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1.
Recent Results Cancer Res ; 214: 71-91, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31473849

RESUMO

Bispecific T cell engagers are antibody constructs directed to a tumor-specific target on the one hand and to CD3-positive T cells on the other hand. Blinatumomab is a compound with specificity for the pan-B cell marker CD19. Clinical activity was tested in relapsed and refractory (R/R) non-Hodgkin's Lymphoma (NHL), R/R acute lymphoblastic leukemia (ALL), and ALL patients with minimal residual disease. Trials have already been started in de novo ALL. The most clinically relevant toxicities are neurologic events and cytokine release syndrome as with other T cell-activating therapies. The mechanisms of resistance are not fully understood. Higher leukemia load and later stage disease represent unfavorable factors. Besides, an upregulation of regulatory T cells and inhibitory molecules like PD-1/PD-L1 may have a role as the loss of target by several mechanisms. The future will show whether the use of bispecifics in ALL can change the standard treatment algorithms and whether bispecific T cell engagers will also be successfully used in other malignant entities.


Assuntos
Anticorpos Biespecíficos/farmacologia , Linfoma não Hodgkin/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Linfócitos T/citologia , Antígenos CD19 , Ensaios Clínicos como Assunto , Humanos , Neoplasia Residual/terapia
2.
Urol Clin North Am ; 46(3): 419-427, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31277736

RESUMO

Growing teratoma syndrome (GTS) is a rare clinical phenomenon in patients with nonseminomatous germ cell cancer defined by growing metastatic mass during ongoing or directly after completed chemotherapy with timely decreasing tumor markers and postpubertal teratoma exclusively after resection. GTS was first described in 1982, and few reports have been published. The limited number of studies and the resulting lack of exact knowledge about development, differentiation, and treatment of GTS leaves several clinical problems regarding treatment and follow-up unsolved. This review provides an overview of clinical diagnosis and disease management and an approach to explain the molecular development of GTS.


Assuntos
Teratoma/patologia , Teratoma/terapia , Neoplasias Testiculares/patologia , Neoplasias Testiculares/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Terapia Combinada , Diagnóstico Diferencial , Progressão da Doença , Humanos , Metástase Linfática , Masculino , Estadiamento de Neoplasias , Neoplasia Residual/patologia , Neoplasia Residual/terapia , Prognóstico , Neoplasias Retroperitoneais/secundário , Neoplasias Retroperitoneais/terapia , Síndrome
3.
Methods Mol Biol ; 1909: 47-73, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30580422

RESUMO

Liquid biopsy is a new diagnostic concept to investigate the molecular features of solid tumors by blood, saliva, urine, and any other body fluids which show a source of potential biomarkers. In cancer patients, it is a simple and less invasive mean, representing a sustainable alternative to interrogate all tumor cells longitudinally, quantifying and characterizing the biological materials (DNAs, RNAs, proteins) which originate from cancer tissues. Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) analysis from a simple blood draw received enormous attention for the related clinical research results. A rich scientific literature demonstrates that liquid biopsy is a valid instrument to assess the tumor biomarkers in real time and profile the cancer genotype in diagnostic and prognostic field, as well to quantify minimal residual disease, during patient follow-up. This could be a breakthrough for a companion diagnostic and personalized medicine. Liquid biopsy needs further implementation in the methodological aspects as well as cost-based assessment. The number of new molecular diagnostic assays increases day by day, but the standards for their adoption and clinical validation are still to be achieved.


Assuntos
DNA Tumoral Circulante/sangue , Biópsia Líquida/métodos , Neoplasias/diagnóstico , Células Neoplásicas Circulantes/patologia , Animais , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Gerenciamento Clínico , Humanos , Mutação , Neoplasia Residual/sangue , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Neoplasia Residual/terapia , Neoplasias/sangue , Neoplasias/genética , Neoplasias/terapia , Células Neoplásicas Circulantes/metabolismo , Prognóstico
4.
Clin. transl. oncol. (Print) ; 20(8): 1011-1017, ago. 2018. tab, graf
Artigo em Inglês | IBECS | ID: ibc-173684

RESUMO

Purpose: We investigated the role of adjuvant concurrent chemoradiation therapy (CCRT) in patients with a microscopically positive resection margin (R1) after curative resection for extrahepatic cholangiocarcinoma (EHCC). Methods/patients: A total of 84 patients treated with curative resection for EHCC were included. Fifty-two patients with negative resection margins did not receive any adjuvant treatments (R0 + S group). The remaining 32 patients with microscopically positive resection margins received either adjuvant CCRT (R1 + CCRT group, n = 19) or adjuvant radiation therapy (RT) alone (R1 + RT group, n = 13). Results: During the median follow-up period of 26 months, the 2-year locoregional recurrence-free survival (LRRFS), disease-free survival (DFS), and overall survival rates (OS) were: 81.8, 62.6, and 61.5% for R0 + S group; 71.8, 57.8, and 57.9% for R1 + CCRT group; and 16.8, 9.6, and 15.4% for R1 + RT group, respectively. Multivariate analysis revealed that the R1 + CCRT group did not show any significant difference in survival rates compared with the R0 + S group. The R1 + RT group had lower LRRFS [hazard ratio (HR) 3.008; p = 0.044], DFS (HR 2.364; p = 0.022), and OS (HR 2.417; p = 0.011) when compared with the R0 + S and R1 + CCRT group. Conclusions: A lack of significant survival difference between R0 + S group and R1 + CCRT group suggests that adjuvant CCRT ameliorates the negative effect of microscopic positive resection margin. In contrast, adjuvant RT alone is appeared to be inadequate for controlling microscopically residual tumor


No disponible


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Quimiorradioterapia/métodos , Neoplasia Residual/terapia , Colangiocarcinoma/terapia , Neoplasias dos Ductos Biliares/terapia , Neoplasia Residual/patologia , Colangiocarcinoma/patologia , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Extra-Hepáticos/patologia , Taxa de Sobrevida , Margens de Excisão
5.
Strahlenther Onkol ; 194(9): 797-805, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29974132

RESUMO

Neoadjuvant chemotherapy (NACT) has been widely adopted into the multidisciplinary management of breast cancer. The prognostic impact of treatment response has been clearly demonstrated. However, the impact of treatment response on the indication for adjuvant radiotherapy is unclear. This review summarizes important implications of NACT and treatment response on the risk of recurrence and locoregional multidisciplinary management from the standpoint of radiation oncology.


Assuntos
Neoplasias da Mama/terapia , Quimioterapia Adjuvante/métodos , Mastectomia , Terapia Neoadjuvante/métodos , Radioterapia Adjuvante , Neoplasias da Mama/patologia , Terapia Combinada , Intervalo Livre de Doença , Seguimentos , Humanos , Comunicação Interdisciplinar , Colaboração Intersetorial , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Neoplasia Residual/patologia , Neoplasia Residual/terapia , Prognóstico , Biópsia de Linfonodo Sentinela
6.
Biosystems ; 165: 99-105, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29408212

RESUMO

Population dynamics of regulatory T cells (Treg) are crucial for the underlying interplay between leukemic and immune cells in progression of acute myeloid leukemia (AML). The goal of this work is to elucidate the dynamics of a model that includes Treg, which can be qualitatively assessed by accumulating clinical findings on the impact of activated immune cell infusion after selective Treg depletion. We constructed an ordinary differential equation model to describe the dynamics of three components in AML: leukemic blast cells, mature regulatory T cells (Treg), and mature effective T cells (Teff), including cytotoxic T lymphocytes. The model includes promotion of Treg expansion by leukemic blast cells, leukemic stem cell and progenitor cell targeting by Teff, and Treg-mediated Teff suppression, and exhibits two coexisting, stable steady states, corresponding to high leukemic cell load at diagnosis or relapse, and to long-term complete remission. Our model is capable of explaining the clinical findings that the survival of patients with AML after allogeneic stem cell transplantation is influenced by the duration of complete remission, and that cut-off minimal residual disease thresholds associated with a 100% relapse rate are identified in AML.


Assuntos
Sistema Imunitário/imunologia , Leucemia Mieloide Aguda/imunologia , Recidiva Local de Neoplasia/imunologia , Neoplasia Residual/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/imunologia , Humanos , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Neoplasia Residual/patologia , Neoplasia Residual/terapia , Prognóstico , Indução de Remissão , Taxa de Sobrevida
7.
Med. clín (Ed. impr.) ; 150(4): 144-149, feb. 2018. tab
Artigo em Espanhol | IBECS | ID: ibc-170611

RESUMO

La evaluación de la enfermedad mínima residual (EMR) es un objetivo importante en el tratamiento de la leucemia linfocítica crónica (LLC). Su obtención es predictiva de una supervivencia libre de progresión (SLP) y una supervivencia global prolongadas y podría considerarse una variable subrogada de la SLP en el contexto del tratamiento con quimioinmunoterapia. La evaluación de la EMR mediante citometría de flujo o técnicas moleculares en la era de los nuevos inhibidores de BCR o Bcl-2 podría identificar la secuencia de tratamiento más coste-efectiva y la duración de la misma. Una aproximación terapéutica guiada por el nivel de EMR también podría determinar qué pacientes se beneficiarían de un tratamiento de consolidación o de una finalización precoz del mismo. En esta revisión discutimos los diferentes métodos de análisis de la EMR, qué muestras deben ser analizadas, el papel futuro de la detección del ADN tumoral circulante y el papel potencial de la negatividad de la EMR en la práctica clínica en la era moderna del tratamiento de la LLC (AU)


Minimal residual disease (MRD) assessment is an important endpoint in the treatment of chronic lymphocytic leukaemia (CLL). It is highly predictive of prolonged progression-free survival (PFS) and overall survival and could be considered a surrogate for PFS in the context of chemoimmunotherapy based treatment. Evaluation of MRD level by flow cytometry or molecular techniques in the era of the new BCR and Bcl-2 targeted inhibitors could identify the most cost-effective and durable treatment sequencing. A therapeutic approach guided by the level of MRD might also determine which patients would benefit from an early stop or consolidation therapy. In this review, we discuss the different MRD methods of analysis, which source of tumour samples must be analysed, the future role of the detection of circulating tumour DNA, and the potential role of MRD negativity in clinical practice in the modern era of CLL therapy (AU)


Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Neoplasia Residual/etiologia , Leucemia Linfocítica Crônica de Células B/complicações , Leucemia Linfocítica Crônica de Células B/diagnóstico , DNA de Neoplasias/análise , Imunoterapia , Fosfotransferases/antagonistas & inibidores , Leucemia Linfocítica Crônica de Células B/terapia , Citometria de Fluxo/métodos , Leucemia Linfocítica Crônica de Células B/genética , Neoplasia Residual/terapia , Terapia Combinada/métodos
8.
Clin Transl Oncol ; 20(8): 1011-1017, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29256155

RESUMO

PURPOSE: We investigated the role of adjuvant concurrent chemoradiation therapy (CCRT) in patients with a microscopically positive resection margin (R1) after curative resection for extrahepatic cholangiocarcinoma (EHCC). METHODS/PATIENTS: A total of 84 patients treated with curative resection for EHCC were included. Fifty-two patients with negative resection margins did not receive any adjuvant treatments (R0 + S group). The remaining 32 patients with microscopically positive resection margins received either adjuvant CCRT (R1 + CCRT group, n = 19) or adjuvant radiation therapy (RT) alone (R1 + RT group, n = 13). RESULTS: During the median follow-up period of 26 months, the 2-year locoregional recurrence-free survival (LRRFS), disease-free survival (DFS), and overall survival rates (OS) were: 81.8, 62.6, and 61.5% for R0 + S group; 71.8, 57.8, and 57.9% for R1 + CCRT group; and 16.8, 9.6, and 15.4% for R1 + RT group, respectively. Multivariate analysis revealed that the R1 + CCRT group did not show any significant difference in survival rates compared with the R0 + S group. The R1 + RT group had lower LRRFS [hazard ratio (HR) 3.008; p = 0.044], DFS (HR 2.364; p = 0.022), and OS (HR 2.417; p = 0.011) when compared with the R0 + S and R1 + CCRT group. CONCLUSIONS: A lack of significant survival difference between R0 + S group and R1 + CCRT group suggests that adjuvant CCRT ameliorates the negative effect of microscopic positive resection margin. In contrast, adjuvant RT alone is appeared to be inadequate for controlling microscopically residual tumor.


Assuntos
Neoplasias dos Ductos Biliares/terapia , Quimiorradioterapia Adjuvante/mortalidade , Quimiorradioterapia/mortalidade , Colangiocarcinoma/terapia , Recidiva Local de Neoplasia/terapia , Neoplasia Residual/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/cirurgia , Colangiocarcinoma/patologia , Colangiocarcinoma/cirurgia , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Neoplasia Residual/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
9.
J Surg Oncol ; 117(2): 191-197, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28876456

RESUMO

BACKGROUND AND OBJECTIVES: To clarify the detectability of gadolinium ethoxybenzyl diethylene-triamine pantaacetic acid enhanced magnetic resonance imaging (EOB-MRI) and contrast-enhanced intraoperative-ultrasonography (CE-IOUS) for residual disease in disappearing colorectal liver metastases (DLMs) and to seek a better management for DLMs. METHODS: Eighty-two patients who underwent hepatectomy after chemotherapy for colorectal liver metastases were retrospectively reviewed. Lesions which disappear on post-chemotherapy contrast-enhance CT were defined as DLMs. All the patients underwent EOB-MRI and CE-IOUS. With pathologic evaluation for resected specimens and clinical observation of anatomically corresponding site for non-resected lesions, detectability of residual disease in DLMs were estimated between these two imaging modalities. RESULTS: Twenty (18%) patients presented with 111 DLMs, and EOB-MRI and CE-IOUS identified 64 (57.6%) and 62 (55.9%), respectively. Residual disease was pathologically confirmed for 69.2% in resected specimens and clinically estimated in 33.3% for non-resected DLMs. EOB-MRI showed a higher accuracy of prediction of residual disease compared with CE-IOUS (0.90 vs 0.70). Of the 11 non-resected lesions which were undetected with CE-IOUS and regrew after surgery, 9 (81.8%) were detected on EOB-MRI. CONCLUSIONS: EOB-MRI may be superior to CE-IOUS in detecting residual tumors for DLMs. Maximum attempt of resection would be needed for visualized lesions in EOB-MRI.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/diagnóstico por imagem , Hepatectomia , Neoplasias Hepáticas/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Neoplasia Residual/diagnóstico por imagem , Ultrassonografia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Meios de Contraste , Gerenciamento Clínico , Feminino , Seguimentos , Gadolínio DTPA , Humanos , Cuidados Intraoperatórios , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/patologia , Neoplasia Residual/terapia , Prognóstico , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
10.
Eur J Surg Oncol ; 44(3): 332-337, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28687430

RESUMO

Lateral neck lymph node metastases in well differentiated thyroid cancer are common, ranging from 30% to 60%, with the majority of these foci identifiable only as microscopic deposits. A skilled ultrasound evaluation of the lymph nodes in the lateral neck is recommended for all patients presenting with newly diagnosed thyroid cancer undergoing surgical management. Ultrasound guided fine needle aspiration biopsy may be used to cytologically confirm suspected lateral neck nodal metastases prior to surgery. For patients with large volume nodal disease, extranodal extension, or multiple nodal metastases, computed tomography (CT) scan of the neck with contrast is an important additional imaging modality to accurately localize disease prior to surgery. Primary surgical management for lateral neck disease typically includes lateral neck dissection in conjunction with total thyroidectomy. Postoperative adjuvant radioactive iodine is typically recommended for patients with clinically evident nodal metastases, or for those with over 5 micrometastatic nodes. In the recurrent or persisting disease setting, complete surgical resection of local and regional disease remains the main treatment approach. However, sub-centimeter nodal disease may take an indolent course, and active surveillance may be a reasonable approach in selected clinical circumstances. Conversely, external beam radiation therapy (EBRT) may be considered for scenarios with unresectable disease, or microscopic residual disease following surgery in a clinically unfavorable setting. Two multi-kinase inhibitors (sorafenib and lenvatinib) are now FDA approved for treatment of RAI refractory thyroid cancer and now play an important role in the management of progressive, metastatic and surgically incurable disease.


Assuntos
Carcinoma Papilar/terapia , Neoplasias da Glândula Tireoide/terapia , Biópsia por Agulha Fina , Carcinoma Papilar/diagnóstico por imagem , Carcinoma Papilar/patologia , Terapia Combinada , Humanos , Biópsia Guiada por Imagem , Metástase Linfática/patologia , Esvaziamento Cervical , Micrometástase de Neoplasia/patologia , Neoplasia Residual/patologia , Neoplasia Residual/terapia , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/patologia , Tireoidectomia , Tomografia Computadorizada por Raios X , Ultrassonografia
11.
Clin Adv Hematol Oncol ; 15(11): 859-867, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29200419

RESUMO

Advances in detecting traces of leukemia that were previously unidentifiable have increasingly led to the incorporation of information about residual disease into clinical decision making for patients with leukemia in both the postinduction and consolidation settings. This review discusses current concepts related to minimal residual disease (MRD), which is defined as submicroscopic disease detected during morphologic complete remission. The focus is on acute myeloid leukemia (AML). Basic methods for detecting MRD include flow cytometry, reverse transcription-polymerase chain reaction, and mutation analysis. Several studies using these assays have demonstrated prognostic implications based on MRD-positive vs MRD-negative status. As our understanding of the biological factors responsible for MRD in AML evolves, residual disease should be evaluated in the context of other prognostic markers. Current therapeutic options for managing MRD in AML are limited, and the clinical implications of a positive MRD test result can be significant. Regarding individual patients, an evidence-based approach must be applied while the institution- and assay-specific differences that currently exist are considered. Challenges associated with MRD assessment, such as the limited standardization of available assays and the paucity of effective agents to eradicate MRD, will need to be overcome before physicians who treat leukemia can use MRD as a tool for clinical management.


Assuntos
Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Neoplasia Residual/diagnóstico , Neoplasia Residual/terapia , Animais , Análise Mutacional de DNA , Gerenciamento Clínico , Citometria de Fluxo , Regulação Leucêmica da Expressão Gênica , Humanos , Cariotipagem , Leucemia Mieloide Aguda/genética , Neoplasia Residual/genética , Prognóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa
12.
Leuk Res ; 63: 22-27, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29096332

RESUMO

We analyzed the outcome of allogeneic stem cell transplantation (allo-SCT) in acute myeloid leukemia (AML) patients according to molecular Minimal Residual Disease (MRD) status prior to allo-SCT. MRD was assessed by the quantitative expression of the pan-leukemic marker Wilms' tumor (WT1) gene, according to the validated LeukemiaNet method. Between 2005 and 2016, 122 consecutive AML patients, WT1 positive at diagnosis, received allo-SCT in cytologic complete remission (cCR). The median age at SCT was 53 years (range 18-70). Quantitative analysis of WT1 gene expression (bone marrow samples) was available in all cases both at diagnosis (100% of samples overexpressed WT1 with a mean of 8607±8187 copies/104 Abelson) and immediately before allo-SCT. Eighty one cases (66%) were MRD-WT1 negative (WT1 <250 copies) and 41/122 (44%) cases were MRD-WT1 positive (WT1 >250 copies) prior to allo-SCT. We evaluated post-SCT overall survival (OS), disease free survival (DFS) and relapse rate (RR), according to MRD-WT1 status pre-SCT. Both post-allo-SCT OS and DFS were significantly improved in patients who were MRD-WT1 negative at the time of SCT compared with those who were MRD-WT1 positive, with a median OS and DFS not reached in the MRD-WT1 negative group and 9 and 8 months, respectively, in the WT1 positive group (OS log-rank p<0.0001; hazard ratio [HR] 3.9, 95% confidence interval [95% CI] 2.0-7.38; DFS log-rank p<0.0001; HR 3.73, 95% CI 2.0-6.72). The RR after SCT was 15% (12/81) in pre-SCT MRD-WT1 negative cases and 44% (18/41) in MRD-WT1 positive cases (p=0.00073). Univariate analysis showed that MRD-WT1 negativity pre-SCT and grade <2 acute GVHD were significant prognostic factors for improved OS and DFS. However multivariate analysis showed MRD-WT1 negativity pre-SCT was the only independent prognostic factor for improved OS and DFS. These data show that pre allo-SCT molecular MRD evaluation using WT1 expression is a powerful predictor of post allo-SCT outcomes in AML undergoing SCT in cCR. Patients with both cCR and MRD-WT1 negativity before SCT have a very good outcome with lower RR and improved OS. The pre allo-SCT MRD-WT1 stratification in AML is a valuable tool to identify patients at high risk of post-SCT relapse, and can influence conditioning regimen intensification and/or post-SCT preemptive strategies.


Assuntos
Biomarcadores Tumorais/metabolismo , Leucemia Mieloide Aguda/patologia , Recidiva Local de Neoplasia/patologia , Neoplasia Residual/patologia , Transplante de Células-Tronco , Proteínas WT1/metabolismo , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/genética , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/terapia , Neoplasia Residual/genética , Neoplasia Residual/terapia , Prognóstico , Indução de Remissão , Taxa de Sobrevida , Transplante Homólogo , Proteínas WT1/genética , Adulto Jovem
13.
Oncol Res Treat ; 40(11): 691-696, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29069663

RESUMO

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents a treatment option for a diversity of advanced hematopoietic malignancies providing hope for long-term responses especially due to immunogenic effects associated with the treatment modality. Despite respectable progress in the field, relapses and/or opportunistic infections are major reasons for the high treatment-related mortality. However, a number of novel immunotherapeutic approaches using defined cell populations have been developed to directly target residual malignant cells as well as defined infectious diseases. We here provide an overview of current adoptive cellular immunotherapies in the context of allo-HSCT and close with an outlook on new directions within the field.


Assuntos
Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Imunoterapia Adotiva/métodos , Aloenxertos , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/mortalidade , Humanos , Imunoterapia Adotiva/efeitos adversos , Neoplasia Residual/imunologia , Neoplasia Residual/mortalidade , Neoplasia Residual/terapia , Prognóstico , Taxa de Sobrevida
14.
Oncol Res Treat ; 40(11): 682-690, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29041012

RESUMO

The identification of human Wilms' tumor gene 1 (WT1) protein-derived cytotoxic T lymphocyte (CTL) epitopes and the in vivo efficacy of WT1 peptide-based immunotherapy in a mouse model were reported in 2000. This successful basic research led to clinical studies of a WT1 peptide vaccine, and a positive impact on clinical response was first demonstrated in 2003 in the form of a reduction in blast cells of vaccine-treated patients with myelodysplastic syndromes (MDS). Since then, data on WT1 peptide vaccine-treated patients with immunological and/or clinical response have been accumulated. MDS and acute myeloid leukemia were the major target diseases to provide proof of concept for the therapeutic potential of the WT1 peptide vaccine. WT1 vaccination-induced clinical responses or usefulness were also shown for chronic myeloid leukemia, multiple myeloma, and acute lymphoblastic leukemia, as well as various types of solid cancers. Non-Hodgkin's lymphoma and myeloproliferative neoplasms may also be target diseases because of their WT1 expression. Of note, recent clinical studies have demonstrated that patients with hematological malignancies who have minimal residual disease after chemotherapy or allogeneic hematopoietic stem cell transplantation may be cured by WT1 peptide vaccination. Further enhancement of the efficacy and usefulness of the WT1 peptide vaccine is expected.


Assuntos
Vacinas Anticâncer/administração & dosagem , Epitopos de Linfócito T/imunologia , Neoplasias Hematológicas/terapia , Vacinas de Subunidades/administração & dosagem , Proteínas WT1/genética , Animais , Vacinas Anticâncer/imunologia , Estudos Clínicos como Assunto , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/imunologia , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Camundongos , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/terapia , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/terapia , Neoplasia Residual/imunologia , Neoplasia Residual/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Resultado do Tratamento , Vacinas de Subunidades/imunologia
15.
Ann Surg Oncol ; 24(13): 3818-3824, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29027138

RESUMO

BACKGROUND: The prognosis for patients with diffuse malignant peritoneal mesothelioma has dramatically improved with cytoreductive surgery and intraperitoneal chemotherapy. Little is known about disease recurrence after treatment. We analyzed the time to and predictors of recurrence in a large cohort of optimally treated patients. METHODS: We examined 113 patients completing a two-stage cytoreduction and intraperitoneal chemotherapy protocol. All patients achieved optimal surgical resection with completeness of cytoreduction (CC) score ≤ 1 and were divided into two groups based on absence (Group A) or presence (Group B) of gross disease at the outset of the second operation. Predictors of disease recurrence and recurrence-free survival (RFS) were determined using Cox proportional hazard regression modeling, and estimates were obtained by using the Kaplan-Meier method. RESULTS: Forty-six percent of patients had no gross evidence of disease at the second operation; the remaining 54% were cytoreduced to CC ≤ 1 (Group B). Forty-two percent of patients developed disease recurrence with a median recurrence-free survival of 38.5 months for the cohort; 79% of these received a form of iterative treatment. There was no statistically significant difference in recurrence-free survival between Group A (median RFS: 44.6 months) and B (median RFS: 35.5 months) (log-rank test, p = 0.06). Additionally, the only variable significantly associated with RFS was male gender (hazard ratio [HR] 1.98, 95% confidence interval [CI] 1.16-3.38). CONCLUSIONS: Absence of gross disease at the second operation was not statistically protective against recurrence compared with presence of quantifiable residual disease (Group B) that was effectively cytoreduced. Long-term disease surveillance is recommended, because recurrence continues years after treatment. Where a question of recurrence arises on surveillance, males may benefit from a higher degree of suspicion.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia do Câncer por Perfusão Regional , Procedimentos Cirúrgicos de Citorredução , Hipertermia Induzida , Neoplasias Pulmonares/patologia , Mesotelioma/patologia , Recidiva Local de Neoplasia/patologia , Neoplasias Peritoneais/secundário , Adulto , Estudos de Coortes , Terapia Combinada , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/terapia , Metástase Linfática , Masculino , Mesotelioma/terapia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/terapia , Neoplasia Residual/patologia , Neoplasia Residual/terapia , Neoplasias Peritoneais/terapia , Prognóstico , Taxa de Sobrevida
16.
J Hematol Oncol ; 10(1): 134, 2017 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-28676064

RESUMO

BACKGROUND: This study compared the effects of pre-transplantation minimal residual disease (pre-MRD) on outcomes in AML patients who underwent human leukocyte antigen-matched sibling donor transplantation (MSDT) or who received unmanipulated haploidentical allografts. METHODS: A retrospective study (n = 339) and a prospective study (n = 340) were performed. MRD was determined using multiparameter flow cytometry. RESULTS: Either after retrospective or prospective analysis, patients with negative pre-MRD (pre-MRDneg) had a lower incidence of relapse than those with positive pre-MRD (pre-MRDpos) in MSDT settings (P < 0.001 for all), but relapse was comparable in Haplo-SCT settings for patients with pre-MRDneg versus pre-MRDpos (P = 0.866 and 0.161, respectively). In either the retrospective (n = 65) or the prospective study (n = 76), pre-MRDpos subjects receiving Haplo-SCT experienced a lower incidence of relapse than those who underwent MSDT (P < 0.001 and p = 0.017, respectively). Of the patients with pre-MRDpos in either the total (n = 141) or the subgroup excluding cases which received donor lymphocyte infusion (DLI; n = 105), those who underwent MSDT had a higher incidence of relapse than those receiving haplo-SCT (P < 0.01 for all). Multivariate analysis showed that, for pre-MRDpos cases, haplo-SCT was associated with a low incidence of relapse and with better LFS and OS in either retrospective group, prospective group, combination groups, or subgroup not including cases which received DLI. CONCLUSIONS: The results indicated that, for pre-MRD-positive AML patients, haplo-SCT was associated with lower incidence of relapse and better survival, suggesting a stronger anti-leukemia effect.


Assuntos
Doença Enxerto-Hospedeiro/etiologia , Antígenos HLA/genética , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/terapia , Neoplasia Residual/terapia , Doadores de Tecidos , Adolescente , Adulto , Aloenxertos/metabolismo , Aloenxertos/transplante , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Citometria de Fluxo , Doença Enxerto-Hospedeiro/genética , Haploidia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/genética , Estudos Prospectivos , Estudos Retrospectivos , Irmãos , Análise de Sobrevida , Transplante Homólogo/efeitos adversos , Transplante Homólogo/métodos , Resultado do Tratamento , Adulto Jovem
17.
Blood ; 130(13): 1543-1552, 2017 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-28698205

RESUMO

Antibody therapy constitutes a major advance in the treatment of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). To evaluate the efficacy and the mechanisms of action of CD19 monoclonal antibody therapy in pediatric BCP-ALL, we tested an Fc-engineered CD19 antibody carrying the S239D/I332E mutation for improved effector cell recruitment (CD19-DE). Patient-derived xenografts (PDX) of pediatric mixed-lineage leukemia gene (MLL)-rearranged ALL were established in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. Antibody CD19-DE was efficient in prolonging the survival of NSG mice in a minimal residual disease (MRD) model. The majority of surviving mice remained polymerase chain reaction (PCR)-MRD negative after treatment. When antibody therapy was initiated in overt leukemia, antibody CD19-DE was still efficient in prolonging survival of xenografted mice in comparison with nontreated control animals, but the effects were less pronounced than in the MRD setting. Importantly, the combination of antibody CD19-DE and cytoreduction by chemotherapy (dexamethasone, vincristine, PEG-asparaginase) resulted in significantly improved survival rates in xenografted mice. Antibody CD19-DE treatment was also efficient in a randomized phase 2-like PDX trial using 13 MLL-rearranged BCP-ALL samples. Macrophage depletion by liposomal clodronate resulted in a reversal of the beneficial effects of CD19-DE, suggesting an important role for macrophages as effector cells. In support of this finding, CD19-DE was found to enhance phagocytosis of patient-derived ALL blasts by human macrophages in vitro. Thus, Fc-engineered CD19 antibodies may represent a promising treatment option for infants and children with MLL-rearranged BCP-ALL who have a poor outcome when treated with chemotherapy only.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Animais , Anticorpos/genética , Anticorpos/uso terapêutico , Antígenos CD19/genética , Antígenos CD19/imunologia , Feminino , Xenoenxertos , Humanos , Fragmentos Fc das Imunoglobulinas/genética , Lactente , Macrófagos/citologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Neoplasia Residual/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Células Tumorais Cultivadas
18.
Magn Reson Imaging ; 42: 88-94, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28627463

RESUMO

PURPOSE: The potential of diffusion weighted imaging (DWI) in assessing pathologic response and surgical margins in locally advanced breast cancer patients (n=38) undergoing neoadjuvant chemotherapy was investigated. METHODS: DWI was performed at pre-therapy (Tp0), after I (Tp1) and III (Tp3) NACT at 1.5T. Apparent diffusion coefficient (ADC) of whole tumor (ADCWT), solid tumor (ADCST), intra-tumoral necrosis (ADCNec) was determined. Further, ADC of 6 consecutive shells (5mm thickness each) including tumor margin to outside tumor margins (OM1 to OM5) was calculated and the data analyzed to define surgical margins. RESULTS: Of 38 patients, 6 were pathological complete responders (pCR), 19 partial responders (pPR) and 13 were non-responders (pNR). Significant increase was observed in ADCST and ADCWT in pCR and pPR following therapy. Pre-therapy ADC was significantly lower in pCR compared to pPR and pNR indicating the heterogeneous nature of tumor which may affect drug perfusion and consequently the response. ADC of outside margins (OM1, OM2, and OM3) was significantly different among pCR, pPR and pNR at Tp3 which may serve as response predictive parameter. Further, at Tp3, ADC of outside margins (OM1, OM2, and OM3) was significantly lower compared to that seen at Tp0 in pCR, indicating the presence of residual disease in these shells. CONCLUSION: Pre-surgery information may serve as a guide to define cancer free margins and the extent of residual disease which may be useful in planning breast conservation surgery.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/terapia , Imagem de Difusão por Ressonância Magnética , Terapia Neoadjuvante , Neoplasia Residual/terapia , Adulto , Idoso , Área Sob a Curva , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Estudos de Coortes , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Mastectomia , Pessoa de Meia-Idade , Necrose , Curva ROC , Indução de Remissão , Resultado do Tratamento , Adulto Jovem
19.
Expert Rev Hematol ; 10(7): 627-636, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28504024

RESUMO

INTRODUCTION: Myelofibrosis (MF) is the most aggressive form among Philadelphia negative (Ph-) myeloproliferative neoplasms (MPNs). In the last years, the mutational landscape of MF has expanded remarkably by the identification of additional recurrent mutations, called subclonal mutations. Areas covered: Here we describe the available data about the currently identified subclonal mutations and their prognostic value in MF patients. We also review the practical value of including such molecular information in available prognostic models for both outcome prediction and possibly treatment decision with regards to transplant indication. Lastly, we covered the available data on the application of molecular markers for minimal residual disease (MRD) monitoring after transplantation. Expert commentary: The demonstration of the prognostic value of additional mutations suggests to define this molecular profile at diagnosis and when an allogeneic transplant can be advised, particularly in younger patients. The presence of molecular markers might offer the possibility to evaluate the depth of remission and to monitor MRD after transplantation. Prospective clinical studies are needed to validate the use of this molecular data in the routine clinical practice.


Assuntos
Mutação , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/etiologia , Biomarcadores , Evolução Clonal/genética , Predisposição Genética para Doença , Transplante de Células-Tronco Hematopoéticas , Humanos , Janus Quinase 2/genética , Neoplasia Residual/diagnóstico , Neoplasia Residual/terapia , Mielofibrose Primária/terapia , Prognóstico , Proteínas Repressoras/genética , Transplante Homólogo , Resultado do Tratamento
20.
Expert Rev Hematol ; 10(6): 563-574, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28475434

RESUMO

INTRODUCTION: Current standards for monitoring the response of acute myeloid leukemia (AML) are based on morphologic assessments of the bone marrow and recovery of peripheral blood counts. A growing experience is being developed to enhance the detection of small amounts of AML, or minimal residual disease (MRD). Areas covered: Available techniques include multi-color flow cytometry (MFC) of leukemia associated immunophenotypes (LAIP), quantitative reverse transcriptase polymerase chain reaction (QRT-PCR) for detecting fusion and mutated genes (RUNX1-RUNX1T1, CBFB-MYH11, and NPM1), overexpression of genes such as WT1, and next generation sequencing (NGS) for MRD. Expert commentary: While MRD monitoring is standard of care in some leukemia subsets such as acute promyelocytic leukemia, this approach for the broader AML population does not universally predict outcomes as some patients may experience relapse in the setting of undetectable leukemia while others show no obvious disease progression despite MRD positivity. However, there are instances where MRD can identify patients at increased risk for relapse that may change recommended therapy. Currently, prospective investigations to define clinically relevant MRD thresholds are ongoing. Risk-adapted trials are needed to best define the use of MRD in the follow up of AML patients after initial induction therapy.


Assuntos
Tomada de Decisões , Leucemia Promielocítica Aguda/sangue , Leucemia Promielocítica Aguda/terapia , Citometria de Fluxo/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Monitorização Fisiológica/métodos , Neoplasia Residual/irrigação sanguínea , Neoplasia Residual/terapia , Proteínas de Fusão Oncogênica/sangue , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos
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