RESUMEN
PURPOSE: To evaluate efficacy and safety of vaccination with StroVac compared to placebo in patients with recurrent urinary tract infections (rUTI). MATERIAL AND METHODS: We performed a prospective, double-blinded, placebo-controlled study in patients with uncomplicated rUTI. Patients received three single intramuscular injections with StroVac every two weeks. Primary endpoint was the number of bacterial urinary tract infections (UTI) over 13.5 months after randomization and adjusted by the respective "baseline" value when comparing verum and placebo group. Secondary endpoints were the number of patients with non-recurrence, time to first recurrence, frequency of recurrences, and patients' self-assessment of quality of life using a validated questionnaire. RESULTS: 376 patients were randomized to both groups between January 2012 and March 2015. Mean age was 44.4 years. Patients were mainly female (98.4%). In the StroVac group (n = 188), the number of UTIs was reduced from 5.5 to 1.2, in the placebo group (n = 188) from 5.4 to 1.3 (p = 0.63). In patients with ≥ 7 UTIs prior to study inclusion, StroVac was statistically significantly superior to placebo (p = 0.048). However, in all other secondary endpoints, no statistical differences between the two groups could be seen (all p > 0.3). CONCLUSION: StroVac reduced the number of clinically relevant UTIs like in former studies but did not show statistically significant better results than the chosen placebo. Most likely, that was due to a, since confirmed, prophylactic effect of the chosen placebo itself. Therefore, placebo-controlled and double-blinded studies using a different ineffective placebo preparation are needed to determine the importance of StroVac in prophylaxis of rUTI.
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Infecciones Bacterianas , Infecciones Urinarias , Humanos , Femenino , Adulto , Masculino , Estudios Prospectivos , Calidad de Vida , Infecciones Urinarias/tratamiento farmacológico , Método Doble Ciego , BacteriasRESUMEN
T lymphocyte non-Hodgkin's lymphoma (T-NHL) represents an aggressive and largely therapy-resistant subtype of lymphoid malignancies. As deregulated apoptosis is a frequent hallmark of lymphomagenesis, we analyzed gene expression profiles and protein levels of primary human T-NHL samples for various apoptotic regulators. We identified the apoptotic regulator MCL-1 as the only pro-survival BCL-2 family member to be highly expressed throughout all human T-NHL subtypes. Functional validation of pro-survival protein members of the BCL-2 family in two independent T-NHL mouse models identified that the partial loss of Mcl-1 significantly delayed T-NHL development in vivo. Moreover, the inducible reduction of MCL-1 protein levels in lymphoma-burdened mice severely impaired the continued survival of T-NHL cells, increased their susceptibility to chemotherapeutics and delayed lymphoma progression. Lymphoma viability remained unaffected by the genetic deletion or pharmacological inhibition of all alternative BCL-2 family members. Consistent with a therapeutic window for MCL-1 treatment within the context of the whole organism, we observed an only minimal toxicity after systemic heterozygous loss of Mcl-1 in vivo. We conclude that re-activation of mitochondrial apoptosis by blockade of MCL-1 represents a promising therapeutic strategy to treat T-cell lymphoma.
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Proteínas Reguladoras de la Apoptosis/genética , Apoptosis , Linfoma de Células T/química , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/análisis , Animales , Proteínas Reguladoras de la Apoptosis/análisis , Supervivencia Celular , Resistencia a Antineoplásicos , Perfilación de la Expresión Génica , Humanos , Linfoma de Células T/patología , Ratones , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidores , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/fisiología , Proteínas Proto-Oncogénicas c-bcl-2/genéticaRESUMEN
Deregulated apoptosis is an identifying feature of myelodysplastic syndromes (MDS). Whereas apoptosis is increased in the bone marrow (BM) of low-risk MDS patients, progression to high-risk MDS correlates with an acquired resistance to apoptosis and an aberrant expression of BCL-2 proteins. To overcome the acquired apoptotic resistance in high-risk MDS, we investigated the induction of apoptosis by inhibition of pro-survival BCL-2 proteins using the BCL-2/-XL/-W inhibitor ABT-737 or the BCL-2-selective inhibitor ABT-199. We characterized a cohort of 124 primary human BM samples from MDS/secondary acute myeloid leukemia (sAML) patients and 57 healthy, age-matched controls. Inhibition of anti-apoptotic BCL-2 proteins was specifically toxic for BM cells from high-risk MDS and sAML patients, whereas low-risk MDS or healthy controls remained unaffected. Notably, ABT-737 or ABT-199 treatment was capable of targeting the MDS stem/progenitor compartment in high-risk MDS/sAML samples as shown by the reduction in CD34(+) cells and the decreased colony-forming capacity. Elevated expression of MCL-1 conveyed resistance against both compounds. Protection by stromal cells only partially inhibited induction of apoptosis. Collectively, our data show that the apoptotic resistance observed in high-risk MDS/sAML cells can be overcome by the ABT-737 or ABT-199 treatment and implies that BH3 mimetics might delay disease progression in higher-risk MDS or sAML patients.
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Apoptosis/efectos de los fármacos , Compuestos de Bifenilo/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Síndromes Mielodisplásicos/tratamiento farmacológico , Nitrofenoles/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Células Madre/efectos de los fármacos , Sulfonamidas/farmacología , Células Cultivadas , Humanos , Síndromes Mielodisplásicos/patología , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/análisis , Piperazinas/farmacologíaRESUMEN
Despite major improvements in allogeneic hematopoietic cell transplantation over the past decades, corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) cause high mortality. Preclinical evidence indicates the potent anti-inflammatory properties of the JAK1/2 inhibitor ruxolitinib. In this retrospective survey, 19 stem cell transplant centers in Europe and the United States reported outcome data from 95 patients who had received ruxolitinib as salvage therapy for SR-GVHD. Patients were classified as having SR-aGVHD (n=54, all grades III or IV) or SR-cGVHD (n=41, all moderate or severe). The median number of previous GVHD-therapies was 3 for both SR-aGVHD (1-7) and SR-cGVHD (1-10). The overall response rate was 81.5% (44/54) in SR-aGVHD including 25 complete responses (46.3%), while for SR-cGVHD the ORR was 85.4% (35/41). Of those patients responding to ruxolitinib, the rate of GVHD-relapse was 6.8% (3/44) and 5.7% (2/35) for SR-aGVHD and SR-cGVHD, respectively. The 6-month-survival was 79% (67.3-90.7%, 95% confidence interval (CI)) and 97.4% (92.3-100%, 95% CI) for SR-aGVHD and SR-cGVHD, respectively. Cytopenia and cytomegalovirus-reactivation were observed during ruxolitinib treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. Ruxolitinib may constitute a promising new treatment option for SR-aGVHD and SR-cGVHD that should be validated in a prospective trial.
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Corticoesteroides/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Neoplasias Hematológicas/complicaciones , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Pirazoles/uso terapéutico , Terapia Recuperativa , Adulto , Anciano , Animales , Modelos Animales de Enfermedad , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/mortalidad , Neoplasias Hematológicas/terapia , Humanos , Quinasas Janus/antagonistas & inhibidores , Masculino , Ratones , Persona de Mediana Edad , Estadificación de Neoplasias , Nitrilos , Pronóstico , Pirimidinas , Recurrencia , Estudios Retrospectivos , Tasa de Supervivencia , Trasplante Homólogo , Adulto JovenRESUMEN
Cyclin-dependent kinase subunit 1 (Cks1) is a critical rate-limiting component of the Skp1-Cullin1-Skp2 (SCF(Skp2)) ubiquitin ligase that controls cell cycle inhibitor abundance. Cyclin-dependent kinase (Cdk) inhibitors (CKIs) regulate hematopoietic stem cell (HSC) self-renewal, regeneration after cytotoxic stress and tumor cell proliferation. We thus studied the role of Cks1 in HSC and in a prototypic stem cell disorder, chronic myeloid leukemia (CML). Cks1 transcript was highly expressed in Lin-Sca-1+Kit+ (LSK) HSC, and the loss resulted in accumulation of the SCF(Skp2)/Cks1 substrates p21, p27, p57 and p130 particularly in CD150+ LSK cells. This accumulation correlated with decreased proliferation and accumulation of Cks1(-/-) HSC, slower regeneration after stress and prolonged HSC quiescence. At the hematopoietic progenitor (HPC) level, loss of Cks1 sensitized towards apoptosis. In CML, Cks1 expression was increased, and treatment with the Abl kinase inhibitor, imatinib, reduced Cks1 expression. Also, we found that Cks1 is critical for Bcr-Abl-induced cytokine-independent clonogenic activity. In conclusion, our study presents a novel function of Cks1 in maintaining HSC/HPC homeostasis and shows that Cks1 is a possible target in therapies aimed at the SCF(Skp2)/Cks1 complex that controls CKI abundance and cancer cell proliferation.
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Quinasas CDC2-CDC28/metabolismo , Ciclo Celular/fisiología , Proliferación Celular/fisiología , Células Madre Hematopoyéticas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Animales , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Citocinas/metabolismo , Células Madre Hematopoyéticas/efectos de los fármacos , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Ratones , Ratones Endogámicos C57BL , Regeneración/efectos de los fármacos , Proteínas Quinasas Asociadas a Fase-S/metabolismoRESUMEN
Lung cancer is the leading cause of cancer-related deaths worldwide. Recently, we have shown that Notch1 inhibition resulted in substantial cell death of non-small cell lung cancer (NSCLC) cells in vitro. New compounds targeting Notch signal transduction have been developed and are now being tested in clinical trials. However, the tumorigenic role of individual Notch receptors in vivo remains largely unclear. Using a Kras(G12D)-driven endogenous NSCLC mouse model, we analyzed the effect of conditional Notch1 and Notch2 receptor deletion on NSCLC tumorigenesis. Notch1 deficiency led to a reduced early tumor formation and lower activity of MAPK compared with the controls. Unexpectedly, Notch2 deletion resulted in a dramatically increased carcinogenesis and increased MAPK activity. These mice died significantly earlier due to rapidly growing tumor burden. We found that Notch1 regulates Ras/MAPK pathway via HES1-induced repression of the DUSP1 promoter encoding a phosphatase specifically suppressing pERK1/2. Interestingly, Notch1 but not Notch2 ablation leads to decreased HES1 and DUSP1 expression. However, Notch2-depleted tumors showed an appreciable increase in ß-catenin expression, a known activator of HES1 and important lung cancer oncogene. Characteristically for ß-catenin upregulation, we found that the majority of Notch2-deficient tumors revealed an undifferentiated phenotype as determined by their morphology, E-Cadherin and TTF1 expression levels. In addition, these carcinomas showed aggressive growth patterns with bronchus invasion and obstruction. Together, we show that Notch2 mediates differentiation and has tumor suppressor functions during lung carcinogenesis, whereas Notch1 promotes tumor initiation and progression. These data are further supported by immunohistochemical analysis of human NSCLC samples showing loss or downregulation of Notch2 compared with normal lung tissue. In conclusion, this is the first study characterizing the in vivo functions of Notch1 and Notch2 in Kras(G12D)-driven NSCLC tumorigenesis. These data highlight the clinical importance of a thorough understanding of Notch signaling especially with regard to Notch-targeted therapies.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Transformación Celular Neoplásica/genética , Receptor Notch1/biosíntesis , Receptor Notch2/biosíntesis , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/biosíntesis , Carcinoma de Pulmón de Células no Pequeñas/patología , Proliferación Celular/genética , Modelos Animales de Enfermedad , Fosfatasa 1 de Especificidad Dual/biosíntesis , Regulación Neoplásica de la Expresión Génica , Proteínas de Homeodominio/biosíntesis , Humanos , Ratones , Proteínas Proto-Oncogénicas p21(ras)/genética , Receptor Notch1/genética , Receptor Notch2/genética , Transducción de Señal/genética , Factor de Transcripción HES-1 , beta Catenina/biosíntesisRESUMEN
The SH2-containing adaptor protein Grb10 was first identified in a yeast screen as a new binding partner for BCR-ABL and associates with BCR-ABL in a tyrosine-dependent manner. However, its function in BCR-ABL-mediated leukemogenesis in vivo is still unknown. Here we describe an important role of Grb10 in BCR-ABL-induced leukemia by using a versatile system for efficient oncogene expression and simultaneous Grb10 knockdown from a single vector. Primary bone marrow (BM) cells coexpressing Grb10-miR/BCR-ABL showed a significant decrease in colony formation and cell cycle progression. Transplantation of Grb10miR/BCR-ABL- or control-miR/BCR-ABL- transduced BM leads to a CML/B-ALL-like phenotype with significantly delayed disease onset and progression resulting in prolonged overall survival in Grb10-miR-transplanted mice. Methylcellulose experiments exhibit additive effects of imatinib treatment and Grb10 knockdown. Cell cycle analysis suggests an anti-proliferative effect of Grb10 knockdown in BCR-ABL(+) primary BM cells. However, Grb10 abrogation was not capable of completely abolishing the BCR-ABL-induced disease. Our findings were confirmed in the human BCR-ABL(+) cell line K562, where we demonstrate reduced viability, cell cycle progression and induction of apoptosis by stable Grb10 microRNA expression. Taken together, our results suggest that Grb10 knockdown in vivo leads to impaired proliferation, longer survival and reduced colony formation, suggesting an important role of Grb10 in BCR-ABL-mediated leukemogenesis.
Asunto(s)
Células de la Médula Ósea/patología , Proteínas de Fusión bcr-abl/genética , Proteína Adaptadora GRB10/genética , Regulación Leucémica de la Expresión Génica , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Benzamidas/farmacología , Células de la Médula Ósea/metabolismo , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Proteínas de Fusión bcr-abl/metabolismo , Proteína Adaptadora GRB10/antagonistas & inhibidores , Proteína Adaptadora GRB10/metabolismo , Humanos , Mesilato de Imatinib , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Ratones , Ratones Endogámicos BALB C , MicroARNs/genética , MicroARNs/metabolismo , Piperazinas/farmacología , Cultivo Primario de Células , Pirimidinas/farmacología , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de SeñalRESUMEN
T cells have been proven to be therapeutically effective in patients with relapsed leukemias, although target antigens on leukemic cells as well as T-cell receptors (TCRs), potentially recognizing those antigens, are mostly unknown. We have applied an immunopeptidomic approach and isolated human leukocyte antigen (HLA) ligands from primary leukemia cells. We identified a number of ligands derived from different genes that are restrictedly expressed in the hematopoietic system. We exemplarily selected myeloperoxidase (MPO) as a potential target and isolated a high-avidity TCR with specificity for a HLA-B*07:02-(HLA-B7)-restricted epitope of MPO in the single HLA-mismatched setting. T cells transgenic for this TCR demonstrated high peptide and antigen specificity as well as leukemia reactivity in vitro and in vivo. In contrast, no significant on- and off-target toxicity could be observed. In conclusion, we here demonstrate, exemplarily for MPO, that leukemia-derived HLA ligands can be selected for specific effector tool development to redirect T cells to be used for graft manipulation or adoptive T-cell therapies in diverse transplant settings. This approach can be extended to other HLA ligands and HLA molecules in order to provide better treatment options for this life-threatening disease.
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Antígenos HLA/inmunología , Leucemia Mieloide/genética , Leucemia Mieloide/inmunología , Péptidos/inmunología , Peroxidasa/inmunología , Receptores de Antígenos de Linfocitos T/genética , Linfocitos T/inmunología , Linfocitos T/metabolismo , Animales , Presentación de Antígeno/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Línea Celular , Supervivencia Celular/genética , Supervivencia Celular/inmunología , Modelos Animales de Enfermedad , Mapeo Epitopo , Epítopos de Linfocito T/química , Epítopos de Linfocito T/inmunología , Antígenos HLA/metabolismo , Antígeno HLA-B7/inmunología , Antígeno HLA-B7/metabolismo , Xenoinjertos , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Leucemia Mieloide/metabolismo , Leucemia Mieloide/mortalidad , Ligandos , Ratones , Péptidos/metabolismo , Peroxidasa/química , Peroxidasa/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Especificidad del Receptor de Antígeno de Linfocitos T/inmunología , Transducción GenéticaAsunto(s)
Antineoplásicos/uso terapéutico , Benzotiazoles/uso terapéutico , Indoles/uso terapéutico , Leucemia Mieloide Aguda/genética , Mutación , Compuestos de Fenilurea/uso terapéutico , Pirroles/uso terapéutico , Estaurosporina/análogos & derivados , Tirosina Quinasa 3 Similar a fms/genética , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Persona de Mediana Edad , Estaurosporina/uso terapéutico , Sunitinib , Tirosina Quinasa 3 Similar a fms/fisiologíaRESUMEN
PURPOSE: To evaluate frequency and severity of adverse drug reactions (ADRs) and its economic consequences after standard dose (immuno-)chemotherapy (CT) of non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Subanalysis of a prospective, multicentre, longitudinal, observational cohort study; data were collected from patient interviews and pre-planned chart reviews. Costs were aggregated per CT line and presented from provider perspective. RESULTS: A total of 120 consecutive NSCLC patients (mean age, 63.0 ± 8.4 (SD) years; men, 64.2%; ECOG (Eastern Cooperative Oncology Group) performance status <2, 84.3%; tumour stage III/IV, 85%; history of comorbidity, 93.3%) receiving 130 CT lines were evaluated. 80% of CT lines were associated with grade 3 or 4 ADRs, 22.3% developed potential life-threatening complications, 77.7% were associated with at least one hospital stay (inpatient, 63.9%; outpatient/day clinic 39.2%, ICU 6.9%), with a mean cumulative number of 12.8 (±14.0 SD) hospital days. Mean (median) toxicity management costs per CT line (TMC-TL) amounted to 3,366 (1,406) and were found to be higher for first-line compared to second-line treatment: 3,677 (1,599) vs. 2,475 (518). TMC-TL were particularly high in CT lines with ICU care 12,207 (9,960). Eight out of 11 ICU stays were associated with grade 3 or 4 infections. Nine CT lines with ICU care accounted for 25% of total expenses (109,861 out of 437,580). CONCLUSIONS: In first-line NSCLC treatment, in particular, CT toxicity management is expensive. Asymmetric cost distribution seems to be triggered by infection associated ICU care. Its avoidance should reduce patients' clinical burden and have considerable economic implications. Nevertheless, comparative observational studies have to confirm estimated savings.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/economía , Quimioterapia de Inducción/efectos adversos , Quimioterapia de Inducción/economía , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/economía , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/economía , Comorbilidad , Femenino , Alemania , Costos de Hospital , Humanos , Tiempo de Internación/economía , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
Chronic lymphocytic leukemia (CLL) has a high prevalence in western countries and remains incurable to date. Here, we provide evidence that the multikinase inhibitor sorafenib induces apoptosis in primary CLL cells. This strong pro-apoptotic effect is not restricted to any subgroup of patients, based on Binet stage and the expression of ZAP70 or CD38. Mechanistically, sorafenib-induced cell death is preceded by a rapid downregulation of Mcl-1 through the inhibition of protein translation. Subsequently, the cell intrinsic apoptotic pathway is activated, indicated by destabilization of the mitochondrial membrane potential and activation of caspase-3 and -9. In contrast to sorafenib, the monoclonal vascular epidermal growth factor (VEGF)-antibody bevacizumab failed to induce apoptosis in CLL cells, suggesting that sorafenib induces cell death irrespectively of VEGF signalling. Notably, although sorafenib inhibits phosphorylation of the Scr-kinase Lck, knock-down of Lck did not induce apoptosis in CLL cells. Of note, the pro-apoptotic effect of sorafenib is not restricted to cell-cycle arrested cells, but is also maintained in proliferating CLL cells. In addition, we provide evidence that sorafenib can overcome drug resistance in CLL cells protected by microenvironmental signals from stromal cells. Conclusively, sorafenib is highly active in CLL and may compose a new therapeutic option for patients who relapse after immunochemotherapy.
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Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Bencenosulfonatos/farmacología , Leucemia Linfocítica Crónica de Células B/patología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Piridinas/farmacología , Citometría de Flujo , Humanos , Leucemia Linfocítica Crónica de Células B/metabolismo , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/genética , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Fosforilación/efectos de los fármacos , ARN Interferente Pequeño/genética , Receptores del Factor de Crecimiento Derivado de Plaquetas/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Sorafenib , Células del Estroma/metabolismo , Células Tumorales CultivadasRESUMEN
BACKGROUND: Multidrug chemotherapy (CT) is still associated with relevant side-effects. We assessed, under current practice patterns, frequency and severity of CT-induced toxicity and its economic consequences. PATIENTS AND METHODS: Prospective, multicentre, longitudinal, observational cohort study with lymphoproliferative disorder (LPD) and non-small-cell lung cancer (NSCLC) patients, receiving first- or second-line (immuno-) CT (excluding myeloablative CT). Data were collected from patient interviews and preplanned chart reviews. Costs in 2007 euros are presented from the provider perspective. RESULTS: Two hundred and seventy-three patients (n = 153 LPD; n = 120 NSCLC) undergoing a total of 1004 CT cycles were assessable (age ≥65 years, 40%; female, 36%; Eastern Cooperative Oncology Group performance status ≥2, 11%; tumour stage ≥III, 56%; history of comorbidity, 80%). Fifty percent of cycles were associated with grade 3/4 toxicity and 37% (n = 371) with at least one hospital stay (outpatient/day care n = 154; intensive care n = 19). Mean (median) toxicity-related costs amounted to 1032 (86) per cycle. Costs rose exponentially with the number of grade 3/4 adverse drug reactions (ADRs) and were highest in cycles affected by more than four ADRs, 10 881 (5455); in cycles with intensive care, 14 121 (8833); and in cycles affected by grade 3/4 infections and febrile neutropenia/leukopenia, 7093 (4531) and 5170 (2899), respectively. Five percent of CT cycles accounted for 56% of total expenses. CONCLUSIONS: Individualised supportive care strategies are needed. Future research should focus on identifying toxicity clusters and patient characteristics predictive for high costs.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/economía , Recursos en Salud/estadística & datos numéricos , Neoplasias Pulmonares/economía , Trastornos Linfoproliferativos/economía , Protocolos de Quimioterapia Combinada Antineoplásica/economía , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Estudios de Cohortes , Femenino , Alemania , Costos de la Atención en Salud , Recursos en Salud/economía , Humanos , Estudios Longitudinales , Neoplasias Pulmonares/tratamiento farmacológico , Trastornos Linfoproliferativos/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
Myeloproliferation with prominent eosinophilia is associated with rearrangements of PDGFR-A or -B. The most common rearrangement is FIP1L1-PDGFRA (FP). The majority of patients with PDGFR-rearranged myeloproliferation respond to treatment with imatinib. In contrast to BCR-ABL-positive chronic myelogenous leukemia, only few cases of imatinib resistance and mutations of the FP kinase domain have been described so far. We hypothesized that the number of critical residues mediating imatinib resistance in FP in contrast to BCR-ABL might be limited. We performed an established systematic and comprehensive in vitro resistance screen to determine the pattern and frequency of possible TKI resistance mutations in FP. We identified 27 different FP kinase domain mutations including 25 novel variants, which attenuated response to imatinib, nilotinib or sorafenib. However, the majority of these exchanges did not confer complete inhibitor resistance. At clinically achievable drug concentrations, FP/T674I predominated with imatinib, whereas with nilotinib and sorafenib, FP/D842V and the compound mutation T674I+T874I became prevalent. Our results suggest that the PDGFR kinase domain contains a limited number of residues where exchanges critically interfere with binding of and inhibition by available PDGFR kinase inhibitors at achievable concentrations, which might explain the low frequency of imatinib resistance in this patient population. In addition, these findings would help to select the appropriate second-line drug in cases of imatinib-resistant disease and may be translated to other neoplasms driven by activated forms of PDGFR-A or -B.
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Antineoplásicos/farmacología , Resistencia a Antineoplásicos/genética , Trastornos Mieloproliferativos/genética , Inhibidores de Proteínas Quinasas/farmacología , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/química , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Secuencia de Aminoácidos , Benzamidas , Bencenosulfonatos/farmacología , Western Blotting , Línea Celular Tumoral , Humanos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Mutación , Trastornos Mieloproliferativos/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Piperazinas/farmacología , Estructura Terciaria de Proteína , Piridinas/farmacología , Pirimidinas/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sorafenib , Relación Estructura-ActividadRESUMEN
The FMS-like tyrosine kinase 3 (FLT3) is highly expressed in acute myeloid leukemia (AML). Internal tandem duplications (ITD) of the juxtamembrane domain lead to the constitutive activation of the FLT3 kinase inducing the activation of multiple genes, which may result in the expression of leukemia-associated antigens (LAAs). We analyzed the regulation of LAA in FLT3-wild-type (WT)- and FLT3-ITD(+) myeloid cells to identify potential targets for antigen-specific immunotherapy for AML patients. Antigens, such as PR-3, RHAMM, Survivin, WT-1 and PRAME, were upregulated by constitutively active FLT3-ITD as well as FLT3-WT activated by FLT3 ligand (FL). Cytotoxic T-cell (CTL) clones against PR-3, RHAMM, Survivin and an AML-directed CTL clone recognized AML cell lines and primary AML blasts expressing FLT3-ITD, as well as FLT3-WT(+) myeloid dendritic cells in the presence of FL. Downregulation of FLT3 led to the abolishment of CTL recognition. Comparing our findings concerning LAA upregulation by the FLT3 kinase with those already made for the Bcr-Abl kinase, we found analogies in the LAA expression pattern. Antigens upregulated by both FLT3 and Bcr-Abl may be promising targets for the development of immunotherapeutical approaches against myeloid leukemia of different origin.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencenosulfonatos/uso terapéutico , Indoles/uso terapéutico , Leucemia Mielomonocítica Crónica/genética , Mutación , Piridinas/uso terapéutico , Pirroles/uso terapéutico , Tirosina Quinasa 3 Similar a fms/genética , Anciano , Femenino , Humanos , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Sorafenib , SunitinibRESUMEN
BACKGROUND: Cetuximab enhances the efficacy of chemotherapy in several cancer types. This trial assessed the activity of cetuximab and chemotherapy in advanced gastric cancer. METHODS: Patients with previously untreated, metastatic, gastric cancer received cetuximab 400 mg m(-2) at first infusion followed by weekly infusions of 250 mg m(-2) combined with FUFOX (oxaliplatin 50 mg m(-2), 5-FU 2000 mg m(-2), and DL-folinic acid 200 mg m(-2) d1, 8, 15 and 22 qd36). The primary endpoint was tumour response. RESULTS: Overall, 52 patients were enrolled. The most common grade 3/4 toxicities were diarrhoea (33%), and skin toxicity (24%). Efficacy was evaluable in 46 patients who showed a response rate of 65% (CI 95%: 50-79%) including four complete responses. Time to progression (TTP) was 7.6 months (CI 95%: 5.0-10.1 months) and overall survival (OS) was 9.5 months (CI 95%: 7.9-11.1 months). Epidermal growth factor receptor (EGFR) was detectable in 60% of tumours but showed no correlation with treatment outcome. A KRAS mutation was found in only 1 of 32 (3%) tumour samples analysed. CONCLUSION: Cetuximab plus FUFOX showed an interesting high response rate in metastatic gastric cancer. Cetuximab plus platinum-fluoropyrimidine chemotherapy is at present being investigated in a phase III randomised controlled trial.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Cetuximab , Progresión de la Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Masculino , Persona de Mediana Edad , Mutación , Metástasis de la Neoplasia , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Oxaliplatino , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas p21(ras) , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidad , Proteínas ras/genéticaRESUMEN
ZAP-70 is a key signaling molecule in T cells. It couples the antigen-activated T-cell receptor to downstream signaling pathways. Its expression in leukemic B-cells derived from a subgroup of patients with chronic lymphocytic leukemia (CLL) is associated with an aggressive course of the disease. However, its implication for the pathogenesis of aggressive CLL is still unclear. In this study, we show that the expression of ZAP-70 enhances the signals associated with the B-cell receptor, recruiting protein kinase C-betaII (PKC-betaII) into lipid raft domains. Subsequently, PKC-betaII is activated and shuttles from the plasma membrane to the mitochondria. We unravel that the antiapoptotic protein Bcl-2 and its antagonistic BH3-protein Bim(EL) are putative substrates for PKC-betaII. PKC-betaII-mediated phosphorylation of Bcl-2 augments its antiapoptotic function by increasing its ability to sequester more pro-apoptotic Bim(EL.) In addition, the phosphorylation of Bim(EL) by PKC-betaII leads to its proteasomal degradation. These changes confer leukemic cells to a more antiapoptotic state with aggressiveness of the disease. Most importantly, these molecular changes can be therapeutically targeted with the small molecule inhibitor Enzastaurin. We provide evidence that this compound is highly active in leukemic cells and augments the cytotoxic effects of standard chemotherapeutic drugs.