[Surgical Experience with Three Cases of Open-window Thoracostomy for Chronic Empyema Under Local Anesthesia].

We may encounter patients with chronic empyema for whom open-window thoracostomy is unavoidable. However, patients with chronic empyema are sometimes at high-risk for surgery under general anesthesia. We, herein, present our surgical experience with three chronic empyema cases who underwent open-window thoracostomy under local anesthesia. Indications for open-window thoracostomy under local anesthesia were raised PaCO2 in Case 1, old age and poor performance status in Case 2, and a history of esophageal reconstruction and vocal cordoplasty in Case 3. All patients were well during the surgery. Case 1 developed type 2 respiratory failure postoperatively and had to be put on a ventilator, but finally recuperated. The sedatives used could have exacerbated raised PaCO2 in this patient, and careful selection of anesthetic agents is mandatory. Considering pain and stress that patients suffer during open-window thoracostomy under local anesthesia, case selection is necessary. Nevertheless, we believe that open-window thoracostomy under local anesthesia is an effective option for high-risk patients.

Surgical Management of Mycobacterial Infections and Related Complex Pleural Space Problems: From History to Modern Day.

Owing to the advent of effective drugs for tuberculosis in the mid-twentieth century, few cases require surgery for active tuberculosis in the present day in areas where effective drugs are available. However, surgical techniques developed to combat tuberculosis in the predrug era are still useful to manage the challenging chest pathology of our time surgically, such as destroyed lung or postresectional empyema. Thoracoplasty and open window thoracostomy are representative procedures and discussed in detail in this review.

Pharmacokinetics and Adverse Effects of Clofazimine in the Treatment of Pulmonary Non-Tuberculous Mycobacterial Infection.

Clofazimine (CFZ) is used to treat pulmonary non-tuberculous mycobacterial (NTM) infection; however, its pharmacokinetics remain unexplored in patients with pulmonary NTM, and the relationship between CFZ serum concentration and adverse effects has not been investigated. The objectives of this study were to characterize the pharmacokinetics of CFZ in pulmonary NTM disease treatment and to investigate the relationship between the steady-state CFZ serum concentration and adverse effects. A prospective observational study was conducted on 45 patients with pulmonary NTM treated with CFZ (UMIN000041053). A maximum of five serum samples per patient were taken at the CFZ trough, and serum concentration was measured using high-performance liquid chromatography-mass spectrometry (HPLC-MS). The pharmacokinetics of CFZ were analyzed using a nonlinear mixed effect model. The relationships among steady-state CFZ serum concentration and adverse effects, pigmentation, and heart rate-corrected QT (QTc) interval were investigated. Twenty-six patients had M. avium or M. intracellulare infection and nineteen had M. abscessus infection. The primary CFZ dosage was 50 mg/day. The estimated apparent CFZ clearance, apparent volume of distribution, and half-life were 2.4 L/h, 2,960 L, and 36 days, respectively. The combined use of rifampicin and CFZ significantly reduced CFZ exposure by 22%. Although there was no relationship between CFZ serum concentration and pigmentation intensity, the QTc interval was significantly correlated with CFZ serum concentration. The estimation of accurate pharmacokinetics for CFZ required approximately 5 months of monitoring. The relationship between the serum concentration and specific adverse effects of CFZ confirmed that CFZ serum concentration was not associated with pigmentation but did affect the QTc interval.

The combined use of long non-coding RNA HOTAIR and polycomb group protein EZH2 as a prognostic marker of lung adenocarcinoma.

BACKGROUND: The long non-coding RNA Hox transcript antisense intergenic RNA (HOTAIR) and polycomb group protein Enhancer of zeste homolog 2 (EZH2) function cooperatively in carcinogenesis. However, their combined usage as prognostic markers for lung adenocarcinoma remains unverified. MATERIALS AND METHODS: To validate their combined usage, we measured the expression of both genes in the surgical samples from 83 adenocarcinoma cases using quantitative real-time PCR and analyzed the association between the gene expressions and various clinicopathological factors. We also examined the EZH2 protein levels using immunohistochemistry. Finally, we analyzed the association between their expression status and the overall survival using 54 stage I cases. RESULTS: Both genes were expressed at significantly higher levels in adenocarcinoma tissues than normal lung. EZH2 expression, but not HOTAIR expression, was significantly higher in solid adenocarcinoma than in other subtypes. In the survival analysis using stage-I cases, both HOTAIR expression and EZH2 protein levels were associated with a worse prognosis. The overall survival was highest in the low-HOTAIR and low-EZH2 group (low-low), followed by the high-low or low-high group and the high-high group. According to the multivariate analysis, the high-high status of HOTAIR-EZH2 (protein) was significantly associated with a worse prognosis than the low-low group. CONCLUSION: More accurate prognoses would be possible by simultaneously measuring both genes than measuring either. The high-HOTAIR and high-EZH2 (protein) status, compared to the low-low, is proposed as an independent prognostic marker for stage I cases. Thus, it would serve as a potential biomarker for anti-EZH2 therapy.

Analysis of factors predicting the application of chemical pleurodesis for pneumothorax: An observational study.

ABSTRACT: Chemical pleurodesis is performed in pneumothorax patients to treat nonresolving air leakage or prevent recurrence. However, factors that might predict the need for chemical pleurodesis remain unknown. Therefore, this study investigated predictive factors for the application of chemical pleurodesis for pneumothorax.We retrospectively analyzed 401 adult pneumothorax patients who underwent chest tube drain insertion during hospitalization at Fukujuji Hospital from January 2016 to December 2020. The patients were divided into 3 groups: the pleurodesis group, comprising 89 patients treated with chemical pleurodesis; the nonpleurodesis group, comprising 206 patients treated without chemical pleurodesis; and the surgical group, comprising 106 patients treated surgically. Data for patients in the pleurodesis group were compared to those in the nonpleurodesis or surgical group, and a predictive score of the application of chemical pleurodesis for pneumothorax was developed.Compared with the nonpleurodesis group, in the pleurodesis group, patient age was higher (P < .001), emphysema (n = 33 (37.1%) vs 70 (34.0%), P = .045), and interstitial pneumonitis (n = 19 (21.3%) vs 19 (9.2%), P = .022) were more common causes, and chest tube suction was more common (n = 78 (87.96%) vs n = 123 (59.7%), P < .001). Similar results were found between the pleurodesis and surgical groups. We developed a score for predicting the application of chemical pleurodesis for pneumothorax, including the following factors: age ≥55 years; presence of emphysema and/or interstitial pneumonitis; and use of chest tube suction. The score for the pleurodesis group showed a high area under the receiver operating characteristic curve compared with that for the nonpleurodesis group (0.776 [95% confidence interval]: 0.725-0.827). With a score of 2 as the cutoff value, the sensitivity was 91.0% and the specificity was 52.4%. In a comparison between the pleurodesis and surgical groups, the predicting score showed the high AUC of 0.904 (95% confidence interval: 0.863-0.945).This study reveals predictive factors for the application of chemical pleurodesis and provides a predictive score including 3 factors.

Outcomes of Surgical Treatment for Mycobacterium abscessus Complex Pulmonary Disease.

BACKGROUND: Mycobacterium abscessus complex pulmonary disease is notoriously difficult to treat by medication alone. We report our experience with resectional surgery combined with preoperative and postoperative multidrug chemotherapy for the treatment of patients with M. abscessus complex pulmonary disease. METHODS: This is a retrospective review of 33 patients undergoing lung resection for M. abscessus complex pulmonary disease at a single center in Japan between January 2008 and December 2019. RESULTS: The median age of patients was 54.0 (interquartile range [IQR], 49.0-66.0) years; 27 (81.8%) were female. Nodular-bronchiectatic was the most common disease type (n = 24, 72.7%). Disease was limited in 18 (54.5%) patients and extensive in 15 (45.5%). The median duration of preoperative multidrug chemotherapy employing oral and parenteral antibiotics was 10.0 (IQR, 3.0-18.0) months. A total of 34 anatomical lung resections were performed as follows: 22 lobectomies, 5 segmentectomies, 4 combined resections, 2 bilobectomies, and 1 pneumonectomy. No operative mortalities and 4 (13.3%) morbidities occurred. The median duration of multidrug chemotherapy after the surgery was 18.0 (IQR, 12.0-31.0) months. Postoperative sputum-negative status was achieved in 31 (93.9%) patients; all 23 patients obtaining preoperative negative conversion remained negative, and 8 (80.0%) of 10 patients with preoperative positive sputum became negative postoperatively. Recurrence was observed in 2 (6.5%) patients. The recurrence-free probabilities were 96.3%, 96.3%, and 80.2% at 1 year, 3 years, and 5 years, respectively. CONCLUSIONS: Combined with preoperative and postoperative multidrug chemotherapy, resectional surgery can be performed safely and achieve favorable outcomes for patients with M. abscessus complex pulmonary disease.

A Novel Approach to Extensive Clarithromycin-Resistant Mycobacterium avium Complex Pulmonary Disease.

A 48-year-old woman with extensive clarithromycin-resistant Mycobacterium avium complex pulmonary disease (MAC-PD) was successfully treated by left lower lobectomy and lingulectomy following combination treatment of intravenous/inhaled amikacin plus bronchial occlusion by Endobronchial Watanabe Spigots (EWSs). A left pneumonectomy was initially indicated for removing all the lesions, but the procedure would have been barely tolerated by the patient. However, her preoperative combination treatment sufficiently reduced the lesions requiring resection to allow surgical preservation of the left upper division. This novel approach might be promising for patients with Mycobacterium avium complex lung disease whose pulmonary reserve will not allow an extensive parenchymal resection.

Physical Function and Health-Related Quality of Life after Surgery for Nontuberculous Mycobacterial Pulmonary Disease: A Prospective Cohort Study.

PURPOSE: To investigate the exercise capacity and health-related quality of life (HRQOL) of surgical patients with nontuberculous mycobacterial pulmonary disease (NTM-PD) preoperatively versus 6 months postoperatively. METHODS: This prospective observational study included patients with NTM-PD and was conducted at a single center. The intervention was surgical resection plus perioperative and post-discharge physical therapy. The physical function was assessed preoperatively and 6 months postoperatively using the 6-minute walk test (6MWT). HRQOL was assessed preoperatively and 6 months postoperatively using the Short-Form 36 (SF-36) health survey questionnaire and St. George's Respiratory Questionnaire. The postoperative HRQOL was compared between patients with and without preoperative clinical symptoms. RESULTS: In total, 35 patients were analyzed. The preoperatively symptomatic group had significantly lower preoperative HRQOL than the preoperatively asymptomatic group (p <0.05). Compared with preoperatively, there were significant improvements at 6 months postoperatively in the 6MWT (p <0.01) and HRQOL, mainly in the SF-36 mental component summary (p <0.01). The SF-36 mental component summary in the preoperatively symptomatic group was very significantly improved from preoperatively to 6 months postoperatively (p <0.05). CONCLUSION: The combination of surgical treatment and physical therapy for NTM-PD contributes to improvements in physical function and HRQOL.

Residual Destructive Lesions and Surgical Outcome in Mycobacterium avium Complex Pulmonary Disease.

BACKGROUND: Successful surgical treatment of patients with Mycobacterium avium complex pulmonary disease is thought to require complete removal of parenchymal destructive lesions. This study aimed to evaluate the short-term and long-term outcomes and the predictors of microbiological recurrence after surgery for M avium complex pulmonary disease. METHODS: We conducted a retrospective review of 184 patients undergoing unilateral lung resection for M avium complex pulmonary disease at a single center in Japan between January 2008 and December 2017. RESULTS: Median age of the 184 patients was 55.5 years; 133 were female (72.3%). All but 2 patients had anatomical lung resection. A total of 116 patients had limited disease and underwent complete resection (63.0%); the remaining 68 patients had extensive disease and underwent debulking surgery (37.0%). No operative mortalities occurred. In 18 of 184 patients, 21 morbidities occurred (9.8%), including 3 bronchopleural fistulas (1.6%). Postoperative sputum-negative status was achieved in 183 patients (99.5%). Microbiological recurrences occurred in 15 patients (8.2%). By multivariate analysis, extensive disease was an independent risk factor for recurrence (hazard ratio, 5.432; 95% confidence interval, 1.372-21.50; P = .016). Recurrence-free rates were significantly higher in patients with limited disease compared with those with extensive disease (99.0%, 97.4%, and 95.0% versus 93.0%, 89.2%, and 75.1% at 1, 3, and 5 years, respectively; P < .001). CONCLUSIONS: Complete resection of parenchymal destructive lesions can achieve excellent microbiological control for patients with limited M avium complex pulmonary disease. The efficacy of debulking surgery in patients with extensive disease needs further investigation.

[Nontuberculous Mycobacteriosis Resistant for Chemotherapy which was Suspected to Coexist with Lung Cancer].

Nontuberculous mycobacteriosis (NTM) has been increasing recently. The treatment of choice of NTM is chemotherapy. Surgical treatment is sometimes indicated for patients with refractory NTM. When NTM lesion is enlarging despite of chemotherapy, there are 2 possibilities:intractable NTM and co-existing lung cancer. A 67-year-old male had been treated for fibro-cavitary NTM in the right upper lobe with chemotherapy. The cavitary lesion, however, was growing in spite of 6 months treatment. We suspected of a co-existing lung cancer because SCC level and standardized uptake value (SUV) in positron emission tomography (PET)-computed tomography (CT) were high. Bronchoscopy was performed but revealed no malignancy. He underwent a right upper lobectomy and the intraoperative pathology indicated NTM with no malignancy. After the operation, SCC levels decreased. This is a rare case with preoperative high SCC level which seemed to be related to NTM lesion.

Proteomic Profiling Reveals the Architecture of Granulomatous Lesions Caused by Tuberculosis and Mycobacterium avium Complex Lung Disease.

Tuberculosis (TB) and Mycobacterium avium complex lung disease (MAC-LD) are both characterized pathologically by granuloma lesions, which are typically composed of a necrotic caseum at the center surrounded by fibrotic cells and lymphocytes. Although the histological characterization of TB and MAC-LD granulomas has been well-documented, their molecular signatures have not been fully evaluated. In this research we applied mass spectrometry-based proteomics combined with laser microdissection to investigate the unique protein markers in human mycobacterial granulomatous lesions. Comparing the protein abundance between caseous and cellular sub-compartments of mycobacterial granulomas, we found distinct differences. Proteins involved in cellular metabolism in transcription and translation were abundant in cellular regions, while in caseous regions proteins related to antimicrobial response accumulated. To investigate the determinants of their heterogeneity, we compared the protein abundance in caseous regions between TB and MAC-LD granulomas. We found that several proteins were significantly abundant in the MAC-LD caseum of which proteomic profiles were different from those of the TB caseum. Immunohistochemistry demonstrated that one of these proteins, Angiogenin, specifically localized to the caseous regions of selected MAC-LD granulomas. We also detected peptides derived from mycobacterial proteins in the granulomas of both diseases. This study provides new insights into the architecture of granulomatous lesions in TB and MAC-LD.

Surgical management of non-cystic fibrosis bronchiectasis.

Non-cystic fibrosis bronchiectasis (bronchiectasis) is an abnormal dilatation of the bronchi and bronchioles, resulting from a prolonged recurrent infectious process due to various causes and predisposing factors. This disease has several etiologies and affects a heterogeneous population of patients. The most important viewpoint for the surgical management of bronchiectasis is to select appropriate candidates for surgery and conduct suitable anatomic lung resections at the right time under appropriate conditions. The ideal candidates for lung resection are symptomatic patients with focal disease due to truly localized bronchial pathology regardless of optimal and absolute medical management.

Pulmonary adenocarcinoma in situ: analyses of a large series with reference to smoking, driver mutations, and receptor tyrosine kinase pathway activation.

Lung adenocarcinomas in situ (AISs) often occur in individuals who have never smoked, although smoking is one of the main causes of lung cancer. To characterize AIS and, in particular, determine how AIS might be related to smoking, we collected a large number of AIS cases and examined clinicopathologic features, EGFR and KRAS mutation status, and activation status of receptor tyrosine kinase downstream signal pathways, including pAkt, pERK, and pStat3, using immunohistochemistry. We identified 110 AISs (36 smokers and 74 nonsmokers) among 1549 adenocarcinomas resected surgically during 1995 to 2010. Between the AIS of smokers and nonsmokers, only the sex ratio was significantly different; all the other clinicopathologic factors including TTF-1 and driver mutations were not significantly different: EGFR and KRAS mutation rates (smokers:nonsmokers) were 61:58 (%) (P=0.7) and 6.1:1.4 (%) (P=0.2), respectively, whereas, in invasive adenocarcinomas, the rates were 41:69 (%) (P<0.001) and 9.4:2.3 (%) (P<0.04), respectively. For pAkt and pERK, around 40% to 50% of AISs were positive, and for pStat3, >80% were positive, with no significant differences between smokers and nonsmokers with AIS. Mucinous AIS (n=8) rarely harbored KRAS mutations and expressed significantly less pStat3 (P<0.001) than nonmucinous AIS. Taken together, AIS occurs predominantly in female individuals and nonsmokers. However, characteristics of AIS arising in smokers and nonsmokers were similar in terms of cell lineage, driver mutations, and receptor tyrosine kinase pathway activation. Our results suggest that smoking is not a major cause of AIS. Rather, smoking may play a role in progression of AIS to invasive adenocarcinoma with AIS features.

[Remarkable improvement in dyspnea following bronchofiberscopic ethanol injection therapy -a case report].

A 69-year-old man with squamous cell carcinoma( SCC) of the left lower lobe of the lung underwent lobectomy. One year later, radiography performed during check-up revealed pneumonia. After 1 week, he was admitted to the hospital because of dyspnea. Three tumors in his trachea and bronchus had narrowed the respiratory tract, and these were diagnosed as recurrence of SCC. The patient was treated with radiation and bronchofiberscopic ethanol injection (BEI) therapy, following which the tumors reduced remarkably in size; he recovered from respiratory insufficiency and was able to go home. He stayed home for 2 months; however, tumor enlargement was detected subsequently and the patient was at risk of suffocation. This time, the patient received combination therapy that included radiation, TS-1, and BEI. Subsequently, his respiratory airway reopened. BEI offers a quick and safe treatment option and has a rapid effect; therefore, we consider it useful for the treatment of malignant tracheobronchial stenosis.

ASCL1-coexpression profiling but not single gene expression profiling defines lung adenocarcinomas of neuroendocrine nature with poor prognosis.

BACKGROUND: Lung adenocarcinoma is heterogeneous regarding histology, etiology and prognosis. Although there have been several attempts to find a subgroup with poor prognosis, it is unclear whether or not adenocarcinoma with neuroendocrine (NE) nature has unfavorable prognosis. MATERIALS AND METHODS: To elucidate whether a subtype of adenocarcinoma with NE nature has poor prognosis, we performed gene expression profiling by cDNA microarray for 262 Japanese lung cancer and 30 normal lung samples, including 171 adenocarcinomas, 56 squamous cell carcinomas and 35 NE tumors. A co-expression gene set with ASCL1, an NE master gene, was utilized to classify tumors by non-negative matrix factorization, followed by validation using an ASCL1 knock-down gene set in DMS79 cells as well as an independent cohort (n=139) derived from public microarray databases as a test set. RESULTS: The co-expression gene set classified the adenocarcinomas into alveolar cell (AL), squamoid, and NE subtypes. The NE subtype, which clustered together almost all the NE tumors, had significantly poorer prognosis than the AL subtype that clustered with normal lung samples (p=0.0075). The knock-down gene set also classified the 171 adenocarcinomas into three subtypes and this NE subtype also had the poorest prognosis. The co-expression gene set classified the independent database-derived American cohort into two subtypes, with the NE subtype having poorer prognosis. None of the single NE gene expression was found to be linked to survival difference. CONCLUSION: Co-expression gene set with ASCL1, rather than single NE gene expression, successfully identifies an NE subtype of lung adenocarcinoma with poor prognosis.

Risk factors that affect the surgical outcome in the management of focal bronchiectasis in a developed country.

BACKGROUND: The purpose of this study was to demonstrate our surgical experience for focal bronchiectasis in the setting of modern diagnostic modalities and state-of-the-art medical treatment in a developed country. METHODS: Thirty-one patients undergoing 33 lung resections for the treatment of focal bronchiectasis from 1991 to 2009 were reviewed. The mean age was 54 years. Twenty-nine patients (94%) were female; 21 patients (68%) had nontuberculous mycobacterial infection; and 22 patients (71%) received preoperative multiple-drug regimens containing clarithromycin. Five patients (16%) were in an immunocompromised status. All were diagnosed by chest computed tomography scan, and either the right middle lobe or left lingula were involved in 29 (94%). The curve for relapse-free interval was estimated by Kaplan-Meier methods. The factors that affected this curve were examined using Cox's regression analysis. RESULTS: Operative morbidity and mortality were 18% and 0%, respectively. All patients became asymptomatic postoperatively. During the median follow-up of 48 months (11 to 216), 8 patients (26%) experienced recurrence, and the mean relapse-free interval was 34 months (3 to 216). By univariate analysis, an immunocompromised status (p=0.017), Pseudomonas aeruginosa infection (p=0.040), the preoperative extent of bronchiectatic lesion (p=0.013), and the extent of residual bronchiectasis after surgery (p=0.003) were significantly associated with the shorter relapse-free interval. By multivariate analysis, an immunocompromised status (p=0.039), Pseudomonas aeruginosa infection (p=0.033), and the extent of residual bronchiectasis (p=0.009) were independent and significant factors. CONCLUSIONS: Complete resection of bronchiectasis while the disease is localized and is free from Pseudomonas aeruginosa infection is the key for a success. Also, immunocompromised status was suggested to be a risk factor.

Percutaneous cardiopulmonary support of video-assisted metastasectomy for a patient with lung cancer following pneumonectomy.

We describe herein a case of a 68-year-old woman with primary lung cancer who had undergone induction chemoradiotherapy and then a right pneumonectomy for non-small cell cancer (adenocarcinoma). Twenty-one months later, the cancer had metastasized to the brain, which was treated with 2-knife radiosurgery. She had been well for up to 32 months; however, the chest radiography and chest computed tomography (CT) demonstrated a nodule in the left upper lobe of the lung that was gradually growing. We preformed a partial resection of the left upper lobe by video-assisted thoracic surgery (VATS) under percutaneous cardiopulmonary support (PCPS), considering the oxygenation requirement of the patient. PCPS was applied via venoarterial (V-A) bypass, and the hemodynamic status of the patient was mostly stable. The postoperative course was uneventful, and the patient has no evidence of metastatic lung cancer, 10 months postoperatively, indicating that the minimally invasive VATS under PCPS was successful and safe. Although few reports have been described and some key questions remain unanswered, the method appears to be promising.

Different morbidity after pneumonectomy: multidrug-resistant tuberculosis versus non-tuberculous mycobacterial infection.

To assess whether there is any difference in postoperative morbidity and mortality after pneumonectomy between patients with multidrug-resistant tuberculosis (MDR-TB) and patients with non-tuberculous mycobacterial (NTM) infections. Between January 2000 and December 2007, 61 patients with MDR-TB and 60 patients with NTM infections underwent 66 and 64 pulmonary resections, respectively. Of these, 33 patients were analyzed who underwent a pneumonectomy, including 22 patients with MDR-TB (seven right, 15 left) and 11 patients with NTM infections (seven right, four left). All bronchial stumps were covered with the latissimus dorsi. Patients with NTM infections were predominantly more female, older, thinner, and presented with a higher frequency of culture-positive sputum at operation than patients with MDR-TB. Operative mortality was zero. Morbidities were bronchial stump dehiscence (n=1) and mycobacterial empyema (n=1) for patients with MDR-TB, and acute respiratory failure (n=1), bronchial stump dehiscence (n=5) and mycobacterial empyema (n=2) for patients with NTM infections. Prevalence of bronchial stump dehiscence was significantly higher in patients with NTM infections (P=0.010). Five of six dehiscences occurred after right pneumonectomy. The optimal management of the bronchial stump in the setting of pneumonectomy for NTM infections needs further investigation.

Activation status of receptor tyrosine kinase downstream pathways in primary lung adenocarcinoma with reference of KRAS and EGFR mutations.

The activation status of signal transduction pathways involving receptor tyrosine kinases and its association with EGFR or KRAS mutations have been widely studied using cancer cell lines, although it is still uncertain in primary tumors. To study the activation status of main components of growth factor-induced pathways, phosphorylated Akt (pAkt), extracellular signal-regulated kinases 1 and 2 (pERK) and other downstream proteins were immunohistochemically examined using surgical samples of 193 primary lung adenocarcinomas. Also, thyroid transcription factor-1 (TTF-1) expression and mutation status of EGFR and KRAS were examined. Advanced tumor stages (p<0.001), negative TTF-1 expression (p<0.001) and Akt activation (p=0.015) were independent and significant poor prognostic markers. Akt activation related to advanced stage (p=0.021), invasiveness (p=0.004), and not to mutations. TTF-1 expression associated with never-smoker (p=0.013), pre- or minimally invasiveness (p<0.001) and EGFR mutations (p=0.017) as well as with pERK (p=0.039) expression. EGFR mutations did not correlated with pAkt and pERK expression, which was different from the results based on cultured cells, while KRAS mutations were solely and significantly linked to ERK activation (p=0.009). In lung adenocarcinoma, tumors with TTF-1 expression have distinct characteristics regarding mutations, signal protein activation and clinical issues. Moreover, this property was revealed to be important in outcome estimation at any tumor stage, whereas Akt activation is abnormally affected according to the tumor stage regardless of their cell origin. The signal proteins were differently related to mutation status from cultured cells.