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Background: Eribulin provided significant overall survival (OS) benefit in heavily pretreated advanced breast cancer patients in the EMBRACE trial. We investigated the use of eribulin in daily clinical practice, the relative effectiveness of eribulin versus non-eribulin chemotherapy, and the safety of eribulin in real-world patients included in the SOutheast Netherlands Advanced BREast cancer (SONABRE) registry.Material and methods: Patients treated with eribulin and eligible patients for eribulin who received a different chemotherapy (i.e., non-eribulin group) in ten hospitals in 2013-2017 were included. A multivariate matching algorithm was applied to correct for differences in baseline characteristics between the groups, including the number of previous treatment lines. Progression-free survival (PFS) and OS of eribulin were compared with the matched non-eribulin group through Kaplan-Meier curves and multivariate Cox proportional hazard models. The occurrence of dose delay and reduction was described.Results: Forty-five patients received eribulin according to its registration criteria and 74 patients were eligible for eribulin but received non-eribulin chemotherapy. Matching increased the similarity in baseline characteristics between the eribulin and non-eribulin groups. Median PFS was 3.5 months (95% confidence interval (CI): 2.7-5.5) in the eribulin group and 3.2 months (95% CI: 2.0-4.8) in the matched non-eribulin group (adjusted hazard ratio (HR): 0.83, 95% CI: 0.49-1.38). Median OS was 5.9 months (95% CI: 4.6-11.0) and 5.2 months (95% CI: 4.6-9.5) in the eribulin and non-eribulin groups, respectively (adjusted HR: 0.66, 95% CI: 0.38-1.13). Dose delay or reduction occurred in 14 patients (31%) receiving eribulin.Conclusions: No difference in PFS and OS was observed between eribulin and non-eribulin treated patients. Eribulin had a manageable toxicity profile.
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Neoplasias de la Mama/tratamiento farmacológico , Furanos/uso terapéutico , Cetonas/uso terapéutico , Adulto , Anciano , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/patología , Femenino , Humanos , Persona de Mediana Edad , Análisis Multivariante , Países Bajos/epidemiología , Sistema de Registros , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Background: In 2013, eribulin was reimbursed under a coverage with evidence development (CED) as third or later chemotherapy line for advanced breast cancer (ABC) patients in the Netherlands because of uncertain cost effectiveness. In 2016, the final decision of reimbursing eribulin was taken without considering the evidence collected during CED research. We analysed the cost effectiveness of eribulin versus non-eribulin chemotherapy, using real-world data.Methods: A three health states (progression-free, progressed disease, dead) partitioned survival model was developed. The SOuth East Netherlands Advanced BREast Cancer (SONABRE) registry informed the effectiveness and costs inputs. Health state utility values were obtained from the literature. Incremental cost-effectiveness ratio (ICER) between the eribulin and matched non-eribulin chemotherapy was estimated. Deterministic and probabilistic sensitivity analyses and scenario analyses were performed. The financial risk (i.e., the expected value of perfect information (EVPI) plus the expected monetary loss (eML) associated with reimbursing eribulin) and budget impact associated with reimbursing eribulin were calculated.Results: Eribulin led to higher health benefits (0.07 quality-adjusted life year (QALY)) and costs (15,321) compared with non-eribulin chemotherapy. This resulted in an ICER of 220,608. At a 80,000 per QALY threshold, the risk of reimbursing eribulin was 9,791 per patient (EVPI 13, eML 9,778). Scaled up to the Dutch population, the estimated annual budget impact was 1.9 million and the annual risk of reimbursing eribulin was 2.7 million.Conclusion: From a Dutch societal perspective, eribulin is not cost effective when considering its list price as third and later chemotherapy line for ABC patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Costos de los Medicamentos/estadística & datos numéricos , Furanos/uso terapéutico , Cetonas/uso terapéutico , Modelos Económicos , Protocolos de Quimioterapia Combinada Antineoplásica/economía , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/economía , Neoplasias de la Mama/mortalidad , Simulación por Computador , Análisis Costo-Beneficio , Progresión de la Enfermedad , Femenino , Furanos/economía , Humanos , Reembolso de Seguro de Salud/economía , Reembolso de Seguro de Salud/estadística & datos numéricos , Cetonas/economía , Persona de Mediana Edad , Países Bajos/epidemiología , Supervivencia sin Progresión , Años de Vida Ajustados por Calidad de Vida , Sistema de Registros/estadística & datos numéricosRESUMEN
BACKGROUND: The objective of this study was to present initial systemic treatment choices and the outcome of hormone receptor-positive (HR+) metastatic breast cancer. PATIENTS AND METHODS: All the 815 consecutive patients diagnosed with metastatic breast cancer in 2007-2009 in eight participating hospitals were identified. From the 611 patients with HR+ disease, a total of 520 patients with HER2-negative (HER2-) breast cancer were included. Initial palliative systemic treatment was registered. Progression-free survival (PFS) and overall survival (OS) per initial palliative systemic therapy were obtained using the Kaplan-Meier method and compared using the log-rank test. RESULTS: From the total of 520 patients with HR+/HER2- metastatic breast cancer, 482 patients (93%) received any palliative systemic therapy. Patients that received initial chemotherapy (n = 116) were significantly younger, had less comorbidity, had received more prior adjuvant systemic therapy and were less likely to have bone metastasis only compared with patients that received initial endocrine therapy (n = 366). Median PFS of initial palliative chemotherapy was 5.3 months [95% confidence interval (CI) 4.2-6.2] and of initial endocrine therapy 13.3 months (95% CI 11.3-15.5), with a median OS of 16.1 and 36.9 months, respectively. Initial chemotherapy was also associated with worse outcome in terms of PFS and OS after adjustment for prognostic factors. CONCLUSIONS: A high percentage of patients with HR+ disease received initial palliative chemotherapy, which was associated with worse outcome, even after adjustment of relevant prognostic factors.
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Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Cuidados Paliativos/métodos , Anciano , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia/patología , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Resultado del TratamientoRESUMEN
BACKGROUND: We aimed to determine the prognostic impact of time between primary breast cancer and diagnosis of distant metastasis (metastatic-free interval, MFI) on the survival of metastatic breast cancer patients. METHODS: Consecutive patients diagnosed with metastatic breast cancer in 2007-2009 in eight hospitals in the Southeast of the Netherlands were included and categorised based on MFI. Survival curves were estimated using the Kaplan-Meier method. Cox proportional hazards model was used to determine the prognostic impact of de novo metastatic breast cancer vs recurrent metastatic breast cancer (MFI ⩽24 months and >24 months), adjusted for age, hormone receptor and HER2 status, initial site of metastasis and use of prior (neo)adjuvant systemic therapy. RESULTS: Eight hundred and fifteen patients were included and divided in three subgroups based on MFI; 154 patients with de novo metastatic breast cancer, 176 patients with MFI <24 months and 485 patients with MFI >24 months. Patients with de novo metastatic breast cancer had a prolonged survival compared with patients with recurrent metastatic breast cancer with MFI <24 months (median 29.4 vs 9.1 months, P<0.0001), but no difference in survival compared with patients with recurrent metastatic breast cancer with MFI >24 months (median, 29.4 vs 27.9 months, P=0.73). Adjusting for other prognostic factors, patients with MFI <24 months had increased mortality risk (hazard ratio 1.97, 95% CI 1.49-2.60, P<0.0001) compared with patients with de novo metastatic breast cancer. When comparing recurrent metastatic breast cancer with MFI >24 months with de novo metastatic breast cancer no significant difference in mortality risk was found. The association between MFI and survival was seen irrespective of use of (neo)adjuvant systemic therapy. CONCLUSION: Patients with de novo metastatic breast cancer had a significantly better outcome when compared with patients with MFI <24 months, irrespective of the use of prior adjuvant systemic therapy in the latter group. However, compared with patients with MFI >24 months, patients with de novo metastatic breast cancer had similar outcome.
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Neoplasias de la Mama/mortalidad , Recurrencia Local de Neoplasia/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Estadificación de Neoplasias , Pronóstico , Tasa de SupervivenciaRESUMEN
INTRODUCTION: Adrenocortical carcinoma (ACC) is a rare disease which is considered resistant to many treatments. The role of radiotherapy in ACC remains unclear. In general radiotherapy is thought to be ineffective for the treatment of ACC, and therefore not often used. However, recent reports suggest the opposite. The aim of this study was to perform a retrospective analysis to evaluate the application of radiotherapy in Dutch ACC patients, and to determine the occurrence of response. MATERIALS AND METHODS: The Dutch ACC Registry (no.=159) was screened for patients who had received radiotherapy between 1990 and 2008. Tumor response evaluation was performed according to the Response Evaluation Criteria In Solid Tumors (RECIST). RESULTS: Only 13 patients (8% of registered patients) had received radiation therapy of whom 6 were irradiated for the palliation of painful bone metastases. In all patients this radiation resulted in pain relief. Three patients received adjuvant tumor bed radiation after resection. Four patients were radiated on irresectable tumor recurrence or tumor metastases. Two patients died soon after radiation therapy and therefore follow-up information regarding tumor response after radiation therapy of 2 patients was available. Interestingly, partial tumor response according to RECIST criteria, was observed in both patients. CONCLUSION: ACC can be sensitive to radiotherapy and should be considered in the treatment of advanced ACC, particularly in worrisome lesions. The role of radiotherapy in advanced ACC is to complement a systemic treatment such as mitotane or classic cytotoxic agents.
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Neoplasias de la Corteza Suprarrenal/radioterapia , Carcinoma Corticosuprarrenal/radioterapia , Neoplasias de la Corteza Suprarrenal/diagnóstico , Neoplasias de la Corteza Suprarrenal/mortalidad , Neoplasias de la Corteza Suprarrenal/patología , Carcinoma Corticosuprarrenal/diagnóstico , Carcinoma Corticosuprarrenal/mortalidad , Carcinoma Corticosuprarrenal/patología , Anciano , Neoplasias Óseas/mortalidad , Neoplasias Óseas/secundario , Femenino , Humanos , Masculino , Persona de Mediana Edad , Países Bajos , Radiografía Abdominal , Radioterapia Adyuvante , Recurrencia , Sistema de Registros , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: We aimed to assess the implementation and effectiveness of exemestane plus everolimus treatment per hospital type in real-life, shortly after approval of everolimus. METHODS: Advanced breast cancer patients treated with exemestane plus everolimus in 2012-2014 were included from the SONABRE registry. Progression-free survival (PFS) and a 12-week conditional PFS (post-hoc) were estimated by Kaplan-Meier method. The multivariable Cox proportional hazards model was performed by type of hospital and adjusted for patient, tumour and treatment characteristics. RESULTS: We included 122 patients, comprising 48 patients treated in academic (Nâ¯=â¯1), 56 in teaching (Nâ¯=â¯4), and 18 in non-teaching (Nâ¯=â¯2) hospitals. The median PFS was 6.3 months (95% Confidence Interval (CI) 4.0-8.6) overall, and 8.5 months (95% CI 7.7-9.3), 4.2 months (95% CI 2.0-6.3), and 5.5 months (95% CI 4.2-6.7) for the patients treated in academic, teaching and non-teaching hospitals, respectively. The adjusted Hazard Ratio (HR) for PFS-events was 1.5 (95% CI 1.0-2.2) and 1.0 (95% CI 0.5-1.9) respectively for patients treated at teaching and non-teaching hospitals versus the academic hospital. The adjusted HR for 12-week conditional PFS-events was not different between hospital types. In the first 12-week treatment period, treatment was discontinued due to early progression in one out of 48 patients in the academic versus nine out of 74 patients in the non-academic hospitals, confirmed by imaging in one and two patients, respectively. CONCLUSIONS: In our study, the median PFS was borderline significantly different between hospital types, possibly the result of a different assessment approach in the first 12-week treatment period.
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Androstadienos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Everolimus/uso terapéutico , Anciano , Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/metabolismo , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Países Bajos , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Resultado del TratamientoRESUMEN
INTRODUCTION: The aim of our analysis was to assess the real-world cost-effectiveness of bevacizumab in addition to taxane treatment versus taxane monotherapy for HER2-negative metastatic breast cancer compared with the cost-effectiveness based on the efficacy results from a trial. METHODS: A state transition model was built to estimate costs, life years (LYs) and quality-adjusted life years (QALYs) for both treatments. Two scenarios were examined: a real-world scenario and a trial-based scenario in which transition probabilities were primarily based on a real-world cohort study and the E2100 trial, respectively. In both scenarios, costs and utility parameter estimates were extracted from the real-world cohort study. Moreover, the Dutch health care perspective was adopted. RESULTS: In both the real-world and trial scenarios, bevacizumab-taxane is more expensive (incremental costs of 56,213 and 52,750, respectively) and more effective (incremental QALYs of 0.362 and 0.189, respectively) than taxane monotherapy. In the real-world scenario, bevacizumab-taxane compared to taxane monotherapy led to an incremental cost-effectiveness ratio (ICER) of 155,261 per QALY gained. In the trial scenario, the ICER amounted to 278,711 per QALY gained. CONCLUSION: According to the Dutch informal threshold, bevacizumab in addition to taxane treatment was not considered cost-effective for HER2-negative metastatic breast cancer both in a real-world and in a trial scenario.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/economía , Bevacizumab/administración & dosificación , Bevacizumab/economía , Neoplasias de la Mama/economía , Hidrocarburos Aromáticos con Puentes/economía , Análisis Costo-Beneficio , Progresión de la Enfermedad , Docetaxel , Femenino , Recursos en Salud/economía , Recursos en Salud/estadística & datos numéricos , Humanos , Estimación de Kaplan-Meier , Países Bajos , Paclitaxel/administración & dosificación , Paclitaxel/economía , Años de Vida Ajustados por Calidad de Vida , Receptor ErbB-2/metabolismo , Taxoides/administración & dosificación , Taxoides/economíaAsunto(s)
Técnicas de Ablación , Ablación por Catéter , Fallo Hepático , Neoplasias Hepáticas , Trombosis de la Vena , Humanos , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/cirugía , Microondas , Resultado del Tratamiento , Trombosis de la Vena/diagnóstico por imagen , Trombosis de la Vena/etiologíaRESUMEN
PURPOSE: To study whether there is a relationship between transplanted cell dose and rate of hematopoietic recovery after peripheral-blood stem-cell (PBSC) transplantation, and to obtain an indication whether specific subsets of CD34+ cell populations contribute to rapid recovery of neutrophils or platelets. PATIENTS AND METHODS: Based on data from 59 patients, we calculated for each day after PBSC transplantation the dose of CD34+ cells that resulted in rapid recovery of either neutrophils or platelets in the majority (> 70%) of patients. Using dual-color flow cytometry, subsets of peripheral-blood CD34+ cells were quantified and the numbers of CD34+ cells belonging to each of the reinfused subsets correlated with hematopoietic recovery following high-dose chemotherapy. RESULTS: The calculated threshold values with a high probability of engraftment showed a steep dose-effect relationship between CD34+ cell dose and time to recovery of both neutrophils or platelets. Predominantly CD34+ cells with the phenotype of myeloid precursors were mobilized. A minority of CD34+ cells expressed the erythroid and megakaryocytic lineage-associated antigens and a low but distinct population of CD34+ cells expressed antigens associated with multipotent stem cells. Analysis showed that the number of CD34+CD33- cells (r = -.74, P < .05), as well as the number of CD34+CD41+ cells (r = -.81, P < .005), correlated significantly better with time to neutrophil and platelet recovery, respectively, than with the total number of CD34+ cells (r = -.55 and r = -.56, respectively). CONCLUSION: The numbers of CD34+CD33- cells and CD34+CD41+ cells may help to predict short-term repopulation capacity of PBSCs, especially when relatively low numbers of CD34+ cells per kilogram are reinfused.
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Antígenos CD/metabolismo , Hematopoyesis , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/inmunología , Adolescente , Adulto , Antígenos CD34 , Antígenos de Diferenciación Mielomonocítica/metabolismo , Antígenos de Superficie/metabolismo , Citometría de Flujo/métodos , Humanos , Inmunofenotipificación , Recuento de Leucocitos , Persona de Mediana Edad , Análisis Multivariante , Neutrófilos , Recuento de Plaquetas , Lectina 3 Similar a Ig de Unión al Ácido SiálicoRESUMEN
Three patients, two Moroccan men aged 27 and 25 and a Turkish man aged 25, presented with haemoptysis caused by pulmonary aneurysm. The aneurysms had formed as a complication of Behçet's disease. Two of them were treated with high doses of corticosteroids. One man recovered and another died as a consequence of massive haemoptysis. The third man underwent emergency thoracotomy and pneumectomy due to massive haemoptysis. Postoperatively he was treated with cyclosporine resulting in full recovery. Behçet's disease is a multisystem vasculitis characterised by orogenital ulcerations and uveitis. In a minority of cases pulmonary aneurysms develop, often causing massive haemoptysis. Aneurysms are often accompanied by venous thrombosis. Treatment consists of immunosuppressive therapy. Nevertheless a considerable number of patients die following massive haemoptysis.
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Aneurisma/complicaciones , Síndrome de Behçet/complicaciones , Hemoptisis/etiología , Arteria Pulmonar , Corticoesteroides/uso terapéutico , Adulto , Aneurisma/etiología , Síndrome de Behçet/mortalidad , Síndrome de Behçet/patología , Resultado Fatal , Hemoptisis/tratamiento farmacológico , Humanos , Masculino , Embolia Pulmonar/complicaciones , Resultado del TratamientoRESUMEN
OBJECTIVE: We have previously demonstrated that detection of syncytium-inducing (SI) HIV-1 in asymptomatic seropositive individuals is associated with rapid progression to AIDS. In the present study, we sought to develop and evaluate an HIV-1 phenotyping assay for the screening of large numbers of individuals. METHODS: Efficiency of HIV-1 isolation from patient peripheral blood mononuclear cells (PBMC) was studied with donor PBMC or seven different CD4+ T-cell lines as target cells. The biological phenotype of sequential isolates from 20 long-term asymptomatic HIV-1-seropositive individuals was determined by two different assays. RESULTS: Non-SI isolates, efficiently recovered by cocultivation with donor PBMC, were never isolated with T-cell lines as target cells. Direct cocultivation with MT-2 cells, but not with six other CD4+ T-cells, resulted in the efficient recovery of SI isolates. HIV-1 MT-2 tropism and SI capacity were shown to be coupled properties at the clonal level. SI isolates emerged in 10 out of 20 longitudinally-studied individuals. In these long-term infected individuals, appearance of SI isolates was associated with progression to AIDS. CONCLUSIONS: Direct cocultivation of patient PBMC with the MT-2 cell line is a sensitive, specific and convenient method to detect SI isolates. The availability of an assay suitable for the screening of large groups allows further study of the value of HIV-1 biological phenotyping as a prognostic marker.
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Síndrome de Inmunodeficiencia Adquirida/microbiología , Células Gigantes/citología , Infecciones por VIH/microbiología , VIH-1/fisiología , Síndrome de Inmunodeficiencia Adquirida/fisiopatología , Línea Celular , Células Cultivadas , Infecciones por VIH/fisiopatología , VIH-1/crecimiento & desarrollo , VIH-1/aislamiento & purificación , Humanos , Monocitos/citología , Monocitos/microbiología , Fenotipo , Linfocitos T/citología , Linfocitos T/microbiología , Replicación ViralRESUMEN
The introduction of carboplatin as a replacement for cisplatin into treatment strategies against ovarian cancer has ameliorated major toxicities related to cisplatin, but carboplatin-evoked myelosuppression requires further study, especially since the addition of growth factors for bone marrow and hematologic support has been introduced into clinical practice. Since higher doses of platinating agents seem to be related to higher response rates, the protective effect of interleukin-3 on 800 mg carboplatin, a twofold increment over the usual dose, was studied. A modest myeloprotective potency was documented in the second treatment cycle of this aggressive chemotherapy program, but this effect tapered away in subsequent treatment courses, which occasionally included severe side effects (eg, headache, kidney function impairments). Another study addressed the anemia frequently observed with both cisplatin- and carboplatin-based treatment regimens in ovarian cancer, which is probably related to low erythropoietin levels. Very preliminary analysis of an ongoing phase III trial studying two erythropoietin doses given continuously subcutaneously versus a retrospective analysis of a "control group" (drawn from historical data on the occurrence of anemia in cisplatin- and/or carboplatin-treated patients) has shown beneficial effects of erythropoietin during treatment with these platinating agents.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/administración & dosificación , Eritropoyetina/administración & dosificación , Interleucina-3/administración & dosificación , Neoplasias Ováricas/tratamiento farmacológico , Adulto , Anciano , Anemia/inducido químicamente , Anemia/prevención & control , Carboplatino/efectos adversos , Cisplatino/administración & dosificación , Eritropoyetina/uso terapéutico , Femenino , Humanos , Interleucina-3/efectos adversos , Interleucina-3/uso terapéutico , Persona de Mediana Edad , Neutropenia/inducido químicamente , Neutropenia/prevención & control , Proteínas Recombinantes/administración & dosificación , Trombocitopenia/inducido químicamente , Trombocitopenia/prevención & controlRESUMEN
UNLABELLED: This paper reports on two patients with a long-standing diagnosis of an ENETS stage IV neuroendocrine tumour (NET) of the small intestine who developed neurological symptoms. The first patient only had bulbar symptoms and tested positive for acetylcholine receptor antibodies. The second patient had more classical symptoms of fatigable diplopia and muscle weakness of the legs, but no detectable antibodies. The diagnosis of paraneoplastical myasthenia gravis (MG) was postulated. Both patients were treated with pyridostigmine for MG and octreotide for the NETs. Interestingly, treatment of the NETs resulted in improvement of myasthenic symptoms. Paraneoplastic MG has been described to occur with certain malignancies, mainly thymoma. Herein, we prove that the association with gastrointestinal NETs, however, rare, is also one to be considered by clinicians dealing with either of these diseases. The pathogenesis has yet to be elucidated. LEARNING POINTS: NETs are rare malignancies with a wide variety of symptoms.Paraneoplastic MG can occur with various types of malignancies.Herein, we provide evidence of paraneoplastic MG in association with a grade IV NET of the small intestine.Treatment of the NETs resulted in remission of myasthenic symptoms in one patient.
RESUMEN
We report on a patient with myelodysplastic syndrome (MDS), classified as refractory anaemia with excess of blasts-2, and histiocytoid Sweet's syndrome. The skin lesions disappeared after initiation of corticosteroids and doxycycline. Remarkably, two months later a complete remission of the MDS occurred. Fourteen months later both the skin lesions and the MDS relapsed. Antileukaemic activity following reversion of the impaired cellular immunity due to an increased number of natural killer cells in his bone marrow may be responsible for this rare event. Inhibition of T-cell mediated myelosuppression by corticosteroids or a proapoptotic effect of doxycycline may have attributed as well.
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Corticoesteroides/uso terapéutico , Anemia Refractaria con Exceso de Blastos/tratamiento farmacológico , Antibacterianos/uso terapéutico , Doxiciclina/uso terapéutico , Inmunosupresores/uso terapéutico , Síndrome de Sweet/complicaciones , Anciano , Anemia Refractaria con Exceso de Blastos/complicaciones , Resultado Fatal , Humanos , Células Asesinas Naturales , Masculino , Recurrencia , Inducción de Remisión , Síndrome de Sweet/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Two clinical studies were undertaken to study the toxicity profile and effects of interleukin-3 (rhIL-3) on chemotherapy-induced myelosuppression. Fifteen patients with recurrent ovarian carcinoma were treated with high dose carboplatin (800 mg m-2). All patients received 5.0 micrograms/kg/d rhIL-3 subcutaneously but timing and duration of rhIL-3 treatment differed. Constitutional symptoms were the major toxicity and in addition to the carboplatin-induced nausea and vomiting the combination was poorly tolerated. In 5/15 patients receiving high dose carboplatin rhIL-3 administration was discontinued due to nephrotoxicity (2 x), hypotension, severe malaise and bone pain. In this study, rhIL-3 ameliorated chemotherapy-induced neutropenia as well as thrombocytopenia and reduced the requirement for platelet transfusions in the second cycle of chemotherapy. However, rhIL-3 failed to prevent cumulative platelet toxicity. In the second study 12 patients with small cell undifferentiated cancers were treated with carboplatin, etoposide and ifosfamide. Three dose levels of rhIL-3 were explored (0.125, 5.0 and 7.5 micrograms/kg/d). In this study, toxicity of the treatment was mild, however, no beneficial haematologic effects of rhIL-3 could be demonstrated. In conclusion, the haematological effects of rhIL-3 were modest and dependent on the chemotherapeutic regimen, timing and duration of rhIL-3 treatment (in relation to the expected nadir). In general rhIL-3-induced toxicity was mild, but combination with high dose carboplatin could be hazardous if rhIL-3 is initiated at 24 h after the cytostatic agent.
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Antineoplásicos/efectos adversos , Médula Ósea/efectos de los fármacos , Carcinoma de Células Pequeñas/tratamiento farmacológico , Interleucina-3/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Adulto , Anciano , Antígenos CD/análisis , Antígenos CD34 , Femenino , Humanos , Interleucina-3/efectos adversos , Persona de Mediana Edad , Neutrófilos/efectos de los fármacos , Recuento de Plaquetas/efectos de los fármacos , Proteínas Recombinantes/uso terapéuticoRESUMEN
Adhesion of CD34+ hematopoietic progenitor cells (HPCs) to sinusoidal endothelium probably plays a key role in homing of transplanted CD34+ HPCs to the bone marrow (BM). We have investigated the role of various adhesion molecules in the interaction of purified CD34+ HPCs derived from BM or peripheral blood (PB) and a human BM-derived endothelial cell line. Adhesion of CD34+ HPCs to endothelial cells was measured with the use of a double-color flow microfluorimetric adhesion assay. In this assay, adhesion is measured under stirring conditions, simulating blood flow in sinusoidal marrow vessels. Adhesion of PB CD34+ cells to human BM endothelial cells (HBMECs) was observed only after interleukin (IL)-1beta prestimulation of the endothelial cells. This adhesion was strongly increased after addition of phorbol-myristate acetate (PMA). Adhesion of PB CD34+ cells to IL-1beta-prestimulated HBMECs was inhibited by blocking monoclonal antibodies (mAbs) against E-selectin and by neuraminidase treatment of the PB CD34+ cells. mAbs against very late activation antigen (VLA)-4 inhibited adhesion only when the E-selectin-mediated interaction was prevented. No clear inhibiting effect was found with blocking mAbs against beta2-integrins. Stimulation with the beta1-integrin-activating mAb, 8A2, induced adhesion of CD34+ cells to endothelial cells. In conclusion, stimulation of both endothelial cells and CD34+ HPCs is necessary for adhesion of CD34+ HPCs to endothelial cells. We furthermore demonstrated that E-selectin and VLA-4 mediated this adhesion.
Asunto(s)
Células de la Médula Ósea/citología , Selectina E/farmacología , Endotelio Vascular/citología , Células Madre Hematopoyéticas/citología , Integrinas/fisiología , Receptores Mensajeros de Linfocitos/fisiología , Molécula 1 de Adhesión Celular Vascular , Antígenos CD34/sangre , Adhesión Celular/efectos de los fármacos , Adhesión Celular/inmunología , Línea Celular , Células Madre Hematopoyéticas/inmunología , Humanos , Integrina alfa4beta1 , Molécula 1 de Adhesión Celular Vascular/fisiologíaRESUMEN
The composition of human immunodeficiency virus type 1 (HIV-1) clonal populations at different stages of infection and in different compartments was analyzed. Biological HIV-1 clones were obtained by primary isolation from patient peripheral blood mononuclear cells under limiting dilution conditions, with either blood donor peripheral blood lymphocytes or monocyte-derived macrophages (MDM) as target cells, and the biological phenotype of the clones was analyzed. In asymptomatic individuals, low frequencies of HIV-1 clones were observed. These clones were non-syncytium inducing and preferentially monocytotropic. In individuals progressing to disease, a 100-fold increase in frequencies of productively HIV-1-infected cells was observed as a result of a selective expansion of nonmonocytotropic clones. In a person progressing to AIDS within 19 months after infection, only syncytium-inducing clones were detected, shifting from MDM-tropic to non-MDM-tropic over time. From his virus donor, a patient with wasting syndrome, only syncytium-inducing clones, mostly non-MDM-tropic, were recovered. Parallel clonal analysis of HIV-1 populations in cells present in bronchoalveolar lavage fluid and peripheral blood from an AIDS patient revealed a qualitatively and quantitatively more monocytotropic virus population in the lung compartment than in peripheral blood at the same time point. These findings indicate that monocytotropic HIV-1 clones, probably generated in the tissues, are responsible for the persistence of HIV-1 infection and that progression of HIV-1 infection is associated with a selective increase of T-cell-tropic, nonmonocytotropic HIV-1 variants in peripheral blood.
Asunto(s)
Infecciones por VIH/patología , VIH-1/patogenicidad , Monocitos/microbiología , Linfocitos T/microbiología , Síndrome de Inmunodeficiencia Adquirida/patología , Líquido del Lavado Bronquioalveolar/patología , Humanos , Factores de TiempoRESUMEN
In the present study, we show by adhesion assays and ultrastructural studies that platelets can bind to CD34+ cells from human blood and bone marrow and that this interaction interferes with the accurate detection of endogenously expressed platelet glycoproteins (GPs). The interaction between these cells was found to be reversible, dependent on divalent cations, and mediated by P-selectin. Enzymatic characterization showed the involvement of sialic acid residues, protein(s). The demonstration of mRNA for the P-selectin glycoprotein ligand 1 (PSGL-1) in the CD34+ cells by polymerase chain reaction (PCR) analysis suggests that this molecule is present in these cells. Under conditions that prevent platelet adhesion, a small but distinct subpopulation of CD34+ cells diffusely expressed the platelet GPIIb/IIIa complex. These cells were visualized by immunochemical studies. Furthermore, synthesis of mRNA for GPIIb and GPIIIa by CD34+ cells was shown using PCR analysis. The semiquantitative PCR results show relatively higher amounts of GPIIb mRNA than of PF4 mRNA in CD34+CD41+ cells in comparison with this ratio in platelets. This finding is a strong indication that the PCR results are not caused by contaminating adhering platelets. MoAbs against GPIa GPIb alpha, GPV, P-selectin, and the alpha-chain of the vitronectin receptor did not react with CD34+ cells. The number of CD34+ cells expressing GPIIb/IIIa present in peripheral blood stem cell (PBSC) transplants was determined and was correlated with platelet recovery after intensive chemotherapy in 27 patients. The number of CD34+CD41+ cells correlated significantly better with the time of platelet recovery after PBSC transplantation (r = .83, P = .04) than did the total number of CD34+ cells (r = .55). Statistical analysis produced a threshold value for rapid platelet recovery of 0.34 x 10(6) CD34+CD41+ cells/kg. This study suggests that if performed in the presence of EDTA the flow cytometric measurement of GPIIb/IIIa on CD34+ cells provides the most accurate indication of the platelet reconstitutive capacity of the PBSC transplant.
Asunto(s)
Antígenos CD34/análisis , Antígenos de Diferenciación/análisis , Artefactos , Citometría de Flujo , Megacariocitos/citología , Selectina-P , Adhesividad Plaquetaria/efectos de los fármacos , Glicoproteínas de Membrana Plaquetaria/biosíntesis , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Secuencia de Bases , Células Sanguíneas , Médula Ósea/patología , Diferenciación Celular , Ácido Edético/farmacología , Filgrastim , Factor Estimulante de Colonias de Granulocitos/farmacología , Cardiopatías/patología , Cardiopatías/cirugía , Hematopoyesis/efectos de los fármacos , Trasplante de Células Madre Hematopoyéticas , Humanos , Inmunofenotipificación , Megacariocitos/química , Metaloendopeptidasas/farmacología , Datos de Secuencia Molecular , Neoplasias/sangre , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Neoplasias/terapia , Neuraminidasa/farmacología , Elastasa Pancreática/farmacología , Activación Plaquetaria/efectos de los fármacos , Glicoproteínas de Membrana Plaquetaria/genética , Reacción en Cadena de la Polimerasa , Proteínas Recombinantes/farmacología , Trombina/farmacología , Tripsina/farmacologíaRESUMEN
Adhesion molecules play a role in the migration of hematopoietic progenitor cells and regulation of hematopoiesis. To study whether the mobilization process is associated with changes in expression of adhesion molecules, the expression of CD31, CD44, L-selectin, sialyl Lewisx, beta 1 integrins very late antigen 4 (VLA-4) and VLA-5, and beta 2 integrins lymphocyte function-associated 1 and Mac-1 was measured on either bone marrow (BM) CD34+ cells or on peripheral blood CD34+ cells mobilized with a combination of granulocyte colony-stimulating factor (G-CSF) and chemotherapy. beta 1 integrin VLA-4 was expressed at a significantly lower concentration on peripheral blood progenitor cells than on BM CD34+ cells, procured either during steady-state hematopoiesis or at the time of leukocytapheresis. No differences in the level of expression were found for the other adhesion molecules. To obtain insight in which adhesion molecules may participate in the homing of peripheral blood stem cells (PBSCs), the number of CD34+ cells expressing these adhesion molecules present in leukocytapheresis material was quantified and correlated with hematopoietic recovery after intensive chemotherapy in 27 patients. The number of CD34+ cells in the subset defined by L-selectin expression correlated significantly better with time to platelet recovery after PBSC transplantation (r = -.86) than did the total number of CD34+ cells (r = -.55). Statistical analysis of the relationship between the number of CD34+L-selectin+ cells and platelet recovery resulted in a threshold value for rapid platelet recovery of 2.1 x 10(6) CD34+ L-selectin+ cells/kg. A rapid platelet recovery (< or = 14 days) was observed in 13 of 15 patients who received > or = 2.1 x 10(6) CD34+ L-selectin+ cells/kg (median, 11 days; range, 7 to 16 days), whereas 10 of 12 patients who received less double positive cells had a relative slow platelet recovery (median, 20 days; range, 13 to 37 days). The L-selectin+ subpopulation of CD34+ cells also correlated better with time to neutrophil recovery (r = -.70) than did the total number of reinfused CD34+ cells (r = -.51). However, this latter difference failed to reach statistical significance. This study suggests that L-selectin is involved in the homing of CD34+ cells after PBSC transplantation.