RESUMEN
Hemifacial microsomia (HFM) is a rare, multisystemic congenital disease with estimated frequency of 1/26370 births in Europe. Most cases are sporadic and caused by unilateral abnormal morphogenesis of the first and second pharyngeal arches. The aim of this study is to define the types and frequency of maxillofacial and systemic malformations in HFM patients. This is a case series study of patients with HFM evaluated at a single institution. Data were acquired through history, physical examination, photographs, diagnostic radiology, and laboratory and analyzed by the FileMakerPro database on 95 patients (54F; 41M) of which 89 met the inclusion criteria. Mandibular hypoplasia was observed in 86 patients with right-side preponderance (50). One patient had bilateral mandibular hypoplasia. Seventy-four had external ear anomalies (anotia or microtia). Eleven had bilateral malformed ears. Hearing impairment, associated with stenosis or atresia of the external ear canal, was found in 69 patients (eight with bilateral canal defects). Ocular anomalies were seen in 41 (23 with dermoid cysts) and 39 had orbital malformations. Facial nerve paralysis was observed in 38 patients. Cleft lip/palate (10), preauricular tags (55), and macrostomia (41) were also described. A total of 73/86 had systemic malformations, mainly vertebral (40), genitourinary (25), and cardiovascular (28). Sixteen had cerebral anomalies (four with intellectual disability). All patients suspected of HFM should undergo a complete systematic clinical and imaging investigation to define the full scope of anomalies. Since the disease is rare and complex, affected patients should be monitored by specialized multidisciplinary team centers.
Asunto(s)
Labio Leporino/genética , Asimetría Facial/genética , Síndrome de Goldenhar/genética , Anomalías Maxilofaciales/genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Adolescente , Niño , Preescolar , Labio Leporino/diagnóstico , Labio Leporino/fisiopatología , Fisura del Paladar/diagnóstico , Fisura del Paladar/genética , Fisura del Paladar/fisiopatología , Oído Externo/anomalías , Asimetría Facial/diagnóstico , Asimetría Facial/fisiopatología , Femenino , Síndrome de Goldenhar/diagnóstico , Síndrome de Goldenhar/fisiopatología , Humanos , Lactante , Masculino , Mandíbula/anomalías , Anomalías Maxilofaciales/diagnóstico , Anomalías Maxilofaciales/fisiopatología , Persona de Mediana Edad , Adulto JovenRESUMEN
Blockade of the epidermal growth factor receptor (EGFR) with the monoclonal antibodies cetuximab or panitumumab is effective in a subset of colorectal cancers (CRCs), but the emergence of resistance limits the efficacy of these therapeutic agents. At relapse, the majority of patients develop RAS mutations, while a subset acquires EGFR extracellular domain (ECD) mutations. Here we find that patients who experience greater and longer responses to EGFR blockade preferentially develop EGFR ECD mutations, while RAS mutations emerge more frequently in patients with smaller tumour shrinkage and shorter progression-free survival. In circulating cell-free tumour DNA of patients treated with anti-EGFR antibodies, RAS mutations emerge earlier than EGFR ECD variants. Subclonal RAS but not EGFR ECD mutations are present in CRC samples obtained before exposure to EGFR blockade. These data indicate that clonal evolution of drug-resistant cells is associated with the clinical outcome of CRC patients treated with anti-EGFR antibodies.
Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Resistencia a Antineoplásicos/genética , Receptores ErbB/antagonistas & inhibidores , Genes erbB-1 , Genes ras , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/farmacología , Evolución Clonal , Neoplasias Colorrectales/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , MutaciónRESUMEN
BACKGROUND: Transient tachypnea of the newborn is characterized by tachypnea and signs of respiratory distress. Transient tachypnea typically appears within the first two hours of life in term and late preterm newborns. Although transient tachypnea of the newborn is usually a self limited condition, it is associated with wheezing syndromes in late childhood. The rationale for the use of epinephrine (adrenaline) for transient tachypnea of the newborn is based on studies showing that ß-agonists can accelerate the rate of alveolar fluid clearance. OBJECTIVES: To assess whether epinephrine compared to placebo, no treatment or any other drugs (excluding salbutamol) is effective and safe in the treatment of transient tachypnea of the newborn in infants born at 34 weeks' gestational age or more. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, 2016, Issue 3), MEDLINE (1996 to March 2016), EMBASE (1980 to March 2016) and CINAHL (1982 to March 2016). We applied no language restrictions. We searched the abstracts of the major congresses in the field (Perinatal Society of Australia and New Zealand and Pediatric Academic Societies) from 2000 to 2015. SELECTION CRITERIA: Randomized controlled trials, quasi-randomized controlled trials and cluster trials comparing epinephrine versus placebo or no treatment or any other drugs administered to infants born at 34 weeks' gestational age or more and less than three days of age with transient tachypnea of the newborn. DATA COLLECTION AND ANALYSIS: For the included trial, two review authors independently extracted data (e.g. number of participants, birth weight, gestational age, duration of oxygen therapy (hours), need for continuous positive airway pressure and need for mechanical ventilation, duration of mechanical ventilation, etc.) and assessed the risk of bias (e.g. adequacy of randomization, blinding, completeness of follow-up). The primary outcomes considered in this review were duration of oxygen therapy (hours), need for continuous positive airway pressure and need for mechanical ventilation. MAIN RESULTS: One trial, which included 20 infants, met the inclusion criteria of this review. Study authors administered three doses of nebulized 2.25% racemic epinephrine or placebo. We found no differences between the two group in the duration of supplemental oxygen therapy (mean difference (MD) -6.60, 95% confidence interval (CI) -54.80 to 41.60 hours) and need for mechanical ventilation (risk ratio (RR) 0.67, 95% CI 0.08 to 5.88; risk difference (RD) -0.07, 95% CI -0.46 to 0.32). Among secondary outcomes, we found no differences in terms of initiation of oral feeding. The quality of the evidence was limited due to the imprecision of the estimates. AUTHORS' CONCLUSIONS: At present there is insufficient evidence to determine the efficacy and safety of epinephrine in the management of transient tachypnea of the newborn.
Asunto(s)
Agonistas Adrenérgicos beta/uso terapéutico , Epinefrina/uso terapéutico , Taquipnea Transitoria del Recién Nacido/tratamiento farmacológico , Humanos , Recién Nacido , Terapia por Inhalación de Oxígeno/estadística & datos numéricos , Ensayos Clínicos Controlados Aleatorios como Asunto , Respiración Artificial/estadística & datos numéricosRESUMEN
Molecular targeted drugs are clinically effective anti-cancer therapies. However, tumours treated with single agents usually develop resistance. Here we use colorectal cancer (CRC) as a model to study how the acquisition of resistance to EGFR-targeted therapies can be restrained. Pathway-oriented genetic screens reveal that CRC cells escape from EGFR blockade by downstream activation of RAS-MEK signalling. Following treatment of CRC cells with anti-EGFR, anti-MEK or the combination of the two drugs, we find that EGFR blockade alone triggers acquired resistance in weeks, while combinatorial treatment does not induce resistance. In patient-derived xenografts, EGFR-MEK combination prevents the development of resistance. We employ mathematical modelling to provide a quantitative understanding of the dynamics of response and resistance to these single and combination therapies. Mechanistically, we find that the EGFR-MEK Combo blockade triggers Bcl-2 and Mcl-1 downregulation and initiates apoptosis. These results provide the rationale for clinical trials aimed at preventing rather than intercepting resistance.