Development, Histological, and Ultrastructural Evaluation of Sheep Hyperimmune Serum Therapy for COVID-19 / Desarrollo, Evaluación Histológica y Ultraestructural de la Terapia con Suero Hiperinmune de Oveja para COVID-19

SUMMARY: In response to the threat posed by new variants of SARS-CoV-2 and the urgent need for effective treatments in the absence of vaccines, the aim of this study was to develop a rapid and cost-effective hyperimmune serum (HS) derived from sheep and assess its efficacy. The utilization of a halal-certified, easily maintained in certain geographic regions, easy-to-handle animal such as sheep could provide a viable alternative to the expensive option of horses. Sheep were immunized with a whole inactivated SARS-CoV- 2 antigen to produce HS, which was evaluated for neutralizing potency using the PRNT50 assay. K18-hACE2 transgenic mice (n=35) were divided into three groups: control, SARS-CoV-2 exposure through inhalation, and SARS-CoV-2 exposed mice treated with HS. HS efficacy was assessed through serum proinflammatory cytokine levels, qRT-PCR analysis, histopathological examination of lungs and hearts, and transmission electron microscopy. Purified HS exhibited significant neutralizing activity (1/24,576). The SARS-CoV-2+HS group showed lower levels of TNF-α, IL-10, and IL-6 (P<0.01) and relatively lower levels of MCP-1 compared to the SARS-CoV-2 group. HS prevented death, reduced viral RNA levels in the lungs and hearts, protected against severe interstitial pneumonia, preserved lung tissue integrity, and prevented myocyte damage, while the SARS-CoV-2 group exhibited viral presence in the lungs. This study successfully developed a sheep-derived HS against the entire SARS-CoV-2 virus, resulting in a significant reduction in infection severity, inflammation, and systemic cytokine production. The findings hold promise for treating severe COVID-19 cases, including emerging viral variants, and immunocompromised patients.

En respuesta a la amenaza que suponen las nuevas variantes del SARS-CoV-2 y la urgente necesidad de tratamientos eficaces en ausencia de vacunas, el objetivo de este estudio fue desarrollar un suero hiperinmune (HS) rápido y rentable derivado de ovejas. y evaluar su eficacia. La utilización de un animal con certificación halal, de fácil mantenimiento en determinadas regiones geográficas y de fácil manejo, como las ovejas, podría proporcionar una alternativa viable a la costosa opción de los caballos. Las ovejas fueron inmunizadas con un antígeno de SARS-CoV-2 completamente inactivado para producir HS, cuya potencia neutralizante se evaluó mediante el ensayo PRNT50. Los ratones transgénicos K18-hACE2 (n = 35) se dividieron en tres grupos: control, exposición al SARS-CoV-2 mediante inhalación y ratones expuestos al SARS-CoV-2 tratados con HS. La eficacia de HS se evaluó mediante niveles de citoquinas proinflamatorias en suero, análisis qRT-PCR, examen histopatológico de pulmones y corazones y microscopía electrónica de transmisión. El HS purificado exhibió una actividad neutralizante significativa (1/24,576). El grupo SARS-CoV-2+HS mostró niveles más bajos de TNF-α, IL-10 e IL-6 (P<0,01) y niveles relativamente más bajos de MCP-1 en comparación con el grupo SARS-CoV-2. HS evitó la muerte, redujo los niveles de ARN viral en los pulmones y el corazón, protegió contra la neumonía intersticial grave, preservó la integridad del tejido pulmonar y evitó el daño de los miocitos, mientras que el grupo SARS-CoV-2 exhibió presencia viral en los pulmones. Este estudio desarrolló con éxito un HS derivado de ovejas contra todo el virus SARS-CoV-2, lo que resultó en una reducción significativa de la gravedad de la infección, la inflamación y la producción sistémica de citocinas. Los hallazgos son prometedores para el tratamiento de casos graves de COVID- 19, incluidas las variantes virales emergentes y los pacientes inmunocomprometidos.

Diabetes mellitus tipo 1 de presentación súbita inducida por inhibidores del punto de control inmunitario en el tratamiento de cáncer avanzado. Serie de casos / Sudden onset type 1 diabetes mellitus induced by immune checkpoint inhibitors in the treatment of advanced cancer. Cases report

Tres pacientes con cáncer avanzado en tratamiento con inhibidores del punto de control inmunitario (inmune checkpoint inhibitors, ICIs), sin antecedentes de diabetes mellitus (DM), ingresaron al Servicio de Urgencias con poliuria, polidipsia y pérdida de peso, y diagnóstico de cetoacidosis diabética, sin evidencia clínica de infección. Fueron tratados con líquidos e infusión de insulina pasando luego a un régimen de insulina bolo basal que continuó después del alta. Las pruebas de detección de autoanticuerpos para DM resultaron negativas, y se les diagnosticó DM inducida por ICIs, pembrolizumab en dos de ellos y nivolumab en el otro. El propósito de esta serie de casos es demostrar el desarrollo de la DM1 en forma aguda en pacientes tratados con inhibidores de PD-1. Sobre la base de estos casos y la literatura revisada, se buscaron determinar las características clínicas, y sugerir estrategias para la identificación, control, tratamiento precoz y seguimiento de los pacientes tratados con ICIs a fin de minimizar el impacto de la disfunción autoinmune.

Three patients with advanced cancer, treated with inmune checkpoint inhibitors (ICIs), with no history of diabetes mellitus (DM), were admitted to the Emergency Department with polyuria, polydipsia, and weight loss and a diagnosis of diabetic ketoacidosis without clinical evidence of infection. They were treated with fluids and insulin infusion transitioning to a basal-bolus insulin regimen, which continued after discharge. Autoantibody detection tests for DM were negative and they were diagnosed with DM induced by ICIs, pembrolizumab in two of them, and nivolumab in another. The purpose of this case report is to show the development of DM1 in an acute form in patients treated with PD-1 inhibitors. Based on these cases and the reviewed literature, we seek to identify clinical characteristics and suggest strategies for the proper identification, control, treatment, and follow-up of patients treated with ICIs to minimize the impact of autoimmune dysfunction.

Inmunoterapia para el tratamiento del cáncer de cabeza y cuello ¿dónde estamos y hacia dónde vamos? / Immunotherapy for the treatment of head and neck cancer: where are we and where are we going?

El cáncer de cabeza y cuello comprende a todos aquellos tumores que se desarrollan en el tracto aerodigestivo superior, una de las características de éstos es su diversidad, que no es solo desde el punto de vista histológico y etiológico, sino que incluyen diversas formas de presentación, progresión y enfoques terapéuticos. Son de causa multifactorial, siendo el alcohol y el tabaco los principales factores de riesgo asociados; en los últimos años se ha relacionado a ciertos virus con potencial oncogénico con la génesis tumoral, entre ellos al Virus del Papiloma Humano, lo que ha permitido modificar el sistema de estadificación tumor primario-nodos linfáticos cancerosos-metástasis (TNM); presentándolo ahora en dos grandes grupos acorde a la Proteína supresora de tumores P16: P16+ y P16-,los cuales tienen características y manejo diferente. En vista de la heterogeneidad de la enfermedad, son diversos los tratamientos que se ha empleados para el manejo de la misma, entre ellos cirugía, radioterapia, quimioterapia e/o inmunoterapia; ésta última terapéutica, está dirigida hacia la estimulación del sistema inmune del paciente con la finalidad de generar la destrucción de las células tumorales, se realizan previo a una intervención quirúrgica para reducir el tamaño del tumor. Una forma destacable, es la del bloqueo de puntos de control inmunitarios, especialmente hacia proteínas de control inmune moduladoras de respuesta de células T, como los anti-PD-1 y los anti-CTLA-4. La inmunoterapia cada vez va tomando más protagonismo en oncología, en especial las formas de evasión de las reacciones inmunitarias por parte de las células cancerígenas(AU)

Head and neck cancer includes all those tumors that develop in the upper aerodigestive tract, one of the characteristics of these is their heterogeneity, which is not only from the histological and etiological, but also include various forms of presentation, progression and therapeutic approaches.They have a multifactorial cause, with alcohol and tobacco being the main associated risk factors, however, in recent year scertain viruses with oncogenic potential have been linked to tumor genesis, including HPV, which has made it possible tomodify the TNM staging system; now presenting it in two large groups, P16+ and P16-, which have different characteristics and management. In view of the heterogeneity of the disease, there are various treatments that have been used to manageit, including surgery, radiotherapy, chemotherapy and/ orimmunotherapy which will be determined taking into account the location and tumor extension. The latter treatment, is aimedat stimulating the patient's immune system in order to generate the destruction of tumor cells, are performed prior to a surgical intervention to reduce the size of the tumor. A remarkable therapy is that of blocking immune checkpoints, especially anti-PD-1 and anti-CTLA. Immunotherapy is becoming more and more prominent, however, there is still much to discover, so we believe that we should continue investigating the ways of evasion of immune reactions by cancer cells(AU)

Cetoacidosis diabética como debut de diabetes mellitus inmunomediada en paciente en tratamiento con inhibidores de checkpoint / Diabetic ketoacidosis as debut of immune-mediated diabetes mellitus in a patient in treatment with immune checkpoint inhibitors

Los inhibidores de checkpoint (ICP) son anticuerpos usados en inmunoterapia contra el cáncer. Uno de sus blancos de acción es el receptor de muerte celular programada-1 (PD-1), el cual es importante para mantener la tolerancia inmunitaria. Sin embargo, este mecanismo se asocia a riesgo de eventos adversos relacionados a la inmunidad que pueden afectar a múltiples órganos incluyendo el sistema endocrino. Se describe el caso inhabitual de un paciente que a los 18 meses de terapia con ICP debutó con cetoacidosis diabética (CAD).

Immune checkpoint inhibitors consist in antibodies used in immunotherapy against cancer. One of their targets is the programmed cell death-1 (PD-1) receptor, which is important in maintaining self-tolerance. However, this mechanism is associated with a risk for immune-related adverse events potentially affecting multiple organs, including the endocrine system. We describe the unusual case of a patient who, after 18 months of treatment with an immune checkpoint inhibitor, debuted with diabetic ketoacidosis

Supervivencia extendida con pembrolizumab en un paciente con cáncer de pulmón no microcítico estadio IV: Reporte de caso / Extendedsurvival with pembrolizumab in a patient with stage IV non-small cell lung cancer:A case report

Introducción:La inmunoterapia con pembrolizumab ha mejorado el pronóstico del cáncer de pulmón metastásico. En el presente caso se presenta la supervivencia extendidad y evolución de un paciente específico.Caso clínico:Hombre de 66 años, fumador. Diagnosticado de masa pulmonar en lóbulo infe-rior izquierdo de dimensiones 9 x 8 cm, con metástasis supra e infratentoriales intraaxiliares. Taller diagnóstico: Establecida como neoplasia de pulmón en estadio IVc, se comprobó el estado de PDL1 que positivo en un 80 % de la muestra de masa pulmonar. Debuta con me-tástasis cerebrales.Evolución: Se inció inmunoterapia con Pembrolizumab, el cual se mantubo hasta la presencia de un efecto secundario atribuido al pembrolizumab, cumpliendo 30meses de supervivencia hasta el cierre de esta observación no se reportó la muerte del paciente.Conclusiones:En el presente reporte, la determinación del biomarcador histológico PDL1 po-sitivo en cáncer de pulmón ayudo a prescribir un tratamiento con inmunoterpia dirigida, lo que demostró aumentar la supervivencia más allá que el tratamiento convencional con quimiote-rapia

Introduction: Immunotherapy with pembrolizumab has improved the prognosis of metastatic lung cancer. A specific patient's extended survival and evolution is presented in the present case.Clinical case: 66-year-old man, smoker. Diagnosed with a lung mass in the left lower lobe measuring 9 x 8 cm, with supra and infratentorial intra-axial metastases.Diagnostic workshop: To establisha stage IVc lung neoplasm, 80% of the lung mass sample was confirmed to be positive for PDL1.Evolution: Immunotherapy was started with Pembrolizumab, which was maintained until the presence of a side effect attributed to pembrolizumab, completing 30 months of survival until the closure of this observation, the patient's death was not reported.Conclusions: In the present report, the determination of the positive histological biomarker PDL1 in lung cancer helped prescribe treatment with targeted immunotherapy, which was shown to increase survival beyond conventional treatment with chemotherapy

CAR-T cell therapy for multiple myeloma: a practical toolkit for treatment in Brazil

ABSTRACT Introduction Chimeric antigen receptor T (CAR-T) cell therapy is an emerging treatment option for relapsed/refractory multiple myeloma (RRMM) that is a multi-step process involving various stakeholders. Appropriate education on the practical logistics is therefore paramount to ensure treatment success. Methods A group of key opinion leaders met to explore the key elements of setting up and running a CAR-T center in Brazil. For each step in the CAR-T cell therapy process, the experts agreed on basic requirements, gave their key recommendations from practical experience, and considered any remaining unanswered questions. Results This paper presents best-practice recommendations and advice on how to overcome common challenges for each step in the CAR-T cell therapy process, with a focus on the current situation in Brazil. Key themes throughout the process are collaboration within the multidisciplinary team and with the referring physician, along with communication and education for patients and their caregivers. Conclusion We believe that the expert insights presented in this paper, in particular on optimal patient selection and timing of CAR-T cell therapy, will deepen understanding of the CAR-T process and aid implementation of this novel therapy for patients with RRMM in Brazil.

Estudio exploratorio de eficacia de ivermectina combinada a α- PD-1 en cáncer colorrectal resistente a quimioinmunoterapia / EXPLORATORY EFFECTIVENESS STUDY OF IVERMECTIN COMBINED WITH α-PD-1 IN CHEMOTHERAPY RESISTANT COLORRECTAL CANCER

[RESUMEN]. Las terapias inmunológicas con inhibidores de checkpoints (ICIs) han revolucionado el abordaje del cáncer colorrectal (CCR), pero su efectividad se restringe a tumores inmunorreactivos con deficiencia en la reparación de errores tipo mismatch (dMMR). La ivermectina (IVM), un agente antiparasitario, se propone como posible estrategia terapéutica debido a su impacto en la muerte celular inmunogénica (MCI) y la reversión de resistencia a medicamentos. La investigación evaluó el efecto antineoplásico de IVM combinado con α-PD-1 empleando el modelo murino CT-26, una línea de CCR KRAS-mutada y competentes para MMR. El análisis bioinformático mediante la plataforma GEPIA2 empleandola base TCGA confirmó la expresión diferencial de blancos moleculares de IVM en tejido tumoral versus normal, siendo más alta en tumores con inestabilidad microsatelital baja (MSI-L)/microsatelital estable (MSS) que en inestabilidad microsatelital alta (MSI-H). En experimentos in vitro, CT-26 mostró alta sensibilidad a IVM (IC50: 11 µM, luego de exposición por 72 horas), alterando el metabolismo y aumentando la secreción de IL-6. El análisis proteómico identificó 17 proteínas sobreexpresadas y 8 inhibidas, relacionadas con evasión inmunológica y proliferación celular. En ratones BALB/c portadores de tumores CT-26, la terapia combinada de IVM y α-PD-1 redujo significativamente el crecimiento tumoral y la progresión metastásica. La preinmunización con células CT-26 tratadas con IVM disminuyó la incidencia y la progresión tumoral. IVM podría potenciar la respuesta a ICIs en tumores "fríos". Estos hallazgos sugieren que la combinación de IVM y α-PD-1 puede mejorar la inmunorreactividad y respuesta terapéutica en CCR.

[ABSTRACT]. Matrix Assisted Laser DesorptionIonization ­ Time of Flight ­ MassSpectrometry (MALDI-TOF-MS) has emerged as anoutstandingtechnique in thefieldofclinicalmicrobiology, with a simple methodology and deliveryof precise results in anexceptionally short timeframe. Thistechnology has garnered notable success in recentyears, establishing as a fundamental toolboth in thecharacterizationofmicroorganisms and translationalresearch.Thecombinationoftheinherentfeaturesofthistechniquewiththepotentialof machine learninganalysis has provento be ofgreatvalue in clinicalmicrobiology, particularly in theantibioticresistancefield. Itsapplication has acceleratedbacterial diagnosis and opened new perspectives in criticalareasof medicine, such sepsis and oncology. In Argentina, several research groups actively contributing to its expansión, applying MALDI-TOF-MS in the fight against infectious diseases, including the COVID-19 pandemic. Theseeffortspromiseto continue drivingresearch and clinical diagnosis in the country and worldwide.

Avaliação por imagem de medidas esplênicas e tímicas como biomarcadores de resposta em pacientes com câncer tratados com imunoterapia / Imaging evaluation of thymic and splenic measurements as response biomarkers in cancer patients treated with immunotherapy

INTRODUÇÃO: Em menos de duas décadas, a imunoterapia consolidou-se como um dos pilares do tratamento do câncer. Apesar da sua potencial elevada eficácia e resposta duradoura, a proporção de pacientes que apresentam resposta objetiva é relativamente baixa e existem poucos biomarcadores para selecionar os pacientes com maior potencial de resposta. OBJETIVO: Nossa hipótese era de que era possível avaliar globalmente o sistema imune do paciente através da mensuração por imagem do timo e do baço e usar essas métricas como fator prognóstico e preditivo de resposta a bloqueadores de checkpoint. RESULTADOS: Os principais resultados foram: 1) As medidas tímicas não se correlacionam com a sobrevida em pacientes tratados com imunoterapia; 2) Há aumento do volume esplênico após o uso de imunoterapia na maior parte dos pacientes, mas o grau de aumento não se correlaciona com resposta à terapia; 3) Maior volume esplênico está associado a pior sobrevida livre de progressão em pacientes com melanoma tratados com imunoterapia, mas essa correlação não pôde ser replicada em outros tipos tumorais. CONCLUSÃO: a espessura tímica não se correlaciona com desfechos clínicos em pacientes oncológicos tratados com imunoterapia. Menor volume esplênico antes de iniciar imunoterapia está relacionada a melhor prognóstico em pacientes com melanoma, mas não em outros tipos tumorais.

INTRODUCTION: In less than two decades, immunotherapy has established itself as one of the pillars of cancer treatment. Despite its potentially high efficacy and long-lasting response, the proportion of patients who have an objective response is relatively low and there are few biomarkers to select patients with the greatest response potential. OBJECTIVE: Our hypothesis was that it was possible to assess the patient's immune system globally by measuring the thymus and spleen by imaging and using these metrics as a prognostic and predictive factor of response to immune checkpoint inhibitors. RESULTS: The main results were: 1) Thymic measurements do not correlate with survival in patients treated with immunotherapy; 2) There is an increase in splenic volume after the use of immunotherapy in most patients, but the degree of increase does not correlate with response to therapy; 3) Greater splenic volume is associated with worse progression free survival in patients with melanoma treated with immunotherapy, but this correlation could not be replicated in other tumor types. CONCLUSION: thymic thickness does not correlate with clinical outcomes in cancer patients treated with immunotherapy. Smaller splenic volume before starting immunotherapy is associated with better prognosis in patients with melanoma, but not other tumor types

Comparação da fadiga relacionada ao câncer de pacientes em tratamento com imunoterápicos ou quimioterápicos / Comparison of cancer-related fatigue in patients undergoing treatment with immunotherapeutic or chemotherapeutic drugs

INTRODUÇÃO: A Fadiga Relaciona ao Câncer (FRC) é uma "sensação persistente e subjetiva de cansaço e esgotamento físico, emocional, e/ou cognitivo, relacionado com o câncer ou o tratamento do mesmo, que não é proporcional à atividade recente e que interfere na capacidade funcional". A FRC, que atinge até 80% dos pacientes, é relatada principalmente por pacientes em tratamento quimioterápico. OBJETIVO: Comparar a fadiga relacionada ao câncer de pessoas com tumores sólidos em tratamento com imunoterapia ou quimioterapia. METODOLOGIA: Foi um estudo observacional transversal analítico, em pacientes adultos, de ambos os sexos, com câncer sólido, que no momento da coleta estavam exclusivamente em tratamento com quimioterápicos ou imunoterápicos. Os voluntários foram separados em dois grupos: grupo Imunoterapia e grupo Quimioterapia. Os instrumentos de avaliação foram: questionário de Avaliação Funcional da Terapia de Doenças Crônicas ­ Fadiga (FACIT-F), que avalia a percepção de fadiga da pessoa em tratamento do câncer. A dinamometria com o dinamômetro Jamar® para avaliar força de preensão manual e teste de velocidade da marcha de 4 metros (VM4M) para avaliar a velocidade da marcha. RESULTADOS: Em relação a velocidade da marcha, o grupo imuno apresentou velocidade média de 1,43 m/s e o grupo quimio apresentou velocidade média de 1,41m/s. Esses resultados apresentam que os pacientes avaliados não apresentaram lentidão de marcha e não tem diferença estatística entre os grupos (p=0.43). Em relação à força de preensão manual, observamos que não tem diferença estatística entre os grupos estudados (p=0,13 mão direita e p=0,10 mão esquerda), porém observamos que o grupo Imunoterapia contém valores maiores de média e mediana para a força de preensão palmar em ambas as mãos, permitindo afirmar que nos pacientes estudados em tratamentos com imunoterápicos apresentaram maior força de preensão manual. Em relação ao inventário de fadiga observa-se que, na amostra estudada, a média do escore final comprova que o grupo Imunoterapia tem menor ocorrência de fadiga (p=0.01). CONCLUSÃO: Não houve diferença estatística entre os grupos na velocidade da marcha e na força de preensão manual. No inventário de fadiga o grupo imunoterapia apresentou menor ocorrência de fadiga com diferença significativa.

INTRODUTION: Cancer Relational Fatigue (CRF) is a "persistent and subjective feeling of tiredness and physical, emotional, and/or cognitive exhaustion, related to cancer or its treatment, which is not proportional to recent activity and which interferes in functional capacity". CRF that meets up to 80% of patients is mainly reported by chemotherapy treatment. Patients being treated with immunotherapics report less fatigue. OBJECTIVE: Compare cancer-related fatigue in people with solid tumors undergoing exclusive immmunotherapy or chemotherapy treatments. This was an observational, cross-sectional and analytical study conducted with adult patients of both genders. The volunteers were distributed in two groups, namely, Immunotherapy and Chemotherapy. The assessment instruments were as follows: Functional Assessment Questionnaire of Chronic Illness Therapy ­ Fatigue (FACIT-F), dynamometry with a Jamar® dynamometer to assess hand grip strength and the 4-meter gait speed (4MGS) test. RESULTS: In relation to gait speed, the Immunotherapy group presented a mean speed of 1.43 m/s while the mean speed in the Chemotherapy group was 1.41 m/s. These results indicate that the patients evaluated did not present low gait speed and do not statistically differ between the groups (p=0.43). In relation to hand grip strength, we did not observe any significant difference between the groups under study (p=0.13 right hand and p=0.10 left hand). However, we noticed that the Immunotherapy group has higher mean and median values for hand grip strength in both hands, allowing us to assert that the patients studied in immunotherapy treatments presented greater hand grip strength. In relation to the fatigue inventory, in the sample studied it is observed that the final score mean proves that the Immunotherapy group presents lower occurrence of fatigue (p=0.01). CONCLUSION: There was no statistical difference between the groups in gait speed and handgrip strength. In the fatigue inventory, the immunotherapy group had a lower occurrence of fatigue with a significant difference.

Uso de belimumabe em paciente com lúpus eritematoso sistêmico refratário ao tratamento convencional: relato de caso / Use of belimumab in a patient with systemic lupus erythematosus refractory to conventional treatment: case report

O lúpus eritematoso sistêmico (LES) é uma doença de caráter imunomediado, ocasionada por fatores hormonais, ambientais e genéticos. Caracteriza-se pela presença de autoanticorpos reativos para diferentes células e tecidos, apresentando manifestações clínicas diversificadas, períodos de exacerbação e remissão, o que dificulta o tratamento desses pacientes. Este relato de caso destaca o progresso do uso de anticorpo monoclonal humano em uma paciente do gênero feminino, diagnosticada com LES em maio de 2019, aos 30 anos, e, por ser refratária ao tratamento medicamentoso convencional, utilizou o tratamento com anticorpo monoclonal humano belimumabe, com início em setembro de 2019. O belimumabe é um anticorpo monoclonal humano que se liga à proteína estimuladora de linfócito B (BLyS) solúvel, inclusive dos autorreativos, e desta maneira, reduz a diferenciação de linfócitos B em plasmócitos, diminuindo os níveis de IgG sérica e dos anticorpos anti-dsDNA, além de melhorar o quadro clínico dos pacientes. Apesar de ser um medicamento biológico de alto custo, diminui drasticamente os sintomas clínicos do LES, possibilitando a redução do uso do corticoide e os efeitos consequentes de seu uso, além de reestabelecer os parâmetros laboratoriais alterados pela doença, sem alteração de indicadores hepáticos e renais. O LES não tem cura, logo, o objetivo do tratamento é diminuir os sintomas e conter as fases ativas da doença.

Systemic lupus erythematosus is an immune-mediated disease caused by hormonal, environmental and genetic factors. It is characterized by the presence of reactive autoantibodies to different cells and tissues, with diverse clinical manifestations and periods of exacerbation and remission, which complicates treatment. This case report highlights progress with the use of a human monoclonal antibody in a woman diagnosed with systemic lupus erythematosus in May 2019 (at age 30). Since she was refractory to conventional drugs, belimumab treatment was begun in September 2019. Belimumab is a human monoclonal antibody that binds to soluble B lymphocyte-stimulating proteins, including self-reactive ones, and reduces the differentiation of B lymphocytes into plasma cells, decreasing the serum IgG and anti-dsDNA antibody levels, in addition to improving patient clinical status. Despite being a high-cost biological drug, it drastically reduces the clinical symptoms of systemic lupus erythematosus, enabling reduced used of corticosteroids and their effects, in addition to reestablishing laboratory parameters altered by the disease, without changing liver and kidney indicators. Since systemic lupus erythematosus has no cure, the goal of treatment is to reduce symptoms and the active phases of the disease.

Gestión de riesgos aplicado al diseño de un nuevo proceso productivo de un inmunoterapéutico del Centro de Ingeniería Genética y Biotecnología / Risk management applied to the design of a new production process for an immunotherapeutic from the Center for Genetic Engineering and Biotechnology

El estudio expone las acciones dirigidas a la reducción de los riesgos en el diseño de un nuevo proceso de producción del ingrediente farmacéutico activo de un inmunoterapéutico producido en el Centro de Ingeniería Genética y Biotecnología. El análisis modal de fallas y efectos fue conducido por un equipo multidisciplinario del referido centro. La administración de riesgos a la calidad se aplicó a la tecnología de obtención de una proteína recombinante con uso diagnóstico que se proponía transferir a la Dirección de Desarrollo Tecnológico. El riesgo en el diseño de un nuevo proceso de producción evaluó las fallas de mayor influencia en el bajo recobrado y el incumplimiento de las especificaciones de calidad del inmunoterapéutico. Las causas potenciales de estos fallas fueron: la insuficiente cantidad de viales de los bancos de células, el medio de cultivo complejo con componentes de origen bovino, la incorrecta manipulación de las muestras por los operarios, el uso de equipamiento no adecuado, los parámetros de operación (agitación, pH y conductividad) fuera de límites de especificación con efecto sobre la pureza por el alto porcentaje de contaminantes del hospedero; así como, un medio filtrante inadecuado unido a una incorrecta preparación del sistema de filtración redundantes en un producto no estéril. Las acciones llevaron a modificaciones en la tecnología propuesta por la Dirección de Investigaciones Biomédicas que permitió el diseño de un nuevo proceso productivo para un biofarmacéutico destinado al tratamiento de enfermedades virales crónicas(AU)

The study aimed at reducing risks in the design of a new production process for the active pharmaceutical ingredient of an immunotherapeutic produced at the Center for Genetic Engineering and Biotechnology. The failure mode and effects analysis were conducted by a multidisciplinary team from the center. Quality risk management was applied to the technology for obtaining a recombinant protein for diagnostic use that was proposed to be transferred to Technological Development Division. The risk analyses evaluated the greatest influence on low recovery and non-compliance with the immunotherapeutic quality specifications. The potential causes of the failures were: the insufficient number of vials in cell banks, the complex culture medium with components of bovine origin, the samples handling errors by the operators, the use of inappropriate equipment, the parameters of operation (agitation, pH and conductivity) outside specification limits affecting purity due to the high percentage of contaminants from the host; as well as, the inadequate filtering medium together with an incorrect preparation of the redundant filtration system in a non-sterile product. The actions could modify the technology proposed by Biomedical Research Division that allowed the design of a new production process of a biopharmaceutical product for the treatment of chronic viral diseases(AU)

Manejo multidisciplinario de las metástasis cerebrales: una revisión actualizada y un cambio de paradigma / Multidisciplinary management of brain metastases: An updated review and paradigm shift

Introducción: Las metástasis cerebrales (MC) representan una problemática importante de la salud pública, en promedio el 30% de los pacientes oncológicos desarrollarán MC siendo importante causa de morbilidad, ansiedad y mortalidad. El tratamiento con radioterapia, cirugía y sistémico son los pilares para el tratamiento y han tenido una evolución importante en la última década. Propósito de la revisión: Se proporciona información actualizada en relación a epidemiología, diagnóstico, pronóstico y tratamiento de metástasis cerebrales desde un enfoque multidisciplinariopara lograr individualizar su abordaje con el objetivo de proporcionar control oncológico y calidad de vida. También se discuten el acceso a nuevas terapias sistémicas, técnicas quirúrgicas y disponibilidad de tecnología para ofrecer técnicas avanzadas de radioterapia.Men saje principal: Conocer mutaciones específicas y receptores diana de los tumores permite elegir quimio-inmunoterapia o terapias dirigidas actuales que ofrecen mejor potencial de control tanto a nivel sistémico como intracraneal. La secuenciación de los tratamientos sistémicos y locales (cirugía, radio-cirugía, radioterapia holocraneal) deben ser discutidos desde un enfoque multidisciplinario Conclusión: Es importante poder estimar el pronóstico de los pacientes con MC, esto determinarla conducta terapéutica que puede variar desde cuidados sintomáticos hasta tratamientos más agresivos como resección neuroquirúrgica o radiocirugía.

In troduction:Brain metastases (BMs) represent a significant public health problem. An average of 30% of cancer patients develop BM, which is a significant cause of morbidity, anxiety, and mortality. Radio-therapy, surgery, and systemic treatment are the mainstays of treatment and have evolved significantly in the last decade.Pu rpose of the review: Updated information on the epidemiology, diagnosis, prognosis, and treatment of brain metastases from a multidisciplinary approach is provided to enable an individualized approach aimed at cancer control and quality of life. Access to new systemic therapies, surgical techniques, and availability of technology for advanced radiotherapy techniques are also discussed.Mai n message: Knowledge of specific mutations and targets of tumor receptors allows the selection of chemoimmunotherapy or current targeted therapies that offer better control potential at the systemic and intracranial levels. The sequence of systemic and local treatments (surgery, radiosurgery, whole brain radiation therapy) should be discussed as part of a multidisciplinary approach.C o nclusion: It is essential to estimate the prognosis of patients with BM, given that this will determine the therapeuticbehavior that can range from symptomatic care to more aggressive treatments such as neurosurgical resection or radiosurgery

House dust mite fauna characterization in the city of Rio de Janeiro and its importance in allergy diagnosis / Caracterização da fauna dos ácaros de poeira na cidade do Rio de Janeiro e sua importância em diagnósticos de alergias

Introduction: The home environment is one of the most favorable spaces for the development of mites because of its low light, humidity, and temperature. Thus, it contributes to the growing cases of allergies among atopic individuals. Objective: To investigate the faunal profile of house dust mites in the city of Rio de Janeiro and the allergenic potential in this region. Methods: Thirty dust samples were collected from homes in the city of Rio de Janeiro, and the species found were classified according to their morphology, family, and genus by classification key. For the collection region, the total protein level was assessed by the Lowry method and electrophoresis under denaturing conditions (SDSPAGE). Results: There was a predominance of Pyroglyphidae mites, accounting for 84.9% of samples; Tyrophagus putrescentiae accounted for 8%, Blomia tropicalis for 6%, Cheyletus malaccensis for 1%, and Acarus siro for 0.1%. The allergen protein content of the samples was the following: group 1 ­ 25 kDa (Der 1, Der p 1, and Blo t 1), group 2 ­ 15 kDa (Der f 2, Der 2, Tyr p 2, and Blo t 2), and group 3 ­ 29-30 kDa (Der f 3 and Blo t 3), which indicates that people in this region are susceptible to sensitization to these mites. Conclusion: Knowledge of the mite fauna in the region under study allows the guidance of health care professionals to perform skin tests for specific mites and conduct treatment according to the pool of mite extracts containing antigens, making immunotherapy more effective.

Introdução: O ambiente domiciliar é um dos espaços favoráveis para o desenvolvimento de ácaros, tendo em vista a baixa luminosidade, umidade e temperatura, o que contribui para os crescentes casos de alergias em indivíduos atópicos. Objetivo: Investigar o perfil faunístico dos ácaros na cidade do Rio de Janeiro e o potencial alergêncio para essa região. Métodos: Foram coletadas 30 amostras de poeira em residências na cidade do Rio de Janeiro, e as espécies encontradas foram classificadas quanto à morfologia, família e o gênero por chave de classificação. Para as regiões das coletas, a carga total de proteínas contendo os alérgenos foi determinada pelo método de Lowry e eletroforese em condições desnaturantes (SDS-PAGE). Resultados: Os resultados mostram a predominância de 84,9% de ácaros da família Pyroglyphidae; para os demais ácaros o percentual corresponde a 8% Tyrophagus putrescentiae, 6% Blomia tropicalis, 1% Cheyletus malaccensis, e 0,1% de Acarus siro. O conteúdo proteico alergêncio constituinte das amostras foram, grupo 1: 25 kDa (Der 1, Der p 1 e Blo t 1); grupo 2: 15 kDa (Der f 2, Der 2, Tyr p 2 e Blo t 2); e para o grupo 3: 29-30 kDa (Der f 3 e Blo t 3), o que indica uma região passível à sensibilização de indivíduos por estes ácaros. Conclusão: O conhecimento da acarofauna nas regiões em estudo permite orientar a comunidade médica quanto à realização de testes cutâneos, além da terapêutica a partir do pool de extratos de ácaros contendo os antígenos, a fim de tornar a imunoterapia mais eficaz.

Diretriz Latino-americana sobre o Diagnóstico e Tratamento da Alergia Ocular ­ Em nome da Sociedade Latinoamericana de Alergia, Asma e Imunologia (SLAAI) / Latin American Guideline on the Diagnosis and Treatment of Ocular Allergy ­ On behalf of the Latin American Society of Allergy, Asthma and Immunology (SLAAI)

A alergia ocular, também conhecida como conjuntivite alérgica (CA), é uma reação de hipersensibilidade mediada por imunoglobulina E (IgE) do olho desencadeada por aeroalérgenos, principalmente ácaros da poeira doméstica e pólen de gramíneas. Os sintomas geralmente consistem em prurido ocular ou periocular, lacrimejamento e olhos vermelhos que podem estar presentes durante todo o ano ou sazonalmente. A alergia ocular tem frequência elevada, é subdiagnosticada e pode ser debilitante para o paciente. É potencialmente danosa para a visão, nos casos em que ocasiona cicatrização corneana grave, e na maioria dos pacientes associa-se a outros quadros alérgicos, principalmente rinite, asma e dermatite atópica. É classificada em conjuntivite alérgica perene, conjuntivite alérgica sazonal, ceratoconjuntivite atópica e ceratoconjuntivite vernal. O diagnóstico procura evidenciar o agente etiológico e a confirmação se dá pela realização do teste de provocação conjuntival. O tratamento baseia-se em evitar o contato com os desencadeantes, lubrificação, anti-histamínicos tópicos, estabilizadores de mastócitos, imunossupressores e imunoterapia específica com o objetivo de obter o controle e prevenir as complicações da doença.

Ocular allergy, also known as allergic conjunctivitis, is an immunoglobulin E-mediated hypersensitivity reaction of the eye triggered by airborne allergens, primarily house dust mites and grass pollen. Symptoms usually consist of ocular or periocular itching, watery eyes, and red eyes that may be present year-round or seasonally. Ocular allergy has a high frequency, is underdiagnosed, and can be debilitating for the patient. It is potentially harmful to vision in cases of severe corneal scarring, and in most patients, it is associated with other allergic conditions, especially rhinitis, asthma, and atopic dermatitis. It is classified as perennial allergic conjunctivitis, seasonal allergic conjunctivitis, atopic keratoconjunctivitis, and vernal keratoconjunctivitis. Diagnosis seeks to identify the etiologic agent, and confirmation is given by conjunctival provocation testing. Treatment is based on avoiding contact with triggers, lubrication, topical antihistamines, mast cell stabilizers, immunosuppressants, and specific immunotherapy with the aim of achieving control and preventing disease complications.

La inhibición de los puntos de control inmunológico, una terapia en evolución: remembranza del Premio Nobel de Medicina 2018 / Immune checkpoint inhibitors: a breakthrough in cancer therapy

Professors James P. Allison and Tasuku Honjo were awarded with the 2018 Nobel Prize in Medicine for their contributions in cancer immunotherapy. The latter is a breakthrough in cancer therapy, aimed to overcome tumor-induced immunosuppression, leading to the reactivation of the immune system against cancer cells. Under physiological conditions, the CTLA-4 and PD-1 proteins expressed on T-cells and discovered by the awarded scientists, lead to immune tolerance. Cancer cells exploit these control points to enhance the inhibition of T-cells. The expression of PD ligands (PD-L1) in tumor cells and CTLA-4 ligands in antigen presenting cells, which bind the PD-1 receptor and CTLA-4 respectively, block anti-tumor immunity. This situation led to a biotechnological race focused on the development of effective antibodies able to "turn-on" the immune system cheated by the tumor. Anti-CTLA-4 and anti-PD-1 antibodies improve life-expectancy in cancer patients. In this review, we perform an historical overview of Professors Allison and Honjo contribution, as well as the immunological basis of this new and powerful therapeutic strategy, highlighting the clinical benefits of such intervention.