Immunohistochemistry and clinical value of sirtuin 2 in non-metastasized non-small cell lung cancer.

BACKGROUND: This study aimed to define whether sirtuin 2 (SIRT2) expression levels are related to the prognosis of non-small cell lung cancer (NSCLC) patients. METHODS: A survival analysis was carried out using the Kaplan-Meier (KM) plotter database. Immunohistochemical staining was performed and KM's method was used to estimate the survival rates for SIRT2 expression in 72 clinical samples. RESULTS: A survival analysis of 1,926 NSCLC patients showed that patients with low SIRT2 expression levels had significantly longer overall survival (OS) than those with high SIRT2 expression levels (P=0.0077; HR =1.19). In 72 non-metastasized NSCLC tissues, the positive rate of SIRT2 expression was 90.3% (65/72), among which, the positive expression rates of squamous cell carcinoma (SCC) and adenocarcinoma (ADC) were 96.4% (27/28) and 85.4% (35/41), respectively. Survival analysis showed that patients with low SIRT2 expression levels had significantly longer median survival time (MST) than those with high SIRT2 expression levels (15.0 versus 14.0 months, P=0.029). Furthermore, the results of subgroup analysis demonstrated patients with low SIRT2 expression levels had significantly longer survival time in ADC group (15.0 versus 12.0 months, P=0.022), but there wasn't significant difference in SCC group (15.0 versus 14.0 months, P=0.932). A multivariate Cox proportional hazards model, which included gender, age, TNM stage, differentiation and SIRT2 expression, showed that SIRT2 expression was an independent factor related to prognosis [HR =1.903, 95% confidence interval (95% CI): 1.085-3.339, P=0.025]. CONCLUSIONS: SIRT2 expression levels were significantly related to the survival time of patients with lung ADC but not SCC. Our study indicated SIRT2 was perhaps a specific prognostic biomarker for non-metastasized lung ADC.

SPOP promotes FADD degradation and inhibits NF-κB activity in non-small cell lung cancer.

FAS-associated protein with death domain (FADD) is the pivotal adaptor protein, which transmits apoptotic signals mediated by the death receptors. Here we report that high FADD protein level predicts poor prognosis of non-small cell lung cancer (NSCLC) patients and its protein level is mainly regulated by the 26S proteasome. We also found that ubiquitin ligase SPOP (speckle-type POZ protein) binds to FADD and mediates its degradation, which can be blocked by MG132 treatment. Notably, SPOP inhibits NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activity and its target genes expression via FADD. These results reveal the function of SPOP-FADDNFκB axis in NSCLC cells, which is associated with prognosis of NSCLC patients.

Visceral pleural invasion in lung adenocarcinoma ≤3 cm with ground-glass opacity: a clinical, pathological and radiological study.

BACKGROUND: Visceral pleural invasion (VPI) had been demonstrated as an aggressive sign in non-small cell lung cancers (NSCLC). However, its incidence and clinical relevance in early lung cancer showing ground glass nodules (GGNs) has not been clarified. METHODS: All consecutive surgically treated patients with solitary GGNs between 2009 and 2013 were reviewed retrospectively. Inclusion criteria were defined as lesions ≤3 cm with pleura abutting on computed tomography (CT) scan and pathologically confirmed NSCLC. RESULTS: Out of 156 enrolled patients, 38 had pathologically confirmed VPI. The incidence of VPI was 41.5% (27/65) if the tumor diameter was larger than 2.0 cm and 14.3% (13/91) if diameter was smaller than 2.0 cm (P<0.001). Further, the incidence was 17.4% (12/69) in pure GGNs and 32.2% (28/87) in part-solid GGNs (P=0.040). The tumor size and the nodule nodule-pleural relationship were significant predictors of positive VPI. In cases with pleural indentation, attachment, and closeness, the incidence was 38.1%, 25.5%, and 5.3%, respectively (P=0.001). All cases were PL0 and PL1, with no PL2 cases observed. CONCLUSIONS: Although VPI was visible in both pure/mix GGNs, it was more common in larger (>2 cm) GGNs. The radiographic findings of nodule abutment or a pleural tag did not reliably predict or exclude VPI. In patients with GGNs, a low rate of PL2 invasion may be observed.

Mosquito coil exposure associated with small cell lung cancer: A report of three cases.

Mosquito coils, which are commonly used as residential insecticides in Asia, contain different concentrations of octachlorodipropyl ether (S-2) as a synergist or an active ingredient. As bis(chloromethyl) ether (BCME) is an extremely potent lung carcinogen that can be produced by the thermolytic degradation of S-2, contact with mosquito coils is likely to expose individuals to a certain level of BCME, and therefore increase the risk of lung cancer. However, the significance of exposure is uncertain, as clinical and epidemiological studies concerning mosquito coil users and workers are lacking. The present study describes three cases of small cell lung cancer treated at the Shanghai Pulmonary Hospital that were likely to be the result of exposure to mosquito coils. All patients had worked in the mosquito coil manufacturing industry, with an mean occupational duration of 9.1 years, and presented with similar respiratory symptoms, such as cough and dyspnea. Upon diagnosis, no metastasis to other organs was identified in any of the cases. Subsequently, the three patients were treated with chemotherapy as well as radiotherapy in one case, however, all patients succumbed to the disease, with a mean overall survival time of 10.7 months. We conclude that contact with mosquito coils is likely to expose individuals to a level of S-2 that may increase the risk of SCLC.

Is neoadjuvant chemotherapy mandatory for limited-disease small-cell lung cancer?

OBJECTIVES: The present study attempted to evaluate the role of neoadjuvant chemotherapy combined with surgery in limited-disease small-cell lung cancer (LD-SCLC). METHODS: A retrospective analysis was performed on 106 LD-SCLC patients who underwent complete resections from February 2000 to February 2012 in Shanghai Pulmonary Hospital. Among these cases, two cycles of neoadjuvant chemotherapies were administered to all pathologically confirmed patients [Group Neoadjuvant (Group N)]. For those without pathology, operations followed by adjuvant chemotherapies were performed [Group Adjuvant (Group A)]. Prognostic features and overall survival (OS) were compared using the log-rank test and calculated using the Kaplan-Meier method. RESULTS: Group N included 47 cases and Group A included 59 cases. A total of 57 patients were male and 49 were female, with a mean age of 56.1 ± 10.2 years. A total of 41 patients were at pathological stage (p-Stage) IIIa, and 65 patients were at I or II. The overall 5-year survival rate (5-YS) was 28%. The 5-YS for p-Stage I-II (n = 65) was significantly better than that of p-Stage III (n = 41) (35 vs 20%, P = 0.034). For p-Stage IIIa (pN2 positive), the 5-YS of Group N was significantly better than that of Group A (34 vs 12%, P = 0.020). The median overall survival for Group N and Group A in IIIa (pN2 positive) LD-SCLC patients were 46 and 15 months (P = 0.009), respectively. Multivariate analysis for survival showed mediastinal lymph node involvement; surgery and histopathology of SCLC were both significant independent predictors of long-term survival. CONCLUSIONS: Neoadjuvant chemotherapy combined with surgery provided reasonable options for pIIIa-N2 LD-SCLC patients, which can give them a better chance of survival.

Etoposide-cisplatin alternating with vinorelbine-cisplatin versus etoposide-cisplatin alone in patients with extensive disease combined with small cell lung cancer.

BACKGROUND: The aim of this study was to evaluate the efficacy of alternating etoposide-cisplatin and vinorelbine-cisplatin (EP-NP) compared with an etoposide-cisplatin (EP) regimen for advanced combined small cell carcinomas. MATERIALS AND METHODS: Histologically confirmed combined small cell carcinoma patients who met the inclusion criteria were randomly assigned (1:1) into either the EP-NP setting (group A) or the EP setting (group B). The primary endpoint was progression-free survival in patients who received at least one dose of treatment. RESULTS: Eighty-two patients entered into this trial, 42 in group A and 40 in group B. The objective response rates in group A and group B were 42.9% and 32.5%, respectively (p=0.334). Survival analysis showed that median progression-free survival was 6.1 months in group A, which was significantly longer than the 4.1 months in group B (p=0.041). However, as to overall survival, no significant difference was found between the two groups (11.0 vs 10.1 months in groups A and B, respectively, p=0.545). No unexpected side effects were observed in either group. CONCLUSIONS: The EP-NP regimen for combined small cell carcinomas prolonged progression- free survival compared with the EP regimen. Further clinical investigations are warranted.

Prognostic role of station 3A mediastinal nodes for non-small-cell lung cancers.

OBJECTIVES: Station 3A nodes have been commonly neglected in surgical practice. This retrospective study collected information on the incidence and risk factors of Station 3A node to ascertain the prognostic role of 3A nodal involvement. METHODS: A total of 180 consecutive pN2 (stage IIIa) non-small-cell lung cancer (NSCLC) cases who underwent systemic lymphadenectomy and contained Station 3A nodes were enrolled. Survival rates were calculated according to the final pathology of Station 3A lymph node: Station 3A node (+) and Station 3A node (-). Statistical analysis was conducted using Kaplan-Meier and Cox regression models. RESULTS: Station 3A nodal metastasis was validated in 32 cases, and the incidence of Station 3A node involvement was 17.8%. Station 3A nodes involvement was strongly associated with the metastatic status of Station 4R nodes and histological nature of pulmonary cancer. The overall 3-year survival was 53% and median survival time was 40.6 months. The 3-year survival difference was significant between Station 3A node (-) and Station 3A node (+) (63 vs 22%, χ(2) = 16.426, P < 0.001). Moreover, the overall 3-year survival was closely related with the number of involved nodal zones (χ(2) = 31.156, P < 0.001). Multivariate analysis showed two statistically significant risk factors for survival including metastasis of Station 3A node and the number of positive nodal zones (hazard ratios [HR]: 2.702; 95% confidence intervals [CI]: 1.008-7.242; P = 0.027; and HR: 7.404; 95% CI: 3.263-16.936, P < 0.001, respectively). CONCLUSIONS: The involvement of Station 3A lymph nodes predicts poor prognosis of right-sided stage pIIIa-N2 NSCLC patients. Therefore, systemic lymphadenectomy for right-sided cancers should include Station 3A nodes when ascertaining a complete resection.

Local extension at the hilum region is associated with worse long-term survival in stage I non-small cell lung cancers.

BACKGROUND: The prognostic significance of hilar structures invasion, which remains undefined for non-small cell lung cancer (NSCLC), may have potential application for cancer staging. Tumor extension along the bronchus and pulmonary vessels was examined for survival significance. METHODS: In all, 213 pathologically proved central-type stage I NSCLC cases were enrolled. Four study groups were assigned based on the extent of resections: standard lobectomy (group L, n=32), bronchoplastic procedures (group B, n=94), standard lobectomy combined with pulmonary angioplasty (group A, n=48), and bronchial sleeve resection combined with pulmonary artery angioplasty (group BA, n=39). Univariate and multivariate analysis were performed by the Kaplan-Meier method and the Cox regression model. RESULTS: There were 2 postoperative deaths (pulmonary embolism and serious pulmonary infection). Complications were noted in 39 patients (18.3%). Among these patients, the overall 5-year survival rate was 60.2%±0.05%, with a median survival time of 75.0±7.5 months. The 5-year survival rates of subgroups were 79.5%, 59.7%, 59.0%, and 47.9%, respectively for groups L, B, A, and BA. Univariate analysis indicated tumor size, bronchial invasion, arterial involvement, and type of operation as closely associated with long-term survival. Multivariate analysis indicated that type of operation and tumor size were the most prominent prognostic factors of 5-year survival. CONCLUSIONS: Proximal tumor extension into bronchus, invasions into extrapericardial pulmonary vessels, and tumor size were the most important risk factors for 5-year survival with central-type stage I NSCLC. Tumor extension in the hilum was highly related to prognosis and might provide pertinent information to accurately define a tumor ("T") subclass.

Radical mediastinal nodal removal improves disease-free survival for pulmonary low-grade malignant tumors.

PURPOSE: To investigate the prognostic role of radical lymph node dissection in treatment for pulmonary Low Grade Malignant Tumors (LGMTs); specifically, on the extent of nodal removal and its impact on long-term survival. METHODS: A total of 93 LGMTs cases underwent surgical resection and were histopathologically confirmed. Overall survival rates and disease-free survival were respectively calculated according to the extent of lymph node resection and histopathological grades of tumors. Risk factors of nodal involvement and survival predictors were calculated via multivariate analysis. Life table, Kaplan-Meier, and Cox regression models were used for the statistical analysis. RESULTS: Thirty-eight cases of carcinoid, 17 adenoid cystic carcinomas, and 38 mucoepidermoid carcinomas were included in the current study. Twenty-one cases were high-grade and 72 were low-grade. A total of 813 lymph nodes were removed, at an average of 8.7±5.4 nodes per patient. The numbers of harvested nodes were 11.8±4.5, in the study group via radical nodal removal and 4.0±2.4 nodes per patient in the nodal sampling group. Eleven cases showed lymph nodal involvement (5 mediastinal and 6 hilar lymph node metastasis). No significant differences of overall survival was found among the different histological types (p=0.939), or the extent of nodal removal (p=0.971). Meanwhile, there was a significant difference of disease-free survival (DFS) rates according to the extent of nodal removal (5-YS: 97% of radical nodal dissection vs. 78% of nodal sampling, p=0.038). Overall survival and disease-free survival were closely associated with histological grading (OS: 78% of high grade vs. 97% of low grade, p=0.001; DFS: 57% of high grade vs. 97% of low grade, p<0.0001). CONCLUSIONS: Radical lymph node dissection improved disease-free survival for pulmonary low-grade malignant tumors, although no obvious improvement on overall survival was noticed. Histological grade was the most important prognostic factor in LGMTs.

Re-appraisal of N2 disease by lymphatic drainage pattern for non-small-cell lung cancers: by terms of nodal stations, zones, chains, and a composite.

PURPOSE: N2 non-small-cell lung cancer (NSCLC) is a heterogeneous disease with an extremely wide range of 5-year survival rates. A composite method of sub-classification for N2 is likely to provide a more accurate method to more finely differentiate prognosis of N2 disease. METHODS: A total of 720 pN2 (T1-4N2M0) NSCLC cases were enrolled in our retrospective analysis of the proposed composite method. Survival rates were respectively calculated according to the N2 stratification methods: singly by "nodal stations", "nodal zones", or "nodal chains", or by combination of all three. Statistical analysis was carried out by Kaplan-Meier and Cox regression models. RESULTS: A total of 10,199 lymph nodes (8059 mediastinal; 2140 hilar and intra-lobar) were removed. By nodal station, there were 173 cases of single-station involvement and 547 multi-stations. By nodal zone, there were 413 single-zone involvement and 307 with multiple zones. By nodal chain, there were 311 cases with single-chain and 409 multi-chain involvements. The overall 5-year survival was 20% and median survival time was 27.52 months. The 5-year survival was significantly better for cases of single-zone involvement, as compared to multi-zones (29% vs. 6%, p<0.0001). The 5-year survival rates of single- and multi-chains involvement were 36% and 8%, respectively (p<0.0001). When taking all of the above grouping methods into consideration, the N2 disease state could be further sub-classified into two subgroups with respective survival rates of 36% and 7% (p<0.0001). Subgroup I was composed of individuals with single-chain involvement and having either one or two station metastasis; individuals with any other metastasis combinations formed Subgroup II. Multivariate analysis revealed that the composite sub-classification method, number of positive lymph nodes, ratio of nodal metastasis, and pT information were the most important risk factors of 5-year survival. CONCLUSIONS: By combining the three N2 stratification methods based on "stations", "zones", and "chains" into one composite method, prognosis prediction was more accurate for N2 NSCLC disease. Single nodal chain involvement, which may be either one or two nodal stations metastasis, is associated with best outcome for pN2 patients.

Define relative incomplete resection by highest mediastinal lymph node metastasis for non-small cell lung cancers: rationale based on prognosis analysis.

PURPOSE: Present research aimed to explore the rationale of defining RIR operations by metastatic status of highest nodes. PATIENTS AND METHODS: 549 surgical patients, bearing pN2-NSCLCs, were enrolled in the current study. R1/R2 nodes on the right side and L4 nodes on the left were taken as the highest mediastinal lymph nodes. The operations were defined "Complete Resection (CR)" if the highest nodes were negative. Operations were otherwise "Relative Incomplete Resections (RIR)" if the nodes were positive. Exclusion criteria included: metastatic carcinomas or small cell lung cancer, prior history of induction therapy, exploratory thoracotomy, palliative resection, and massive pleural dissemination, as well as cases without "highest" mediastinal nodal pathology. The survival rate was calculated using the life-table and Kaplan-Meier method. Comparisons between groups were calculated using the Log-rank test. RESULTS: A total of 6865 lymph nodes (5705 mediastinal and 1160 regional, average 12.6±6.4 nodes for each patient) were removed. Total cases included 246 RIR (100 left and 146 right side) and 303 CR (108 left and 195 right). The overall 5-year survival rate was 22% and the median survival time was 28.29 months. Five-year survival rates of the CR and RIR group were statistically significant (29% and 13%, respectively p<0.0001). L4 and R1/R2 lymph nodes had similar position for defining RIR; no obvious survival difference was indicated between either side (p=0.464 in CR groups, p=0.647 in RIR groups). N2 subcategories and skip-metastasis were closely associated with highest nodal involvement (p<0.0001). Multivariate analysis showed CR/RIR assignment, tumor size, N2 disease stratification, pathological T status, and number of positive mediastinal nodes were risk factors for 5-year survival in the present case series. CONCLUSION: Involvement of the highest mediastinal lymph nodes is highly predictive of poor prognosis and indicates an advanced stage of the disease. Therefore, it may be appropriate to assign R1/R2 or L4 as criterion for defining RIR or CR cases in surgical NSCLC cases.