Multicentre, prospective, observational study investigating the most appropriate surgical option that can prevent the recurrence of primary spontaneous pneumothorax after surgery: the PATCH study, protocol.

INTRODUCTION: Thoracoscopic surgery is performed for refractory or recurrent primary spontaneous pneumothorax (PSP). To reduce postoperative recurrence, additional treatment is occasionally adopted during surgery after bulla resection. However, the most effective method has not been fully elucidated. Furthermore, the preference for additional treatment varies among countries, and its efficacy in preventing recurrence must be evaluated based on settings tailored for the conditions of a specific country. The number of registries collecting detailed data about PSP surgery is limited. Therefore, to address this issue, a prospective multicentre observational study was performed. METHODS AND ANALYSIS: This multicentre, prospective, observational study will enrol 450 participants aged between 16 and 40 years who initially underwent PSP surgery. Data about demographic characteristics, disease and family history, surgical details, and CT scan findings will be collected. Follow-up must be conducted until 3 years after surgery or in the event of recurrence, whichever came first. Patients without recurrence will undergo annual follow-up until 3 years after surgery. The primary outcome is the rate of recurrence within 2 years after surgery. A multivariate analysis will be performed to compare the efficacy of different surgical options. Then, adverse outcomes correlated with various treatments and the feasibility of treatment methods will be compared. ETHICS AND DISSEMINATION: This study was approved by the local ethics committee of all participating centres. The findings will be available in 2025, and they can be used as a basis for clinical decision-making regarding appropriate options for the initial PSP surgery. TRIAL REGISTRATION NUMBER: NCT04758143.

CERS6 required for cell migration and metastasis in lung cancer.

Sphingolipids constitute a class of bio-reactive molecules that transmit signals and exhibit a variety of physical properties in various cell types, though their functions in cancer pathogenesis have yet to be elucidated. Analyses of gene expression profiles of clinical specimens and a panel of cell lines revealed that the ceramide synthase gene CERS6 was overexpressed in non-small-cell lung cancer (NSCLC) tissues, while elevated expression was shown to be associated with poor prognosis and lymph node metastasis. NSCLC profile and in vitro luciferase analysis results suggested that CERS6 overexpression is promoted, at least in part, by reduced miR-101 expression. Under a reduced CERS6 expression condition, the ceramide profile became altered, which was determined to be associated with decreased cell migration and invasion activities in vitro. Furthermore, CERS6 knockdown suppressed RAC1-positive lamellipodia/ruffling formation and attenuated lung metastasis efficiency in mice, while forced expression of CERS6 resulted in an opposite phenotype in examined cell lines. Based on these findings, we consider that ceramide synthesis by CERS6 has important roles in lung cancer migration and metastasis.

Radiological findings and surgical outcomes of pulmonary metastases originating from biliary tract carcinoma.

PURPOSE: Metastasis to the lungs arising from biliary tract carcinoma (BTC) is extremely rare, and the patient characteristics and prognosis are not well known. We aimed to identify the imaging findings of pulmonary metastases originating from BTC and the eligible indications for surgical treatment. METHODS: Fifteen patients who underwent pulmonary resection for metastases originating from BTC were retrospectively analyzed. RESULTS: The primary sites included cholangiocarcinoma (n = 12) and gallbladder carcinoma (n = 3), and all cases were histologically diagnosed as well to moderately differentiated adenocarcinomas. The median disease-free interval between resection for the primary site and the detection of pulmonary metastasis was 30 months (range 0-144 months). Nine patients had a single lesion, and six had multiple lesions. As features of pulmonary lesions on thin-section computed tomography (CT), many appeared as solid nodules with smooth margins, whereas six lesions were concomitant with spiculation or pleural indentation, three with air bronchogram or ground-glass attenuation, and one with intra-tumoral cavity, and six cases with solitary pulmonary lesion were diagnosed as primary lung cancer before metastasectomy. The 3-year survival rate in the 11 patients who underwent complete metastasectomy was 45%. A disease-free interval of more than 3 years (p = 0.03) and single lesion (p < 0.01) were significant prognostic factors. CONCLUSIONS: The CT findings of pulmonary metastases from BTCs sometimes resemble the characteristic findings of primary lung cancer. A long disease-free interval and single lesion are therefore considered to be good surgical indicators.

A bilateral approach to extended thymectomy using the da Vinci Surgical System for patients with myasthenia gravis.

PURPOSE: We adopted a bilateral approach to complete robotic extended thymectomy with the excision of the pericardial fat tissue from both sides and analyzed the initial outcomes. METHODS: The patient cart was docked first from the left shoulder side. After dissection of the thymus and right pericardial fat tissue, the cart was temporarily rolled out, and the bed was rotated approximately 90° clockwise. The cart was then re-docked from the right-side shoulder, and extended thymectomy was performed via the left-side approach. The outcomes were compared with four cases of unilateral approach performed for mediastinal tumor in the same term. RESULTS: Four patients with myasthenia gravis (two of whom had stage I thymoma) underwent extended thymectomy by the bilateral approach. The mean operative time was 288 min, and the console time was 146 min in the right side and 67 min in the left side. The resected thymus and surrounding adipose tissue were almost symmetrical, in contrast with those obtained via the unilateral approach. No remarkable events were noted. CONCLUSION: Bilateral extended thymectomy for myasthenia gravis patients was safe and reasonable based on the initial outcomes.

Clinical impact of the lower limit of normal of FEV1/FVC on survival in lung cancer patients undergoing thoracic surgery.

BACKGROUND: Previously, it has been shown that using a fixed ratio of FEV1/FVC of 0.7 to classify airway obstruction could not predict survival outcomes in lung cancer patients undergoing thoracic surgery. We demonstrated that use of the lower limit of normal (LLN) of FEV1/FVC may allow better risk stratification for postoperative outcomes in patients with chronic obstructive pulmonary disease (COPD) patients. Nevertheless, it remained unclear whether survival outcomes in this population could be predicted by LLN-defined airway obstruction. OBJECTIVE: To evaluate the clinical relevance of LLN-defined airway obstruction to survival outcomes. METHODS: The clinical relevance of LLN-defined airway obstruction was analyzed and compared in 699 subjects, using Kaplan-Meier curves and the log-rank test. A Cox regression model was used to explore prognostic risk factors. RESULTS: One hundred-and-seventy-eight subjects were assigned to the below-LLN group, in which airflow obstruction determined by the FEV1/FVC ratio was below the LLN. Five hundred-and-twenty-one subjects were assigned to the above-LLN group. The below-LLN group had a worse overall survival (OS) and disease-free survival (DFS) than the above-LLN group. The diffusing capacity of the lung for carbon monoxide and the ratio of the inspiratory capacity divided to the total lung capacity were independent risk factors for OS and DFS. CONCLUSIONS: A standardized assessment of LLN-defined airway obstruction may allow risk stratification for survival likelihood in lung cancer patients who undergo thoracic surgery.

Targeting ceramide synthase 6-dependent metastasis-prone phenotype in lung cancer cells.

Sphingolipids make up a family of molecules associated with an array of biological functions, including cell death and migration. Sphingolipids are often altered in cancer, though how these alterations lead to tumor formation and progression is largely unknown. Here, we analyzed non-small-cell lung cancer (NSCLC) specimens and cell lines and determined that ceramide synthase 6 (CERS6) is markedly overexpressed compared with controls. Elevated CERS6 expression was due in part to reduction of microRNA-101 (miR-101) and was associated with increased invasion and poor prognosis. CERS6 knockdown in NSCLC cells altered the ceramide profile, resulting in decreased cell migration and invasion in vitro, and decreased the frequency of RAC1-positive lamellipodia formation while CERS6 overexpression promoted it. In murine models, CERS6 knockdown in transplanted NSCLC cells attenuated lung metastasis. Furthermore, combined treatment with l-α-dimyristoylphosphatidylcholine liposome and the glucosylceramide synthase inhibitor D-PDMP induced cell death in association with ceramide accumulation and promoted cancer cell apoptosis and tumor regression in murine models. Together, these results indicate that CERS6-dependent ceramide synthesis and maintenance of ceramide in the cellular membrane are essential for lamellipodia formation and metastasis. Moreover, these results suggest that targeting this homeostasis has potential as a therapeutic strategy for CERS6-overexpressing NSCLC.

The prognostic impact of pulmonary metastasectomy in recurrent gynecologic cancers: a retrospective single-institution study.

The aim was to examine the impact of pulmonary metastasectomy in patients with recurrent gynecologic cancers. Thirty-seven patients with isolated lung metastases (< 3 nodules) in recurrent epithelial gynecologic cancers were treated at Nagoya University Hospital between 1985 and 2013. The clinicopathological data for the 23 patients who underwent surgical resection were retrospectively analyzed, and their survival was compared with patients who received chemotherapy only. The median age at the time of surgery was 56 years (range 28-77). The studied population comprised 7 patients with 2 or 3 nodules and 8 patients with chemoresistant tumors, including fourteen cervical, 4 endometrial, and 5 ovarian primary tumors, with 5-year overall survivals (OSs) after surgery of 61, 100, and 100%, respectively. The survival of recurrence-free interval after initial treatment (>2 years) was significantly favorable (5-year OS 100% vs. 41.7%, p=0.006). Among the 6 patients with re-recurrence of lung metastases, 5 patients underwent a second pulmonary metastasectomy, and all of the patients are currently alive without disease. None of the 29 operations yielded severe complications. Although the survival rate showed a tendency to be higher in the surgery group than in the chemotherapy-only group, no significant difference was observed (5-year OS 81.7% vs. 49.5%, p=0.072). Our results indicate that pulmonary metastasectomy contributed to long-term survival with a low-risk of complications. Surgery to remove isolated lung metastases might provide a favorable prognosis for patients with long recurrence-free intervals and for patients with chemoresistant or re-recurrent tumors.

Comparisons of the clinicopathological features and survival outcomes between lung cancer patients with adenocarcinoma and squamous cell carcinoma.

OBJECTIVE: Patients with lung cancer should be treated according to histological subtype because of the disparities in tumor aggressiveness and treatment responses. It is important to re-evaluate the clinicopathological features of the two major subtypes of lung cancer, adenocarcinoma (AD) and squamous cell carcinoma (SQ). METHODS: We retrospectively analyzed data on the clinicopathological features and outcomes of 2059 patients with pulmonary AD and pulmonary SQ who had undergone complete resection at Nagoya University Hospital and Aichi Cancer Center between 1995 and 2012. RESULTS: The cohort consisted of 1587 patients with AD (77 %) and 472 with SQ (23 %). Female gender, no history of smoking, and small tumor size were distinct characteristics of AD patients, and a higher age was a characteristic of SQ patients (p < 0.0001). A significant difference was observed in overall survival, with 5-year survival rates of 78 % in AD patients and 63 % in SQ patients. Patients with stage IA and IB SQ had significantly worse outcomes than patients with AD at the same stage (p < 0.0001). Because no survival difference was observed between SQ patients with stage IA, IB, and IIA tumors (p = 0.75), these patients were considered to have proposed stage IIA disease. Then, comparable survival curves were obtained between stages II and IIIA SQ and AD. CONCLUSIONS: Patients with stage I SQ had significantly worse outcomes than patients with stage I AD. A newly defined stage grouping for SQ patients provided outcomes comparable to those of AD patients.

The contact length between the tumor contour and the lung on computed tomography is a risk factor for pleural recurrence after complete resection of thymoma.

OBJECTIVE: Among the perioperative findings which included patient characteristics and imaging, surgical, and pathological findings of the tumor, the risk factors for pleural recurrence (PR) after complete resection of thymoma were explored. METHODS: Fifty-three patients with Masaoka stage I to III thymoma who underwent complete resection, and five patients with stage IVa disease accompanied with pleural dissemination were analyzed. In these cohorts, the patients were divided into a non-recurrence (NR) group, PR group and stage IVa group. The maximum tumor diameter (TD) and the contact length between the tumor contour and the lung (CLTL) were measured at the maximum section of the tumor on axial computed tomography. A multivariate analysis including gender, age, TD, CLTL, tumor adhesion to the lung, Masaoka stage, and WHO histological type was performed to estimate risk factors for PR. RESULTS: The median follow-up period was 76.9 months. PR developed in six patients. The mean TDs were 44 mm in the NR group, 62 mm in the PR group and 73 mm in the stage IVa group, respectively. The mean CLTLs were 47, 90 and 96 mm, respectively. The CLTLs of the PR group were significantly longer than those of the NR group (p < 0.001), although the TDs were not significantly different between the two groups. The multivariate analysis indicated that CLTL was only a risk factor for PR (p = 0.046). CONCLUSION: The CLTL was significantly associated with the PR after complete resection of thymoma.

Primary malignant melanoma of the thymus: report of a case.

A 61-year-old male was admitted to our hospital complaining of bloody sputum. A chest roentgenogram revealed a clearly demarcated mass located in the anterior mediastinum. Positron emission tomography revealed abnormal accumulation of (18)F-fluorodeoxy glucose only in the anterior mediastinal tumor. A computed tomography-guided needle aspiration biopsy was performed, and the tumor was diagnosed as a malignant melanoma. Although the skin, eyeballs, oral cavity, nasal cavity, etc., were closely evaluated, no other lesion of malignant melanoma was detected except the mediastinal tumor. Hence, this tumor was diagnosed as a primary malignant melanoma. We performed total thymectomy, including the tumor, and combined resection of the adhesive bilateral lungs, pericardium and left brachiocephalic vein. Because the tumor was histologically surrounded by thymus tissue, we diagnosed it as a primary mediastinal malignant melanoma that originated in the thymus. Although the patient's postoperative course was uneventful, he complained of back pain 5 months after the operation. Multiple bone metastases were found, and he received chemotherapy and radiotherapy, and is currently alive with disease 14 months after the primary treatment.

Micronodular thymoma with lymphoid stroma: an immunohistochemical study of the distribution of Langerhans cells and mature dendritic cells in six patients.

AIMS: Micronodular thymoma with lymphoid stroma (MNT) is an uncommon variant of thymoma, characterized by multiple small nodules consisting of type A thymoma-like cells, which are separated by abundant B lymphocytes. The aim of the study was to elucidate the pathogenesis of the stromal lymphoid hyperplasia, which is currently unclear. METHODS AND RESULTS: We retrieved six cases of MNT, and immunohistochemically examined the number and distribution of Langerhans cells (LCs) and mature dendritic cells (DCs), and compared them with those in type A and type AB thymomas. Many LCs were present within the small tumour nests, but LCs were rarely seen in the stroma (75.5/HPF versus 6.1/HPF, P < 0.0001). In contrast, mature DCs were present mainly in the surrounding stroma rather than within the tumour nodules (63.5/HPF versus 6.0/HPF, P < 0.0001), forming clusters with mature T lymphocytes adjacent to lymphoid follicles. In large nodules, as well as in type A and type AB thymomas, a few scattered LCs and DCs were identified. All patients were still alive and well. CONCLUSIONS: Our results suggest that LCs take up tumour antigens and migrate to the stroma, where they mature and form clusters with T lymphocytes to activate them, resulting in lymphoid follicle formation. The favourable clinical behaviour may be attributable to the immune response induced by LCs.

Preoperative plasma D-dimer level is an independent prognostic factor in patients with completely resected non-small cell lung cancer.

PURPOSE: The plasma D-dimer (D-dimer) level, a marker of hypercoagulation, has been reported to be associated with survival in several types of cancers. This retrospective study was conducted to evaluate the prognostic significance of the preoperative D-dimer level in patients with completely resected non-small cell lung cancer (NSCLC). METHODS: A total of 237 completely resected NSCLC patients were included in this study. In addition to age, sex, the smoking status, etc., the association between the preoperative D-dimer level and survival was explored. RESULTS: The patients were divided into three groups according to the D-dimer level: group A (≤ 0.50 µg/ml, n = 76), group B (0.51-0.86 µg/ml, n = 79) and group C (>0.86 µg/ml, n = 82). The 5-year overall survival rate was 89.6 % (95 % confidence interval (CI) 77.7-95.3) for group A, 75.1 % (95 % CI 62.3-83.6) for group B and 60.1 % (95 % CI 46.8-71.1) for group C (P trend <0.001). A multivariate survival analysis showed that the D-dimer level (group B vs. group A HR 4.25, group C vs. group A HR 4.11) was an independent significant prognostic factor, in addition to age, sex, the pathological stage and the serum carcinoembryonic antigen level. CONCLUSIONS: The preoperative D-dimer level is an independent prognostic factor in patients with completely resected NSCLC.

The ABO blood group is an independent prognostic factor in patients with resected non-small cell lung cancer.

BACKGROUND: The ABO blood group is reported to be associated with the incidence and patient survival for several types of malignancies. We conducted a retrospective study to evaluate the prognostic significance of the ABO blood group in patients with resected non-small cell lung cancer (NSCLC). METHODS: A total of 333 patients (218 men and 115 women) with resected NSCLC were included in this study. In addition to age, sex, smoking status, preoperative serum carcinoembryonic antigen (CEA) level, operative procedure, histology of tumors, pathological stage (p-stage), and adjuvant therapy, the association between the ABO blood group and survival was explored. RESULTS: The 5-year overall and disease-free survival rates were 83.0% and 71.6% for blood group O, 67.2% and 62.3% for blood group A, 68.8% and 68.8% for blood group B and 69.2% and 65.3% for blood group AB, respectively. A multivariate analysis for overall survival showed the ABO blood group (group A vs. group O: HR 2.47, group AB vs. group O: HR 3.62) to be an independent significant prognostic factor, in addition to age, sex, smoking status, p-stage, and serum CEA level. A multivariate analysis for disease-free survival also showed the ABO blood group to be an independent significant prognostic factor. CONCLUSIONS: The ABO blood group is an independent prognostic factor in patients with resected NSCLC. Studies of other larger cohorts are therefore needed to confirm the relationship between the ABO blood group and the prognosis among patients with resected NSCLC.

Therapeutic surgery without a definitive diagnosis can be an option in selected patients with suspected lung cancer.

OBJECTIVES: With the recent improvements in the diagnostic accuracy of radiographic modalities, it might be an option to perform therapeutic surgery without a definitive diagnosis for selected patients with suspected lung cancer based on the findings of diagnostic imaging. METHODS: Between April 2008 and December 2012, all nodules without a definitive diagnosis were classified into five categories according to the probability of lung cancer based on the diagnostic imaging: Category 1 (Benign), Category 2 (Probably benign), Category 3 (Intermediate), Category 4 (Suspected malignancy) and Category 5 (Highly suggestive of malignancy). In this study, the 232 surgical candidates for suspected clinical stage I lung cancer without a preoperative definitive diagnosis were considered to be Category 3 (n = 29), Category 4 (n = 46) and Category 5 (n = 157). Eighty-two patients (72% of Category 3, 46% of Category 4 and 25% of Category 5) had an intraoperative diagnosis during surgery, whereas the remaining 150 patients did not. The final pathological diagnosis and surgical outcomes were analysed. RESULTS: The final pathological diagnosis of the 232 suspicious nodules revealed 214 lung cancers (52% of Category 3, 93% of Category 4 and 99% of Category 5). Wedge resection was performed for all seven benign tumours. In the multiple regression analysis, intraoperative diagnosis was a significant factor for the length of the operation. In the multivariate logistic regression analysis, the length of the operation was a significant factor predicting both the postoperative morbidity and a prolonged hospital stay. CONCLUSIONS: Based on a careful clinical decision made using the current diagnostic imaging strategies, patients with a high probability of lung cancer are good candidates for therapeutic surgery, even without a preoperative or intraoperative definitive diagnosis.

Surgical management of locally advanced lung cancer.

Majority of cases of lung cancer are detected at an advanced stage; such patients are usually treated with chemotherapy and radiotherapy, and the prognosis is frequently poor. Surgical resection remains the only reliable curative method for the treatment of lung cancer, and combined resection of the primary tumor and involved neighboring structures is performed when possible in patients with locally advanced disease. In the TNM classification, tumors with direct extrapulmonary extension are subdivided based on the anatomic extent of disease and its potential for surgical treatment: T3 lesions with limited, circumscribed extension are thought to be potentially surgically resectable, whereas T4 tumors with extensive extension are considered unresectable. Although surgical treatment for T3 lesions is generally accepted, the outcome is frequently not satisfactory. On the other hand, advanced surgical techniques are now being applied for T4 lesions due to improvements in surgery and anesthesiology and progress in combined treatment modalities. In the present staging, T4N0-1M0 lesions are categorized as stage IIIA disease, and T4 tumors without mediastinal nodal metastasis are now considered to be potentially curable if complete resection is possible. This article reviews the modern surgical management of patients with lung cancer invading neighboring structures, including the chest wall, superior sulcus, diaphragm, tracheal carina, left atrium, superior vena cava, aorta and vertebrae. Furthermore, the surgical treatment of carcinomatous pleuritis, which was categorized as T4 disease in the previous TNM classification, is also assessed, and the role of surgical resection in cases of locally advanced lung cancer is discussed.

Spontaneous regression of thymic epithelial tumours.

We herein report the cases of 3 patients with thymic epithelial tumours, including two thymomas and a carcinoma, where the tumours spontaneously regressed in size. The patients were all female ranging in age from 32 to 43 years. During 1 or 2 months without any treatment, the tumours regressed by 25-59% in size. The pleural effusion observed in 2 patients also disappeared during the same period. Pathological examinations revealed areas of necrosis or cystic changes within the two thymomas. Among the patients with thymic epithelial tumours, the existence of this rare disease entity must be recognized.

FDG PET/CT is useful for detecting infiltration to the port site in patients with malignant pleural mesothelioma.

OBJECTIVE: One reason for the poor outcomes of multimodality therapies, including macroscopic complete resection, in patients with malignant pleural mesothelioma (MPM) is the difficulty of correctly staging the disease, which can result in incomplete resection. The purpose of this study was to investigate the aspects of tumor infiltration to the port site and the usefulness of preoperative FDG PET/CT for diagnosing MPM. METHODS: Between June 2007 and May 2013, 21 patients who underwent surgical treatment with curative intent for MPM that had been previously diagnosed on a video-assisted thoracic surgery (VATS) biopsy were included in this study. RESULTS: There were 17 males and four females, with a mean age of 63 years. The accumulation of FDG at the port site was observed in all nine patients with tumor infiltration to the port site, whereas this feature was not noted in 15 patients without tumor extension to the port site. There were more positive lymph node cases in the infiltration group than in the non-infiltration group (p = 0.02). No significant differences in survival were observed between the patients with and without tumor infiltration to the port site. CONCLUSIONS: FDG PET/CT is useful for detecting tumor infiltration of MPM to the port site and may help to prevent local recurrence, especially port site relapse, following macroscopic complete resection. However, this condition is related to tumor aggressiveness; therefore, performing careful staging and determining the appropriate treatment strategy are required in such patients.

Primary pulmonary solitary fibrous tumour with brain metastases.

Solitary fibrous tumour (SFT) is a mesenchymal neoplasm of subendothelial origin that can be found in all anatomical locations, but rarely in the lungs. A 71-year old female was referred to our hospital because of the increase in size of a solitary pulmonary mass. Chest contrast-enhanced dynamic computed tomography showed a well-circumscribed lobulated mass measuring 3.1×1.6 cm in the posterior segment of the right upper lobe of the lung. Positron emission tomography with 18F-fluorodeoxyglucose (FDG) demonstrated that the mass had high FDG uptake. A right upper lobectomy of the lung and mediastinal lymphadenectomy were performed. The tumour was pathologically diagnosed as an SFT. Seven months later, the patient was found to have brain metastases of the tumour, which led to dizziness. A craniotomy and successive radiosurgery with a gamma knife were performed for the metastatic tumours. She is still alive without evidence of disease 12 months after the treatment of the metastases. Pulmonary SFT seldom behaves aggressively, and only two previous cases of primary pulmonary SFT with brain metastases have been reported. Local therapy including surgery and radiotherapy against metastases from SFT could help improve the survival of such patients.