Detection of circulating tumor cells with a novel microfluidic system in malignant pleural mesothelioma.

Detection of rare tumor cells circulating in the blood (CTCs) presents technical challenges. CellSearch, the only approved system for clinical use, fails to capture epithelial cell adhesion molecule-negative CTCs such as malignant pleural mesothelioma (MPM). We have developed a novel microfluidic device (CTC-chip) in which any Ab to capture CTCs is conjugated. The CTC-chip was coated with an Ab against podoplanin that is abundantly expressed on MPM. Circulating tumor cell-detection performance was evaluated in experimental models in which MPM cells were spiked in blood sampled from a healthy volunteer and in clinical samples drawn from MPM patients. The CTC-chip showed superior CTC-detection performance over CellSearch in experimental models (sensitivity, 63.3%-64.5% vs 0%-1.1%; P < .001) and in clinical samples (CTC-positivity, 68.8% vs 6.3%; P < .001). A receiver operating characteristic (ROC) analysis showed that the CTC test provided a significant diagnostic performance in discrimination of unresectable disease from resectable disease (area under the ROC curve, 0.851; P = .003). The higher CTC count (≥2 cells/mL) was significantly associated with a poor prognosis (P = .030). The novel CTC-chip enabled sensitive detection of CTCs, which provided significant diagnostic and prognostic information in MPM.

Immunohistochemical Expression and Serum Levels of CD44 as Prognostic Indicators in Patients with Non-Small Cell Lung Cancer.

BACKGROUND/OBJECTIVES: CD44 is often expressed in various types of tumor cells and involved in a number of biological behaviors of malignancy. The present study focused on the clinical significance of the expression of CD44st and CD44v6 in non-small cell lung cancer (NSCLC). METHODS: The cohort consisted of 261 consecutive patients who had undergone complete resection of NSCLC. CD44 expression was evaluated in surgical specimens by immunohistochemical staining. Serum CD44 levels were determined using a sandwich ELISA (enzyme-linked immunosorbent assay). RESULTS: In the immunohistochemical analysis, significant correlations were observed between CD44 expression and clinicopathological factors such as the T factor, N factor, pathological stage, and histological type. The 5-year survival rates according to CD44v6 expression were 65.8 and 80.6% in the higher and lower expression groups, respectively (p = 0.0053). According to ELISA, the group with higher expression of serum CD44v6 also showed a significantly more unfavorable prognosis than the lower expression group (p = 0.014). According to multivariate analysis using these significant variables, serum CD44v6 level was found to be an independent prognostic factor (p = 0.048). CONCLUSIONS: CD44v6 overexpression and higher serum CD44v6 levels were found to be significantly unfavorable prognostic factors.

[Intrapericardial Vessel Management for Lung Cancer Surgery].

Intrapericardial vessel management is one of the necessary techniques for respiratory surgeons. We collected cases that had undergone intrapericardial vessel management for lung cancer, and herein discuss the practical performance and safety of this treatment method. We identified 23 (5.6%) of 413 patients who had undergone lung cancer surgery during the 30-month period from January 2011 to June 2013 at our institution. Twenty cases had large sized tumors near the hilum. Three cases demonstrated severe adhesion in the intrathoracic region due to a previous operation. The lung cancer staging was stage ⅠA in 1 case, stage ⅠB in 4 cases, stage ⅡB in 5 cases, stage ⅢA in 11 cases, stage ⅢB in 1 case, and stage Ⅳ in 1 case. We performed lobectomy in 11 cases, bilobectomy in 6 cases, and pneumonectomy in 6 cases. The average operation time was 366 minutes (137-965). Post operative complications were observed in five cases, including two cases of air-leakage and three cases of arrhythmia. All cases were able to walk on foot at discharge. It is important to clearly understand intrapericardial anatomy in order to carry out successful intrapericadial vessel management.

Primary Adenoid Cystic Carcinoma of the Peripheral Lungs.

We herein report a very rare case of adenoid cystic carcinoma of the peripheral lungs. A 77-year-old female visited a family physician for aortitis syndrome, diabetes mellitus and hyperlipidemia. A follow-up chest computed tomography scan for aortitis syndrome revealed a nodule in the middle lobe of the right lung. Although a transbronchial lung biopsy was attempted, a definitive diagnosis could not be made. Because the possibility of lung malignancy could not be ruled out, thoracoscopic wedge resection of the middle lobe was performed. The intraoperative pathological diagnosis revealed carcinoma of the lungs and we performed middle lobectomy under complete video-assisted thoracoscopic surgery. A histopathological examination demonstrated an adenoid cystic carcinoma with a characteristic cribriform structure.

[Student education with using training simulator for endoscopic surgery].

Video-assisted thoracic surgery (VATS) has become popular in the field of chest surgery. Recently, there has been a gradual reduction in the number of surgeons in Japan, which thus increases concerns regarding a potential shortage in the number of surgeons in the future. In this study, we evaluated the efficacy of using a surgical simulator with an endoscopic simulator to provide practical training for 245 medical students. Three different tests were performed with a one-week interval between each test, and the task completion time between the 1st and 2nd training sessions was then analyzed. A reduction in the time required to perform the tasks was observed. In addition, 95% of the subjects had a positive opinion regarding the application of the device for practical training, while 85% reported an increased interest in surgery. No significant relationships were observed between the task completion time and the degree of proficiency in performing the task or between the results of students choosing to become surgeons and those not choosing to become surgeons in the future according to a follow-up study. The students who later decided to become surgeons tended to express a positive opinion on the questionnaire compared with the non-departmental staff. As a result, providing student education using a training simulator for endoscopic surgery is therefore considered to have a beneficial effect in increasing the number of medical school students who later decide to become surgeons.

Evaluation of undiagnosed solitary lung nodules according to the probability of malignancy in the American College of Chest Physicians (ACCP) evidence-based clinical practice guidelines.

BACKGROUND: This study retrospectively investigated the clinical significance of undiagnosed solitary lung nodules removed by surgical resection. PATIENTS AND METHODS: We retrospectively collected data on the age, smoking, cancer history, nodule size, location and spiculation of 241 patients who had nodules measuring 7 mm to 30 mm and a final diagnosis established by histopathology. We compared the final diagnosis of each patient with the probability of malignancy (POM) which was proposed by the American College of Chest Physicians (ACCP) guidelines. RESULTS: Of the 241 patients, 203 patients were diagnosed to have a malignant lung tumor, while 38 patients were diagnosed with benign disease. There were significant differences in the patients with malignant and benign disease in terms of their age, smoking history, nodule size and spiculation. The mean value and the standard deviation of the POM in patients with malignant tumors were 51.7 + 26.1%, and that of patients with benign lesions was 34.6 + 26.7%. The area under the receiver operating characteristic (ROC) curve (AUC) was 0.67. The best cut-off value provided from the ROC curve was 22.6. When the cut-off value was set at 22.6, the sensitivity was 83%, specificity 52%, positive predictive value 90%, negative predictive value 36% and accuracy 77%, respectively. CONCLUSIONS: The clinical prediction model proposed in the ACCP guidelines showed unsatisfactory results in terms of the differential diagnosis between malignant disease and benign disease of solitary lung nodules in our study, because the specificity, negative predictive value and AUC were relatively low.

Intrapleural chemotherapy improves the survival of non-small cell lung cancer patients with positive pleural lavage cytology.

PURPOSE: Information regarding the treatment of pleural lavage cytology (PLC)-positive patients is still limited. This study evaluated the efficacy of intrapleural chemotherapy (IPC) in PLC-positive patients. METHODS: Three hundred eighty-six of the 567 lung cancer patients who underwent surgery had undergone PLC after thoracotomy, following by a complete resection were evaluated. IPC was performed after surgery, and cisplatin or adriamycin was injected intrapleurally through the thoracic tube. RESULTS: The pathological diagnosis showed that 17 patients (4.4 %) were positive for (or suspected to have) malignancy in their PLC. The univariate and multivariate analysis showed that only pleural invasion was a significant predictor of a PLC-positive status. The 5-year overall survival in PLC-positive patients was 38 % and that in PLC-negative patients was 84 %. Both the univariate (p < 0.01) and multivariate (p = 0.045) analyses showed that the status of PLC was significantly associated with the overall survival. Eight of the 17 PLC-positive patients underwent IPC. The 2-year OS rate in the patients treated with IPC was 88 % and that of those without IPC was 44 (p = 0.04). CONCLUSION: IPC improved the postoperative survival in PLC-positive NSCLC patients, and a further prospective evaluation regarding this therapy is warranted.

Pneumonectomy for non-small cell lung cancer.

PURPOSE: To assess the mortality, complications and major morbidity of pneumonectomy for non-small cell lung cancer (NSCLC) and to establish the importance of various prognostic factors. METHODS: We reviewed retrospectively the hospital records of 71 consecutive patients who underwent pneumonectomy for NSCLC between 1992 and 2007 to evaluate the significance of risk factors for an adverse outcome. Patients were divided into two period groups according to the period when they were treated: early (1992-1999; n = 47) and late (2000-2007; n = 24). RESULTS: Both the 30-day and the in-hospital mortality rates were 4.2 % (3/71). Complications developed in 31.3 % (22/71) and overall 5-year survival was 23.1 %. Pathological stage III or more, T3 or more, and N2 or more were risk factors of an adverse outcome. Survival was not significantly influenced by histological type, the side of surgery, or curability. The 5-year survival rates for the early and late periods were 19.6 and 32.9 %, respectively. There were more patients with clinical N2 or 3 disease in the early period than in the late period (66.0 vs. 33.3 %). CONCLUSIONS: Pneumonectomy is associated with acceptable overall morbidity and mortality; however, patients with pathological stage III or more, T3 or more, and N2 or more disease require special consideration. Pneumonectomy should be performed only in selected patients.

Primary pulmonary Ewing's sarcoma: report of a case.

The Ewing's sarcoma family of tumors has been reported to originate in a variety of sites, most commonly in the extremities. We herein describe a rare case of primary pulmonary Ewing's sarcoma in a patient with a family history of sarcoma. The patient was a 42-year-old male, who presented with hemoptysis. Chest radiographs revealed a pulmonary mass in the right lower lobe. Clinical and radiological examinations (computed tomography and positron emission tomography) revealed that the lesion was a primary lesion. The lesion was resected by right lower lobectomy. The tumor was located in the pulmonary parenchyma, and there was no evidence of an extrapulmonary involvement by the tumor. Histologically, the tumor was composed of uniform cells with round nuclei and scant cytoplasm which were arranged in cohesive lobules with rare pseudorosette formation. Immunohistochemically, the tumor cells were positive for CD99, and negative for epithelial markers, neuroendocrine markers, myogenic markers and lymphoma markers. This diagnosis was further supported by the cytogenic and reverse transcriptase-polymerase chain reaction findings of EWS/FLI-1 fusion transcripts. This demonstrated the presence of a very rare primary pulmonary Ewing's sarcoma. The patient was treated with chemotherapy after the operation because Ewing's sarcoma is an aggressive neoplasm. The patient has had no recurrent disease for 6 months after the operation.

[Chest wall reconstruction with rectus abdominis musculocutaneous flap for sternum osteomyelitis after radiation].

We report a case of reconstruction of radiation ulcer on the chest wall and sternum osteomyelitis using a rectus abdominis musculocutaneous flap. A case of 67-year-old woman, Halsted operation was performed for right breast cancer, 23 years ago. After 4 years, transcatheter arterial injection and radiation therapy was performed to treat recurrence of parasternal lymph nodes. Since then, she had been without recurrence of the tumor, but suffered from repeated scabbing of parasternal skin. In 2009, she suffered from pain, redness and purulent discharge of the wound, and diagnosed with sternum osteomyelitis. She was admitted to our hospital and underwent debridement of sternum, and the resection of surrounding skin. Sixteen days later, reconstruction using a rectus abdominis musculocutaneous flap was performed. Twenty months after the operation, she is well without any evidence of recurrence.

Serum immunogloblins might be useful predictors of immune-related adverse events after immune checkpoint inhibitor usage in lung cancer.

We herein report a 79-year-old woman who underwent surgery had recurred non-small cell lung cancer and developed irAEs following ICI treatment. During ICI treatment, we conducted monthly measurements of the serum antibody levels in this patient, including those which were both tumor- (anti-p53 antibody) and nonspecific (immunoglobulins). Anti-p53 antibodies and IgM had not increased during ICI treatment, but the serum levels of IgG and IgA had gradually increased before the occurrence of irAEs. These results suggest that monitoring serum immunoglobulin levels might enable the early detection of ICI-induced immune responses in patients with lung cancer.

Evaluation of topoisomerase I/topoisomerase IIalpha status in esophageal cancer.

Human DNA topoisomerases I and IIalpha (Topo-I and -II alpha) are essential for vital cellular processes such as DNA replication, transcription, translation, recombination, and repair. The purpose of this study was to investigate the clinical significance of the expression of Topo-I and Topo-II alpha. Twenty-nine specimens of esophageal squamous cell carcinoma from patients who had been treated by complete resection of the esophageal tumor were studied by an immunohistochemical analysis. High expression of Topo I and II alpha was identified in 48.7% and 55.2% of tumors, respectively. Neither the Topo-I nor -II alpha expression level had any association with clinical characteristics, including differentiation and the depth of tumor invasion, lymph node metastasis, or the patient prognosis. However, a significant positive correlation was observed between the expression levels of Topo-I and Topo-II alpha. Our study results underscore the potential role of topoisomerase expression in esophageal cancer and further exploratory investigation is necessary to evaluate topoisomerase expression as a surrogate marker in chemotherapy with topoisomerase inhibitor for esophageal cancer.

Efficacy and safety of immune checkpoint inhibitor monotherapy in elderly patients with non-small cell lung cancer.

The efficacy and safety of immune checkpoint inhibitor (ICI) monotherapy in elderly patients with non-small cell lung cancer (NSCLC) remain unclear, especially in patients older than 80 years. We retrospectively reviewed the records of 10 patients older than 80 years with NSCLCs treated by ICIs. The median age was 85 years (range, 82-93 years), and 7 patients were men. The median length of follow-up was 13 months (range, 4.5-23 months). Eight patients had adenocarcinoma (3 of whom had exon 19 deletions), and two had squamous cell carcinoma. Expression of programmed cell death ligand 1 (PD-L1) was ≥ 50% in 3 patients, between 1% and 49% in 4 patients, < 1% in 1 patient, and undetected in 2 patients. Patients with undetected PD-L1 underwent transbronchial lung biopsy. Performance status was graded zero, one, and two in two, seven, and one patients, respectively. First-, second-, and third-line treatments were administered to three, three, and four patients, respectively. The 2-year overall survival rate was 30.0% (median, 285 days). Time to treatment failure rate on the 2 years was 10.0% (median, 167 days). One patient achieved a partial response, and one achieved a complete response. ICI-associated adverse events occurred in five patients. In summary, ICIs were effective in some patients older than 80 years; however, some experienced adverse effects. Elderly patients must be selected carefully for ICI treatment.

Mediastinal lymph node metastases in lung cancer presenting as pure ground-glass nodules: A surgical case report.

INTRODUCTION: Generally, lung cancer representing as Ground-glass nodules is associated with an early stage and good prognosis. However, we herein report a rare case of pure ground-glass nodules with mediastinal lymph node metastases. PRESENTATION OF CASE: A 69-year-old man underwent video assisted thoracic surgery right upper lobectomy with mediastinal lymph node dissection due to multifocal Ground-glass nodules in the right upper lobe of the lung. Histopathologically, six lung adenocarcinomas were present simultaneously. Furthermore, we detected mediastinal lymph nodes metastases that contain micropapillary component. The lung lesion containing micropapillary component was a pure Ground-glass nodule that adjoining pulmonary bulla on CT findings. DISCUSSION: Generally, lung cancer presenting as pure ground-glass nodules is associated with an early stage and good prognosis. However, the necessity of evaluating the mediastinal lymph nodes in pure ground-glass nodules is controversial. It is reported that lung cancer adjoining the wall of a bulla tends to have a poor prognosis, even when small in size. Therefore, Ground-glass nodules with metastases might have a different pathogenesis than other nodules. CONCLUSION: Adenocarcinoma appearing as pure Ground-glass nodules is associated with early stage lung cancer and a good prognosis. However, the findings in our patient indicate the importance and necessity of evaluating the mediastinal lymph nodes for metastases intraoperatively.

Difficulty of treatment for pleural epithelioid hemangioendothelioma: a report of a case.

We herein report the case of a 62-year-old man who underwent extrapleural pneumonectomy (EPP) for pleural epithelial hemangioendothelioma (EHE) diagnosed by a pleural biopsy. Pre-operative computed tomography revealed diffuse pleural thickening and pleural effusion in the right thoracic cavity, although metastasis to neither the lymph nodes nor distant organs was detected. We decided to perform EPP based on surgical findings that the tumor had invaded the lung parenchyma. A pathological examination revealed tumor invasion of the lung parenchyma, blood vessel, pericardium, diaphragm and bronchial wall. Despite aggressive treatment, tumor recurrence was detected about 1 month after surgery. Although we controlled the tumor progression using pazopanib, the patient ultimately died 3.5 months after the operation. Pleural EHE is a very rare disease that has a poor prognosis due to its high malignant potential. It is important to formulate strategies matched to individual cases based on disease progression and invasiveness of treatment.

Gefitinib and a ventriculo-peritoneal shunt to manage carcinomatous meningitis from non-small-cell lung cancer: report of two cases.

The prognosis of patients with carcinomatous meningitis from non-small-cell lung cancer (NSCLC) remains poor, and the available treatment options for the lung cancer do not relieve the severe symptoms of this sequela. We report the successful treatment of two cases of carcinomatous meningitis caused by NSCLC, using gefitinib and a ventriculo-peritoneal (V-P) shunt. The first patient was a 43-year-old woman with pT1N0M0 adenocarcinoma. Multiple brain and vertebral metastases were found 13 months after surgery. She had undergone gamma-knife radiosurgery for the brain metastases, radiotherapy for the vertebral metastases, and two regimens of systemic chemotherapy, before carcinomatous meningitis was diagnosed. She was given gefitinib, and then a V-P shunt was placed. She continued to take gefitinib and was free of subjected symptoms for 5 months until she died. The second patient was a 64-year-old woman with cT4N0M0 adenocarcinoma. After local chemotherapy using cisplatin and OK-432 for carcinomatosis pleuritis and two regimens of systemic chemotherapy, carcinomatous meningitis was detected. A V-P shunt was placed, and she was sequentially given gefitinib. At her 15-month follow-up, she was free of symptoms of carcinomatous meningitis. No adverse effects or shunt problems were detected in either patient. This therapeutic modality may liberate carcinomatous meningitis patients with severe symptoms from hospitalization and improve their quality of life.

Thymic papillary adenocarcinoma coexisting with type A thymoma: A case report.

INTRODUCTION: Thymic papillary adenocarcinoma is rare. Further, thymic papillary adenocarcinoma coexisting with type A thymoma is extremely rare. Surgery remains the only effective treatment for this disease. PRESENTATION OF CASE: An 84-year-old Japanese woman presented to our institute due to abnormal chest computed tomography (CT) findings showing a 45 × 40 × 40-mm tumor located in the anterior mediastinum. A malignant tumor was suspected based on the CT findings and high serum levels of carcinoembryonic antigen. Mediastinal tumor resection was performed via video-assisted thoracic surgery through the left thoracic approach. This patient was discharged from our institute without any problems at six days post-operation. DISCUSSION: This report has three major implications. First, one of the tumors was papillary adenocarcinoma. Primary papillary adenocarcinoma of the thymus is exceedingly rare. Second, papillary adenocarcinoma and type A thymoma coexisted in this tumor. Third, epithelial thymic tumor should be resected completely, since complete resection has been reported to be associated with an improved prognosis. CONCLUSION: We encountered a rare case of thymic papillary adenocarcinoma coexisting with type A thymoma.

What is the best treatment strategy for primary spontaneous pneumothorax? A retrospective study.

BACKGROUND: Several treatment strategies are available for primary spontaneous pneumothorax (PSP). Surgical procedures are also performed in patients with PSP without an absolute indication for surgery. This study was performed to investigate the best treatment strategy for PSP by comparison of the recurrence rate. MATERIALS AND METHODS: From January 2006 to December 2013, 149 patients with PSP aged ≤50 years were treated in our institution. We reviewed the recurrence rate of PSP for each treatment strategy and evaluated the association between the recurrence rate of PSP with the clinicopathological characteristics. We also compared the surgery and non-surgery groups. RESULTS: A significant difference in the PSP recurrence rate was found between the surgery and non-surgery groups (22% vs. 52%, respectively; p < 0.001), patients aged ≥22 and < 22 years (16% vs. 44%, respectively; p < 0.001), and smokers and nonsmokers (13% vs. 43%, respectively; p < 0.001). There were also significant differences in the multivariate analysis (p < 0.001, p = 0.050, and p = 0.001, respectively). In the surgery group, the PSP recurrence rate was significantly different between patients aged ≥22 and < 22 years (7% vs. 38%, respectively; p < 0.001) and smokers and nonsmokers (5% vs. 33%, respectively; p = 0.002). No significant differences were found in the non-surgery group. CONCLUSIONS: In the surgical treatment of PSP, it is desirable that smokers stop using tobacco and that patients are ≥22 years old. Moreover, when surgery is being considered, the best timing seems to be when air leakage is present because the air leakage sites can be resected.

Prognostic factors of advanced or postoperative recurrent non-small cell lung cancer targeted with immune check point inhibitors.

BACKGROUND: Although immune checkpoint inhibitors (ICIs) for non-small cell lung cancer (NSCLC) have been established as one of standard therapy, the prognostic factors of ICIs remain unclear, aside from the programed cell death-ligand 1 (PD-L1) expression of tumor cells. The aim of this study was to determine the prognostic factors of ICIs. METHODS: We analyzed the clinicopathological data of 44 cases of advanced NSCLC targeted with ICIs in our hospital, between February 2016 and February 2018, in order to determine the prognostic factors of ICIs. We also reviewed the literature regarding ICIs. RESULT: We retrospectively analyzed the 44 cases (26 nivolumab and 18 pembrolizumab cases). These patients were 38 men and 6 women, comprising 13 cases of adenocarcinoma, 29 squamous cell carcinoma and 2 unclassified types. Seven patients were using first-line therapy and while the others were using second-line therapy or later. Epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) mutations were negative in all the cases. The response rate and disease control rate were 20.5% and 51.3%, respectively. The median progression-free survival time and median survival time were 146 days and 257 days, respectively. We observed five severe adverse effects (AEs) (three cases of interstitial pneumonia, one of liver dysfunction and one of adrenal failure), that were resolved by steroid pulse therapy. In multivariate analyses, the Eastern Cooperative Oncology Group performance status (ECOG PS), pathological type, standardized uptake value (SUV) on positron emission tomography (PET), white blood cell (WBC) count, neutrophil, neutrophil-to-lymphocyte ratio (NLR), lactate dehydrogenase (LDH) and albumin were independently prognostic factors. There were no significant differences in the prognosis between nivolumab and pembrolizumab. CONCLUSIONS: ICIs were effective in 44 treated NSCLC cases. Our analysis suggests that while ICIs are effective in treating patients, candidates must be carefully selected and cautiously observed.

Capture of mesothelioma cells with 'universal' CTC-chip.

Malignant mesothelioma (MM) is a highly aggressive malignant tumor, predominantly associated with job-related exposure to asbestos. Development of effective and non-invasive modalities for diagnosis is an important issue in occupational medicine. Circulating tumor cells (CTCs), which are tumor cells that are shed from primary tumors and circulate in the peripheral blood, may be detected at an earlier stage than malignant tumors, and detection of CTCs may provide a novel insight into the diagnosis of MM. In a previous study evaluating clinical utility of CTCs, detected with a widely used system 'CellSearch', the authors indicated a significant however insufficient capability in the diagnosis of MM, suggesting need for a more sensitive system. Accordingly, the authors developed a novel microfluidic system to capture CTCs (CTC-chip), and demonstrated that the CTC-chip effectively captured MM cells (ACC-MESO-4) spiked in the blood by conjugating an anti-podoplanin antibody. The results of the present study demonstrated that the CTC-chip coated with the anti-podoplanin antibody captured another MM cell (ACC-MESO-1). However, the capture efficiencies were lower than those for ACC-MESO-4. In addition, an anti-mesothelin antibody was used to capture CTCs, however the CTC-chip coated with the anti-mesothelin antibody failed to effectively capture MM cells, possibly due to low mesothelin expression. Overall, the CTC-chip may capture specific types of CTCs by conjugating any antibody against an antigen expressed on CTCs, and may be a useful system for the diagnosis of malignant tumors, including MM.