BRAF Mutation Status Concordance Between Primary Cutaneous Melanomas and Corresponding Metastases: A Review of the Latest Evidence. / Concordancia mutacional de BRAF entre melanoma primario cutáneo y sus correspondientes metástasis. Revisión de la evidencia actual.

The identification of B-Raf proto-oncongene (BRAF) mutation and the emergence of targeted therapy marked a turning point in the treatment of melanoma. The study of mutation status concordance between primary tumors and metastases in this cancer has major treatment implications as it facilitates the selection of candidates for targeted therapy. This review analyzes the evidence on the level of mutation status concordance between primary tumors and different types of metastases in cutaneous melanoma and provides an overview of the advantages and disadvantages of the various methods used to detect BRAF mutations.

Facial Angiofibroma Severity Index (FASI): reliability assessment of a new tool developed to measure severity and responsiveness to therapy in tuberous sclerosis-associated facial angiofibroma.

BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder characterized by the development of multisystem hamartomatous tumours. Topical sirolimus has recently been suggested as a potential treatment for TSC-associated facial angiofibroma (FA). AIM: To validate a reproducible scale created for the assessment of clinical severity and treatment response in these patients. METHODS: We developed a new tool, the Facial Angiofibroma Severity Index (FASI) to evaluate the grade of erythema and the size and extent of FAs. In total, 30 different photographs of patients with TSC were shown to 56 dermatologists at each evaluation. Three evaluations using the same photographs but in a different random order were performed 1 week apart. Test and retest reliability and interobserver reproducibility were determined. RESULTS: There was good agreement between the investigators. Inter-rater reliability showed strong correlations (> 0.98; range 0.97-0.99) with inter-rater correlation coefficients (ICCs) for the FASI. The global estimated kappa coefficient for the degree of intra-rater agreement (test-retest) was 0.94 (range 0.91-0.97). CONCLUSIONS: The FASI is a valid and reliable tool for measuring the clinical severity of TSC-associated FAs, which can be applied in clinical practice to evaluate the response to treatment in these patients.

Ichthyosis vulgaris: the filaggrin mutation disease.

Ichthyosis vulgaris is caused by loss-of-function mutations in the filaggrin gene (FLG) and is characterized clinically by xerosis, scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. According to the published studies presented in this review article, FLG mutations are observed in approximately 7·7% of Europeans and 3·0% of Asians, but appear to be infrequent in darker-skinned populations. This clinical review article provides an overview of ichthyosis vulgaris epidemiology, related disorders and pathomechanisms. Not only does ichthyosis vulgaris possess a wide clinical spectrum, recent studies suggest that carriers of FLG mutations may have a generally altered risk of developing common diseases, even beyond atopic disorders. Mechanistic studies have shown increased penetration of allergens and chemicals in filaggrin-deficient skin, and epidemiological studies have found higher levels of hand eczema, irritant contact dermatitis, nickel sensitization and serum vitamin D levels. When relevant, individuals should be informed about an increased risk of developing dermatitis when repeatedly or continuously exposed to nickel or irritants. Moreover, with our current knowledge, individuals with ichthyosis vulgaris should be protected against neonatal exposure to cats to prevent atopic dermatitis and should abstain from smoking to prevent asthma. Finally, they should be advised against excessive exposure to factors that decrease skin barrier functions and increase the risk of atopic dermatitis.

[Accessory breast on the vulva]. / Mama ectópica vulvar.

We describe a 24-year-old woman with a subcutaneous swelling in the left inferior pubic region. Histology revealed ectopic breast tissue. Vulvar tumors are uncommon and the presence of ectopic breast tissue in this region is extremely rare. In these cases, patients usually consult for a mass that varies in size with hormonal changes, typically during pregnancy or breast-feeding, or that has associated neoplastic changes. In our patient, the mass had grown progressively with no identifiable underlying hormonal association or neoplasm. We therefore classified it as ectopic breast tissue presenting as a subcutaneous mass.

Mechanism of the schultz-dale reaction in the denervated diaphragmatic muscle of the Guinea pig.

The mechanism of the contractions elicited by specific antigens in immunologically sensitized muscle tissue (Schultz-Dale responses) has been investigated on single fibers of denervated guinea pig hemidiaphragms. This preparation can be either actively or passively allergized, showing Schultz-Dale responses similar to those of visceral muscle. Specific antigens were applied with an electrically operated microtap to discrete areas of the cell surface while recording the electrical activity with intracellular microelectrodes. In this manner, a depolarizing action of the antigens on the muscle membrane was demonstrated. Brief applications of antigen gave rise to phasic potential changes (antigen potentials) similar to those elicited in the same fibers with acetylcholine-filled microtaps. However, antigen potentials occur only in denervated fibers sensitized to the specific antigen or closely related proteins; they are not seen in either innervated fibers of allergized animals or in denervated, nonallergized fibers. Repeated antigen application to the same area of the fiber causes a local irreversible desensitization. The antigen potentials are associated with a reduction in the resistance of the muscle membrane, similar to that caused by acetylcholine. It is concluded that besides causing the liberation of biogenic amines from the mast cells, antigens exert a direct action on the permeability of the muscle membrane; the molecules of antibody adsorbed to the cells appear to act as specific chemoreceptors for the antigen.

Effect of stress on the Schultz-Dale reaction in guinea pig aorta.

The smooth muscle of thoracic aorta from guinea pig sensitized with egg albumin (EA) produced an anaphylactic contraction when it was exposed to EA. Experiments were performed to evaluate stress effects on the anaphylactic contraction in guinea pig aortic rings. Two types of stressors were used as immunosuppressor stimuli: physical restraint and shaking of the animals. Both stressors diminished the amplitude of the Schultz-Dale contraction in aortic rings from sensitized guinea pig. The shake stress stimulus interrupted several times during each session induced higher immunosuppression in animals in which the active sensitization and the stress sessions began the same day. Severe restraint stress, prior to active immunization, also suppressed significantly the anaphylactic response. The Schulz-Dale reaction in guinea pig aorta seems to be a valuable technique to study the stress effects on the anaphylactic response.

Anaphylactic reaction in smooth muscle from the duck.

1. To know if the absence of desensitization in the chicken is characteristic of avian tissues, we studied the anaphylactic reaction in the duck. The contractions elicited in pieces of small intestine of actively immunized ducks upon exposure to the specific antigen, or Schultz-Dale reaction, were compared to similar responses of sensitized chicken and guinea pig intestine. 2. The smooth muscle from chicken actively sensitized contracts, when it is exposed in vitro to the specific antigen. Maximal tension, developed during anaphylactic reaction, is kept until the preparation is washed. New exposure of the muscle to the antigen causes it to develop tension again. This means that exposure to the antigen does not desensitize chicken intestine. 3. Intestinal smooth muscle from sensitized duck developed tension when the specific antigen was added to the bath; the tension was transitory and soon reached the basal line, even before washing the antigen. Contrary to the observations in the chicken smooth muscle, a second antigen dose failed to elicit a contraction of the duck intestine. Duck smooth muscle behaved like mammalian tissue. Exposure to the antigen desensitized duck intestine. 4. On multiple sensitized duck, the order of addition of antigens and their desensitization, did not alter the anaphylactic response to each antigen. 5. These observations are discussed in terms of the known properties of duck antibodies.

Ca2+-agonistic effects of diazepam, a benzodiazepine 1-4 derivative, on isolated mouse and guinea pig left atria.

In normal Krebs solution, diazepam (1.75X10(-4) M) increased the action potential duration in a reversible form and caused a positive inotropic effect on mouse auricular muscle (4). 2.) Further studies on diazepam action on electrical and mechanical activity of left auricular muscle from mouse and guinea pig, in preparations electrically driven, showed that diazepam induces an increase in action potential duration measured at 20% repolarization, a decrease in the rate of spike depolarization, and modifies the conduction velocity of the action potential. 3.) Diazepam produced in preparation with spontaneous activity, positive chronotropic and inotropic effects, and positive inotropic effect in electrically driven preparations. 4.) The change in action potential duration induced by diazepam on mouse preparations was higher than on guinea pig preparations, ca.X3. 5.) These findings support that diazepam action may be due to an increase in the inward calcium current and a reduction in the inward sodium current.

Anaphylactic contraction of guinea pig smooth muscle passively sensitized with chicken antiserum.

1. Actively sensitized guinea pig intestine responds, typically, with a large contraction to the first application of antigen (Ag). This is followed by a spontaneous relaxation of the tissue, while still in the presence of the Ag and a rapid desensitization, i.e. further exposures to Ag fail to evoke new contractions. 2. In contrast when the guinea pig was passively immunized with chicken antiserum, the first dose of Ag produced a sustained contraction. The second and third doses elicited contractions of comparable magnitude and no desensitization occurred. 3. In addition, consecutive Schultz-Dale reactions of guinea pig intestine or uterus from animals passively sensitized with chicken antiserum showed a consistent potentiation. They reached a maximal amplitude when the tissue was exposed to the Ag 6-7 times. Such a potentiation is abolished by storing the preparations up to 48 hr at 4 degrees C. 4. The tissues from chickens passively immunized with homologous antisera showed the same behaviour as those taken from actively sensitized chicken, i.e. no desensitization was observed. 5. These results agree with those previously observed in our laboratory suggesting the existence of a special property of the chicken antibodies (Ab). Indeed, the characteristic features of the anaphylactic reaction in actively sensitized chickens were transmitted to both chickens and guinea pigs passively sensitized with chicken Ab's.

Lead acetate action on anaphylactic response of guinea pig smooth muscle.

Experiments were performed to evaluate lead acetate effects on the anaphylactic contraction in guinea pigs smooth muscles. Aortic rings from guinea pigs exposed to lead acetate developed an anaphylactic contraction significantly lower than the contraction induced by the antigen in controls. In the smooth muscle of the intestine, lead acetate did not modify the anaphylactic response. Lead induced immunosuppression of the anaphylactic response of aortic rings, whereas sodium acetate had no effect on the anaphylactic reaction of the guinea pig smooth muscle. The amplitude of the norepinephrine contraction was not modified by lead nor by sodium acetate.

Influence of formamide on the electrical and mechanical properties of the guinea pig ventricle.

1. Guinea pig papillary muscle in vitro upon exposure of Formamide (FMD) exerts a dose dependent positive inotropic effect. 2. The increase in tension developed by papillary muscle is associated with a marked decrease in the duration of the action potential. 3. The increase in extracellular calcium concentration does not modify the positive inotropic effect, but increases the duration of the action potential. 4. FMD markedly potentiate the increase in tension induced by caffeine 3 M suggesting a possible synergetic effect upon the release of Ca2+ ions from the S.R. 5. These experiments suggest that FMD increases the intracellular calcium concentration by exerting a direct action on intracellular calcium stores.

Effect of the length of degenerating phrenic nerve fibres on the anaphylactic contraction of the diaphragm.

1. The effect of denervation on the anaphylactic contraction of the diaphragm from actively sensitized guinea pig has been studied. 2. The section of the phrenic nerve took place at cervical and thoracic levels. The sensitization of the animal took place several days before sectioning, simultaneously with denervation and after denervation. 3. The anaphylactic contractions were observed from the fourth day after thoracic denervation, and from the sixth day when denervation was in the cervical region. 4. The hypersensitivity to ACh in the denervated diaphragmatic muscle was present 24 hr after sectioning the phrenic nerve and reached its maximum 3-4 days after. 5. These results support the idea that denervation caused some changes in the membrane of the skeletal muscle fibres to allow the fixation of antibodies. These denervation changes are dependent on the length of the peripheral nerve left to degenerate. Anaphylactic contractions appeared earlier in those animals where phrenic nerve sections were closer to the diaphragmatic muscle.