RESUMEN
BACKGROUND: Thymic carcinoma (TC) is a rare tumor with aggressive behavior. Chemotherapy with carboplatin plus paclitaxel represents the treatment of choice for advanced disease. Antiangiogenic drugs, including ramucirumab, have shown activity in previously treated patients. The RELEVENT trial was designed to evaluate the activity and safety of ramucirumab plus chemotherapy as first-line treatment in advanced TC. PATIENTS AND METHODS: This phase II trial was conducted within the Italian TYME network. Eligible patients had treatment-naïve advanced TC. They received ramucirumab, carboplatin and paclitaxel for six cycles, followed by ramucirumab maintenance until disease progression or intolerable toxicity. Primary endpoint was objective response rate (ORR) according to RECIST v1.1 as assessed by the investigator. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Centralized radiologic review was carried out. RESULTS: From November 2018 to June 2023, 52 patients were screened and 35 were enrolled. Median age was 60.8 years, 71.4% of patients were male and 85.7% had Masaoka-Koga stage IVB. The Eastern Cooperative Oncology Group performance status was 0 in 68.5% and 1 in 31.4% of patients. At the present analysis carried out some months after the interim analysis (earlier than expected) on 35 patients, ORR was 80.0% [95% confidence interval (CI) 63.1% to 91.6%]. At the centralized radiological review of 33/35 assessable patients, ORR was 57.6% (95% CI 39.2% to 74.5%). After a median follow-up of 31.6 months, median PFS was 18.1 months (95% CI 10.8-52.3 months) and median OS was 43.8 months (95% CI 31.9 months-not reached). Thirty-two out of 35 patients (91.4%) experienced at least one treatment-related adverse event (AE), of which 48.6% were AE ≥ grade 3. CONCLUSIONS: In previously untreated advanced TC, the addition of ramucirumab to carboplatin and paclitaxel showed the highest activity compared to historical controls, with a manageable safety profile. Despite the small number of patients, given the rarity of the disease, the trial results support the consideration of this combination as first-line treatment in TC.
RESUMEN
BACKGROUND AND OBJECTIVES: Neuromyelitis optica spectrum disorder (NMOSD) is a chronic CNS demyelinating autoimmune disorder targeting the astrocyte antigen aquaporin-4 (AQP4), typically presenting with optic neuritis, transverse myelitis, and brain syndromes. Cognitive dysfunction (CD) in NMOSD is under-recognized and poorly understood. The purpose of this study was to evaluate the prevalence and clinical variables associated with CD in NMOSD. METHODS: This observational retrospective study with longitudinal follow-up describes a clinical cohort seen in the Collaborative International Research in Clinical and Longitudinal Experience Study in NMOSD. Serial Montreal Cognitive Assessments (MoCAs) were performed upon enrollment and at 6-month intervals to evaluate longitudinal cognitive function relative to demographic and disease-related factors. We used 2-tailed t test, analysis of variance, the χ2 test, linear regression for univariable and adjusted analyses and simultaneous linear regression and mixed-effects model for multivariable analyses. RESULTS: Thirty-four percent (75/219) of patients met criteria for CD (MoCA <26); 29% (64/219) showed mild dysfunction (MoCA 20-26/30), and 5% (11/219) showed moderate (MoCA <20/30) dysfunction. Patients with less neurologic disability and lower pain scores had higher MoCA scores (95% CI 0.24-0.65 and 95% CI 0.09-0.42, respectively). Patients with at least high school education scored higher on the MoCA (95% CI 2.2-5). When comparing patients dichotomized for CD, patients never on rituximab scored higher than patients only treated with rituximab (p < 0.029). There was no significant association between annualized relapse rate, age, sex, disease duration, AQP4 serostatus or brain lesions, and CD. CD was more pronounced among Black than White patients (95% CI -2.7 to -0.7). Multivariable analysis of serial MoCA did not indicate change (p = 0.715). Descriptive analysis of serial MoCA showed 30% (45/150) of patients with worsening MoCA performance had impaired language and verbal recall. DISCUSSION: To our knowledge, this is the largest study of diverse cohort to investigate CD in patients with NMOSD. Our findings demonstrate 34% of patients with NMOSD experience mild-to-moderate CD, while 30% of patients demonstrated decline on serial testing. The substantial prevalence of CD in this pilot report highlights the need for improved and validated screening tools and comprehensive measures to investigate CD in NMOSD.
Asunto(s)
Disfunción Cognitiva , Neuromielitis Óptica , Humanos , Neuromielitis Óptica/complicaciones , Neuromielitis Óptica/epidemiología , Prevalencia , Estudios Retrospectivos , Rituximab , Recurrencia Local de Neoplasia , Disfunción Cognitiva/epidemiología , Acuaporina 4RESUMEN
OBJECTIVES: To assess associations between outcome and cardiopulmonary resuscitation (CPR) quality for in-hospital cardiac arrest (IHCA) in children with medical cardiac, surgical cardiac, or noncardiac disease. DESIGN: Secondary analysis of a multicenter cluster randomized trial, the ICU-RESUScitation Project (NCT02837497, 2016-2021). SETTING: Eighteen PICUs. PATIENTS: Children less than or equal to 18 years old and greater than or equal to 37 weeks postconceptual age receiving chest compressions (CC) of any duration during the study. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 1,100 children with IHCA, there were 273 medical cardiac (25%), 383 surgical cardiac (35%), and 444 noncardiac (40%) cases. Favorable neurologic outcome was defined as no more than moderate disability or no worsening from baseline Pediatric Cerebral Performance Category at discharge. The medical cardiac group had lower odds of survival with favorable neurologic outcomes compared with the noncardiac group (48% vs 55%; adjusted odds ratio [aOR] [95% CI], aOR 0.59 [95% CI, 0.39-0.87], p = 0.008) and surgical cardiac group (48% vs 58%; aOR 0.64 [95% CI, 0.45-0.9], p = 0.01). We failed to identify a difference in favorable outcomes between surgical cardiac and noncardiac groups. We also failed to identify differences in CC rate, CC fraction, ventilation rate, intra-arrest average target diastolic or systolic blood pressure between medical cardiac versus noncardiac, and surgical cardiac versus noncardiac groups. The surgical cardiac group had lower odds of achieving target CC depth compared to the noncardiac group (OR 0.15 [95% CI, 0.02-0.52], p = 0.001). We failed to identify a difference in the percentage of patients achieving target CC depth when comparing medical cardiac versus noncardiac groups. CONCLUSIONS: In pediatric IHCA, medical cardiac patients had lower odds of survival with favorable neurologic outcomes compared with noncardiac and surgical cardiac patients. We failed to find differences in CPR quality between medical cardiac and noncardiac patients, but there were lower odds of achieving target CC depth in surgical cardiac compared to noncardiac patients.
Asunto(s)
Procedimientos Quirúrgicos Cardíacos , Reanimación Cardiopulmonar , Paro Cardíaco , Cardiopatías , Niño , Humanos , Paro Cardíaco/terapia , Cardiopatías/complicaciones , Cardiopatías/terapia , HospitalesRESUMEN
BACKGROUND: Supported by laboratory and clinical investigations of adult cardiopulmonary arrest, resuscitation guidelines recommend monitoring end-tidal carbon dioxide (ETCO2) as an indicator of cardiopulmonary resuscitation (CPR) quality, but they note that "specific values to guide therapy have not been established in children." METHODS: This prospective observational cohort study was a National Heart, Lung, and Blood Institute-funded ancillary study of children in the ICU-RESUS trial (Intensive Care Unit-Resuscitation Project; NCT02837497). Hospitalized children (≤18 years of age and ≥37 weeks postgestational age) who received chest compressions of any duration for cardiopulmonary arrest, had an endotracheal or tracheostomy tube at the start of CPR, and evaluable intra-arrest ETCO2 data were included. The primary exposure was event-level average ETCO2 during the first 10 minutes of CPR (dichotomized as ≥20 mm Hg versus <20 mm Hg on the basis of adult literature). The primary outcome was survival to hospital discharge. Secondary outcomes were sustained return of spontaneous circulation, survival to discharge with favorable neurological outcome, and new morbidity among survivors. Poisson regression measured associations between ETCO2 and outcomes as well as the association between ETCO2 and other CPR characteristics: (1) invasively measured systolic and diastolic blood pressures, and (2) CPR quality and chest compression mechanics metrics (ie, time to CPR start; chest compression rate, depth, and fraction; ventilation rate). RESULTS: Among 234 included patients, 133 (57%) had an event-level average ETCO2 ≥20 mm Hg. After controlling for a priori covariates, average ETCO2 ≥20 mm Hg was associated with a higher incidence of survival to hospital discharge (86/133 [65%] versus 48/101 [48%]; adjusted relative risk, 1.33 [95% CI, 1.04-1.69]; P=0.023) and return of spontaneous circulation (95/133 [71%] versus 59/101 [58%]; adjusted relative risk, 1.22 [95% CI, 1.00-1.49]; P=0.046) compared with lower values. ETCO2 ≥20 mm Hg was not associated with survival with favorable neurological outcome or new morbidity among survivors. Average 2 ≥20 mm Hg was associated with higher systolic and diastolic blood pressures during CPR, lower CPR ventilation rates, and briefer pre-CPR arrest durations compared with lower values. Chest compression rate, depth, and fraction did not differ between ETCO2 groups. CONCLUSIONS: In this multicenter study of children with in-hospital cardiopulmonary arrest, ETCO2 ≥20 mm Hg was associated with better outcomes and higher intra-arrest blood pressures, but not with chest compression quality metrics.
Asunto(s)
Reanimación Cardiopulmonar , Paro Cardíaco , Niño , Humanos , Dióxido de Carbono , Alta del Paciente , Estudios Prospectivos , AdolescenteRESUMEN
AIM: To evaluate associations between characteristics of simulated point-of-care cardiopulmonary resuscitation (CPR) training with simulated and actual intensive care unit (ICU) CPR performance, and with outcomes of children after in-hospital cardiac arrest. METHODS: This is a pre-specified secondary analysis of the ICU-RESUScitation Project; a prospective, multicentre cluster randomized interventional trial conducted in 18 ICUs from October 2016-March 2021. Point-of-care bedside simulations with real-time feedback to allow multidisciplinary ICU staff to practice CPR on a portable manikin were performed and quality metrics (rate, depth, release velocity, chest compression fraction) were recorded. Actual CPR performance was recorded for children 37 weeks post-conceptual age to 18 years who received chest compressions of any duration, and included intra-arrest haemodynamics and CPR mechanics. Outcomes included survival to hospital discharge with favourable neurologic status. RESULTS: Overall, 18,912 point-of-care simulations were included. Simulation characteristics associated with both simulation and actual performance included site, participant discipline, and timing of simulation training. Simulation characteristics were not associated with survival with favourable neurologic outcome. However, participants in the top 3 sites for improvement in survival with favourable neurologic outcome were more likely to have participated in a simulation in the past month, on a weekday day, to be nurses, and to achieve targeted depth of compression and chest compression fraction goals during simulations than the bottom 3 sites. CONCLUSIONS: Point-of-care simulation characteristics were associated with both simulated and actual CPR performance. More recent simulation, increased nursing participation, and simulation training during daytime hours may improve CPR performance.
Asunto(s)
Reanimación Cardiopulmonar , Paro Cardíaco , Niño , Humanos , Reanimación Cardiopulmonar/educación , Estudios Prospectivos , Paro Cardíaco/terapia , Competencia Clínica , Hospitales PediátricosRESUMEN
BACKGROUND: IMpower010 (NCT02486718) demonstrated significantly improved disease-free survival (DFS) with adjuvant atezolizumab versus best supportive care (BSC) following platinum-based chemotherapy in the programmed death-ligand 1 (PD-L1)-positive and all stage II-IIIA non-small-cell lung cancer (NSCLC) populations, at the DFS interim analysis. Results of the first interim analysis of overall survival (OS) are reported here. PATIENT AND METHODS: The design, participants, and primary-endpoint DFS outcomes have been reported for this phase III, open-label, 1 : 1 randomised study of atezolizumab (1200 mg q3w; 16 cycles) versus BSC after adjuvant platinum-based chemotherapy (1-4 cycles) in adults with completely resected stage IB (≥4 cm)-IIIA NSCLC (per the Union Internationale Contre le Cancer and American Joint Committee on Cancer staging system, 7th edition). Key secondary endpoints included OS in the stage IB-IIIA intent-to-treat (ITT) population and safety in randomised treated patients. The first pre-specified interim analysis of OS was conducted after 251 deaths in the ITT population. Exploratory analyses included OS by baseline PD-L1 expression level (SP263 assay). RESULTS: At a median of 45.3 months' follow-up on 18 April 2022, 127 of 507 patients (25%) in the atezolizumab arm and 124 of 498 (24.9%) in the BSC arm had died. The median OS in the ITT population was not estimable; the stratified hazard ratio (HR) was 0.995 [95% confidence interval (CI) 0.78-1.28]. The stratified OS HRs (95% CI) were 0.95 (0.74-1.24) in the stage II-IIIA (n = 882), 0.71 (0.49-1.03) in the stage II-IIIA PD-L1 tumour cell (TC) ≥1% (n = 476), and 0.43 (95% CI 0.24-0.78) in the stage II-IIIA PD-L1 TC ≥50% (n = 229) populations. Atezolizumab-related adverse event incidences remained unchanged since the previous analysis [grade 3/4 in 53 (10.7%) and grade 5 in 4 (0.8%) of 495 patients, respectively]. CONCLUSIONS: Although OS remains immature for the ITT population, these data indicate a positive trend favouring atezolizumab in PD-L1 subgroup analyses, primarily driven by the PD-L1 TC ≥50% stage II-IIIA subgroup. No new safety signals were observed after 13 months' additional follow-up. Together, these findings support the positive benefit-risk profile of adjuvant atezolizumab in this setting.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Adulto , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Antígeno B7-H1/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/cirugía , Resultado del Tratamiento , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
OBJECTIVES: Arterial diastolic blood pressure (DBP) greater than 25 mm Hg in infants and greater than 30 mm Hg in children greater than 1 year old during cardiopulmonary resuscitation (CPR) was associated with survival to hospital discharge in one prospective study. We sought to validate these potential hemodynamic targets in a larger multicenter cohort. DESIGN: Prospective observational study. SETTING: Eighteen PICUs in the ICU-RESUScitation prospective trial from October 2016 to March 2020. PATIENTS: Children less than or equal to 18 years old with CPR greater than 30 seconds and invasive blood pressure (BP) monitoring during CPR. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Invasive BP waveform data and Utstein-style CPR data were collected, including prearrest patient characteristics, intra-arrest interventions, and outcomes. Primary outcome was survival to hospital discharge, and secondary outcomes were return of spontaneous circulation (ROSC) and survival to hospital discharge with favorable neurologic outcome. Multivariable Poisson regression models with robust error estimates evaluated the association of DBP greater than 25 mm Hg in infants and greater than 30 mm Hg in older children with these outcomes. Among 1,129 children with inhospital cardiac arrests, 413 had evaluable DBP data. Overall, 85.5% of the patients attained thresholds of mean DBP greater than or equal to 25 mm Hg in infants and greater than or equal to 30 mm Hg in older children. Initial return of circulation occurred in 91.5% and 25% by placement on extracorporeal membrane oxygenator. Survival to hospital discharge occurred in 58.6%, and survival with favorable neurologic outcome in 55.4% (i.e. 94.6% of survivors had favorable neurologic outcomes). Mean DBP greater than 25 mm Hg for infants and greater than 30 mm Hg for older children was significantly associated with survival to discharge (adjusted relative risk [aRR], 1.32; 1.01-1.74; p = 0.03) and ROSC (aRR, 1.49; 1.12-1.97; p = 0.002) but did not reach significance for survival to hospital discharge with favorable neurologic outcome (aRR, 1.30; 0.98-1.72; p = 0.051). CONCLUSIONS: These validation data demonstrate that achieving mean DBP during CPR greater than 25 mm Hg for infants and greater than 30 mm Hg for older children is associated with higher rates of survival to hospital discharge, providing potential targets for DBP during CPR.
Asunto(s)
Reanimación Cardiopulmonar , Paro Cardíaco , Lactante , Niño , Humanos , Adolescente , Estudios Prospectivos , Presión Sanguínea , Alta del PacienteRESUMEN
OBJECTIVES: To evaluate associations between sodium bicarbonate use and outcomes during pediatric in-hospital cardiac arrest (p-IHCA). DESIGN: Prespecified secondary analysis of a prospective, multicenter cluster randomized interventional trial. SETTING: Eighteen participating ICUs of the ICU-RESUScitation Project (NCT02837497). PATIENTS: Children less than or equal to 18 years old and greater than or equal to 37 weeks post conceptual age who received chest compressions of any duration from October 2016 to March 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Child and event characteristics, prearrest laboratory values (2-6 hr prior to p-IHCA), pre- and intraarrest hemodynamics, and outcomes were collected. In a propensity score weighted cohort, the relationships between sodium bicarbonate use and outcomes were assessed. The primary outcome was survival to hospital discharge. Secondary outcomes included return of spontaneous circulation (ROSC) and survival to hospital discharge with favorable neurologic outcome. Of 1,100 index cardiopulmonary resuscitation events, median age was 0.63 years (interquartile range, 0.19-3.81 yr); 528 (48.0%) received sodium bicarbonate; 773 (70.3%) achieved ROSC; 642 (58.4%) survived to hospital discharge; and 596 (54.2%) survived to hospital discharge with favorable neurologic outcome. Among the weighted cohort, sodium bicarbonate use was associated with lower survival to hospital discharge rate (adjusted odds ratio [aOR], 0.7; 95% CI, 0.54-0.92; p = 0.01) and lower survival to hospital discharge with favorable neurologic outcome rate (aOR, 0.69; 95% CI, 0.53-0.91; p = 0.007). Sodium bicarbonate use was not associated with ROSC (aOR, 0.91; 95% CI, 0.62-1.34; p = 0.621). CONCLUSIONS: In this propensity weighted multicenter cohort study of p-IHCA, sodium bicarbonate use was common and associated with lower rates of survival to hospital discharge.
Asunto(s)
Reanimación Cardiopulmonar , Paro Cardíaco , Niño , Estudios de Cohortes , Paro Cardíaco/tratamiento farmacológico , Humanos , Lactante , Unidades de Cuidados Intensivos , Estudios Prospectivos , Bicarbonato de Sodio/uso terapéuticoRESUMEN
Importance: Approximately 40% of children who experience an in-hospital cardiac arrest survive to hospital discharge. Achieving threshold intra-arrest diastolic blood pressure (BP) targets during cardiopulmonary resuscitation (CPR) and systolic BP targets after the return of circulation may be associated with improved outcomes. Objective: To evaluate the effectiveness of a bundled intervention comprising physiologically focused CPR training at the point of care and structured clinical event debriefings. Design, Setting, and Participants: A parallel, hybrid stepped-wedge, cluster randomized trial (Improving Outcomes from Pediatric Cardiac Arrest-the ICU-Resuscitation Project [ICU-RESUS]) involving 18 pediatric intensive care units (ICUs) from 10 clinical sites in the US. In this hybrid trial, 2 clinical sites were randomized to remain in the intervention group and 2 in the control group for the duration of the study, and 6 were randomized to transition from the control condition to the intervention in a stepped-wedge fashion. The index (first) CPR events of 1129 pediatric ICU patients were included between October 1, 2016, and March 31, 2021, and were followed up to hospital discharge (final follow-up was April 30, 2021). Intervention: During the intervention period (n = 526 patients), a 2-part ICU resuscitation quality improvement bundle was implemented, consisting of CPR training at the point of care on a manikin (48 trainings/unit per month) and structured physiologically focused debriefings of cardiac arrest events (1 debriefing/unit per month). The control period (n = 548 patients) consisted of usual pediatric ICU management of cardiac arrest. Main Outcomes and Measures: The primary outcome was survival to hospital discharge with a favorable neurologic outcome defined as a Pediatric Cerebral Performance Category score of 1 to 3 or no change from baseline (score range, 1 [normal] to 6 [brain death or death]). The secondary outcome was survival to hospital discharge. Results: Among 1389 cardiac arrests experienced by 1276 patients, 1129 index CPR events (median patient age, 0.6 [IQR, 0.2-3.8] years; 499 girls [44%]) were included and 1074 were analyzed in the primary analysis. There was no significant difference in the primary outcome of survival to hospital discharge with favorable neurologic outcomes in the intervention group (53.8%) vs control (52.4%); risk difference (RD), 3.2% (95% CI, -4.6% to 11.4%); adjusted OR, 1.08 (95% CI, 0.76 to 1.53). There was also no significant difference in survival to hospital discharge in the intervention group (58.0%) vs control group (56.8%); RD, 1.6% (95% CI, -6.2% to 9.7%); adjusted OR, 1.03 (95% CI, 0.73 to 1.47). Conclusions and Relevance: In this randomized clinical trial conducted in 18 pediatric intensive care units, a bundled intervention of cardiopulmonary resuscitation training at the point of care and physiologically focused structured debriefing, compared with usual care, did not significantly improve patient survival to hospital discharge with favorable neurologic outcome among pediatric patients who experienced cardiac arrest in the ICU. Trial Registration: ClinicalTrials.gov Identifier: NCT02837497.
Asunto(s)
Reanimación Cardiopulmonar/educación , Paro Cardíaco/terapia , Enfermedades del Sistema Nervioso/etiología , Mejoramiento de la Calidad , Adolescente , Presión Sanguínea , Niño , Preescolar , Competencia Clínica , Femenino , Paro Cardíaco/complicaciones , Mortalidad Hospitalaria , Humanos , Lactante , Recién Nacido , Unidades de Cuidado Intensivo Pediátrico , Masculino , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
OBJECTIVES: No clear evidence of which surgical procedure should be performed for early stage mesothelioma is available to date. We analyzed our 10-year experience in the treatment of early stage mesothelioma with surgery and Hyperthermic IntraTHOracic Chemotherapy. METHODS: We retrospectively analyzed all cases of histologically proven epithelioid or biphasic IMIG stage I and II mesothelioma that we operated between 2005 and 2014. We performed an open pleurectomy and partial decortication of any visible lesion on the visceral pleura in all cases and both diaphragm and pericardium were always spared; Hyperthermic IntraTHOracic Chemotherapy was ran using Cisplatin 80 mg/m2 and Doxorubicin 25 mg/m2 at a target temperature of 42.5 °C for 60 min. RESULTS: We operated on 26 patients (23 male and 3 female); epithelioid tumor was diagnosed in 23 cases. Twelve patients were in IMIG stage I and 14 in IMIG stage II; median overall survival for all patients, stage I and II were 35.6, 46 and 23 months respectively and disease free survival was 18, 18 and 16 months respectively. Our results for stage I were better than those reported in literature and were similar for stage II. We observe no 30- and 90- mortality and the rate of severe complication (all CTCAE stage 3) were 30%; the median postoperative stay was 7.5 days. CONCLUSIONS: Our lung sparing approach for the treatment of pleural mesothelioma in early stages allows promising long term outcomes with a complete sparing of pulmonary and diaphragmatic function. Larger studies are needed to confirm our good results.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Mesotelioma/terapia , Neoplasias Pleurales/terapia , Anciano , Cisplatino/administración & dosificación , Terapia Combinada , Doxorrubicina/administración & dosificación , Femenino , Humanos , Hipertermia Inducida , Tiempo de Internación , Masculino , Mesotelioma/patología , Persona de Mediana Edad , Estadificación de Neoplasias , Tratamientos Conservadores del Órgano , Neoplasias Pleurales/patología , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Tasa de Supervivencia , Procedimientos Quirúrgicos TorácicosRESUMEN
BACKGROUND: Agents targeting programmed death-1 receptor (PD-1) and its ligand (PD-L1) are showing promising results in non-small-cell lung cancer (NSCLC). It is unknown whether PD-1/PD-L1 are differently expressed in oncogene-addicted NSCLC. METHODS: We analysed a cohort of 125 NSCLC patients, including 56 EGFR mutated, 29 KRAS mutated, 10 ALK translocated and 30 EGFR/KRAS/ALK wild type. PD-L1 and PD-1 expression were assessed by immunohistochemistry. All cases with moderate or strong staining (2+/3+) in >5% of tumour cells were considered as positive. RESULTS: PD-1 positive (+) was significantly associated with current smoking status (P=0.02) and with the presence of KRAS mutations (P=0.006), whereas PD-L1+ was significantly associated to adenocarcinoma histology (P=0.005) and with presence of EGFR mutations (P=0.001). In patients treated with EGFR tyrosine kinase inhibitors (N=95), sensitivity to gefitinib or erlotinib was higher in PD-L1+ vs PD-L1 negative in terms of the response rate (RR: P=0.01) time to progression (TTP: P<0.0001) and survival (OS: P=0.09), with no difference in PD1+ vs PD-1 negative. In the subset of 54 EGFR mutated patients, TTP was significantly longer in PD-L1+ than in PD-L1 negative (P=0.01). CONCLUSIONS: PD-1 and PD-L1 are differentially expressed in oncogene-addicted NSCLC supporting further investigation of specific checkpoint inhibitors in combination with targeted therapies.
Asunto(s)
Antígeno B7-H1/biosíntesis , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/metabolismo , Receptor de Muerte Celular Programada 1/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Estudios de Cohortes , Femenino , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
BACKGROUND: The randomized, phase III AVAPERL trial evaluated the safety and efficacy of bevacizumab maintenance with or without pemetrexed in nonsquamous nonsmall-cell lung cancer (nsNSCLC). Progression-free survival (PFS) was significantly prolonged with bevacizumab-pemetrexed, but overall survival (OS) data were immature. In this article, we report an independent, updated analysis of survival outcomes in AVAPERL. PATIENTS AND METHODS: Patients with advanced nsNSCLC received first-line bevacizumab (7.5 mg/kg), cisplatin (75 mg/m(2)), and pemetrexed (500 mg/m(2)) every 3 weeks (q3w) for four cycles. Nonprogressing patients were randomized to maintenance bevacizumab (7.5 mg/kg) or bevacizumab-pemetrexed (500 mg/m(2)) q3w until progression or consent withdrawal. The primary end point of the trial was PFS; in this independent OS analysis, participating study centers were contacted to collect survival data on patients still alive at the time of the first analysis. RESULTS: A total of 376 patients received induction treatment. Disease control was confirmed in 71.9% of patients; 253 patients were randomized to maintenance treatment with bevacizumab (n = 125) or bevacizumab-pemetrexed (n = 128). At a median follow-up of 14.8 months, patients allocated to bevacizumab-pemetrexed had significantly improved PFS versus those on bevacizumab when measured from randomization [7.4 versus 3.7 months, hazard ratio (HR), 0.57, 95% confidence interval (CI) 0.44-0.75); P < 0.0001]. OS events occurred in 58% of all patients. OS was numerically longer with bevacizumab-pemetrexed versus bevacizumab when measured from randomization [17.1 versus 13.2 months, HR 0.87 (0.63-1.21); P = 0.29]. Second-line therapy was administered in 77% and 70% of patients in the bevacizumab and bevacizumab-pemetrexed arms, respectively. No new adverse events were reported during this updated analysis. CONCLUSION: In an unselected population of nsNSCLC patients achieving disease control on platinum-based induction therapy, maintenance with bevacizumab-pemetrexed was associated with a nonsignificant increase in OS over bevacizumab alone.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adenocarcinoma/mortalidad , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Bevacizumab , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Cisplatino/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Glutamatos/administración & dosificación , Guanina/administración & dosificación , Guanina/análogos & derivados , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/mortalidad , Quimioterapia de Mantención , Masculino , Persona de Mediana Edad , Pemetrexed , Modelos de Riesgos Proporcionales , Calidad de Vida , Resultado del TratamientoRESUMEN
OBJECTIVE: The majority of patients with lung cancer are treated on the basis of a diagnosis made from the analysis of a small tumour biopsy or a cytological sample and histotype is becoming a critical variable in clinical workup as it has led to the introduction of newer biologically targeted therapies. Consequently, simply classifying cancers as small cell lung cancers or non-small cell lung cancers is no longer sufficient. METHODS: From 2009 to 2011, a review of the histo-cytological database was conducted to identify all small biopsy and cytology specimens collected for diagnostic purposes in patients with a thoracic lesion. In total, 941 patients were studied by examining exfoliative and/or aspirative cytological samples. To establish the accuracy of these methods, cytological and biopsy diagnoses were compared with each other and with subsequent resection specimens when available. Moreover, during the diagnostic workup, we examined a validated panel of immunohistochemical markers. RESULTS: The diagnostic concordance of pre-operative diagnoses with surgical samples was high in both cytology and biopsy samples [κ = 0.71, confidence interval (CI) = 0.6-0.81; P < 0.0001 and κ = 0.61, CI = 0.41-0.82; P < 0.0001 respectively; good agreement] but concordance between cytology and biopsy was moderate (κ = 0.5, CI = 0.43-0.54; P < 0.0001). Immunohistochemistry-aided diagnoses were definitive for histotype in 92.8% of both cytology (206/222) and biopsy (155/167) specimens. CONCLUSION: We found that lung cancer diagnosis and subtyping of cytology and biopsy samples are highly feasible and concordant; thus, the diagnostic approach to lung cancer does not require more invasive procedures.
Asunto(s)
Citodiagnóstico/métodos , Inmunohistoquímica , Neoplasias Pulmonares/diagnóstico , Anciano , Femenino , Técnicas Histológicas , Humanos , Neoplasias Pulmonares/clasificación , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Sorafenib is a small-molecule multitargeted kinase inhibitor that blocks the activation of C-RAF, B-RAF, c-KIT, FLT-3, RET, vascular endothelial growth factor receptor 2 (VEGFR-2), VEGFR-3 and platelet-derived growth factor receptor ß. The aim of this multicenter, randomized phase II study was to evaluate clinical activity and safety of sorafenib in combination with erlotinib or gemcitabine in unselected untreated elderly patients with non-small-cell lung cancer (NSCLC). METHODS: The trial was designed to select the most promising sorafenib-containing combination in previously untreated elderly (≥70 years) stage IIIB or IV NSCLC patients, with performance status of zero to two. Patients were randomly assigned to one of the following combinations: gemcitabine, 1200 mg/m(2) days 1 and 8, every 21 days, for a maximum of six cycles, plus sorafenib, 800 mg/day, until disease progression or unacceptable toxicity (arm 1); or erlotinib, 150 mg/day, plus sorafenib, 800 mg/day, until disease progression or unacceptable toxicity (arm 2). A selection design was applied with 1-year survival rate as the primary end point of the study, requiring 58 patients. RESULTS: Sixty patients were randomly allocated to the study (31 patients in arm 1 and 29 patients in arm 2). After a median follow-up of 15 months, 10 patients [32%, 95% confidence interval (CI) 16% to 49%] in arm 1 and 13 patients (45%, 95% CI 27% to 63%) in arm 2 were alive at 1 year. Median overall survival was 6.6 and 12.6 months in arm 1 and arm 2, respectively. Observed toxic effects were consistent with the expected drug profiles. CONCLUSIONS: The combination of erlotinib and sorafenib was feasible in elderly patients with advanced NSCLC and was associated with a higher 1-year survival rate than the other arm. According to the selection design, this combination warrants further investigation in phase III trials.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adenocarcinoma Bronquioloalveolar/tratamiento farmacológico , Adenocarcinoma Bronquioloalveolar/mortalidad , Anciano , Anciano de 80 o más Años , Bencenosulfonatos/administración & dosificación , Carcinoma de Células Grandes/tratamiento farmacológico , Carcinoma de Células Grandes/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/mortalidad , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Clorhidrato de Erlotinib , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/mortalidad , Masculino , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Piridinas/administración & dosificación , Quinazolinas/administración & dosificación , Sorafenib , Tasa de Supervivencia , Resultado del Tratamiento , GemcitabinaAsunto(s)
Lupus Eritematoso Cutáneo/diagnóstico , Síndromes Paraneoplásicos/diagnóstico , Síndrome de Stevens-Johnson/diagnóstico , Anciano , Carcinoma de Células Escamosas/complicaciones , Diagnóstico Diferencial , Humanos , Neoplasias Pulmonares/complicaciones , Lupus Eritematoso Cutáneo/etiología , Masculino , Síndromes Paraneoplásicos/etiologíaRESUMEN
Pleural Malignant Mesothelioma (MM) is a highly aggressive neoplasm with a poor survival rate, hard diagnosis and treatment. The incidence of MM in Western Europe countries is expected to increase drammatically in the next 10-15 years. In spite of this drammatic scenario, at this time the only instruments for screening and early diagnosis are based on radiological tests with evident ethical and economical problems. For this reason, some authors are evaluating biological indicators with the significance of screening and early diagnosis markers. One of the most promising marker is serum mesothelin (SMRP). SMRP levels appeares to be significantly related to MM and its clinical (diagnostic/prognostic) usefulnes has been suggested. The purpose of this research is to show SMRP trend in relation both to the course of the disease and the response to therapies in some Epithelioid MM patients. The analysis of SMRP levels in these patients suggests that it may be a useful marker for monitoring the response to treatment. In fact, it was observed that SMRP increases in patients who did not respond to therapy, it tends to remain stable when therapies results into a clinical stabilization, while it decreases after surgical procedure and in case of clinical improvement.
Asunto(s)
Glicoproteínas de Membrana/sangre , Mesotelioma/sangre , Neoplasias Pleurales/sangre , Anciano , Femenino , Proteínas Ligadas a GPI , Humanos , Masculino , Mesotelina , Persona de Mediana EdadRESUMEN
Recently, the number of previously asbestos-exposed workers performing, at our department, medical exams aimed at an early diagnosis of asbestos-related tumors, has been progressively increasing. The diagnostical protocol we propose to these subjects include both radiological exams and some serum markers such as mesothelin and osteopontin. In this case-report we illustrate the history of a worker who, after having diagnosed a pulmonary asbestosis, developed a Lung Cancer. The significance of this case is based on the importance of the high mesothelin dosage which prompted further radiological exams resulting into the final diagnosis. In spite of the early diagnosis and treatment the patient finally died. Nevertheless, serum markers like mesothelin and osteopontin (especially the first) may result very helpful in monitoring and screening the population of workers previously exposed to asbestos.
Asunto(s)
Amianto/efectos adversos , Asbestosis/complicaciones , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/etiología , Glicoproteínas de Membrana/sangre , Exposición Profesional/efectos adversos , Exposición Profesional/análisis , Proteínas Ligadas a GPI , Humanos , Masculino , Mesotelina , Persona de Mediana Edad , Vigilancia de la PoblaciónRESUMEN
High dosages of Serum Mesothelin have been demonstrated to be significantly associated to Pleural Malignant Mesothelioma. We recently demonstrated that Serum Mesothelin may be clinically helpful both for diagnostic and prognostic purposes, with the best cut-off corresponding to 1 nM. We also discovered that high levels of Serum Mesothelin are significantly associated to Lung Cancer. The usefulness of this marker in secondary prevention has been suggested, though never demonstrated. We therefore started a long-term prospective cohort study including previously asbestos-exposed workers. These subjects periodically underwent both radiological tests and serum mesothelin dosages. As a mid-term goal of this longitudinal study we decided to check the variability of mesothelin dosages, comparing baseline and follow-up values, as well as the possible correlation with age, duration of exposure, smoking, any abnormality of respiratory functional tests (RFT) and/or radiological tests. At baseline, Mesothelin mean value was 0.66 +/- 0.4 (range 0.08-2.2 nM). Both age (p = 0.04) and abnormal thoracic TC (p = 0.04) were significantly correlated with increased serum mesothelin levels and increasing age. No association was found between baseline mesothelin levels and duration of asbestos exposure (p = 0.5), smoking habits (p = 0.2), abnormal RFT, DLCO (carbon monoxide diffusing capacity) or thoracic X-ray. No significant variation was observed between mesothelin values at baseline and at follow-up (p = 0.2).
Asunto(s)
Amianto/efectos adversos , Glicoproteínas de Membrana/sangre , Exposición Profesional/análisis , Adulto , Anciano , Femenino , Estudios de Seguimiento , Proteínas Ligadas a GPI , Humanos , Masculino , Mesotelina , Mesotelioma/sangre , Mesotelioma/diagnóstico , Mesotelioma/etiología , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
BACKGROUND: Surgery is the choice treatment for symptomatic tracheal obstruction due to malignant thyroid disease. Few additional therapeutic alternatives are available: radiotherapy (RT), chemotherapy (CT) or radioiodine therapy (1311). Only few studies on interventional bronchoscopy (IB) as well as alternative or palliative procedures have been reported so far. This study is a retrospective report of results of IB performed in patients with severe tracheal obstruction due to advanced thyroid cancer. SETTING: Pulmonary and Endocrinology Units of a University Hospital. PATIENTS AND INTERVENTIONS: From January 2, 2000 to March 1, 2004 14 consecutive patients [5 males, mean age: 62.2+/-10.7 (SD) yr] underwent IB due to tracheal obstruction for anaplastic (ATC: 7 patients), differentiated (DTC: 5), medullary (MTC: 1) and non-epithelial malignant (NEMN: 1) thyroid cancer. Eight out of 14 patients had local advanced inoperable disease, 6 had local relapse after surgery, 1311 or RT. Ten out of 14 patients suffered from severe dyspnea. In 4 patients airway patency was maintained by insertion of a stent; in 3 the tracheal lesion was removed by Nd-YAG laser; in 7 both procedures were performed. RESULTS: All 10 patients with dyspnea showed an improvement in symptoms. Early and late complications were observed in 4 and in 3 patients, respectively. All but 4 DTC patients died 11.9+/-14.2 months after the diagnosis (4.20+/-5.1 after IB). In 4 DTC patients still alive 90.7+/-59.2 since diagnosis and 16.7+/-9.2 months since IB, the airway dilatations allowed further treatments like 131-I and/or RT. CONCLUSIONS: Interventional bronchoscopy, including Nd-YAG laser and airways stenting are alternatives to surgery in inoperable thyroid-induced tracheal obstruction. Moreover, airway dilatation improves dyspnea and may allow further treatment.