Hepatocellular carcinoma risk-stratification based on ASGR1 in circulating epithelial cells for cancer interception.

Purpose: Lack of diagnostic and prognostic biomarkers in hepatocellular carcinoma impedes stratifying patients based on their risk of developing cancer. The aim of this study was to evaluate phenotypic and genetic heterogeneity of circulating epithelial cells (CECs) based on asialoglycoprotein receptor 1 (ASGR1) and miR-122-5p expression as potential diagnostic and prognostic tools in patients with hepatocellular carcinoma (HCC) and liver cirrhosis (LC). Methods: Peripheral blood samples were extracted from LC and HCC patients at different disease stages. CECs were isolated using positive immunomagnetic selection. Genetic and phenotypic characterization was validated by double immunocytochemistry for cytokeratin (CK) and ASGR1 or by in situ hybridization with miR-122-5p and CECs were visualized by confocal microscopy. Results: The presence of CECs increased HCC risk by 2.58-fold, however, this was only significant for patients with previous LC (p = 0.028) and not for those without prior LC (p = 0.23). Furthermore, the number of CECs lacking ASGR1 expression correlated significantly with HCC incidence and absence of miR-122-5p expression (p = 0.014; r = 0.23). Finally, overall survival was significantly greater for patients at earlier cancer stages (p = 0.018), but this difference was only maintained in the group with the presence of CECs (p = 0.021) whereas progression-free survival was influenced by the absence of ASGR1 expression. Conclusion: Identification and characterization of CECs by ASGR1 and/or miR-122-5p expression may be used as a risk-stratification tool in LC patients, as it was shown to be an independent prognostic and risk-stratification marker in LC and early disease stage HCC patients.

Exchange of cellular components between platelets and tumor cells: impact on tumor cells behavior.

Background: Platelets are active players in tumorigenesis, although the exact interactive mechanisms and their direct impact on tumor cells remain largely unknown. Methods: Bidirectional transference of lipids, proteins and RNA between platelets and tumor cells and its impact on tumor cell behavior and tumor process are analyzed in this work. Phenotypic, genetic and functional modifications induced by platelets were analyzed both in tumor cell lines and in circulating tumor cells (CTCs). Results: Data from these assays showed that platelets transferred structural components to tumor cells with higher efficiency than tumor cells to platelets (p = 0.001). This biological interplay occurred by direct contact, internalization or via extracellular vesicles. As a result, tumor cells acquired platelet markers (CD61 and CD42), showed decreased EpCAM, expressed epithelial-to-mesenchymal transition markers, and increased proliferation rates. Moreover, we were able to detect CD61 in CTCs from early and advanced prostate cancer. Conclusions: Our results demonstrated, for the first time, that platelets educate tumor cells by highly efficient transference of lipids, proteins and RNA through different mechanisms. These results suggest that tumor cells and CTCs might acquire highly dynamic and aggressive phenotypes due to platelets interaction including EMT, stem-like phenotype and high proliferative rates.

Deep Phenotypic Characterisation of CTCs by Combination of Microfluidic Isolation (IsoFlux) and Imaging Flow Cytometry (ImageStream).

The isolation of circulating tumour cells (CTCs) in colorectal cancer (CRC) mostly relies on the expression of epithelial markers such as EpCAM, and phenotypic characterisation is usually performed under fluorescence microscopy with only one or two additional markers. This limits the ability to detect different CTC subpopulations based on multiple markers. The aim of this work was to develop a novel protocol combining two platforms (IsoFluxTM and ImageStream®X) to improve CTC evaluation. Cancer cell lines and peripheral blood from healthy donors were used to evaluate the efficiency of each platform independently and in combination. Peripheral blood was extracted from 16 early CRC patients (before loco-regional surgery) to demonstrate the suitability of the protocol for CTC assessment. Additionally, peripheral blood was extracted from nine patients one month after surgery to validate the utility of our protocol for identifying CTC subpopulation changes over time. Results: Our protocol had a mean recovery efficiency of 69.5% and a limit of detection of at least four cells per millilitre. We developed an analysis method to reduce noise from magnetic beads used for CTC isolation. CTCs were isolated from CRC patients with a median of 37 CTCs (IQ 13.0-85.5) at baseline. CTCs from CRC patients were significantly (p < 0.0001) larger than cytokeratin (CK)-negative cells, and patients were stratified into two groups based on BRAFV600E and PD-L1 expression on CK-positive cells. The changes observed over time included not only the number of CTCs but also their distribution into four different subpopulations defined according to BRAFV600E and PD-L1 positivity. We developed a novel protocol for semi-automatic CTC isolation and phenotypic characterisation by combining two platforms. Assessment of CTCs from early CRC patients using our protocol allowed the identification of two clusters of patients with changing phenotypes over time.

Cross-Resistance to Abiraterone and Enzalutamide in Castration Resistance Prostate Cancer Cellular Models Is Mediated by AR Transcriptional Reactivation.

Androgen deprivation therapy (ADT) and novel hormonal agents (NHAs) (Abiraterone and Enzalutamide) are the goal standard for metastatic prostate cancer (PCa) treatment. Although ADT is initially effective, a subsequent castration resistance status (CRPC) is commonly developed. The expression of androgen receptor (AR) alternative splicing isoforms (AR-V7 and AR-V9) has been associated to CRPC. However, resistance mechanisms to novel NHAs are not yet well understood. Androgen-dependent PCa cell lines were used to generate resistant models to ADT only or in combination with Abiraterone and/or Enzalutamide (concomitant models). Functional and genetic analyses were performed for each resistance model by real-time cell monitoring assays, flow cytometry and RT-qPCR. In androgen-dependent PCa cells, the administration of Abiraterone and/or Enzalutamide as first-line treatment involved a critical inhibition of AR activity associated with a significant cell growth inhibition. Genetic analyses on ADT-resistant PCa cell lines showed that the CRPC phenotype was accompanied by overexpression of AR full-length and AR target genes, but not necessarily AR-V7 and/or AR-V9 isoforms. These ADT resistant cell lines showed higher proliferation rates, migration and invasion abilities. Importantly, ADT resistance induced cross-resistance to Abiraterone and/or Enzalutamide. Similarly, concomitant models possessed an elevated expression of AR full-length and proliferation rates and acquired cross-resistance to its alternative NHA as second-line treatment.

Antioxidants for the Treatment of Breast Cancer: Are We There Yet?

Breast cancer is the most frequent cancer and the leading cause of cancer death in women. Oxidative stress and the generation of reactive oxygen species (ROS) have been related to cancer progression. Compared to their normal counterparts, tumor cells show higher ROS levels and tight regulation of REDOX homeostasis to maintain a low degree of oxidative stress. Traditionally antioxidants have been extensively investigated to counteract breast carcinogenesis and tumor progression as chemopreventive agents; however, there is growing evidence indicating their potential as adjuvants for the treatment of breast cancer. Aimed to elucidate whether antioxidants could be a reality in the management of breast cancer patients, this review focuses on the latest investigations regarding the ambivalent role of antioxidants in the development of breast cancer, with special attention to the results derived from clinical trials, as well as their potential use as plausible agents in combination therapy and their power to ameliorate the side effects attributed to standard therapeutics. Data retrieved herein suggest that antioxidants play an important role in breast cancer prevention and the improvement of therapeutic efficacy; nevertheless, appropriate patient stratification based on "redoxidomics" or tumor subtype is mandatory in order to define the dosage for future standardized and personalized treatments of patients.

Sandwich-Type Electrochemical Paper-Based Immunosensor for Claudin 7 and CD81 Dual Determination on Extracellular Vesicles from Breast Cancer Patients.

This study is focused on identifying novel epithelial markers in circulating extracellular vesicles (EVs) through the development of a dual sandwich-type electrochemical paper-based immunosensor for Claudin 7 and CD81 determination, as well as its validation in breast cancer (BC) patients. This immunosensor allows for rapid, sensitive, and label-free detection of these two relevant BC biomarkers. Under optimum conditions, the limit of detection for Claudin 7 was 0.4 pg mL-1, with a wide linear range of 2 to 1000 pg mL-1, while for CD81, the limit of detection was 3 pg mL-1, with a wide linear range of 0.01 to 10 ng mL-1. Finally, we validated Claudin 7 and CD81 determination in EVs from 60 BC patients and 20 healthy volunteers, reporting higher diagnostic accuracy than the one observed with classical diagnostic markers. This analysis provides a low-cost, specific, versatile, and user-friendly strategy as a robust and reliable tool for early BC diagnosis.

Drug Repurposing for Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer which presents a high rate of relapse, metastasis, and mortality. Nowadays, the absence of approved specific targeted therapies to eradicate TNBC remains one of the main challenges in clinical practice. Drug discovery is a long and costly process that can be dramatically improved by drug repurposing, which identifies new uses for existing drugs, both approved and investigational. Drug repositioning benefits from improvements in computational methods related to chemoinformatics, genomics, and systems biology. To the best of our knowledge, we propose a novel and inclusive classification of those approaches whereby drug repurposing can be achieved in silico: structure-based, transcriptional signatures-based, biological networks-based, and data-mining-based drug repositioning. This review specially emphasizes the most relevant research, both at preclinical and clinical settings, aimed at repurposing pre-existing drugs to treat TNBC on the basis of molecular mechanisms and signaling pathways such as androgen receptor, adrenergic receptor, STAT3, nitric oxide synthase, or AXL. Finally, because of the ability and relevance of cancer stem cells (CSCs) to drive tumor aggressiveness and poor clinical outcome, we also focus on those molecules repurposed to specifically target this cell population to tackle recurrence and metastases associated with the progression of TNBC.

Strategies for Isolation and Phenotypic, Genetic, and Functional Characterization of Circulating Tumor Cells.

From the medical and scientific point of view, we are witnessing important changes in the way we approach diseases, and consequently in the way we manage patients [...].

Precision Prevention and Cancer Interception: The New Challenges of Liquid Biopsy.

Despite major therapeutic progress, most advanced solid tumors are still incurable. Cancer interception is the active way to combat cancer onset, and development of this approach within high-risk populations seems a logical first step. Until now, strategies for the identification of high-risk subjects have been based on low-sensitivity and low-specificity assays. However, new liquid biopsy assays, "the Rosetta Stone of the new biomedicine era," with the ability to identify circulating biomarkers with unprecedented sensitivity, promise to revolutionize cancer management. This review focuses on novel liquid biopsy approaches and the applications to cancer interception. Cancer interception involves the identification of biomarkers associated with developing cancer, and includes genetic and epigenetic alterations, as well as circulating tumor cells and circulating epithelial cells in individuals at risk, and the implementation of therapeutic strategies to prevent the beginning of cancer and to stop its development. Large prospective studies are needed to confirm the potential role of liquid biopsy for early detection of precancer lesions and tumors.

High plasma levels of soluble P-Selectin and Factor VIII predict venous thromboembolism in non-small cell lung cancer patients: The Thrombo-Nsclc risk score.

INTRODUCTION: Venous thromboembolism (VTE) is common in non-small cell lung cancer (NSCLC) patients undergoing systemic chemotherapy. The usefulness of Khorana score (KRS) to predict risk in lung cancer patients is limited, and the identification of patients who would benefit most from thromboprophylaxis is challenging. We aimed to identify variables whose values before chemotherapy helped in predicting VTE occurrence, and build a model to assess VTE risk. MATERIALS AND METHODS: A cohort of newly diagnosed NSCLC patients to undergo outpatient chemotherapy, not under anticoagulant treatment, was recruited. Pre-chemotherapy demographic, clinical, analytical and tumor-specific variables were collected. Patients were prospectively followed-up for 12 months to record VTE events. Bivariate and multivariate analyses were performed to identify VTE-associated variables, and a prediction model was built and compared with KRS. RESULTS: 90 patients were recruited, 18 of whom had a VTE event during follow-up. High baseline levels of factor VIII (FVIII) and, especially, soluble P-selectin (sP-selectin), were independently associated with VTE risk (hazard ratio [HR] 4.15, 95% confidence interval [CI] 1.17-14.71, and 66.40 [8.70-506.69], respectively). Our so-called Thrombo-NSCLC risk score, which assigns 1 and 3 points to high FVIII and sP-selectin values, respectively, was significantly better than KRS in predicting VTE (area under the curve [AUC] 0.93 vs. 0.55, sensitivity 94.4 vs. 35.0%, specificity 93.1 vs. 60.0%). Our prediction model showed significant discriminating capacity between high risk vs. intermediate/low risk patients, while KRS did not. CONCLUSIONS: The Thrombo-NSCLC risk score may be useful to identify those NSCLC patients who would benefit most from thromboprophylaxis.

Challenges and opportunities of cfDNA analysis implementation in clinical practice: Perspective of the International Society of Liquid Biopsy (ISLB).

Precision medicine was born with the development of new diagnostic techniques and targeted drugs, yielding better outcomes in cancer care. With the evolution and increasing sensitivity for detecting oncogenic drivers, liquid biopsies (LBs), specifically cell-free DNA (cfDNA) analysis, have been proposed as a minimally-invasive technique for genomic profiling. Ranging from sequencing techniques to PCR-based methods and other more complex strategies, this approach, currently applicable in some solid tumors with robust evidence, is showing promising opportunities in other cancers. However, difficulties in validating their clinical utility exist within limitation at different levels among several techniques, reporting of the results, lack of appropriate clinical trial designs, and unknown economic impact. One of the aims of the ISLB is to create recommendations to develop reliable and sustainable diagnostic, prognostic and predictive tools using LBs. This paper is addressing these objectives, helping the healthcare providers and scientific community to understand the potential of LB.

EGFR detection in extracellular vesicles of breast cancer patients through immunosensor based on silica-chitosan nanoplatform.

In the present work, we designed a microfluidic electrochemical immunosensor with enough sensibility and precision to quantify epithermal growth factor receptor (EGFR) in plasma extracellular vesicles (EVs) of plasma from breast cancer patients. The sensor employs SiNPs coated with chitosan (SiNPs-CH) as reaction's platform, based on the covalently immobilization of monoclonal anti-EGFR on SiNPs-CH retained in the central channel (CC) of the microfluidic device. The synthetized SiNPs-CH were characterized by UV-visible spectroscopy (UV-visible), energy dispersive spectrometry (EDS), Nanoparticle Tracking Analysis (NTA) and transmission electron microscopy (TEM). EGFR was quantified by a direct sandwich immunoassay measuring through a horseradish peroxidase (HRP)-conjugated anti-EGFR. The enzymatic product (benzoquinone) was detected by reduction at - 100 mV on a sputtering gold electrode. The measured current was directly proportional to the level of EGFR in human serum samples. The linear range was from 0 ng mL-1 to 50 ng mL-1. The detection limit was 1.37 pg mL-1, and the within- and between-assay coefficients of variation were below 6.25%. Finally, plasma samples from 30 early breast cancer patients and 20 healthy donor were analyzed by the novel method. EGFR levels in EVs (EVs-EGFR) were significantly higher than in the healthy control group (p = 0.002) and also, more sensitivity and specificity than normal serum markers like CEA and CA15.3 has been observed. EVs-EGFR concentration correlates with EGFR tumor status (p = 0.0003) as well as it correlate with the tumor size and pathological grade. To conclude, plasma EVs are suitable for proteomic characterization of cancer disease, as long as the employed method has sufficient sensitivity, like the case of immune-electrochemical nanosensors with incremented reaction surface.

GSTM1 gene expression and copy number variation in prostate cancer patients-Effect of chemical exposures and physical activity.

BACKGROUND: Many etiological factors have been related to prostate cancer (CaP) development, progression, and survival, such as age, population origin, geographic area, occupational exposures, and nutrition and lifestyle factors. However, physical activity affords health benefits to cancer patients, including those with CaP. Glutathione S-Transferases enzymes have been linked to CaP because of their role in the detoxification of a wide variety of potential carcinogens, steroid hormones and xenobiotics. Among the different glutathione S-transferases isoforms, null genotype for GSTM1 has been associated with an increased risk of CaP, although data are controversial. As the relationship between copy number variation and gene expression of GSTM1 in CaP remains unexplored, this study analyzed GSTM1 gene expression and/or dosage effect on CaP risk and aggressiveness. The potential protective role of physical activity was also explored. METHODS: Three hundred and seventeen patients (159 non-CaP and 158 CaP) were recruited from the Service of Urology (Hospital Virgen de las Nieves, Granada, Spain) over the period 2012 to 2014 and were followed-up until January 2018 to ensure a correct classification of control and patients. Individuals were classified in each group based on histological analysis of tissue biopsy, along with data on PSA level, Gleason score and T stage in patients with biopsies positive for CaP. Individuals with a negative biopsy were considered as controls. All controls underwent a systematic 20-core ultrasound guided biopsy in order to limit the false negative rate. Genomic DNA was extracted from peripheral blood to determine the exact copy numbers of GSTM1, and RNA was extracted from prostate tissue samples to determine GSTM1 gene expression. Both analyses were performed using the qPCR method. A questionnaire was administered to all patients to assess environmental exposures, lifestyle, and physical activity. The association of GSTM1 copy number variation and expression with the rest of variables was assessed by chi-square test and the Mann-Whitney test. Multiple logistic regression was used to assess which factors were associated with the risk of CaP. RESULTS: The presence of 1 or 2 copies of the GSTM1 gene was not less prevalent in CaP compared to non-CaP patients; however, a significant decreased GSTM1 gene expression was observed in CaP tissue relative to non-CaP tissue (P = 0.003). CaP patients with environmental exposure to dust and smoke, and smoking habit had a significantly decreased GSTM1 gene expression (and near-significantly decreased for living in urban areas) as compared to non-CaP patients with the same exposures. In addition, physical activity was significantly associated with a lower risk of CaP (P = 0.006) and with increased GSTM1 gene expression (P = 0.002). CONCLUSIONS: A reduced GSTM1 gene expression in prostate tissue was observed in CaP patients with some environmental chemical exposures. Intriguingly, physical activity might play a protective role against CaP development, possibly as a result of increasing GSTM1 gene expression in prostate tissue. However, this observation warrants further confirmation.

Hydroxytyrosol inhibits cancer stem cells and the metastatic capacity of triple-negative breast cancer cell lines by the simultaneous targeting of epithelial-to-mesenchymal transition, Wnt/ß-catenin and TGFß signaling pathways.

PURPOSE: This study was aimed to determine the impact of hydroxytyrosol (HT), a minor compound found in olive oil, on breast cancer stem cells (BCSCs) and the migration capacity of triple-negative breast cancer (TNBC) cell lines through the alteration of epithelial-to-mesenchymal transition (EMT) and embryonic signaling pathways. METHODS: BCSCs self-renewal was determined by the mammosphere-forming efficiency in SUM159PT, BT549, MDA-MB-231 and Hs578T TNBC cell lines. Flow cytometric analysis of CD44+/CD24-/low and aldehyde dehydrogenase positive (ALDH+) subpopulations, migration by the "wound healing assay", invasion and Western blot of EMT markers and TGFß signaling were investigated in SUM159PT, BT549 and MDA-MB-231 cell lines. Wnt/ß-catenin signaling was assessed by Western blot in BT549 cells expressing WNT1 and MDA-MB-231 cells. Changes in TGFß activity was determined by SMAD Binding Element (SBE) reporter assay. RESULTS: HT reduced BCSCs self-renewal, ALDH+ (aldehyde dehydrogenase) and CD44+/CD24-/low subpopulations, tumor cell migration and invasion. Consistently, HT suppressed Wnt/ß-catenin signaling by decreasing p-LRP6, LRP6, ß-catenin and cyclin D1 protein expression and the EMT markers SLUG, ZEB1, SNAIL and VIMENTIN. Finally, HT inhibited p-SMAD2/3 and SMAD2/3 in SUM159PT, BT549 and MDA-MB-231 cells, what was correlated with a less TGFß activity. CONCLUSION: In conclusion, we report for the first time the inhibitory role of HT on BCSCs and tumor cell migration by targeting EMT, Wnt/ß-catenin and TGFß signaling pathways. Our findings highlight the importance of the chemopreventive compound HT as a novel candidate to be investigated as an alternative targeted therapy for TNBC.

Circulating tumor cells criteria (CyCAR) versus standard RECIST criteria for treatment response assessment in metastatic colorectal cancer patients.

BACKGROUND: The use of circulating tumor cells (CTCs) as indicators of treatment response in metastatic colorectal cancer (mCRC) needs to be clarified. The objective of this study is to compare the Response Evaluation Criteria in Solid Tumors (RECIST) with the Cytologic Criteria Assessing Response (CyCAR), based on the presence and phenotypic characterization of CTCs, as indicators of FOLFOX-bevacizumab treatment response. METHODS: 77 mCRC blood samples from FOLFOX-bevacizumab treated patients were analyzed to isolate CTCs before and after (12 and 24 weeks) treatment, using an immunomagnetic separation method. VEGFR expression was identified by double immunostaining. RESULTS: We observed a decrease of CTCs (42.8 vs. 18.2%) and VEGFR positivity (69.7% vs. 41.7%) after treatment. According to RECIST, 6.45% of the patients did not show any clinical benefit, whereas 93.55% patients showed a favorable response at 12 weeks. According to CyCAR, 29% had a non-favorable response and 71% patients did not. No significant differences were found between the response assessment by RECIST and CyCAR at 12 or 24 weeks. However, in the multivariate analysis, RECIST at 12 weeks and CyCAR at 24 weeks were independent prognostic factors for OS (HR: 0.1, 95% CI 0.02-0.58 and HR: 0.35, 95% CI 0.12-0.99 respectively). CONCLUSIONS: CyCAR results were comparable to RECIST in evaluating the response in mCRC and can be used as an alternative when the limitation of RECIST requires additional response analysis techniques.

Activating Transcription Factor 4 Modulates TGFß-Induced Aggressiveness in Triple-Negative Breast Cancer via SMAD2/3/4 and mTORC2 Signaling.

Purpose: On the basis of the identified stress-independent cellular functions of activating transcription factor 4 (ATF4), we reported enhanced ATF4 levels in MCF10A cells treated with TGFß1. ATF4 is overexpressed in patients with triple-negative breast cancer (TNBC), but its impact on patient survival and the underlying mechanisms remain unknown. We aimed to determine ATF4 effects on patients with breast cancer survival and TNBC aggressiveness, and the relationships between TGFß and ATF4. Defining the signaling pathways may help us identify a cell signaling-tailored gene signature.Experimental Design: Patient survival data were determined by Kaplan-Meier analysis. Relationship between TGFß and ATF4, their effects on aggressiveness (tumor proliferation, metastasis, and stemness), and the underlying pathways were analyzed in three TNBC cell lines and in vivo using patient-derived xenografts (PDX).Results: ATF4 overexpression correlated with TNBC patient survival decrease and a SMAD-dependent crosstalk between ATF4 and TGFß was identified. ATF4 expression inhibition reduced migration, invasiveness, mammosphere-forming efficiency, proliferation, epithelial-mesenchymal transition, and antiapoptotic and stemness marker levels. In PDX models, ATF4 silencing decreased metastases, tumor growth, and relapse after chemotherapy. ATF4 was shown to be active downstream of SMAD2/3/4 and mTORC2, regulating TGFß/SMAD and mTOR/RAC1-RHOA pathways independently of stress. We defined an eight-gene signature with prognostic potential, altered in 45% of 2,509 patients with breast cancer.Conclusions: ATF4 may represent a valuable prognostic biomarker and therapeutic target in patients with TNBC, and we identified a cell signaling pathway-based gene signature that may contribute to the development of combinatorial targeted therapies for breast cancer. Clin Cancer Res; 24(22); 5697-709. ©2018 AACR.

Necrolisis epidérmica tóxica: un paradigma de enfermedad crítica / Toxic epidermal necrolysis: a paradigm of critical illness

RESUMEN La necrolisis epidérmica tóxica es una reacción cutánea adversa de tipo inmunológico secundaria en la mayor parte de los casos a la administración de un fármaco. La necrolisis epidérmica tóxica, el síndrome de Steven Johnson y el eritema exudativo multiforme forman parte del mismo espectro de enfermedad. La mortalidad de la necrolisis epidérmica tóxica es alrededor del 30%. La fisiopatología de la necrolisis epidérmica tóxica es semejante en muchos aspectos a la de las quemaduras dérmicas superficiales. La afectación mucosa del epitelio ocular y genital se asocia con secuelas graves si no se trata de forma temprana. Se acepta en general que los pacientes con necrolisis epidérmica tóxica son tratados mejor en unidades de grandes quemados, donde existe experiencia en el manejo de enfermos con pérdida cutánea extensa. El tratamiento es de soporte, eliminación y cobertura con derivados biosintéticos de la piel de las zonas afectadas, tratamiento de la afectación mucosa, y tratamiento inmunosupresor específico. De los tratamientos ensayados sólo se usa actualmente en la mayor parte de los centros la inmunoglobulina G y la ciclosporina A, aun cuando no existe evidencia sólida para recomendar ningún tratamiento específico. Entre los aspectos particulares del tratamiento de esta enfermedad se encuentra la prevención de secuelas relacionadas con la formación de sinequias, los cuidados oculares para prevenir secuelas graves que pueden conducir a la ceguera, y el tratamiento específico inmunosupresor. Un mejor conocimiento de los principios del manejo de la necrolisis epidérmica tóxica llevará a un mejor manejo de la enfermedad, a una mayor supervivencia y una menor prevalencia de las secuelas.

ABSTRACT Toxic epidermal necrolysis is an adverse immunological skin reaction secondary in most cases to the administration of a drug. Toxic epidermal necrolysis, Stevens-Johnson syndrome, and multiform exudative erythema are part of the same disease spectrum. The mortality rate from toxic epidermal necrolysis is approximately 30%. The pathophysiology of toxic epidermal necrolysis is similar in many respects to that of superficial skin burns. Mucosal involvement of the ocular and genital epithelium is associated with serious sequelae if the condition is not treated early. It is generally accepted that patients with toxic epidermal necrolysis are better treated in burn units, which are experienced in the management of patients with extensive skin loss. Treatment includes support, elimination, and coverage with biosynthetic derivatives of the skin in affected areas, treatment of mucosal involvement, and specific immunosuppressive treatment. Of the treatments tested, only immunoglobulin G and cyclosporin A are currently used in most centers, even though there is no solid evidence to recommend any specific treatment. The particular aspects of the treatment of this disease include the prevention of sequelae related to the formation of synechiae, eye care to prevent serious sequelae that can lead to blindness, and specific immunosuppressive treatment. Better knowledge of the management principles of toxic epidermal necrolysis will lead to better disease management, higher survival rates, and lower prevalence of sequelae.