Early prediction of resistance to tyrosine kinase inhibitors by plasma monitoring of EGFR mutations in NSCLC: a new algorithm for patient selection and personalized treatment.

In Non-Small-Cell Lung Cancer (NSCLC) patients treated with Tyrosine Kinase-Inhibitors (TKIs) therapy, the emergence of acquired resistance can be investigated by plasma monitoring of circulating tumor DNA (ctDNA). A series of 116 patients with EGFR-positive lung adenocarcinomas were treated with first/second generation EGFR TKIs. At clinical progression, 64 (55%) EGFR T790M plasma positive patients were subjected to second line-treatment with osimertinib and strictly monitored during the first month of therapy. Plasma analysis by the EGFR Cobas test showed in 57 (89%) cases a substantial decrease in the levels of the sensitizing EGFR mutant allele (sEGFRma), down to a not detectable value. These patients were defined as plasmatic good responders (PGR). In 7 (11%) patients, the sEGFRma did not drop to zero (plasmatic poor responders, PPR). In these latter cases, Massive Parallel Sequencing (MPS) analysis at the end of the first month and at clinical progression showed the presence of resistant-inducing mutations, including MET and HER2 gene amplification, KRAS and PIK3CA gene mutations. PPR showed disease progression in 5 (71%) cases, stable disease in 2 (29%) cases, and a shorter median Progression-free survival (PFS) (4.3 ± 1.1 months) than that observed in PGR (13.3 ± 1.2 months) (P < 0.0001). Our data indicate that plasma monitoring by a simple RT-PCR-based EGFR mutation test in the first month of treatment may be useful for a rapid identification of patients to be subjected to further characterization by MPS. A diagnostic algorithm for an early detection of resistance-inducing mutations and patient management is reported.

A phase II study of cetuximab/irinotecan in patients with heavily pretreated metastatic colorectal cancer: predictive value of early specific toxicities.

BACKGROUND: This study was designed to evaluate the predictive value of early specific toxicities on efficacy of weekly irinotecan/cetuximab administered as salvage therapy in patients with metastatic colorectal cancer (CRC) refractory to oxaliplatin and irinotecan. PATIENTS AND METHODS: Seventy patients received a regimen composed of weekly irinotecan 125 mg/m2 as a 1-hour intravenous infusion and cetuximab 400 mg/m2 infused over 2 hours as the initial dose and 250 mg/m2 infused over 1 hour for subsequent administrations. A single treatment cycle was composed of 4 weekly irinotecan infusions followed by 2 weeks of rest. The predictive value of adverse events (AEs) attributable to cetuximab (rash) and major toxicities attributable to irinotecan (gastrointestinal [GI] and hematologic) were observed after the first cycle of treatment and, therefore, correlated to activity and efficacy of cetuximab and weekly irinotecan. RESULTS: Sixty-six of 70 patients received >or= 1 cycle of chemotherapy and were therefore evaluable for response. Overall, toxicity observed was generally mild and manageable. According to an intent-to-treat analysis, a partial response was exhibited in 15.7% of patients, with a median progression-free survival (PFS) and median overall survival time of 4 months and 9 months, respectively. As expected, PFS (P = .01) and median survival (P = .04) correlated strongly with the presence and severity of the rash. Surprisingly, the presence of at least moderate hematologic and GI toxicity was associated with improved PFS (P = .03). CONCLUSION: Our data suggest that irinotecan-induced AEs might predict a better outcome in advanced CRC. This finding would identify a different subset of patients-those likely to benefit from a renewed sensitivity to irinotecan induced by cetuximab.

Effects of trimetazidine on myocardial perfusion and left ventricular systolic function in type 2 diabetic patients with ischemic cardiomyopathy.

AIMS: To determine whether short-term treatment with trimetazidine (TMZ), an antiischemic agent that directly inhibits fatty acid oxidation and results in stimulation of glucose oxidation, may improve myocardial perfusion and left ventricular systolic function in diabetic patients with ischemic cardiomyopathy. METHODS AND RESULTS: We studied 34 clinically stable patients with type 2 diabetes mellitus (DM) and documented multivessel coronary artery disease (29 men and 5 women, mean age 54 +/- 9 years) with depressed systolic function (left ventricular ejection fraction 38 +/- 6%). Patients were randomized into two groups. One group received TMZ (20 mg tid) for 3 months (n = 19), while another group received a placebo during the same period (n = 15). On study entry and at 3 months, all patients underwent a gated Single Photon Emission Computed Tomography (SPECT) myocardial scintigraphy with a 2-day stress(Bruce)-rest protocol (500 MBq tetrofosmin). At 3 months, TMZ-treated patients had a significant improvement in systolic wall thickening (P < 0.05) and ejection fraction (P = 0.007) as compared with control patients. These effects were more marked in patients with more severe reversible perfusion defects on initial evaluation and were not associated with changes in myocardial defects (P = 0.38). Total exercise time was also improved in TMZ-treated patients (20.5%, P < 0.05 vs. controls). CONCLUSIONS: In diabetic cardiomyopathy, short-term TMZ improved left ventricular systolic function and functional capacity despite no change in myocardial perfusion. These benefits were more evident in patients with more severe perfusion defects on initial evaluation, suggesting that chronic myocardial ischemia is a requirement for the effects of TMZ on left ventricular systolic performance.

10-year exercise training in chronic heart failure: a randomized controlled trial.

OBJECTIVES: This study investigated the effect of a very long-term exercise training program is not known in chronic heart failure (CHF) patients. BACKGROUND: We previously showed that long-term moderate exercise training (ET) improves functional capacity and quality of life in New York Heart Association class II and III CHF patients. METHODS: We studied 123 patients with CHF whose condition was stable over the previous 3 months. After randomization, a trained group (T group, n = 63) underwent a supervised ET at 60% of peak oxygen consumption (Vo(2)), 2 times weekly for 10 years, whereas a nontrained group (NT group, n = 60) did not exercise formally. The ET program was supervised and performed mostly at a coronary club with periodic control sessions twice yearly at the hospital's gym. RESULTS: In the T group, peak Vo(2) was more than 60% of age- and gender-predicted maximum Vo(2) each year during the 10-year study (p < 0.05 vs. the NT group). In NT patients, peak Vo(2) decreased progressively with an average of 52 ± 8% of maximum Vo(2) predicted. Ventilation relative to carbon dioxide output (VE/Vco(2)) slope was significantly lower (35 ± 9) in T patients versus NT patients (42 ± 11, p < 0.01). Quality-of-life score was significantly better in the T group versus the NT group (43 ± 12 vs. 58 ± 14, p < 0.05). During the 10-year study, T patients had a significant lower rate of hospital readmission (hazard ratio: 0.64, p < 0.001) and cardiac mortality (hazard ratio: 0.68, p < 0.001) than controls. Multivariate analysis selected peak Vo(2) and resting heart rate as independent predictors of events. CONCLUSIONS: Moderate supervised ET performed twice weekly for 10 years maintains functional capacity of more than 60% of maximum Vo(2) and confers a sustained improvement in quality of life compared with NT patients. These sustained improvements are associated with reduction in major cardiovascular events, including hospitalizations for CHF and cardiac mortality.

Exercise-induced myocardial ischaemia detected by cardiopulmonary exercise testing.

BACKGROUND: The objective of the study was to identify the parameter(s) of cardiopulmonary exercise testing (CPET) that can detect exercise-induced myocardial ischaemia (EIMI), and to determine its diagnostic accuracy for identifying patients with coronary artery disease (CAD). METHODS AND RESULTS: We prospectively studied 202 consecutive patients (173 men, 29 women, mean age 55.7+/-10.8 years) with documented CAD. All patients underwent an incremental exercise stress testing (ECG-St) with breath-by-breath gas exchange analysis, followed by a 2-day stress/rest gated SPECT myocardial scintigraphy (GSMS) as the gold standard for ischaemia detection. ROC analysis selected a two-variable model-O(2)pulse flattening duration, calculated from the onset of myocardial ischaemia to peak exercise, and deltaVO(2)/deltawork rate slope-to predict EIMI by CPET. GSMS identified 140 patients with reversible myocardial defects, with a Summed Difference Score (SDS) of 9.7+/-2.8, and excluded EIMI in 62 (SDS 1.3+/-1.6). ECG-St had low sensitivity (46%) and specificity (66%) to diagnose EIMI as compared with CPET (87% and 74%, respectively). CONCLUSIONS: The addition of gas exchange analysis improves the diagnostic accuracy of standard ECG stress testing in identifying EIMI. A two-variable model based on O(2)pulse flattening duration and deltaVO(2)/deltawork rate slope had the highest predictive ability to identify EIMI.