Characterization and applicability of a novel physiologically relevant 3D-tetraculture bronchial model for in vitro assessment of respiratory sensitization.

Chemical Respiratory Allergy (CRA) is triggered after exposure to Low Molecular Weight (LMW) sensitizers and manifests clinically as asthma and rhinitis. From a risk/toxicity assessment point of view, there are few methods, none of them validated, for evaluating the respiratory sensitization potential of chemicals once the in vivo-based models usually employed for inhalation toxicity addressment do not comprise allergenicity endpoints specifically. Based on that, we developed, characterized, and evaluated the applicability of a 3D-tetraculture airway model reconstructed with bronchial epithelial, fibroblasts, endothelial and monocytic cell lines. Moreover, we exposed the tissue to maleic anhydride (MA) aerosols to challenge the model and subsequently assessed inflammatory and functional aspects of the tissue. The reconstructed tissue presented phenotypic biomarkers compatible with human bronchial epithelium, and MA aerosol exposure triggered an increased IL-8 and IL-6 production, reactive oxygen species (ROS) formation, and apoptosis of epithelial cells. Besides, augmented IL-8 production by monocytic cells was also found, correlating with dendritic cell activation within the co-culture model after MA exposure. Our results demonstrated that the 3D-tetraculture bronchial model presents hallmarks related to human airways' structure and function. Additionally, exposure to a respiratory sensitizer induced inflammatory and functional alterations in the reconstructed tissue, rendering it a valuable tool for exploring the mechanistic framework of chemically induced respiratory sensitization.

Toxicidad sistémica y pulmonar por inmunoterapia: revisión narrativa a propósito de un caso / Systemic and pulmonary toxicity from immunotherapy: A narrative review and a clinical case report

En el último tiempo, la inmunoterapia se ha convertido en una opción terapéutica para diversos tipos de neoplasias, aumentando la sobrevida en muchos casos, pero también los efectos adversos asociados. Existen tres tipos de inmunoterapia utilizados en cáncer: Terapia de células T con receptor de antígeno quimérico (CAR-T), destacando como reacciones adversas el síndrome liberador de citoquinas (CRS) y el síndrome de neurotoxicidad (ICANS); Anticuerpos monoclonales (AcM), cuyos efectos adversos más comunes están relacionados con reacciones de hipersensibilidad; y los Inhibidores de puntos de control inmunitario (ICI) con toxicidad pulmonar claramente reportada. Para un correcto manejo de estas reacciones adversas se requiere un alto índice de sospecha, un adecuado diagnóstico diferencial y un tratamiento oportuno, basado principalmente en corticoides y guiado por criterios de gravedad. Se presenta el caso de un paciente con reacción granulomatosa sarcoidea posterior al uso de Nivolumab.

In recent times, immunotherapy has emerged as a therapeutic option for various neoplasms, significantly improving survival rates in many cases, albeit with associated adverse effects. There are three types of immunotherapy commonly used in cancer treatment: Chimeric Antigen Receptor T-cell Therapy (CAR-T), notable for adverse reactions such as Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS); Monoclonal Antibodies (mAbs), with the most common adverse effects being hypersensitivity reactions; and Immune Checkpoint Inhibitors (ICI), with well-documented pulmonary toxicity. Adequate management of these adverse reactions requires a high index of suspicion, accurate differential diagnosis, and timely treatment, primarily based on corticosteroids and guided by severity criteria. We present a case of a patient with granulomatous sarcoid-like reaction following the use of Nivolumab.

Toxicidad pulmonar por pembrolizumab / Pulmonary Toxicity of Pembrolizumab

Se presenta el caso de un paciente con diagnóstico de adenocarcinoma de pulmón metastásico que, luego de realizar cinco meses de tratamiento con pembrolizumab, presentó neumonitis grado 2, interpretada como toxicidad por pembrolizumab con buena respuesta y resolución de los infiltrados con la suspensión del inmunomodulador y la administración de corticoides(AU)

We present the case of a patient diagnosed with metastatic lung adenocarcinoma who, after five months of treatment with pembrolizumab, presented grade 2 pneumonitis, interpreted as pembrolizumab toxicity, with a good response and resolution of the infiltrates with the suspension of the immunomodulator and the administration of corticosteroids(AU)

Dasatinib-Related Pulmonary Toxicity / Toxicidad pulmonar por dasatinib

ABSTRACT 70-year-old male patient with chronic myeloid leukemia receiving treatment with dasatinib develops respiratory failure associated with pulmonary toxicity related to such drug.

RESUMEN Paciente de sexo masculino, 70 años, con leucemia mieloide crónica en tratamiento con dasatinib, desarrolla insuficiencia respiratoria asociada a toxicidad pulmonar por dicho fármaco.

Toxicidad pulmonar por dasatinib / Dasatinib-Related Pulmonary Toxicity

Paciente de sexo masculino, 70 años, con leucemia mieloide crónica en tratamiento con dasatinib, desarrolla insuficiencia respiratoria asociada a toxicidad pulmonar por dicho fármaco.

70-year-old male patient with chronic myeloid leukemia receiving treatment with da satinib develops respiratory failure associated with pulmonary toxicity related to such drug.

Ex vivo pulmonary assay applied for screening of toxicity potential of chemicals.

Acute inhalation toxicity testing for chemical classification and labeling has been performed using animal models, however, these models have limited predictibility of the toxicity on the respiratory system. Thus, non-animal models have been emerging as alternatives for preclinical assessment of respiratory toxicity of chemicals, comprising in chemico, in vitro, ex vivo, and in silico approaches. In this study, we characterized and evaluated the applicability of a new ex vivo bovine bronchial model for addressing key aspects of pulmonary toxicity. Standardized bronchial fragments were cultured at an air-liquid interface for seven days showing cell viability, morphology, and function during the ex vivo time of cultivation. Different exposure ways, liquid or aerosol exposure, were also studied using paraformaldehyde (PFA) as a positive control. In a concentration-dependent manner, a decrease in tissue viability was observed for aerosols instead of direct liquid exposure upon tissue surface. Moreover, PFA exposure allowed the addressment of several damage biomarkers, including epithelium thickness, mitochondrial activity, ROS production, and caspase-3 activation. Besides, the bronquial tissue was exposed to chemicals from different UN GHS inhalation toxicity categories and presented a concentration-dependent response for most of the evaluated materials. The proposed airway ex vivo model represents a low-cost and reproducible tool applicable for pulmonary toxicity assessment of chemicals.

[Acute amiodarone pulmonary toxicity with low impregnation dose: case report]. / Toxicidad pulmonar aguda por amiodarona con dosis baja de impregnación: reporte de caso.

Amiodarone, considered a potent antiarrhythmic, is known to cause pulmonary toxicity. Chronic interstitial pneumonitis is the most common presentation. However, acute pulmonary toxicity is rare and has a higher case fatality rate. We present a 61-year-old patient with persistent atrial fibrillation who, after a one-month treatment with oral amiodarone at a low dose impregnation of 400 mg/day, develops acute pulmonary toxicity, with radiographic and tomographic resolution after antiarrhythmic suspension and steroid treatment.

Se sabe que la amiodarona, un potente antiarrítmico, causa toxicidad pulmonar. La neumonitis intersticial crónica es la presentación más común. Sin embargo, la toxicidad pulmonar aguda es rara y provoca una mayor mortalidad. Se presenta un paciente de 61 años con fibrilación auricular persistente que, tras tratamiento por un mes con amiodarona vía oral a dosis baja de impregnación de 400 miligramos al día, desarrolló toxicidad pulmonar aguda secundaria al antiarrítmico confirmada por radiografía y tomografía. Su caso tuvo resolución después de la suspensión del fármaco y tratamiento con esteroides.

Toxicidad pulmonar aguda por amiodarona con dosis baja de impregnación: reporte de caso / Acute amiodarone pulmonary toxicity with low impregnation dose: case report

Se sabe que la amiodarona, un potente antiarrítmico, causa toxicidad pulmonar. La neumonitis intersticial crónica es la presentación más común. Sin embargo, la toxicidad pulmonar aguda es rara y provoca una mayor mortalidad. Se presenta un paciente de 61 años con fibrilación auricular persistente que, tras tratamiento por un mes con amiodarona vía oral a dosis baja de impregnación de 400 miligramos al día, desarrolló toxicidad pulmonar aguda secundaria al antiarrítmico confirmada por radiografía y tomografía. Su caso tuvo resolución después de la suspensión del fármaco y tratamiento con esteroides.

Amiodarone, considered a potent antiarrhythmic, is known to cause pulmonary toxicity. Chronic interstitial pneumonitis is the most common presentation. However, acute pulmonary toxicity is rare and has a higher case fatality rate. We present a 61-year-old patient with persistent atrial fibrillation who, after a one-month treatment with oral amiodarone at a low dose impregnation of 400 mg/day, develops acute pulmonary toxicity, with radiographic and tomographic resolution after antiarrhythmic suspension and steroid treatment.

Efeitos da vareniclina no tecido pulmonar em modelo animal / Effects of varenicline on lung tissue in the animal model

RESUMO Objetivo O objetivo deste estudo foi investigar os efeitos agudos e crônicos da vareniclina no tecido pulmonar em um estudo experimental. Métodos Um total de 34 ratos foi alocado aleatoriamente em grupos de estudo (vareniclina) e controle. Assim, os ratos foram divididos em dois grupos: (i) grupo controle e (ii) grupo vareniclina. A seguir, os ratos de cada grupo foram, por sua vez, subdivididos igualmente em agudos (C1; V1) e crônicos (C2; V2), e todos os ratos dos grupos agudos e crônicos foram sacrificados sob anestesia: no 45.º dia, para o grupo agudo [C1 (n=5) e V1 (n=12)], e no 90.º dia, para o grupo crônico [C2 (n=5) e V2 (n=12)], respectivamente. Em seguida, foram realizadas análises bioquímicas e histopatológicas. Resultados Trinta e quatro ratos completaram o estudo. Destes ratos, 24 estavam no grupo vareniclina e 10 no grupo controle. Na exposição crônica à vareniclina, os níveis de oxidante composto por malondialdeído (MDA) e mieloperoxidase (MPO) aumentaram, e os níveis de superóxido dismutase (SOD), catalase (CAT), glutationa (GSH) e glutationa peroxidase (GPx), nomeados como antioxidantes, diminuiram significativamente quando comparados com o grupo controle. Os níveis de MDA e MPO também foram significativamente mais elevados e os níveis de SOD, CAT, GPx e GSH foram significativamente mais baixos no grupo vareniclina crônico, quando comparado ao grupo vareniclina agudo. Estes achados também foram confirmados por observações histopatológicas. Conclusões Este é o primeiro estudo que avaliou os efeitos pulmonares da vareniclina experimentalmente em um modelo animal. Observamos que o tratamento crônico da vareniclina causa inflamação e lesão pulmonar.

ABSTRACT Objective This study aimed to investigate acute and chronic effects of varenicline on lung tissue in an experimental study. Methods A total of 34 rats were randomly allocated into study (varenicline) and control groups. The rats were divided into two groups (i) control group, (ii) varenicline group. Then, the rats in the each group were sub-divided equally in turn as acute (C1; V1) and chronic (C2; V2) ; all rats of acute and chronic groups were sacrificed under the anesthesia on the 45th day for acute group [C1 (n=5) and V1 (n=12)] and the 90th day for chronic group [C2 (n=5) and V2 (n=12)], respectively. Thus, biochemical and histopathological analysis were carried out. Results Thirty four rats completed the study, 24 were in varenicline group and 10 were in control group. In chronic exposure to varenicline, oxidant levels comprising of malondialdehyde (MDA), and myeloperoxidase (MPO) increased and superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and glutathione peroxidase (GPx) levels, named as antioxidants, decreased significantly when compared to the control group. MDA and MPO levels were also significantly higher and SOD, CAT, GPx, GSH levels were also significantly lower in chronic varenicline group when compared to acute varenicline group. These findings were also supported by histopathological observations. Conclusion This is the first study, which evaluated pulmonary effects of varenicline experimentally on an animal model. It was observed that chronic varenicline treatments cause inflammation and lung cell injury.

Cáncer de mama: técnica de posición mama prona en pacientes con estadios I y II / Breast cancer: breast prone position technique in patients with stage I and II

En el tratamiento del cáncer de mama, son varias las técnicas que se describen en materia de radioterapia oncológica. Objetivo: La investigación pretendió analizar la técnica de mama prona en cuanto a beneficio para las pacientes con cáncer de mama estadios I y II en el servicio de radioterapia oncológica y medicina nuclear del Hospital Universitario de Caracas. Métodos: Se trata de un estudio descriptivo, prospectivo y comparativo con una muestra conformada por 20 pacientes. Los casos se registraron en el instrumento de recolección de datos del paciente. Para este estudio se emplearon las técnicas de la estadística descriptiva. Resultados: La frecuencia de pacientes atendidas tuvo un aumento interanual entre 35 % y 40 %. El 60 % de las pacientes presentaron estadio IB, 25 % IA y 15 % con estadio IIA. Conclusión: La posición prona es una técnica reproducible que beneficia principalmente a las pacientes con mamas grandes y/o péndulas, permite protección del corazón excluyendo el haz del rayo a nivel cardiaco(AU)

In the treatment of breast cancer, there are several techniques that are described in terms of radiation therapy. Objetive: The research aimed to analyze the prone breast technique in terms of benefit for patients with stage I and II breast cancer in the oncological radiotherapy and nuclear medicine service of the University Hospital of Caracas. Methods: This is a descriptive, prospective and comparative study with a sample consisting of 20 patients. The cases were recorded in the patient data collection instrument. For this study, the techniques of descriptive statistics were used. Results: the frequency of patients attended had an interannual increase between 35 % and 40 %. 60 % of the patients presented stage IB, 25 % IA and 15 % with stage IIA. Conclusion: The prone position is a reproducible technique that mainly benefits the patients with large breasts and / or pendulums, allows protection of the heart excluding the beam of the ray at cardiac level(AU)

Neumonía intersticial asociada a sirolimus en un paciente con trasplante hepático / Sirolimus-associated interstitial pneumonitis in a liver transplant recipient

Con la utilización de sirolimus en pacientes trasplantados, se han reportado casos de neumonitis intersticial, bronquiolitis obliterante y neumonía organizada. Nosotros describimos un caso de toxicidad pulmonar asociada al uso de sirolimus en un paciente de 59 años con trasplante hepático, revisamos los reportes de caso donde se describía toxicidad pulmonar asociada al uso de sirolimus en pacientes con trasplante hepático, con el objetivo de encontrar similitudes en factores de riesgo, manifestaciones clínicas y desenlaces. De los cinco casos reportados desde enero de 2000, incluyendo el presente, encontramos que las manifestaciones clínicas fueron similares presentándose fiebre, disnea, fatiga, tos y hemoptisis. Con la suspensión del medicamento, los pacientes resolvieron sus signos, síntomas y hallazgos imagenológicos. La toxicidad pulmonar asociada a sirolimus debe ser considerada como diagnóstico diferencial de aquellos pacientes con trasplante hepático que reciban este medicamento y presenten manifestaciones respiratorias, pues la suspensión del medicamento lleva a la resolución del cuadro.

Sirolimus is an immunosuppressive drug that has been used during the past few years. Sirolimus is indicated in rescue therapies and to reduce the secondary toxic effects of calcineurin inhibitors. This drug has been associated with infrequent but severe pulmonary toxicity. Cases of interstitial pneumonitis, bronchiolitis obliterans with organizing pneumonia, and alveolar proteinosis have been described. We describe a case of pulmonary toxicity associated with the use of sirolimus in a 59-yr-old liver transplant recipient. We also review all reported cases of sirolimus-associated lung toxicity among liver transplantation recipients, with the intention of understanding the risk factors, the clinical picture and the outcomes of this complication. Five cases have been reported since January 2000, including the present case. Clinical presentation is similar, with fever, dyspnea, fatigue, cough, and hemoptysis. Discontinuation of the drug led to resolution of clinical and radiographic findings. Sirolimus-induced pulmonary toxicity is a serious condition and should be considered in the differential diagnosis of liver recipients presenting with respiratory findings. Discontinuation of the drug is associated with resolution of the pulmonary compromise.

A importância do reconhecimento precoce da toxicidade pulmonar por amiodarona: a propósito de cinco casos / The importance of early recognizing of pulmonary toxicity by amiodarone: a report of five cases

Amiodarona é um agente antiarrítmico, com reconhecida toxicidade para os pulmões. Tal efeito adverso é geralmente relacionado à dose utilizada e duração da terapia, embora existam relatos de que esses não são os únicos preditores da toxicidade. A partir do atendimento, em um curto intervalo de tempo, de cinco pacientes com toxicidade pulmonar por amiodarona no Serviço de Pneumologia do Hospital São Lucas da PUCRS são revisados os critérios clínicos e diagnósticos de tal situação. Conclui-se pela conveniência de alto índice de suspeição clínica de avaliação, em todos os pacientes em uso da droga, da função pulmonar completa, inclusive com difusão pelo monóxido de carbono. A realização de espirometria convencional e gasometria arterial são úteis somente em casos avançados (AU)

Amiodarone is a commonly used anti-arrhythmic agent, with well-recognized lung toxicity. Such adverse effect is usually related to the dose and duration of the treatment, although there are reports showing that these are not the only predictors of toxicity. Following the occurrence of five cases diagnosed in a short period of time at the Serviço de Pneumologia do Hospital São Lucas da PUCRS, we reviewed clinical criteria and diagnostic procedures to assess such clinical situation. We conclude that is necessary a high clinical suspicion rate and for the need of pulmonary function evaluation, including carbon monoxide diffusion capacity, in all patients using the drug. Spirometry and arterial blood gases are useful only in severe cases (AU)