RESUMO
According to the cancer stem cell (CSC) hypothesis, CSCs are the only cancer cells that can give rise to and sustain all cells that constitute a cancer as they possess inherent or acquired self-renewal potential, and their elimination is required and potentially sufficient to achieve a cure. Whilst establishing CSC identity remains challenging in most cancers, studies of low-intermediate risk myelodysplastic syndromes (MDS), other chronic myeloid malignancies and clonal haematopoiesis of indeterminant potential (CHIP) strongly support that the primary target cell usually resides in the rare haematopoietic stem cell (HSC) compartment. This probably reflects the unique self-renewal potential of HSCs in normal human haematopoiesis, combined with the somatic initiating genomic driver lesion not conferring extensive self-renewal potential to downstream progenitor cells. Mutational 'fate mapping' further supports that HSCs are the only disease-propagating cells in low-intermediate risk MDS, but that MDS-propagating potential might be extended to progenitors upon disease progression. The clinical importance of MDS stem cells has been highlighted through the demonstration of selective persistence of MDS stem cells in patients at complete remission in response to therapy. This implies that MDS stem cells might possess unique resistance mechanisms responsible for relapses following otherwise efficient treatments. Specific surveillance of MDS stem cells should be considered to assess the efficiency of therapies and as an early indicator of emerging relapses in patients in clinical remission. Moreover, further molecular characterization of purified MDS stem cells should facilitate identification and validation of improved and more stem cell-specific therapies for MDS.
Assuntos
Células-Tronco Hematopoéticas/patologia , Síndromes Mielodisplásicas/patologia , Células-Tronco Neoplásicas/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Leucemia Mieloide/patologia , Mutação , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/terapia , Fenótipo , Indução de Remissão , Fatores de RiscoRESUMO
Bone metastases in patients with solid tumours (ST) and bone lesions in patients with haematological malignancies (HM) are common. Associated skeletal-related events (SREs) cause severe pain, reduced quality of life and place a burden on health care resources. Bone-targeted agents can reduce the risk of SREs. We evaluated the management of bone metastasis/lesions in five European countries (France, Germany, Italy, Spain and the UK) by an observational chart audit. In total, 881 physicians completed brief questionnaires on 17 193 patients during the observation period, and detailed questionnaires for a further 9303 individuals. Patient cases were weighted according to the probability of inclusion. Although a large proportion of patients with bone metastases/lesions were receiving bisphosphonates, many had their treatment stopped (ST, 19%; HM, 36%) or will never be treated (ST, 18%; HM, 13%). The results were generally similar across the countries, although German patients were more likely to have asymptomatic bone lesions detected during routine imaging. In conclusion, many patients who could benefit from bone-targeted agents do not receive bisphosphonates and many have their treatment stopped when they could benefit from continued treatment. Developing treatment guidelines, educating physicians and increasing the availability of new agents could benefit patients and reduce costs.
Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Difosfonatos/uso terapêutico , Neoplasias , Idoso , Neoplasias Ósseas/secundário , Europa (Continente) , Feminino , Neoplasias Hematológicas , Humanos , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Tempo para o Tratamento , Resultado do TratamentoRESUMO
BACKGROUND: The use of potential surrogate end points for overall survival, such as disease-free survival (DFS) or time-to-treatment failure (TTF) is increasingly common in randomized controlled trials (RCTs) in cancer. However, the definition of time-to-event (TTE) end points is rarely precise and lacks uniformity across trials. End point definition can impact trial results by affecting estimation of treatment effect and statistical power. The DATECAN initiative (Definition for the Assessment of Time-to-event End points in CANcer trials) aims to provide recommendations for definitions of TTE end points. We report guidelines for RCT in sarcomas and gastrointestinal stromal tumors (GIST). METHODS: We first carried out a literature review to identify TTE end points (primary or secondary) reported in publications of RCT. An international multidisciplinary panel of experts proposed recommendations for the definitions of these end points. Recommendations were developed through a validated consensus method formalizing the degree of agreement among experts. RESULTS: Recommended guidelines for the definition of TTE end points commonly used in RCT for sarcomas and GIST are provided for adjuvant and metastatic settings, including DFS, TTF, time to progression and others. CONCLUSION: Use of standardized definitions should facilitate comparison of trials' results, and improve the quality of trial design and reporting. These guidelines could be of particular interest to research scientists involved in the design, conduct, reporting or assessment of RCT such as investigators, statisticians, reviewers, editors or regulatory authorities.
Assuntos
Determinação de Ponto Final/normas , Tumores do Estroma Gastrointestinal/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto/normas , Projetos de Pesquisa/normas , Sarcoma/terapia , Terminologia como Assunto , Consenso , Técnica Delphi , Progressão da Doença , Intervalo Livre de Doença , Determinação de Ponto Final/classificação , Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/mortalidade , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto/classificação , Sarcoma/diagnóstico , Sarcoma/mortalidade , Fatores de Tempo , Falha de TratamentoRESUMO
BACKGROUND: HOX gene expression is altered in many cancers; previous microarray revealed changes in HOX gene expression in head and neck squamous cell carcinoma (HNSCC), particularly HOXD10. METHODS: HOXD10 expression was assessed by qPCR and immunoblotting in vitro and by immunohistochemistry (IHC) in tissues. Low-expressing cells were stably transfected with HOXD10 and the phenotype assessed with MTS, migration and adhesion assays and compared with the effects of siRNA knockdown in high-HOXD10-expressing cells. Novel HOXD10 targets were identified using expression microarrays, confirmed by reporter assay, and validated in tissues using IHC. RESULTS: HOXD10 expression was low in NOKs, high in most primary tumour cells, and low in lymph node metastasis cells, a pattern confirmed using IHC in tissues. Overexpression of HOXD10 decreased cell invasion but increased proliferation, adhesion and migration, with knockdown causing reciprocal effects. There was no consistent effect on apoptosis. Microarray analysis identified several putative HOXD10-responsive genes, including angiomotin (AMOT-p80) and miR-146a. These were confirmed as HOXD10 targets by reporter assay. Manipulation of AMOT-p80 expression resulted in phenotypic changes similar to those on manipulation of HOXD10 expression. CONCLUSIONS: HOXD10 expression varies by stage of disease and produces differential effects: high expression giving cancer cells a proliferative and migratory advantage, and low expression may support invasion/metastasis, in part, by modulating AMOT-p80 levels.
Assuntos
Carcinoma de Células Escamosas/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Proteínas de Homeodomínio/fisiologia , Fatores de Transcrição/fisiologia , Angiomotinas , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas de Membrana/genética , MicroRNAs/genética , Proteínas dos Microfilamentos , Análise de Sequência com Séries de Oligonucleotídeos , Regiões Promotoras Genéticas , Carcinoma de Células Escamosas de Cabeça e Pescoço , TranscriptomaRESUMO
Human NK cells express cell surface class I MHC receptors (killer cell immunoglobulin-like receptor, KIR) in a probabilistic manner. Previous studies have shown that a distal promoter acts in conjunction with a proximal bidirectional promoter to control the selective activation of KIR genes. We report here the presence of an intron 2 promoter in several KIR genes that produce a spliced antisense transcript. This long noncoding RNA (lncRNA) transcript contains antisense sequence complementary to KIR-coding exons 1 and 2 as well as the proximal promoter region of the KIR genes. The antisense promoter contains myeloid zinc finger 1 (MZF-1)-binding sites, a transcription factor found in hematopoietic progenitors and myeloid precursors. The KIR antisense lncRNA was detected only in progenitor cells or pluripotent cell lines, suggesting a function that is specific for stem cells. Overexpression of MZF-1 in developing NK cells led to decreased KIR expression, consistent with a role for the KIR antisense lncRNA in silencing KIR gene expression early in development.
Assuntos
Células-Tronco Embrionárias/metabolismo , Células-Tronco Pluripotentes/metabolismo , RNA Longo não Codificante/genética , Receptores KIR/genética , Sítios de Ligação , Éxons , Inativação Gênica , Células HEK293 , Células HeLa , Humanos , Íntrons , Fatores de Transcrição Kruppel-Like/química , Fatores de Transcrição Kruppel-Like/metabolismo , Regiões Promotoras Genéticas , RNA Antissenso/química , RNA Antissenso/genética , RNA Antissenso/metabolismo , RNA Longo não Codificante/química , RNA Longo não Codificante/metabolismo , Receptores KIR/metabolismoRESUMO
BACKGROUND: Thalidomide has potent anti-inflammatory and anti-angiogenic properties. It was evaluated in combination with chemotherapy in two randomised placebo-controlled trials in patients with small cell lung cancer (SCLC, n=724) and advanced non-small cell lung cancer (NSCLC, n=722). Neither study demonstrated an improvement in overall survival with the addition of thalidomide to chemotherapy. This study investigated circulating angiogenic biomarkers in a subset of these patients. METHODS: Serial plasma samples were collected in a cohort of patients enrolled in these two trials (n=95). Vascular endothelial growth factor (VEGF), soluble truncated form of VEGF receptor-2 (sVEGFR-2), interleukin-8 (IL-8), tumour necrosis factor-α (TNF-α), basic fibroblast growth factor (bFGF) and soluble intercellular adhesion molecule-1 (sICAM-1) levels were measured by enzyme-linked immunosorbent assays. Results were correlated with patient clinical data including stage, response rate and progression-free survival (PFS). RESULTS: Baseline biomarker levels were not significantly different between SCLC and NSCLC. For pooled treatment groups, limited stage SCLC was associated with lower baseline VEGF (P=0.046), sICAM-1 (P=0.008) and IL-8 (P=0.070) than extensive stage disease. Low baseline IL-8 was associated with a significantly improved PFS in both SCLC and NSCLC (P=0.028), and a greater reduction in IL-8 was associated with a significantly improved tumour response (P=0.035). Baseline angiogenic factor levels, however, did not predict response to thalidomide. CONCLUSION: Circulating angiogenic biomarkers did not identify patients who benefited from thalidomide treatment.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Neoplasias Pulmonares/sangue , Neovascularização Patológica/sangue , Carcinoma de Pequenas Células do Pulmão/sangue , Talidomida/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Ensaios Clínicos Fase III como Assunto , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Etoposídeo/administração & dosagem , Feminino , Fator 2 de Crescimento de Fibroblastos/sangue , Humanos , Molécula 1 de Adesão Intercelular/sangue , Interleucina-8/sangue , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Análise Multivariada , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/mortalidade , Modelos de Riscos Proporcionais , Ensaios Clínicos Controlados Aleatórios como Assunto , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/mortalidade , Análise de Sobrevida , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/sangue , GencitabinaRESUMO
AIM: To define the utility of intravenous contrast administration in the PET-CT (PET-CTc) in patients with lymphoma in order to determine its possible indications. MATERIAL AND METHODS: 78 patients with lymphoma were prospectively evaluated. All underwent simultaneous PET-CTc scans in a hybrid system for staging (8), evaluation of response to treatment (29), suspicion of recurrence (9) and complete remission control (48). The PET scan was acquired by a conventional method and the diagnostic CT scan was performed according to radiological protocol. Both examinations were evaluated blinded and independently, analyzing 28 anatomical locations in order to determine the degree of agreement. Final diagnosis was established by the clinician based on the histological study, results of other diagnostic techniques or clinical follow-up. RESULTS: The final result of both techniques were concordant in 87/94 studies (92.5%). A total of 158 (36 FP) pathological locations were detected with PET-CT and 189 (71 FP) with CTc, with 72 locations being discordant between both techniques. Global sensitivity, specificity, PPV and NPV were 93%, 98%, 77% and 99%; and 94%, 97%, 62% and 99%, respectively. CONCLUSIONS: Administration of intravenous contrast does not seem to provide any advantage in the determination of nodal and extranodal disease in lymphoma patients. The low prevalence of disease probably accounts for the limited PPV of both techniques. An increase of our sample size, with a greater homogeneity of the groups, should offer more reliable results.
Assuntos
Meios de Contraste/administração & dosagem , Linfoma/diagnóstico , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto JovemRESUMO
AIMS: Previous studies have defined prognostic factors predicting a favourable response to treatment and long-term survival in small cell lung cancer (SCLC) patients. Here we sought specific pre-treatment features predicting early death in SCLC. MATERIALS AND METHODS: An exploratory cohort of 62 patients with poor prognosis SCLC and a separate confirmatory independent cohort of 152 unselected SCLC patients were identified to determine risk factors for early death, defined as within 8 weeks of diagnosis. RESULTS: In an exploratory cohort of patients with poor prognosis SCLC, 46 received chemotherapy and 16 patients received no chemotherapy. Multivariate analysis of chemotherapy patients showed a raised serum urea to be predictive of early death - increasing the risk by 13-fold (odds ratio 13.3, 95% confidence interval=2.8-64). In a separate cohort of 152 unselected SCLC patients, 123 received chemotherapy and 29 did not. Logistic regression analysis of treated patients showed that performance status >2 (P=0.009), urea>upper limit of normal (P=0.01), neutrophil count >10 (P=0.024) and weight loss >10% (P=0.03) significantly contributed to the risk of early death. Of note, raised serum urea increased the risk of early death by 12-fold (odds ratio 11.8, 95% confidence interval=1.8-76.9). CONCLUSION: We have shown that pre-treatment raised serum urea is a significant predictor of early death. This readily available information will be useful for assessing SCLC patients at the bedside and discussing the risks of chemotherapy with them.
Assuntos
Biomarcadores Tumorais , Carcinoma de Células Pequenas/sangue , Carcinoma de Células Pequenas/tratamento farmacológico , Carcinoma de Células Pequenas/mortalidade , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Ureia/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Pequenas/fisiopatologia , Feminino , Humanos , Neoplasias Pulmonares/fisiopatologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Prognóstico , Análise de SobrevidaRESUMO
In the search for novel antiproliferative agents for small cell lung cancer (SCLC), we found the neuropeptide antagonist [Arg6, D-Trp7,9,MePhe8]substance P(6-11) to be effective in vitro. In murine Swiss 3T3 cells [Arg6,D-Trp7,9,MePhe8]substance P(6-11) was identified as a potent inhibitor of vasopressin-stimulated DNA synthesis which also blocks [3H]vasopressin binding to specific cell-surface receptors. It was a less potent antagonist of gastrin-releasing peptide and bradykinin in these cells but did not block the effects of other mitogens. In SCLC cell lines, [Arg6,D-Trp7,9,MePhe8]substance P(6-11) inhibited colony-formation in soft agarose and growth in liquid culture in a dose-dependent manner. It also blocked receptor-mediated Ca2+ mobilization induced by vasopressin, bradykinin, cholecystokinin, galanin, gastrin-releasing peptide, and neurotensin. We suggest that broad-spectrum neuropeptide antagonists can block multiple autocrine and paracrine growth loops in SCLC and could be useful therapeutic agents.
Assuntos
Carcinoma de Células Pequenas/patologia , DNA de Neoplasias/biossíntese , Neoplasias Pulmonares/patologia , Fragmentos de Peptídeos/farmacologia , Proteínas Recombinantes , Substância P/análogos & derivados , Animais , Bradicinina/antagonistas & inibidores , Cálcio/metabolismo , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Ensaios de Seleção de Medicamentos Antitumorais , Peptídeo Liberador de Gastrina , Humanos , Camundongos , Fragmentos de Peptídeos/antagonistas & inibidores , Peptídeos/antagonistas & inibidores , Substância P/antagonistas & inibidores , Substância P/farmacologia , Células Tumorais Cultivadas , Vasopressinas/antagonistas & inibidores , Vasopressinas/farmacologiaRESUMO
The neuron-restrictive silencer factor [NRSF (RE-1 silencing transcription factor/X box repressor)] is a transcriptional silencer, which we have previously implicated in deregulation of the vasopressin promoter in small cell lung cancer (SCLC). Here we describe a novel splice variant of the NRSF transcript, which is highly expressed in SCLCs. The variant was detected in both established cell lines and primary SCLC cultures as well as in some primitive neuroectodermal tumor biopsies. It was present at very low levels in human brain tissue, non-SCLC tumors, and normal bronchial epithelium. This human splice variant, which is massively overexpressed in SCLCs, incorporates a 50-bp insert between exons 5 and 6, introducing a stop codon and predicting translation of a truncated NRSF isoform. We propose that the encoded isoform may antagonize repression of the vasopressin promoter and other "neuronal" genes with neuron-restrictive silencer elements in SCLCs. Thus, up-regulated expression of this NRSF isoform may be a key early factor in defining the neuroendocrine phenotype of these tumors. The NRSF splice variant represents a specific clinical marker that could prove useful in detection of the majority of SCLCs.
Assuntos
Processamento Alternativo , Biomarcadores Tumorais/genética , Carcinoma de Células Pequenas/genética , Inativação Gênica , Variação Genética , Neoplasias Pulmonares/genética , Tumores Neuroectodérmicos/genética , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Sequência de Aminoácidos , Sequência de Bases , Biópsia , Carcinoma Pulmonar de Células não Pequenas/genética , Códon de Terminação , Células HeLa , Humanos , Dados de Sequência Molecular , Tumores Neuroectodérmicos/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição Gênica , Células Tumorais CultivadasRESUMO
Arginine vasopressin (AVP) is often expressed in small cell lung cancer (SCLC), and a 65-bp AVP minimal promoter fragment is sufficient to restrict activity to SCLC in vitro. We now describe a motif with homology to the neuron-restrictive silencer element (NRSE) within this fragment. Electrophoretic mobility shift analysis demonstrated that multiple specific complexes are bound by this motif. These complexes are cross-competed with a characterized SCG10 NRSE probe and do not bind to the AVP probe with a specific mutation in the NRSE. The complexes vary in mobility between lung tumor cell lines, showing different levels of AVP expression, and some are differentially bound in SCLC. Overexpression of a neuron-restrictive silencer factor expression construct can silence reporter gene expression supported by the AVP promoter in SCLC, although this was dependent on both the level of endogenous AVP expression in the cells and putative enhancer elements in larger promoter constructs. Activation of the proximal AVP promoter in SCLC is therefore proposed to, at least partially, rely on modulation of normal repressor activity at the NRSE.
Assuntos
Arginina Vasopressina/genética , Carcinoma de Células Pequenas/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Neurônios/metabolismo , Regiões Promotoras Genéticas , Proteínas Repressoras/fisiologia , Dedos de Zinco , Humanos , Células Tumorais CultivadasRESUMO
BACKGROUND: Lung cancer is the most common cancer and smoking is the principal cause. Due to poor survival rates, symptom palliation and promotion of health-related quality of life (HRQoL) are primary outcomes for lung cancer patients. Given the established relationship between smoking and lung cancer, patients who have smoked may feel stigmatised or guilty after diagnosis, and more pessimistic about their illness and likely outcomes. This may have adverse implications for HRQoL. OBJECTIVES: We explored HRQoL and support experiences among newly diagnosed patients with advanced lung cancer. DESIGN: Semistructured interviews were conducted with nine patients and analysed using interpretative phenomenological analysis. RESULTS: Patients described the physical, emotional and social impact of disease on HRQoL. Fear of compromising their immune system and adjusting to new relationship roles had a wide-ranging effect on patients' HRQoL. Patients acknowledged links between lung cancer and smoking but some continued to smoke. They were sensitive to the opinions of medical staff about smoking especially those who continued to smoke or recently quit. CONCLUSIONS: We conclude that staff should give clearer advice about the adverse implications of continued smoking. We discuss the potential value of diagnosis as a teachable moment for promoting smoking cessation among patients and family members.
Assuntos
Neoplasias Pulmonares/psicologia , Qualidade de Vida/psicologia , Fumar/efeitos adversos , Adaptação Psicológica , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cuidados Paliativos , Pesquisa Qualitativa , Abandono do Hábito de Fumar/psicologiaRESUMO
We report details of a family with classic Li-Fraumeni syndrome in which there is a mutation in codon 344 of the tumour suppressor gene TP53. Codon 344 is a key residue within the tetramerisation domain, and the amino acid substitution of a proline for a leucine is predicted to have profound implications for tetramerisation and potentially DNA binding. This is the first report of a mutation at this residue in either sporadic tumours or in the germline and the first report of a germline mutation within the tetramerisation domain. The family does not appear to be remarkable in the spectrum of tumours, and there is loss of the wild-type allele in a leiomyosarcoma from the proband. A cell line has been established from the tumour of the proband and cytogenetic and molecular studies carried out, providing an extensive analysis in this family.
Assuntos
Códon/genética , Genes p53/genética , Síndrome de Li-Fraumeni/genética , Mutação Puntual/genética , Adulto , Alelos , Sequência de Bases , Feminino , Genótipo , Humanos , Cariotipagem , Masculino , Dados de Sequência Molecular , Linhagem , Análise de Sequência de DNARESUMO
PURPOSE: To support multicyclic, dose-intensive chemotherapy, we assessed the effects of reinfusing hematopoietic progenitors collected at each cycle in leukapheresis product or whole blood. PATIENTS AND METHODS: Twenty-five patients with small-cell lung cancer (SCLC) were treated with six cycles of ifosfamide, carboplatin, and etoposide (ICE) with granulocyte colony-stimulating factor (G-CSF) 300 micrograms/d subcutaneously (SC) on days 4 to 15. Hematopoietic progenitors collected during each cycle were reinfused on day 3 of the next cycle. Cohort 1 (n = 6) was treated every 3 weeks, with leukapheresis after 2 weeks and cryopreservation of the leukapheresis product. Chemotherapy was given if the WBC count was > or = 3 x 10(9)/L and platelet count > or = 100 x 10(9)/L. Cohort 2 (n = 7) was treated every 2 weeks, with leukapheresis on day 1 of the next cycle and storage of the leukapheresis product at 4 degrees C. Cohort 3 (n = 12) was treated every 2 weeks, with 500 to 750 mL of blood drawn by venesection on day 1 of the next cycle and stored at 4 degrees C. In cohorts 2 and 3, chemotherapy was given if the WBC count was > or = 3 x 10(9)/L and platelet count > or = 30 x 10(9)/L. Blood and leukapheresis products were assayed for hematopoietic progenitors. RESULTS: ICE chemotherapy with G-CSF was effective in mobilizing blood progenitors (median, 120-fold). Long-term cultures showed no evidence of stem-cell depletion. The cytotoxic dose-intensity of standard every-4-weeks ICE is 100%. In the first three cycles, it was 134% (median) in cohort 1 and 200% in cohorts 2 and 3 (P < .0001). Toxicity and supportive care requirements were not increased. CONCLUSION: The dose-intensity of ICE chemotherapy can be doubled by reinfusing hematopoietic progenitors collected by leukapheresis or venesection and stored at 4 degrees C.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma de Células Pequenas/terapia , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Neoplasias Pulmonares/terapia , Adulto , Transfusão de Sangue Autóloga , Carboplatina/administração & dosagem , Carcinoma de Células Pequenas/sangue , Carcinoma de Células Pequenas/mortalidade , Causas de Morte , Terapia Combinada , Etoposídeo/administração & dosagem , Estudos de Viabilidade , Feminino , Humanos , Ifosfamida/administração & dosagem , Leucaférese , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Transfusão de PlaquetasRESUMO
PURPOSE: The use of granulocyte colony-stimulating factor (G-CSF) to increase cytotoxic dose-intensity was assessed in a randomized trial in better-prognosis small-cell lung cancer (SCLC). Both control and G-CSF arms were subject to the same dose-intensification strategy. PATIENTS AND METHODS: Patients with newly diagnosed SCLC and either no or one adverse prognostic factor were randomized to receive vincristine, ifosfamide, carboplatin, and etoposide (VICE) alone or with recombinant human (rHu)G-CSF (lenograstim) 5 micrograms/kg/d between cycles. Six chemotherapy cycles were given, with prophylactic cranial irradiation after cycle 1 and thoracic irradiation after cycle 3. There was no fixed dose interval. In both arms, patients were eligible for re-treatment when the WBC count was > or = 3 x 10(9)/L and platelet count was > or = 100 x 10(9)/L. No dose reductions were permitted. Dose-intensity was expressed relative to standard every-4-weeks VICE. RESULTS: Sixty-five consecutive patients in one institution were randomized to control (n = 31) or G-CSF (n = 34). WBC and neutrophil counts were consistently higher in G-CSF patients than in the control group, but there were no significant differences in the incidence of febrile neutropenia, antibiotic or transfusion requirements, or days in hospital. In both treatment arms, the median dose-intensity was greater than one for each cycle (control group, P = .0009; G-CSF group, P = .0001). The G-CSF group received a significantly higher dose-intensity than the control group, with the greatest difference in the first three cycles (1.34 v 1.17, P = .001). There were more chemotherapy-related deaths in the G-CSF group than in the control group (six v one), but this group had a better 2-year survival rate (32% with G-CSF, 95% confidence interval [CI], 16 to 48; 15% with controls, 95% CI, 2 to 27). CONCLUSION: The dose-intensity of VICE chemotherapy was increased in both groups. Patients randomized to receive G-CSF achieved a significantly higher dose-intensity than controls. Despite early toxicity, they had a better 2-year survival rate.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma de Células Pequenas/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carcinoma de Células Pequenas/sangue , Carcinoma de Células Pequenas/mortalidade , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Humanos , Ifosfamida/administração & dosagem , Ifosfamida/efeitos adversos , Lenograstim , Contagem de Leucócitos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neutrófilos , Prognóstico , Proteínas Recombinantes/uso terapêutico , Taxa de Sobrevida , Vincristina/administração & dosagem , Vincristina/efeitos adversosRESUMO
PURPOSE: Small-cell lung cancer (SCLC) is exquisitely chemosensitive, but few patients are cured by conventional chemoradiotherapy. Recent studies suggest that increased cytotoxic dose-intensity might improve survival. In this randomized phase II study, we tested the feasibility of dose intensification using sequential reinfusion of hematopoietic progenitors in whole blood. PATIENTS AND METHODS: SCLC patients with a favorable prognosis were treated with six cycles of ifosfamide, carboplatin, and etoposide (ICE), at 4-week (standard treatment) or 2-week (intensified treatment) intervals. Intensified treatment was supported by daily subcutaneous filgrastim injections and reinfusion of 750 mL of autologous blood collected immediately before each cycle. RESULTS: Fifty consecutive patients were randomized to standard (n = 25) or intensified (n = 25) ICE. A total of 94% completed at least three treatment cycles, and 70% completed six cycles; 96% of treatments were given at full dose. The planned dose-intensity was 1.0 for standard and 2.0 for intensified ICE. The median received dose-intensity for cycles 1 through 3 was 0.99 (range, 0.33 to 1.02) for the standard treatment arm and 1.80 (range, 0.99 to 1.97) for the intensified treatment arm (P <.001). Over all six cycles, the median received dose-intensity was 0.95 (range, 0.17 to 1.03) for the standard treatment arm and 1.60 (range, 0.60 to 2.01) for the intensified treatment arm (P <.001). Febrile neutropenia was more common on the standard treatment arm (84% v 56%), resulting in more days of intravenous antibiotics (median, 10 v 3 days; P =.035). Transfusion requirements were similar in the two groups. CONCLUSION: Sequential reinfusion of hematopoietic progenitors in whole blood can safely support substantial increases in dose-intensity of ICE chemotherapy for SCLC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Pequenas/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Plaquetas/citologia , Plaquetas/efeitos dos fármacos , Carboplatina/administração & dosagem , Terapia Combinada , Relação Dose-Resposta a Droga , Etoposídeo/administração & dosagem , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Ifosfamida/administração & dosagem , Masculino , Mesna/administração & dosagem , Pessoa de Meia-Idade , Contagem de Plaquetas , Qualidade de VidaRESUMO
PURPOSE: To compare standard and intensive treatment strategies for patients with high-grade non-Hodgkin's lymphoma (NHL) of poor prognosis, defined by the international prognostic index. PATIENTS AND METHODS: Thirty-four patients received standard chemotherapy with 11 weeks of doxorubicin, cyclophosphamide, vincristine, bleomycin, etoposide, prednisolone, and methotrexate (VAPEC-B), and 33 received intensive treatment with 7 weeks of VAPEC-B, three cycles of ifosfamide/cytarabine, then high-dose busulfan/cyclophosphamide followed by autologous blood progenitor-cell (BPC) transplantation. RESULTS: Twelve of 33 patients in the intensive group and 26 of 34 patients in the standard group have died. The median follow-up time for the surviving patients is 31 months and 68 months, respectively. At 2 years, the actuarial estimates of event-free survival (EFS) were 61% versus 35% (P = .01) and of overall survival, 64% versus 35% (P = .01). A significant reduction in the event rate (progression or death) was maintained after adjustment for age and the number of risk factors. The estimated risk of experiencing an event was 0.37 (95% confidence interval [CI], 0.16 to 0.84) in the intensive group compared with the standard group. CONCLUSION: Patients with poor prognostic features who received high-dose therapy and BPC rescue had a superior EFS. The survival differences observed in this study justify a formal comparison in a randomized study.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma não Hodgkin/terapia , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bleomicina/administração & dosagem , Bussulfano/administração & dosagem , Terapia Combinada , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , Etoposídeo/administração & dosagem , Humanos , Ifosfamida/administração & dosagem , Linfoma não Hodgkin/mortalidade , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Prednisolona/administração & dosagem , Prognóstico , Taxa de Sobrevida , Transplante Autólogo , Vincristina/administração & dosagemRESUMO
PURPOSE: To assess whether granulocyte-macrophage colony-stimulating factor (GM-CSF) reduces the toxicity of chemotherapy and alters delivered dose-intensity. To assess the feasibility of dose-intensification of chemotherapy in small-cell lung cancer (SCLC) and determine whether it has an impact on outcome. MATERIALS AND METHODS: Patients with good- or intermediate-prognosis SCLC entered a prospective multicenter study that involved a 2 x 2 factorial design with randomization to six cycles of chemotherapy with ifosfamide 5 g/m2, carboplatin 300 mg/m2, etoposide 120 mg/m2 intravenously (I.V.) on days 1 and 2 and 240 mg/m2 orally on day 3, and vincristine 0.5 mg/m2 I.V. on day 15 (V-ICE) every 3 weeks (intensified arm) or every 4 weeks (standard arm). A second double-blind randomization to subcutaneous GM-CSF (250 microg/m2/d) or placebo for 14 days between chemotherapy cycles was made. RESULTS: Three hundred patients were entered. Myelosuppression was the main toxicity, with no significant difference in the incidence or grade between treatment groups. The incidence of febrile neutropenia and bacteriologically confirmed sepsis was unaffected by chemotherapy schedule or use of GM-CSF. Twenty-six percent greater dose-intensity was delivered in the intensified arm, with a trend for greater dose-intensity for those who received GM-CSF. Eighty-three percent of patients achieved a response (51% complete response [CR] rate), with no significant difference in response rates between treatment groups. Survival was significantly increased in the intensified compared with the standard arm (P = .0014); median survival rates were 443 versus 351 days and 2-year survival rates were 33% versus 18%, respectively. CONCLUSION: GM-CSF does not reduce the incidence of complications from myelosuppression of aggressive chemotherapy. Dose intensification of V-ICE to a 3-week schedule in SCLC is not associated with increased toxicity, but appears to improve survival significantly. Future studies should aim to deliver chemotherapy in maximal-tolerated dose-intensities.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Pequenas/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carcinoma de Células Pequenas/mortalidade , Método Duplo-Cego , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Humanos , Ifosfamida/administração & dosagem , Ifosfamida/efeitos adversos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Taxa de Sobrevida , Vincristina/administração & dosagem , Vincristina/efeitos adversosRESUMO
PURPOSE: This was the first randomized study to investigate the efficacy of peripheral-blood progenitor cell (PBPC) mobilization using stem-cell factor (SCF) in combination with filgrastim (G-CSF) following chemotherapy compared with filgrastim alone following chemotherapy. PATIENTS AND METHODS: Forty-eight patients with ovarian cancer were treated with cyclophosphamide and randomized to receive filgrastim 5 microg/kg alone or filgrastim 5 microg/kg plus SCF. The dose of SCF was cohort-dependent (5, 10, 15, and 20 microg/kg), with 12 patients in each cohort, nine of whom received SCF plus filgrastim and the remaining three patients who received filgrastim alone. On recovery from the WBC nadir, patients underwent a single apheresis. RESULTS: SCF in combination with filgrastim following chemotherapy enhanced the mobilization of progenitor cells compared with that produced by filgrastim alone following chemotherapy. This enhancement was dose-dependent for colony-forming unit-granulocyte-macrophage (CFU-GM), burst-forming unit-erythrocyte (BFU-E), and CD34+ cells in both the peripheral blood and apheresis product. In the apheresis product, threefold to fivefold increases in median CD34+ and progenitor cell yields were obtained in patients treated with SCF 20 microg/kg plus filgrastim compared with yields obtained in patients treated with filgrastim alone. Peripheral blood values of CFU-GM, BFU-E, and CD34+ cells per milliliter remained above defined threshold levels longer with higher doses of SCF. The higher doses of SCF offer a greater window of opportunity in which to perform the apheresis to achieve high yields. CONCLUSION: SCF (15 or 20 microg/kg) in combination with filgrastim following chemotherapy is an effective way of increasing progenitor cell yields compared with filgrastim alone following chemotherapy.
Assuntos
Antineoplásicos/administração & dosagem , Carcinoma/terapia , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas , Neoplasias Ovarianas/terapia , Fator de Células-Tronco/administração & dosagem , Adulto , Idoso , Antígenos CD34/análise , Antineoplásicos/efeitos adversos , Remoção de Componentes Sanguíneos , Carcinoma/sangue , Ensaio de Unidades Formadoras de Colônias , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Células Precursoras Eritroides , Feminino , Filgrastim , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/sangue , Proteínas Recombinantes , Fator de Células-Tronco/efeitos adversosRESUMO
Hodgkin's disease (HD) is a complex lymphoma-like disease which occurs as four main subtypes, nodular sclerosing (NS), mixed cellularity (MC), lymphocyte predominant (LP) and lymphocyte depleted (LD). Suggestions from epidemiological studies that HD may represent an unusual response to infection imply that the lack of previous response could be due to genetic factors. Following recent reports suggesting that there is an increased frequency of HLA-DPB1*0301 in Hodgkins disease, we have studied DPB1 in two series of patients using molecular typing methods. One series is a retrospective group of 118 patients over the age of 15 years from a single centre, and the other is a multi-centre prospective group of 45 patients between the age of 16 and 24 years. In both series, the percentage of HD patients with DPB1*0301 is greater than in the controls, confirming that this seems to be an HD-susceptibility allele. However, extension of the analysis in relation to HD subtype shows that the increase in *0301 is present in nodular sclerosing (NS), mixed cellularity (MC) and lymphocyte predominant patients (LP) HD patients, but preliminary evidence suggests an increase in *0401, and possibly *0501 in MC- and LP-HD. The DPB1 hypervariable region (HVR) amino-acid motif Asp55, Glu56 (*0301-like, HVR-C) is increased in NS compared with non-NS (ie MC+LP), whereas the frequency of Ala55, Ala56 (*0401-like) is increased in non-NS compared with NS. Conversely, Asp84, Glu85Ala86(*0301-like, HVR-F) motif is more frequent in NS than non-NS patients, but there is no increase in Gly84, Gly855, Pro86 (*0401-like). These findings suggest that genetic susceptibility in HD may reside at the level of HVR-encoded DPB1 peptide-binding residues, rather than with a specific allele, and that this may in some way influence the HD subtype.