RESUMEN
Small molecules, mainly tyrosine kinase inhibitors, are currently used in various malignancies. Lapatinib, a dual inhibitor of EGFR/HER2 tyrosine kinases, has demonstrated effectiveness in brain metastases from HER2-overexpressing breast cancer. It also appears to sensitize EGFR-expressing cell lines to radiation. To evaluate the efficacy of lapatinib in combination with whole brain radiotherapy (WBRT) in patients with brain metastases from non-small cell lung cancer (NSCLC) and breast cancer, as assessed by volumetric analysis by MRI. 81 patients were treated with WBRT (30 Gy in ten fractions) in combination with lapatinib 1250 mg once daily, followed by lapatinib 1500 mg once daily for a total 6 weeks. 21 patients had primary breast cancer and 60 patients NSCLC. Pre- and post-treatment MRI scans in a compact disk for central volumetric assessment were available for 43 patients. 27 patients (62.8%) achieved partial response, 15 patients (34.9%) had stable disease and only one patient (2.3%) had disease progression. Response was not associated to EGFR protein expression. All 81 patients were assessed for safety. The large majority of the adverse events were mild. Eight deaths occurred, four of which were considered related to the study drugs but there were also other contributing factors. Nine cases of serious infections were observed in eight patients, but they were also receiving dexamethasone. Lapatinib in combination with WBRT in patients with brain metastases from breast cancer and NSCLC is a feasible approach that can be further studied in larger clinical trials.
Asunto(s)
Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/terapia , Neoplasias de la Mama/patología , Carcinoma de Pulmón de Células no Pequeñas/patología , Quimioradioterapia , Neoplasias Pulmonares/patología , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Encéfalo/efectos de la radiación , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias de la Mama/terapia , Carcinoma de Pulmón de Células no Pequeñas/terapia , Quimioradioterapia/efectos adversos , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Lapatinib , Neoplasias Pulmonares/terapia , Masculino , Persona de Mediana Edad , Quinazolinas/efectos adversos , Quinazolinas/uso terapéutico , Resultado del TratamientoRESUMEN
PURPOSE: To identify prognostic molecular profiles in patients with mRCC treated with sunitinib, we performed immunohistochemical analysis for VEGF and PI3K/Akt/mTOR pathway components. METHODS: The immunohistochemical expression of VEGF, p85α, p110γ, PTEN, p-Akt, p-mTOR, p-4E-BP1 and p-p70S6K was studied in 79 patients with mRCC who received first-line treatment with sunitinib. Expression was correlated with clinicopathological features and survival. RESULTS: VEGF was highly expressed (median H-Score 150), while positivity for the markers of the PI3K/Akt/mTOR pathway was: p85α 43/66 (65 %), p110γ41/60 (68 %), PTEN 32/64 (50 %), p-Akt57/63 (90 %), p-mTOR48/64 (75 %), p-4E-BP1 58/64 (90 %) and p-p70S6K 60/65 (92 %). No single immunohistochemical marker was found to have prognostic significance. Instead, the combination of increased p-mTOR and low VEGF expression was adversely correlated with overall survival (OS) (3.2 vs. 16.9 months, P = 0.001). CONCLUSION: Immunohistochemistry for VEGF and p-mTOR proteins may discriminate patients refractory to first-line sunitinib with poor prognosis. Prospective validation of our findings is needed.
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Carcinoma de Células Renales/metabolismo , Neoplasias Renales/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/secundario , Proteínas de Ciclo Celular , Fosfatidilinositol 3-Quinasa Clase Ia , Fosfatidilinositol 3-Quinasa Clase Ib/metabolismo , Femenino , Humanos , Inmunohistoquímica , Indoles/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Fosfohidrolasa PTEN/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfoproteínas/metabolismo , Pronóstico , Pirroles/uso terapéutico , Estudios Retrospectivos , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Sunitinib , Tasa de SupervivenciaRESUMEN
BACKGROUND & AIMS: GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib) is a prospective, observational registry study evaluating the safety of sorafenib and treatment practices in hepatocellular carcinoma patients. This large global database allowed for assessment of the use and tolerability of sorafenib in patients with liver dysfunction. METHODS: Baseline characteristics and medical/treatment history were collected in patients for whom a decision to treat with sorafenib had been made. Adverse event, dosing, and outcomes data were collected during follow-up. RESULTS: In the overall safety population (n=3202), 1968 patients (61%) had Child-Pugh A status and 666 (21%) had Child-Pugh B. The majority of Child-Pugh A (72%) and Child-Pugh B (70%) patients received an initial sorafenib dose of 800mg, consistent with the label, and dose reduction rates were 40% and 29%, respectively. The type and incidence of adverse events were generally consistent across Child-Pugh subgroups. The incidence of drug-related adverse events leading to discontinuation was similar between Child-Pugh A and Child-Pugh B patients (17% and 21%). In the intent-to-treat population (n=3213), median overall survival (months [95% confidence interval]) was longer in Child-Pugh A patients (13.6 [12.8-14.7]) compared with Child-Pugh B patients (5.2 [4.6-6.3]). CONCLUSIONS: In clinical practice, the safety profile of sorafenib appeared to be consistent across Child-Pugh A and Child-Pugh B patients. Findings suggest sorafenib may be safely used in some Child-Pugh B patients and indicate the importance of careful patient evaluation when making treatment decisions. LAY SUMMARY: The GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib) study is a large prospective registry of patients with liver cancer who were treated with sorafenib. The aims were to evaluate the safety and tolerability of sorafenib among those in which the liver was not functioning properly. The study showed that the safety profile of sorafenib was consistent across patients with preserved liver function and those in which the liver was not functioning properly, and therefore, suggesting that sorafenib may be a valid treatment for some patients with liver impairment.
Asunto(s)
Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Antineoplásicos , Carcinoma Hepatocelular , Niño , Humanos , Neoplasias Hepáticas , Niacinamida/uso terapéutico , Estudios Prospectivos , Sistema de Registros , SorafenibRESUMEN
The purpose of this study is to investigate whether the outcome of breast cancer (BC) patients treated with adjuvant chemotherapy is affected by co-mutated TP53 and PIK3CA according to stromal tumor-infiltrating lymphocytes (TILs). Paraffin tumors of all clinical subtypes from 1661 patients with operable breast cancer who were treated within 4 adjuvant trials with anthracycline-taxanes chemotherapy were informative for TP53 and PIK3CA mutation status (semiconductor sequencing genotyping) and for stromal TILs density. Disease-free survival (DFS) was examined. TP53 mutations were associated with higher (p < 0.001) and PIK3CA with lower (p = 0.004) TILs in an ER /PgR-specific manner (p < 0.001). Mutations did not affect the favorable DFS of patients with lymphocyte-predominant (LP) BC. Within non-LPBC, PIK3CA-only mutations conferred best, while TP53-PIK3CA co-mutations (6 % of all tumors) conferred worst DFS (HR 0.59; 95 % CI 0.44-0.79; p = 0.001 for PIK3CA-only). TP53-only mutations were unfavorable in patients with lower TILs, while patients with lower TILs performed worse if their tumors carried TP53-only mutations (interaction p = 0.046). Multivariate analysis revealed favorable PIK3CA-only mutations in non-LPBC (HR 0.64; 95 % CI 0.47-0.88; p = 0.007), and unfavorable TP53 mutations in ER/PgRpos/HER2neg (HR 1.55; 95 % CI 1.07-2.24; p = 0.021). Mutations did not interact with TILs in non-LP triple-negative and HER2-positive patients. TP53 and PIK3CA mutations appear to have diverse effects on the outcome of early BC patients, according to whether these genes are co-mutated or not, and for TP53 according to TILs density and ER/PgR-status. These findings need to be considered when evaluating the effect of these two most frequently mutated genes in the context of large clinical trials.
Asunto(s)
Antraciclinas/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Fosfatidilinositol 3-Quinasa Clase I/genética , Linfocitos Infiltrantes de Tumor/patología , Mutación , Taxoides/uso terapéutico , Proteína p53 Supresora de Tumor/genética , Adulto , Anciano , Anciano de 80 o más Años , Antraciclinas/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/genética , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Femenino , Humanos , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Persona de Mediana Edad , Estudios Prospectivos , Estudios Retrospectivos , Análisis de Supervivencia , Taxoides/farmacología , Adulto JovenRESUMEN
PURPOSE: To evaluate transarterial chemoembolization (TACE) use prior to and concomitantly with sorafenib in patients with unresectable hepatocellular carcinoma (HCC) across different global regions. MATERIALS AND METHODS: GIDEON is an observational registry study of more than 3000 HCC patients. Patients with histologically, cytologically, or radiographically diagnosed HCC, and for whom a decision had been made to treat with sorafenib, were eligible. Patients were enrolled into the registry from 39 countries beginning in January 2009, with the last patient follow-up in April 2012. Detailed data on treatment history, treatment patterns, adverse events, and outcomes were collected. All treatment decisions were at the discretion of the treating physicians. Documented approval from local ethics committees was obtained, and all patients provided signed informed consent. Descriptive statistics, including minimum, median, and maximum, were calculated for metric data, and frequency tables for categorical data. Kaplan-Meier estimates with 95% confidence intervals were calculated for survival end points. RESULTS: A total of 3202 patients were eligible for safety analysis, of whom 2631 (82.2%) were male. Median age was 62 years (range, 15-98 years). A total of 1511 (47.2%) patients underwent TACE prior to sorafenib; 325 (10.1%) underwent TACE concomitantly. TACE prior to sorafenib was more common in Japan and Asia-Pacific compared with all other regions (362 [71.3%] and 560 [60.3%] vs 12-209 [13.3%-37.1%]). Adverse events were reported in 2732 (85.3%) patients overall, with no notable differences in the incidence of adverse events, regardless of TACE treatment history. Overall survival was 12.7 months in prior-TACE patients, 9.2 months in non-prior-TACE patients, 21.6 months in concomitant-TACE patients, and 9.7 months in non-concomitant-TACE patients. CONCLUSION: Global variation exists in TACE use in sorafenib-treated HCC patients. The combination of TACE with sorafenib appears to be a well-tolerated and viable therapeutic approach.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/terapia , Quimioembolización Terapéutica/métodos , Neoplasias Hepáticas/terapia , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Terapia Combinada , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Niacinamida/uso terapéutico , Sorafenib , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND & AIMS: Treatment approaches for hepatocellular carcinoma (HCC) vary across countries, but these differences and their potential impact on outcomes have not been comprehensively assessed. Data from the multinational GIDEON (Global Investigation of therapeutic DEcisions in HCC and Of its treatment with sorafeNib) registry evaluated differences in patient characteristics, practice patterns and outcomes in HCC across geographical regions in patients who received sorafenib. METHODS: GIDEON is a non-randomised, observational registry study conducted in 39 countries across five global regions. HCC patients in whom a decision to treat with sorafenib was made in clinical practice and according to local practices were included. RESULTS: 3202 patients were evaluable for safety analysis: Asia-Pacific (n = 928), Japan (n = 508), Europe (n = 1113), USA (n = 563) and Latin America (n = 90). Patients in Japan had earlier-stage disease at initial diagnosis compared with patients in other regions (Barcelona Clinic Liver Cancer stage A; 43.7% vs 9.1-24.3%). Use of locoregional therapies before sorafenib, including transarterial chemoembolisation, was more common in Japan (84.4%) and Asia-Pacific (67.2%) compared with the USA (49.4%) and Europe (43.5%). Treatment patterns with respect to sorafenib also differed, with a shorter duration of treatment reported in the USA and Asia-Pacific. Time from initial diagnosis to death was longer in Japan compared with other regions (median, 79.6 months vs 14.8-25.0 months). CONCLUSIONS: Data from GIDEON highlight regional variations in the management of HCC and patient outcomes. Greater standardisation of management may help optimise outcomes for HCC patients.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/terapia , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/terapia , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Quimioembolización Terapéutica , Manejo de la Enfermedad , Detección Precoz del Cáncer , Europa (Continente) , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Niacinamida/efectos adversos , Niacinamida/uso terapéutico , Islas del Pacífico , Compuestos de Fenilurea/efectos adversos , Sistema de Registros , Sorafenib , Adulto JovenRESUMEN
Endothelin-1 (ET-1) is a multifunctional peptide exerting its effects via receptors A and B. ET-1 and its receptors, endothelin axis (ET axis), play a promoting role in cancer biology. Alterations of proteins of ET axis have been detected in non-metastatic muscle-invasive bladder cancer (NMMIBC). The objective of this study is to investigate the potential role of ET-1 tumor expression as a biomarker of prognosis, compared to other prognostic parameters (epidemiologic and pathologic), in NMMIBC. We prospectively included 40 consecutive, primary, high-grade NMMIBC patients. Tumor specimens after initial transurethral resection were stained immunohistochemically for ET-1. The ET-1 evaluation of expression was based on staining intensity (SI) of ET-1. SI was classified according to an arbitrary four-tiered scale (negative = 0, mild = 1, moderate = 2, strong = 3). Epidemiologic and pathologic parameters were analyzed, using univariate and multivariate statistics, for disease progression, progression-free survival (PFS), and overall survival (OS). ET-1 overexpression (SI = 3) was the unique parameter which associated significantly, both in univariate (log-rank test, p = 0.033) and multivariate (Cox regression analysis, p = 0.045, HR = 4.849, 95 % CI: 1.039-22.624) analysis, with an increased hazard ratio of progression. ET-1 overexpression (SI = 3) was also the unique parameter which associated, marginally significantly in univariate analysis (log-rank test, p = 0.056) and highly significantly in multivariate analysis (Cox regression analysis, p = 0.005, HR = 7.001, 95 % CI: 1.782-27.501), with an increased hazard ratio of death. Overexpression of ET-1 may be a potential biomarker of unfavorable prognosis in NMMIBC patients.
Asunto(s)
Biomarcadores de Tumor/biosíntesis , Endotelina-1/biosíntesis , Neoplasias de los Músculos/genética , Neoplasias de la Vejiga Urinaria/genética , Adulto , Anciano , Biomarcadores de Tumor/genética , Supervivencia sin Enfermedad , Endotelina-1/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Neoplasias de los Músculos/patología , Músculos/patología , Invasividad Neoplásica/genética , Pronóstico , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
AIMS: To evaluate sorafenib dosing and safety in the Global Investigation of therapeutic GIDEON study's European subpopulation. PATIENTS & METHODS: Patient demographics, disease characteristics and treatment history were recorded at enrollment; dose, adverse events and efficacy were recorded at follow-up. RESULTS: Of 1113 evaluable patients, 82% started on 800 mg/day sorafenib; patients starting on 400 mg/day were slightly older, had baseline characteristics indicative of greater disease progression and higher adverse events incidences (96 vs 88%). Treatment duration (18.0 vs 13.0 weeks) and median overall survival (12.1 vs 9.4 months) were longer in patients receiving 800 mg/day. CONCLUSION: Imbalances in independent predictive factors may have led to longer survival in patients receiving 800 mg/day sorafenib; nonetheless, results suggest that the majority can start on this dose.
Asunto(s)
Antineoplásicos/administración & dosificación , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Carcinoma Hepatocelular/etiología , Femenino , Humanos , Neoplasias Hepáticas/etiología , Masculino , Persona de Mediana Edad , Niacinamida/administración & dosificación , Niacinamida/efectos adversos , Compuestos de Fenilurea/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Sorafenib , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Dose-dense sequential chemotherapy including anthracyclines and taxanes has been established in the adjuvant setting of high-risk operable breast cancer. However, the preferable taxane and optimal schedule of administration in a dose-dense regimen have not been defined yet. METHODS: From July 2005 to November 2008, 1001 patients (990 eligible) were randomized to receive, every 2 weeks, 3 cycles of epirubicin 110 mg/m2 followed by 3 cycles of paclitaxel 200 mg/m2 followed by 3 cycles of intensified CMF (Arm A; 333 patients), or 3 cycles of epirubicin followed by 3 cycles of CMF, as in Arm A, followed 3 weeks later by 9 weekly cycles of docetaxel 35 mg/m2 (Arm B; 331), or 9 weekly cycles of paclitaxel 80 mg/m2 (Arm C; 326). Trastuzumab was administered for one year to HER2-positive patients post-radiation. RESULTS: At a median follow-up of 60.5 months, the 3-year disease-free survival (DFS) rate was 86%, 90% and 88%, for Arms A, B and C, respectively, while the 3-year overall survival (OS) rate was 96% in all arms. No differences were found in DFS or OS between the combined B and C Arms versus Arm A (DFS: HR = 0.81, 95% CI: 0.59-1.11, P = 0.20; OS: HR = 0.84, 95% CI: 0.55-1.30, P = 0.43). Among the 255 patients who received trastuzumab, 189 patients (74%) completed 1 year of treatment uneventfully. In all arms, the most frequently reported severe adverse events were neutropenia (30% vs. 27% vs. 26%) and leucopenia (12% vs. 13% vs. 12%), while febrile neutropenia occurred in fifty-one patients (6% vs. 4% vs. 5%). Patients in Arm A experienced more often severe pain (P = 0.002), neurological complications (P = 0.004) and allergic reactions (P = 0.004), while patients in Arm B suffered more often from severe skin reactions (P = 0.020). CONCLUSIONS: No significant differences in survival between the regimens were found in the present phase III trial. Taxane scheduling influenced the type of severe toxicities. HER2-positive patients demonstrated comparable 3-year DFS and OS rates with those reported in other similar studies. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12610000151033.
Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Trastuzumab , Adulto JovenRESUMEN
High-grade gliomas represent a group of aggressive brain tumors with poor prognosis due to an inherent capacity of persistent cell growth and survival. The ubiquitin-proteasome system (UPS) is an intracellular machinery responsible for protein turnover. Emerging evidence implicates various proteins targeted for degradation by the UPS in key survival and proliferation signaling pathways of these tumors. In this review, we discuss the involvement of UPS in the regulation of several mediators and effectors of these pathways in malignant gliomas.
Asunto(s)
Neoplasias Encefálicas/enzimología , Proliferación Celular , Glioma/enzimología , Complejo de la Endopetidasa Proteasomal/metabolismo , Ubiquitina/metabolismo , Animales , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Supervivencia Celular , Glioma/metabolismo , Glioma/patología , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Development of drug resistance after standard chemotherapy for glioblastoma multiforme (GBM) with temozolomide (TMZ) is associated with poor prognosis of GBM patients and is at least partially mediated by a direct DNA repair pathway involving O6-methylguanine methyltransferase (MGMT). This enzyme is under post-translational control by a multisubunit proteolytic cellular machinery, the 26S proteasome. Inhibition of the proteasome by bortezomib (BZ), a boronic acid dipeptide already in clinical use for the treatment of myeloma, has been demonstrated to induce growth arrest and apoptosis in GBM cells. In this study we investigated the effect of sequential treatment with BZ and TMZ on cell proliferation-viability and apoptosis of the human T98G and U87 GBM cell lines. We also tested for an effect of treatment on MGMT expression and important upstream regulators of the latter, including nuclear factor kappa B (NFκB), p44/42 mitogen-activated protein kinase (MAPK), p53, signal transducer and activator of transcription 3 (STAT3) and hypoxia-inducible factor 1α (HIF-1α). The sequence of drug administration for maximal cytotoxicity favored BZ prior to TMZ in T98G cells while the opposite was the case for U87 cells. Maximal efficacy was associated with downregulation of MGMT, reduced IκBα-mediated proteasome-dependent nuclear accumulation of NFκB, attenuation of p44/42 MAPK, AKT and STAT3 activation, and stabilization of p53 and inactive HIF-1α. Collectively, these results suggest that proteasome inhibition by BZ overcomes MGMT-mediated GBM chemoresistance, with scheduling of administration being critical for obtaining the maximal tumoricidal effect of combination with TMZ.
Asunto(s)
Antineoplásicos/administración & dosificación , Ácidos Borónicos/administración & dosificación , Dacarbazina/análogos & derivados , Resistencia a Antineoplásicos/efectos de los fármacos , O(6)-Metilguanina-ADN Metiltransferasa/antagonistas & inhibidores , Pirazinas/administración & dosificación , Bortezomib , Línea Celular Tumoral , Dacarbazina/administración & dosificación , Resistencia a Antineoplásicos/fisiología , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , FN-kappa B/metabolismo , O(6)-Metilguanina-ADN Metiltransferasa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor de Transcripción STAT3/metabolismo , Temozolomida , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
The efficacy of treatment for glioblastoma multiforme is currently limited by the development of resistance, particularly, but not exclusively, due to the expression of the DNA repair enzyme O6-methylguanine methyltransferase (MGMT) in a significant proportion of astrocytic tumors. MGMT is post-translationally regulated by the 26S proteasome, a multi-subunit organelle responsible for degradation of misfolded cellular proteins. The boronic acid dipeptide bortezomib is the first and only proteasome inhibitor in clinical use so far, and has been reported as a strategy to restrict growth and promote apoptosis of glioblastoma cells. In this study we investigated the effect of bortezomib on MGMT expression in T98G cells, looking for an effect on the nuclear factor kappa B (NFκB) pathway, which is a major player in MGMT regulation and is also under tight control by the ubiquitin-proteasome system. Administration of bortezomib led to a significant reduction of T98G cell viability and induction of DNA fragmentation. These effects coincided with reduced expression of MGMT transcript levels, and a decrease in cellular amount and IκBα-mediated, proteasomal activity-dependent nuclear translocation of NFκB. In addition, bortezomib-induced phosphorylation of the translation initiation factor 2alpha (eIF2α) was in parallel with translational repression of MGMT. Taken together, these results suggest a novel role for bortezomib as a potent MGMT inhibitor and support its ongoing testing as a chemosensitizer in glioblastoma.
Asunto(s)
Ácidos Borónicos/farmacología , Neoplasias Encefálicas/enzimología , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Regulación hacia Abajo/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioblastoma/enzimología , Glioblastoma/genética , Pirazinas/farmacología , Proteínas Supresoras de Tumor/genética , Apoptosis/efectos de los fármacos , Apoptosis/genética , Bortezomib , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Metilasas de Modificación del ADN/metabolismo , Enzimas Reparadoras del ADN/metabolismo , Regulación hacia Abajo/genética , Factor 2 Eucariótico de Iniciación/metabolismo , Glioblastoma/patología , Humanos , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
The 26S proteasome constitutes an essential degradation apparatus involved in the consistent recycling of misfolded and damaged proteins inside cells. The aberrant activation of the proteasome has been widely observed in various types of cancers and implicated in the development and progression of carcinogenesis. In the era of targeted therapies, the clinical use of proteasome inhibitors necessitates a better understanding of the molecular mechanisms of cell death responsible for their cytotoxic action, which are reviewed here in the context of sensitization of malignant gliomas, a tumor type particularly refractory to conventional treatments.
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Apoptosis/efectos de los fármacos , Glioma/tratamiento farmacológico , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Inhibidores de Proteasoma/uso terapéutico , Autofagia/fisiología , Glioma/metabolismo , Humanos , Necrosis/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismoRESUMEN
CUZD1, the CUB, and zona pellucida-like domains-containing protein 1, is a newly identified antigen of pancreatic autoantibodies (PAB) giving a reticulogranular pattern in patients with inflammatory bowel diseases, and in particular Crohn's disease. The exact mechanisms by which this pancreatic antigen becomes the target of IBD-specific pancreatic autoantibodies are unclear. At the same time, evolving data strongly support a role for CUZD1 in carcinogenesis. Human CUZD1 is mapped at chromosome 10q26.13 and the loss of this region is a frequent event in various malignant tumours. mRNA overexpression of CUZD1 has been noted in ovarian cancer and serum levels of CUZD1 are elevated in women with ovarian cancer and patients suffering from pancreatic cancer. CUZD1 appears to be one of the relatively few biomarkers that serve as both cancer biomarker and autoantigen of autoantibodies in an autoimmune disease unrelated to cancerous organs. This review discusses the role of CUZD1 in cancer and autoimmunity. We anticipate that a better understanding of the function of CUZD1 will help us to understand how it becomes the focus of an autoimmune attack specifically targeting the intestine and its enigmatic role in carcinogenesis.
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Autoanticuerpos/biosíntesis , Carcinogénesis/genética , Enfermedades Inflamatorias del Intestino/genética , Proteínas de la Membrana/genética , Neoplasias Ováricas/genética , Neoplasias Pancreáticas/genética , Autoanticuerpos/inmunología , Autoantígenos/inmunología , Biomarcadores/metabolismo , Carcinogénesis/inmunología , Carcinogénesis/patología , Cromosomas Humanos Par 10 , Femenino , Humanos , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/patología , Intestinos/inmunología , Intestinos/patología , Masculino , Proteínas de la Membrana/inmunología , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/patología , Páncreas/inmunología , Páncreas/patología , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patologíaRESUMEN
AIM: Enhanced Recovery After Surgery (ERAS) protocols have been proven to optimize postoperative outcomes; however, misuse of opioid analgesics can still hinder postoperative recovery due to related side effects and potential complications. INTRODUCTION: To determine if the implementation of ERAS protocol in post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) patients could help with reducing postoperative pain and opioid use. METHODS: A case-control study of consecutive testicular cancer patients with indications for PCRLPND, who were offered Conventional Post-operative Management (CPM) or ERAS protocol. Outcomes of interest included Visual Analogue Scale (VAS)-assessed pain level at postoperative days 3, 7, and 30, and Morphine-Equivalent Doses (MEDs)/postoperative day. Intraoperative parameters and postoperative complications were recorded. Parametric and non-parametric tests were used for statistical analysis. RESULTS: In total, 100 opioid-naïve PC-RPLND patients were studied. CPM and ERAS groups (36 and 64 patients, respectively) had similar demographic and baseline clinical characteristics). ERAS group patients had significantly lower blood loss (p = 0.005), blood transfusion rate (p < 0.001), and duration of the procedure (p < 0.001). Post-operative complications were comparable between groups. Nausea and bowel disorders were numerically but not statistically more frequent in the CPM group. ERAS patients had shorter mean hospital stay (5.3 ± 1.4 vs. 7.4 ± 1.6 days, p < 0.001), lower daily MEDs (4.73 ± 2.63 vs. 7.04 ± 2.29, p < 0.001), and lower VAS scores on post-operative day 7 (3.89 ± 1.07 vs. 4.67 ± 1.17, p = 0.001). Post-operative pain was similar between groups on post-operative days 3 and 30. CONCLUSION: Systematic implementation of ERAS protocol after PC-RPLND improves pain management, optimizes patient recovery, and prevents over-prescription of opioid analgesics.
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BACKGROUND: Upregulation of nuclear factor kappa B (NFκB) activity and neuroendocrine differentiation are two mechanisms known to be involved in prostate cancer (PC) progression to castration resistance. We have observed that major components of these pathways, including NFκB, proteasome, neutral endopeptidase (NEP) and endothelin 1 (ET-1), exhibit an inverse and mirror image pattern in androgen-dependent (AD) and -independent (AI) states in vitro. METHODS: We have now investigated for evidence of a direct mechanistic connection between these pathways with the use of immunocytochemistry (ICC), western blot analysis, electrophoretic mobility shift assay (EMSA) and proteasome activity assessment. RESULTS: Neuropeptide (NP) stimulation induced nuclear translocation of NFκB in a dose-dependent manner in AI cells, also evident as reduced total inhibitor κB (IκB) levels and increased DNA binding in EMSA. These effects were preceded by increased 20 S proteasome activity at lower doses and at earlier times and were at least partially reversed under conditions of NP deprivation induced by specific NP receptor inhibitors, as well as NFκB, IκB kinase (IKK) and proteasome inhibitors. AD cells showed no appreciable nuclear translocation upon NP stimulation, with less intense DNA binding signal on EMSA. CONCLUSIONS: Our results support evidence for a direct mechanistic connection between the NPs and NFκB/proteasome signaling pathways, with a distinct NP-induced profile in the more aggressive AI cancer state.
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BACKGROUND: The aim was to compare two standard chemotherapy regimens combined with bevacizumab as first-line treatment in patients with metastatic colorectal cancer. METHODS: Patients previously untreated for metastatic disease were randomized in: group A (irinotecan, capecitabine, bevacizumab, every 3 weeks; XELIRI-bevacizumab) and group B (irinotecan, leucovorin, fluorouracil, bevacizumab, every 2 weeks; FOLFIRI-bevacizumab). Primary endpoint was progression-free survival (PFS). Plasma concentrations of nitric oxide, osteopontin, TGF-ß1 and VEGF-A were measured at baseline and during treatment. RESULTS: Among 285 eligible patients, 143 were randomized to group A and 142 to group B. Fifty-five patients (38.5%) in group A and 57 (40.1%) in group B responded (p = 0.81). After a median follow-up of 42 months, median PFS was 10.2 and 10.8 months (p = 0.74), while median OS was 20.0 and 25.3 months (p = 0.099), for groups A and B, respectively. Most frequent grade 3-4 toxicities (group A vs group B) were neutropenia (13% vs 22%, p = 0.053) and diarrhea (19% vs 11%, p = 0.082). Baseline plasma osteopontin concentrations demonstrated prognostic significance for both PFS and OS. CONCLUSIONS: This trial did not show significant differences in efficacy between the groups. However, the toxicity profile was different. Baseline plasma osteopontin concentrations demonstrated independent prognostic significance. ( REGISTRATION NUMBER: ACTRN12610000270011).
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Proteínas Angiogénicas/sangre , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab , Biomarcadores/sangre , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Capecitabina , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Humanos , Irinotecán , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Osteopontina/sangre , Resultado del TratamientoRESUMEN
Interleukin (IL)-8 promotes cellular proliferation and angiogenesis in patients with non-small-cell lung cancer (NSCLC) and may be related to cachexia. Our aim was to investigate the relationship of IL-8 levels with nutritional status, and clinical outcome of patients with NSCLC. Patients with metastatic NSCLC referred for first-line therapy were eligible. Baseline IL-8 levels were measured in plasma. The Mini Nutritional Assessment (MNA) was used for the evaluation of the nutritional status, and patients were classified into 3 groups: A (score 24-30) "well nourished," B (score 17-23.5) "risk of malnutrition," and C (0-16.5) "malnourishment." Response to first-line chemotherapy, time-to-tumor progression (TTP), and overall survival (OS) were also recorded. In total, 114 patients (101 males, 88.5%; mean age = 67.5 yr) were evaluated. Performance status was 0-1 in 62% of the patients. According to the MNA, the majority of patients (71%) was either at nutritional risk or malnourished. IL-8 levels were significantly different between MNA groups (P = 0.023) and correlated with TTP (P = 0.013) and OS (P = 0.001) in univariate analysis. Baseline IL-8 levels correlate with the nutritional status of patients with metastatic NSCLC, suggesting that this cytokine may be related with cachexia.
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Carcinoma de Pulmón de Células no Pequeñas/sangre , Interleucina-8/sangre , Neoplasias Pulmonares/sangre , Estado Nutricional , Anciano , Caquexia/sangre , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Desnutrición/sangre , Persona de Mediana Edad , Análisis Multivariante , Evaluación Nutricional , Valor Predictivo de las Pruebas , PronósticoRESUMEN
BACKGROUND AND AIM: Cancer cachexia is a metabolic syndrome related with poor outcome. Cytokines play a key role in the pathophysiology of that syndrome. The aim of this study was to investigate the potential correlations between nutritional status, systemic inflammation, and psychological distress in cancer patients. The prognostic significance of the recorded parameters was also assessed. PATIENTS AND METHODS: Patients with metastatic lung cancer were eligible. Mini Nutritional Assessment (MNA) was used for the evaluation of nutritional status, Glasgow Prognostic Score (GPS) for the estimation of systemic inflammation, and Hospital Anxiety and Depression Scale (HADS) for psychological assessment. RESULTS: Totally, 122 patients were enrolled (71.3% with NSCLC and 28.7% with SCLC). The following correlations were observed: MNA and GPS (r = 0.289, p = 0.001), MNA and HADS (depression scale) (r = 0.275, p = 0.002), GPS and HADS (depression scale) (r = 0.256, p = 0.004), and GPS and HADS (anxiety scale) (r =0.194, p =0.033). In univariate analysis, GPS (p = 0.002) and MNA (p = 0.010) emerged as significant predictors of survival. In multivariate analysis, both MNA (p = 0.032) and GPS (p = 0.020) retained their importance. CONCLUSIONS: This study highlights the associations between nutritional status, systemic inflammation, and psychological distress, supporting their common underlying pathophysiological mechanisms and further suggesting the necessity of a holistic anti-cachectic approach.
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Reacción de Fase Aguda/etiología , Depresión/etiología , Neoplasias Pulmonares/psicología , Estado Nutricional , Adulto , Anciano , Anciano de 80 o más Años , Proteína C-Reactiva/metabolismo , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Pronóstico , Medición de Riesgo , Albúmina Sérica/análisis , Encuestas y CuestionariosRESUMEN
BACKGROUND: Loss of normal cell cycle control is an early event in the evolution of cancer. The expression of cyclin-dependent kinase (CDK) inhibitors p16 and p27 has been previously associated with progression of prostate cancer (PC). 70 patients diagnosed with early stage PCwere treated with radical prostatectomy (RP) at our institution and their tumor specimens were immunohistochemically evaluated for expression of p16 and p27. Available clinical data of time to PSA recurrence were correlated with the examined parameters and combined with pre-operative PSA level, Gleason score and pathological TNM (pT) stage assessment. RESULTS: Nuclear overexpression of p16 was not associated with time to biochemical failure (BF) (p = 0.572). Same was the case for nuclear p27 overexpression (p = 1.000). Also, no significant correlations were found between either p16 or p27, and pre-operative PSA level, pT stage and Gleason grade. pT stage emerged as the only independent prognostic factor for biochemical recurrence (p = 0.01). CONCLUSIONS: These data question previously reported data supporting the prognostic relevance of both p16 and p27 proteins in early PC.