Use of CAR-T cells for the treatment of relapsed and refractory multiple myeloma: a systematic review / Uso de células CAR-T no tratamento de mieloma múltiplo recidivado e refratário: uma revisão sistemática

A systematic review of published articles based on randomized clinical trials was conducted to ascertain the efficacy or perspective of using CAR-T cell therapy for refractory multiple myeloma. The PubMed database was searched with the combination of terms "multiple myeloma", "refractory multiple myeloma", "CAR T-cell", and the PRISMA criteria were followed. Of the 78 articles found, only 5 were selected. The studies used different treatment protocols and four different types of CAR-T cells. All studies obtained interesting results in terms of increased progression-free survival and negative minimal residual disease responses. Some authors detected an expansion of CAR-T cells and noted dose-dependent relationship between treatment effectiveness and serum BCMA levels. Although the results were promising, a small number of patients still relapsed a few months after CAR-T cell infusion. Therefore, this new line of therapy should be further investigated, as it significantly increases progression-free survival and improves quality of life.

Uma revisão sistemática de artigos publicados com base em ensaios clínicos randomizados foi realizada para verificar a eficácia ou perspectiva do uso da terapia com células CAR-T para mieloma múltiplo refratário. Foi pesquisada a base de dados PubMed com a combinação dos termos "multiple myeloma", "refratory multiple myeloma", "CAR T-cell" e foram seguidos os critérios PRISMA. Dos 78 artigos encontrados, apenas 5 foram selecionados. Os estudos utilizaram diferentes protocolos de tratamento e quatro tipos diferentes de células CAR-T. Todos os estudos obtiveram resultados interessantes em termos de aumento da sobrevida livre de progressão e respostas negativas à doença residual mínima. Alguns autores detectaram uma expansão das células CAR-T e observaram uma relação dose-dependente entre a eficácia do tratamento e os níveis séricos de BCMA. Embora os resultados tenham sido promissores, um pequeno número de pacientes ainda apresentou recaída alguns meses após a infusão de células CAR-T. Portanto, esta nova linha de terapia deve ser mais investigada, pois aumenta significativamente a sobrevida livre de progressão e melhora a qualidade de vida.

Adult-onset idiopathic opsoclonus-myoclonus syndrome / Síndrome de opsoclonia-mioclonia idiopática de início adulto

ABSTRACT Purpose: Opsoclonus-myoclonus syndrome is extremely uncommon in adults with an autoimmune pathophysiology. Because of the rarity of the syndrome, international recognition of opsoclonus-myoclonus-ataxia syndrome needs to be improved urgently. Therefore, the goal of this study was to raise the awareness of the opsoclonus-myoclonus-ataxia syndrome and help doctors in better diagnosing and using immunotherapy. Methods: We present a case study of an adult-onset case of idiopathic opsoclonus-myoclonus syndrome characterized by spontaneous arrhythmic multidirectional conjugate eye movements, myoclonus, ataxia, sleep disorders, and intense fear. Additionally, we conduct a literature search and summarize the pathophysiology, clinical presentation, diagnosis, and treatment of opsoclonus-myoclonus-ataxia syndrome. Results: Immunotherapies successfully treated the patient's opsoclonus, myoclonus, and ataxia. Further, the article also includes an update summary of the opsoclonus-myoclonus-ataxia syndrome. Conclusion: The prevalence of residual sequela in adults with opsoclonus-myoclonus-ataxia syndrome is low. Early diagnosis and treatment may result in a better prognosis. Furthermore, combined immunotherapy is expected to reduce the incidence of refractory and reoccurring opsoclonus-myoclonus-ataxia syndrome.

RESUMO Objetivo: A síndrome de opsoclonia-mioclonia é extremamente rara em adultos e tem uma fisiopatologia autoimune. Devido à raridade dessa síndrome, o reconhecimento da síndrome de opsoclonia-mioclonia-ataxia precisa melhorar urgentemente em todo o mundo. Assim sendo, este estudo visou aumentar a conscientização sobre a síndrome de opsoclonia-mioclonia-ataxia e ajudar os médicos para um melhor diagnóstico e o uso correto da imunoterapia. Métodos: Este é o relato de um caso adulto de síndrome de opsoclonia-mioclonia idiopática com movimentos oculares conjugados, multidirecionais, arrítmicos e espontâneos, mioclonia, ataxia, distúrbios do sono e medo intenso. Além disso, foram pesquisadas as publicações recentes relevantes e resumiu-se a fisiopatologia, a apresentação clínica, o diagnóstico e o tratamento da síndrome de opsoclonia-mioclonia-ataxia. Resultados: A paciente recuperou-se totalmente da opsoclonia, da mioclonia e da ataxia através de imunoterapia. O artigo também fornece um resumo atualizado sobre a síndrome de opsoclonia-mioclonia-ataxia. Conclusão: Adultos com síndrome de opsoclonia-mioclonia-ataxia têm uma baixa frequência de sequelas residuais. O diagnóstico e o tratamento precoces podem levar a melhores prognósticos. Espera-se que a imunoterapia combinada reduza a incidência da síndrome de opsoclonia-mioclonia-ataxia refratária e recorrente.

Vitreous metastasis from cutaneous melanoma: diagnosis and management / Metástase vítrea de melanoma cutâneo: diagnóstico e tratamento

ABSTRACT Purpose: To report the clinical findings, treatments, and outcomes in a series of patients with vitreous metastasis from cutaneous melanoma. Methods: This single-center, retrospective, interventional case series included patients with biopsy-confirmed vitreous metastasis from cutaneous melanoma diagnosed between 1997 and 2020. Standard 23- or 25-gauge pars plana vitrectomy was performed for diagnostic sampling. Sclerotomies were treated with double or triple freeze-thaw cryotherapy. Perioperative intravitreal injections of melphalan (32 µg/0.075 mL) were administered, when indicated. Visual acuity, intraocular pressure, and systemic and ocular treatment responses were reported. Results: Five eyes of five patients with unilateral vitreous metastasis from cutaneous melanoma were identified. The median age at diagnosis was 84 (range, 37-88) years. The median follow-up after ophthalmic diagnosis was 28 (8.5-36) months; one patient did not have a follow-up. The initial visual acuity ranged from 20/30 to hand motions. Baseline clinical findings included pigmented or non-pigmented cellular infiltration of the vitreous (5/5), anterior segment (4/5), and retina (3/5). Four patients had secondary glaucoma. Systemic therapy included checkpoint inhibitor immunotherapy (n=3, all with partial/complete response), systemic chemotherapy (n=2), surgical resection (n=3), and radiation (n=2). The median time from primary diagnosis to vitreous metastasis was 2 (2-15) years. One patient had an active systemic disease at the time of vitreous metastasis. The final visual acuity ranged from 20/40 to no light perception. Ophthalmic treatment included vitrectomy in all five patients, intravitreal administration of melphalan in three, and intravitreal administration of methotrexate in one. One patient required enucleation, and histopathology revealed extensive invasion by melanoma cells. Conclusions: Vitreous metastasis from cutaneous melanoma can present as a diffuse infiltration of pigmented or non-pigmented cells into the vitreous and may be misdiagnosed as uveitis. Diagnostic pars plana vitrectomy and periodic intravitreal chemotherapy may be indicated.

RESUMO Objetivo: Descrever os achados clínicos, tratamentos, e desfechos em uma série de pacientes com me tástases vítreas de melanoma cutâneo. Métodos: Série retrospectiva de casos de único centro com intervenção. Pacientes incluídos tiveram seu diagnóstico de MVMC confirmado por biópsia entre 1997 e 2020. Vitrectomia via pars plana com 23 ou 25 gauge foram realizadas para obter espécimens. Esclerotomias foram tratadas com crioterapia em duplo ou triplo congelamento. Injeção intravítrea perioperatória de melfalano (32 ug/0,075 mL) foi administrada quando necessário. Foram relatados acuidade visual, pressão intraocular, resposta terapêutica sistêmica e ocular. Resultados: Cinco olhos de 5 pacientes com metástases vítreas de melanoma cutâneo unilateral foram identificados. Idade média de diagnóstico foi 84 anos (variando de 37-88). Seguimento médio após diagnóstico oftalmológico foi 28 (8,5-36) meses; 1 paciente não teve acompanhamento. Acuidade visual inicial variou de 20/30 a movimentos de mão. Achados clínicos iniciais incluíram infiltração de células pigmentadas e não-pigmentadas no vítreo (5/5), segmento anterior (4/5), e retina (3/5). Quatro pacientes tiveram glaucoma secundário. Tratamento sistêmico incluiu imunoterapia com inibidores da via de sinalização (3 - todos com resposta parcial/completa), quimioterapia sistêmica (2), ressecção cirúrgica (3), e irradiação (2). Intervalo médio entre diagnóstico primário e metástases vítreas foi 2 (2-15) anos. Um paciente teve doença sistêmica ativa simultânea as metástases vítreas. Acuidade visual final variou entre 20/40 e SPL. Tratamento oftalmológico incluiu vitrectomia nos 5 pacientes, melfalano intravítreo em 3 e metotrexato intravítreo em 1. Um paciente precisou de enucleação. A histopatologia revelou invasão celular extensa de melanoma. Conclusões: Metástases vítreas de melanoma cutâneo pode se manifestar como uma infiltração difusa de células pigmentadas e não-pigmentadas no vítreo e erroneamente diagnosticada como uveites. Vitrectomia diagnóstica e quimioterapia intravítrea periódica podem estar indicadas.

Oropharyngeal colostrum immunotherapy and risk reduction of mortality in very low birth weight premature newborns: a clinical trial

Abstract Objective To evaluate the effect of oropharyngeal colostrum immunotherapy (OCI) on the mortality of preterm newborns (PTNB) with very low birth weight (VLBW). Method Non-randomized clinical trial, carried out with 138 mother-child pairs attended at a public maternity hospital. The treatment group used raw colostrum, dripping 4 drops (0.2 ml) into the oropharyngeal mucosa, totaling 8 administrations in 24 h, up to the 7th complete day of life (OCI). The control group was composed of newborns admitted to the same maternity hospital before the implementation of the OCI. Analyzes were performed: descriptive, bivariate, multiple logistic regression, and survival analysis, with a significance level of 5% and 95% CI. Results The treatment group had an RR of death of 0.26 (95% CI = 0.07-0.67; p= 0.00), adjusted for maternal age, marital status, gestational hypertension, type of delivery, number of prenatal visits, and birth weight. Number Needed to Treat (NNT) demonstrated that for every 5 individuals treated with OCI, one death was prevented NNT = 4.9 (95% CI = 1.84-5.20); however, for PTNB with VLBW who remained hospitalized for 50, 100 and 150 days, the NNT reduces to 4, 4 and 3, respectively. Conclusion The OCI proved to be a beneficial intervention, since it reduced the risk of mortality in PTNB with VLBW when compared to the control group.

Research progress on m5C methylation and its prospects in tumor immunotherapy / 口腔疾病防治

@#Epigenetic modification plays an important role in the biological regulatory process of eukaryotic cells. Tumor immunotherapy is an important means and clinical strategy for the treatment of some cancers. 5-Methylcytosine (m5C) is an important component of the epigenetic regulatory network discovered after m6A and has become a new topic for life science research in recent years. The m5C methylation of RNA can affect the fate of the modified RNA molecules and play an important role in various biological processes, including RNA stability, protein synthesis and transcriptional regulation. Recent studies have shown that m5C writers, erasers and readers are related to a variety of cellular biological processes and systemic diseases, including the occurrence, metastasis and tumor immune microenvironment. m5C methylation can widely affect gene expression and the biological process of tumorigenesis and development at multiple levels, but its specific mechanism and potential interaction with other epigenetic modifications in tumor immunotherapy are still unclear, and its regulatory mechanism, risk assessment and role in targeted therapy for malignant tumors need to be further studied. This article will review the dynamic regulatory network of m5C, the biological role of m5C modification in solid tumors and potential targets in tumor immunotherapy.

Construction and self-activation detection of yeast two-hybrid bait plasmid of human programmed cell death ligand 1 immunoglobulin variable region domain gene / 中国生物制品学杂志

@#Objective To construct a yeast two-hybrid recombinant bait plasmid of human programmed cell death ligand 1(PD-L1)immunoglobulin variable region(IgV)domain gene,detect its expression in yeast and detect the cytotoxicity and self-activation of PD-L1 IgV protein as well as the interaction between PD-L1 IgV and human thioredoxin(hTrx).Methods Human PD-L1 was analyzed by bioinformatics method,and primers were designed to amplify PD-L1 IgV domain based on the coding region of PD-L1 gene registered in NCBI GenBank database. PCR amplification was carried out with pENTERPD-L1 plasmid as template,and then cloned into yeast two-hybrid bait vector pGBKT7. The recombinant bait plasmid and pGBKT7 empty vector were transformed into Y2HGold yeast cells respectively,and the PD-L1 IgV gene and its expression were detected by PCR and Western blot;Meanwhile,the protein toxicity and self-activation of PD-L1 IgV were detected,and the interaction between PD-L1 IgV and hTrx was detected by drip plate method.Results The bioinformatics analysis results of PD-L1 were consistent with related reports. The recombinant bait plasmid pGBKT7-PD-L1 IgV was correctly constructed,and Y2HGold positive clone was obtained,in which PD-L1 IgV was stably expressed. The empty vector pGBKT7 and recombinant bait plasmid pGBKT7-PD-L1 IgV grew well on SD/-Trp and SD/-Trp/X-α-Gal plates with the same colony size and number and white colony,but they did not grow on SD/-Trp/X-α-Gal/AbA plates,which indicated that PD-L1 IgV protein had no toxicity and no self-activation effect on yeast. The results of drip plates test showed that all experimental groups grew well on SD/-Trp/-Leu plate,while only positive control group grew on SD/-Trp/-Leu/X-α-Gal/AbA plate and showed blue color,which indicated that bait protein PD-L1 IgV and hTrx did not self-activate,and there was no interaction between them.Conclusion Recombinant human PD-L1 IgV bait plasmid was successfully constructed. PD-L1 IgV protein showed no toxicity and self-activation effect on yeast cells,and there was no interaction between PD-L1 IgV and hTrx. Subsequently,hTrx can be used to construct a peptide aptamer library,from which peptide aptamers that specifically bind to PD-L1 IgV can be screened.

Formation of Hyperprogression of Immunotherapy from Perspective of "Yang Deficiency and Toxin Knot" and Role of "Five Views on Differentiation and Treatment" Intervention / 中国实验方剂学杂志

Immune checkpoint inhibitors （ICIs） have shown good efficacy in tumor treatment and have changed the landscape of tumor treatment. However， some patients treated with ICIs have not only failed to achieve the desired therapeutic effect， but also developed an atypical response pattern of abnormally accelerated tumor growth， namely hyperprogressive disease （HPD）. The pathogenesis of HPD is still unclear and it is difficult to diagnose， which poses a challenge for clinical identification and treatment decisions. Exploring the underlying mechanism of HPD is important to improve the effect of immunotherapy. Based on the theory of "Yang deficiency and toxic knot"， this paper discussed the mechanism of HPD in immunotherapy from the perspective of "spleen and kidney Yang deficiency and hefty toxic pathogens". It was concluded that the inactivation of p53 oncogene and immunosuppressive microenvironment were the manifestations of the deficiency of healthy qi in the body and declined yang in the spleen and kidney， serving as an important basis for the occurrence of HPD. Adverse reactions caused by ICIs belong to the category of "drug toxicity". The occurrence and development of murine double minute 2 （MDM2）/murine double minute 4 （MDM4） activation， epidermal growth factor receptor （EGFR） mutation， and tumor inflammatory microenvironment are the manifestations of the hyperactivity of pathogenic Qi， conflict of cancer toxicity and drug toxicity， and being hefty by virtue of deficiency， which can promote the abnormal proliferation of tumor cells， and they are the core pathogenic elements of HPD and are closely related to disease prognosis. In terms of treatment， under the guidance of the theory of "five views on differentiation and treatment" （time-space view， core view， symptom view， precision view， and disease-before-onset view）， which was summarized according to the clinical practice of this research team， this paper， taking the prevention and treatment of HPD as the entry point， formulated traditional Chinese medicine （TCM） compounds to reinforce healthy Qi and warm Yang and realize the dynamic management of the whole spatiotemporal cycle， and removed toxins and resisted cancer to realize the all-round systemic intervention of the specimen. Additionally， targets were enriched in the macro-clinical manifestations and microscopic pathological changes of HPD to improve the targeting of drug selection and the precision of prevention and treatment， giving full play to the unique therapeutic advantages of TCM， and providing new ideas for the clinical application of TCM in the prevention and treatment of HPD.

Current management of patients with cutaneous melanoma with a positive sentinel lymph node / Tratamiento actual de pacientes con melanoma cutáneo y ganglio centinela positivo

Abstract Introduction : Immediate completion lymph node dissection (CLND) performed in patients with a positive sentinel lymph node biopsy (SLNB) cutaneous melanoma is not associated with improved melanoma specific survival versus active surveillance (AS) using nodal ul trasound. Clinical practice experience and outcomes of AS and adjuvant therapy is now starting to be published in literature. Methods : Retrospective analysis of patients with a positive-SLNB between June/2017-February/2022. Impact of management on any-site recurrence free survival (RFS), isolated nodal recurrence (INR), distant metasta sis-free survival (DMFS) and melanoma-specific survival (MSS) was evaluated. Results : From 126 SLNB, 31 (24.6%) were positive: 24 received AS and 7 CLND. Twenty-one (68%) received ad juvant therapy (AS, 67% and CLND, 71%). With a median follow-up of 18 months, 10 patients developed recur rent disease with an estimated 2-yr RFS of 73% (CI95%, 0.55-0.86) (30% in AS group vs. 43% in dissection group; P = 0.65). Four died of melanoma with an estimated 2-yr MSS of 82% (CI 95%, 0.63-0.92) and no differences between AS and CLND groups (P = 0.21). Estimated 2-yr DMFS of the whole cohort was 76% (CI 95%, 0.57-0.88) with no differences between groups (P = 0.33). Conclusion : Active surveillance strategy has been adopted for most positive-SLNB cutaneous melanoma patients. Adjuvant therapy without immediate CLND was delivered in nearly 70% of patients. Our results align with outcomes of randomized control trials and previous real-world data.

Resumen Introducción : La linfadenectomía inmediata (LI) re alizada en pacientes con biopsia de ganglio centinela (BGC) positivo por melanoma cutáneo no está asociada a mejoría en la supervivencia libre de enfermedad vs. vigilancia activa (VA). Resultados oncológicos y experi encia en la práctica clínica con dicha conducta asociados a tratamiento adyuvante comienzan a ser publicados en la literatura. Métodos : Análisis retrospectivo incluyendo paci entes con BGC-positiva por melanoma cutáneo entre junio/2017-febrero/2022. Se evaluó impacto del manejo en: supervivencia libre de recurrencia (SLR), recurren cia ganglionar aislada (RGA), supervivencia libre de metástasis a distancia (SLMD) y supervivencia libre de enfermedad (SLE). Resultados : De 126 pacientes, 31 (24.6%) fueron positi vos: en 24 se realizó VA y en 7 LI. Veintiún pacientes (68%) recibieron tratamiento adyuvante (VA, 67% y LI, 71%). Con una media de seguimiento de 18 meses, 10 pacientes presentaron recurrencia de la enfermedad con una SLR estimada a 2 años del 73% (CI95%, 0.55-0.86) (30% en VA vs. 43% en LI; P = 0.65). Cuatro murieron de melanoma con una SLE a 2 años del 82% (CI 95%, 0.63-0.92); sin diferencia entre ambos grupos (P = 0.21). La SLMD a 2 años de toda la cohorte fue de 76% (CI 95%, 0.57-0.88; P = 0.33). Conclusión : La vigilancia activa se ha adoptado como conducta para la mayoría de los pacientes con BGC-positivo. El tratamiento adyuvante sin linfadenectomía inmediata se realizó en cerca del 70% de nuestra serie. Los resultados de nuestra serie son similares a los re portados en la literatura.

Encefalitis por inhibidores del punto de control inmunitario / Encephalitis associated to immune checkpoint inhibitors

Resumen Los inhibidores del punto de control inmunitario han demostrado mejorar el pronóstico de múltiples enfer medades oncológicas. Recientemente se han reportado eventos adversos relacionados a la inmunoterapia. La to xicidad neurológica es poco frecuente. Se presenta el caso de un paciente con encefalitis relacionada con inhibido res del punto de control inmunitario.

Abstract Immune checkpoint inhibitors have been shown to improve the prognosis of multiple oncological diseases. Recently, adverse events related to immunotherapy have been reported. Neurologic toxicity is infrequent. We pre sent the case of a patient with encephalitis associated to immune checkpoint inhibitors.

Autoimmune encephalitis related to nivolumab followed by tumor regression / Encefalitis autoinmune relacionada con nivolumab se guida de regresión tumoral

Abstract Immune checkpoints inhibitors have shown a re markable improvement in overall survival of stage IV renal cell carcinoma patients. Nevertheless, there is a wide range of immune-related adverse events (IRAE) that arise from these revolutionary treatments. Autoim mune encephalitis is a rare but severe central nervous system IRAE in these cancer patients. The severities of these IRAEs preclude patients from continuing im munotherapy treatment. Few cases of autoimmune encephalitis with immunotherapy have been described in the literature and optimal clinical management of these events as well as patient's immune-mediated response after treatment suspension is still unclear. Here, we report a case of a 67 years-old woman with stage IV renal cell carcinoma under treatment with nivolumab who developed autoimmune encephalitis. After high doses of corticosteroids patient's condition improved significantly with full recovery after 5 days of treatment. Even though nivolumab was not reinstalled, a persistent response of her oncologic disease was evi denced. We expect that this case can contribute to the existing literature of both subjects, the management of autoimmune encephalitis as grade IV immune related adverse event and the responses of immune checkpoint inhibitors after IRAE.

Resumen Los inhibidores de puntos de control inmunológico han mostrado una importante mejoría en la supervi vencia global de los pacientes con carcinoma de riñón estadio IV. Sin embargo, existe una amplia variedad de efectos adversos inmunomediados que surgen a partir de estos tratamientos revolucionarios. La encefalitis au toinmune es un infrecuente pero grave efecto adverso inmunomediado del sistema nervioso central en estos pacientes. La gravedad de este cuadro impide que los pa cientes continúen con el tratamiento de inmunoterapia. Se han descrito pocos casos de encefalitis autoinmune con inmunoterapia en la literatura y aún no está claro el manejo clínico óptimo de estos eventos, ni cómo continua la respuesta inmunomediada después de la suspensión del tratamiento. Presentamos el caso de una mujer de 67 años con carcinoma de células renales estadio IV que desarrolló encefalitis autoinmune durante el tratamiento con nivolumab. La paciente mejoró significativamente luego del inicio del tratamiento con altas dosis de cor ticoides, con una recuperación completa después de 5 días del mismo. Si bien el nivolumab no se reinició, se evidenció una respuesta persistente de su enfermedad oncológica. Esperamos que este caso pueda contribuir a la literatura existente de ambos temas, el manejo de la encefalitis autoinmune como efecto adverso inmunome diado grado IV y las respuestas que se obtienen con la inmunoterapia luego de estos efectos adversos.

Analysis of the costs of the basic care line for sickle cell disease in Brazilian children under 5 years of age

ABSTRACT Objective: To evaluate and estimate the cost of basic care in sickle cell disease (SCD) for patients under five years of age, within the scope of the Unified Health System (SUS) and to discuss the costs related to possible complications of the disease from the literature. Methods: The main management and conduct recommendations in the SCD up to five years of age, with healthy and baseline health status, were extracted from the Basic Guidelines of the Care Line in the SCD of the Ministry of Health. Systematic data regarding costs of medicines were extracted from the Medicine Market Regulation Chamber. The SUS Table of Procedures, Medicines and Orthotics, Prosthetics and Auxiliary Means of Movement Management System was the guide for the values of complementary exams, as well as for medical consultations. The values applied to calculate the vaccination schedule were extracted from the Pan American Health Organization, adopting the perspective of the SUS-paying costs. Results: The total cost obtained for basic care of SCD in children up to five years of age, including the use of antibiotic prophylaxis, immunizations and the performance of transcranial Doppler ultrasound in the prevention and early detection of cerebrovascular accidents was, on average, $1020.96. Conclusion: The cost-effectiveness of prophylaxis in SCD, up to five years of age, exceeds the expenses resulting from hospitalizations due to complications of the disease. The study of expenses associated with SCD could be used to establish public policies, improve prevention strategies and treat the symptoms and complications of the disease.

Comparación de la mortalidad en pacientes en quimioterapia o inmunoterapia durante y antes de la pandemia de COVID-19. Estudio multicéntrico de cohortes emparejadas en Argentina / Comparison of mortality in patients on chemotherapy or immunotherapy during and before COVID-19 pandemic. Multicenter matched cohort study in Argentina

RESUMEN Objetivos. Comparar la mortalidad por todas las causas de pacientes oncológicos no vacunados que recibieron quimioterapia o inmunoterapia durante la pandemia, con aquellos tratados antes de la pandemia. Materiales y métodos. Realizamos un estudio de cohortes en cuatro hospitales terciarios en Argentina. Pacientes ambulatorios con una neoplasia sólida de cualquier estadio en tratamiento citotóxico o inmune intravenoso fueron elegibles. La cohorte pandémica se enroló durante la fase inicial del brote y se comparó con una cohorte de un período anterior a la pandemia utilizando emparejamiento por puntuación de propensión (PSM, por sus siglas en inglés). Los sujetos se emparejaron por edad, sexo, seguro de salud, factores de riesgo para complicaciones graves por COVID-19, estado funcional, tipo de cáncer y tratamiento, línea de tratamiento e índice de masa corporal. La mortalidad por todas las causas se estimó en ambas cohortes después de seis meses de seguimiento. Resultados. 169 pacientes fueron reclutados entre abril y agosto de 2020 para la cohorte pandémica y 377 para la cohorte prepandémica en el mismo período de 2019, 168 pacientes fueron emparejados. Luego de la PSM, la mortalidad por todas las causas fue del 17,9% en la cohorte pandémica y del 18,5% en la cohorte prepandémica, Riesgo Relativo: 0,97 (intervalo de confianza al 95 %: 0,61-1,52; p=0,888). En la cohorte pandémica, 30/168 pacientes fallecieron, ninguno por infección por COVID-19. Conclusiones. No hemos observado un aumento de mortalidad en pacientes ambulatorios no vacunados en tratamiento oncológico endovenoso activo durante la pandemia por COVID-19.

ABSTRACT Objectives. To compare all-cause mortality of unvaccinated oncology patients who received chemotherapy or immunotherapy during the pandemic with those treated before the pandemic. Materials and methods. We conducted a cohort study in four tertiary hospitals in Argentina. Outpatients with a solid neoplasm of any stage under-going cytotoxic or intravenous immunotherapy were eligible. The pandemic cohort was enrolled during the initial phase of the outbreak and compared with a pre-pandemic cohort using propensity score matching (PSM). Subjects were matched for age, sex, health insurance, risk factors for severe COVID-19 complications, performance status, cancer type and treatment, line of treatment, and body mass index. All-cause mortality was estimated for both cohorts after 6 months of follow-up. Results. A total of 169 patients were recruited between April and August 2020 for the pandemic cohort and 377 for the pre-pandemic cohort in the same months of 2019; 168 patients were matched. After PSM, all-cause mortality was 17.9% in the pandemic cohort and 18.5% in the pre-pandemic cohort; the Relative Risk was 0.97 (95 % confidence interval: 0.61-1.52; p=0.888). In the pandemic cohort, 30/168 patients died, but none from COVID-19. Conclusions. Our findings show that the mortality rate of unvaccinated ambulatory patients on active intravenous oncology treatment during the COVID-19 pandemic did not increase.

Use of monoclonal antibodies in cancer immunotherapy: types and mechanisms of action / Uso de anticuerpos monoclonales en la inmunoterapia del cáncer: tipos y mecanismos de acción

Abstract Immunotherapy is one of the most innovative treatments in the current field of oncology and consists of stimulating the immune system to eliminate tumoral cells. Monoclonal antibodies (mAbs) are glycoproteins secreted by B-cells capable of recognizing and neutralizing foreign organisms or antigens. Structurally, they are composed of two heavy and two light chains. The generation of therapeutic mAbs is one of the most developed and fastest-growing areas of the biotechnological and pharmaceutical industries and is an important adjunct to cancer therapy. Several antibodies have been approved for human administration and can be mouse-derived, chimeric, humanized, or fully human. mAbs main mechanism of action includes the lysis of the tumoral cells through inducing apoptosis, phagocytosis, complement activation, or signaling inhibition.

Resumen La inmunoterapia es un tratamiento innovador para la oncología actual, que consiste en la estimulación del sistema inmunitario para la eliminación de las células tumorales. Los anticuerpos monoclonales (mAbs) son glicoproteínas secretadas por los linfocitos B, capaces de reconocer y neutralizar organismos extraños o antígenos. Estructuralmente se componen de dos cadenas pesadas y dos cadenas ligeras. La generación de mAbs terapéuticos es una de las áreas de mayor crecimiento en la industria biotecnológica y farmacéutica y representa un complemento importante en la terapia del cáncer. Existen diversos mAbs que han sido aprobados para su administración en humanos, y pueden ser derivados de ratón, quiméricos, humanizados o completamente humanos. Los mecanismos de acción consisten principalmente en la lisis de las células tumorales a través de la inducción de la apoptosis, fagocitosis, activación del complemento o inhibición de la señalización celular.

Anaphylaxis and systemic mastocytosis caused by Solenopsis invicta stings / Anafilaxia e mastocitose sistêmica ocasionada pela Solenopsis invicta

Indolent systemic mastocytosis is a rare disease characterized by an increased number of mast cells in the bone marrow and other tissues, such as the liver, spleen, lymph nodes, and skin. Patients with indolent systemic mastocytosis and high serum tryptase levels are at risk for Hymenoptera venom-induced anaphylaxis. Hymenoptera venom immunotherapy in patients with specific IgE is safe and effective. While some patients can receive ultra-rush venom immunotherapy with minimal side effects, omalizumab effectively protects against anaphylaxis during the build-up phase.

A mastocitose sistêmica indolente é uma doença rara caracterizada por um número aumentado de mastócitos na medula óssea e em outros tecidos, como fígado, baço, linfonodos e pele. Pacientes com mastocitose sistêmica indolente e altos níveis séricos de triptase correm risco de anafilaxia induzida pelo veneno dos Hymenoptera. A imunoterapia com veneno de himenópteros em pacientes com IgE específica é segura e eficaz. Embora alguns pacientes possam receber imunoterapia com veneno ultrarrápido com efeitos colaterais mínimos, o omalizumabe protegeu efetivamente contra a anafilaxia durante a fase de acúmulo.

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)

PD-L1 and PD-L2 expression in colorectal cancer

Context: The programmed death-1 (PD-1) is an immune checkpoint molecule that suppresses T-cell response. The binding of PD-1 to PD-L1/PD-L2 results cytokine production, and T-cell proliferation are reduced. Tumors expressing PD-L1 and PD-L2 escape from cytotoxic T-cells and are exposed to tumor progression. For this reason, immunotherapy has become a new option in the treatment of cancer. Aims: In this study, we examined the PD-L1 and PD-L2 expression in colorectal carcinoma (CRC), and evaluated the relationship between clinicopathological parameters and CD8+ T cells. Methods and Material: We evaluated CD8 expression in tumor-infiltrating lymphocytes and surrounding tumor lymphocytes with PD-L1, PD-L2 staining in tumor cells and immune cells formalin-fixed paraffin embedded samples of 124 patient diagnosed with CRC. Statistical Analysis Used: Pearson Chi-Square, Fisher Exact Chi-Square, and Pearson Exact Chi-Square analyses were used in the analysis of the cross tables. Survival distributions predicted Kaplan--Meier method and it was evaluated using log-rank statistics. Results: In our study, a significant correlation was found between PD-L1 expression and female sex and tumors with medullary morphology. No expression of PD-L2 was observed in tumors containing medullary morphology, and a statistically inverse relationship was observed between PD-L2 and the medullary component. PD-L1 positive tumor-infiltrating lymphocytes were determined to be an important predictor for recurrence-free survival. Conclusions: We believe that the evaluation of these parameters may be useful in the selection of patients who will benefit from immunotherapy in CRC cases.

Versatile Use of Mycobacterium indicus pranii (MIP) Vaccine

Mycobacterium indicus pranii (MIP) earlier known as Mw is a soil-borne, non-pathogenic, saprophytic and rapidly growing strain of mycobacteria. MIP is approved as a vaccine/ immunomodulator for various indications including mycobacterium infections like leprosy in humans. Its administration has resulted in satisfactory clinical improvement, accelerated bacillary clearance, and increased immune responses to Mycobacterium leprae antigens, thereby shortening the full recovery time of the patients. It also shares its antigens with M.tuberculosis. In the last decade, RCTs have been done establishing immunotherapeutic properties of MIP in the treatment of leprosy, tuberculosis, warts and experimently in leishmaniasis. Through its immune inducing and cytotoxic property, it has also proved beneficial for human use especially in treating lung cancer. The beneficial role of it is also being explored in breast, cervical, oral, liver, and bladder cancers. Various studies on MIP have shown that it has immune-modulating properties in humans. The curiosity of the human mind has led to it being tried in Covid treatment trials. The results have shown that administering MIP has lowered inflammatory markers in Covid 19 patients, promising us for it to be a potential treatment option. More RCTs with a larger sample size should be done to establish this. Cytokine storm seen in bacterial sepsis is also decreased with MIP administration. Considering the encouraging results in hastening recovery in various diseases it appears that MIP is perhaps not being exploited to its fullest potential

Research progress of immunotherapies on correction of immunoparalysis in sepsis / 药学实践杂志

Immunoparalysis is the main cause of death in patients with intermediate and terminal sepsis. The correction of immunoparalysis is an important direction of sepsis treatment. In the pathological process of sepsis, a variety of factors contribute to the imbalanced secretion of cytokines, weakened function of antigen-presenting cells, apoptosis and depletion of lymphocytes, and ultimately lead to immunoparalysis, secondary infection, and even patient deaths. Cytokines such as GM-CSF, IFN-γ, IL-7, and IL-15, immune checkpoint-related therapies such as PD-1/PD-L1 antibodies, CTLA-4 antibodies, TIM-3 antibodies, and LAG-3 antibodies, and immunoreactive substances such as thymosin α1 and immunoglobulin might be beneficial to correct the immune paralysis of patients. the progress of immunotherapy to correct immune paralysis in sepsis were reviewed in this article.

Sphincter preservation operation and comprehensive treatment for ultra-low rectal cancer / 中华消化外科杂志

In the past 20 years, the multidisciplinary treatment model based on evidence-based medicine has significantly increased the rate of sphincter-preservation operation for rectal cancer. How to preserve rectum and anal function, avoid permanent colostomy, and improve post-operative quality of life of patients while ensuring radical resection of tumor, remains to be a key and hot topic in surgical treatment of rectal cancer. Based on literatures and clinical experiences, the authors summarize issues of sphincter preservation operation and comprehensive treatment, including intersphincteric resection, conformal sphincter preservation operation, total neoadjuvant therapy and radioimmunotherapy, for ultra-low rectal cancer, in order to provide reference for the colleagues.

Clinical research advance in immunotherapy of pancreatic cancer / 中华消化外科杂志

Pancreatic cancer is one of the most common tumors in digestive system, which is characterized by insidious clinical symptoms, strong invasion, easy metastasis and high mortality. In recent years, immunotherapy is a new direction to the treatment of solid tumors, but its applica-tion in pancreatic cancer is limited by tumor microenvironment of pancreatic cancer. The authors systematically analyze the tumor microenvironment of pancreatic cancer, summarize the clinical researches related to pancreatic cancer immunotherapy, and discuss the prospect of pancreatic cancer immunotherapy.