Gray matter differences associated with menopausal hormone therapy in menopausal women: a DARTEL-based VBM study.

Menopausal hormone therapy (MHT) in women can reduce troublesome menopause symptoms and prevent cognitive decline. This cross-sectional study investigated the MHT-related effect on brain morphology and its association with sex hormones in menopausal women by using an optimized diffeomorphic anatomical registration through exponentiated Lie algebra (DARTEL)-based voxel-based morphometry (VBM) method. Twenty-one menopausal women without MHT (noMHT) and 20 menopausal women with MHT were included in this study. Magnetic resonance imaging data were processed using SPM 12 with DARTEL-based VBM whole brain analysis approach. A 2-sample t-test and analysis of covariance (ANCOVA) adjusting for age and total intracranial volume were used to compare GM volume between noMHT and MHT women. The association between MHT (treatment period, hormones levels) and brain volume variations were analyzed by Spearman correlation. MHT women showed significantly larger volumes of the superior/middle/inferior frontal gyri, hypothalamus, inferior temporal gyrus, parahippocampal gyrus, hippocampus, cerebellar cortex, postcentral gyrus, precuneus, angular gyrus, supplementary motor area, superior occipital gyrus, and precentral gyrus compared to the noMHT women. The volumes of the angular gyrus and hypothalamus in MHT women positively correlated with treatment period. On the other hand, the hypothalamic volume negatively correlated with FSH and LH levels, and the volumes of the inferior frontal gyrus, and angular gyrus negatively correlated with progesterone levels, respectively. MHT-treated women showed larger GM volume than noMHT women. The anatomical structures that showed greater volume in association with MHT included the deep brain areas, frontal, temporal, parietal, and occipital gyri.

Comparison of Core Body Temperatures in Patients Administered Remimazolam or Propofol during Robotic-Assisted and Laparoscopic Radical Prostatectomy.

Background and Objectives: Different types of anesthetics affect thermoregulatory mechanisms, such as the redistribution of body temperature, loss of skin heat, or inhibition of thermoregulatory vasoconstriction. Therefore, we compared remimazolam with propofol in terms of core body temperature in patients undergoing robotic-assisted and laparoscopic radical prostatectomy. Materials and methods: Ninety patients were randomly assigned to either the propofol−remifentanil (PR) group or the remimazolam−remifentanil (RR) group. The PR group (n = 45) received effect-site concentrations of 6.0 µg/mL of propofol and 4 ng/mL of remifentanil, followed by 0.9 mg/kg of 1% rocuronium and maintenance with effect-site concentrations of 2−4 µg/mL of propofol and 3 ng/mL of remifentanil. The RR group (n = 45) received remimazolam 6 mg/kg/h by continuous intravenous infusion and the effect-site concentration of 4 ng/mL of remifentanil, followed by 0.9 mg/kg of 1% rocuronium, remimazolam 1−3 mg/kg/h, and remifentanil 3 ng/mL. The primary outcome was core body temperature, and secondary outcomes included vasoconstriction threshold (°C) and time to onset of vasoconstriction (min). Results: The core body temperature in the RR group was significantly higher at 60, 80, 100, 120, 140, 160, and 180 min after induction than in the PR group (p < 0.01). The vasoconstriction threshold was significantly higher in the RR group (35.2 ± 0.4) than in the PR group (34.8 ± 0.3) (p < 0.01). The time to onset of vasoconstriction was significantly less in the RR group (150.5 ± 10.2) than in the PR group (158.5 ± 8.4) (p < 0.01). However, the incidence of intraoperative hypothermia was not significant between two groups. Conclusions: Remimazolam appears to reduce vasoconstriction threshold less than and had a faster onset of vasoconstriction, resulting in superior thermoregulatory control.

Effects of Female Reproductive Hormone Levels on Inadvertent Intraoperative Hypothermia during Laparoscopic Gynecologic Surgery: A Retrospective Study.

Background and Objectives: Female reproductive hormones may affect core body temperature. This study aimed to investigate the effects of female reproductive hormones on inadvertent intraoperative hypothermia in patients who underwent laparoscopic gynecologic surgery under general anesthesia. Materials and Methods: This retrospective study included 660 menstruating and menopausal female patients aged 19-65 years. The patients were divided into two groups according to the occurrence of inadvertent intraoperative hypothermia: non-hypothermia group (N = 472) and hypothermia group (N = 188). After propensity score matching, 312 patients (N = 156 in each group) were analyzed to investigate the association between intraoperative hypothermia and female reproductive hormones. As potential predictors of inadvertent hypothermia, the levels of female reproductive hormones were analyzed using binary logistic regression. Results: The association of estradiol (r = -0.218, p = 0.000) and progesterone (r = -0.235, p = 0.000) levels with inadvertent intraoperative hypothermia was significant but weakly negative before matching; however, it was significant and moderately negative after matching (r = -0.326, p = 0.000 and r = -0.485, p = 0.000, respectively). In a binary logistic analysis, the odds ratio for estradiol was 0.995 (p = 0.014, 0.993 < 95% confidence interval [CI] < 0.998) before matching and 0.993 (p = 0.000, 0.862 < 95% CI < 0.930) after matching, and that for progesterone was 0.895 (p = 0.000, 0.862 < 95% CI < 0.930) before matching and 0.833 (p = 0.014, 0.990 < 95% CI < 0.996) after matching. Conclusions: Estradiol and progesterone levels were associated with inadvertent intraoperative hypothermia. However, the odds ratio for female reproductive hormone levels was close to 1. Therefore, female reproductive hormones may not be a risk factor for hypothermia during gynecologic surgery under general anesthesia. However, a small sample size in this study limits the generalizability of the results.

Impact of the Timing of Rocuronium Injection after Propofol Administration on Temporal Summation of Pain in Gynecologic Laparoscopic Surgery: A Prospective and Controlled Study.

Purpose: Temporal summation of pain, which is defined as the perception of greater pain evoked by repetitive painful stimuli, varies among individuals. This study aimed at determining the impact of the timing of rocuronium after induction with propofol on the temporal summation of pain. Methods: One hundred patients aged 19-60 years underwent gynecologic laparoscopic surgery. Patients were randomly assigned to one of the two groups: group PRi received immediate injections of rocuronium after propofol administration and group PRd received rocuronium injections when the bispectral index score (BIS) decreased to <60 after propofol administration. The grade of rocuronium-induced withdrawal movement (RIWM) according to the timing of propofol injection, the incidence and severity of propofol injection pain (PIP), rescue analgesics, visual analog scale (VAS) score after surgery for postoperative pain, patient-controlled analgesia (PCA) opioid consumption, association between PIP and the grade of RIWM, and associations between PIP, the grade of RIWM, and postoperative pain outcomes were measured. Results: The differences between the incidence and severity of PIP in the two groups were not significant. The grade of the RIWM in the PRd group was significantly reduced compared with the PRi group. Rescue analgesics, severity for postoperative pain, and PCA opioid consumption were not significant. Correlations between the incidence and severity of PIP and the grade of RIWM were weakly negative. Correlations between the grade of RIWM and pain outcomes were moderately positive, but correlations between the severity for PIP and the postoperative pain outcomes were negligible. Conclusion: The timing of rocuronium administration after propofol injection played a role in reducing RIWM. The grade of RIWM was significantly related to pain outcomes compared with the severity of PIP. Therefore, delayed rocuronium injection after induction with propofol reduced temporal summation of pain.

Searching for an ideal cervical cancer screening model to reduce false-negative errors in a country with high prevalence of cervical cancer.

The purpose of this study was to develop an ideal cervical cancer screening model to reduce false-negative errors in Korea where there is a high prevalence of cervical cancer. We conducted a cross-sectional study including 33,531 women who underwent routine cervical cancer screening in Korea. Colposcopic examinations were performed after abnormal results on their screening tests. Diagnostic capacities including sensitivity, specificity, and false-negative rate of each screening scenario were analysed at the CIN1 or worse (CIN1+) threshold with colposcopic biopsy results considered the gold standard. A total of 4117 women had valid results for Papanicolaou (Pap) cytology, human papilloma virus (HPV) tests, cervicography, and colposcopically directed biopsy were included in this study. The disease prevalence of CIN1+ was 38.1%. Pap-alone resulted in the highest false-negative rate of 46.9%, followed by HPV-alone at 25.1%, cervicography-alone at 18.7%, Pap/HPV-combined at 15.0%, Pap/cervicography-combined at 6.9% and Pap/HPV/cervicography-combined at 2.9% in a sample of 1570 women with CIN1+ lesions. Therefore, cervicography demonstrated excellent performance for the detection of CIN or cervical cancer and markedly reduced false-negative errors when used in combination with Pap cytology and HPV tests.IMPACT STATEMENTWhat is already known on this subject? False-negative rate of Pap smears is as high as approximately 40-50%. Limitations of the Papanicolaou (Pap) test have led to the development of new screening programmes for cervical cancer, such as combination screenings with human papillomavirus (HPV) tests or cervicography.What do the results of this study add? Pap-alone resulted in the highest false-negative rate of 46.9%, followed by HPV-alone at 25.1%, cervicography-alone at 18.7%, Pap/HPV-combined at 15.0%, Pap/cervicography-combined at 6.9% and Pap/HPV/cervicography-combined at 2.9% in a sample of 1570 women with CIN1+ lesions.What are the implications of these findings for clinical practice and/or further research? Cervicography demonstrated excellent performance for the detection of CIN or cervical cancer and markedly reduced false negative errors when used in combination with Pap cytology and HPV tests.

Screening capacity and cost-effectiveness of the human papillomavirus test versus cervicography as an adjunctive test to Pap cytology to detect high-grade cervical dysplasia.

OBJECTIVE: This study compared the screening capacities and cost-effectiveness of the human papillomavirus (HPV) test versus cervicography as an adjunctive test to Papanicolaou (Pap) cytology to detect high-grade cervical neoplasia in Korea, a country with a high prevalence of cervical cancer. STUDY DESIGN: Of 33,531 Korean women who underwent cervicography as a screening test for cervical cancer between January 2015 and December 2016, we retrospectively analyzed the records of 4117 women who simultaneously or subsequently underwent Pap cytology, an HPV test, cervicography, and colposcopically directed biopsy. At a threshold of cervical intraepithelial neoplasia grade 2 or worse (CIN2+), based on colposcopic biopsy, we compared the diagnostic capacities and cost-effectiveness of these screening tools. RESULTS: The CIN2+ prevalence was 10.8% (446 of 4117 women) and the positive rate of high-risk HPV was 61.0% (2511 of 4117 women). Cervicography as an adjunctive to Pap cytology was a more sensitive test (97.5% vs 93.7%) with a higher odds ratio (15.65 vs 5.86) than the HPV test for detection of CIN2+ (P-value = 0.003). Moreover, the cost of cervicography co-testing was 23% less than that of HPV co-testing, decreasing the cost per patient with CIN2+ lesions from $1474 to $1135. CONCLUSION: Cervicography and Pap co-testing had superior screening capacity and cost-effectiveness for detection of preinvasive cervical lesions than HPV and Pap co-testing and may be an effective and cost-saving screening strategy in clinical practice in country with a high prevalence of cervical cancer.

Diagnostic Significance of Measuring Vascular Endothelial Growth Factor for the Differentiation between Malignant and Tuberculous Pleural Effusion.

Malignancy and tuberculosis are common causes of lymphocytic exudative pleural effusion. However, it is occasionally difficult to differentiate malignant pleural effusion from tuberculous pleural effusion. Vascular endothelial growth factor (VEGF) is a critical cytokine in the pathogenesis of malignant pleural effusion. Endocan is a dermatan sulfate proteoglycan that is secreted by endothelial cells. Importantly, endocan mediates the vascular growth-promoting action of VEGF. The aim of this study was to evaluate the diagnostic significance of VEGF and endocan in pleural effusion. We thus measured the levels of VEGF and endocan in the pleural effusion and serum samples of patients with lung cancer (n = 59) and those with tuberculosis (n = 32) by enzyme-linked immunosorbent assay. Lung cancer included 40 cases of adenocarcinoma, 13 of squamous cell carcinoma, and 6 of small cell carcinoma. Pleural effusion VEGF levels were significantly higher in the malignant group than in the tuberculosis group (2,091.47 ± 1,624.80 pg/mL vs. 1,291.05 ± 1,100.53 pg/mL, P < 0.05), whereas pleural effusion endocan levels were similar between the two groups (1.22 ± 0.74 ng/mL vs. 0.87 ± 0.53 ng/mL). The areas under the curve of VEGF and endocan were 0.73 and 0.52, respectively. Notably, the VEGF levels were similar in malignant pleural effusion, irrespective of the histological type of lung cancer. Moreover, no significant difference was found in the serum VEGF and endocan levels between patients with lung cancer and those with tuberculosis. In conclusion, high VEGF levels in pleural effusion are suggestive of malignant pleural effusion.

HNRNPA1, a Splicing Regulator, Is an Effective Target Protein for Cervical Cancer Detection: Comparison With Conventional Tumor Markers.

OBJECTIVE: Heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1), serine/arginine-rich splicing factor 1 (SRSF1), and SRSF3 are splicing regulators associated with oncogenesis. However, the alterations of SF proteins and their diagnostic values in cervical cancer are unclear. To apply SFs clinically, effective marker selection and characterization of the target organ properties are essential. MATERIALS AND METHODS: We concurrently analyzed HNRNPA1, SRSF1, SRSF3, and the conventional tumor markers squamous cell carcinoma antigen (SCCA) and carcinoembryonic antigen (CEA) in cervical tissue samples (n = 127) using semiquantitative immunoblotting. In addition, we compared them with p16 (cyclin-dependent kinase inhibitor 2A [CDKN2A]), which has shown high diagnostic efficacy in immunohistochemical staining studies and has been proposed as a candidate protein for point-of-care screening biochemical tests of cervical neoplasia. RESULTS: HNRNPA1, higher molecular weight forms of SRSF1 (SRSF1-HMws), SRSF3, CEA, and p16 levels were higher (P < 0.05) in cervical carcinoma tissue samples than in nontumoral cervical tissue samples. However, the levels of SRSF1-Total (sum of SRSF1-HMws and a lower molecular weight form of SRSF1) and SCCA, a commonly used cervical tumor marker, were not different between carcinoma and nontumoral tissue samples. In paired sample comparisons, HNRNPA1 (94%) showed the highest incidence of up-regulation (carcinoma/nontumor, >1.5) in cervical carcinoma, followed by p16 (84%), SRSF1-HMws (69%), SRSF3 (66%), CEA (66 %), SCCA (32%), and SRSF1-Total (31%). HNRNPA1 (92%) and p16 (91%) presented the two highest diagnostic accuracies for cervical carcinoma, which were superior to those of SRSF3 (75%), SRSF1-HMws (72%), CEA (72%), SCCA (59%), and SRSF1-Total (55%). CONCLUSIONS: Our results identified that HNRNPA1 is the best diagnostic marker among the SFs and conventional markers given its excellent diagnostic efficacy for cervical carcinoma, and it has a p16-comparable diagnostic value. We suggest that HNRNPA1 is an additional effective target protein for developing cervical cancer detection tools.

Celecoxib and sulindac inhibit TGF-ß1-induced epithelial-mesenchymal transition and suppress lung cancer migration and invasion via downregulation of sirtuin 1.

The non-steroidal anti-inflammatory drugs (NSAIDs) celecoxib and sulindac have been reported to suppress lung cancer migration and invasion. The class III deacetylase sirtuin 1 (SIRT1) possesses both pro- and anticarcinogenic properties. However, its role in inhibition of lung cancer cell epithelial-mesenchymal transition (EMT) by NSAIDs is not clearly known. We attempted to investigate the potential use of NSAIDs as inhibitors of TGF-ß1-induced EMT in A549 cells, and the underlying mechanisms of suppression of lung cancer migration and invasion by celecoxib and sulindac. We demonstrated that celecoxib and sulindac were effective in preventing TGF-ß1-induced EMT, as indicated by upregulation of the epithelial marker, E-cadherin, and downregulation of mesenchymal markers and transcription factors. Moreover, celecoxib and sulindac could inhibit TGF-ß1-enhanced migration and invasion of A549 cells. SIRT1 downregulation enhanced the reversal of TGF-ß1-induced EMT by celecoxib or sulindac. In contrast, SIRT1 upregulation promoted TGF-ß1-induced EMT. Taken together, these results indicate that celecoxib and sulindac can inhibit TGF-ß1-induced EMT and suppress lung cancer cell migration and invasion via downregulation of SIRT1. Our findings implicate overexpressed SIRT1 as a potential therapeutic target to reverse TGF-ß1-induced EMT and to prevent lung cancer cell migration and invasion.

Pemetrexed induces apoptosis in malignant mesothelioma and lung cancer cells through activation of reactive oxygen species and inhibition of sirtuin 1.

Pemetrexed is a multitargeted antifolate used for the treatment of malignant mesothelioma and non-small cell lung cancer (NSCLC). However, the mechanism by which pemetrexed induces apoptosis remains unclear. In the present study, we investigated the involvement of reactive oxygen species (ROS) and sirtuin 1 (SIRT1) in pemetrexed-induced apoptosis in MSTO-211 malignant mesothelioma cells and A549 NSCLC cells. Pemetrexed enhanced caspase-dependent apoptosis, induced intracellular ROS generation, and downregulated SIRT1 in the MSTO-211 and A549 cells. Pemetrexed-induced apoptosis, which was prevented by pretreatment with N-acetyl-cysteine (NAC), was mediated by effects on the mitochondria, including mitochondrial membrane potential transition (MPT) and cytosolic release of cytochrome c, and also involved regulation of SIRT1 expression. Interference with SIRT1 expression using siRNA enhanced pemetrexed-induced apoptosis through mitochondrial dysfunction and ROS generation, whereas resveratrol, an activator of SIRT1, protected against pemetrexed-induced apoptosis. These results show that pemetrexed induces apoptosis in MSTO-211 mesothelioma cells and A549 NSCLC cells through mitochondrial dysfunction mediated by ROS accumulation and SIRT1 downregulation.

Enhanced apoptosis by pemetrexed and simvastatin in malignant mesothelioma and lung cancer cells by reactive oxygen species-dependent mitochondrial dysfunction and Bim induction.

Pemetrexed is a multitarget antifolate currently used for the treatment of malignant mesothelioma and non-small cell lung cancer (NSCLC). Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors used primarily for hyperlidpidemia, have been studied for their antiproliferative and pro-apoptotic effects. However, the effects of simvastatin on pemetrexed-induced apoptosis have not been investigated. In this study, we investigated whether combination treatment with pemetrexed and simvastatin potentiates the apoptotic activity above that is seen with either drug alone in malignant mesothelioma and NSCLC cells. We found that the combination of pemetrexed and simvastatin induced more extensive caspase-dependent apoptosis than either drug alone in malignant mesothelioma cells (MSTO-211) or NSCLC cells (A549). In addition, reactive oxygen species (ROS) generation in cells treated with both pemetrexed and simvastatin was markedly increased compared to cells treated with either pemetrexed or simvastatin alone. Combination treatment also increased the loss of mitochondrial membrane potential, increased cytosolic release of cytochrome c, and altered expression of inhibitor of apoptosis proteins (IAP) and B-cell lymphoma-2 (Bcl-2) families of apoptosis related proteins. On the other hand, pretreatment with N-acetylcysteine (NAC) prevented apoptosis and mitochondrial dysfunction by pemetrexed and simvastatin. In addition, Bim siRNA conferred protection against apoptosis induced by pemetrexed and simvastatin. These results suggest that combination of pemetrexed and simvastatin potentiates their apoptotic activity beyond that of either drug alone in malignant mesothelioma and lung cancer cells. This activity is mediated through ROS-dependent mitochondrial dysfunction and Bim induction.

Effect of simvastatin on the resistance to EGFR tyrosine kinase inhibitors in a non-small cell lung cancer with the T790M mutation of EGFR.

Although non-small cell lung cancer (NSCLC) tumors with activating mutations in the epidermal growth factor receptor (EGFR) are highly responsive to EGFR tyrosine kinase inhibitors (TKIs) including gefitinib and erlotinib, development of acquired resistance is almost inevitable. Statins show antitumor activity, but it is unknown whether they can reverse EGFR-TKIs resistance in NSCLC with the T790M mutation of EGFR. This study investigated overcoming resistance to EGFR-TKI using simvastatin. We demonstrated that addition of simvastatin to gefitinib enhanced caspase-dependent apoptosis in T790M mutant NSCLC cells. Simvastatin also strongly inhibited AKT activation, leading to suppression of ß-catenin activity and the expression of its targets, survivin and cyclin D1. Both insulin treatment and AKT overexpression markedly increased p-ß-catenin and survivin levels, even in the presence of gefitinib and simvastatin. However, inhibition of AKT by siRNA or LY294002 treatment decreased p-ß-catenin and survivin levels. To determine the role of survivin in simvastatin-induced apoptosis of gefitinib-resistant NSCLC, we showed that the proportion of apoptotic cells following treatment with survivin siRNA and the gefitinib-simvastatin combination was greater than the theoretical additive effects, whereas survivin up-regulation could confer protection against gefitinib and simvastatin-induced apoptosis. Similar results were obtained in erlotinib and simvastatin-treated HCC827/ER cells. These findings suggest that survivin is a key molecule that renders T790M mutant NSCLC cells resistant to apoptosis induced by EGFR-TKIs and simvastatin. Overall, these data indicate that simvastatin may overcome EGFR-TKI resistance in T790M mutant NSCLCs via an AKT/ß-catenin signaling-dependent down-regulation of survivin and apoptosis induction.

Synergistic induction of apoptosis by sulindac and simvastatin in A549 human lung cancer cells via reactive oxygen species-dependent mitochondrial dysfunction.

Prevention of lung cancer is more feasible and holds greater promise when different agents are used in combination to target multiple processes during carcinogenesis. The mechanisms by which non-steroidal anti-inflammatory drugs and statins inhibit cancer cell growth and induce apoptosis are not fully understood. This study was designed to investigate lung cancer chemoprevention through a mechanism-based approach using sulindac at low doses in combination with simvastatin. We found that sulindac-induced cytotoxicity was significantly enhanced in the presence of simvastatin. The combination of sulindac and simvastatin induced more extensive caspase-dependent apoptosis in A549 cells compared to that induced with either drug alone. The combination of sulindac and simvastatin also increased the loss of mitochondrial transmembrane potential (∆Ψm) and the cytosolic release of cytochrome c. In addition, ROS generation in cells treated with both sulindac and simvastatin was markedly increased compared to cells treated with either sulindac or simvastatin alone. The enhancement of ROS generation by sulindac and simvastatin was abrogated by pretreatment with NAC, which also prevented apoptosis and mitochondrial dysfunction induced by sulindac and simvastatin. These results suggest that sulindac and simvastatin-induced ROS generation in A549 lung cancer cells causes their accumulation in mitochondria, triggering the release of apoptogenic molecules from the mitochondria to the cytosol, and thus leading to caspase activation and cell death.

Prx1 modulates the chemosensitivity of lung cancer to docetaxel through suppression of FOXO1-induced apoptosis.

The expression levels of Prx1 are frequently elevated in several human cancers, including lung cancer and may confer increased resistance to treatment. In this study, we investigated the role of Prx1 in docetaxel-induced apoptosis in A549 lung cancer cells. To test whether Prx1 knockdown affected the sensitivity of A549 cells to docetaxel treatment, we generated short hairpin RNA (shRNA) constructs targeting Prx1 and analyzed the effect of Prx1 knockdown on growth and apoptosis. Tumor growth was evaluated in scrambled shRNA- or shPrx1-infected A549 cell tumors receiving docetaxel treatment. In addition, mechanistic information was gathered by western blot analysis from cell lysates of scrambled- and shPrx1-infected A549 cells pretreated with or without LY294002 and subsequently treated with docetaxel. We found that Prx1 knockdown resulted in enhanced docetaxel-induced cytotoxicity in a dose-dependent manner. In vivo, the growth rate of shPrx1-infected A549 tumors was significantly reduced compared to that of scrambled shRNA-infected A549 tumors. Prx1 knockdown also augmented the inhibitory effects of docetaxel on tumor growth. Prx1 knockdown increased the apoptotic potential through activation of the caspase cascade and suppressed docetaxel-induced phosphorylation of Akt and its substrate forkhead box O1 (FOXO1). Moreover, treatment with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 reduced the phosphorylation of FOXO1 and increased the cytotoxicity of docetaxel in A549 cells. Our findings suggest that Prx1 may modulate the chemosensitivity of lung cancer to docetaxel through suppression of FOXO1-induced apoptosis.

Diagnostic value and prognostic significance of pleural C-reactive protein in lung cancer patients with malignant pleural effusions.

PURPOSE: C-reactive protein (CRP) has been implicated in various inflammatory and advanced malignant states. Increased serum CRP (s-CRP) levels have been shown to be associated with independent prognostic factors for survival in patients with advanced lung cancer. However, only few studies have focused on the role of CRP in pleural effusions. This study aimed to evaluate the diagnostic and prognostic value of pleural CRP (p-CRP) in lung cancer patients with malignant pleural effusion (MPE). MATERIALS AND METHODS: Pleural effusion (PE) samples were collected from patients with MPE (68 lung cancers; 12 extrathoracic tumors), and from 68 patients with various benign conditions (31 with pneumonia; 37 with tuberculosis). Concentrations of p- and s-CRP were measured by enzyme-linked immunosorbent assay. CRP level in pleural fluid and its association with survival were examined. RESULTS: p-CRP levels correlated with s-CRP levels (r=0.82, p<0.0001). For the differential diagnosis of MPE and benign PE, the area under the receiver operating characteristic curve was greater for p-CRP (0.86) than for s-CRP (0.77). High p-CRP expression significantly correlated with shorter overall survival (p=0.006). P-CRP was independent prognostic factor significantly associated with overall survival on multivariated analysis (p=0.0001). The relative risk of death for lung cancer patients with high p-CRP levels was 3.909 (95% confidence interval, 2.000-7.639). CONCLUSION: P-CRP is superior to s-CRP in determining pleural fluid etiology. Quantitative measurement of p-CRP might be a useful complementary diagnostic and prognostic test for lung cancer patients with MPE.

Elevated survivin is associated with a poor response to chemotherapy and reduced survival in lung cancer with malignant pleural effusions.

Survivin has been shown to inhibit apoptosis, enhance proliferation and promote angiogenesis. This study aimed to identify diagnostic value of survivin protein in malignant pleural effusion (MPE) and to investigate the prediction of response to chemotherapy and the prognostic role on pleural survivin in lung cancer patients with MPE. Pleural effusion samples were collected from 67 patients with MPE (58 lung cancers; 9 extrathoracic tumors), and from 68 patients with benign conditions (31 with pneumonia; 37 with tuberculosis). Concentrations of pleural fluid survivin, Cyfra 21-1, and carcinoembryonic antigen (CEA) were measured by enzyme-linked immunosorbent assay. The expression profile of survivin in pleural fluid, and its association with survival, were investigated. Survivin levels were significantly elevated in patients with MPE, especially primary lung cancer than in those of benign origin. Survivin, Cyfra 21-1, and CEA varied in diagnostic accuracy for differentiating MPE from benign pleural effusion by 67.5, 68.3, and 93.4%, respectively. Lung cancer patients with MPE who were positive for survivin expression were more refractory to chemotherapy (P = 0.003). Positive for survivin expression was correlated with a reduced overall survival in univariate (P = 0.0001) and multivariate (P = 0.004) analyses. Using the appropriate cut-off points, CEA in pleural fluid has a higher accuracy than other tumor markers, and that survivin has a low diagnostic accuracy for differentiating MPE from benign pleural effusion. Our findings suggest that positive survivin expression may be used as a predictor of a poor response to chemotherapy and shorter survival in lung cancer patients with MPE.

Apoptotic induction by simvastatin in human lung cancer A549 cells via Akt signaling dependent down-regulation of survivin.

Statins, HMG-CoA reductase inhibitors have been studied for their antiproliferative and proapototic effects. Recently, statin-induced apoptosis has been associated with down-regulation of survivin expression in cancer cells. However, the mechanism of deregulated survivin by simvastatin on lung cancer is still unclear. Herein, we demonstrated that simvastatin induced caspase-dependent apoptosis in A549 lung cancer cells. Simvastatin also resulted in a decrease in the expression of phosphorylated Akt. In addition, simvastatin effectively down-regulated survivin mRNA and protein, but not cIAP-1 and cIAP-2. The combination of simvastatin and 10 µM LY294002 (non-toxic dose) augmented apoptosis significantly, as evidenced by cleavage of PARP. The immunoreactive band of survivin was markedly decreased in cells treated with 50 µM LY294002 (toxic dose) as well as by the combination of simvastatin and 10 µM LY294002. Moreover, survivin down-regulation by RNA interference induced apoptosis accompanied by an increase in hypodiploid DNA content. Taken together, these data suggest that the anti-cancer effect of simvastatin via induction of apoptosis is related to Akt signaling dependent down-regulation of survivin in lung cancer A549 cells.