Hiroyuki Oizumi

Promoter hypermethylation of tumor suppressor and tumor-related genes in non-small cell lung cancers

Aberrant methylation of promoter CpG islands is known to be a major inactivation mechanism of tumor suppressor and tumor‐related genes. To determine the clinicopathological significance of gene promoter methylation in non‐small cell lung cancer (NSCLC), we examined the promoter methylation status of the APC, DAP‐kinase, E‐cadherin, GSTP1, hMLH1, p16, RASSF1A and RUNX3 genes in 75 NSCLCs and corresponding non‐neoplastic lung tissues by methylation‐specific PCR (MSP). The frequencies of methylation in NSCLCs and corresponding non‐neoplastic lung tissues were: 37% (28 of 75) and 48% (36 of 75) for APC, 28% (21 of 75) and 13% (10 of 75) for DAP‐kinase, 29% (22 of 75) and 15% (11 of 75) for E‐cadherin, 1% (1 of 75) and 0% (0 of 75) for GSTP1, 7% (5 of 75) and 0% (0 of 75) for hMLH1, 31% (23 of 75) and 0% (0 of 75) for p16, 43% (32 of 75) and 4% (3 of 75) for RASSF1A, and 20% (15 of 75) and 3% (2 of 75) for RUNX3, respectively. Methylation of p16 was more frequent in squamous cell carcinomas than in adenocarcinomas (P<0.05), and was associated with tobacco smoking (P<0.05). On the contrary, methylation of APC and RUNX3 was more frequent in adenocarcinomas than in squamous cell carcinomas (P<0.05). Thus, a different set of genes is thought to undergo promoter methylation, which leads to the development of different histologies. In addition, methylation of p16, RASSF1A and RUNX3 was mostly cancer‐specific (P<0.05), and may be utilized as a molecular diagnostic marker of NSCLCs.

Anatomic thoracoscopic pulmonary segmentectomy under 3-dimensional multidetector computed tomography simulation: A report of 52 consecutive cases

OBJECTIVE The purpose of this retrospective study was to evaluate the efficacy of anatomic thoracoscopic pulmonary segmentectomy performed under the guidance of 3-dimensional multidetector computed tomography simulation. METHODS Between September 2004 and June 2009, 52 patients (median age, 68 years; range, 16-85 years) underwent thoracoscopic segmentectomy without mini-thoracotomy. Images were obtained by using 64-channel multidetector computed tomography and a contrast agent. The pulmonary arteriovenous structure was mainly determined using a 3-dimensional volume-rendering method. The preoperative simulation was performed at the initial stage of the study and the intraoperative at a later stage. The simulated images were used to identify the venous branches in the affected segment for division and the intersegmental veins to be preserved. Four 5- to 20-mm ports were used. Segmentectomy was performed by separating the pulmonary arteries and bronchi followed by dissection along the intersegmental plane. RESULTS Fifty-one patients underwent a complete thoracoscopic segmentectomy. A mini-thoracotomy was performed in 1 case because of arterial bleeding. The success rate of segmentectomies under complete thoracoscopy was 98%. The procedure was classified into 3 categories according to the degree of surgical difficulty. Before introducing the simulation, there were 4 easy cases and 1 fairly difficult case. After introducing preoperative simulation, 7 cases were classified as fairly difficult among 12 segmentectomy cases. Furthermore, 7 cases of difficult segmentectomy were performed using intraoperative simulation. No local recurrence or metastasis and no mortality were observed during the follow-up. CONCLUSIONS Thoracoscopic pulmonary segmentectomy under 3-dimensional multidetector computed tomography simulation is a safe technique.

Frequent epigenetic silencing of the p16 gene in non-small cell lung cancers of tobacco smokers.

Epidemiological studies have demonstrated a causal link between tobacco smoking and lung cancer. We investigated the association between inactivation of the p16 gene and tobacco smoking in 51 non‐small cell lung cancers (NSCLCs). Aberrations of the p16 gene were studied by PCR single‐strand conformation polymorphism analysis, followed by direct sequencing, microsatellite analysis, methylation‐specific PCR, and immunohistochemistry. Mutations were detected in 3.9% (2/51) of the tumors; the tumors carrying mutations were from smokers. The incidences of loss of heterozygosity, homozygous deletion, and promoter methylation in 37 smokers vs. 14 non‐smokers were; 45.9% vs. 28.6%, 16.2% vs. 7.1%, and 35.1% vs. 7.1%, respectively. Among these, only the association between promoter methylation and tobacco smoking was statistically significant (P<0.05). Therefore, epigenetic aberration is considered to be a major causative event in p16 silencing by tobacco smoking. Loss of p16 protein expression was apparent in 49% (25/51) of the tumors, and was associated with tobacco smoking (P<0.05) and with histological type (P<0.05). These findings suggest that tobacco smoking leads to inactivation of the p16 gene mainly through the epigenetic mechanism, ultimately increasing the risk of NSCLC, especially the squamous cell histological type.

Role of diffusion-weighted magnetic resonance imaging for predicting of tumor invasiveness for clinical stage IA non-small cell lung cancer

OBJECTIVES Recently, diffusion-weighted MR imaging (DWI) for the whole body has become available for clinical use, as has been previously used for the central nervous system. Favorable results have been reported using this imaging system to differentiate between benign and malignant lesions in some organs, and to correlate with the degree of cell differentiation in lung cancer. The purpose of this study was to assess the role of DWI for predicting tumor invasiveness of non-small cell lung cancers (NSCLC), especially for clinical stage IA patients. METHODS From January 2006 to September 2007, preoperative DWI and 18F-FDG-PET/CT were performed on 41 patients with clinical stage IA NSCLC who had undergone curative operations. Lung cancers that exhibited nodal, lymphovascular or pleural invasion were defined as invasive lung cancers. Nodules with strong dark signal, as observed by DWI in spinal cords, were defined as DWI-positive. We analyzed the associations between the pathological findings and the following preoperative clinical factors: age, gender, smoking history, preoperative CEA levels (<5.0 or >/=5.0ng/ml), preoperative tumor size, SUV max on PET/CT (<5.0 or >/=5.0) and DWI (positive or negative). RESULTS A total of 15 lesions (37%) were assessed as DWI-positive and 26 lesions (63%) were DWI-negative. Univariate analyses showed positive correlations for development of invasive cancer with the preoperative CEA level (p=0.049), SUV max (p=0.001) and DWI (p<0.001). Multivariate analysis showed that DWI (p=0.005) was an independent predictive factor for tumor invasiveness. CONCLUSION Our results suggest that DWI might be a useful method for predicting tumor invasiveness for clinical stage IA NSCLC.

Total thoracoscopic pulmonary segmentectomy

OBJECTIVE In lung resection, thoracoscopy has been mainly used for wedge resection and lobectomy. There have been very few reports on pulmonary segmentectomy, mainly because of its complex nature. The present report evaluates the safety and efficacy of thoracoscopic pulmonary segmentectomy for the treatment of benign lung diseases or small lung carcinomas. METHODS The study involved 30 patients who underwent thoracoscopic segmentectomy without a minithoracotomy from September 2004 to March 2008. The median age of the patients was 69 years (range, 16-81 years). Four 5-20 mm ports were used. The pulmonary vessels were ligated, and the bronchi were closed using a stapler. An electrocautery was used for intersegmental dissection. Chest tubes were inserted in all cases. RESULTS Twenty-eight patients underwent complete thoracoscopic segmentectomy. A minithoracotomy was created in one case because of arterial bleeding, and open lobectomy was performed in another case owing to the diagnosis of small cell carcinoma. The operative time ranged from 147 to 425 min (median time, 216 min). The inserted chest tubes were maintained in position for 1-7 days (median duration, 1 day). One patient developed subcutaneous emphysema that spontaneously resolved. No mortality was observed for 30 days after the surgery. Further, no local recurrence or metastases were observed during follow-up in cases of malignancy. CONCLUSIONS Thoracoscopic pulmonary segmentectomy is a feasible and safe technique. Reduced postoperative pain and an improved cosmetic outcome are considered advantages of this minimally invasive procedure.

Anatomical Lung Segmentectomy Simulated by Computed Tomographic Angiography

We describe the benefits of simulating lung segmentectomy by using multi-detector computed tomographic angiography. Preoperative determination of the anatomical, intersegmental plane is possible by visualizing the branches of the pulmonary veins. This new technique could be useful in thoracoscopic segmentectomy of the lung.

Surgery of giant bulla with tube drainage and bronchofiberoptic bronchial occlusion

A case of emphysematous bullae and right lung cancer is presented. At first, left giant bulla was managed by minithoracotomy and tube drainage combined with bronchofiberoptic bronchial occlusion to preserve the respiratory function. Four weeks later, right lung cancer was successfully resected.

Removal of cartilage rings of the graft and omentopexy for extended tracheal autotransplantation

BACKGROUND One of the serious problems in longer-size tracheal transplantation is infection or severe stenosis of the graft, probably caused by an inadequate blood supply even with omentopexy. For obtaining an appropriate blood supply, we experimentally developed a new technique that included removal of some cartilage rings of the graft and omentopexy. METHODS Twenty-one adult mongrel dogs were used. In group A (n = 11), a nine-cartilage ring length of the trachea in which six of nine rings were removed, leaving one cartilage ring at each end of the graft and another in the center, was autotransplanted with omentopexy. Two artificial tracheal rings outside the graft were used for maintaining the lumen. In group B (n = 10), a nine-cartilage ring length of the trachea was autotransplanted with omentopexy. RESULTS In group A, all dogs survived until being sacrificed, whereas 5 group B dogs died of graft infection and mediastinitis (p<0.05 versus group A). Mucosal blood flow of the graft in group A was normal and higher than in group B (p<0.05). Grade of the graft stenosis at death or sacrifice was 14%+/-1% in group A and 58%+/-25% in group B (p<0.05). CONCLUSIONS Removal of some cartilage rings improved blood supply to the graft and resulted in satisfactory survival and nonsignificant tracheal stenosis in extended tracheal autotransplantation.

Slip knot bronchial ligation method for thoracoscopic lung segmentectomy.

We report a novel monofilament slip knot technique for bronchial ligation and for visualization of the anatomic plane during lung segmentectomy. After threading the bronchus, a slip knot is made outside the thorax. During lung ventilation, one end of the string is pulled, and the knot slips to reach the bronchus without a knot-pusher. Bronchial ligation is then performed to block the outflow of segmental air while the segment remains expanded, whereas the other segments become collapsed. This technique allows identification of the anatomic intersegmental plane, facilitating thoracoscopic anatomic lung segmentectomy.

Port-Access Thoracoscopic Anatomical Segmentectomy for Pediatric Intralobar Pulmonary Sequestration

This report describes successful port-access thoracoscopic anatomical left lateral and posterior basal (S9 + 10) lung segmentectomy performed for intralobar pulmonary sequestration (ILPS) in a 5-year-old girl with recurrent pneumonia. Computed tomography revealed a multilocular lung abscess and an anomalous artery arising from the left gastric artery supplying the affected segment. After diagnosing ILPS, we performed thoracoscopic anatomical S9 + 10 segmentectomy. We consider thoracoscopic lung segmentectomy to be an important therapeutic option for pediatric ILPS.