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.

Anti-CD20 Antibody and Calcineurin Inhibitor Combination Therapy Effectively Suppresses Antibody-Mediated Rejection in Murine Orthotopic Lung Transplantation.

Antibody-mediated rejection (AMR) is a risk factor for chronic lung allograft dysfunction, which impedes long-term survival after lung transplantation. There are no reports evaluating the efficacy of the single use of anti-CD20 antibodies (aCD20s) in addition to calcineurin inhibitors in preventing AMR. Thus, this study aimed to evaluate the efficacy of aCD20 treatment in a murine orthotopic lung transplantation model. Murine left lung transplantation was performed using a major alloantigen strain mismatch model (BALBc (H-2d) → C57BL/6 (BL/6) (H-2b)). There were four groups: isograft (BL/6→BL/6) (Iso control), no-medication (Allo control), cyclosporine A (CyA) treated, and CyA plus murine aCD20 (CyA+aCD20) treated groups. Severe neutrophil capillaritis, arteritis, and positive lung C4d staining were observed in the allograft model and CyA-only-treated groups. These findings were significantly improved in the CyA+aCD20 group compared with those in the Allo control and CyA groups. The B cell population in the spleen, lymph node, and graft lung as well as the levels of serum donor-specific IgM and interferon γ were significantly lower in the CyA+aCD20 group than in the CyA group. Calcineurin inhibitor-mediated immunosuppression combined with aCD20 therapy effectively suppressed AMR in lung transplantation by reducing donor-specific antibodies and complement activation.

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.

Loss of stromal cell Thy-1 plays a critical role in lipopolysaccharide induced chronic lung allograft dysfunction.

BACKGROUND: Long-term survival of lung transplants lags behind other solid organs due to early onset of a fibrotic form of chronic rejection known as chronic lung allograft dysfunction (CLAD). Preventing CLAD is difficult as multiple immunologic and physiologic insults contribute to its development. Targeting fibroblast activation, which is the final common pathway leading to CLAD, offers the opportunity to ameliorate fibrosis irrespective of the initiating insult. Thy-1 is a surface glycoprotein that controls fibroblast differentiation and activation. METHODS: To study the role of Thy-1 in CLAD, we utilized the minor antigen mismatched C57BL/6 (B6wild-type) or B6Thy-1-/-→C57BL/10 (B10) model of murine orthotopic lung transplantation with postoperative bacterial infection modeled by intratracheal lipopolysaccharide (LPS) administration. The effects of LPS on Thy-1 expression, proliferation, and gene expression were assessed in fibroblasts in vitro and the therapeutic potential of Thy-1 replacement was assessed in vivo. RESULTS: More severe CLAD was evident in B6Thy-1-/- →B10 grafts compared to B6wild-type →B10 grafts. LPS further accentuated fibrosis in B6wild-type →B10 grafts with some, but limited, effects on B6Thy-1-/- →B10 grafts. LPS contributed to Thy-1 loss from Thy-1(+) fibroblasts in vitro due to a decrease in mRNA expression. In addition, LPS promoted proliferation and upregulation of multiple inflammatory pathways in Thy-1(-) fibroblasts by gene expression analysis. Most importantly, replacement of Thy-1 through exogenous administration ameliorated the fibrotic phenotype post-LPS mediated modeling of infection. CONCLUSIONS: Our findings suggest that the loss of Thy-1 on fibroblasts is a previously unrecognized cause of CLAD and its replacement may offer therapeutic applications for amelioration of this disease post-transplantation in the setting of infectious stress responses.

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.

Differential gene analysis during the development of obliterative bronchiolitis in a murine orthotopic lung transplantation model: A comprehensive transcriptome-based analysis.

BACKGROUND: Obliterative bronchiolitis (OB) is a known issue during minor histocompatibility antigen (mHA) disparity during lung transplantation. This study evaluated gene expression in a murine orthotropic lung transplantation model using microarray analysis. METHODS: Left lungs from C57BL/10(H-2b) donor mice were transplanted into mHA-mismatched C57BL/6(H-2b) recipient mice. Three groups (OB, non-OB, and sham controls) were confirmed pathologically and analyzed. Gene expression changes in the lung grafts were determined by microarray and immunohistochemical staining, and genes were verified by quantitative PCR in the lungs and mediastinal lymph nodes (LNs). RESULTS: A total of 1343 genes were upregulated in the OB lungs compared to the sham group. Significant upregulation was observed for genes related to innate, e.g. Tlr2 and CCL3 and adaptive immunity, e.g. H2-ab1 and Il-21. Positive labeling for MHC class II antigen was observed in the bronchial epithelium of OB accompanied with B cells. We found increased Tlr2, Ccl3, H2-ab1, Il-21, Ighg3, Ifng, and Pdcd1 mRNA expression in the OB lung, and increased Il-21, Ighg3, and Pdcd1 expression in the OB LNs. CONCLUSIONS: Adaptive and innate immune reactions were involved in OB after lung transplantation, and genetic examination of related genes could be used for detection of OB.

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.

Deciphering the role of eosinophils in solid organ transplantation.

Eosinophils are rare granulocytes that belong to the innate arm of the immune system. This cell population is traditionally defined as a destructive and cytotoxic mediator in asthma and helminth infection. Limited data in transplantation have suggested that eosinophils play a similar role in potentiating deleterious organ inflammation and immunologic rejection. Contrary to this long-held notion, recent data have uncovered the possibility that eosinophils play an alternative role in immune homeostasis, defense against a wide range of pathogens, as well as downregulation of deleterious inflammation. Specifically, translational data from small animal models of lung transplantation have demonstrated a critical role for eosinophils in the downregulation of alloimmunity. These findings shed new light on the unique immunologic features of the lung allograft and demonstrate that environmental polarization may alter the phenotype and function of leukocyte populations previously thought to be static in nature. In this review, we provide an update on eosinophils in the homeostasis of the lung as well as other solid organs.

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.