RESUMEN
AIMS: Biomarker-driven therapies have not been developed for infant medulloblastoma (iMB). We sought to robustly sub-classify iMB, and proffer strategies for personalized, risk-adapted therapies. METHODS: We characterized the iMB molecular landscape, including second-generation subtyping, and the associated retrospective clinical experience, using large independent discovery/validation cohorts (n = 387). RESULTS: iMBGrp3 (42%) and iMBSHH (40%) subgroups predominated. iMBGrp3 harboured second-generation subtypes II/III/IV. Subtype II strongly associated with large-cell/anaplastic pathology (LCA; 23%) and MYC amplification (19%), defining a very-high-risk group (0% 10yr overall survival (OS)), which progressed rapidly on all therapies; novel approaches are urgently required. Subtype VII (predominant within iMBGrp4 ) and subtype IV tumours were standard risk (80% OS) using upfront CSI-based therapies; randomized-controlled trials of upfront radiation-sparing and/or second-line radiotherapy should be considered. Seventy-five per cent of iMBSHH showed DN/MBEN histopathology in discovery and validation cohorts (P < 0.0001); central pathology review determined diagnosis of histological variants to WHO standards. In multivariable models, non-DN/MBEN pathology was associated significantly with worse outcomes within iMBSHH . iMBSHH harboured two distinct subtypes (iMBSHH-I/II ). Within the discriminated favourable-risk iMBSHH DN/MBEN patient group, iMBSHH-II had significantly better progression-free survival than iMBSHH-I , offering opportunities for risk-adapted stratification of upfront therapies. Both iMBSHH-I and iMBSHH-II showed notable rescue rates (56% combined post-relapse survival), further supporting delay of irradiation. Survival models and risk factors described were reproducible in independent cohorts, strongly supporting their further investigation and development. CONCLUSIONS: Investigations of large, retrospective cohorts have enabled the comprehensive and robust characterization of molecular heterogeneity within iMB. Novel subtypes are clinically significant and subgroup-dependent survival models highlight opportunities for biomarker-directed therapies.
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Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/patología , Meduloblastoma/genética , Meduloblastoma/patología , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Pronóstico , Estudios RetrospectivosRESUMEN
BACKGROUND AND PURPOSE: In addition to the 4 histopathologically defined entities of medulloblastoma, 4 distinct genetically defined subgroups have been included in the World Health Organization classification of 2016. The smallest subgroup is the medulloblastoma with activated wingless pathway. The goal of this study was to identify a typical MR imaging morphology in a larger number of pediatric patients with wingless pathway medulloblastoma. MATERIALS AND METHODS: From January 2001 to October 2017, of 75 patients with histologically confirmed and molecularly subgrouped wingless pathway medulloblastomas recruited to the German Pediatric Brain Tumor (HIT) trials, 38 patients (median age, 12.8 ± 4.6 years at diagnosis; 24 [63.2%] female) had preoperative imaging that passed the entry criteria for this study. Images were rated by the local standardized imaging criteria of the National Reference Center of Neuroradiology. Additionally, a modified laterality score was used to determine tumor localization and extension. RESULTS: Twenty-eight of 38 (73.7%) were primary midline tumors but with a lateral tendency in 39.3%. One extensively eccentric midline tumor was rated by the laterality score as in an off-midline position. Five tumors were found in the cerebellopontine angle; 3, in the deep white matter; and 2, in a cerebellar hemisphere. Leptomeningeal dissemination was rare (11.5%). In 60.5%, intratumoral blood-degradation products were found, and 26.3% showed cysts with blood contents. CONCLUSIONS: According to our observations, wingless pathway medulloblastomas are not preferentially off-midline tumors as postulated in previous studies with smaller wingless pathway medulloblastoma cohorts. Dense intratumoral blood-degradation products and cysts with blood contents are frequently found and might help to differentiate wingless pathway medulloblastoma from other medulloblastoma subtypes.
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Neoplasias Cerebelosas/diagnóstico por imagen , Neoplasias Cerebelosas/genética , Meduloblastoma/diagnóstico por imagen , Meduloblastoma/genética , Vía de Señalización Wnt/genética , Adolescente , Neoplasias Cerebelosas/patología , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Lactante , Masculino , Meduloblastoma/patología , Mutación , Estudios Retrospectivos , Adulto JovenRESUMEN
Rapid and reliable detection of disease-associated DNA methylation patterns has major potential to advance molecular diagnostics and underpin research investigations. We describe the development and validation of minimal methylation classifier (MIMIC), combining CpG signature design from genome-wide datasets, multiplex-PCR and detection by single-base extension and MALDI-TOF mass spectrometry, in a novel method to assess multi-locus DNA methylation profiles within routine clinically-applicable assays. We illustrate the application of MIMIC to successfully identify the methylation-dependent diagnostic molecular subgroups of medulloblastoma (the most common malignant childhood brain tumour), using scant/low-quality samples remaining from the most recently completed pan-European medulloblastoma clinical trial, refractory to analysis by conventional genome-wide DNA methylation analysis. Using this approach, we identify critical DNA methylation patterns from previously inaccessible cohorts, and reveal novel survival differences between the medulloblastoma disease subgroups with significant potential for clinical exploitation.
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Neoplasias Encefálicas/genética , Metilación de ADN , Pruebas Genéticas/métodos , Meduloblastoma/genética , Análisis de Secuencia de ADN/métodos , Neoplasias Encefálicas/diagnóstico , Niño , Islas de CpG , Predisposición Genética a la Enfermedad , Humanos , Meduloblastoma/diagnóstico , Programas InformáticosRESUMEN
The identification of key tumorigenic events in Sonic Hedgehog (SHH) subgroup medulloblastomas (MBSHH) will be essential for the development of individualized therapies and improved outcomes. However, beyond confirmation of characteristic SHH pathway mutations, recent genome-wide sequencing studies have not revealed commonly mutated genes with widespread relevance as potential therapeutic targets. We therefore examined any role for epigenetic DNA methylation events in MBSHH using a cross-species approach to candidate identification, prioritization and validation. MBSHH-associated DNA methylation events were first identified in 216 subgrouped human medulloblastomas (50 MBSHH, 28 Wnt/Wingless, 44 Group 3 and 94 Group 4) and their conservation then assessed in tumors arising from four independent murine models of Shh medulloblastoma, alongside any role in tumorigenesis using functional assessments in mouse and human models. This strategy identified widespread regional CpG hypo-methylation of VAV1, leading to its elevated expression, as a conserved aberrant epigenetic event, which characterizes the majority of MBSHH tumors in both species, and is associated with a poor outcome in MBSHH patients. Moreover, direct modulation of VAV1 in mouse and human models revealed a critical role in tumor maintenance, and its abrogation markedly reduced medulloblastoma growth. Further, Vav1 activity regulated granule neuron precursor germinal zone exit and migration initiation in an ex vivo model of early postnatal cerebellar development. These findings establish VAV1 as a critical epigenetically regulated oncogene with a key role in MBSHH maintenance, and highlight its potential as a validated therapeutic target and prognostic biomarker for the improved therapy of medulloblastoma.
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Metilación de ADN/genética , Epigénesis Genética , Meduloblastoma/genética , Proteínas Proto-Oncogénicas c-vav/genética , Animales , Proliferación Celular , Transformación Celular Neoplásica/genética , Islas de CpG/genética , Humanos , Meduloblastoma/patología , Ratones , Neuronas/metabolismo , Neuronas/patología , Proteínas Proto-Oncogénicas c-vav/biosíntesis , Transducción de Señal , Ensayos Antitumor por Modelo de XenoinjertoAsunto(s)
Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Células Pequeñas/diagnóstico , Carcinoma de Células Pequeñas/terapia , Conducta Cooperativa , Comunicación Interdisciplinaria , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Síndrome de Pancoast/diagnóstico , Síndrome de Pancoast/terapia , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/prevención & control , Carcinoma de Células Pequeñas/patología , Carcinoma de Células Pequeñas/prevención & control , Terapia Combinada , Diagnóstico Precoz , Estudios de Seguimiento , Alemania , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/prevención & control , Estadificación de Neoplasias , Síndrome de Pancoast/patología , Síndrome de Pancoast/prevención & control , Sociedades MédicasRESUMEN
BACKGROUND: Yolk sac tumours (YSTs) and germinomas are the two major pure histological subtypes of germ cell tumours. To date, the role of DNA methylation in the aetiology of this class of tumour has only been analysed in adult testicular forms and with respect to only a few genes. METHODS: A bank of paediatric tumours was analysed for global methylation of LINE-1 repeat elements and global methylation of regulatory elements using GoldenGate methylation arrays. RESULTS: Both germinomas and YSTs exhibited significant global hypomethylation of LINE-1 elements. However, in germinomas, methylation of gene regulatory regions differed little from control samples, whereas YSTs exhibited increased methylation at a large proportion of the loci tested, showing a 'methylator' phenotype, including silencing of genes associated with Caspase-8-dependent apoptosis. Furthermore, we found that the methylator phenotype of YSTs was coincident with higher levels of expression of the DNA methyltransferase, DNA (cytosine-5)-methyltransferase 3B, suggesting a mechanism underlying the phenotype. CONCLUSION: Epigenetic silencing of a large number of potential tumour suppressor genes in YSTs might explain why they exhibit a more aggressive natural history than germinomas and silencing of genes associated with Caspase-8-dependent cell death might explain the relative resistance of YSTs to conventional therapy.
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Caspasa 8/metabolismo , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Metilación de ADN , Silenciador del Gen , Genes Supresores de Tumor , Neoplasias de Células Germinales y Embrionarias/tratamiento farmacológico , Neoplasias de Células Germinales y Embrionarias/genética , Apoptosis , Niño , Preescolar , Análisis por Conglomerados , Resistencia a Antineoplásicos , Tumor del Seno Endodérmico/tratamiento farmacológico , Tumor del Seno Endodérmico/genética , Femenino , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Germinoma/tratamiento farmacológico , Germinoma/genética , Humanos , Masculino , Análisis por Micromatrices , Neoplasias de Células Germinales y Embrionarias/patología , Fenotipo , Reacción en Cadena de la Polimerasa , Reproducibilidad de los Resultados , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , ADN Metiltransferasa 3BAsunto(s)
Cuidados Posteriores , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/prevención & control , Carcinoma de Pulmón de Células no Pequeñas/terapia , Medicina Basada en la Evidencia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/prevención & control , Neoplasias Pulmonares/terapia , Carcinoma de Pulmón de Células no Pequeñas/etiología , Terapia Combinada , Conducta Cooperativa , Estudios Transversales , Diagnóstico Precoz , Estudios de Seguimiento , Alemania , Humanos , Incidencia , Comunicación Interdisciplinaria , Neoplasias Pulmonares/etiología , Estadificación de Neoplasias , Cuidados Paliativos , Grupo de Atención al Paciente , Pronóstico , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
BACKGROUND: The study aimed to demonstrate the noninferiority of capecitabine to 5-fluorouracil (5-FU)/folinic acid (FA), in relation to progression-free survival (PFS) after first-line treatment of metastatic colorectal cancer and the benefit of adding celecoxib (C) to irinotecan/fluoropyrimidine regimens compared with placebo (P). PATIENTS AND METHODS: Patients were randomly assigned to receive FOLFIRI: irinotecan (180 mg/m(2) i.v. on days 1, 15 and 22); FA (200 mg/m(2) i.v. on days 1, 2, 15, 16, 29 and 30); 5-FU (400 mg/m(2) i.v. bolus, then 22-h, 600 mg/m(2) infusion) or CAPIRI: irinotecan (250 mg/m(2) i.v. infusion on days 1 and 22); capecitabine p.o. (1000 mg/m(2) b.i.d. on days 1-15 and 22-36). Patients were additionally randomly assigned to receive either placebo or celecoxib (800 mg: 2 x 200 mg b.i.d.). RESULTS: The trial was closed following eight deaths unrelated to disease progression in the 85 enrolled (629 planned) patients. Response rates were 22% for CAPIRI + C, 48% for CAPIRI + P, 32% for FOLFIRI + C and 46% for FOLFIRI + P. Median PFS and overall survival (OS) times were shorter for CAPIRI versus FOLFIRI (PFS 5.9 versus 9.6 months and OS 14.8 versus 19.9 months) and celecoxib versus placebo (PFS 6.9 versus 7.8 months and OS 18.3 versus 19.9 months). CONCLUSION: Due to the small sample size following early termination, no definitive conclusions can be drawn in relation to the noninferiority of CAPIRI compared with FOLFIRI.
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Adenocarcinoma/secundario , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Adenocarcinoma/tratamiento farmacológico , Adulto , Anciano , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/análogos & derivados , Capecitabina , Celecoxib , Neoplasias Colorrectales/patología , Inhibidores de la Ciclooxigenasa 2/administración & dosificación , Inhibidores de la Ciclooxigenasa 2/efectos adversos , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Diarrea/inducido químicamente , Método Doble Ciego , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Fluorouracilo/análogos & derivados , Humanos , Infusiones Intravenosas , Irinotecán , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Embolia Pulmonar/inducido químicamente , Pirazoles/administración & dosificación , Pirazoles/efectos adversos , Choque Séptico/etiología , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Análisis de SupervivenciaRESUMEN
To investigate whether statins reduce the concentration of MMP-9 in the aortic wall, we randomised patients undergoing elective open repair of an abdominal aortic aneurysm (AAA) to a pre-operative course of either simvastatin or placebo. MMPs in aortic biopsies were measured using gelatin zymography. Although recruitment closed early because of increasing statin use among eligible patients, with only 21 patients we demonstrated a 40% reduction in MMP-9 levels in the AAA wall in patients randomised to simvastatin. This provides a possible molecular mechanism to explain the reportedly beneficial effects of statins to slow AAA growth.
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Aorta/efectos de los fármacos , Aorta/cirugía , Aneurisma de la Aorta Abdominal/tratamiento farmacológico , Aneurisma de la Aorta Abdominal/cirugía , Inhibidores de la Metaloproteinasa de la Matriz , Inhibidores de Proteasas/uso terapéutico , Simvastatina/uso terapéutico , Procedimientos Quirúrgicos Vasculares , Anciano , Aorta/enzimología , Aorta/patología , Aneurisma de la Aorta Abdominal/enzimología , Aneurisma de la Aorta Abdominal/patología , Procedimientos Quirúrgicos Electivos , Femenino , Humanos , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Cuidados Preoperatorios , Inhibidores de Proteasas/farmacología , Simvastatina/farmacología , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Loss of elastin is the initiating event in abdominal aortic aneurysm (AAA) formation, whereas loss of collagen is required for continued expansion. The elastolytic matrix metalloproteinases (MMPs) 2 and 9 are well described, but the source of excessive collagenolysis remains undefined. The aim of this study was to determine the expression of MMP-8, a potent type I collagenase, in normal aorta and AAA. METHODS: Infrarenal aortic biopsies were taken from 40 AAA and ten age-matched normal aortas. The concentrations of MMP-8 protein and its inhibitors, tissue inhibitor of metalloproteinase (TIMP) 1 and TIMP-2, were quantified by enzyme-linked immunosorbent assay. Immunohistochemistry was used to localize MMP-8 expression. RESULTS: MMP-8 concentrations were significantly raised in AAA compared with normal aorta (active MMP-8: 4.5 versus 0.5 ng per mg protein, P < 0.001; total MMP-8: 16.6 versus 2.8 ng per mg protein, P < 0.001). Levels of TIMP-1 and TIMP-2 were significantly lower in AAA than in normal aortic samples (TIMP-1: 142.2 versus 302.8 ng per mg protein; P = 0.010; TIMP-2: 9.2 versus 33.1 ng per mg protein, P < 0.001). Immunohistochemistry localized MMP-8 to mesenchymal cells within the adventitia of the aortic wall. CONCLUSION: The high concentration of MMP-8 in aortic aneurysms represents a potent pathway for collagen degradation, and hence aneurysm formation and expansion.
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Aorta Abdominal/metabolismo , Aneurisma de la Aorta Abdominal/enzimología , Metaloproteinasa 8 de la Matriz/metabolismo , Anciano , Aneurisma de la Aorta Abdominal/patología , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunohistoquímica/métodos , Masculino , Persona de Mediana Edad , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Inhibidor Tisular de Metaloproteinasa-2/metabolismoRESUMEN
BACKGROUND: The fibrous cap of atherosclerotic plaques is composed predominantly of type I and III collagen. Unstable carotid plaques are characterized by rupture of their cap, leading to thromboembolism and stroke. The proteolytic mechanisms causing plaque disruption are undefined, but the collagenolytic matrix metalloproteinase (MMP) -1, -8, and -13 may be implicated. The aim of this study was to quantify the concentrations of these collagenases in carotid plaques and to determine their relationship to markers of plaque instability. METHODS AND RESULTS: Atherosclerotic plaques were collected from 159 patients undergoing carotid endarterectomy. The presence and timing of carotid territory symptoms were ascertained. Preoperative embolization was recorded by transcranial Doppler. Each plaque was assessed for histological features of instability. Plaque MMP concentrations were quantified with ELISA. Significantly higher concentrations of active MMP-8 were observed in the plaques of symptomatic patients (20.5 versus 11.4 ng/g; P=0.0002), in plaques of emboli-positive patients (22.7 versus 13.5 ng/g; P=0.0037), and in those plaques showing histological evidence of rupture (20.8 versus 14.7 ng/g; P=0.0036). No differences were seen in the levels of MMP-1 and MMP-13. Immunohistochemistry, in situ hybridization, and colocalization studies confirmed the presence of MMP-8 protein and mRNA within the plaque, which colocalized with macrophages. CONCLUSIONS: These data suggest that the active form of MMP-8 may be partly responsible for degradation of the collagen cap of atherosclerotic plaques. This enzyme represents an attractive target for drug therapy aimed at stabilizing vulnerable plaques.
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Enfermedades de las Arterias Carótidas/enzimología , Enfermedades de las Arterias Carótidas/patología , Metaloproteinasa 8 de la Matriz/metabolismo , Anciano , Enfermedades de las Arterias Carótidas/diagnóstico , Femenino , Humanos , Inmunohistoquímica , Hibridación in Situ , Embolia Intracraneal/diagnóstico , Masculino , Metaloproteinasa 8 de la Matriz/análisis , Metaloproteinasa 8 de la Matriz/genética , Metaloproteinasas de la Matriz/metabolismo , Persona de Mediana Edad , ARN Mensajero/análisis , Inhibidores Tisulares de Metaloproteinasas/metabolismoRESUMEN
OBJECTIVES: To study plasma MMP-9 levels before and after carotid endarterectomy (CEA). DESIGN: Observational study. METHODS: Pre-operative (morning of surgery) and post-operative (48 h) plasma samples were obtained from 75 consecutive patients undergoing CEA. MMP-9 concentrations were quantified using ELISA. Transcranial Doppler monitoring was performed on each patient to detect particulate embolisation during the dissection phase of the CEA, until the application of carotid clamps. RESULTS: The median post-operative plasma MMP-9 level of emboli-positive patients was significantly higher than their median pre-operative value (14.9 ng/ml vs. 8.8 ng/ml; p=0.038). However, no significant difference was seen in the plasma MMP-9 level of emboli-negative patients (7.7 ng/ml vs. 7.1 ng/ml; p=0.364). A greater rise was seen in the median plasma MMP-9 levels of those patients suffering >2 emboli (from 3.4 to 19.3 ng/ml; p=0.041) than those patients suffering 1 or 2 emboli (from 10.1 to 12.8 ng/ml; p=0.340). CONCLUSIONS: Plasma MMP-9 only rises after CEA in patients with evidence of embolisation. This increase is more pronounced in those with high numbers of emboli. These data suggest that the increase in MMP-9 is due to cerebral damage caused by embolisation.
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Endarterectomía Carotidea , Embolia Intracraneal/sangre , Metaloproteinasa 9 de la Matriz/sangre , Inhibidor Tisular de Metaloproteinasa-1/sangre , Anciano , Anciano de 80 o más Años , Arterias Cerebrales/diagnóstico por imagen , Femenino , Humanos , Masculino , Persona de Mediana Edad , Periodo Posoperatorio , Ultrasonografía Doppler TranscranealRESUMEN
The association of antiphospholipid antibodies (APA) has been reported in several cases of patients with non-Hodgkin's lymphoma (NHL) with or without thromboembolic complications. The purpose of this study was to analyse systematically the prevalence of APA and its clinical significance in lymphoma patients. Sera of 90 consecutive unselected patients with NHL were tested for the presence of anticardiolipin (aCL) antibodies and anti-beta2-glycoprotein-I (anti-beta2-GPI) antibodies. The patients were followed up over a median period of 14 months to note the occurrence of thromboembolism. We found APA in 24 out of 90 NHL patients (26.6%). Elevated APA were more often detected in women and in the elderly. The presence of elevated APA was not correlated with the histology and the stage of the lymphoma. None of the 24 patients with elevated APA developed a thromboembolic event in the follow-up period. Thromboembolic events were observed in 12 patients (13.3%), all with negative APA. High APA titres and the combination of positive aCL- and anti-beta2-GPI antibodies, features which are known to be more strongly correlated with thrombosis among patients with antiphospholipid syndrome and systemic lupus erythematous (SLE), were very uncommon in our cohort of NHL patients (3.3%). Vessel compression by lymphoma but not elevated APA remains the main cause of thrombosis in NHL patients.
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Anticuerpos Anticardiolipina/sangre , Autoanticuerpos/sangre , Glicoproteínas/inmunología , Linfoma no Hodgkin/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Incidencia , Linfoma no Hodgkin/complicaciones , Linfoma no Hodgkin/inmunología , Masculino , Persona de Mediana Edad , Factores de Riesgo , Estudios Seroepidemiológicos , Tromboembolia/epidemiología , Tromboembolia/etiología , beta 2 Glicoproteína IRESUMEN
Myelosuppression is a common side effect in elderly patients undergoing chemotherapy. Neutropenia and anemia cause considerable morbidity, may increase mortality, and can result in a worse outcome of treatment in elderly patients compared to younger patients with comparable type and stage of disease. The availability and proven efficacy of hematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (EPO) have had a considerable impact on supportive care in cancer patients: Several randomized trials have demonstrated a reduction of neutropenia and the frequency of severe infections in elderly patients treated with G-CSF following myelotoxic chemotherapy compared with patients without growth factor support. Both for G-CSF and for recombinant human erythropoietin (rHu-EPO) several studies have demonstrated the safety and effectiveness of these molecules in elderly patients with regard to increasing hemoglobin concentrations, improving quality of life (rHu-EPO), and neutrophil recovery. Although a positive effect of the use of growth factors on overall survival in elderly cancer patients is not yet proven, a reduction of chemotherapy-induced side effects could clearly be shown. The National Comprehensive Cancer Network (NCCN) of cancer centers has recommended that all patients aged 70 years and older treated with CHOP or cytotoxic chemotherapy of comparable intensity should receive prophylactic G-CSF administration, and that the hemoglobin concentration be maintained at >or=12 g/dl in elderly patients undergoing chemotherapy.
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Anemia/tratamiento farmacológico , Antineoplásicos/efectos adversos , Eritropoyetina/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos y Macrófagos/administración & dosificación , Neoplasias/tratamiento farmacológico , Neutropenia/tratamiento farmacológico , Anciano , Anemia/inducido químicamente , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/efectos adversos , Ciclofosfamida/uso terapéutico , Doxorrubicina/efectos adversos , Doxorrubicina/uso terapéutico , Humanos , Neutropenia/inducido químicamente , Prednisona/efectos adversos , Prednisona/uso terapéutico , Proteínas Recombinantes , Vincristina/efectos adversos , Vincristina/uso terapéuticoRESUMEN
The number of elderly patients with non-Hodgkin's lymphomas (NHL) is continuously increasing. The diagnostic and staging procedures should be carried out in elderly patients as careful as in younger patients. Furthermore, for treatment decisions geriatric assessment and the patient's preferences concerning therapy are essential and have to be considered. The treatment of indolent NHL depends on the stage of the disease and the clinical status of the patient. Most of the patients with limited indolent NHL can be treated with curative intent using localized irradiation. Treatment of patients with advanced indolent NHL is palliative. In contrast, all stages of aggressive NHL can also be treated with curative intent in elderly patients. In limited aggressive NHL standard treatment consists of polychemotherapy followed by involved field irradiation. Standard treatment of advanced aggressive NHL is polychemotherapy with cyclophosphamide, adriamycin, vincristine and prednisone (CHOP). The goal for the near future is to improve perspectives for elderly patients with NHL. One way is to treat as many of these patients as possible according to current standards. In the field of geriatric oncology, one of the questions we are often confronted with is the limitation of treatment, especially in frail patients. This issue is closely associated with ethical considerations which are discussed in another paper.
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Linfoma no Hodgkin/radioterapia , Anciano , Quimioterapia Adyuvante , Terapia Combinada , Evaluación Geriátrica , Humanos , Linfoma no Hodgkin/tratamiento farmacológico , Linfoma no Hodgkin/mortalidad , Linfoma no Hodgkin/patología , Estadificación de Neoplasias , Cuidados Paliativos , Tasa de SupervivenciaRESUMEN
Treatment of Multiple Myeloma in the Elderly: Consensus of the Cooperative Group of Geriatric Oncology of the DGHO and DGG Multiple myeloma is an illness of old age. Often, in elderly people the diagnosis is delayed by the fact that bone pain, which is the most frequently presenting symptom, is not correctly interpreted because this is a common complaint in the elderly. In contrast to younger patients with multiple myeloma, elderly patients often present with infections at diagnosis. After the diagnosis is established, careful observation is very important. This applies both to patients who require still no therapy and to patients under treatment. In order to optimize the care of older patients, apart from tumor-specific investigations multidimensional geriatric assessment is helpful. This specifically applies for multiple myeloma which predisposes the patient to 'instability' and 'immobility', both belonging to the typical geriatric symptoms. Geriatric assessment may also be helpful in the selection of those elderly patients who are candidates for a possible prognosis-improving experimental intense chemotherapy. For the majority of the elderly patients in need of treatment the standard is melphalan/prednisone accompanied by one of the biphosphonates. Nevertheless, in order to improve prospects also for this group of patients, as many elderly patients as possible should be included into studies. This is the only way to compile valid recommendations for the treatment of elderly patients with multiple myeloma.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Evaluación Geriátrica , Mieloma Múltiple/tratamiento farmacológico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ensayos Clínicos como Asunto , Difosfonatos/administración & dosificación , Difosfonatos/efectos adversos , Humanos , Melfalán/administración & dosificación , Melfalán/efectos adversos , Mieloma Múltiple/diagnóstico , Prednisona/administración & dosificación , Prednisona/efectos adversos , PronósticoRESUMEN
Mobilised peripheral blood stem cells are widely used for autografting in patients with chronic myeloid leukaemia (CML) and it is generally thought that a high proportion of Ph-negative progenitor cells in the graft is desirable. We report here the results of 91 stem cell mobilisations performed with various chemotherapy regimens followed by G-CSF. We show that mobilisation of Ph-negative cells is possible after diagnosis as well as in advanced stages of the disease. The yield of Ph-negative cells is highly dependent on the chemotherapy regimen: while the combination of idarubicin and cytarabin for 3-5 days (IC3-5) mobilised Ph-negative cells in most patients, high-dose cyclophosphamide was ineffective. Mobilisation of Ph-negative progenitor cells after IC3 was at least as effective as after IC5; however, less apheresis sessions were required, and toxicity was much reduced after IC3. Compared to historical controls, IC was equally effective as the widely used ICE/miniICE (idarubicin, cytarabin, etoposide) protocol. No correlation was found between graft quality and the cytogenetic response to subsequent treatment with interferon-alpha. We conclude that IC3 is an effective and well-tolerated regimen for mobilising Ph-negative cells that compares well with more aggressive approaches such as IC5 and ICE/miniICE.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Movilización de Célula Madre Hematopoyética/métodos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Ciclofosfamida/administración & dosificación , Ciclofosfamida/normas , Ciclofosfamida/toxicidad , Citarabina/administración & dosificación , Citarabina/normas , Citarabina/toxicidad , Femenino , Supervivencia de Injerto/efectos de los fármacos , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/normas , Factor Estimulante de Colonias de Granulocitos/toxicidad , Movilización de Célula Madre Hematopoyética/normas , Humanos , Idarrubicina/administración & dosificación , Idarrubicina/normas , Idarrubicina/toxicidad , Interferón-alfa/administración & dosificación , Leucaféresis/normas , Masculino , Persona de Mediana Edad , Cromosoma FiladelfiaRESUMEN
In order to determine if age and comorbidity influence the tolerability of the cytoprotective agent amifostine, we compared side effects related to amifostine in patients > or = 70 years (group I) with patients < 70 years (group II). We evaluated 268 consecutive administrations of amifostine (119 in group I and 149 in group II, respectively), given i.v. at a dose of 740 mg/m(2) just before platinum-, taxol- or cyclophosphamide-based chemotherapy. Transient hypotension was the most common side effect occurring in association with amifostine. Decreases in systolic blood pressure > 20 mmHg were of similar frequency in both groups (27.1 versus 28.8% of amifostine infusions in group I and II, respectively). Hypotension did not result in medical sequelae in any of the patients. The amifostine infusion was interrupted 16 times in group I and 8 times in group II, respectively, mainly due to hypotension, but could be restarted after a few minutes in all patients except for three cases in group I. Patients in group II more often suffered from nausea/vomiting than in group II (20.8 versus 10.0% in group I). Other subjective symptoms (e.g. warmed, flushed sensation, sneezing, metallic taste, mouth dryness, dizziness and sleepiness) and hypocalcemia occurred with a similar frequency in both groups. Adverse effects associated with amifostine were not observed more frequently in elderly patients than in younger ones, although more elderly patients had a comorbidity than the younger ones.
Asunto(s)
Amifostina/administración & dosificación , Amifostina/toxicidad , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Hipocalcemia/epidemiología , Linfoma no Hodgkin/tratamiento farmacológico , Náusea/epidemiología , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Antihipertensivos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Ciclofosfamida/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Doxorrubicina/administración & dosificación , Epirrubicina/administración & dosificación , Neoplasias Esofágicas/tratamiento farmacológico , Femenino , Fluorouracilo/administración & dosificación , Humanos , Hipertensión/complicaciones , Hipocalcemia/inducido químicamente , Hipotensión/inducido químicamente , Infusiones Intravenosas , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Paclitaxel/administración & dosificación , Neoplasias Pancreáticas/tratamiento farmacológico , Platino (Metal)/administración & dosificación , Prednisona/administración & dosificación , Premedicación , Estudios Retrospectivos , Vincristina/administración & dosificación , GemcitabinaRESUMEN
The influence of underlying disease on documented infections has rarely been addressed in patients treated with high-dose chemotherapy (HDCT) and subsequent autologous peripheral blood stem cell transplantation (PBSCT). Because autografting has been used most frequently for malignant lymphomas and breast cancer, we analyzed in a retrospective study the data of 100 consecutive adult patients with either malignant lymphomas (group A, n = 50) or breast cancer (group B, n = 50) treated with HDCT at a single institution. The number of autografted CD34+ cells was not statistically different in either group. In this paper, we show for the first time that there is a significant difference in clinically or microbiologically documented infections in these groups of patients: documented infections occurred in 30% of malignant lymphoma patients but only in 4% of breast cancer patients (P=0.001). Of all isolated microorganisms, 78% were gram-positive. Because most of the documented infections were due to staphylococci, further studies should prospectively evaluate preventive measures to reduce the high incidence of these infections. This is especially important for lymphoma patients, who can be regarded as a high-risk group concerning gram-positive bacteremia.