Promising Effects of Afatinib on Leptomeningeal Carcinomatosis Derived from Erlotinib-resistant Lung Adenocarcinoma.

We herein report a case of a 67-year-old woman previously treated with erlotinib for adenocarcinoma with an epidermal growth factor receptor (EGFR) mutation in exon 19, which rapidly developed to progressive symptomatic leptomeningeal carcinomatosis. The primary tumor and lung metastases also worsened and the performance status (PS) score declined to 3. With a re-biopsy from the pulmonary metastases, the T790M mutation was detected by the cobas EGFR mutation test, but not the cycleave test, although an exon 19 deletion was detected by both of the tests. A week after afatinib initiation, the neurological symptoms disappeared and the PS improved to 1 with a radiological response in all disease sites. Chest physicians should consider the use of afatinib for patients with leptomeningeal carcinomatosis from 1st-generation EGFR-TKI resistant adenocarcinoma, regardless of the PS score and the presence of the T790M mutation in the extracranial lesion.

Impairment of Coronary Flow Reserve Evaluated by Phase Contrast Cine-Magnetic Resonance Imaging in Patients With Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Phase contrast (PC) cine-magnetic resonance imaging (MRI) of the coronary sinus allows for noninvasive evaluation of coronary flow reserve (CFR), which is an index of left ventricular microvascular function. The objective of this study was to investigate coronary flow reserve in patients with heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: We studied 25 patients with HFpEF (mean and SD of age: 73±7 years), 13 with hypertensive left ventricular hypertrophy (LVH) (67±10 years), and 18 controls (65±15 years). Breath-hold PC cine-MRI images of the coronary sinus were obtained to assess blood flow at rest and during ATP infusion. CFR was calculated as coronary sinus blood flow during ATP infusion divided by coronary sinus blood flow at rest. Impairment of CFR was defined as CFR <2.5 according to a previous study. The majority (76%) of HFpEF patients had decreased CFR. CFR was significantly decreased in HFpEF patients in comparison to hypertensive LVH patients and control subjects (CFR: 2.21±0.55 in HFpEF vs 3.05±0.74 in hypertensive LVH, 3.83±0.73 in controls; P<0.001 by 1-way ANOVA). According to multivariable linear regression analysis, CFR independently and significantly correlated with serum brain natriuretic peptide level (ß=-68.0; 95% CI, -116.2 to -19.7; P=0.007). CONCLUSIONS: CFR was significantly lower in patients with HFpEF than in hypertensive LVH patients and controls. These results indicated that impairment of CFR might be a pathophysiological factor for HFpEF and might be related to HFpEF disease severity.

Incremental prognostic value of the SYNTAX score to late gadolinium-enhanced magnetic resonance images for patients with stable coronary artery disease.

The prognostic significance of the SYNTAX (Synergy between PCI with Taxus and cardiac surgery) score has recently been demonstrated in patients with stable multivessel or left main coronary artery disease (CAD). The present study determines whether adding the SYNTAX score to Framingham risk score (FRS), left ventricular ejection fraction (LVEF) and presence of myocardial infarction (MI) by late gadolinium enhancement (LGE) magnetic resonance imaging can improve the risk stratification in patients with stable CAD. We calculated the SYNTAX score in 161 patients with stable CAD (mean age: 66 ± 10 years old). During a mean follow-up of 2.3 years, 56 (35 %) of 161 patients developed cardiovascular events defined as cardiovascular death, non-fatal MI, cerebral infarction, unstable angina pectoris, hospitalization due to heart failure and revascularization. Multivariate Cox regression analysis selected triglycerides [hazard ratio (HR): 1.005 (95 % confidence interval (CI): 1.001-1.008), p < 0.008], presence of LGE [HR: 6.329 (95 % CI: 2.662-15.05), p < 0.001] and the SYNTAX score [HR: 1.085 (95 % CI: 1.044-1.127), p < 0.001] as risk factors for future cardiovascular events. Adding the SYNTAX score to FRS, EF and LGE significantly improved the net reclassification index (NRI) [40.4 % (95 % CI: 18.1-54.8 %), p < 0.05] with an increase in C-statistics of 0.089 (from 0.707 to 0.796). An increase in C-statistics and significant improvement of NRI showed that adding the SYNTAX score to the FRS, LVEF and LGE incrementally improved risk stratification in patient with stable CAD.

Prognostic significance of quantitative assessment of focal myocardial fibrosis in patients with heart failure with preserved ejection fraction.

BACKGROUND: The aim of this study was to investigate the prognostic value of myocardial focal fibrosis quantified by late gadolinium enhanced (LGE) magnetic resonance imaging (MRI) in patients with heart failure with preserved ejection fraction (HFpEF). METHODS: One-hundred eleven HFpEF patients (mean age: 70 ± 14 years, 55 (50%) female) were enrolled. We excluded patients with previous history of coronary artery disease and/or ischemic pattern of hyper enhancement on LGE MRI. Myocardial enhancement was defined using signal intensity >2SD above the mean signal intensity of a remote myocardium. Major adverse cardiovascular events were defined as cardiovascular death and heart failure requiring hospitalization. RESULTS: During a mean follow up period of 851 ± 609 days, 10 events (2 cardiovascular death, 8 hospitalization for heart failure decompensation) were observed. Area under the receiver operating characteristics curve of LGE% for the detection of future events was 0.721 (95% CI: 0.628-0.802). Multivariate Cox proportional hazard analysis showed that LGE% is an independent predictor of future events after the adjustment with prognostic 5 factors - age, diabetes mellitus, New York Heart Association classification, history of heart failure hospitalization and left ventricular ejection fraction - which were identified in the I-PRESERVE study (Irbesartan in Heart Failure with Preserved Ejection Fraction Study) (hazard ratio=7.913, 95% CI: 1.603-39.05, P=0.012). CONCLUSIONS: Larger size of LGE was significantly associated with high rate of future cardiovascular death and heart failure hospitalization, suggesting that the quantification of myocardial focal fibrosis by LGE MRI could be useful for the risk stratification in HFpEF patients.

Prognostic value of cardiovascular magnetic resonance derived right ventricular function in patients with interstitial lung disease.

BACKGROUND: Cardiovascular magnetic resonance (CMR) provides non-invasive and more accurate assessment of right ventricular (RV) function in comparison to echocardiography. Recent study demonstrated that assessment of RV function by echocardiography was an independent predictor for mortality in patients with interstitial lung disease (ILD). The purpose of this study was to determine the prognostic significance of CMR derived RV ejection fraction (RVEF) in ILD patients. METHODS: We enrolled 76 patients with ILD and 24 controls in the current study. By using 1.5 T CMR scanner equipped with 32 channel cardiac coils, we performed steady-state free precession cine CMR to assess the RVEF. RV systolic dysfunction (RVSD) was defined as RVEF ≤45.0% calculated by long axis slices. Pulmonary hypertension (PH) was defined as mean pulmonary artery pressure (mPAP) of more than 25 mmHg at rest in the setting of pulmonary capillary wedge pressure ≤15 mmHg. RESULTS: The median RVEF was 59.2% in controls (n = 24), 53.8% in ILD patients without PH (n = 42) and 43.1% in ILD patients with PH (n = 13) (p < 0.001 by one-way ANOVA). During a mean follow-up of 386 days, 18 patients with RVSD had 11 severe events (3 deaths, 3 right heart failure, 3 exacerbation of dyspnea requiring oxygen, 2 pneumonia requiring hospitalization). In contrast, only 2 exacerbation of dyspnea requiring oxygen were observed in 58 patients without RVSD. Multivariate Cox regression analysis showed that RVEF independently predicted future events, after adjusting for age, sex and RVFAC by echocardiography (hazard ratio: 0.889, 95% confidence interval: 0.809-0.976, p = 0.014). CONCLUSIONS: The current study demonstrated that RVSD in ILD patients can be clearly detected by cine CMR. Importantly, low prevalence of PH (17%) indicated that population included many mild ILD patients. CMR derived RVEF might be useful for the risk stratification and clinical management of ILD patients.

Self-association of PAR-3-mediated by the conserved N-terminal domain contributes to the development of epithelial tight junctions.

PAR-3 is a scaffold-like PDZ-containing protein that forms a complex with PAR-6 and atypical protein kinase C (PAR-3-atypical protein kinase C-PAR-6 complex) and contributes to the establishment of cell polarity in a wide variety of biological contexts. In mammalian epithelial cells, it localizes to tight junctions, the most apical end of epithelial cell-cell junctions, and contributes to the formation of functional tight junctions. However, the mechanism by which PAR-3 localizes to tight junctions and contributes to their formation remains to be clarified. Here we show that the N-terminal conserved region, CR1-(1-86), and the sequence 937-1,024 are required for its recruitment to the most apical side of the cell-cell contact region in epithelial Madin-Darby canine kidney cells. We also show that CR1 self-associates to form an oligomeric complex in vivo and in vitro. Further, overexpression of CR1 in Madin-Darby canine kidney cells disturbs the distribution of atypical protein kinase C and PAR-6 as well as PAR-3 and delays the formation of functional tight junctions. These results support the notion that the CR1-mediated self-association of the PAR-3-containing protein complex plays a role during the formation of functional tight junctions.