presented intense immunoexpression for MDM2, CDK4, CD117, c-myc, PDGFRA, and p16. PDGFRA, HTERT, and pan-TRK gained expression, while p16 lost intensity, being weaker in both the local recurrences and xenografts. The three cases showed amplification of MDM2 by FISH. NGS analysis revealed amplifications in the CDK4, PDGFRA, and KIT genes, together with BRAF mutation and KRAS amplification. P16 was expressed in all cases, losing intensity in local recurrence and xenografts. Two new alterations, a BRAF mutation and a KRAS amplification, were detected by NGS in different tumors, opening up new therapeutic options for these patients.
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Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Xenoinjertos , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Sarcoma/patología , Mutación , Neoplasias de los Tejidos Blandos/genética , Proteínas Tirosina Quinasas Receptoras/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Amplificación de Genes , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Quinasa 4 Dependiente de la Ciclina/genética , Quinasa 4 Dependiente de la Ciclina/metabolismoRESUMEN
A limited number of effective therapies are currently available to treat human coronavirus SARS-CoV-2 and other human coronaviruses, which are responsible for nearly a third of global cases of the common cold. The possibility of new emerging coronaviruses demands powerful new antiviral strategies. Lactoferrin is a well-known protein that possesses anti-inflammatory and immunomodulatory activities, and it has previously shown antiviral activity against several viruses, including SARS-CoV-2. To increase this antiviral activity, here we present bovine liposomal lactoferrin. Liposomal encapsulation of the compound was proven to increase permeability, bioavailability, and time release. In the present work, we compare the antiviral activity of free and liposomal bovine lactoferrin against HCoV229E and SARS-CoV-2 in vitro and in human primary bronchial epithelial cells, and we demonstrated that the liposomal form exerts a more potent antiviral activity than its free form at non-cytotoxic doses.
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COVID-19 , Coronavirus Humano 229E , Virus ARN , Humanos , Antivirales/farmacología , Antivirales/uso terapéutico , SARS-CoV-2 , Lactoferrina/farmacología , LiposomasRESUMEN
OBJECTIVES: We explored features of the angiosarcoma (AS) tumor microenvironment to discover subtypes that may respond to immunotherapy. METHODS: Thirty-two ASs were included. Tumors were studied by histology, immunohistochemistry (IHC), and gene expression profile using the HTG EdgeSeq Precision Immuno-Oncology Assay. RESULTS: Comparing cutaneous and noncutaneous ASs, the second group showed 155 deregulated genes, and unsupervised hierarchical clustering (UHC) delineated two groups: the first mostly cutaneous AS and the second mainly noncutaneous AS. Cutaneous ASs showed a significantly higher proportion of T cells, natural killer cells, and naive B cells. ASs without MYC amplification revealed a higher immunoscore in comparison with ASs with MYC amplification. PD-L1 was significantly overexpressed in ASs without MYC amplification. UHC showed 135 deregulated genes differentially expressed when comparing ASs from the non-head and neck area with patients who had AS in the head and neck area. ASs from the head and neck area showed high immunoscore. PD1/PD-L1 content was significantly more highly expressed in ASs from the head and neck area. IHC and HTG gene expression profiling revealed a significant correlation between PD1, CD8, and CD20 protein expression but not PD-L1. CONCLUSIONS: Our HTG analyses confirmed a high degree of tumor and microenvironment heterogeneity. Cutaneous ASs, ASs without MYC amplification, and ASs located in the head and neck area seem to be the most immunogenic subtypes in our series.
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Hemangiosarcoma , Neoplasias Cutáneas , Humanos , Antígeno B7-H1 , Hemangiosarcoma/genética , Pronóstico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Microambiente TumoralRESUMEN
Solitary fibrous tumor (SFT) is a rare type of mesenchymal lesion with variable clinical presentation in which specific clinicopathologic factors have been related to patient outcome. SFT shares an important morphologic and immunohistochemical overlap with other sarcomas, hence the differential diagnosis is challenging. Although molecular studies provide significant clues, especially in the differential diagnosis with other neoplasms, a thorough hematoxylin and eosin analysis and the integration of phenotypical, clinical, and radiological features remain an essential tool in SFT diagnosis. In this review, we discuss some emerging issues still under debate in SFT.