A chronic high-fat diet does not exacerbate muscle atrophy in fast-twitch skeletal muscle of aged mice.

NEW FINDINGS: What is the central question of this study? Ageing leads to a loss of mass in skeletal muscle, but the effect of obesity on ageing-related muscle wasting is unclear. In this study, we aimed to demonstrate the specific effect of obesity on fast-twitch skeletal muscle in ageing. What is the main finding and its importance? Our findings show that the obesity induced by long-term ingestion of a high-fat diet does not aggravate muscle wasting in fast-twitch skeletal muscle of aged mice, indicating that the present study provides morphological characteristics for skeletal muscle of sarcopenic obesity. ABSTRACT: Obesity and ageing reduce muscle mass and lead to deficits in muscle maintenance, but it is not known whether obesity accelerates muscle wasting additively in the setting of ageing. We investigated morphological characteristics in fast-twitch extensor digitorum longus (EDL) muscle of mice fed a low-fat diet (LFD) or a high-fat diet (HFD) for 4 or 20 months. The fast-twitch EDL muscle was harvested, and the muscle fibre-type composition, individual muscle cross-sectional area and myotube diameter were measured. We found an increase in the percentage of type IIa and IIx myosin heavy chain fibres in the whole EDL muscle, but a decrease in type IIB myosin heavy chain in both HFD protocols. The cross-sectional area and myofibre diameter were lower in both groups of aged mice (after 20 months of LFD or HFD) compared with young mice (after 4 months of the diets), but there were no differences between mice fed LFD or HFD for 20 months. These data suggest that long-term feeding of HFD does not aggravate muscle wasting in fast-twitch EDL muscle of male mice.

Prevalence of coronary calcification on preoperative computed tomography and its management in thoracic surgery.

PURPOSE: We investigated the preoperative assessment of coronary artery calcification using computed tomography for appropriate intraoperative management to reduce the risk of perioperative cardiac complications during pulmonary resection. METHODS: Patients (n = 665) who underwent anatomical lung resection were examined. The extent of preoperative asymptomatic coronary artery stenosis or cardiac complications in patients with coronary artery calcification was assessed. In addition, the risk factors for perioperative cardiac complications were determined. RESULTS: Coronary artery calcification was detected in 233 (35.0%) asymptomatic patients. Nineteen (8.2%) patients with coronary artery calcification had coronary artery stenosis ≥ 75%. Percutaneous coronary intervention was performed preoperatively (n = 3) and postoperatively (n = 10), and preoperative drug intervention was performed in 10 cases. One case of severe postoperative cardiac complications and 20 cases of mild postoperative cardiac complications, including those without coronary artery calcification, occurred. Patients with calcified coronary arteries were at risk of cardiovascular complications in the perioperative period. However, patients with coronary artery calcification who underwent preoperative cardiology intervention had no significant perioperative cardiovascular complications. CONCLUSIONS: Coronary artery calcification detected on preoperative computed tomography is a risk factor for perioperative cardiovascular complications. Early intervention may reduce the risk of such complications.

[Resection of Lung Cancer with Chest Wall Invasion Using Posterior Paramedian Incision].

We report a case of lung cancer with chest wall invasion resected with the posterior paramedian incision. A man in his 60s exhibited hemosputum and cough. Chest X-ray revealed a large mass below the right hilum. A 6.3 cm soft tissue mass with central cavity invading to the lower posterior chest wall was found on chest computed tomography( CT). The tumor was diagnosed as squamous cell carcinoma by transcutaneous lung biopsy( TCLB). Thoracoscopic hilar dissection of the right lower lobe with dissection of the mediastinal lymph nodes were preceded to the en-bloc resection of the invaded chest wall with less invasive manner by the posterior paramedian incision.

Prognostic Impact of the ABCC11/MRP8 Polymorphism in Adjuvant Oral Chemotherapy with S-1 for Non-Small Cell Lung Cancer.

BACKGROUND: Postoperative 1-year administration of S-1, an oral derivative of 5-fluorouracil (5-FU), was shown to be feasible in lung cancer. The 5-year survival rates of postoperative patients treated with S-1 adjuvant chemotherapy and the prognostic impact of clinicopathological factors were examined. METHODS: The data of 50 patients with curatively resected pathological stage IB to IIIA non-small cell lung cancer, who were treated with S-1 postoperatively, were analyzed. The prognostic impacts of 22 clinicopathological factors including expressions of the 5-FU pathway enzymes were evaluated. A single-nucleotide polymorphism (SNP), i.e. 538G>A (rs17822931), of ABCC11/MRP8, which encodes a 5-FU excretion enzyme that is known as an earwax type determinant, was also evaluated. RESULTS: The 5-year overall and relapse-free survival rates were 72.5 and 67.5%, respectively. A performance status ≥ 1, lymphatic vessel invasion, blood vessel invasion, and the A/A type of SNP538, which is responsible for the dry earwax type, were significantly associated with shorter relapse-free survivals. In 34 patients who showed a relative performance of 70% or more for chemotherapy, multivariate survival analysis indicated significant hazard ratios only for the A/A type of SNP538 (p = 0.007). CONCLUSIONS: S-1 has sufficient power as adjuvant chemotherapy. However, its effect might be small in the dry earwax type patient group in an adjuvant setting.

Thoracoscopic versus transsternal resection for early stage thymoma: long-term outcomes.

PURPOSE: This study was undertaken to investigate the efficacy of a video-assisted thoracoscopic (VATS) approach for stage I and II thymoma through comparisons with the transsternal approach. METHODS: The indications for VATS resection were clinical stage I or II thymoma, a tumor less than 50 mm, located within the thymic lobes and separated from the brachiocephalic vein. Data were collected between 1995 and 2007. RESULTS: Twenty-seven patients underwent total thymectomy (15 by VATS and 12 by the transsternal approach). The mean tumor size was 36.3 (22-50) mm for VATS and 37.6 (15-55) mm for the transsternal group (p = 0.7862). The mean lengths of the operation were 249.8 min and 227.9 min (p = 0.2728), respectively. The mean intraoperative blood loss was significantly lower in VATS, at 92.3 ml, than the 225.1 ml lost in the transsternal group (p = 0.0020). The morbidity rates were 13.3 and 8.3% (p = 0.6812), respectively. There was no mortality in either group. The mean follow-up periods were 109.0 (37-145) months following VATS and 102.0 (44-175) months following the transsternal approach. One stage II patient developed pleural dissemination three years after VATS resection. Other patients survived with no recurrence. CONCLUSIONS: VATS resection of early stage thymoma can be performed with less bleeding and with a comparable prognosis to the transsternal approach. VATS resection should thus be considered as a viable option for treatment.

Double vision approach applied by two teams for retrosternal gastric conduit for gastric tube cancer.

Gastric tube cancer is classically treated with resection through a midline sternal incision. However, because of its invasiveness and limited reconstructive potential, transdiaphragmatic laparoscopic or thoracoscopic dissection of the gastric tube has been investigated. As resection from only the abdominal or thoracic cavity is difficult, we performed surgery with a thoracic surgeon approaching from the thoracic cavity and an abdominal surgeon simultaneously approaching from the cervical and abdominal regions. The gastric tube may be tightly adhered to the back of the sternum, cervicothoracic transition or thoracoabdominal transition. Dissection can be safely performed by operating from two directions simultaneously, the neck and chest or chest and abdomen, to successfully withdraw the gastric tube from the abdominal cavity. We performed this surgery in four cases. This collaborative operation provided a good surgical view and allowed for safe dissection of the gastric tube without requiring sternotomy.

Lifetime Follow-Up of a Patient with Metastatic Prostate Cancer Undergoing Multiple Surgical Resections: A Case Report.

BACKGROUND Prostate cancer (PC) often metastasizes after primary resection, and long-term survival following surgical removal of multiple pulmonary metastases is rare. We present a case of a surgeon who demonstrated long-term survival after overcoming repeated surgical challenges for multiple pulmonary metastases from PC. CASE REPORT Twenty-six years ago, a 62-year-old man initially reported discomfort during urination. A prostate examination revealed mildly elevated prostate-specific antigen (PSA) levels. Six months later, PC was diagnosed, and a radical prostatectomy was performed, revealing moderately differentiated adenocarcinoma but no vessel infiltration. At 9 years after the operation, three 10-mm nodules were detected in the right lung. Then, surgical biopsy by wedge pulmonary resection revealed metastatic PC, and therefore, right lower lobectomy including all nodules was planned. Although postoperative maintenance with luteinizing hormone-releasing hormone agonists kept the low PSA levels for 3 years, other newly limited metastases were observed in the opposite left lung, necessitating more surgeries of partial left lung resection. Six years later, a third lung metastasis was detected, as well as mild increases in the tumor size and PSA level, and the patient died 26 years after the initial PC intervention because of malnutrition for 1 year after sustaining bone compression fractures due to a fall, and not due to PC progression. CONCLUSIONS Repeated surgical resections for slow-growing metastatic pulmonary PC was an alternative treatment that facilitated favorable survival and a good quality of life for 26 years in the present case.

Pulmonary Coccidioidomycosis Complicated by Nontuberculous Mycobacterial Pulmonary Diseases with a Literature Review.

Following an endobronchial examination, a young mine supervisor was treated with antibiotics for a pulmonary nontuberculous mycobacterial infection for approximately one year. However, a review of the radiological findings revealed a different possibility. Accordingly, pulmonary resection was performed, and histopathological analysis revealed numerous yeast-like fungi. Since the patient had stayed in the southwestern United States for two months in 2009, eight years previously, coccidioidomycosis was strongly suspected. The diagnosis of coccidioidomycosis was subsequently confirmed by serology and polymerase chain reaction testing of the excised specimen. Here, we report an educational case that emphasizes the importance of meticulous medical history-taking and awareness of endemic mycoses in other countries in the context of globalization.

Adult-onset hereditary pulmonary alveolar proteinosis caused by a single-base deletion in CSF2RB.

BACKGROUND: Disruption of granulocyte/macrophage colony-stimulating factor (GM-CSF) signalling causes pulmonary alveolar proteinosis (PAP). Rarely, genetic defects in neonatal or infant-onset PAP have been identified in CSF2RA. However, no report has clearly identified any function-associated genetic defect in CSF2RB. METHODS AND RESULTS: The patient was diagnosed with PAP at the age of 36 and developed respiratory failure. She was negative for GM-CSF autoantibody and had no underlying disease. Signalling and genetic defects in GM-CSF receptor were screened. GM-CSF-stimulated STAT5 phosphorylation was not observed and GM-CSF-Rßc expression was defective in the patient's blood cells. Genetic screening revealed a homozygous, single-base deletion at nt 631 in exon 6 of CSF2RB on chromosome 22, which caused reductions in GM-CSF dependent signalling and function. Both parents, who were second cousins, showed no pulmonary symptoms, and had normal GM-CSF-signalling, but had a CSF2RB allele with the identical deletion, indicating that the mutant allele may give rise to PAP in an autosomal recessive manner. CONCLUSIONS: This is the first report identifying a genetic defect in CSF2RB that causes deficiency of GM-CSF-Rßc expression and impaired signalling downstream. These results suggested that GM-CSF signalling was compensated by other signalling pathways, leading to adult-onset PAP.

[Minimally invasive surgery for thymic disease].

This study describes minimally invasive surgery using video-assisted thoracic surgery (VATS) for thymic diseases. Our procedure has been changed in the last decade from sternum-lifting thoracoscopic surgery with mini-thoracotomy to complete thoracoscopic surgery. Indications for this method include benign thymic disease, non-invasive thymoma or myasthenia gravis (MG). We performed these procedures for 27 cases, including 12 cases of thymic cyst, 10 cases of thymoma without MG, 3 cases of thymoma with MG and 2 cases of MG alone. In all cases of thymoma, tumor size was less than 5 cm. Complete VATS, VATS with mini-thoracotomy and sternum-lifting VATS were performed in 20, 4 and 3 patients, respectively. Complications were phrenic nerve palsy in 2 cases and postoperative bleeding in 1 case. We always use ultrasonic devices in this procedure. No recurrences have been identified in any cases. Even though definitive evidence is lacking for use of a unilateral approach with VATS for thymoma and MG, VATS thymectomy appears acceptable as a less-invasive procedure with less pain and rapid recovery.

[Leiomyosarcoma of pulmonary artery origin diagnosed preoperatively].

A 59-year-old woman was pointed out isotope uptake at the right pulmonary hilum by positron emission tomography/computed tomography (PET/CT) performed for postoperative follow up of thyroid cancer. Chest enhanced CT showed a mass in the right pulmonary artery, which was diagnosed as sarcoma of pulmonary artery origin by a transcatheter biopsy. Chemotherapy by doxorubicin with anticoagulation therapy was started 1st due to the secondary pulmonary hypertension. Pulmonary hypertension was improved, but the size of the tumor enlarged. She underwent right pneumonectomy with mediastinal dissection. The tumor was completely resected, but brain metastases developed. Postoperative pathological diagnosis was leiomyosarcoma. A rare case of preoperatively diagnosed pulmonary arterial sarcoma was reported.

Preoperative inhalation therapy for patients with chronic obstructive pulmonary disease undergoing lung surgery: a retrospective study.

BACKGROUND: Research shows that even the short-term administration of inhaled drugs immediately before surgery can improve respiratory function in surgical candidates with chronic obstructive pulmonary disease (COPD). However, the long-term efficacies of different types of long-acting inhaled agents when used during a short preoperative period remain unclear. Therefore, we evaluated the efficacies of short-term, preoperative long-acting muscarinic antagonists (LAMAs), inhaled corticosteroids with long-acting ß2-agonists (ICSs/LABAs), and long-acting muscarinic antagonists with long-acting ß2-agonists (LAMAs/LABAs) in patients with COPD after lung resection. METHODS: Patients who underwent anatomical lung resections between April 2010 and March 2020 were divided into the non-COPD (193 patients) and COPD (241 patients) groups. The COPD group underwent preoperative treatment with either a LAMA (51 patients), an ICS/LABA (112 patients), or a LAMA/LABA (78 patients) for almost 1 month, with pulmonary function tests performed initially, just before surgery, and at 1 and 6 months after surgery. Improvement in preoperative respiratory function by inhalation therapy and the maintenance of improvement in respiratory function after surgery were examined in each group. RESULTS: The COPD group had significantly higher proportions of men, older patients, smokers, and histopathologic types except for adenocarcinoma than the non-COPD group; however, there were neither differences in sex, age, percentage of smokers, or histopathologic type among the inhalant groups within the COPD group nor were there differences in percentage of GOLD stage, preoperative inhalation period, or percentage of resected lobes in lobectomy. Preoperative increases in forced expiratory volume in 1.0 s (FEV1.0) were significantly higher in the COPD group (129.07 ± 11.29 mL) than in the non-COPD group (-2.32 ± 12.93 mL) (p < 0.0001). At 6 months, there was no significant difference in residual FEV1.0 between the COPD-LAMA/LABA (2017.46 ± 62.43 mL) and non-COPD groups (2046.93 ± 40.53 mL). The FEV1.0 reduction rate was more suppressed in the COPD-LAMA/LABA group than in the non-COPD group at 1 and 6 months after surgery. CONCLUSIONS: Short-term, preoperative, inhaled pharmacotherapies, particularly LAMAs/LABAs, were effective at improving respiratory function in patients with COPD; thus, these agents are recommended for use in this population.

Protease inhibitor nafamostat mesilate attenuates complement activation and improves function of xenografts in a discordant lung perfusion model.

BACKGROUND: Anti-complement activity of nafamostat mesilate (FUT-175) is strong including its variety of pharmacological effects. The effect of FUT-175 for xenografts in an ex vivo guinea pig-to-rat lung perfusion model was evaluated. METHODS: Heparinized Lewis rat blood was used to perfuse the lungs in three groups (n = 6 each). Group I used Lewis rat left lung for donor, Group X used guinea pig left lung for donor, and Group XF used guinea pig left lung for donor, which was perfused with Lewis rat blood with 0.2 mg/ml of FUT-175. Complement activity causing 50% hemolysis (CH50) in the perfusion blood and pulmonary function either before or during perfusion were serially measured. Pathological assessments of the lungs were also carried out after perfusion. RESULTS: The duration of satisfactory pulmonary function was significantly increased in Group XF. Complement activity causing 50% hemolysis in Group XF decreased more significantly compared to Group X. FUT-175 suppressed both the increase in pulmonary arterial pressure and airway resistance, and the decrease in dynamic lung compliance. In Group X, pathology showed intra-alveolar hemorrhage, perivascular edema, and medial thickening with endothelial swelling of the pulmonary arteries. In Group XF, less changes were observed compared to Group X. Group X showed deposition of IgM, IgG, and C3 at the endothelium of arteries, which was fewer in Group XF, and even fewer in Group I. CONCLUSIONS: This study suggests that FUT-175 inhibited complement activation and improved lung xenograft function. FUT-175 ameliorates hyperacute rejection in a guinea pig-to-rat ex vivo xenogeneic lung perfusion model.

Living-donor lobar lung transplantation for pulmonary alveolar proteinosis in an adult: report of a case.

A 43-year-old woman with pulmonary alveolar proteinosis (PAP) was successfully treated with living-donor lobar lung transplantation (LDLLT). The patient's PAP had been diagnosed at age 35. She had been treated with repeated bronchoalveolar lavage and granulocyte-macrophage colony-stimulating factor (GM-CSF) inhalation therapy despite having no serum anti-GM-CSF autoantibodies. At age 42, her respiratory condition became critical and she underwent transplantation from two donors. While careful observation was needed for the recurrence of PAP in the transplanted lungs, she was functioning well without oxygen therapy 1 year after transplantation. This appears to be the first report of LDLLT for PAP in an adult.

Immediate single lobar retransplantation for primary graft dysfunction after living-donor lobar lung transplantation: Report of a case.

A 24-year-old man with cystic fibrosis underwent living-donor lobar lung transplantation (LDLLT) with grafts donated from his father, who had mild cirrhosis, and his uncle. The graft from his father failed, and retransplantation was required 44 h after LDLLT, using his sister's left lower lobe. The retransplantation was successful; 18 months postoperatively, the recipient and all three donors are doing well. The favorable outcome was achieved owing to the complete assessment of all potential donors in advance, and the appropriate decision to perform retransplantation in a timely manner. Whether this life-saving retransplant procedure for unexpected primary graft dysfunction after LDLLT can be justified requires further experience and a longer follow-up.

Successful Endovascular Treatment for Middle Cerebral Artery Occlusion Caused by the Thrombus Formation in the Pulmonary Vein Stump Following Left Upper Lung Lobectomy.

Thrombus formation in the pulmonary vein (PV) stump after lung resection can cause rare cases of cerebral infarction. These infarctions can result in embolism and ischemia in the relatively large intracranial vessels, severely impacting the quality of life (QOL) of these patients. We performed endovascular thrombectomy successfully for this rare complication after lung lobectomy. A 73-year-old woman with paroxysmal atrial fibrillation (AF) suffered from sudden left complete hemiplegia 19 days after undergoing a left upper lung lobectomy (LUL). Magnetic resonance imaging (MRI) showed middle cerebral artery occlusion. Her left hemiplegia improved after the endovascular thrombectomy. Cardiogenic embolism was first suspected, but contrast-enhanced computed tomography (CECT) showed thrombus formation in the PV stump. We continued anticoagulant therapy, and the thrombus resolved completely two months after the stroke. Our patient had a relatively good outcome due to the immediate reperfusion of the affected area. This embolic source may be overlooked because AF frequently occurs after thoracic surgeries. Care should be taken during the postoperative phase to avoid overlooking these emboli. All thoracic surgeons should be informed about mechanical thrombectomy as an effective treatment for postoperative cerebral infarction.

Multiple focal pure ground-glass opacities on high-resolution CT images: Clinical significance in patients with lung cancer.

OBJECTIVE: The purpose of this study was to evaluate the clinical significance of multiple focal pure ground-glass opacities (GGOs) on high-resolution CT images of patients with lung cancer. MATERIALS AND METHODS: The cases of 23 patients with proven lung cancer and associated multiple focal pure GGOs on high-resolution CT images were retrospectively reviewed. The number, size, distribution, and morphologic characteristics of focal pure GGOs were evaluated. Serial changes in focal pure GGOs that were not surgically resected were analyzed at follow-up high-resolution CT. RESULTS: The number of focal pure GGOs was 196 in total. The size of the opacities ranged from 2 to 30 mm in largest diameter. Lung cancer and focal pure GGOs were seen in the same lobe and/or in the other lobes. One hundred seventy-one of the lesions (87%) had a well-defined border or round shape. Histologic findings were obtained for 15 lesions representing 74 focal pure GGOs that were surgically resected: 11 atypical adenomatous hyperplasia lesions, three bronchioloalveolar carcinomas, and one lesion of focal fibrosis. In 110 of the cases of focal pure GGOs, all of which were followed up with HRCT for a median duration of 1,351 days, the size of 105 lesions (95%) did not change, the size of one decreased, and four lesions disappeared. CONCLUSION: The size of most focal pure GGOs associated with lung cancer did not change during the follow-up period. Most of the small number of lesions histologically diagnosed were atypical adenomatous hyperplasia or bronchioloalveolar carcinoma. These data justify the therapeutic strategy of resecting the primary tumor without therapeutic intervention in the remaining focal pure GGOs.

Expression of keratinocyte growth factor and its receptor in rat tracheal cartilage: possible involvement in wound healing of the damaged cartilage.

Keratinocyte growth factor (KGF) is involved in the development and regeneration of a variety of tissues. To clarify the role of KGF in cartilage wound healing, we examined the expression of KGF and its receptor (KGFR) immunohistochemically in the wound healing area of rat tracheal cartilage, and the direct effect of recombinant KGF on the proliferation and differentiation of primary cultures of rat chondrocytes. KGF was found in the cytoplasm of both chondrocytes and perichondrial cells. On the other hand, KGFR was detected only in the plasma membrane of chondrocytes. Although the expression of KGF was similar in the cartilage and perichondrial area before and after injury, KGFR expression was induced after injury and limited to proliferating chondrocytes. The staining pattern of KGF and KGFR was same in the mature and the immature rat tracheal cartilage. Moreover, in vitro experiments using primary cultured chondrocytes revealed that KGF at 200 ng/ml significantly increased the number of chondrocytes (~1.5-fold), and significantly reduced acid mucopolysaccharide production. These results indicate that KGF stimulates chondrocyte proliferation, suggesting that KGF could therapeutically modulate the wound healing process in the tracheal cartilage.

Thoracoscopic plication of the membranous portion of crescent-type tracheobronchomalacia in an elderly patient: a case report.

BACKGROUND: It is presumed that tracheobronchomalacia in adults is caused by airway pressure-induced injury due to chronic cough related to pulmonary emphysema or chronic bronchitis. Commonly, a posterolateral approach using stabilizing materials is the surgical technique of choice for treating tracheobronchomalacia. We report a case in which thoracoscopic plication of the membranous portion was performed instead of airway stent placement for tracheobronchomalacia in an elderly individual. CASE PRESENTATION: An 87-year-old man who had been treated for bronchial asthma, pulmonary emphysema, and tracheobronchomalacia was admitted to our hospital with acute exacerbation of dyspnea. The patient underwent tracheal intubation, which was followed by tracheostomy 16 days later. Insertion of the tip of the adjustable-length tracheostomy tube to the end of the stenotic lesion enabled him to breathe spontaneously. However, conservative management failed due to recurrent pneumonia caused by the tracheobronchomalacia. Crescent-type tracheobronchomalacia (Johnson's classification grade III) was diagnosed, and the main narrowed area of the trachea was assumed to be approximately 3-10 cm from the tracheal bifurcation. A thoracoscopic approach was selected because a posterolateral approach was considered too invasive considering the patient's age and general condition. We placed eight stitches on the tracheal membranous portion and four stitches on the membranous portion of the right main bronchus, using the horizontal mattress suture technique. The use of foreign materials was avoided because meropenem-resistant Pseudomonas aeruginosa was cultured in a tracheal specimen. Immediately after the operation, the expiratory airway stenosis improved, and subsequently, spontaneous ventilation was possible using a normal type of tracheostomy tube instead of an adjustable-length tracheostomy tube. CONCLUSIONS: Tracheobronchomalacia is not a rare condition in patients with chronic obstructive pulmonary disease. The thoracoscopic approach is less invasive than the posterolateral approach and is suitable in cases that are otherwise refractory to medical treatment. We believe that thoracoscopy may be a useful treatment option in cases where conservative treatment is not appropriate.

Impact of somatic mutations on prognosis in resected non-small-cell lung cancer: The Japan Molecular Epidemiology for lung cancer study.

BACKGROUND: To report the follow up data and clinical outcomes of the JME study (UMIN 000008177), a prospective, multicenter, molecular epidemiology examination of 876 surgically resected non-small-cell lung cancer (NSCLC) cases, and the impact of somatic mutations (72 cancer-associated genes) on recurrence-free survival (RFS) and overall survival (OS). METHODS: Patients were enrolled between July 2012 and December 2013, with follow up to 30th November 2017. A Cox proportional hazards model was used to assess the impact of gene mutations on RFS and OS, considering sex, smoking history, age, stage, histology, EGFR, KRAS, TP53, and number of coexisting mutations. RESULTS: Of 876 patients, 172 had ≥2 somatic mutations. Median follow-up was 48.4 months. On multivariate analysis, number of coexisting mutations (≥2 vs 0 or 1, HR = 2.012, 95% CI: 1.488-2.695), age (≥70 vs <70 years, HR = 1.583, 95% CI: 1.229-2.049), gender (male vs female, HR = 1.503, 95% CI: 1.045-2.170) and pathological stage (II vs I, HR = 3.386, 95% CI: 2.447-4.646; ≥III vs I, HR = 6.307, 95% CI: 4.680-8.476) were significantly associated with RFS, while EGFR mutation (yes vs no, HR = 0.482, 95% CI: 0.309-0.736), number of coexisting mutations (≥2 vs 0 or 1, HR = 1.695, 95% CI: 1.143-2.467), age (≥70 vs <70 years, HR = 1.932, 95% CI: 1.385-2.726), and pathological stage (II vs I, HR = 2.209, 95% CI: 1.431-3.347; ≥III vs I, HR = 5.286, 95% CI: 3.682-7.566) were also significant for OS. CONCLUSION: A smaller number of coexisting mutations, earlier stage, and younger age were associated with longer RFS and OS, while EGFR mutations were significantly associated with improved OS.