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.

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.

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.

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.