A prophylaxis study of acute exacerbation of interstitial pneumonia after lung cancer surgery.

INTRODUCTION: Acute exacerbation of interstitial pneumonia (AE-IP) is a lethal complication after lung surgery. We conducted a prospective, multi-institutional phase II trial to assess the efficacy and safety of prophylactic measures. METHOD: Patients with lung cancer with dorsal subpleural fibrotic changes occupying three or more segments of both lower lobes and planned anatomical lung resection were enrolled. Prior to surgery, patients received a 125-mg bolus injection of methylprednisolone and continuous intravenous infusion of sivelestat sodium hydrate (sivelestat) for 2 days. RESULTS: Sixty-nine patients were analysed. Preoperative high-resolution computed tomography (HRCT) showed 37 (53.6%) cases presented with usual interstitial pneumonia (UIP) and possible UIP pattern. There were 60 lobectomies and 9 segmentectomies. Thirty-eight cases were in clinical stage I. No adverse events associated with prophylaxis were observed. There were four cases of AE-IP (5.8%), higher than the expected 2.0%. Three of the four cases showed inconsistencies with the UIP pattern in preoperative HRCT and were pathologically diagnosed as UIP. All patients died of respiratory failure. Overall, 89.9% were diagnosed as idiopathic interstitial pneumonias; UIP was found in 48 patients (69.6%). Severe post-operative complications occurred in 11.6% of the cases. There were 35 deaths, 17 cases of lung cancer and 11 cases related to interstitial pneumonias. The overall survival rate at 3 years was 41.8% of the total and 47.2% of cases with clinical stage I. CONCLUSIONS: Perioperative use of sivelestat and low-dose methylprednisolone in patients with anatomical lung resection was safe but did not prove to be a prophylactic effect for AE-IP.

Computer-aided Quantification of Pulmonary Fibrosis in Patients with Lung Cancer: Relationship to Disease-free Survival.

Background Interstitial lung abnormalities (ILAs) are present at CT in about 10% of individuals undergoing lung cancer screening. The relationship between histologic findings of ILAs and their influence on patient prognosis remains unknown. Purpose To evaluate the percentage of ILAs at preoperative CT, as measured by radiologists and a computer-aided detection (CAD) software, as a predictor of disease-free survival in patients with lung cancer. Materials and Methods This retrospective study evaluated 217 consecutive patients who underwent complete resection of lung cancer from April 2010 to December 2015. Two radiologists, blinded to the patients' clinical information, scored percentage fibrosis extent and determined whether ILAs and the usual interstitial pneumonia (UIP) pattern were present. They assessed ILA progression at follow-up CT. Two pathologists determined the presence of an UIP pattern. Percentage fibrosis extent was also measured by using CAD. Binary logistic regression analysis was performed to determine whether the CAD percentage fibrosis extent was associated with ILA at CT. Multivariable Cox regression analysis was used to evaluate the significance of CAD percentage fibrosis extent as a predictor of prognosis. Results The radiologists classified 47 patients with ILAs and 24 patients with a UIP pattern at chest CT. The pathologists detected a UIP pattern in 25 patients. CT abnormalities showed progression over a 2-year period in all patients with histologic evidence of UIP. After adjustment for age, sex, and smoking index, the CAD percentage fibrosis extent was independently associated with ILA (odds ratio: 3.1; 95% confidence interval [CI]: 2.1, 4.7; P < .001). After adjustment for age, forced expiratory volume in 1 second (percentage predicted) radiologist-assessed percentage fibrosis extent, and pathologic stage, CAD percentage fibrosis extent was independently associated with worse disease-free survival (hazard ratio: 1.3; 95% CI: 1.1, 1.6; P < .001). Conclusion Greater computer-aided detection percentage fibrosis extent at preoperative CT independently predicted worse disease-free survival in patients with lung cancer. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Goo in this issue.

Update on the potential significance of psammoma bodies in lung adenocarcinoma from a modern perspective.

AIMS: Psammoma bodies are concentrically lamellated microscopic structures made of calcium. They are commonly observed in papillary carcinomas of the thyroid gland and serous papillary adenocarcinomas of the ovary, but are also occasionally detected in lung adenocarcinomas. Only one study, published in 1972, has systematically described the significance of psammoma bodies in lung adenocarcinomas. The aim of this study was to update the significance of psammoma bodies in lung adenocarcinomas from a modern perspective. METHODS AND RESULTS: Psammoma bodies were detected in 7.2% (59/822) of the adenocarcinomas examined, among which the papillary (20.3%, 12/59) and acinar (44.1%, 26/59) histological subtypes, with the feature of a terminal respiratory unit (91.5%, 54/59), were dominant. Malignant potential (cell growth activity measured by Ki67 labelling, lymph node metastasis, and postoperative survival) did not significantly differ between adenocarcinomas with and without psammoma bodies. On the basis of cytogenetic features, adenocarcinomas with psammoma bodies were preferentially affected by tyrosine kinase inhibitor (TKI)-targetable driver mutations [EGFR (69.8%, 37/53), ALK (13.2%, 7/53), and ROS1 (1.9%, 1/53)]. Multivariate analyses confirmed that psammoma bodies may constitute an independent predictor for these mutations, particularly EGFR and ALK mutations. CONCLUSIONS: Psammoma bodies may predict a favourable response of lung adenocarcinomas to TKIs.

A molecular pathological study of four cases of ciliated muconodular papillary tumors of the lung.

Ciliated muconodular papillary tumors (CMPTs) are a recently categorized benign or low-grade malignant neoplasm that develops in the peripheral lung. Only about 40 cases have been reported to date, and the clinicopathological characteristics have yet to be defined in detail. Here, we present four cases of CMPTs with a focus on their immunohistochemical profiles and driver gene mutations. These tumors were a papillary proliferation of a mixture of ciliated, mucous, and basal cells located in the peripheral lung. Ciliated, mucous and basal cells were positive for TTF-1 when using the clone SPT24, but negative for HNF-4α. Basal cells were positive for p40. Mucous cells in some tumors were positive for MUC5AC and MUC6. The Ki-67 index was less than 5%, and strong expression of p53 was not detected. Three of the four tumors had a BRAF (V600E) driver mutation, an EGFR (del E746-T751/S752V) driver mutation, or driver mutations in both EGFR (E709G) and KRAS (G12V). These mutation types are rare for any histological type of lung cancer. The present results confirmed that CMPT is a neoplasm with immunohistochemical features and driver gene mutations that are distinct from those of common lung tumors.

The pathological features of idiopathic interstitial pneumonia-associated pulmonary adenocarcinomas.

AIMS: To investigate the pathological features of idiopathic interstitial pneumonia (IIP)-associated pulmonary adenocarcinoma. METHODS AND RESULTS: Surgically resected adenocarcinomas associated with IIP (the IIP group) and adenocarcinomas without IIP (the non-IIP group) were subjected to analysis. Adenocarcinomas in the IIP group were subdivided into two groups: one group included tumours connected to bronchiolar metaplasia in honeycomb lesions (the H-IIP group), and the other included tumours unrelated to honeycomb lesions (the NH-IIP group). Histomorphological appearance and immunohistochemical expression were compared among the H-IIP group, the NH-IIP group, and the non-IIP group. Most of the tumour cells in the H-IIP group had a tall, columnar shape that showed similar features to proximal bronchial epithelium, whereas tumour cells in the NH-IIP group and the non-IIP group had a club-like shape that showed similar features to respiratory bronchiolar/alveolar epithelium. Adenocarcinomas in the H-IIP group tended to be negative for thyroid transcription factor-1 (TTF-1) and positive for hepatocyte nuclear factor-4α (HNF-4α). The frequency of EGFR mutations was significantly lower in adenocarcinomas in the H-IIP group, although the frequencies of KRAS and ALK mutations did not differ among the three groups. CONCLUSIONS: Idiopathic interstitial pneumonia-associated pulmonary adenocarcinomas, especially those arising from honeycomb lesions, have distinct pathological features.

The potential significance of alpha-enolase (ENO1) in lung adenocarcinomas - A utility of the immunohistochemical expression in pathologic diagnosis.

We herein analyzed the relationships among the immunohistochemical expression of alpha-enolase (ENO1) and clinicopathological factors in order to define the significance of ENO1 in lung adenocarcinomas (ADCs). ENO1 expression was detected in most of the ADCs examined (95.8%), but not in bronchial and alveolar epithelia. ENO1 expression was typically observed in the cytoplasm among most ADCs (95.8%), but was also detected in the nucleus (56.3%). The levels were significantly higher in terminal respiratory unit (TRU) cytological subtype ADCs. Neither cytoplasmic nor nuclear expression was associated with any other clinicopathological factors including post-operative survival and growth activity. These results suggest that ENO1 is a crucial factor promoting neoplastic transformation exclusively in TRU subtype ADCs. We also investigated the potential utility of the immunohistochemical expression of ENO1 to differentiate TRU-type ADC cells from the reactive hyperplasia of pneumocytes and bronchiolar epithelial cells because difficulties are associated with discriminating these lesions in small biopsy specimens. The sensitivity and specificity of ENO1 (cytoplasmic/nuclear) were 87.5%/37.5% and 88.9%/100%, respectively, which are superior to those of p53 (18.8% and 100%). ENO1 has potential as a biomarker to assist in the histopathological detection of TRU subtype ADC cells.

Prognostic value of the IASLC/ATS/ERS classification of lung adenocarcinoma in stage I disease of Japanese cases.

A new classification of adenocarcinoma (ADC) was proposed by the International Association for the Study of Lung Cancer, the American Thoracic Society, and the European Respiratory Society (IASLC/ATS/ERS) in 2011. The present study evaluates its prognostic value in stage I disease of Japanese cases. One-hundred-and-seventy-nine cases with pathological stage I ADC were classified according to the new classification system and their association with disease recurrence was analyzed. Eighteen (10.1%) and 24 (13.4%) cases were adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA), respectively. One-hundred-and-thirty-seven cases (76.5%) were invasive adenocarcinoma (IVA), in which 43 (24.0%) were lepidic (LEP), 59 (33.0%) were acinar (ACN), 16 (8.9%) were papillary (PAP), 1 (0.6%) was micropapillary (MPAP), 12 (6.7%) were solid predominant subtypes (SOL), and 6 (3.4%) were invasive mucinous adenocarcinoma (MUC). The5-year disease-free survivals (DFS) of patients with AIS and MIA were 100%. Those of LEP, ACN, PAP, SOL and MUC were 93.5%, 83.7%, 75.0%, 44.4% and 62.5%, respectively. Multivariate analysis showed that high-histological grade (SOL, MPAP, MUC) had an independent prognostic value to predict post-operative recurrence (HR 3.661, 95% CI 1.421-9.437, P = 0.007). In conclusion, the present study demonstrates a prognostic value of the 2011 IASLC/ATS/ERS classification of ADC in Japanese cases.

Expression of the potential cancer stem cell markers, CD133, CD44, ALDH1, and ß-catenin, in primary lung adenocarcinoma--their prognostic significance.

The present study investigated expression profiles of the potential CSC markers including CD133, CD44, ALDH1, and ß-catenin, and evaluated their prognostic value in lung adenocarcinomas. One-hundred-and-seventy-seven tumors (stage I) were immunohistochemically examined for the expression of these markers, and thresholds to subdivide expression levels were determined using receiver operating characteristics curves. Tumors with high levels of CD133 (adjusted hazard ratio (HR) 4.55 (95% confidence interval (CI) 1.26-16.40, P = 0.021), CD44 (HR 3.73, 95% CI 1.20-11.58, P = 0.023) or ALDH1 (HR 3.61, 95% CI 1.09-12.3, P = 0.036), but not ß-catenin (HR 2.43, 95% CI 0.59-10.8, P = 0.220), showed a significantly higher risk of recurrence than the corresponding low expressers. In conclusion, levels of CD133, CD44, and ALDH1 had independent prognostic value to predict the recurrence of lung adenocarcinoma.

Impact of the first surge of the coronavirus disease pandemic on general thoracic surgery practices in Kanagawa: a questionnaire survey by the Kanagawa General Thoracic Surgical Study Group.

OBJECTIVES: The first surge in severe acute respiratory syndrome coronavirus 2 infection had a significant impact on health care institutions. Understanding how the pandemic affected general thoracic surgery would provide valuable data for establishing a health care protocol for upcoming surges. METHODS: A questionnaire survey on coronavirus disease-related patient statistics and health care was conducted between February 2020 and June 2020 across 14 facilities affiliated with the Kanagawa General Thoracic Surgery Study Group. RESULTS: The average number of newly referred patients from February to June 2020 was 65% of that during the same period in 2019. Six facilities placed restrictions on medical care services, among which four restricted surgeries. At all institutions and those placed on surgical restriction, the total number of surgeries under general anesthesia was 92% and 78%, the total number of primary lung cancers was 94% and 86%, and the total number of surgeries for pneumothorax was 71% and 77% of that in the preceding year, respectively. Infection control and insufficient resources of the medical material were the most influential factors impacting the medical institutions' decision to restrict the services provided. CONCLUSIONS: Restrictions on surgery had a significant impact on the care provided by general thoracic surgery departments. To avoid patient inconvenience, establishing a collaborative system that refers patients to operational medical institutions in case of medical treatment restrictions may be useful.

Radiological unilateral pleuroparenchymal fibroelastosis as a notable late complication after lung cancer surgery: incidence and perioperative associated factors.

OBJECTIVES: Pleuroparenchymal fibroelastosis (PPFE) is a rare idiopathic interstitial pneumonia characterized by pleural-parenchymal involvement, predominantly in the upper lobes. Unilateral upper lung field pulmonary fibrosis (upper-PF) that is radiologically consistent with PPFE reportedly develops after lung cancer surgery in the operated side and presents many clinical characteristics in common with PPFE. However, the incidence and perioperative associated factors remain unclear. METHODS: All consecutive patients with lung cancer resected completely from 2008 to 2016 were investigated retrospectively. Pre-/postoperative characteristics were compared between patients with and without unilateral upper-PF. Cumulative incidence curves were estimated using competing risk analysis. RESULTS: Among the 587 included patients, 25 patients (4.3%) were diagnosed as unilateral upper-PF. The 3-, 5- and 10-year cumulative incidence of unilateral upper-PF was 2.3%, 3.3% and 5.3%, respectively. In multivariable analysis, male sex, presence of a pulmonary apical cap, lobar resection and low % vital capacity (%VC < 80%) were independent perioperative associated factors. The 10-year cumulative incidence was 6.3% in patients treated with lobar resection, 8.0% in male patients, 10.3% in patients with pulmonary apical cap and 14.5% in patients with low %VC. Postoperative pleural effusion at 6 months after surgery was much more common in the patients who later developed unilateral upper-PF (96.0% vs 24.2%). This pleural effusion persisted and was accompanied thereafter by pleural thickening and subpleural pulmonary fibrosis. During the clinical courses of 25 patients with unilateral upper-PF, 18 patients presented symptoms related to upper-PF and 6 patients died. CONCLUSIONS: Unilateral upper-PF is an occasional but under-recognized late complication after lung cancer surgery.

Early growth response-1 induces and enhances vascular endothelial growth factor-A expression in lung cancer cells.

Vascular endothelial growth factor-A (VEGF-A) is crucial for angiogenesis, vascular permeability, and metastasis during tumor development. We demonstrate here that early growth response-1 (EGR-1), which is induced by the extracellular signal-regulated kinase (ERK) pathway activation, activates VEGF-A in lung cancer cells. Increased EGR-1 expression was found in adenocarcinoma cells carrying mutant K-RAS or EGFR genes. Hypoxic culture, siRNA experiment, luciferase assays, chromatin immunoprecipitation, electrophoretic mobility shift assays, and quantitative RT-PCR using EGR-1-inducible lung cancer cells demonstrated that EGR-1 binds to the proximal region of the VEGF-A promoter, activates VEGF-A expression, and enhances hypoxia inducible factor 1alpha (HIF-1alpha)-mediated VEGF-A expression. The EGR-1 modulator, NAB-2, was rapidly induced by increased levels of EGR-1. Pathology samples of human lung adenocarcinomas revealed correlations between EGR-1/HIF-1alpha and VEGF-A expressions and relative elevation of EGR-1 and VEGF-A expression in mutant K-RAS- or EGFR-carrying adenocarcinomas. Both EGR-1 and VEGF-A expression increased as tumors dedifferentiated, whereas HIF-1alpha expression did not. Although weak correlation was found between EGR-1 and NAB-2 expressions on the whole, NAB-2 expression decreased as tumors dedifferentiated, and inhibition of DNA methyltransferase/histone deacetylase increased NAB-2 expression in lung cancer cells despite no epigenetic alteration in the NAB-2 promoter. These findings suggest that EGR-1 plays important roles on VEGF-A expression in lung cancer cells, and epigenetic silencing of transactivator(s) associated with NAB-2 expression might also contribute to upregulate VEGF-A expression.

Insulin-like growth factor binding protein-4 gene silencing in lung adenocarcinomas.

Gene silencing by promoter hypermethylation plays an important role in molecular pathogenesis. We previously reported that insulin-like growth factor (IGF) binding protein-4 (IGFBP-4), which inhibits IGF-dependent growth, is expressed via early growth response-1 (EGR-1) and is often silenced in cultivated lung cancer cells. The purpose of the present study was to clarify clinicopathological factors associated with IGFBP-4 gene silencing in lung adenocarcinomas. Seventy-six surgically resected adenocarcinomas (20 well-, 35 moderately-, and 21 poorly-differentiated) were subjected to methylation-specific polymerase chain reaction (PCR) analysis for EGR-1-binding sites located in the IGFBP-4 promoter and immunohistochemistry for IGFBP-4, EGR-1, and Ki-67. Thirty-two adenocarcinomas (42%) revealed IGFBP-4 promoter hypermethylation, and the severity inversely correlated with the level of IGFBP-4 expression (P < 0.0001) and tumor differentiation (well versus poor, P = 0.0278; well/moderate versus poor, P = 0.0395). Furthermore, there was a negative correlation between Ki-67 labeling index and IGFBP-4 expression (P = 0.0361). These findings suggest that the expression of IGFBP-4 in adenocarcinoma cells in vivo is downregulated by epigenetic silencing in association with tumor differentiation, resulting in disruption of the mechanism of IGFBP-4-mediated growth inhibition.

Intermediate bronchial kinking after right upper lobectomy for lung cancer.

BACKGROUND: Bronchial kinking after lung lobectomy is likely, whereas that of the intermediate bronchus after right upper lobectomy is often not recognized. The aim of this study was to examine the clinical implications of this condition. METHODS: One-hundred cases of right upper lobectomy for primary lung cancer were reviewed. The cases were divided into groups with intermediate (group A) and non-intermediate (group B) bronchial kinking, and the patient characteristics and postoperative outcomes were compared. The remaining lower lobe deformation was also evaluated using the angle formed by the intrathoracic tracheal line and posterior fissure on reconstructed sagittal computed tomography. RESULTS: There were 23 cases in group A which had a higher rate of bronchial calcification, older age, and female sex, whereas and smoking and pulmonary emphysema were less frequent. Three cases in group A had respiratory symptoms such as wheezing and respiratory noise, while only one case of middle lobe atelectasis was found in group B. In multivariate analysis, upper mediastinal lymph node dissection was an independent factor for non-intermediate bronchial kinking. The lower lobe was significantly more expanded in group A than in group B. CONCLUSIONS: Intermediate bronchial kinking correlates with postoperative respiratory symptoms and was less likely after upper mediastinal lymph node dissection.

A spectrum of Thymic mucosa-associated lymphoid tissue lymphoma and Thymic amyloidosis in the patient with Auto immune disease: a case series.

BACKGROUND: The thymus is associated with an immunodeficient status, autoimmune disease (AD), and the common thymic tumor, thymoma. We encountered two rare thymic tumors, thymic mucosa-associated lymphoid tissue (MALT) lymphoma and localized thymic amyloidosis, both in the presence of Sjögren's syndrome (SjS). This suggests a possible link between rare thymic tumors and SjS. Therefore, we reviewed cases of thymic tumors to examine the spectrum of these tumors in patients with AD. METHODS: The clinical information of thymic amyloidosis and MALT lymphoma surgically treated at Kanagawa Cardiovascular and Respiratory Center, and Yokohama City University Hospital from January 2010 to December 2019 were reviewed. The correlation between resected thymic tumors at same period and ADs were also investigated. RESULTS: There were 5 cases of thymic amyloidosis and MALT lymphoma. ALL cases had coexistent ADs (4 SjS, 1 SSc). The median age was 66 (38-76) year-old, and 4 of the patients were female. Three cases had already diagnosed as ADs before detection of tumors. Only SSc case was received preceding steroid medication. Two cases diagnosed as SjS at the same time of the operation. The median maximum tumor diameter was 70 mm. On chest computed tomography (CT), tumors contained solid part and some cystic part at various rated. Calcification was recognized with appearance of amyloid deposition. All patients were surgically treated with total thymectomy and they are alive without recurrence. At the same period, there were 163 resected thymic tumors, including amyloidosis, MALT lymphoma, thymoma, thymic cancer, neuroendocrine tumor and so on. Among them, nine patients (5.5%) had ADs. There was a correlation between ADs and thymic MALT lymphoma/amyloidosis (P<0.001). CONCLUSIONS: We propose a process for tumorigenesis of thymic MALT lymphoma and amyloidosis. Underlying AD causes persistent and chronic inflammatory reactions. In this theory, ADs, especially SjS, might be important underlying conditions in formation of rare tumors. When the clinician encounters a patient with AD, routine chest CT is recommended and may provide thymic tumors. Conversely, in case of mediastinum tumor, screening test for AD is also recommended.

Fungus ball removal with video-cavernoscopy for complex aspergilloma.

OBJECTIVE: Complete resection with a clear margin is the only curative treatment for pulmonary aspergilloma. This requires a high-level technique, especially for complex aspergilloma (CA), because of patient conditions and wide dense adhesions. Fungus ball removal is used palliatively to control hemoptysis, rather than as a radical procedure, and may be performed using video-cavernoscopy as a simple and repeatable method. In this study, we examined this approach as an alternative treatment for CA. METHODS: Eight cases of fungus ball removal with video-cavernoscopy (video-cavernoscopic removal) treated at our center were retrospectively reviewed. The patient characteristics and surgical outcomes were compared with those of patients treated with one-stage radical surgery. RESULTS: There were 8 subjects (7 males, 1 female; median age 65 years) in the video-cavernoscopic removal group and 25 subjects (19 males, 6 females; median age 56 years) in the one-stage radical surgery group. The video-cavernoscopic removal group had a higher rate of emphysematous lung (p = 0.001), a lower body mass index (p = 0.039), and a lower percent vital capacity (p = 0.027). All cases in this group had preoperative hemoptysis that ceased after the procedure. Video-cavernoscopic removal was less invasive based on a shorter operative time (p = 0.000), less blood loss (p = 0.002), and a lower Common Terminology Criteria for Adverse Events grade (p = 0.023). However, four cases in this group (50%) relapsed with a median disease-free survival period of 471.5 days. CONCLUSIONS: Fungus ball removal with video-cavernoscopy is a simple technique for the prevention and control of massive hemoptysis that may be an alternative treatment for CA.

Down-regulation of DUSP6 expression in lung cancer: its mechanism and potential role in carcinogenesis.

Our preliminary studies revealed that oncogenic KRAS (KRAS/V12) dramatically suppressed the growth of immortalized airway epithelial cells (NHBE-T, with viral antigen-inactivated p53 and RB proteins). This process appeared to be a novel event, different from the so-called premature senescence that is induced by either p53 or RB, suggesting the existence of a novel tumor suppressor that functions downstream of oncogenic KRAS. After a comprehensive search for genes whose expression levels were modulated by KRAS/V12, we focused on DUSP6, a pivotal negative feedback regulator of the RAS-ERK pathway. A dominant-negative DUSP6 mutant, however, failed to rescue KRAS/V12-induced growth suppression, but conferred a stronger anchorage-independent growth activity to the surviving subpopulation of cells generated from KRAS/V12-transduced NHBE-T. DUSP6 expression levels were found to be weaker in most lung cancer cell lines than in NHBE-T, and DUSP6 restoration suppressed cellular growth. In primary lung cancers, DUSP6 expression levels decreased as both growth activity and histological grade of the tumor increased. Loss of heterozygosity of the DUSP6 locus was found in 17.7% of cases and was associated with reduced expression levels. These results suggest that DUSP6 is a growth suppressor whose inactivation could promote the progression of lung cancer. We have here identified an important factor involved in carcinogenesis through a comprehensive search for downstream targets of oncogenic KRAS.

Down-regulation of FXYD3 expression in human lung cancers: its mechanism and potential role in carcinogenesis.

FXYD3 is a FXYD-containing Na,K-ATPase ion channel regulator first identified as a protein overexpressed in murine breast tumors initiated by oncogenic ras or neu. However, our preliminary study revealed that FXYD3 expression was down-regulated in oncogenic KRAS-transduced airway epithelial cells. This contradiction led us to investigate the role of FXYD3 in carcinogenesis of the lung. FXYD3 mRNA and protein levels were lower in most of the lung cancer cell lines than in either the noncancerous lung tissue or airway epithelial cells. Protein levels were also lower in a considerable proportion of primary lung cancers than in nontumoral airway epithelia; FXYD3 expression levels decreased in parallel with the dedifferentiation process. Also, a somatic point mutation, g55c (D19H), was found in one cell line. Forced expression of the wild-type FXYD3, but not the mutant, restored the well-demarcated distribution of cortical actin in cancer cells that had lost FXYD3 expression, suggesting FXYD3 plays a role in the maintenance of cytoskeletal integrity. However, no association between FXYD3 expression and its promoter's methylation status was observed. Therefore, inactivation of FXYD3 through a gene mutation or unknown mechanism could be one cause of the atypical shapes of cancer cells and play a potential role in the progression of lung cancer.

Neuroendocrine cancer-specific up-regulating mechanism of insulin-like growth factor binding protein-2 in small cell lung cancer.

Small cell lung cancer (SCLC) exhibits insulin-like growth factor-dependent growth. SCLC is the most aggressive among known in vivo lung cancers, whereas in vitro growth of SCLC is paradoxically slow as compared with that of non-SCLC (NSCLC). In this study, we demonstrate that SCLC cells overexpress insulin-like growth factor binding protein (IGFBP)-2 via NeuroD, a neuroendocrine cell-specific transcription factor. Chromatin immunoprecipitation, electrophoretic mobility shift, and IGFBP-2 promoter assays all revealed that NeuroD binds to the E-box in the 5'-untranslated region of IGFBP-2. A NeuroD transgene in both airway epithelial and NSCLC cells up-regulated the transcription of IGFBP-2 and retarded cell growth. Recombinant IGFBP-2 repressed the growth of both airway epithelial and NSCLC cells in a dose-dependent manner. A NeuroD-specific small interfering RNA repressed IGFBP-2 expression in SCLC, and neutralization of IGFBP-2 and an IGFBP-2-specific small interfering RNA increased SCLC cell growth. Pathological samples of SCLC also expressed IGFBP-2 abundantly, as compared with NSCLC, and showed only rare (8%) IGFBP-2 promoter methylation, whereas the IGFBP-2 promoter was methylated in 71% of adenocarcinomas and 29% of squamous cell carcinomas. These findings suggest that 1) SCLC has an IGFBP-2 overexpression mechanism distinct from NSCLC, 2) secreted IGFBP-2 contributes to the slow growth of SCLC in vitro, and 3) the epigenetic alterations in the IGFBP-2 promoter contribute to the striking differences in IGFBP-2 expression between SCLC and NSCLC in vivo.

A case of intrathoracic desmoid tumor with pulmonary Mycobacterium abscessus disease.

A 68-year-old man who was on treatment for pulmonary Mycobacterium avium complex complained a worsening of sputum. Although he archived negative sputum culture two months ago, sputum culture tests revealed the newly isolation of Mycobacterium abscessus repeatedly. Chest computed tomography showed newly-appeared extra-pulmonary mass lesion in contact with a cyst at the bottom of his right lung. From the results of contrast-enhanced magnetic resonance imaging, we first suspected loculated pleural effusion due to Mycobacterium abscessus infection. A thoracoscopic examination was performed as the right pneumothorax developed, and the pleural lesion was successfully resected and diagnosed as an intrathoracic desmoid tumor. Intrathoracic desmoid tumor is very rare, and this is the first report of a case with pulmonary Mycobacterium abscessus disease.

Bronchoscopy as a Useful Examination for Determining Surgical Treatment Indications in Refractory Mycobacterium avium Complex Lung Disease Patients with Bilateral Lesions.

We herein report three cases of refractory Mycobacterium avium complex (MAC) disease successfully treated surgically despite the MAC lesions being present bilaterally. Of note, although two patients did not present with any respiratory symptom, bronchoscopy clearly revealed a major excretory lesion with a large amount of purulent sputum in all patients. Because an excretory lesion was localized, surgical resection was performed, and the mycobacterial sputum smear became negative in all patients. Bronchoscopy may be a useful examination for detecting major excretory lesions with purulent sputum, which can disseminate to other lobes, and for determining the surgical indications of refractory MAC patients, regardless of the presence of respiratory symptoms.