Masaoki Ito

Prediction for prognosis of resected pT1a-1bN0M0 adenocarcinoma based on tumor size and histological status: relationship of TNM and IASLC/ATS/ERS classifications.

OBJECTIVES This study aimed to estimate the relationship between 7th TNM classification and IASLC/ATS/ERS classification with regard to tumor size and pathological status and to determine the utility of these classifications for predicting prognosis in resected node-negative adenocarcinoma with tumor size ≤2.0 cm and >2.0-3.0 cm. MATERIALS AND METHODS We reviewed 321 pN0M0 lung adenocarcinoma cases resected at Hiroshima University Hospital from January 1991 to December 2010. Histological differences between T1a and T1b based on the IASLC/ATS/ERS classification were estimated and followed by evaluation of overall survival (OS) and recurrence-free interval (RFI) based on differences in tumor size and histological features. RESULTS We found 188 cases of pT1a-1bN0M0 (135 T1a, 53 T1b). Pathological T1a tumors included significantly more adenocarcinoma in situ (AIS) cases and minimally invasive adenocarcinoma (MIA) cases than T1b tumors (60.7% vs 18.8%, respectively; p<0.0001), while more invasive adenocarcinoma cases were included in pT1b. By considering the two classifications simultaneously, the 5-year OS rates of T1a AIS/MIA, T1b AIS/MIA, T1a invasive adenocarcinoma, and T1b invasive adenocarcinoma were 97.5%, 87.5%, 95.8%, and 86.8%, respectively. The 5-year RFIs of T1a AIS/MIA, T1b AIS/MIA, T1a invasive adenocarcinoma, and T1b invasive adenocarcinoma were 100%, 100%, 91.3%, and 72.5%, respectively. T1a AIS/MIA and T1b AIS/MIA could be separated as good prognostic cases with a 100% RFI. Multivariate analysis indicated that only T1b invasive adenocarcinoma was an independent factor for predicting recurrence (p=0.001). CONCLUSION Compared to a single classification, combining TNM and IASLC/ATS/ERS classifications could provide more detail information concerning disease recurrence. AIS and MIA should be handled equally, regardless of tumor size, because their non-/less invasive status is more useful for predicting prognosis than their tumor size classification. In contrast, the T descriptors based on TNM classification are important for predicting prognosis in invasive adenocarcinoma.

Classifications of N2 Non–Small-Cell Lung Cancer Based on the Number and Rate of Metastatic Mediastinal Lymph Nodes

BACKGROUND Subdivisions of N2 non-small-cell lung cancer (NSCLC) cases based on metastatic status of mediastinal and non-mediastinal lymph nodes have been proposed. This study aimed to evaluate N2 disease classification by mediastinal lymph nodes alone. PATIENTS AND METHODS We reviewed 187 patients with NSCLC pN1-N2 who were surgically treated to evaluate the proposed classifications: number, rate, nodal zone of metastatic lymph nodes. We evaluated N2 disease classification based on mediastinal lymph nodes alone in 136 pN2 cases. RESULTS The number (1-2, 3-5, and 6 ≤) or rate (15%≥, 15%< to 40%>, and 40%≤) classification based on all metastatic lymph nodes was validated by the log-rank test and Cox proportional hazards model. After reclassification by number or rate of metastatic mediastinal lymph nodes alone, a significant difference was maintained among all groups except between the 3-5 and 6 ≤ groups. The 5-year survival rates of the 1-2, 3-5, and 6 ≤ groups were 63.4%, 32.4%, and 18.2%, respectively (1-2 vs. 3-5, P = .015; 3-5 vs. 6 ≤, P = .134). With rate classification, the 5-year survival rates of the 15%≥, 15%-40% (15%< to 40%>), and 40%≤ groups were 56.0%, 27.3%, and 5.04%, respectively (15%≥ vs. 15%-40%, P = .011; 15-40% vs. 40%≤, P = .011). The Spearmans rank correlation coefficient showed a highly significant correlation of metastatic status between mediastinal lymph nodes and all lymph nodes (both P < .001). CONCLUSION Classification by number and rate of mediastinal lymph nodes alone enabled subdivision of N2 NSCLC cases. Metastatic status of mediastinal lymph nodes reflects that of all lymph nodes and is prognostic indicators.

Outcomes after lobar versus sublobar resection for clinical stage I non−small cell lung cancer in patients with interstitial lung disease

Objective: Since the prognosis after standard lobectomy for non−small cell lung cancer (NSCLC) in patients with interstitial lung disease (ILD) is poor, we investigated the possibility of sublobar resection for the improvement of the surgical results in such patients. Methods: Of 796 consecutive patients with clinical stage I NSCLC who underwent pulmonary resection, 107 were diagnosed with ILD using high‐resolution computed tomography (HRCT). Overall survivals (OS) were compared between patients with non‐ILD and those with ILD or between patients with ILD who underwent lobectomy and those who underwent sublobar resection. ILD patterns consisted of usual interstitial pneumonia (UIP), possible UIP, and inconsistent with UIP. The log‐rank statistics and Cox proportional hazard models were used to test for survival differences. Results: OS was significantly lower in patients with “ILD inconsistent with UIP” pattern (hazard ratio [HR], 2.66; 95% confidence interval [CI], 1.19‐5.97; P = .014), or “ILD with possible UIP or UIP” patterns (HR, 2.38; 95% CI, 1.76‐3.21; P < .001) compared with patients with non‐ILD. No significant difference in OS was observed between patients with ILD who underwent either lobectomy or sublobar resection (HR, 1.82; 95% CI, 0.81‐4.06; P = .19). Multivariable Cox analysis demonstrated diffusing capacity of the lung for carbon monoxide (HR, 0.95; 95% CI, 0.91‐0.99; P = .009) and not surgical procedure (HR, 2.76; 95% CI, 0.83‐9.16; P = .099), as an independent prognostic factor for OS. Conclusions: Sublobar resection may be a potential alternative choice for clinical stage I NSCLC with ILD on HRCT.

Prognostic impact of the primary tumor location based on the hilar structures in non-small cell lung cancer with mediastinal lymph node metastasis

The status of mediastinal lymph node metastasis is one of the main factors determining the treatment strategy for non-small cell lung cancer (NSCLC), but the primary tumor location is not considered crucial in the tumor-node-metastasis (TMN) classification at present. The aim of this study was to estimate the prognostic value of the primary tumor location on the basis of the hilar structures in NSCLC with mediastinal lymph node metastasis. We retrospectively reviewed the cases of 337 consecutive patients who underwent surgical resection for NSCLC between 1995 and 2004, divided the pN2 NSCLC cases (n=40) into central- and peripheral-type tumors according to the distance of the primary tumor from the first branch of the extrapulmonary bronchus, and compared the surgical outcomes between these tumor groups. Eighteen and twenty-two cases were classified as central- and peripheral-type tumors, respectively. The 5-year survival rate was significantly better for patients with central-type tumors than peripheral-type tumors (51.5% vs. 21.2%, P=0.034). The location-specific prognostic tendency was noted irrespective of the presence (n=13) or absence of skip metastasis. In a multivariate Cox analysis of the N2 NSCLC cases, the primary tumor location was a significant (P=0.026) prognostic factor for overall survival. In conclusion, evaluation of the primary tumor location based on the hilar structures is useful to predict the prognosis in N2 NSCLC.

Novel application for pseudopodia proteomics using excimer laser ablation and two-dimensional difference gel electrophoresis

We developed a novel application to conduct pseudopodia proteomics. Pseudopodia are ventral actin-rich protrusions and play functional roles in cell migrations. Identification of pseudopodia proteins leads to a further understanding of malignant phenotypes of tumor cells and novel therapeutic strategies. In our application, tumor cells were placed on a fibronectin-coated porous membrane to form pseudopodia. According to the motile potentials of the cells, the cells formed pseudopodial microprocesses in the pores. An excimer laser, which was used for ophthalmic refractive surgeries, horizontally ablated cells at the membrane surface to remove the cell body. The microscopic observations and the protein expression studies suggested that the laser treatment caused no apparent damages to pseudopodia. Proteins in whole cells and pseudopodia fractions were individually solubilized, labeled with a highly sensitive fluorescent dye, and separated using two-dimensional difference gel electrophoresis. Among 2508 protein spots observed, 211 had different intensity between whole cells and pseudopodia fractions (more than fourfold differences and P-value of <0.05). The protein enrichment depended on the pore size. Mass spectrometric protein identification revealed 46 pseudopodia-localizing proteins. The localization of novel pseudopodia-localizing proteins such as RAB1A, HSP90B, TDRD7, and vimentin was confirmed using immunohistochemical examinations. The previous studies demonstrated that these four proteins may function in the cell migration process. This method will provide insights into the molecular details of pseudopodia and a further understanding of malignant phenotypes of tumor cells and novel therapeutic strategies.

Unilateral Absence of the Left Pulmonary Artery Accompanied by Right Lung Cancer

Unilateral absence of a pulmonary artery is a rare congenital anomaly that is often accompanied by other cardiovascular anomalies. Surgical treatment for this rare disease is usually performed only on the abnormal side. We report on a case of unilateral absence of a pulmonary artery that was complicated by contralateral primary lung cancer. We performed a right middle lobectomy despite the absence of the left pulmonary artery and detected changes in respiratory function during the operation. The present case provides information on the surgical tolerability and predictable morbidity following lung resection of the normal side in unilateral absence of a pulmonary artery.

Postoperative complications and prognosis after lobar resection versus sublobar resection in elderly patients with clinical Stage I non-small-cell lung cancer

OBJECTIVES The study aimed to investigate the outcomes of sublobar resection in elderly patients with non-small-cell lung cancer. METHODS A total of 205 patients aged ≥75 years were identified from 794 consecutive patients who underwent complete surgical resection for clinical Stage I non-small-cell lung cancer. The outcomes of lobectomy and sublobar resection were compared. Propensity scores were estimated for multivariable analyses and matching. RESULTS Sublobar resection (n = 99) was more frequently performed than lobectomy (n = 106) in older patients (P = 0.027) and those with lower maximum standardized uptake on positron emission tomography (P < 0.001), lower T stage (P < 0.001), lower %vital capacity (P = 0.007) and lower %diffusing capacity of the lungs for carbon monoxide (P = 0.025). Severe (≥Grade IIIa) postoperative complications occurred more frequently with lobectomy (11 of 106 procedures, 10.4%) than with sublobar resection (5 of 99, 5.1%; P = 0.16). In propensity score-adjusted multivariable analysis, lobectomy was an independent predictive factor for severe postoperative complications (odds ratio 3.49, 95% confidence interval 1.01-12.05; P = 0.048). Overall survival (OS) was not significantly different following lobectomy (5-year OS 67.2%) or sublobar resection (5-year OS 73.9%; P = 0.93). In multivariable analysis, the surgical procedure was not an independent predictive factor for OS (lobectomy: hazard ratio 1.03, 95% confidence interval 0.49-2.16; P = 0.94). CONCLUSIONS Sublobar resection may be the optimal procedure in elderly patients with clinical Stage I non-small-cell lung cancer and is associated with less severe postoperative complications than lobectomy and similar OS.

Inhibition of MEK, a canonical KRAS pathway effector in KRAS mutant NSCLC

KRAS mutant NSCLC cells require active nuclear export of Iκβα (also known as NFKBIA), a negative regulatory protein of NF-κB signaling, for maintaining survival signaling (1-3). Nuclear export receptor XPO1 correlates with KRAS mutation status.

Increased risk of recurrence in resected EGFR-positive pN0M0 invasive lung adenocarcinoma: Recurrent risk of EGFR mutation in LAD

This study was conducted to evaluate the prognostic and recurrent impact of EGFR mutation status in resected pN0M0 lung adenocarcinoma with consideration of the histological subtype.

Metachronous Lung Cancer post Pleurectomy/Decortication

Pleurectomy/decortication is a surgical procedure for malignant pleural mesothelioma (MPM) and has been proposed as an alternative to extrapleural pneumonectomy. We report a second primary lung cancer developing after pleurectomy/decortication for MPM. A 59-year-old man was diagnosed with MPM on the right side and underwent pleurectomy/decortication. Follow-up computed tomography detected a nodule in the right upper lobe that was diagnosed as adenocarcinoma by wedge resection. Lung cancer and MPM are associated with asbestos exposure. However, predicting lung cancer after treatment for MPM is difficult. Careful follow-up of the spared lung is necessary for detecting second primary lung cancer or MPM recurrence.