Tratamiento y evolución de la encefalitis inmunomediada en edad pediátrica, serie de casos / Treatment and outcome of immune-mediated encephalitis in children, a case series

Introducción: La encefalitis por anticuerpos contra el receptor N-metil.D.aspartato (NMDA-R) es un trastorno inflamatorio del sistema nervioso central (SNC) en el cual autoanticuerpos dirigidos hacia la subunidad NR1 del receptor N-metil-D aspartato (NMDA) desarrollan un conjunto de síntomas neuropsiquiátricos, convulsiones y movimientos anormales. El tratamiento recomendado incluye metilprednisolona (MP) y gamaglobulina (IVIg), y/o recambio plasmático terapéutico (RPT); y en caso de no respuesta: rituximab (RTX) y/o ciclofosfamida (CFM). Objetivos: Analizar características clínicas, bioquímicas, electroencefalograma (EEG), resonancia magnética (RM) cerebral, tratamientos recibidos y resultados observados en una serie de pacientes con encefalitis autoinmune (EA) probable o confirmada. Materiales y métodos: Analizamos las historias clínicas de pacientes menores a 17 años que cumplían criterios diagnósticos de Graus (2016) para EA probable, con seguimiento mayor a 6 meses, internados en el Hospital Garrahan entre 2008 y 2023. El diagnóstico se definió por la identificación de anticuerpos anti-NMDAR (N-metil D-aspartato) en líquido cefalorraquídeo (LCR) por ensayo basado en células - cell bassed assay (CBA). Resultados: Reunieron criterios de EA probable 94 pacientes con una edad media de 89.5 meses, 51% mujeres. Se dividieron en dos grupos: seropositivos y seronegativos de acuerdo al resultado del biomarcador. Seropositivos 45/94. El síntoma inicial más frecuente fue: convulsiones. El 28% requirió ingreso a Unidad de Cuidados Intensivos (UCI). 4 pacientes seropositivos y 1 seronegativo tuvieron encefalitis por el virus del herpes simple (Om) previamente. En una paciente seronegativa se diagnosticó teratoma ovárico. Hallazgos de estudios complementarios: LCR patológico en el 29%, RM cerebral en el 52%, EEG en el 74%. El tratamiento de primera línea más empleado fue MP + IVIg. El 46% de los pacientes presentó recuperación completa. Entre los pacientes que recibieron RTX, el 65% tuvo una recuperación completa. Ningún paciente que recibió RTX presentó recaída. Conclusión: Ante la sospecha de EA se debe considerar el inicio temprano de inmunoterapia para favorecer la rápida recuperación funcional. Se recomienda el uso temprano de RTX en los casos con presentación grave o respuesta subóptima al tratamiento de primera línea para beneficiar la respuesta clínica y reducir el riesgo de recaída (AU)

Introduction: Encephalitis due to antibodies against the N-methyl-D-aspartate receptor (NMDA-R) is an inflammatory disorder of the central nervous system (CNS) in which autoantibodies directed against the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor develop a set of neuropsychiatric symptoms, seizures, and abnormal movements. The recommended treatment includes methylprednisolone (MP) and intravenous immunoglobulin (IVIg), and/or therapeutic plasma exchange (TPE); and in case of non-response: rituximab (RTX) and/or cyclophosphamide (CFM). Objectives: To analyze clinical, biochemical, electroencephalogram (EEG), magnetic resonance imaging (MRI) of the brain, treatments received, and outcomes observed in a series of patients with probable or confirmed autoimmune encephalitis (AE). Materials and methods: We analyzed the medical records of patients under 17 years of age who met Graus' diagnostic criteria (2016) for probable AE, with follow-up of more than 6 months, hospitalized at Hospital Garrahan between 2008 and 2023. Diagnosis was defined by the identification of anti-NMDAR antibodies (N-methyl D-aspartate) in cerebrospinal fluid (CSF) by cell-based assay (CBA). Results: Ninety-four patients met criteria for probable AE with a mean age of 89.5 months, 51% female. They were divided into two groups: seropositive and seronegative according to the biomarker result. Seropositive 45/94. The most frequent initial symptom was seizures. Twenty-eight percent required admission to the Intensive Care Unit (ICU). Four seropositive patients and one seronegative patient had previously had herpes simplex encephalitis (Om). Ovarian teratoma was diagnosed in one seronegative patient. Findings of complementary studies: Pathological CSF in 29%, brain MRI in 52%, EEG in 74%. The most commonly used first-line treatment was MP + IVIg. Forty-six percent of patients experienced complete recovery. Among patients who received RTX, 65% had complete recovery. No patient who received RTX experienced relapse. Conclusion: In the suspicion of AE, early initiation of immunotherapy should be considered to promote rapid functional recovery. Early use of RTX is recommended in cases with severe presentation or suboptimal response to first-line treatment to benefit clinical response and reduce the risk of relapse (AU)

Significados atribuídos por mulheres com câncer de mama ao grupo de apoio / Meanings attributed by women with breast cancer to a support group / Significados atribuidos por las mujeres con cáncer de mama al grupo de apoyo

A sobrevivência ao câncer de mama é um problema de saúde pública que demanda serviços especializados com foco na reabilitação psicossocial. Entre as necessidades identificadas nesse contexto está o incentivo à adoção de estratégias de promoção de autocuidados pelas mulheres. Uma das estratégias adotadas consiste no grupo de apoio psicológico, que auxilia as pacientes a enfrentar a longa jornada do tratamento. Assim, o objetivo deste estudo é compreender os significados produzidos por mulheres com câncer de mama sobre sua participação em um grupo de apoio. Trata-se de um estudo qualitativo, descritivo e exploratório realizado com dez mulheres com câncer de mama usuárias de um serviço de reabilitação para mastectomizadas. Como referencial metodológico foi utilizada a Teoria Fundamentada nos Dados. A coleta de dados foi realizada por meio de entrevista aberta em profundidade e os conteúdos foram transcritos e codificados. A análise indutiva e o método de comparação constante foram aplicados nos processos de codificação aberta, axial e seletiva, que permitiram identificar três categorias nucleares: percepção das atividades realizadas no grupo, identificação de benefícios e barreiras do convívio no grupo e transformações decorrentes da participação. As participantes significaram sua presença no grupo como fonte de acolhimento, apoio, desenvolvimento de recursos pessoais e amizades, contribuindo para promover sua qualidade de sobrevida. Além dos potenciais benefícios, também foram identificadas barreiras que podem dificultar a adesão e continuidade da participação no grupo, o que sugere a necessidade de incorporar no cuidado um olhar para as dimensões subjetivas da saúde da mulher.(AU)

Surviving breast cancer is a public health problem and depends on services focused on psychosocial rehabilitation. Healthcare providers must encourage women to adopt strategies to promote their self-care. The psychological support group is a resource that helps women to face the long journey of treatment. This study aimed to understand the meanings women with breast cancer produced about their participation in a support group. This exploratory cross-sectional study was carried out with 10 women with breast cancer who use a rehabilitation service for mastectomized patients. Grounded Theory was used as a methodological reference. An open in-depth interview was applied for data collection. The contents were transcribed and coded. Inductive analysis and the constant comparison method were applied in the open, axial, and selective coding processes, which enabled the identification of three core categories: perception of the activities carried out in the group, identification of benefits and barriers of living in the group, and transformations resulting from participation. Participants denote their involvement with the group as a source of shelter, support, development of personal resources and friendships that helps promoting quality of life. Besides these potential benefits, participants also evinced barriers that can hinder adherence and continuity of participation in the group, suggesting the importance of incorporating a look at the subjective dimensions of women's health into care.(AU)

Sobrevivir al cáncer de mama es un problema de salud pública que depende de los servicios centrados en la rehabilitación psicosocial. Entre las necesidades identificadas en esta materia se encuentra el uso de estrategias para promover el autocuidado. Uno de los recursos que ayuda a afrontar el largo camino del tratamiento es el grupo de apoyo psicológico. El objetivo de este estudio es conocer los significados que producen las mujeres con cáncer de mama sobre su participación en un grupo de apoyo. Se trata de un estudio cualitativo, descriptivo y exploratorio, realizado con diez mujeres con cáncer de mama usuarias de un servicio de rehabilitación para mastectomizadas. Como referencia metodológica se utilizó la teoría fundamentada en los datos. Se aplicó una entrevista abierta en profundidad para la recogida de datos, cuyos contenidos fueron transcritos y codificados. El análisis inductivo y el método de comparación constante se aplicaron en los procesos de codificación abierta, axial y selectiva, lo que permitió identificar tres categorías centrales: percepción de las actividades realizadas en el grupo, identificación de los beneficios y las barreras de vivir en el grupo y transformaciones resultantes de la participación. Las mujeres denotan su participación en el grupo como una fuente de acogida, apoyo, desarrollo de recursos personales y amistades, que ayuda a promover la calidad de vida. Además de los beneficios potenciales, también se identificaron barreras que pueden dificultar la adherencia y continuidad de la participación en el grupo, lo que sugiere la necesidad de incorporar en la atención una mirada centrada en las dimensiones subjetivas de la salud de las mujeres.(AU)

γδ T cells: Major advances in basic and clinical research in tumor immunotherapy / 中华医学杂志(英文版)

γδ T cells are a kind of innate immune T cell. They have not attracted sufficient attention because they account for only a small proportion of all immune cells, and many basic factors related to these cells remain unclear. However, in recent years, with the rapid development of tumor immunotherapy, γδ T cells have attracted increasing attention because of their ability to exert cytotoxic effects on most tumor cells without major histocompatibility complex (MHC) restriction. An increasing number of basic studies have focused on the development, antigen recognition, activation, and antitumor immune response of γδ T cells. Additionally, γδ T cell-based immunotherapeutic strategies are being developed, and the number of clinical trials investigating such strategies is increasing. This review mainly summarizes the progress of basic research and the clinical application of γδ T cells in tumor immunotherapy to provide a theoretical basis for further the development of γδ T cell-based strategies in the future.

A Cocktail of Natural Compounds Holds Promise for New Immunotherapeutic Potential in Head and Neck Cancer / 中国结合医学杂志

OBJECTIVE@#To obtain detailed understanding on the gene regulation of natural compounds in altering prognosis of head and neck squamous cell carcinomas (HNSC).@*METHODS@#Gene expression data of HNSC samples and peripheral blood mononuclear cells (PBMCs) of HNSC patients were collected from Gene Expression Omnibus (GEO). Differential gene expression analysis of GEO datasets were achieved by the GEO2R tool. Common differentially expressed gerres (DEGs) were screened by comparing DEGs of HNSC with those of PBMCs. The combination was further analyzed for regulating pathways and biological processes that were affected.@*RESULTS@#Totally 110 DEGs were retrieved and identified to be involved in biological processes related to tumor regulation. Then 102 natural compounds were screened for a combination such that the expression of all 110 commonly DEGs was altered. A combination of salidroside, ginsenoside Rd, oridonin, britanin, and scutellarein was chosen. A multifaceted, multi-dimensional tumor regression was showed by altering autophagy, apoptosis, inhibiting cell proliferation, angiogenesis, metastasis and inflammatory cytokines production.@*CONCLUSIONS@#This study has helped develop a unique combination of natural compounds that will markedly reduce the propensity of development of drug resistance in tumors and immune evasion by tumors. The result is crucial to developing a combinatorial natural therapeutic cocktail with accentuated immunotherapeutic potential.

Research Progress of Granulocytic Myeloid-derived Suppressor Cells in Non-small Cell Lung Cancer / 中国肺癌杂志

Granulocytic myeloid-derived suppressor cells (G-MDSCs) are one of the main subgroups of MDSCs, which are widely enriched in most cancers. It can inhibit the killing function of T-lymphocyte through the expression of arginase-1 (Arg-1) and reactive oxygen species (ROS), reshape the tumor immune microenvironment, and promote the occurrence and development of tumors. In recent years, more and more studies have found that G-MDSCs are significantly correlated with the prognosis and immunotherapy efficacy of patients with non-small cell lung cancer, and the use of drugs specifically targeting the recruitment, differentiation and function of G-MDSCs can effectively inhibit tumor progression. This article reviews the immunosuppressive effect of G-MDSCs in non-small cell lung cancer and the progress of related pathway targeting drugs.
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Progress of Immunotherapy in EGFR-mutated Advanced Non-small Cell Lung Cancer / 中国肺癌杂志

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are currently the first-line standard of care for patients with non-small cell lung cancer (NSCLC) that harbor EGFR mutations. Nevertheless, resistance to EGFR-TKIs is inevitable. In recent years, although immune checkpoint inhibitors (ICIs) have significantly shifted the treatment paradigm in advanced NSCLC without driver mutation, clinical benefits of these agents are limited in patients with EGFR-mutated NSCLC. Compared with wild-type tumors, tumors with EGFR mutations show more heterogeneity in the expression level of programmed cell death ligand 1 (PD-L1), tumor mutational burden (TMB), and other tumor microenvironment (TME) characteristics. Whether ICIs are suitable for NSCLC patients with EGFR mutations is still worth exploring. In this review, we summarized the clinical data with regard to the efficacy of ICIs in patients with EGFR-mutated NSCLC and deciphered the unique TME in EGFR-mutated NSCLC.
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Predictive Value of Peripheral Blood Biomarkers in the Treatment of Lung Cancer Patients with Anti PD-1 Immunotherapy / 中国肺癌杂志

BACKGROUND@#The application of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) antibodies has greatly improved the clinical outcomes of lung cancer patients. Here, we retrospectively analyzed the efficacy of PD-1 antibody therapy in locally advanced non-surgical or metastatic lung cancer patients, and preliminarily explored the correlation between peripheral blood biomarkers and clinical responses.@*METHODS@#We conducted a single center study that included 61 IIIA-IV lung cancer patients who received PD-1 antibody treatment from March 2020 to December 2021, and collected the medical record data on PD-1 antibody first-line or second-line treatment. The levels of multiple Th1 and Th2 cytokines in the patient's peripheral blood serum, as well as the phenotype of peripheral blood T cells, were detected and analyzed.@*RESULTS@#All the patients completed at least 2 cycles of PD-1 monoclonal antibody treatment. Among them, 42 patients (68.9%) achieved partial response (PR); 7 patients (11.5%) had stable disease (SD); and 12 patients (19.7%) had progressive disease (PD). The levels of peripheral blood interferon gamma (IFN-γ) (P=0.023), tumor necrosis factor α (TNF-α) (P=0.007) and interleukin 5 (IL-5) (P=0.002) before treatment were higher in patients of the disease control rate (DCR) (PR+SD) group than in the PD group. In addition, the decrease in absolute peripheral blood lymphocyte count after PD-1 antibody treatment was associated with disease progression (P=0.023). Moreover, the levels of IL-5 (P=0.0027) and IL-10 (P=0.0208) in the blood serum after immunotherapy were significantly increased compared to baseline.@*CONCLUSIONS@#Peripheral blood serum IFN-γ, TNF-α and IL-5 in lung cancer patients have certain roles in predicting the clinical efficacy of anti-PD-1 therapy. The decrease in absolute peripheral blood lymphocyte count in lung cancer patients is related to disease progression, but large-scale prospective studies are needed to further elucidate the value of these biomarkers.

Research progress on immunotherapy based on NK cells for hepatocellular carcinoma / 细胞与分子免疫学杂志

Hepatocellular carcinoma (HCC) is well characterized as a heterogeneous disease. Its late-stage diagnosis and chemotherapy resistance make it one of the refractory tumors in China. Natural killer (NK) cells play a significant role in immune surveillance. However, NK cells become dysfunctional in the progression of HCC, leading to tumor immune escape. This article reviews the recent progress on different strategies of NK cell-based immunotherapy in treating HCC, including direct adoptive NK cell transfer, gene engineering in NK cell, NK cell receptor targeting, immunosuppressive microenvironment modification, and tumor toxicity enhancement by cytokines or traditional Chinese medicine. These NK cell-based strategies have shown promising therapeutic potential.

Progress in targeted inhibition of aerobic glycolysis combined with immunotherapy for renal cell carcinoma / 细胞与分子免疫学杂志

Tumor aerobic glycolysis is one of the main features of tumor metabolic reprogramming. This abnormal glycolytic metabolism provides bioenergy and biomaterials for tumor growth and proliferation. It is worth noting that aerobic glycolysis will not only provide biological materials and energy for tumor cells, but also help tumor cells to escape immune surveillance through regulation of immune microenvironment, thereby resisting tumor immunotherapy and promoting tumor progression. Based on the pathogenesis of renal cell carcinoma, this paper describes the characteristics of aerobic glycolysis, the effect of glycolytic metabolism on the immune microenvironment of renal cell carcinoma, the effect of glycolysis inhibitors on the immune microenvironment of renal cell carcinoma, and the prospect of glycolysis inhibitors combined with immune checkpoint inhibitors in the treatment of renal cell carcinoma.

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)

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.

Inibidores epigenéticos como reguladores de linfócitos T CD8+ humanos / Epigenetic inhibitors as regulators of human CD8 T lymphocytes

Linfócitos T CD8 são células chave na resposta antitumoral. Uma vez ativadas, sofrem mudanças epigenéticas, adquirem fenótipos distintos e sua função está ligada ao potencial citotóxico e produção de mediadores inflamatórios. Porém, na resposta antitumoral, tais células encontram-se disfuncionais. Assim, estratégias capazes de reprogramar as células TCD8 podem aumentar sua eficácia. Inibidores epigenéticos são capazes de modular o perfil de células T CD4, mas os efeitos em células T CD8 ainda não estão totalmente esclarecidos. Portanto, buscamos identificar possíveis inibidores epigenéticos que sejam capazes de modular a atividade e o perfil fenotípico de linfócitos T CD8. Para tal, células T CD8 foram isoladas por sorting a partir de PBMC de doadores saudáveis e cultivados em placas de 96 poços na presença de coquetel de ativação (DynaBeads anti-CD3/CD28, IFN- e IL-2 recombinantes) e 1µM de diferentes inibidores epigenéticos (MS023, A485, L-MOSES, A-196, GSKLSD1, A366). Linfócitos T CD8 não estimulados e linfócitos T CD8 ativados na ausência de inibidores epigenéticos foram utilizados como controles. Após 4 ou 8 dias de cultura, as células foram coletadas e analisadas por citometria de fluxo para avaliação de marcadores ligados à ativação (CD69), função (IFN- e granzima B), diferenciação (CCR7, CD45RA) e exaustão (PD-1, TIGIT). As células foram adquiridas no citômetro de fluxo BD FACSymphony A5, e a análise estatística foi feita através do software GraphPad Prism 9. Realizamos ensaios in vitro nos quais células T CD8 foram ativadas na presença ou não de diferentes inibidores, com um deles apresentando intenso potencial de modular células T CD8: o A485, um inibidor seletivo do bromodomínio p300/CBP. Os nossos dados mostram que o A485 aumentou a ativação celular, evidenciado pelo aumento da frequência de células TCD8+CD69+. Este inibidor também foi capaz de modular o fenótipo de memória das células T, polarizando-as para um perfil TN/TSCM, diferentemente do controle e dos outros inibidores, que induziram um perfil TEM (células T efetoras de memória). Após oito dias, o tratamento com o inibidor A485 resultou em menor frequência de células PD-1+ e de células TIGIT+ em comparação com o controle. De relevância clínica, o inibidor A485 foi capaz de modular células CAR-T anti-CD19 isoladas de produtos de infusão, aumentando a frequência do marcador CD69 e modulando seu perfil fenotípico, menos diferenciado, em comparação ao controle. Além disso, o inibidor A485 potencializou a ação antitumoral das células CAR-T anti-CD19 em ensaios de co-cultura com a linhagem celular Daudi CD19+. Em resumo, os nossos dados mostram que a inibição de p300/CBP induz um perfil TN/TSCM em células T CD8 ativadas e em células CAR-T, potencializando as suas atividades antitumorais. Posto que a retenção do perfil TN/TSCM favorece o controle tumoral, esses achados podem ter implicações clínicas para pacientes com doenças hematológicas e com tumores sólidos.

CD8 T lymphocytes are key cells for the induction of antitumor responses. Once activated, these cells undergo epigenetic changes, acquire distinct phenotypes, and their function is linked to the production of cytotoxic and inflammatory mediators. However, these cells are dysfunctional within the tumor microenvironment. Therefore, strategies capable of reprogramming CD8 T cells can enhance their antitumor efficacy. Previous studies have shown that epigenetic inhibitors can modulate the profile of CD4 T cells, but the effects on CD8 T cells are still to be clarified. Thus, we aimed to identify possible epigenetic inhibitors that can modulate the activity and phenotype of CD8 T lymphocytes. To do this, CD8 T lymphocytes were isolated by cell sorting from healthy blood samples and cultured in 96-well plates in the presence of a polyclonal stimulatory cocktail (i.e., anti-CD3/CD28 DynaBeads, recombinant (r)IFN-, and rIL-2) along with 1µM of different epigenetic inhibitors (i.e., MS023, A485, LMOSES, GSKLSD1, and A366). Unstimulated CD8 T lymphocytes and polyclonally-stimulated CD8 T lymphocytes in the absence of epigenetic inhibitors were used as controls. After 4 or 8 days of culture, the cells were analyzed by flow cytometry for the assessment of cell markers related to activation (CD69), function (IFN- and granzyme B), differentiation (CCR7 and CD45RA) and exhaustion (PD-1 and TIGIT). Cells were acquired by the BD FACSymphony A5 cytometer, and statistical analyses were done using the GraphPad Prism 9 software. First, we conducted in vitro assays in which CD8 T cells were activated in the presence or absence of different inhibitors. A485, a p300/CBP bromodomain inhibitor, showed a potent modulatory effect on CD8 T cells. The inhibitor A485 increased T cell activation, observed by the increased frequency of CD69+ CD8 T cells. This inhibitor could also modulate the T cell memory phenotype, polarizing them towards a TN/TSCM profile, unlike the control and the other inhibitors, which polarized them towards to the TEM (effector memory T cells) profile. When the analyses were conducted after eight days of culture, we observed that the treatment with the A485 inhibitor resulted in a lower frequency of PD-1+ and TIGIT+ T cells compared with CD8 T cells activated in the absence of the inhibitor. Of clinical relevance, A485 was able to modulate anti-CD19 CAR-T cells isolated from pre-infusion products by positively regulating the frequency of CD69+ CAR-T cells and modulating their memory phenotype, keeping these cells less differentiated. In addition, A485 potentiated the in vitro antitumor activity of antiCD19 CAR-T cells in co-culture assays with the CD19+ Daudi cell line. In summary, our data show that the p300/CBP inhibition induces the TN/TSCM profile in CD8 T cells and CAR-T cells, thus boosting their antitumor activitiesSince the TN/TSCM phenotype has been shown to be favorable for tumor control, these findings can be of clinical interest for patients with hematological malignancies and solid tumors.

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

O mundo privado na UTI: análise da internação de pacientes oncológicos / The private world in the ICU: analysis of the hospitalization of oncology patientes / El mundo privado en la UCI: análisis de la hospitalización de pacientes oncológicos

O presente estudo buscou investigar a percepção que pacientes adultos de uma unidade de terapia intensiva (UTI) oncológica têm acerca da experiência de internação nesse setor. Trata-se de uma pesquisa de abordagem qualitativa e de compreensão. Sete pacientes de um hospital de câncer na região Sul do país foram pesquisados. Eles responderam a uma entrevista semiestruturada, a qual foi gravada e posteriormente transcrita, o que possibilitou o acesso às concepções prévias desses sujeitos acerca da UTI, aspectos psicológicos presentes durante a internação e concepções posteriores à experiência de internamento na unidade. Tais informações foram interpretadas por meio da análise de conteúdo. A partir dos resultados, foi possível verificar que a experiência de internação em contextos de terapia intensiva pode ser afetada, favorável ou desfavoravelmente, pelo conjunto de regras que o paciente traz consigo acerca do que é a UTI. Além disso, foi possível compreender também que os estímulos aversivos existentes nesse ambiente podem ser atenuados pela presença da família e por uma relação acolhedora e sensível com a equipe de saúde, favorecendo, assim, o repertório de enfrentamento do paciente frente a esse momento crítico de saúde.(AU)

This study aims to investigate the perception of adult patients in an oncology intensive care unit (ICU) regarding the experience of hospitalization in this sector. This is a research with a qualitative approach and understanding. Seven patients from a cancer hospital in the southern region of the country were surveyed. They answered a semi-structured interview, which was recorded and later transcribed, on the subjects' previous conceptions about the ICU, psychological aspects present during hospitalization, and conceptions subsequent to the hospitalization experience in the Unit. Such information was interpreted through content analysis. From the results, it was possible to verify that the experience of hospitalization in intensive care contexts can be affected, favorably or unfavorably, by the set of rules that the patient brings with them about what the ICU is. In addition, it was also possible to understand that the aversive stimulus existing in this environment can be attenuated by the presence of the family and by a welcoming and sensitive relationship with the health team, thus favoring the patient's coping repertoire when facing a critical moment of health.(AU)

Este estudio pretendió investigar la percepción que tienen los pacientes adultos sobre la experiencia de hospitalización en una Unidad de Cuidados Intensivos (UCI) de oncología. Se trata de una investigación con enfoque cualitativo y de comprensión. Participaron siete pacientes de un hospital oncológico en la región Sur de Brasil. Se aplicó una entrevista semiestructurada, que fue grabada y, posteriormente, transcrita, lo que permitió acceder a las concepciones previas de los sujetos sobre la UCI, los aspectos psicológicos presentes durante la hospitalización y las concepciones posteriores a la experiencia de internación en la Unidad. Dicha información se interpretó mediante análisis de contenido. A partir de los resultados, fue posible constatar que la experiencia de hospitalización en cuidados intensivos puede ser afectada favorable o desfavorablemente por el conjunto de normas que el paciente trae consigo sobre qué es la UTI. Además, se constató que los estímulos adversos existentes en este ambiente pueden mitigarse mediante la presencia de la familia y la relación acogedora y sensible con el equipo de salud, lo que favorece así el repertorio de afrontamiento del paciente ante este momento crítico de salud.(AU)

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.

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