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BACKGROUND: Carboplatin and paclitaxel (CP) have been the standard of care for advanced/recurrent endometrial cancer (EC) for many years. However, this chemotherapy combination shows limited efficacy and recurrences often occur in less than 12 months. ABTL0812 is a novel drug that selectively kill cancer cells by cytotoxic autophagy and has shown anticancer efficacy in preclinical models of EC in combination with CP. METHODS: ENDOLUNG was an open-label, phase 1/2 clinical trial designed to determine the safety and efficacy of Ibrilatazar (ABTL0812) with CP in patients with advanced/recurrent EC and non-irradiable stage III and IV squamous non-small cell lung cancer (sq-NSCLC). The phase 1 part consisted of a 3 + 3 de-escalation design followed by an expansion cohort with 12 patients. The primary endpoint was safety. ABTL0812 starting dose was 1300 mg tid combined with carboplatin at area under the curve (AUC) 5 and paclitaxel at 175 mg/m2 both administered every 21 days for up to 8 cycles. The phase 2 part included a total of 51 patients. The primary endpoint was overall response rate (ORR) and the secondary endpoints included duration of response (DOR), progression-free survival (PFS) and overall survival (OS). RESULTS: During the phase 1 only one dose limiting toxicity (DLT), a grade 4 neutropenia, was observed in 1 out of 6 patients, thus no de-escalation was applied. One additional DLT, a grade 3 febrile neutropenia, was observed in the expansion cohort, thus the recommended phase 2 dose (RP2D) for ABTL0812 was established at 1300 mg tid. Most frequent hematological adverse events (AE) of the combination were neutropenia (52.9%), anemia (37.3%) and thrombocytopenia (19.6%). Nausea (66.7%), asthenia (66.7%), diarrhea (54.9%) and vomiting (54.9%) were the most frequent non-hematological adverse events (AEs). The combination of ABTL0812 plus CP showed an ORR of 65.8% (13.2% complete response and 52.6% partial response) with a median DOR of 7.4 months (95% CI: 6.3-10.8 months). Median PFS was 9.8 months (95% CI: 6.6-10.6) and median OS 23.6 months (95% CI 6.4-ND). Pharmacokinetic parameters were compatible with target engagement observed in preclinical studies, and blood pharmacodynamic biomarkers indicated sustained target regulation during, at least, 28 days after starting the treatment. CONCLUSIONS: This study suggests that the combination of ABTL0812 with CP is safe and feasible with an encouraging activity in patients with advanced/recurrent EC. Our data warrant further confirmation in prospective randomized trials. TRIAL REGISTRATION: EU Clinical Trial Register, EudraCT number 2016-001352-21 and National Clinical Trials Number, NCT03366480. Registration on 19 September 2016.
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Protocolos de Quimioterapia Combinada Antineoplásica , Carboplatino , Neoplasias Endometriales , Recurrencia Local de Neoplasia , Paclitaxel , Femenino , Humanos , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéutico , Paclitaxel/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/administración & dosificación , Carboplatino/uso terapéutico , Persona de Mediana Edad , Anciano , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Autofagia/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Adulto , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patologíaRESUMEN
Purpose: High-mobility group box 1 protein (HMGB1) is subject to exportin 1 (XPO1)-dependent nuclear export, and it is involved in functions implicated in resistance to immunotherapy. We investigated whether HMGB1 mRNA expression was associated with response to immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC). Patients and Methods: RNA was isolated from pretreatment biopsies of patients with advanced NSCLC treated with ICI. Gene expression analysis of several genes, including HMGB1, was conducted using the NanoString Counter analysis system (PanCancer Immune Profiling Panel). Western blotting analysis and cell viability assays in EGFR and KRAS mutant cell lines were carried out. Evaluation of the antitumoral effect of ICI in combination with XPO1 blocker (selinexor) and trametinib was determined in a murine Lewis lung carcinoma model. Results: HMGB1 mRNA levels in NSCLC patients treated with ICI correlated with progression-free survival (PFS) (median PFS 9.0 versus 18.0 months, P=0.008, hazard ratio=0.30 in high versus low HMGB1). After TNF-α stimulation, HMGB1 accumulates in the cytoplasm of PC9 cells, but this accumulation can be prevented by using selinexor or antiretroviral drugs. Erlotinib or osimertinib with selinexor in EGFR-mutant cells and trametinib plus selinexor in KRAS mutant abolish tumor cell proliferation. Selinexor with a PD-1 inhibitor with or without trametinib abrogates the tumor growth in the murine Lewis lung cancer model. Conclusion: An in-depth exploration of the functions of HMGB1 mRNA and protein is expected to uncover new potential targets and provide a basis for treating metastatic NSCLC in combination with ICI.
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BACKGROUND: Platinum-sensitivity is a phenotypic biomarker of Poly (ADP-ribose) polymerase inhibitors (PARPi) sensitivity in histotypes where PARPi are approved. Approximately one-third of non-small cell lung cancers (NSCLC) are platinum-sensitive. The double-blind, randomized phase II PIPSeN (NCT02679963) study evaluated olaparib, a PARPi, as maintenance therapy for patients with platinum-sensitive advanced NSCLC. METHODS: Chemonaïve patients with ECOG performance status of 0-1, platinum-sensitive, EGFR- and ALK-wild-type, stage IIIB-IV NSCLC were randomized (R) to receive either olaparib (O) maintenance or a placebo (P). The primary objective was progression-free survival (PFS) from R. Secondary objectives included overall survival (OS) and safety. With an anticipated hazard ratio of 0.65, 144 patients were required to be randomized, and approximately 500 patients enrolled. RESULTS: The trial was prematurely terminated because anti-PD(L)1 therapy was approved during the trial recruitment. A total of 182 patients were enrolled, with 60 patients randomized: 33 and 27 in the O and P arms, respectively. Patient and tumor characteristics were well-balanced between arms, except for alcohol intake (33% vs 11% in the O and P arms, respectively, p = 0.043). The median PFS was 2.9 and 2.0 months in the O and P arms, respectively (logrank p = 0.99). The median OS was 9.4 and 9.5 months in the O and P arms, respectively (p = 0.28). Grade ≥3 toxicities occurred in 15 and 8 patients in O and P arms, with no new safety concerns. CONCLUSION: PIPSeN was terminated early after enrollment of only 50% of the pre-planned population, thus being statistically underpowered. Olaparib maintenance did neither improve median PFS nor OS in this patient population.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Método Doble Ciego , Neoplasias Pulmonares/patología , Quimioterapia de Mantención , Ftalazinas/efectos adversos , Piperazinas/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversosRESUMEN
SEOM-GECP Clinical guidelines for diagnosis, treatment and follow-up of small-cell lung cancer (SCLC) (2022) (AU)
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Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Etopósido/uso terapéutico , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamiento farmacológico , Platino (Metal)/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Estudios de Seguimiento , Sociedades Médicas , EspañaAsunto(s)
Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Etopósido/uso terapéutico , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamiento farmacológico , Platino (Metal)/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Estudios de Seguimiento , Sociedades Médicas , EspañaRESUMEN
Introducción. El COVID-19 supuso en Madrid la reorganización de la asistencia sanitaria. El objetivo de este estudio es describir el perfil sociodemográfico y clínico en los pacientes psiquiátricos que ingresaron en el Hospital Gregorio Marañón durante el confinamiento. Material y métodos. Se realizó un estudio trasversal retrospectivo en el que se recogieron datos de todos los ingresos en nuestra unidad de hospitalización psiquiatría del 15 de marzo al30 de mayo de los años 2019 y 2020. Se elaboró un protocolo que incluía variables clínicas y sociodemográficas, junto a una serie de variables referidas al año previo al ingreso. Además de estadísticos descriptivos, utilizamos la t de Student para comparar variables cuantitativas y χ² para las cualitativas. Resultados. En 2020 la población atendida aumento un312,5%, mientras los ingresos subieron únicamente un 2,5%.El nivel socioeconómico fue significativamente más bajo en 2020 (χ²=18,041; p=0,001). El número de hospitalizaciones previas era significativamente mayor en los pacientes de 2019 (t=2.147; p=0.032), pero las variables que medían únicamente el año previo registraban más tiempo de psicopatología (χ²=7,407; p=0,025) y de hospitalización(χ²=16,765; p=0,000) en 2020, así como relaciones familiares más disfuncionales (χ²=33,819; p=0,000) y menor autonomía(χ²=6,387; p=0,041). La duración del ingreso índice fue significativamente menor en 2020 (t=2.977; p=0.003). Existían también diferencias significativas en el motivo del ingreso, el diagnóstico y el consumo de sustancias. Conclusiones. Observamos una disminución de la asistencia a los servicios de urgencia y de la necesidad de ingreso hospitalario y un aumento en la proporción de ingresos en personas con contexto socio-familiar desfavorable y con trastornos psicóticos y bipolares. (AU)
Introduction. COVID-19 led to a reorganization of healthcare in Madrid. The objective of this study is to describe thesociodemographic and clinical profile of psychiatric patients admitted to Gregorio Marañón Hospital during lockdown. Methods. A retrospective cross-sectional study was conducted and data were collected from all admissions to ourpsychiatric unit from March 15 to May 30, 2019 and 2020. Aprotocol was developed including clinical and sociodemographic variables and a series of variables referring to theyear prior to admission. In addition to descriptive statistics,we used Students t test to compare quantitative variables and χ² for qualitative variables. Results. In 2020, the attended population increased by312.5%, while admissions increased only 2.5%.Socioeconomic status was significantly lower in 2020 (χ²=18.041; p=0.001). The number of previous hospitalizations was significantly higher in 2019patients (t=2,147; p=0.032), but the variables that measured only the previous year reflected more time of psychopathology (χ²=7.407; p=0.025) and hospitalization (χ²=16,765; p = 0.000) in 2020, as well as more dysfunctional family relationships (χ²=33.819; p=0.000) and less autonomy (χ²=6.387; p=0.041). The index admission was significantly shorter in 2020 (t=2.977; p=0.003). There were also significant differences in the reason for admission, diagnosis, and substance use. Conclusions. There was a decrease in attendance to emergency services and the need for hospital admissions and an increase in the proportion of admissions in people with an unfavorable social and family background and with psychotic and bipolar disorders.
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Humanos , Tratamiento Psiquiátrico Involuntario , Infecciones por Coronavirus/epidemiología , Demografía , Hospitalización , 24436 , Pandemias , España/epidemiología , Estudios Transversales , Estudios Retrospectivos , Antropología Cultural , Confinamiento ControladoRESUMEN
Third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have shown impressive results in EGFR mutant lung cancer (LC) patients in terms of disease control rate with a positive impact on overall survival. Nevertheless, after months of treatment with targeted therapy, progression inevitably occurs. Some patients develop oligoprogression and local treatment is required for optimal disease control while maintaining EGFR-TKIs. This work features a clinical case of a patient harboring an EGFR mutant LC undergoing oligoprogression to EGFR-TKIs, first into the brain and afterward to the primary tumor, requiring local ablative strategies, including primary tumor resection three years after the start of osimertinib. Currently, the patient is still alive and continues with a complete response upon EGFR-TKIs maintenance. Hence, oligoprogression, even in driven oncogenic tumors, represents a distinct biological entity and potential curative disease that deserves particular consideration in multidisciplinary tumor boards. In this case, tumor primary resection after three years of the initial diagnosis represents a paradigm shift in the treatment of EGFR mutant patients.
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Background Anti-angiogenic agents are reported to exert clinical activity in patients with epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC). We evaluated the outcomes of the combination of docetaxel plus nintedanib in refractory NSCLC patients harboring EGFR mutations. Methods We retrospectively analyzed 19 patients with advanced EGFR-mutant NSCLC who had progressed to EGFR tyrosine kinase inhibitors (TKI) and platinum-based chemotherapy receiving docetaxel and nintedanib at 14 Spanish institutions from January 2013 to December 2019. KaplanMeier and log-rank tests were used to evaluate progression-free survival (PFS) and overall survival (OS). Results Median age was 58.9 years (range 42.881), 73.7% were female. All patients were Caucasian, and 73.7% were never or light smokers. The baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 01 in 94.7% of patients. All patients had adenocarcinoma. Brain and liver metastases were present in 47.4% and 31.6% of patients, respectively. The most common EGFR mutations were exon 19 deletion (52.6%) and exon 21 L858R mutation (36.8%); 47.4% patients presented the EGFR T790M. 94.8% of the patients had received 23 previous treatment lines. Docetaxel was administered at 75 mg/m2/3 weeks to 16 patients, at 60 mg/m2 to 2 patients and at 45 mg/m2 to one patient. Nintedanib was given until disease progression or unacceptable toxicity at 200 mg twice daily except in 2 patients who received 150 mg twice daily and one patient who received 100 mg/12 h. With a median follow-up of 11.4 months (138), the median PFS was 6.1 months [95% confidence interval (CI), 4.97.3] and the median OS 10.1 months (95% CI 5.914.3). The objective response rate (ORR) was 44.4% (23.766.8%) and the disease control rate (DCR) 72.2% (49.488.5%) (AU)
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Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Adenocarcinoma del Pulmón/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Docetaxel/administración & dosificación , Adenocarcinoma del Pulmón/patología , Neoplasias Pulmonares/patología , Estudios de Seguimiento , Análisis de SupervivenciaRESUMEN
PURPOSE: Osimertinib has proven efficacy in EGFR T790M mutation-positive non-small cell lung cancer (NSCLC) patients; however, its benefits have not been evaluated in a real-world setting. METHODS: ASTRIS is a single-arm, open-label, multinational study to evaluate the efficacy and safety of osimertinib for the treatment of EGFR T790M mutation-positive NSCLC. We present the study design and preliminary cut-off analysis results (as of October 2017) describing the baseline characteristics and methodology for T790M mutation detection in the Spanish cohort. RESULTS: The Spanish cohort included 131 patients from a total 3014 patients. Forty patients (28.1%) were still undergoing therapy at the time of cut-off; 68.7% were women and 97.7% were Caucasian, with a mean age of 64.8 (SD 11.7) years. The most common type of sample for evaluating T790M mutations was tissue (55.0%), and samples were obtained from the primary tumor in 61.1% of cases. Mutation analysis was performed by the local laboratory in 60.3% of cases and using the Roche Cobas® EGFR assay in 43.5% of cases. CONCLUSIONS: ASTRIS is expected to confirm the benefits of osimertinib in a real-world setting. Data on real-world practices for the detection of the EGFR T790M mutation may provide additional information for the designing of guidelines for best practices
OBJETIVO: Osimertinib ha probado su eficacia en los pacientes de cáncer de pulmón no microcítico (CPNM) positivo a la mutación de EGFR T790M; sin embargo, sus beneficios no han sido evaluados en el mundo real. MÉTODOS: ASTRIS es un estudio de brazo único, abierto y multinacional para evaluar la eficacia y la seguridad de osimertinib para el tratamiento del CPNM positivo a la mutación de EGFR T790M. Presentamos el diseño del estudio y los resultados del análisis del punto de corte (octubre de 2017), que describe las características basales y la metodología de la detección de la mutación de T790M en la cohorte española. RESULTADOS: La cohorte española incluyó 131 pacientes de entre un total de 3.014 sujetos. Cuarenta pacientes (28,1%) seguían en terapia en el momento del punto de corte, el 68,7% eran mujeres y el 97,7% eran caucásicos, con una edad media de 64,8 (DE: 11,7) años. El tipo más común de muestra para evaluar las mutaciones de T790M fue tisular (55%), habiéndose obtenido las muestras del tumor primario en el 61,1% de los casos. El análisis de la mutación fue realizado por parte del laboratorio local en el 60,3% de los casos, utilizando el ensayo Roche Cobas® EGFR en el 43,5% de los casos. CONCLUSIONES: Se espera que ASTRIS confirme los beneficios de osimertinib en el mundo real. Los datos sobre las prácticas en el mundo real para la detección de la mutación de EGFR T790M podrían proporcionar información adicional para aportar directrices sobre las mejores prácticas
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Humanos , Masculino , Femenino , Anciano , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Mutación/genética , Receptores ErbB/genética , Antineoplásicos/uso terapéutico , Acrilamidas/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Resultado del Tratamiento , GenotipoRESUMEN
Indicaciones para la atención de pacientes con valores alterados de la función renal por parte de los servicios de emergencia, especialmente en los casos en que es necesario indicar hemodiálisis de urgencia.
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Adulto , Humanos , Diálisis/instrumentación , Diálisis/métodos , Servicios Médicos de Urgencia/organización & administración , Servicios Médicos de Urgencia/provisión & distribución , Unidades de Hemodiálisis en Hospital/organización & administraciónRESUMEN
Indicaciones para la atención de pacientes con valores alterados de la función renal por parte de los servicios de emergencia, especialmente en los casos en que es necesario indicar hemodiálisis de urgencia.(AU)