Nobuyuki Kondo

Sirolimus treatment for recurrent lymphangioleiomyomatosis after lung transplantation.

Pulmonary lymphangioleiomyomatosis is a rare disease that generally progresses to respiratory failure. We experienced a patient who had recurring lymphangioleiomyomatosis in the transplanted lungs. A chest computed tomographic scan showed a progressing emphysematous change. The patient had a subclinical extent of pan-circumferential stricture at the distal site of the left bronchial anastomosis. We treated the patient with sirolimus for three years. Chest computed tomography showed no sign of exacerbation during the late 3 years, whereas pulmonary function test revealed a slight increase after the use of sirolimus. Bronchial stricture also disappeared almost completely. This is the first reported case with sirolimus treatment for post-transplant recurrent lymphangioleiomyomatosis.

Thrombin induces rapid disassembly of claudin-5 from the tight junction of endothelial cells.

The cell-to-cell junction of endothelial cells (ECs) regulates the fence function of the vascular system. Previously we showed that ECs derived from embryonic stem cells (i.e., EECs) develop to form stable endothelial sheets in monolayer cultures. Immunohistochemical analysis revealed that these EECs formed intercellular junctions with the help of vascular endothelial cadherin (VECD) and claudin-5. In this study, we investigated the response of EC sheets to stimuli that are known to increase vascular permeability. While vascular endothelial growth factor A and histamine disrupted the EC junction by enhancing contraction of EECs, thrombin affected specifically the localization of claudin-5 at this junction. We could not detect any significant effect of thrombin on the localization of VECD. Concerning thrombin receptors, EECs expressed protease-activated receptor 1 (PAR1) but not PAR4. Consistent with this expression pattern, PAR1 agonists eliminated claudin-5 as effectively as thrombin itself. This is the first report to show that claudin-5 can be disassembled from the EC junction in a signal-dependent manner and to suggest that claudin-5 mobilization is a cause of PAR1-induced increase in vascular permeability.

Excision of an invasive thymoma: a cure for ulcerative colitis?

Thymoma is often associated with other diseases, including autoimmune diseases and endocrine disorders. Ulcerative colitis is a nonspecific inflammatory disease and is thought to be an immune-mediated disorder; however, coincidence of thymoma and ulcerative colitis is rare. We treated a 51-year-old woman with invasive thymoma and ulcerative colitis. After excision of the invasive thymoma with partial resections of pericardium, left lung, brachiocephalic vein, and left phrenic nerve, the ulcerative colitis was cured.

Expression of endothelial cell-specific adhesion molecules in lungs after cardiac arrest

OBJECTIVES A method to compensate for donor shortages could be donation after cardiac death. In this study, we considered endothelial cell-specific molecules, claudin-5 and VE-cadherin, as possible biomarkers predicting lung injury against warm ischemia. We investigated how the expression of these molecules could change after cardiac arrest in a mouse lung, comparing other molecules presumably relating with ischemia. METHODS At given intervals after cardiac arrest, the lungs were harvested. Quantitative analysis of mRNA expression of claudin-5, VE-cadherin, IL-1beta, IL-10, HIF-alpha, Egr-1, VEGF, Ang-1 and Ang-2 genes in lung tissues with several periods of warm ischemia was performed. RESULTS Regarding endothelial cell-specific molecules, there were significant differences in both claudin-5 and VE-cadherin mRNA expression between 0 h and 4 h after cardiac arrest. IL-1beta mRNA expression 1 h, 2 h and 4 h after cardiac arrest increased significantly, compared with that at 0 h. There were no significant differences with the other genes. CONCLUSIONS We found that it took more time for claudin-5 and VE-cadherin mRNA expression to change significantly than IL-1beta mRNA expression; therefore, endothelial cell-specific molecules, claudin-5 and VE-cadherin, might be no better candidates for clinical use than IL-1beta.

Circulating tumor cells as a potential biomarker in selecting patients for pulmonary metastasectomy from colorectal cancer: report of a case.

Pulmonary metastasectomy is indicated for selected patients with metastatic colorectal cancer. A 43-year-old woman presented with solitary pulmonary metastasis from descending colon cancer and pulmonary metastasectomy was performed because of absence of any other active metastasis as well as normal serum carcinoembryonic antigen value. However, she died due to early development of nodal and bone metastases within 6 months after thoracotomy. The presence of circulating tumor cells (CTCs) in the peripheral blood (6 CTCs/7.5 ml) was the only factor to predict such a poor prognosis, suggesting that the CTC test is useful in selecting patients for pulmonary metastasectomy.

A Multicenter Feasibility Study of EBUS-TBNA for Potentially Operable Non-Small Cell Lung Cancer: The JMTO LC07-02 Study (UMIN000001280)

Background: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a standard procedure for the pathological evaluation of the mediastinal nodal (N2) status of lung cancer; however, its feasibility in potentially operable patients with suspicion of minimal N2 disease remains unestablished. Patients and Methods: A prospective multicenter study was conducted to assess the feasibility of EBUS-TBNA in this setting. Patients with clinical stage IIIA-N2 non-small cell lung cancer (NSCLC) and mediastinal nodal enlargement on computed tomography (CT) were eligible; patients were ineligible when CT revealed bulky (> 3 cm in the long-axis diameter) N2 or multiple (≥ 3) station N2. If EBUS-TBNA revealed negative results, surgical staging procedures were mandatory. Results: Among 20 eligible patients, EBUS-TBNA provided pathological confirmation of N2 disease (true-positive) in 12 patients. Among 8 patients with negative results with EBUS-TBNA, 4 patients were pathologically diagnosed as having N2 disease with surgical staging procedures (false-negative), and 4 were finally diagnosed as having non-N2 disease with nodal dissection by thoracotomy (true-negative). As a result, the sensitivity of EBUS-TBNA for N2 evaluation (primary endpoint) was 75.0% (95% confidence interval 47.6-92.7%). No grade 3-5 adverse event were documented. Conclusion: EBUS-TBNA is potentially safe and useful in the pathological evaluation of N2 status even in potentially operable NSCLC patients with suspicion of minimal N2 disease on preoperative CT.

Positive correlation between postoperative tumor recur-rence and changes in circulating tumor cell counts in pul-monary venous blood (pvCTC) during surgical manipulation in non-small cell lung cancer

Background In non-small cell lung cancer (NSCLC), circulating tumor cells (CTC) are shed and circulate to the peripheral blood through the pulmonary vein. Previously, CTC count in pulmonary venous blood (pvCTC) was shown to significantly increase after surgical manipulation. Therefore, we assessed the correlation between the changes in the pvCTC count (ΔpvCTC) and clinical outcomes. Methods Consecutive patients with peripheral-type, NSCLC, who underwent lobectomy or bi-lobectomy through open thoracotomy, were enrolled prospectively. Before and after lobectomy, 2.5 mL of blood was drawn from the associated lobar pulmonary vein (PV), and was served for the quantitative evaluation of CTC using the CellSearch® system. The cut-off point of ΔpvCTC was determined according to clinical outcomes and ΔpvCTC using receiver operation characteristic (ROC) curve. Then the correlation between ΔpvCTC and clinical outcomes was evaluated by Kaplan-Meier analyses and log-rank test. In addition, the correlation between ΔpvCTC and perioperative variables was assessed. Results A total of 30 patients were enrolled, tumor recurrence occurred in 11 patients over a median follow-up of 64.4 months. Of these, 7 patients had distant metastasis and 4 had local recurrence. The median ΔpvCTC was 49 cells/2.5 mL, and pvCTC-count was increased during surgical manipulation in 24 patients (80%). We divided patients into two groups based on ΔpvCTC with the cut-off value as 119 cells/2.5 mL according to ROC curve. Significant shorter time to distant metastasis (TDM) (P=0.0123) was observed in high ΔpvCTC group (ΔpvCTC ≥119 cells/2.5 mL) than low ΔpvCTC group (ΔpvCTC <119 cells/ 2.5mL). Neither disease-free survival (DFS) nor overall survival (OS) was significantly correlated with ΔpvCTC. Conclusions Increasing pvCTC count during surgical manipulation was significantly correlated with postoperative distant metastasis in completely resected NSCLC patients. Significant shorter TDM was observed in patient with high ΔpvCTC group.

The clinical value of circulating tumour cells (CTCs) in patients undergoing pulmonary metastasectomy for metastatic colorectal cancer

Background Circulating tumour cells (CTCs) are a potential surrogate for distant metastasis and are considered a useful clinical prognostic marker for metastatic colorectal cancer (mCRC). This prospective study evaluated the preoperative CTC count as a prognostic factor for pulmonary metastasectomy in mCRC patients. Methods Seventy-nine mCRC patients who underwent curative-intent pulmonary metastasectomy were included. Preoperatively, 7.5 mL of peripheral blood from each patient was quantitatively evaluated for CTCs with the CellSearch® system. The clinical significance of CTC count was evaluated according to Kaplan-Meier analyses and log-rank test. Multivariate analyses of the perioperative variables were performed. Results The distribution of CTC counts were as follows; 0 in 66 patients (83.5%), 1 in eight patients (10.1%), 2 in three patients (3.8%), and 3 and 6 in one patient (1.3%). The patients with multiple CTCs (CTC count ≥2) had significant shorter disease-free survival (DFS) (P=0.005, median DFS; 19.8 vs. 8.6 months) and overall survival (OS) (P=0.035, median DFS; not reached vs. 37.8 months), respectively. Multivariate analysis showed the patients with multiple CTCs had elevated risk of recurrence [hazard ratio (HR), 3.28; 95% confidence interval (CI), 1.24-8.67; P=0.017]. Conclusions The detected rate of CTCs was quite low in mCRC patients who underwent pulmonary metastasectomy. The patient with multiple CTCs had shorter DFS in this study. The larger prospective clinical study is needed to establish the meaning of CTC in mCRC candidate for pulmonary metastasectomy.

A rare case of pleomorphic adenoma with difficult diagnosis using biopsy

An 85-year-old woman was found to have a nodule in the left S6 of the lung on computed tomography (CT); the pathological diagnosis from the CT-guided biopsy was adenoid cystic carcinoma. We accordingly performed left lower lobectomy. Pathologically, the biphasic cell population showed admixtures in varying proportions of epithelial and stromal elements, thereby indicating pleomorphic adenoma (PA). PA of the lung is extremely rare with reports of only 20 patients so far. Interestingly, this case was difficult to diagnose using CT-guided biopsy because the overview and biphasic cell population obtained on biopsy were garbled. Here we have reported our rare experience of PA.

Lung metastases in an atypical type A thymoma variant

A 35-year-old woman had undergone extensive thymothymectomy for type A thymoma several years ago. However, two small lung nodules were found 4 and 5 years after surgery. After a partial lung resection to remove these nodules, pathology revealed that they were metastases of the type A thymoma. A pathological re-evaluation confirmed that the primary tumor had in fact been an atypical type A thymoma variant, a subset added to the WHO classification in 2015. Pathology should be re-evaluated in all patients diagnosed with type A thymoma before 2015 since they may have the more aggressive atypical type A thymoma variant.