Sufeng Chen

Tumor-associated macrophages provide a suitable microenvironment for non-small lung cancer invasion and progression.

OBJECTIVE It remains largely unknown whether tumor-associated macrophages (TAMs) are involved in invasion and metastasis of human lung cancer. The aim of our study was to obtain an accurate overview of the broad range of changes occurring in monocytes that develop into TAMs, and the roles of TAMs during the progression of non-small cell lung cancer. METHODS TAM was isolated from 98 primary lung cancer tissues by short term cultivation in serum-free medium. The mRNA expression levels of 9 genes, including EGF, Cathepsin K, Cathepsin S, COX-2, MMP-9, PDGF, uPA, VEGFA, HGF, were evaluated by real-time PCR in 98 NSCLC. The relationships between those gene expression levels and clinicopathological features were investigated. The effects of conditioned medium from TAMs on the invasive properties of different lung cancer cell lines were measured using Transwell chambers. RESULTS We successfully achieved up to 95% purity of TAM, derived from 98 primary lung cancer tissues. TAM expressed high levels of Cathepsin K, COX-2, MMP-9, PDGF-B, uPA, VEGFA, and HGF. Phenotypic expression on TAMs, like MMP9, was shown to be correlated with disease progression by analyzing lung cancer tissues. Conditioned medium from TAM significantly increased cell migration and invasion in SPC-A1 cells, H460 cells and A549 cells. Anti-uPA and anti-MMP-9, but not anti-VEGF monoclonal antibodies, can inhibit TAM-induced invasion. The increase of invasiveness in the lung cancer cell lines was also correlated with their gelatinase activity, through MMP9. CONCLUSIONS Short-term culture in serum free medium is an effective way to isolate TAM in NSCLC. The results of this study also demonstrated that those up-regulated genes in TAMs contributed to suitable microenvironments for lung cancer invasion and metastasis. These findings may be useful in developing novel therapeutic strategies to prevent lung cancer progression.

Increased IL-10 mRNA expression in tumor-associated macrophage correlated with late stage of lung cancer

BackgroundMonocyte recruited into the tumor and maturation to tumor-associated macrophage (TAM). Interleukin-10(IL-10) is a potent immunosuppressive cytokine, which can be secreted from both primary tumor and stromal cells. However, there are controversies regarding its role in the progression of cancer. So it is important to isolate TAM from tumor cells to study the role of IL-10 in the progress of cancer. The aim of our study was to determine whether IL-10 expressed by TAM correlated with clinicopathological factors in NSCLC.MethodsTAM in NSCLC was isolated by short-term culture in serum free medium with the modification to literature reports. The mRNA expression levels of IL-10, cathepsin B, cathepsin S, which were closely related with TAM according to the literatures, were evaluated by Quantitative real-time RT-PCR in 63 NSCLC. The relationships between their expression levels and clinicopathological features were investigated.ResultsWe successfully achieved up to 95% purity of TAM, derived from 63 primary lung cancer tissues. TAM expressed high levels of IL-10, cathepsin B in NSCLC. High levels of IL-10 in TAM significantly correlated with stage, tumor size, lymph node metastasis, lymphovascular invasion or histologic poor differentiation.ConclusionsOur results revealed that TAM with high levels of IL-10 expression may play an important role in the progression of non-small cell lung cancer. The data also suggested that TAMs may involve in tumor immunosuppression through overexpressed IL-10. Additionally, the phenotype of isolated TAM can be potentially used to predict clinicopathological features as well.

The expression of prolyl hydroxylase domain enzymes are up-regulated and negatively correlated with Bcl-2 in non-small cell lung cancer

The prolyl hydroxylase domain enzymes (PHDs) play the most notable role in cellular oxygen sensing and oxygen homeostasis, the transcription of PHD genes are involved in the protection against hypoxia and oxidative stress. Intratumoral hypoxia exists in malignant solid tumors primarily due to rapid cancer cell proliferation with high metabolic demands and defective structural and functional vasculature. Previous studies have demonstrated that all the three PHDs have the ability to hydroxylate hypoxia inducible factor (HIF) polypeptides, which are the key molecules in maintaining the oxygen homeostasis. However, PHDs play multiple physiological and pathological roles. There is scant data regarding expression of PHDs genes in non-small cell lung cancer (NSCLC) tissues. In Addition, the relationship between PHDs and apoptosis has never been explored in NSCLC. In this article, we examined the expression of PHD genes and their relationship with the tumor behavior and apoptosis-associated factors in NSCLC. Our results indicated that the expression of PHDs was much higher in lung cancer tissue than that of adjacent normal tissue, and the high expression of PHD3 was associated with early tumor stage and well differentiation in NSCLC. Moreover, increased PHD3 expression was significantly correlated with the low expression of Bcl-2, suggesting its potential role in inducing apoptosis.

Refinement of Minimally Invasive Esophagectomy Techniques After 15 Years of Experience

IntoductionIn an effort to reduce the morbidity and mortality associated with open esophagectomy, a minimally invasive approach to esophagectomy was introduced at the University of Pittsburgh Medical Center (UPMC) in 1996. The objective of this article is to discuss the optimization and refinement of minimally invasive esophagectomy (MIE) techniques over the 15-year experience at UPMC. We also reviewed the literature on technical improvements in MIE.MethodLiterature highlights for MIE and related meta-analyses comparing open esophagectomy and MIE were reviewed. The rationale and outcomes of techniques refinements were discussed in detail. ResultsMost meta-analyses and systematic reviews confirm the feasibility and safety of MIE and suggest similar oncologic outcomes as compared with open esophagectomy. Since 1996, over 1,000 minimally invasive esophagectomies have been performed at UPMC. We have made several refinements to the MIE procedure that we believe significantly improved our surgical outcomes. It included adjustment of width of the gastric conduit, application of omental flap, and conversion from minimally invasive, three-hole esophagectomy to minimally invasive Ivor Lewis esophagectomy.ConclusionMIE became a mainstay in the surgical treatment of esophageal cancer at UPMC. The technical improvements detailed above make the UPMC approach to MIE a feasible, safe, and efficient procedure.

Pulmonary benign metastasizing leiomyoma from uterine leiomyoma

BackgroundBenign metastasizing leiomyoma (BML) occurs in a low proportion of uterine leiomyomas and treatment methods for BML are diverse and controversial. The study introduces preliminary experiences in the diagnosis and treatment of BML with the purpose of finding a suitable management strategy for these patients.MethodsThree patients with BML were treated in our department from April 2008 to July 2012. Each of these patients presented with multiple nodules in both lungs, where we performed video-assisted thoracoscopic wedge resection to harvest enough tissue for histopathologic and immunohistochemical examination. The patients were treated with medical castration or surgical castration after the diagnosis of BML.ResultsThe ultimate pathologic results ruled out the possibility of leiomyosarcoma and other metastatic diseases, and confirmed that the pulmonary lesions were BML. The lung lesions remained stable in two patients who were treated by surgical castration, and the lung nodules regressed in one patient treated with gonadotropin-releasing hormone analogues.ConclusionsThe diagnosis of BML is based on the medical history of uterine myomas and histopathologic and immunohistochemical examination of lung nodules. Video-assisted thoracoscopic wedge resection is the best way to harvest tissue for diagnosis. The better outcomes in BML seem to call for medical intervention, either chemical or surgical, after diagnosis is made.

Comparison of Ivor-Lewis vs Sweet esophagectomy for esophageal squamous cell carcinoma: a randomized clinical trial.

IMPORTANCE Sweet esophagectomy is performed widely in China, while the Ivor-Lewis procedure, with potential benefit of an extended lymphadenectomy, is limitedly conducted owing to concern for a higher risk for morbidity. Thus, the role of the Ivor-Lewis procedure for thoracic esophageal cancer needs further investigation. OBJECTIVE To determine whether Ivor-Lewis esophagectomy is associated with increased postoperative complications compared with the Sweet procedure. DESIGN, SETTING, AND PARTICIPANTS A randomized clinical trial was conducted from May 2010 to July 2012 at Fudan University Shanghai Cancer Center, Shanghai, China, of 300 patients with resectable squamous cell carcinoma in the middle and lower third of the thoracic esophagus. Intent-to-treat analysis was performed. INTERVENTIONS Patients were randomly assigned to receive either the Ivor-Lewis (n = 150) or Sweet (n = 150) esophagectomy. MAIN OUTCOMES AND MEASURES The primary outcome of this clinical trial was operative morbidity (any surgical or nonsurgical complications). Secondary outcomes included oncologic efficacy (number of lymph nodes resected and positive lymph nodes), postoperative mortality (30-day and in-hospital mortality), and patient discharge. RESULTS Resection without macroscopical residual (R0/R1) was achieved in 149 of 150 patients in each group. Although there was no significant difference between the 2 groups regarding the incidence of each single complication, a significantly higher morbidity rate was found in the Sweet group (62 of 150 [41.3%]) than in the Ivor-Lewis group (45 of 150 [30%]) (P = .04). More patients in the Sweet group (8 of 150 [5.3%]) received reoperations than in the Ivor-Lewis group (1 of 150 [0.7%]) (P = .04). The median hospital stay was 18 days in the Sweet group vs 16 days in the Ivor-Lewis group (P = .002). Postoperative mortality rates in the Ivor-Lewis (1 of 150) and Sweet (3 of 150) groups were 0.7% and 2.0%, respectively (P = .25). More lymph nodes were removed during Ivor-Lewis esophagectomy than during the Sweet procedure (22 vs 18, P < .001). CONCLUSIONS AND RELEVANCE Early results of this study demonstrate that the Ivor-Lewis procedure can be performed with lower rates of postoperative complications and more lymph node retrieval. Ivor-Lewis and Sweet esophagectomies are both safe procedures with low operative mortalities. TRIAL REGISTRATION clinicaltrials.gov Identifier:NCT01047111.

Is bronchoscopy necessary in the preoperative workup of a solitary pulmonary nodule

OBJECTIVE This study evaluated the role of conventional bronchoscopy in the preoperative workup of patients with solitary pulmonary nodules (SPNs). METHODS Patients with SPNs of unknown origin were enrolled for preoperative bronchoscopy at our institution. Bronchoscopic findings were prospectively collected, and their impact on planned therapy was analyzed. RESULTS A total of 1026 patients were included. Bronchoscopy identified unsuspected findings in 80 (7.8%) of them, with a total of 826 (80.5%) malignant nodules. Referent values for bronchoscopic detection of malignant SPNs were: accuracy, 24.3% (95% confidence interval [CI]: 21.7%-27.0%); sensitivity, 5.9% (95% CI: 4.5%-7.4%); specificity, 100%; and negative predictive value, 20.5% (95% CI: 18.0%-22.9%). Malignant bronchoscopic findings were more common in male patients (odds ratio [OR] = 2.1, 95% CI: 1.1-3.9, P = .021) and large nodules (OR = 2.3, 95% CI: 1.6-3.3, P < .001). Surgery was cancelled in 2 (0.2%) patients and modified in 36 (3.5%) patients because of bronchoscopic findings. In all, for 268 (26.1%) SPNs that presented with ground-glass opacity, the bronchoscopy was unrevealing. CONCLUSIONS In the preoperative evaluation of SPN, bronchoscopy is most likely to reveal malignancy in larger SPNs and in male patients. Bronchoscopy is not indicated in SPNs that present with ground-glass opacity on computed tomography scan.

Prognostic value of Bcl-2 expression in patients with non-small-cell lung cancer: a meta-analysis and systemic review

Objective B-cell-lymphoma-2 (Bcl-2) is a proto-oncogene that plays an important role in the regulation of apoptosis and cell survival. However, there are much conflicting data in the literature concerning the association between Bcl-2 and prognosis in non-small-cell lung cancer (NSCLC). There is little in the way of meta-analysis focused on Bcl-2 and its effect on NSCLC prognosis. This study was performed to provide an assessment of whether expression levels of Bcl-2 are associated with prognosis in patients with NSCLC. Materials and methods We searched PubMed, the Cochrane Library, and China National Knowledge Infrastructure for all eligible studies. The combined hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) in terms of overall survival were evaluated. Results Fifty published studies including 6,863 patients with lung cancer were included in this meta-analysis. Overall, Bcl-2 was expressed in 33% of the NSCLC tumors studied. Our analysis indicates that NSCLC patients with Bcl-2-positive expression have a better prognosis than those with Bcl-2-negative expression in both Asian and non-Asian study populations (HR 0.79, 95% CI 0.72–0.87, P<0.00001). However, Bcl-2-positive expression seems to have no significant impact on survival of stage I NSCLC patients. Conclusion Our results indicated that Bcl-2 might be a useful prognostic marker for NSCLC generally. Larger clinical trials are needed to confirm the prognostic value of Bcl-2 in stage I NSCLC.

Enhancement of Polyethylene Terephthalate Artificial Ligament Graft Osseointegration using a Periosteum Patch in a Goat Model.

The purpose of this study is to investigate whether a periosteum patch could enhance polyethylene terephthalate (PET) artificial ligament graft osseointegration in a bone tunnel. 12 female goats underwent ACL reconstruction with a PET artificial ligament graft in the right knees. Right knees in 6 goats were reconstructed with periosteum patch-enveloped PET grafts (Periosteum group) in the tibia bone tunnel, whereas the other 6 goats had no periosteum patch and served as the Control group. All the goats were sacrificed at 12 months after surgery. 3 tibial-graft complex samples in each group were harvested consecutively for microcomputed tomography (micro-CT) scan, magnetic resonance imaging (MRI) scan and histological evaluation. The other 3 tibial-graft complex samples in each group were harvested for biomechanical testing. The mean pull-out load of the Periosteum group (208±25 N) at 12 months was significantly higher than that of the Control group (107±13 N) (p=0.0044). According to the micro-CT scan, more new bone formation was observed at the graft-bone interface in the Periosteum group compared with the Control group. Furthermore, MRI showed that the Periosteum group appeared to have a better graft osseointegration within the bone tunnel compared with the Control group. Histologically, application of a periosteum patch induced more new bone and Sharpeys fiber formation between the graft and bone tunnel compared with the controls. The study has shown that periosteum enveloping of the PET artificial ligament has a positive effect in the induction of artificial ligament osseointegration within the bone tunnel.

Meta-analysis comparing doublet and single cytotoxic agent therapy as first-line treatment in elderly patients with advanced nonsmall-cell lung cancer

Objective To perform a systematic review and meta-analysis comparing doublet versus single agent therapy in elderly patients with advanced nonsmall-cell lung cancer (NSCLC). Methods PubMed® and Cochrane databases, and American Society of Clinical Oncology, World Congress of Lung Cancer, and European Society of Medical Oncology abstracts were searched. Endpoints were overall survival (OS), 1-year survival rate (1-year SR), overall response rate (ORR), and grade 3/4 adverse events. Subgroup analyses were based on chemotherapy regimens and race. Results Out of 11 studies (13 randomized trials; n = 2782), doublet therapy was associated with significantly increased OS (hazard ratio [HR] 0.89, 95% confidence interval [CI] 0.83, 0.95), 1-year SR (risk ratio [RR] 1.15, 95% CI 1.04, 1.28), and ORR (RR 1.39, 95% CI 1.39, 1.86) versus single-agents. Chemotherapy regimen-based subgroup analyses favoured platinum-based doublet therapy for OS (RR 0.71, 95% CI 0.60, 0.84), 1-year SR (RR 1.28, 95% CI 1.11, 1.47), and ORR (RR 1.88, 95% CI 1.49, 2.38). Race-based subgroup analyses revealed increased benefit from doublet therapy in Asian populations for ORR (RR 1.70, 95% CI 1.29, 2.23) but not increased survival benefit. Higher incidences of grade 3/4 anaemia (RR 2.23, 95% CI 1.61, 3.09), thrombocytopenia (RR 2.47, 95% CI 1.17, 5.20), and fatigue (RR 1.36, 95% CI 1.06, 1.74) were observed with doublet versus single-agent therapy. Conclusions Doublet therapy was associated with significantly increased OS, 1-year SR and ORR compared with single agent therapy. Race may be considered when choosing doublet versus single-agent therapy as first-line treatment of NSCLC in elderly patients.