Targeting PD-1/PD-L1 inhibits rejection in a heterotopic tracheal allograft model of lung transplantation.

Immune checkpoint molecules such as programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) have revolutionized the field of lung cancer treatment. As part of our study, we examined the role of these proteins in acute rejection in a mouse model of heterotopic tracheal transplantation. Recipient mice were untreated (Allo group) or treated with anti-PD-L1 (aPDL1 group) or PD-L1 Fc recombinant protein (PD-L1 Fc group). A further group of C57BL/6 mice received isografts (Iso group). The occlusion rate was significantly higher in the Allo group than in the Iso group (p = 0.0075), and also higher in the aPD-L1 group (p = 0.0066) and lower in the PD-L1 Fc group (p = 0.030) than in the Allo group. PD-L1 Fc recombinant protein treatment significantly decreased interleukin-6 and interferon-γ levels and reduced the CD4+/CD8+ T cell ratio, without increasing PD-1 and T-cell immunoglobulin mucin 3 expression in CD4+ T cells. These data suggest that PD-L1 Fc recombinant protein decreases the levels of inflammatory cytokines and the proportion of CD4+ T cells without exhaustion. The PD-L1-mediated immune checkpoint mechanism was associated with rejection in the murine tracheal transplant model, suggesting a potential novel target for immunotherapy in lung transplantation.

Association of frequent hypermethylation with high grade histological subtype in lung adenocarcinoma.

Lung adenocarcinoma is classified morphologically into five histological subtypes according to the WHO classification. While each histological subtype correlates with a distinct prognosis, the molecular basis has not been fully elucidated. Here we conducted DNA methylation analysis of 30 lung adenocarcinoma cases annotated with the predominant histological subtypes and three normal lung cases using the Infinium BeadChip. Unsupervised hierarchical clustering analysis revealed three subgroups with different methylation levels: high-, intermediate-, and low-methylation epigenotypes (HME, IME, and LME). Micropapillary pattern (MPP)-predominant cases and those with MPP components were significantly enriched in HME (p = 0.02 and p = 0.03, respectively). HME cases showed a significantly poor prognosis for recurrence-free survival (p < 0.001) and overall survival (p = 0.006). We identified 365 HME marker genes specifically hypermethylated in HME cases with enrichment of "cell morphogenesis" related genes; 305 IME marker genes hypermethylated in HME and IME, but not in LME, with enrichment "embryonic organ morphogenesis"-related genes; 257 Common marker genes hypermethylated commonly in all cancer cases, with enrichment of "regionalization"-related genes. We extracted surrogate markers for each epigenotype and designed pyrosequencing primers for five HME markers (TCERG1L, CXCL12, FAM181B, HOXA11, GAD2), three IME markers (TBX18, ZNF154, NWD2) and three Common markers (SCT, GJD2, BARHL2). DNA methylation profiling using Infinium data was validated by pyrosequencing, and HME cases defined by pyrosequencing results also showed the worse recurrence-free survival. In conclusion, lung adenocarcinomas are stratified into subtypes with distinct DNA methylation levels, and the high-methylation subtype correlated with MPP-predominant cases and those with MPP components and showed a poor prognosis.

Modified Clagett procedure for acute pleural empyema.

Pleural empyema often requires surgical intervention; however, surgical invasiveness should be minimized. We utilized the modified Claget procedure as an alternative to thoracoplasty for acute pleural empyema with a dead space. The procedure was performed as follows: first, 500 mg of kanamycin and 500,000 units of polymyxin sulfate dissolved in 10-100 ml saline was instilled intrapleurally via tube thoracostomy. The chest tube was clamped overnight and then removed. The modified Clagett procedure might be effective for acute pleural empyema with a dead space without pulmonary or bronchopleural fistula. We report our successful experience of performing modified Clagett procedure for pleural empyema with a dead space, through a detailed case presentation.

Efficacy and safety of intraoperative cone-beam CT-guided localization of small pulmonary nodules.

OBJECTIVES: This study aimed to evaluate the efficacy and safety of intraoperative cone-beam computed tomography-guided video-assisted thoracoscopic surgery wedge resection of impalpable small pulmonary nodules. METHODS: This was a single-centre phase 2 trial conducted between April 2018 and March 2019. Peripheral small pulmonary nodules, defined as either ground-glass opacity-dominant (>50%) nodules measuring ≤3 cm in diameter (ground-glass opacity-dominant type) or nodules measuring ≤2 cm in diameter located deeper than the nodule diameter from the visceral pleura (deep solid type), were eligible for resection using a cone-beam computed tomography-guided thoracoscopic manner. The primary end-point was macroscopic complete resection, and secondary end-points were: nodule extraction rate, operation time, localization time, marking accuracy, microscopic complete resection and safety. RESULTS: Twenty-two nodules, in 9 men and 11 women with a mean age of 64.3 years, were visualized and resected. The nodules were located in the right upper, middle and lower lobes in 3, 1 and 5 patients, respectively, and in the left upper and lower lobes in 5 and 8 patients, respectively. Seven nodules were ground-glass opacity-dominant types, and 15 were deep solid types. Cone-beam computed tomography could clearly image all nodules. The mean time for localization was 17.4 min. The mean operation time was 110.7 min. Macroscopic complete resection was accomplished in 21 nodules (95.5%). Microscopic complete resection was achieved in all nodules (100%). Postoperative air leakage and bleeding were observed in 1 patient (5%). CONCLUSIONS: Cone-beam computed tomography might be a safe and useful guide for video-assisted thoracoscopic surgery wedge resection of impalpable peripheral pulmonary nodules. DATE AND NUMBER OF IRB APPROVAL: 15 November 2017, 381. CLINICAL TRIAL REGISTRATION NUMBER: UMIN 000030388.

Hematopoietic loss of Y chromosome leads to cardiac fibrosis and heart failure mortality.

Hematopoietic mosaic loss of Y chromosome (mLOY) is associated with increased risk of mortality and age-related diseases in men, but the causal and mechanistic relationships have yet to be established. Here, we show that male mice reconstituted with bone marrow cells lacking the Y chromosome display increased mortality and age-related profibrotic pathologies including reduced cardiac function. Cardiac macrophages lacking the Y chromosome exhibited polarization toward a more fibrotic phenotype, and treatment with a transforming growth factor ß1-neutralizing antibody ameliorated cardiac dysfunction in mLOY mice. A prospective study revealed that mLOY in blood is associated with an increased risk for cardiovascular disease and heart failure-associated mortality. Together, these results indicate that hematopoietic mLOY causally contributes to fibrosis, cardiac dysfunction, and mortality in men.

Antibodies against complement component C5 prevent antibody-mediated rejection after lung transplantation in murine orthotopic models with skin-graft-induced pre-sensitization.

OBJECTIVE: Antibody-mediated rejection (AMR) could induce acute or chronic graft failure during organ transplantation. Several reports have shown that anti-C5 antibodies are effective against AMR after kidney transplantation. However, few reports have assessed the efficacy of anti-C5 antibodies against AMR after lung transplantation. Therefore, this study aimed to evaluate the efficacy of this novel therapy against AMR after lung transplantation. METHODS: BALB/c and C57BL/6 mice were used as donors and recipients. One group was pre-sensitized (PS) by skin transplantation 14 days before lung transplantation. The other group was non-sensitized (NS). Orthotopic left-lung transplantation was performed in both groups. Animals were killed at 2 or 7 days after lung transplantation and evaluated for histopathology, C4d immunostaining, and serum donor-specific antibodies (DSAs) (n = 5 per group). Isograft (IS) models with C57BL/6 mice were used as controls. To evaluate the efficacy of C5 inhibition, other animals, which received similar treatments to those in the PS group, were treated with anti-C5 antibodies, cyclosporine/methylprednisolone, anti-C5 antibodies/cyclosporine/methylprednisolone, or isotype-matched irrelevant control monoclonal antibodies (n = 5 per group). RESULTS: Two days after lung transplantation, the NS group exhibited mild, localized graft-rejection features (rejection score: 0.45 ± 0.08, p = 0.107). The PS group exhibited AMR features with a significantly higher rejection score (2.29 ± 0.42, p = 0.001), C4d vascular-endothelium deposition, and substantial presence of serum DSA. On day 7 after lung transplantation, both groups showed extensive graft alveolar wall destruction, and high acute-rejection scores. Mice receiving anti-C5 antibodies or anti-C5/antibodies/cyclosporine/methylprednisolone demonstrated significantly lower acute-rejection scores (0.63 ± 0.23, p = 0.002; 0.59 ± 0.22, p = 0.001, respectively) than those receiving isotype control antibodies. CONCLUSIONS: Murine orthotopic allograft lung transplant models met the clinical diagnosis and pathogenesis classification criteria of AMR. In these models, anti-C5 antibodies suppressed AMR. Therefore, anti-C5 therapy may be effective against AMR after lung transplantation.

[The Basic Research of Antigen-antibody Reaction in Lung Transplantation].

Lung transplantation has become popular in Japan, showing better survival rate than other countries. However, the results are still not satisfactory compared with other solid organ transplantation. One of the reasons for this might be that knowledge on donor-specific antibodies or antibody-related rejection, which has been attracting attention these days, is less than that of kidney or liver transplantation. Our laboratory has continued basic research in this field using rodent lung transplantation model. We have previously shown that type V collagen is associated in chronic rejection as an autoimmune, and that oral administration of type V collagen induces tolerance. The murine chronic rejection model of the minor antigen mismatch was developed, and involvement of the humoral immunity and role of the complement activation were shown. We are now studying the effects of immune checkpoint molecules, which play a central role in the field of cancer therapy, on rejection after lung transplantation. We are also working to verify the effects of anti-complement drugs and molecular targeted drugs in the future treatment on rejection.

Retargeting IL-2 Signaling to NKG2D-Expressing Tumor-Infiltrating Leukocytes Improves Adoptive Transfer Immunotherapy.

Ex vivo expansion followed by reinfusion of tumor-infiltrating leukocytes (TILs) has been used successfully for the treatment of multiple malignancies. Most protocols rely on the use of the cytokine IL-2 to expand TILs prior to reinfusion. In addition, TIL administration relies on systemic administration of IL-2 after reinfusion to support transferred cell survival. The use of IL-2, however, can be problematic because of its preferential expansion of regulatory T and myeloid cells as well as its systemic side effects. In this study, we describe the use of a novel IL-2 mutant retargeted to NKG2D rather than the high-affinity IL-2R for TIL-mediated immunotherapy in a murine model of malignant melanoma. We demonstrate that the NKG2D-retargeted IL-2 (called OMCPmutIL-2) preferentially expands TIL-resident CTLs, such as CD8+ T cells, NK cells, and γδT cells, whereas wild-type IL-2 provides a growth advantage for CD4+Foxp3+ T cells as well as myeloid cells. OMCPmutIL-2-expanded CTLs express higher levels of tumor-homing receptors, such as LFA-1, CD49a, and CXCR3, which correlate with TIL localization to the tumor bed after i.v. injection. Consistent with this, OMCPmutIL-2-expanded TILs provided superior tumor control compared with those expanded in wild-type IL-2. Our data demonstrate that adoptive transfer immunotherapy can be improved by rational retargeting of cytokine signaling to NKG2D-expressing CTLs rather than indiscriminate expansion of all TILs.

Genetic alterations in squamous cell lung cancer associated with idiopathic pulmonary fibrosis.

Patients with idiopathic pulmonary fibrosis (IPF) are at higher risk of developing lung cancers including squamous cell lung carcinoma (SCC), which typically carries a poor prognosis. Although the molecular basis of cancer development subsequent to IPF has not been fully investigated, we recently reported two epigenetic phenotypes characterized by frequent and infrequent DNA hypermethylation in SCC, and an association of the infrequent hypermethylation phenotype with IPF-associated SCCs. Here, we conducted targeted exon sequencing in SCCs with and without IPF using the Human Lung Cancer Panel to investigate the genetic basis of IPF-associated SCC. SCCs with and without IPF displayed comparable numbers of total mutations (137 ± 22 vs 131 ± 27, P = .5), nonsynonymous mutations (72 ± 14 vs 69 ± 16, P = .5), indels (3.0 ± 3.5 vs 3.0 ± 3.9, P = 1) and synonymous mutations (62 ± 9.1 vs 60 ± 12, P = .5). Signature 1 was the predominant signature in SCCs with and without IPF. SETD2 and NFE2L2 mutations were significantly associated with IPF (44% vs 13%, P = .03 for SETD2; 38% vs 10%, P = .04 for NFE2L2). MYC amplification, assessed by copy number variant analysis, was also significantly associated with IPF (18.8% vs 0%, P = .04). Mutations in TP53 and CDKN2A were observed relatively frequently in SCCs with frequent hypermethylation (P = .02 for TP53 and P = .06 for CDKN2A). Survival analysis revealed that the SETD2 mutation was significantly associated with worse prognosis (P = .04). Collectively, we found frequent involvement of SETD2 and NFE2L2 mutations and MYC amplification in SCCs with IPF, and an association of a SETD2 mutation with poorer prognosis.

Cell Tracking Suggests Pathophysiological and Therapeutic Role of Bone Marrow Cells in Sugen5416/Hypoxia Rat Model of Pulmonary Arterial Hypertension.

BACKGROUND: The mechanism of vascular remodelling in pulmonary arterial hypertension (PAH) remains unclear. Hence, defining the origin of cells constituting intractable vascular lesions in PAH is expected to facilitate therapeutic progress. Herein, we aimed to evaluate the origin of intractable vascular lesions in PAH rodent models via bone marrow (BM) and orthotopic lung transplantation (LT). METHODS: To trace BM-derived cells, we prepared chimeric rats transplanted with BM cells from green fluorescent protein (GFP) transgenic rats. Male rats were transplanted with lungs obtained from female rats and vice versa. Pulmonary hypertension was induced in the transplanted rats via Sugen5416 treatment and subsequent chronic hypoxia (Su/Hx). RESULTS: In the chimeric Su/Hx models, GFP-positive cells were observed in the pulmonary vascular area. Moreover, the right ventricular systolic pressure was significantly lower compared with wild-type Su/Hx rats without BM transplantation (P = 0.009). PAH suppression was also observed in rats that received allograft transplanted BM transplantation. In male rats that received LT and Su/Hx, BM-derived cells carrying the Y chromosome were also detected in neointimal occlusive lesions of the transplanted lungs received from female rats. CONCLUSIONS: BM-derived cells participate in pulmonary vascular remodelling in the Su/Hx rat model, whereas BM transplantation may contribute to suppression of development of PAH.

Is needle biopsy a risk factor of pleural recurrence after surgery for non-small cell lung cancer?

BACKGROUND: Tumor seeding, whereby malignant cells are deposited along the needle tract, is considered to be a potential hazard of needle biopsies. The aim of this study is to elucidate the relationship between needle biopsies for lung tumor, such as a preoperative computed tomography-guided needle biopsy (PCTGNB) or an intraoperative fine-needle aspiration biopsy (IFNAB), and ipsilateral pleural recurrence (PR) after lung cancer surgery. METHODS: Between 2008 and 2017, 1,047 patients with non-small cell lung cancer (NSCLC) underwent curative lung resection in our institution. They were divided into two groups: those in whom the first recurrent site was the ipsilateral pleural cavity (PR group) and the others (control group). Risk factors of PR were investigated retrospectively. RESULTS: Recurrence was observed in 191 patients (18.2%), 25 of whom were categorized to the PR group (17 malignant effusion, 10 dissemination). Pathological tumor [2-4], lymph nodes [1-2], pleural, lymphatic and vascular invasion (each ≥1) factors and patients who underwent PCTGNB were more frequently observed in the PR group than in the control group (each P<0.01) whereas the proportion of patients who underwent IFNAB was not significant. A multivariate analysis identified pathological lymph node factor and the frequency of PCTGNB as independent risk factors for PR with hazard ratios of 7.33 (95% CI, 2.93-19.8; P<0.01) and 6.92 (95% CI, 2.25-17.8; P<0.01), respectively. CONCLUSIONS: PCTGNB is a risk factor of PR but IFNAB is not. Indications for PCTGNB should be carefully determined.

High expression of CXCL14 is a biomarker of lung adenocarcinoma with micropapillary pattern.

Lung adenocarcinoma with micropapillary pattern (MPP) has an aggressive malignant behavior. Limited resection should be avoided because of its high recurrence rate. If adenocarcinoma with MPP is diagnosed preoperatively, the selection of proper treatment is possible. To explore a preoperative biomarker for diagnosing MPP, we undertook RNA sequencing analysis of 25 clinical samples as the training set, including 6 MPP, 16 other adenocarcinoma subtypes, and 3 normal lung tissues. Unsupervised hierarchical clustering analysis suggested a presence of subgroup with MPP showing different gene expression phenotype. We extracted differentially expressed genes with high expression levels in MPP samples, and chose VSIG1, CXCL14, and BAMBI as candidate biomarkers for MPP. Reverse transcription-quantitative PCR analysis confirmed a significantly higher expression of VSIG1 (P = .03) and CXCL14 (P = .02) in MPP than others. In a validation set of 4 MPP and 4 non-MPP samples, CXCL14 expression was validated to be significantly higher in MPP than in non-MPP (P = .04). Comparing a total of 10 MPP and 20 non-MPP samples, the area under the curve of CXCL14 to distinguish MPP from others was 0.89. The threshold value was 0.0116, corresponding to sensitivity 80% and specificity 90%. In immunostaining of CXCL14, the staining score was significantly higher in MPP cases than others, where not only the MPP component but also other components showed heterogeneous staining in adenocarcinoma tissues with MPP. Moreover, a higher staining score of CXCL14 was significantly associated with poorer prognosis in all patients (P = .01) or within cases in stage I-III (P = .01). In summary, we identified CXCL14 as a possible diagnostic biomarker of MPP.

A low DNA methylation epigenotype in lung squamous cell carcinoma and its association with idiopathic pulmonary fibrosis and poorer prognosis.

Patients with idiopathic pulmonary fibrosis (IPF) have higher risk of developing lung cancer, for example, squamous cell carcinoma (SCC), and show poor prognosis, while the molecular basis has not been fully investigated. Here we conducted DNA methylome analysis of lung SCC using 20 SCC samples with/without IPF, and noncancerous lung tissue samples from smokers/nonsmokers, using Infinium HumanMethylation 450K array. SCC was clustered into low- and high-methylation epigenotypes by hierarchical clustering analysis. Genes hypermethylated in SCC significantly included genes targeted by polycomb repressive complex in embryonic stem cells, and genes associated with Gene Ontology terms, for example, "transcription" and "cell adhesion," while genes hypermethylated specifically in high-methylation subgroup significantly included genes associated with "negative regulation of growth." Low-methylation subgroup significantly correlated with IPF (78%, vs. 17% in high-methylation subgroup, p = 0.04), and the correlation was validated by additional Infinium analysis of SCC samples (n = 44 in total), and data from The Cancer Genome Atlas (n = 390). The correlation between low-methylation subgroup and IPF was further validated by quantitative methylation analysis of marker genes commonly hypermethylated in SCC (HOXA2, HOXA9 and PCDHGB6), and markers specifically hypermethylated in high-methylation subgroup (DLEC1, CFTR, MT1M, CRIP3 and ALDH7A1) in 77 SCC cases using pyrosequencing (p = 0.003). Furthermore, low-methylation epigenotype significantly correlated with poorer prognosis among all SCC patients, or among patients without IPF. Multivariate analysis showed that low-methylation epigenotype is an independent predictor of poor prognosis. These may suggest that lung SCC could be stratified into molecular subtypes with distinct prognosis, and low-methylation lung SCC that significantly correlates with IPF shows unfavorable outcome.

Precise Anatomical Sublobar Resection Using a 3D Medical Image Analyzer and Fluorescence-Guided Surgery With Transbronchial Instillation of Indocyanine Green.

We developed a novel approach combined with 3D image analyzer and infrared thoracoscopy for pulmonary sublobar resection. The purpose of this study was to investigate the feasibility of this procedure. From October 2014 to April 2018, 65 cases were enrolled, and 58 cases were evaluated. For each case, several virtual sublobar resections were created by 3D image analyzer preoperatively. The surgical margin was measured in each simulated sublobar resection and the most appropriate procedure was selected. Surgical resection with matching virtual sublobar resection was performed using infrared thoracoscopy with transbronchial indocyanine green (ICG) instillation. We evaluated the border clarity of ICG fluorescence to investigate success of ICG injection and compared pre- and postoperative CTs to determine whether the correct area could be removed according to the simulation. We also compared short-term surgical outcomes between the ICG cases and historical segmentectomy cases by propensity score matching. The success rate of transbronchial ICG injections was 89.2% (58/65). These 58 patients were eligible for evaluation of our procedure. Sublobar resection included subsegmental resection (5), simple segmentectomy (15), complex segmentectomy (16), and extended segmentectomy (22). The shortest distances to the surgical margin by simulation and by actual measurement were 21.5 ± 11.2 mm and 23.5 ± 8.3, respectively (P = 0.190). Fifty-four of 58 cases underwent sublobar resection matched with the simulation (93.1% concordance rate). Operative results and short-term outcomes were similar between the 2 groups by propensity score matching. ICG-guided sublobar resection by transbronchial ICG instillation is feasible and applicable to any type of sublobar resection.

Evaluating vertebral artery dominancy before T4 lung cancer surgery requiring subclavian artery reconstruction.

PURPOSES: To evaluate vertebral artery (VA) dominancy and the risk of brain infarction in T4 lung cancer patients with tumor invasion into the subclavian artery. METHODS: We reconstructed the subclavian artery in 10 patients with T4 non-small cell lung cancer. The histological stages were IIIA in eight patients and IIIB in two patients. We evaluated the VA dominancy by performing a four-vessel study preoperatively and investigated the relationship between the methods of VA treatment and postoperative brain complications, retrospectively. RESULTS: Seven patients had a superior sulcus tumor (SST) and three had direct invasion into the mediastinum. Based on the tumor location, a transmanublial approach was used in five patients and a posterolateral hook incision was used in the other five. All subclavian artery (SA) reconstructions were done using an artificial woven graft. Preoperative angiography of the VA revealed poor development of the contralateral side in two patients. One of these patients suffered a severe brain infarction on postoperative day 2, which proved fatal. In the other patient, the VA was connected to the left SA graft by a side-to-end anastomosis and there was no postoperative brain complication. CONCLUSIONS: Preoperative SA and VA angiography is mandatory for identifying the need for VA reconstruction in lung cancer patients with major arterial invasion.

Mini grasping basket forceps for endobronchial foreign body removal in pediatric patients.

BACKGROUND: Appropriate device selection is crucial for endobronchial foreign body removal using a bronchoscope. In pediatric patients, bronchoscopy requires the use of a thin device due to the narrow access to the airway, limiting the range of useful endobronchial devices. We herein review our experience in endobronchial foreign body removal with a focus on the type of bronchoscope and the instruments used in comparison with the literature, and investigate the utility of mini grasping basket forceps (FG-55D, Olympus® ; and Zero Tip™ , Airway Retrieval Basket, Boston Scientific). METHODS: Between April 2008 and April 2016, foreign bodies were removed from the airway of 12 pediatric patients by bronchoscopy. These cases are reviewed in this study. The clinical presentation, location and characteristics of the foreign bodies, and the type of bronchoscope and instruments used were analyzed. RESULTS: A consecutive series of 12 pediatric patients was retrospectively reviewed, and the therapeutic characteristics investigated. Nuts were the most frequently observed foreign body. Seven of the 12 pediatric patients required an ultrathin bronchoscope (diameter, 2.8 mm) for foreign body removal. Only one patient required a rigid scope in addition to flexible bronchoscopy. The most frequently used instrument was a mini grasping basket forceps (n = 7; 58%), which was used with a 1.2 mm instrument channel (n = 4; 33%). CONCLUSIONS: The use of a mini grasping basket forceps in combination with an ultrathin flexible bronchoscope was useful for removing smooth, soft materials such as a nuts or beans in pediatric cases.

Concomitant Interstitial Lung Disease Is a Risk Factor for Pleural Invasion in Lung Cancer.

BACKGROUND: Lung carcinoma is often associated with interstitial lung disease (ILD), and the prognosis of lung cancer accompanied by ILD is unfavorable. In this study, cases of patients with primary lung cancer with or without ILD were reviewed to analyze surgical outcome, with special interest in the conformity of clinical and pathologic stages, pathologic findings of pleural invasion, malignant pleurisy first detected at the time of thoracotomy, and survival. METHODS: Retrospective chart review was performed for 1,264 primary lung cancer patients who underwent surgery from 2004 to 2015. Concomitant ILD was diagnosed by pathological examination or preoperative chest computed tomography findings. RESULTS: ILD was found in 104 patients (8.2%) with primary lung cancer. Conformity of clinical and pathological stages in the ILD-positive patients was poor, with a lower kappa value than that for the 1,160 ILD-negative patients (0.34 versus 0.51). The ILD group had significantly higher incidences of pleural invasion and unexpected malignant pleurisy than did the non-ILD group (for pleural invasion, 49.0% versus 24.5%, p < 0.0001; for malignant pleurisy, 7.69% versus 1.47%, p < 0.0001). The 5-year overall survival rates of the ILD group showed significantly lower than those of the non-ILD group (45.2% versus 70.1%; p = 0.0014) after propensity score matching. CONCLUSIONS: In lung cancer, the concomitant existence of ILD is a risk factor for pleural invasion. Concomitant ILD might cause underestimation of clinical staging, increase the chance of unexpected malignant pleurisy during surgery, and shorten survival time.

[The History and Development of Experimental Rodent Models of Chronic Lung Allograft Dysfunction after Lung Transplantation].

Chronic lung allograft dysfunction (CLAD) is a critical impediment to the long-term survival after lung transplantation. A rat orthotopic lung transplantation model was developed in the early 1970s, and using this model, our laboratory has shown that the immunopathogenesis of CLAD involves both allogeneic immunity and autoimmunity. However, further investigation of CLAD is limited by the scarcity of transgenic and knockout strains. The model most widely used to study CLAD, the mouse model of heterotopic tracheal transplantation, has some incomplete pathophysiologic features of CLAD, which limits the utility of this model. Unlike other solid organ transplants, vascularized and aerated murine lung transplantation has only recently been developed. We have also reported that minor, but not major, histocompatibility antigens mismatch induced the development of CLAD in murine orthotopic lung transplants and that CLAD development was interleukin-17-dependent. This mini-review underscores the history and development of rodent models of CLAD after lung transplant, including the findings from our previous studies. In addition, the future direction of rodent models is also discussed.

Impact of combined pulmonary fibrosis and emphysema on surgical complications and long-term survival in patients undergoing surgery for non-small-cell lung cancer.

PURPOSE: The outcome of radical surgery for lung cancer was investigated in patients with combined pulmonary fibrosis and emphysema (CPFE). METHODS: A retrospective chart review involved 250 patients with lung cancer who underwent pulmonary resection at Tokyo Women's Medical University Yachiyo Medical Center between 2008 and 2012. Based on the status of nontumor-bearing lung evaluated by preoperative computed tomography (CT), the patients were divided into normal, emphysema, interstitial pneumonia (IP), and CPFE groups, and their clinical characteristics and surgical outcome were analyzed. RESULTS: The normal, emphysema, IP, and CPFE groups comprised 124 (49.6%), 108 (43.2%), seven (2.8%), and eleven (4.4%) patients, respectively. The 5-year survival rate of the CPFE group (18.7%) was significantly lower than that of the normal (77.5%) and emphysema groups (67.1%) (P<0.0001 and P=0.0027, respectively) but equivalent to that of the IP group (44.4%) (P=0.2928). In a subset analysis of cancer stage, the 5-year overall survival rate of the CPFE group in stage I (n=8, 21.4%) was also lower than that of the normal group and emphysema group in stage I (n=91, 84.9% and n=70, 81.1%; P<0.0001 and P<0.0001, respectively). During entire observation period, the CPFE group was more likely to die of respiratory failure (27.2%) compared with the normal and emphysema groups (P<0.0001). Multivariate analysis of prognostic factors using Cox proportional hazard model identified CPFE as an independent risk factor (P=0.009). CONCLUSION: CPFE patients have a poorer prognosis than those with emphysema alone or with normal lung on CT finding. The intensive evaluation of preoperative CT images is important, and radical surgery for lung cancer should be decided carefully when patients concomitantly harbor CPFE, because of unfavorable prognosis.

Living Donor Lung Transplantation for Pleuroparenchymal Fibroelastosis.

We report the first patient with pleuroparenchymal fibroelastosis (PPFE) to undergo living donor bilateral lobar lung transplantation. The patient was diagnosed with secondary PPFE as a late complication of chemotherapy that included high-dose cyclophosphamide for mature B-cell lymphocytic leukemia. Although the patient maintained complete remission, dry cough and back pain appeared 8 years after the chemotherapy. He had repeated bilateral pneumothoraces, and his respiratory condition gradually deteriorated because of progressive pleural thickening and parenchymal fibrosis. He underwent living-donor bilateral lobar lung transplantation with an inverse transplant on the left side.