Preparations of trans- and cis-µ-1,2-Peroxodiiron(III) Complexes.

The iron(II) complex with cis,cis-1,3,5-tris(benzylamino)cyclohexane (Bn3CY) (1) has been synthesized and characterized, which reacted with dioxygen to form the peroxo complex 2 in acetone at -60 °C. On the basis of spectroscopic measurements for 2, it was confirmed that the peroxo complex 2 has a trans-µ-1,2 fashion. Additionally, the peroxo complex 2 was reacted with benzoate anion as a bridging agent to give a peroxo complex 3. The results of resonance Raman and 1H-NMR studies supported that the peroxo complex 3 is a cis-µ-1,2-peroxodiiron(III) complex. These spectral features were interpreted by using DFT calculations.

Antidepressants induce toxicity in human placental BeWo cells.

Selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake inhibitors (SNRIs), and noradrenergic and specific serotonergic antidepressants (NaSSAs) are broadly used for the treatment of depression. Depression is one of the most common psychiatric disorders in pregnant women and SSRIs are commonly prescribed for depression during pregnancy. The placenta regulates the transport of nutrients and oxygen between the maternal and fetal circulation, and is essential for the survival and growth of the fetus. The present study investigated the effects of antidepressants on human placental BeWo cells. BeWo cell viability was significantly decreased following exposure to sertraline (SSRI), paroxetine (SSRI), fluvoxamine (SSRI), and duloxetine (SNRI), whereas escitalopram (SSRI), venlafaxine (SNRI), and mirtazapine (NaSSA) showed little or no effects. Extracellular lactate dehydrogenase activity was increased by sertraline, paroxetine, fluvoxamine, and duloxetine, indicating toxicity to the cells. Sertraline increased the production of cellular reactive oxygen species (ROS) and decreased the mitochondrial membrane potential. Sertraline decreased the cellular ATP content in a time and concentration-dependent manner. Caspase-3/7 activity and apoptotic cells, detected using the phosphatidylserine-specific fluorescent probe Apotracker Green, were increased by sertraline. Our findings suggest that antidepressants, such as sertraline, paroxetine, fluvoxamine, and duloxetine, induce toxicity in human placental BeWo cells. Sertraline may induce ROS-dependent apoptosis in human placental cells. These results are useful for further studies to determine the optimal dosage of antidepressants for pregnant women.

Thoracoscopic partial resection without using a stapler. (complete republication).

Thoracoscopic partial pulmonary resection for small peripheral nodules without using a stapler has been introduced to our hospital. After partial resection was performed with electrocautery, two different methods of surface sealing were used: a coagulation method (C method) with Soft Coagulation alone, and a coagulation-suturing method (CS method) with Soft Coagulation combined with continuous suturing. The clinical outcomes of the two methods were retrospectively compared in this study. The C method was used in 19 lesions of 18 cases, and the CS method was used in 20 lesions of 19 cases. Primary lung cancer was the most frequent diagnosis (22 lesions of 21 cases). There were no differences between the two groups in the size and depth of the lesions. Operative time was longer with the CS method than with the C method. Postoperative air leakage was a complication in 4 cases with the C method, and one of them required re-do surgery, whereas only one case with the CS method had temporary air leakage. Postoperative computed tomography showed cavitation in 3 C method cases and 5 CS method cases, all without related symptoms. There were no local recurrences at resected sites. In conclusion, the C method was technically easy to perform, but air leakage may be prolonged after surgery. The CS method may have the advantage of causing less air leakage than the C method, but mastering the technique is important to shorten operative time.

[Perioperative Management of Lung Cancer Patients with atrial fibrillation being treated by antiplatelet or anticoagulant therapy].

In an aging society, the high incidence of surgery for the patients with ischemic heart disease(IHD)or atrial fibrillation(Af) under antiplatelet or anticoagulant therapy is a great problem. Interruption of antiplatelet or anticoagulant oral agents in the perioperative period may increase the risk of coronary or cerebral events. We retrospectively reviewed the surgical outcomes for lung cancer patients with IHD or Af. We reviewed 135 patients with lung cancer(41~88 years;97 men) who had preoperative oral administration of antiplatelet or anticoagulant drugs for IHD or Af between 2005 and 2012 at 2 centers, and analyzed retrospectively the perioperative medications and complications. IHD, Af and vasospastic angina(VSA) were complicated in 94, 33 and 8 patients, respectively. Drugeluted and bare-metal stents had been placed in 18 and 19 patients. Oral agents were aspirin in 68 patients, ticlopidine in 10 patients, clopidogrel in 15 patients and warfarin in 25 patients. These agents were stopped 2 to 60 days before surgery. Perioperative heparinization was performed in 22 patients. Oral agents were restarted after confirmation of hemostasis and no need for further invasive treatment. The surgical procedures were lobectomy in 88 patients, segmentectomy in 19 and partial resection in 25. There were no hemorrhagic or thromboembolic complications in a perioperative period except 1 case of pulmonary hemorrhage and 1 case of cerebral infarction. No perioperative hospital death was documented. Short-term interruption of antiplatelet or anticoagulant drugs before lung cancer surgery and heparinization was acceptable from the view of perioperative outcomes.

Clinical experience of sleeve lobectomy with bronchoplasty using a continuous absorbable barbed suture.

Anastomosis in bronchoplasty is usually performed using interrupted sutures, which are considered safe, reliable, and secure. However, placing interrupted sutures can be complex and time-consuming. There have been recent reports of continuous suturing using standard suture materials in bronchoplasty. We have experienced four cases of sleeve lobectomy with bronchial anastomosis in continuous fashion using a novel absorbable barbed suture device, the V-Loc™ wound closure device (Covidien, USA), which facilitates secure wound closure without knot-tying. Two patients underwent sleeve upper lobectomy and two underwent sleeve upper-middle lobectomy. Surgical approach was completely thoracoscopic in one patient and open in three. There were no intraoperative difficulties such as cutting or loosening, and a leak test was negative in all cases. One patient had pneumonia postoperatively and developed anastomotic stenosis 4 months after surgery, which did not require treatment. All patients were alive, without local recurrence, at a mean follow-up of 11.5 months postoperatively.

Overexpression of G protein-coupled receptor 87 correlates with poorer tumor differentiation and higher tumor proliferation in non-small-cell lung cancer.

G protein-coupled receptor 87 (GPR87) is a newly deorphanized member of the transmembrane G protein-coupled receptor family. Recently, GPR87 was suggested to contribute to the viability of human tumor cells and overexpression of GPR87 mRNA was detected in a number of malignant tumors, including lung cancer. We performed a retrospective study of GPR87 expression in association with clinical characteristics and biological markers in non-small-cell lung cancer (NSCLC). We investigated a total of 123 patients with NSCLC who underwent surgery between 1999 and 2004 (58 adenocarcinomas, 53 squamous cell carcinomas and 12 others). Immunohistochemistry was used to evaluate the intratumoral expression of GPR87 and the Ki-67 proliferation index. The TUNEL method was also used to investigate tumor apoptosis. A total of 63 tumors (51.2%) were found to be GPR87-positive. These tumors were more frequently encountered among squamous cell carcinomas rather than among adenocarcinomas (62.3 vs. 43.1%, respectively; P=0.044) and were significantly more frequently poorly and moderately differentiated rather than well differentiated (P=0.029). Moreover, the Ki-67 index was significantly higher in GPR87-positive compared to GPR87-negative tumors (57.0 vs. 40.0%, respectively; P=0.002). The overall survival was significantly worse for patients with GPR87-positive compared to those with GPR87-negative tumors (P=0.029). The Cox regression analyses also demonstrated that the GPR87 status was a significant prognostic factor for NSCLC patients [hazard ratio=2.053; P=0.018). The present study demonstrated that in NSCLC, the overexpression of GPR87 is significantly associated with poorer differentiation and higher proliferation. During the progression of NSCLC, GPR87 overexpression may be associated with the acquisition of a more aggressive phenotype and, therefore, is a potentially useful target for prognostication and treatment.

Clinical relevance of decreased oxygen saturation during 6-min walk test in preoperative physiologic assessment for lung cancer surgery.

OBJECTIVE: The Japanese Association for Chest Surgery (JACS) has released guidelines on preoperative physiologic assessment for lung cancer surgery. However, cardiopulmonary exercise testing (CPET), which is recommended for patients with poor pulmonary function, is available only in limited institutions. We investigated the possibility of 6-min walk test (6MWT) as a substitute of maximum oxygen consumption test (VO(2)max) on preoperative physiologic assessment for lung cancer surgery. METHODS: The relationship between VO(2)max and 6MWT was retrospectively analyzed in 51 subjects other than lung cancer patients. Following the preliminary analysis, we modified the risk assessment in the JACS guidelines by substituting 6MWT for VO(2)max, and patients who underwent lung cancer surgery were retrospectively assessed using the modified assessment. RESULTS: Analysis of the correlation between VO(2)max and 6MWT revealed VO(2)max to be significantly correlated to minimum SpO(2) (SpO(2)min) and maximum decrease in SpO(2) (ΔSpO(2)) during 6MWT. Receiver operating characteristic analysis revealed that SpO(2)min and ΔSpO(2) were predictable for a VO(2)max of 15 mL/kg/min, which is the borderline between the average- and increased-risk groups in the JACS guidelines. A total of 1,066 patients were assigned to the average- or increased-risk group according to the modified JACS guidelines using the criteria of SpO(2)min < 91 % and ΔSpO(2) > 4 %. The increased-risk group was significantly inferior to the average-risk group in Home Oxygen Therapy induction rate, cardiopulmonary-related 30- and 90-day mortality (p < 0.001). CONCLUSIONS: In clinical practice, decreased saturation during 6MWT may be simple and substitutive for CPET in risk assessment for lung cancer surgery using the JACS guidelines.

Chemotherapy followed by surgery on the basis of biomarker examination for patients with advanced non-small cell lung cancer.

BACKGROUND/AIM: We have previously reported that low expression of excision repair cross-complementing-1 (ERCC1), class III ß-tubulin (tubulin), thymidylate synthase (TYMS) and ribonucleotide reductase-M1 (RRM1) is indicative of a favorable prognosis in patients with c-N2,3 non-small cell lung cancer (NSCLC) treated with surgery after induction chemoradiotherapy. In the present study, we prospectively explored the tailor-made treatment menu for induction chemotherapy according to the status of biomarkers, and evaluated the biomarker status pre- and post-chemotherapy. PATIENTS AND METHODS: Twenty-five patients with pathologically-proven NSCLC who were not appropriate candidates for initial surgery were enrolled (October 2010 to June 2012, stage IIIA/B/IV1a/1b;14/5/2/4 respectively). Immunohistochemistry was performed to evaluate intratumoral expression of biomarkers. Epidermal growth factor receptor (EGFR) mutation was evaluated by direct sequencing. Two to four cycles of chemotherapy were performed with or without concurrent radiation (50 Gy). RESULTS: Docetaxel (n=12), pemetrexed (n=4), S-1 (n=4), docetaxel-plus-bevacizumab (n=3), and pemetrexed-plus-bevacizumab (n=2), in combination with platinum were selected for the therapeutic regimen. Twenty-one (84.0%) patients exhibited good partial response, and underwent complete resection without major morbidity or mortality. Of these 21 patients, four achieved a pathologically-complete response (PCR), and 10 achieved a major pathological response. The 3-year overall survival rate was 58.7% for the 25 patients overall, and the 2-year overall survival rate was 73.6% for patients who underwent surgery. Among the 17 patients who underwent resection (except for four with PCR), the status of ERCC1, tubulin, TYMS, RRM1 and EGFR changed markedly after chemotherapy in six patients, eleven patients, eight patients, nine patients and one patient, respectively. CONCLUSION: Chemotherapy followed by surgery on the basis of biomarker examination is a challenging approach for patients with advanced NSCLC who otherwise have poor outcomes. Post-chemotherapy biomarker status changed markedly in many cases.

Innovative method using circulating tumor cells for prediction of the effects of induction therapy on locally advanced non-small cell lung cancer.

BACKGROUND: The existence of circulating tumor cells (CTCs) in patients with lung cancer has been reported. The purpose of this study was to assess whether CTCs are predictive of the pathological effects of induction chemoradiotherapy for patients with non-small cell lung cancer. METHODS: Patients who underwent induction chemoradiotherapy followed by surgery were compared with those who underwent surgery alone. Peripheral and pulmonary venous blood samples from the involved lobe were collected intraoperatively, and the number of CTCs was counted using the CellSearch™ system, an epithelial cell adhesion molecule-based immunomagnetic technique. RESULTS: Of the 9 patients who underwent induction therapy, 4 achieved pathological CR, 4 achieved major response, and 1 achieved minor response. All patients who underwent induction therapy and surgery alone were negative for CTCs in peripheral blood. In the induction therapy group, 4 patients showing pathological CR were negative for CTCs in pulmonary venous blood (pvCTCs) and 5 showing major/minor response were positive (mean, 57.8 cells). The numbers of CTCs in patients showing major/minor response were significantly higher than those in patients showing pathological CR (p = 0.012, Mann-Whitney U test). All 6 patients undergoing surgery alone were positive for pvCTCs (mean, 207.5 cells), showing a significant difference from those undergoing induction therapy (p = 0.038). CONCLUSIONS: The existence of CTCs in pulmonary venous blood reflects pathological non-CR, and therapeutic pathological response may be predicted by pvCTC measurement.

[Predictor of intrathoracic lymph node metastasis in peripheral non-small cell lung cancers 20 mm or less in greatest dimension].

PURPOSES: To assess the independent predictor of lymph node metastasis( LNM) in peripheral smallsized non-small cell lung cancers (NSCLCs), we conducted a clinicopathologic analysis of patients with small-sized NSCLCs with and without intrathoracic LNM. METHODS: We retrospectively studied 213 patients who had undergone surgical resection of NSCLCs 20 mm or less in diameter. Categories of patient characteristics were divided into 2 groups based on clinicopathologic features, and the incidence of LNM was compared. Univariate and multivariate analyses of factors affecting overall survival( OS) were also conducted. RESULTS: In pN1-2 group (n=19), the incidence of elevated (>5 ng/dl) of preoperative carcinoembryonic antigen (CEA) and larger tumor size (>10 mm) was significantly higher than that in pN0 group (n=194) [p=0.0004, 0.0025]. Preoperatively, 73.7% patients were diagnosed as having lower stage in N-staging. Multivariate analysis identified only pN staging as an independent prognostic factor (p=0.002). CONCLUSIONS: It is likely that preoperative CEA and tumor size are useful in selecting patients with micro-N1-2 disease among those with small-sized NSCLCs. Our results indicate that limited resection should be avoided in patients with elevated CEA or tumors more than 10 mm in size, even if preoperative radiographic findings suggest no intrathoracic LNM.

Prognostic factors in patients after lobectomy for p-T1aN0M0 adenocarcinoma.

OBJECTIVES: The seventh edition of the TNM Classification of Malignant Tumours was published in 2009. This study was conducted to investigate the prognostic factors of p-T1aN0M0 pulmonary adenocarcinoma, which is the earliest stage defined in the new TNM classification. METHODS: We retrospectively studied 122 patients who underwent lobectomy at our institution for p-T1aN0M0 adenocarcinoma, as re-categorized in the seventh TNM classification. The patients were separated into groups on the basis of the following clinicopathologic parameters: age, < 70 vs. > 70 years; gender, male vs. female; preoperative serum carcinoembryonic antigen (CEA) level, < 5.0 vs. ≥ 5.0 ng/dl; tumour size, <10 vs. >10 mm; intratumoral vascular or lymphatic invasion, positive vs. negative. Univariate and multivariate analyses of disease-free survival were performed. RESULTS: The median follow-up period was 41.4 months. Univariate analysis showed that prognostic factors such as age, CEA elevation and intratumoral vascular or lymphatic invasion were significant (age, < 70 vs. > 70 years; 97.1% vs. 82.0%, P = 0.0027; preoperative serum CEA level, < 5.0 vs. > 5.0 ng/dl; 93.3% vs. 33.3%, P < 0.0001; intratumoral vascular or lymphatic invasion, positive vs. negative; 31.3% vs. 96.5%, P < 0.0001). Multivariate analysis demonstrated that only intratumoral vascular or lymphatic invasion was a significantly independent prognostic factor (P = 0.0039, Hazard Ratio, 0.066; 95% Confidence Interval, 0.011-0.419). CONCLUSIONS: Intratumoral vascular or lymphatic invasion should always be studied and included in the final pathology report in order to consider potential clinical and therapeutic relevance. The efficacy of adjuvant chemotherapy for these patients should also be evaluated in clinical trials.

[Prognosis of surgically treated large cell neuroendocrine carcinoma].

Large cell neuroendocrine carcinoma (LCNEC) is a relatively rare tumor in malignant lung neoplasms. The prognosis of LCNEC is poor and there is no consensus on the treatment for LCNEC. We report our retrospective assessment of 11 patients of LCNEC from 1999 to 2008. Three of 11 patients had malignant exudate at thoracotomy. Seven patients received limited resection. There was a recurrence even after complete surgical resection in its early stage. Four patients received platinum-based chemotherapy for adjuvant therapy or recurrence. The response to platinum-based chemotherapy was relatively good and may be comparable to that of small cell lung cancer. The overall 5-year survival rate was 30.3%. Pulmonary LCNEC represents an aggressive tumor and multimodal treatment is required.

Clinicopathological study of p-T1aN0M0 non-small-cell lung cancer, as defined in the seventh edition of the TNM classification of malignant tumors.

OBJECTIVE: The seventh edition of the TNM Classification of Malignant Tumours was published in 2009. The present study was conducted to investigate the clinicopathological features of p-T1aN0M0 non-small-cell lung cancer, which is the earliest stage defined in the new tumor, node, metastasis (TNM) classification, in relation to patient prognosis. METHODS: We retrospectively studied 162 patients, who underwent surgical resection at our institution for p-T1aN0M0 non-small-cell lung cancer, as re-categorized in the seventh TNM classification. Univariate and multivariate analyses of disease-free survival were performed. RESULTS: The mean tumor size was 13.2 ± 4.7 mm. The maximum tumor diameter was >10 mm in 104 cases (64.6%), and ≤ 10 mm in 58 (35.4%). The median follow-up period was 44.5 months. Univariate analysis showed that the 5-year disease-free survival rate of patients with and without preoperative serum carcinoembryonic antigen elevation was 50.8% and 95.1% (P<0.0001), respectively, that of patients with and without blood vessel or lymphatic invasion was 40.0% and 95.8% (positive vs negative, P<0.0001), respectively, and that of patients aged ≥ 70 years and <70 years was 86.8% and 96.1% (P=0.014), respectively. Multivariate analysis including these three clinicopathologic factors demonstrated that preoperative elevation of the carcinoembryonic antigen level and blood vessel or lymphatic invasion were independent prognostic factors. CONCLUSION: In patients with p-T1aN0M0 non-small-cell lung cancer, an elevated preoperative carcinoembryonic antigen level and blood vessel or lymphatic invasion tend to affect prognosis to a greater degree than tumor size. Therefore, the efficacy of adjuvant chemotherapy for these patients should be evaluated in clinical trials.

Usefulness of [18F]fluoro-2-deoxy-D-glucose positron emission tomography for predicting the World Health Organization malignancy grade of thymic epithelial tumors.

OBJECTIVE: The objective of this study was to investigate whether the maximum standardized uptake value (SUVmax) determined using positron emission tomography with [(18)F]fluoro-2-deoxy-D-glucose ((18)FDG-PET) can predict the grade of malignancy of thymic epithelial tumors based on the World Health Organization (WHO) classification. METHODS: We retrospectively analyzed 13 patients with thymic epithelial tumors, who underwent (18)FDG-PET examination before treatment. The patients were subdivided into a thymoma group and a thymic carcinoma group, and the two were compared clinicopathologically. RESULTS: There were six men and seven women, ranging in age from 36 to 78 years (mean, 58.8 ± 13.3 years). Mean tumor size was 47.3 ± 26.0mm, and the WHO classification was type A in two patients, type AB in none, type B1 in one, type B2 in three, type B3 in two, and thymic carcinoma in five. Thus, eight patients had thymoma and five had thymic carcinoma. The Masaoka stage was I in four patients, II in four, III in three, and IV in two. Mean pre-treatment SUVmax for the tumors overall was 5.24 ± 3.10, with a range of 1.73-11.21. Mean SUVmax in the thymic carcinoma group was 8.15 ± 7.88, and that in the thymoma group was 3.43 ± 2.19, the difference being significant (P = 0.002). CONCLUSIONS: A significant relationship was observed between SUVmax and morphological classification by the WHO system for this cohort of thymic epithelial tumors. Pre-treatment SUVmax may be useful for differentiating thymoma from thymic carcinoma.

A new application for the heart positioner in operations for mediastinal tumors.

We applied a heart positioner during operations to remove large mediastinal tumors. Fixing and lifting the tumor with this device allowed a good view behind the tumor. Separating the tumor from surrounding structures was easy and safe, with no risk of insult. The device caused no damage to the tumor capsule. This could represent a novel method to remove large mediastinal tumors safely and effectively.

Expression of ERCC1 and class III ß-tubulin is associated with the survival of resected stage III non-small cell lung cancer patients treated with induction chemoradiotherapy using carboplatin-taxane.

Several molecules have been proven to be associated with responsiveness to chemotherapy. A clinical study on the expression of excision repair cross-complementing (ERCC)-1 and class III ß-tubulin was conducted in advanced stage non-small cell lung cancer (NSCLC) patients. We investigated 34 resected stage III NSCLC patients treated with induction chemoradiotherapy using carboplatin-taxane. Immunohistochemistry was performed to evaluate the intratumoral expression of ERCC1 and class III ß-tubulin. Nineteen tumors (55.9%) were ERCC1-high and 11 (32.4%) were class III ß-tubulin-high. There was no correlation between ERCC1 and class III ß-tubulin expression (r=0.208). Regarding the pathological effect of induction therapy, the percentage of ERCC1-positive tumor cells was lower in tumors with a major response than in tumors with a minor response (P=0.0851). The percentage of class III ß-tubulin-positive tumor cells was significantly lower in tumors with a major response than in tumors with a minor response (P=0.0105). Regarding patient survival, the overall survival was significantly higher in patients with ERCC1-low tumors than in those with ERCC1-high tumors (P=0.0034). The overall survival was also significantly higher in patients with class III ß-tubulin-low tumors than in those with class III ß-tubulin-high tumors (P=0.0185). Cox regression analysis also demonstrated that ERCC1 (P=0.0467) and class III ß-tubulin statuses (P=0.0237) were significant prognostic factors. Co-evaluations of the intratumoral expression of ERCC1 and class III ß-tubulin are clinically useful for identifying patient populations responsive to chemotherapy using carboplatin-taxane.

Obliteration of empyema space by vascularized anterolateral thigh flaps.

Closure of the fistula and an appropriate choice of obliterating agents are crucial for the treatment of empyema with bronchopleural fistula. The choice of the material to be used for obliteration of the pleural space is a difficult one in some patients, such as those with empyema, developing after omentectomy, laparotomy, posterolateral thoracotomy, and so forth. The use of free anterolateral thigh flaps for obliteration of the pleural space generally needs a satisfactory vascular network around the thorax. We report two successfully treated cases of empyema with bronchial fistula, which were otherwise difficult to manage, in which a free anterolateral thigh musculocutaneous flap anastomosed to the superior thyroid vessels used to obliterate the pleural space.

Dual time point FDG PET for evaluation of malignant pleural mesothelioma.

OBJECTIVE: To evaluate whether 2-deoxy-2-18F-fluoro-D-glucose (FDG) positron emission tomography (PET) is more useful in differentiating malignant from benign pleural lesions, and whether delayed FDG PET imaging can improve the diagnostic performance in patients with suspicion of malignant pleural mesothelioma (MPM). METHODS: Thirty-three patients who were suspected of having MPM were examined with FDG PET. PET imaging (whole body) was performed at 60 min (early) post-FDG injection and repeated at 120 min (delayed) after injection only in the thoracic region. We evaluated the FDG uptake visually and semiquantitatively. The semiquantitative analysis using the standardized uptake value (SUV) was determined for both early and delayed images (SUVearly and SUVdelayed, respectively). RESULTS: The final diagnosis was MPM in 17 patients and benign pleural disease in 16 patients. The sensitivity, specificity, and accuracy to detect MPM on both early and delayed PET were all 88%. The mean value of SUVdelayed in MPM was significantly higher than that of SUVearly (P < 0.001). The mean values of SUVearly and SUVdelayed in MPM were significantly higher than the corresponding values in benign pleural disease (P < 0.01, respectively). CONCLUSION: FDG PET seems to be a useful imaging modality for differential diagnosis of MPM. In addition, the diagnostic performance on delayed PET was the same as that on early PET, although SUVdelayed was significantly higher than SUVearly in patients with MPM.

Wnt1 overexpression promotes tumour progression in non-small cell lung cancer.

BACKGROUND: The Wnt gene family is involved in embryogenesis and tumourigenesis. We investigated the clinical significance of Wnt1 expression in non-small cell lung cancer (NSCLC). METHOD: We studied 216 NSCLC patients. Immunohistochemistry was performed to investigate the Wnt1 expression in relation to the expression of beta-catenin and Wnt-targets, including c-Myc, Cyclin D1, VEGF-A and MMP-7. The Ki-67 proliferation index and the intratumoural microvessel density (IMD) were also evaluated. RESULTS: The ratio of tumours with an aberrant beta-catenin expression was significantly higher in Wnt1-positive tumours than in Wnt1-negative tumours (p<0.0001). The Wnt1 expression significantly correlated with the expression of c-Myc (p<0.0001), Cyclin D1 (p<0.0001), VEGF-A (p=0.0160), MMP-7 (p<0.0001), the Ki-67 index (p=0.0048) and the IMD (p=0.0267). Furthermore, the Wnt1 status was a significant prognostic factor for NSCLC patients (p=0.0127). CONCLUSIONS: The Wnt1 overexpression is associated with the expression of tumour-associated Wnt-targets, tumour proliferation, angiogenesis and a poor prognosis in NSCLCs.