Yasunori Shikada

Platelet-derived growth factor-AA is an essential and autocrine regulator of vascular endothelial growth factor expression in non-small cell lung carcinomas.

It is widely accepted that angiogenesis is required for tumor progression. Vascular endothelial growth factor (VEGF) is a key molecule for tumor angiogenesis; however, its expressional regulation is not well understood during all stages of tumorigenesis. Using cell lines and surgical specimens of human non-small cell lung cancers (NSCLCs), we here show that platelet-derived growth factor-AA (PDGF-AA) is an essential autocrine regulator for VEGF expression. To directly assess the expression of PDGF-AA-dependent VEGF and its roles in tumorigenesis, we stably transfected established cell lines with their antisense genes. In addition, the levels of PDGF-AA and VEGF expression in surgical sections were measured and compared with clinicopathologic findings such as tumor size and patient prognosis. PDGF-AA tightly regulated VEGF expression and had a greater effect on tumor size and patient prognosis than did VEGF in both cell lines and surgical sections. PDGF-AA expression was not seen in the atypical adenomatous hyperplasia at all, whereas VEGF was occasionally seen. Furthermore, the frequency of VEGF expression was higher in advanced NSCLCs than in precancerous lesions, which was tightly correspondent to the results for PDGF-AA. These results indicate that PDGF-AA is an important regulator of the frequency and level of VEGF expression during the transition from a precancerous lesion to advanced cancer. The PDGF-AA/VEGF axis, therefore, may be a ubiquitous autocrine system for enhancing angiogenic signals, and PDGF-AA, and its related pathways could be a more efficient target of antiangiogenic therapy for cancers than VEGF and its pathways.

Essential Role of PDGFRα-p70S6K Signaling in Mesenchymal Cells During Therapeutic and Tumor Angiogenesis In Vivo: Role of PDGFRα During Angiogenesis

Discovery of the common and ubiquitous molecular targets for the disruption of angiogenesis, that are independent of the characteristics of malignant tumors, is desired to develop the more effective antitumor drugs. In this study, we propose that the platelet-derived growth factor receptor-&agr;(PDGFR&agr;)-p70S6K signal transduction pathway in mesenchymal cells, which is required for functional angiogenesis induced by fibroblast growth factor-2, is the potent candidate. Using murine limb ischemia as a tumor-free assay system, we demonstrated that p70S6K inhibitor rapamycin (RAPA) targets mesenchymal cells to shut down the sustained expression of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), via silencing of the PDGFR&agr;-p70S6K pathway. Irrespective of the varied expression profiles of angiogenic factors in each tumor tested, RAPA constantly led the tumors to dormancy and severe ischemia in the time course, even associated with upregulated expression of VEGF from tumors. Because RAPA showed only a minimal effect to hypoxia-related expression of VEGF in culture, these results suggest that RAPA targets the host-vasculature rather than tumor itself in vivo. Thus, our current study indicates that the PDGFR&agr;-p70S6K pathway is an essential regulator for FGF-2–mediated therapeutic neovascularization, as well as for the host-derived vasculature but not tumors during tumor angiogenesis, via controlling continuity of expression of multiple angiogenic growth factors.

Non-small cell lung cancer in never smokers as a representative ‘non-smoking-associated lung cancer’: epidemiology and clinical features

Recent interest in lung cancer without a history of tobacco smoking has led to the classification of a distinct disease entity of ‘non-smoking-associated lung cancer’. In this review article, we have made an overview of the recent literature concerning both the epidemiology and clinical features of lung cancer in never smokers, and have brought ‘non-smoking-associated lung cancer’ into relief. The etiology of lung cancer in never smokers remains indefinite although many putative risk factors have been described including secondhand smoking, occupational exposures, pre-existing lung diseases, diet, estrogen exposure, etc. Non-small cell lung cancer (NSCLC) in never smokers is clinically characterized by an increased incidence in females and a higher occurrence of adenocarcinoma in comparison to NSCLC in ever smokers in both surgical patients and non-resectable advanced-stage patients. Furthermore, the prognosis of never-smoking NSCLC is better than that of smoking-related NSCLC in both surgical patients and non-resectable advanced-stage patients. Recently recognized novel gene mutations such as EGFR (epidermal growth factor receptor) mutations are largely limited to never smokers or light smokers, and the expression of this gene is responsible for the clinical efficacy of gefitinib, an epidermal growth factor receptor-tyrosine kinase inhibitor. NSCLC with the EML4 (echinoderm microtubule-associated protein-like 4)-ALK (anaplastic lymphoma kinase) fusion gene is also more likely to occur in never smokers and in those with adenocarcinoma histology, and is expected to benefit from ALK inhibitors. In consideration of the future increase in never-smoking NSCLC or ‘non-smoking-associated lung cancer’, both clinical trials and investigations are needed.

Diabetic Microangiopathy in Ischemic Limb Is a Disease of Disturbance of the Platelet-Derived Growth Factor-BB/Protein Kinase C Axis but Not of Impaired Expression of Angiogenic Factors

Diabetic foot is caused by microangiopathy and is suggested to be a result of impaired angiogenesis. Using a severe hindlimb ischemia model of streptozotocin-induced diabetic mice (STZ-DM), we show that diabetic foot is a disease solely of the disturbance of platelet-derived growth factor B-chain homodimer (PDGF-BB) expression but not responses of angiogenic factors. STZ-DM mice frequently lost their hindlimbs after induced ischemia, whereas non-DM mice did not. Screening of angiogenesis-related factors revealed that only the expression of PDGF-BB was impaired in the STZ-DM mice on baseline, as well as over a time course after limb ischemia. Supplementation of the PDGF-B gene resulted in the prevention of autoamputation, and, furthermore, a protein kinase C (PKC) inhibitor restored the PDGF-BB expression and also resulted in complete rescue of the limbs of the STZ-DM mice. Inhibition of overproduction of advanced-glycation end product resulted in dephosphorylation of PKC-&agr; and restored expression of PDGF-BB irrespective of blood sugar and HbA1c, indicating that advanced-glycation end product is an essential regulator for PKC/PDGF-BB in diabetic state. These findings are clear evidence indicating that diabetic vascular complications are caused by impairment of the PKC/PDGF-B axis, but not by the impaired expression of angiogenic factors, and possibly imply the molecular target of diabetic foot.

Prognostic impact of local treatment against postoperative oligometastases in non-small cell lung cancer.

In this study, we investigated prognostic factors associated with survival after distantly metastatic recurrence in surgically resected non‐small cell lung cancer (NSCLC), and clarified the influence of local treatment on the prognosis for oligometastatic recurrence.

Differences in the expression of epithelial–mesenchymal transition related molecules between primary tumors and pulmonary metastatic tumors in colorectal cancer

PurposeEpithelial–mesenchymal transition (EMT) is a key event in cancer metastasis. This study immunohistochemically examined the expression of EMT-related molecules in both primary colorectal cancer and pulmonary metastases, and analyzed the expression pattern.MethodsTen patients with colorectal cancer that underwent surgical resections for both the primary tumor and metastatic pulmonary tumors were included. The expression status of EMT-related molecules was examined using immunohistochemical staining.ResultsNine of the 10 cases maintained the expression of both E-cadherin and β-catenin in the primary site. The expression of E-cadherin and β-catenin in the pulmonary metastatic site was preserved in 10 and 12 out of 15 metastatic lesions, respectively. The EMT-related transcription factor, Twist, was positively expressed in all 10 cases, Smad interacting protein 1 (Sip1) in 9, Snail in 4 and Slug in 3 of the primary sites. On the other hand, staining for Twist, Sip1 and Snail at the metastatic pulmonary site, was negative in all 10 cases.ConclusionThe expression of EMT-related transcription factors in metastatic pulmonary tumors from colorectal cancer decreased in comparison to the primary tumors. These findings suggested that the expression status of EMT-related transcription factors might play an important role in the implantation of metastatic foci.

The impact of cardiovascular comorbidities on the outcome of surgery for non-small-cell lung cancer.

OBJECTIVE The presence of cardiovascular comorbidity in non-small-cell lung cancer (NSCLC) patients increases with age. Therefore, the influence of cardiovascular comorbidity in NSCLC patients on their short- or long-term prognosis remains controversial. This study evaluated the possible risk factors related to the short-term and long-term survivals in NSCLC patients with cardiovascular comorbidity. METHODS One thousand one hundred and sixty-two consecutive patients with NSCLC who had undergone a surgical resection between 1984 and 2010 were enrolled in this study. A total of 360 (31%) patients with cardiovascular comorbidities were analysed to identify the risk factors for postoperative complications and prognostic factors. RESULTS The patients with cardiovascular comorbidity included 301 with hypertension, 28 with coronary artery disease, 35 with peripheral vascular disease, 23 with arrhythmia and 11 with abdominal aortic aneurysm. Eighty-three patients exhibited more than one type of comorbidity. The postoperative cardiovascular morbidity rates were 3.6% in the cardiovascular comorbidity patients and 3.3% among patients without cardiovascular comorbidity (P = 0.73). No correlation was observed between preoperative cardiovascular comorbidity and postoperative pulmonary complications (P = 0.52). The operative mortality rates were 1.0% for the cardiovascular comorbidity patients and 0.8% for the other patients (P = 0.51). No difference in the postoperative outcomes was observed between the patients with and without cardiovascular comorbidity. The 5-year survival rates were 62.5% in comparison with 65.4% among patients without cardiovascular comorbidity (P = 0.48). CONCLUSIONS Patients with cardiovascular comorbidity were not found to be at increased risk of mortality and morbidity following surgery for NSCLC. In addition, cardiovascular comorbidity did not influence the long-term outcomes of patients after a pulmonary resection for NSCLC.

Initial Experience of Single-Incision Thoracoscopic Surgery for 100 Patients with Primary Spontaneous Pneumothorax

PURPOSE The aim of this retrospective study was to evaluate single-incision thoracoscopic surgery (SITS) for primary spontaneous pneumothorax (PSP). METHODS Among 141 patients who underwent surgery for PSP from July 2009 to December 2013, a total of 100 patients underwent SITS. Their data were examined for clinical characteristics and surgical results. RESULTS More patients with younger age, female sex, and who had social indications were treated by SITS than by three-port video-assisted thoracic surgery (VATS). The mean operative time for SITS was 48.8 min. There were no conversions from SITS to three-port VATS or thoracotomy. After SITS, the median duration of chest drainage was 1 day, and the median hospital stay was 2 days. Early complications included one surgical-site infection and one case of air leakage. Four patients (4.0%) had ipsilateral recurrence of PSP. CONCLUSION SITS is feasible when performed for selected patients with PSP. Long-term follow-up and further examinations are required to evaluate patient selection, efficacy, and comparability of SITS with conventional open and three-port VATS approaches.

Anterior mediastinal gastroenteric cyst containing pancreatic tissue influenced the diabetes mellitus status

The mediastinal gastroenteric cyst is a rare developmental cyst. In general, the majority of mediastinal gastroenteric cysts are recognized in infancy and are commonly located in the posterior mediastinum. In addition, gastroenteric cysts occasionally contain pancreatic tissue; however, no studies have reported that these cysts influenced the diabetes mellitus status of the patient. We report here an extremely rare case of an adult gastroenteric cyst with pancreatic tissue originating from the anterior mediastinum, influencing the severity of diabetes mellitus in a patient. This case report presents two remarkable findings. First, the location of the gastroenteric cyst (anterior mediastinum) and the patients age at the time of detection (adulthood) were extremely rare. Secondly, the present case is also unusual in terms of glycometabolism. As this tumour decreased in size, the glycosylated haemoglobin value increased, which suggested a worsening of the patients diabetes mellitus. The diabetes mellitus further worsened after removal of the tumour.

Localized pleural amyloidosis: report of a case

We herein describe an asymptomatic 31-year-old male who was admitted for an investigation of an abnormal pleural tumor detected by chest radiography. We performed various preoperative investigations including fluorodeoxyglucose-positron emission tomography. The maximum standardized uptake value (SUVmax) was 2.2, and malignancy could not be ruled out. We therefore carried out a thoracoscopy-assisted partial resection of the right upper lobe combined with a parietal pleurectomy. The pathological examination showed that there was a tumor localized with pleural amyloidosis.