Prospective analysis of liquid biopsies of advanced non-small cell lung cancer patients after progression to targeted therapies using GeneReader NGS platform.

BACKGROUND: In a significant percentage of advanced non-small cell lung cancer (NSCLC) patients, tumor tissue is unavailable or insufficient for genetic analyses at time to progression. We prospectively analyzed the appearance of genetic alterations associated with resistance in liquid biopsies of advanced NSCLC patients progressing to targeted therapies using the NGS platform. METHODS: A total of 24 NSCLC patients were included in the study, 22 progressing to tyrosine kinase inhibitors and two to other treatments. Liquid biopsies samples were obtained and analyzed using the GeneReadTM QIAact Lung DNA UMI Panel, designed to enrich specific target regions and containing 550 variant positions in 19 selected genes frequently altered in lung cancer tumors. Previously, a retrospective validation of the panel was performed in clinical samples. RESULTS: Of the 21 patients progressing to tyrosine kinase inhibitors with valid results in liquid biopsy, NGS analysis identified a potential mechanism of resistance in 12 (57%). The most common were acquired mutations in ALK and EGFR, which appeared in 8/21 patients (38%), followed by amplifications in 5/21 patients (24%), and KRAS mutations in one patient (5%). Loss of the p.T790M was also identified in two patients progressing to osimertinib. Three of the 21 (14%) patients presented two or more concomitant alterations associated with resistance. Finally, an EGFR amplification was found in the only patient progressing to immunotherapy included in the study. CONCLUSIONS: NGS analysis in liquid biopsies of patients progressing to targeted therapies using the GeneReader platform is feasible and can help the oncologist to make treatment decisions.

Phase II clinical trial with gemcitabine and paclitaxel sequential monotherapy as first-line treatment for advanced non-small-cell lung cancer (SLCG 01-04).

BACKGROUND: In advanced-stage (IIIB or IV) non-small-cell lung cancer (NSCLC), combination chemotherapy has demonstrated response rates of 20% and a 1-year survival rate of 30%. We conducted a multicentre, open-label, nonrandomised phase II trial to determine the efficacy and tolerability of sequential monotherapy with gemcitabine followed by paclitaxel in chemotherapy-naïve patients with advanced NSCLC. MATERIALS AND METHODS: Between December 2002 and July 2004, the Spanish Lung Cancer Group (SLCG) conducted a study in which 34 patients with advanced (stage IIIB or IV) NSCLC received 1200 mg/m(2) of i.v. gemcitabine on days 1, 8 and 15 of each 28-day cycle for a total of 3 cycles followed by 100 mg/m(2) of weekly i.v. paclitaxel for a maximum of 8 weeks. If objective response or stable disease was achieved, 70 mg/m(2) of weekly i.v. paclitaxel was maintained until disease progression was evident or toxic effects were intolerable. Lung Cancer Symptom Scale (LCSS) analysis was performed. Baseline levels of serum VEGF, EGFR, telomerase reverse transcriptase (hTERT) and K-ras mutations were analysed. The primary endpoint was the objective response rate. RESULTS: The median age of the 34 patients who were enrolled was 67 years (range 46-77), but later 8 patients were excluded; 78.8% were men, 81.8% had performance status 1 and also 81.8% had metastatic disease at diagnosis. The objective response rate was 28% (95% CI, 14.2-47.8); the median overall survival was 7.2 months (95% CI, 2.1-12.3) and the median time to progression (TTP) was 3.1 months (95% CI, 2.5-5.3). Grade 3 or 4 drug-related haematological toxicities were observed in 6 patients. Patients with lower baseline serum VEGF levels had significantly longer survival. CONCLUSIONS: Sequential therapy with gemcitabine followed by paclitaxel was well tolerated with a low proportion of grade 3 or 4 adverse events, the absence of unexpected toxicity and with an improvement in quality of life. Unfortunately, the response rate did not meet the minimally required rate of 20% and the study was prematurely closed. VEGF was identified as a poor prognostic factor for TTP and survival.

Minor myocardial damage detected by troponin T is a powerful predictor of long-term prognosis in patients with acute decompensated heart failure.

BACKGROUND: The progression of chronic heart failure (CHF) is characterized by frequent exacerbation requiring hospitalization and high mortality. Clinical deterioration is triggered by many factors that could promote ongoing myocytes injury. We sought to determine whether a specific marker of cardiac injury, troponin T (cTnT), is associated with prognosis in acute decompensated heart failure (ADHF). METHODS: One hundred and eighty-four consecutive patients with ADHF were enrolled in the absence of an acute coronary syndrome. A cTnT value> or =0.1 ng/ml in samples drawn at 6, 12 or 24 h after hospital admission was considered abnormal. RESULTS: Increased levels of cTnT were found in 58 patients (31.5%, group 1). There were no significant differences between group 1 and patients with cTnT<0.1 ng/ml (group 2) in terms of demographic and clinical characteristics, although ischemic etiology was more prevalent in group 1 (51.7% vs. 31.7%, p=0.009). During follow-up, the mortality in groups 1 and 2 was 31% and 17.5% (p=0.038, OR=2.13, 95% CI: 1.03-4.69), respectively. The 3-year free-CHF readmission survival in group 1 and 2 was 25% and 53% (log rank test p=0.015). In a Cox proportional hazard model, poor tissue perfusion (HR=2.46, 95% CI=1.31-4.6), previous infarction (HR=1.99, 95% CI=1.02-3.9) and cTnT> or =0.1 ng/ml (HR=1.74, 95% CI=1.05-2.9) emerged as the independent predictors of long-term outcome. CONCLUSIONS: One third of patients with decompensated CHF had elevated levels of cTnT. Troponin T was an independent long-term prognostic marker of morbidity and mortality and it suggests a role of biochemical risk stratification in this setting.

High levels of troponin T are associated with ventricular remodeling and adverse in-hospital outcome in heart failure.

BACKGROUND: Heart failure progression is associated with ventricular remodeling and ongoing myofibrillar degradation. We hypothesized that myocardial damage, detected by high levels of troponin T, would correlate with echocardiographic measurements of left ventricular remodeling and worse in-hospital course in decompensated heart failure. MATERIAL/METHODS: 159 patients with decompensated heart failure without acute coronary event were included. A troponin T value >0.2 ng/ml in samples taken 6, 12 or 24 hours after admission was considered abnormal. RESULTS: High troponin T levels were identified in 24 patients (15%) (Group 1). Mean age for group 1 was 65.9 vs. 63.7 years in patients with troponin T<0.2 (Group 2) (p=ns). Ischemic etiology in groups 1 and 2 was found in 58.3 and 38.5% (p=0.07). Two-dimensional echocardiograms in groups 1 and 2 revealed higher left ventricular diameters, diastolic (61.7+/-10 vs. 56.9+/-10.3 mm, p=0.041) as well as systolic (49.4+/-13.5 vs. 42.0+/-12.0 mm, p=0.012), and lower ejection fraction (30.1+/-14 vs. 39.0+/-17.7%, p=0.03). Incidence of combined end point of death or refractory heart failure was 20.8 and 3.7% in groups 1 and 2 (p=0.007; OR=6.8; CI95%=1.5-31.2). In a multiple regression model, a history of infarction and chronic obstructive pulmonary disease, tissue hypoperfusion, radiographic pulmonary edema, and high troponin T levels emerged as the independent predictors. CONCLUSIONS: High troponin T levels were found in 15% of patients with acute exacerbation of heart failure; this finding was independently associated with worse prognosis. Echocardiograms suggested that more severe ventricular remodeling is one subjacent mechanism related with biochemically detected myocardial injury in this setting.

Indicadores pronósticos en la angina inestable: papel de la troponina T cuantitativa / Prognostic markers in unstable angina: role of the quantitative T-troponine determination

Con el objetivo de identificar marcadores pronósticos en la angina inestable fueron incluídos en este estudio 335 pacientes, a quienes se les realizaron determinaciones de CPK, CK-MB y troponina T entre 6 y 24 horas. A 30 días el 21,9 por ciento tuvo una angina refractaria y el 11,4 por ciento sufrió infarto o murió. Una troponina T mayor o igual 0,1 ng/ml fue considerada positiva, detectándose en el 23,7 por ciento. La angina recurrente y una troponina T > 0,1 ng/ml se asociaron, en el análisis multivariado, con la evolución a infarto o muerte; mientras que ambos predictores, el angor de reposo y el alto riesgo inicial, son marcadores independientes de la evolución a infarto, óbito o angina refractaria

Indicadores pronósticos en la angina inestable: papel de la troponina T cuantitativa / Prognostic markers in unstable angina: role of the quantitative T-troponine determination

Con el objetivo de identificar marcadores pronósticos en la angina inestable fueron incluídos en este estudio 335 pacientes, a quienes se les realizaron determinaciones de CPK, CK-MB y troponina T entre 6 y 24 horas. A 30 días el 21,9 por ciento tuvo una angina refractaria y el 11,4 por ciento sufrió infarto o murió. Una troponina T mayor o igual 0,1 ng/ml fue considerada positiva, detectándose en el 23,7 por ciento. La angina recurrente y una troponina T > 0,1 ng/ml se asociaron, en el análisis multivariado, con la evolución a infarto o muerte; mientras que ambos predictores, el angor de reposo y el alto riesgo inicial, son marcadores independientes de la evolución a infarto, óbito o angina refractaria (AU)