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BACKGROUND: We compared the efficacy of the antiviral agent, remdesivir, versus standard-of-care treatment in adults with severe coronavirus disease 2019 (COVID-19) using data from a phase 3 remdesivir trial and a retrospective cohort of patients with severe COVID-19 treated with standard of care. METHODS: GS-US-540-5773 is an ongoing phase 3, randomized, open-label trial comparing two courses of remdesivir (remdesivir-cohort). GS-US-540-5807 is an ongoing real-world, retrospective cohort study of clinical outcomes in patients receiving standard-of-care treatment (non-remdesivir-cohort). Inclusion criteria were similar between studies: patients had confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, were hospitalized, had oxygen saturation ≤94% on room air or required supplemental oxygen, and had pulmonary infiltrates. Stabilized inverse probability of treatment weighted multivariable logistic regression was used to estimate the treatment effect of remdesivir versus standard of care. The primary endpoint was the proportion of patients with recovery on day 14, dichotomized from a 7-point clinical status ordinal scale. A key secondary endpoint was mortality. RESULTS: After the inverse probability of treatment weighting procedure, 312 and 818 patients were counted in the remdesivir- and non-remdesivir-cohorts, respectively. At day 14, 74.4% of patients in the remdesivir-cohort had recovered versus 59.0% in the non-remdesivir-cohort (adjusted odds ratio [aOR] 2.03: 95% confidence interval [CI]: 1.34-3.08, P < .001). At day 14, 7.6% of patients in the remdesivir-cohort had died versus 12.5% in the non-remdesivir-cohort (aOR 0.38, 95% CI: .22-.68, P = .001). CONCLUSIONS: In this comparative analysis, by day 14, remdesivir was associated with significantly greater recovery and 62% reduced odds of death versus standard-of-care treatment in patients with severe COVID-19. CLINICAL TRIALS REGISTRATION: NCT04292899 and EUPAS34303.
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Tratamiento Farmacológico de COVID-19 , Adenosina Monofosfato/análogos & derivados , Adulto , Alanina/análogos & derivados , Antivirales/uso terapéutico , Estudios de Cohortes , Humanos , Saturación de Oxígeno , Estudios Retrospectivos , SARS-CoV-2 , Nivel de Atención , Resultado del TratamientoRESUMEN
Mixed Effects Models for Repeated Measures (MMRM) is often used in clinical trials with longitudinal data. However, there has not been an in-depth examination available on how investigators can implement interim analysis while also controlling the overall alpha for clinical trials under an MMRM analysis framework. Statistical independence among measurements, which is often assumed in group sequential testing (GST), is not valid under an MMRM framework due to the correlations induced by longitudinal within-subject measurements. Therefore, methods associated with GST derived under independence need to be adjusted accordingly. While these correlations can be estimated from the study data, regulatory agencies may not accept results based on these estimated correlations since there is no guarantee that the overall alpha is strongly controlled. In this article, we propose a new AC-Hybrid-approach for controlling the overall alpha. The AC-Hybrid-approach has two key attributes. First, we apply the MMRM analysis framework on all available data at every analysis timepoint. Second, we use complete-case information fractions to derive the group sequential stopping boundaries. We prove that the overall alpha is controlled regardless of the correlations among within-subject measurements. We also show the impact of this approach on the alpha and the power through examples.
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Bioestadística/métodos , Ensayos Clínicos Fase II como Asunto/estadística & datos numéricos , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Proyectos de Investigación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Ensayos Clínicos Fase II como Asunto/métodos , Interpretación Estadística de Datos , Venas Hepáticas/efectos de los fármacos , Venas Hepáticas/fisiopatología , Humanos , Modelos Estadísticos , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Presión Portal/efectos de los fármacos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Análisis de Regresión , Proyectos de Investigación/estadística & datos numéricos , Factores de Tiempo , Resultado del TratamientoRESUMEN
Expression of the tumor suppressor gene TUSC2 is reduced or absent in most lung cancers and is associated with worse overall survival. In this study, we restored TUSC2 gene expression in several wild type EGFR non-small cell lung cancer (NSCLC) cell lines resistant to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib and analyzed their sensitivity to erlotinib in vitro and in vivo. A significant inhibition of cell growth and colony formation was observed with TUSC2 transient and stable expression. TUSC2-erlotinib cooperativity in vitro could be reproduced in vivo in subcutaneous tumor growth and lung metastasis formation lung cancer xenograft mouse models. Combination treatment with intravenous TUSC2 nanovesicles and erlotinib synergistically inhibited tumor growth and metastasis, and increased apoptotic activity. High-throughput qRT-PCR array analysis enabling multi-parallel expression profile analysis of eighty six receptor and non-receptor tyrosine kinase genes revealed a significant decrease of FGFR2 expression level, suggesting a potential role of FGFR2 in TUSC2-enhanced sensitivity to erlotinib. Western blots showed inhibition of FGFR2 by TUSC2 transient transfection, and marked increase of PARP, an apoptotic marker, cleavage level after TUSC2-erlotinb combined treatment. Suppression of FGFR2 by AZD4547 or gene knockdown enhanced sensitivity to erlotinib in some but not all tested cell lines. TUSC2 inhibits mTOR activation and the latter cell lines were responsive to the mTOR inhibitor rapamycin combined with erlotinib. These results suggest that TUSC2 restoration in wild type EGFR NSCLC may overcome erlotinib resistance, and identify FGFR2 and mTOR as critical regulators of this activity in varying cellular contexts. The therapeutic activity of TUSC2 could extend the use of erlotinib to lung cancer patients with wildtype EGFR.
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Receptores ErbB/metabolismo , Clorhidrato de Erlotinib/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Transducción de Señal/efectos de los fármacos , Proteínas Supresoras de Tumor/metabolismo , Animales , Apoptosis/efectos de los fármacos , Benzamidas/farmacología , Benzamidas/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Clorhidrato de Erlotinib/farmacología , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Pulmonares/patología , Ratones , Metástasis de la Neoplasia , Piperazinas/farmacología , Piperazinas/uso terapéutico , Pirazoles/farmacología , Pirazoles/uso terapéutico , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/metabolismo , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Resultado del Tratamiento , Ensayo de Tumor de Célula MadreRESUMEN
TUSC2-defective gene expression is detected in the majority of lung cancers and is associated with worse overall survival. We analyzed the effects of TUSC2 re-expression on tumor cell sensitivity to the AKT inhibitor, MK2206, and explored their mutual signaling connections, in vitro and in vivo. TUSC2 transient expression in three LKB1-defective non-small cell lung cancer (NSCLC) cell lines combined with MK2206 treatment resulted in increased repression of cell viability and colony formation, and increased apoptotic activity. In contrast, TUSC2 did not affect the response to MK2206 treatment for two LKB1-wild type NSCLC cell lines. In vivo, TUSC2 systemic delivery, by nanoparticle gene transfer, combined with MK2206 treatment markedly inhibited growth of tumors in a human LKB1-defective H322 lung cancer xenograft mouse model. Biochemical analysis showed that TUSC2 transient expression in LKB1-defective NSCLC cells significantly stimulated AMP-activated protein kinase (AMPK) phosphorylation and enzymatic activity. More importantly, AMPK gene knockdown abrogated TUSC2-MK2206 cooperation, as evidenced by reduced sensitivity to the combined treatment. Together, TUSC2 re-expression and MK2206 treatment was more effective in inhibiting the phosphorylation and kinase activities of AKT and mTOR proteins than either single agent alone. In conclusion, these findings support the hypothesis that TUSC2 expression status is a biological variable that potentiates MK2206 sensitivity in LKB1-defective NSCLC cells, and identifies the AMPK/AKT/mTOR signaling axis as an important regulator of this activity.
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Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Resistencia a Antineoplásicos/genética , Compuestos Heterocíclicos con 3 Anillos/farmacología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Supresoras de Tumor/genética , Quinasas de la Proteína-Quinasa Activada por el AMP , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Supervivencia Celular , Modelos Animales de Enfermedad , Expresión Génica , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Ratones , Fosforilación/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/deficiencia , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismo , Carga Tumoral/efectos de los fármacos , Carga Tumoral/genética , Ensayo de Tumor de Célula Madre , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND AND PURPOSE: We propose to adaptively insert new doses during the course of a dose-finding trial when none of the prespecified doses in the trial are acceptable, for example, have tolerable toxicity. METHODS: Our procedure uses an activation rule to determine whether a new dose is needed and an inverse dose-response algorithm to estimate new doses to be inserted into the trial. RESULTS: The proposed method can be applied to both one-agent and two-agent trials. In application to a Phase I trial about advanced ovarian cancer, our method selected a new dose that is better than all prespecified doses in at least 44% simulations. The effectiveness of the procedure was also demonstrated in a simulation study. LIMITATIONS: The proposed method is applicable to dose-finding trials with binary responses. CONCLUSIONS: We believe that with the added adaptive dose insertion, traditional dose-finding trials will have better chances of locating desirable doses. In addition, by allowing for dose insertion, unnecessary trial suspension due to lack of acceptable doses can be avoided.
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Algoritmos , Ensayos Clínicos como Asunto/métodos , Relación Dosis-Respuesta a Droga , Modelos Estadísticos , Proyectos de Investigación , Ensayos Clínicos Fase I como Asunto/métodos , Simulación por Computador , Femenino , Humanos , Neoplasias Ováricas/tratamiento farmacológicoRESUMEN
PURPOSE: Ras/Raf/mitogen-activated protein-extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK signaling is critical for tumor cell proliferation and survival. Selumetinib is a potent, selective, and orally available MEK1/2 inhibitor. In this study, we evaluated the therapeutic efficacy of selumetinib alone or with cediranib, an orally available potent inhibitor of all three VEGF receptor (VEGFR) tyrosine kinases, in murine orthotopic non-small cell lung carcinoma (NSCLC) models. EXPERIMENTAL DESIGN: NCI-H441 or NCI-H460 KRAS-mutant human NSCLC cells were injected into the lungs of mice. Mice were randomly assigned to treatment with selumetinib, cediranib, paclitaxel, selumetinib plus cediranib, or control. When controls became moribund, all animals were sacrificed and assessed for lung tumor burden and locoregional metastasis. Lung tumors and adjacent normal tissues were subjected to immunohistochemical analyses. RESULTS: Selumetinib inhibited lung tumor growth and, particularly at higher dose, reduced locoregional metastasis, as did cediranib. Combining selumetinib and cediranib markedly enhanced their antitumor effects, with near complete suppression of metastasis. Immunohistochemistry of tumor tissues revealed that selumetinib alone or with cediranib reduced ERK phosphorylation, angiogenesis, and tumor cell proliferation and increased apoptosis. The antiangiogenic and apoptotic effects were substantially enhanced when the agents were combined. Selumetinib also inhibited lung tumor VEGF production and VEGFR signaling. CONCLUSIONS: In this study, we evaluated therapy directed against MEK combined with antiangiogenic therapy in distinct orthotopic NSCLC models. MEK inhibition resulted in potent antiangiogenic effects with decreased VEGF expression and signaling. Combining selumetinib with cediranib enhanced their antitumor and antiangiogenic effects. We conclude that combining selumetinib and cediranib represents a promising strategy for the treatment of NSCLC.
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Bencimidazoles/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Quinazolinas/administración & dosificación , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencimidazoles/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Progresión de la Enfermedad , Humanos , Masculino , Ratones , Ratones Desnudos , Terapia Molecular Dirigida , Neovascularización Patológica/tratamiento farmacológico , Paclitaxel/administración & dosificación , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas p21(ras) , Quinazolinas/uso terapéutico , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas ras/genéticaRESUMEN
BACKGROUND: Anemia is an expected consequence of intensive chemotherapy regimens administered to patients with acute leukemia. This study was designed to determine whether epoetin alpha would decrease the number of transfusion events and units of packed erythrocytes (PRBCs) transfused, and the secondary objective was to study the effects of epoetin alpha on quality of life (QOL) and complete remission (CR) rates. METHODS: Patients with acute lymphoblastic leukemia (ALL), lymphoblastic lymphoma (LL), or Burkitt lymphoma (BL) who were receiving frontline myelosuppressive chemotherapy were randomized to receive epoetin alpha or no epoetin during the first 6 cycles of their planned chemotherapy. QOL was assessed by using the Edmonton Symptom Assessment Scale (ESAS) and the Functional Assessment of Cancer Therapy (FACT)-Anemia questionnaires. RESULTS: Fifty-five patients were randomized to receive epoetin alpha, and 54 patients received no epoetin. Transfusion data were available for 79 of 81 evaluable patients (98%) who completed the treatment/observation period. The trial was stopped early because of poor accrual before the target of 123 evaluable patients was met. A mean of 10.6 units of PRBCs over 5 months were administered to those who received epoetin alpha compared with 13 units for those who did not receive epoetin (P = .04). There was no significant difference in QOL as assessed by the FACT-Anemia or ESAS instruments. The CR rate and the 3-year CR duration were not affected adversely by use of epoetin alpha. CONCLUSIONS: Epoetin alpha decreased the number of PRBC transfusions and did not appear to have a negative impact on remission duration. No difference in QOL was observed.
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Anemia/tratamiento farmacológico , Linfoma de Burkitt/complicaciones , Transfusión de Eritrocitos , Eritropoyetina/uso terapéutico , Hematínicos/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anemia/inducido químicamente , Anemia/mortalidad , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Transfusión Sanguínea , Linfoma de Burkitt/tratamiento farmacológico , Linfoma de Burkitt/mortalidad , Epoetina alfa , Femenino , Hemoglobinas/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Calidad de Vida , Proteínas Recombinantes/uso terapéutico , Inducción de Remisión , Encuestas y Cuestionarios , Tasa de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
We introduce a nonparametric Bayesian model for a phase II clinical trial with patients presenting different subtypes of the disease under study. The objective is to estimate the success probability of an experimental therapy for each subtype. We consider the case when small sample sizes require extensive borrowing of information across subtypes, but the subtypes are not a priori exchangeable. The lack of a priori exchangeability hinders the straightforward use of traditional hierarchical models to implement borrowing of strength across disease subtypes. We introduce instead a random partition model for the set of disease subtypes. This is a variation of the product partition model that allows us to model a nonexchangeable prior structure. Like a hierarchical model, the proposed clustering approach considers all observations, across all disease subtypes, to estimate individual success probabilities. But in contrast to standard hierarchical models, the model considers disease subtypes a priori nonexchangeable. This implies that when assessing the success probability for a particular type our model borrows more information from the outcome of the patients sharing the same prognosis than from the others. Our data arise from a phase II clinical trial of patients with sarcoma, a rare type of cancer affecting connective or supportive tissues and soft tissue (e.g., cartilage and fat). Each patient presents one subtype of the disease and subtypes are grouped by good, intermediate, and poor prognosis. The prior model should respect the varying prognosis across disease subtypes. The practical motivation for the proposed approach is that the number of accrued patients within each disease subtype is small. Thus it is not possible to carry out a clinical study of possible new therapies for rare conditions, because it would be impossible to plan for sufficiently large sample size to achieve the desired power. We carry out a simulation study to compare the proposed model with a model that assumes similar success probabilities for all subtypes with the same prognosis, i.e., a fixed partition of subtypes by prognosis. When the assumption is satisfied the two models perform comparably. But the proposed model outperforms the competing model when the assumption is incorrect.
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Biometría/métodos , Teorema de Bayes , Ensayos Clínicos Fase II como Asunto/estadística & datos numéricos , Simulación por Computador , Interpretación Estadística de Datos , Humanos , Modelos Estadísticos , Pronóstico , Tamaño de la Muestra , Sarcoma/clasificación , Estadísticas no ParamétricasRESUMEN
Our goal is to model the joint distribution of a series of 4×2×2×2 contingency tables for which some of the data are partially collapsed (i.e., aggregated in as few as two dimensions). More specifically, the joint distribution of 4 clinical characteristics in breast cancer patients is estimated. These characteristics include estrogen receptor status (positive/negative), nodal involvement (positive/negative), HER2-neu expression (positive/negative), and stage of disease (I, II, III, IV). The joint distribution of the first three characteristics is estimated conditional on stage of disease and we propose a dynamic model for the conditional probabilities that let them evolve as the stage of disease progresses. The dynamic model is based on a series of Dirichlet distributions whose parameters are related by a Markov prior structure (called dynamic Dirichlet prior). This model makes use of information across disease stage (known as "borrowing strength") and provides a way of estimating the distribution of patients with particular tumor characteristics. In addition, since some of the data sources are aggregated, a data augmentation technique is proposed to carry out a meta-analysis of the different datasets.
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OBJECT: Insular gliomas can be resected with acceptable rates of neurological morbidity, but little is known with regard to impairment of higher-order neurocognitive functions. The frequency and functional impact of neurocognitive deficits in patients with gliomas has until recently been underappreciated. The authors therefore examined neurocognitive function in patients with insular gliomas and compared the findings in this group to those in a matched control group of patients with gliomas in nearby brain regions. METHODS: Thirty-three patients with WHO Grade II or III insular gliomas participated in neuropsychological evaluations before and after resection. To establish whether the pattern of neurocognitive performance was different from that of other patients with tumors in neighboring areas, patients with insular tumors were matched with control patients for age, educational level, preoperative Karnofsky Performance Scale score, tumor side, grade, and volume. The control group comprised patients in whom gliomas had been resected from frontal, temporal, and parietal areas near the insula. Baseline pre- and postoperative neurocognitive test results were compared between and within groups. RESULTS: Preoperative neurocognitive impairment was common in both insular and control groups. Patients with insular tumors had significantly worse preoperative performance on naming tests. In both groups, postoperative decline occurred in most neurocognitive domains. There were no statistically significant differences between patients in the insular and control groups with regard to rates of postoperative decline on any test. However, there were trends suggesting differential cognitive performance postoperatively, because patients with insular tumors were more likely to experience greater decline in learning and memory. Neurological morbidity was similar to prior rates reported in the literature. CONCLUSIONS: Few statistically significant differences in cognitive function were observed between patients in the insular and control groups at either the pre- or postoperative evaluation, although there was a trend for patients with insular tumors to exhibit greater postoperative decline in learning and memory. Although technically more challenging, surgery for insular region glioma appears feasible without profound neurological or cognitive morbidity for many patients.
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Neoplasias Encefálicas/epidemiología , Neoplasias Encefálicas/cirugía , Corteza Cerebral/patología , Trastornos del Conocimiento/epidemiología , Glioma/epidemiología , Glioma/cirugía , Adulto , Neoplasias Encefálicas/patología , Femenino , Glioma/patología , Humanos , Masculino , Persona de Mediana Edad , Morbilidad , Trastornos del Movimiento/epidemiología , Periodo Posoperatorio , Periodo Preoperatorio , Pronóstico , Trastornos del Habla/epidemiología , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Activating enhancer-binding protein-2ß (AP2ß) is a transcription factor involved in apoptosis. The purpose of the current study was to assess the cellular location and level of AP2ß in non-small cell lung cancer (NSCLC) and normal lung tissue and investigate whether the level and localization of AP2ß expression is predictive of overall survival in patients with stage I NSCLC. METHODS: We performed immunohistochemical analysis of tissue microarrays (TMAs) prepared from stage I NSCLC specimens with adjacent normal lung tissue from two independent sets of patients who underwent lung resection with curative intent at our institution. The AP2ß intensity was assessed in TMAs, and AP2ß staining patterns were classified as either diffuse or nucleolar in the TMAs. The AP2ß intensity and localization were analyzed for correlation with patients' survival. RESULTS: Immunohistochemical analysis of TMAs showed that the intensity of AP2ß immunohistochemical staining did not correlate with overall survival. When location of AP2ß was analyzed in TMAs, all of the normal lung tissue had diffuse pattern of AP2ß. In the first set of NSCLC, patients with nucleolar pattern had a significantly lower 5-year survival rate than patients with diffuse pattern (67% versus 100%; p=0.004); this finding was confirmed in the second set (64% versus 91%; p=0.02). Multivariate analysis revealed that nucleolar pattern was an independent predictor of poor overall survival in both sets. CONCLUSIONS: The AP2ß, which is located in the nucleoplasm in normal lung tissue, is found in either nucleoplasm or nucleoli in NSCLC. The patients with AP2ß in the nucleoli had poor survival compared with patients with AP2ß in the cytoplasm.
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Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/metabolismo , Estadificación de Neoplasias , Factor de Transcripción AP-2/biosíntesis , Anciano , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/biosíntesis , Western Blotting , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Núcleo Celular/química , Citoplasma/química , Progresión de la Enfermedad , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Texas/epidemiología , Células Tumorales CultivadasRESUMEN
Bone marrow-derived mesenchymal stem cells (MSCs) have been shown to localize to gliomas and deliver therapeutic agents. However, the clinical translation of MSCs remains poorly defined because previous studies relied on glioma models with uncertain relevance to human disease, typically xenograft models in immunocompromised mice. To address this shortcoming, we used the RCAS/Ntv-a system, in which endogenous gliomas that recapitulate the tumor and stromal features of human gliomas develop in immunocompetent mice. MSCs were harvested from bone marrow of Ntv-a mice and injected into the carotid artery of Ntv-a mice previously inoculated with RCAS-PDGF-B and RCAS-IGFBP2 to induce malignant gliomas (n = 9). MSCs were labeled with luciferase for in vivo bioluminescence imaging (BLI). After intra-arterial injection, BLI revealed MSCs in the right frontal lobe in seven of nine mice. At necropsy, gliomas were detected within the right frontal lobe in all these mice, correlating with the location of the MSCs. In the two mice without MSCs based on BLI, no tumor was found, indicating that MSC localization was tumor specific. In another cohort of mice (n = 9), MSCs were labeled with SP-DiI, a fluorescent vital dye. After intra-arterial injection, fluorescence microscopy revealed SP-DiI-labeled MSCs throughout tumors 1 to 7 days after injection but not in nontumoral areas of the brain. MSCs injected intravenously did not localize to tumors (n = 12). We conclude that syngeneic MSCs are capable of homing to endogenous gliomas in immunocompetent mice. These findings support the use of MSCs as tumor-specific delivery vehicles for treating gliomas.
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Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Células Madre Mesenquimatosas/metabolismo , Animales , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Diferenciación Celular , Colorantes Fluorescentes , Glioma/genética , Glioma/patología , Humanos , Inyecciones Intraarteriales , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/citología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Factor de Crecimiento Derivado de Plaquetas/genética , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Coloración y Etiquetado , Tropismo/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: VEGF and infiltrating myeloid cells are known regulators of tumor angiogenesis and vascular permeability in glioblastoma. We investigated potential blood-based markers associated with radiographic changes to aflibercept, which binds VEGF and placental growth factor (PlGF) in patients with recurrent glioblastoma. EXPERIMENTAL DESIGN: In this single-arm phase II trial, aflibercept was given intravenously every two weeks until disease progression. Plasma and peripheral blood mononuclear cells were collected at baseline and 24 hours, 14 days, and 28 days posttreatment. Plasma cytokines and angiogenic factors were quantified by using ELISA and multiplex bead assays, and myeloid cells were assessed by flow cytometry in a subset of patients. RESULTS: Circulating levels of VEGF significantly decreased 24 hours after treatment with aflibercept, coincident with radiographic response observed by MRI. PlGF initially decreased 24 hours posttreatment but increased significantly by days 14 and 28. Lower baseline levels of PlGF, elevated baseline levels of CTACK/CCL27, MCP3/CCL7, MIF, and IP-10/CXCL10, and a decrease in VEGFR1(+) monocytes from baseline to 24 hours were all associated with improved response. Tumor progression was associated with increases in circulating matrix metalloproteinase 9. CONCLUSIONS: These data suggest that decreases in VEGF posttreatment are associated with radiographic response to aflibercept. Elevated baseline chemokines of monocyte lineage in responding patients supports a role for myeloid cells and chemokines as potential biomarkers and regulators of glioma angiogenesis.
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Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/metabolismo , Glioblastoma/tratamiento farmacológico , Proteínas Recombinantes de Fusión/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Inductores de la Angiogénesis/sangre , Citocinas/sangre , Progresión de la Enfermedad , Glioblastoma/diagnóstico por imagen , Glioblastoma/metabolismo , Humanos , Proteínas de la Membrana/sangre , Terapia Molecular Dirigida , Monocitos/metabolismo , Radiografía , Receptores de Factores de Crecimiento Endotelial Vascular , Recurrencia , Factor A de Crecimiento Endotelial Vascular/orina , Receptor 1 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND: Treatment options for patients with advanced head and neck squamous cell carcinoma (HNSCC) are scarce. This phase 2 study was conducted to evaluate the safety, tolerability, pharmacokinetics, and efficacy of dasatinib in this setting. METHODS: Patients with recurrent and/or metastatic HNSCC after platinum-based therapy were treated with dasatinib either orally or via percutaneous feeding gastrostomy (PFG). Primary endpoints were 12-week progression-free survival (PFS) and objective response rate with a 2-stage design and early withdrawal if the 12-week PFS rate was ≤20% and no patients had an objective response (OR). Forty-nine serum cytokines and angiogenic factors (CAFs) were analyzed from treated patients. RESULTS: Of the 15 patients enrolled, 12 were evaluable for response, and all patients were evaluable for toxicity. No OR was observed and 2 patients (16.7%) had stable disease (SD) at 8 weeks. The median treatment duration was 59 days, the median time to disease progression was 3.9 weeks, and the median survival was 26 weeks. One patient required a dose reduction, 3 patients required dose interruptions, and 4 patients were hospitalized for toxicity. Dasatinib inhibited c-Src both when administered orally and via PFG. Greater mean drug exposure, decreased half-life, and greater maximum concentration were observed in patients receiving dasatinib via PFG. Eleven baseline CAFs were associated with treatment outcome and 1 CAF, macrophage migration inhibitory factor, was found to be differentially modulated in correlation with SD versus disease progression. CONCLUSIONS: Single-agent dasatinib failed to demonstrate significant activity in patients with advanced HNSCC, despite c-Src inhibition. The toxicity profile was consistent with that reported in other solid tumors, and the drug can be given via PFG tube.
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Antineoplásicos/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Tiazoles/uso terapéutico , Carcinoma de Células Escamosas/patología , Niño , Citocinas/análisis , Dasatinib , Supervivencia sin Enfermedad , Femenino , Neoplasias de Cabeza y Cuello/patología , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Pirimidinas/efectos adversos , Pirimidinas/farmacocinética , Tiazoles/efectos adversos , Tiazoles/farmacocinéticaRESUMEN
We evaluated the efficacy of temozolomide (TMZ) or lomustine (CCNU) in combination with 6-thioguanine, capecitabine, and celecoxib for the treatment of recurrent high-grade glioma. Forty-three patients with recurrent glioblastoma and 31 patients with recurrent anaplastic glioma (AG) were enrolled in this open-label, non-comparative study. Patients previously treated with TMZ received CCNU while all others received TMZ; all patients received 6-thioguanine, capecitabine, and celecoxib. Endpoints were 12-month progression-free survival (PFS) for patients with AG, 6-month PFS for patients with glioblastoma, duration of PFS, and MRI-based objective response rates. Results from the TMZ and CCNU treatment arms were combined in the final analysis because there was no statistically significant difference between them. Thirty-eight patients with glioblastoma were treated with the lomustine-based regimen, and five received the TMZ-based regimen. For the 43 glioblastoma patients, the objective response rate was 12 and 33% had stable disease; the 6-month PFS was 14% and median overall survival 32 weeks. For the 31 AG patients, the combined objective response rate was 26 and 42% had stable disease; the 12 month PFS was 44%. Treatment was reasonably well tolerated with hematological toxicity common and more frequent with CCNU than TMZ. The combination therapy with 6-thioguanine, capecitabine and celecoxib plus CCNU or TMZ does not appear to be more effective than other alkylating agent schedules for patients with recurrent glioblastoma. The combination, however, is promising for patients with recurrent high-grade AG.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Gliosarcoma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Capecitabina , Celecoxib , Dacarbazina/administración & dosificación , Dacarbazina/análogos & derivados , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Humanos , Lomustina/administración & dosificación , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Estudios Prospectivos , Pirazoles/administración & dosificación , Sulfonamidas/administración & dosificación , Tasa de Supervivencia , Temozolomida , Tioguanina/administración & dosificación , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: To conduct a controlled trial of bevacizumab for the treatment of symptomatic radiation necrosis of the brain. METHODS AND MATERIALS: A total of 14 patients were entered into a placebo-controlled randomized double-blind study of bevacizumab for the treatment of central nervous system radiation necrosis. All patients were required to have radiographic or biopsy proof of central nervous system radiation necrosis and progressive neurologic symptoms or signs. Eligible patients had undergone irradiation for head-and-neck carcinoma, meningioma, or low- to mid-grade glioma. Patients were randomized to receive intravenous saline or bevacizumab at 3-week intervals. The magnetic resonance imaging findings 3 weeks after the second treatment and clinical signs and symptoms defined the response or progression. RESULTS: The volumes of necrosis estimated on T(2)-weighted fluid-attenuated inversion recovery and T(1)-weighted gadolinium-enhanced magnetic resonance imaging scans demonstrated that although no patient receiving placebo responded (0 of 7), all bevacizumab-treated patients did so (5 of 5 randomized and 7 of 7 crossover) with decreases in T(2)-weighted fluid-attenuated inversion recovery and T(1)-weighted gadolinium-enhanced volumes and a decrease in endothelial transfer constant. All bevacizumab-treated patients-and none of the placebo-treated patients-showed improvement in neurologic symptoms or signs. At a median of 10 months after the last dose of bevacizumab in patients receiving all four study doses, only 2 patients had experienced a recurrence of magnetic resonance imaging changes consistent with progressive radiation necrosis; one patient received a single additional dose of bevacizumab and the other patient received two doses. CONCLUSION: The Class I evidence of bevacizumab efficacy from the present study in the treatment of central nervous system radiation necrosis justifies consideration of this treatment option for people with radiation necrosis secondary to the treatment of head-and-neck cancer and brain cancer.
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Anticuerpos Monoclonales/uso terapéutico , Encéfalo/patología , Fármacos Neuroprotectores/uso terapéutico , Traumatismos por Radiación/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales Humanizados , Bevacizumab , Encéfalo/efectos de la radiación , Neoplasias Encefálicas/radioterapia , Sistema Nervioso Central/efectos de la radiación , Estudios Cruzados , Método Doble Ciego , Femenino , Glioma/radioterapia , Neoplasias de Cabeza y Cuello/radioterapia , Humanos , Imagen por Resonancia Magnética , Masculino , Neoplasias Meníngeas/radioterapia , Meningioma/radioterapia , Persona de Mediana Edad , Necrosis/tratamiento farmacológico , Necrosis/etiología , PlacebosRESUMEN
AZD6244 and MK2206 are targeted small-molecule drugs that inhibit MEK and AKT respectively. The efficacy of this combination in lung cancer is unknown. Our previous work showed the importance of activated AKT in mediating resistance of non-small cell lung cancer (NSCLC) to AZD6244. Thus we hypothesized that dual inhibition of both downstream MEK and AKT pathways would induce synergistic antitumor activity. In this study, we evaluated the efficacy of AZD6244 and MK2206 individually on a large panel of lung cancer cell lines. Then, we treated 28 human lung cancer cell lines with a combination of AZD6244 and MK2206 at clinically applicable drug molar ratios. The AZD6244-MK2206 combination therapy resulted in a synergistic effect on inhibition of lung cancer cell growth compared to the results of single drug treatment alone. MK2206 enhanced AZD6244-induced Bim overexpression and apoptosis in A549 and H157 cells. When we tested the combination of AZD6244 and MK2206 at ratios of 8â¶1, 4â¶1, 2â¶1, and 1â¶8, we found that the synergistic effect of the combination therapy was ratio-dependent. At ratios of 8â¶1, 4â¶1, and 2â¶1, the drug combination consistently demonstrated synergy, whereas decreasing the ratio to 1â¶8 resulted in a loss of synergy and produced an additive or antagonistic effect in most cell lines. Furthermore, the AZD6244-MK2206 combination therapy showed synergy in the suppression of A549 and H157 xenograft tumor growth and increased mean animal survival time. The AZD6244-MK2206 combination therapy resulted in effective inhibition of both p-ERK and p-AKT expression in tumor tissue. In addition, a significant increase of apoptosis was detected in tumor tissue from mice treated with AZD6244-MK2206 compared with that from the single agent treated mice. Our study suggests that the combination of AZD6244 and MK2206 has a significant synergistic effect on tumor growth in vitro and in vivo and leads to increased survival rates in mice bearing highly aggressive human lung tumors.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencimidazoles/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Bencimidazoles/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Femenino , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Análisis de Supervivencia , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Some studies (but not others) suggested that high doses are beneficial in small cell lung cancer (SCLC). We hypothesized that dose-response curve (DRC) shape reflects resistance mechanisms. METHODS: We reviewed published SCLC clinical trials and converted response rates into estimated mean tumor cell kill, assuming killing is proportional to reduction in tumor volume. Mean % cell survival was plotted versus planned dose intensity. Nonlinear and linear meta-regression analyses (weighted according to the number of patients in each study) were used to assess DRC characteristics. RESULTS: Although associations between dose and cell survival were not statistically significant, DRCs sloped downward for five of seven agents across all doses and for all seven when lowest doses were excluded. Maximum mean cell kill across all drugs and doses was approximately 90%, suggesting that there may be a maximum achievable tumor cell kill irrespective of number of agents or drug doses. CONCLUSIONS: Downward DRC slopes suggest that maintaining relatively high doses may possibly maximize palliation, although the associations between dose and slope did not achieve statistical significance, and slopes for most drugs tended to be shallow. DRC flattening at higher doses would preclude cure and would suggest that "saturable passive resistance" (deficiency of factors required for cell killing) limits maximum achievable cell kill. An example of factors that could flatten the DRC at higher doses and lead to saturable passive resistance would be presence of quiescent, noncycling cells.
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Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos , Neoplasias Pulmonares/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Humanos , Neoplasias Pulmonares/patología , Metaanálisis como Asunto , Estadificación de Neoplasias , Carcinoma Pulmonar de Células Pequeñas/patología , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Building on earlier work, the toxicity probability interval (TPI) method, we present a modified TPI (mTPI) design that is calibration-free for phase I trials. PURPOSE: Our goal is to improve the trial conduct and provide more effective designs while maintaining the simplicity of the original TPI design. METHODS: Like the TPI method, the mTPI consists of a practical dose-finding scheme guided by the posterior inference for a simple Bayesian model. However, the new method proposes improved dose-finding decision rules based on a new statistic, the unit probability mass (UPM). For a given interval and a probability distribution, the UPM is defined as the ratio of the probability mass of the interval to the length of the interval. RESULTS: The improvement through the use of the UPM for dose finding is threefold: (1) the mTPI method appears to be safer than the TPI method in that it puts fewer patients on toxic doses; (2) the mTPI method eliminates the need for calibrating two key parameters, which is required in the TPI method and is a known difficult issue; and (3) the mTPI method corresponds to the Bayes rule under a decision theoretic framework and possesses additional desirable large- and small-sample properties. LIMITATION: The proposed method is applicable to dose-finding trials with a binary toxicity endpoint. CONCLUSION: The new method mTPI is essentially calibration free and exhibits improved performance over the TPI method. These features make the mTPI a desirable choice for the design of practical trials.
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Teorema de Bayes , Ensayos Clínicos como Asunto/métodos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Dosis Máxima Tolerada , Probabilidad , Algoritmos , Humanos , Modelos Estadísticos , Modelos Teóricos , Estadística como AsuntoRESUMEN
PURPOSE: Src family kinases (SFKs) promote cancer progression and are commonly expressed in non-small-cell lung cancer (NSCLC), but the clinical effects of SFK inhibition in NSCLC are unknown. We conducted a phase II trial of the SFK inhibitor dasatinib for advanced NSCLC. We tested the hypotheses that the activation of epidermal growth factor receptor (EGFR) or SFK or modulation of serum cytokines may predict a response to dasatinib. PATIENTS AND METHODS: Patients received dasatinib as first-line therapy. Response was measured by tumor size on computed tomography scans and by metabolic activity on positron emission tomography scans. Tissue samples taken before patients received dasatinib were tested for EGFR and Kras mutation and phosphorylated SFK expression. RESULTS: Thirty-four patients were enrolled. The overall disease control rate (partial responses plus stable disease) for dasatinib was 43%. One patient had a partial response to therapy. Eleven patients (32%) had a metabolic response to dasatinib. SFK activation and EGFR and Kras mutations in tumor tissue did not predict response to dasatinib. Significant toxicities included fatigue and dyspnea. The presence of a pleural effusion before dasatanib therapy predicted the development of a clinically significant effusion during therapy. CONCLUSION: Dasatinib as a single agent had modest clinical activity that was lower than that generally observed in patients with NSCLC who receive chemotherapy. Pleural effusion was an expected and problematic toxicity that was successfully treated with steroids, diuretics, and dose interruptions. Marked activity in one patient and prolonged stable disease in four others suggested a potential subpopulation of patients with dasatinib-sensitive NSCLC.