Shinya Tane

Psf3 is a prognostic biomarker in lung adenocarcinoma

Psf3 is a member of the evolutionarily conserved heterotetrameric complex GINS (Go-Ichi-Ni-San), which consists of Sld5, Psf1, Psf2, and Psf3. Previous studies have suggested that some GINS complex members are upregulated in cancer, but the status of Psf3 expression in lung adenocarcinoma has not been investigated. The objective of the current study was to determine whether Psf3 plays a role in lung adenocarcinoma by investigating clinical samples. We investigated the status of Psf3 expression in cancer cells of 125 consecutive resected lung adenocarcinomas by immunohistochemistry. Increased Psf3 expression was observed in 27 (21.6%) of the 125 cases. Further, univariate analysis and log-rank test indicated a significant association between Psf3 expression and lower overall survival rate (P = 0.0001 and P < 0.0001, respectively). Multivariate analysis also indicated a statistically significant association between increased Psf3 expression and lower overall survival rate (hazard ratio, 5.2; P = 0.0027). In a subgroup analysis of only stage I patients, increased Psf3 expression was also significantly associated with a lower overall survival rate (P = 0.0008, log-rank test). Moreover, the Ki67 index level was higher in the Psf3-positive group than in the Psf3-low positive group (P < 0.0001, Mann-Whitney U-test). Our results indicated that Psf3 can serve as a prognostic biomarker in lung adenocarcinoma.

MT1-MMP plays an important role in an invasive activity of malignant pleural mesothelioma cell☆

Malignant pleural mesothelioma (MPM) has a poor prognosis and is a treatment resistant tumor, which is increasing in frequency throughout the world. The poor prognosis is due to the aggressive local invasiveness rather than distant metastasis. In this study, we established a cell line of malignant mesothelioma from a clinical specimen and assessed the relationship between the expression of MT1-MMP and the invasion ability of that line, as well as the cultured cells of several other lines, using the simple method that we created previously. We established a cell line from a clinical specimen from a patient with malignant mesothelioma. We assessed the invasive activities of MPM cells in an easy-to-prepare double-layered collagen gel hemisphere (DL-CGH) system that enabled us to visualize cell movements during invasion. To assess the role of MT1-MMP in the invasive activity of MPM cells, we knocked down its expression by RNA interference (RNAi). The invasion assay with DL-CGH revealed that a high expression of MT1-MMP in MPM cells was associated with aggressive invasive activity. The RNAi of MT1-MMP indicated that the expression of MT1-MMP might have a crucial role in the invasiveness of MPM cells. The MT1-MMP expression in MPM cells is related to their capacity for locally aggressive spreading into the pleura and the surrounding tissues, and MT1-MMP should be a suitable molecular target for the suppression of the invasiveness of MPM.

Significant role of Psf3 expression in non-small-cell lung cancer

The GINS complex associates with cell division cycle (Cdc) protein 45 and mini‐chromosome maintenance (Mcm) proteins 2–7 to form the Cdc45–Mcm–GINS (CMG) complex, which is essential for DNA duplication. One member of the GINS complex is Psf3. We previously found that increased Psf3 expression was strongly associated with poor survival in lung adenocarcinoma. Here, we investigated the role of Psf3 expression in non‐small‐cell lung cancer (NSCLC). We verified Psf3 expression in human NSCLC tissues (180 patients) and cell lines. Immunohistochemical analysis revealed that the overexpression of Psf3 was significantly associated with vessel invasion (P = 0.016), lymphatic invasion (P = 0.002), and pleural invasion (P = 0.036). The overall survival rate in patients with Psf3 overexpression was significantly lower than that in patients without Psf3 overexpression (P = 0.006). Multivariate survival analysis revealed Psf3 expression to be an independent risk factor for an unfavorable outcome (P = 0.049). A proximal ligation assay showed interactions between Psf3 and other CMG components (such as Mcm2 and Cdc45) in both NSCLC specimens and cell lines, indicating that Psf3 acted as the CMG complex, which could lead to excessive proliferation. Knockdown of Psf3 inhibited the proliferation of both cell lines by delaying the S phase, which revealed that Psf3 played an important role in cancer proliferation. Thus, Psf3 acted as the CMG complex, promoting excessive proliferation. These results suggest that Psf3 inhibition might be a therapeutic target for NSCLC with Psf3 overexpression.

Outcomes of segmentectomy for cT1bN0M0 lung adenocarcinoma and squamous cell carcinoma: a possible association with pathological invasion

OBJECTIVES We evaluated the clinical benefit of segmentectomy for patients with cT1bN0M0 lung cancer. METHODS We retrospectively reviewed the medical records of 178 patients who underwent lobectomy or segmentectomy for cT1bN0M0 lung adenocarcinoma and squamous cell carcinoma from January 1995 to December 2005. We investigated the association of surgical outcomes with the presence of pathological invasion. RESULTS The median follow-up period was 93.4 months. Of 178 patients, 37 were scheduled for segmentectomy, but 6 of these patients were switched to receive lobectomy due to surgical N1 or N2 in 3 patients and insufficient surgical margins in 3 patients. In total, 31 patients underwent segmentectomy, and 147 underwent lobectomy. The 5-year overall survival (OS) was similar between the patients who underwent lobectomy (5-year OS, 81.6%) and segmentectomy (5-year OS, 77.4%, P = 0.73). Among pN0 patients without pathological invasion, there was no difference in OS between patients who underwent lobectomy (5-year OS, 89.9%) and segmentectomy (5-year OS, 88.9%, P = 0.80). In contrast, among pN0 patients with pathological invasion, OS was greater in patients who underwent lobectomy (5-year OS, 80.9%) than in those who underwent segmentectomy (5-year OS, 54.6%; P = 0.19). Moreover, a significantly higher rate of local and local + distant recurrence was observed in patients who underwent segmentectomy (45%) than in those who underwent lobectomy (15%) in this group (P = 0.02). CONCLUSIONS The results of our study suggest that segmentectomy may not be recommended for cT1b tumours if pathological invasion is suspected before surgery.

Ewing's sarcoma family of tumors originating in the main bronchus

Ewings sarcoma family tumors (ESFT), which include Ewings sarcoma and primitive neuroectodermal tumors (PNET), have been reported to originate in a variety of sites, mostly in the extremities. Previous reports have shown ESFT originating in the thoracic region, such as chest wall and peripheral lung. We herein report the first case of the ESFT that originated in the main bronchus. Endobronchial snare resection was followed by five courses of chemotherapy (VDC‐IE; including vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide) and sequential radiation. After the treatment, the patients condition has improved, and he has remained disease‐free for the past year.

Radically resected epithelioid angiosarcoma that originated in the mediastinum

Angiosarcoma is a rare neoplasm, accounting for only 1%–2% of all sarcomas. It occurs most frequently in the skin and soft tissue and rarely in the thoracic region. To our knowledge, a mediastinal angiosarcoma is extremely rare. We report on the surgical resection of a rare case of giant epithelioid angiosarcoma originating in the anterior mediastinum, followed by six courses of adjuvant chemotherapy (doxorubicin + ifosfamide). The patient is alive and asymptomatic 1 year after surgery. As the prognosis for unresectable cases is generally dismal, surgical resection and adjuvant therapy can be an option for mediastinal angiosarcoma.

The efficacy of 320-detector row computed tomography for the assessment of preoperative pulmonary vasculature of candidates for pulmonary segmentectomy

OBJECTIVES The purpose of this study was to compare the efficacy of 320-detector row computed tomography (CT) with that of 64-detector row CT for three-dimensional assessment of pulmonary vasculature of candidates for pulmonary segmentectomy. METHODS We included 32 patients who underwent both 320- and 64-detector CT before pulmonary segmentectomy, which was performed by cutting the pulmonary artery and bronchi of the affected segment followed by dissection of the intersegmental plane along the intersegmental vein. Before the operation, three-dimensional pulmonary vasculature images were obtained for each patient, and the arteries and intersegmental veins of the affected segments were identified. Two thoracic surgeons independently assessed the vessels with visual scoring systems, and kappa analysis was used to determine interobserver agreement. The Wilcoxon signed-rank test was used to compare the visual scores for the assessment of the visualization capabilities of the two methods. In addition, the final determination of pulmonary vasculature at a given site was made by consensus from thoracic surgeons during operation, and receiver operating characteristic analysis was performed to compare their efficacy of pulmonary vasculature assessment. Sensitivity, specificity and accuracy of either method were also compared by means of McNemars test. RESULTS Of the 32 cases, there were no operative complications, but 1 patient died of postoperative idiopathic interstitial pneumonia. Visualization scores for the pulmonary vessels were significantly higher for 320- than those for 64-detector CT (P < 0.0001 for the affected arteries and P < 0.0001 for the intersegmental veins). As for pulmonary vasculature assessment, the areas under the curve showed no statistically significant differences in between the two methods, while the specificity and accuracy of intersegemental vein assessment were significantly better for 320- than those for 64-detector row CT (P < 0.05). Interobserver agreement for the assessment yielded by either method was almost perfect for all cases. CONCLUSIONS Three hundred and twenty-detector row CT is more useful than conventional 64-detector row CT for preoperative three-dimensional assessment of pulmonary vasculature, especially when we identify the intersegmental veins, in candidates for pulmonary segmentectomy.

Clinical significance of the 'not otherwise specified ' subtype in candidates for resectable non‑small cell lung cancer

The histological subtype of non-small-cell lung cancer (NSCLC) is a significant factor when selecting treatment strategies. However, cases are occasionally encountered that are diagnosed as ‘not otherwise specified’ (NOS) prior to surgery, due to an uncertain histological subtype. The present study investigated the prognostic significance of the NOS subtype for patients with resectable NSCLC. Between 2001 and 2011, 1,913 patients were diagnosed with NSCLC using transbronchial biopsy and underwent surgical resection at two facilities in Japan. Of these patients, 151 (7.9%) were pre-operatively diagnosed with NSCLC-NOS (NOS group) and the remainder had confirmed histological subtypes (confirmed group). The present study compared the clinicopathological features and prognoses of these groups. Analyses of resected specimens revealed that pleomorphic cell carcinoma, large cell neuroendocrine cell carcinoma, large cell carcinoma and adenosquamous carcinoma were significantly more common in the NOS group than in the confirmed group (P<0.001, P=0.002, P=0.019 and P=0.014, respectively). The five-year survival rate was significantly poorer in the NOS group (60.5 vs. 67.1%; P=0.010), particularly for stage I disease (70.8 vs. 80.7%; P=0.007). The results of a multivariate analysis of overall survival indicated that NOS was a significant independent prognostic factor (hazard ratio, 1.40; 95% confidence interval, 1.02–1.86; P=0.041). These results indicated that pre-operative NOS was significantly associated with poorer survival, including for stage I disease. In conjunction with other clinicopathological parameters, NOS can be a useful prognostic factor when deciding on a treatment strategy for NSCLC.

Pulmonary large cell neuroendocrine carcinoma exhibiting extensive pagetoid spread in the bronchial epithelium: A case report

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare and aggressive malignant tumor, which was proposed as a novel type of neuroendocrine tumor in 1991. Although it is categorized as a non-small cell lung carcinoma, the precise pathological condition is unknown due to its rare occurrence. The present study outlines the case of a patient presenting with an LCNEC that exhibited pagetoid spread from the region of the primary tumor to the bronchial epithelium (distance, >30 mm). The pagetoid spread was unconfirmed preoperatively, however, was identified by intraoperative rapid diagnosis. This caused us to suffer the perioperative decision of additional resection and resulted in an incomplete resection, as suture of the bronchus was not possible. Pagetoid spread, which is often apparent in the breast, presents as a rare pattern of infiltration of cancer cells when a massive carcinoma is identified beneath the intraepithelial spread. Although preoperative diagnosis of pagetoid spread is difficult due to its rarity and undefined clinical features, it is important for surgeons and pathologists treating lung cancer patients to be aware of potential pagetoid spread in the thoracic region.

Operative outcomes of thoracoscopic lobectomy for non-small-cell lung cancer.

Aim We examined the advantages of thoracoscopy over thoracotomy in terms of perioperative outcomes and toleration of adjuvant chemotherapy. Methods Between April 2010 and March 2013, 657 patients with non-small-cell lung cancer who underwent lobectomy were classified into thoracoscopy (308 patients) and thoracotomy (349 patients) groups and compared. Results The thoracoscopy group had less blood loss compared to the thoracotomy group (p < 0.001). When limiting the analysis to pathological stage I patients, the results were similar (p < 0.001). In addition, the difference in blood loss between the 2 groups was greater in patients with severe pleural adhesions. The postoperative morbidity of the thoracoscopy group was significantly less than that of the thoracotomy group (13.3% vs. 21.2%, p < 0.001), and this result was similar when analyzing the pathological stage I patients (12.6% vs. 20.6%, p = 0.001). A higher percentage of the thoracoscopy group received both the full planned course and dose of adjuvant chemotherapy compared to the thoracotomy group (84.2% vs. 65.8%, p = 0.032). Conclusions These results indicate that totally thoracoscopic lobectomy is the more beneficial surgical approach with regard to the incidence of postoperative complications and toleration of adjuvant chemotherapy.