Ex Vivo Expanded and Activated Natural Killer Cells Prolong the Overall Survival of Mice with Glioblastoma-like Cell-Derived Tumors.

Glioblastoma (GBM) is the leading malignant intracranial tumor and is associated with a poor prognosis. Highly purified, activated natural killer (NK) cells, designated as genuine induced NK cells (GiNKs), represent a promising immunotherapy for GBM. We evaluated the anti-tumor effect of GiNKs in association with the programmed death 1(PD-1)/PD-ligand 1 (PD-L1) immune checkpoint pathway. We determined the level of PD-1 expression, a receptor known to down-regulate the immune response against malignancy, on GiNKs. PD-L1 expression on glioma cell lines (GBM-like cell line U87MG, and GBM cell line T98G) was also determined. To evaluate the anti-tumor activity of GiNKs in vivo, we used a xenograft model of subcutaneously implanted U87MG cells in immunocompromised NOG mice. The GiNKs expressed very low levels of PD-1. Although PD-L1 was expressed on U87MG and T98G cells, the expression levels were highly variable. Our xenograft model revealed that the retro-orbital administration of GiNKs and interleukin-2 (IL-2) prolonged the survival of NOG mice bearing subcutaneous U87MG-derived tumors. PD-1 blocking antibodies did not have an additive effect with GiNKs for prolonging survival. GiNKs may represent a promising cell-based immunotherapy for patients with GBM and are minimally affected by the PD-1/PD-L1 immune evasion axis in GBM.

[Effectiveness of Osimertinib for Postoperative Recurrence of Lung Cancer with L861Q Activating EGFR Mutation:Report of a Case].

A 69-year-old woman was referred to our hospital because of an abnormal shadow on a chest roentgenogram at a medical check-up. Chest computed tomography showed a 2.5 cm-diameter tumor in the right pulmonary lower lobe. Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) could not detect the other lesions. The patient underwent thoracoscopic right lower lobe lobectomy for lung adenocarcinoma. Pathological diagnosis was invasive adenocarcinoma (pT1cN0M0). EGFR status was positive for the L861Q mutation in exon 21. At 31 months after surgery, the recurrence appeared as vertebral and multiple pulmonary lesions, and the treatment with osimertinib showed satisfactory response seven months after starting the treatment.

Implications of Preoperative Transbronchial Lung Biopsy for Non-small Cell Lung Cancer Less than 3-cm.

BACKGROUND/AIM: Transbronchial lung biopsy (TBLB) has been recommended for patients with suspected lung cancer. However, its diagnostic value is limited to small lesions, and some studies have indicated that biopsy might be related to metastasis and/or dissemination. This study aimed to evaluate the outcomes after preoperative TBLB for non-small cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Data were reviewed from 371 patients with resected pN0 NSCLC less than 3-cm. Patients were divided into two groups: TBLB and Non-TBLB. Recurrence-free survival (RFS) curves were plotted using the Kaplan-Meier method. Cox regression analyses were used to evaluate the hazard ratio (HR) with the endpoint RFS. RESULTS: The 5-year RFS rates were 75.5% in the TBLB group and 91.4% in the Non-TBLB group (p<0.001). Poor RFS was independently associated with TBLB (HR=2.491, 95%CI=1.337-4.640; p=0.004). CONCLUSION: Preoperative TBLB may adversely affect RFS among NSCLC patients with small size tumours.

Surgical treatment for secondary spontaneous pneumothorax: a risk factor analysis.

PURPOSE: While surgery is an effective treatment for secondary spontaneous pneumothorax (SSP), it can be difficult, because affected patients are usually in a poor general condition. The present study investigated the risk factors of postoperative complications after surgery for SSP. METHODS: Eighty-eight patients with SSP who underwent surgery from January 2006 to March 2018 were investigated. Clinical data were reviewed, and a multivariate analysis was performed. RESULTS: Eighty-four patients (95%) were males, and the median patient age was 72 years. Underlying lung diseases were chronic obstructive pulmonary disease in 58 patients (65.9%), interstitial pneumonia in 26 (29.5%), and others in 4 (4.5%). Postoperative complications developed in 21 patients (24%). Hospital mortality/prolonged length of stay occurred in 6 patients (7%). A multivariate analysis showed that the preoperative performance status (performance status 0-2 vs. 3, hazard ratio: 6.570, 95% confidence interval: 1.980-21.800) was an independent predictor of postoperative complications. CONCLUSION: Surgery for SSP contributed to early chest tube removal and favorable outcomes. However, rare fatal events occurred, and the patient performance status was a risk factor for postoperative complications. A careful evaluation of each patient's performance status is needed to determine the need for surgical intervention for SSP.

A case of a rare non-invasive lung adenocarcinoma.

BACKGROUND: According to the WHO classification, adenocarcinoma in situ (AIS) is a localised small (≤3 cm) adenocarcinoma whose growth is restricted to neoplastic cells along pre-existing alveolar structures, lacking stromal, lymphovascular, or pleural invasion. There is no evidence to define AIS as having a tumour size of ≤3 cm. It is extremely rare for adenocarcinomas with pure lepidic growth lacking invasion to be >3.0 cm. The biological characteristics of these large AISs should be revealed. PRESENTATION OF CASE: The patient was an 82-year-old asymptomatic woman. Chest computed tomography showed a 6-cm-diameter pure ground-glass opacity in the left lower lung. The patient underwent lobectomy. On histologic examination, the tumour was restricted to neoplastic cells along pre-existing alveolar structures, lacking stromal, vascular, alveolar space, and pleural invasion. Papillary patterns were absent. Initially, the histopathological diagnosis was AIS, but the total tumour diameter exceeded 3 cm. The final pathological diagnosis was lepidic adenocarcinoma lacking an invasive component and harbouring an EGFR exon 20 insertion V774_C775insHV mutation using next-generation sequencing (NGS). CONCLUSION: We report a rare case of lepidic adenocarcinoma with a total tumour diameter of 6 cm and without an invasive component. Although EGFR mutations are oncogenic driver mutations, AISs have fewer EGFR mutations than invasive adenocarcinomas do. An adenocarcinoma that progresses to AIS, not stepwise progression, might have uncommon mutations and might be another type of adenocarcinoma. NGS could be useful for detecting uncommon genes that reveal the biological characteristics of AIS, and may contribute to the validation of next TNM classification.

Wedge Resection of Tumor Before Lobectomy for Lung Cancer Could Be a No-touch Isolation Technique.

BACKGROUND/AIM: Circulating tumor cells (CTCs) can be a surrogate biomarker of prospective prognosis. Surgical manipulation can promote the dissemination of CTCs. Prognosis improvement is expected with the no-touch isolation technique (NTIT), preventing surgical manipulation. The Wedge resection of the tumor site before lobectomy could prevent surgical manipulation during lobectomy for non-small cell lung cancer (NSCLC) and reduce the shedding of tumor cells, similar to a NTIT. This study aimed to evaluate the effect of wedge resection technique. PATIENTS AND METHODS: A total of 624 resected NSCLC patients were retrospectively analyzed. Patients were divided in two groups: Wedge and Non-Wedge. Overall survival (OS) curves were plotted using the Kaplan-Meier method. RESULTS: The 5-year OS rates were 89.9% and 84.0% in the Wedge and Non-Wedge groups, respectively (p=0.033). CONCLUSION: The OS in the Wedge group was significantly better than that in the Non-Wedge group. Wedge resection technique for NSCLC may be a NTIT.

Cluster circulating tumor cells in surgical cases of lung cancer.

OBJECTIVES: A cancer lesion sheds tumor cells into the circulating blood as circulating tumor cells (CTCs). Since cluster CTCs have been considered as precursor lesions of metastasis, their clinical implication was investigated in this study according to the preoperative status of cluster CTC detection in surgical cases of clinically early-stage lung cancer. METHODS: Among 104 surgical patients of early-stage lung cancer, CTCs were extracted from the peripheral blood before surgery using a micro-pore size selection method (ScreenCell®) and diagnosed microscopically. Implications of detecting cluster CTC were assessed according to the prognosis and clinicopathological characteristics. RESULTS: The status of CTC detection was not detected in 77 cases (74.0%), single CTC only detection in 7 cases (6.7%), and cluster CTC detected in 20 cases (19.2%). Patients with cluster CTCs exhibited significantly lower recurrence-free survival and overall survival than did patients of other groups. In addition, in hazard ratio analysis, the hazard ratios were independent of other predictors of poor prognosis, and detection of cluster CTCs was associated with predictors of poor prognosis. CONCLUSION: Cluster CTCs were detected in cases where the original lung cancer lesion had clinical predictors of poor prognosis and were independent negative predictors of survival.

A case of atypical thymic carcinoid mimicking a paraganglioma.

BACKGROUND: Thymic atypical carcinoid has high recurrence and metastasis rates due to frequent lymph node metastases. The aim of the study is to report a case of atypical thymic carcinoid mimicking a paraganglioma and to further explain the benefits of using median sternotomy (MS) approach even in thymic epithelial tumours (TETs) sized less than 5 cm. CASE PRESENTATION: The patient was a 59-year-old asymptomatic man. During a medical check-up, positron emission tomography/computed tomography (PET/CT) showed a 4.5 cm-diameter thymus with remarkable uptake. Thoracic surgery was performed to completely remove the tumour with lymph node dissection using MS because of possible malignancy. Although MS is accepted as the standard approach for TETs, minimally invasive thoracotomy (MIT) has emerged over recent decades. Maintaining surgical safety is priority; MIT is generally selected in <5-cm-diameter tumours. Here, we considered that the tumour could be resected using MIT. However, because PET/CT showed marked uptake, we selected the MS approach. Thus, MS can be applied even for small-sized TETs. CONCLUSION: Thymic atypical carcinoid should be considered when PET/CT shows high-uptake tumours in the anterior mediastinum. Clinicians should consider using the MS approach, even if the tumour is <5 cm.

Effectiveness of Intraoperative Pulmonary Wedge Resection of Tumor Site Before Lobectomy for Early Lung Adenocarcinoma.

BACKGROUND/AIM: Circulating tumor cells (CTCs) are tumor cells shed from tumor sites and circulate in the peripheral blood. CTCs can be a surrogate biomarker of recurrence and prognosis. Because surgical manipulation could promote CTCs, it is important to reduce CTCs during surgery. This study aimed to evaluate the effectiveness of intraoperative wedge resection of the tumor site before lobectomy. PATIENTS AND METHODS: A total of 297 resected stage I lung adenocarcinoma patients were retrospectively reviewed. Patients were divided into two groups: Wedge and Non-Wedge. Recurrence-free survival (RFS) curves were plotted using the Kaplan-Meier method. Cox regression analyses were used to evaluate the hazard ratio (HR) with the endpoint RFS. RESULTS: The 5-year RFS rates were 92.9% and 85.5%, in Wedge and Non-Wedge groups, respectively (p=0.006). Wedge resection was an independent factor associated with RFS (HR=0.342, 95%CI=0.141-0.830, p=0.018). CONCLUSION: Wedge resection before lobectomy for lung adenocarcinoma patients can improve RFS rates.

Preoperative Detection of Pleural Adhesions Using Ultrasonography for Ipsilateral Secondary Thoracic Surgery Patients.

BACKGROUND/AIM: Video-assisted thoracic surgery (VATS) for ipsilateral reoperations is challenging because of the potential for pleural adhesions. Insertion of the initial port can lead to lung injury because of the blinded intrathoracic area. We assessed the usefulness of ultrasonography before VATS to reduce the incidence of lung injury at the time of the initial port insertion during secondary ipsilateral VATS. PATIENTS AND METHODS: Thirty-three patients who underwent repeat VATS for ipsilateral pulmonary lesions were included. All patients underwent preoperative ultrasonography to assess the possible presence of pleural adhesions using the lung sliding sign. RESULTS: Seven adhesions were found at the VATS ports. Two of these adhesions were not evaluated as pleural adhesions using ultrasonography; however, they were loose. All initial ports were inserted without lung injury. There were no major complications. CONCLUSION: Preoperative detection of pleural adhesions using ultrasonography can determine the best initial port for secondary ipsilateral VATS.

[Preoperative Detection of Pleural Adhesions Using Transthoracic Ultrasonography].

Recently, there has been an increase in the experience of lung surgery in cases with a history of thoracotomy or pneumonia. In these cases, pleural adhesion is often seen and makes the surgery to be difficult. Especially in thoracoscopic surgery, lung damage must be care at the 1st port insertion. In this report, the usefulness of the extent of pleural adhesion to the chest wall before surgery by using a transthoracic ultrasonography was assessed. Between April 2017 and September 2018, 32 patients underwent preoperative ultrasound examination, and 128 ports were evaluated whether had adhesions or not using lung sliding sign. All patients of 128, 24 adhesions were found at surgery, resulting in 14 true positive, 10 false negative, 0 false positive, and 104 true negative findings [sensitivity:58.3% (14/24), specificity: 100.0% (104/104), accuracy:92.2% (118/128)]. Especially, about the 1st port, accuracy was 93.8 % (30/32). In Conclusion, preoperative transthoracic ultrasonography could provide useful information on the pleural adhesion leading safe initial thoracoscopic access without lung injury.

Ultrasonography for Detecting Adhesions: Aspirin Continuation for Lung Resection Patients.

BACKGROUND/AIM: Aspirin reduces cardiovascular disease and/or stroke risks. However, perioperative aspirin use remains controversial. We assessed the efficacy of ultrasonography to facilitate video-assisted thoracic surgery (VATS). We analyzed the perioperative management of patients using aspirin and its association with bleeding events during lung cancer surgery. PATIENTS AND METHODS: A total of 38 patients who underwent VATS after continuing or discontinuing aspirin were examined. Ultrasound was performed preoperatively to evaluate the pleural adhesions. Fisher's exact test was used to analyze correlations between the two groups. RESULTS: Dense adhesions were found at VATS ports using ultrasonography (accuracy: 100%). No differences were detected in bleeding, thrombotic events, or operative times between the aspirin and non-aspirin groups. There were differences in bleeding (p=0.009) and operative times (p=0.021) between the dense adhesion and non-dense adhesion groups. CONCLUSION: Preoperative detection of pleural adhesions using ultrasonography was useful in selecting pulmonary resection patients who continued aspirin perioperatively.

Analysis of Histological Grade in Resected Lung-invasive Adenocarcinoma.

BACKGROUND/AIM: Although the histological grading systems (Grading) with respect to lung adenocarcinoma are defined using architectural approaches in the eighth cancer Tumor, Node, and Metastasis (TNM) Classification, the prognostic value of the architectural subtypes in advanced stages of the disease remains unclear. We aimed to assess which Grading was more suitable as a prognostic factor: i) (conventional) Grading based on differentiation or ii) (new) Grading based on architectural subtypes. PATIENTS AND METHODS: We analyzed the outcomes and Gradings of resected 449 patients with adenocarcinoma using receiver operating characteristic (ROC) curves. RESULTS: The tumor histological grade of 147 out of 449 patients changed using the results from the revised Grading. In these 147 patients, ROC curves showed that the area under the curve was 0.710 using the conventional Grading and 0.567 using the new Grading. CONCLUSION: The conventional Grading might be more suitable for lung adenocarcinoma recurrence compared to the new Grading.

Prognostic impact of underlying lung disease in pulmonary wedge resection for lung cancer.

BACKGROUND: Pulmonary wedge resection is an option for lung cancer patients with limited cardiopulmonary preservation. As the impact of underlying lung status on the prognosis of such patients remains unclear, we assessed this issue. METHODS: A total of 149 borderline surgical candidates with localized lung cancer who had undergone wedge resection were retrospectively investigated. Clinical variables related to perioperative morbidity, local control rate, and oncological outcomes based on underlying lung disease were analyzed. RESULTS: According to the risk analysis of postoperative complications, underlying lung disease did not influence the surgical morbidity. Postoperative recurrence occurred in 65 patients (locoregional recurrence in 36, distant metastasis in 12, and both simultaneously in 17). Multivariate analysis revealed that emphysema on computed tomography (CT) [hazard ratio (HR) 0.45; 95% confidence interval (CI) 0.21-0.99] was an independent indicator of locoregional recurrence. Forty-four patients died of lung cancer and 29 of other causes. Multivariate analysis demonstrated that interstitial lung disease on CT (HR 1.98; 95% CI 1.01-3.89) was a predictor of poor prognosis. CONCLUSION: Pulmonary wedge resection can be safely undergone by lung cancer patients regardless of pulmonary comorbidity, although underlying lung disease may influence the prognosis after wedge resection.

A case of a Müllerian cyst arising in the posterior mediastinum.

A mediastinal Müllerian cyst is composed of heterotopic cystic Müllerian tissue resembling structures of the fallopian tube. We herein report a case of a mediastinal Müllerian cyst discovered during a medical check-up of a 41-year-old woman. She had no symptoms but had been diagnosed with hyperprolactinemia at the age of 24 years, for which she received hormonal therapy for 3 years. Chest computed tomography demonstrated a 3-cm-diameter cystic tumor in front of the Th10 vertebra. Thoracic surgery was performed to remove the tumor. The tumor was a monolocular cyst covered with a thin capsule, and pathological examination showed a thin-walled cyst lined by ciliated or non-ciliated columnar cells resembling tubal epithelium. Immunohistochemical analysis showed positive expression for paired box gene 8 and estrogen and progesterone receptors. The pathological diagnosis was a Müllerian cyst. A Müllerian cyst should be always be considered in patients with a mediastinal cyst.

Histological Grade: Analysis of Prognosis of Non-small Cell Lung Cancer After Complete Resection.

BACKGROUND/AIM: Although the 2015 World Health Organization Classification reported that histological grading may be helpful in lung cancer management, a widely accepted histological grading system with clearly defined criteria and demonstrable clinical significance has not been developed. We investigated the prognoses of patients with resected non-small cell lung cancer (NSCLC) to identify prognostic factors, especially histological grade. MATERIALS AND METHODS: The medical records of 531 patients between 2010 and 2015 were retrospectively reviewed. Overall survival (OS) curve was plotted using the Kaplan-Meier method. Cox regression analyses were used to evaluate the hazard ratio (HR) with endpoint of OS. RESULTS: The 5-year OS rate in groups with histological grade 1, grade 2, and grade 3+4 groups was 95.8%, 85.7%, and 72.1%, respectively (p<0.001). Multivariate analysis identified histological grade and vascular invasion as independent predictors of OS [histological grade: HR=1.533, p=0.002]. CONCLUSION: Histological grade was an independent prognostic factor of patients resected for all stages of NSCLC.

Clinical and pathological characteristics of surgically resected intrapulmonary lymph nodes: Can they be differentiated from other malignant nodules?

BACKGROUND: Intrapulmonary lymph nodes (IPLNs) are often recognized as sub-centimeter solid pulmonary nodules (SCPNs). The present study investigated their clinical and pathological characteristics to allow clinicians to distinguish them from malignant nodules. METHODS: Among 194 SCPNs surgically resected between 2006 and 2016, 26 IPLNs were investigated histopathologically. In addition, 145 resected malignant SCPNs were compared radiographically with the 26 IPLNs. RESULTS: Radiographically, most IPLNs were in a middle or lower lobe, and all lesions were within 20 mm of the visceral pleura. Enlargement was seen in one lesion. Three lesions demonstrated linear density contiguous to pleura (LD), and 13 lesions were adjacent to the peripheral pulmonary vein (APV). Microscopically, all IPLNs showed adjacency to pulmonary veins, 23 showed interlobular septa extending from the IPLN, and 18 were surrounded by a dilatated lymphoid channel. Radiographical findings of LD and APV were also seen in malignant SCPNs (LD, 12/145; APV, 25/145). Comparative analysis revealed that enlargement and APV were significant predictors differentiating IPLNs from malignant SCPNs. The sensitivity/specificity of enlargement and APV were 92%/92% and 17%/50%, respectively. CONCLUSIONS: IPLNs show typical high-resolution computed tomography findings that reflect their histopathological characteristics. Such findings help identify IPLNs prior to surgery. Specifically, enlargement and APV may differentiate IPLNs from malignant SCPNs. However, atypical cases are also possible, and radiological findings are not specific for differentiating IPLNs from malignant lesions. Thus, clinicians should consider surgical exploration when diagnosing SCPNs.

Endobronchial Watanabe Spigots for Treatment of Pyopneumothorax due to Nontuberculous Mycobacteriosis in a Patient with Rheumatoid Arthritis: A Case Report Based on Past Experience.

Nontuberculous mycobacterial lung disease sometimes causes pneumothorax and empyema, which are often intractable because of patients' background factors. Biological products used in the treatment of rheumatoid arthritis have caused the problem of an increase in infection rates as a side effect, one of which is nontuberculous mycobacteriosis (NTM). On the basis of past experience, we report the case of a patient who had a history of undergoing treatment with biological products against rheumatoid arthritis. The patient was treated for NTM-induced pyopneumothorax by endoscopic bronchial occlusion therapy using endobronchial Watanabe spigots.

[Prognostic Significance of Mode of Nodal Involvement in Pulmonary pN1 Squamous Cell Carcinoma].

According to the tumor, node, metastasis (TNM) classification of the Union for International Cancer Control (UICC) and the International Association for the Study of Lung Cancer (IASLC), N factor is defined by the anatomic extent of the metastatic lymph nodes, but is not related to the metastatic pattern. N1 is defined as "metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension". Lymph node involvement is one of the most important prognosistic factors in non-small cell lung cancer patients. Squamous cell carcinoma (SCC) arises in the central airway and directly invades adjacent lymph nodes more frequently compared to the other histologic types. We retrospectively evaluated the prognostic impact of lymph node involvement patterns in pulmonary pN1 squamous cell carcinoma (SCC) patients. The clinical records of 23 patients with pN1 SCC who underwent complete resection and systematic lymph node dissection at our institute were retrospectively reviewed. We classified the patient into 2 N1 groups based on the nodal involvement pattern:metastatic N1 nodes involved directly by the main tumor (direct group) and metastatic N1 nodes not directly involved by the main tumor (separate group). The direct group consisted of 10 patients, and the separate group comprised 13 patients. There were no significant difference in the gender, tumor size, surgical procedure, and number of metastatic lymph nodes. Overall survival and disease-free survival curves were plotted using the Kaplan-Meier method, and the statistical differences between both groups was determined by the log-rank test. P values <0.05 were considered statistically significant. The direct group had a much better 5-year overall survival rate of 100.0% compared with 55.9% for the separate group (p=0.037). The N factors in TNM classification are defined only by anatomical location. However, our results suggest that the mode of nodal involvement in pulmonary pN1 SCC might be a prognostic factor. Accordingly, it is likely that biological behaviors are different between direct metastasis and separate metastasis. Since there are some limitations in this study:its retrospective design and small sample size, the clinical implication of direct extension to N1 lymph nodes needs to be confirmed by a large scale prospective study in the future.