記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: No proven treatment after the development of primary graft dysfunction (PGD) is currently available. Here we established a novel strategy of in vivo lung perfusion (IVLP) for the treatment of PGD. IVLP involves the application of an in vivo isolated perfusion circuit to an implanted lung. This study aimed to explore the effectiveness of IVLP versus conventional post-lung transplant (LTx) extracorporeal membrane oxygenation (ECMO) treatment using an experimental swine LTx PGD model. METHODS: After 1.5-h warm ischemia of the donor lungs, a left LTx was performed. Following the confirmation of PGD development, pigs were divided into three groups (n = 5 each): control (no intervention), ECMO, and IVLP. After 2 h of treatment, a 4-h functional assessment was conducted and samples obtained. RESULTS: Significantly better oxygenation were achieved in the IVLP group (p ≤ 0.001). Recovery was confirmed immediately and maintained during the following 4-h observation. The IVLP group also demonstrated better lung compliance than the control group (p = 0.045). A histological evaluation showed that the lung injury score and terminal deoxynucleotidyl transferase dUTP nick end labeling assay showed significantly fewer injuries and a better result in the wet-to-dry weight ratio in the IVLP group. CONCLUSIONS: A two-hour IVLP is technically feasible and allows for prompt recovery from PGD after LTx. The posttransplant short-duration IVLP strategy can complement or overcome the limitations of the current practice for donor assessment and PGD management.

DOI： 10.1016/j.healun.2023.10.011

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cancer-associated fibroblasts (CAFs) are important components in the tumor microenvironment, and we sought to identify effective therapeutic targets in CAFs for non-small cell lung cancer (NSCLC). In this study, we established fibroblast cell lines from the cancerous and non-cancerous parts of surgical lung specimens from patients with NSCLC and evaluated the differences in behaviors towards NSCLC cells. RNA sequencing analysis was performed to investigate the differentially expressed genes between normal fibroblasts (NFs) and CAFs, and we identified that the expression of periostin (POSTN), which is known to be overexpressed in various solid tumors and promote cancer progression, was significantly higher in CAFs than in NFs. POSTN increased cell proliferation via NSCLC cells' ERK pathway activation and induced epithelial-mesenchymal transition (EMT), which improved migration in vitro. In addition, POSTN knockdown in CAFs suppressed these effects, and in vivo experiments demonstrated that the POSTN knockdown improved the sensitivity of EGFR-mutant NSCLC cells for osimertinib treatment. Collectively, our results showed that CAF-derived POSTN is involved in tumor growth, migration, EMT induction, and drug resistance in NSCLC. Targeting CAF-secreted POSTN could be a potential therapeutic strategy for NSCLC. KEY MESSAGES: • POSTN is significantly upregulated in CAFs compared to normal fibroblasts in NCSLC. • POSTN increases cell proliferation via activation of the NSCLC cells' ERK pathway. • POSTN induces EMT in NSCLC cells and improves the migration ability. • POSTN knockdown improves the sensitivity for osimertinib in EGFR-mutant NSCLC cells.

DOI： 10.1007/s00109-023-02384-7

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記述言語：英語  

DOI： 10.1038/s41598-023-43995-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1245/s10434-023-14311-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The presence of tumor-infiltrating lymphocytes (TILs) and tertiary lymphoid structures (TLSs) in tumor tissue has been related to the prognosis in various malignancies. Meanwhile, neutrophil-to-lymphocyte ratio (NLR) as a systemic inflammation marker also has been associated with the prognosis in them. However, few reports have investigated the relationship between pulmonary metastases from sarcoma and these biomarkers. METHODS: We retrospectively recruited 102 patients undergoing metastasectomy for pulmonary metastases from uterine leiomyosarcoma at Okayama University Hospital from January 2006 to December 2019. TILs and TLSs were evaluated by immunohistochemical staining of surgically resected specimens of pulmonary metastases using anti-CD3/CD8/CD103/Foxp3/CD20 antibodies. NLR was calculated from the blood examination immediately before the most recent pulmonary metastasectomy. We elucidated the relationship between the prognosis and these factors. Because we considered that the status of tumor tissue and systemic inflammation were equally valuable, we also assessed the impact of the combination of TILs or TLSs and NLR on the prognosis. RESULTS: As for TILs, CD3-positive cells and CD8-positive cells were correlated with the prognosis. The prognosis was significantly better in patients with CD3-high group, CD8-high group, TLSs-high group, and NLR-low group, respectively. The prognosis of CD8-high/NLR-low group and TLSs-high/NLR-low group was significantly better than that of CD8-low/NLR-high group and TLSs-low/NLR-high group, respectively. CONCLUSIONS: CD3-positive TILs, CD8-positive TILs, TLSs, and NLR are correlated with the prognosis, respectively. The combination of CD8-positive TILs or TLSs and NLR may be the indicators to predict the prognosis of patients with pulmonary metastases from uterine leiomyosarcoma.

DOI： 10.1245/s10434-023-14176-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Chronic lung allograft dysfunction (CLAD) is a known long-term fatal disorder after lung transplantation. In this study, we evaluated the CLAD classification of the International Society for Heart and Lung Transplantation (ISHLT) for living-donor lobar lung transplantation (LDLLT). METHODS: We conducted a single-center retrospective review of data from 73 patients who underwent bilateral LDLLT between 1998 and 2019. Factors related to opacity on computed tomography (CT) and restriction on pulmonary function tests (PFTs) were also analyzed. RESULTS: Overall, 26 (36%) patients were diagnosed with CLAD, including restrictive allograft syndrome (RAS), n = 10 (38.5%); bronchiolitis obliterans syndrome (BOS), n = 8 (30.8%); mixed, n = 1 (3.8%); undefined, n = 2 (7.7%); and unclassified, n = 5 (19.2%). The 5-year survival rate after the CLAD onset was 60.7%. The survival of patients with BOS was significantly better than that of patients with RAS (p = 0.012). In particular, patients with restriction on PFT had a significantly worse survival than those without restriction (p = 0.001). CONCLUSIONS: CLAD after bilateral LDLLT does not have a major impact on the recipient survival, especially in patients with BOS. Restriction on PFT may predict a particularly poor prognosis in patients with CLAD after bilateral LDLLT.

DOI： 10.1007/s00595-023-02729-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1245/s10434-023-14005-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Primary lung tumors are sometimes resected when either pleural dissemination (PD) or malignant pleural effusion (MPE) exists. This study clarified the prognostic factors for non-small cell lung cancer (NSCLC) with either PD and MPE, or both, detected during or after surgery. PATIENTS AND METHODS: We examined patients with NSCLC from a multicenter database who had either PD, MPE, or both, detected during or after surgery between 2005 and 2015. Hazard ratios and 95% confidence intervals were estimated using the Cox proportional hazards model adjusted for potential confounding factors. RESULTS: Among 9463 registered patients, PD, MPE, or both, were found in 114 patients with NSCLC during or after surgery. Primary tumor resection and exploratory thoracotomy were performed in 65 and 49 patients, respectively. In univariate analysis, adenocarcinoma, clinically undetected lymph node metastasis (c-N0 or unknown), EGFR mutation, and combination of chemotherapy or tyrosine kinase inhibitors after surgery were better prognostic factors for overall survival (OS), whereas in the multivariate analysis, adenocarcinoma, clinically undetected lymph node metastasis, and EGFR mutation were favorable independent prognostic factors in OS. Additionally, limited to patients with EGFR mutation, patients with primary lung tumor resection showed a significantly better 5-year OS than those with exploratory thoracotomy (86.4 vs. 44.8%; p < 0.001). CONCLUSION: Our findings show that surgical resection of primary tumors could improve the prognosis of patients with PD, MPE, or both, detected during or after surgery when the tumors harbor an EGFR mutation.

DOI： 10.1245/s10434-023-13791-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Although the performance lung transplantation (LTx) in the elderly (≥ 60 years) has increased globally, the situation in Japan remains quite different, because the age limit at registration for cadaveric transplantation is 60 years. We investigated the long-term outcomes of LTx in the elderly in Japan. METHODS: This was a single-center retrospective study. We divided the patients into two groups according to age: the younger group (< 60 years; Y group; n = 194) and the elderly group (≥ 60 years; E group; n = 10). We performed three-to-one propensity score matching to compare the long-term survival between the E and Y groups. RESULTS: In the E group, the survival rate was significantly worse (p = 0.003), and single-LTx was more frequent (p = 0.036). There was a significant difference in the indications for LTx between the two groups (p < 0.001). The 5-year survival rate after single-LTx in the E group was significantly lower than that in the Y group (p = 0.006). After propensity score matching, the 5-year survival rates of the two groups were comparable (p = 0.55). However, the 5-year survival rate after single-LTx in the E group was significantly lower than that in the Y group (p = 0.007). CONCLUSION: Elderly patients showed acceptable long-term survival after LTx.

DOI： 10.1007/s00595-023-02699-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Renal dysfunction is a long-term complication associated with an increased mortality after lung transplantation (LT). We investigated the association of single-nucleotide polymorphisms (SNPs) with the development of renal dysfunction after LT using a Japanese-specific SNP array. First, eligible samples of 34 LT recipients were genotyped using the SNP array and divided into two groups, according to the presence of homozygous and heterozygous combinations of mutant alleles of the 162 renal-related SNPs. To identify candidate SNPs, the renal function tests were compared between the two groups for each SNP. Next, we investigated the association between the candidate SNPs and the time course of changes of the estimated glomerular filtration rate (eGFR) in the 99 recipients until 10 years after the LT. ΔeGFR was defined as the difference between the postoperative and preoperative eGFR values. Eight SNPs were identified as the candidate SNPs in the 34 recipients. Validation analysis of these 8 candidate SNPs in all the 99 recipients showed that three SNPs, namely, rs10277115, rs4690095, and rs792064, were associated with significant changes of the ΔeGFR. Pre-transplant identification of high-risk patients for the development of renal dysfunction after LT based on the presence of these SNPs might contribute to providing personalized medicine.

DOI： 10.1038/s41598-023-36143-y

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記述言語：英語  

Pulmonary alveolar proteinosis (PAP) affecting transplanted lungs is not well recognized. Herein, we report two cases of PAP after lung transplantation (LTx). The first case was a 4-year-old boy with hereditary pulmonary fibrosis who underwent bilateral LTx and presented with respiratory distress on postoperative day (POD) 23. He was initially treated for acute rejection, died due to infection on POD 248, and was diagnosed with PAP at autopsy. The second case involved a 52-year-old man with idiopathic pulmonary fibrosis who underwent bilateral LTx. On POD 99, chest computed tomography revealed ground-glass opacities. Bronchoalveolar lavage and transbronchial biopsy led to a diagnosis of PAP. Follow-up with immunosuppression tapering resulted in clinical and radiological improvement. PAP after lung transplantation mimics common acute rejection; however, is potentially transient or resolved with tapering immunosuppression, as observed in the second case. Transplant physicians should be aware of this rare complication to avoid misconducting immunosuppressive management.

DOI： 10.1002/rcr2.1160

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器外科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: The prognostic nutrition index (PNI), calculated using serum albumin and total lymphocyte count, is a recent topical index related to inflammation. Preoperative PNI is regarded as a new preoperative prognostic score in lung transplantation (LTx). This study aimed to investigate the impact of PNI at the time of registration as a prognostic parameter of mortality on the waiting list for LTx. METHODS: A retrospective review was conducted on the data of 132 adult patients registered for LTx in our department between January 2013 and June 2020. Patients who finally received LTx were analyzed as censored data. The overall survival was evaluated using the Kaplan-Meier method for pre-registered clinical factors including the PNI at the time of registration. Overall survival was calculated from the date of listing to the Japan Organ Transplant Network to the date of death. RESULTS: The low-PNI group had a significantly worse prognosis. Multivariate analysis demonstrated that age (p = 0.023), idiopathic interstitial pneumonia (p < 0.001), lung allocation score (LAS) (p < 0.001), and PNI (p < 0.001) were independent prognostic factors for waitlist mortality. CONCLUSIONS: PNI at the time of registration can be an independent prognostic parameter in registered candidates for LTx.

DOI： 10.1007/s11748-022-01895-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: S100A8/A9 is a damage-associated molecule that augments systemic inflammation. However, its role in the acute phase after lung transplantation (LTx) remains elusive. This study aimed to determine S100A8/A9 levels after lung transplantation (LTx) and evaluate their impact on overall survival (OS) and chronic lung allograft dysfunction (CLAD)-free survival. METHODS: Sixty patients were enrolled in this study, and their plasma S100A8/A9 levels were measured on days 0, 1, 2, and 3 after LTx. The association of S100A8/A9 levels with OS and CLAD-free survival was assessed using univariate and multivariate Cox regression analyses. RESULTS: S100A8/A9 levels were elevated in a time-dependent manner until 3 days after LTx. Ischemic time was significantly longer in the high S100A8/9 group than in the low S100A8/A9 group (p = .017). Patients with high S100A8/A9 levels (> 2844 ng/mL) had worse prognosis (p = .031) and shorter CLAD-free survival (p = .045) in the Kaplan-Meier survival analysis than those with low levels. Furthermore, multivariate Cox regression analysis showed that high S100A8/A9 levels were a determinant of poor OS (hazard ratio [HR]: 3.7; 95% confidence interval [CI]: 1.2-12; p = .028) and poor CLAD-free survival (HR: 4.1; 95% CI: 1.1-15; p = .03). In patients with a low primary graft dysfunction grade (0-2), a high level of S100A8/A9 was also a poor prognostic factor. CONCLUSIONS: Our study provided novel insights into the role of S100A8/A9 as a prognostic biomarker and a potential therapeutic target for LTx.

DOI： 10.1111/ctr.15006

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: MicroRNAs (miRNAs) involved in the pathogenesis of pulmonary fibrosis have been shown to be associated with the development of chronic lung allograft dysfunction (CLAD) after lung transplantation (LT). We investigated the role of circulating miRNAs in the diagnosis of CLAD after bilateral LT, including cadaveric LT (CLT) and living-donor lobar LT (LDLLT). METHODS: The subjects of this retrospective study were 37 recipients of bilateral CLT (n = 23) and LDLLT (n = 14), and they were divided into a non-CLAD group (n = 24) and a CLAD group (n = 13). The plasma miRNA levels of the two groups were compared, and correlations between their miRNAs levels and percent baseline forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and total lung capacity (TLC) values were calculated from one year before to one year after the diagnosis of CLAD. RESULTS: The plasma levels of both miR-21 and miR-155 at the time of the diagnosis of CLAD were significantly higher in the CLAD group than in the non-CLAD group (miR-21, P = 0.0013; miR-155, P = 0.042). The miR-21 levels were significantly correlated with the percent baseline FEV1, FVC, and TLC value of one year before and at the time of diagnosis of CLAD (P < 0.05). A receiver operating characteristic curve analysis of the performance of miR-21 levels in the diagnosis of CLAD yielded an area under the curve of 0.89. CONCLUSION: Circulating miR-21 appears to be of potential value in diagnosing CLAD after bilateral LT.

DOI： 10.1016/j.heliyon.2023.e14903

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記述言語：日本語   出版者・発行元：(一社)日本外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：日本語   出版者・発行元：(一社)日本外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本外科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: Ipsilateral reoperation after pulmonary lobectomy is often challenging because of adhesions from the previous surgery. In this study, we retrospectively examined the surgical outcome and prognosis of ipsilateral anatomical resection for lung cancer after pulmonary lobectomy using a multicentre database. METHODS: We evaluated the perioperative outcomes and overall survival of 51 patients who underwent pulmonary lobectomy followed by ipsilateral anatomical resection for lung cancer between January 2012 and December 2018. In addition, patients with stage I non-small cell lung cancer (NSCLC) were compared with 3411 patients with stage I lung cancer who underwent pulmonary resection without prior ipsilateral lobectomy. RESULTS: Ipsilateral anatomical resections included 10 completion pneumonectomies, 19 pulmonary lobectomies and 22 pulmonary segmentectomies. Operative time was 312.2 ± 134.5 min and intraoperative bleeding was 522.2 ± 797.5 ml. Intraoperative and postoperative complications occurred in 9 and 15 patients, respectively. However, the 5-year overall survival rate after anatomical resection followed by ipsilateral lobectomy was 83.5%. Furthermore, in patients with c-stage I NSCLC, anatomical resection followed by ipsilateral lobectomy was not associated with worse survival than anatomical resection without prior ipsilateral lobectomy. CONCLUSIONS: Anatomical resection following ipsilateral lobectomy is associated with a high frequency of intraoperative and postoperative complications. However, the 5-year overall survival in patients with c-stage I NSCLC who underwent ipsilateral anatomical resection after pulmonary lobectomy is comparable to that in patients who underwent anatomical resection without prior pulmonary lobectomy.

DOI： 10.1093/ejcts/ezad048

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Living-donor lobar lung transplantation is an alternative procedure to deceased donation lung transplantation. It involves graft donation from healthy donors; however, only a few reports have discussed its long-term prognosis in living lung donors and their associated health-related quality of life. This study aimed to examine living lung donors' health-related quality of life. METHODS: In our cross-sectional survey of living lung donors, we assessed health-related quality of life based on three key aspects (physical, mental, and social health) using the 36-Item Short Form Health Survey. We also evaluated chronic postoperative pain and postoperative breathlessness using the numeric rating scale and the modified Medical Research Council Dyspnea scale, respectively. RESULTS: We obtained consent from 117 of 174 living lung donors. The average scores of the living lung donors on the 36-Item Short Form Health Survey were higher than the national average. However, some donors had poorer physical, mental, and social health, with lower summary scores than the national averages. Low mental component summary predictors included donor age (<40 years; odds ratio = 10.2; p<.001) and recipient age (<18 years; odds ratio = 2.73; p<.032). Low role-social component summary predictors included high lung allocation score (≥50; odds ratio = 3.94, p<.002) and recipient death (odds ratio = 3.64; p = .005). There were no predictors for physical component summary. Additionally, many donors did not complain of pain or dyspnea. CONCLUSIONS: Living lung donors maintained acceptable long-term health-related quality of life after surgery. Potential donors should be informed of relevant risk factors, and high-risk donors should receive appropriate support. This article is protected by copyright. All rights reserved.

DOI： 10.1111/ctr.14927

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

(1) Background: Lung ischemia-reperfusion (IR) injury increases the mortality and morbidity of patients undergoing lung transplantation. The objective of this study was to identify the key initiator of lung IR injury and to evaluate pharmacological therapeutic approaches using a functional inhibitor against the identified molecule. (2) Methods: Using a mouse hilar clamp model, the combination of RNA sequencing and histological investigations revealed that neutrophil-derived S100A8/A9 plays a central role in inflammatory reactions during lung IR injury. Mice were assigned to sham and IR groups with or without the injection of anti-S100A8/A9 neutralizing monoclonal antibody (mAb). (3) Results: Anti-S100A8/A9 mAb treatment significantly attenuated plasma S100A8/A9 levels compared with control IgG. As evaluated by oxygenation capacity and neutrophil infiltration, the antibody treatment dramatically ameliorated the IR injury. The gene expression levels of cytokines and chemokines induced by IR injury were significantly reduced by the neutralizing antibody. Furthermore, the antibody treatment significantly reduced TUNEL-positive cells, indicating the presence of apoptotic cells. (4) Conclusions: We identified S100A8/A9 as a novel therapeutic target against lung IR injury.

DOI： 10.3390/bioengineering9110673

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The safety of salvage lung resection after immune checkpoint inhibitor (ICI) therapy in patients with advanced non-small cell lung cancer (NSCLC) is not well understood. METHODS: In this retrospective multicenter study, we reviewed perioperative morbidity and mortality rates in 11 patients (8 men, 3 women; median age 70 years) who underwent salvage lung resection for unresectable NSCLC after ICI therapy in the 4 years since 2017. Operative factors were also compared according to operating time (> 6 h, n = 7; < 6 h, n = 4). RESULTS: The clinical stage at the time of diagnosis was IIIA in 2 patients, IIIB in 4, IVA in 2, and IVB in 3. Eight patients received pembrolizumab and 3 received durvalumab. Two patients received an ICI agent alone, 3 underwent chemoradiotherapy, and 6 received chemotherapy. Lobectomy was performed in 10 cases and bilobectomy in 1 case. All patients underwent complete resection. Median operating time was 429 (range 169-570) min with a median blood loss of 199 (range 10-5, 140) mL. The only intraoperative complication was damage to the pulmonary artery. The perioperative morbidity and mortality rates were 27% and 0%, respectively. The 90-day mortality rate was 9% (1 patient died of acute exacerbation of interstitial pneumonia). Patients in whom the operating time was > 6 h more frequently had lymph node metastasis at the time of initial diagnosis (100% vs 25%, p = 0.02). CONCLUSIONS: Salvage lung resection was tolerated after ICI therapy in these patients. Lymph node metastasis at the time of initial diagnosis might make salvage surgery difficult.

DOI： 10.1007/s11748-022-01798-3

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記述言語：日本語   出版者・発行元：(一社)日本外科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although bronchiolitis obliterans syndrome (BOS) is a major cause of death after lung transplantation, an effective drug therapy for BOS has not yet developed. Here, we assessed the effectiveness of a neutralizing anti-S100 calcium binding protein (S100) A8/A9 antibody against BOS. A murine model of heterotopic tracheal transplantation was used. Mice were intraperitoneally administered control IgG or the S100A8/A9 antibody on day 0 and twice per week until they were sacrificed. Tissue sections were used to evaluate the obstruction ratio, epithelium-preservation ratio, α-smooth muscle actin (SMA)-positive myofibroblast infiltration, and luminal cell death. Quantitative reverse transcriptase-polymerase chain reaction analysis was performed to analyze the mRNA-expression levels of collagen, inflammatory cytokines, and chemokines on days 7, 14, and 21. The anti-S100A8/A9 antibody significantly improved the obstruction ratio and epithelium-preservation ratio, with less α-SMA-positive myofibroblast infiltration compared to the control group. Antibody treatment reduced the type-III collagen: type-I collagen gene-expression ratio. The antibody also significantly suppressed the number of dead cells in the graft lumen. The expression levels of tumor growth factor β1 and C-C motif chemokine 2 on day 21, but not those of interleukin-1β, interleukin-6, and tumor necrosis factor α, were significantly suppressed by S100A8/A9 antibody treatment. These findings suggest that S100A8/A9 may be a potential therapeutic target for BOS after lung transplantation.

DOI： 10.1016/j.bbrc.2022.08.087

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Brain-dead donors are susceptible to pulmonary atelectasis (AT). In procurement surgery, lung recruitment under circulatory conditions and cold-flushing for atelectatic donor lungs often provoke graft injury due to the acute blood inflow. We hypothesized that lung recruitment without blood circulation can mitigate graft injury. This study aimed to examine the benefits of lung recruitment subsequent to cardiac arrest using a porcine lung-transplant model. Methods: Thirteen donor pigs were categorized into the non-atelectatic (No-AT) group (n=3) representing a healthy control group; AT-BCR group (n=5), in which AT was reverted by conventional blood-circulated recruitment (BCR); and AT-no-BCR group (n=5), in which AT was reverted by no-BCR following circulatory arrest. In the atelectatic donor models, the left main bronchus was ligated for 24 hours prior to lung procurement. Left lung transplantation (LTx) was subsequently performed in the thirteen recipient pigs. After 6 hours evaluation, the recipients were euthanized and the lung grafts were excised. Results: The post-transplant PaO2/FiO2 ratio was significantly higher in the AT-no-BCR group than in the AT-BCR group (P=0.015). Wet/dry ratio, histological findings of graft injury and tissue interleukin-8 expression in the AT-no-BCR group were similar to those of the No-AT group. Conclusions: Lung recruitment without circulation after circulatory arrest could be more protective for atelectatic donor lung than the conventional procedure.

DOI： 10.21037/jtd-22-226

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment that mediate resistance of cancer cells to anticancer drugs. Tranilast is an antiallergic drug that suppresses the release of cytokines from various inflammatory cells. In this study, we investigated the inhibitory effect of tranilast on the interactions between non-small cell lung cancer (NSCLC) cells and the CAFs in the tumor microenvironment. Three EGFR-mutant NSCLC cell lines, two KRAS-mutant cell lines and three CAFs derived from NSCLC patients were used. To mimic the tumor microenvironment, the NSCLC cells were co-cultured with the CAFs in vitro, and the molecular profiles and sensitivity to molecular targeted therapy were assessed. Crosstalk between NSCLC cells and CAFs induced multiple biological effects on the NSCLC cells both in vivo and in vitro, including activation of the STAT3 signaling pathway, promotion of xenograft tumor growth, induction of epithelial-mesenchymal transition (EMT), and acquisition of resistance to molecular-targeted therapy, including of EGFR-mutant NSCLC cells to osimertinib and of KRAS-mutant NSCLC cells to selumetinib. Treatment with tranilast led to inhibition of IL-6 secretion from the CAFs, which, in turn, resulted in inhibition of CAF-induced phospho-STAT3 upregulation. Tranilast also inhibited CAF-induced EMT in the NSCLC cells. Finally, combined administration of tranilast with molecular-targeted therapy reversed the CAF-mediated resistance of the NSCLC cells to the molecular-targeted drugs, both in vitro and in vivo. Our results showed that combined administration of tranilast with molecular-targeted therapy is a possible new treatment strategy to overcome drug resistance caused by cancer- CAF interaction.

DOI： 10.1111/cas.15502

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

This study aimed to determine the optimal position and port placement during robotic resection for various mediastinal tumors. For anterior mediastinal tumors, total or extended thymectomy is commonly performed in the supine position using the lateral or subxiphoid approach. Although it is unclear which approach is better during robotic thymectomy, technical advantages of subxiphoid approach are beneficial for patients with myasthenia who require extended thymectomy. Partial thymectomy is performed in the supine position using a lateral approach. Superior, middle, and posterior mediastinal tumors are resected in the decubitus position using the lateral approach, whereas dumbbell tumor resection, which requires a posterior approach, can be performed in the prone position. The position and port placement should be chosen depending on the size, location, and aggressiveness of the tumor. In this study, we describe how to choose which of these different robotic approaches can be used based on our experience and previous reports.

DOI： 10.3390/jpm12081195

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記述言語：日本語   出版者・発行元：(有)科学評論社  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Survivors of head and neck cancer (HNC) often develop second primary lung cancer (SPLC), due to a common risk factor, that is, smoking. Our multicenter experience has been reviewed to evaluate how the history of diagnosis of HNC affects the outcomes of patients undergoing pulmonary resection for SPLC. METHODS: A multicenter retrospective analysis of patients hospitalized between January 2012 and December 2018 has been performed. From a cohort of 4,521 patients undergoing therapeutic pulmonary resection for primary non-small cell lung cancer, 100 patients with previous history of HNC (HNC group) have been identified. They were compared with a control group consisting of 200 patients without HNC history from the same cohort pair-matched with operating facility, age, sex, and pathological stage of lung cancer. RESULTS: At the time of surgery for SPLC, the HNC group showed malnutrition with lower prognostic nutritional index (PNI) compared with the control group (p < 0.001). The HNC group were determined to have postoperative complications more frequently (p = 0.02). The 5-year overall survival rates in the HNC and control groups were 59.0% and 83.2%, respectively (p < 0.001). Statistically, HNC history, lower PNI, squamous cell lung cancer, and TNM stage were identified to be independently associated with poor survival. CONCLUSIONS: Patients with SPLC following primary HNC often present with malnutrition and are predisposed to have postoperative complications and poor survival after pulmonary resection.

DOI： 10.1016/j.athoracsur.2022.04.052

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

One-step nucleic acid amplification (OSNA) is a rapid intraoperative molecular detection technique for sentinel node assessment via the quantitative measurement of target cytokeratin 19 (CK19) mRNA to determine the presence of metastasis. It has been validated in breast cancer but its application in lung cancer has not been adequately investigated. 214 LNs from 105 patients with 100 primary lung cancers, 2 occult primary lung tumors, and 3 metastatic lung tumors, who underwent surgical lung resection with LN dissection between February 2018 and January 2020, were assessed. Resected LNs were divided into two parts: one was snap-frozen for OSNA and the other underwent rapidly frozen histological examination. Intraoperatively collected LNs were evaluated by OSNA using loop-mediated isothermal amplification and compared with intraoperative pathological diagnosis as a control. Among 214 LNs, 14 were detected as positive by OSNA, and 11 were positive by both OSNA and intraoperative pathological diagnosis. The sensitivity and specificity of OSNA was 84.6% and 98.5%, respectively. The results of 5 of 214 LNs were discordant, and the remainder all matched (11 positive and 198 negative) with a concordance rate of 97.7%. Although the analysis of public mRNA expression data from cBioPortal showed that CK19 expression varies greatly depending on the cancer type and histological subtype, the results of the five cases, except for primary lung cancer, were consistent. OSNA provides sufficient diagnostic accuracy and speed and can be applied to the intraoperative diagnosis of LN metastasis for non-small cell lung cancer.

DOI： 10.1038/s41598-022-11064-4

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記述言語：日本語   出版者・発行元：(NPO)日本医工学治療学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Soft-tissue sarcomas are rare malignancies that consist of many different histologic subtypes and arise in various locations in the body. In patients with lung metastases from retroperitoneal sarcomas, the long-term outcomes and prognostic factors are unknown. This study is a retrospective review of patients undergoing pulmonary metastasectomy for retroperitoneal sarcoma metastases at one institution, with the purpose of determining prognostic factors and clinical outcomes. METHODS: This is a single-center, retrospective cohort study of patients undergoing pulmonary metastasectomy for lung metastases from various sarcomas at Okayama University Hospital from January 2006 to December 2018. The Kaplan-Meier method and log-rank test were used for the analyses, and cut-off values of continuous variables were determined by a receiver operating characteristic curve analysis. RESULTS: Twenty-four patients underwent the first pulmonary metastasectomy for lung metastases from retroperitoneal sarcoma in our hospital. Leiomyosarcoma was the most common histologic subtype of retroperitoneal sarcoma (79.2%, n = 19). Median overall survival was 49.9 months, and the 3-year and 5-year survival rates after the first pulmonary metastasectomy were 62.5% and 26.4% respectively. In univariate analysis, age ≥56 years, disease-free interval < 15 months, and size of metastasis (≥ 27 mm) were associated with poor survival. CONCLUSION: Pulmonary metastasectomy can be considered as an effective management strategy in retroperitoneal sarcoma patients with lung metastases in appropriately selected cases, just as it is for other sarcomas.

DOI： 10.1186/s12957-022-02552-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: We herein review the outcomes of paediatric lung transplantation (LTx) and analyse subgroups divided by age. METHODS: We retrospectively reviewed 43 consecutive paediatric LTx recipients (< 18 years old: cadaveric LTx [n = 9], living-donor lobar LTx [n = 34]). We also analysed subgroups of patients 1-6 years old (n = 10) and 7-17 years old (n = 33). RESULTS: The 1-, 5- and 10-year overall survival (OS) rates in paediatric recipients were 93%, 82% and 67%, respectively. The 1-, 5- and 10-year graft dysfunction (GD)-free survival rates in paediatric recipients were 85%, 59% and 31%, respectively. The 1- and 5-year OS in the 1- to 6-year-old vs. 7- to 17-year-old groups were 70% vs. 100% and 48% vs. 93%, respectively (p < 0.0001). The 1- and 5-year GD-free survival rates in the 1- to 6-year-old vs. 7- to 17-year-old groups were 60% vs. 93% and 24% vs. 69%, respectively (p = 0.024). The 1- to 6-year-old group showed higher rates of non-standard LTx (p = 0.0001), interstitial pneumonia (p = 0.004) and ventilator dependency (p = 0.007) than the 7- to 17-year-old group. CONCLUSION: Paediatric recipients under 7 years old seemed to have a higher risk of mortality and GD than those 7 years old and older.

DOI： 10.1007/s00595-022-02492-w

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記述言語：英語  

Congenital lobar emphysema (CLE) is defined as the hyperinflation of pulmonary lobes due to obstruction of the flow of air via a known or unknown etiology, which causes pressure symptoms in the adjacent organs. CLE is mainly diagnosed in the neonatal period, and very few adult cases have been reported. Here we report a 34-year-old male with muscular dystrophy who was diagnosed with CLE on examination. He underwent a right lower lobectomy via 3-portal completely video-assisted thoracoscopic surgery, and his symptoms improved. Thoracoscopic surgery helped preserve the respiratory muscles and led to the improvement of respiratory function in this patient.

DOI： 10.18926/AMO/63217

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Post-transplant lymphoproliferative disorder (PTLD) is a major complication of lung transplantation (LTx). However, few studies on PTLD in Asian populations have been reported. We explored the characteristics of Japanese PTLD cases after LTx. METHODS: We retrospectively reviewed 195 cases of LTx at our institute. We summarized the clinical experiences of 7 PTLD cases and analyzed the patient characteristics and survival outcomes of patients with (n = 7) and without (n = 188) PTLD. RESULTS: All PTLD patients were taking corticosteroids preoperatively (p = 0.0030), and the duration of preoperative corticosteroid therapy was significantly longer in the PTLD group (p = 0.0064) than in the non-PTLD group. The overall survival after LTx was significantly worse in the PTLD group (p = 0.027) than in the non-PLTD group. Among the three patients who died within 1 year after the PTLD onset, two died of opportunistic infections without residual PTLD lesions. Chronic lung allograft dysfunction (CLAD) or bronchiolitis obliterans at an autopsy were diagnosed after PTLD treatment in four cases. CONCLUSIONS: Long-term preoperative corticosteroid therapy may be a risk factor for PTLD after LTx. Opportunistic infections are lethal complications of PTLD, regardless of the effectiveness of PTLD treatment. CLAD occurs at a high rate after PTLD treatment, and close monitoring is required.

DOI： 10.1007/s00595-021-02390-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

During ischemia reperfusion (IR) injury, high mobility group box 1 (HMGB1), a chromatin binding protein, is released from necrotic cells and triggers inflammatory responses. We assessed the therapeutic effect of a neutralizing anti-HMGB1 monoclonal antibody (mAb) on lung IR injury. A murine hilar clamp model of IR was used, where mice were divided into sham and IR groups with intravenous administration of anti-HMGB 1 mAb or control mAb. We analyzed the effect of anti-HMGB1 mAb against IR injury by assessing lung oxygenation, lung injury score, neutrophil infiltration, expression of proinflammatory cytokines and chemokines, levels of mitogen-activated protein kinase (MAPK) signaling, and measurement of apoptotic cells. Anti-HMGB1 mAb significantly decreased the plasma level of HMGB1 elevated by IR. The severity of IR injury represented by oxygenation capacity, lung injury score, and neutrophil infiltration was significantly improved by anti-HMGB1 mAb treatment. The expression of proinflammatory factors, including IL-1β, IL-6, IL-12, TNF-α, CXCL-1, and CXCL-2, and phosphorylation of p38 MAPK were both significantly reduced by anti-HMGB1 mAb treatment. Furthermore, anti-HMGB1 mAb treatment suppressed apoptosis, as determined through TUNEL assays. Overall, anti-HMGB1 mAb ameliorated lung IR injury by reducing inflammatory responses and apoptosis. Our findings indicate that anti-HMGB1 mAb has potential for use as a therapeutic to improve IR injury symptoms during lung transplantation.

DOI： 10.1016/j.bbrc.2021.08.015

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記述言語：日本語   出版者・発行元：日本臨床外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Idiopathic multicentric Castleman disease (iMCD) is a rare polyclonal lymphoproliferative disease caused by the overrepresentation of interleukin-6 (IL-6). Tocilizumab (TCZ) is a humanized monoclonal antibody that binds to the IL-6 receptor and is approved for the treatment of iMCD. The efficacy and tolerability of TCZ in patients with iMCD undergoing lung transplantation (LTx) remain unknown. CASE PRESENTATION: We present the case of a 48-year-old iMCD patient with end-stage lung disease (ESLD) who was successfully treated with cadaveric single-LTx. Intravenous TCZ was used to stabilize the iMCD patient every 2 weeks, except for withdrawal immediately after LTx. At 32 month post-transplant, the patient remained asymptomatic without evidence of rejection, development of de novo donor-specific antibody (DSA), and recurrent iMCD in the native lung. CONCLUSIONS: Single-LTx can be a feasible treatment option for ESLD caused by iMCD. TCZ can be used safely and may be beneficial in recipients with iMCD, and TCZ in combination with usual immunosuppression can be helpful in stabilizing iMCD patients pre- and post-LTx.

DOI： 10.1186/s40792-021-01297-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

PURPOSE: Current evidence suggests that the neutrophil-to-lymphocyte ratio (NLR) is a prognostic factor in several types of cancer. In this study, we aimed to evaluate the prognostic impact of clinicopathological factors, including postoperative NLR, in patients with locally advanced non-small-cell lung cancer (LA-NSCLC) who underwent surgery after chemoradiotherapy (CRT) with or without postoperative adjuvant chemotherapy. METHODS: The medical records of LA-NSCLC patients treated with trimodality therapy at our institution between June 1999 and May 2019 were reviewed. The association between several clinicopathological factors and overall survival (OS) was analyzed. RESULTS: A total of 168 patients were included in this study. Regarding the prognosis, the 5-year OS rate was 68.1%, and the 2-year recurrence-free survival rate was 66.1% in the entire population. In multivariate analysis, we identified that high postoperative NLR, not pretreatment or preoperative NLR, was one of the independent factors for unfavorable OS (NLR high vs NLR low; hazard ratio = 2.45, 95% confidence interval: 1.53-3.94, p < 0.001). In addition, among patients with high postoperative NLR, patients who received postoperative adjuvant chemotherapy showed significantly better 5-year OS compared with those who did not (p = 0.016). On the other hand, postoperative adjuvant chemotherapy had no impact on the prognosis in patients with low NLR (p = 0.19). CONCLUSIONS: Our results suggest that high postoperative NLR was not only an independent unfavorable prognostic factor in patients with LA-NSCLC who were treated with trimodality therapy, but also a promising indicator for postoperative treatment in this population.

DOI： 10.1245/s10434-021-09690-9

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その他リンク： https://link.springer.com/article/10.1245/s10434-021-09690-9/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

<title>Abstract</title>
An incomplete interlobar fissure makes thoracoscopic lobectomy difficult and is predictive of morbidity after thoracoscopic lobectomy. This report demonstrates the robot-assisted thoracoscopic (RATS) lobectomy technique for patients with severe incomplete interlobar fissures. A fissureless approach was chosen for pulmonary resection. Near-infrared fluorescence imaging with intravenous indocyanine green (ICG) was used to detect the interlobar line after transection of the bronchus, pulmonary artery and vein. Interlobar fissure was identified and divided by robotic staplers. This combined technique using ICG and fissureless lobectomy made RATS lobectomy safe for patients with severe incomplete interlobar fissures.

DOI： 10.1093/jscr/rjab336

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

PURPOSE: Decreased irisin levels may be associated with the development of emphysema. Similarly, emphysematous changes may develop in patients with chronic lung allograft dysfunction (CLAD) after living-donor lobar lung transplantation (LDLLT). We investigated the severity of emphysematous changes and the relationship between irisin levels and CLAD after bilateral LDLLT and cadaveric lung transplantation (CLT). METHODS: The subjects of this retrospective study were 59 recipients of bilateral LDLLT (n = 31) or CLT (n = 28), divided into a non-CLAD group (n = 41), a LDLLT-CLAD group (n = 11), and a CLT-CLAD group (n = 7). We compared the severity of emphysematous changes, the skeletal muscle mass, and the plasma irisin levels among the groups. RESULTS: The emphysematous changes were significantly more severe in the LDLLT-CLAD and CLT-CLAD groups (p = 0.046 and 0.036), especially in patients with bronchiolitis obliterans syndrome (BOS), than in the non-CLAD group. Although the skeletal muscle mass was similar in all the groups, the plasma irisin levels were significantly lower in the LDLLT-CLAD group (p = 0.022), especially in the patients with BOS after LDLLT, than in the non-CLAD group. CONCLUSION: Emphysematous changes and lower levels of plasma irisin were associated with CLAD, especially in patients with BOS, after bilateral LDLLT.

DOI： 10.1007/s00595-021-02339-w

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その他リンク： https://link.springer.com/article/10.1007/s00595-021-02339-w/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

PURPOSE: The number of elderly patients who undergo surgery is increasing, even though they are at a high risk due to a decreased physical strength. Furthermore, sarcopenia is generally associated with a poor prognosis in patients with non-small cell lung cancer (NSCLC). METHODS: This study included NSCLC patients  ≥ 65 years old who underwent pulmonary resection in our hospital between 2012 and 2015. Sarcopenia was assessed using the psoas muscle mass index based on computed tomography at the level of the third lumbar vertebra. We elucidated the impact of sarcopenia on short- and long-term outcomes after surgery. RESULTS: We enrolled 259 patients, including 179 with sarcopenia. Patients with sarcopenia before surgery tended to have postoperative complications (p = 0.0521), although they did not show a poor prognosis. In patients with sarcopenia, a multivariate analysis revealed that postoperative complications and the progression of sarcopenia 1 year after surgery were significant risk factors for a poor prognosis (p = 0.0169 and 0.00370, respectively). CONCLUSIONS: The progression of sarcopenia after surgery is associated with a poor prognosis in elderly NSCLC patients with sarcopenia. A strategy to prevent postoperative progressive sarcopenia may be necessary for improving the clinical outcome of this population.

DOI： 10.1007/s00595-020-02221-1

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その他リンク： https://link.springer.com/article/10.1007/s00595-020-02221-1/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

Hyper-immunoglobulin E syndrome (HIES) is one of the primary immunodeficiencies characterized by recurrent staphylococcal skin and lung infections that result in lung destruction and critically diminished pulmonary function. Despite the lack of definitive treatment, there have been no reports of successful lung transplantation (LTx) for HIES patients. We report the case of a 42-year-old female HIES patient with progressive bronchiectasis whose pulmonary infection was controlled prior to transplantation and subsequent LTx was uneventful. LTx may be feasible in HIES if the patient is immunologically stable preoperatively, and peri-operative infections, especially Aspergillus infections, are well-controlled.

DOI： 10.1016/j.athoracsur.2021.05.088

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

PURPOSE: The effect of uniportal video-assisted thoracoscopic surgery (uni-VATS) versus that of conventional VATS on postoperative quality of life (QOL) is unclear. This prospective randomized controlled study compared uni-VATS and conventional 3-port VATS in terms of QOL and patient satisfaction. METHODS: The subjects of this study were 84 patients with pulmonary nodules or bullous formation, randomized to undergo uniportal or conventional 3-port video-assisted thoracoscopic partial lung resection. The primary endpoint was postoperative pain, assessed using a numeric rating scale on postoperative day (POD) 1. RESULTS: No differences were found in the numeric rating scale on POD 1 after uni-VATS and conventional 3-port VATS. There were also no differences in blood loss, operative time, complication rate, surgical margin, analgesic requirement, vital capacity (VC), forced expiratory volume in 1 s (FEV1), the 6-min walk test (6MWT), C-reactive protein (CRP) levels, white blood cell count (WBC), or duration of chest tube drainage and hospital stay. Differences were found in the numeric rating scale on days 2, 3, 5, and 10 and in the patient satisfaction score on PODs 5 and 10. CONCLUSIONS: Uni-VATS is associated with less chest pain and better patient satisfaction in the short term but without differences in complication rates or surgical margins from the lesions. CLINICAL TRIAL REGISTRY NUMBER: University Hospital Medical Information Network Clinical Trial Registry (UMIN000015340 http://www.umin.ac.jp/english/ ).

DOI： 10.1007/s00595-021-02294-6

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その他リンク： https://link.springer.com/article/10.1007/s00595-021-02294-6/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

<title>Abstract</title>
A 24-year-old man presented with a dumbbell-shaped right posterior mediastinal mass. The patient was placed in the prone position following general anaesthesia and intubation. After laminectomy and dissection of the dorsal part of the tumour using a posterior approach were performed, the tumour was completely resected using a robotic approach in the thoracic cavity without repositioning. This is the first report of robotic resection for posterior mediastinal tumour in the prone position as well as a novel combined posterior approach and robotic resection for dumbbell tumours.

DOI： 10.1093/icvts/ivab117

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: The prognostic nutritional index (PNI), calculated based on the serum albumin levels and the total lymphocyte count, has been identified as a predictor of clinical outcomes in various fields of surgery. In this study, we investigated the relationship between the PNI and the lung allocation score (LAS) as well as the impact of the PNI on the outcomes of both cadaveric lung transplantation (CLT) and living-donor lobar lung transplantation (LDLLT). METHODS: We reviewed retrospective data for 127 recipients of lung transplantation (LT), including 71 recipients of CLT and 56 recipients of LDLLT. RESULTS: The PNI was correlated significantly and negatively with the LAS (r = - 0.40, P = 0.0000037). Multivariate analysis revealed that age (P = 0.00093), BMI (P = 0.00087), and PNI (P = 0.0046) were independent prognostic factors of a worse outcome after LT. In a subgroup analysis, survival after both CLT (P = 0.015) and LDLLT (P = 0.041) was significantly worse in the low PNI group than in the high PNI group. CONCLUSION: Preoperative nutritional evaluations using the PNI can assist with the assessment of disease severity in LT recipients and may predict survival after both CLT and LDLLT.

DOI： 10.1007/s00595-021-02244-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Bronchopleural fistula (BPF) is a severe complication following lung resection. We present the case of a patient with a history of advanced lung cancer, who had undergone induction chemoradiotherapy followed by right middle and lower lobectomy, and who developed BPF after completion right pneumonectomy. Although we had covered the bronchial stump with an omental pedicled flap, BPF was found on postoperative day 19. We covered the fistula with n-butyl-2-cyanoacrylate (NBCA) using bronchoscopy. Although we had to repeat the NBCA treatment, we ultimately cured the patient's BPF and no recurrence was observed up to 15.2 months after surgery.

DOI： 10.18926/AMO/61440

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

In patients with interstitial pneumonia, pulmonary fibrosis is an irreversible condition that can cause respiratory failure. Novel treatments for pulmonary fibrosis are necessary. Inflammation is thought to activate lung fibroblasts, resulting in pulmonary fibrosis. Of the known inflammatory molecules, we have focused on S100A8/A9 from the onset of inflammation to the subsequent progression of inflammation. Our findings confirmed the high expression of S100A8/A9 in specimens from patients with pulmonary fibrosis. An active role of S100A8/A9 was demonstrated not only in the proliferation of fibroblasts but also in the fibroblasts' differentiation to myofibroblasts (the active form of fibroblasts). S100A8/A9 also forced fibroblasts to upregulate the production of collagen. These effects were induced via the receptor of S100A8/A9, i.e., the receptor for advanced glycation end products (RAGE), on fibroblasts. The anti-S100A8/A9 neutralizing antibody inhibited the effects of S100A8/A9 on fibroblasts and suppressed the progression of fibrosis in bleomycin (BLM)-induced pulmonary fibrosis mouse model. Our findings strongly suggest a crucial role of S100A8/A9 in pulmonary fibrosis and the usefulness of S100A8/A9-targeting therapy for fibrosis interstitial pneumonia. HIGHLIGHTS: S100A8/A9 level is highly upregulated in the IPF patients' lungs as well as the blood. S100A8/A9 promotes not only the growth of fibroblasts but also differentiation to myofibroblasts. The cell surface RAGE acts as a crucial receptor to the extracellular S100A8/A9 in fibroblasts. The anti-S100A8/A9 antibody effectively suppresses the progression of IPF in a mouse model. In idiopathic pulmonary fibrosis (IPF), S100A8/A9, a heterodimer composed of S100A8 and S100A9 proteins, plays a crucial role in the onset of inflammation and the subsequent formation of a feed-forward inflammatory loop that promotes fibrosis. (1) The local, pronounced increase in S100A8/A9 in the injured inflammatory lung region-which is provided mainly by the activated neutrophils and macrophages-exerts strong inflammatory signals accompanied by dozens of inflammatory soluble factors including cytokines, chemokines, and growth factors that further act to produce and secrete S100A8/A9, eventually making a sustainable inflammatory circuit that supplies an indefinite presence of S100A8/A9 in the extracellular space with a mal-increased level. (2) The elevated S100A8/A9 compels fibroblasts to activate through receptor for advanced glycation end products (RAGE), one of the major S100A8/A9 receptors, resulting in the activation of NFκB, leading to fibroblast mal-events (e.g., elevated cell proliferation and transdifferentiation to myofibroblasts) that actively produce not only inflammatory cytokines but also collagen matrices. (3) Finally, the S100A8/A9-derived activation of lung fibroblasts under a chronic inflammation state leads to fibrosis events and constantly worsens fibrosis in the lung. Taken together, these findings suggest that the extracellular S100A8/A9 heterodimer protein is a novel mainstay soluble factor for IPF that exerts many functions as described above (1-3). Against this background, we herein applied the developed S100A8/A9 neutralizing antibody to prevent IPF. The IPF imitating lung fibrosis in an IPF mouse model was effectively blocked by treatment with the antibody, leading to enhanced survival. The developed S100A8/A9 antibody, as an innovative novel biologic, may help shed light on the difficulties encountered with IPF therapy in clinical settings.

DOI： 10.1007/s00109-020-02001-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Sarcomas are among the most refractory malignant tumors and often recur as pulmonary metastasis. Although the presence of a high neutrophil-to-lymphocyte ratio (NLR) has been associated with the prognosis of several malignancies, the relationship between the NLR and sarcoma with pulmonary metastasis is unclear. We investigated the impact of the NLR in patients who underwent surgical resection for metastatic lung tumors from various sarcomas. METHODS: The subjects of this retrospective study were 158 patients with metastatic lung tumors from various sarcomas, who underwent initial pulmonary metastasectomy between 2006 and 2015. We examined the clinicopathological variables, including the NLR and the characteristics of surgical procedures. Survival was estimated by the Kaplan-Meier method and prognostic factors were evaluated by multivariate analysis. RESULTS: Multivariate analysis revealed significantly better survival of the group with an NLR < 2.26 immediately before the most recent pulmonary metastasectomy, in addition to such factors as the largest resected lesion being < 22 mm, a disease-free interval of > 2 years, and 3 or more pulmonary metastasectomies. CONCLUSION: The NLR immediately before the most recent pulmonary metastasectomy is a novel independent prognostic factor, which may be helpful when considering repeated pulmonary metastasectomy.

DOI： 10.1007/s00595-020-02093-5

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記述言語：日本語   出版者・発行元：(一社)日本外科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objectives: The molecular mechanisms underlying post-operative pericardial adhesions remain poorly understood. We aimed to unveil the temporal molecular and cellular mechanisms underlying tissue dynamics during adhesion formation, including inflammation, angiogenesis, and fibrosis. Methods and Results: We visualized cell-based tissue dynamics during pericardial adhesion using histological evaluations. To determine the molecular mechanism, RNA-seq was performed. Chemical inhibitors were administered to confirm the molecular mechanism underlying adhesion formation. A high degree of adhesion formation was observed during the stages in which collagen production was promoted. Histological analyses showed that arterioles excessively sprouted from pericardial tissues after the accumulation of neutrophils on the heart surface in mice as well as humans. The combination of RNA-seq and histological analyses revealed that hyperproliferative endothelial and smooth muscle cells with dedifferentiation appeared in cytokine-exposed sprouting vessels and adhesion tissue but not in quiescent vessels in the heart. SMAD2/3 and ERK activation was observed in sprouting vessels. The simultaneous abrogation of PI3K/ERK or TGF-β/MMP9 signaling significantly decreased angiogenic sprouting, followed by inhibition of adhesion formation. Depleting MMP9-positive neutrophils shortened mice survival and decreased angiogenic sprouting and fibrosis in the adhesion. Our data suggest that TGF-β/matrix metalloproteinase-dependent tissue remodeling and PI3K/ERK signaling activation might contribute to unique angiogenesis with dedifferentiation of vascular smooth muscle cells from the contractile to the synthetic phenotype for fibrosis in the pericardial cavity. Conclusions: Our findings provide new insights in developing prevention strategies for pericardial adhesions by targeting the recruitment of vascular cells from heart tissues.

DOI： 10.3389/fcvm.2021.761591

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Trimodality therapy, comprised of induction chemoradiotherapy (iCRT) followed by surgery, is a highly invasive treatment option for locally advanced non-small cell lung cancers (LA-NSCLCs; defined as a heterogenous disease). We conducted this study to investigate the prognostic nutritional index (PNI) of LA-NSCLC patients undergoing trimodality therapy, which has not been studied in detail before. METHODS: The subjects of this retrospective study were 127 patients who underwent trimodality therapy between 1999 and 2016. We measured the PNI at three points: before iCRT (pre-iCRT), before the operation, and after the operation. RESULTS: PNIs decreased significantly as treatment progressed. Patients with clinical T3/4 (cT3/4) disease had a significantly lower PNI than those with cT1/2 disease, but the extent of lymph-node metastasis did not affect the PNI at any point. Using the cut-off values of receiver-operating curve analyses, multivariable analyses revealed that a high PNI pre-iCRT correlated significantly with a better survival of LA-NSCLC patients, especially those with cT3/4 disease (hazard ratio 3.84; 95% confidential interval 1.34-12.5, P = 0.012). CONCLUSIONS: Measuring the PNI before trimodality therapy is important for predicting the clinical outcome of patients with LA-NSCLC, with differing predictive ability according to the disease extent. Perioperative intensive nutritional intervention must be considered for patients who undergo trimodality therapy for LA-NSCLC.

DOI： 10.1007/s00595-020-02067-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Pulmonary metastasectomy could be considered one of the treatment options for disease control in sarcoma patients with pulmonary metastases; however, there is little consensus regarding the suitable criteria for predicting the likely outcomes in these patients. The aim of this study was to establish a prognostic benefit scoring system based on preoperatively examined prognostic factors for sarcoma patients with pulmonary metastases. METHODS: This was a single-center, retrospective cohort study conducted in a cohort of 135 sarcoma patients who underwent a first pulmonary metastasectomy at Okayama University Hospital between January 2006 and December 2015. Based on the results of a multivariable logistic regression analysis performed to determine the factors influencing 3-year mortality, a Sarcoma Lung Metastasis Score was created and its correlation with 3-year survival was analyzed. RESULTS: The results of the multivariate analysis revealed significant differences in the disease-free interval (< 2 years vs. ≥ 2 years; odds ratio (OR) 4.22, 95% confidence interval (CI) 1.67-10.70), maximum tumor diameter (≥ 15 mm vs. < 15 mm; OR 3.86, 95% CI 1.75-8.52), and number of pulmonary metastases (≥ 6 vs. < 6; OR 2.65, 95% CI 1.06-6.620). The Sarcoma Lung Metastasis Score, which was defined as the total score of these three factors, reliably predicted 3-year survival (score: 0, 89.5%; 1, 63.2%; 2, 39.0%; 3, 10.5%). CONCLUSIONS: Our newly proposed simple Sarcoma Lung Metastasis Score appears to be a useful prognostic predictor for sarcoma patients with pulmonary metastases, in that it could be helpful for the selection of appropriate treatments for these patients.

DOI： 10.1245/s10434-020-09272-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Trimodality therapy is a treatment option for patients with locally advanced non-small cell lung cancer (LA-NSCLC). Thoracic radiation has both early (radiation pneumonitis) and late (chronic lung injury: CLI) adverse effects on the lung. While CLI is expected to result in various problems in long-term survivors, these manifestations have not been precisely investigated. METHODS: We enrolled 112 LA-NSCLC patients who had received induction chemoradiotherapy followed by surgery, and then undergone follow-up computed tomography (CT) every 6 months for >1 year. All chest CT images were reviewed to evaluate any injury of the pulmonary parenchyma. RESULTS: CLI at 1 year after surgery and its progression (pCLI) were observed in 94 (84%) and 38 (34%) patients, respectively. Progressive lung fibrosis (PLF) as the first manifestation of pCLI was most frequent after right middle and/or lower lobectomy. Cavity formation was the subsequent manifestation after PLF, and chronic infection was the final stage of CLI. The cumulative rate of chronic infection was 76.4% at 10 years in patients with cavity formation. Ten patients with chronic infection included seven cases of pulmonary aspergillosis and two cases of cavity infections with methicillin-resistant Staphylococcus aureus or Stenotrophomonas maltophili. Among them, 4 patients required surgical interventions including completion pneumonectomy or fenestration. CONCLUSIONS: CLI is a common incidence after trimodality therapy for LA-NSCLC. CLI frequently results in cavity formation, which is a precursor of highly refractory chronic infections requiring surgical intervention. Appropriate management needs to be established for CLI developing after trimodality therapy.

DOI： 10.1016/j.athoracsur.2020.07.068

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: The non-technical skills for surgeons (NOTSS) system was developed as a tool to assess surgical skills for patient safety during surgery. This study aimed to develop a NOTSS-based training system for surgical trainees to acquire non-technical skills using a chest surgery scenario in a wet lab. Materials and methods: Trainees were categorized into three subgroups according to the years of experience as follows: Level A: 6 years or more; Level B: 3-5 years; and Level C: 1-2 years. Three stages of surgical procedure were designed: 1. chest wall resection and right upper lobe lobectomy, 2. right middle lobe sleeve lobectomy, and 3. right lower lobe lobectomy. One instructor was assigned to each operation table, who evaluated each participant's NOTSS scores consisting of 16 elements. Results: When comparing average NOTSS score of all the three procedures, significant differences were observed between Level A, B, and C trainees. As an example of varying elements by procedure, Level A trainees demonstrated differences in Situation Awareness, and a significant difference was observed in Level C trainees regarding the elements of Decision Making. On the contrary, no significant difference was observed among Level B trainees. In the comparison between first-time and experienced participants, a significant improvement was observed in some elements in Level B and C trainees. Conclusion: This study highlights the usefulness and feasibility of the NOTSS scoring system for surgeons with different experiences and the effectiveness of providing feedback to trainees during intraoperative handoffs in a wet lab.

DOI： 10.1016/j.amsu.2020.07.062

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記述言語：英語  

We encountered a rare case of thymic cyst accompanied by mediastinitis. A 39-year-old Japanese male presented with fever and chest pain. The chest CT revealed a mass composed of a lobular cystic lesion with inflammation, suggesting the onset of mediastinitis. A definitive histological diagnosis was not obtained, and we performed a thymectomy. Pathologically, the thymic cyst was accompanied by multiple cavities, mimicking thymic cysts, caused by the inflammatory abscess. The surrounding adipose tissue showed inflammatory cell infiltrations with chronic fibrosis. These findings indicate that clinicians should be aware that thymic cysts may cause severe mediastinitis.

DOI： 10.18926/AMO/60804

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: The scheduled administration of intravenous acetaminophen (scheduled-IV-AcA) is one of the more effective multimodal analgesic approaches for postoperative pain in abdominal/orthopedic surgeries. However, there is little evidence concerning scheduled-IV-AcA after general thoracic surgery, especially when limited to video-assisted thoracoscopic surgery (VATS). We investigated the efficacy of scheduled-IV-AcA administration in patients after undergoing VATS. METHODS: Ninety-nine patients who underwent VATS lobectomy or segmentectomy via an 8-cm access window and 1 camera port were retrospectively reviewed by categorizing them into groups either with scheduled-IV-AcA (Group AcA: n = 29) or without it (Group non-AcA: n = 70). Group AcA received 1 g of IV-AcA every 6 h from the end of the operation until the end of POD2. Postoperative pain was measured using a numeric rating scale (NRS) three times per day until discharge. RESULTS: NRS scores were significantly lower in Group AcA with motion (on POD1 to the first point of POD2) than in Group non-AcA. Group non-AcA was also more likely to use additional analgesics than Group AcA (39% vs. 17%, p = 0.058). CONCLUSIONS: Scheduled-IV-AcA administration is a safe and effective multimodal analgesic approach in patients undergoing VATS pulmonary resection via an 8-cm access window.

DOI： 10.1007/s00595-020-02127-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The epithelial-mesenchymal transition (EMT) is a key process in tumor progression and metastasis and is also associated with drug resistance. Thus, controlling EMT status is a research of interest to conquer the malignant tumors. MATERIALS AND METHODS: A drug repositioning analysis of transcriptomic data from a public cell line database identified monensin, a widely used in veterinary medicine, as a candidate EMT inhibitor that suppresses the conversion of the EMT phenotype. Using TGF-β-induced EMT cell line models, the effects of monensin on the EMT status and EMT-mediated drug resistance were assessed. RESULTS: TGF-β treatment induced EMT in non-small cell lung cancer (NSCLC) cell lines and the EGFR-mutant NSCLC cell lines with TGF-β-induced EMT acquired resistance to EGFR-tyrosine kinase inhibitor. The addition of monensin effectively suppressed the TGF-β-induced-EMT conversion, and restored the growth inhibition and the induction of apoptosis by the EGFR-tyrosine kinase inhibitor. CONCLUSION: Our data suggested that combined therapy with monensin might be a useful strategy for preventing EMT-mediated acquired drug resistance.

DOI： 10.1016/j.bbrc.2020.06.077

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Some long-term survivors after surgery for locally advanced non-small cell lung cancer (NSCLC) treated with induction chemoradiotherapy (trimodality treatment) develop chronic pulmonary aspergillosis (CPA). The aim of our study was to assess the characteristics and outcomes of CPA that develops after trimodality treatment. METHODS: We retrospectively reviewed the data of 187 NSCLC patients who underwent trimodality treatment between 1999 and 2018. RESULTS: Six male ever-smoker patients developed CPA. All 6 patients had undergone extended resection for NSCLC and had a history of either adjuvant chemotherapy (n = 3) or radiation pneumonitis (n = 4). Among the 4 patients with CPA localized in a single lung, 3 patients were treated surgically (completion pneumonectomy or cavernostomy) and 1 patient was treated with antifungal therapy alone. Both treatments led to the improved control of CPA. In contrast, patients with CPA in both lungs were not candidates for surgery, and died of CPA. The survival rates after trimodality treatment in the CPA group and the group without CPA were comparable (10-year survival rate, 50.0% vs. 57.6%, P = 0.59). CONCLUSION: The early diagnosis of CPA localized in a single lung after NSCLC surgery is critical to improving control and survival in patients with CPA.

DOI： 10.1007/s00595-020-01960-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Because chronic lung allograft dysfunction (CLAD) develops predominantly on one side after bilateral living-donor lobar lung transplantation (LDLLT), lung perfusion scintigraphy (Q-scinti) was expected to show a perfusion shift to the contralateral unaffected lung with the development of CLAD. Our study examined the potential usefulness of Q-scinti in the diagnosis of CLAD after bilateral LDLLT. We conducted a single-center retrospective cohort study of 58 recipients of bilateral LDLLT. The unilateral shift values on Q-scinti were calculated and compared between the CLAD group (N = 27) and the non-CLAD group (N = 31) from 5 years before to 5 years after the diagnosis of CLAD. The unilateral shift values in Q-scinti were significantly higher in the CLAD group than in the non-CLAD group from 5 years before the diagnosis of CLAD to 5 years after the diagnosis (P < 0.05). The unilateral shift values in Q-scinti were significantly correlated with the percent baseline values of the forced expiratory volume in 1 s (P = 0.0037), the total lung capacity (P = 0.0028), and the forced vital capacity (P = 0.00024) at the diagnosis of CLAD. In patients developing unilateral CLAD after bilateral LDLLT, Q-scinti showed a unilateral perfusion shift to the contralateral unaffected lung. Thus, Q-scinti appears to have the potential to predict unilateral CLAD after bilateral LDLLT.

DOI： 10.1038/s41598-020-67433-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: The therapeutic strategy for patients with non-small-cell lung cancer (NSCLC) harboring the BRAF non-V600E mutation has not been established. LY3009120, a newly discovered pan-RAF inhibitor, has shown strong antitumor effects in cancers with various BRAF genotypes. This study investigated the antitumor effects of LY3009120 in NSCLC cells harboring the BRAF non-V600E mutation. MATERIALS AND METHODS: We examined the antitumor effects of LY3009120 by MTS assay and flow cytometry. We analyzed the expression status of proteins by western blot. The mouse xenograft models were used for the in vivo experiments. RESULTS: LY3009120 suppressed BRAF-related downstream pathway molecules and induced cleavage of poly ADP-ribose polymerase in all examined NSCLC cell lines. LY3009120 also inhibited in vivo tumor growth in NSCLC cells harboring the BRAF non-V600E mutation. CONCLUSION: LY3009120 is a potent therapeutic agent for patients with BRAF non-V600E mutant NSCLC.

DOI： 10.21873/anticanres.14237

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掲載種別：研究論文（学術雑誌）  

Copyright © 2020. Published by Elsevier Inc. PURPOSE: Micro-RNAs (miRNAs) regulate genes by selectively silencing their target messenger RNAs. Recently, serum levels of miRNA related to pulmonary fibrosis (miR-21 and miR-155), have been shown to be associated with the development of chronic lung allograft dysfunction (CLAD) after cadaveric lung transplantation (CLT). We investigated the relationship between miRNAs levels and CLAD after bilateral living-donor lobar lung transplantation (LDLLT) and CLT. METHODS: Blood samples were collected from a total of 70 patients who underwent bilateral LDLLT (n=39) and bilateral CLT (n=31), including patients with CLAD (the CLAD group, n=25) and those without CLAD (the non-CLAD group, n=45). Plasma miRNA levels (miR-21 and miR-155) were quantified using real-time PCR and compared between the two groups. The relationship between miRNA levels and the results of pulmonary function tests at the onset of CLAD was assessed. Appropriate cut-off values of miRNA levels were set for the diagnosis of CLAD. RESULTS: The median follow-up period was 3074 (1071-7523) days. Plasma miRNA levels of the CLAD group were significantly higher than those of the non-CLAD group (miR-21, P<0.001; miR-155, P=0.013) (Fig. 1). In the CLAD group, miRNA levels after LDLLT were comparable to those after CLT. Moreover, miRNA levels were significantly negatively correlated with the baseline values of forced expiratory volume in 1 second (FEV1) (miR-21, P<0.001; miR-155, P=0.039) and those of total lung cavity (TLC) (miR-21, P<0.001; miR-155, P=0.0012) (Fig. 2). An ROC analysis of the performance of miR-21 level as a marker of CLAD yielded an AUC of 0.94 at a threshold level of 6.51. Patients with miR-21 level≥6.51 showed significantly better CLAD-free survival than those with miR-21 level<6.51 (P<0.001) (Fig. 3). CONCLUSION: Plasma miRNA levels are associated with the development of CLAD after bilateral LDLLT and CLT, and might be a potential biomarker for the diagnosis of CLAD.

DOI： 10.1016/j.healun.2020.01.792

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掲載種別：研究論文（学術雑誌）  

Copyright © 2020. Published by Elsevier Inc. PURPOSE: The preoperative nutritional status affects the clinical outcome of surgery. To predict the clinical outcome, a prognostic nutritional index (PNI) calculated using serum albumin levels (ALB) and total lymphocyte count (TLC) has been shown to be valuable in various fields of surgery. In this study, we investigated the relationship between PNI and lung allocation score (LAS) as well as the impact of PNI on outcomes of lung transplantation (LT), including cadaveric lung transplantation (CLT) and living-donor lobar lung transplantation (LDLLT). METHODS: Between June 2003 and August 2016, a total of 127 patients underwent LT at Okayama University Hospital, including 71 recipients of CLT and 56 recipients of LDLLT. The PNI was calculated by the following equation: PNI = (10 × ALB(g/dl)+(0.005 × TLC(/mm3)). The overall survival was evaluated by univariate analysis (the log rank test) and multivariate analysis (the Cox proportional hazard regression model) using preoperative factors, including sex, age, BMI, diagnosis, oxygen concentration, mechanical ventilation, tracheostomy, ECMO support, use of glucocorticoids, serum creatinine level, diabetes mellitus, LAS, and PNI. RESULTS: PNI was significantly negatively correlated with LAS (r=-0.3, P=0.00062) (Fig. 1A). The univariate analysis revealed that the overall survival was significantly worse in the patients with age>28 (P=0.047), BMI<24.2 (P=0.0098), LAS>58.04 (P=0.000072), PNI<46.35 (P=0.018) (Fig. 1B). The multivariate analysis demonstrated that age (P=0.00093), BMI (P=0.0024), and PNI (P=0.0047) were independent prognostic factors of worse outcome. In the subgroup analysis, low PNI is a significant prognostic factor of worse survival after CLT (P=0.015) (Fig. 1C) and LDLLT (P=0.041) (Fig. 1D). CONCLUSION: Preoperative nutritional evaluation using PNI could contribute to the assessment of LT recipient's severity and predict survival after both CLT and LDLLT.

DOI： 10.1016/j.healun.2020.01.700

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Lung transplantation (LT) is a reliable therapeutic option for end-stage pulmonary lymphangioleiomyomatosis (LAM). Long-term outcome of LAM recipients after LT remains unknown. The aim of this study was to describe the outcomes of LT for LAM with a long-term follow-up, comparing those for other diseases in the same period. METHODS: We retrospectively reviewed consecutive 145 LT recipients between 1998 and 2015 at Okayama University Hospital with minimum 3-year follow-up. RESULTS: Twelve LAM recipients including nine sporadic-LAM and three tuberous sclerosis complex -LAM were identified. Nine of 12 underwent bilateral LT including four living-donor lobar LT. There was no significant difference in overall survival between the two groups. (P = 0.15). Chronic lung allograft dysfunction free survival rate in LAM compared with other diseases tended to be better (P = 0.058). However, the rate of requiring hemodialysis was significantly higher in LAM recipients than in the recipients of other diseases (P = 0.047). Notably, 8 of 12 (67%) LAM patients encountered LAM-related complication including chylothorax and pneumothorax, seven (58%) had proliferative diseases consisting of renal angiomyolipoma and recurrent LAM. Nine patients required mTOR inhibitors for LAM-related problems, contributing to improved control of LAM-related problems. While all nine recipients of bilateral LT have still survived, two patients died of diseases in their native lungs and one required re-LT among three recipients of single LT. CONCLUSION: Although the rates of LAM-related complications were unexpectedly high in the long term, LT is a feasible therapeutic option for patients with advanced pulmonary LAM.

DOI： 10.1111/crj.13108

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT is the most sensitive non-invasive imaging method for the detection of tumor metastasis and recurrence, but sometimes reveals false-positive results. Herein, we report two cases of false-positive results on PET/CT scans along with elevated serum carcinoembryonic antigen (CEA) levels, mimicking local recurrence after pulmonary segmentectomy. CASE PRESENTATION: Case 1; A 75-year-old woman underwent thoracoscopic left basal segmentectomy for primary lung cancer. Follow-up at 6 months after the surgery revealed serum CEA level elevation and chest CT showed a nodule measuring 25 × 22 mm in the residual left lower lobe. PET/CT revealed FDG uptake in the nodule diagnosed as local recurrence of lung cancer, and the patient underwent partial resection of the nodule. Microscopic examination of the resected specimen revealed granuloma caused by polyglycolic acid (PGA) sheet. Case 2; A 58-year-old man underwent VATS right S1 segmentectomy for lung metastasis from rectal carcinoma. Serum CEA levels gradually increased after surgery, and PET/CT revealed FDG uptake in the stump diagnosed as local recurrence of the lung metastasis. The patient underwent completion lobectomy 6 months after the segmentectomy, and the pathology of the resected specimen revealed an inflammatory granuloma caused by PGA suture. CONCLUSIONS: Although suture and stapler granulomas have been reported, granuloma caused by PGA sheets has never been reported. Postoperative recurrence of lung cancer should be diagnosed with not only PET/CT scans and serum tumor markers but also pathological findings, to avoid unnecessary treatment such as chemotherapy, radiation, and difficult reoperation.

DOI： 10.1186/s13019-020-1055-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Ischemia-reperfusion injury (IRI) after lung transplantation mainly contributes to the development of primary graft dysfunction. The Sprouty-related EVH1-domain-containing (SPRED) protein family inhibits the mitogen activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) pathway. Our study was aimed at examining the role of SPRED2 in IRI in mice that received orthotopic lung transplantation. Syngeneic mouse lung transplantation was performed in wild-type C57BL/6 J (WT) mice and Spred2 knockout (Spred2-/-) mice on the C57BL/6 J background from the WT donor. Four hours after reperfusion, blood gas analysis was performed, and lung grafts were sacrificed and analyzed. By using arterial oxygen tension measurements and histological evaluation using Lung Injury Score, we revealed more severe IRI in the grafts transplanted to Spred2-/- recipients, which manifested as exacerbated airway epithelial cell damage, interstitial edema with hemorrhage and neutrophil infiltration. Intragraft ERK1/2 activation and expression levels of proinflammatory cytokines and chemokines in Spred2-/- recipients were higher than those in WT recipients. SPRED2 plays an important role in protecting the lungs from IRI in lung transplantation recipients. We suggest that focused treatments suppressing the activity of the MAPK/ERK pathway in transplantation recipients could be the potential therapeutic option for the prevention of lung IRI.

DOI： 10.1016/j.trim.2019.101242

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: The differences in chronic lung allograft dysfunction (CLAD) between living-donor lobar lung transplantation (LDLLT) and cadaveric lung transplantation (CLT) remain unclear. We conducted this study to compare the impact of CLAD on the outcomes after LDLLT vs. CLT. METHODS: We conducted a retrospective review of the data of 97 recipients of bilateral lung transplantation, including 51 recipients of LDLLT and 46 recipients of CLT. RESULTS: The CLAD-free survival and overall survival after LDLLT were similar to those after CLT. CLAD and restrictive allograft syndrome (RAS), but not bronchiolitis obliterans syndrome (BOS), developed significantly later after LDLLT than after CLT (p = 0.015 and p = 0.035). Consequently, patients with CLAD and RAS, but not those with BOS, after LDLLT had a significantly better overall survival than those after CLT (p = 0.037 and p = 0.0006). Furthermore, after the diagnosis of CLAD, the survival of patients with RAS after LDLLT tended to be better than that after CLT (p = 0.083). CONCLUSION: CLAD, especially RAS, appears to develop later after LDLLT than after CLT and seems to have a lower impact on the overall survival after LDLLT than that after CLT.

DOI： 10.1007/s00595-019-01782-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Postoperative pericardial adhesions are considered a risk factor for redo cardiac surgery. Several large- and medium-size animal models of pericardial adhesions have been reported, but small animal models for investigating the development of anti-adhesion materials and molecular mechanisms of this condition are lacking. In this study, we aimed to establish a simple mouse model of pericardial adhesions to address this gap. METHODS: We administered blood, minocycline, picibanil, and talc into the murine pericardial cavity via one-shot injection. Micro-computed tomography analyses of contrast agent-injected mice were carried out for methodological evaluation. We investigated various dosages and treatment durations for molecules identified to be inducers of pericardial adhesion. The adhesive grade was quantified by scoring the strength and volume of adhesion tissues at sacrificed time points. Histological staining with hematoxylin and eosin and Masson's trichrome, and immunostaining for F4/80 or αSMA was performed to investigate the structural features of pericardial adhesions, and pathological features of the pericardial adhesion tissue were compared with human clinical specimens. RESULTS: Administration of talc resulted in the most extensive pericardial adhesions. Micro-computed tomography imaging data confirmed that accurate injection into the pericardial cavity was achieved. We found the optimal condition for the formation of strong pericardial adhesions to be injection of 2.5 mg/g talc for 2 weeks. Furthermore, histological analysis showed that talc administration led to an invasion of myofibroblasts and macrophages in the pericardial cavity and epicardium, consistent with pathological findings in patients with left ventricular assistive devices. CONCLUSIONS: We successfully established a simple mouse model of talc-induced pericardial adhesions, which mimics human pathology and could contribute to solving the clinical issues related to pericardial adhesions.

DOI： 10.1186/s13019-019-0940-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The 90-kDa heat-shock protein (HSP90) is a chaperone protein expressed at high levels in cancer cells and is involved in the folding or stabilization of several client proteins, including epidermal growth factor receptor (EGFR). Ganetespib is a second-generation HSP90 inhibitor with a potent antitumor effect against various cancer types. MATERIALS AND METHODS: This study examined the antitumor effect of ganetespib in EGFR-mutant non-small cell lung cancer (NSCLC) cells and experimentally established EGFR-tyrosine kinase inhibitor (TKI)-resistant cells harboring various resistance mechanisms, including EGFR T790M mutation, met proto-oncogene amplification, and epithelial-mesenchymal transition. RESULTS: Ganetespib showed a potent antitumor effect at low concentrations, suppressing EGFR-related downstream pathway molecules and inducing cleavage of poly ADP-ribose polymerase in all examined EGFR-TKI-resistant cell lines in vitro. Ganetespib also inhibited in vivo tumor growth in resistant cells harboring EGFR T790M. CONCLUSION: Ganetespib might be a promising therapeutic option for the treatment of patients with EGFR-TKI-resistant NSCLC.

DOI： 10.21873/anticanres.13283

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: Radical surgery with systematic upper mediastinal node dissection for primary lung cancer can cause recurrent laryngeal nerve (RLN) paralysis, but this is poorly reported. METHODS: We retrospectively reviewed the clinical data for consecutive patients who underwent radical surgery for primary lung cancer with an observation period of at least 12 months. During follow-up, hoarseness and vocal fold movement were assessed clinically and laryngoscopically, respectively. RESULTS: Of the 365 patients included in this study, 22 (6.0%) experienced hoarseness as a complication. All 22 patients who experienced hoarseness had undergone upper mediastinal node dissection. Although 1 of the 22 patients refused to undergo laryngoscopy, we assessed the vocal fold movement in the remaining patients (95.5%). Among these, 5 patients (23.8%) had right RLN paralysis, and 15 (71.4%) had left RLN paralysis and showed no sign of RLN paralysis. Over 1-24 months, vocal cord movement improved in 61.1% (11/18); and over 1-28 months, hoarseness improved in 72.7% (16/22). All patients with right RLN paralysis improved without further treatment. CONCLUSIONS: We conclude that extensive follow-up is necessary to discern whether hoarseness is a temporary or permanent complication of radical surgery in patients with primary lung cancer who have undergone systematic lymph node dissection.

DOI： 10.1093/ejcts/ezy246

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Patients with squamous cell carcinoma (SqCC) of the lung sometimes have a comorbid pulmonary disease such as pulmonary emphysema or an interstitial lung disease (ILD), both of which negatively affect patient outcome. The aim of this study was to determine the outcome of patients in a multicenter database who underwent surgery for cT1aN0M0 peripheral SqCC lung cancer. Methods: The medical records of a total of 228 eligible patients from seven institutions were reviewed to evaluate the impact of concomitant impaired pulmonary function and other clinicopathological factors on overall survival (OS) and relapse-free survival (RFS). Results: Six patients with positive or unclear tumor margins were excluded. Of the 222 remaining study patients, 42 (18.9%) and 97 (43.7%) patients were found to have coexisting restrictive or obstructive ventilatory impairment, respectively. Over a median follow-up period of 30.6 months, the 5-year OS and RFS were 69.0% and 62.6%, respectively. By multivariate analysis, ILDs identified on high-resolution computed tomography (HRCT), pulmonary function test results indicating a restrictive ventilatory impairment, and wedge resection were found to be independent risk factors for poor OS. An increased level of serum squamous cell carcinoma antigen (SCC-Ag) (>1.5 ng/mL) and the same risk factors for poor OS were independent risk factors for recurrence. Among patients who underwent anatomical lung resection (lobectomy and segmentectomy, n=173), a restrictive ventilatory impairment was an independent risk factor for poor OS, and increased serum SCC-Ag level, ILDs on HRCT, and restrictive ventilatory impairment were independent risk factors for poor RFS by multivariate analysis. Factors such as visceral pleural invasion, and lymphatic or vascular invasion were not significantly associated with outcome. Conclusions: A restrictive ventilatory impairment negatively affects the outcome of patients with cT1aN0M0 peripheral SqCC lung cancer.

DOI： 10.21037/jtd.2017.10.70

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Lung injury is a life-threatening complication in patients with liver dysfunction. We recently provided an experimental lung injury model in mouse with common bile duct ligation. In this study, we aimed to characterize the pathologic and biochemical features of lung tissues in common bile duct ligation mice using a proteomic approach. METHODS: Common bile ducts of BALB/c mice, 8 weeks of age, were ligated operatively. CD31-expressing pulmonary cells were sorted with immunomagnetic microbeads, and protein profiles were examined by 2-dimensional gel electrophoresis. Based on the results of protein identification, immunohistochemistry and quantitative reverse transcription polymerase chain reaction were carried out in pulmonary and hepatic tissues. RESULTS: Two-dimensional gel electrophoresis revealed 3 major inflammation-associated proteins exhibiting considerable increases in the number of CD31-positive pulmonary cells after common bile duct ligation. Mass spectrometry analysis identified these proteins as SerpinB1a (48 kDa), ANXA1 (46 kDa), and S100A9 (16 kDa). Furthermore, the 3 proteins were more highly expressed in dilated pulmonary blood vessels of common bile duct ligation mice, in which neutrophils and monocytes were prominent, as shown by immunohistochemistry. More importantly, SerpinB1a mRNA and protein were significantly upregulated in the liver, whereas S100A9 and ANXA1 mRNA and protein were upregulated in the lungs, as shown by quantitative reverse transcription polymerase chain reaction and Western blotting. CONCLUSION: We identified 3 proteins that were highly expressed in the lung after common bile duct ligation using a proteomics-based approach.

DOI： 10.1016/j.surg.2016.12.017

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Spirometry is sometimes difficult to perform in elderly patients and in those with severe respiratory distress. The forced-oscillation technique (FOT) is a simple and noninvasive method of measuring respiratory impedance. The aim of this study was to determine if FOT data reflect spirometric indices. PATIENTS AND METHODS: Patients underwent both FOT and spirometry procedures prior to inclusion in development (n=1,089) and validation (n=552) studies. Multivariate linear regression analysis was performed to identify FOT parameters predictive of vital capacity (VC), forced VC (FVC), and forced expiratory volume in 1 second (FEV1). A regression equation was used to calculate estimated VC, FVC, and FEV1. We then determined whether the estimated data reflected spirometric indices. Agreement between actual and estimated spirometry data was assessed by Bland-Altman analysis. RESULTS: Significant correlations were observed between actual and estimated VC, FVC, and FEV1 values (all r>0.8 and P<0.001). These results were deemed robust by a separate validation study (all r>0.8 and P<0.001). Bias between the actual data and estimated data for VC, FVC, and FEV1 in the development study was 0.007 L (95% limits of agreement [LOA] 0.907 and -0.893 L), -0.064 L (95% LOA 0.843 and -0.971 L), and -0.039 L (95% LOA 0.735 and -0.814 L), respectively. On the other hand, bias between the actual data and estimated data for VC, FVC, and FEV1 in the validation study was -0.201 L (95% LOA 0.62 and -1.022 L), -0.262 L (95% LOA 0.582 and -1.106 L), and -0.174 L (95% LOA 0.576 and -0.923 L), respectively, suggesting that the estimated data in the validation study did not have high accuracy. CONCLUSION: Further studies are needed to generate more accurate regression equations for spirometric indices based on FOT measurements.

DOI： 10.2147/COPD.S143721

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掲載種別：研究論文（学術雑誌）  

© 2016 The Japanese Society of Internal Medicine. Pneumothorax associated with thoracic endometriosis (TE) generally occurs in women around 30 years old and it usually affects the right pleural cavity. We herein report two cases of TE associated with left-sided pneumothorax in young women. The prevalence of TE in younger patients may be underestimated if these cases are treated as spontaneous pneumothorax. Pneumothorax occurring in younger patients has not been reported to show laterality. TE-related or catamenial pneumothorax in young women must therefore represent a different clinical entity from the condition seen in older patients.

DOI： 10.2169/internalmedicine.55.7187

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Early growth response-1 (Egr-1) has been shown to be a trigger-switch transcription factor that is involved in lung ischemia-reperfusion injury (IRI). METHODS: Mouse lung transplants were performed in wild-type (WT) C57BL/6 and Egr1-knockout (KO) mice in the following donor → recipient combinations: WT → WT, KO → WT, WT → KO, and KO → KO to determine whether the presence of Egr-1 in the donor or recipient is the most critical factor for IRI. Pulmonary grafts were retrieved after 18 hours of ischemia after 4 hours of reperfusion. We analyzed graft function by analyzing arterial blood gas and histology in each combination and assessed the effects of Egr1 depletion on inflammatory cytokines that are regulated by Egr-1 as well on polymorphonuclear neutrophil (PMN) infiltration. RESULTS: Deletion of Egr1 improved pulmonary graft function in the following order of donor → recipient combinations: WT → WT < WT → KO < KO → WT < KO → KO. Polymerase chain reaction assays for Il1B, Il6, Mcp1, Mip2, Icam1, and Cox2 showed significantly lower expression levels in the KO → KO group than in the other groups. Immunohistochemistry demonstrated clear Egr-1 expression in the nuclei of pulmonary artery endothelial cells and PMN cytoplasm in the WT grafts. Flow cytometry analysis showed that Egr1 deletion reduced PMN infiltration and that the extent of reduction correlated with graft function. CONCLUSIONS: Both graft and recipient Egr-1 played a role in lung IRI, but the graft side contributed more to this phenomenon through regulation of PMN infiltration. Donor Egr-1 expression in pulmonary artery endothelial cells may play an important role in PMN infiltration, which results in IRI after lung transplantation.

DOI： 10.1097/TP.0000000000000783

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記述言語：日本語   出版者・発行元：日本気胸・嚢胞性肺疾患学会  

自然気胸に対する単孔式胸腔鏡手術(VATS)の有用性について検討した。自然気胸に対してVATS肺部分切除を施行した41例を対象とし、3-port VATS(I群)30例、単孔式VATS(II群)11例であった。II群は問題なく手術を終了し、術後経過も良好であった。平均手術時間は、I群70.3±5.2分に対して、II群63.2±8.6分であったが、両群間に有意差は認めなかった。術中出血量、自動縫合器使用本数も両群間で有意差はなかった。術後の平均ドレーン留置期間はI群2.0±0.2日に対して、II群1.3±0.3日で、II群で有意に短かった。術後合併症はI群で肺瘻遷延を1例認めたのみで、II群には認めなかったが、両群間で有意差は認めなかった。I群で2例、II群でで1例の再発を認めたが、両群間で有意差は認めなかった。術後の平均観察期間はI群のほうが長かったが、両群間で有意差は認めなかった。

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Granular cell tumor (GCT) is found in various organs but is rare in the mediastinum. We report a case of mediastinal GCT in a 19-year-old woman who presented with left ptosis and miosis. CT and MRI revealed a 29-mm well-circumscribed tumor located close to the first thoracic vertebra with features suggesting a neurogenic tumor. The tumor was completely excised using single-port video-assisted thoracoscopic surgery. Histopathological and immunohistochemical analysis revealed that the tumor was a benign GCT. Postoperatively, left ptosis and miosis had improved slightly. To our knowledge, this is the first report regarding mediastinal GCT presenting with preoperative Horner's syndrome.

DOI： 10.5761/atcs.cr.15-00112

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 71-year-old man diagnosed with lung cancer in the right lower lobe with invasion to the middle lobe underwent right lower and middle lobectomy with mediastinal lymph node dissection. The cancer was pathologically diagnosed as stage IIB (pT3N0M0) with combined squamous cell carcinoma and an atypical carcinoid tumour. To the best of our knowledge, this is the first report of a combined atypical carcinoid tumour and non-small cell lung cancer. This case further expands the histological spectrum of combined neuroendocrine tumours.

DOI： 10.2169/internalmedicine.54.3846

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Liver dysfunction and cirrhosis affect vasculature in several organ systems and cause impairment of organ functions, thereby increasing morbidity and mortality. Establishment of a mouse model of hepatopulmonary syndrome (HPS) would provide greater insights into the genetic basis of the disease. Our objectives were to establish a mouse model of lung injury after common bile duct ligation (CBDL) and to investigate pulmonary pathogenesis for application in future therapeutic approaches. METHODS: Eight-week-old Balb/c mice were subjected to CBDL. Immunohistochemical analyses and real-time quantitative reverse transcriptional polymerase chain reaction were performed on pulmonary tissues. The presence of HPS markers was detected by western blot and microarray analyses. RESULTS: We observed extensive proliferation of CD31-positive pulmonary vascular endothelial cells at 2 weeks after CBDL and identified 10 upregulated and 9 down-regulated proteins that were associated with angiogenesis. TNF-α and MMP-9 were highly expressed at 3 weeks after CBDL and were less expressed in the lungs of the control group. CONCLUSIONS: We constructed a mouse lung injury model by using CBDL. Contrary to our expectation, lung pathology in our mouse model exhibited differences from that of rat models, and the mechanisms responsible for these differences are unknown. This phenomenon may be explained by contrasting processes related to TNF induction of angiogenic signaling pathways in the inflammatory phase. Thus, we suggest that our mouse model can be applied to pulmonary pathological analyses in the inflammatory phase, i.e., to systemic inflammatory response syndrome, acute lung injury, and multiple organ dysfunction syndrome.

DOI： 10.1371/journal.pone.0094550

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掲載種別：研究論文（学術雑誌）  

Diffuse pulmonary arteriovenous malformations (AVMs) are associated with a poor prognosis and the therapeutic strategy remains controversial. We describe a pediatric patient with diffuse pulmonary AVMs associated with hereditary hemorrhagic telangiectasia (HHT), who presented with two cerebral AVMs in the parietal and occipital lobes as well. Of note, successful bilateral lung transplantation not only improved the hypoxemia but also resulted in size reduction of the cerebral AVMs. Although it is essential to consider involvements other than pulmonary AVMs, especially brain AVMs, to decide the indication, lung transplantation can be a viable therapeutic option for patients with diffuse pulmonary AVMs and HHT. The authors describe a successful lung transplant in a patient with diffuse pulmonary arteriovenous malformations and hereditary hemorrhagic telangiectasia, focusing on its potential to improve cerebral arteriovenous malformations. © Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.

DOI： 10.1111/ajt.12499

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Ischemia reperfusion injury (IRI) remains a significant cause of morbidity and mortality after lung transplantation. Early growth response-1 (EGR1) drives the expression of inflammatory mediators and has an important role in IRI. We hypothesized that the severe IRI caused by a long preservation induces a specific expression pattern of EGR1 and its target genes which would correlate with the lung graft function. METHODS: SD rat lungs were preserved at 4 °C for 3 or 18 h, then transplanted and reperfused. Pulmonary grafts were evaluated for the blood gas oxygenation and pathological findings. The intra-graft mRNA levels of EGR1 and its downstream target genes were measured by real-time PCR. A Western blotting analysis of the EGR1 expression was used to validate the changes in the protein level. RESULTS: There was upregulation of EGR1, MIP-2 and PAI-1 when there was prolonged hypothermic preservation. The expression levels of MIP-2 and PAI-1 were observed to increase for up to 4 h in the 18 h preserved lungs. There were no differences in the expression levels of IL-1β and ICAM-1 between the lungs subjected to short and long periods of ischemia. CONCLUSIONS: Our data showed that prolonged hypothermic graft preservation deteriorates the pulmonary graft function, which was associated with the induction of EGR1 and its downstream target genes, which may aggravate IRI following lung transplantation.

DOI： 10.1007/s00595-012-0234-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Two cases of postpericardiotomy syndrome (PPS) after thymothymectomy associated with pericardiotomy are described. The incidence of PPS in cardiac operations is reportedly 10-30%. Although no reports have been described in the English literature, our retrospective analysis revealed similar incidents following mediastinal tumor operation associated with pericardiotomy in cardiac surgery. Clinicians should thus be aware of this syndrome.

DOI： 10.1007/s11748-012-0021-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

It has been 5 years since our team reported the first successful model of orthotopic single lung transplantation in the mouse. There has been great demand for this technique due to the obvious experimental advantages the mouse offers over other large and small animal models of lung transplantation. These include the availability of mouse-specific reagents as well as knockout and transgenic technology. Our laboratory has utilized this mouse model to study both immunological and non-immunological mechanisms of lung transplant physiology while others have focused on models of chronic rejection. It is surprising that despite our initial publication in 2007 only few other laboratories have published data using this model. This is likely due to the technical complexity of the surgical technique and perioperative complications, which can limit recipient survival. As two of the authors (XL and WL) have a combined experience of over 2500 left and right single lung transplants, this review will summarize their experience and delineate tips and tricks necessary for successful transplantation. We will also describe technical advances made since the original description of the model.

DOI： 10.3978/j.issn.2072-1439.2012.06.02

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Although lung transplantation from donation after cardiac death (DCD), especially uncontrolled DCD, is limited by warm ischemic periods, the molecular mechanism of warm ischemia-reperfusion-injury (IRI) has not been well elucidated. The purpose of this study was to clarify the particular longitudinal mechanisms of molecular factors involved in warm IRI. METHODS: Cold ischemic-time (CIT)-group lungs were retrieved and subjected to 3-h of cold preservation, whereas warm ischemic-time (WIT)-group lungs were retrieved after 3-h of warm ischemia. Orthotopic rat lung transplantation was performed and the grafts were reperfused for 1 or 4-h. The graft functions, gene expression, and activation of inflammatory molecules in the grafts were analyzed. Exhaled-carbon-monoxide-concentration (ExCO-C) was measured during reperfusion. RESULTS: Only the WIT-group showed obvious primary graft dysfunction at 1-h reperfusion, but the graft function was recovered during 4-h reperfusion. Most of pro-inflammatory cytokines and stress-induced molecules showed different expression and activation patterns between CIT and WIT groups. In the WIT-group, the expressions of anti-inflammatory molecules, IL-10 and HO-1, were significantly increased at 1-h reperfusion compared to the CIT-group, and these high levels were maintained through 4-h reperfusion. Furthermore, ExCO-C levels in the WIT-group increased immediately after reperfusion compared to the CIT-group. CONCLUSIONS: This study indicates that warm IRI may involve a different mechanism than cold IRI and anti-inflammatory pathways may play important roles in the graft recovery after lung transplantation from uncontrolled DCD.

DOI： 10.1016/j.trim.2011.11.002

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: Acute allograft rejection is one of the significant complications occurring in lung transplant recipients. Early growth response-1 (Egr-1), zinc-finger-type transcription factor, is known as a master switch regulator of diverse chemical mediators. We used an orthotopic mouse model of left lung transplant to elucidate the function of Egr-1 in acute pulmonary rejection. METHODS: Left lung grafts retrieved from C57BL/6 wild mice or C57BL/6 Egr-1-null mice were orthotopically transplanted into BALB/c mice; the lungs were harvested at day 1, 3, 5 or 7 after lung transplantation. The grade of acute rejection was histopathologically evaluated. The intragraft gene expression levels of Egr-1 and downstream target mediators were quantitatively measured by real-time polymerase chain reaction. Immunohistochemical analysis was used to determine the location and distribution of the Egr-1 protein in the pulmonary graft. RESULTS: Severe acute rejection was observed in allografts from wild-type mice at 5 days after transplantation. Only minimal rejection was seen in the lung graft from Egr-1-null donor mice at 5 days after transplantation. Strong upregulation of Egr-1 mRNA transcripts was observed at day 1, which then decreased during the next 5 days. The mRNA of Egr-1 target mediators [interleukin-1-beta (IL-1β), monocyte chemotactic protein-1 (MCP-1) and plasminogen activator inhibitor-1] reached maximal levels at day 5. Egr-1-null allografts exhibited significantly lower expressions of IL-1β and MCP-1 mRNA (P < 0.05). CONCLUSIONS: Our study showed that deletion of Egr-1 in lung allografts ameliorates severe acute rejection with the reduction of expression levels of chemical mediators, implying a new possible strategy for treating acute pulmonary allograft rejection.

DOI： 10.1093/ejcts/ezr030

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The mechanisms by which innate immune signals regulate alloimmune responses remain poorly understood. In the present study, we show by intravital 2-photon microscopy direct interactions between graft-infiltrating neutrophils and donor CD11c(+) dendritic cells (DCs) within orthotopic lung allografts immediately after reperfusion. Neutrophils isolated from the airways of lung transplantation recipients stimulate donor DCs in a contact-dependent fashion to augment their production of IL-12 and expand alloantigen-specific IFN-γ(+) T cells. DC IL-12 expression is largely regulated by degranulation and induced by TNF-α associated with the neutrophil plasma membrane. Extended cold ischemic graft storage enhances G-CSF-mediated granulopoiesis and neutrophil graft infiltration, resulting in exacerbation of ischemia-reperfusion injury after lung transplantation. Ischemia reperfusion injury prevents immunosuppression-mediated acceptance of mouse lung allografts unless G-CSF-mediated granulopoiesis is inhibited. Our findings identify granulopoiesis-mediated augmentation of alloimmunity as a novel link between innate and adaptive immune responses after organ transplantation.

DOI： 10.1182/blood-2011-04-347823

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掲載種別：研究論文（国際会議プロシーディングス）  

Accepting organs donated after cardiac death (DCD) is an effective approach to the donor shortage. However, lung transplantations from DCD donors show severe rapid pulmonary graft dysfunction (PGD) followed by warm ischemiareperfusion injury (IRI). This study sought to clarify the molecular mediators in warm IRI, including activation of mitogen-activated protein kinase (MAPK) and the downstream cascades. We performed single left lung transplantation using organs from male Sprague-Dawley rats after 0 (CIT group), 30 (30WIT group), or 180 (180WIT group) minutes of warm ischemia time. Pulmonary graft functions were estimated by blood gas analysis. At 1 hour after reperfusion, the phosphorylation status of MAPKs (ERK, p38, and JNK) and the gene expression levels of transcription factors (Egr-1 and ATF-3) and immune mediators (MCP-1, MIP-2, PAI-1, ICAM-1, TNF-α, IL-1β, IL-6, and COX-2) in the grafts were examined using Western blotting and real-time polymerase chain reaction assays. Severe PGD was observed in the 180WIT group compared with transplanted lungs in the other groups, which exhibited good pulmonary graft function. ERK and JNK activations, as well as mRNA levels of transcription factors (Egr-1 and ATF3) significantly increased with greater warm ischemic times. The pattern of JNK activation correlated with the severity of PGD. MCP-1, ICAM-1, IL-1β, IL-6, and COX-2 were also up-regulated among the 180WIT group, although MIP-2 and PAI-1 showed no significant differences among the groups. We suggest that the ERK and JNK pathways may play important roles to induce the injury caused by prolonged warm ischemia followed by reperfusion in the setting of lung transplantation from DCD donors. © 2011 Published by Elsevier Inc.

DOI： 10.1016/j.transproceed.2011.09.075

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The safety and perioperative problems of primary lung cancer surgery after curative chemoradiotherapy (CRT) for thoracic esophageal cancer (EC) are controversial. We retrospectively evaluated six patients who had received curative CRT for EC from 2003 to 2009, in whom the lung nodule was identified as a primary lung cancer and who subsequently underwent pulmonary resection. The treatment for EC consisted of chemotherapy with cisplatin and 5-fluorouracil with concurrent curative thoracic radiotherapy (60 Gy). The median age at the surgery was 75 years (range 69-80 years). The median time from radiation to pulmonary resection was 26 months (range 7-70 months). All patients had a predicted postoperative forced expiratory volume in 1 s (FEV(1))% of >40% before lung surgery. The surgical difficulty involves mediastinal lymph node dissection following tissue fibrotic changes after thoracic radiation. Postoperative complications occurred in two patients, and included arrhythmia and empyema. The patient who developed empyema had a massive pericardial effusion after CRT and underwent pericardial fenestration at the time of pulmonary resection. There was no operative mortality. Lung cancer surgery after curative CRT for EC is feasible in carefully evaluated and selected patients.

DOI： 10.1510/icvts.2010.263509

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We report an extremely rare case of pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma with a pulmonary arteriovenous fistula (PAVF). A 60-year-old woman with vulvar carcinoma was admitted to our hospital for further examination of an abnormal shadow on chest computed tomography (CT). She showed hypoxemia in the arterial blood gas analysis. (18)F-Fluorodeoxyglucose positron emission tomography (FDG-PET) showed consolidations in the left lower lobe and soft-tissue density lesions in the anterior mediastinum. Each lesion showed heterogeneous FDG uptake. Although needle biopsy of these lesions was performed, a pathological diagnosis was not obtained. For the evaluation of hypoxemia, chest contrast-enhanced CT was performed, and a PAVF in the consolidation of the left lower lobe was revealed. For diagnostic and therapeutic purposes, we performed left lower lobectomy under video-assisted thoracoscopic surgery. In the surgical specimen the PAVF measured 3 cm, and histopathological examination revealed pulmonary MALT lymphoma adjacent to the PAVF.

DOI： 10.1007/s11748-010-0671-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Signaling pathways that target I-κB kinase β (IKKβ) activation stimulate the expression of nuclear factor (NF)-κB-dependent genes and are thus believed to primarily promote inflammation and injury in solid organ grafts. METHODS: We examined the role of IKKβ in a mouse model of lung transplantation-mediated ischemia-reperfusion injury using NF-κB essential modulator (NEMO)-binding domain (NBD) peptide to pharmacologically inhibit IKK activation. As myeloid cells are primarily responsible for the production of acute inflammatory mediators after lung transplantation, we also investigated the effects of myeloid cell-specific IKKβ gene deletion on acute lung graft injury by transplanting mutant mice. RESULTS: When NBD was administered at a dose that partially inhibits IKKβ activation, we observed attenuated lung graft injury and blunted expression of intragraft proinflammatory mediators. Surprisingly, when the dose of NBD was increased to a level that ablates intragraft IKKβ activation, graft inflammation, and injury were significantly worse compared with recipients treated with control peptide. Similar to lung recipients with pharmacologically ablated IKKβ activity, donor-recipient transplant combinations with a myeloid cell-specific IKKβ gene deletion had marked intragraft inflammation and poor lung function. CONCLUSIONS: Our data show maintenance of IKKβ activity is critical for promoting graft homeostasis with important implications for targeting NF-κB-dependent signaling pathways for treating acute lung injury.

DOI： 10.1097/TP.0b013e31820ba2a0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Lung grafts can be perfused ex vivo for 2 hours without edema formation; however, prolonged ex vivo lung perfusion (EVLP) eventually induces lung injury. This study evaluated the change in proinflammatory cytokines of the perfusate during EVLP and investigated the effect of cytokine removal using an adsorbent membrane. METHODS: Porcine heart-lung blocks were harvested after electrically induced cardiac arrest and underwent 12-hour EVLP with an adsorbent membrane (membrane group: n = 5) and without an adsorbent membrane (control group: n = 6). RESULTS: In the control group, both tumor necrosis factor-alpha and interleukin 8 levels were elevated in the perfusate 2 hours after perfusion. Although tumor necrosis factor-alpha and interleukin 8 levels were significantly lower in the membrane group than in the control group during the EVLP period, there was no significant difference in oxygenation, pulmonary vascular resistance, edema formation, or myeloperoxidase activity between the two groups. CONCLUSIONS: Tumor necrosis factor-alpha and interleukin 8 levels of the perfusate were elevated during EVLP. Although adverse effects of these inflammatory cytokines were anticipated, removal of inflammatory cytokines by the adsorbent membrane did not improve lung function during prolonged EVLP. Factors other than the cytokines may play a major role in causing lung injury during EVLP. Further research is needed to investigate the real mechanism of lung graft injury during prolonged EVLP and to establish longer EVLP duration for graft treatment. This strategy could contribute to the salvage of potentially damaged lungs, especially from cardiac death donors, and to expansion of the donor pool.

DOI： 10.1016/j.athoracsur.2010.02.077

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掲載種別：研究論文（学術雑誌）  

Graft rejection remains a formidable problem contributing to poor outcomes after lung transplantation. Blocking chemokine pathways have yielded promising results in some organ transplant systems. Previous clinical studies have demonstrated upregulation of CCR2 ligands following lung transplantation. Moreover, lung injury is attenuated in CCR2-deficient mice in several inflammatory models. In this study, we examined the role of CCR2 in monocyte recruitment and alloimmune responses in a mouse model of vascularized orthotopic lung transplantation. The CCR2 ligand MCP-1 is upregulated in serum and allografts following lung transplantation. CCR2 is critical for the mobilization of monocytes from the bone marrow into the bloodstream and for the accumulation of CD11c+ cells within lung allografts. A portion of graft-infiltrating recipient CD11c+ cells expresses both recipient and donor MHC molecules. Two-photon imaging demonstrates that recipient CD11c+ cells are associated with recipient T cells within the graft. While recipient CCR2 deficiency does not prevent acute lung rejection and is associated with increased graft infiltration by T cells, it significantly reduces CD4+ Th1 indirect and direct allorecognition. Thus, CCR2 may be a potential target to attenuate alloimmune responses after lung transplantation. © 2010 The American Society of Transplantation and the American Society of Transplant Surgeons.

DOI： 10.1111/j.1600-6143.2010.03101.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hepatotoxicity, including cholestasis, is a rare but significant complication of treatment with calcineurin inhibitors. Timely life-saving therapy with revision of immunosuppression is mandatory. A 43-year-old woman with pulmonary hypertension was found to have severe cholestasis (serum bilirubin up to 35 mg/dL) after a living-donor lobar lung transplantation. Calcineurin-inhibitor cholestasis markedly improved after withdrawal of the calcineurin inhibitor, initiation of sirolimus, and interleukin-2 receptor blockade. Awareness of the diagnostic criteria of this rare posttransplant complication is important to initiate timely therapy.

DOI： 10.1016/j.athoracsur.2009.09.081

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 21-year-old man with pulmonary fibrosis and a 27-year-old woman with idiopathic pulmonary hypertension, who were in pulmonary hypertensive crisis, were successfully treated by using venoarterial extracorporeal membrane oxygenation, followed by living-donor lobar lung transplantation. In both of the patients, bridging time of extracorporeal membrane oxygenation to lung transplantation was 2 days, and both could be weaned from cardiopulmonary support immediately after transplantation in the operating room. No major complications were seen, including primary graft dysfunction. The cardiopulmonary functions of these patients markedly improved after living-donor lobar lung transplantation.

DOI： 10.1016/j.athoracsur.2009.07.089

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Endothelial cells express the ectoenzyme ectonucleoside adenosine triphosphate diphosphohydrolase, an apyrase that inhibits vascular inflammation by catalyzing the hydrolysis of adenosine triphosphate and adenosine diphosphate. However, ectonucleoside adenosine triphosphate diphosphohydrolase expression is rapidly lost following oxidative stress, leading to the potential for adenosine triphosphate and related purigenic nucleotides to exacerbate acute solid organ inflammation and injury. We asked if administration of a soluble recombinant apyrase APT102 attenuates lung graft injury in a cold ischemia reperfusion model of rat syngeneic orthotopic lung transplantation. METHODS: Male Fisher 344 donor lungs were cold preserved in a low-potassium dextrose solution in the presence or absence of APT102 for 18 hours prior to transplantation into syngeneic male Fisher 344 recipients. Seven minutes after reperfusion, lung transplant recipients received either a bolus of APT102 or vehicle (saline solution). Four hours after reperfusion, APT102- and saline solution-treated groups were evaluated for lung graft function and inflammation. RESULTS: APT102 significantly reduced lung graft extracellular pools of adenosine triphosphate and adenosine diphosphate, improved oxygenation, and protected against pulmonary edema. Apyrase treatment was associated with attenuated neutrophil graft sequestration and less evidence of tissue inflammation as assessed by myeloperoxidase activity, expression of proinflammatory mediators, and numbers of apoptotic endothelial cells. CONCLUSIONS: Administration of a soluble recombinant apyrase promotes lung function and limits the tissue damage induced by prolonged cold storage, indicating that extracellular purigenic nucleotides play a key role in promoting ischemia-reperfusion injury following lung transplantation.

DOI： 10.1016/j.jtcvs.2009.04.049

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

It is the prevailing view that adaptive immune responses are initiated in secondary lymphoid organs. Studies using alymphoplastic mice have shown that secondary lymphoid organs are essential to initiate allograft rejection of skin, heart, and small bowel. The high immunogenicity of lungs is well recognized and allograft rejection remains a major contributing factor to poor outcomes after lung transplantation. We show in this study that alloreactive T cells are initially primed within lung allografts and not in secondary lymphoid organs following transplantation. In contrast to other organs, lungs are acutely rejected in the absence of secondary lymphoid organs. Two-photon microscopy revealed that recipient T cells cluster predominantly around lung-resident, donor-derived CD11c(+) cells early after engraftment. These findings demonstrate for the first time that alloimmune responses following lung transplantation are initiated in the graft itself and therefore identify a novel, potentially clinically relevant mechanism of lung allograft rejection.

DOI： 10.4049/jimmunol.0803514

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掲載種別：研究論文（学術雑誌）  

Lung allografts are considered to be more immunogenic than other solid organs. Little is known about the effectiveness of immunosuppressive regimens after lung transplantation. Herein, we describe a novel model of murine vascularized orthotopic lung transplantation we used to study the effects of costimulatory blockade on lung rejection. Transplants were performed in the Balb → B6 strain combination. Recipients were either not immunosuppressed or received perioperative CD40/CD40L and CD28/B7 costimulatory blockade. Nonimmunosupressed Balb/c → B6 lung transplants had severe acute rejection 7 days after transplantation and CD8+ T cells outnumbered CD4+ T cells within the allografts. Alternatively, B6 recipients that received perioperative costimulatory blockade had minimal inflammation and there were nearly equal numbers of CD8+ and CD4+ T cells in these grafts. Approximately one third of graft-infiltrating CD4+ T cells expressed Foxp3. CD4+ T cells isolated from these grafts induced apoptosis of alloreactive CD8+ T cells that were stimulated with donor splenocytes in vitro. In contrast with wild-type B6 recipient mice, we observed severe rejection of Balb/c lungs 7 days after transplantation into Bcl-2 transgenic B6 recipients that had received costimulatory blockade. CD8+ T cells outnumbered CD4+ T cells in these immunosuppressed Bcl-2 transgenic recipients and, compared with immunosuppressed wild-type B6 recipients, a lower percentage of graft-infiltrating CD4+ T cells expressed Foxp3, and a higher percentage of graft-infiltrating CD8+ T cells expressed intereferon-γ. Thus, our results show that perioperative blockade of the CD40/CD40L and CD28/B7 costimulatory pathways markedly ameliorates acute rejection of lung allografts in wild type but not Bcl-2 transgenic recipients. © 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.transproceed.2008.10.068

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掲載種別：研究論文（学術雑誌）  

In lung grafts, ischemia-reperfusion signals rapidly induce the recruitment and differentiation of host monocytes into macrophages and dendritic cells. The nature of ischemia-reperfusion signals are antigen independent, but have been hypothesized to initiate Toll-like receptor (TLR) and interleukin (IL)-1R-mediated signaling pathways that are thought to potentiate alloimmune responses. We wondered whether MyD88, an adaptor molecule critical for both TLR and IL-1R-mediated inflammatory responses, regulated monocyte differentiation in a mouse model of vascularized orthotopic lung transplantation. Orthotopic left lung transplants were performed in the following syngeneic combinations: CD45.1+ B6 → CD45.2+ MyD88-/- and CD45.1+ B6 → CD45.2+ B6. One day later, recipient-derived dendritic cells and macrophage numbers were assessed in the bronchiolar lavage by FACS analysis. Compared with the bronchiolar lavage of wildtype recipients, MyD88-/- recipients had lower numbers of dendritic cells in lung graft airways that were of recipient origin. Lower numbers of newly differentiated lung graft dendritic cells was coincident with the appearance of higher numbers of undifferentiated monocytes in the lung airways of MyD88-/- recipients as compared with wild-type recipients. Moreover, adoptive transfer experiments demonstrated that MyD88-/- monocytes were poorer at differentiating into lung dendritic cells as compared with wild-type monocytes. Taken together, these data show that MyD88 regulates graft-infiltrating monocyte differentiation and suggests a mechanism by which TLR/IL-1R-signaling pathways control adaptive responses in lung allografts through controlling monocyte fate. © 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.transproceed.2008.09.064

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Unlike transplantation of other solid organs, vascularized mouse lung transplantation has only recently been developed. In this protocol, we describe a detailed method for performing a vascularized and aerated mouse orthotopic lung transplant, which to date represents the most physiological mouse model of lung transplantation. The procedure is divided into two separate portions consisting of donor harvest followed by implantation using the cuff technique for bronchovascular anastomoses. After a training period spanning several months, the procedure can be successfully mastered and, in experienced hands, requires approximately 90 min to perform. After an initial learning curve, perioperative survival is close to 100%. As the donor hematopoietic cells in the transplanted lung are replaced by those of the host over time, thereby creating a 'chimeric lung,' this model represents a novel research tool for the study of transplantation biology as well as other disease processes, such as malignancies.

DOI： 10.1038/nprot.2008.218

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

This report describes a new experimental procedure, a rat unilateral, orthotopic lung transplantation with cold storage, and evaluates its relevancy and reliability to study the early events during cold ischemia/reperfusion (I/R) injury. This model, using the cuff technique, does not require extensive training and is relatively easy to be established. The model can induce reproducible degrees of pulmonary graft injury including impaired gas exchange, proinflammatory cytokine upregulation, or inflammatory infiltrates, depending on the preservation time. The results are consistent with the previous clinical evidence, thus suggesting that this model is a valid and reliable animal model of cold I/R injury.

DOI： 10.1007/s00595-008-3929-x

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DOI： 10.1097/TP.0b013e318190b0be

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DOI： 10.1016/j.athoracsur.2008.07.062

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DOI： 10.1016/j.healun.2008.05.012

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jtcvs.2007.12.047

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Acute rejection continues to present a major obstacle to successful lung transplantation. Although CD4(+) T lymphocytes are critical for the rejection of some solid organ grafts, the role of CD4(+) T cells in the rejection of lung allografts is largely unknown. In this study, we demonstrate in a novel model of orthotopic vascularized mouse lung transplantation that acute rejection of lung allografts is independent of CD4(+) T cell-mediated allorecognition pathways. CD4(+) T cell-independent rejection occurs in the absence of donor-derived graft-resident hematopoietic APCs. Furthermore, blockade of the CD28/B7 costimulatory pathways attenuates acute lung allograft rejection in the absence of CD4(+) T cells, but does not delay acute rejection when CD4(+) T cells are present. Our results provide new mechanistic insight into the acute rejection of lung allografts and highlight the importance of identifying differences in pathways that regulate the rejection of various organs.

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DOI： 10.1016/j.jtcvs.2007.10.010

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DOI： 10.2741/2772

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DOI： 10.1007/s00595-008-3781-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Lung transplantation remains the only therapeutic option for many patients suffering from end-stage pulmonary disease. Long-term success after lung transplantation is severely limited by the development of bronchiolitis obliterans. The murine heterotopic tracheal transplantation model has been widely used for studies investigating pathogenesis of obliterative airway disease and immunosuppressive strategies to prevent its development. Despite its utility, this model employs proximal airway that lacks airflow and is not vascularized. We have developed a novel model of orthotopic vascularized lung transplantation in the mouse, which leads to severe vascular rejection in allogeneic strain combinations. Here we characterize differences in the fate of airway epithelial cells in nonimmunosuppressed heterotopic tracheal and vascularized lung allograft models over 28 days. Up-regulation of growth factors that are thought to be critical for the development of airway fibrosis and interstitial collagen deposition were similar in both models. However, while loss of airway epithelial cells occurred in the tracheal model, airway epithelium remained intact and fully differentiated in lung allografts, despite profound vascular rejection. Moreover, we demonstrate expression of the anti-apoptotic protein Bcl-2 in airway epithelial cells of acutely rejected lung allografts. These findings suggest that in addition to alloimmune responses, other stimuli may be required for the destruction of airway epithelial cells. Thus, the model of vascularized mouse lung transplantation may provide a new and more physiologic experimental tool to study the interaction between immune and nonimmune mechanisms affecting airway pathology in lung allografts.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Outcomes after lung transplantation are markedly inferior to those after other solid organ transplants. A better understanding of cellular and molecular mechanisms contributing to lung graft injury will be critical to improve outcomes. Advances in this field have been hampered by the lack of a mouse model of lung transplantation. Here, we report a mouse model of vascularized aerated single lung transplantation utilizing cuff techniques. We show that syngeneic grafts have normal histological appearance with minimal infiltration of T lymphocytes. Allogeneic grafts show acute cellular rejection with infiltration of T lymphocytes and recipient-type antigen presenting cells. Our data show that we have developed a physiological model of lung transplantation in the mouse, which provides ample opportunity for the study of nonimmune and immune mechanisms that contribute to lung allograft injury.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Ischemia reperfusion (I/R) injury following lung transplantation is exacerbated by the destruction of the endothelial cell barrier leading to pulmonary edema and dysregulated activated lymphocyte migration. Sphingosine 1-phosphate (S1P), a G-coupled protein receptor (GPCR) agonist, has been previously shown to promote endothelial cell tight junction formation and prevent monocyte chemotaxis. We asked if S1P treatment could improve pulmonary function and attenuate I/R injury following syngeneic rat lung transplantation. In comparison to vehicle-treated recipients, S1P administered before reperfusion significantly improved recipient oxygenation following transplantation. Improved graft function was associated with reduced inflammatory signaling pathway activation along with attenuated intragraft levels of MIP-2, TNF-alpha and IL-1beta. Moreover, S1P-treated recipients had significantly less apoptotic endothelial cells, pulmonary edema and graft accumulation of neutrophils than did vehicle-treated recipients. Thus our data show that S1P improves lung tissue homeostasis following reperfusion by enhancing endothelial barrier function and blunting monocytic graft infiltration and inflammation.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: We previously reported that post-mortem heparinization by closed-chest cardiac massage within 30 minutes after cardiac arrest is beneficial in lung transplantation (LTx) from non-heart-beating donors (NHBDs) by preventing formation of microthrombi. In this study, we evaluated the effects of post-mortem administration of urokinase 60 minutes after cardiac arrest. METHODS: Left LTx was performed in 12 pairs of mongrel dogs. Donors were sacrificed and left at room temperature for 2 hours. In Group 1 (n = 6), heparin sodium (1,000 U/kg) was administered intravenously 60 minutes after cardiac arrest, then closed-chest cardiac massage was performed for 1 minute to distribute the heparin. In Group 2 (n = 6), the donors were treated as in Group 1, except, in addition to heparin sodium, urokinase (120,000 U) was administered intravenously before and at the end of cardiac massage. After 2 hours of cardiac arrest, donor lungs were flushed with low-potassium dextran glucose solution. After left LTx, the right pulmonary artery was ligated, and recipients were followed up for 3 hours. Uni- and multivariate repeat analyses were performed to obtain statistical data. RESULTS: Group 2 had significantly better arterial oxygen tension, lower pulmonary vascular resistance and lower wet/dry weight ratio of the transplanted lung than Group 1. d-dimer level during the warm ischemia was significantly lower in Group 2 than in Group 1. CONCLUSIONS: Post-mortem administration of urokinase along with heparin is beneficial in LTx from NHBDs by fibrinolytic action on already formed pulmonary microthrombi in the cadaver donor lungs.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: We previously reported that post-mortem heparinization by closed-chest cardiac massage is beneficial in lung transplantation from non-heart-beating donors by preventing formation of microthrombi. In this study, we evaluated the optimal time for post-mortem heparinization in canine lung transplantation from non-heart-beating donors. METHODS: Left lung transplantation was performed in 25 weight-matched pairs of mongrel dogs. Donors were killed with an intravenous injection of potassium chloride and left at room temperature for 2 hours. The cadaver donors were assigned randomly to one of five study groups. In Group H0, heparin sodium (1,000 U/kg) was given intravenously before cardiac arrest. In Groups H10, H30, H45 and H60, heparin sodium (1,000 U/kg) was given intravenously 10, 30, 45 and 60 minutes after cardiac arrest, respectively, followed by closed-chest cardiac massage for 2 minutes. After 2 hours of cardiac arrest, donor lungs were flushed with low-potassium dextran glucose solution and preserved for 60 minutes. After left lung allotransplantation, the right pulmonary artery was ligated, and recipient animals were followed up for 3 hours. Uni- and multivariate repeat analyses were utilized for statistical assessment. RESULTS: After transplantation, gas exchange was significantly worse in Groups H45 and H60 than in Groups H0, H10 and H30. Thrombin/anti-thrombin III complex concentration during warm ischemia was significantly higher in Groups H30, H45 and H60 than in Groups H0 and H10. CONCLUSIONS: The optimal time for post-mortem heparinization in lung transplantation from non-heart-beating donors is approximately 30 minutes after cardiac arrest.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: We recently reported a technique of unilateral double lobar lung transplantation (UDLLT) in a canine model that was associated with satisfactory early pulmonary function. The purpose of the present experimental study was to assess the quality of bronchial healing, complication rates, survival rates and long-term pulmonary function of this new transplantation technique. METHODS: Unilateral double lobar lung transplantation was performed in 14 weight-matched pairs of dogs. In recipient animals, two grafts obtained from donor animals were implanted in the right hemithorax after right pneumonectomy. One graft (left graft) was implanted as a right upper lobe in an upside-down position and the other (right graft) was implanted in the natural anatomic position. The immunosuppressed recipients were observed for 3 weeks. Transplanted graft function was assessed under left main pulmonary artery occlusion at 1 and 3 weeks after transplantation. RESULTS: All animals survived the operation. Pulmonary artery kinking (3/14, 21%) and pulmonary venous thrombus (4/14, 29%) were exclusively observed in the graft implanted in the upside-down position. These complications decreased as the number of transplantations increased. Two of the first seven (29%) and five of the last seven recipient dogs (71%) survived for 3 weeks with excellent pulmonary function and good bronchial healing. CONCLUSIONS: This procedure was associated with a high complication incidence in the non-anatomically positioned graft. However, a precise surgical technique could decrease these complications. This technically demanding procedure provided excellent pulmonary function and good bronchial healing.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Experimental gene therapy is a promising strategy to prevent ischemia-reperfusion (I/R) injury and allograft rejection after lung transplantation, and methods will eventually be needed to characterize pulmonary transgene expression in vivo in humans. Therefore, we studied positron emission tomography (PET) as a means of performing in vivo molecular imaging in rodent models of lung transplantation. Rats were transfected endotracheally with adenovirus encoding a fusion gene of a mutant Herpes simplex virus-1 thymidine kinase and the green fluorescent protein gene (the former serving as an imaging reporter gene). Twenty-four hours after transfection, lungs were transplanted in groups representing normal transplantation, I/R injury and acute allograft rejection. Imaging was obtained either 24 h after transplantation to study reperfusion injury or 4 days after transplantation to study graft rejection. After imaging, lungs were excised and analyzed for thymidine kinase activity. Imaging detected transgene expression in transplanted lungs even in the presence of acute rejection or I/R injury. The PET imaging signal correlated with in vitro lung tissue assays of thymidine kinase activity (r(2) = 0.534). Thus, noninvasive molecular imaging with PET is a feasible, sensitive and quantitative method for characterizing pulmonary transgene expression in experimental lung transplantation.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Microthrombus formation appears to be one of the major detrimental factors in lung transplantation from non-heart-beating donors. The purpose of this study was to evaluate the effects of postmortem heparinization by closed-chest cardiac massage in a canine model of left single-lung allotransplantation from non-heart-beating donors. METHODS: Left lung transplantation was performed in 18 weight-matched pairs of mongrel dogs. Donors were killed with an intravenous injection of potassium chloride and left at room temperature for 2 hours. The cadaveric donors were assigned randomly to one of the three groups. In group 1 (n = 6), no heparin was given as a control. In group 2 (n = 6), heparin sodium (1000 U/kg) was administered intravenously before cardiac arrest. In group 3 (n = 6), heparin sodium (1000 U/kg) was administered intravenously 10 minutes after death, then closed-chest cardiac massage was performed for 2 minutes. After 2 hours of cardiac arrest, donor lungs were flushed with low-potassium dextran-glucose solution and preserved for 60 minutes. After left lung transplantation, the right pulmonary artery was ligated, and recipient animals were followed up for 3 hours. Univariate and multivariate repeated analyses were used for statistics. RESULTS: Both groups 2 and 3 had significantly better gas exchange and lower pulmonary vascular resistance than group 1. Changes in thrombin-antithrombin III complex concentration during the warm ischemia indicated that postmortem heparinization suppressed clotting activation in the donor. CONCLUSIONS: Postmortem heparinization by cardiac massage is beneficial in lung transplantation from non-heart beating donors by preventing microthrombus formation.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Bilateral living-donor lobar lung transplantation has become an accepted alternative to cadaveric lung transplantation. Because only one lobe is implanted in each chest cavity, this procedure seems to be best suited for children and small adults. The purpose of this study was to develop a technique of unilateral double lobar lung transplantation that can be applied to large adult patients. METHODS: Unilateral double lobar lung transplantation was performed in 6 weight-matched pairs of dogs. In donor animals the right middle, lower, and cardiac lobes were separated as a right graft, and the left lower lobe was separated as a left graft. In recipient animals these 2 grafts were implanted in the right hemithorax after right pneumonectomy. The left graft was implanted as a right upper lobe, having been rotated 180 degrees along the vertical axis and then 180 degrees along the horizontal axis. The right graft was implanted in the natural anatomic position. Function of the transplanted grafts was assessed for 3 hours after ligation of the left main pulmonary artery while the animals were ventilated with 100% oxygen. RESULTS: Morphologic adaptation of the 2 grafts in the right hemithorax was found to be excellent. All 6 animals survived the assessment period with excellent pulmonary function. At the end of the 3-hour assessment period, the arterial oxygen tension was 519 +/- 31 mm Hg, and the mean pulmonary artery pressure was 30.5 +/- 1.7 mm Hg. CONCLUSIONS: Unilateral double lobar lung transplantation was technically possible and associated with satisfactory early pulmonary function in a canine experimental model.

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記述言語：英語   出版者・発行元：Elsevier {BV}  

DOI： 10.1016/j.healun.2023.02.1279

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記述言語：日本語   出版者・発行元：(一社)日本外科学会  

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記述言語：日本語   出版者・発行元：日本心脈管作動物質学会  

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記述言語：日本語   出版者・発行元：(NPO)日本医工学治療学会  

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記述言語：英語   出版者・発行元：Elsevier {BV}  

DOI： 10.1016/j.healun.2022.01.623

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記述言語：英語   出版者・発行元：Elsevier {BV}  

DOI： 10.1016/j.healun.2022.01.112

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記述言語：英語   出版者・発行元：Elsevier {BV}  

DOI： 10.1016/j.healun.2022.01.1512

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記述言語：英語   出版者・発行元：Elsevier {BV}  

INTRODUCTION: The percentage of low attenuation area (%LAA) on computed tomography (CT) is useful for evaluating lung emphysema, and higher %LAA was observed in patients with chronic lung allograft dysfunction (CLAD). This study investigated the relationship between the %LAA and the development of CLAD after bilateral lung transplantation (LT). METHODS: We conducted a single-center retrospective study of 75 recipients who underwent bilateral LT; the recipients were divided into a CLAD group (n = 30) and a non-CLAD group (n = 45). The %LAA was calculated using CT and compared between the two groups from 4 years before to 4 years after the diagnosis of CLAD. The relationships between the %LAA and the percent baseline values of the pulmonary function test parameters were also calculated. RESULTS: The %LAA was significantly higher in the CLAD group than in the non-CLAD group from 2 years before to 2 years after the diagnosis of CLAD (P < .05). In particular, patients with bronchiolitis obliterans syndrome (BOS) exhibited significant differences even from 4 years before to 4 years after diagnosis (P < .05). Significant negative correlations between the %LAA and the percent baseline values of the forced expiratory volume in 1 s (r = -.36, P = .0031), the forced vital capacity (r = -.27, P = .027), and the total lung capacity (r = -.40, P < .001) were seen at the time of CLAD diagnosis. CONCLUSION: The %LAA on CT was associated with the development of CLAD and appears to have the potential to predict CLAD, especially BOS, after bilateral LT.

DOI： 10.1016/j.healun.2022.01.247

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記述言語：英語   出版者・発行元：Elsevier {BV}  

DOI： 10.1016/j.healun.2022.01.040

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記述言語：英語   出版者・発行元：Elsevier {BV}  

DOI： 10.1016/j.healun.2022.01.191

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記述言語：日本語   出版者・発行元：(一社)日本外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本内視鏡外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(一社)日本胸部外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本胸部外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本胸部外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本胸部外科学会  

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記述言語：日本語   出版者・発行元：日本臨床外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(一社)日本胸部外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本胸部外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本胸部外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本胸部外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(一社)日本胸部外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本胸部外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本胸部外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本胸部外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本外科学会  

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記述言語：英語   出版者・発行元：Elsevier {BV}  

DOI： 10.1016/j.healun.2021.01.1007

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記述言語：英語   出版者・発行元：Elsevier {BV}  

DOI： 10.1016/j.healun.2021.01.452

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記述言語：英語   出版者・発行元：Elsevier {BV}  

DOI： 10.1016/j.healun.2021.01.867

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記述言語：英語   出版者・発行元：Elsevier {BV}  

DOI： 10.1016/j.healun.2021.01.884

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記述言語：英語   出版者・発行元：Elsevier {BV}  

DOI： 10.1016/j.healun.2021.01.455

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記述言語：英語   出版者・発行元：Elsevier {BV}  

DOI： 10.1016/j.healun.2021.01.977

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記述言語：英語   出版者・発行元：Elsevier {BV}  

DOI： 10.1016/j.healun.2021.01.995

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：日本語   出版者・発行元：兵庫県外科医会  

J-GLOBAL

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J06456&link_issn=&doc_id=20210507180001&doc_link_id=%2Ffi1hyogo%2F2021%2F005500%2F001%2F0005-0009%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Ffi1hyogo%2F2021%2F005500%2F001%2F0005-0009%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

転移性肺腫瘍による続発性気胸は時に経験されるが、その原発腫瘍としては肉腫、特に骨肉腫による報告が多い。今回、骨肉腫の治療終了後、気胸の発症を契機に骨肉腫の肺転移を診断し、その後全身化学療法を施行して無再発生存を得ている症例を経験したので報告する。症例は14歳の男性で、左脛骨原発の骨肉腫と診断され、腫瘍広範切除術と人工関節置換術が施行された。術後化学療法が行われ、治療終了約6ヵ月後に右自然気胸となった。画像上、肺転移巣を疑う陰影は認めなかったが、右上葉胸膜直下に5mm大の嚢胞を認めた。術中同部位からの気漏を確認し、肺部分切除術を施行した。組織学的に骨肉腫の肺転移であり、胸膜直下の転移巣による胸膜の破綻が気胸の原因であると考えられた。骨肉腫の既往や治療後経過観察中に気胸を発症した場合は、骨肉腫の肺転移を疑い、診断と治療を兼ねた外科切除が有用であると考えられた。(著者抄録)

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J02256&link_issn=&doc_id=20210125360005&doc_link_id=10.2995%2Fjacsurg.35.27&url=https%3A%2F%2Fdoi.org%2F10.2995%2Fjacsurg.35.27&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

記述言語：日本語   出版者・発行元：(一社)日本外科学会  

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J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：日本臨床外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本心臓血管外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本心臓血管外科学会  

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J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本胸部外科学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：一般社団法人 日本移植学会  

【背景】日本における高齢者レシピエントの長期成績に関しての報告は少ない．今回当院における高齢者レシピエントの長期成績について後方視的に検討した.【対象と方法】1998年1月～2020年1月に施行した18歳以上の肺移植症例161例を対象とした.60歳以上の高齢群(H群：n=10)と18-59歳の非高齢群(L群:n=151)の2群に分けて,全生存期間(OS)およびCLAD発症までの期間(CFS)について解析を行った.【結果】H群ではL群と比較して片肺移植(p=0.03),間質性肺炎(p=0.02),男性(p=0.04)の割合が有意に多かった.BMI,ドナー年齢,総虚血時間,LASスコアには有意差は認めなかった.H群とL群の5年OSはそれぞれ51.9%と75.5%であり,有意差を認めた(p=0.02).H群とL群の5年CFSはそれぞれ53.3%と72.5%であった.サブグループ解析では，H群の片肺移植症例(5年:OS 25%)は両肺移植症例(5年OS:75%)と比較してOSが悪い傾向にあった(p=0.08)が，H群の両肺移植症例はL群の両肺移植症例(5年OS:74.2%)と比較しても同等の成績であった（p=0.5）.【結語】60歳以上のレシピエントの成績は60歳未満と比較し不良だが，両肺移植がより望ましい可能性が示唆された.

DOI： 10.11386/jst.55.supplement_253_1

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J-GLOBAL

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J-GLOBAL

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記述言語：日本語   出版者・発行元：一般社団法人 日本移植学会  

【背景】低侵襲に血液や体液を採取し解析を行うLiquid biopsyは、癌領域では既に臨床応用され治療方針の決定に一役買っているが、移植領域ではまだ発展途上である。当科では肺移植におけるLiquid biopsyとして、ドナー由来血中遊離DNA（dd-cf-DNA）とマイクロRNA（miRNA）を標的にした研究を行ってきたため、その成果を報告する。【方法】ドナーとレシピエントの一塩基多型を比較してdd-cf-DNAを測定し、生体肺移植後の急性拒絶反応（AR）における診断的意義を検討した。次にレシピエントのみの検体で評価できるmiRNAを測定し、脳死・生体肺移植後の移植片慢性機能不全（CLAD）における診断的意義を検討した。【結果】dd-cf-DNAは、感染群（p=0.028）や安定群（p=0.001）よりAR群で有意に増加しており、生体肺移植後ARの診断に有用であった（Sci Rep 2018）。また線維化に関与するmiRNAが、非CLAD群よりCLAD群で有意に増加しており（p=0.008）、一秒量の変化率とも相関し（p=0.014）、CLAD診断に有用であった。【結論】肺移植のLiquid biopsy として、dd-cf-DNAは生体肺移植後ARの診断に、またmiRNAはCLADの診断に有用である。今後の臨床応用を目指して症例数の集積と簡便で精度の高い方法の開発が望まれる。

DOI： 10.11386/jst.55.supplement_242_2

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

副腎皮質癌は稀な疾患で、しばしばその診断に難渋するため、進行した症例が多く予後不良とされる。症例は60歳代女性、検診発見の胸部異常陰影を精査したところ、両側多発肺結節と左副腎腫瘍を指摘された。左副腎腫瘍摘出術を施行し、副腎皮質癌と診断された。多発肺結節に対して両側肺部分切除術を施行し、副腎皮質癌の肺転移と診断した。術後化学療法としてミトタンの投与を開始したが、再度両側肺の新たな結節を認め、計5回の肺部分切除術を施行した。いずれも副腎皮質癌の肺転移と診断した。副腎皮質癌術後5年10ヵ月が経過しているが、現在も生存中である。両側多発肺転移を伴った副腎皮質癌であったが、原発巣の切除後、肺転移巣を積極的に外科的切除することにより、比較的長期生存を得られる可能性が示唆された。(著者抄録)

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J02256&link_issn=&doc_id=20191119350007&doc_link_id=10.2995%2Fjacsurg.33.714&url=https%3A%2F%2Fdoi.org%2F10.2995%2Fjacsurg.33.714&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：英語   出版者・発行元：Elsevier {BV}  

DOI： 10.1016/j.jtho.2019.08.1966

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記述言語：英語   出版者・発行元：Elsevier {BV}  

DOI： 10.1016/j.jtho.2019.08.2453

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記述言語：英語   出版者・発行元：Elsevier {BV}  

DOI： 10.1016/j.jtho.2019.08.672

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記述言語：英語   出版者・発行元：Elsevier {BV}  

DOI： 10.1016/j.jtho.2019.08.1425

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記述言語：英語   出版者・発行元：Elsevier {BV}  

DOI： 10.1016/j.jtho.2019.08.1261

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記述言語：英語   出版者・発行元：Elsevier {BV}  

DOI： 10.1016/j.jtho.2019.08.1994

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：日本語   出版者・発行元：(一社)日本外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：日本語   出版者・発行元：(一社)日本外科学会  

CiNii Article

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その他リンク： http://search.jamas.or.jp/link/ui/2020037540

記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：日本語   出版者・発行元：岡山医学会  

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記述言語：日本語   出版者・発行元：コ・メディカル形態機能学会  

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記述言語：日本語   出版者・発行元：岡山医学会  

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記述言語：日本語   出版者・発行元：(一社)日本外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：英語   出版者・発行元：Elsevier {BV}  

DOI： 10.1016/j.healun.2019.01.1041

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記述言語：英語   出版者・発行元：Elsevier {BV}  

DOI： 10.1016/j.healun.2019.01.853

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記述言語：英語   出版者・発行元：Elsevier {BV}  

DOI： 10.1016/j.healun.2019.01.1036

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記述言語：英語   出版者・発行元：Elsevier {BV}  

DOI： 10.1016/j.healun.2019.01.1040

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記述言語：英語   出版者・発行元：Elsevier {BV}  

DOI： 10.1016/j.healun.2019.01.077

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本内視鏡外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本内視鏡外科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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