RESUMEN
BACKGROUND: The number of patients suffering from human papillomavirus (HPV)-associated oropharyngeal cancer has increased in recent decades. To date, the role of medical therapy in patients with squamous cell carcinoma of the head and neck region has only been established in the refractory or metastatic setting (r/m HNSCC). OBJECTIVE: What are the current treatment options for patients with r/m HNSCC or r/m oropharyngeal cancer? MATERIALS AND METHODS: A literature search was conducted on systemic treatment of oropharyngeal cancer and r/m HNSCC. RESULTS: There is currently no standard treatment for patients with oropharyngeal cancer in refractory or metastatic stages. Since 2017, immunotherapy with checkpoint inhibitors has become increasingly important in the treatment of r/m HNSCC patients. First-line therapy was recently adapted based on the results of the KEYNOTE-48 (KN048) study. For selected patients with r/m HNSCC, there now exists a chemotherapy-free treatment option. Use of immunotherapy also in earlier stages of HNSCC can be expected in the near future. CONCLUSION: Medical therapy of r/m HNSCC patients is in a period of great change. Treatment is increasingly based on combination therapy with checkpoint inhibitors.
Asunto(s)
Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias Orofaríngeas , Carcinoma de Células Escamosas/tratamiento farmacológico , Humanos , Neoplasias Orofaríngeas/terapia , Papillomaviridae , Carcinoma de Células Escamosas de Cabeza y CuelloRESUMEN
Chronic myeloid leukemia (CML)-study IV was designed to explore whether treatment with imatinib (IM) at 400 mg/day (n=400) could be optimized by doubling the dose (n=420), adding interferon (IFN) (n=430) or cytarabine (n=158) or using IM after IFN-failure (n=128). From July 2002 to March 2012, 1551 newly diagnosed patients in chronic phase were randomized into a 5-arm study. The study was powered to detect a survival difference of 5% at 5 years. After a median observation time of 9.5 years, 10-year overall survival was 82%, 10-year progression-free survival was 80% and 10-year relative survival was 92%. Survival between IM400 mg and any experimental arm was not different. In a multivariate analysis, risk group, major-route chromosomal aberrations, comorbidities, smoking and treatment center (academic vs other) influenced survival significantly, but not any form of treatment optimization. Patients reaching the molecular response milestones at 3, 6 and 12 months had a significant survival advantage. For responders, monotherapy with IM400 mg provides a close to normal life expectancy independent of the time to response. Survival is more determined by patients' and disease factors than by initial treatment selection. Although improvements are also needed for refractory disease, more life-time can currently be gained by carefully addressing non-CML determinants of survival.
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Antineoplásicos/uso terapéutico , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Análisis de Supervivencia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Relación Dosis-Respuesta a Droga , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: This multicentre, open-label, randomized, controlled phase II study evaluated cilengitide in combination with cetuximab and platinum-based chemotherapy, compared with cetuximab and chemotherapy alone, as first-line treatment of patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients were randomized 1:1:1 to receive cetuximab plus platinum-based chemotherapy alone (control), or combined with cilengitide 2000 mg 1×/week i.v. (CIL-once) or 2×/week i.v. (CIL-twice). A protocol amendment limited enrolment to patients with epidermal growth factor receptor (EGFR) histoscore ≥200 and closed the CIL-twice arm for practical feasibility issues. Primary end point was progression-free survival (PFS; independent read); secondary end points included overall survival (OS), safety, and biomarker analyses. A comparison between the CIL-once and control arms is reported, both for the total cohorts, as well as for patients with EGFR histoscore ≥200. RESULTS: There were 85 patients in the CIL-once group and 84 in the control group. The PFS (independent read) was 6.2 versus 5.0 months for CIL-once versus control [hazard ratio (HR) 0.72; P = 0.085]; for patients with EGFR histoscore ≥200, PFS was 6.8 versus 5.6 months, respectively (HR 0.57; P = 0.0446). Median OS was 13.6 for CIL-once versus 9.7 months for control (HR 0.81; P = 0.265). In patients with EGFR ≥200, OS was 13.2 versus 11.8 months, respectively (HR 0.95; P = 0.855). No major differences in adverse events between CIL-once and control were reported; nausea (59% versus 56%, respectively) and neutropenia (54% versus 46%, respectively) were the most frequent. There was no increased incidence of thromboembolic events or haemorrhage in cilengitide-treated patients. αvß3 and αvß5 expression was neither a predictive nor a prognostic indicator. CONCLUSIONS: The addition of cilengitide to cetuximab/chemotherapy indicated potential clinical activity, with a trend for PFS difference in the independent-read analysis. However, the observed inconsistencies across end points suggest additional investigations are required to substantiate a potential role of other integrin inhibitors in NSCLC treatment. CLINICAL TRIAL REGISTRATION ID NUMBER: NCT00842712.
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Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Cetuximab/administración & dosificación , Cisplatino/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Receptores ErbB/metabolismo , Femenino , Humanos , Integrina alfaVbeta3/metabolismo , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Receptores de Vitronectina/metabolismo , Venenos de Serpiente/administración & dosificación , Resultado del Tratamiento , Vinblastina/administración & dosificación , Vinblastina/análogos & derivados , Vinorelbina , GemcitabinaAsunto(s)
Errores Diagnósticos , Tumor del Glomo Yugular/diagnóstico , Mieloma Múltiple/diagnóstico , Angiografía , Quimioradioterapia Adyuvante , Terapia Combinada , Femenino , Estudios de Seguimiento , Tumor del Glomo Yugular/irrigación sanguínea , Tumor del Glomo Yugular/patología , Tumor del Glomo Yugular/cirugía , Pruebas Auditivas , Humanos , Imagen por Resonancia Magnética , Persona de Mediana Edad , Mieloma Múltiple/irrigación sanguínea , Mieloma Múltiple/patología , Mieloma Múltiple/cirugía , Invasividad Neoplásica , Tomografía Computarizada por Rayos XRESUMEN
UNLABELLED: Early assessment of response at 3 months of tyrosine kinase inhibitor treatment has become an important tool to predict favorable outcome. We sought to investigate the impact of relative changes of BCR-ABL transcript levels within the initial 3 months of therapy. In order to achieve accurate data for high BCR-ABL levels at diagnosis, beta glucuronidase (GUS) was used as a reference gene. Within the German CML-Study IV, samples of 408 imatinib-treated patients were available in a single laboratory for both times, diagnosis and 3 months on treatment. In total, 301 of these were treatment-naïve at sample collection. RESULTS: (i) with regard to absolute transcript levels at diagnosis, no predictive cutoff could be identified; (ii) at 3 months, an individual reduction of BCR-ABL transcripts to the 0.35-fold of baseline level (0.46-log reduction, that is, roughly half-log) separated best (high risk: 16% of patients, 5-year overall survival (OS) 83% vs 98%, hazard ratio (HR) 6.3, P=0.001); (iii) at 3 months, a 6% BCR-ABL(IS) cutoff derived from BCR-ABL/GUS yielded a good and sensitive discrimination (high risk: 22% of patients, 5-year OS 85% vs 98%, HR 6.1, P=0.002). Patients at risk of disease progression can be identified precisely by the lack of a half-log reduction of BCR-ABL transcripts at 3 months.
Asunto(s)
Antineoplásicos/uso terapéutico , Benzamidas/uso terapéutico , Proteínas de Fusión bcr-abl/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Glucuronidasa/metabolismo , Humanos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Riesgo , Sensibilidad y Especificidad , Resultado del Tratamiento , Adulto JovenRESUMEN
Determination of red cell volume (RCV) might contribute to establishing the diagnosis of polycythemia vera (PV). A novel simplified method to detect RCV through CO rebreathing is nowadays applied in healthy young individuals but was not tested in a clinical or PV setting. The aim of the present study is to evaluate whether this spirometric approach is applicable in older subjects and contributes to PV diagnosis in a proof-of-concept approach. At first, RCV was determined by the optimized CO-rebreathing method in healthy subjects >50 years of age (n = 81, age 66 ± 9 years). Failure rate and age distribution of subjects who failed with CO rebreathing were analyzed. Then, RCV was measured in male PV patients (n = 7) and compared to healthy male controls (n = 35). RCV values in relation to several anthropometric references (body weight, body surface area (BSA), lean body mass (LBM)) were calculated to determine the sensitivity and specificity of established RCV thresholds when using optimized CO rebreathing. In healthy subjects, test failure rate was 9.9 %, but failure was not associated with age. Sensitivity and specificity (sens/spec) to detect PV was 100 %/83 % using the criteria of the PV study group. Using criteria based on BSA, sens/spec was 14 %/100 %. An arbitrary threshold of 50 ml/kg LBM yielded sens/spec of 100 %/97 %. In conclusion, this proof-of-concept indicates that optimized CO rebreathing is applicable in older subjects and allows determining RCV for the diagnosis of PV. Normalized values for RCV measures obtained from CO rebreathing are needed to grant sufficient sensitivity and/or specificity.
Asunto(s)
Monóxido de Carbono/metabolismo , Volumen de Eritrocitos/fisiología , Hemoglobinas/metabolismo , Inhalación/fisiología , Policitemia Vera/diagnóstico , Policitemia Vera/metabolismo , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Policitemia Vera/fisiopatología , Estudios Retrospectivos , Espirometría/métodos , Espirometría/normasRESUMEN
Grb2-associated binder 2 (Gab2) serves as a critical amplifier in the signaling network of Bcr-Abl, the driver of chronic myeloid leukemia (CML). Despite the success of tyrosine kinase inhibitors (TKIs) in CML treatment, TKI resistance, caused by mutations in Bcr-Abl or aberrant activity of its network partners, remains a clinical problem. Using inducible expression and knockdown systems, we analyzed the role of Gab2 in Bcr-Abl signaling in human CML cells, especially with respect to TKI sensitivity. We show for the first time that Gab2 signaling protects CML cells from various Bcr-Abl inhibitors (imatinib, nilotinib, dasatinib and GNF-2), whereas Gab2 knockdown or haploinsufficiency leads to increased TKI sensitivity. We dissected the underlying molecular mechanism using various Gab2 mutants and kinase inhibitors and identified the Shp2/Ras/ERK and the PI3K/AKT/mTOR axes as the two critical signaling pathways. Gab2-mediated TKI resistance was associated with persistent phosphorylation of Gab2 Y452, a PI3K recruitment site, and consistent with this finding, the protective effect of Gab2 was completely abolished by the combination of dasatinib with the dual PI3K/mTOR inhibitor NVP-BEZ235. The identification of Gab2 as a novel modulator of TKI sensitivity in CML suggests that Gab2 could be exploited as a biomarker and therapeutic target in TKI-resistant disease.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Resistencia a Antineoplásicos , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas 14-3-3/metabolismo , Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Proteínas Adaptadoras Transductoras de Señales/genética , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica , Benzamidas , Western Blotting , Dasatinib , Femenino , Estudios de Seguimiento , Humanos , Mesilato de Imatinib , Imidazoles/farmacología , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Persona de Mediana Edad , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Fosforilación/efectos de los fármacos , Piperazinas/farmacología , Pronóstico , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pirimidinas/farmacología , Quinolinas/farmacología , ARN Interferente Pequeño/genética , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismo , Tiazoles/farmacología , Células Tumorales CultivadasRESUMEN
BACKGROUND: Stereotactic ablative body radiotherapy (SBRT, SABR) is being increasingly applied because of its high local efficacy, e.g., for small lung tumors. However, the optimum dosage is still under discussion. Here, we report data on 45 lung lesions [non-small cell lung cancer (NSCLC) or metastases] in 39 patients treated between 2009 and 2010 by SABR. PATIENTS AND METHODS: SABR was performed with total doses of 35 Gy (5 fractions) or 37.5 Gy (3 fractions) prescribed to the 60% isodose line encompassing the planning target volume. Three-monthly follow-up CT scans were supplemented by FDG-PET/CT if clinically indicated. RESULTS: The median follow-up was 17 months. Local progression-free survival rates were 90.5% (all patients), 95.0% (NSCLC), and 81.8% (metastases) at 1 year. At 2 years, the respective local progression-free survival rates were 80.5%, 95.0%, and 59.7%. Overall survival rates were 71.1% (all patients), 65.4% (NSCLC), and 83.3% (metastases) at 1 year. Overall survival rates at 2 years were 52.7%, 45.9%, and 66.7%, respectively. Acute side effects were mild. CONCLUSION: With the moderate dose schedule used, well-tolerated SABR led to favorable local tumor control as in other published series. Standardization in reporting the dose prescription for SABR is needed to allow comparison of different series in order to determine optimum dosage.
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Carcinoma de Pulmón de Células no Pequeñas/cirugía , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/cirugía , Radiocirugia/métodos , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Mediciones del Volumen Pulmonar , Masculino , Persona de Mediana Edad , Imagen Multimodal , Estadificación de Neoplasias , Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos XRESUMEN
Malignant pleural mesothelioma (MMP) is a highly aggressive tumor arising of the pleural mesothelium. Asbestos exposure is the main factor involved in the pathogenesis of MMP and according to the late ban of this agent in 2005 the peak incidence in Europe is expected in the next twenty years. The highly aggressive behaviour of this tumor results in a poor prognosis with a mean overall survival between 7 and 9 months. Despite the progress made in diagnosis and therapy of this entity the optimal treatment remains a subject of debate. In this article we review the current state of treatment and diagnosis.
Asunto(s)
Amianto/envenenamiento , Mesotelioma/diagnóstico , Mesotelioma/terapia , Neoplasias Pleurales/diagnóstico , Neoplasias Pleurales/terapia , Humanos , Mesotelioma/etiología , Neoplasias Pleurales/etiologíaRESUMEN
In the face of competing first-line treatment options for CML, early prediction of prognosis on imatinib is desirable to assure favorable survival or otherwise consider the use of a second-generation tyrosine kinase inhibitor (TKI). A total of 1303 newly diagnosed imatinib-treated patients (pts) were investigated to correlate molecular and cytogenetic response at 3 and 6 months with progression-free and overall survival (PFS, OS). The persistence of BCR-ABL transcript levels >10% according to the international scale (BCR-ABL(IS)) at 3 months separated a high-risk group (28% of pts; 5-year OS: 87%) from a group with >1-10% BCR-ABL(IS) (41% of pts; 5-year OS: 94%; P=0.012) and from a group with ≤1% BCR-ABL(IS) (31% of pts; 5-year OS: 97%; P=0.004). Cytogenetics identified high-risk pts by >35% Philadelphia chromosome-positive metaphases (Ph+, 27% of pts; 5-year OS: 87%) compared with ≤35% Ph+ (73% of pts; 5-year OS: 95%; P=0.036). At 6 months, >1% BCR-ABL(IS) (37% of pts; 5-year OS: 89%) was associated with inferior survival compared with ≤1% (63% of pts; 5-year OS: 97%; P<0.001) and correspondingly >0% Ph+ (34% of pts; 5-year OS: 91%) compared with 0% Ph+ (66% of pts; 5-year OS: 97%; P=0.015). Treatment optimization is recommended for pts missing these landmarks.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Benzamidas , Citarabina/administración & dosificación , Análisis Citogenético , Progresión de la Enfermedad , Femenino , Proteínas de Fusión bcr-abl/genética , Humanos , Mesilato de Imatinib , Interferones/administración & dosificación , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Masculino , Persona de Mediana Edad , Piperazinas/administración & dosificación , Pronóstico , Pirimidinas/administración & dosificación , Inducción de Remisión , Tasa de Supervivencia , Adulto JovenAsunto(s)
Purgación de la Médula Ósea , Receptores Frizzled , Trasplante de Células Madre de Sangre Periférica , Neoplasias Peritoneales/terapia , Receptores Acoplados a Proteínas G , Neoplasias de los Tejidos Blandos/terapia , Adulto , Terapia Combinada , Humanos , Neoplasias Peritoneales/patología , Neoplasias de los Tejidos Blandos/patología , Trasplante AutólogoRESUMEN
BACKGROUND: The aim of this study is to determine feasibility and efficacy of the combination regimen gemcitabine, oxaliplatin, and paclitaxel (GOP) in patients with cisplatin-refractory or multiply relapsed germ-cell tumors. PATIENTS AND METHODS: From April 2003 to October 2006, 41 patients refractory to cisplatin-based chemotherapy or with relapse after high-dose chemotherapy (HDCT) plus stem-cell support (peripheral blood stem-cell transplantation: PBSCT) received 800 mg/m2 gemcitabine, 80 mg/m2 paclitaxel (Taxol), both on days 1 + 8, and oxaliplatin 130 mg/m2 on day 1 of a 3-week cycle for a minimum of two cycles. Primary end point was response rate. Patients were pretreated with a median of two lines of platin-based chemotherapy (range, 1-3), and 78% had relapsed after HDCT/PBSCT. RESULTS: Seventy-three percent of patients had relapsed within 3 months after the last cisplatin-based chemotherapy. Five percent of the patients achieved a complete response, and 34% and 12% a marker-negative and marker-positive partial response, respectively (overall response rate 51%). After a median follow-up of 5 months (range, 0-20), 15% of the patients remain in complete remission after GOP chemotherapy +/- residual tumor resection with a median response duration of 8 months (1 to 17+). Main toxicity was leucocytopenia grade 3/4 in 15%, anemia in 7%, and thrombocytopenia in 49% of the patients. CONCLUSION: Combination chemotherapy with GOP is feasible and effective with acceptable toxicity in patients with treatment-refractory germ-cell tumors.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de Células Germinales y Embrionarias/tratamiento farmacológico , Neoplasias Testiculares/tratamiento farmacológico , Adulto , Anemia/inducido químicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Resistencia a Antineoplásicos , Estudios de Factibilidad , Humanos , Leucopenia/inducido químicamente , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias de Células Germinales y Embrionarias/secundario , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Paclitaxel/administración & dosificación , Neoplasias Testiculares/patología , Trombocitopenia/inducido químicamente , Resultado del Tratamiento , GemcitabinaRESUMEN
A 19-year-old female underwent orthotopic liver transplantation for acute hepatic failure because of fulminant Wilson's disease. Three months post transplantation she developed systemic fungal meningoencephalitis and obstructive hydrocephalus that required cerebrospinal fluid (CSF) shunting by a ventriculo-atrial shunt. Subsequently, she contracted Staphylococcus epidermidis bacteremia, ventriculitis, and shunt infection. Treatment with vancomycin either by conventional intravenous (i.v.) or continuous i.v. injection proved ineffective because of insufficient drug concentrations in the CSF. Eradication of S. epidermidis from CSF and cure of chronic ventriculitis and shunt infection was readily achieved by delivering vancomycin by intraventricular injection (5 mg/24 h) via an extraventricular drain together with continuous i.v. infusion (4 g/24 h) over a period of 18 days. This treatment was well tolerated and free of untoward side effects despite the patient's chronic immunosuppression subsequent to liver transplantation. Intraventricular injection of vancomycin is an effective and safe procedure to eradicate S. epidermidis from the central nervous system when i.v. vancomycin treatment fails.
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Antibacterianos/administración & dosificación , Infecciones Fúngicas del Sistema Nervioso Central/etiología , Infecciones Fúngicas del Sistema Nervioso Central/terapia , Derivaciones del Líquido Cefalorraquídeo/efectos adversos , Trasplante de Hígado/efectos adversos , Meningitis Fúngica/etiología , Meningitis Fúngica/terapia , Complicaciones Posoperatorias , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/etiología , Staphylococcus epidermidis , Vancomicina/administración & dosificación , Adulto , Femenino , Rechazo de Injerto/prevención & control , Degeneración Hepatolenticular/terapia , Humanos , Inmunosupresores/administración & dosificación , Inyecciones Intravenosas , Inyecciones Intraventriculares , Factores de Tiempo , Resultado del TratamientoRESUMEN
AIMS: To carry out an immunohistochemical study on bone marrow (BM) biopsy specimens in 75 patients with chronic myelogenous leukaemia (CML) on long-term STI571 therapy. METHODS AND RESULTS: Sequential BM specimens taken at intervals of 21 +/- 6 months were investigated by enzyme- and immunohistochemistry including proliferating cell nuclear antigen and apoptosis. Evaluation was performed either by semiquantitative scoring or by morphometry (CD61+ megakaryopoiesis). In 41 patients with chronic phase CML, treatment resulted in a significant decrease in cellularity and neutrophil granulopoiesis contrasting with an accumulation of erythroid precursor cells. Morphometry showed a reduction of abnormal micromegakaryocytes consistent with normalization. Regression of myelofibrosis was identified in eight of 15 patients, whereas progression occurred in 17 patients; mostly in those with acceleration and blastic crisis. The increased post-treatment incidence of reactive lymphoid nodules was remarkable. Myeloblasts, CD34+ progenitors and immature myelomonocytic cells initially decreased, but recurred in 14 patients who later developed a relapse. STI571 exerted an inhibitory effect on cell proliferation associated with enhanced apoptosis in responding patients. CONCLUSION: Long-term treatment with STI571 exerts pronounced changes on BM histopathology that not only involve haematopoiesis and stromal constituents, but also proliferation and apoptosis.
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Células de la Médula Ósea/patología , Leucemia Mielógena Crónica BCR-ABL Positiva/sangre , Piperazinas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/uso terapéutico , Antígenos CD34/análisis , Antineoplásicos/uso terapéutico , Benzamidas , Biopsia , Células de la Médula Ósea/química , Células de la Médula Ósea/efectos de los fármacos , Femenino , Humanos , Mesilato de Imatinib , Inmunohistoquímica , Integrina beta3/análisis , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Masculino , Persona de Mediana Edad , Antígeno Nuclear de Célula en Proliferación/análisis , Inhibidores de Proteínas Quinasas/uso terapéutico , Factores de TiempoRESUMEN
Preliminary data are available about bone marrow (BM) changes in patients with chronic myeloid leukemia (CML) who received the molecularly targeted and highly effective tyrosine kinase inhibitor Imatinib mesylate (STI571). This review is focused on a systematic assessment of BM features detectable at different stages of CML (stable, accelerated, blastic) following long-term (more than 10 months) treatment. By applying enzyme- and immunohistochemistry including monoclonal antibodies visualizing proliferating cell nuclear antigen (PCNA) and apoptosis (anti-apostatin), a more elaborate insight into alterations affecting hematopoiesis and the stroma compartment was gained. In patients with stable-phase CML therapy resulted in a significant reduction in cellularity, neutrophil granulopoiesis and number of megakaryocytes, accompanied by a retrieval of erythroid precursors. In patients with Imatinib as the only treatment morphometric analysis of CD61+ megakaryopoiesis was in keeping with a significant decrease in maturation defects implying a lesser amount of atypical micromegakaryocytes almost consistent with normalization. Moreover, a reduction of the initially enhanced (CD34+) microvessel density was detectable associated with a decrease in luminal distension. Regression of marked to moderate myelofibrosis was recognizable in about 70% of patients especially in the accelerated and blastic phases. The amount of myeloblasts, CD34+ progenitor cells and lysozyme-expressing immature myelomonocytic cells declined with treatment, but recurred in about 19% of patients that developed a leukemic relapse after 21+/-6 months of therapy. Data on proliferative activity and apoptosis in general supported in vitro findings concerning the inhibitory effect of this agent on growth associated with a tendency for stimulated apoptosis, at least in responding patients.
Asunto(s)
Médula Ósea/efectos de los fármacos , Médula Ósea/patología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Apoptosis/efectos de los fármacos , Benzamidas , Médula Ósea/irrigación sanguínea , Proliferación Celular/efectos de los fármacos , Hematopoyesis/efectos de los fármacos , Humanos , Mesilato de Imatinib , Microcirculación/efectos de los fármacos , Microcirculación/patología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Células del Estroma/efectos de los fármacos , Células del Estroma/patologíaRESUMEN
BACKGROUND: To evaluate the long-term benefit from high-dose chemotherapy (HDCT) with autologous stem-cell transplantation (ASCT), as part of the initial treatment for patients with chemosensitive, high-grade B non-Hodgkin's lymphoma (hg B-NHL), stratified according to the age-adjusted International Prognostic Index (aaIPI). PATIENTS AND METHODS: Eligible patients were 33 consecutive hg B-NHL patients responding to first-line chemotherapy and fulfilling at least one of the following criteria: stage III or IV, bulky disease, elevated lactate dehydrogenase or failure to achieve complete remission (CR). Twenty-two of 33 patients (67%) had two or three risk factors with respect to the aaIPI. All patients received HDCT with ASCT after a minimum of 6 weeks of VACOP-B standard therapy and VIP-E for mobilization. RESULTS: After ASCT, 31 patients (94%) achieved CR. No treatment-related death occurred. The cumulative incidence of relapse at a medium follow-up of 10 years is 16% for 31 of 33 patients achieving CR. Twenty-five of 33 patients are in sustained CR with a disease-free survival of 76% [95% confidence interval (CI) 67% to 86%]. The overall survival at a median follow-up of 122 months (range 86-148) is 79% (95% CI 68% to 89%). CONCLUSIONS: The results suggest that up-front HDCT with ASCT may improve long-term outcome in high-risk patients with chemotherapy-sensitive hg B-NHL when compared to historic populations treated solely with dose-intense chemotherapy. We observed that long-term survival of high-risk (two to three risk factors) patients is comparable to low-risk (zero to one risk factor) patients after HDCT and ASCT with a low incidence of late relapse.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bleomicina/uso terapéutico , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Etopósido/uso terapéutico , Linfoma de Células B/terapia , Linfoma no Hodgkin/terapia , Prednisona/uso terapéutico , Trasplante de Células Madre , Vincristina/uso terapéutico , Adulto , Factores de Edad , Bleomicina/administración & dosificación , Ciclofosfamida/administración & dosificación , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Doxorrubicina/administración & dosificación , Etopósido/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Linfoma de Células B/tratamiento farmacológico , Linfoma no Hodgkin/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Prednisona/administración & dosificación , Pronóstico , Recurrencia , Factores de Riesgo , Factores de Tiempo , Trasplante Autólogo , Resultado del Tratamiento , Vincristina/administración & dosificaciónRESUMEN
Mast cell leukemia (MCL) is a rare form of aggressive mastocytosis with a reported median survival below 6 months. Casuistic reports suggest the effectiveness of allogeneic bone marrow transplantation (BMT) for MCL. However, these reports lack clear evidence for a graft-versus-mast-cell (GvMC) effect. We prospectively investigated the GvMC at different time points after allogeneic BMT and donor-lymphocyte infusions (DLI). Samples were gathered from a patient with MCL treated with allogeneic BMT from an unrelated HLA identical donor. Parameters for detection of a GvMC effect included flow cytometrical analysis of mast cell (MC) populations in peripheral blood and BM, BM smear and histology, chimerism analysis of flow cytometrically sorted BM CD117+/CD34- MC and testing for anti-mast cell reactivity of donor lymphocytes by interferon (IFN)-gamma ELISPOT. DLIs reduced MC from 5 to 0.5%. MC chimerism analysis demonstrated a complete recipient genotype after BMT, suggesting that the persistent mastocytosis was part of residual neoplastic disease. At 3.7 years after BMT, there is some evidence for relapse. In summary, BMT and DLIs attenuated the mastocytosis from an aggressive to an indolent form and may have improved the patients' prognosis. The in vitro data of our study indicate for the first time the existence of a GvMC effect.
Asunto(s)
Trasplante de Médula Ósea/fisiología , Reacción Injerto-Huésped/fisiología , Leucemia de Mastocitos/terapia , Transfusión de Linfocitos , Adulto , Médula Ósea/patología , Humanos , Leucemia de Mastocitos/patología , Masculino , Mastocitos/patología , Resultado del TratamientoRESUMEN
In chronic myeloid leukemia following therapy with Imatinib (STI571) hematologic and cytogenetic response is associated with conspicuous changes of bone marrow morphology. However, it is not known to which extent these alterations are accompanied by a loss of the bcr/abl translocation. To study regression of the leukemic cell population we recruited 14 patients lacking pretreatment. Therapy resulted in a reduction of CD61(+) megakaryopoiesis. Dwarf megakaryocytes characteristic for this disorder were replaced by large, normally appearing cells of this lineage. Morphometric analysis confirmed the significant decrease in the number of micromegakaryocytes and yielded planimetric parameters in keeping with normalization. Moreover, a fluorescence in-situ hybridization study in five patients of this cohort revealed that before therapy 70% of all myeloid cells exhibited the bcr/abl gene. Regarding megakaryopoiesis about 65% of the micromegakaryocytes displayed positive signals. Following treatment these bcr/abl(+) cell populations decreased significantly while the emerging large megakaryocytes lacked a proper labeling. Because cytogenetic response and reduction of atypical micromegakaryocytes are linked, this feature may be useful to monitor therapeutic efficacy.
Asunto(s)
Genes abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Biopsia , Médula Ósea/patología , Humanos , Hibridación in Situ , Hibridación Fluorescente in SituRESUMEN
Telomerase activity and telomere maintenance have been associated with immortality in tumor and embryonic stem cells. Whereas most normal somatic cells are telomerase negative, low levels of this enzyme have been found in adult stem cells from the skin, gut and the hematopoietic system. Here, we show that telomerase activity is not detectable in human mesenchymal stem cells (hMSCs), which have the phenotype SH2+, SH3+, SH4+, CD29+, CD44+, CD14-, CD34- and CD45-, and have the capacity to differentiate into adipocytes, chondrocytes and osteoblasts. These data suggest that hMSCs have a different telomere biology compared to other adult stem cells. Alternatively, true mesenchymal stem cells might be a very rare subpopulation that have a detection level that is below the sensitivity of the TRAP assay.
Asunto(s)
Mesodermo/citología , Células Madre/enzimología , Telomerasa/metabolismo , Antígenos CD/metabolismo , Células de la Médula Ósea/enzimología , Diferenciación Celular , Humanos , InmunofenotipificaciónRESUMEN
Assessment of mixed chimerism is of particular interest for allogeneic bone marrow or peripheral blood stem cell transplantation with reduced-intensity conditioning in order to study contribution of donor-type and host-type lymphohematopoiesis. Because the length of telomere repeat sequences is frequently shorter in leukemic compared to normal hematopoietic cells, this telomere repeat polymorphism might be a useful marker to analyze mixed chimerism in selected patients with short telomeres. Recently, fluorescence in situ hybridization and flow cytometry (flow-FISH) have been shown to be valuable tools to analyze the mean telomere length in hematopoietic cells. Here, we demonstrate in a case study on a patient with chronic lymphocytic leukemia (CLL) that telomere flow-FISH can in principle be exploited to quantitate the amount of donor- and host-type cells for chimerism analysis based on distinct histogram distributions which reflect cell populations with different telomere length.