Hitoshi Dejima

Exosomal microRNA in plasma as a non‑invasive biomarker for the recurrence of non‑small cell lung cancer

Predictive biomarkers for the recurrence of non-small cell lung cancer (NSCLC) in patients who have received curative resection are important for cancer treatment. The functional microRNAs (miRNAs/miRs) in the exosomes of plasma and serum samples are of interest as stable and non-invasive biomarkers for recurrence in cancer patients. The aim of the present study was to clarify the usefulness of plasma exosomal miRNAs as biomarkers for the prediction of recurrence in NSCLC following curative resection. First, microarray-based expression profiling of miRNAs derived from exosomes in the plasma of 6 patients was employed to identify a biomarker that distinguishes between patients with and without NSCLC recurrence. In the miRNA microarray analyses, the exosomal miR-21 and miR-4257 levels of the NSCLC patients showed marked upregulation in those individuals with recurrence compared with those without recurrence and healthy individuals. These two miRNAs were thus selected as recurrence-specific biomarkers and their potential was evaluated in a separate cohort of 195 NSCLC patients. In comparison to the levels in 30 healthy individuals, exosomal miR-21 and miR-4257 levels showed a significant increase in the NSCLC patients (P<0.01). When evaluating the clinicopathological significance of these miRNAs, exosomal miR-21 showed a significant association with tumor size and tumor-node-metastasis (TNM) stage (P<0.05). Exosomal miR-4257 showed a significant association with histological type, lymphatic invasion and TNM stage (P<0.05). The disease-free survival (DFS) rates of high exosomal miR-21 patients were significantly worse than those of low exosomal miR-21 patients (P<0.05), and the DFS rates of patients with high exosomal miR-4257 levels were significantly worse than those with low exosomal miR-4257 levels (P<0.01). In the Cox multivariate analysis, plasma exosomal miR-21 and miR-4257 expression showed a significance association with DFS (P<0.05). These results suggest that plasma exosomal miR-21 and mir-4257 expression has potential as a predictive biomarker for recurrence in NSCLC patients who have received curative resection.

Qualitative Analysis of Preoperative High-Resolution Computed Tomography: Risk Factors for Pulmonary Complications After Major Lung Resection.

BACKGROUND Postoperative pulmonary complications after major lung resection are strongly associated with mortality. Qualitative findings of emphysema, bronchiectasis, and bronchial wall thickening on high-resolution computed tomography (HRCT) are indicators of chronic obstructive pulmonary disease and may serve as risk factors for pulmonary complications. METHODS The subjects were 347 consecutive patients who underwent single lobectomy for pulmonary malignancy from May 2010 to December 2014. Correlations of pulmonary complications with preoperative clinical factors and HRCT findings were retrospectively examined using multivariate logistic regression analysis to compare the predictive ability for pulmonary complications using clinical variables that were reported to be risk factors. RESULTS Patients who had pulmonary complications were more frequently male (p < 0.001), with a greater smoking history (p < 0.001), lower rate of steroid use (p < 0.001), more frequent emphysema on HRCT (p < 0.001), more frequent bronchiectasis on HRCT (p = 0.002), more frequent bronchial wall thickening on HRCT (p < 0.001), and higher rate of extended resection (p = 0.006). In multivariate analysis, HRCT findings (odds ratio [OR] 12.01, 95% confidence interval [CI]: 5.582 to 25.83, p < 0.001) and extended resection (OR 7.726, 95% CI: 1.678 to 35.57, p = 0.009) were independent risk factors for pulmonary complications. After matching of risk factors between patients with and without pulmonary complication, emphysema (OR 3.394, 95% CI: 1.781 to 6.469, p < 0.001) and bronchial wall thickening (OR 6.250, 95% CI: 2.414 to 16.18, p < 0.001) were independently associated with pulmonary complications in the model with better performance. CONCLUSIONS Qualitative findings on HRCT are independent risk factors for pulmonary complications after lobectomy. Preoperative HRCT may be useful to predict pulmonary complications.

Predictors of long-term compensatory response of pulmonary function following major lung resection for non-small cell lung cancer.

Long‐term pulmonary function which might include compensatory response (CR) significantly influences quality of life of long‐term survivor after major lung resection. We investigated long‐term pulmonary function after major lung resection.

Therapeutic potential of recombinant thrombomodulin for lung injury after pneumonectomy via inhibition of high-mobility group box 1 in mice.

BACKGROUND Surgical acute respiratory distress syndrome (ARDS) is an extremely critical condition which may occur after major lung resection. Despite advances in minimally invasive surgical procedures and progress in the therapeutic management of this disease, prognosis remains poor. In this study, we investigated the contribution of high-mobility group box 1 (HMGB1) in a surgical ARDS model and evaluated the possible therapeutic effect of recombinant thrombomodulin (rTM) for the treatment of surgical ARDS. METHODS C57BL/6J mice underwent left pneumonectomy. rTM was injected at 12 hours before surgery, followed by 12 hours for 3 days after surgery. Lipopolysaccharide (LPS) was administered at 2 hours after surgery. We conducted a histologic analysis and measured HMGB1, IL-6, IL-1&bgr;, and TNF-&agr; in bronchoalveolar lavage fluid on day 3 after pneumonectomy. Data were compared between the treatment groups. RESULTS On histologic analysis, left pneumonectomy followed by LPS administration induced both severe inflammatory cellular infiltration and alveolar wall congestion with hemorrhage. rTM administration rescued these histologic changes. The level of HMGB1, IL-6, IL-1&bgr;, and TNF-&agr; in bronchoalveolar lavage fluid was significantly increased by LPS administration after pneumonectomy and significantly decreased by rTM administration with LPS and pneumonectomy (p < 0.001). Also, LPS alone showed no statistical differences in HMGB1 or proinflammatory cytokine level compared with pneumonectomy (PNX) group. In addition, the survival outcome was also improved by rTM administration. CONCLUSIONS LPS administration after left pneumonectomy could induce the severe lung injury. PNX and LPS have similar contribution to this model and may play a synergistic role in this process. rTM may have the potential therapeutic effect for surgical ARDS via suppression of HMGB1 and the secretion of proinflammatory cytokines induced by the administration of LPS after left pneumonectomy.

Predictors of indocyanine green visualization during fluorescence imaging for segmental plane formation in thoracoscopic anatomical segmentectomy

BACKGROUND To determine factors predicting indocyanine green (ICG) visualization during fluorescence imaging for segmental plane formation in thoracoscopic anatomical segmentectomy. METHODS Intraoperatively, the intravenous ICG fluorescence imaging system during thoracoscopic anatomical segmentectomy obtained fluorescence emitted images of its surfaces during lung segmental plane formation after the administration of 5 mg/body weight of ICG. The subtraction of regularization scale for calculating the exciting peaks of ICG between the planned segments to resect and to remain was defined as ΔIntensity (ΔI). Variables such as the ratio of forced expiratory volume in 1 s to forced vital capacity (%FEV1.0), smoking index (SI), body mass index (BMI), and low attenuation area (LAA) on computed tomography (CT) took a leading part. RESULTS The formation of the segmental plane was successfully accomplished in 98.6% segments and/or subsegments. SI and LAA significantly affected ΔI levels. The area under the receiver operating characteristic curve for the %FEV1.0, SI, and LAA was 0.56, 0.70, and 0.74, respectively. SI >800 and LAA >1.0% were strong predictors of unfavorable ICG visibility (P=0.04 and 0.01, respectively). CONCLUSIONS Fluorescence imaging with ICG was a safe and effective method for segmental plane formation during thoracoscopic anatomical segmentectomy. In spite of its high success rate, unfavorable visibility may potentially occur in patients who are heavy smokers or those with a LAA (>1.0%) on CT.

Immunological effect of local ablation combined with immunotherapy on solid malignancies

Recent comprehensive investigations clarified that immune microenvironment surrounding tumor cells are deeply involved in tumor progression, metastasis, and response to treatment. Furthermore, several immunotherapeutic trials have achieved successful results, and the immunotherapeutic agents are available in clinical practice. To enhance their demonstrated efficacy, combination of immunotherapy and ablation has begun to emerge. Local ablations have considerable advantages as an alternative therapeutic option, especially its minimal invasiveness. In addition, local ablations have shown immune-regulatory effect in preclinical and clinical studies. Although the corresponding mechanisms are still unclear, the local ablations combined with immunotherapy have been suggested in the treatment of several solid malignancies. This article aims to review the published data on the immune-regulatory effects of local ablations including stereotactic body radiotherapy, cryoablation, radiofrequency ablation, and high-intensity-focused ultrasound. We also discuss the value of local ablations combined with immunotherapy. Local ablations have the potential to improve future patient outcomes; however, the effectiveness and safety of local ablations combined with immunotherapy should be further investigated.

A new LigaSure technique for the formation of segmental plane by intravenous indocyanine green fluorescence during thoracoscopic anatomical segmentectomy.

BACKGROUND The purpose of this study was to present a new approach to the formation of a segmental plane by LigaSure (Covidien, Mansfield, MA, USA) with indocyanine green (ICG) fluorescence system during thoracoscopic segmentectomy. METHODS This was a consecutive study that compared 12 patients who underwent a new LigaSure technique (LT) for segmental plane formation during thoracoscopic anatomical segmentectomy with 38 patients who underwent conventional methods using the staple technique (ST). Eleven patients were followed up more than 3 months after discharge. RESULTS The mean age of the patients was 66 years in the LT group and 67 years in ST. The mean duration for the formation of segmental plane and the mean number of staples was 22.8 min and 1.8 per surgery, respectively, in the LT group; and 16.2 min and 3.4 per surgery, respectively, in ST. No patient had a prolonged air leak (PAL) of more than 7 days. Minor air leak was identified early in two and was delayed in one. Two-thirds of patients with early minor air leak had low index of prolonged air leak (IPAL) score. There was no air leak in the patients with high IPAL score. Eventually, we deduced that the cause of the minor air leak was a technical problem. CONCLUSIONS In the formation of segmental plane during thoracoscopic segmentectomy, a combination of ICG fluorescence and LigaSure may be beneficial for patients. As a new operative instrument, LT constitutes, in our opinion, a feasible and easy alternative to other thoracoscopic techniques.

Combined Aortic Resection and Stent Graft Insertion for Local Recurrence of Metastatic Lung Carcinoma Following Stereotactic Radiotherapy: A Case Report

Stereotactic radiotherapy (SRT) is a useful treatment for malignant ling tumors. However, SRT is associated with complications such as high local recurrence rate and radiation-induced lung injury. Herein, we report a case of combined aortic resection for after SRT. An 82-year-old man underwent SRT for the metastatic lung carcinoma of rectal cancer at left lower lobe. Three years later, chest computed tomography showed local recurrence at the site of radiotherapy, with suspected invasion of the descending aorta. Thoracotomy was performed after metastatic lung carcinoma interpolation of a stent graft in the descending aorta. Because the tumor firmly adhered to the aorta, left lower lung lobe and aortic wall resection was performed. Pathological findings revealed fibrous hypertrophy and adhesion between the visceral pleura and aorta. As shown in our case, combined aortic resection and stent graft insertion is an effective minimally invasive and safe treatment for SRT-induced tissue damage.

Usefulness of Plasma Exosomal MicroRNA-451a as a Noninvasive Biomarker for Early Prediction of Recurrence and Prognosis of Non-Small Cell Lung Cancer

Objectives: The aim of this study was to clarify the usefulness of plasma exosomal microRNA-451a (miR-451a) as a novel biomarker for the early prediction of recurrence and prognosis in non-small cell lung cancer (NSCLC) patients after curative resection. Methods: Before surgery, plasma samples were collected and exosomal microRNA (miRNA) levels were evaluated. We first profiled specific exosomal miRNAs related to recurrence in 6 NSCLC patients with stage IA cancer by miRNA microarray. We then validated the usefulness of selected miRNAs as biomarkers using the other 285 NSCLC patients. Results: Plasma exosomal miR-451a showed the highest upregulation in the NSCLC patients with recurrence in the miRNA microarray analysis. A significant positive correlation was demonstrated between exosomal miR-451a levels and NSCLC tissue miR-451a levels. Exosomal miR-451a showed a significant association with lymph node metastasis, vascular invasion, and stage. In stage I, II, or III patients, the overall survival (OS) and disease-free survival (DFS) rates among the high-exosomal-miR-451a patients were significantly worse than those among the low-exosomal-miR-451a patients. In Cox multivariate analysis, exosomal miR-451a showed significance for OS and DFS. Conclusion: Plasma exosomal miR-451a might serve as a reliable biomarker for the prediction of recurrence and prognosis in NSCLC patients with stage I, II, or III cancer.

Impact of pregabalin on early phase post-thoracotomy pain compared with epidural analgesia

Background The purpose of this randomized study was to compare the effects of pregabalin with epidural analgesia on early phase post-thoracotomy pain. Methods This study was conducted on 90 adult patients who underwent thoracotomy. Patients were randomly divided into two groups, an epidural analgesia group, where 45 patients received 0.2% ropivacaine hydrochloride and fentanyl through a thoracic epidural catheter, and a pregabalin group, where 45 patients received 75 mg pregabalin orally twice daily. Both groups were also administered orally with celecoxib along with each treatment. Numerical rating scale (NRS) and sleep interference rate (SIR) were evaluated on the first day, third day, and fifth day after surgery. Anesthetic induction time, operation time, recovery time, the use of additional analgesic drugs and adverse effects were also examined. Results NRS and SIR were significantly lower in the pregabalin group at all time points (P<0.05). The number of patients requiring additional analgesic drugs within 24 hours after surgery showed no difference between the two groups; however, the number was significantly decreased in the pregabalin group after post-operative day 1 (P<0.001). Adverse effects including pneumonia, dysuria, constipation and nausea were identified among many patients in the epidural analgesia group (P<0.05). Operation time and recovery time were the same for both groups, while the epidural analgesia group showed a significantly longer anesthetic induction time (P<0.001). Conclusions Pregabalin is considered to be a safe and effective treatment method which is an alternative to epidural analgesia for acute post-thoracotomy pain.