Kazuro Sugi

Video-assisted Thoracoscopic Lobectomy Achieves a Satisfactory Long-term Prognosis in Patients with Clinical Stage IA Lung Cancer

We designed a prospective trial to determine the long-term prognosis of video-assisted thoracoscopic (VATS) lobectomy versus conventional lobectomy for patients with clinical stage IA (T1N0M0) lung cancer. Between January 1993 and June 1994, 100 consecutive patients with clinical stage IA non-small cell lung carcinoma underwent either conventional lobectomy through an open thoracotomy (open group; n= 52) or VATS lobectomy (VATS group; n= 48). Lymph node dissections were performed in a similar manner in both groups. No significant differences were observed in the number of dissected lymph nodes between the 2 groups. Pathologic N1 and N2 disease was found in 3 and 1 patients, respectively, from the open group, and in 2 and 1 patients, respectively, from the VATS group. During the follow-up period, distant metastases and local or regional recurrences developed in 7 and 3 of the open group patients, respectively, and in 2 and 3 of the VATS group patients, respectively. Two and one of the open and VATS group patients developed second primary cancers, respectively. The overall survival rates 5 years after surgery were 85% and 90% in the open and VATS groups, respectively (log-rank test, p= 0.74; generalized Wilcoxon test, p= 0.91). VATS lobectomy with lymph node dissection achieved an excellent 5-year survival, similar to that achieved by the conventional approach.

Detection of EGFR Gene Mutation in Lung Cancer by Mutant-Enriched Polymerase Chain Reaction Assay

Purpose: Mutations in the epidermal growth factor receptor (EGFR) gene have been reported to be present in non–small cell lung cancer (NSCLC) and related to the responsiveness of tumors to EGFR tyrosine kinase inhibitors, suggesting its usefulness as a biomarker. Because clinical samples contain tumor and normal cells or genes, a highly sensitive assay for detecting mutation is critical for clinical applications. Experimental Design: The mutant-enriched PCR is a rapid and sensitive assay with selective restriction enzyme digestion. We developed the mutant-enriched PCR assay targeting exons 19 and 21 of EGFR and applied the developed assay to detect mutations in 108 cases of surgically resected specimens of NSCLCs, 18 samples of computed tomography (CT)–guided needle lung biopsies, and 20 samples of pleural fluid. In addition, results were then compared with those from direct sequencing and a nonenriched PCR assay. Results: The mutant-enriched PCR that was proved to enrich one mutant of 2 × 103 normal genes detected mutations in 37 cases of 108 resected tumors, seven samples of CT-guided lung biopsies, and seven samples of pleural fluid. Among mutant cases, four resected tumors, two CT-guided lung biopsies, and two pleural fluid were identified as additional mutant cases by the mutant-enriched PCR, which were considered normal based on nonenriched assays. Conclusions: Our results indicate that EGFR mutations are readily detectable by mutant-enriched PCR in various clinical samples. Thus, mutant-enriched PCR may provide a valuable method of potentially detecting a small fraction of mutant genes in heterogeneous specimens, indicating its possible use in clinical application for NSCLC.

Systematic Lymph Node Dissection for Clinically Diagnosed Peripheral Non-Small-Cell Lung Cancer Less Than 2 cm in Diameter

Abstract. The value of radical systematic lymphadenectomy for treatment of early-stage bronchial carcinoma is controversial. We performed a prospective randomized study to address this question. Altogether 115 patients with peripheral non-small-cell lung cancers smaller than 2 cm in diameter were enrolled in this study. They were randomly assigned into a lobectomy with lymph node sampling group (sampling group,n= 56) or a lobectomy with radical systematic lymph node dissection group (dissection group,n= 59). Inclusion criteria were based only on preoperative clinical studies. Four tumors were larger than 2 cm postoperatively. One patient had disseminated disease, and two had intrapulmonary metastases discovered at surgery. Two patients had small-cell carcinoma. There were four with pathologic N1 disease and seven with N2 disease in the dissection group and three with N1 and eight with N2 disease in the sampling group. The numbers of local and distant recurrences were two and six, respectively, in the dissection group and two and five in the sampling group. The overall 5-year survival was 81% in the dissection group and 84% in the sampling group. No significant differences in the recurrence rate or survival was seen between the groups. Our results demonstrate that clinically evaluated peripheral non-small-cell carcinomas smaller than 2 cm in diameter do not require radical systematic mediastinal and hilar lymph node dissection.

Impaired respiratory mechanics in pulmonary emphysema: Evaluation with dynamic breathing MRI

To evaluate impaired respiratory mechanics in pulmonary emphysema, dynamic breathing magnetic resonance imaging (BMRI) was acquired with fast‐gradient echo pulse sequences at fixed thoracic planes over two to three slow, deep respiratory cycles in 6 controls and 28 patients with pulmonary emphysema including 9 patients undergoing lung volume reduction surgery (LVRS). Respiratory motions of the diaphragm and chest wall (D/CW) were assessed by a cineloop view, a fusion display of maximal inspiratory and expiratory images, and the time‐distance curves. By contrast with normal subjects with regular synchronous D/CW motions, the patients frequently showed reduced, irregular, or asynchronous motions, with significant decreases in the maximal amplitude of D/CW motions (MAD and MACW), and the length of apposition of the diaphragm (LAD) (P < 0.0001, P < 0.001, P < 0.01, respectively). After LVRS, nine patients showed improvements in D/CW configuration and mobility, with significantly increased MAD, MACW, and LAD (P < 0.01, P < 0.0001, and P < 0.05, respectively). In 40 studies of 28 patients including the post‐LVRS examinations, the normalized MAD and MACW significantly correlated with %FEV1 (r = 0.881 and r = 0.906; P < 0.0001, respectively). BMRI seems useful for noninvasively and directly assessing the impaired respiratory mechanics associated with abnormal ventilation in pulmonary emphysema, and also for monitoring the effects of LVRS. J. Magn. Reson. Imaging 1999;10:510–520.

Usefulness of EGFR mutation screening in pleural fluid to predict the clinical outcome of gefitinib treated patients with lung cancer

The importance of epidermal growth factor receptor (EGFR) gene mutation has been recognized in nonsmall cell lung cancer (NSCLC), requiring the standardization of mutation screening system including the kind of samples. Here, we examined the EGFR mutation status in 61 pleural fluid samples from NSCLC cases using direct sequencing, nonenriched PCR, mutant‐enriched PCR and peptide nucleic acid‐locked nucleic acid (PNA‐LNA) PCR clamp assay. The mutant‐enriched PCR assay detected 16 mutant cases. Among them, the nonenriched PCR assay failed to detect 3 mutant cases. Regarding the discrepancy between mutant‐enriched PCR and PNA‐LNA PCR clamp assays, 3 cases of exon19‐deletions were detected only by mutant‐enriched PCR assay and no difference at the L858R mutation. There was no difference in results between direct sequencing and nonenriched PCR assay. We also correlated the EGFR mutation with clinical outcome of gefitinib‐treated 29 cases. EGFR mutations were present in 10 cases, revealing 7 partial response and 3 no change (NC). In EGFR wild‐type cases, 10 revealed NC and 9 progressive disease. The responders were significantly more frequent among the EGFR mutant cases than among the wild‐type (p < 0.0001). Overall survival (p = 0.0092) and progression‐free survival (p = 0.018) were significantly longer among the EGFR mutant cases than among the wild‐type. In summary, we evaluated the utility of EGFR mutation screening in pleural fluid using 4 assays that showed some discrepancies arising from the designs of the assays. As clinical importance, the EGFR mutation status in pleural fluid can be a biomarker for the favorable outcome of gefitinib‐treated NSCLC cases.

Video-assisted thoracoscopic lobectomy reduces cytokine production more than conventional open lobectomy

OBJECTIVE We studied cytokine changes after video-assisted thoracoscopic lobectomy and conventional lobectomy in patients with stage IA lung cancer. METHODS From June, 1997, 20 consecutive patients with stage IA non small-cell lung carcinoma underwent either conventional lobectomy via an open thoracotomy (n = 10) or video-assisted thoracoscopic lobectomy (n = 10). The cytokine concentration in serum and pleural fluid were measured for 6 days postoperatively. RESULTS Interleukin-6 and interleukin-8 leads peaked at 3 h or 1 day after surgery. Cytokine levels in pleural fluid were more than 100 times higher than corresponding systemic levels. The increase of interleukin-6 in pleural fluid 3 hours after surgery was significantly smaller in video-assisted thoracoscopic lobectomy (3971 +/- 2793 pg/mL for video-assisted thoracoscopic lobectomy vs. 23274 +/- 8426 pg/mL for open lobectomy). There were no significant differences in the serum interleukin-6 and interleukin-8 concentrations between the 2 groups. CONCLUSION The thoracoscopic approach lessened the increase of cytokines in pleural fluid, but benefits of reduced cytokine production in video-assisted thoracoscopy remain to be clarified.

Phosphoinositide 3-kinase in nitric oxide synthesis in macrophage : Critical dimerization of inducible nitric-oxide synthase

Phosphoinositide 3-kinase (PI3K) has important functions in various biological systems, including immune response. Although the role of PI3K in signaling by antigen-specific receptors of the adaptive immune system has been extensively studied, less is known about the function of PI3K in innate immunity. In the present study, we demonstrate that macrophages deficient for PI3K (p85α regulatory subunit) are impaired in nitric oxide (NO) production upon lipopolysaccharide and interferon-γ stimulation and thus vulnerable for intracellular bacterial infection such as Chlamydophila pneumoniae. Although expression of inducible nitric-oxide synthase (iNOS) is induced normally in PI3K-deficient macrophages, dimer formation of iNOS protein is significantly impaired. The amount of intracellular tetrahydrobiopterin, a critical stabilizing cofactor for iNOS dimerization, is decreased in the absence of PI3K. In addition, induction of GTP cyclohydrolase 1, a rate-limiting enzyme for biosynthesis of tetrahydrobiopterin, is greatly reduced. Our current results demonstrate a critical role of class IA type PI3K in the bactericidal activity of macrophages by regulating their NO production through GTP cyclohydrolase 1 induction.

Comparison of three tracers for detecting sentinel lymph nodes in patients with clinical N0 lung cancer

The goal of this pilot study was to compare three tracers for the detection of sentinel nodes in patients with lung cancer. Forty-eight patients with clinical N0 non-small cell lung cancer were enrolled. Indocyanine green (n=16) or isosulfan blue (n=18) was injected around the tumor intraoperatively, or technetium tin colloid was injected preoperatively under CT guidance (n=14). Sentinel nodes were detected in 6.3% of patients injected with indocyanine green, 50.0% of patients injected with isosulfan blue, and 64.3% of patients injected with technetium tin colloid. The detection rate achieved with indocyanine green was significantly lower than with the other two tracers. A false-negative sentinel node was seen in 1 patient using isosulfan blue. Both isosulfan blue and technetium tin colloid seem to be suitable for intraoperative sentinel node mapping in patients with lung cancer.

Long-term prognosis of video-assisted limited surgery for early lung cancer §

OBJECTIVE The present intervention study was conducted to prospectively evaluate the long-term prognosis for video-assisted limited surgery, such as wedge resection and segmentectomy, for clinically early lung cancers depending on findings in high-resolution computed tomography (HRCT). SUBJECTS AND METHODS Patients were enrolled in the study between 2001 and 2004, and followed up for five subsequent years. Of these patients, those with a clinical stage IA lung cancer mainly comprising a ground glass-opacity (GGO) less than 1.5 cm across underwent thoracoscopic wedge resection of the lung (Group A). Patients with a tumour less than 2.0 cm in diameter, not classified in Group A, underwent video-assisted segmentectomy and hilar lymph node dissection with lobe-specific mediastinal nodes sampling (Group B). For patients with a tumour less than 3.0 cm in diameter, not classified in to any of the foregoing two groups, underwent video-assisted lobectomy and hilar and mediastinal lymph node dissection (Group C). RESULTS During the case registration period, 159 patients were registered for enrollment in the study (21 for Group A, 43 for Group B and 95 for Group C). Of the patients in Groups A and B, 28% were shifted to a surgical procedure involving a larger volume resected; 6% of the entire study population were shifted to thoracotomy. All patients completed the 5-year follow-up. The recurrence-free survival rate was 100% for Group A, 90.5% for Group B and 94.5% for Group C, with no significant difference among the groups. The total recurrence rate was 11.9% with localised recurrences observed in 6.3% of the patients and remote recurrences in 5.7%. The localised recurrences observed included stump recurrence in one case of Group B, and malignant pleural effusions/pleural dissemination in two cases of Group B and one case of Group C. Intrathoracic lymph node recurrences were observed in one case of Group B and five cases of Group C. CONCLUSIONS The present intervention study showed that thoracoscopic-limited surgery for clinically early lung cancers depending on findings in preoperative HRCT is feasible and appropriate from the viewpoint of oncology.

Cost Analysis for Thoracoscopy: Thoracoscopic Wedge Resection and Lobectomy

We reviewed our experience with video-assisted thoracic surgeyr (VATS) in our most recent 80 patients for the purpose of cost analysis. The costs incurred in the patients undergoing a VATS wedge resection for nodules (n=30) and a VATS lobectomy for lung cancer (n=10) were compared with the costs in similar patients undergoing a wedge resection (n=20) and lobectomy (n=20) using open techniques. The disposable instrument costs were US