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.

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 Kaposi's sarcoma and Castleman's disease in a HIV-negative patient. Response to rituximab and doxorubicin / Sarcoma de Kaposi y enfermedad de Castleman simultáneos en un paciente VIH negativo. Respuesta a rituximab y doxorrubicina

No disponible

Valoración del sobrecrecimiento y traslocación bacterianos en el hígado graso no alcohólico, en pacientes con obesidad mórbida / An assessment of bacterial overgrowth and translocation in the non-alcoholic fatty liver of patients with morbid obesity

Antecedentes: se ha propuesto que el sobrecrecimiento bacteriano del intestino delgado (SBID) y la traslocación bacteriana a través de la pared intestinal se relacionan con el hígado graso no alcohólico (HGNA). El objetivo del presente estudio ha sido estudiar dicha relación en obesos mórbidos. Pacientes y métodos: se incluyeron consecutivamente pacientes con obesidad mórbida previo a su intervención de cirugía bariátrica. Los criterios de exclusión fueron: biopsia hepática normal, otras causas de enfermedad hepática o atrofia de la mucosa duodenal. Se realizó una gastroscopia para cultivo del aspirado duodenal, biopsias duodenales y extracción de sangre venosa periférica para estudio de lipopolisacárido (LPS) y proteína de unión del LPS (LBP). La biopsia hepática se realizó durante la intervención quirúrgica. Resultados: se incluyeron 71 pacientes; 26 fueron excluidos por biopsia hepática normal. Cuarenta y cinco tenían HGNA. Dieciocho eran varones, con edad media de 45,8 años (22-69) e índice de masa corporal (IMC) de 47,8 kg/m2 (37-58); el 25% tuvo SBID en el cultivo del aspirado duodenal. Existió significación estadística entre niveles de LBP y SBID con el grado de esteatosis (p < 0,05 y p = 0,077, respectivamente). No existió relación estadística con el índice de esteatohepatitis no alcohólica (EHNA), aunque sí hubo una tendencia a su asociación. Los niveles de LPS no guardaron relación con el grado de esteatosis o el índice de EHNA. Conclusiones: en pacientes con obesidad mórbida e HGNA se observan mayores niveles circulantes de LBP y mayor frecuencia de SBID cuanto mayor es el grado de esteatosis hepática

Background: small intestinal bacterial overgrowth (SIBO) and bacterial translocation across the intestinal wall have been allegedly associated with non-alcoholic fatty liver (NAFL). Our goal was to study such alleged association in morbidly obese patients. Patients and methods: patients with morbid obesity were consecutively included prior to bariatric surgery. Exclusion criteria included normal liver biopsy, other causes of liver disease, and duodenal mucosal atrophy. A gastroscopy was performed for duodenal aspirate culture and duodenal biopsy, and peripheral venous blood was drawn to assess lipopolysaccharide (LPS) and LPS-binding protein (LBP) levels. A liver biopsy was carried out during surgery. Results: seventy-one patients were included; 26 were excluded because of normal liver biopsy. Forty-five had NAFL. Eighteen were male, mean age was 45.8 years (22-69), and BMI was 47.8 kg/m2 (37-58). A total of 25% had SIBO in their duodenal aspirate culture. There was statistical significance for the association of LBP levels and SIBO with steatosis grade (p < 0.05 and p = 0.077, respectively). There was no statistical association with non-alcoholic steatohepatitis (NASH) index, but a trend towards association was found. LPS levels were not associated with steatosis grade or NASH index. Conclusions: the higher the grade of liver steatosis, the higher were the circulating LBP levels and SIBO rates seen in patients with morbid obesity and NAFL

An assessment of bacterial overgrowth and translocation in the non-alcoholic fatty liver of patients with morbid obesity.

BACKGROUND: small intestinal bacterial overgrowth (SIBO) and bacterial translocation across the intestinal wall have been allegedly associated with non-alcoholic fatty liver (NAFL). Our goal was to study such alleged association in morbidly obese patients. PATIENTS AND METHODS: patients with morbid obesity were consecutively included prior to bariatric surgery. Exclusion criteria included normal liver biopsy, other causes of liver disease, and duodenal mucosal atrophy. A gastroscopy was performed for duodenal aspirate culture and duodenal biopsy, and peripheral venous blood was drawn to assess lipopolysaccharide (LPS) and LPS-binding protein (LBP) levels. A liver biopsy was carried out during surgery. RESULTS: seventy-one patients were included; 26 were excluded because of normal liver biopsy. Forty-five had NAFL. Eighteen were male, mean age was 45.8 years (22-69), and BMI was 47.8 kg/m2 (37-58). A total of 25% had SIBO in their duodenal aspirate culture. There was statistical significance for the association of LBP levels and SIBO with steatosis grade (p < 0.05 and p = 0.077, respectively). There was no statistical association with non-alcoholic steatohepatitis (NASH) index, but a trend towards association was found. LPS levels were not associated with steatosis grade or NASH index. CONCLUSIONS: the higher the grade of liver steatosis, the higher were the circulating LBP levels and SIBO rates seen in patients with morbid obesity and NAFL.

Dermatosis papular acantolítica de la vulva con buena respuesta a tacrólimus tópico.

Papular acantholytic dermatosis of the vulva is a rare, chronic disorder and is an entity that remains to be fully understood. It shares clinical and histopathological overlap with Darier disease and Hailey-Hailey disease. We describe a 30-year-old woman with papular acantholytic dermatosis of the vulva. The lesions consisted of whitish papules and erosions on the labia majora. Histologically, there was hyperkeratosis and focal parakeratosis with acantholytic and dyskeratotic cells. She did not respond completely to topical steroids but clinical improvement occurred after the use of topical tacrolimus.

Granulomas cutáneos no infecciosos en inmunodeficiencia común variable / Non-infectious skin granulomas in a common variable immunodeficiency

La inmunodeficiencia variable común es una inmunodeficiencia primaria por hipogamaglobulinemia de IgG e IgA poco frecuente en la población. Clásicamente se presenta durante la juventud y se diagnostica durante la investigación de infecciones respiratorias y gastrointestinales a repetición. Estos pacientes pueden además presentar enfermedades autoinmunes, inflamatorias, neoplásicas, malabsorción y problemas granulomatosos no infecciosos, que afectan el pulmón, ganglios, bazo, hígado, y menos usualmente la piel. Presentamos el caso de una paciente diagnosticada de inmunodeficiencia variable común que se presenta en la consulta dermatológica con múltiples nódulos eritemato-costrosos en miembros, donde se hallaron únicamente granulomas asépticos (AU)

Common variable immunodeficiency is a rare, primary immunodeficiency characterized by hypogammaglobulinemia of IgG and IgA. It classically presents as recurrent respiratory and gastrointestinal infections in young patients, who may also have autoimmune and inflammatory disease, malignancies, malabsorption and non-infectious granulomas, mainly located in the lung, lymph nodes, spleen, liver and, less frequently, in the skin. We report the case of a patient diagnosed with common variable immunodeficiency who presented in the dermatology clinic with multiple, erythematous, crusted nodules on the limbs. Only aseptic granulomas were found (AU)

Effectiveness of serological markers of eosinophil activity in monitoring eosinophilic esophagitis.

BACKGROUND: it is necessary to find serological markers accessible in clinical practice to prevent the need to perform repeated endoscopies. OBJECTIVE: to assess the efficacy of eosinophil activity markers in monitoring eosinophilic esophagitis (EoE). MATERIAL AND METHODS: thirty patients were included prospectively, all under dietary treatment -diets excluding 6 foods, and allergy test based diet (skin prick test and specific IgE). The variables assessed were demographic parameters, eosinophil cationic protein (ECP) levels (µg/mL), total IgE (KU/L), peripheral blood eosinophils (PBE) (U/mm³), and the maximum peak of eosinophils/hpf in esophageal biopsies. The variation found between these figures was assessed in line with response to dietary treatment. RESULTS: thirty patients (66.7% males; mean age 33.43 years) were included in the study, 22 responders and 8 non-responders. Ninety percent presented a personal history of atopy. No significant decrease was detected in serum total IgE and ECP after diet in responder and nonresponders. However, the PBE decreased significantly in responders but not in nonresponders, PBE in responders (pre-diet. 397.27 vs. post-diet 276.81, p = 0.024) and non-responders PBE (pre-diet. 460 vs. post-diet 317.5, p = 0.23). CONCLUSION: serum total IgE and ECP do not act as markers for EoE activity. However PBE may play a role in this regard, bearing in mind that this parameter may be influenced by concomitant atopic conditions.

Metástasis peritoneales en cáncer de mama / Peritoneal carcinomatosis due to metastatic spread of lobular carcinoma of the breast

El cáncer de mama lobulillar infiltrante presenta un especial tropismo sobre la cavidad peritoneal, aparato genitourinario y gastrointestinal. Describimos 2 casos de carcinomatosis peritoneal secundaria a la diseminación metastásica de un carcinoma lobulillar infiltrante de mama. El diagnóstico se hizo años después de la aparición del tumor primario. La carcinomatosis peritoneal (asociada a metástasis genitourinarias y/o gastrointestinales) en cáncer de mama es rara, siendo más frecuente en el tipo lobulillar infiltrante. Su diagnóstico es difícil dada la inespecificidad de la sintomatología y el largo periodo que, con frecuencia, ocurre desde el diagnóstico inicial del tumor mamario hasta la afectación peritoneal. La sospecha clínica y el estudio histológico-inmunohistoquímico ayudan a diferenciar entre un tumor primario de cavidad peritoneal y metástasis de carcinoma de mama. Debe individualizarse el tratamiento en cada caso (AU)

Invasive lobular breast cancer has a special tropism for the peritoneal cavity and gastrointestinal and genitourinary systems. We describe 2 cases of peritoneal carcinomatosis secondary to metastatic spread of lobular carcinoma of the breast. The diagnosis was made several years after detection of the primary tumor. The peritoneal carcinomatosis (with genitourinary or gastrointestinal metastases) in breast cancer is rare and is most frequent in invasive lobular carcinoma. Diagnosis is difficult because the symptoms are often nonspecific and there is often a long interval between the initial diagnosis of breast cancer and peritoneal involvement. Clinical suspicion and histological-immunohistochemical study help to differentiate between a primary tumor of the peritoneal cavity and the presence of metastatic breast carcinoma. Treatment should be individualized in each patient (AU)

Síndrome del ganglio linfático mesentérico cavitado: una rara complicación de la enfermedad celiaca / Cavitating mesenteric lymph node syndrome: a rare complication of celiac disease

Dentro de las numerosas complicaciones de la enfermedad celiaca, el síndrome del ganglio linfático mesentérico cavitado se considera una de las más infrecuentes, siendo escasas las series de casos publicadas en la literatura. Su etiología y su mecanismo fisiopatológico se desconocen pero debido a su alta tasa de mortalidad, situada en torno al 50%, es conveniente reconocerla de forma precoz para así instaurar un tratamiento adecuado lo antes posible(AU)

Among the many complications of celiac disease, mesenteric lymph node syndrome cavitated is considered one of the rarest, there is few case series published in the literature. The etiology and pathophysiology are unknown but because of its high mortality rate, estimated to be around 50%, it should recognize at an early stage in order to institute appropriate therapy as soon as possible(AU)

Recurrencia del tumor ovárico de las células de la granulosa / Recurrence of ovarian granulosa cell tumor

Presentamos el caso de una mujer de 79 años, con antecedentes de un supuesto fibroma ovárico, que comienza con un cuadro de dolor en fosa ilíaca izquierda y leucocitosis, siendo diagnosticada de diverticulitis. Durante el estudio, incidentalmente se descubre una masa en la pared abdominal anterior que resultó ser una recidiva de un tumor de células de la granulosa. Realizamos una revisión bibliográfica de esta patología centrándonos, fundamentalmente, en sus aspectos clínicos y terapéuticos. Se trata de una neoplasia muy poco frecuente, sobre la que hay pocos estudios, que se caracteriza por su larga historia natural y su tendencia a recurrir años después del diagnóstico (AU)

We present the case of a 79-year-old woman who was misdiagnosed with an ovarian fibroma 5 years previously. The patient presented with pain in the right iliac fossa with leukocytosis and was diagnosed with diverticulitis. A mass was incidentally found in the anterior abdominal wall, which was later confirmed as metastasis from a granulosa cell tumor of the ovary. We provide a literature review, focussing on the clinical findings and treatment of this tumor. Few reports have been published of this uncommon entity, characterized by a long natural history and tendency to recur years after the initial diagnosis (AU)

Cavitating mesenteric lymph node syndrome: a rare complication of celiac disease.

Among the many complications of celiac disease, mesenteric lymph node syndrome cavitated is considered one of the rarest, there is few case series published in the literature. The etiology and pathophysiology are unknown but because of its high mortality rate, estimated to be around 50%, it should recognize at an early stage in order to institute appropriate therapy as soon as possible.

Bocio amiloide secundario a enfermedad de Crohn / Amyloid goiter secondary to Crohn’s disease

La amiloidosis secundaria, en la mayoría de los casos, tiene un origen neoplásico o es secundaria a enfermedades inflamatorias crónicas. La mayoría de las amiloidosis secundarias son descubiertas por proteinuria o síndrome nefrótico, debido a amiloidosis renal. Sólo en un pequeño porcentaje hay afección clínicamente significativa de la glándula tiroidea, aunque no es infrecuente encontrar depósito de amiloide en autopsias. Describimos a continuación un caso de bocio amiloide. La paciente había sido diagnosticada de enfermedad de Crohn hacía 7 años y presentaba insuficiencia renal de causa no filiada. Fue remitida a nuestro servicio para estudio de bocio descubierto casualmente. La paciente fue sometida a tiroidectomía por un crecimiento progresivo de la glándula tiroidea con síntomas compresivos. La anatomía patológica se correspondió con bocio amiloide (AU)

Hipertensión secundaria a Síndrome de Cushing / Hypertension secondary to Cushing syndrome

En un pequeño grupo de hipertensos puede identifi carse una causa, responsable del aumento de las cifras de presión arterial, como el Síndrome de Cushing, que supone el 0,2-0,6% de los casos. Presentamosel caso de un paciente diagnosticado de hipertensión secundaria a Síndrome de Cushing

In a small group of hypertensive patients a cause of elevated blood pressure levels can be identifi ed,such as Cushing syndrome, which corresponds to 0.2-0.6% of cases. We present the case of a patient diagnosed with hypertension secondary to Cushing Syndrome

Paniculitis asociada a dermatomiositis amiopática / Panniculitis associated with amyopathic dermatomyositis

Las manifestaciones cutáneas clásicas de la dermatomiositis son bien conocidas, pero no así las lesiones de paniculitis en el contexto de esta conectivopatía. Desde su primera descripción no hay más de 17 casos de dermatomiositis con lesiones de paniculitis, y ninguno de ellos corresponde a una dermatomiositis amiopática. Se presenta el caso de una paciente mujer de 61 años diagnosticada de dermatomiositis amiopática que desarrolló lesiones de paniculitis a los 3 años del primer diagnóstico. Destacamos la buena evolución clínica de la paciente durante 7 años de seguimiento en los que no se han observado enfermedades subyacentes. Parece que la presencia de paniculitis en el contexto de una dermatomiositis implica mejor pronóstico, tanto en la respuesta al tratamiento como en la menor frecuencia de procesos malignos asociados (AU)