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Solid tumors represent the most common type of cancer in humans and are classified into sarcomas, lymphomas, and carcinomas based on the originating cells. Among these, carcinomas, which arise from epithelial and glandular cells lining the body's tissues, are the most prevalent. Around the world, a significant increase in the incidence of solid tumors is observed during recent years. In this context, efforts to discover more effective cancer treatments have led to a deeper understanding of the tumor microenvironment (TME) and its components. Currently, the interactions between cancer cells and elements of the TME are being intensely investigated. Remarkable progress in research is noted, largely owing to the development of advanced in vitro models, such as tumor-on-a-chip models that assist in understanding and ultimately discovering new effective treatments for a specific type of cancer. The purpose of this article is to provide a review of the TME and cancer cell components, along with the advances on tumor-on-a-chip models designed to mimic tumors, offering a perspective on the current state of the art. Recent studies using this kind of microdevices that reproduce the TME have allowed a better understanding of the cancer and its treatments. Nevertheless, current applications of this technology present some limitations that must be overcome to achieve a broad application by researchers looking for a deeper knowledge of cancer and new strategies to improve current therapies.
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BACKGROUND: Co-inhibitor and co-stimulator mediators trigger actions that result in immunological homeostasis and are being evaluated as potential therapeutic targets in gastric cancer (GC). OBJECTIVE: To evaluate the soluble levels of sPD-1, sPD-L1, sPD-L2, sTIM-3, sGal9, sGITR, and sGITRL in GC patients. METHODS: The cross-sectional study was carried out at the Hospital de Cancer de Pernambuco, Brazil between 2017 and 2018. A total of 74 GC patients and 30 healthy controls were included. RESULTS: Low levels of sPD1 (p = 0.0179), sPDL2 (p = 0.0003), and sGal9 (p < 0.0001), and higher levels of sPDL1 (p = 0.004), sTIM-3 (p = 0.0072), sGITR (p = 0.0179), and sGITRL (p = 0.0055) compared to the control group. High sPD-1, sTIM-3, and sGal9 levels in stage IV compared I/II and III (p < 0.05). High sPDL1, sGal9, and sGITRL levels in esophagogastric junction compared to body and Pylorus/Antrum groups (p < 0.05). No significant differences were observed in sPD1, sPDL1, sPDL2, sTIM3, sGal9, sGITR, and sGITRL levels between the intestinal, diffuse, and mixed GC groups. Low sGITR levels in GC patients who died within the first 24 months compared to the who survived (p = 0.0332). CONCLUSIONS: There is an association of sPD1, sTIM-3, and sGal9 with disease progression and sGITR with death, these mediators may be potential prognostic biomarkers in GC.
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SMYD4 is a member of the SMYD family that has lysine methyltransferase function. Little is known about the roles of SMYD4 in cancer. The aim of this study is to investigate genetic alterations in the SMYD4 gene across the most prevalent solid tumors and determine its potential as a biomarker. We performed an integrative multi-platform analysis of the most common mutations, copy number alterations (CNAs), and mRNA expression levels of the SMYD family genes using cohorts available at the Cancer Genome Atlas (TCGA), cBioPortal, and the Catalogue of Somatic Mutations in Cancer (COSMIC). SMYD genes displayed a lower frequency of mutations across the studied tumors, with none of the SMYD4 mutations detected demonstrating sufficient discriminatory power to serve as a biomarker. In terms of CNAs, SMYD4 consistently exhibited heterozygous loss and downregulation across all tumors evaluated. Moreover, SMYD4 showed low expression in tumor samples compared to normal samples, except for stomach adenocarcinoma. SMYD4 demonstrated a frequent negative correlation with other members of the SMYD family and a positive correlation between CNAs and mRNA expression. Additionally, patients with low SMYD4 expression in STAD and LUAD tumors exhibited significantly poorer overall survival. SMYD4 demonstrated its role as a tumor suppressor in the majority of tumors evaluated. The consistent downregulation of SMYD4, coupled with its association with cancer progression, underscores its potential usefulness as a biomarker.
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Mutação , Neoplasias , Humanos , Neoplasias/genética , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Variações do Número de Cópias de DNA , Histona-Lisina N-Metiltransferase/genéticaRESUMO
Indeed, tumors are a significant health concern worldwide, and understanding the underlying mechanisms of tumor development is crucial for effective prevention and treatment. Epigenetics, which refers to changes in gene expression that are not caused by alterations in the DNA sequence itself, plays a critical role in the entire process of tumor development. It goes without saying that the effect of methylation on tumors is a significant aspect of epigenetics. Among the methylation modifications, DNA methylation is an important part, which plays a regulatory role in tumor-related genes. Ten-eleven translocation 2 (TET2) is a highly influential protein involved in the modification of DNA methylation. Its primary role is associated with the suppression of tumor development, making it a significant player in cancer research. However, TET2 is frequently mentioned in hematological diseases, its role in solid tumors has received little attention. Studying the changes of TET2 in solid tumors and the regulatory mechanism will facilitate its investigation as a clinical target for targeted therapy and may also provide directions for clinical treatment of malignant tumors.
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Metilação de DNA , Proteínas de Ligação a DNA , Dioxigenases , Epigênese Genética , Neoplasias , Proteínas Proto-Oncogênicas , Humanos , Neoplasias/genética , Neoplasias/terapia , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genéticaRESUMO
Despite significant efforts to control cancer progression and to improve oncology treatment outcomes, recurrence and tumor resistance are frequently observed in cancer patients. These problems are partly related to the presence of cancer stem cells (CSCs). Photodynamic therapy (PDT) has been developed as a therapeutic approach for solid tumors; however, it remains unclear how this therapy can affect CSCs. In this review, we focus on the effects of PDT on CSCs and the possible changes in the CSC population after PDT exposure. Tumor response to PDT varies according to the photosensitizer and light parameters employed, but most studies have reported the successful elimination of CSCs after PDT. However, some studies have reported that CSCs were more resistant to PDT than non-CSCs due to the increased efflux of photosensitizer molecules and the action of autophagy. Additionally, using different PDT approaches to target the CSCs resulted in increased sensitivity, reduction of sphere formation, invasiveness, stem cell phenotype, and improved response to chemotherapy. Lastly, although mainly limited to in vitro studies, PDT, combined with targeted therapies and/or chemotherapy, could successfully target CSCs in different solid tumors and promote the reduction of stemness, suggesting a promising therapeutic approach requiring evaluation in robust pre-clinical studies.
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Neoplasias , Fotoquimioterapia , Humanos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fotoquimioterapia/métodos , Células-Tronco NeoplásicasRESUMO
Background: Malignant Superior Vena Cava Syndrome (SVCS) corresponds to the clinical manifestations due to the restriction of venous return to the right atrium secondary to obstruction of the superior vena cava and/or its main tributaries for a tumor. Endovascular management has proven to be safe, effective and cause a fast symptomatic relief in patients with SVCS. There is limited evidence in factors associated with outcomes in malignant setting for this procedure. Materials and methods: An analytical retrospective study was conducted and included patients that underwent endovascular management for malignant SVCS at the National Cancer Institute of Colombia between May 2016 and May 2021. Clinical and technical variables were analyzed to found associations with outcomes in these patients. Results: 54 patients were analyzed. Successful procedure rate was 94.4 %. At 10 months, the OS of the entire cohort of patients was 25 %. Patients with breast or lung cancer (P = 0.031), unsuccessful procedure (P = 0.011), and also with short time of symptoms to the date of the endovascular procedure (P = 0.027) had worse OS. Multivariate analysis showed that lung cancer [HR = 2.55, 95%IC:(1.21-5.36)] and left internal jugular vein or left Innominate vein distal stent attachment [HR = 3.27, 95%IC:(1.31-8.15)] were independent factors for worst OS. Conclusions: Based in the high success rate of the endovascular management and the better outcome in patients with early and successful procedure, this procedure should be considered as part of the multimodal treatment in patients with SVCS independent of the clinical scenario and the oncological diagnosis.
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The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a membrane receptor that plays a key role in development. It is highly expressed during the embryonic stage and relatively low in some normal adult tissues. Malignancies such as leukemia, lymphoma, and some solid tumors overexpress ROR1, making it a promising target for cancer treatment. Moreover, immunotherapy with autologous T-cells engineered to express a ROR1-specific chimeric antigen receptor (ROR1 CAR-T cells) has emerged as a personalized therapeutic option for patients with tumor recurrence after conventional treatments. However, tumor cell heterogeneity and tumor microenvironment (TME) hinder successful clinical outcomes. This review briefly describes the biological functions of ROR1 and its relevance as a tumor therapeutic target, as well as the architecture, activity, evaluation, and safety of some ROR1 CAR-T cells used in basic research and clinical trials. Finally, the feasibility of applying the ROR1 CAR-T cell strategy in combination with therapies targeting other tumor antigens or with inhibitors that prevent tumor antigenic escape is also discussed. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT02706392.
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BACKGROUND: Difficulties in cancer services access increase the burden of disease and mortality in rural areas, and telehealth can be a useful tool to address these inequalities. OBJECTIVE: We aimed to describe the outcomes of patients in rural and urban areas with solid tumors managed by oncologists through telemedicine. METHODS: We conducted a retrospective cohort study of patients with solid tumors from March to December 2020. A total of 1270 subjects with solid tumors were included, 704 living in urban areas and 566 in rural areas. RESULTS: The most frequent tumors were breast (51.8%) and prostate (12.4%). The trend of telemedicine care was similar for both populations; in-person care was more frequent in the urban population. There were no differences in referral to the emergency room, need for hospitalization, and mortality for both groups. CONCLUSION: Telemedicine is a care modality that reduces barriers in the care of patients with solid tumors, evidencing similar outcomes regardless of living in rural or urban areas.
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Neoplasias , Telemedicina , Masculino , Humanos , Estudos Retrospectivos , América Latina , Neoplasias/epidemiologia , Neoplasias/terapia , População Rural , HospitaisRESUMO
Due to their key role in the pathogenesis of cancer through the regulation of apoptosis, the B-cell leukemia/lymphoma-2 (BCL-2) family proteins have been an attractive target for cancer therapy for the past decades. Throughout the years, many Bcl-2 family inhibitors have been developed, with Venetoclax being now successfully used in treating hematological malignancies. Although their effectiveness in the treatment of solid tumors is yet to be established, some preclinical evidence indicates their possible clinical application. This review aims to summarize current data from completed clinical trials that used Bcl-2 protein family inhibitors as monotherapy or in combination with other agents for the treatment of solid malignancies. We managed to include clinical trials of various phases which analyze the pharmacokinetics and pharmacodynamics of the drugs, as well as the effectiveness and adverse effects. Active and recruiting clinical trials are also briefly presented and future prospects and challenges are discussed.
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Antineoplásicos , Neoplasias Hematológicas , Leucemia Linfocítica Crônica de Células B , Humanos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Antineoplásicos/efeitos adversos , Leucemia Linfocítica Crônica de Células B/metabolismo , Apoptose , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologiaRESUMO
ABSTRACT Objective To describe the radiological characteristics of hepatocellular carcinoma (HCC) lesions that achieved a complete response following drug-eluting bead transarterial chemoembolization (DEB-TACE) preceding liver transplantation. Methods This single-center case-control study enrolled patients with hepatocellular carcinoma who underwent neoadjuvant DEB-TACE therapy, were followed up with contrast-enhanced magnetic resonance imaging or computed tomography, and were successively evaluated according to the modified Response Evaluation Criteria in Solid Tumors. The HCCs were divided into two groups based on their diameter (Group A: ≤3cm; Group B: 3cm). Viability was assessed using the Kaplan-Meier method according to tumor size categories. The relationship between tumor variables was analyzed using bivariate Cox regression. Results Three-hundred and twenty-eight patients with 667 hepatocellular carcinomas who underwent their first DEB-TACE session were enrolled. A total of 105 hepatocellular carcinomas in 59 patients exhibited complete response after the initial DEB-TACE session and were divided into Group A (92 HCCs) and Group B (13 HCCs). The diameter in Group A decreased significantly compared to the pre-procedure size until the second assessment (p<0.001), with no subsequent reduction in diameter, despite maintaining a complete response. In Group B, the reduction in diameter remained significant compared with the initial value until the sixth imaging evaluation (p=0.014). The average reduction was 45.1% for Group B and a maximum of 14.9% in Group A. Conclusion HCCs >3cm exhibited a greater reduction in size and a longer time to recurrence. HCCs ≤3cm had a shorter relapse time. The recurrence rates were similar. These findings may aid in planning for liver transplantation.
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The complete regression of clear cell renal cell carcinoma (ccRCC) obtained pre-clinically with anti-carbonic anhydrase IX (CAIX) G36 chimeric antigen receptor (CAR) T cells in doses equivalent to â 108 CAR T cells/kg renewed the potential of this target to treat ccRCC and other tumors in hypoxia. The immune checkpoint blockade (ICB) brought durable clinical responses in advanced ccRCC and other tumors. Here, we tested CD8α/4-1BB compared to CD28-based anti-CAIX CAR peripheral blood mononuclear cells (PBMCs) releasing anti-programmed cell death ligand-1 (PD-L1) IgG4 for human ccRCC treatment in vitro and in an orthotopic NSG mice model in vivo. Using a â 107 CAR PBMCs cells/kg dose, anti-CAIX CD28 CAR T cells releasing anti-PD-L1 IgG highly decrease both tumor volume and weight in vivo, avoiding the occurrence of metastasis. This antitumoral superiority of CD28-based CAR PBMCs cells compared to 4-1BB occurred under ICB via PD-L1. Furthermore, the T cell exhaustion status in peripheral CD4 T cells, additionally to CD8, was critical for CAR T cells efficiency. The lack of hepatotoxicity and nephrotoxicity upon the administration of a 107 CAR PMBCs cells/kg dose is the basis for carrying out clinical trials using anti-CAIX CD28 CAR PBMCs cells releasing anti-PD-L1 antibodies or anti-CAIX 4-1BB CAR T cells, offering exciting new prospects for the treatment of refractory ccRCC and hypoxic tumors.
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Antígeno B7-H1 , Anidrase Carbônica IX , Carcinoma de Células Renais , Neoplasias Renais , Receptores de Antígenos Quiméricos , Animais , Anticorpos/imunologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígenos CD28 , Anidrase Carbônica IX/imunologia , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/terapia , Inibidores de Checkpoint Imunológico , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Leucócitos Mononucleares/patologia , Camundongos , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologiaRESUMO
Solid tumors including skin, lung, breast, colon, and prostate cancers comprise the most diagnosed cancers worldwide. Treatment of such cancers is still challenging specially in the advanced/metastatic setting. The growing understanding of the tumor microenvironment has revolutionized the cancer therapy paradigms. Targeting programmed death-1 (PD-1)/PD-L1 immune checkpoint has been extensively studied over this decade as a new trend in the management of hard-to-treat cancers by harnessing the power of the immune system to eradicate the tumors. Yet, low response rate and resistance were observed when immunotherapies were tested as monotherapy. This urged the need to develop combinatorial regimens of immunotherapy with other immune modulatory agents to enhance its therapeutic potential and help in reverting the resistance. Epigenetic modifiers such as histone deacetylase inhibitors (HDACIs) showed favorable effects on modulating the tumor microenvironment along with the host immune cells. This qualified HDACIs as an attractive candidate class to be tested in combination with immunotherapy. In this review we cover the ongoing clinical trials that investigate the safety and/or the efficacy of HDACI/immunotherapy combinations in solid tumors including skin cancer, prostate cancer, breast cancer, colorectal cancer, lung cancer and recapitulates areas for future research.
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Inibidores de Histona Desacetilases , Neoplasias Pulmonares , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Imunoterapia , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Terapia de Alvo Molecular , Microambiente TumoralRESUMO
INTRODUÇÃO: Tromboembolismo venoso (TEV) apresenta incidência elevada em pacientes oncológicos e é importante causa de morbimortalidade nesse grupo. Fatores relacionados ao paciente, ao câncer ou mesmo aos tratamentos empregados podem associar-se com um maior risco de eventos trombóticos venosos. Entretanto, o tema ainda é pouco compreendido e pouco estudado na população brasileira. OBJETIVOS: Avaliar comparativamente aspectos demográficos, histopatológicos e clínicos em pacientes com neoplasias sólidas que apresentaram ou não TEV. Avaliar possíveis fatores associados a eventos tromboembólicos venosos. Analisar as características dos eventos tromboembólicos venosos identificados. MÉTODOS: Trata-se de um estudo observacional, retrospectivo, etiológico, tipo caso controle, não pareado. Foram selecionados pacientes diagnosticados com câncer entre 2014 e 2019, acompanhados no Hospital das Clínicas da Universidade Federal de Minas Gerais, um serviço público de referência em oncologia. Casos foram definidos como pacientes com diagnóstico de TEV (desfecho) e controles aqueles sem eventos trombóticos. A exposição avaliada foi a realização de algum tratamento oncológico específico (quimioterápico, endócrino, radioterápico ou cirúrgico). Variáveis de relevância clínica foram selecionadas para análise univariada (idade, sexo, estadiamento da doença, sítios tumorais conforme escore de Khorana, realização de tratamento oncológico específico, realização de tratamentos conhecidamente trombogênicos) e potenciais fatores de confusão foram adicionados para análise multivariada. Todos os dados foram coletados por meio de revisão de prontuários médicos. RESULTADOS: Foram incluídos 91 pacientes no grupo casos e 182 no grupo controles (1:2). Ambos os grupos foram semelhantes em relação às características demográficas, histopatológicas e clínicas, porém o grupo casos apresentou maior taxa de mortalidade (30,8% versus 15,9%, p=0,04). Em análise univariada, estadiamento avançado foi associado a maior risco de TEV (OR 1,85; IC 95% 1,04-3,30; p=0,036) e tratamento com hormonioterapia foi fator protetor (OR 0,41; IC 95% 0,21-0,82; p=0,010). Após adição de fatores confundidores, análises multivariadaa mantiveram terapia endócrina associada a menor risco de TEV (OR 0,18; IC 95% 0,07-0,47; p=0,000 e OR 0,41; IC 95% 0,20-0,86; p=0,018), sem identificação de fatores de risco. Internação hospitalar (35,2%) e cirurgia (23,1%) foram os principais fatores de risco presentes nos três meses que precederam os eventos. Trombose venosa profunda (TVP) em membros inferiores ocorreu em 54,9% dos casos e tromboembolismo pulmonar (TEP) em 37,4%. Em relação ao tratamento para TEV, 52,7% dos pacientes fizeram uso de varfarina e 40,7% de novos anticoagulantes orais. CONCLUSÃO: TEV é importante causa de mortalidade em pacientes oncológicos, uma população bastante heterogênea, em que fatores associados podem se comportar de formas diferentes. No presente estudo, hormonioterapia foi fator de proteção para TEV, possivelmente porque pacientes com indicação de terapia endócrina apresentam doença inicial ou metastática controlada, com menor risco para eventos tromboembólicos venosos.
INTRODUCTION: Venous thromboembolism (VTE) has a high incidence in cancer patients, being a cause of significant morbidity and mortality in this group. Several factors are associated with a higher risk of thrombotic events, which may be related to the patient, cancer or even the treatments used. However, this topic is still poorly understood and there are few studies in the Brazilian population. OBJECTIVES: To comparatively evaluate demographic, histopathological and clinical aspects in patients with solid tumors who had or did not have VTE. To assess possible factors associated with venous thromboembolic events. To analyze the characteristics of the venous thromboembolic events. METHODS: This is an observational, retrospective, etiological, case-control, unpaired study. Were selected patients diagnosed with cancer between 2014 and 2019 and treated at the Hospital das Clínicas da Universidade Federal de Minas Gerais, a public service of reference in oncology. Cases were defined as patients diagnosed with VTE (outcome) and controls as those without thrombotic events. Exposure was defined as receiving a specific oncological treatment (chemotherapy, endocrine therapy, radiotherapy or surgery). Clinically relevant variables were selected for univariate analysis (age, sex, disease staging, tumor sites according to Khorana score, specific oncological treatment, known thrombogenic treatments) and potential confounders were added for multivariate analysis. All data were collected by reviewing medical records. RESULTS: Ninety-one patients were included in the case group and 182 in the control group (1:2). Both groups were similar in terms of demographic, histopathological and clinical characteristics, but the case group had a higher mortality rate (30.8% versus 15.9%, p=0.04). In univariate analysis, advanced staging was associated with a higher risk of VTE (OR 1,85; CI 95% 1,04-3,30; p=0,036) and treatment with hormone therapy was a protective factor (OR 0,41; CI 95% 0,21-0,82; p=0,010). After adding confounding factors, multivariate analyzes maintained endocrine therapy associated with a lower risk of VTE (OR 0.18; 95% CI 0.07-0.47; p=0.000 and OR 0.41; 95% CI 0.20- 0.86; p=0.018), without identifying risk factors. Hospitalization (35.2%) and surgery (23.1%) were the main risk factors present in the three months preceding the events. Lower extremity deep venous thrombosis (DVT) occurred in 54.9% of cases and pulmonary embolism (PE) in 37.4%. About treatment for VTE, 52.7% of the patients used warfarin and 40.7% used new oral anticoagulants. CONCLUSION: VTE is an important cause of mortality in cancer patients, a very heterogeneous population, in which associated factors can behave in different ways. In the present study, hormone therapy was a protective factor for VTE, possibly because patients with indication for endocrine therapy have initial or controlled metastatic disease, with a lower risk for venous thromboembolic events.
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Tromboembolia Venosa/patologia , Tromboembolia Venosa/epidemiologia , Neoplasias , Dissertação AcadêmicaRESUMO
INTRODUCTION: The CYP450 complex participates in the metabolism of ifosfamide, an antineoplastic drug used to treat solid tumors. CYP450 genes contain several single nucleotide polymorphisms (SNPs) that confer different activity towards the enzyme. The aim of our study was to analyze gene frequencies of allelic variants and their association with ifosfamide blood levels and patient prognosis. MATERIAL AND METHODS: 148 DNA samples from children were analyzed. Genotyping was performed by real-time PCR with TaqMan probes and ifosfamide levels were determined in dried blood drop by UPLCMS/MS. RESULTS: Ifosfamide levels increased according to the genotype, and patients with the variant rs1799853 in CYP2C9 genotype CC had lower levels of ifosfamide (median = 1.8 µmol/l, Q25 0.9-Q75 4.6) compared with patients with genotype TT + CT (median = 2.8 µmol/l, Q25 1.9-Q75 5.1), p < 0.001. In the case of the rs2740574 variant in the CYP3A4 gene, patients with normal genotype (TT) presented median = 1.4 µmol/l, (Q25 0.7-Q75 2.7), while patients with the CC + TC genotype had higher levels of ifosfamide (median = 2.0 µmol/l, Q25 1.0-Q75 4.3), p = 0.024. In addition, patients with CC + CT genotype of this variant had a higher risk of non-response to treatment compared to patients with TT genotype (RR = 1.3, 95% CI: 1.07-1.59, p = 0.03). CONCLUSIONS: Polymorphisms in CYP2C9 and CYP3A4 genes are associated with high levels of ifosfamide. In addition, the polymorphism rs2740574 in CYP3A4 was associated with a worse therapeutic response.
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Resumen Una de las herramientas más novedosas en inmunoterapias adoptivas contra leucemias y tumores malignos es el uso del receptor de antígeno quimérico "CAR". El receptor CAR ha sido ampliamente utilizada en células T (células CAR-T) potenciando su eficacia en el reconocimiento y eliminación de tumores, obteniéndose a la fecha terapias basadas en esta tecnología. No obstante, las células CAR-T llegan a repercutir negativamente en la salud del paciente, presentando el síndrome neurológico de efecto inmune asociado a células (ICANS) y el síndrome de lanzamiento de citocinas (SLC). Como consecuencia, el paciente necesita ser hospitalizado durante la terapia. Además, el coste de manufactura y terapia es elevado, siendo una tecnología limitada a un sector muy bajo de la población. En este trabajo, mencionamos el empleo de una terapia emergente de células asesinas naturales (NK) con el receptor CAR (CAR-NK), que cuentan con muchas ventajas por encima de las células CAR-T. Las células CAR-NK conservan su capacidad citotóxica en contra de tumores gracias a su acción dependiente de receptores activadores e inhibidores, por lo que el receptor CAR, solo estimula sus habilidades y persistencia. Sumado a esto, el coste de una terapia de células CAR-NK podría resultar redituable debido a la capacidad de las células CAR-NK de eliminar múltiples células tumorales sin generar daño colateral en el paciente. Aquí analizamos las características de los múltiples receptores CAR y los fenotipos de células NK que han sido utilizados durante múltiples ensayos (NK-92, células NK de sangre cordal y periférica, y células NK iPSC).
Abstract One of the novel and effective devices against leukemia and solid tumors in adoptive immunotherapies is the use of the chimeric antigen receptor "CAR". CAR technology has been widely used in T-cells (CAR-T cells) empowering its efficacy on the identification and elimination of tumor cells, getting today certain drugs based on this technology. Nevertheless, CAR-T cells can have a negative impact on patient health, causing in many cases immune effector cell-associated neurotoxicity syndrome (ICANS) and cytokine release syndrome (CRS). As a consequence, the patient will have to be hospitalized for the duration of therapy. Moreover, the cost of manufacture and therapy is quite expensive, limiting its use to a low range of people. On the other hand, we analyze the advantages of Natural Killer cells with the CAR receptor (CAR-NK), which have many plusses over CAR-T cells. CAR-NK cells retain their cytotoxic abilities against tumor cells due their activator/ inhibitor receptors balance. Thus, the CAR receptor technology just increases their skills and persistence. Furthermore, CAR-NK therapy could be more profitable since CAR-NK can eliminate multiple tumor cells without generating collateral damage on patient health. Here, we discuss the characteristics of the multiples CAR receptors in general and the NK types cells that have been used in trials demonstrating their viable emerging therapy (NK-92, cord and peripheral blood NK cells, and iPSC-derived NK cells).
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Humanos , Leucemia , Terapêutica , Imunoterapia Adotiva , Síndrome da Liberação de CitocinaRESUMO
Early diagnosis of pediatric cancer is key for adequate patient management and improved outcome. Although multiparameter flow cytometry (MFC) has proven of great utility in the diagnosis and classification of hematologic malignancies, its application to non-hematopoietic pediatric tumors remains limited. Here we designed and prospectively validated a new single eight-color antibody combination-solid tumor orientation tube, STOT-for diagnostic screening of pediatric cancer by MFC. A total of 476 samples (139 tumor mass, 138 bone marrow, 86 lymph node, 58 peripheral blood, and 55 other body fluid samples) from 296 patients with diagnostic suspicion of pediatric cancer were analyzed by MFC vs. conventional diagnostic procedures. STOT was designed after several design-test-evaluate-redesign cycles based on a large panel of monoclonal antibody combinations tested on 301 samples. In its final version, STOT consists of a single 8-color/12-marker antibody combination (CD99-CD8/numyogenin/CD4-EpCAM/CD56/GD2/smCD3-CD19/cyCD3-CD271/CD45). Prospective validation of STOT in 149 samples showed concordant results with the patient WHO/ICCC-3 diagnosis in 138/149 cases (92.6%). These included: 63/63 (100%) reactive/disease-free samples, 43/44 (98%) malignant and 4/4 (100%) benign non-hematopoietic tumors together with 28/38 (74%) leukemia/lymphoma cases; the only exception was Hodgkin lymphoma that required additional markers to be stained. In addition, STOT allowed accurate discrimination among the four most common subtypes of malignant CD45- CD56++ non-hematopoietic solid tumors: 13/13 (GD2++ numyogenin- CD271-/+ nuMyoD1- CD99- EpCAM-) neuroblastoma samples, 5/5 (GD2- numyogenin++ CD271++ nuMyoD1++ CD99-/+ EpCAM-) rhabdomyosarcomas, 2/2 (GD2-/+ numyogenin- CD271+ nuMyoD1- CD99+ EpCAM-) Ewing sarcoma family of tumors, and 7/7 (GD2- numyogenin- CD271+ nuMyoD1- CD99- EpCAM+) Wilms tumors. In summary, here we designed and validated a new standardized antibody combination and MFC assay for diagnostic screening of pediatric solid tumors that might contribute to fast and accurate diagnostic orientation and classification of pediatric cancer in routine clinical practice.
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PURPOSE: Oral mucositis is a painful condition that occurs in patients who undergo chemotherapy. Due to the worsening of oral mucositis, the patient may progress to a worse clinical condition and interrupt antineoplastic treatment. There is little literature on low-power laser therapy in chemotherapy for other solid tumors. The purpose of this study was to investigate whether low-level laser therapy (LLLT) applied before chemotherapy could prevent oral mucositis in patients with solid tumors. METHODS: Laser therapy was applied at a frequency of 630nm, with a dose of 2J / cm2, for the prevention of oral mucositis induced by chemotherapy specifically for non-hematological tumors. Epidemiological data, total neutrophils, general side effects, development of oral mucositis and degree, and the performance of low-power laser therapy to prevent oral mucositis were collected. The involvement of oxidative stress was evaluated by the enzyme superoxide dismutase (SOD) through blood samples, before and after chemotherapy treatments. RESULTS: LLLT in the proposed protocol is efficient in reducing the development of oral mucositis (only at grade I/II) in patients under chemotherapy and able to reduce the severity of oral mucosal lesions, in patients who developed mucositis after the use of the laser for prevention. All individuals who underwent LLLT protocol did not show a significant reduction of SOD activity after the last chemotherapy cycle. CONCLUSIONS: The prophylactic laser therapy protocol proposed by the study, defined at a frequency of 630nm, a dose of 2J / cm2, demonstrated the ability to decrease the occurrence of oral mucositis in patients undergoing chemotherapy protocols to solid tumors. This effect could be related to preserved SOD activity, as it was observed that oral mucositis is related to leukopenia and reduced SOD activity and LLLT protocol prevented the decrease of SOD activity.
Assuntos
Terapia com Luz de Baixa Intensidade/métodos , Neoplasias/tratamento farmacológico , Estomatite/prevenção & controle , Superóxido Dismutase/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/efeitos adversos , Carboplatina/uso terapêutico , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/enzimologia , Neoplasias/patologia , Estresse Oxidativo , Paclitaxel/efeitos adversos , Paclitaxel/uso terapêutico , Estomatite/induzido quimicamente , Estomatite/enzimologiaRESUMO
BACKGROUND: Changesin nutritional status can constitute a risk factor for reduced tolerance and effectiveness of antineoplastic treatment. Knowledge of the nutritional status of pediatric patients is important for implementing interventions to improve outcomes. We aimed to evaluate nutritional status at diagnosis and throughout therapy in pediatric patients with solid tumors. OBJECTIVES: To study the prevalence of malnutrition at diagnosis, compare different assessment tools, and examine longitudinal changes in nutritional status during the treatment of pediatric patients with solid tumors in a Brazilian institution. METHODS: This prospective single-center study enrolled patients with solid tumors (age <19 years) from June 2017 to May 2018. Nutritional evaluations were performed at diagnosis and after 3 and 6 months of treatment. z-Scores for height for age (H/A) and body mass index for age (BMI/A) were calculated using the Anthro/AnthroPlus software and mid-upper arm circumference (MUAC) percentile was used for nutritional classification. RESULTS: The prevalence of nutritional status at diagnosis was 29.3% malnourished, 49.5% adequate, and 21.2% overweight/obese. Nutritional status improved during the first 3 months of treatment, with a reduction in the proportion of malnourished patients and an increased number of patients with adequate nutritional status. CONCLUSIONS: The two combined indices, BMI/A and MUAC, facilitated the diagnosis of a greater number of patients with solid tumors who had nutritional alterations. A high prevalence of malnutrition was present at diagnosis. Nutritional status improved in the first 3 months of treatment and could be related to the multidisciplinary institutional approach following the diagnosis.
Assuntos
Desnutrição , Neoplasias , Adolescente , Antropometria , Índice de Massa Corporal , Criança , Países em Desenvolvimento , Humanos , Desnutrição/diagnóstico , Desnutrição/etiologia , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Estado Nutricional , Estudos Prospectivos , Adulto JovemRESUMO
CIGB-552 is a synthetic peptide that interacts with COMMD1 and upregulates its protein levels. The objectives of this phase I study were safety, pharmacokinetic profile, evaluation of the lymphocytes CD4+ and CD8+ and preliminary activity in patients with advanced tumors. A 3 + 3 dose-escalation design with seven dose levels was implemented. Patients were included until a grade 3 related adverse event occurred and the maximum tolerated dose was reached. The patients received subcutaneous administration of CIGB-552 three times per week for 2 weeks. Single-dose plasma pharmacokinetics was characterized at two dose levels, and tumor responses were classified by RECIST 1.1. Twenty-four patients received CIGB-552. Dose-limiting toxicity was associated with a transient grade 3 pruritic maculopapular rash at a dose of 7.0 mg. The maximum tolerated dose was defined as 4.7 mg. Ten patients were assessable for immunological status. Seven patients had significant changes in the ratio CD4/CD8 in response to CIGB-552 treatment; three patients did not modify the immunological status. Stable disease was observed in five patients, including two metastatic soft sarcomas. We conclude that CIGB-552 at dose 4.7 mg was well tolerated with no significant adverse events and appeared to provide some clinical benefits.
Assuntos
Antineoplásicos/administração & dosagem , Peptídeos Penetradores de Células/administração & dosagem , NF-kappa B/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Peptídeos Penetradores de Células/efeitos adversos , Peptídeos Penetradores de Células/farmacocinética , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/metabolismo , Neoplasias/patologia , Projetos de Pesquisa , Resultado do TratamentoRESUMO
PURPOSE: Hypomagnesemia has been associated with febrile neutropenia (FN) in pediatric patients receiving cisplatin-based chemotherapy (CDDPBC). The primary aim was to determine whether oral magnesium supplementation reduces FN episodes in pediatric patients with solid tumors treated with CDDPBC. METHOD: This randomized clinical trial, with open-label, single-center, parallel group and superiority design was conducted in Hospital Infantil de Mexico Federico Gomez at Mexico City. Children ≥ 9 years with solid tumors that were to receive a CDDPBC cycle were invited to participate. Each chemotherapy cycle with CDDPBC was randomly assigned to receive oral magnesium supplementation (250 mg/day) or not receive magnesium supplementation (control group). Efficacy was determined by relative risks (RR) with 95% confidence intervals (95% CI) as well as with numbers needed to treat (NNT). Active surveillance was conducted to assess safety in both groups. Analyses were carried out by intention to treat. ClinicalTrials.gov number NCT03449693. RESULTS: One hundred and one chemotherapy cycles with CDDPBC were analyzed (50 in the magnesium supplement arm and 51 in control group). Baseline clinical characteristics were similar comparing both groups. Oral magnesium supplementation reduces FN episodes compared to control group [RR 0.53, (95% CI 0.32-0.89), NNT = 4]. In the supplemented group, patients had fewer episodes of septic shock secondary to FN [RR 0.43, (95% CI 0.02-0.94), NNT = 6] and FN appeared on average 5 days later (p = 0.031). Hypomagnesemia episodes and adverse events were similar across both groups. CONCLUSION: Oral supplementation with magnesium reduces FN episodes neutropenia in pediatric patients with solid tumors treated with CDDPBC.