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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.

Purpose: The resistance to the EGFR tyrosine kinase inhibitors (TKI) is a major concern in non–small cell lung cancer (NSCLC) treatment. T790M mutation in EGFR accounts for nearly 50% of the acquired resistance to EGFR-TKIs. Earlier studies suggested that T790M mutation was also detected in TKI-naïve NSCLCs in a small cohort. Here, we use an ultra-sensitive droplet digital PCR (ddPCR) technique to address the incidence and clinical significance of pretreatment T790M in a larger cohort.Experimental Design: ddPCR was established as follows: wild-type or T790M mutation-containing DNA fragments were cloned into plasmids. Candidate threshold was identified using wild-type plasmid, normal human genomic DNA, and human A549 cell line DNA, which expresses wild type. Surgically resected tumor tissues from 373 NSCLC patients with EGFR-activating mutations were then examined for the presence of T790M using ddPCR.Results: Our data revealed a linear performance for this ddPCR method (R2 = 0.998) with an analytical sensitivity of approximately 0.001%. The overall incidence of the pretreatment T790M mutation was 79.9% (298/373), and the frequency ranged from 0.009% to 26.9%. The T790M mutation was detected more frequently in patients with a larger tumor size (P = 0.019) and those with common EGFR-activating mutations (P = 0.022), as compared with the others.Conclusions: The ultra-sensitive ddPCR assay revealed that pretreatment T790M was found in the majority of NSCLC patients with EGFR-activating mutations. ddPCR should be utilized for detailed assessment of the impact of the low frequency pretreatment T790M mutation on treatment with EGFR-TKIs. Clin Cancer Res; 21(15); 3552–60. ©2015 AACR.

Supplementary Figures S1-8. Figure S1: Flowchart for mutation call. Figure S2: Quantification of performance of ddPCR analysis for EGFR T790M mutation. Figure S3: Analytical sensitivity of 0.001% for the ddPCR assay. Figure S4: Determination of false-positive events from wild-type control DNA and normal human genomic DNA. Figure S5: Determination of false-positive events in genomic DNA from formalin-fixed paraffin-embedded (FFPE) A549 cells. Figure S6: Detection of EGFR T790M mutant alleles in patients with EGFR T790M-containing primary tumors. Figure S7: Comparison of T790M mutation detection in 6 samples by different operators. Figure S8: Reproducibility of ddPCR analysis from 16 T790M-positive samples.

Supplementary Materials and Methods, Reference and Supplementary Figure Legends

Supplementary Tables S1-5. Table S1: Primers and probes used for droplet digital PCR (ddPCR). Table S2: Determination of the limit of blank (LOB) from wild-type control DNA, normal human genomic DNA, and EGFR wild-type A549 genomic DNA. Table S3: Determination of the limit of blank (LOB) using genomic DNA from adjacent normal tissue samples of EGFR-activating mutation positive adenocarcinoma and EGFR wild-type squamous cell carcinoma. Table S4: Concordance between ddPCR and deep sequencing of EGFR T790M mutation. Table S5: Distribution of amplifiable DNA concentrations in the 377 analyzed samples.

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.

Obesity and aging reduce muscle mass and leads to deficits in muscle maintenance, but it is unknown whether obesity additively accelerates muscle wasting in the setting of aging. The present study investigated morphological characteristics in fast-twitch dominant muscle of mice fed a low-fat diet (LFD) or a high-fat diet (HFD) for 4 or 20 mo. The fast-twitch extensor digitorum longus muscle was isolated, and the composition of muscle fiber type, individual muscle cross-sectional area (CSA), and myotube diameter were measured. Increased the percentage of type IIa myosin heavy chain (MHC) fibers, whereas decreased type IIB MHC in both HFD protocols. The CSA and myofiber diameter were lower in both 20 mo LFD and HFD fed mice compared to 4 mo mice, but there were no differences between 20-mo LFD and HFD-fed mice. These data suggest that long term of HFD feeding does not aggravated muscle wasting in fast-twitch dominant muscle of aged mice.

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.

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, A prospective, multi‐center, molecular epidemiology study of 876 surgically resected non‐small cell lung cancer cases, and the impact of somatic mutations (72 cancer‐associated genes) on recurrence‐free survival and overall survival (OS). A smaller number of co‐existing mutations, earlier stage, and younger age were associated with longer recurrence free survival and OS, while epidermal growth factor receptor mutations were significantly associated with improved OS.

Epidermal growth factor receptor (EGFR) mutations have been used as the strongest predictor of effectiveness of treatment with EGFR tyrosine kinase inhibitors (TKIs). Three most common EGFR mutations (L858R, exon 19 deletion, and T790M) are known to be major selection markers for EGFR-TKIs therapy. Here, we developed a multiplex picodroplet digital PCR (ddPCR) assay to detect 3 common EGFR mutations in 1 reaction. Serial-dilution experiments with genomic DNA harboring EGFR mutations revealed linear performance, with analytical sensitivity ~ 0.01% for each mutation. All 33 EGFR-activating mutations detected in formalin-fixed paraffin-embedded (FFPE) tissue samples by the conventional method were also detected by this multiplex assay. Owing to the higher sensitivity, an additional mutation (T790M; including an ultra-low-level mutation, Highlights • An ultrasensitive multiplex picodroplet digital PCR (ddPCR) assay to detect 3 common EGFR mutations in 1 reaction was developed. • This multiplex mutation detection of common mutations of EGFR is a feasible alternative. • A rare pretreatment EGFR mutation (T790M) with a mutant allele frequency below 0.1% was detected via this multiplex assay. Three most common EGFR mutations (L858R, exon 19 deletion, and T790M) are known to be major selection markers for EGFR-TKI therapy. In this article, we developed a multiplex picodroplet digital PCR (ddPCR) assay to detect 3 common EGFR mutations in 1 reaction with 0.01% sensitivity. All 33 EGFR-activating mutations detected in FFPE samples by the conventional method were also detected by this multiplex assay. Owing to the higher sensitivity, an additional mutation was detected in the same reaction. Results of this proof-of-principle study on clinical samples indicate clinical utility of multiplex ddPCR for screening for multiple EGFR mutations.

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.

Purpose This study was designed to evaluate the feasibility of concurrent induction chemoradiotherapy (CRT) using S-1, an oral fluoropyrimidine derivative, plus cisplatin followed by surgery in locally advanced non-small cell lung cancer (NSCLC). Patients and methods We defined locally advanced NSCLC as pathologically proven chest wall invasion or hilar and/or mediastinal lymph node metastases by endobronchial ultrasound-guided transbronchial needle aspiration. Twenty-three patients were enrolled in this study from May 2011 to April 2014. The patients received S-1 40mg/m 2 orally twice daily on days 1 through 14 and 29 through 42, and cisplatin 60mg/m 2 was injected intravenously on days 8 and 36. The patients also underwent radiotherapy and received a total dose of 40Gy in 20 fractions beginning on day 1. Surgical resection was performed from 4 to 6 weeks after completion of the induction treatment. Results Of the 23 eligible patients, 18 had stage IIIA and 5 had stage IIB NSCLC. Twenty patients (87.0%) completed induction CRT and underwent surgical resection. Representative grade 3 adverse reactions were neutropenia (21.7%) and leukocytopenia (8.7%); no grade 4 adverse reactions were observed. Radiologically, 7 (30.4%) of the 23 patients achieved partial response and were therefore radiologically downstaged. Twenty patients were curatively resected. Six (26.1%) complete responses were identified and 12 cases (52.2%) were histopathologically downstaged by induction CRT. Conclusion Concurrent induction CRT using S-1 plus cisplatin is a feasible and promising new treatment modality for locally advanced NSCLC. Evaluation of histopathological downstaging revealed sufficient anti-cancer effects for preoperative treatment. MicroAbstract Because chemoradiotherapy (CRT) using cisplatin and S-1, an oral fluoropyrimidine, is effective for unresectable non-small cell lung cancer, the feasibility of this therapy in a neoadjuvant setting was evaluated in a multicenter phase II study. Toxicities were very mild and 87.0% of the 23 patients completed induction CRT. This protocol seems feasible and is considered an option among preoperative therapies.

Purpose: The resistance to the EGFR tyrosine kinase inhibitors (TKI) is a major concern in non–small cell lung cancer (NSCLC) treatment. T790M mutation in EGFR accounts for nearly 50% of the acquired resistance to EGFR-TKIs. Earlier studies suggested that T790M mutation was also detected in TKI-naïve NSCLCs in a small cohort. Here, we use an ultra-sensitive droplet digital PCR (ddPCR) technique to address the incidence and clinical significance of pretreatment T790M in a larger cohort. Experimental Design: ddPCR was established as follows: wild-type or T790M mutation-containing DNA fragments were cloned into plasmids. Candidate threshold was identified using wild-type plasmid, normal human genomic DNA, and human A549 cell line DNA, which expresses wild type. Surgically resected tumor tissues from 373 NSCLC patients with EGFR-activating mutations were then examined for the presence of T790M using ddPCR. Results: Our data revealed a linear performance for this ddPCR method (R2 = 0.998) with an analytical sensitivity of approximately 0.001%. The overall incidence of the pretreatment T790M mutation was 79.9% (298/373), and the frequency ranged from 0.009% to 26.9%. The T790M mutation was detected more frequently in patients with a larger tumor size (P = 0.019) and those with common EGFR-activating mutations (P = 0.022), as compared with the others. Conclusions: The ultra-sensitive ddPCR assay revealed that pretreatment T790M was found in the majority of NSCLC patients with EGFR-activating mutations. ddPCR should be utilized for detailed assessment of the impact of the low frequency pretreatment T790M mutation on treatment with EGFR-TKIs. Clin Cancer Res; 21(15); 3552–60. ©2015 AACR.

The operative morbidity rate in elderly patients with lung cancer is high in comparison to nonelderly patients, probably because of the increase in comorbidities that occurs with aging. However, previous reports were retrospective and were performed at single institutions; thus, the preoperative comorbidities and operative morbidity could not be fully assessed. We conducted a multi-institutional prospective observational study of elderly patients (>75 years of age) with a completely resected non–small cell lung cancer. From March 2014 to April 2015, 264 patients from 22 hospitals affiliated with the National Hospital Organization in Japan were prospectively registered in the present study. The primary end point was operative morbidity (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0). The secondary end points were operative mortality and the risk factors for operative morbidity. Preoperative comorbidities were assessed according to the Adult Comorbidity Evaluation-27 index. The mean age at the time of surgery was 79.3 years (range 75-90 years). Forty-one percent of the patients were >80 years of age. Twenty-six percent underwent sublobar resection. The incidence of morbidities of any grade was 43.2% (90% confidence interval: 38.2%-48.2%). Respiratory system-related morbidity (19.3%), followed by cardiovascular system-related morbidity (10.2%), was the most common morbidity. The in-hospital mortality rate was 1.1% (3 of 264 patients). A multivariate analysis of the risk factors for operative morbidity showed that both Adult Comorbidity Evaluation-27 grade and the blood loss volume were significant factors. The results of the present prospective multi-institutional study should be used as a reference in the surgical treatment of elderly patients with lung cancer.

Although follow-up surveillance after resection for lung cancer is commonly performed in clinical practice, there is no standard follow-up program. We attempted to establish follow-up examination schedules that we considered would be acceptable to the majority of doctors, and would like to propose them as standard postoperative follow-up pathways.We carried out a retrospective analysis of patients' data and reviewed the time of detection of recurrence and the site of recurrence after resection. Published papers were also reviewed. The postoperative follow-up pathways were established based on these data.The follow-up period was set at as 5 years after resection, and physical examinations, chest radiography, chest CT and blood examination are recommended. Two follow-up pathways were proposed taking the risk of recurrence into consideration: the Risk of recurrence-based pathway and the Comprehensive pathway. In the Risk of recurrence-based pathway, the follow-up examination schedule is modified according to the risk of recurrence. In the Comprehensive pathway, a single universal examination schedule is recommended for all patients. The choice between these two pathways is left to the discretion of the attending doctor.We proposed two follow-up pathways, based on retrospective analysis of patients' data and a review of published papers, which we considered would be acceptable to the majority of doctors and would be suited to the current medical environment in Japan. A prospective study to evaluate the efficacy of the follow-up pathways is ongoing.

Objectives: Chest tube insertion seems to be one important factor leading to intercostal nerve impairment. The purpose of this prospective study was to objectively evaluate intercostal nerve damage using current perception threshold testing in association with chest tube insertion. Methods: Sixteen patients were enrolled in this study. Intercostal nerve function was assessed with a series of 2000-Hz (Aβ fiber), 250-Hz (Aδ fiber), and 5-Hz (C fiber) stimuli using current perception threshold testing (Neurometer CPT/C R). Current perception threshold values at chest tube insertion were measured before surgery, during chest tube insertion and after removal of the chest tube. Intensities of ongoing pain were also assessed using a numeric rating scale (0-10). Results: Current perception thresholds at each frequency after surgery were significantly higher than before surgery. Numeric rating scale scores for pain were significantly reduced from 3.3 to 1.9 after removal of the chest tube (p = 0.004). The correlation between current perception threshold value at 2000 Hz and intensity of ongoing pain was marginally significant (p = 0.058). Conclusions: This is the first study to objectively evaluate intercostal nerve damage at chest tube insertion. The results confirmed that chest tube insertion has clearly deleterious effects on intercostal nerve function., General Thoracic and Cardiovascular Surgery, 62(1), pp.58-63; 2014

A rare case of a patient with primary adenocarcinoma of the middle lobe bronchus that was successfully treated with rigid bronchoscopy followed by middle sleeve lobectomy is reported. The patient was a 75-year-old man who presented with low-grade fever and cough. Chest computed tomography showed obstructive pneumonia of the lower lobe and a polypoid lesion in the truncus intermedius. Middle sleeve lobectomy and mediastinal lymphadenectomy were performed following recovery of respiratory function after partial resection of the tumor with rigid bronchoscopy. There was no sign of tumor recurrence and metastasis over 32 months of follow-up. We should be aware of tracheal or bronchial tumor in patients with prolonged asthma-like symptoms. Palliative resection with rigid bronchoscopy was useful to make the correct diagnosis, evaluate the extent of the tumor, and protect the right lower lobe.

We report a rare case of a papillary fibroelastoma (PFE) in the apex of the left ventricle.An 81-year-old woman with nonspecific symptoms was shown to have a mobile mass deep in the left ventricle. With videoscopic assistance, removal of the mass was accomplished through the mitral valve via a midline sternotomy under cardiopulmonary bypass. The tumor arose from a miniature tendinous chord in the apex, and histological examination revealed PFE. Videoscopy facilitated safe and effective removal of the lesion in this case.

Background: Lung transplantation cases have immunosuppression maintained using a calcineurin inhibitor, anti-metabolites, and steroid. Case Report: We report 2 clinical cases in which anti-metabolites (mycophenolate mofetil) were successfully withdrawn after living donor lobar lung transplantation by monitoring immune function using the ImmuKnow® assay. In the first case, a 43-year-old woman underwent living donor lobar lung transplantation for pulmonary alveolar proteinosis. Two healthy relatives donated a lower lobe each. Immunosuppression was maintained using tacrolimus, mycophenolate mofetil, and steroid. Six months posttransplantation, she developed invasive pulmonary aspergillosis. During anti-fungal treatment, we withdrew mycophenolate mofetil and tacrolimus trough levels were kept around 8 ng/mL. Despite the resulting low-level immunosuppression, the ImmuKnow assay showed immune function to be in the moderate range with tacrolimus and steroid alone, encouraging us to maintain this strategy to avoid recurrence of invasive pulmonary aspergillosis. In the second case, a 24-year-old man underwent living donor lobar lung transplantation for cystic fibrosis. Two healthy relatives donated a lower lobe each. Immunosuppression was maintained using tacrolimus, mycophenolate mofetil, and steroid. Five months posttransplantation, he developed persistent Pseudomonas aeruginosa pneumonia derived from the paranasal sinuses. Under ImmuKnow assay monitoring, mycophenolate mofetil was withdrawn, but immune function was maintained within the moderate range using tacrolimus and steroid alone. Discussion: Respiratory function in both cases was maintained; no findings of bronchiolitis obliterans syndrome were noted during this period. To the best of our knowledge, no reports have described successful anti-metabolite withdrawal in lung transplantation with ImmuKnow monitoring. Immune evaluation by ImmuKnow could offer a useful method to monitor and control immune status, particularly among recipients susceptible to infection, revealing that moderate immune function could be maintained using tacrolimus and steroid in living donor lobar lung transplantation., Transplantation Proceedings, 45(1), pp.356-359; 2013

Purpose Oncogenic driver mutations are critical for lung cancer development and serve as therapeutic targets. However, their associations with environmental factors are not fully understood. We aimed to elucidate the relationship between tumor developmental biology and exposure to environmental factors. Patients and Methods This was a prospective, multicenter, molecular epidemiology study. Eligible patients were those with newly diagnosed stages I to IIIB non–small-cell lung cancer (NSCLC) who underwent surgery. The tumors were examined for somatic mutations in 72 cancer-associated genes by targeted deep sequencing, estrogen receptor β (ERβ) expression using immunohistochemical staining, and infection with any of 37 types of human papillomavirus (HPV) using a polymerase chain reaction–based microarray system. Detailed information on patient demographics and environmental factors was obtained from a comprehensive questionnaire. Results From July 2012 to December 2013, 957 patients were enrolled, and molecular analyses were performed on 876 samples (from 441 ever- and 435 never-smokers). Oncogenic driver mutations in P53 and KRAS increased proportionally with smoking status, whereas mutations in EGFR and SMAD4 decreased. KRAS mutations in smokers and SMAD4 mutations were observed more frequently in proportion to body mass index. TP53 and NFE2L2 mutations were observed more frequently in advanced NSCLC stages. As for never-smokers, no environmental factors were significantly associated with mutational changes. EGFR mutations and TP53 mutations were observed more frequently in women and in men, respectively. Mutations in these two genes were also potentially associated with ERβ expression. Only three patients (0.3%) were HPV positive. Conclusion The mutational spectrum is associated with smoking, body mass index, and other environmental factors, as well as with ERβ expression. Little association was observed between HPV and NSCLC.

We herein report an unusual case of invasive thymoma with venous intraluminal extension. The thymoma extended into the superior vena cava, the left brachiocephalic vein, and the proximal portion of the left jugular and subclavian veins intraluminally. It was suggested that the tumor had a discrete intravascular growth via the thymic vein into the left brachiocephalic vein and extended into the proximal portion of the left jugular and subclavian veins in the opposite direction of the venous stream.

Background: Oral adjuvant chemotherapy without hospitalization might reduce the physiological and psychological burden on patients if effectiveness could be guaranteed. We conducted a multicenter feasibility study using S-1, an oral derivative of 5-fluorouracil, as postoperative adjuvant chemotherapy in patients with curatively resected pathologically stage IB-IIIA non-small-cell lung cancer. Patients and Methods: Adjuvant chemotherapy comprised 8 courses (4-week administration, 2-week withdrawal) of S-1 at 80-120 mg per day. Fifty-one patients from 7 institutions were enrolled in this pilot study, from June 2005 to March 2007. The primary end point was the completion rate of scheduled adjuvant chemotherapy. Secondary end points were the incidence and grade of adverse reactions. Results: Fifty patients were eligible. The completion rate for the planned 8 courses of S-1 administration was 72.0% (36 patients). Total percentage administration amount was 71.1%. Grade 3 adverse reactions such as neutropenia (4.0%), anorexia (4.0%), thrombopenia (2.0%), anemia (2.0%), elevated total bilirubin (2.0%), hypokalemia (2.0%), nausea (2.0%), and diarrhea (2.0%) were observed, but no grade 4 adverse effects were encountered. Overall and relapse-free survival rates at 3 years were 87.7% and 69.4%, respectively. Conclusions: Postoperative 1-year administration of S-1 seems feasible as oral adjuvant chemotherapy for lung cancer. The oral formulation and low incidence of adverse reactions permit treatment on an outpatient basis. The present study would be reasonable to follow up with a properly powered phase III trial., Clinical Lung Cancer, 13(6), pp.464-469; 2012

Tagawa T. Protease inhibitor nafamostat mesilate attenuates complement activation and improves function of xenografts in a discordant lung perfusion model. Xenotransplantation 2011; 18: 315–319. © 2011 John Wiley & Sons A/S. Abstract: 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.

Objective: Chronic pain is a common complication after thoracic surgery. The most important factor appears to be intercostal nerve damage. The purpose of this prospective study was to objectively evaluate intercostal nerve damage associated with post-thoracotomy pain after three surgical procedures using current perception threshold testing. Methods: The 32 patients were classified into three groups: the video-assisted thoracic surgery group (n=7), the video-assisted minithoracotomy with metal retractors group (n=15), and the conventional thoracotomy group (n=10). Intercostal nerve function was assessed by a series of 2000-Hz (Aβ fiber), 250-Hz (Aδ fiber), and 5-Hz (C fiber) stimuli using current perception threshold testing (Neurometer CPT/C(®)). The current perception threshold values were measured before and 1, 2, 4, 12, and 24 weeks after surgery. The intensities of ongoing pain were also assessed using a numeric rating scale (0-10). Results: The video-assisted thoracic surgery group showed no changes in any current perception threshold values and no residual pain more than 12 weeks after surgery. The video-assisted minithoracotomy with metal retractors group and the conventional thoracotomy group showed significantly higher current perception threshold values at 2000Hz 1 week after surgery (p=0.0013, p=0.0012, respectively), with pain in approximately 70% of patients 12 weeks after surgery. The correlation between current perception threshold values at 2000Hz and the intensities of ongoing pain 4 and 12 weeks after surgery was significant (p=0.03, p=0.04, respectively). Conclusions: This is the first study that objectively evaluated pain after video-assisted thoracic surgery. The results suggest that the Aβ and Aδ fibers play a significant role in the development of intercostal nerve damage. The current perception threshold values clearly demonstrated that video-assisted thoracic surgery is a less-invasive procedure resulting in less post-thoracotomy pain and, they have some possibilities to objectively evaluate the ongoing pain after surgery., European journal of cardio-thoracic surgery, 39(6), pp.1033-1039; 2011

The aim of this study was to evaluate the clinical outcomes of chest wall reconstruction using a new, expanded polytetrafluoroethylene prosthesis, 'DualMesh'. Between December 2005 and March 2010, chest wall reconstruction using 2-mm DualMesh was performed in 11 patients. The indication for resection was primary lung cancer in six patients, malignant mesothelioma in one patient, recurrent lung cancer in one patient, recurrent invasive thymoma in one patient, postirradiated osteomyelitis in one patient, and chondro-hamartoma in one patient. The mean observation period was 23 months, and four cases were observed for more than three years. There were no operative deaths and no wound infections. There were two postoperative complications: prolonged air leakage occurred in a patient with pulmonary emphysema who underwent right lower lobectomy, and slight paradoxical respiration occurred in the patient who underwent resection of the entire sternal body for osteomyelitis. Follow-up chest computed tomography was performed routinely. No dehiscence occurred in any cases. Chest wall reconstruction using DualMesh demonstrated acceptable durability and biocompatibility, even after long-term follow-up. DualMesh has the potential to become an ideal prosthesis for the bony chest wall as an alternative to conventional polytetrafluoroethylene or polypropylene grafts.

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.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.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.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.

8549Background: We previously reported molecular profiling as a primary endpoint in a prospective multicenter molecular epidemiology study, collecting 876 surgically resected NSCLC and examining 72...

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., Acta Histochemica et Cytochemica, 43(3), pp.89-98; 2010

Cystic fibrosis (CF) is rare in Japan. We encountered a CF case with drug-resistant Pseudomonas aeruginosa infection and successfully performed lung transplant from living related donors. A combination of betalactams and aminoglycosides for drug-resistant P. aeruginosa infection was administered before lung transplantation. Intravenous colistin was also used immediately before and after transplant surgery. Gram staining of respiratory specimens was performed every day after surgery and it was useful in monitoring infection status. Strict monitoring of infections by the Gram staining and culture of respiratory specimens is considered to be effective in preventing lower respiratory infection in lung transplantation., Internal Medicine, 49(21), pp.2353-2358; 2010

Diffuse alveolar hemorrhage (DAH) syndrome is potentially fatal. We encountered a nearly fatal case of DAH possibly due to intravenous itraconazole (ITCZ). A 53-year-old man with chronic pulmonary aspergillosis underwent pneumonectomy of the left lung 15 days prior to the onset of DAH, which was confirmed by bronchoalveloar lavage. The battery of diagnostic evaluations performed revealed no other positive etiological factor, leading to the diagnosis of DAH possibly induced by intravenous ITCZ with a positive drug lymphocyte stimulation test. The patient did not respond to pulse methylprednisolone therapy, but responded dramatically to direct hemoperfusion using a polymyxin B-immobilized fiber column (PMX) therapy., Internal Medicine, 49(5), pp.497-500; 2010

60歳男性．胸部単純写真で左下肺野に腫瘤影を指摘された．CTでは左下葉に径15cmの巨大腫瘤を認め，肺門・縦隔リンパ節腫大も認めた．CTガイド下肺生検にて肺多形癌と診断された．cT3N2M0 Stage III Aで，腫瘍の急速な増大と血痰を繰り返すため，手術を施行した．巨大な腫瘍により下葉の可動性はなく肺静脈処理を先行させることは困難であり，葉間肺動脈，下葉気管支，舌区気管支，舌区静脈の順に処理し，最後に下肺静脈をステープラで切離した．その後，右橈骨動脈ラインの圧波形が平底化し，触知不能，冷感が出現し，塞栓閉塞を疑った．術後血管造影で上腕動脈の閉塞を認め，緊急塞栓除去術を施行した．血管内腔は腫瘍栓で閉塞しており，病理診断でも腫瘍塞栓であった．肺切除術に伴う腫瘍塞栓はまれであるが，肺静脈に浸潤が疑われる症例では，術前の評価方法や術中の操作に考慮すべき点がある．

背景．HIV感染者に発症する肺癌は海外において近年増加傾向にあるが，本邦における手術報告例は少ない．症例．57歳男性．肺炎を契機にHIV陽性と診断され，HAART（highly active antiretroviral therapy）内服開始となった．HIV感染診断5年後の胸部単純写真で左上肺野に結節影を指摘された．胸部CTでは左S1+2に21 mm大の結節を認め，PETでも同部と肺門リンパ節に集積が見られた．気管支鏡下擦過細胞診で診断は得られなかったが肺癌を強く疑った（cT1N1M0，stage IIA）．血液曝露を少なくする目的もあり胸腔鏡下左上葉切除術を施行した．最終病理診断は腺癌で，進行度はpT1N2M0，stage IIIAであった．経過は良好で術後9日目に退院した．周術期を通じて職業感染対策のため血液曝露の機会を極力少なくするなど工夫を行った．結論．HIV感染合併肺癌でもHIV感染が良好に制御されていて全身状態が良好であれば通常と同様に手術が可能である．胸腔鏡下手術は血液汚染が少なく，感染防止に有用であった．

Distant metastasis of benign pleomorphic adenoma of salivary glands rarely occurs, and these neoplasms have been termed metastasizing pleomorphic adenoma. We present a rare case of metastasizing pleomorphic adenoma of the submandibular gland with lung and bone metastases obtained MR images and pathological findings. On MRI, the lesions were depicted as an area of high signal intensity on T2-weighted images (WI), reflecting myxoid or/and chondroid matrices. Metastasizing pleomorphic adenoma should be considered as a differential diagnosis when a pulmonary lesion shows high signal intensity on T2-WI and the patient has a medical history of salivary pleomorphic adenoma., European Journal of Radiology Extra, 72(2), pp.e69-e72; 2009

BACKGROUND: The present study aimed to elucidate the relationship between microvessel count (MVC) according to CD34 expression and prognosis in intrahepatic cholangiocarcinoma (ICC) patients who underwent hepatectomy based on our preliminary study. METHODS: Relationships between MVC and clinicopathological factors were examined in 37 ICC patients. CD34 expression was analyzed using immunohistochemical methods. RESULTS: Median MVC for ICC patients was 140/mm(2), which was applied as a cutoff value. Lower MVC was significantly associated with larger tumor size, periductal infiltrating type, and advanced Japanese tumor-node-metastasis stage (p < 0.05). Univariate survival analysis identified higher carcinoembryonic antigen level, periductal infiltrating type, poor histological differentiation, and lower MVC as significantly associated with lower 5-year survival rates. The 5-year survival rate in the higher-MVC group was significantly greater than that in the lower-MVC group (44% vs. 7%, p = 0.048). According to Cox multivariate survival analysis, only periductal infiltrating type on macroscopic examination was identified as a significant independent risk factor for poor survival after hepatectomy (risk ratio 4.8; p = 0.006), not MVC (1.1; p = 0.82). CONCLUSION: Tumor MVC might offer a useful prognostic marker of ICC patient survival after hepatectomy and further investigation in a larger series is warranted., Annals of Surgical Oncology, 16(8), pp.2123-2129; 2009

A 68-year-old Japanese man with Sjögren's syndrome was pointed out to have a nodular shadow in the anterior mediastinum. The tumor was resected under video-assisted thoracoscopy and it was pathologically diagnosed to be thymic mucosa-associated lymphoid tissue (MALT) lymphoma. There has been no recurrence for 17 months after surgery. Mucosa-associated lymphoid tissue lymphoma of the thymus is rare, and its pathological diagnosis requires sufficient knowledge and experience. Since thymic MALT lymphoma is distinct from MALT lymphoma of other sites in several ways, including gene abnormalities and geographic distribution, an alternative oncogenic pathway and the influence of racial and/or environmental factors must be considered to be involved. However, since the number of reported thymic MALT lymphomas is limited, these issues are still unclear. The accumulation of further similar cases will help to elucidate various issues concerning thymic MALT lymphoma associated with Sjögren's syndrome.

PURPOSE The treatment strategy for patients with non–small-cell lung cancer (NSCLC) involving ipsilateral mediastinal lymph nodes is still controversial. We performed a phase II feasibility study of induction chemotherapy followed by surgery for patients with pathologic N2 NSCLC. PATIENTS AND METHODS Patients with mediastinoscopy- positive stage IIIA N2 NSCLC received 2 cycles of cisplatin 80 mg/m2, vinorelbine 25 mg/m2, and mitomycin-C 8 mg/m2. Patients without progressive disease underwent thoracotomy and lobectomy with lymph node dissections 2-4 weeks later. RESULTS From January 2000 to July 2004, 24 eligible patients (15 men, 9 women) were enrolled. Induction chemotherapy was completed as planned in 23 patients (95.8%). Hematological toxicity was the primary grade 3/4 toxicity. Twelve (50%) patients achieved a partial response. Twenty-three patients underwent surgical resection, and complete resection was achieved in 22 patients (95.7%). There were no surgery-related deaths. Pathologic complete response in metastatic lymph nodes was achieved in 5 patients. With a median follow-up of 5.4 years (range, 2.88-7.7 years), the estimated 5-year survival was 51.8% (95% CI, 41.3-62.3) and progression-free survival was 46.6% (95% CI, 36–57.2). CONCLUSION Induction chemotherapy followed by surgery for patients with pathologic N2 NSCLC was feasible and associated with high response to lymph node metastasis and good survival.

Bronchoscopic lung volume reduction (BLVR) for severe emphysema is less invasive than lung volume reduction surgery. Fibroblast growth factor-2 (FGF-2) has been reported to enhance fibrogenesis and angiogenesis. The aim of this study was to investigate the feasibility of BLVR with the FGF-2, and ability to reduce lung volume and promote recovery of lung function. The BLVR based on FGF-2 is less invasive than surgical procedures, and can be performed repeatedly if the effectiveness of volume reduction is inadequate. This simple bronchoscopic approach allows selective reduction in the volume of the emphysematous parenchyma, and intratracheal administration of FGF-2 induces an increase in pulmonary blood flow, thus allowing recovery of pulmonary function.

肺に穿破した縦隔成熟型奇形腫の2症例を経験し，その病因，臨床像について文献的考察を加え報告する．症例1は19歳女性．前胸部痛で来院，胸部CTで径3cmの前縦隔腫瘍を指摘され成熟型奇形腫の診断で手術を行った．手術所見では腫瘍は右肺上葉と強固に癒着しており，上葉部分切除および心膜合併切除を伴う腫瘍切除術を行った．組織学的には腫瘍は豊富な膵組織を有する成熟型奇形腫で，肺実質内に穿破していた．症例2は35歳女性．右胸部痛と血痰で来院，胸部X線で右中肺野に腫瘤影を指摘され，胸部CT，MRIで前縦隔奇形腫が疑われた．術中所見では腫瘍は右肺に穿破しており中葉切除を伴う腫瘍切除術を施行した．組織学的診断で成熟型奇形腫の肺内穿破と診断した．本疾患は多彩な臨床症状を呈し，確定診断に苦慮することも多いが今回MRIが有用であった．

症例は31歳，男性．生来健康であった．嚥下時の違和感が出現し持続するため近医受診した．胸部単純写真にて気管の右方偏位，CTにて上縦隔腫瘍を指摘され，精査加療目的に当科紹介となった．術前に確定診断を得ることができず，手術を施行したところ微小甲状腺癌の縦隔リンパ節転移であり，甲状腺左葉切除，左頚部郭清，縦隔腫瘍切除，左反回神経切除と再建，気管8リング合併切除再建を行った．術後経過は良好で，気管縫合不全や狭窄などの合併症はなく軽快退院した．現在術後12ヵ月経過したが，明らかな再発を認めず外来にて経過観察中である．縦隔腫瘍の鑑別疾患として，甲状腺癌の縦隔リンパ節転移も念頭においた精査が必要であると思われた．

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.