Characteristics, Management, and Prognostic Implications of Adverse Effects of Immune Checkpoint Inhibitors: A Systematic Review. / Revisión sistemática de los efectos adversos cutáneos causados por fármacos inhibidores de los puntos de control inmunitario: características, manejo y pronóstico.

Immune checkpoint inhibitors (ICIs) have significantly advanced the treatment of cancer. They are not, however, free of adverse effects. These effects are called immune-related adverse events (irAEs) and often involve the skin. Most of the information on cutaneous irAEs comes from clinical practice. We therefore conducted a thorough review of the characteristics of cutaneous irAEs, recommendations for treatment, and their association with prognosis. The most common events are exanthema, pruritus, vitiligo, and hair loss, although ICIs can cause a wide range of cutaneous dermatoses. The reported association observed between certain reactions and a favorable response to cancer treatment should be interpreted with caution. Dermatologists should be involved in the multidisciplinary care of patients being treated with ICIs as they have an essential role in the diagnosis and treatment of cutaneous irAEs.

Revisión sistemática de los efectos adversos cutáneos causados por fármacos inhibidores de los puntos de control inmunitario: características, manejo y pronóstico / Characteristics, Management, and Prognostic Implications of Adverse Effects of Immune Checkpoint Inhibitors: A Systematic Review

Los fármacos inhibidores de los puntos de control inmunitario han supuesto un importante avance en el tratamiento oncológico. Sin embargo, su uso no está exento de reacciones no deseadas, denominadas efectos adversos inmunorrelacionados, siendo los cutáneos particularmente frecuentes. El conocimiento que tenemos sobre los efectos adversos inmunorrelacionados cutáneos procede fundamentalmente de la práctica clínica. Por lo tanto, en este trabajo se revisan en detalle sus características, así como las recomendaciones sobre su tratamiento y sus implicaciones pronósticas. Los más frecuentes son el exantema, el prurito, el vitíligo y la alopecia; sin embargo, estos fármacos pueden producir una amplia variedad de dermatosis. La asociación observada entre ciertos tipos de reacciones cutáneas con una respuesta oncológica favorable al tratamiento debe interpretarse con cautela. El dermatólogo ha de participar en el cuidado multidisciplinar de estos pacientes, pues desempeña un papel fundamental en el diagnóstico y el tratamiento de estas reacciones cutáneas adversas (AU)

Immune checkpoint inhibitors (ICIs) have significantly advanced the treatment of cancer. They are not, however, free of adverse effects. These effects are called immune-related adverse events (irAEs) and often involve the skin. Most of the information on cutaneous irAEs comes from clinical practice. We therefore conducted a thorough review of the characteristics of cutaneous irAEs, recommendations for treatment, and their association with prognosis. The most common events are exanthema, pruritus, vitiligo, and hair loss, although ICIs can cause a wide range of cutaneous dermatoses. The reported association observed between certain reactions and a favorable response to cancer treatment should be interpreted with caution. Dermatologists should be involved in the multidisciplinary care of patients being treated with ICIs as they have an essential role in the diagnosis and treatment of cutaneous irAEs (AU)

[Translated article] Characteristics, Management, and Prognostic Implications of Adverse Effects of Immune Checkpoint Inhibitors: A Systematic Review / Revisión sistemática de los efectos adversos cutáneos causados por fármacos inhibidores de los puntos de control inmunitario: características, manejo y pronóstico

Immune checkpoint inhibitors (ICIs) have significantly advanced the treatment of cancer. They are not, however, free of adverse effects. These effects are called immune-related adverse events (irAEs) and often involve the skin. Most of the information on cutaneous irAEs comes from clinical practice. We therefore conducted a thorough review of the characteristics of cutaneous irAEs, recommendations for treatment, and their association with prognosis. The most common events are exanthema, pruritus, vitiligo, and hair loss, although ICIs can cause a wide range of cutaneous dermatoses. The reported association observed between certain reactions and a favorable response to cancer treatment should be interpreted with caution. Dermatologists should be involved in the multidisciplinary care of patients being treated with ICIs as they have an essential role in the diagnosis and treatment of cutaneous irAEs (AU)

Los fármacos inhibidores de los puntos de control inmunitario han supuesto un importante avance en el tratamiento oncológico. Sin embargo, su uso no está exento de reacciones no deseadas, denominadas efectos adversos inmunorrelacionados, siendo los cutáneos particularmente frecuentes. El conocimiento que tenemos sobre los efectos adversos inmunorrelacionados cutáneos procede fundamentalmente de la práctica clínica. Por lo tanto, en este trabajo se revisan en detalle sus características, así como las recomendaciones sobre su tratamiento y sus implicaciones pronósticas. Los más frecuentes son el exantema, el prurito, el vitíligo y la alopecia; sin embargo, estos fármacos pueden producir una amplia variedad de dermatosis. La asociación observada entre ciertos tipos de reacciones cutáneas con una respuesta oncológica favorable al tratamiento debe interpretarse con cautela. El dermatólogo ha de participar en el cuidado multidisciplinar de estos pacientes, pues desempeña un papel fundamental en el diagnóstico y el tratamiento de estas reacciones cutáneas adversas (AU)

A continuous spectrophotometric assay for determination of the aureusidin synthase activity of tyrosinase.

INTRODUCTION: Aurones (aureusidin glycosides) are plant flavonoids that provide yellow colour to the flowers of some ornamental plants. In this study we analyse the capacity of tyrosinase to catalyse the synthesis of aureusidin by tyrosinase from the chalcone THC (2',4',6',4-tetrahydroxychalcone). OBJECTIVE: To develop a simple continuous spectrophotometric assay for the analysis of the spectrophotometric and kinetic characteristics of THC oxidation by tyrosinase. METHODOLOGY: THC oxidation was routinely assayed by measuring the increase in absorbance at 415 nm vs. reaction time. RESULTS: According to the mechanism proposed for tyrosinase, the enzymatic reaction involves the o-hydroxylation of the monophenol THC to the o-diphenol (PHC, 2',4',6',3,4 - pentahydroxychalcone), which is then oxidised to the corresponding o-quinone in a second enzymatic step. This product is highly unstable and thus undergoes a series of fast chemical reactions to produce aureusidin. In these experimental conditions, the optimum pH for THC oxidation is 4.5. The progress curves obtained for THC oxidation showed the appearance of a lag period. The following kinetic parameters were also determined: K(m )= 0.12 mM, V(m )= 13 microM/min, V(m)/K(m )= 0.11/min. CONCLUSION: This method has made it possible to analyse the spectrophotometric and kinetic characteristics of THC by tyrosinase. This procedure has the advantages of a short analysis time, straightforward measurement techniques and reproducibility. In addition, it also allows the study of tyrosinase inhibitors, such as tropolone.

[The current health system and the spirit of May 68]. / El sistema sanitario vigente y el ideario de mayo 68.

Forty years after the 68 May revolt, we have thought of interest to retrieve part of the revolutionary ideology concerning the role of medical practice in the society they would to change. In essence they said: the current organization of health care, although masked by mysticism, provides political support to the dominant class and favours socio-economic exploitation. Relevant features of medical structures, the hospital, the traditional medical mentality, the biologistic paradigm, etc. reinforce the hierarchical order in the capitalist society.

El sistema sanitario vigente y el ideario de mayo 68 / The current health system and the spirit of may 68

Se cumplen ahora cuarenta años de la última revoluciónlibertaria en Europa. En el recuerdo queda laacción directa en las calles y la ocupación de fábricas,pero hubo también una ideología revolucionaria pococonocida por su falta de estructuración y por la rapidezcon la que se disolvió la revuelta.En este artículo se revisan algunos aspectos de sucrítica a la organización sanitaria a la que consideranun factor más del sometimiento del asalariado, y unsoporte de la clase dominante. A través de sus elementosmás característicos, el paradigma organicista, el papeldel hospital y la ideología médica se consolida el ordensocial (AU)

Forty years after the ´68 May revolt, we havethought of interest to retrieve part of the revolutionaryideology concerning the rol of medical practice in thesociety they would to change.In essence they said: the current organization ofhealth care, although masked by mysticism, providespolitical support to the dominant class and favourssocio-economic exploitation. Relevant features of medicalstructures, the hospital, the traditional medicalmentality, the biologistic paradigm, etc. reinforce thehierarchical order in the capitalist society (AU)

[Association between cerebral infarction and malignant glioma]. / Asociación de infarto cerebral y glioma maligno.

INTRODUCTION: It is very rare for cerebral infarction to be the first symptom of an intracranial tumour. Only three cases have been reported in which cerebral infarction is thought to have been caused by the arterial compromise triggered by incipient high grade gliomas that are not yet visible in radiological tests. CASE REPORT: A 46-year-old male with no relevant medical history or cardiovascular risk factors who presented with acute hemiplegia on the right-hand side of the body and a significantly impaired level of consciousness. Computerised axial tomography of the brain showed a left frontal malignant ischemic infarct that exerted an important mass effect. The patient was submitted to a left-side frontoparietal decompressive craniectomy. Post-operative progress was good and the patient even recovered his normal level of consciousness, although he was left with right hemiparesis and conduction dysphasia. Seven months after the craniectomy the patient experienced a progressive deterioration with symptoms of endocranial hypertension. Magnetic resonance imaging of the brain revealed the presence of a highly malignant tumour in the previously infarcted territory. A histological study of the excised lesion showed it to be a glioblastoma multiforme. CONCLUSIONS: The proximity in time, as well as the identical location of the two lesions, led us to think that the glioblastoma, although not yet visible in radiological explorations, affected a branch of the middle cerebral artery and gave rise to the infarct. Therefore, in the presence of a cerebral infarct in patients with no risk factors for suffering a brain vascular pathology, it is advisable to carry out a radiological follow-up so as to be able to diagnose a possible lesion due to a tumour.

Asociación de infarto cerebral y glioma maligno / Association between cerebral infarction and malignant glioma

Introducción. La primera manifestación de un tumor intracraneal raramente es la aparición de un infarto cerebral. Tan sólo se han documentado tres casos en los que se considera como causa de un infarto cerebral la afectación arterial provocada por gliomas incipientes de alto grado aún no visibles radiológicamente. Caso clínico. Se trata de un varón de 46 años sin antecedentes médicos de interés ni factores de riesgo cardiovasculares que presentó de manera aguda una manifiesta hemiplejía derecha y deterioro importante del nivel de conciencia. En la tomografía axial computarizada craneal se demostró un infarto isquémico maligno frontal izquierdo que ejercía un gran efecto de masa. Se practicó una craniectomía descompresiva frontoparietal izquierda. El posoperatorio fue favorable y el paciente recuperó hasta la normalidad su nivel de conciencia, aunque quedó con una hemiparesia derecha y disfasia de conducción. Siete meses después de la craniectomía, experimentó un deterioro progresivo con clínica de hipertensión endocraneal. La resonancia magnética cerebral demostró la presencia de un tumor de alto grado de malignidad sobre el territorio previamente infartado. El estudio histológico de la lesión resecada determinó que se trataba de un glioblastoma multiforme. Conclusión. La cercanía en el tiempo, así como la idéntica localización de ambas lesiones, hace pensar que el glioblastoma, no siendo aún visible radiológicamente, comprimió o invadió una rama de la arteria cerebral media y originó el infarto. Por tanto, ante la presencia de un infarto cerebral en un paciente sin factores de riesgo para sufrir patología vascular cerebral, sería recomendable realizar un seguimiento radiológico posterior con el fin de diagnosticar una posible lesión tumoral

Introduction. It is very rare for cerebral infarction to be the first symptom of an intracranial tumour. Only three cases have been reported in which cerebral infarction is thought to have been caused by the arterial compromise triggered by incipient high grade gliomas that are not yet visible in radiological tests. Case report. A 46-year-old male with no relevant medical history or cardiovascular risk factors who presented with acute hemiplegia on the right-hand side of the body and a significantly impaired level of consciousness. Computerised axial tomography of the brain showed a left frontal malignant ischemic infarct that exerted an important mass effect. The patient was submitted to a left-side frontoparietal decompressive craniectomy. Post-operative progress was good and the patient even recovered his normal level of consciousness, although he was left with right hemiparesis and conduction dysphasia. Seven months after the craniectomy the patient experienced a progressive deterioration with symptoms of endocranial hypertension. Magnetic resonance imaging of the brain revealed the presence of a highly malignant tumour in the previously infarcted territory. A histological study of the excised lesion showed it to be a glioblastoma multiforme. Conclusions. The proximity in time, as well as the identical location of the two lesions, led us to think that the glioblastoma, although not yet visible in radiological explorations, affected a branch of the middle cerebral artery and gave rise to the infarct. Therefore, in the presence of a cerebral infarct in patients with no risk factors for suffering a brain vascular pathology, it is advisable to carry out a radiological follow-up so as to be able to diagnose a possible lesion due to a tumour

Kinetic analysis of catechin oxidation by polyphenol oxidase at neutral pH.

Catechin oxidation by peach polyphenol oxidase was performed in a pH range of 3.5-8.0. At acidic pH, maximal spectral changes were observed at 390nm and at pH 7.5, at 430nm. Catechin oxidation was studied at pH 7.5 to avoid the formation of free radicals. The results obtained allowed us to propose a pathway for the enzymatic oxidation of catechin, according to which enzymatic oxidation produces the corresponding catechin-o-quinone, which suffers the nucleophilic attack of another catechin unit, leading to the formation of a dimer. This dimer is then oxidized by the enzymatically generated o-quinone. The progress curves obtained for catechin oxidation by PPO showed a lag period, whose length changed with enzyme and substrate concentrations, and which must have been caused by the chemical reactions taking place after the enzymatic reaction. The results obtained by simulation of the model produced the same qualitative dependences as obtained experimentally.

Determination of the phospholipase activity of patatin by a continuous spectrophotometric assay.

Patatin is a family of glycoproteins that accounts for 30-40% of the total soluble protein in potato (Solanum tuberosum L.) tubers. This protein has been reported to serve as a storage protein and also to exhibit lipid phospholipase activity. This paper describes a simple continuous spectrophotometric method for assaying patatin phospholipase activity. The procedure is based on a coupled enzymatic assay using [1,2-dilinoleoyl] PC as the phospholipase substrate and lipoxygenase as the coupling enzyme. In the procedure developed in this work, lipoxygenase oxidizes the linoleic acid released by the phospholipase activity of patatin. This activity can then be followed spectrophotometrically by recording the increase in absorbance at 234 nm that results from the formation of the corresponding hydroperoxide from linoleic acid by the action of lipoxygenase. The optimal assay concentrations of patatin and lipoxygenase were established. Phospholipase activity varied with pH, reaching its optimal value at pH 9.5. Scans of the deoxycholate concentration pointed to an optimal detergent concentration of 3 mM. Phospholipid hydrolysis followed classical Michaelis-Menten kinetics (Vm = 9.8 x 10(-3) micromol/min x microg protein, Km = 7.8 microM, Vm/Km = 1.3 min(-1) x microg protein). This method proved to be specific since there was no activity in the absence of patatin. It also had the advantages of a short analysis time and the use of commercially nonradiolabeled and inexpensive substrates, which are, furthermore, natural substrates of phospholipase.

A continuous spectrophotometric assay for phospholipase A(2) activity.

This paper describes a simple continuous spectrophotometric method for assaying phospholipase A(2) (PLA(2)) activity. The procedure is based on a coupled enzymatic assay, using dilinoleoyl phosphatidylcholine as phospholipase substrate and lipoxygenase as coupling enzyme. The linoleic acid released by phospholipase was oxidized by lipoxygenase and then phospholipase activity was followed spectrophotometrically by measuring the increase in absorbance at 234 nm due to the formation of the corresponding hydroperoxide from the linoleic acid. The optimal assay concentrations of hog pancreatic phospholipase A(2) and lipoxygenase were established. PLA(2) activity varied with pH, reaching its optimal value at pH 8.5. Scans of the deoxycholate concentration pointed to an optimal detergent concentration of 3mM. Phospholipid hydrolysis followed classical Michaelis-Menten kinetics (V(m)=1.8 microM/min, K(m)=4.5 microM, V(m)/K(m)=0.4 min(-1)). This assay also allows PLA(2) inhibitors, such as p-bromophenacyl bromide or dehydroabietylamine acetate, to be studied. This method was proved to be specific since there was no activity in the absence of phospholipase A(2). It also has the advantages of a short analysis time and the use of commercially nonradiolabeled and inexpensive substrates, which are, furthermore, natural substrates of phospholipase A(2).

Characterization of patatin esterase activity in AOT-isooctane reverse micelles.

Patatin is a family of glycoproteins that accounts for 30-40% of the total soluble protein in potato (Solanum tuberosum L.) tubers. This protein has been reported not only to serve as a storage protein but also to exhibit lipid acyl hydrolase (LAH) activity. In this study patatin is characterized in AOT-isooctane reverse micelles. The influence on the enzymatic activity of characteristic parameters of reverse micelles, w(o) (= H(2)O/AOT), and the percentage of H(2)O, theta, were investigated. The results obtained show that patatin esterase activity varies with w(o) but remains constant throughout the range of theta values studied. The variation with w(o) showed that the activity follows an S-shaped behavior pattern, reaching a maximum at about w(o) = 20 for 2% H(2)O. Patatin esterase activity was compared with p-nitrophenyl (PNP) fatty acid esters of different chain lengths. The activity was much higher for PNP-caprylate. The pH optimum was 6.0, different from the value obtained when patatin esterase activity was measured in mixed micelle systems. The optimal temperature was 35 degrees C, above which the activity decreased to almost zero. The kinetic parameters were also evaluated (K(m) = 10 mM, V(m) = 158 microM/min, V(m)/K(m) = 15.8 x 10(-3) min(-1)). This paper shows the suitability of reverse micelles for measuring patatin esterase activity, since it allows the study of the enzyme in similar conditions to that prevailing in vivo.

Hysteresis and positive cooperativity of iceberg lettuce polyphenol oxidase.

A kinetic study of the diphenolase activity of latent polyphenol oxidase (PPO), purified from Iceberg lettuce (Lactuca sativa L), revealed a sigmoid relationship between the reaction rate and the substrate concentration with a high Hill coefficient (n(H) = 3.8). This positive cooperativity had not been previously described for any PPO. Furthermore, the enzyme showed a lag phase in the expression of this activity, suggesting a hysteretic nature of the enzyme. The kinetic behavior, the latency and the lag phase varied at different steps of the purification process. PPO showed hyperbolic or cooperative kinetics depending on the pH assay and the sodium dodecyl sulfate (SDS) concentration. Substrate-induced slow conformational change of the oligomeric enzyme is suggested. The conformational change would be toward a more active enzyme form with higher affinity for the substrate and favoured by acid pH and SDS.

[Preoperative embolization in meningioma of the ponto-cerebellar angle. Indications and advantages]. / Embolización preoperatoria en un meningioma del ángulo ponto-cerebeloso. Indicaciones y ventajas.

Preoperative embolization of meningiomas has been performed in order to reduce surgical hemorrhage during the removal of these vascularized tumors. In this paper we emphasize the fact that occlusion of the tumoral vessels by artificial emboli produces an ischemic necrosis that greatly helps tumor exeresis. This is especially useful in meningiomas of certain localizations requiring complex surgical approaches. In our case, a giant ponto-cerebellar meningioma was dried up totally and then removed with relative ease through a conventional suboccipítal lateral craniectomy. The technique, indications and control of preoperative embolization are reviewed.

Evidence for a tetrameric form of iceberg lettuce (Lactuca sativa L.) polyphenol oxidase: purification and characterization.

Polyphenol oxidase from iceberg lettuce (Lactuca sativa L.) chloroplasts was released from the thylakoid-membrane by sonication, and it was extensively purified to homogeneity as judged by SDS-PAGE. Purification was achieved by ammonium sulfate fractionation, gel-filtration chromatography, and ion-exchange chromatography. Two molecular forms were separated by gel-filtration chromatography with apparent molecular masses of 188 and 49 kDa. Both forms were characterized by sedimentation analysis with S(20,W) values of 10.2 and 4.1 S, respectively. For the high-molecular-weight form purified to homogeneity, denaturing SDS-PAGE indicated a molecular mass of 60 kDa. Thus, from these data we suggest that lettuce polyphenol oxidase is a tetramer of identical subunits.

Competitive inhibition of mushroom tyrosinase by 4-substituted benzaldehydes.

A kinetic study of the inhibition of mushroom tyrosinase by 4-substituted benzaldehydes showed that these compounds behave as classical competitive inhibitors, inhibiting the oxidation of L-3,4-dihydroxyphenylalanine (L-DOPA) by mushroom tyrosinase (o-diphenolase activity). The kinetic parameter (K(I)) characterizing this inhibition was evaluated for all of the seven compounds assayed. Cuminaldehyde showed the most potent inhibitory activity (K(I) = 9 microM). It also inhibited the oxidation of L-tyrosine by mushroom tyrosinase (o-monophenolase activity) in a competitive manner. The corresponding kinetic parameter for this inhibition was evaluated (K(I) = 0.12 mM).

An octaethylene glycol monododecyl ether-based mixed micellar assay for determining the lipid acyl hydrolase activity of patatin.

Patatin was extracted from potato tubers (Solanum tuberosum L. cv. Spunta) and purified to homogeneity by ammonium sulfate salt fractionation and one sole chromatographic step. A spectrophotometric mixed micellar assay for patatin lipid acyl hydrolase (LAH) activity was designed with the detergent octaethylene glycol monododecyl ether (C12E8). Patatin LAH used p-nitrophenyl butyrate (PNP-butyrate) as substrate when solubilized in (C12E8) micelles. In the mixed micellar system, patatin LAH responds to the PNP-butyrate surface concentration expressed as mol% (= [PNP-butyratel x 100/([detergentl critical micellar concentration)) and not to the molarity of PNP-butyrate. The kinetic parameters were determined; Vmax was independent of the mixed micelle concentration, as was Km, when expressed as mol%. However, Km was dependent on C12E8 concentration when expressed in molar concentration. C12E8/PNP-butyrate proved to be a reliable system for assaying patatin LAH activity and is superior to the commonly used Triton X-100 and SDS methods. It permits investigation of the substrate requirements of patatin LAH activity because the concentration-independent Km can be determined both in mol% and as the absolute number of substrate molecules per micelle. In addition, the detergent did not affect the enzyme activity.

Characterization of monophenolase activity of polyphenol oxidase from iceberg lettuce.

Polyphenol oxidase (EC 1.14.18.1), a thylakoid membrane-bound enzyme, was isolated by sonication of osmotically shocked chloroplasts from iceberg lettuce (Lactuca sativa). The enzyme showed monophenolase activity when assayed on (p-hydroxyphenyl)propionic acid with 3-methyl-2-benzothiazolinone hydrazone in a reliable continuous spectrophotometric method, with high sensitivity, accuracy, and precision. The monophenolase activity showed a lag period before the steady-state rate (V(ss)) was reached. Both kinetic parameters, the lag period and the steady-state rate, depended on the pH, the enzyme and substrate concentrations, and the presence of catalytic amounts of o-diphenol. This activity shows inhibition by high substrate concentration. The experimental results correspond with the mechanism previously described for PPO from other sources. Kinetic constants K(m), V(max), and K(i) were determined.

[Long-term results of surgical pharyngectomy (uvulo-palato-pharyngoplasty) versus office CO2 laser (L.A.U.P.) for the treatment of uncomplicated snoring]. / Résultats à long terme de la pharyngotomie chirurgicale classique (uvulo-palato-pharyngoplastie) versus laser CO2 en ambulatoire dans le traitement de la ronchopathie simple.

Two treatments are habitually proposed for snoring without obstructive sleep apnea syndrome: the surgical pharyngotomy, and the treatment by laser done in the office. Our study analyses retrospectively, by telephone questionnaire, a group of 168 snorers, without obstructive sleep apnea syndrome, treated by pharyngotomy (n = 71) or CO2 laser (n = 97) between 1989 and 1993. Results after a mean follow-up of 5 years, with a minimal of 3 years, show for the two procedures the same efficacity, and an equivalent prevalence of side effects. The rate of satisfaction for the patient and her bed-partner is about 50%, in relation to a degradation of therapeutic effect in the long run. We propose to precisely the results and the indications of the surgery and the laser for treatment of uncomplicated rhonchopathy.