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.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: Technical considerations and the learning curve.

Over the past decade, there has been a considerable increase in the utilization of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in the management of patients with peritoneal metastases. This is due to improved safety and favorable oncologic outcomes, including curative potential. CRS/HIPEC has a steep learning curve and requires familiarity with peritonectomy procedures. This review will outline the technical aspects and learning curve of CRS/HIPEC.

Chylous ascytis causing abdominal distension after laparoscopic radical nephrectomy.

OBJECTIVE: To report a case of large chylous ascytis as a late complication of a laparoscopic nephrectomy for renal tumor. METHODS: A 62 year old patient was admitted with general deterioration and abdominal distension due to chylous ascites. Abdominal ultrasound and CT led to the diagnosis. Paracentesis confirmed the presence of a large peritoneal chylous fluid effusion. RESULTS: The patient was treated by punction and placement of a percutaneous drainage. A large amount of lymphatic fluid was obtained after punction with a progressive decrease. Medical treatment included low sodium and low fat diet, together with medium chain fast absorbing triglycerides, protein supplements, diuretics and somatostatin analogues (octeotride). The patient's progress was satisfactory after several days of treatment. CONCLUSIONS: Chylous ascites is a rare complication of laparoscopic nephrectomy, but it has a favorable course if managed conservatively. Meticulous clipping of the retroperitoneal lymph vessels is recommended to prevent the formation of chylous ascites, especially when discharging the renal vascular pedicle during nephrectomy or extensive lymphadenectomy.

Perineurial cells in granular cell tumors and neoplasms with perineural invasion: an immunohistochemical study.

Granular cell tumors (GCT) are nerve sheath neoplasms composed of Schwann cells with granular cytoplasm. Perineurial cells are the cellular component of the perineurium and of perineuriomas, neoplasms supposedly derived from perineurial cells. However, perineurial cells have also been found in other Schwann cell-derived tumors. These cells have not been well studied in GCTs. We studied the presence of perineurial cells in a series of 24 GCTs with EMA, claudin-1, and Glut-1, which are immunohistochemical markers for perineurial cells. Three cases lacked nerve fascicles. Three cases showed no perineurial proliferation (grade 0), 7 showed grade 1 proliferation, and 11 showed grade 2 proliferation. For comparison, we studied 17 cases of neoplasms with perineural invasion (PNI): 7 cutaneous neoplasms [squamous cell carcinomas (n = 3), cutaneous lymphoma, malignant melanoma, eccrine carcinoma, congenital neurotropic nevus (n = 1 each)] and 10 noncutaneous tumors [prostatic (n = 2), gastric (n = 2), and colonic (n = 2) adenocarcinomas; invasive ductal carcinoma of breast (n = 2); urothelial carcinoma of bladder (n = 1); and oral squamous cell carcinoma (n = 1)] with the same antibodies for perineurial cells. We found perineurial cell proliferation in 10 cases, 6 grade 1, and 4 grade 2. These perineurial cells were limited to the areas around the nerve fascicles. Most of the tumor was devoid of perineurial cells. Thus, it was interpreted more as a hyperplastic or reactive phenomenon than a neoplastic component. Claudin-1 was the most sensitive of the 3 markers that we used. Such proliferation was less intense in non-GCTs. In conclusion, proliferation of perineurial cells in GCTs and neoplasms with PNI is a common finding that had not been previously studied. It seems to be a non-neoplastic phenomenon.

Road Safety Perception Questionnaire (RSPQ) in Latin America: A Development and Validation Study.

Background: Although public bodies need to know drivers' perception of road safety, in Latin America there are no valid and reliable instruments that propose an integral dimensionality. The objective of this study was to design and validate a Road Safety Perception Questionnaire (RSPQ). Methodology: The design included a review of the available evidence and expert knowledge to select the dimensional items for the instrument. A pilot test was carried out to determine possible corrections and adjustments to the questionnaire, after which a Confirmatory Factor Analysis was performed on a stratified sample of 736 Ecuadorian drivers to determine its reliability and construct validity. Results: The results suggest that the RSPQ has a clear factorial structure with high factorial weight items and good internal consistency. The results of the 41-item model grouped into six dimensions (human, vehicle, road infrastructure, regulatory framework and intervention measures, socioeconomic and driving precautions) obtained the best adjustment indexes at the absolute, incremental and parsimonious levels. Conclusions: The preliminary RSPQ evidence can be considered a valid and reliable instrument to assess drivers' perception of road safety.

Analysis and Prediction of Vehicle Kilometers Traveled: A Case Study in Spain.

Knowledge of the kilometers traveled by vehicles is essential in transport and road safety studies as an indicator of exposure and mobility. Its application in the determination of user risk indices in a disaggregated manner is of great interest to the scientific community and the authorities in charge of ensuring road safety on highways. This study used a sample of the data recorded during passenger vehicle inspections at Vehicle Technical Inspection stations and housed in a data warehouse managed by the General Directorate for Traffic of Spain. This study has three notable characteristics: (1) a novel data source is explored, (2) the methodology developed applies to other types of vehicles, with the level of disaggregation the data allows, and (3) pattern extraction and the estimate of mobility contribute to the continuous and necessary improvement of road safety indicators and are aligned with goal 3 (Good Health and Well-Being: Target 3.6) of The United Nations Sustainable Development Goals of the 2030 Agenda. An Operational Data Warehouse was created from the sample received, which helped in obtaining inference values for the kilometers traveled by Spanish fleet vehicles with a level of disaggregation that, to the knowledge of the authors, was unreachable with advanced statistical models. Three machine learning methods, CART, random forest, and gradient boosting, were optimized and compared based on the performance metrics of the models. The three methods identified the age, engine size, and tare weight of passenger vehicles as the factors with greatest influence on their travel patterns.

Driver Liability Assessment in Vehicle Collisions in Spain.

An accurate estimation of exposure is essential for road collision rate estimation, which is key when evaluating the impact of road safety measures. The quasi-induced exposure method was developed to estimate relative exposure for different driver groups based on its main hypothesis: the not-at-fault drivers involved in two-vehicle collisions are taken as a random sample of driver populations. Liability assignment is thus crucial in this method to identify not-at-fault drivers, but often no liability labels are given in collision records, so unsupervised analysis tools are required. To date, most researchers consider only driver and speed offences in liability assignment, but an open question is if more information could be added. To this end, in this paper, the visual clustering technique of self-organizing maps (SOM) has been applied to better understand the multivariate structure in the data, to find out the most important variables for driver liability, analyzing their influence, and to identify relevant liability patterns. The results show that alcohol/drug use could be influential on liability and further analysis is required for disability and sudden illness. More information has been used, given that a larger proportion of the data was considered. SOM thus appears as a promising tool for liability assessment.

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.

Total synthesis of the putative structure of stemonidine: the definitive proof of misassignment.

[structure: see text] The total synthesis of the putative structure of the Stemona alkaloid stemonidine has been completed. The key transformations include a 1,3-dipolar cycloaddition of a chiral nitrone derived from (S)-prolinol and a spirolactonization process involving the generation of the critical stereocenter. The NMR data of the synthetic material do not match those reported for the natural product. It is concluded that the structure assigned to stemonidine is incorrect, and it must be reassigned as stemospironine.

Methodological development for selection of significant predictors explaining fatal road accidents.

Identification of the most relevant factors for explaining road accident occurrence is an important issue in road safety research, particularly for future decision-making processes in transport policy. However model selection for this particular purpose is still an ongoing research. In this paper we propose a methodological development for model selection which addresses both explanatory variable and adequate model selection issues. A variable selection procedure, TIM (two-input model) method is carried out by combining neural network design and statistical approaches. The error structure of the fitted model is assumed to follow an autoregressive process. All models are estimated using Markov Chain Monte Carlo method where the model parameters are assigned non-informative prior distributions. The final model is built using the results of the variable selection. For the application of the proposed methodology the number of fatal accidents in Spain during 2000-2011 was used. This indicator has experienced the maximum reduction internationally during the indicated years thus making it an interesting time series from a road safety policy perspective. Hence the identification of the variables that have affected this reduction is of particular interest for future decision making. The results of the variable selection process show that the selected variables are main subjects of road safety policy measures.