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1.
Cell Stem Cell ; 24(1): 25-40, 2019 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-30595497

RESUMO

Tumors are composed of non-homogeneous cell populations exhibiting varying degrees of genetic and functional heterogeneity. Cancer stem cells (CSCs) are capable of sustaining tumors by manipulating genetic and non-genetic factors to metastasize, resist treatment, and maintain the tumor microenvironment. Understanding the key traits and mechanisms of CSC survival provides opportunities to improve patient outcomes via improved prognostic models and therapeutics. Here, we review the clinical significance of CSCs and results of potential CSC-targeting therapies in various cancers. We discuss barriers to translating cues from pre-clinical models into clinical applications and propose new strategies for rational design of future anti-CSC trials.

2.
Nat Commun ; 9(1): 578, 2018 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-29422613

RESUMO

Tumors adapt their phenotypes during growth and in response to therapies through dynamic changes in cellular processes. Connexin proteins enable such dynamic changes during development, and their dysregulation leads to disease states. The gap junction communication channels formed by connexins have been reported to exhibit tumor-suppressive functions, including in triple-negative breast cancer (TNBC). However, we find that connexin 26 (Cx26) is elevated in self-renewing cancer stem cells (CSCs) and is necessary and sufficient for their maintenance. Cx26 promotes CSC self-renewal by forming a signaling complex with the pluripotency transcription factor NANOG and focal adhesion kinase (FAK), resulting in NANOG stabilization and FAK activation. This FAK/NANOG-containing complex is not formed in mammary epithelial or luminal breast cancer cells. These findings challenge the paradigm that connexins are tumor suppressors in TNBC and reveal a unique function for Cx26 in regulating the core self-renewal signaling that controls CSC maintenance.

3.
Blood Cancer J ; 8(1): 4, 2018 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-29321554

RESUMO

Intermediate-risk acute myeloid leukemia (IR-AML) is a clinically heterogeneous disease, for which optimal post-remission therapy is debated. The utility of next-generation sequencing information in decision making for IR-AML has yet to be elucidated. We retrospectively studied 100 IR-AML patients, defined by European Leukemia Net classification, who had mutational information at diagnosis, received intensive chemotherapy and achieved complete remission (CR) at Cleveland Clinic (CC). The Cancer Genome Atlas (TCGA) data were used for validation. In the CC cohort, median age was 58.5 years, 64% had normal cytogenetics, and 31% required >1 induction cycles to achieve CR1. In univariable analysis, patients carrying mutations in DNMT3A, U2AF1, and EZH2 had worse overall and relapse-free survival. After adjusting for other variables, the presence of these mutations maintained an independent effect on survival in both CC and TCGA cohorts. Patients who did not have the mutations and underwent hematopoietic cell transplant (HCT) had the best outcomes. HCT improved outcomes for patients who had these mutations. RUNX1 or ASXL1 mutations did not predict survival, and performance of HCT did not confer a significant survival benefit. Our results provide evidence of clinical utility in considering mutation screening to stratify IR-AML patients after CR1 to guide therapeutic decisions.


Assuntos
DNA (Citosina-5-)-Metiltransferases/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Leucemia Mieloide Aguda , Fator de Processamento U2AF/genética , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Mutação , Estudos Prospectivos , Fatores de Risco , Taxa de Sobrevida
4.
Leuk Lymphoma ; 59(2): 363-371, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28693363

RESUMO

Outcomes of relapsed adult acute lymphoblastic leukemia (ALL) have improved over time with the introduction of new therapies as well as better supportive care. However, there is still a need for easy-to-use and accurate prognostic tools for patients in first relapse. Whether complete response (CR) with incomplete count recovery (CRh) can be grouped with CR in relapsed ALL trials has not been formally studied. We analyzed 106 ALL patients at first relapse who were treated at three academic centers and achieved CR/CRh. White blood cell count at initial diagnosis and receiving hematopoietic cell transplant (HCT) were independent predictors of overall survival after relapse, while minimal residual disease (MRD) positivity and performance of HCT were predictors of relapse free survival (RFS). Patients who achieved MRD negativity and underwent HCT had the best outcomes. Our results suggest that MRD is a more powerful predictor of outcome than CRh.


Assuntos
Contagem de Leucócitos , Neoplasia Residual/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Adolescente , Adulto , Idoso , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Indução de Remissão , Retratamento , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
5.
Cancer Res ; 77(19): 5222-5227, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28928129

RESUMO

The second International Cancer Stem Cell Conference in Cleveland, Ohio, on September 20-23, 2016, convened 330 attendees from academic, industrial, and clinical organizations. It featured a debate on the concepts and challenges of the cancer stem cells (CSC) as well as CSC-centered scientific sessions on clinical trials, genetics and epigenetics, tumor microenvironment, immune suppression, metastasis, therapeutic resistance, and emerging novel concepts. The conference hosted 35 renowned speakers, 100 posters, 20 short talks, and a preconference workshop. The reported advances of CSC research and therapies fostered new collaborations across national and international borders, and inspired the next generation's young scientists. Cancer Res; 77(19); 5222-7. ©2017 AACR.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/patologia , Células-Tronco Neoplásicas/patologia , Microambiente Tumoral/efeitos dos fármacos , Animais , Epigênese Genética , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Células-Tronco Neoplásicas/efeitos dos fármacos
6.
J Exp Med ; 214(9): 2715-2732, 2017 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-28838952

RESUMO

Effective targeting of cancer stem cells (CSCs) requires neutralization of self-renewal and chemoresistance, but these phenotypes are often regulated by distinct molecular mechanisms. Here we report the ability to target both of these phenotypes via CD55, an intrinsic cell surface complement inhibitor, which was identified in a comparative analysis between CSCs and non-CSCs in endometrioid cancer models. In this context, CD55 functions in a complement-independent manner and required lipid raft localization for CSC maintenance and cisplatin resistance. CD55 regulated self-renewal and core pluripotency genes via ROR2/JNK signaling and in parallel cisplatin resistance via lymphocyte-specific protein tyrosine kinase (LCK) signaling, which induced DNA repair genes. Targeting LCK signaling via saracatinib, an inhibitor currently undergoing clinical evaluation, sensitized chemoresistant cells to cisplatin. Collectively, our findings identify CD55 as a unique signaling node that drives self-renewal and therapeutic resistance through a bifurcating signaling axis and provides an opportunity to target both signaling pathways in endometrioid tumors.


Assuntos
Antineoplásicos/uso terapêutico , Antígenos CD55/fisiologia , Autorrenovação Celular/fisiologia , Cisplatino/uso terapêutico , Neoplasias do Endométrio/fisiopatologia , Animais , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Neoplasias do Endométrio/tratamento farmacológico , Feminino , Camundongos , Camundongos SCID , Transplante de Neoplasias , Células-Tronco Neoplásicas/fisiologia , Transdução de Sinais
7.
Am J Hematol ; 92(10): 989-996, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28612386

RESUMO

International prognostic index (IPI) has remained the primary prognostic tool in diffuse large B cell lymphoma (DLBCL) for more than 20 years. Even though the disease is more common in older population, the impact of comorbidities, dose reductions, and treatment-related adverse events (TAEs) on the outcome in elderly DLBCL patients has not been well established. We studied 413 consecutive patients aged ≥ 60 years who were treated at the Cleveland Clinic. The median age at diagnosis was 69 years, 58% of patients had high IPI score, and 85% had low Charlson comorbidity index (CCI). Forty percent of patients required dose reductions during treatment, 78% achieved CR, and 70% experienced at least one grade II-IV TAE. High IPI score, high CCI, reduced dose chemotherapy, TAE, and hospitalization were significant predictors of death and relapse. In multivariable analysis, high IPI and CCI were independent predictors of overall and progression free survival. A simple model combining IPI and CCI could reliably distinguish three prognostically separate risk groups. Our results suggest that incorporation of CCI in current prognostic models can improve prognostication of older DLBCL patients and CCI might be a valuable tool in evaluating the eligibility of older patients for clinical trial enrollment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Linfoma Difuso de Grandes Células B , Idoso , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/efeitos adversos , Anticorpos Monoclonais Murinos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Comorbidade , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Feminino , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/epidemiologia , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Vincristina/uso terapêutico
8.
J Hematol Oncol ; 10(1): 93, 2017 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-28420416

RESUMO

Acute myeloid leukemia (AML) is characterized by clinical and biological heterogeneity. Despite the advances in our understanding of its pathobiology, the chemotherapy-directed management has remained largely unchanged in the past 40 years. However, various novel agents have demonstrated clinical activity, either as single agents (e.g., isocitrate dehydrogenase (IDH) inhibitors, vadastuximab) or in combination with standard induction/consolidation at diagnosis and with salvage regimens at relapse. The classes of agents described in this review include novel cytotoxic chemotherapies (CPX-351 and vosaroxin), epigenetic modifiers (guadecitabine, IDH inhibitors, histone deacetylase (HDAC) inhibitors, bromodomain and extraterminal (BET) inhibitors), FMS-like tyrosine kinase receptor 3 (FLT3) inhibitors, and antibody-drug conjugates (vadastuximab), as well as cell cycle inhibitors (volasertib), B-cell lymphoma 2 (BCL-2) inhibitors, and aminopeptidase inhibitors. These agents are actively undergoing clinical investigation alone or in combination with available chemotherapy.


Assuntos
Antineoplásicos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Quimioterapia Combinada/métodos , Quimioterapia Combinada/tendências , Humanos
9.
JCO Clin Cancer Inform ; 1: 1-14, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-30657399

RESUMO

PURPOSE: Drug development in oncology is resource intensive, time consuming, and frequently unsuccessful. Here, we hypothesized that therapeutic benefit of published phase I studies of antimyeloma investigational agents was associated with advancement to phase II and future regulatory approval. PATIENTS AND METHODS: Seventy four phase I trials that treated patients with multiple myeloma (n = 2,408) conducted from 2004 to 2015 were analyzed to assess drug safety, efficacy, phase advancement, and regulatory approval. RESULTS: The median overall response rate (ORR) for all single-agent trials evaluated was 13.2%. However, the ORR in trials that advanced to phase II was 19%, whereas it was only 4% in trials that failed to advance. The median ORR was 23% for trials testing agents that were ultimately approved by the US Food and Drug Administration compared with only 8% for trials testing agents that were not approved (hazard ratio, 2.21; 95% CI, 2.01 to 2.61; P = .012). Importantly, the absolute number of phase I trials in multiple myeloma, but not the success rate, significantly increased over the period studied. The proportion of industry-sponsored trials also steadily increased over that same period. The ratio of initial dose to maximum tolerated dose was 0.29, suggesting that many patients were undertreated. CONCLUSION: Investigational agents with higher ORRs in phase I trials were more likely to advance to phase II trials and achieve US Food and Drug Administration approval. Our results suggest that designing phase I trials to maximize the antimyeloma efficacy of a given compound may lead to more successful and cost-effective drug development.


Assuntos
Antineoplásicos/uso terapêutico , Drogas em Investigação/uso terapêutico , Mieloma Múltiplo/epidemiologia , Mieloma Múltiplo/terapia , Antineoplásicos/administração & dosagem , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Aprovação de Drogas , Drogas em Investigação/administração & dosagem , Feminino , Humanos , Masculino , Prognóstico , Resultado do Tratamento , Estados Unidos , United States Food and Drug Administration
10.
Methods Mol Biol ; 1516: 319-333, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27221339

RESUMO

Cancer stem cells have been identified in primary tumors, patient derived xenografts, and established cancer cell lines. The development of reporters has enabled investigators to rapidly enrich for these cells and more importantly track these cells in real time. Here we describe the current state of the reporter field and their use and limitations in multiple cancers.


Assuntos
Genes Reporter/genética , Biologia Molecular/métodos , Neoplasias/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Humanos , Proteína Homeobox Nanog/genética , Proteína Homeobox Nanog/metabolismo , Neoplasias/patologia , Células-Tronco Neoplásicas/patologia
11.
Oncotarget ; 7(21): 30511-22, 2016 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-27105520

RESUMO

The mainstay of treatment for ovarian cancer is platinum-based cytotoxic chemotherapy. However, therapeutic resistance and recurrence is a common eventuality for nearly all ovarian cancer patients, resulting in poor median survival. Recurrence is postulated to be driven by a population of self-renewing, therapeutically resistant cancer stem cells (CSCs). A current limitation in CSC studies is the inability to interrogate their dynamic changes in real time. Here we utilized a GFP reporter driven by the NANOG-promoter to enrich and track ovarian CSCs. Using this approach, we identified a population of cells with CSC properties including enhanced expression of stem cell transcription factors, self-renewal, and tumor initiation. We also observed elevations in CSC properties in cisplatin-resistant ovarian cancer cells as compared to cisplatin-naïve ovarian cancer cells. CD49f, a marker for CSCs in other solid tumors, enriched CSCs in cisplatin-resistant and -naïve cells. NANOG-GFP enriched CSCs (GFP+ cells) were more resistant to cisplatin as compared to GFP-negative cells. Moreover, upon cisplatin treatment, the GFP signal intensity and NANOG expression increased in GFP-negative cells, indicating that cisplatin was able to induce the CSC state. Taken together, we describe a reporter-based strategy that allows for determination of the CSC state in real time and can be used to detect the induction of the CSC state upon cisplatin treatment. As cisplatin may provide an inductive stress for the stem cell state, future efforts should focus on combining cytotoxic chemotherapy with a CSC targeted therapy for greater clinical utility.


Assuntos
Autorrenovação Celular/genética , Cisplatino/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Neoplasias Ovarianas/genética , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Feminino , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Proteína Homeobox Nanog/genética , Proteína Homeobox Nanog/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Regiões Promotoras Genéticas/genética , Imagem com Lapso de Tempo/métodos , Transplante Heterólogo
12.
Pathol Oncol Res ; 21(4): 1209-16, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26037169

RESUMO

Current methods for diagnosis and staging of prostate adenocarcinoma are not sensitive enough to distinguish between patients with indolent disease and those that should receive radical treatment. Epithelial-mesenchymal transition (EMT) is a well-characterized process involved in tumor invasion and metastasis. The aim of this study is to analyze the expression of ß-catenin, Snail, and E-cadherin in prostate cancer patients with prospective evaluation of their value in predicting disease-free survival (DFS). One-hundred-and-three consecutive prostate carcinoma patients who underwent radical prostatectomy and 35 patients with benign prostate hyperplasia (BPH) were enrolled. Age, initial PSA level, tumor size and clinical stage were documented for adenocarcinoma patients and they were enrolled in active surveillance with serum PSA levels. Recurrence was defined as PSA level of ≥ 0.2 ng/ml on at least 2 occasions over a 2-month period. Immunohistochemical staining intensity was scored as negative, weakly positive, moderately positive, and strongly positive. For Snail and ß-catenin immunoreaction, the tumors were considered nuclear positive when more than 5 % of the nuclei of tumor cells were positively stained. Patients with prostate cancer had weaker ß-catenin (p < 0.0001), Snail (p = 0.006), and E-cadherin (p = 0.02) staining when compared to BPH patients and the frequency of nuclear positivity for ß-catenin and Snail were higher in adenocarcinoma group (p < 0.0001). Increased expression and nuclear positivity of ß-catenin were associated with advanced stage (p = 0.012 and p = 0.003) and higher tumor volume (p = 0.013 and p = 0.002). Additionally, patients with increased Snail expression had higher Gleason scores and tumor volume at presentation (p = 0.008 and p = 0.004). However, there were no significant DFS differences in adenocarcinoma patients who did and did not have ß-catenin, Snail, and E-cadherin expression as assessed with log-rank test. Expressions of ß-catenin, Snail, and E-cadherin were significantly lower in prostate cancer patients compared to BPH patients and both ß-catenin and Snail had nuclear staining pattern in patients with adenocarcinoma. However, none of these markers predicted DFS in 36-month follow up of our cohort.


Assuntos
Adenocarcinoma/patologia , Biomarcadores Tumorais/metabolismo , Caderinas/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Neoplasias da Próstata/patologia , Fatores de Transcrição/metabolismo , beta Catenina/metabolismo , Adenocarcinoma/metabolismo , Intervalo Livre de Doença , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Prospectivos , Prostatectomia/métodos , Neoplasias da Próstata/metabolismo , Fatores de Transcrição da Família Snail
13.
Clin Exp Rheumatol ; 33(6 Suppl 94): S30-5, 2015 Nov-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25797433

RESUMO

OBJECTIVES: To evaluate the frequency of suicidal ideation among Behçet's syndrome (BS) patients compared to healthy and diseased controls and to delineate possible factors predicting an increase in suicidal ideation. METHODS: We included consecutive BS patients attending our outpatient clinic, patients with ankylosing spondylitis (AS) and healthy hospital staff as controls. Suicidal ideation was assessed by a standard questionnaire. Linear regression was used to identify the factors associated with suicidal ideation, such as demographic and clinical features, drugs, disease activity assessed using the Behçet's disease current activity form (BDCAF) for BS patients and BASDAI for AS patients, Behçet's disease quality of life (BDQoL) and Beck depression inventory (BDI) score. RESULTS: We surveyed 303 BS patients, 52 AS patients and 106 healthy controls. Suicidal thoughts, as reflected by a positive response to the first three items of the questionnaire, were higher among BS patients with major organ involvement (42%) than those with mucocutaneous involvement (35%) and the control groups. There were significantly more BS patients with active major organ involvement who had thought to terminate their lives without plans within the last year (25.5%) compared to those with active mucocutaneous involvement (8.7%) and active AS patients (10%) (p=0.012). Patient-reported joint pain (ß=-0.155, p=0.046), BDQoL (ß=0.176, p=0.032), and BDI (ß=0.017, p<0.0001) scores, suicidal thoughts before the onset of BS (ß=-0.124, p=0.043), neurologic involvement (ß=0.119, p=0.047) and past prednisone use (ß=0.212, p=0.005) were independent predictors of suicidal thoughts. CONCLUSIONS: BS patients with major organ involvement have increased thoughts of suicide during the active stages of their disease. A number of risk factors could help physicians to identify patients with increased suicidal thoughts.


Assuntos
Síndrome de Behçet/psicologia , Ideação Suicida , Adulto , Idade de Início , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/epidemiologia , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Efeitos Psicossociais da Doença , Estudos Transversais , Depressão/diagnóstico , Depressão/epidemiologia , Depressão/psicologia , Feminino , Humanos , Modelos Lineares , Masculino , Prognóstico , Qualidade de Vida , Fatores de Risco , Índice de Gravidade de Doença , Inquéritos e Questionários , Fatores de Tempo , Turquia/epidemiologia , Adulto Jovem
14.
Curr Med Chem ; 22(16): 1976-85, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25666786

RESUMO

Behcet's s yndrome (BS) is a multisystem vasculitis with frequent mucocutaneous, joint, eye and visceral organ involvement. From early 2000s, biologic drugs have been increasingly used in the management of BS, enabling rapid and complete remission in most cases with critical organ involvement. Despite the current experience with steroids and traditional immunosuppressives, biologics are exceptionally promising for treatment of resistant cases. Among the biologics used in BS, TNF-alpha antagonists are the oldest and their efficacy has been proven in recalcitrant ocular, vascular, gastrointestinal and neurologic involvements. These drugs have significantly reduced morbidity and mortality in BS and they have an acceptable safety profile. Tocilizumab, an IL6 receptor antibody, has been shown to be effective in BS patients with neurologic involvement and amyloidosis, and IL1ß antagonists such as anakinra, canakinumab, gevokizumab were effective in the management of ocular involvement. Studies investigating the efficacy of daclizumab, IL2 receptor antibody, and secukinumab, IL17 monoclonal antibody, in the management of BS with eye involvement failed to demonstrate significant clinical improvement and both studies were halted. A monoclonal vascular endothelial growth factor antagonist, bevacizumab, was shown to be effective in BS-related macular edema. Alemtuzumab and ustekinumab are among other biologics which were effective in controlling disease symptoms. In this review, we discuss the efficacy and safety of various recently developed biologic agents targeting different pathways involved in the pathogenesis of BS.


Assuntos
Síndrome de Behçet/tratamento farmacológico , Fatores Biológicos/uso terapêutico , Humanos
17.
Leuk Res ; 38(6): 699-705, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24720908

RESUMO

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and despite the intense combination chemotherapy, cure rates are less than 90%. Several prognostic parameters, including nonneoplastic hematologic cell counts during induction phase, are suggested to predict outcome in ALL. We analyzed 242 ALL patients treated in our center to investigate individual prognostic parameters and the impact of delays on disease outcome. Age at diagnosis, risk groups, extramedullary involvement, t(9;22), prednisone response, bone marrow response at days 15 and 33, day 15 platelet count, day 33 lymphocyte, monocyte, and platelet counts, treatment delay, sepsis, and omission of day 64 cyclophosphamide were valuable predictors of survival in univariate analysis. However only the age, CNS involvement, omission of cyclophosphamide, and total delay during treatment were associated with survival in multivariate analysis. Omission of second cyclophosphamide dose had no impact on survival of standard risk group patients, but adversely affected the long term survival of medium risk group (MRG) patients. The second dose might be given with the first dose on day 36 to MRG patients to prevent delays. Day 15 and 33 platelet counts are promising predictors of survival in low income countries where assessment of minimal residual disease is difficult, but this data needs further consolidation.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos
18.
Rheumatology (Oxford) ; 53(5): 828-33, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24369417

RESUMO

OBJECTIVES: Behçet's syndrome (BS) follows an active course during the childbearing years in both men and women. We formally surveyed the infertility rate and the effect of drugs and types of organ involvement on fertility in BS. METHODS: We compared fertility among BS patients with and without major organ involvement with those with FMF, AS and healthy controls. A structured interview was performed and the medical records of the patients were reviewed to confirm the sites of involvement and drugs they used during their entire follow-up. RESULTS: The number of female patients who were not able to ever conceive, who were not able to conceive before or after disease onset or who were able to conceive late or only with assisted reproductive technology was not increased among the BS group. The same was true for the male patients to successfully achieve a conception and/or father a child. The average number of children, miscarriages, terminations and ectopic pregnancies were similar among the groups. Infertility was more common in BS patients with major organ involvement who used cyclophosphamide (CYC) compared with those who did not (P = 0.009). CONCLUSION: Infertility is not appreciably increased among BS patients attending a dedicated outpatient clinic. Major organ involvement does not increase the risk of infertility and CYC is the only drug that seems to compromise fertility in BS.


Assuntos
Síndrome de Behçet/complicações , Síndrome de Behçet/tratamento farmacológico , Infertilidade Feminina/epidemiologia , Infertilidade Masculina/epidemiologia , Adulto , Estudos de Casos e Controles , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Febre Familiar do Mediterrâneo/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Espondilite Anquilosante/complicações
19.
Crit Rev Oncol Hematol ; 88(2): 253-71, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23755890

RESUMO

Dendritic cell tumors are extremely rare and current knowledge on these tumors is limited. The characteristics of three dendritic cell sarcoma subtypes and their optimal treatment approaches are not fully clarified. We aimed to make a systematic review of the literature and enrich the current data with five new cases. Pooled analysis of 462 reported cases revealed that the tumor had no age, gender or racial predilection. Our analysis suggests that the young age, advanced stage, intraabdominal involvement and unfavorable histological features (i.e. large tumor size, absence of lymphoplasmacytic infiltration, coagulative necrosis, high mitotic count) may predict poor prognosis. Subtypes of this tumor have different clinical behaviors with interdigitating dendritic cell sarcoma being the most aggressive form. In general, surgery is the most effective treatment modality and adjuvant radiotherapy has no significant effect on overall survival of patients. The role of chemotherapy for the management of advanced disease is controversial.


Assuntos
Células Dendríticas/patologia , Transtornos Histiocíticos Malignos/patologia , Sarcoma/patologia , Adulto , Feminino , Transtornos Histiocíticos Malignos/diagnóstico , Transtornos Histiocíticos Malignos/mortalidade , Transtornos Histiocíticos Malignos/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Sarcoma/diagnóstico , Sarcoma/mortalidade , Sarcoma/terapia , Resultado do Tratamento , Carga Tumoral
20.
Int J Clin Exp Pathol ; 6(6): 1068-75, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23696924

RESUMO

UNLABELLED: Primary central nervous system lymphoma (PCNSL) is defined as the involvement of brain, leptomeninges, eyes or spinal cord by non-Hodgkin lymphoma. The role of various prognostic markers in predicting adverse outcome is debated. OBJECTIVES: To investigate the clinical and immunohistochemical findings of immunocompetent PCNSL cases (39 cases) diagnosed at the study center, and evaluate the influence of potential prognostic factors on overall survival (OS) of patients. METHODS: Data regarding patient characteristics, neuroimaging, pathological and immunohistochemical features and follow-up were obtained from patient records. The influence of potential prognostic parameters on OS was investigated by log-rank test and Cox regression analysis. RESULTS: Patients who received combined chemotherapy and radiotherapy had a significantly better OS when compared to chemotherapy alone. Other variables included in this study were not associated with a significant survival advantage. CONCLUSION: In this study, we failed to demonstrate a relationship between different clinicopathological variables and OS of patients. Prospective studies with large patient series are needed to investigate other potential prognostic factors.


Assuntos
Neoplasias do Sistema Nervoso Central/imunologia , Imunocompetência , Linfoma não Hodgkin/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Neoplasias do Sistema Nervoso Central/mortalidade , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/terapia , Quimiorradioterapia , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfoma não Hodgkin/mortalidade , Linfoma não Hodgkin/patologia , Linfoma não Hodgkin/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Turquia , Adulto Jovem
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