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 XenoinjertoRESUMEN
Lymph node angio- and lymphangio-genesis have been shown to play an important role in the premetastatic niche of sentinel lymph nodes. In the current study we have investigated the association of angio- and lympangio-genesis related parameters in metastatic sentinel lymph nodes of patients with melanoma with the presence of nonsentinel and distant organ metastasis. Peritumoral and intratumoral relative blood and lymphatic vessel areas (evaluated by Chalkley method), blood and lymphatic microvessel densities, and the rates of blood and lymphatic vessel proliferation were assessed in primary tumors and sentinel lymph node metastasis of 44 patients with melanoma using CD34/Ki-67 and D240/Ki-67 immunohistochemical double staining. Primary melanoma exhibited significantly higher rate of lymphatic proliferation compared with its lymph node metastasis (P < 0.05), while lymph node metastasis showed significantly higher rate of blood vessel proliferation (P < 0.05). Using multivariate logistic regression model, the rate of peritumoral lymphatic proliferation was inversely associated with positive nonsentinel lymph node status (P < 0.05), whereas the rate of intratumoral blood vessel proliferation was associated with distant organ metastasis (P < 0.05). Using multivariate Cox regression analysis, the rate of intratumoral blood vessel proliferation was also inversely associated with overall survival of patients with melanoma (P < 0.05).
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Ganglios Linfáticos/patología , Linfangiogénesis , Vasos Linfáticos/patología , Melanoma/secundario , Microvasos/patología , Neovascularización Patológica , Neoplasias Cutáneas/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Biopsia , Proliferación Celular , Distribución de Chi-Cuadrado , Femenino , Humanos , Receptores de Hialuranos/análisis , Inmunohistoquímica , Estimación de Kaplan-Meier , Antígeno Ki-67/análisis , Modelos Logísticos , Ganglios Linfáticos/química , Metástasis Linfática , Vasos Linfáticos/química , Masculino , Melanoma/irrigación sanguínea , Melanoma/química , Melanoma/mortalidad , Microvasos/química , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Modelos de Riesgos Proporcionales , Neoplasias Cutáneas/irrigación sanguínea , Neoplasias Cutáneas/química , Neoplasias Cutáneas/mortalidad , EspañaRESUMEN
BACKGROUND: Many observational studies investigated the prognostic significance of angiogenesis and lymphangiogenesis in patients with melanoma. However, the obtained results are rather contradictory, probably due to the lack of the consensus methodology. METHODS: To investigate the prognostic significance of angiogenesis and lymphangiogenesis-related parameters in patients with melanoma, we performed a retrospective investigation following the consensus recommendations for angiogenesis and lymphangiogenesis quantification in solid tumors and reporting recommendations for tumor marker (REMARK) criteria for reporting the results. Blood and lymphatic vessel Chalkley scores, endothelial cell proliferation fractions and microvessel densities were quantified using a double immunostaining for endothelial marker CD34 or lymphendothelial marker D240 and the proliferation marker Ki-67 in 196 patients with melanoma. These parameters were evaluated separately for peritumoral (PT) and intratumoral areas and were correlated with outcome. RESULTS: In multivariate analysis PT D240 Chalkley score was identified as a strongest predictor for sentinel lymph node metastases, non-sentinel lymph node metastases, distant metastases, disease free survival and overall survival in patients with melanoma. CONCLUSIONS: If additional studies corroborate our findings, we believe that the inclusion of PT D240 Chalkley counts to the routine pathology examination of melanoma samples would provide additional information for identifying high-risk patients.
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Melanoma/irrigación sanguínea , Melanoma/patología , Neoplasias Cutáneas/irrigación sanguínea , Neoplasias Cutáneas/patología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales de Origen Murino/química , Antígenos CD34/metabolismo , Biomarcadores de Tumor/metabolismo , Supervivencia sin Enfermedad , Femenino , Humanos , Antígeno Ki-67/metabolismo , Ganglios Linfáticos/patología , Linfangiogénesis , Metástasis Linfática , Masculino , Melanoma/metabolismo , Persona de Mediana Edad , Neovascularización Patológica/patología , Estudios Retrospectivos , Biopsia del Ganglio Linfático Centinela/métodos , Neoplasias Cutáneas/metabolismo , Análisis de Supervivencia , Factor C de Crecimiento Endotelial Vascular/metabolismo , Melanoma Cutáneo MalignoRESUMEN
Differences in gene expression between melanomas arising on skin intermittently and chronically sun-exposed areas were described. Additionally, several studies have shown differences in clinical characteristics and prognosis, suggesting distinct biological pathways in the development of these tumors. We performed a retrospective investigation aimed on evaluation of the differences in angiogenesis and lymphangiogenesis between melanomas arising on skin with and without signs of chronic sun-induced damage. For that purpose, we evaluated relative blood and lymphatic vessel areas, blood and lymphatic endothelial cell proliferation fractions, separately for peritumoral and intratumoral areas. We have shown that melanomas arising on sun-exposed skin exhibit lower angiogenic and lymphangiogenic potentials and better prognosis than those arising on skin without signs of chronic sun-induced damage.
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Vasos Linfáticos/patología , Melanoma/patología , Neovascularización Patológica/patología , Neoplasias Cutáneas/patología , Adulto , Anciano , Anciano de 80 o más Años , Humanos , Inmunohistoquímica , Linfangiogénesis , Persona de Mediana Edad , Estudios Retrospectivos , Luz Solar/efectos adversos , Adulto JovenRESUMEN
Hemophagocytic lymphohistiocytosis (HLH) is a rare but fatal disorder characterized by the proliferation and infiltration of macrophages and hyperactivated T lymphocytes that escape from the physiological control pathways and favour the existence of an environment of excessive inflammation and tissue destruction. HLH has been classified into two types: a primary or familial autosomal recessive form, caused by mutations in genes encoding proteins involved in the granule-dependent cytotoxic pathway (familial hemophagocytic lymphohistiocytosis [FHL] types 1-5); and other secondary or acquired form, generally associated with infections, malignancy, autoimmune diseases, metabolic disorders or primary immunodeficiencies. Since the first familial hemophagocytic lymphohistiocytosis-2 (FHL2) causative mutation in the PRF1 gene was described in 1999, more than 200 mutations have been identified to date. Here, we report the first case of very late-onset FHL2 in a Spanish 72-year-old female with splenomegaly, hypertriglyceridemia, hypofibrinogenemia, pancytopenia and marrow hemophagocytosis harbouring in heterozygosity two PRF1 variants proposed as causative in this study. The heterozygous mutation c.445G>A (p.Gly149Ser) identified in the exon 2 results in a missense mutation previously described as a probable pathogenic variant associated with the development of FHL2. Affecting the same exon, c.272C>T (p.Ala91Val) is the most prevalent variant of this gene. Although it was initially classified as benign, recent studies support its potential pathogenic role, considering it a variant of uncertain significance associated with a risk of developing FHL2. The genetic confirmation of FHL made possible an adequate counselling to the patient and direct relatives and provided important information for her control and follow-up.
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Linfohistiocitosis Hemofagocítica , Humanos , Femenino , Anciano , Linfohistiocitosis Hemofagocítica/diagnóstico , Linfohistiocitosis Hemofagocítica/genética , Perforina/genética , España , Mutación , Mutación Missense , Proteínas Musculares/genética , Factores de Transcripción/genética , Proteínas con Homeodominio LIM/genéticaRESUMEN
PURPOSE: To evaluate the clinical outcomes, MRI imaging and histological characteristics of biopsy samples of the tendon from patients in whom rotator cuff repair was previously performed with a bioinductive type I bovine collagen implants. METHODS: Prospective study of 30 patients with partial or complete rotator cuff tears who underwent arthroscopic repair and augmentation with a resorbable type I bovine collagen implant. Preoperatively and at 6 and 12 months after surgery, the VAS, ASES and Constant-Murley scores were evaluated and an MRI study was performed. At 6 months, biopsies of the resulting tissue were obtained and examined histologically. RESULTS: Patients experienced statistically significant and sustained improvement from baseline for all scores and the mean tendon thickness increased by 1.84 mm. Magnetic resonance imaging evidence of complete healing was found in 27 patients and a considerable reduction in defect size, greater than 50%, was shown in 3. In all samples obtained, the new tissue generated had the histological appearance of a tendon, and was indistinguishable from the native tendon. There was no evidence of any remaining collagen implant. CONCLUSIONS: Biopsies of tissue formed from bioinductive type I bovine collagen implants showed, six months after surgery, the generation of a neotendon indistinguishable from the native one. Histology and MRI imaging, revealed complete integration of the implant and absence of inflammatory or foreign body reactions. The clinical parameters, thickness and MRI signal of the tendon improved significantly at 6 months, regardless of the type and size of the tear, and remained unchanged until 12 months. LEVEL OF EVIDENCE: Level IV, case series.
RESUMEN
Oxidative stress is involved in ischemia-reperfusion injury and allograft rejection after transplantation. We studied two well-known antioxidants, melatonin and ascorbic acid (AA), in relation to the survival of a pancreas transplantation model without immunosuppression. Forty-eight Landrace pigs were divided into three groups (n = 16 each; eight donors and eight recipients) that received melatonin, AA, or no antioxidant therapy (controls). Melatonin and AA were administered (10 mg/kg body weight) intravenously to donors and recipients during surgery and on postoperative days 1-7. The molecules were also added (5 mm) to a University of Wisconsin preservation solution during organ cold storage. Melatonin significantly delayed acute rejection and prolonged allograft survival (25.1 ± 7.7 days) compared with the controls (8.1 ± 0.8 days, P = 0.013) and the AA group (9.4 ± 1.6 days, P = 0.049). Melatonin reduced indicators of oxidative stress, malondialdehyde, and 4-hydroxyalkenals, in pancreatic samples collected during procurement, cold ischemia, and reperfusion. Melatonin also reduced serum pig-major acute-phase protein/inter-α-trypsin inhibitor heavy chain 4 (pMAP/ITIH(4)) in the early post-transplantation period. AA only partially reduced oxidative damage 30 min postreperfusion and failed to prevent pMAP/ITIH(4) elevations. These findings suggested that melatonin may be a useful therapeutic tool for organ transplantation.
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Antioxidantes/uso terapéutico , Ácido Ascórbico/uso terapéutico , Supervivencia de Injerto/efectos de los fármacos , Melatonina/uso terapéutico , Trasplante de Páncreas/métodos , alfa-Globulinas/metabolismo , Animales , Femenino , Estrés Oxidativo/efectos de los fármacos , Porcinos , Trasplante HomólogoRESUMEN
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.
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Sarcoma , Tetrahidroisoquinolinas , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/uso terapéutico , Daño del ADN , Reparación del ADN/genética , Dioxoles/efectos adversos , Humanos , Estudios Retrospectivos , Sarcoma/tratamiento farmacológico , Sarcoma/genética , Tetrahidroisoquinolinas/efectos adversos , Trabectedina/uso terapéuticoRESUMEN
The proportion of cancer patients with tumours that harbour a potentially targetable genomic alteration is increasing considerably. The diagnosis of these genomic alterations can lead to tailoring of treatment, at the onset of disease or during progression, as well as providing additional, predictive information on the efficacy of immunotherapy. However, in up to 25% of cases, the initial tissue biopsy is inadequate for precision oncology and, in many cases, tumour genomic profiling at progression is not possible due to technical limitations of obtaining new tumour tissue specimens. Efficient diagnostic alternatives are therefore required for molecular stratification, such as liquid biopsy. This technique enables the evaluation of the tumour genomic profile dynamically and as well as capturing intra-patient genomic heterogeneity. To date, there are several diagnostic techniques available for use in liquid biopsy, each with different precision and performance levels. The objective of this consensus statement of the Spanish Society of Pathology (SEAP) and the Spanish Society of Medical Oncology (SEOM) is to evaluate the viability and effectiveness of the different methodological approaches of liquid biopsy in cancer patients, and the potential application of this method to current clinical practice. The experts contributing to this consensus statement agree that, according to current evidence, liquid biopsy is an acceptable alternative to tumour tissue biopsy for the study of biomarkers in various clinical settings. It is therefore important to standardise pre-analytical and analytical procedures to ensure reproducibility and to generate structured and accessible clinical reports. It is essential to appoint multidisciplinary tumour molecular committees to oversee these processes and to enable the most suitable therapeutic decisions for each patient according to the genomic profile.
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Biopsia Líquida , Oncología Médica , Neoplasias , Medicina de Precisión , Biomarcadores de Tumor , Humanos , Neoplasias/diagnóstico , Reproducibilidad de los Resultados , Sociedades MédicasRESUMEN
INTRODUCTION: There are limited findings available on KIT-negative GIST-like (KNGL) population. Also, KIT expression may be post-transcriptionally regulated by miRNA221 and miRNA222. Hence, the aim of this study is to characterize KNGL population, by differential gene expression, and to analyze miRNA221/222 expression and their prognostic value in KNGL patients. METHODS: KIT, PDGFRA, DOG1, IGF1R, MIR221 and MIR222 expression levels were determined by qRT-PCR. We also analyzed KIT and PDGFRA mutations, DOG1 expression, by immunohistochemistry, along with clinical and pathological data. Disease-free survival (DFS) and overall survival (OS) differences were calculated using Log-rank test. RESULTS: Hierarchical cluster analyses from gene expression data identified two groups: group I had KIT, DOG1 and PDGFRA overexpression and IGF1R underexpression and group II had overexpression of IGF1R and low expression of KIT, DOG1 and PDGFRA. Group II had a significant worse OS (p = 0.013) in all the series, and showed a tendency for worse OS (p = 0.11), when analyzed only the localized cases. MiRNA222 expression was significantly lower in a control subset of KIT-positive GIST (p < 0.001). OS was significantly worse in KNGL cases with higher expression of MIR221 (p = 0.028) or MIR222 (p = 0.014). CONCLUSIONS: We identified two distinct KNGL subsets, with a different prognostic value. Increased levels of miRNA221/222, which are associated with worse OS, could explain the absence of KIT protein expression of most KNGL tumors.
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No disponible
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Humanos , Patología , Técnicos Medios en Salud , Especialización , Brechas de la Práctica ProfesionalRESUMEN
We report a case of a man with a tumour of the palm that grew slowly for five years, being repeatedly diagnosed as a synovial cyst. Histopathological diagnosis showed an aggressive digital papillary adenocarcinoma. Thirty-eight months postoperatively there was neither recurrence nor signs of metastases.
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Adenocarcinoma Papilar/diagnóstico , Mano , Neoplasias de las Glándulas Sudoríparas/diagnóstico , Adenocarcinoma Papilar/patología , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de las Glándulas Sudoríparas/patologíaRESUMEN
Los pacientes con cáncer y alteraciones oncogénicas potencialmente tratables están aumentando de forma considerable. El diagnóstico de estas alteraciones permite frecuentemente realizar un tratamiento personalizado inicial o a la progresión, así como conocer información predictiva sobre la eficacia de la inmunoterapia. Sin embargo, en un 25% de los casos, la biopsia de tejido inicial no es informativa o no es posible realizar el perfil genómico tumoral a la progresión por la dificultad para obtener nuevas biopsias de tejido tumoral. Por ello, son necesarias alternativas diagnósticas eficaces para la estratificación molecular, que permitan una valoración dinámica del perfil genómico tumoral, como la biopsia líquida, reflejando además la heterogeneidad genómica en el seno del mismo paciente. Actualmente, existen distintas técnicas diagnósticas de biopsia líquida, cada una con distintos grados de precisión y rendimiento. El objetivo de este consenso de la Sociedad Española de Anatomía Patológica (SEAP) y la Sociedad Española de Oncología Médica (SEOM) es evaluar la viabilidad y efectividad de las distintas técnicas de biopsia líquida en el paciente con cáncer en la práctica clínica diaria. Los expertos de este consenso concluyen que la biopsia líquida es una alternativa aceptable a la biopsia de tejido para el estudio de biomarcadores. Sin embargo, es importante estandarizar los procedimientos preanalíticos y analíticos, garantizar su reproducibilidad, así como generar informes clínicos estructurados y comprensibles. La implementación de comités multidisciplinares de evaluación de las alteraciones moleculares es fundamental para mejorar estos procesos y favorecer las decisiones terapéuticas más adecuadas para cada paciente con cáncer en función de perfil genómico
The proportion of cancer patients with tumours that harbour a potentially targetable genomic alteration is increasing considerably. The diagnosis of these genomic alterations can lead to tailoring of treatment, at the onset of disease or during progression, as well as providing additional, predictive information on the efficacy of immunotherapy. However, in up to 25% of cases, the initial tissue biopsy is inadequate for precision oncology and, in many cases, tumour genomic profiling at progression is not possible due to technical limitations of obtaining new tumour tissue specimens. Efficient diagnostic alternatives are therefore required for molecular stratification, such as liquid biopsy. This technique enables the evaluation of the tumour genomic profile dynamically and as well as capturing intra-patient genomic heterogeneity. To date, there are several diagnostic techniques available for use in liquid biopsy, each with different precision and performance levels. The objective of this consensus statement of the Spanish Society of Pathology (SEAP) and the Spanish Society of Medical Oncology (SEOM) is to evaluate the viability and effectiveness of the different methodological approaches of liquid biopsy in cancer patients, and the potential application of this method to current clinical practice. The experts contributing to this consensus statement agree that, according to current evidence, liquid biopsy is an acceptable alternative to tumour tissue biopsy for the study of biomarkers in various clinical settings. It is therefore important to standardise pre-analytical and analytical procedures to ensure reproducibility and to generate structured and accessible clinical reports. It is essential to appoint multidisciplinary tumour molecular committees to oversee these processes and to enable the most suitable therapeutic decisions for each patient according to the genomic profile