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ABSTRACT Introduction: B cell acute lymphoblastic leukemia-lymphoma (B-ALL) accounts for approximately 75% of ALL cases and is observed in children and adults. Recent advances in disease diagnosis, stratification and prognostication have led to a better characterization of different subgroups of ALL. Notwithstanding the significant improvement in the complete remission rate of B-ALL, patients with minimal residual disease (MRD) and relapsed/refractory (R/R) settings suffer from poor outcomes. Hypothesis: However, novel therapies, such as agents targeting tyrosine kinases or the CD20 molecule, combination therapies and improved supportive care, have changed the treatment landscape of B-ALL. Method and results: Meanwhile, blinatumomab has been FDA-approved for MRD-positive or R/R B-ALL patients. Blinatumomab is a bispecific T cell engager containing the CD3 and CD19 that recognize domains redirecting cytotoxic T cells to lyse B cells. Promising outcomes, including long-term overall survival and improved MRD-negative response rates, have been reported in patients who received this drug. Adding blinatumomab to new ALL regimens seems promising for achieving better outcomes in poor prognosis B-ALL patients. Nevertheless, the neurotoxicity and cytokine release syndrome are the two major adverse events following the blinatumomab therapy. Conclusion: This review summarizes the function and effectiveness of blinatumomab in R/R and MRD positive B-ALL patients. Furthermore, blinatumomab's positive and negative aspects as a novel therapy for B-ALL patients have been briefly discussed.
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Humanos , Masculino , Feminino , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras , LinfomaRESUMO
INTRODUCTION: B cell acute lymphoblastic leukemia-lymphoma (B-ALL) accounts for approximately 75% of ALL cases and is observed in children and adults. Recent advances in disease diagnosis, stratification and prognostication have led to a better characterization of different subgroups of ALL. Notwithstanding the significant improvement in the complete remission rate of B-ALL, patients with minimal residual disease (MRD) and relapsed/refractory (R/R) settings suffer from poor outcomes. HYPOTHESIS: However, novel therapies, such as agents targeting tyrosine kinases or the CD20 molecule, combination therapies and improved supportive care, have changed the treatment landscape of B-ALL. METHOD AND RESULTS: Meanwhile, blinatumomab has been FDA-approved for MRD-positive or R/R B-ALL patients. Blinatumomab is a bispecific T cell engager containing the CD3 and CD19 that recognize domains redirecting cytotoxic T cells to lyse B cells. Promising outcomes, including long-term overall survival and improved MRD-negative response rates, have been reported in patients who received this drug. Adding blinatumomab to new ALL regimens seems promising for achieving better outcomes in poor prognosis B-ALL patients. Nevertheless, the neurotoxicity and cytokine release syndrome are the two major adverse events following the blinatumomab therapy. CONCLUSION: This review summarizes the function and effectiveness of blinatumomab in R/R and MRD positive B-ALL patients. Furthermore, blinatumomab's positive and negative aspects as a novel therapy for B-ALL patients have been briefly discussed.
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A pesar de los avances en los protocolos de tratamiento y en las medidas de soporte en pacientes con Leucemia Mieloide Aguda (LMA), 27% presentan recaídas de la enfermedad. Esto se debe, entre otras causas, a la persistencia de pequeñas cantidades de células malignas (blastos) resistentes a la terapia. Estas pequeñas cantidades de blastos remanentes se denominan Enfermedad Mínima Residual (EMR). La determinación de EMR requiere de técnicas no solo muy sensibles, sino también específicas, y permite evaluar la respuesta individual a la terapia. La introducción de la EMR como parámetro de respuesta y estratificación está bien definida en Leucemia Linfoblástica Aguda (LLA). Por el contrario, aunque existen publicaciones sobre el impacto pronóstico de la EMR en LMA, aún no se encuentra incluida en forma sistemática en los protocolos nacionales actuales, entre otros motivos, por lo laborioso de la determinación y por la necesidad de validación de la misma. Debe tenerse en cuenta que el inmunofenotipo de los blastos mieloides suele ser más heterogéneo que el de los blastos en LLA, presentando, en muchos casos, subpoblaciones diferentes entre sí, lo cual dificulta su detección certera y no hay consenso definido en cuanto a la metodología más eficaz. En este trabajo describimos una nueva estrategia de marcación y análisis estandarizada en un estudio multicéntrico internacional para LMA y la utilidad de la EMR como parámetro de respuesta y de estratificación. Asimismo, detallamos los resultados preliminares de nuestra cohorte de pacientes (AU)
Despite the improvement in treatment and supportive care of patients with Acute Myeloid Leukemia (AML), 27% of them relapse. This is due to the persistence of small amounts of malignant cells (blasts) resistant to therapy, among other causes. These small amounts of blasts are called Minimal Residual Disease (MRD). The determination of MRD requires not only techniques with high sensitivity but also with high specificity, and allows to evaluate the individual response to treatment. The introduction of MRD as a response parameter is well established in Acute Lymphoblastic Leukemia (ALL), and it is used in current stratification protocols. On the other hand, even though there are some reports regarding the prognostic impact of MRD in AML, it is still not included in the current national protocols due to the lack of validation of the determination, among other causes. This is due to the fact that the immunophenotype of myeloid blasts is more heterogeneous than in ALL, presenting different subpopulations, which difficults their accurate detection. Thus, there is still no consensus regarding the most effective approach. In this article, we describe a new staining and analysis strategy standardized by an international multicentric study, and the utility of EMR as a response and stratification parameter. Additionally, we show the preliminary results of our patient cohort. (AU)
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Humanos , Recém-Nascido , Lactente , Pré-Escolar , Criança , Adolescente , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Imunofenotipagem/instrumentação , Neoplasia Residual/diagnóstico , Citometria de Fluxo/instrumentaçãoRESUMO
OPINION STATEMENT: Treatment of chronic lymphocytic leukemia (CLL) has evolved dramatically during the last decade, from chemoimmunotherapy (CIT)-based therapies to newer B-cell receptor (BCR) signaling targeting agents, which are sometimes given as continuous schemes. Response to treatment was traditionally defined according to clinical variables designed to assign a response category. Interest in assessing for deeper responses in CLL by the means of measurable residual disease (MRD) testing has been the subject of research during the last several years. Analyses and sub-analyses of clinical trials have shown that achieving undetectable MRD (uMRD) in CLL is an important prognostic factor. In this review, we summarize the available evidence about MRD in CLL, from the various assays available for measurement, the compartment to test, the impact of reaching uMRD according to the treatment regimen, and the results of fixed duration treatment guided by MRD trials. Finally, we summarize how MRD can be incorporated in clinical practice and how it may guide fixed duration treatment in the future should evidence continue to accumulate in that direction.
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Leucemia Linfocítica Crônica de Células B , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Imunoterapia/métodos , Neoplasia Residual/diagnósticoRESUMO
Localized melanoma is easy to remove by surgery, resulting in a high five-year relative survival rate. However, when disseminated the disease management is challenging. The use of immunotherapies, such as anti-checkpoint monoclonal antibodies, has improved treatment options but still only a small percentage of patients responds to these expensive treatments. In this work, we apply a bacteria-based immunotherapy using LVR01, an attenuated Salmonella enterica serovar Typhimurium, as neoadjuvant therapy one week before surgery in a preclinical disseminated murine melanoma model. LVR01 administration resulted in tumor growth retardation prior to tumor resection, due to a rapid upregulation of inflammatory genes in the tumor microenvironment. As a consequence, cell infiltration increased, particularly neutrophils, macrophages and NK cells, being the latter involved in Salmonella anti-tumor activity. Besides, tumor-draining lymph node infiltration is characterized by reinvigorated CD4+ and CD8+ lymphocytes. Induced immune response could account for the prevention or delay of tumor recurrence and appearance of metastasis, resulting in a prolonged overall survival after surgery. Furthermore, upon rechallenge mice show partial protection, suggesting the existence of specific memory against melanoma. We propose that neoadjuvant LVR01 treatment could represent an interesting inexpensive alternative that may ease tumor resection, while preventing tumor recurrence in patients with melanoma.
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INTRODUCTION: To determine if there was an association of the ALC (absolute lymphocyte count) and LCP (lymphocytopenia) with the expression of MMP-2 in bone marrow micro-metastasis, the changes occurring during follow-up and association with biochemical failure. METHODS AND PATIENTS: One month after surgery blood and bone marrow samples were taken to determine the presence of micro-metastasis, the presence of circulating prostate cells (CPCs) and ALC. CPCs and micro-metastasis were detected using immunocytochemistry and MMP-2 expression determined in micro-metastasis. Only men positive for micro-metastasis participated in the study. At end follow blood was taken for serum PSA, ALC and CPCs, if the ALC decreased by more than 10% bone marrow sampling was repeated and MMP-2 expression determined, similarly for men with BF. Men who had stable ALCs had an end of study evaluation of the bone marrow. RESULTS: 402 men underwent radical prostatectomy, one month post surgery 79 men were positive for only bone marrow micro-metastasis and formed the study group; of whom 36/79 (45%) underwent BF. Clinical pathological findings were not significantly different between men with or without BF. In men with BF the ALC was significantly lower one-month post surgery. The 5 and 10 year Kaplan-Meier survival was 100% at 5-years and 65% at 10-years for the whole cohort. Men without BF had stable ALCs. A decrease of >10% in the ALC was associated with increasing MMP-2 expression in the micro-metastasis and surrounding stromal tissue, the appearance of CPCs 6-12 months later and BF. CONCLUSIONS: the immune host-tumour cell interaction in the microenvironment is dynamic and changes with time. A decreasing ALC may be a valuable marker in identifying men with high risk of BF and changes in immune mediated dormancy before the PSA rises.
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Neoplasias da Medula Óssea , Neoplasias Ósseas , Metaloproteinase 2 da Matriz/metabolismo , Células Neoplásicas Circulantes , Neoplasias da Próstata , Medula Óssea/patologia , Neoplasias Ósseas/cirurgia , Humanos , Masculino , Recidiva Local de Neoplasia/patologia , Células Neoplásicas Circulantes/patologia , Próstata/patologia , Antígeno Prostático Específico , Prostatectomia , Neoplasias da Próstata/patologia , Microambiente TumoralRESUMO
INTRODUCTION: Minimal residual disease (MRD) is the net result of the biological properties of disseminated tumour cells and the effect of the immune system and treatment to eliminate them. The aim of this study was to analyse the effect of combined chemotherapy on the immune function as determined by the neutrophil-lymphocyte ratio (NLR) and if it was associated with changes in the subtype of minimal residual disease and outcome in stage III colon cancer. METHODS AND PATIENTS: A prospective, single centre observational study; the NLR was determined immediately prior to and one, two and three months after completing chemotherapy. Circulating tumour cells (CTCs) and bone marrow micro-metastasis (mM) using immunocytochemistry with anti-CEA were determined prior to and one month after chemotherapy. The association of changes in the NLR with MRD subtypes classified as Group I (negative for CTCs and mM), Group II (positive for mM) and Group III (positive for CTCs) as a result of chemotherapy and five-year disease free progression (DFS) analysed. RESULTS: One hundred and eighty eight patients participated of whom 83 (44.9%) relapsed. In non-relapsing patients the NLR significantly increased and was higher after chemotherapy compared with relapsing patients. Significant increases in the NLR were associated with changes to a better MRD prognostic subtype and decreases with a worse MRD subtype. Neither baseline NLR nor MRD subtype predicted response to chemotherapy. DFS for MRD subgroups were 88%, 56% and 6% for Groups I to III respectively. CONCLUSIONS: Immune function as measured by the NLR is associated with MRD prognostic subtypes, improvements in the NLR are associated with improvements in MRD post chemotherapy but neither baseline NLR or MRD predicted outcome.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/sangue , Neoplasias do Colo/tratamento farmacológico , Contagem de Leucócitos , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo/patologia , Intervalo Livre de Doença , Feminino , Fluoruracila/uso terapêutico , Humanos , Leucovorina/uso terapêutico , Linfócitos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasia Residual , Células Neoplásicas Circulantes , Neutrófilos/efeitos dos fármacos , Compostos Organoplatínicos/uso terapêutico , Prognóstico , Estudos Prospectivos , Resultado do TratamentoRESUMO
BACKGROUND: This study aims to describe immunophenotypic explorations at diagnosis and follow up of a pediatric patient with leukemic phase of ALK+ anaplastic large cell lymphoma (ALCL) by multiparametric flow cytometry (MFC). CASE: An 8-color MFC combination of antibodies allowed to identify neoplastic cells in concentrations until 0.02% during minimal residual disease (MRD) monitoring. Immunophenotypic shifts occurred in key markers as CD30, CD7, CD2, and CD5, however neoplastic cells were clearly discriminated from normal populations. CONCLUSION: MFC can be a useful tool for ALCL diagnosis and MRD monitoring and may support therapeutic decisions.
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Linfoma Anaplásico de Células Grandes , Quinase do Linfoma Anaplásico , Criança , Progressão da Doença , Citometria de Fluxo , Humanos , Imunofenotipagem , Linfoma Anaplásico de Células Grandes/diagnóstico , Linfoma Anaplásico de Células Grandes/patologia , Neoplasia Residual/diagnósticoRESUMO
AIM: Minimal residual disease (MRD) is the net result of the biological properties of disseminated tumour cells and the effect of the immune system and treatment to eliminate them. The aim of this work is to report the changes in MRD status and immune function (lymphocyte count) after FOLFOX chemotherapy, and the outcome in Stage III colon cancer patients. METHOD: This study is a prospective, single-centre observational study. Lymphocyte counts were determined prior to and 1, 2 and 3 months after the completion of chemotherapy. Circulating tumour cells (CTCs) and bone marrow micrometastases were determined using immunocytochemistry with anticarcinoembryonic antigen prior to and 1 month after chemotherapy. MRD was classified as negative (Group I), micrometastasis positive only (Group II) and CTC positive (Group III). Changes in lymphocyte counts and MRD subtype following chemotherapy and relapse-free progression were analysed. RESULTS: Of the total of 185 patients, 83 (44.9%) relapsed. The risk of relapse significantly increased from Groups I to III (p < 0.001) and with decreasing lymphocyte count (p < 0.01). The lymphocyte count significantly decreased from Groups I to III (p < 0.001). Multivariance Cox regression analysis showed hazard ratios of 3.58 (Group II), 17.43 (Group III) and 0.39 (lymphocyte count) in predicting relapse. Following chemotherapy, improved lymphocyte count was associated with improved MRD subtype (p < 0.0001). Neither baseline lymphocyte count nor MRD subtype predicted response to chemotherapy. Five-year relapse-free survival for combined lymphocyte-MRD subtypes was 95%, 57% and 5% for Groups I to III, respectively (p < 0.001). CONCLUSION: Following chemotherapy, improvements in immune function were associated with improved MRD subtype and a better relapse-free survival.
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Neoplasias do Colo , Recidiva Local de Neoplasia , Neoplasias do Colo/tratamento farmacológico , Intervalo Livre de Doença , Humanos , Neoplasia Residual , Prognóstico , Estudos Prospectivos , Resultado do TratamentoRESUMO
Abstract Introduction: The minimal residual disease (MRD) status plays a crucial role in the treatment of acute lymphoblastic leukemia (ALL) and is currently used in most therapeutic protocols to guide the appropriate therapeutic decision. Therefore, it is imperative that laboratories offer accurate and reliable results through well standardized technical processes by establishing rigorous operating procedures. Method: Our goal is to propose a monoclonal antibody (MoAb) panel for MRD detection in ALL and provide recommendations intended for flow cytometry laboratories that work on 4-color flow cytometry platforms. Results and conclusion: The document includes pre-analytical and analytical procedures, quality control assurance, technical procedures, as well as the information that needs to be included in the reports for clinicians.
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Humanos , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras , Citometria de FluxoRESUMO
OBJECTIVE: Within 5 years after curative surgery for stage II colon cancer 25% of patients will relapse due to minimal residual disease (MRD). MRD is the net result of the biological properties of subpopulations of primary tumour cells which enable them to disseminate, implant in distant tissues and survive and the immune system's ability to eliminate them. We hypothesize that markers of immune dysfunction such as the systemic inflammation index (SII) are associated with the sub-type of MRD defined by bone marrow micro-metastasis (mM) and circulating tumour cells (CTCs). A higher immune dysfunction being associated with a more aggressive MRD and worse prognosis. METHODS AND PATIENTS: Blood and bone marrow samples were taken to detect CTCs and mM using immunocytochemistry with anti-CEA one month after surgery. The SII, absolute neutrophil, platelet and lymphocyte counts (ANC, APC, ALC) were determined immediately pre-surgery and one month post-surgery. These were compared with the sub-types of MRD; Group I MRD (-); Group II mM positive and Group III CTC positive; cut-off values of SII of >700 and >900 were used. Follow-up was for up to 5 years or relapse and survival curves using Kaplan-Meier (KM) were calculated. RESULTS: One hundred and eighty one patients (99 women) participated, mean age 68 years, median follow up 4.04 years; I: = 105 patients, II: N= 36 patients, III: N=40 patients. The SII significantly decreased post-surgery only in Group I patients. The frequency of SII >700 and >900 was significantly higher in Group III, between Groups I and II there was no significant difference. The SII was significantly associated with the number of CTCs detected. The 5-year KM was 98% Group I, 68% Group II and 7% Group III. CONCLUSIONS: The results of the study suggest that the severity of immune dysfunction as determined by the SII is associated with differing sub-types of MRD and a worse prognosis; increasing immune dysfunction is associated with a more aggressive CTC positive MRD sub-type; a more severe immune dysfunction is associated with a higher number of CTCs detected.
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Plaquetas/patologia , Colectomia/mortalidade , Neoplasias do Colo/mortalidade , Inflamação/mortalidade , Linfócitos/patologia , Neoplasia Residual/mortalidade , Neutrófilos/patologia , Idoso , Biomarcadores Tumorais/análise , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Neoplasias do Colo/cirurgia , Feminino , Seguimentos , Humanos , Inflamação/imunologia , Inflamação/patologia , Inflamação/cirurgia , Masculino , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Neoplasia Residual/imunologia , Neoplasia Residual/patologia , Neoplasia Residual/cirurgia , Células Neoplásicas Circulantes/patologia , Prognóstico , Estudos Prospectivos , Taxa de SobrevidaRESUMO
Cancer genomics has evolved over the years from understanding the pathogenesis of cancer to screening the future possibilities of cancer occurrence. Understanding the genetic profile of tumors holds a prognostic as well as a predictive value in this era of therapeutic surveillance, molecular remission, and precision medicine. Identifying molecular markers in tumors is the current standard of approach, and requires an efficient combination of an accessible sample type and a profoundly sensitive technique. Liquid biopsy or cell-free DNA has evolved as a novel sample type with promising results in recent years. Although cell-free DNA has significant role in various cancer types, this review focuses on its application in Non-Hodgkin's Lymphoma. Beginning with the current concept and clinical relevance of minimal residual disease in Non-Hodgkin's lymphoma, we discuss the literature on circulating DNA and its evolving application in the realm of cutting-edge technology.
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DNA Tumoral Circulante/sangue , Linfoma não Hodgkin/genética , Linfoma não Hodgkin/patologia , Biomarcadores Tumorais/sangue , Ácidos Nucleicos Livres/sangue , Citometria de Fluxo , Marcadores Genéticos , Técnicas de Genotipagem , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Biópsia Líquida , Linfoma/sangue , Linfoma/genética , Linfoma não Hodgkin/sangue , Linfoma não Hodgkin/diagnóstico por imagem , Mutação , Neoplasia Residual/sangue , Neoplasia Residual/genética , Neoplasia Residual/patologia , Reação em Cadeia da Polimerase/métodos , Tomografia por Emissão de Pósitrons , Medicina de Precisão , Prognóstico , Transcriptoma , Translocação GenéticaAssuntos
Recidiva Local de Neoplasia/epidemiologia , Neoplasia Residual/imunologia , Células Neoplásicas Circulantes/patologia , Evasão Tumoral , Imunidade Adaptativa , Antineoplásicos , Quimioterapia Adjuvante , Intervalo Livre de Doença , Humanos , Imunidade Inata , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/prevenção & controle , Neoplasia Residual/tratamento farmacológico , Neoplasia Residual/mortalidade , Neoplasia Residual/patologia , Células Neoplásicas Circulantes/efeitos dos fármacos , Células Neoplásicas Circulantes/imunologia , PrognósticoRESUMO
Minimal Residual Disease (MRD) is the most important independent prognostic factor in acute lymphoblastic leukemia (ALL) and refers to the deep level of measurable disease in cases with complete remission by conventional pathologic analysis, especially by cytomorphology. MRD can be detected by multiparametric flow cytometry, molecular approaches such as quantitative polymerase chain reaction for immunoglobulin and T-cell receptor (IG/TR) gene rearrangements or fusion genes transcript, and high-throughput sequencing for IG/TR. Despite the proven clinical usefulness in detecting MRD, these methods have differences in sensitivity, specificity, applicability, turnaround time and cost. Knowing and understanding these differences, as well as the principles and limitations of each technology, is essential to laboratory standardization and correct interpretation of MRD results in line with treatment time points, therapeutic settings, and clinical trials. Here, we review the methodological approaches to measure MRD in ALL and discuss the advantages and limitations of the most commonly used techniques.
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Neoplasia Residual/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Animais , Linfócitos B/patologia , Citometria de Fluxo/métodos , Fusão Gênica , Rearranjo Gênico , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Imunoglobulina G/genética , Neoplasia Residual/genética , Neoplasia Residual/patologia , Reação em Cadeia da Polimerase/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/patologiaRESUMO
INTRODUCTION: Minimal residual disease (MRD) is a cornerstone for stratification of upfront B-lymphoblastic leukemia (B-ALL) treatment protocols to decrease relapse risk. Although its detection by flow cytometry (FC) and real-time quantitative polymerase has clinical usefulness, evidence suggests that methods with increased sensitivity could lead to improved outcomes. The aim of this study was to develop an amplicon-based assay followed by high-throughput sequencing of the immunoglobulin heavy chain variable region for MRD detection in B-ALL. METHODS: We analyzed 84 samples, 27 from diagnosis, 5 from relapse, 40 from post-treatment samples, and 12 from healthy controls. RESULTS: Our assay was able to identify more neoplastic clones at diagnosis than Sanger sequencing including incomplete DJ rearrangements. From the 40 MRD samples evaluated 21 were positive by our new approach on high-throughput sequencing assay, but only 15 of these were positive by FC. The remaining 19 were negative by the two techniques. CONCLUSION: We have developed a novel approach on high-sensitive assay for MRD detection in B-ALL, which could add clinical value in the management of patients, especially in cases negative for MRD by FC.
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Cadeias Pesadas de Imunoglobulinas/genética , Neoplasia Residual/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasia Residual/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnósticoRESUMO
B-cell acute lymphocytic leukemia (B-ALL) is the main neoplasia affecting children worldwide, in which cytotoxic chemotherapy remains the main treatment modality. In this study, we analyzed the profile of inflammatory markers concerning oxidative stress and cytokines in 17 B-ALL patients. Peripheral blood (PB) and bone marrow (BM) samples were collected and evaluated for the pro-oxidative status (nitric oxide products-NOx and hydroperoxides), antioxidants (sulfhydryl groups-SH and total radical-trapping antioxidant parameter-TRAP), and cytokines (TNF-α, IFN-γ), at diagnosis (D0) to and the end of the induction phase (D28). At D28, hydroperoxides were higher in PB, concomitant to TNF-α levels. INF-γ was increased in the BM at D28. Hydroperoxides were higher in patients presenting malignant cells in BM and/or PB after treatment, a condition named minimal residual disease (MRD) when compared to those without MRD at D28. These findings suggest that oxidative stress and cytokines vary across the B-ALL induction phase, and lipid peroxidation is a potential marker associated with MRD status.
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INTRODUCTION: The minimal residual disease (MRD) status plays a crucial role in the treatment of acute lymphoblastic leukemia (ALL) and is currently used in most therapeutic protocols to guide the appropriate therapeutic decision. Therefore, it is imperative that laboratories offer accurate and reliable results through well standardized technical processes by establishing rigorous operating procedures. METHOD: Our goal is to propose a monoclonal antibody (MoAb) panel for MRD detection in ALL and provide recommendations intended for flow cytometry laboratories that work on 4-color flow cytometry platforms. RESULTS AND CONCLUSION: The document includes pre-analytical and analytical procedures, quality control assurance, technical procedures, as well as the information that needs to be included in the reports for clinicians.
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AIM: Despite curative surgery, 25% of patients with Stage II colorectal cancer will relapse due to minimal residual disease (MRD). Markers of immune function, such as the neutrophil to lymphocyte ratio (NLR), may be associated with MRD defined by bone marrow micro-metastasis (mM) and circulating tumour cells (CTCs). METHOD: A prospective cohort study of consecutive patients with Stage II colon cancer patients attended at a single centre between 2007 and 2014. Blood and bone marrow samples were taken to detect CTCs and mM using immunocytochemistry with anti-carcinoembryonic antigen 1 month after surgery. The NLR and absolute neutrophil and lymphocyte counts were determined immediately pre-surgery and 1 month post-surgery. These were compared with the sub-types of MRD: group I MRD(-); group II mM positive and group III CTC positive. Cut-off values of the NLR of >3.0 and >5.0 were used. Follow-up was for up to 5 years or relapse and disease-free survival (DFS) was calculated using Kaplan-Meier analysis. RESULTS: In all, 181 patients (99 women) participated. Mean age was 68 years. Median follow-up was 4.04 years: I, N = 105; II, N = 36; III, N = 40. The NLR significantly decreased post-surgery only in group I patients. The frequency of NLR >3.0 and >5.0 was significantly higher in group III; between groups I and II there was no significant difference. 5-year DFS was 98% in group I, 68% in group II and 7% in group III. CONCLUSIONS: Patients with a significantly higher immune dysfunction had a shorter time to disease progression, a worse DFS and the presence of CTCs.
OBJETIVO: En los primeros 5 años tras cirugía curativa para cáncer de colon en estadio II, el 25% de los pacientes tendrá una recidiva tumoral a causa de la presencia de enfermedad mínima residual (EMR). La hipótesis del presente estudio es que los marcadores de la función inmune, como la ratio neutrófilos- linfocitos (RNL), están asociados con el subtipo de EMR, clasificado por la presencia de micro-metástasis de médula ósea (mM) o células tumorales circulantes (CTCs) y con los resultados oncológicos. MÉTODOS Y PACIENTES: Se trata de un estudio prospectivo, observacional, monocéntrico que incluye una serie consecutiva de pacientes con cáncer del colon en estadio II tratados con cirugía curativa entre 2007 y 2014. Se tomaron muestras de sangre y médula ósea para detectar CTCs y mM mediante inmuno-citoquímica con anticuerpos anti-CEA un mes después de la cirugía. El numero de neutrófilos y linfocitos y el RNL se determinaron antes y un mes después de la cirugía y sus valores se compararon entre los diferentes grupos de EMR: grupo I, sin evidencia de EMR; Grupo II con mM positivo; Grupo III con CTCs positivo. El seguimiento oncológico fue de hasta 5 años y se calcularon las curvas de sobrevivencia libre de enfermedad (SLE) utilizando las curvas de Kaplan-Meier. RESULTADOS: se incluyeron en el presente estudio 181 pacientes (99 mujeres), con una edad media de 68 años y una mediana de seguimiento de 4,04 años; de acuerdo con la presencia de EMR se clasificaron los pacientes en Grupo I (n=105), Grupo II (n=36) y Grupo III (n=40). El RNL disminuyó significativamente después de la cirugía solo en el Grupo I. El porcentaje de pacientes con RNL> 3,0 y > 5,0 fue significativamente mayor en el Grupo III, sin diferencias significativas entre los Grupos I y II. La SLE a 5 años fue del 98% en el Grupo I, 68% en el Grupo II y 7% en el Grupo III. CONCLUSIONES: Los pacientes con una peor disfunción inmunológica presentan una recidiva mas precoz, una peor SLE y la presencia de células tumorales circulantes.