Daisuke Hokka

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.

Sirt1 is a tumor promoter in lung adenocarcinoma

Sirtuin 1 (Sirt1) is a nicotinamide adenine dinucleotide-dependent class III histone deacetylase. It reportedly can repress cellular apoptosis and senescence to affect DNA repair, stress response and aging. Notably, previous data have indicated that Sirt1 is both a tumor promoter and a tumor suppressor in tumorigenesis. However, Sirt1 expression in primary lung adenocarcinoma remains unknown. Immunohistochemical staining was performed to investigate Sirt1 expression in cancer cells in 125 consecutive resected cases of primary lung adenocarcinoma. Sirt1 expression was found to be increased in 26 (20.8%) of the 125 cases, which correlated significantly with five clinicopathological factors: Ki67 index, hypoxia-inducible factor 1 (HIF1) molecule expression, tumor-node-metastasis (TNM) classification, pulmonary vein invasion and lymphatic duct invasion. In the Sirt1-positive expression group, Sirt1 expression correlated with a higher Ki67 index and higher TNM classification, particularly for lymph node invasion and metastasis, and with a higher number of pulmonary vein invasion and lymphatic duct invasion. Additionally, a negative correlation was identified between HIF1-positive expression and Sirt1-negative expression. These results indicate that Sirt1 overexpression plays a promotional role in tumorigenesis and is closely associated with invasion and metastasis and, thus, it may be associated with prognosis.

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.

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.

Surgery for malignant lesions of the chest which extensively involved the mediastinum, lung, and heart

ObjectiveRadical resection for thoracic malignancies that invade the great vessels or heart structure is an uncommon, high-risk operation. To help surgeons determine therapeutic strategy, we reviewed the patient characteristics and outcomes of combined thoracic and cardiovascular surgery for thoracic malignancies.MethodsSurgical resections of lung cancer, mediastinal tumor and pulmonary artery sarcoma invading great vessels or heart structures were reviewed from the literature.ResultsPneumonectomy was often performed for lung cancer invading the aorta, superior vena cava, and left atrium. Complete resection (R0), no mediastinal lymph node metastasis and without using cardiopulmonary bypass led to a good prognosis. Induction therapy was often performed for complete resection. Regarding mediastinal tumors, thymic epithelial tumors or germ cell tumors occasionally invaded the great vessels or heart structures. For these malignancies, multimodality therapy was often performed, and complete resection could be one of the prognostic factors. The resection of primary pulmonary artery sarcoma (PPAS) is also a combined thoracic and cardiovascular surgery. The primary treatment for PPAS is surgical resection; specifically, pulmonary endarterectomy and pneumonectomy, because PPAS has substantial resistance to chemotherapy or radiotherapy. The prognosis of PPAS is poor, but surgical resection has potential for long-term survival.ConclusionAlthough these surgeries are uncommon and invasive for the patients, selecting appropriate patients, aggressive multimodality therapy, and performing combined thoracic and cardiovascular surgery can contribute to a good outcome.

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.

ROS1‑rearranged high‑PD‑L1‑expressing lung adenocarcinoma manifesting as mediastinal tumor: A case report

ROS proto-oncogene 1 receptor tyrosine kinase (ROS1)-rearranged lung cancer is rare and comprises only 1% of lung adenocarcinoma cases. It has recently been reported to have good response to crizotinib, a tyrosine kinase inhibitor of anaplastic lymphoma kinase. Driver oncogene mutations with approved therapies seldom coexist with a high expression of Programmed death-ligand 1 (PD-L1). The present case report describes a rare case of ROS1 rearrangement with high-PD-L1-expressing occult lung adenocarcinoma. A 32-year-old woman presented with chest pain and a prolonged cough. Chest computed tomography (CT) revealed a 57×36-mm tumor in the mediastinum, with no tumors detected in other regions. Positron emission tomography (PET)-CT showed a strong fluorodeoxyglucose accumulation in the tumor (SUVmax 13.2). Mediastinal tumor resection was completely resected using a video-assisted thoracic surgery approach. Pathological examination showed the tumor cells were positive for thyroid transcription factor 1, Napsin-A, ROS1, and PD-L1 (tumor proportion score >99%). ROS1 rearrangement was confirmed by fluorescence in situ hybridization. The mediastinal tumor was diagnosed as mediastinal lymph node metastasis of ROS1-rearranged PD-L1 high-expression undifferentiated lung adenocarcinoma (pathological stage 3, TxN2M0). Two months after the operation, the CT scan showed multiple mediastinum lymph nodes metastases with rapid tumor growth. The patient achieved a complete response after three cycles of S-1 plus cisplatin with concurrent radiotherapy 60 Gy/30 Fr.