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Asbestos-related mesotheliomas belong to the group of the most frequent occupational diseases in Germany, reaching about 1,000 new cases per year. The disease has a dismal prognosis because most tumors remain asymptomatic for a long time and therefore are diagnosed as incidental findings at later stages.During the last decade the German Social Accident Insurance (DGUV) has made considerable efforts to prepone the diagnosis in order to detect the disease at earliest possible stages. These efforts resulted in new findings showing that, in a high-risk group, a combination of the biomarkers calretinin and mesothelin was able to advance the diagnosis up to 12 months.Ideally, the diagnosis of a mesothelioma at an early stage has to be accompanied by the best possible individualized therapy. Standard therapeutic strategies are surgery and chemotherapy, added by radiotherapy and psycho-oncology. In recent years, several new therapeutic avenues are being explored. This review comprehensively presents both old and new therapeutic options in mesothelioma, based on international Leitlinien and new studies.
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Amianto , Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Exposición Profesional , Neoplasias Pleurales , Amianto/efectos adversos , Consenso , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Mesotelioma/diagnóstico , Mesotelioma/terapia , Neoplasias Pleurales/diagnóstico , Neoplasias Pleurales/terapiaAsunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Aprendizaje Automático , Modelos Genéticos , Adulto , Anciano , Anciano de 80 o más Años , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Biopsia , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Resistencia a Antineoplásicos/genética , Humanos , Pulmón/inmunología , Pulmón/patología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Mutación , Valor Predictivo de las Pruebas , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismoRESUMEN
At the Metrology Light Source (MLS), the compact electron storage ring of the Physikalisch-Technische Bundesanstalt (PTB) with a circumference of 48 m, a specific operation mode with two stable closed orbits for stored electrons was realized by transverse resonance island buckets. One of these orbits is closing only after three turns. In combination with single-bunch operation, the new mode was applied for electron time-of-flight spectroscopy with an interval of the synchrotron radiation pulses which is three times the revolution period at the MLS of 160 ns. The achievement is of significant importance for PTB's future programs of angular-resolved electron spectroscopy with synchrotron radiation and similar projects at other compact electron storage rings. The scheme applied here for selecting the photons originating from a particular orbit by optical imaging has been used before in fs slicing applications and may be relevant for the BESSY VSR project of the Helmholtz-Zentrum Berlin.
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BACKGROUND: Combination of selumetinib plus docetaxel provided clinical benefit in a previous phase II trial for patients with KRAS-mutant advanced non-small-cell lung cancer (NSCLC). The phase II SELECT-2 trial investigated safety and efficacy of selumetinib plus docetaxel for patients with advanced or metastatic NSCLC. PATIENTS AND METHODS: Patients who had disease progression after first-line anti-cancer therapy were randomized (2 : 2 : 1) to selumetinib 75 mg b.i.d. plus docetaxel 60 or 75 mg/m2 (SEL + DOC 60; SEL + DOC 75), or placebo plus docetaxel 75 mg/m2 (PBO + DOC 75). Patients were initially enrolled independently of KRAS mutation status, but the protocol was amended to include only patients with centrally confirmed KRAS wild-type NSCLC. Primary end point was progression-free survival (PFS; RECIST 1.1); statistical analyses compared each selumetinib group with PBO + DOC 75 for KRAS wild-type and overall (KRAS mutant or wild-type) populations. RESULTS: A total of 212 patients were randomized; 69% were KRAS wild-type. There were no statistically significant improvements in PFS or overall survival for overall or KRAS wild-type populations in either selumetinib group compared with PBO + DOC 75. Overall population median PFS for SEL + DOC 60, SEL + DOC 75 compared with PBO + DOC 75 was 3.0, 4.2, and 4.3 months, HRs: 1.12 (90% CI: 0.8, 1.61) and 0.92 (90% CI: 0.65, 1.31), respectively. In the overall population, a higher objective response rate (ORR; investigator assessed) was observed for SEL + DOC 75 (33%) compared with PBO + DOC 75 (14%); odds ratio: 3.26 (90% CI: 1.47, 7.95). Overall the tolerability profile of SEL + DOC was consistent with historical data, without new or unexpected safety concerns identified. CONCLUSION: The primary end point (PFS) was not met. The higher ORR with SEL + DOC 75 did not translate into prolonged PFS for the overall or KRAS wild-type patient populations. No clinical benefit was observed with SEL + DOC in KRAS wild-type patients compared with docetaxel alone. No unexpected safety concerns were reported. TRIAL IDENTIFIER: Clinicaltrials.gov NCT01750281.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bencimidazoles/administración & dosificación , Bencimidazoles/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Supervivencia sin Enfermedad , Docetaxel , Método Doble Ciego , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Proteínas Proto-Oncogénicas p21(ras)/genética , Taxoides/administración & dosificación , Taxoides/efectos adversosRESUMEN
BACKGROUND: Large-cell neuroendocrine carcinoma of the lung (LCNEC) is a rare disease with poor prognosis and limited treatment options. Neuroendocrine tumors frequently show overactivation of the mTOR pathway. Based on the good activity of the mTOR inhibitor everolimus in different types of neuroendocrine tumors and the results of a previous phase I trial, we evaluated the efficacy and safety of everolimus in combination with carboplatin and paclitaxel as upfront treatment for patients with advanced LCNEC. PATIENTS AND METHODS: In this prospective, multicenter phase II trial chemotherapy-naive patients with stage IV LCNEC received 5 mg everolimus daily combined with paclitaxel 175 mg/m2 and carboplatin AUC 5 every 3 weeks for a maximum of four cycles followed by maintenance everolimus 5 mg daily until progression. Efficacy parameters were determined based on central radiologic assessment. RESULTS: Forty-nine patients with a mean age of 62 ±9 years and a predominance of male (71%) smokers (98%) were enrolled in 10 German centers. The overall response rate was 45% (95% confidence interval [CI] 31%-60%), the disease control rate 74% (CI 59%-85%), the median progression-free survival 4.4 (CI 3.2-6) months and the median overall survival 9.9 (CI 6.9-11.7) months. The progression-free survival rate at 3 months (primary end point) was 76% (CI 64%-88%) according to Kaplan-Meier. Grade-3/4 toxicities occurred in 51% of patients and mainly consisted of general physical health deterioration (8%), cytopenias (24%), infections (10%) and gastrointestinal problems (8%). Typical everolimus-related adverse events, like stomatitis, rash and ocular problems occurred only in a minority of patients (<15%) and were exclusively of grade 1-2. CONCLUSION: Everolimus in combination with carboplatin and paclitaxel is an effective and well-tolerated first-line treatment for patients with metastatic LCNEC. REGISTERED CLINICAL TRIAL NUMBERS: EudraCT number 2010-022273-34, NCT01317615.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Grandes/tratamiento farmacológico , Carcinoma Neuroendocrino/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Carboplatino/administración & dosificación , Carcinoma de Células Grandes/patología , Carcinoma Neuroendocrino/patología , Everolimus/administración & dosificación , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Paclitaxel/administración & dosificación , Estudios ProspectivosRESUMEN
Background: Heart exposure to ionizing irradiation can cause ischaemic heart disease. The partial heart volume receiving ≥5 Gy (heartV5) was supposed to be an independent prognostic factor for survival after radiochemotherapy for locally advanced non-small-cell lung cancer (NSCLC). But validation of the latter hypothesis is needed under the concurrent risks of lung cancer patients. Patients and methods: The ESPATUE phase III trial recruited patients with potentially operable IIIA(N2)/selected IIIB NSCLC between 01/2004 and 01/2013. Cisplatin/paclitaxel induction chemotherapy was given followed by neoadjuvant radiochemotherapy (RT/CT) to 45 Gy (1.5 Gy bid/concurrent cisplatin/vinorelbine). Operable patients were randomized to definitive RT/CT(arm A) or surgery (arm B) and therefore were treated at two different total dose levels of radiotherapy. HeartV5 and mean heart dose (MHD) were obtained from the 3D radiotherapy plans, the prognostic value was analysed using multivariable proportional hazard analysis. Results: A total of 161 patients were randomized in ESPATUE, heartV5 and MHD were obtained from the 3D radiotherapy plans for 155 of these [male/female:105/50, median age 58 (33-74) years, stage IIIA/IIIB: 54/101]. Power analysis revealed a power of 80% of this dataset to detect a prognostic value of heartV5 of the size found in RTOG 0617. Multivariable analysis did not identify heartV5 as an independent prognostic factor for survival adjusting for tumour and clinical characteristics with [hazard ratio 1.005 (0.995-1.015), P = 0.30] or without lower lobe tumour location [hazard ratio 0.999 (0.986-1.012), P = 0.83]. There was no influence of heartV5 on death without tumour progression. Tumour progression, and pneumonia were the leading causes of death representing 65% and 14% of the observed deaths. Conclusions: HeartV5 could not be validated as an independent prognostic factor for survival after neoadjuvant or definitive conformal radiochemotherapy. Tumour progression was the predominant cause of death. Register No: Z5 - 22461/2 - 2002-017 (German Federal Office for Radiation Protection).
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Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/terapia , Adulto , Anciano , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Quimioradioterapia/efectos adversos , Relación Dosis-Respuesta en la Radiación , Femenino , Corazón/efectos de la radiación , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Miocardio/patología , Estadificación de Neoplasias , Pronóstico , Modelos de Riesgos Proporcionales , Traumatismos por Radiación/diagnóstico , Traumatismos por Radiación/etiología , Resultado del TratamientoRESUMEN
PURPOSE: Assessment of several clinical factors on progression-free (PFS) and overall survival (OS) in NSCLC patients (pts.) (stage IV) with mutated epidermal growth factor receptor (EGFRm+) treated with gefitinib (gef) or with chemotherapy (CT) under real-world conditions. METHODS: 285 EGFRm+ pts. of the non-interventional REASON study treated with gef (nâ=â206) or CT (nâ=â79) as first-line therapy or with gef (nâ=â213) or CT (nâ=â61) in any line throughout the course of therapy were analyzed according to age, gender, smoking history and histology. RESULTS: Compared with CT, patients treated with gef showed prolongation of PFS and OS in all subgroups. PFS was significantly increased in women and non-smokers. OS was significantly increased in women, non-smokers, (ex)-smokers, patients with adenocarcinoma and elderly patients when treated with gef compared to CT. Female gender turned out to be an independent positive predictive factor for OS in patients treated with gef (HRmale: 1.74, pâ=â0.0009). CONCLUSION: A clinical benefit of gef was shown for all analyzed clinical subgroups of EGFRm+ pts. This was confirmed for the female gender in a multivariate analysis.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Quinazolinas/administración & dosificación , Fumar/epidemiología , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Supervivencia sin Enfermedad , Receptores ErbB/genética , Femenino , Gefitinib , Alemania/epidemiología , Humanos , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Prevalencia , Factores de Riesgo , Distribución por Sexo , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Variable chemotherapy exposure may cause toxicity or lack of efficacy. This study was initiated to validate pharmacokinetically (PK)-guided paclitaxel dosing in patients with advanced non-small-cell lung cancer (NSCLC) to avoid supra- or subtherapeutic exposure. PATIENTS AND METHODS: Patients with newly diagnosed, advanced NSCLC were randomly assigned to receive up to 6 cycles of 3-weekly carboplatin AUC 6 or cisplatin 80 mg/m(2) either with standard paclitaxel at 200 mg/m(2) (arm A) or PK-guided dosing of paclitaxel (arm B). In arm B, initial paclitaxel dose was adjusted to body surface area, age, sex, and subsequent doses were guided by neutropenia and previous-cycle paclitaxel exposure [time above a plasma concentration of 0.05 µM (Tc>0.05)] determined from a single blood sample on day 2. The primary end point was grade 4 neutropenia; secondary end points included neuropathy, radiological response, progression-free survival (PFS) and overall survival (OS). RESULTS: Among 365 patients randomly assigned, grade 4 neutropenia was similar in both arms (19% versus 16%; P = 0.10). Neuropathy grade ≥2 (38% versus 23%, P < 0.001) and grade ≥3 (9% versus 2%, P < 0.001) was significantly lower in arm B, independent of the platinum drug used. The median final paclitaxel dose was significantly lower in arm B (199 versus 150 mg/m(2), P < 0.001). Response rate was similar in arms A and B (31% versus 27%, P = 0.405), as was adjusted median PFS [5.5 versus 4.9 months, hazard ratio (HR) 1.16, 95% confidence interval (CI) 0.91-1.49, P = 0.228] and OS (10.1 versus 9.5 months, HR 1.05, 95% CI 0.81-1.37, P = 0.682). CONCLUSION: PK-guided dosing of paclitaxel does not improve severe neutropenia, but reduces paclitaxel-associated neuropathy and thereby improves the benefit-risk profile in patients with advanced NSCLC. CLINICAL TRIAL INFORMATION: NCT01326767 (https://clinicaltrials.gov/ct2/show/NCT01326767).
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Carboplatino/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Cisplatino/administración & dosificación , Paclitaxel/administración & dosificación , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carboplatino/efectos adversos , Carboplatino/farmacocinética , Carcinoma de Pulmón de Células no Pequeñas/patología , Cisplatino/efectos adversos , Cisplatino/farmacocinética , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/clasificación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Paclitaxel/efectos adversos , Paclitaxel/farmacocinéticaRESUMEN
PURPOSE: To analyze the influence of the localization of mutations in the epidermal growth factor receptor (EGFR) gene on progression-free (PFS) and overall survival (OS) in patients (pts) with locally advanced or metastatic non-small cell lung cancer (NSCLC) treated with gefitinib (gef) or chemotherapy (CT) under real world conditions within the REASON study. METHODS: Subgroups of pts with mutations in exon 19 (nâ=â141), 18/20 (nâ=â43), and 21 (nâ=â104) were analyzed for PFS and OS according to gef or CT treatment and compared using the log-rank test. RESULTS: Pts with mutations in exon 19 and 18/20 treated with gef as first line therapy showed increased PFS and OS compared to CT. This increase was statistically significant in pts with exon 19 mutation (11.3 vs. 6.5 months), but was not found in pts with exon 21 mutation (9.1 vs. 9.3 months). Also, OS was significantly increased in patients with mutation in exon 19 treated with gef ever over all treatment lines compared to CT (21.8 vs. 10.6 months), whereas this was not found in pts with mutation in exon 21 (14.1 vs. 13.9 months). CONCLUSION: Localization and nature of EGFR mutations influences gefitinib treatment outcomes under routine conditions and should therefore be analyzed in detail.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Exones/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Quinazolinas/uso terapéutico , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Supervivencia sin Enfermedad , Receptores ErbB/genética , Femenino , Gefitinib , Marcadores Genéticos/genética , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Alemania , Humanos , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Pruebas de Farmacogenómica/métodos , Mutación Puntual/genética , Prevalencia , Traumatismos por Radiación , Reproducibilidad de los Resultados , Factores de Riesgo , Sensibilidad y Especificidad , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: We report final results with extended follow-up from a global, expanded-access trial that pre-regulatory approval provided sunitinib to metastatic renal cell carcinoma (mRCC) patients, ineligible for registration-directed trials. METHODS: Patients ⩾18 years received oral sunitinib 50 mg per day on a 4-weeks-on-2-weeks-off schedule. Safety was assessed regularly. Tumour measurements were scheduled per local practice. RESULTS: A total of 4543 patients received sunitinib. Median treatment duration and follow-up were 7.5 and 13.6 months. Objective response rate was 16% (95% confidence interval (CI): 15-17). Median progression-free survival (PFS) and overall survival (OS) were 9.4 months (95% CI: 8.8-10.0) and 18.7 months (95% CI: 17.5-19.5). Median PFS in subgroups of interest: aged ⩾65 years (33%), 10.1 months; Eastern Cooperative Oncology Group performance status ⩾2 (14%), 3.5 months; non-clear cell histology (12%), 6.0 months; and brain metastases (7%), 5.3 months. OS was strongly associated with the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model (n=4065). The most common grade 3/4 treatment-related adverse events were thrombocytopenia (10%), fatigue (9%), and asthenia, neutropenia, and hand-foot syndrome (each 7%). CONCLUSION: Final analysis of the sunitinib expanded-access trial provided a good opportunity to evaluate the long-term side effects of a tyrosine kinase inhibitor used worldwide in mRCC. Efficacy and safety findings were consistent with previous results.
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Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Indoles/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Metástasis de la Neoplasia , Pirroles/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Carcinoma de Células Renales/patología , Femenino , Humanos , Indoles/efectos adversos , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Pirroles/efectos adversos , Sunitinib , Adulto JovenRESUMEN
To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The 2nd ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, first-line/second and further lines of treatment in advanced disease, early-stage disease and locally advanced disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on locally advanced disease.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/terapia , Pulmón , Broncoscopía , Carboplatino/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/patología , Quimioterapia Adyuvante , Cisplatino/administración & dosificación , Manejo de la Enfermedad , Biopsia por Aspiración con Aguja Fina Guiada por Ultrasonido Endoscópico , Etopósido/administración & dosificación , Europa (Continente) , Humanos , Pulmón/diagnóstico por imagen , Pulmón/patología , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patología , Ganglios Linfáticos/patología , Mediastino , Imagen Multimodal , Neumonectomía , Tomografía de Emisión de Positrones , Radioterapia Adyuvante , Sociedades Médicas , Tomografía Computarizada por Rayos X , Vinblastina/administración & dosificación , Vinblastina/análogos & derivados , VinorelbinaRESUMEN
OBJECTIVES: Pulmonary adenocarcinomas (ADC) can be sub-grouped based on dominant oncogenic drivers. EGFR mutations define an entity of metastatic ADC with favorable prognosis and high susceptibility to EGFR tyrosine kinase inhibition. In contrast, the clinical impact of additional ERBB family members in ADC is less defined. To this end we prospectively studied HER2 expression, gene amplification, and mutation in relation to outcome of patients with advanced or metastatic ADC. MATERIALS AND METHODS: Diagnostic tumor biopsies from 193 sequential patients with stage III/IV ADC were prospectively studied for HER2 expression by immunohistochemistry (IHC). Cases with IHC scores 2+ or 3+ were analyzed by HER2 chromogenic in situ hybridization (CISH), and sequencing of HER2 exons 20 and 23. Additional prospectively determined biomarkers included PTEN, cMET, pAKT, and pERK expression, KRAS, EGFR, BRAF and PIK3CA mutations, and ALK fluorescence ISH (FISH). RESULTS AND CONCLUSION: HER2-IHC was feasible in 176 (91.2%) cases. Of 53 (30%) cases with IHC scores 2+/3+, 45 (85%) could be studied by CISH and 34 (64%) by sequencing. The lower number of HER2-mutational analyses resulted from exhaustion of tumor tissue and DNA following mutational analysis of KRAS, EGFR, BRAF and PIK3CA. HER2 amplification was detected in 4 cases (2.3%), while no mutation was found. HER2 expression correlated with expression of pAKT and cMET. Expression of HER2 and pAKT was associated with favorable overall survival in stage IV disease. HER2-expressing ADC more frequently harbored KRAS mutations, while HER2 expression was absent in all 4 cases with BRAF mutation. HER2-IHC was not predictive of HER2 gene amplification or mutation, which both were rare events in prospectively studied patients with advanced or metastatic ADC. Expression of HER2 and pAKT define a population of patients with stage IV ADC with a distinct disease course, who could benefit from specifically tailored pharmacotherapies.
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Adenocarcinoma/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias Pulmonares/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Receptor ErbB-2/metabolismo , Adenocarcinoma/mortalidad , Adenocarcinoma/secundario , Anciano , Análisis Mutacional de ADN , Femenino , Amplificación de Genes , Expresión Génica , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor ErbB-2/genética , Transducción de SeñalAsunto(s)
Biomarcadores de Tumor/genética , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas/métodos , Técnicas de Diagnóstico Molecular/métodos , Neoplasias/diagnóstico , Neoplasias/genética , Polimorfismo de Nucleótido Simple/genética , Medicina Basada en la Evidencia , Marcadores Genéticos/genética , HumanosRESUMEN
Caspase-2 represents the most conserved member of the caspase family, which exhibits features of both initiator and effector caspases. Using ribonucleoprotein (RNP)-immunoprecipitation assay, we identified the proapoptotic caspase-2L encoding mRNA as a novel target of the ubiquitous RNA-binding protein HuR in DLD-1 colon carcinoma cells. Unexpectedly, crosslinking-RNP and RNA probe pull-down experiments revealed that HuR binds exclusively to the caspase-2-5' untranslated region (UTR) despite that the 3' UTR of the mRNA bears several adenylate- and uridylate-rich elements representing the prototypical HuR binding sites. By using RNAi-mediated loss-of-function approach, we observed that HuR regulates the mRNA and in turn the protein levels of caspase-2 in a negative manner. Silencing of HuR did not affect the stability of caspase-2 mRNA but resulted in an increased redistribution of caspase-2 transcripts from RNP particles to translational active polysomes implicating that HuR exerts a direct repressive effect on caspase-2 translation. Consistently, in vitro translation of a luciferase reporter gene under the control of an upstream caspase-2-5'UTR was strongly impaired after the addition of recombinant HuR, whereas translation of caspase-2 coding region without the 5'UTR is not affected by HuR confirming the functional role of the caspase-2-5'UTR. Functionally, an elevation in caspase-2 level by HuR knockdown correlated with an increased sensitivity of cells to apoptosis induced by staurosporine- and pore-forming toxins as implicated by their significant accumulation in the sub G1 phase and an increase in caspase-2, -3 and poly ADP-ribose polymerase cleavage, respectively. Importantly, HuR knockdown cells remained insensitive toward STS-induced apoptosis if cells were additionally transfected with caspase-2-specific siRNAs. Collectively, our findings support the hypothesis that HuR by acting as an endogenous inhibitor of caspase-2-driven apoptosis may essentially contribute to the antiapoptotic program of adenocarcinoma cells by HuR.
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Adenocarcinoma/genética , Apoptosis , Caspasa 2/genética , Neoplasias del Colon/genética , Cisteína Endopeptidasas/genética , Proteínas ELAV/metabolismo , Regiones no Traducidas 3' , Regiones no Traducidas 5' , Adenocarcinoma/enzimología , Adenocarcinoma/metabolismo , Adenocarcinoma/fisiopatología , Caspasa 2/metabolismo , Línea Celular Tumoral , Neoplasias del Colon/enzimología , Neoplasias del Colon/metabolismo , Neoplasias del Colon/fisiopatología , Cisteína Endopeptidasas/metabolismo , Proteínas ELAV/genética , Humanos , Unión Proteica , Biosíntesis de Proteínas , Transcripción Genética , Regulación hacia ArribaRESUMEN
The aim of this study was to retrospectively analyze the long-term effectiveness of combined chemoradiation as the definitive treatment of locally advanced cancers of the cervical esophagus. Patients received high-dose external beam radiotherapy and concurrent cisplatin-based chemotherapy. Some patients received intraluminal brachytherapy as a boost. In addition, a majority of the patients received cisplatin-based induction chemotherapy before definitive chemoradiation. Fifty-five patients (46 men, 9 women, median age 58 years, range 35-72 years) with cancers of the cervical esophagus (stage II: 20; stage III: 35 patients) were treated with definitive chemoradiation (median dose 60 Gy, range 50-70 Gy). Actuarial overall survival rates at 2, 3, 5, and 10 years were 35%, 29%, 25%, and 10%, respectively. Thirteen long-term survivors were observed with a follow-up of more than 5 years. Neither gender nor age, tumor length, tumor grade, or clinically detectable lymph node metastases was significant prognostic factors for survival. Twenty-four patients (44%) developed local or regional recurrences, 15 (27%) distant metastases, and 8 (15%) patients developed a second malignancy. Acute and late toxicity of this treatment schedule was moderate. Concurrent chemoradiation offers a chance of long-term survival for locally advanced unresectable carcinomas of the cervical esophagus, with long-term survival rates above 24% and acceptable toxicity. These results substantiate the use of chemoradiation as a curative treatment option for cervical esophageal cancer.
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Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/terapia , Quimioradioterapia/métodos , Neoplasias Esofágicas/terapia , Esófago/patología , Adenocarcinoma/patología , Adulto , Anciano , Braquiterapia , Carcinoma de Células Escamosas/patología , Cisplatino/administración & dosificación , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago , Etopósido/administración & dosificación , Femenino , Fluorouracilo/administración & dosificación , Humanos , Quimioterapia de Inducción/métodos , Leucovorina/administración & dosificación , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Cuello , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Pt-(GpG) intrastrand crosslinks are the major DNA adducts induced by platinum-based anticancer drugs. In the cell lines and mouse models, the persistence of these lesions correlates significantly with cell damage. Here we studied Pt-(GpG) DNA adducts in circulating tumour cells (CTC) treated with cisplatin in medium upfront to systemic therapy from patients with advanced non-small-cell lung cancer (NSCLC). METHODS: Blood was drawn before systemic treatment and the CD45/CD15-depleted fraction of mononuclear cells was exposed to cisplatin, verified for the presence of CTC by pan-cytokeratin (pCK) staining and immunoanalysed for the level of Pt-(GpG) in DNA. RESULTS: Immunostaining for pCK, CD45 and subsequently for Pt-(GpG) adducts in the cisplatin-exposed cells (ex vivo) at different time points depicted distinct differences for adduct persistence in CTC between responders vs non-responders. CONCLUSION: Pt-(GpG) adducts can be detected in CTC from NSCLC patients and assessing their kinetics may constitute a clinically feasible biomarker for response prediction and dose individualisation of platinum-based chemotherapy. This functional pre-therapeutic test might represent a more biological approach than measuring protein factors or other molecular markers.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Aductos de ADN/biosíntesis , Fosfatos de Dinucleósidos/química , Neoplasias Pulmonares/tratamiento farmacológico , Platino (Metal)/química , Anciano , Cisplatino/farmacología , Cisplatino/uso terapéutico , Aductos de ADN/genética , Humanos , Antígenos Comunes de Leucocito/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Antígeno Lewis X/metabolismo , Persona de Mediana Edad , Células Neoplásicas Circulantes , Células Tumorales CultivadasAsunto(s)
Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Antineoplásicos/uso terapéutico , Broncoscopía , Carcinoma de Pulmón de Células no Pequeñas/epidemiología , Detección Precoz del Cáncer , Europa (Continente) , Estudios de Seguimiento , Humanos , Pulmón/patología , Pulmón/efectos de la radiación , Pulmón/cirugía , Neoplasias Pulmonares/epidemiología , Estadificación de Neoplasias , Medición de Riesgo , Fumar/epidemiología , Cese del Hábito de FumarRESUMEN
Auger (L3M4,5M4,5) and X-ray photoionization spectra (2p, 3d) of mass-selected CuN-clusters supported by a thin natural silica layer are presented in the size range N = 8-55 atoms per cluster. The Auger spectra of all clusters are shifted to a lower kinetic energy with respect to the spectrum of the bulk. Furthermore the Auger energy decreases systematically with decreasing cluster size. The binding energies of the 2p and 3d valence states are higher than the corresponding bulk values. Using the energy of the Auger main line, the corresponding core hole peak and the centroid of the self-convoluted 3d valence band the on-site Coulomb interaction energy Udd of the two-hole final state as a function of cluster size has been determined.
RESUMEN
BACKGROUND: Radiation dose escalation within definitive radiochemotherapy (RTx/CTx) was not successful for stage III non-small cell lung cancer (NSCLC) using conventional fractionation (CF). Accelerated-hyperfractionation (AHF) counteracts tumour cell repopulation. In this observational study, the effects of neoadjuvant RTx/CTx using AHF or CF were studied by histopathology and using the survival end-point. METHODS: Data from all consecutive lung cancer patients treated with neoadjuvant RTx/CTx and thoracotomy between 08/2000 and 06/2012 were analysed. Patients received induction chemotherapy (cisplatin-doublets) followed by concurrent RTx/CTx using AHF (45 Gy/1.5 Gy bid) or CF-RTx (46 Gy/2 Gy qd). For estimating the AHF versus CF treatment effects, multivariate analysis (MA), propensity score weighting (PS), and instrumental variable analysis (IV) were used. FINDINGS: 239 patients were treated, median age 58 (34-78)years, stage II/IIIA/B: 19/88/132, squamous cell/adenocarcinomas/other: 98/107/34; AHF/CF-RTx 112/127 patients. No significant differences between both groups, in tumour related factors (age, gender, Charlson comorbiditiy score, lactate dehydrogenase (LDH), haemoglobin, stage, histopathology and grading), existed. Crude rates of pathologic complete responses (pCR) in AHF and CF groups were 37% and 24% respectively. The dose fractionation effect on pCR was significant (p ⩽ 0.006, PS and IV analyses). There was a significant dependence of pCR on biologically effective dose. pCR also depended on treatment time (MA, p = 0.04; PS, p = 0.0004). Median treatment time was 22 d or 31 d using AHF or CF (p<0.0001), respectively. Adenocarcinomas had lower pCR rates in comparison to other histologies. Five-year survival of patients with pCR was 65%, independent of the fractionation. INTERPRETATION: This large monoinstitutional analysis demonstrates an increased effect of AHF on pCR of lung cancer which modifies overall survival.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/terapia , Quimioradioterapia Adyuvante/métodos , Neoplasias Pulmonares/terapia , Adulto , Anciano , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Quimioradioterapia Adyuvante/mortalidad , Cisplatino/administración & dosificación , Terapia Combinada , Fraccionamiento de la Dosis de Radiación , Etopósido/administración & dosificación , Femenino , Humanos , Quimioterapia de Inducción/métodos , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Puntaje de Propensión , Resultado del TratamientoRESUMEN
BACKGROUND: Cetuximab and docetaxel have single-agent activity in squamous cell carcinoma of the head and neck (SCCHN). The efficacy of their combination was evaluated in platinum-pretreated patients with recurrent and/or metastatic SCCHN. PATIENTS AND METHODS: A total of 84 patients were treated with docetaxel 35 mg/m(2) weekly for a maximum of 6 cycles and concomitant cetuximab 250 mg/m(2) weekly until disease progression or unacceptable toxicity. The primary endpoint was the objective response rate and secondary endpoints included the response rate in relation to platinum sensitivity, progression-free survival (PFS), overall survival (OS) and toxicity. RESULTS: Nine (11%) patients achieved a partial response and 34 (40%) stable disease, resulting in a disease control rate of 51%. Response to treatment was 49% in previously platinum-sensitive and 50% in previously platinum-resistant disease. The median PFS was 3.1 months and the median OS 6.7 months. The most common grade 3 or 4 adverse events were mucositis (8%), pneumonia (8%), fatigue (8%) and skin reactions (14%). Sepsis occurred in 3 patients. CONCLUSION: Cetuximab plus docetaxel is an active treatment regimen with moderate toxicity in SCCHN patients. However, no superiority in comparison with monotherapy could be shown. Responsiveness and survival were independent of previous platinum sensitivity.