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1.
Br J Cancer ; 124(11): 1795-1802, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33762716

RESUMO

BACKGROUND: Preoperative chemotherapy containing anthracyclines and taxanes is well established in early-stage breast cancer. Previous studies have suggested that the chemotherapy sequence may matter but definitive evidence is missing. ABCSG trial 34 evaluated the activity of the MUC1 vaccine tecemotide when added to neoadjuvant treatment; the study provided the opportunity for the second randomisation to compare two different anthracycline/taxane sequences. METHODS: HER2-negative early-stage breast cancer patients were recruited to this randomised multicentre Phase 2 study. Patients in the chemotherapy cohort (n = 311) were additionally randomised to a conventional or reversed sequence of epirubicin/cyclophosphamide and docetaxel. Residual cancer burden (RCB) with/without tecemotide was defined as primary study endpoint; RCB in the two chemotherapy groups was a key secondary endpoint. RESULTS: No significant differences in terms of RCB 0/I (40.1% vs. 37.2%; P = 0.61) or pathologic complete response (pCR) rates (24.3% vs. 25%, P = 0.89) were observed between conventional or reverse chemotherapy sequence. No new safety signals were reported, and upfront docetaxel did not result in decreased rates of treatment delay or discontinuation. CONCLUSION: Upfront docetaxel did not improve chemotherapy activity or tolerability; these results suggest that upfront neoadjuvant treatment with anthracyclines remains a valid option.

2.
Eur J Cancer ; 134: 99-106, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32502940

RESUMO

BACKGROUND: Neoadjuvant chemotherapy (NaCT) and neoadjuvant endocrine therapy (NET) can reduce pre-operative tumour burden in patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative early-stage breast cancer. This prospective translational study assessed the ability of a 12-gene molecular score (MS; EndoPredict®) to predict response to NaCT or NET within the ABCSG-34 trial. PATIENTS AND METHODS: Hormone receptor (HR)-positive, HER2-negative samples from patients in the ABCSG-34 randomized phase II trial were selected and EndoPredict testing was performed to generate a 12-gene MS. ABCSG-34 patients were assigned to receive either NaCT or NET based on menopausal status, HR expression, grade and Ki67. Response was measured by residual cancer burden (RCB). RESULTS: Patients selected for NaCT generally had high-risk disease by 12-gene MS (125/134), while slightly more patients treated with NET had low-risk disease (44/83). Low-risk NaCT-treated and high-risk NET-treated tumours responded poorly (NPV 100% [95% CI 66.4%-100%] and NPV 92.3% [95% CI 79.1%-98.4%], respectively]. The 12-gene MS significantly predicted treatment response for NaCT (AUC 0.736 [95% CI 0.63-0.84]) and NET (AUC 0.726 [95% CI 0.60-0.85]). CONCLUSIONS: The 12-gene MS predicted RCB after treatment with neoadjuvant therapies for patients with HR-positive, HER2-negative early-stage breast cancer. Tumours with low MS were unlikely to benefit from NaCT, whereas a high MS predicted resistance to NET. This additional biologic information can aid personalized treatment selection in daily practice and builds a strong rationale to use EndoPredict in biomarker-driven studies in the neoadjuvant setting.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Terapia Neoadjuvante , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Quimioterapia Adjuvante , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos
3.
Wien Klin Wochenschr ; 132(15-16): 415-422, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32533444

RESUMO

BACKGROUND: Several clinical trials in chronic phase (CP) chronic myeloid leukemia (CML) showed that early response to tyrosine kinase inhibitor (TKI) treatment results in an improved long-term survival and progression-free survival. This study assessed whether patients achieving early treatment response (ETR; partial cytogenetic response or BCR-ABL1 mRNA ≤10% at 3 months) in daily practice also have a long-term survival benefit. METHODS: The Retrospective Evaluation of Early response in CML for long-term Treatment outcome (R-EFECT), a multicenter, retrospective chart review, documented patients with newly diagnosed CML-CP starting first-line TKI therapy in routine clinical practice. The primary aim was to assess the 5­year overall survival rate. RESULTS: Of the 211 patients from 12 centers across Austria (January 2004-May 2010), 176 (median age, 56 years) were included in the analysis. All patients received first-line therapy with imatinib. Overall, 136 patients (77.3%) achieved ETR (ETR+ group), whereas 40 (22.7%) did not reach ETR (ETR- group). The ETR+ group had higher 5­year overall survival (92.5% vs. 77.5%, P = 0.018) and progression-free survival (95.6% vs. 87.5%, P = 0.06) rates compared with the ETR- group. As expected, more patients in the ETR- group were switched to another TKI. At the last contact, 120 patients were still on imatinib and 44 had switched to another TKI (25 to nilotinib, 15 to dasatinib, and 4 to bosutinib). CONCLUSION: The data are in line with randomized trials demonstrating that ETR is associated with improved survival and thus confirmed these results in patients treated in daily clinical routine.


Assuntos
Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Mieloide de Fase Crônica , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Áustria , Dasatinibe/uso terapêutico , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
4.
Radiat Oncol ; 15(1): 111, 2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32410643

RESUMO

PURPOSE: To report the long-term outcomes of neoadjuvant altered fractionation short-course radiotherapy in 271 consecutive patients with stage II-III rectal cancer. PATIENTS AND METHODS: This was a retrospective single institution study with median follow-up of 101 months (8.4 years). Patients who were alive at the time of analysis in 2018 were contacted to obtain functional outcome data (phone interview). Radiotherapy consisted of 25 Gy in 10 fractions of 2.5 Gy administered twice daily. Median time interval to surgery was 5 days. RESULTS: Local relapse was observed in 12 patients (4.4%) after a median of 28 months. Overall survival after 5 and 10 years was 73 and 55.5%, respectively (corresponding disease-free survival 65.5 and 51%). Of all patients without permanent stoma, 79% reported no low anterior resection syndrome (LARS; 0-20 points), 9% reported LARS with 21-29 points and 12% serious LARS (30-42 points). CONCLUSION: The present radiotherapy regimen was feasible and resulted in low rates of local relapse. Most patients reported good functional outcomes.


Assuntos
Fracionamento da Dose de Radiação , Radioterapia Adjuvante/métodos , Neoplasias Retais/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Terapia Neoadjuvante/mortalidade , Recidiva Local de Neoplasia/epidemiologia , Radioterapia Adjuvante/mortalidade , Neoplasias Retais/mortalidade , Estudos Retrospectivos , Resultado do Tratamento
5.
Eur J Cancer ; 132: 43-52, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32325419

RESUMO

BACKGROUND: Immune-based strategies represent a promising approach in breast cancer (BC) treatment. The glycoprotein mucin-1 (MUC-1) is overexpressed in more than 90% of BC patients, and is targeted by the cancer vaccine tecemotide. We have investigated the efficacy and safety of tecemotide when added to neoadjuvant standard-of-care (SoC) treatment in early BC patients. PATIENTS AND METHODS: A total of 400 patients with HER2-early BC were recruited into this prospective, multicentre, randomised 2-arm academic phase II trial. Patients received preoperative SoC treatment (chemotherapy or endocrine therapy) with or without tecemotide. Postmenopausal women with oestrogen receptor (ER)+++, or ER++ and Ki67 < 14%, and G1,2 tumours ('luminal A' tumours) received 6 months of letrozole. Postmenopausal patients with triple-negative, ER-/+/++ and Ki67 ≥ 14%, and with G3 tumours, as well as premenopausal patients, received four cycles of epirubicin/cyclophosphamide plus four cycles of docetaxel. Primary end-point was residual cancer burden (RCB; 0/I versus II/III) at surgery. Secondary end-points included pathological complete response (pCR), safety, and quality of life. FINDINGS: We observed no significant difference in RCB 0/I rates between patients with (36.4%) and without (31.9%) tecemotide in the overall study population (p = 0.40) nor in endocrine and chemotherapy-treated subgroups (25.0% versus 13.3%, p = 0.17; 39.6% versus 37.8%, p = 0.75, respectively). The addition of tecemotide did not affect overall pCR rates (22.5% versus 17.4%, p = 0.23), MUC-1 expression, or tumour-infiltrating lymphocytes content. Tecemotide did not increase toxicity when compared to SoC therapy alone. INTERPRETATION: Neoadjuvant tecemotide is safe, but does not improve RCB or pCR rates in patients receiving standard neoadjuvant therapy.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Vacinas Anticâncer/uso terapêutico , Glicoproteínas de Membrana/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Segurança do Paciente , Prognóstico , Estudos Prospectivos , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo
6.
Clin Breast Cancer ; 19(1): 58-62, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30197244

RESUMO

BACKGROUND: The purpose of this study was to analyze risk factors for ipsilateral in-breast relapse and inferior disease-free survival (DFS) after standard adjuvant whole-breast radiotherapy (± boost and systemic treatment) as part of a multimodal breast-conserving approach. PATIENTS AND METHODS: Decision trees were built through recursive partitioning analysis (RPA). The median follow-up for all 2161 patients was 114 months (9.5 years). RESULTS: Local relapse in the treated breast was uncommon (actuarial rates after 5 and 10 years were 2.7% and 5.8%, respectively). In RPA, the first split was related to age (52 years), with younger patients having a significantly higher risk of local relapse. The younger patients were stratified further by lymph node ratio (LNR). In patients older than 52 years, lack of endocrine treatment was associated with significantly higher risk. DFS was 80.7% at 10 years. The first split was caused by LNR, and the group with unfavorable LNR (> 0.20) could not be stratified further. Ten-year DFS in this group was as low as 50.6%. Patients with favorable LNR (0-0.20) could be stratified by additional risk factors, in particular primary tumor size. CONCLUSION: RPA is a suitable method to assign patients with early stage breast cancer to different risk groups, both regarding local relapse and DFS. Although age was a major risk factor for local relapse after breast-conserving management, LNR was associated with both endpoints. The systemic treatment approaches used in this study failed to provide satisfactory DFS in patients with LNR > 0.20 and 2 other subgroups.


Assuntos
Neoplasias da Mama/mortalidade , Mastectomia Segmentar/mortalidade , Recidiva Local de Neoplasia/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Taxa de Sobrevida
7.
Clin Exp Metastasis ; 34(6-7): 431-440, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-29134398

RESUMO

Worldwide, colon cancer is among the most common cancer entities. Understanding the molecular background is the key to enable accurate stage determination, which is crucial to assess optimal therapy options. The search for preoperative biomarkers is ongoing. In recent years, several studies have proposed a diagnostic and prognostic role for miRNAs in cancer. Aim of this study was to evaluate miRNA expression patterns correlating with tumor stage, especially lymph node metastasis, in primary colon carcinoma tissue. Screening was accomplished using GeneChip® miRNA v3.0 arrays (Thermo Fisher Scientific, Waltham, MA, USA) and validated via TaqMan® qPCR assays (Thermo Fisher Scientific, Waltham, MA, USA) to investigate miRNA expressions in 168 FFPE and 83 fresh frozen colon carcinoma samples. Regarding lymph node status, analyses displayed no significantly differential miRNA expression. Interestingly, divergent expression of miR-18a-5p, miR-20a-5p, miR-21-5p, miR-152-3p and miR-1973 was detected in stage pT1. Although miRNAs might not represent reliable biomarkers regarding lymph node metastasis status, they could support risk assessment in stage T1 tumors.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias do Colo/genética , Metástase Linfática/genética , MicroRNAs/análise , Estadiamento de Neoplasias/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo/patologia , Feminino , Humanos , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
8.
Haematologica ; 101(7): 839-45, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27036160

RESUMO

Outcome of patients with primary refractory acute myeloid leukemia remains unsatisfactory. We conducted a prospective phase II clinical trial with gemtuzumab ozogamicin (3 mg/m(2) intravenously on day 1), all-trans retinoic acid (45 mg/m(2) orally on days 4-6 and 15 mg/m(2) orally on days 7-28), high-dose cytarabine (3 g/m(2)/12 h intravenously on days 1-3) and mitoxantrone (12 mg/m(2) intravenously on days 2-3) in 93 patients aged 18-60 years refractory to one cycle of induction therapy. Primary end point of the study was response to therapy; secondary end points included evaluation of toxicities, in particular, rate of sinusoidal obstruction syndrome after allogeneic hematopoietic cell transplantation. Complete remission or complete remission with incomplete blood count recovery was achieved in 47 (51%) and partial remission in 10 (11%) patients resulting in an overall response rate of 61.5%; 33 (35.5%) patients had refractory disease and 3 patients (3%) died. Allogeneic hematopoietic cell transplantation was performed in 71 (76%) patients; 6 of the 71 (8.5%) patients developed moderate or severe sinusoidal obstruction syndrome after transplantation. Four-year overall survival rate was 32% (95% confidence interval 24%-43%). Patients responding to salvage therapy and undergoing allogeneic hematopoietic cell transplantation (n=51) had a 4-year survival rate of 49% (95% confidence intervaI 37%-64%). Patients with fms-like tyrosine kinase internal tandem duplication positive acute myeloid leukemia had a poor outcome despite transplantation. In conclusion, the described regimen is an effective and tolerable salvage therapy for patients who are primary refractory to one cycle of conventional intensive induction therapy. (clinicaltrials.gov identifier: 00143975).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/terapia , Adulto , Aminoglicosídeos/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Comorbidade , Quimioterapia de Consolidação , Citarabina/administração & dosagem , Feminino , Gemtuzumab , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Mitoxantrona/administração & dosagem , Indução de Remissão , Terapia de Salvação , Resultado do Tratamento , Tretinoína/administração & dosagem , Adulto Jovem
9.
Radiat Oncol ; 11: 46, 2016 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-27000180

RESUMO

BACKGROUND: To implement total body irradiation (TBI) using volumetric modulated arc therapy (VMAT). We applied the Varian RapidArc™ software to calculate and optimize the dose distribution. Emphasis was placed on applying a homogenous dose to the PTV and on reducing the dose to the lungs. METHODS: From July 2013 to July 2014 seven patients with leukaemia were planned and treated with a VMAT-based TBI-technique with photon energy of 6 MV. The overall planning target volume (PTV), comprising the whole body, had to be split into 8 segments with a subsequent multi-isocentric planning. In a first step a dose optimization of each single segment was performed. In a second step all these elements were calculated in one overall dose-plan, considering particular constraints and weighting factors, to achieve the final total body dose distribution. The quality assurance comprised the verification of the irradiation plans via ArcCheck™ (Sun Nuclear), followed by in vivo dosimetry via dosimeters (MOSFETs) on the patient. RESULTS: The time requirements for treatment planning were high: contouring took 5-6 h, optimization and dose calculation 25-30 h and quality assurance 6-8 h. The couch-time per fraction was 2 h on day one, decreasing to around 1.5 h for the following fractions, including patient information, time for arc positioning, patient positioning verification, mounting of the MOSFETs and irradiation. The mean lung dose was decreased to at least 80 % of the planned total body dose and in the central parts to 50 %. In two cases we additionally pursued a dose reduction of 30 to 50 % in a pre-irradiated brain and in renal insufficiency. All high dose areas were outside the lungs and other OARs. The planned dose was in line with the measured dose via MOSFETs: in the axilla the mean difference between calculated and measured dose was 3.6 % (range 1.1-6.8 %), and for the wrist/hip-inguinal region it was 4.3 % (range 1.1-8.1 %). CONCLUSION: TBI with VMAT provides the benefit of satisfactory dose distribution within the PTV, while selectively reducing the dose to the lungs and, if necessary, in other organs. Planning time, however, is extensive.


Assuntos
Neoplasias Pulmonares/radioterapia , Radiometria/métodos , Radioterapia de Intensidade Modulada/métodos , Irradiação Corporal Total/métodos , Adulto , Humanos , Leucemia/radioterapia , Linfoma de Células T/terapia , Pessoa de Meia-Idade , Órgãos em Risco/efeitos da radiação , Posicionamento do Paciente , Garantia da Qualidade dos Cuidados de Saúde , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador/métodos , Software , Transplante de Células-Tronco/métodos , Fatores de Tempo , Tomografia Computadorizada por Raios X/métodos , Adulto Jovem
10.
Blood ; 121(23): 4769-77, 2013 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-23632886

RESUMO

In this study, we evaluated the frequency and prognostic impact of DNMT3A mutations (DNMT3A(mut)) in 1770 younger adult patients with acute myeloid leukemia (AML) in the context of other genetic alterations and the European LeukemiaNet (ELN) classification. DNMT3A(mut) were found in 20.9% of AMLs and were associated with older age (P < .0001), higher white blood cell counts (P < .0001), cytogenetically normal AML (CN-AML; P < .0001), NPM1 mutations (P < .0001), FLT3 internal tandem duplications (P < .0001), and IDH1/2 mutations (P < .0001). In univariable and multivariable analyses, DNMT3A(mut) did not impact event-free, relapse-free (RFS), or overall survival (OS) in either the entire cohort or in CN-AML; a negative prognostic effect was found only in the ELN unfavorable CN-AML subset (OS, P = .011). In addition, R882 mutations vs non-R882 mutations showed opposite clinical effects-unfavorable for R882 on RFS (all: hazard ratio [HR], 1.29 [P = .026]; CN-AML: HR, 1.38 [P = .018]) and favorable for non-R882 on OS (all: HR, 0.77 [P = .057]; CN-AML: HR, 0.73 [P = .083]). In our statistically high-powered study with minimized selection bias, DNMT3A(mut) represent a frequent genetic lesion in younger adults with AML but have no significant impact on survival end points; only moderate effects on outcome were found, depending on molecular subgroup and DNMT3A(mut) type.


Assuntos
Biomarcadores Tumorais/genética , DNA (Citosina-5-)-Metiltransferases/genética , Leucemia Mieloide Aguda/mortalidade , Mutação/genética , Adolescente , Adulto , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Adulto Jovem
11.
Haematologica ; 97(10): 1562-9, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22511495

RESUMO

BACKGROUND: Previous data suggest that the response of chronic myeloid leukemia cells to imatinib is dose-dependent. The potential benefit of initial dose intensification of imatinib in pre-treated patients with chronic phase chronic myeloid leukemia remains unknown. DESIGN AND METHODS: Two hundred and twenty-seven pre-treated patients with chronic myeloid leukemia in chronic phase were randomly assigned to continuous treatment with a standard dose of imatinib (400 mg/day; n=113) or to 6 months of high-dose induction with imatinib (800 mg/day) followed by a standard dose of imatinib as maintenance therapy (n=114). RESULTS: The rates of major and complete cytogenetic responses were significantly higher in the high-dose arm than in the standard-dose arm at both 3 and 6 months (major cytogenetic responses: 36.8% versus 21.2%, P=0.01 and 50.0% versus 34.5%, P=0.018; complete cytogenetic responses: 22.8% versus 6.2%, P<0.001 and 40.4% versus 16.8%, P<0.001) on the basis of an intention-to-treat analysis. At 12 months, the difference between treatment arms remained statistically significant for complete cytogenetic responses (40.4% versus 24.8%, P=0.012) but not for major cytogenetic responses (49.1% versus 44.2%, P=0.462). The rate of major molecular responses was also significantly better at 3 and 6 months in the high-dose arm (month 3: 14.9% versus 3.5%, P=0.003; month 6: 32.5% versus 8.8%, P<0.001). Overall and progression-free survival rates were comparable between arms, but event-free survival was significantly worse in the high-dose arm (P=0.014). CONCLUSIONS: Standard-dose imatinib remains the standard of care for pre-treated patients with chronic phase chronic myeloid leukemia (Clinicaltrials.gov identifier: NCT00327262).


Assuntos
Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Adolescente , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Feminino , Humanos , Mesilato de Imatinib , Quimioterapia de Indução , Leucemia Mieloide de Fase Crônica/mortalidade , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Resultado do Tratamento , Adulto Jovem
12.
Blood ; 119(25): 5963-71, 2012 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-22508936

RESUMO

The treatment policy of chronic myeloid leukemia (CML), particularly with tyrosine kinase inhibitors, has been influenced by several recent studies that were well designed and rapidly performed, but their interpretation is of some concern because different end points and methodologies were used. To understand and compare the results of the previous and future studies and to translate their conclusion into clinical practice, there is a need for common definitions and methods for analyses of CML studies. A panel of experts was appointed by the European LeukemiaNet with the aim of developing a set of definitions and recommendations to be used in design, analyses, and reporting of phase 3 clinical trials in this disease. This paper summarizes the consensus of the panel on events and major end points of interest in CML. It also focuses on specific issues concerning the intention-to-treat principle and longitudinal data analyses in the context of long-term follow-up. The panel proposes that future clinical trials follow these recommendations.


Assuntos
Ensaios Clínicos Fase III como Assunto/métodos , Ensaios Clínicos Fase III como Assunto/estatística & dados numéricos , Interpretação Estatística de Dados , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Redes Comunitárias/organização & administração , Intervalo Livre de Doença , Determinação de Ponto Final/métodos , Determinação de Ponto Final/estatística & dados numéricos , Europa (Continente) , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/epidemiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Modelos Biológicos , Guias de Prática Clínica como Assunto , Inibidores de Proteínas Quinases/uso terapêutico , Qualidade de Vida , Projetos de Pesquisa , Análise de Sobrevida , Fatores de Tempo , Resultado do Tratamento
13.
Crit Rev Oncol Hematol ; 82(3): 370-7, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21903413

RESUMO

Nilotinib is a second generation ABL tyrosine kinase inhibitor (TKI) that exerts major anti-leukemic effects in newly diagnosed patients with chronic myeloid leukemia (CML) as well as in most patients with imatinib-resistant CML. In freshly diagnosed patients, the anti-leukemic activity of nilotinib exceeds the efficacy of imatinib, and although long-term data for nilotinib are not available yet, the drug has recently been approved for firstline treatment of chronic phase CML in various countries. Still however, several questions concerning the optimal dose, follow-up parameters, long-term safety, and patient selection remain open. Likewise, it remains uncertain whether both Sokal low-risk and high-risk patients should receive nilotinib as frontline therapy in the future. Another question is whether nilotinib can completely eradicate CML in a subset of patients. Furthermore, it remains unclear whether and what comorbidity must be regarded as relative or absolute contra-indication for this TKI. To discuss these issues, the Austrian CML Working Group organized a series of meetings in 2010. In the current article, the outcomes from these discussions are summarized and presented together with recommendations for frontline use of TKIs in various groups of patients with CML. These recommendations should assist in daily practice as well as in the preparation and conduct of clinical trials.


Assuntos
Antineoplásicos/uso terapêutico , Transtornos Cerebrovasculares/tratamento farmacológico , Diabetes Mellitus/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Antineoplásicos/administração & dosagem , Benzamidas , Transtornos Cerebrovasculares/epidemiologia , Transtornos Cerebrovasculares/patologia , Ensaios Clínicos como Assunto , Comorbidade , Contraindicações , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/patologia , Esquema de Medicação , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/epidemiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Seleção de Pacientes , Piperazinas/administração & dosagem , Piperazinas/uso terapêutico , Guias de Prática Clínica como Assunto , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Pirimidinas/administração & dosagem , Resultado do Tratamento
14.
Diagn Pathol ; 6: 19, 2011 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-21401966

RESUMO

BACKGROUND: Characterization of novel fusion genes in acute leukemia is important for gaining information about leukemia genesis. We describe the characterization of a new ETV6 fusion gene in acute myeloid leukemia (AML) FAB M0 as a result of an uncommon translocation involving chromosomes 12 and 15. METHODS: The ETV6 locus at 12p13 was shown to be translocated and to constitute the 5' end of the fusion product by ETV6 break apart fluorescence in situ hybridisation (FISH). To identify a fusion partner 3' rapid amplification of cDNA-ends with polymerase chain reaction (RACE PCR) was performed followed by cloning and sequencing. RESULTS: The NTRK3 gene on chromosome 15 was found to constitute the 3' end of the fusion gene and the underlying ETV6-NTRK3 rearrangement was verified by reverse transcriptase PCR. No RNA of the reciprocal NTRK3-ETV6 fusion gene could be detected. CONCLUSION: We have characterized a novel ETV6-NTRK3 fusion transcript which has not been previously described in AML FAB M0 by FISH and RACE PCR. ETV6-NTRK3 rearrangements have been described in secretory breast carcinoma and congenital fibrosarcoma.


Assuntos
Cromossomos Humanos Par 12 , Cromossomos Humanos Par 15 , Leucemia Mieloide Aguda/genética , Proteínas de Fusão Oncogênica/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Aberrações Cromossômicas , Clonagem Molecular , Análise Mutacional de DNA , DNA de Neoplasias/análise , Rearranjo Gênico , Humanos , Hibridização in Situ Fluorescente , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Pessoa de Meia-Idade
15.
Haematologica ; 95(6): 908-13, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20145273

RESUMO

BACKGROUND: Imatinib 400 mg/day is the standard treatment for patients with chronic phase chronic myeloid leukemia. Recent reports suggested higher and more rapid cytogenetic and molecular responses with higher doses of imatinib. DESIGN AND METHODS: In this prospective international, multicenter phase III study, 227 patients with pre-treated Philadelphia chromosome-positive, BCR-ABL-positive chronic myeloid leukemia were randomized to a standard-dose imatinib arm (400 mg/day) or a high-dose imatinib arm (800 mg/day for 6 months followed by 400 mg/day as maintenance therapy). In this planned interim analysis hematologic, cytogenetic and molecular responses as well as toxicity were evaluated. RESULTS: Compared to the standard-dose, high-dose imatinib led to higher rates of major and complete cytogenetic responses at both 3 months (major: 21% versus 37%, P=0.01; complete: 6% versus 25%, P<0.001) and 6 months (major: 34% versus 54%, P=0.009; complete: 20% versus 44%, P<0.001). This was paralleled by a significantly higher major molecular response rate at 6 months in the high-dose imatinib arm (11.8% versus 30.4%; P=0.003). At 12 months, the rates of major cytogenetic response (the primary end-point) were comparable between the two arms (57% versus 59%). In contrast to non-hematologic toxicities, grade 3/4 hematologic toxicities were more common in the high-dose arm. Cumulative complete cytogenetic response rates were higher in patients without dose reduction in the high-dose arm (61%) than in the patients with no dose reduction in the standard-dose arm (36%) (P=0.014). CONCLUSIONS: This is the first randomized phase III trial in patients with pre-treated chronic phase chronic myeloid leukemia demonstrating improvements in major cytogenetic response, complete cytogenetic response and major molecular response rates with high-dose imatinib therapy (ClinicalTrials.gov Identifier: NCT00327262).


Assuntos
Análise Citogenética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Adolescente , Adulto , Idoso , Benzamidas , Análise Citogenética/métodos , Feminino , Seguimentos , Humanos , Mesilato de Imatinib , Internacionalidade , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Indução de Remissão , Adulto Jovem
16.
Strahlenther Onkol ; 185(7): 431-7, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19714304

RESUMO

PURPOSE: This retrospective analysis of 1,610 women treated for breast cancer and 88 patients with local relapse aims to show the poor survival parameters after local failure and to evaluate risk factors and compare them with other studies and analyses published. PATIENTS AND METHODS: Between 1984 and 1997, 1,610 patients presenting with a total of 1,635 pT1-2 invasive and noninvasive carcinomas of the breast were treated at the authors' institution. The mean age was 57.1 years (range 25-85 years). Treatment protocols involved breast-conserving surgery with or without systemic therapy and whole-breast radiotherapy in all women, followed by a boost dose to the tumor bed according to risk factors for local recurrence. All axillary node-positive patients underwent systemic therapy (six cycles of classic CMF or tamoxifen 20 mg/day for 2-5 years). The time of diagnosis of local relapse was defined as time 0 for the survival curves after local failure. The association of clinicopathologic factors was studied using uni- and multivariate analyses. Survival and local control were calculated by the Kaplan-Meier actuarial method and significance by the log-rank test. RESULTS: After a mean follow-up of 104 months, 88 local failures were recorded (5.4%). Calculated from the time of diagnosis of local relapse, 5-year overall survival (OS) was 62.8%, metastasis-free survival 60.6%, and disease-specific survival 64.2%. In patients with failure during the first 5 years after treatment, the survival parameters were worse (OS 50.6%) compared to those who relapsed after 5 years (OS 78.8%; p < 0.028). Significances were also found for initial T- and N-stage and type of failure (solid tumor vs. diffuse spread). CONCLUSION: This analysis again shows that the survival parameters are worsening after local relapse, especially in case of early occurrence. In breast cancer treatment, therefore, the goal remains to avoid local failure.


Assuntos
Neoplasias da Mama/radioterapia , Neoplasias da Mama/cirurgia , Mastectomia Segmentar , Recidiva Local de Neoplasia/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Metástase Linfática/radioterapia , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Radioterapia Adjuvante , Estudos Retrospectivos , Fatores de Risco
17.
Blood ; 110(6): 2148-57, 2007 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-17537994

RESUMO

Spontaneous Rh phenotype alteration interferes with pretransfusion and prenatal blood group examinations and may potentially indicate hematologic disease. In this study, the molecular background of this biologic phenomenon was investigated. In 9 patients (3 with hematologic disease), routine RhD typing showed a mixture of D-positive and D-negative red cells not attributable to transfusion or hematopoietic stem-cell transplantation. In all patients, congenital and acquired chimerism was excluded by microsatellite analysis. In contrast to D-positive red cells, D-negative subpopulations were also negative for C or E in patients genotyped CcDdee or ccDdEe, respectively, which suggested the presence of erythrocyte precursors with an apparent homozygous cde/cde or hemizygous cde/- genotype. Except for one patient with additional Fy(b) antigen anomaly, no other blood group systems were affected. RH genotyping of single erythropoietic burst-forming units, combined with microsatellite analysis of blood, different tissues, sorted blood cell subsets, and erythropoietic burst-forming units, indicated myeloid lineage-restricted loss of heterozygosity (LOH) of variable chromosome 1 stretches encompassing the RHD/RHCE gene loci. Fluorescent in situ hybridization studies indicated that LOH was caused by either somatic recombination or deletion. Therefore, most cases of spontaneous Rh phenotype splitting appear to be due to hematopoietic mosaicism based on LOH on chromosome 1.


Assuntos
Cromossomos Humanos Par 1/genética , Leucemia Mieloide Aguda/genética , Perda de Heterozigosidade , Mosaicismo , Células Mieloides/patologia , Sistema do Grupo Sanguíneo Rh-Hr/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimerismo , Aberrações Cromossômicas , Eritrócitos , Feminino , Citometria de Fluxo , Genótipo , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Leucemia Mieloide Aguda/sangue , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Fenótipo , Recombinação Genética
18.
J Hematother Stem Cell Res ; 12(4): 367-73, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12965074

RESUMO

A major goal of experimental and clinical hematology is the identification of mechanisms and conditions supporting the expansion of transplantable hematopoietic stem cells. We assessed the expansion potential of CD34+CD71-CD45- cells derived from granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood under recently defined serum-free culture conditions. The CD34+CD71-CD45- cells in mobilized peripheral blood were found to contain the majority (92%+/-5.6) of primitive long-term culture initiating cells (LTCIC) and 53.5%+/-16.7 of the more committed colony-forming cells (CFC). Furthermore, this population represents 23.3%+/-4.1 of the total CD34+ cells and allows reduction of the cell density important for maintenance/expansion of primitive progenitor cells. CD34+ CD71- CD45- cells were cultured in defined serum-free media supplemented with 300 ng each of Flt-3 ligand and stem cell factor (SCF), 60 ng of interleukin (IL)-3, and 20 ng each of IL-6 and G-CSF. Mononuclear cells (MNC) and CFC were expanded 50-fold and 200-fold, respectively; primitive progenitor cells (LTC-IC) were maintained at input values after a total of 10 days of expansion. The addition of IL-15 to our cytokine cocktail expanded LTC-IC 2- to 3-fold and CFC to >500-fold. The data presented should allow clinical manipulation (purging) and expansion procedures with mobilized PBPC harvests without the loss of primitive progenitor cells and could be made applicable for large-scale clinical expansion.


Assuntos
Antígenos CD34/biossíntese , Antígenos CD/biossíntese , Antígenos de Diferenciação de Linfócitos B/biossíntese , Antígenos Comuns de Leucócito/biossíntese , Células-Tronco/metabolismo , ADP-Ribosil Ciclase/biossíntese , ADP-Ribosil Ciclase 1 , Neoplasias da Mama/sangue , Células Cultivadas , Meios de Cultura Livres de Soro/farmacologia , Eritropoetina/metabolismo , Fator Estimulador de Colônias de Granulócitos/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Células-Tronco Hematopoéticas/citologia , Humanos , Interleucina-15/metabolismo , Interleucina-3/metabolismo , Interleucina-6/metabolismo , Linfoma não Hodgkin/sangue , Glicoproteínas de Membrana , Proteínas de Membrana/metabolismo , Metilcelulose/química , Receptores da Transferrina
19.
Immunobiology ; 207(2): 85-93, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12675266

RESUMO

The application of autologous ex-vivo expanded cytotoxic lymphocytes to cancer patients may help to control minimal residual disease. However, the number of effector cells and the resulting antitumoral activity that can be generated in vitro are remarkably variable. Thus, we separately assessed the proliferative and cytotoxic potential of CD56+ CD3- natural killer (NK) and CD56+ CD3+ T-cells in relation to their expression of CD25, CD69, and CD16 in vitro. Two-week lymphocyte cultures from peripheral blood (n = 51) and from G-CSF-mobilized progenitor cell harvests (n = 11) were performed repeatedly from 14 women with breast cancer throughout conventional- and high-dose chemotherapy. A large proportion of CD25+ cells on day 7 of the culture predicted high expandability (r = 0.69, p < 0.00001), while elevated expression of CD69 predicted augmented cytotoxicity (r = 0.72; p = 0.00001) and low expandability (r = -0.69, p < 0.00001). CD25 and CD69 expression were inversely correlated (r = -0.8, p < 0.0001). CD16 expression was not suited to predict functional properties. Additionally, NK-cells were sorted by FACS according to CD25 versus CD69 expression. In a [3H]thymidine incorporation assay the CD25+ NK-cell fraction exhibited a higher proliferation rate than did the CD69+ fraction in all of three experiments. Together, our data suggest that CD69 is a useful marker for cytotoxic activity of NK cells, whereas proliferative potential is indicated by CD25 expression. These findings should help optimizing the ex-vivo generation of large numbers of cytotoxic effector cells for immunotherapy.


Assuntos
Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Biomarcadores , Citotoxicidade Imunológica , Células Matadoras Naturais/imunologia , Receptores de Interleucina-2/imunologia , Linfócitos T/imunologia , Adulto , Antígenos CD/biossíntese , Antígenos de Diferenciação de Linfócitos T/biossíntese , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , Divisão Celular/imunologia , Células Cultivadas , Quimioterapia Combinada , Feminino , Citometria de Fluxo , Fator Estimulador de Colônias de Granulócitos , Humanos , Lectinas Tipo C , Pessoa de Meia-Idade , Receptores de IgG/biossíntese , Receptores de IgG/imunologia , Receptores de Interleucina-2/biossíntese
20.
Arch Med Res ; 34(6): 496-506, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-14734089

RESUMO

Chronic myeloid leukemia (CML) is a malignant myeloproliferative disorder originating from a pluripotent hematopoietic stem cell that acquires a Philadelphia (Ph) chromosome encoding the BCR-ABL oncogenic fusion protein. This molecular abnormality that is thought to be causative in CML was the first acquired chromosome translocation associated with a human malignancy. This chromosomal translocation also makes it possible to precisely distinguish between residual normal (i.e., Ph-, BCR-ABL-) progenitor or stem cells and their leukemic counterpart, Ph+ or BCR-ABL+ progenitor/stem cells in every given sample of a patient with CML. This has provided seminal insights into the molecular and cellular biology of leukemia and also of the process of normal hematopoiesis. CML has become a fascinating model disease for malignancy in general.


Assuntos
Células-Tronco Hematopoéticas/fisiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Animais , Antineoplásicos/farmacologia , Benzamidas , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Proteínas de Fusão bcr-abl/metabolismo , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/fisiopatologia , Cromossomo Filadélfia , Piperazinas/farmacologia , Pirimidinas/farmacologia , Transplante de Células-Tronco
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