Shah-Hwa Chou

Liver metastasis predicts poorer prognosis in stage IV lung adenocarcinoma patients receiving first-line gefitinib

OBJECTIVES Gefitinib is currently used as a first-line therapy in patients of advanced non-small cell lung cancer (NSCLC) with susceptible epidermal growth factor receptor (EGFR) mutations. However, treatment outcomes of these patients vary. This study was conducted to evaluate the impact of specific metastatic sites on treatment outcomes of patients with stage IV lung adenocarcinoma with susceptible EGFR mutations receiving first-line gefitinib, focusing on the impact of liver metastasis. MATERIALS AND METHODS Between October 2009 and April 2014, patients of stage IV lung adenocarcinoma harboring EGFR mutation in exon 19 or 21, who received first-line gefitinib treatment, were enrolled in two hospitals and followed until December 22, 2014. The impacts of various clinical features, including sex, age, smoking history, performance status, EGFR mutation site, metastatic sites, etc., on progression-free survival (PFS) and overall survival (OS) were analyzed. RESULTS A total of 148 patients were eligible for analysis. Patients with liver metastasis on initial diagnosis (n=19) had shorter PFS and OS than those without liver metastasis did (median of PFS, 6.7 vs. 11.2 months, p<0.0001; median of OS, 9.2 vs. 17.5 months, p<0.0001). Multivariable Cox regression analysis showed liver metastasis was an independent poor prognostic factor for PFS (HR=2.939 [95% CI: 1.729-4.997], p<0.0001) and OS (HR=3.300 [95% CI: 1.708-6.373], p=0.0004). CONCLUSION Liver metastasis predicts poorer PFS and OS in stage IV lung adenocarcinoma patients with susceptible gene mutations receiving first-line gefitinib. Further study is warranted to elucidate the underlying mechanisms and find treatment modalities to improve prognosis of these patients.

Attenuation of pulmonary hypertension secondary to left ventricular dysfunction in the rat by Rho-kinase inhibitor fasudil.

Pulmonary hypertension (PH) in left ventricular dysfunction is attributable not only to backward failure of the left ventricle, but also to increased pulmonary vascular resistance (PVR) in some patients. Recently, Rho‐kinase has been known as a potent growth stimulator and mediator of vasoconstriction, and Rho‐kinase inhibitors could ameliorate PVR, little is known about the role of Rho‐kinase in left ventricular dysfunction‐induced PH. We utilized the ascending aortic‐banded rat and assessed the effect of Rho‐kinase inhibitor fasudil on the development of PH secondary to left ventricular dysfunction. Subsequently, in rats subjected to aortic banding for 6 weeks, there were increases in mean pulmonary arterial pressure, pulmonary arteriolar medial thickness, active RhoA, Rho‐kinase II, Rho‐kinase activity, endothelial nitric oxide synthase (eNOS) and endothelin‐1(ET‐1) concomitant with decreased levels in NO and cGMP in the lung. Treatment with fasudil at a dose of 30 mg/kg/day from days 1 to 28 or from days 29 to 42 decreased the mean pulmonary arterial pressure by 57% and 56%, right ventricular hypertrophy by 31% and 30%, pulmonary arteriolar medial thickness by 50% and 50%, and pulmonary expression of Rho‐kinase II by 41% and 28%, respectively, as well as augmented pulmonary expression of eNOS by 16% and 31% and NO by 50% and 76%, respectively, when compared with the vehicle controls. In conclusion, these results suggest that inhibition of Rho‐kinase may provide therapeutic potential for preventing and attenuating the development of PH in left ventricular dysfunction. Further translational study in human is needed to substantiate the findings. Pediatr Pulmonol. 2011; 46:45–59.

Effects of sildenafil on pulmonary hypertension and levels of ET-1, eNOS, and cGMP in aorta-banded rats.

Sildenafil, an oral phosphodiesterase Type 5 inhibitor, has vasodilatory effects through a cGMP-dependent mechanism. We previously showed that aortic banding could result in left ventricular overloading and pulmonary hypertension (PH). In this study, we investigated whether early administration of sildenafil, either immediately after or 2 weeks after aortic banding, could ameliorate the development of PH and alter gene expression of endothelin (ET)-1 and endothelial nitric oxide synthase (eNOS), and alter the levels of cGMP in rats undergoing an ascending aortic banding. Rats (n = 32) were divided into sham-operated and banding groups with or without treatment. The banded rats were further divided into three groups: (i) receiving saline on Days 1–28 (AOB28; n = 8), (ii) receiving saline on Days 1–14 followed by treatment with 50 mg/kg/day sildenafil on Days 15–28 (AOB28/Sil15–28; n = 8), and (iii) receiving 50 mg/kg/day sildenafil on days 1–28 (AOB28/Sil1–28; n = 8). The sham-operated rats were administrated saline on Days 1–28 (n = 8). Four weeks after banding, there was a significant development of PH with pulmonary vascular remodeling. Although both sildenafil-treatment groups had significant increases in cGMP and had reductions in the thickening in the medial layer of pulmonary arteriole, notable attenuation of PH occurred only in the AOB28/Sil1–28 group. PreproET-1 and eNOS messenger RNA (mRNA) expressions were measured by competitive reverse transcription polymerase chain reaction, and eNOS protein was determined by Western blotting. Sildenafil did not alter the elevated ET-1 or preproET-1 mRNA in banded rats. Interestingly, pulmonary eNOS increased in the AOB28/Sil1–28 group. In conclusion, early treatment with sildenafil inhibited the rise in pulmonary arterial pressure and pulmonary vascular remodeling in PH secondary to heart failure, and cGMP, but not ET-1, might be involved. Clinically, early repeated administration of sildenafil may offer an alternative in protecting against PH in heart failure.

Comparison of needlescopic and conventional video-assisted thoracic surgery for primary spontaneous pneumothorax

Abstract Whether the outcome of primary spontaneous pneumothorax (PSP) when treated with needlescopic video-assisted thoracic surgery is positive is still under scrutiny. The present study was conducted to compare the needlescopic approach with the conventional approach. One-hundred and six patients with primary spontaneous pneumothorax who had undergone needlescopic video-assisted thoracic surgery (NVATS) between May 2006 and August 2008 were reviewed. Their age, gender, smoking status, BMI, side of attack, operative indications, operative time, intraoperative blood loss, postoperative length of stay, postoperative pain in visual analog scale (VAS), postoperative recurrence and follow-up period were recorded. These data were compared with those of 89 patients with PSP who had undergone conventional video-assisted thoracic surgery (CVATS) between June 2002 and April 2006. The operative time was shorter (NVATS: 82.36 ± 35.58 min, CVATS: 99.78 ± 35.74 min; p = 0.008) and intraoperative blood loss was less (NVATS: 16.67 ± 25.90 ml, CVATS: 24.36 ± 26.86 ml; p = 0.04) for the NVATS group. The postoperative pain in VAS was significantly less in NVATS. No major complication or mortality was found in either group. For treatment of primary spontaneous pneumothorax, NVATS is a safe and effective option. Further, it has the added benefit of less pain and improved cosmetics.

Statins ameliorate pulmonary hypertension secondary to left ventricular dysfunction through the Rho‐kinase pathway and NADPH oxidase

Pulmonary hypertension (PH) is a devastating disorder, for which no therapy is curative. It has been reported that pulmonary vascular remodeling, associated with increasing mean pulmonary arterial pressure and upregulated expression of endothelial nitric oxide synthase (eNOS), endothelin‐1 (ET‐1), RhoA/RhoH‐kinase results in the development of PH. Oxidative stress and the RhoA/Rho‐kinase pathway are also thought to be involved in the pathophysiology of PH. Statins are 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors (HMG‐CoA reductase inhibitors) with pleiotropic effects and are potential agents for the treatment of PH. In this study, we investigated the beneficial effects of simvastatin on the development of PH secondary to left ventricular dysfunction.

Poorer prognosis in Taiwanese female ever smokers with stage IV lung adenocarcinoma who were readministered a tyrosine kinase inhibitor.

Background Readministering a second epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in patients with lung adenocarcinoma with acquired resistance to an initial EGFR TKI is a common treatment strategy. However, the prognostic factors for the second EGFR TKI are still uncertain. Patients and methods In this retrospective study, we enrolled patients with stage IV lung adenocarcinoma diagnosed between June 2009 and October 2013 at two university-affiliated hospitals in Taiwan. Basic characteristics including age, sex, smoking status, performance status, EGFR mutation status, tumor response, and progression-free survival (PFS) of the second EGFR TKI (PFS2) were recorded. Results A total of 72 patients with stage IV adenocarcinoma with susceptible EGFR gene mutations who had been treated with a second EGFR TKI were enrolled. Survival analysis using the Kaplan–Meier method and log-rank test showed a significant difference in PFS2 when classifying the patients according to smoking history and sex (P=0.0179). When stratifying the patients by sex, a significant difference was found in PFS2 between ever smokers and never smokers in the female (1.87 vs 4.87 months, P=0.0081) but not in the male (2.83 vs 2.9 months, P=0.9605) patients. A reduced multivariate model developed using the backward variable selection method showed that only ever smoking remained an independent poor prognostic factor for PFS2, and that sex and ever smoking remained independent poor prognostic factors for PFS2 in the female patients (hazard ratio [HR] =3.386, 95% confidence interval [CI]: 1.015–11.298, P=0.0473). Conclusion This study is the first to demonstrate that female ever smokers have a poorer PFS if they have acquired resistance to an initial EGFR TKI and receive a second EGFR TKI. Further large-scale studies are urgently needed to elucidate the mechanism.

Use of glutaraldehyde solution in the treatment of acute aortic dissections

We report on a promising method for toughening and strengthening the fragile aortic wall that involves the direct application of a 25% glutaraldehyde solution and that has proved to be both technically simple and safe. The operation was successfully employed in 5 patients with acute aortic dissections, 3 with a Stanford type A and 2 with a type B dissection. Histologic examination of the glutaraldehyde-treated portions of the aortic wall showed no detectable difference between them and the sections of untreated aortic wall. All patients survived the operation. The duration of follow-up ranged from 9 to 31 months (mean, 14.0 months). All 5 patients were in good condition at the time of the last follow-up. The preliminary results indicate that the use of a 25% glutaraldehyde solution to strengthen the aortic wall during operations for the repair of acute aortic dissections, regardless of whether they are type A or type B, may reduce the incidence of catastrophic perioperative bleeding and promote favorable results.

Pemetrexed had significantly better clinical efficacy in patients with stage IV lung adenocarcinoma with susceptible EGFR mutations receiving platinum-based chemotherapy after developing resistance to the first-line gefitinib treatment

Background Increased evidences show that epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors such as gefitinib could prolong progression-free survival (PFS) compared with cytotoxic chemotherapy for metastatic lung nonsquamous cell carcinoma harboring susceptible EGFR mutation, and gefitinib was served as the first-line therapy. However, acquired resistance is inevitable, but the salvage therapies are still unclear. Patients and methods We designed a retrospective study of the salvage therapy and enrolled patients with stage IV lung adenocarcinoma who had mutated EGFR and developed an acquired resistance to the first-line gefitinib in two university-affiliated hospitals in Taiwan during June 2011 to December 2014. Age, sex, smoking history, EGFR gene mutation, performance statuses, response rate, PFS2 (the PFS in salvage therapy), and overall survival (OS2, the OS in salvage therapy) were recorded. Results Two hundred and nine patients with mutated EGFR and who took gefitinib as first-line therapy were identified in the period, and a total of 98 patients who had been treated with salvage therapy with cytotoxic chemotherapy or erlotinib were eligible for this study. The overall response rate of second salvage therapy is 13%, and none of them received erlotinib. Patients who received chemotherapy had a trend for better PFS2 than those who received erlotinib (4.3 months vs 3.0 months, P=0.1417) but not in OS. Furthermore, patients who received platinum-based doublet had a trend for better PFS2 and a significantly better OS2 than those who received chemotherapy without platinum (PFS2: 4.9 months vs 2.6 months, P=0.0584; OS2: 16.1 months vs 6.7 months, P=0.0007). Analyses of the patients receiving platinum-based doublet showed that patients receiving pemetrexed had a significantly better PFS2 (6.4 months vs 4.1 months, P=0.0083) and a trend for better OS2 than those without pemetrexed treatment. Conclusion Pemetrexed-based platinum chemotherapy may be the most optimal therapy in acquired resistance to gefitinib. Further prospective randomized controlled study is needed urgently.

The effects of debanding on the lung expression of ET-1, eNOS, and cGMP in rats with left ventricular pressure overload.

Pulmonary hypertension (PH) usually develops secondary to left ventricular (LV) dysfunction; therefore, it is also called retrograde PH. To investigate our hypothesis that PH is at least partially reversible, as in some congenital heart diseases, in a rat model we investigated whether release of constriction could attenuate pulmonary vascular remodeling and change the expression of endothelin (ET)-1 and endothelial nitric oxide synthase (eNOS). We used rats with LV dysfunction produced by an ascending aortic banding. In this study, there were four groups enrolled: 4-weeks banded (AOB1–28; n = 7), 7-weeks banded (AOB1–49; n = 7), debanded groups (AOB1–28/DeB29–49; n = 7), and rats receiving a sham operation (n = 7). Subsequently, there was significant attenuation of medial hypertrophy in pulmonary arterioles and reversal of PH in the AOB1–28/DeB29–49 group (sham, 19 ± 1.3 mm Hg; AOB1–28, 31 ± 2.7 mm Hg; AOB1–49, 32 ± 2.7 mm Hg; and AOB1–28/DeB29–49, 20 ± 1.3 mm Hg). PreproET-1 mRNA and eNOS mRNA were measured by competitive reverse transcriptase (RT) polymerase chain reaction (PCR), and eNOS was measured by Western blotting. Compared with the banded groups, debanding significantly decreased pulmonary preproET-1 mRNA, pulmonary ET-1 (sham, 210 ± 12 pg/g protein; AOB1–28, 242 ± 12 pg/g protein; AOB1–49, 370 ± 49 pg/g protein; and AOB1–28/DeB29–49, 206 ± 1.9 pg/g protein), and plasma ET-1 levels (sham, 10.1 ± 1.5 pg/ml; AOB1–28, 13.4 ± 2.0 pg/ml; AOB1–49, 15.4 ± 2.0 pg/ml; and AOB1–28/DeB29–49, 10.3 ± 0.9 pg/ml protein). Debanding could not, however, alter pulmonary eNOS, eNOS mRNA, or cGMP. These findings suggest that pulmonary vascular remodeling, increased pulmonary arterial pressure, and upregulation of ET-1 gene expression are all reversible. We infer that it is the upregulated gene expression of ET-1, not eNOS, that is closely related to the development of the PH secondary to 4 weeks of aortic banding.

The Synthetic β-Nitrostyrene Derivative CYT-Rx20 Inhibits Esophageal Tumor Growth and Metastasis via PI3K/AKT and STAT3 Pathways

The β-nitrostyrene family have been implicated for anti-cancer property. However, the pharmacological role of β-nitrostyrene in esophageal cancer remain unclear. Here, a β-nitrostyrene derivative, CYT-Rx20, was synthesized and assessed for its anti-cancer activities and underlying mechanism in esophageal cancer. CYT-Rx20 induced cytotoxicity in esophageal cancer cells by promoting apoptosis through activation of caspase cascade and poly(ADP-ribose) polymerase (PARP) cleavage. Besides, CYT-Rx20 inhibited esophageal cancer cell migration and invasion by regulating the expression of epithelial to mesenchymal transition (EMT) markers. CYT-Rx20 decreased cell viability and migration through suppression of the PI3K/AKT and STAT3 pathways. Of note, the cytotoxicity and anti-migratory effect of CYT-Rx20 were enhanced by co-treatment with SC79 (AKT activator) or colivelin (STAT3 activator), suggesting the dependency of esophageal cancer cells on AKT and STAT3 for survival and migration, an oncogene addiction phenomenon. In xenograft tumor-bearing mice, CYT-Rx20 significantly reduced tumor growth of the implanted esophageal cancer cells accompanied by decreased Ki-67, phospho-AKT, and phospho-STAT3 expression. In orthotopic esophageal cancer mouse model, decreased tumor growth and lung metastasis with reduced Ki-67 and phospho-STAT3 expression were observed in mice treated with CYT-Rx20. Together, our results suggest that CYT-Rx20 is a potential β-nitrostyrene-based anticancer compound against the tumor growth and metastasis of esophageal cancer.