Altered expression of 17­ß­hydroxysteroid dehydrogenase type 2 and its prognostic significance in non­small cell lung cancer.

Numerous studies have reported that oestrogens may contribute to the development of non­small cell lung cancer (NSCLC). Although different steroidogenic enzymes have been detected in the lung, the precise mechanism leading to an exaggerated accumulation of active oestrogens in NSCLC remains unexplained. 17­ß­Hydroxysteroid dehydrogenase type 2 (HSD17B2) is an enzyme involved in oestrogen and androgen inactivation by converting 17­ß­oestradiol into oestrone, and testosterone into 4­androstenedione. Therefore, the enzyme serves an important role in regulation of the intracellular availability of active sex steroids. This study aimed to determine the expression levels of HSD17B2 in lung cancer (LC) and adjacent histopathologically unchanged tissues obtained from 161 patients with NSCLC, and to analyse the association of HSD17B2 with clinicopathological features. For that purpose, reverse transcription­quantitative PCR, western blotting and immunohistochemistry were conducted. The results revealed that the mRNA and protein expression levels of HSD17B2 were significantly decreased in LC tissues compared with matched controls (P<10­6). Conversely, strong cytoplasmic staining of HSD17B2 was detected in the unchanged respiratory epithelium and in glandular cells. Notably, a strong association was detected between reduced HSD17B2 expression and advanced tumour stage, grade and size. Furthermore, it was revealed that HSD17B2 may have potential prognostic significance in NSCLC. A log­rank test revealed the benefit of high HSD17B2 protein expression for the overall survival (OS) of patients (P=0.0017), and multivariate analysis confirmed this finding (hazard ratio=0.21; 95% confidence interval=0.07­0.63; P=0.0043). Stratified analysis in the Kaplan­Meier Plotter database indicated that patients with higher HSD17B2 expression presented better OS and post­progression survival. This beneficial effect was particularly evident in patients with adenocarcinoma and during the early stages of NSCLC. Decreased expression of HSD17B2 appears to be a frequent feature in NSCLC. Retrospective analysis suggests that the HSD17B2 mRNA and protein status might be independent prognostic factors in NSCLC and should be further investigated.

Decreased expression of cytochrome p450 1B1 in non-small cell lung cancer.

Recent studies have associated oestrogen metabolism and cigarette smoking with their carcinogenic impact on the lungs. Compounds commonly found in tobacco smoke induce the activity of CYP1B1, the enzyme responsible for the synthesis of catecholic derivatives of oestrogens. During their redox transformations, these structures can release large amounts of reactive oxygen species or can form DNA adducts, which lead to the decomposition of genetic material. This process may illustrate the synergistic effect of oestrogenic activity and tobacco combustion on oestrogen-dependant lung cancer development. There is considerable evidence suggesting that the level of oestrogen in lung tumours is elevated. Therefore, by using reverse transcription, real-time PCR and Western Blot analysis, we evaluated the CYP1B1 status in tissues from 76 patients diagnosed with non-small cell lung cancer (NSCLC) to confirm whether potential overexpression of CYP1B1 may impact lung cancerogenesis induced by oestrogens. We found significantly lower levels of CYP1B1 transcripts (p=0.00001) and proteins (p=0.000085) in lung tumour material compared to corresponding, histopathologically unchanged tissues. We also analysed the association of CYP1B1 expression with gender, age and clinicopathological data of NSCLC patients. We observed lower amounts of CYP1B1 occurring in the middle stages of LC, regardless of gender, age or histological type of lung cancer.

Early and Late Results of the Nuss Procedure in Surgical Treatment of Pectus Excavatum in Different Age Groups.

BACKGROUND: The aim of this study was a comparison of early and late results in surgical treatment of funnel chest using the Nuss method in patients in various age groups to find the optimal age to perform the corrective procedure. METHODS: Six hundred eighty patients operated on from June 2002 to October 2012 were included in the retrospective analysis. Patients were divided into 3 different age groups: group A = 156 patients from 7 to 14 years, group B = 328 patients aged 15 to 20 years, and group C = 196 patients older than 20 years of age. The mean follow-up was 33 months. RESULTS: Early non-life-threatening complications developed in 238 (35.0%) patients and frequency increased with age (group A, 24.3%; group B, 37.8%; group C, 38.8%; p = 0.0063). Good and very good corrective effects were achieved in 97.7 % of the entire patient population. Recurrence of the deformity was observed more often in younger patients (group A, 3.2 %) than in the other patients (group B, 1.2%; group C, 1.5%), although the difference between the studied groups was not significant (p = 0.3251). CONCLUSIONS: Good cosmetic results obtained with the use of the Nuss operation were not related to the age of the patients. The high incidence of minor complications in older patients seems to be an acceptable cost of a good cosmetic outcome and stable correction. Surgical morbidity is lowest in younger patients; however, the frequency of the recurrence of deformation is higher than in other groups.

Decreased expression of connective tissue growth factor in non-small cell lung cancer is associated with clinicopathological variables and can be restored by epigenetic modifiers.

PURPOSE: Recent studies indicated undisputed contribution of connective tissue growth factor (CTGF) in the development of many cancers, including non-small cell lung cancer (NSCLC). However, the functional role and regulation of CTGF expression during tumorigenesis remain elusive. Our goal was to determine CTGF transcript and protein levels in tumoral and matched control tissues from 98 NSCLC patients, to correlate the results with clinicopathological features and to investigate whether the CTGF expression can be epigenetically regulated in NSCLC. METHODS: We used quantitative PCR, Western blotting and immunohistochemistry to evaluate CTGF expression in lung cancerous and histopathologically unchanged tissues. We tested the impact of 5-Aza-2'-deoxycytidine (5-dAzaC) and trichostatin A (TSA) on CTGF transcript and protein levels in NSCLC cells (A549, Calu-1). DNA methylation status of the CTGF regulatory region was evaluated by bisulfite sequencing. The influence of 5-dAzaC and TSA on NSCLC cells viability and proliferation was monitored by the trypan blue assay. RESULTS: We found significantly decreased levels of CTGF mRNA and protein (both p < 0.0000001) in cancerous tissues of NSCLC patients. Down-regulation of CTGF occurred regardless of gender in all histological subtypes of NSCLC. Moreover, we showed that 5-dAzaC and TSA were able to restore CTGF mRNA and protein contents in NSCLC cells. However, no methylation within CTGF regulatory region was detected. Both compounds significantly reduced NSCLC cells proliferation. CONCLUSIONS: Decreased expression of CTGF is a common feature in NSCLC; however, it can be restored by the chromatin-modifying agents such as 5-dAzaC or TSA and consequently restrain cancer development.

Completion pneumonectomy and chemoradiotherapy as treatment options in local recurrence of non-small-cell lung cancer.

INTRODUCTION: The selection of treatment for local recurrence in patients with non-small-cell lung cancer (NSCLC) depends on the possibility of performing a radical tumor resection, the patient's performance status, and cardiopulmonary efficiency. Compared with chemoradiotherapy, surgical treatment offers a greater chance of long-term survival, but results in completion pneumonectomy and is associated with a relatively high rate of complications. AIM OF THE STUDY: Aim of the study was to evaluate early and long-term results of surgery and conservative treatment (chemoradiotherapy) in patients with local NSCLC recurrence. MATERIAL AND METHODS: Between 1998 and 2011, 1697 NSCLC patients underwent lobectomy or bilobectomy at the Department of Thoracic Surgery in Poznan. Among them, 137 patients (8.1%) were diagnosed with cancer recurrence; chemotherapy or chemoradiotherapy was provided to 116 patients; 21 patients (15.3%) were treated with completion pneumonectomy. The median time from primary surgery to recurrence was 13.4 months. No metastases to N2 lymph nodes were observed among the patients undergoing surgery; in 7 patients N1 lymph node metastases were confirmed. RESULTS: The rate of complications after surgery was significantly higher in comparison with conservative therapy (80.9% vs. 48.3%). Patients treated with surgery were most likely to suffer from complications associated with the circulatory system (80.9%), while hematologic complications were dominant in the group undergoing oncological treatment (41.4%). There were no perioperative deaths after completion pneumonectomy. The age of the patients was the only factor which significantly influenced the incidence of complications in both groups of patients. Analysis of the survival curves demonstrated statistically significant differences in survival between the groups treated with surgery, chemoradiotherapy, and chemotherapy (p = 0.00001). Five-year survival probability was significantly higher among patients treated surgically as compared to patients undergoing systemic therapy. CONCLUSIONS: Despite the significant rate of postoperative complications (mostly circulatory), the long-term results of the surgical treatment of local NSCLC recurrence are more favorable than those achieved with chemoradiotherapy. The success of surgical treatment is conditioned on the exclusion of metastasis in N2 lymph nodes.

Increased expression of proline-, glutamic acid- and leucine-rich protein PELP1 in non-small cell lung cancer.

It has been demonstrated that estrogens are able to enhance lung tumorigenesis by estrogen receptor (ER) pathway. ER signaling is a highly complex process that requires a number of different coactivators, including proline-, glutamic acid- and leucine-rich protein-1 (PELP1). We studied PELP1 transcript and protein levels in cancerous and histopathologically unchanged lung tissues obtained from 73 patients diagnosed with non-small cell lung cancer (NSCLC). We observed increased levels of PELP1 transcript (P=0.00001) and protein (P=0.00001) in tumor tissues compared to adjacent histopathologically unchanged tissues. Significant increase of PELP1 transcript/protein level was found in all patients, regardless of gender (males: P=0.0003/P=0.000003; females: P=0.0005/P=0.02), age (≤ 60 patients: P=0.042/P=0.016; >60 patients: P=0.00001/P=0.00001) or histopathological type of tumor (adenocarcinoma [ADC]: P=0.004/P=0.0006; squamous cell carcinoma [SSC]: P=0.0009/P=0.0008). Increased PELP1 transcript/protein levels were also correlated with some lung cancer stage (1a: P=0.07/P=0.02; 1b: P=0.001/P=0.03; 2a: P=0.012/P=0.001), tumor size (T2a: P=0.0006/P=0.001) and lymph node metastasis (N0: P=0.0003/P=0.0006; N1: P=0.017/P=0.003). Moreover, significant increase in PELP1 transcript level in cancer stage 1a (P=0.02) was observed. PELP1 protein content was higher in tumor tissues of patients with cancer stage 3a (P=0.04) and in T1a tumor size (P=0.03). Our studies demonstrate significantly higher amounts of PELP1 transcript and protein in tumor tissues in patients with NSCLC. Moreover, we also determined the association of PELP1 transcript and protein level with some clinicopathological features of NSCLC.

Increased expression of 17-beta-hydroxysteroid dehydrogenase type 1 in non-small cell lung cancer.

OBJECTIVES: Recent studies indicated that estrogens may influence the development of non-small cell lung cancer (NSCLC). The 17-beta-hydroxysteroid dehydrogenase type 1 (HSD17B1) catalyzes the reduction of estrone (E1) to the highly potent E2. Although the significance of aromatase in an intratumoral E2 production in NSCLC is well established, the role of HSD17B1 remains largely unknown. Therefore, we investigated the expression of HSD17B1 in lung cancerous and corresponding histopathologically unchanged tissues from NSCLC patients and the association between HSD17B1 expression and clinicopathological features. Than, we examined the biological significance of HSD17B1 in NSCLC cells in vitro. We tested the impact of 5-Aza-2'-deoxycytidine (5-dAzaC) on HSD17B1 expression and activity. MATERIALS AND METHODS: We used Real Time quantitative PCR (RT-qPCR), Western blotting and immunohistochemistry to evaluate HSD17B1 expression in tissues obtained from 48 patients with NSCLC. The methylation status of the promoter region of HSD17B1 in A549 and Calu-1 cells was evaluated by bisulfite sequencing. We investigated the effect of 5-dAzaC on HSD17B1 transcript levels (by RT-qPCR) and on HSD17B1 enzyme activity by measuring the conversion of E1 to E2. The xCELLigence System was used for monitoring of cell proliferation. RESULTS: We found a substantial increase of HSD17B1 mRNA and protein amount in NSCLC tissues compared with histopathologically unchanged tissues in the group of male patients. An overexpression of HSD17B1 was associated with squamous cell carcinoma and with lung cancer stage 3A. We showed that 5-dAzaC induces DNA demethylation of HSD17B1 promoter, leading to increased HSD17B1 mRNA levels and protein activity in NSCLC cells. It resulted in enhanced E2 production in both cell lines and supported the proliferation of Calu-1 cells but not A549 cells. CONCLUSION: Increased expression of HSD17B1 in NSCLC may contribute to an elevated intratissue level of E2 and consequently may support the development and spread of cancer.

High costs as a slow down factor of thoracoscopic lobectomy development in Poland - an institutional experience.

INTRODUCTION: Thoracoscopic (VATS) lobectomy after a decade of criticism is nowadays considered as a technically feasible, safe and oncologically proper operation. This approach has some advantages over conventional thoracotomy like: less postoperative pain, shorter hospitalization, fewer postoperative complications, better tolerance of adjuvant chemotherapy with comparable long-term survival rate. The VATS lobectomy is now generally accepted as an important alternative to open lobectomy in early-stage lung cancer. AIM: In the study we analyzed all aspects of introducing video-assisted thoracoscopic surgery (VATS) lobectomy in our institution with special consideration of the costs of the procedure as a potential limiting factor of its widespread development. MATERIAL AND METHODS: The data of 212 consecutive patients with early stage lung cancer operated on during 2008-2011 were selected and analyzed. One hundred and eight patients underwent VATS lobectomy (VATS group) and 104 patients antero-lateral thoracotomy (thoracotomy group). Perioperative outcomes including operating time, blood loss during surgery, postoperative complication rate, length of hospital stay, and duration of chest tube drainage were assessed. The cost evaluation included: all direct theater costs, daily hospital costs, intensive care costs, pharmacy and disposable costs with special consideration of stapling device costs. RESULTS: The mean hospital stay after VATS lobectomy was significantly shorter than after thoracotomy, mean 7 days vs. 10 days (p < 0.0012). The complication rate and ICU admission rate were almost twice as high after thoracotomy than after VATS and were 46% vs. 23% (p < 0.0006) and 42% vs. 22% (p < 0.0027) respectively. Cost analysis showed significantly higher total costs of VATS lobectomy than after thoracotomy (median €2445 vs. €2047). Considerably higher theater costs for VATS compared to thoracotomy, median €1395 vs. €479, were caused mainly by endostapler costs, median €1069 vs. €161. Significantly higher hospital costs and ICU costs after thoracotomy did not compensate high theater costs of VATS lobectomy. CONCLUSIONS: In Polish financial reality and potentially in other middle-income countries significantly higher costs of the procedure can limit widespread introduction of VATS lobectomy in clinical practice.