A real-world study of Afatinib plus ramucirumab in treatment-naïve, EGFR-mutated, non-small cell lung cancer.

BACKGROUND: Recent reports suggested combining ramucirumab with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) to overcome EGFR resistance in non-small cell lung cancer (NSCLC). Nonetheless, evidence supporting the activity of afatinib and ramucirumab is lacking. This study investigated the survival benefits and safety profile of afatinib plus ramucirumab in patients with treatment-naïve, EGFR-mutated, metastatic NSCLC. MATERIALS AND METHODS: The medical records of patients with EGFR-mutated NSCLC were retrospectively retrieved. Patients who received first-line sequential afatinib followed by ramucirumab and the first-line combination of afatinib plus ramucirumab were included. The Kaplan-Meier was used to estimate the progression-free survival (PFS) of all included patients, patients on sequential afatinib followed by ramucirumab (PFS1), and patients on the up-front combination of afatinib and ramucirumab (PFS2). RESULTS: Thirty-three patients were included (25 women; median age: 63 [45-82] years). The median follow-up of the included patients was 17 months (range 6-89 months). the median PFS for the whole cohort was 71 months (95% CI 67.2-74.8) with eight events during the follow-up. The median PFS1 and PFS2 were 71 months (95 CI not defined) and 26 months (95% CI 18.6-33.4), respectively. In terms of OS, the median OS for all patients and patients on sequential treatment was not defined, while the median OS for patients on upfront combination was 30 months (95% CI 20.9-39.1). There was no significant association between EGFR mutation type and PFS1 or PFS2. CONCLUSIONS: Afatinib plus ramucirumab could improve the PFS of patients with EGFR-positive NSCLC at a predictable safety profile. Our data also suggest a survival benefit of adding ramucirumab to afatinib in patients with uncommon mutations, which should be investigated further.

Bay 60-7550, a PDE2 inhibitor, exerts positive inotropic effect of rat heart by increasing PKA-mediated phosphorylation of phospholamban.

This study investigated the hemodynamic effect of Bay 60-7550, a phosphodiesterase type 2 (PDE2) inhibitor, in healthy rat hearts both in vivo and ex vivo and its underlying mechanisms. In vivo rat left ventricular pressure-volume loop, Langendorff isolated rat heart, Ca2+ transient of left ventricular myocyte and Western blot experiments were used in this study. The results demonstrated that Bay 60-7550 (1.5 mg/kg, i. p.) increased the in vivo rat heart contractility by enhancing stroke work, cardiac output, stroke volume, end-diastolic volume, heart rate, and ejection fraction. The simultaneous aortic pressure recording indicated that the systolic blood pressure was increased and diastolic blood pressure was decreased by Bay 60-7550. Also, the arterial elastance which is proportional to the peripheral vessel resistance was significantly decreased. Bay 60-7550 (0.001, 0.01, 0.1, 1 µmol/l) also enhanced the left ventricular development pressure in non-paced and paced modes with a decrease of heart rate in non-paced model. Bay 60-7550 (1 µmol/l) increased SERCA2a activity and SR Ca2+ content and reduced SR Ca2+ leak rate. Furthermore, Bay 60-7550 (0.1 µmol/l) increased the phosphorylation of phospholamban at 16-serine without significantly changing the phosphorylation levels of phospholamban at 17-threonine and RyR2. Bay 60-7550 increased the rat heart contractility and reduced peripheral arterial resistance may be mediated by increasing the phosphorylation of phospholamban and dilating peripheral vessels. PDE2 inhibitors which result in a positive inotropic effect and a decrease in peripheral resistance might serve as a target for developing agents for the treatment of heart failure in clinical settings.

Increased sarcoplasmic/endoplasmic reticulum calcium ATPase 2a activity underlies the mechanism of the positive inotropic effect of ivabradine.

NEW FINDINGS: What is the central question of this study? The therapeutic effect of ivabradine on patients with chronic heart failure and chronic stable angina pectoris is mediated through a reduction in heart rate: what are the haemodynamic characteristics and the mechanism of the inotropic effect? What is the main finding and its importance? Ivabradine has a positive inotropic effect and lowers the heart rate both in vivo and in vitro. These effects are likely mediated by ivabradine's significant increase of the fast component rate constant mediated by sarcoplasmic/endoplasmic reticulum calcium ATPase 2a and decrease of the slow component rate constant that is mediated by the Na+ /Ca2+ exchanger and sarcolemmal Ca2+ -ATPase during the Ca2+ transient decay phase. ABSTRACT: Ivabradine's therapeutic effect is mediated by a reduction of the heart rate; however, its haemodynamic characteristics and the mechanism of its inotropic effect are poorly understood. We aimed to investigate the positive inotropic effect of ivabradine and its underlying mechanism. The results demonstrated that ivabradine increased the positive inotropy of the rat heart in vivo by increasing the stroke work, cardiac output, stroke volume, end-diastolic volume, end-systolic pressure, ejection fraction, ±dP/dtmax , left ventricular end-systolic elastance and systolic blood pressure without altering the diastolic blood pressure and arterial elastance. This inotropic effect was observed in both non-paced and paced rat isolated heart. Ivabradine increased the Ca2+ transient amplitude and the reuptake rates of sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a), lowered the diastolic Ca2+ level and suppressed the combined extrusion rate of the Na+ /Ca2+ exchanger and the sarcolemmal Ca2+ -ATPase. In addition, ivabradine widened the action potential duration, hyperpolarized the resting membrane potential, increased sarcoplasmic reticulum Ca2+ content and reduced Ca2+ leak. Overall, ivabradine had a positive inotropic effect brought about by enhanced SERCA2a activity, which might be mediated by increased phospholamban phosphorylation. The positive inotropic effect along with the lowered heart rate underlies ivabradine's therapeutic effect in heart failure.

[Relationship between nasal inverted papilloma and human papillomavirus subtypes].

OBJECTIVE: To study the distribution of human papillomavirus (HPV) subtypes in nasal inverted papilloma (NIP), and to evaluate the relationship between HPV and NIP. METHODS: Twenty-one HPV subtypes were detected in paraffin-embedded tissues of 101 cases of NIP by flow through hybridization and gene chip (HybriMax), 24 cases of normal nasal mucosa were used as controls. RESULTS: HPV positive rates of NIP were 64.36% (65/101). Benign NIP group, NIP with atypical hyperplasia group, NIP with cancerous group of HPV positive rates were 59.7% (46/77), 81.8% (18/22) and 50% (1/2) respectively. The control group was negative (0/24). The comparison between NIP group and control group was statistically significant (chi(2) = 32.178, P < 0.05). Benign NIP group and NIP with atypical hyperplasia group were compared, but no statistically significance (chi(2) = 3.649, P = 0.056) was found. The constituent ratio of benign NIP group and NIP with atypical hyperplasia group in high, low-risk HPV subtypes infections was compared, a statistically significance (chi(2) = 10.412, P < 0.05) was found. CONCLUSIONS: The occurrence of NIP was related with HPV infection. High-risk HPV subtype infections or multiple infections will prompt benign NIP to NIP with atypical hyperplasia. Understanding the distribution of HPV subtypes in the NIP is helpful to predict the clinical behavior.