松田 安史

PURPOSE: Whereas native lung overinflation has been thought to happen in recipients of single lung transplantation for lymphangioleiomyomatosis because of its increased compliance, there is no study that has reported the details on the change of the native lung volume after single lung transplantation by three-dimensional computed tomography volumetry. The purpose of the present study was to evaluate the lung volume after single lung transplantation for lymphangioleiomyomatosis by three-dimensional computed tomography volumetry and investigate the correlation between the native lung volume change and postoperative pulmonary function. METHODS: We retrospectively reviewed the data of 17 patients who underwent single lung transplantation for lymphangioleiomyomatosis. We defined the ratio of the native lung volume to total lung volume (N/T ratio) as an indicator of overinflation of the native lung. In order to assess changes in the N/T ratio over time, we calculated the rate of change in the N/T ratio which is standardized by the N/T ratio at 1 year after single lung transplantation: rate of change in N/T ratio (%) = {(N/T ratio at a certain year)/(N/T ratio at 1 year)- 1}× 100. RESULTS: We investigated the correlations between the N/T ratio and the pulmonary function test parameters at 1 year and 5 years; however, there was no significant correlation between them. On the other hand, there was a significant negative correlation between the rate of change in the N/T ratio and that in forced expiratory volume in 1 second %predicted (%FEV1) at 5 years after single lung transplantation. CONCLUSION: The single lung transplantation recipients for lymphangioleiomyomatosis showed increased rate of change in the N/T ratio in the long-time course after lung transplantation with the decrease of %FEV1. We expect that these cases will probably cause the overinflation of the native lung in the future.

This study aimed to investigate the unique antioxidative effects of Japanese moringa products, herbal leaf tea and stem tea, using established free radical assays, focusing on superoxide anion (O2-) radical generation systems. Hot-water extracts from moringa teas resulted in different but lower scavenging activities than Trolox in four synthetic free radical models. Interestingly, these extracts further showed higher O2- radical scavenging effects than Trolox in the phenazine methosulfate-NADH-nitroblue tetrazolium and xanthine oxidase assay systems. Incubating human neutrophils in the presence of these tea extracts rather than Trolox effectively suppressed cellular O2- radical generation. Among the eight known phenolic constituents of moringa leaves, caffeic acid and chlorogenic acid may be responsible for the O2-specific radical scavenging capacity stronger than that of Trolox. These results suggest that moringa herbal teas are a good source of natural antioxidants for preventing O2- radical-mediated disorders. Abbreviations: O2-: superoxide anion; ROS: reactive oxygen species; H2O2: hydrogen peroxide; XOD: xanthine oxidase; DPPH: 1,1-diphenyl-2-picrylhydrazyl; ABTS+: 2,2'-azinobis(2-ethylbenzothiazoline-6-sulfonic acid) cation; CPZ+: chlorpromazine cation; PMS: phenazine methosulfate; NBT: nitroblue tetrazolium; PMA: phorbol 12-myristate 13-acetate.

© 2018 Elsevier Inc. Background and Objectives: To treat organ transplant patients with mycobacterial infection, physicians need to pay attention to interaction between drugs used against mycobacteria and immunosuppressants. The purpose of this report is to describe the clinical features of and treatment for mycobacterial infection in lung transplant (LTx) recipients. Methods: To investigate the incidence, treatment, and outcome for mycobacterial infection, we retrospectively reviewed 100 LTx recipients in our program since 2000. Results: Four recipients (4.0%) developed mycobacterial infection. Three recipients took tacrolimus, and 1 received cyclosporine with mycophenolate mofetil and a steroid for immunosuppression. Tuberculosis (TB) was isolated from 2 recipients, and non-tuberculous mycobacteriosis (NTM) was detected in the other 2. We treated the patients with levofloxacin + isoniazid + pyrazinamide + ethambutol (EB) for TB and clarithromycin (CLM) + EB for NTM to avoid interaction of calcineurin inhibitors (CNI: 8-10 ng/mL in trough level) with rifampicin (RFP). In treating the patients with NTM, we were able to maintain an adequate blood concentration of CNI by decreasing the dosage from one-half to one-quarter. All mycobacterial infections were controlled with treatment. In 1 patient with chronic obstructive pulmonary disease (COPD) infected with TB in the native lung, the forced expiratory volume in 1 second (FEV1) unexpectedly increased from 1890 mL before infection to 2320 mL possibly due to organization of the native lung. Conclusions: We were able to manage the mycobacterial infections using drugs other than RFP without any cases of acute rejection under adequate immunosuppression. Organization of the native lung with TB infection unexpectedly resulted in improvement of FEV1 in a COPD patient.

PURPOSE: Lung transplantation is accepted as an effective modality for patients with end-stage pulmonary lymphangioleiomyomatosis (LAM). Generally, bilateral lung transplantation is preferred to single lung transplantation (SLT) for LAM because of native lung-related complications, such as pneumothorax and chylothorax. It remains controversial whether SLT is a suitable surgical option for LAM. The objective of this study was to evaluate the morbidity, mortality and outcome after SLT for LAM in a lung transplant center in Japan. METHODS: We reviewed the records of 29 patients who underwent SLT for LAM in our hospital between March, 2000 and November, 2017. The data collected included the pre-transplant demographics of recipients, surgical characteristics, complications, morbidity, mortality and survival after SLT for LAM. RESULTS: The most common complication after SLT for LAM was contralateral pneumothorax (n = 7; 24.1%). Six of these recipients were treated successfully with chest-tube placement and none required surgery for the pneumothorax. The second-most common complication was chylous pleural effusion (n = 6; 20.7%) and these recipients were all successfully treated by pleurodesis. The 5-year survival rate after SLT for LAM was 79.5%. CONCLUSION: LAM-related complications after SLT for this disease can be managed. SLT is a treatment option and may improve access to lung transplantation for patients with end-stage LAM.

In the original publication, Fig. 3 has been incorrectly published. The correct version of Fig. 3 is given in this Correction.

Both glandular papilloma (GP) and sclerosing pneumocytoma (SP) are rare tumors in the lung. We herein report an extremely rare case of coexistence of these two uncommon tumors. The patient was a 40-year-old Japanese woman with no chief complaint. A solitary nodule of the lung was detected using chest computed tomography. The transbronchial biopsy revealed that the tumor histologically corresponded to GP. The patient subsequently underwent partial resection of the right upper lobe. Histological examination of the resected specimens further revealed that the mass contained two different and independent elements and displayed typically histological features of GP and SP. Molecular analysis further revealed the presence of BRAF V600E and AKT1 E17K mutations in GP, whereas only AKT1 mutation was detected in SP. To our knowledge, this is the first case of coexistence of GP and SP in the bronchiole harboring common AKT1 mutation and different BRAF V600E mutational status.

Inhaled drugs are critical for the treatment of inflammatory airway diseases such as chronic obstructive pulmonary disease (COPD). To develop better therapeutics for pulmonary disease it is of potential importance to understand molecular mechanisms of local biotransformation in the lung. Alveolar epithelial type II (ATII) cells have a key role in homeostasis in the lung, but little is known about expression patterns of genes encoding cytochrome P450 (CYP) enzymes in ATII cells. In addition, alteration of CYP gene expression has not been fully defined in COPD. We previously established a method to purify ATII cells from the adult human lung using fluorescence-activated cell sorting. By employing this technique we determined gene expression patterns of 14 CYP enzymes in ATII cells from nonsmokers (n = 4) and smokers (n = 4), both having normal pulmonary function. Although most CYP genes are highly expressed in primary hepatocytes, we found that CYP1B1 mRNA expression was 7.2-fold higher in ATII compared to hepatocytes (P = .0275). Additionally we noted a 3.0-fold upregulation of CYP2C19 and 50% reduction in CYP2J2 mRNA expressions in ATII cells isolated from patients with COPD (n = 3) compared to smokers without COPD (n = 4). These data, for the first time, detail a comprehensive set of genes encoding CYP enzymes in human ATII cells and highlights differentially expressed CYP mRNAs of patients with COPD. Such understanding may have important implications for the development of novel inhaled drugs.

Background and Aim: Vasohibin-1 (VASH1) is an angiogenesis inhibitor synthesized and secreted by endothelial cells, whose expression is induced by angiogenic stimuli such as vascular endothelial growth factor. We have previously demonstrated that VASH1 is immunohistochemically evident in endothelial cells in the tumor microenvironment of patients with non-small cell lung cancer (NSCLC) and is positively correlated with that of vascular endothelial growth factor in cancer cells. Here, we determined the preoperative plasma concentration of VASH1 in patients with NSCLC and evaluated the association between the preoperative VASH1 levels and certain outcomes. Methods: We analyzed presurgical plasma VASH1 concentrations in a total of 79 lung cancer patients (51 males and 28 females; 34-83 y of age; 46 adenocarcinomas, 27 squamous cell carcinomas, and 6 other types) who underwent lung resection. The impact of preoperative VASH1 level was analyzed using clinical characteristics and prognosis. Results: Plasma VASH1 concentration ranged from 34.1 to 1190.4 fmol/mL. We divided the patients into 3 groups according to plasma VASH1 level for this assessment: low VASH1 group (n = 26), medium VASH1 group (n = 27), and high VASH1 group (n = 26). The death and recurrence rates of the high, medium, and low VASH1 groups were 5.5, 16.2, and 12.7 per 100 person-years, respectively. Multivariate adjusted hazard ratio of death and recurrence of the high VASH1 group was lower than that of the low VASH1 group (hazard ratio 0.42; 95% CI 0.17-0.99). Conclusion: The present analysis suggests that high preoperative plasma VASH1 concentration is associated with better prognosis in patients with NSCLC. We propose preoperative VASH1 level as a biomarker for the prognosis of patients with non-small cell lung carcinoma.

BACKGROUND: Lung transplantation is an effective treatment modality for respiratory failure. Chronic lung infections, including infections caused by nontuberculous mycobacteria (NTM) and Aspergillus, are difficult to control, and uncontrolled infections are relative contraindications for lung transplantation. However, few reports have documented the incidence and outcome of these infections in lung transplant recipients. METHODS: To quantify the incidence and outcomes of colonization and disease caused by NTM and aspergillosis in recipients before and after lung transplantation, we reviewed the medical records and microbiology data from 240 consecutive cadaveric lung transplant recipients between 2000 and 2014. RESULTS: Before lung transplantation, NTM and Aspergillus species were isolated from five (2.1%) and six (2.5%) patients, respectively, out of the total 240 recipients. All patients with NTM infection received treatment, resulting in culture conversion. They had no recurrence after lung transplantation. All patients with aspergillosis received treatment, one of whom had recurrence after lung transplantation. Over a median follow-up period of 3.3 years, NTM species were isolated after transplantation from eight of 240 patients (3.3%). Five of these patients met the criteria for NTM disease, and four of them received treatment. Four patients survived without a worsening of NTM disease. Over the same median follow-up period, Aspergillus species were isolated from seven of 240 patients (2.9%), six of whom received treatment. CONCLUSIONS: Isolation of NTM or Aspergillus species from lung transplant recipients is uncommon. Adequate pre-transplant control and post-transplant management of NTM and Aspergillus infections allows for safe lung transplantation.

BACKGROUND: Lung transplantation is the final lifesaving option for patients with pulmonary complications after hematopoietic stem cell transplantation (HSCT). Patients undergoing HSCT for hematologic diseases are thought to be high-risk candidates for lung transplantation; therefore, few lung transplants are performed for these patients, and few studies have been reported. This study aimed to describe the characteristics and outcomes of lung transplantation in patients with pulmonary complications after HSCT. METHODS: We retrospectively investigated 62 patients who underwent lung transplantation after HSCT. All data were collected from 6 lung transplant centers in Japan. RESULTS: Seventeen patients underwent cadaveric lung transplantation, whereas 45 underwent living-donor lobar lung transplantation (LDLLT). In the LDLLT group, 18 patients underwent LDLLT after HSCT in which one of the donors had also served as a donor for HSCT. Seven patients underwent single LDLLT for which the donor was the same as the patient from whom stem cells were obtained for HSCT. Preoperative hypercapnia was observed in 52 patients (84%). Thirteen patients (21%) required mechanical ventilation preoperatively. Fifty-five patients underwent HSCT for hematologic malignancies, and 4 (7%) relapsed after lung transplantation. The 5-year survival rate was 64.2%. In a multivariable analysis, patients younger than 45 years and those with the same donor for both procedures exhibited significantly better survival (P = 0.012 and 0.041, respectively). CONCLUSIONS: Lung transplantation for pulmonary complications after HSCT was performed safely and yielded better survival, especially in younger recipients for whom both lung transplantation and HSCT involved the same donor.

Background: Mycophenolic acid (MPA) treatment requires therapeutic drug monitoring to improve the outcome after organ transplantation. The aim of this study was to compare two methods, a particle enhanced turbidimetric inhibition immunoassay (PETINIA) and a reference liquid chromatography tandem mass spectrometry (LC-MS/MS) for determining plasma MPA concentrations from Japanese lung transplant recipients. Methods: Plasma MPA concentrations were determined from 20 Japanese lung transplant recipients using LC-MS/MS and the PETINIA on the Dimension Xpand Plus-HM analyzer. Results: The mean MPA concentration measured by PETINIA was significantly higher than that measured by LC-MS/MS (3.26 ± 2.73 μg/mL versus 2.82 ± 2.71 μg/mL, P < 0.0001). The result of the Passing Bablok analysis was a slope of 1.104 (95% confidence interval [CI], 1.036-1.150) and an intercept of 0.229 (95%CI, 0.144-0.315). Bland-Altman analysis revealed PETINIA overestimates plasma MPA concentration by 26.25% and 95%CI from 21.43 to 31.07%. Conclusion: The measurement of MPA by the PETINIA in Japanese lung transplant patients should evaluate the result with attention to positive bias.

Bronchiolitis obliterans after lung transplantation is a major cause of postoperative mortality in which T cell-mediated immunity is known to play an important role. However, the exact contribution of natural killer (NK) cells, which have functions similar to CD8(+) T cells, has not been defined. Here, we assessed the role of NK cells in murine bronchiolitis obliterans through heterotopic tracheal transplantations and found a greater percentage of NK cells in allografts than in isografts. Depletion of NK cells using an anti-NK1.1 antibody attenuated bronchiolitis obliterans in transplant recipients compared with controls. In terms of NK cell effector functions, an improvement in bronchiolitis obliterans was observed in perforin-KO recipient mice compared to wild type (WT). Furthermore, we found upregulation of NKG2D-ligand in allografts and demonstrated the significance of this using grafts expressing Rae-1, a murine NKG2-Dligand, which induced severe bronchiolitis obliterans in WT and Rag-1 KO recipients. This effect was ameliorated by injection of anti-NKG2D blocking antibody. Together, these results suggest that cytotoxicity resulting from activation of NK cells through NKG2D leads to the development of murine bronchiolitis obliterans.

A cross-sectional study is conducted with primary residents attended wet labs at Tohoku University Hospital Advanced Medical Training Center in order to investigate the efficacy of the training, especially focused on the animal ethics. The 41 participants answered questionnaires in regard to non-technical skills, technical skills and ethics before and after the practice. To identify differences in each ethical question between 2 time points, Wilcoxon signed ranks test was used because the data was not normally distributed. As the result of it, all animal ethical questions showed significant differences(0.0016≤p≤0.0380, α=0.05 level of significance). Beside them, only 1 out of 5 general ethical questions showed it (p=0.0137). This outcome verified that the lecture of animal ethics and the observation of animal care in this center fixed in the training curriculum clearly induced participants' psychological movements.

Objective. Pleomorphic carcinoma of the lung is a histological type that was first proposed in 1999. This tumor is rare and accounts for approximately 1.6-2.6% of all cases of lung cancer thus, to date, few studies have described the clinical course of surgical cases. Methods. The characteristics, treatments, histological parameters, and outcomes of 13 patients with pleomorphic carcinoma of the lung who underwent pulmonary resection at Tohoku University from 2007 to 2013 were studied. Results. The ages of the patients ranged from 41 to 84 years (mean, 67 years male, n=9 female, n=4). Lobectomy and partial resection were performed for 11 (bilobectomy, n= 1) and 2 patients, respectively. Seven patients experienced postoperative recurrence within 6 months 5 of the 7 patients died. Disease-free survival ranged from 38 to 2, 801 days (median, 562 days). One patient with single brain metastasis at the time of the initial diagnosis underwent pulmonary resection and received gamma knife treatment. Relapse was observed at the supraclavicular lymph node and was treated with chemotherapy. A complete response was achieved, and this patient remains alive without evident disease at 1, 816 days. Conclusion. Although pleomorphic carcinoma of the lung has a poor prognosis and the efficacy of chemotherapy in treating it is unclear, our results indicate that a sub-section of the population may show a good prognosis.

BACKGROUND: Recurrent hepatocellular carcinoma accompanied by a right atrial tumor thrombus is rare. No standard treatment modality has been established. Surgical treatment may be the only curative treatment; however, surgery has been considered high risk. We herein describe a patient who underwent resection of a recurrent right atrial tumor thrombus under normothermic cardiopulmonary bypass on a beating heart. CASE PRESENTATION: A 60-year-old man underwent a right hepatectomy for hepatocellular carcinoma with diaphragm invasion. During the preoperative cardiac screening, he was diagnosed with an old myocardial infarction with triple-vessel coronary disease. Percutaneous coronary intervention was performed for the left anterior descending artery and left circumflex coronary artery. High-grade stenosis remained in his right coronary artery. Nine months later, computed tomography showed recurrent hepatocellular carcinoma in the diaphragm and a tumor thrombus extending from the suprahepatic inferior vena cava into the right atrium. Surgical resection of the recurrent tumor was performed through a right subcostal incision with xiphoid extension and median sternotomy. The recurrent tumor was incised with the diaphragm and pericardium. Intraoperative ultrasonography revealed that the tumor thrombus was free from right atrium wall invasion and that the right atrium could be clamped just proximal to the tumor thrombus. The right atrium, infrahepatic vena cava, left and middle hepatic veins, and hepatoduodenal ligament were encircled. Cardiopulmonary bypass was performed to prevent ischemic heart disease caused by intraoperative hypotension. Total hepatic vascular exclusion was then performed under normothermic cardiopulmonary bypass on heart beating. The inferior vena cava wall was incised. The tumor thrombus with the diaphragmatic recurrent tumor was resected en bloc. The patient had a favorable clinical course without any complications. CONCLUSION: The recurrent hepatocellular carcinoma in the diaphragm and the right atrial tumor thrombus were safely resected using normothermic cardiopulmonary bypass on heart beating.

PURPOSE: To compare the outcomes and efficacy of awake video-assisted thoracic surgery (VATS) with those of chemical pleurodesis for intractable secondary spontaneous pneumothorax (SSP). METHODS: We analyzed, retrospectively, 60 consecutive patients who underwent awake VATS (n = 22) or chemical pleurodesis (n = 38) for SSP. Using propensity score matching, we identified comparable patient groups (n = 12 each): the awake VATS group and the chemical pleurodesis group. We compared hematologic data on postoperative day 1, postoperative complications including respiratory complications, and the maximum score on the verbal rating scale (VRS) between the groups. Next, we identified comparable patient groups (n = 8 each) for those with controlled air leak after treatment, but not for those with a prolonged air leak. We analyzed data about the day of air leak control, intra-thoracic drainage, and hospital stay to compare awake VATS vs. chemical pleurodesis. RESULTS: After propensity score matching, the rates of recurrent pneumothorax and prolonged air leaks after conservative or surgical treatment were not significantly different. The C-reactive protein level and the VRS score were significantly lower in the awake VATS group. The duration of prolonged air leak, and drainage after treatment were significantly shorter in the awake VATS group. The postoperative hospital stay and the incidence of postoperative complications did not differ between the groups. CONCLUSIONS: We advocate that awake VATS, performed by a skilled thoracic surgeon, is a more feasible surgical option than chemical pleurodesis for patients with intractable SSP.

Lung transplantation is getting to be a common treatment for the end-stage respiratory failure. Therefore we might encounter the various issues associated with infection under immunosuppression. At 1st, virus infections occur by Cytomegalovirus, Epstein-Barr virus, hepatitis B and C virus and John Cunningham virus. The 2nd, bacterial infections exacerbate graft condition by methicillin-resistant Staphylococcus aureus, Pseudomonas, Burkholderia cepacia and coagulase negative staphylococci. The 3rd, fungal infections are induced by Aspergillus, Candida and Cryptococcus. Lastly there is mycobacterial infection. These opportunistic infections contribute poor prognosis for lung transplant recipients, so that we have to manage these infectious diseases.

BACKGROUND: Increasing evidence suggests that interleukin (IL)-17A plays an important role in chronic lung allograft dysfunction (CLAD), characterized by airway and lung parenchymal fibrosis, after lung transplantation. Halofuginone is a plant derivative that has been shown to inhibit Th17 differentiation. The purpose of this study was to examine the effect of halofuginone on CLAD development using a minor alloantigen‒mismatched mouse orthotopic lung transplant model. METHODS: C57BL/6 recipient mice received an orthotopic left lung transplant from C57BL/10 donors, mismatched for minor antigens. Lung transplant recipients received daily intraperitoneal injections of 2.5 μg halofuginone or vehicle alone. Lung grafts were assessed on Days 7, 14, and 28 post-transplant. RESULTS: Compared with control mice, on Day 28 post-transplant, lung grafts of mice treated with halofuginone showed a significant reduction in the percentage of obliterated airways (6.8 ± 4.7% vs 52.5 ± 13.8%, p < 0.01), as well as significantly reduced parenchymal fibrosis (5.5 ± 2.3% vs 35.9 ± 10.9%, p < 0.05). Immunofluorescent staining for IL-17A demonstrated a decreased number and frequency of IL-17A‒positive cells in halofuginone-treated lung grafts on Day 28, as compared with controls. Halofuginone treatment also decreased IL-17A and IL-22 transcripts at Day 14, transforming growth factor-β1 and matrix metalloproteinase-2 transcripts at Days 14 and 28. CONCLUSION: The beneficial effect of halofuginone on development of airway and lung parenchymal fibrosis in the mouse lung transplant model highlights the important role of IL-17A in CLAD and merits further pre-clinical and clinical studies.

Chronic lung allograft dysfunction, the major cause of death following lung transplantation, usually manifests as irreversible airflow obstruction associated with obliterative bronchiolitis (OB), a lesion characterized by chronic inflammation, lymphoid neogenesis, fibroproliferation and small airway obliteration. Spleen tyrosine kinase (Syk), a tyrosine kinase that regulates B cell function and innate immunity, has been implicated in the pathogenesis of chronic inflammation and tissue repair. This study evaluated the role of Syk in development of OB, using anintrapulmonary tracheal transplant model of OB with the conditional Syk-knockout Syk(flox/flox) // rosa26-CreER(T2) mice and a Syk-selective inhibitor, GSK2230413. BALB/c trachea allografts were transplanted into Syk-knockout (Syk(del/del)) mice or wild-type C57BL/6 recipients treated with GSK2230413. At day 28, histological analysis revealed that in the Syk(del/del) and GSK2230413-treated C57BL/6 recipients, the graft lumen remained open compared with allografts transplanted into Syk-expressing (Syk(flox/flox)) and placebo control-treated C57BL/6 recipients. Immunofluorescence showed lymphoid neogenesis with distinct B and T cell zones in control mice. In contrast, lymphoid neogenesis was absent and few B or T cells were found in Syk(del/del) and GSK2230413-treated mice. These observations suggest that inhibition of Syk may be a potential therapeutic strategy for the management of OB following lung transplantation.

Pneumonia in elderly people is mainly caused by silent aspiration due to an age-related impairment of cough and swallowing reflexes. Because most of the patients with lung cancer are elderly people, we hypothesized that the age-related impairment of these protective reflexes might exist or occur in patients undergoing lung surgery, and cause postoperative pneumonia. We revealed that many elderly patients showed depressed swallowing reflex even before surgery and transient attenuation of cough reflex after surgery, and that postoperative pneumonia occurred only in the patients whose cough and/or swallowing reflex was abnormal postoperatively. Then, we prospectively showed that 30 elderly patients who received perioperative intensive oral care, including professional assessment of oral status, dental cleaning, and patient education for self-oral care by dentists, followed by intensive oral care by intensive care unit nurses, and encouragement of self-oral care by floor nurses, did not develop pneumonia after lung resection. In this study, we retrospectively reviewed the execution status of professional oral care by dentists and the occurrence of postoperative pneumonia in 159 consecutive patients aged 65 or older undergoing lung resection from 2013 to 2014. Thoracic surgeons in our institute asked dentists to provide professional oral care before lung resection only in 30.3% of the subjects in 2013, and 45.8% in 2014. Postoperative pneumonia occurred in 3 out of 76 subjects(3.9%)in 2013, and 1 out of 83(1.2%) in 2014. In 2013, 1 patient who did not receive preoperative professional oral care developed aspiration pneumonia postoperatively followed by acute exacerbation of idiopathic pulmonary fibrosis and in-hospital death. We need to make an effective system to provide preoperative professional oral care by dentists especially for elderly patients and high-risk patients before lung resection.

Pulmonary arterial hypertension after arterial switch operation for transposition of the great arteries is an infrequent but life-threatening complication. We report successful lung transplantation in a case of pulmonary hypertension after arterial switch operation. Cardiopulmonary bypass outflow was established through the right subclavian and femoral arteries because of the previous arterial switch operation. Abnormal anatomy and severe pleural and pericardial adhesions as a result of previous operations resulted in prolonged graft ischemic and operation times. Despite delayed left heart adaptation and primary graft dysfunction requiring prolonged extracorporeal membrane oxygenation, the recipient was eventually discharged without activity limitations.

The pulmonary extraction from a brain-dead donor is one of the important elements for the success of lung transplantation, but the current scarcity of practical training opportunities is a major problem. We performed a simulation of the donor surgery of multiple organs using a pig with other extraction teams to provide more training opportunities. The effectiveness of this simulation lies in its potential to improve the surgical procedure;furthermore, it may solve problems associated with communicating with other extraction teams. However, it is difficult to judge whether the donor lung is suitable for transplantation, as it would be inappropriate to use such a lung for simulation in training. Since this simulation system is considered to be effective to solve various problems in the current donor surgery, it should be available more frequently to improve a technical level of the donor surgery and to aid surgeons in the rapid implementation of next-generation techniques.

Lung cancer patients with cardiovascular complications often require antithrombotic therapy. In this study, we discuss the present conditions and future problems associated with the perioperative management of such patients. We examined 36 lung cancer patients undergoing surgery who received antithrombotic therapy for cardiovascular complications. Twenty-one patients were administered unfractionated heparin in the perioperative period (heparin group). Fifteen patients were not administered unfractionated heparin in the perioperative period (no-heparin group). No significant intergroup differences were observed in operating time, intraoperative blood loss, duration of chest tube placement, and the number of hospitalization days. However, 2 serious cases of thromboembolism developed after surgery. One was a case of pulmonary thromboembolism and the other was one of superior mesenteric artery thromboembolism. These results suggest that the appropriate perioperative usage of heparin enables the standard surgical treatment of lung cancer patients with cardiovascular complications. We recommend the use of low-molecular-weight heparin or low-dose unfractionated heparin as the antithrombotic agent after lung cancer surgery.

PURPOSE: The aim of this work was to establish a novel orthotopic human non-small cell lung cancer (NSCLC) murine xenograft model by a nonsurgical, transbronchial approach. DESCRIPTION: Male athymic nude mice and human NSCLC cell lines, including A549, H460, and H520 were used. Under direct visualization of the vocal cords, a 23-gauge blunt-tip slightly curved metal catheter was introduced into the trachea to the bronchus, and 2.5×10(5) tumor cells mixed with Matrigel (BD Biosciences, Mississauga, Ontario, Canada) were administered into the lung. Mice were monitored using weekly microcomputed tomography scans for tumor formation. EVALUATION: When the tumor size reached more than 4 mm in diameter, the animals were euthanized, and the tumor tissue was evaluated histopathologically. Of 37 mice studied, 34 were confirmed to have tumor formation: 29 developed solitary tumors and 5 had multifocal lesions. There was no evidence of extrapleural dissemination or effusion. CONCLUSIONS: Transbronchial delivery of tumor cells enabled the establishment of a novel orthotopic human NSCLC murine xenograft model. This clinically relevant preclinical model bearing a solitary nodule is of value for a variety of in vivo research studies.

Purpose. The aim of this work was to establish a novel orthotopic human non-small cell lung cancer (NSCLC) murine xenograft model by a nonsurgical, transbronchial approach. Description. Male athymic nude mice and human NSCLC cell lines, including A549, H460, and H520 were used. Under direct visualization of the vocal cords, a 23-gauge blunttip slightly curved metal catheter was introduced into the trachea to the bronchus, and 2.5 x 10(5) tumor cells mixed with Matrigel (BD Biosciences, Mississauga, Ontario, Canada) were administered into the lung. Mice were monitored using weekly microcomputed tomography scans for tumor formation. Evaluation. When the tumor size reached more than 4 mm in diameter, the animals were euthanized, and the tumor tissue was evaluated histopathologically. Of 37 mice studied, 34 were confirmed to have tumor formation: 29 developed solitary tumors and 5 had multifocal lesions. There was no evidence of extrapleural dissemination or effusion. Conclusions. Transbronchial delivery of tumor cells enabled the establishment of a novel orthotopic human NSCLC murine xenograft model. This clinically relevant preclinical model bearing a solitary nodule is of value for a variety of in vivo research studies. (C) 2014 by The Society of Thoracic Surgeons

The purpose of the study was to examine the effect of lentivirus-mediated IL-10 gene therapy to target lung allograft rejection in a mouse orthotopic left lung transplantation model. IL-10 may regulate posttransplant immunity mediated by IL-17. Lentivirus-mediated trans-airway luciferase gene transfer to the donor lung resulted in persistent luciferase activity up to 6 months posttransplant in the isograft (B6 to B6); luciferase activity decreased in minor-mismatched allograft lungs (B10 to B6) in association with moderate rejection. Fully MHC-mismatched allograft transplantation (BALB/c to B6) resulted in severe rejection and complete loss of luciferase activity. In minor-mismatched allografts, IL-10-encoding lentivirus gene therapy reduced the acute rejection score compared with the lentivirus-luciferase control at posttransplant day 28 (3.0 +/- 0.6 vs. 2.0 +/- 0.6 (mean +/- SD); p=0.025; n=6/group). IL-10 gene therapy also significantly reduced gene expression of IL-17, IL-23, and retinoic acid-related orphan receptor (ROR)-t without affecting levels of IL-12 and interferon- (IFN-). Cells expressing IL-17 were dramatically reduced in the allograft lung. In conclusion, lentivirus-mediated IL-10 gene therapy significantly reduced expression of IL-17 and other associated genes in the transplanted allograft lung and attenuated posttransplant immune responses after orthotopic lung transplantation.

BACKGROUND: The timing of disease onset may affect the prognosis in chronic lung allograft dysfunction (CLAD). The relationship between the timing of disease onset and the prognosis of CLAD and its sub-types, bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), was examined. METHODS: Clinical records and pulmonary function data of 597 patients who underwent bilateral lung transplantation from 1996 to 2010 and survived for >3 months were examined. RESULTS: Among 155 patients with a final diagnosis of BOS, patient survival after disease onset was significantly different according to disease-onset timing (BOS onset/post-BOS median survival: overall/1,438 days; <1 year/511 days; 1-2 years/1,199 days; 2-3 years/1,403 days; >3 years/did not reach median survival; p < 0.0001). The prognosis of RAS was generally poorer than that of BOS (overall post-RAS median survival, 377 days). Treating non-CLAD, CLAD, BOS, and RAS as time-dependent covariates, recipient sex-adjusted and age-adjusted Cox regression analysis demonstrated an overall mortality risk of BOS (reference: no CLAD) of 6.7 (95% confidence interval, 4.6-9.9). However, when patients survived 3 years without CLAD, the mortality risk of subsequent BOS was only 1.9 (95% confidence interval, 0.8-4.4) compared with no CLAD. The number of RAS patients was too small to obtain sufficient power to estimate time-dependent mortality risk. CONCLUSION: Late-onset BOS showed a better prognosis than early-onset BOS. Studies that do not distinguish BOS from RAS may overestimate the mortality risk of BOS. Multicenter studies will be required to further elucidate risk factors toward the development of better management strategies for CLAD.

BACKGROUND: Obliterative bronchiolitis after lung transplantation is associated with intrapulmonary lymphoid neogenesis. The purpose of this study was to examine the role of lymphoid neogenesis, especially its relationship with secondary lymphoid organs (SLOs) in allograft airway rejection. METHODS: A murine intrapulmonary tracheal transplant model and a conventional subcutaneous tracheal transplant model were tested using wild-type control mice and splenectomized lymphotoxin α knockout (LT) mice deficient in SLOs as recipients. RESULTS: In both subcutaneous and intrapulmonary tracheal transplant models using wild-type animals, tracheal isografts remained open without rejection, whereas allografts showed progressive luminal obliteration after transplantation. Lymphoid neogenesis containing alloreactive T cells was observed in the lungs, which received an intrapulmonary tracheal allograft. Despite a lack of SLOs, intrapulmonary allografts in splenectomized LT mice were rejected and obliterated by day 28, but the rejection of subcutaneous allografts was significantly delayed. Extensive lymphoid neogenesis was observed in the lungs of both intrapulmonary and subcutaneous allograft LT recipients. Increased proliferation of CD4 T cells and B220 B cells was observed in the lungs but not in the thymus or bone marrow. CONCLUSIONS: Intrapulmonary lymphoid neogenesis is capable of mounting alloimmune responses without SLOs. Tracheal allograft rejection occurs as efficiently as in wild-type animals when it is placed in the lungs. Tracheal allograft rejection in the subcutaneous tissue occurs in a delayed manner without SLO in association with intrapulmonary lymphoid neogenesis.

BACKGROUND: Plasma lactate has been used as a marker of poor prognosis in clinical conditions. However, the relationship between lactate production and lung function during acellular normothermic ex vivo lung perfusion (EVLP) is unclear. We investigated the kinetics of lactate metabolism during EVLP and the correlation of this marker with outcomes after transplant. METHODS: Human donor lungs in our clinical EVLP trial (CLs; n = 28) and rejected donor lungs for experimental use (Els; n = 8) were perfused ex vivo using the Toronto technique. Lactate level, lactate/pyruvate (L/P) ratio, and glucose level in the perfusate were measured. In CLs, we examined the relationship between lactate metabolism during EVLP and early post-transplant outcomes. The hypoxia-inducible factor 1 sub-unit 1α (HIF-1α) level in lung tissue was examined in ELs. RESULTS: We performed double-lung EVLP in CLs and single-lung EVLP in ELs. In CLs, the lactate and L/P ratios at the end of EVLP had no correlation with early post-transplant outcomes despite lactate elevation during EVLP. Although lactate elevation was also present in all ELs, we were able to identify 2 groups based on L/P ratio at the end of EVLP. The group with the high L/P ratio had higher airway pressure during EVLP and higher HIF-1α in lung tissue at the end of EVLP. CONCLUSIONS: Lactate increases seen in the EVLP perfusate most often represent physiologic lactate production by the lung in a setting with reduced lactate clearance. Thus, patients who underwent transplantation after EVLP had good outcomes despite lactate elevation during EVLP.

Background. Lymphoid neogenesis is associated with the development of chronic lung allograft dysfunction (CLAD). Activation of stromal resident cells may be an important mechanism of lymphoid neogenesis. Methods. Twenty CLAD lungs explanted for retransplantation were immunohistochemically examined for lymphoid neogenesis, ectopic lymphoid chemokines, and dendritic cells (DCs). Formation of peripheral lymph node addressin (PNAd)+ high endothelial venule (HEV)-like vessels was examined in 134 transbronchial biopsies taken over 2 years posttransplant from 20 consecutive lung transplant recipients. Results. CLAD lungs were characterized by higher grades of CXCL12 in alveolar (P=0.002) and airway epithelial cells (P=0.001), CCL21 + lymph vessels (P=0.01), and infiltration of DC-specific intercellular adhesion molecule-grabbing nonintegrin + immature DCs (P=0.056) than normal control lungs. Activation of stromal resident cells in CLAD lungs was highlighted by formation of lymphoid-like stroma including expression of CCL21 and CXCL13, fibroblastic reticular-like cells and DC-specific lysosome-associated membrane protein+ mature DCs in association with a significantly larger number of lymphoid aggregates (P&lt;0.001) with lymphangitc distribution compared with normal lungs. A larger number of PNAd+ HEV-like vessels were also observed outside of lymphoid aggregates with a lymphangitic distribution (P&lt;0.001). HEV-like vessels in transbronchial biopsies were more graded in lungs that eventually developed CLAD (n=7) than those that did not (n=13) by 3 years after transplantation (P=0.001). Conclusion. Lymphoid neogenesis associated with CLAD accompanies activation of stromal resident cells and formation of lymphoid-like stroma. Induction of PNAd+ HEV-like vessels occurs before the manifestation of CLAD.

We report a patient with left apical lung carcinoma involving the left subclavian artery with the origin of the vertebral artery who had hypoplasia of the right vertebral artery and the bilateral posterior communicating arteries. After induction chemoradiotherapy, a vein graft was used to create a bypass between the left common carotid artery and the vertebral artery, followed by a successful left upper lobectomy with combined resection of the subclavian artery together with the left vertebral artery. Because anatomic variations of vertebral arteries and cerebral arterial circle are known, preoperative evaluation of the cerebral blood flow should be performed and a relevant reconstruction considered. (Ann Thorac Surg 2010; 90:302-3) (C) 2010 by The Society of Thoracic Surgeons

The patient was 70-year-old man. He had complained of general fatigue and hoarseness for 5 months. Chest computed tomography scan demonstrated a large anterior mediastinal tumor. The diagnosis of high grade malignant sarcoma was established with needle biopsy and the complete resection through median sternotomy was conducted. The tumor was histopathologically diagnosed pleomorphic liposarcoma. Six months after operation, right supraclavicular lymph node metastasis was noted. Radiotherapy was performed, but the liver metastasis appeared subsequently 16 months after operation. Pleomorphic type is considered one of the poorest prognostic liposarcoma and should be required special attention.

In the lung, anti-inflammatory actions of glucocorticoids would be determined by 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2), the microsomal enzyme responsible for the breakdown of bio-active glucocorticoids. However, regulation of 11 beta-HSD2 under inflammatory conditions such as acute lung injury is not well understood. In the present study, we examined whether inflammatory Substances would influence the activity and mRNA expression of 11 beta-HSD2 in the lung. In a human bronchial epithelial cell line BEAS-2B, endotoxin inhibited 11 beta-HSD2 enzyme activity in a dose-dependent manner over 48 h with a significant decrease in the mRNA expression. Likewise, tumor necrosis factor (TNF)-alpha inhibited both activity and rnRNA expression of 11 beta-HSD2. The TNF-alpha-dependent decrease in the enzyme activity was completely blocked by anti-TNF-alpha antibody, while antibody alone showed no significant influence on the enzyme activity. An nitric oxide donor (NO) sodium nitropusside or a cGMP analog 8-br-cGMP caused moderate but significant decreases in both activity and rnRNA expression of 11 beta-HSD2. Importantly, treatment of rats with endotoxin significantly decreased both activity and mRNA expression of 11 beta-HSD2 in the lung tissue. We conclude that lung inflammation reduces local glucocorticoid breakdown and augments glucocorticoid action in the lung by down-regulating 11 beta-HSD2 via multiple mechanisms.

Background: Tranilast is an anti-allergic agent known to inhibit the release of histamine, interleukin-1beta, transforming growth factor beta1, and platelet-derived growth factor from various cells and currently is used to treat allergic diseases, keloids, and hypertrophic scars. We evaluated the ability of tranilast to inhibit the development of obliterative airway disease (OAD) in a rat model of heterotopic tracheal transplantation. Methods: We transplanted tracheal segments from donor rats (Brown Norway) into subcutaneous pouches in major histocompatibility complex-incompatible recipient rats (Lewis). At Days 21 and 28 after transplantation, we histologically assessed the harvested allografts scored the degree of OAD, on a scale from zero to 4 as previously described, caused by fibroproliferative tissue. Results: Recipient animals treated orally with 400 mg/kg/day tranilast throughout the experiment showed significantly decreased OAD compared with control animals, with a histologic score of 1.1 +/- 0.4 vs 3.0 +/- 1.3, respectively (mean +/- SD, p = 0.007), at Day 21 after transplantation and 2.0 +/- 1.4 vs 3.9 +/- 0. 4, respectively (mean +/- SD, p = 0.017), at Day 28 after transplantation. Conclusion: These results showed that treatment with tranilast significantly decreased fibroproliferative airway changes associated with allograft rejection in a rat model of tracheal transplantation, suggesting that tranilast may be useful in preventing bronchiolitis obliterans after lung transplantation. Copyright (C) 2004 by the International Society for Heart and Lung Transplantation.