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1.
Ann Oncol ; 31(2): 228-235, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31959339

RESUMO

BACKGROUND: Palliative chemotherapy of advanced oesophageal squamous cell cancer (ESCC) consists of cisplatin/5-fluorouracil (CF) to target epidermal growth factor receptor (EGFR) with panitumumab (P); chemotherapy enhanced overall survival (OS) in advanced colorectal or squamous cell head and neck cancers. With prospective serum and tumour biomarkers, we tested if P added to CF (CFP) improved OS in advanced ESCC. PATIENTS AND METHODS: Eligible patients with confirmed ESCC that was not curatively resectable or did not qualify for definitive radiochemotherapy, were randomised 1 : 1 to receive CF [cisplatin (C) 100 mg/m2 i.v., day 1; 5-fluorouracil (F) 1000 mg/m2 i.v., days 1-4] or CF plus P (9 mg/kg, i.v., day 1, each q3-week cycle) until progressive disease or unacceptable toxicity. Safety was reviewed by the Data Safety Monitoring Board after 40, 70 and 100 patients who completed at least one cycle. After 53 enrolled patients, cisplatin was reduced from 100 mg/m2 to 80 mg/m2. RESULTS: The trial was stopped early based on interim efficacy results triggered by the third safety analysis: median OS (mOS) favoured CF over CFP, regardless of cisplatin dose [hazard ratio (HR) 1.77, 95% confidence interval (CI) 1.06-2.98; P = 0.028]. In the final analysis, mOS was 10.2 versus 9.4 months for CF versus CFP, respectively (HR 1.17, 95% CI 0.79-1.75; P = 0.43). One hundred (70.4%) of 142 patients in the safety population died, 51 (51.0%) with CFP. Most deaths were related to disease progression [44/49 (90%) deaths in CF versus 34/51 (67%) deaths in CFP]; objective responses [27/73 (37.0%)] were identical. The most common serious adverse events were kidney injury [3 (4.3%) versus 7 (9.7%)], general health deterioration [5 (7.1%) versus 5 (6.9%)] and dysphagia [4 (5.7%) versus 4 (5.6%)] in CF versus CFP, respectively. There were three (4.3%) and 17 (23.6%) common terminology criteria for adverse events (CTCAE) grade 5 events in CF versus CFP, respectively. Low soluble (s)EGFR levels were associated with better progression-free survival; sEGFR was induced under CFP. CONCLUSION: EGFR inhibition added to CF did not improve survival in unselected advanced ESCC patients. The results support further liquid biopsy studies. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01627379) and EudraCT (2010-020606-15).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Células Escamosas , Neoplasias Esofágicas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Escamosas/tratamento farmacológico , Cisplatino/efeitos adversos , Intervalo Livre de Doença , Receptores ErbB/genética , Neoplasias Esofágicas/tratamento farmacológico , Fluoruracila/efeitos adversos , Humanos , Panitumumabe , Estudos Prospectivos , Resultado do Tratamento
3.
Ann Oncol ; 29(6): 1386-1393, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29635438

RESUMO

Background: This open-label, phase III trial compared chemoradiation followed by surgery with or without neoadjuvant and adjuvant cetuximab in patients with resectable esophageal carcinoma. Patients and methods: Patients were randomly assigned (1 : 1) to two cycles of chemotherapy (docetaxel 75 mg/m2, cisplatin 75 mg/m2) followed by chemoradiation (45 Gy, docetaxel 20 mg/m2 and cisplatin 25 mg/m2, weekly for 5 weeks) and surgery, with or without neoadjuvant cetuximab 250 mg/m2 weekly and adjuvant cetuximab 500 mg/m2 fortnightly for 3 months. The primary end point was progression-free survival (PFS). Results: In total, 300 patients (median age, 61 years; 88% male; 63% adenocarcinoma; 85% cT3/4a, 90% cN+) were assigned to cetuximab (n = 149) or control (n = 151). The R0-resection rate was 95% for cetuximab versus 97% for control. Postoperative treatment-related mortality was 6% in both arms. Median PFS was 2.9 years [95% confidence interval (CI), 2.0 to not reached] with cetuximab and 2.0 years (95% CI, 1.5-2.8) with control [hazard ratio (HR), 0.79; 95% CI, 0.58-1.07; P = 0.13]. Median overall survival (OS) time was 5.1 years (95% CI, 3.7 to not reached) versus 3.0 years (95% CI, 2.2-4.2) for cetuximab and control, respectively (HR, 0.73; 95% CI, 0.52-1.01; P = 0.055). Time to loco-regional failure after R0-resection was significantly longer for cetuximab (HR 0.53; 95% CI, 0.31-0.90; P = 0.017); time to distant failure did not differ between arms (HR, 1.01; 95% CI, 0.64-1.59, P = 0.97). Cetuximab did not increase adverse events in neoadjuvant or postoperative settings. Conclusion: Adding cetuximab to multimodal therapy significantly improved loco-regional control, and led to clinically relevant, but not-significant improvements in PFS and OS in resectable esophageal carcinoma. Clinical trial information: NCT01107639.


Assuntos
Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia/mortalidade , Neoplasias Esofágicas/terapia , Esofagectomia/mortalidade , Terapia Neoadjuvante/mortalidade , Adenocarcinoma/patologia , Idoso , Carcinoma de Células Escamosas/patologia , Cetuximab/administração & dosagem , Cisplatino/administração & dosagem , Terapia Combinada , Docetaxel/administração & dosagem , Neoplasias Esofágicas/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida
5.
Strahlenther Onkol ; 194(1): 41-49, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29127435

RESUMO

PURPOSE: The major goals of preoperative treatment for locally advanced rectal cancers (LARCs) are improvement of local tumor control, tumor downsizing, and downstaging. Modifications with respect to standardized chemoradiation protocol, e. g., integrating oxaliplatin, are realized with the aim of improving primary tumor response and patient outcome. PATIENTS AND METHODS: In this phase II multicenter study, patients with LARC of the mid- or lower rectum, cT3cNxcM0 as staged by MRI, were included and treated preoperatively with a combination of capecitabine and oxaliplatin following a standardized protocol during radiation. The focus of this long-term analysis was overall (OS) and disease-free survival (DFS). RESULTS: A total of 60 patients (19 women, 41 men, median age 60.5 years) were initially enrolled, 1 patient was excluded (violation of study protocol), and 1 was patient lost of follow-up, leading to a total of 58 patients for long-term analysis. The 3­year OS was 85.5%; 3­year DFS 71.2%. Over time, 15 patients (25.9%) developed tumor recurrence (1 locoregional, 6.7%; 11 distant, 73.3%; 3 locoregional+distant, 20%). Recurrence-specific therapy was planned in the majority of patients, in 9 of 15 patients (60%) with a radical surgical approach. Of these, 4 patients (44.4%) are again tumor-free at the end of investigation. While tumor downsizing (T level) or pathologically complete response did not influence patient survival, lymph node negativity (LNneg) after preoperative chemoradiation showed significant influence. CONCLUSION: LNneg after preoperative treatment for LARC significantly influences patient survival. A radical surgical approach for recurrent LARC (locoregional, distant) should be contemplated when possible as we were able to clearly demonstrate its importance and efficacy.


Assuntos
Adenocarcinoma/patologia , Adenocarcinoma/terapia , Quimiorradioterapia Adjuvante/métodos , Terapia Neoadjuvante/métodos , Compostos Organoplatínicos/administração & dosagem , Neoplasias Retais/patologia , Neoplasias Retais/terapia , Adenocarcinoma/mortalidade , Idoso , Capecitabina/administração & dosagem , Terapia Combinada , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Metástase Linfática/patologia , Metástase Linfática/radioterapia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Estadiamento de Neoplasias , Oxaliplatina , Estudos Prospectivos , Neoplasias Retais/mortalidade
6.
J Cancer Res Clin Oncol ; 139(8): 1337-42, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23666164

RESUMO

PURPOSE: The purpose of this retrospective analysis was to assess efficacy and tolerability of trabectedin in soft tissue sarcoma (STS) in the routine clinical setting. PATIENTS AND METHODS: Efficacy and safety data of trabectedin were retrospectively evaluated in patients with advanced STS who had started treatment with trabectedin at six institutions in Austria between January 2008 and May 2012. RESULTS: Data of 101 adult patients were included in the present analysis. Patients had a median age of 56 years; 59 and 41% received trabectedin as ≤2nd and ≥3rd chemotherapy line for advanced disease, respectively. Median progression-free survival (PFS) and overall survival (OS) were 3.9 and 11.6 months. Median PFS and OS were different in patients who received trabectedin as ≤2nd- or ≥3rd-line treatment: median PFS was 3.9 versus 3.6 months and OS was 15.2 versus 24.8 months, respectively. The extent and severity of trabectedin-induced toxicity were low and manageable. CONCLUSIONS: The activity and tolerability of trabectedin in the routine clinical setting is comparable to outcomes reported in phase II trials already published. Regardless of whether trabectedin was given earlier or later in the course of disease, outcomes did not differ in the cohort of analysed patients.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Dioxóis/uso terapêutico , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Tetra-Hidroisoquinolinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Áustria , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sarcoma/mortalidade , Neoplasias de Tecidos Moles/mortalidade , Trabectedina , Resultado do Tratamento , Adulto Jovem
7.
Oncology ; 84(3): 186-90, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23328311

RESUMO

OBJECTIVE: Treatment of lung cancer patients is changing rapidly and new treatment options have emerged in recent years. In 2007, to guarantee the best treatment procedure for lung cancer patients being treated in our peripheral hospital, we decided to introduce an interdisciplinary tumour videoconference between the Haemato-Oncological Day Hospital in Merano and the Comprehensive Cancer Centre Innsbruck. This retrospective analysis aims to describe the feasibility of such a conference. PATIENTS AND METHODS: Two hundred and three patients with lung cancer treated at the peripheral hospital of Merano between May 2003 until May 2011 were retrospectively analysed. After introduction of the tumour videoconference in 2007, 54% (n = 110) of the patients in this cohort were discussed in the conference. RESULTS: One hundred and four videoconferences were performed. Videoconference was feasible for 110 patients. Radiotherapeutic treatments were prescribed more frequently in patients from the conference group. Overall, major and minor treatment changes were undertaken in 7% (n = 8) and 18% (n = 20), respectively. CONCLUSION: Interdisciplinary tumour videoconference is feasible between a peripheral hospital and a comprehensive cancer centre. Radiotherapeutic treatment was prescribed more frequently, suggesting that such a conference facilitates the access to cancer-centre-specific treatment modalities. Accordingly, tumour videoconference between a peripheral hospital and a cancer centre is to be recommend.


Assuntos
Comunicação Interdisciplinar , Neoplasias Pulmonares/terapia , Planejamento de Assistência ao Paciente , Consulta Remota , Comunicação por Videoconferência , Adenocarcinoma/diagnóstico , Adenocarcinoma/terapia , Idoso , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/terapia , Coleta de Dados , Estudos de Viabilidade , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Carcinoma de Pequenas Células do Pulmão/terapia
8.
Curr Med Res Opin ; 27(2): 355-63, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21166611

RESUMO

BACKGROUND: Anaemia is a highly prevalent condition in cancer patients impacting on morbidity, mortality and quality of life. Darbepoetin alfa (DA) 500 µg administered once every 3 weeks (Q3W) has been shown to be effective in patients with chemotherapy-induced anaemia. OBJECTIVE: This non-interventional study investigated the efficacy and usage patterns of DA 500 µg Q3W in routine clinical practice. RESEARCH DESIGN AND METHODS: Prospective data on adult anaemic cancer patients receiving DA 500 µg Q3W during chemotherapy was collected. Efficacy of DA treatment was measured as the red blood cell transfusion (RBCT) incidence, the change in Hb over time, hospitalisations for anaemia, and the change in Eastern Cooperative Oncology Group (ECOG) performance status between baseline and study end. Usage patterns were evaluated in Hb categories at baseline and week 16, DA dosage information, and adherence to the guidelines issued by the European Organisation for Research and Treatment of Cancer (EORTC). RESULTS: A total of 309 patients were included. The median study duration was 16 weeks and the overall transfusion rate was 19%. Significantly fewer patients required transfusions when DA was initiated at Hb 9.0-10.0 g/dL (19%), as compared to later at a Hb < 9.0 g/dL (50%, p = 0.0002). Transfusion-independent patients had fewer anaemia-related hospitalisations and better ECOG scores at the end of the study. A total of 83% of patients reached a Hb ≥ 11.0 g/dL during weeks 1-16. Physicians' adherence to Hb thresholds for DA initiation as recommended by the EORTC was observed in 83% of patients. CONCLUSIONS: In accordance with the recommended treatment objective for DA to minimise RBCTs, 81% of study patients remained free of RBCTs during DA 500 µg Q3W treatment and at an even higher rate if DA treatment was initiated before Hb fell below 9.0 g/dL.


Assuntos
Anemia/induzido quimicamente , Anemia/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transfusão de Sangue/estatística & dados numéricos , Eritropoetina/análogos & derivados , Neoplasias/tratamento farmacológico , Adulto , Idoso , Algoritmos , Darbepoetina alfa , Relação Dose-Resposta a Droga , Esquema de Medicação , Eritropoetina/administração & dosagem , Feminino , Hematínicos/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Suspensão de Tratamento/estatística & dados numéricos
9.
Q J Nucl Med Mol Imaging ; 54(1): 52-60, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20168286

RESUMO

AIM: Positron emission tomography (PET) of (68)Ga-radiolabelled (SST) somatostatin receptor (R) binding peptides has recently been evaluated in SSTR positive tumor patients. First promising results in lung and thyroid tumor patients with (111)In-DOTA-Lanreotide (DOTA-LAN) scintigraphy have been described. We report our first experience with (68)Ga-labeled DOTA-LAN. METHODS: Eleven patients (3 non small cell lung cancer [NSCLC], 3 small cell lung cancer [SCLC], 3 radioiodine negative thyroid cancer, 2 medullary thyroid cancer [MTC]) were investigated. After intravenous injection of 75-150 MBq (68)Ga-DOTA-LAN dynamic studies were acquired over the tumor site for the first 40 min with a dedicated PET scanner in 3 patients, and 2 partial body scans were acquired at 20 and 50 min p.i. in 2 patients. Whole body acquisitions at 90 min after injection were acquired in all 11 patients. Image reconstruction was performed by iterative reconstruction utilizing additional transmission scans for attenuation correction. Vital parameters were recorded during the PET study and up to 24 h p.i. Blood and urinary sampling was done up to 4 hr after tracer injection in 8 patients. PET results were compared to conventional imaging techniques (CIT), i.e. computed tomography (CT) and/or magnetic resonance imaging (MRI). In 5 patients, (68)Ga-DOTA-LAN was compared with 2-[(18)F]fluoro-2-deoxy-D-glucose ((18)F-FDG). RESULTS: After intravenous (i.v.) injection of (68)Ga-DOTA-LAN the radioactivity in the blood rapidly decreased to less then 20% of the injected dose (ID) within the first 20 min and further decreased to less than 9% ID after 4 h. A cumulative urinary excretion of (68)Ga-DOTA-LAN up to 29.2 + or - 13.2% ID at 4 h was found. No acute side effects were observed. Tumor sites were visualized already during the first min after injection. Comparison of positron emission tomography (PET) and CIT showed concordant results in 3/8 patients and partial concordant results in 5/8 patients with matched results for the primary/recurrent tumor, mediastinal lymph nodes, or adrenal gland metastases. Partial concordant results were seen for the lung, bone, liver and cervical lymph node metastases. Micronodular metastases of the lung and the cerebrum were not visualized by (68)Ga-DOTA-LAN PET. The maximal standardized uptake values of the lung and bone tumor lesions ranged from 6 to 8 g/ml at 90 min p.i.. CONCLUSIONS: (68)Ga-DOTA-LAN visualized the majority of tumor lesions. Further studies are required to assess the clinical value, and to obtain the best imaging protocol of this new PET SSTR tracer.


Assuntos
Compostos Heterocíclicos com 1 Anel , Peptídeos Cíclicos , Tomografia por Emissão de Pósitrons/métodos , Somatostatina/análogos & derivados , Adulto , Idoso , Sequência de Aminoácidos , Feminino , Radioisótopos de Gálio/efeitos adversos , Radioisótopos de Gálio/química , Radioisótopos de Gálio/farmacocinética , Compostos Heterocíclicos com 1 Anel/efeitos adversos , Compostos Heterocíclicos com 1 Anel/química , Compostos Heterocíclicos com 1 Anel/farmacocinética , Humanos , Interpretação de Imagem Assistida por Computador , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Peptídeos Cíclicos/efeitos adversos , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacocinética , Receptores de Somatostatina/metabolismo , Somatostatina/efeitos adversos , Somatostatina/química , Somatostatina/farmacocinética , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia
10.
Anticancer Res ; 28(5B): 2901-5, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-19031932

RESUMO

BACKGROUND: The aim of the study was to evaluate the feasibility and efficacy of an outpatient oxaliplatin/irinotecan chemotherapy in chemonaive patients suffering from unresectable gastric cancer. MATERIALS AND METHODS: Biweekly oxaliplatin (85 mg/m2) and irinotecan (125 mg/m2) was chosen since it has been shown previously in colorectal cancer that oxaliplatin (85 mg/m2) is superior to a lower dose and toxicity of irinotecan is much lower if given fractionated. The irinotecan dose below the maximum tolerated dose takes into consideration concerns about increased toxicity in gastric cancer patients. RESULTS: Forty-three patients with histologically proven gastric adenocarcinoma and no previous palliative chemotherapy were selected. WHO grade 3 and 4 toxicities included neutropenia in 2/43 patients, anemia in 3/43 patients, nausea in 2/43 patients and diarrhea in 4/43 patients. Response rates were assessable in 38 patients as follows: complete response in three patients (8%), partial response in 19 (50%), stable disease in 11 (29%), and progressive disease in 5 patients (13%). The median time-to-progression was 53 months and median overall survival was 9.5 months. CONCLUSION: The outpatient combination of biweekly oxaliplatin/irinotecan was well tolerated and showed a response rate within the range of other first-line combination therapies. The favorable toxicity profile, however, renders oxaliplatin/irinotecan as an alternative first-line regimen.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Assistência Ambulatorial , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/análogos & derivados , Esquema de Medicação , Estudos de Viabilidade , Feminino , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Oxaliplatina
11.
Leukemia ; 19(3): 435-41, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15674418

RESUMO

Xenograft models of chronic phase human chronic myeloid leukemia (CML) have been difficult to develop because of the persistence of normal hematopoietic stem cells in most chronic phase CML patients and the lack of methods to selectively isolate the rarer CML stem cells. To circumvent this problem, we first identified nine patients' samples in which the long-term culture-initiating cells were predominantly leukemic and then transplanted cells from these samples into sublethally irradiated NOD/SCID and NOD/SCID-beta2microglobulin-/- mice. This resulted in the consistent and durable (>5 months) repopulation of both host genotypes with similar numbers of BCR-ABL+/Ph+ cells. The regenerated leukemic cells included an initial, transient population derived from CD34+CD38+ cells as well as more sustained populations derived from CD34+CD38- progenitors, indicative of a hierarchy of transplantable leukemic cells. Analysis of the phenotypes produced revealed a reduced output of B-lineage cells, enhanced myelopoiesis with excessive production of erythroid and megakaropoietic cells and the generation of primitive (CD34+) leukemic cells displaying an autocrine IL-3 and G-CSF phenotype, all characteristics of primary CML cells. These findings demonstrate the validity of this xenograft model of chronic phase human CML, which should enable future investigation of disease pathogenesis and new approaches to therapy.


Assuntos
Modelos Animais de Doenças , Sobrevivência de Enxerto , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/patologia , Leucemia Experimental/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Células-Tronco Neoplásicas/transplante , Animais , Fator Estimulador de Colônias de Granulócitos/genética , Fator Estimulador de Colônias de Granulócitos/metabolismo , Humanos , Interleucina-3/genética , Interleucina-3/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Fenótipo , Quimera por Radiação , Fatores de Tempo , Transplante Heterólogo/métodos
12.
J Clin Pathol ; 56(10): 736-41, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-14514775

RESUMO

AIMS: To investigate the immunohistochemical expression of a panel of biologically relevant markers in patients with non-small cell lung cancer using fresh frozen specimens and to test their prognostic relevance for identification of patients at risk. METHODS: Seventy nine tumour infiltrated lung cancer specimens and 66 adjacent histologically tumour free tissues were analysed; 11 postmortem specimens from patients who did not suffer from a malignant disease served as a control group. Cryostat sections were stained with monoclonal antibodies against epidermal growth factor receptor (EGFR), c-erbB-2, c-erbB-3, CD82, Ki-67, p120, p53, bcl-2, and CD31. RESULTS: At least one of the tested markers was raised above the defined cut off point in 75 of the tumours. In 55, three to six factors were increased. EGFR was raised in 32, c-erbB-2 in 29, c-erbB-3 in 46, p53 in 29, bcl-2 in 26, Ki-67 in 36, p120 in 46, and CD31 in 29. None of the tested parameters was significant in univariate survival analysis. In a second step, three variables were combined (c-erbB3, p53, and microvessel density), and cases with increased expression of two or three parameters proved to have a significantly lower survival probability than those expressing none or only one factor. In the tumour free group only 10 showed raised marker expression. CONCLUSION: Characterisation of tumour cells in surgical specimens with immunohistological markers could help identify those patients at risk for early cancer death who could possibly profit from adjuvant treatment after curative tumour resection.


Assuntos
Antígenos CD , Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/química , Neoplasias Pulmonares/química , Proteínas Proto-Oncogênicas , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Receptores ErbB/análise , Humanos , Imuno-Histoquímica/métodos , Proteína Kangai-1 , Antígeno Ki-67/análise , Glicoproteínas de Membrana/análise , Molécula-1 de Adesão Celular Endotelial a Plaquetas/análise , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/análise , Receptor ErbB-2/análise , Receptor ErbB-3/análise , Risco , Proteína Supressora de Tumor p53/análise
13.
Leuk Res ; 27(5): 405-11, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12620292

RESUMO

This multicenter randomized phase III study was designed to compare the efficacy and toxicity of IFN alpha-2c (3.5 MU/d) in combination with either araC (10 mg/m(2) d1-10) or hydroxyurea (HU: 25 mg/kg per day) in newly diagnosed CML patients. A total of 114 patients were randomized. Following a median observation period of 36 (range 1-73) months the major cytogenetic response rates were 25 and 27% and the 4-year survival probabilities 62.5 and 63% for the araC and HU group, respectively. While the overall toxicity profile was comparable between both groups, patients in the HU arm exhibited a slightly higher degree of WHO grades 3 and 4 non-hematological toxicities.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Feminino , Gastroenteropatias/induzido quimicamente , Doenças Hematológicas/induzido quimicamente , Humanos , Hidroxiureia/administração & dosagem , Hidroxiureia/efeitos adversos , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Leucemia Mieloide de Fase Crônica/mortalidade , Tábuas de Vida , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/induzido quimicamente , Proteínas Recombinantes , Resultado do Tratamento
14.
Leuk Res ; 25(12): 1051-7, 2001 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11684276

RESUMO

To evaluate the role of CD44 variant isoforms (CD44v) in plasma cell dyscrasias, CD44v expression was analysed in bone marrow (BM) biopsies of multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) patients, in biopsies of soft tissue infiltration by MM and in extramedullary plasmacytoma samples. Expression of CD44 isoforms containing the 3v, 4v, 6v or 10v domain was observed in 15, 7, 13 and 5% of 87 samples from 49 consecutive MM cases, but could not be detected in ten normal persons or 11 MGUS patients. In contrast, CD44v9 revealed a broader pattern of expression and was observed in plasma cells in three out of ten normal persons and in three out of 11 MGUS cases. In MM, CD44v9 was detected in 32 out of 87 samples (37%) of BM infiltrates and was associated with an advanced Durie and Salmon stage (P<0.03), a progressive disease (P<0.01) and an IgA subtype (P<0.01). Furthermore, CD44v9 expression was observed in three out of five cases of MM soft tissue infiltrates, was often upregulated during disease progression, was significantly correlated with a shorter overall survival (P<0.03) and emerged as an independent prognostic factor in multivariate analysis (stage: relative risk 1.36, P<0.02; CD44v9 expression: relative risk 1.45, P<0.04). These results substantiate the clinical relevance of CD44v domains in plasma cell disorders and establish CD44v9 as a new independent prognostic parameter in MM.


Assuntos
Receptores de Hialuronatos/análise , Mieloma Múltiplo/mortalidade , Paraproteinemias/metabolismo , Adulto , Idoso , Feminino , Humanos , Receptores de Hialuronatos/fisiologia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/etiologia , Mieloma Múltiplo/metabolismo , Análise Multivariada , Prognóstico , Isoformas de Proteínas , Fatores de Risco , Taxa de Sobrevida
15.
Ann N Y Acad Sci ; 938: 63-70; discussion 70-1, 2001 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11458527

RESUMO

Recent studies with purified hematopoietic stem cells in vitro support a model of stem cell self-renewal control that involves distinct mechanisms regulating permissiveness to and execution of lineage restriction. Such a model predicts the existence of phenotypically separable populations of hematopoietic cells that are pluripotent and either capable or incapable of extensive self-renewal. Such populations have been previously described in the mouse. We describe here the first evidence that such cells can now be identified in humans using different types of immunodeficient mice as hosts.


Assuntos
Hematopoese , Células-Tronco Hematopoéticas/citologia , Animais , Contagem de Células , Diferenciação Celular , Divisão Celular/efeitos dos fármacos , Linhagem da Célula , Células Cultivadas , Ensaio de Unidades Formadoras de Colônias , Citocinas/farmacologia , Citocinas/fisiologia , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/classificação , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Fenótipo , Imunodeficiência Combinada Severa/patologia , Imunodeficiência Combinada Severa/terapia , Microglobulina beta-2/genética
16.
J Clin Invest ; 107(2): 199-206, 2001 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11160136

RESUMO

Increasing use of purified or cultured human hematopoietic cells as transplants has revealed an urgent need for better methods to predict the speed and durability of their engraftment potential. We now show that NOD/SCID-beta2 microglobulin-null (NOD/SCID-beta2m-/-) mice are sequentially engrafted by two distinct and previously unrecognized populations of transplantable human short-term repopulating hematopoietic cells (STRCs), neither of which efficiently engraft NOD/SCID mice. One is predominantly CD34+CD38+ and is myeloid-restricted; the other is predominantly CD34+CD38- and has broader lymphomyeloid differentiation potential. In contrast, the long-term repopulating human cells that generate lymphoid and myeloid progeny in NOD/SCID mice engraft and self-renew in NOD/SCID-beta2m-/- mice equally efficiently. In short-term expansion cultures of adult bone marrow cells, myeloid-restricted STRCs were preferentially amplified (greater than tenfold) and, interestingly, both types of STRC were found to be selectively elevated in mobilized peripheral blood harvests. These results suggest an enhanced sensitivity of STRCs to natural killer cell-mediated rejection. They also provide new in vivo assays for different types of human STRC that may help to predict the engraftment potential of clinical transplants and facilitate future investigation of early stages of human hematopoietic stem cell differentiation.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Microglobulina beta-2/deficiência , Animais , Ciclo Celular , Células-Tronco Hematopoéticas/imunologia , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Fatores de Tempo , Transplante Heterólogo , Microglobulina beta-2/genética
17.
Exp Hematol ; 28(8): 895-906, 2000 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10989190

RESUMO

OBJECTIVE: The purpose of this study was to investigate the effects of interleukin-2 (IL-2) gene-transduced hematopoietic progenitor cells or cytotoxic function and systemic toxicity following syngeneic bone marrow transplantation. MATERIAL AND METHODS: Marrow of 5-fluorouracil pretreated donor mice were transfected with a retroviral vector containing the murine IL-2 gene and transplanted into lethally irradiated syngeneic hosts. RESULTS: Productive insertion of the IL-2 gene could be demonstrated at various intervals post-transplant without impairment of hematopoietic engraftment. Endogenously augmented IL-2 release resulted in a selective increase in CD4(+), CD8(+), and NK1.1(+) population in spleen and bone marrow, as well as significant cytolytic activity against syngeneic leukemia cells in vitro. Our results also illustrate the interdependence among the magnitude of systemic IL-2 levels, the number of IL-2-transduced cells in the transplant inoculum, and the appearance of systemic toxicity. Infusion of marrow transduced with high-titer, high-expressing IL-2 retrovirus resulted in significant morbidity and mortality in the recipients. Our studies demonstrate that mortality was secondary to severe lymphocytic infiltration of liver and lung, which was associated with increased expression of intercellular adhesion molecule-1 and vascular adhesion molecule-1. Reducing the number of IL-2-transduced cells in the bone marrow inoculum, however, resulted in significantly improved survival with no adverse events being evident during the post-transplant period. CONCLUSION: Delivery of IL-2 to the bone marrow can be achieved by transplantation of genetically modified hematopoietic cells, however, the overall feasibility is strongly influenced by the number of transduced cells in the bone marrow inocolum and/or the expression pattern of IL-2 in vivo.


Assuntos
Transplante de Medula Óssea , Citotoxicidade Imunológica , Células-Tronco Hematopoéticas/imunologia , Interleucina-2/genética , Transfecção , Animais , Células da Medula Óssea/imunologia , Contagem de Células , Divisão Celular , Expressão Gênica , Vetores Genéticos , Efeito Enxerto vs Leucemia , Imuno-Histoquímica , Molécula 1 de Adesão Intercelular/análise , Interleucina-2/imunologia , Interleucina-2/farmacologia , Células Matadoras Naturais/imunologia , Cinética , Camundongos , Proteínas Recombinantes/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Baço/citologia , Baço/imunologia , Linfócitos T/imunologia , Molécula 1 de Adesão de Célula Vascular/análise
18.
Leuk Res ; 24(7): 583-7, 2000 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10867132

RESUMO

The efficacy of continuous oral cytarabine ocfosfate (YNK01) (300 mg/day) in combination with interferon alpha (IFNalpha, 5x10(6) IU/day) was evaluated in patients with advanced chronic myelogenous leukemia, who previously failed to respond to IFNalpha-based therapies. Dose escalations up to 900 mg YNK01 were allowed in patients who failed to respond. In view of our results, four patients developed a complete hematological response after YNK01 was started. Among those who initially responded to YNK01, one complete cytogenetic response was achieved 18 months later. Although the data are preliminary, this is the first study showing that continuous administration of YNK01 along with IFNalpha is effective in patients with advanced chronic myelogenous leukemia.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Arabinonucleotídeos/uso terapêutico , Monofosfato de Citidina/análogos & derivados , Monofosfato de Citidina/uso terapêutico , Interferon-alfa/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Arabinonucleotídeos/administração & dosagem , Arabinonucleotídeos/efeitos adversos , Monofosfato de Citidina/administração & dosagem , Monofosfato de Citidina/efeitos adversos , Humanos , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Pessoa de Meia-Idade , Projetos Piloto , Proteínas Recombinantes , Resultado do Tratamento
19.
Leukemia ; 14(6): 1112-21, 2000 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10865977

RESUMO

Neoplastic CD34+ cells from chronic myeloid leukemia (CML) patients proliferate in vitro in the absence of serum or defined growth factors due to an autocrine mechanism involving IL-3 and G-CSF (Jiang et al. Proc Natl Acad Sci USA 1999; 96: 12804). Detailed examination of the various cell types produced in such cultures has now demonstrated the rapid, factor-independent, generation of clonogenic progenitors for all lineages (granulocyte-macrophage, megakaryocyte and erythroid) with the additional appearance within 10 days of large numbers of mature granulocytes, macrophages, and megakaryocytes, as well as occasional erythroid cells. Inclusion of flt3-ligand, Steel factor, IL-3, IL-6, and G-CSF +/- erythropoietin (EPO) in the cultures enhanced only slightly the output of mature cells (except for the erythroid population which was much larger when EPO was added). Analogous subpopulations of normal CD34+ cells produced similar numbers and types of cells but, as expected, only when growth factors were added. Thus primitive CD34+ CML cells proliferating autonomously in vitro recapitulate the full spectrum of differentiation responses of normal CD34+ cells stimulated by IL-3 and G-CSF. These findings point to a role of autocrine IL-3 and G-CSF in the similar multi-lineage expansion of differentiating CD34+ CML cells that occurs in vivo.


Assuntos
Antígenos CD34/imunologia , Diferenciação Celular , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Células-Tronco/imunologia , Linhagem da Célula , Meios de Cultura , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia
20.
Leuk Res ; 23(5): 483-8, 1999 May.
Artigo em Inglês | MEDLINE | ID: mdl-10374862

RESUMO

In a retrospective immunohistochemical study based on 27 patients with stage IV follicle center lymphoma (FCL) the expression of CD44standard (CD44s), LFA-1 (CD11a, CD18), VLA-4 (CD49d, CD29) and ICAM-1 (CD54) was analysed on lymphoma cells in bone marrow infiltrates. The results were correlated to clinical data and overall survival. Our data demonstrate that the expression of LFA-1 on lymphoma cells is predictive for the prognosis of patients with advanced FCL. In detail, patients exhibiting weak to moderate expression (+/++) of CD11 and CD18 showed a significantly shorter median survival (51 months and 33 months, respectively) than did those presenting with strong expression ( ) of the LFA-1 adhesion molecule (P = 0.04 and P = 0.0051, respectively). Furthermore, multivariate analysis identified CD18 as a new independent prognostic factor in patients with advanced FCL. Our findings emphasize the relevance of adhesion molecules for the pathology of FCL and give further support for their impact on clinical course and overall survival.


Assuntos
Antígenos de Neoplasias/análise , Antígeno-1 Associado à Função Linfocitária/análise , Linfoma Difuso de Grandes Células B/imunologia , Adulto , Idoso , Moléculas de Adesão Celular/análise , Feminino , Humanos , Imuno-Histoquímica , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
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