Prognostic impact of LILRB4 expression on tumor-infiltrating cells in resected non-small cell lung cancer.

BACKGROUND: Leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4/ILT3) is an up-and-coming molecule that promotes immune evasion. We have previously reported that LILRB4 facilitates myeloid-derived suppressor cells (MDSCs)-mediated tumor metastasis in mice. This study aimed to investigate the impact of the LILRB4 expression levels on tumor-infiltrating cells on the prognosis of non-small cell lung cancer (NSCLC) patients. METHODS: We immunohistochemically evaluated the LILRB4 expression levels of completely resected 239 NSCLC specimens. Whether the blocking of LILRB4 on human PBMC-derived CD33+ MDSCs inhibited the migration ability of lung cancer cells was also examined using transwell migration assay. RESULTS: The LILRB4 high group, in which patients with a high LILRB4 expression level on tumor-infiltrating cells, showed a shorter overall survival (OS) (p = 0.013) and relapse-free survival (RFS) (p = 0.0017) compared to the LILRB4 low group. Multivariate analyses revealed that a high LILRB4 expression was an independent factor for postoperative recurrence, poor OS and RFS. Even in the cohort background aligned by propensity score matching, OS (p = 0.023) and RFS (p = 0.0046) in the LILRB4 high group were shorter than in the LILRB4 low group. Some of the LILRB4 positive cells were positive for MDSC markers, CD33 and CD14. Transwell migration assay demonstrated that blocking LILRB4 significantly inhibited the migration of human lung cancer cells cocultured with CD33+ MDSCs. CONCLUSION: Together, signals through LILRB4 on tumor-infiltrating cells, including MDSCs, play an essential role in promoting tumor evasion and cancer progression, impacting the recurrence and poor prognosis of patients with resected NSCLC.

Living Donor Lobar Lung Transplant for a Patient With Lung Disease Caused by ABCA3 Gene Mutations: A Case Report.

Recessive gene mutations in ABCA3 cause lethal neonatal respiratory distress, and pediatric and adult interstitial lung disease. The effectiveness of medical treatments is limited and a subset of such patients will eventually require lung transplantation. A 20 months old boy developed interstitial lung disease and was treated with hydroxychloroquine, which had a significant effect. Sequence analysis of ABCA3 gene revealed newly discovered compound heterozygous mutations. His respiratory dysfunction gradually progressed over years and he underwent living-donor lobar lung transplantation (LDLLT) at 8 years of age with his parents serving as bilateral lobar donors. The parents had been genetically examined beforehand and found to be carriers who had one allele with an ABCA3 gene mutation and the other with no mutation. The recipient has been well without chronic lung allograft dysfunction and his parents have been enjoying healthy social lives for 7 years since the operations. LDLLT appears to be a valid option for selected children with ABCA3 gene mutations who are too ill to wait for cadaveric lung transplantation. When relatives of the recipient with ABCA3 gene mutation are deemed potential donors for LDLLT, sequence analyses of the donors are indispensable to exclude the possibility that they are late-onset patients of this recessive hereditary disease.

Pulmonary Hypertension Associated With Hyperthyroidism: A Case Report.

Pulmonary hypertension (PH) has various etiologies and its prognosis is unfavorable without appropriate treatment. We report a case in whom hyperthyroidism was considered as a cause of PH. A 32-year-old woman presented with exertional palpitation and dyspnea. Echocardiography showed an estimated systolic pressure in the pulmonary artery of 50 mmHg (reference value, 15 to 30) with no evidence suggestive of congenital heart disease or acquired heart disease. The level of D-dimer was normal and pulmonary perfusion scintigraphy was unremarkable. Thyroid function tests revealed a biochemically hyperthyroid state with elevated anti-thyroid peroxidase antibodies and thyroid stimulating hormone receptor antibodies, findings consistent with Graves' disease. After the administration of treatment with potassium iodide and thiamazole, her symptoms and PH gradually abated and finally disappeared without any specific treatment for PH.

LILRB4 promotes tumor metastasis by regulating MDSCs and inhibiting miR-1 family miRNAs.

Myeloid-derived suppressor cells (MDSCs) are a population of immune suppressive cells that are involved in tumor-associated immunosuppression, and dominate tumor progression and metastasis. In this study, we report that the leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4, murine ortholog gp49B) orchestrates the polarization of MDSCs to exhibit pro-tumor phenotypes. We found that gp49B deficiency inhibited tumor metastases of cancer cells, and reduced tumor-infiltration of monocytic MDSCs (M-MDSCs) in tumor-bearing mice. Gp49B-/- MDSCs inhibited pro-tumor immune responses, such as activation of Treg cells, promotion of cancer cell migration, and stimulation of tumor angiogenesis. Treatment of wild-type tumor-bearing mice with gp49B-/- M-MDSCs reduced cancer metastasis. Furthermore, gp49B knockout affected plasma exosome composition in terms of increased miR-1 family microRNAs (miRNAs) expression, which correlates with the upregulation of gp49B-/- MDSC-derived anti-tumor miRNAs. Collectively, our findings reveal that LILRB4/gp49B promotes MDSC-mediated tumor metastasis by regulating the M2-polarization of MDSCs and suppressing the secretion of miR-1 family miRNAs, which facilitate tumor migration and invasion. Abbreviations CTLA-4: cytotoxic T-lymphocyte-associated protein-4; FBS: fetal bovine serum; G-MDSCs: granulocytic-MDSCs; GP49B: glycoprotein 49B; HE: hematoxylin-eosin; ICI: immune checkpoint inhibitor; ITIM: immunoreceptor tyrosine-based inhibition motif; LILRB4: leukocyte immunoglobulin-like receptor B4; M-CSF: macrophage colony stimulating factor; MDSC: myeloid-derived suppressor cell; M-MDSC: monocytic MDSC; MMP-9: metallopeptidase-9; mAb: monoclonal antibody; PBS: phosphate-buffered saline; PCR: polymerase chain reaction; PD-1: programmed death-1; PD-L1: programmed death ligand-1; PMN-MDSC: polymorphonuclear-MDSC; qRT-PCR: quantitative reverse transcription PCR; TAM: tumor associated macrophage; TME: tumor microenvironment; TMM: trimmed mean of M value; VEGFA: vascular endothelial growth factor A.

Delayed bronchial perforation after bulla cauterization with soft coagulation system.

BACKGROUND: Soft coagulation is widely used for hemostasis because of its significant advantage in inducing tissue coagulation and denaturation without carbonization. However, a few cases of airway damage have been reported at the site, where soft coagulation was directly applied. CASE PRESENTATION: We encountered an unusual case of delayed perforation of the intermediate bronchial trunk observed on 24 days after cauterization of the right S6 bulla adjacent to the bronchus. Chest computed tomography revealed a large fistula between the intermediate bronchial trunk and the cauterized bulla in the right S6. Bronchoscopy showed a large fistula at the membranous portion of the intermediate bronchial trunk. We presumed that the bronchial perforation resulted from thermal damage to the intermediate bronchial trunk during bulla cauterization and the bronchial perforation induced infection in the bulla. Resection of the infectious bulla and the intermediate bronchial trunk, followed by end-to-end bronchial anastomosis and a pedicled intercostal muscle flap coverage, was performed. CONCLUSIONS: The severe airway damage resulting in perforation developed even without direct contact between the electrode tip and the bronchial wall, provoking the need for special attention to the duration of cauterization and location, where it is used.

Recovery of physical function in lung transplant recipients with sarcopenia.

BACKGROUND: Lung transplant (LTX) can provide a survival benefit and improve physical function for selected patients with advanced pulmonary disease. Sarcopenia is a systemic muscle-failure that can be found in a variety of life stages and disabilities. In this study, we follow the evolution of each variable defined in sarcopenia and the outcomes in LTX recipients with post-transplant sarcopenia. METHODS: Patients who underwent LTX at Tohoku University Hospital between 2013 and 2018 were consecutively included in the retrospective cohort study, with follow-up to 2019. Sarcopenia was defined by low muscle mass (the cross-sectional area (CSA) of erector spinae muscle (ESM) in thoracic CT with a threshold < 17.24 cm2/m2) and either low muscle strength (hand-grip with a threshold of < 26 kg in males and of < 18 kg in females) or physical performance (6-min walk distance with a threshold < 46.5% of predicted distance). RESULTS: Fifty-five recipients were included into the study, of whom 19 patients were defined as sarcopenic and 36 as non-sarcopenic. The muscle mass improved after transplant in both sarcopenic and non-sarcopenic individuals: the median ESM-CSA enlarged from 17.25 cm2/m2 in 2 months post-LTX to 18.55 cm2/m2 in 12 months (p < 0.001) and 17.63 cm2/m2 in 36 months (p < 0.001) in non-sarcopenic individuals, while in sarcopenic patients it improved from 13.36 cm2/m2 in 2 months to 16.31 cm2/m2 in 12 months (p < 0.005) and 18.01 cm2/m2 in 36 months (p < 0.001). The muscle mass in sarcopenia substantially recovered to close to non-sarcopenic conditions within 36-months (p < 0.001 in 2 months and p = 0.951 in 36 months). Accordingly, muscle strength and physical performance in both groups improved over time. No difference in survival was seen in both groups (Log-rank p = 0.096), and sarcopenia was not associated with an overall hazard of death (p = 0.147). There was no difference in the cumulative incidence of chronic lung allograft dysfunction between patients with or without sarcopenia (Log-rank p = 0.529). CONCLUSIONS: Even patients with post-transplant sarcopenia have a chance to recover physical function to levels close to those without sarcopenia several years post LTX.

Targeting stanniocalcin-1-expressing tumor cells elicits efficient antitumor effects in a mouse model of human lung cancer.

Lung cancer is the most common cause of cancer-related death in developed countries; therefore, the generation of effective targeted therapeutic regimens is essential. Recently, gene therapy approaches toward malignant cells have emerged as attractive molecular therapeutics. Previous studies have indicated that stanniocalcin-1 (STC-1), a hormone involved in calcium and phosphate homeostasis, positively regulates proliferation, apoptosis resistance, and glucose metabolism in lung cancer cell lines. In this study, we investigated if targeting STC-1 in tumor cells could be a promising strategy for lung cancer gene therapy. We confirmed that STC-1 levels in peripheral blood were higher in lung cancer patients than in healthy donors and that STC-1 expression was observed in five out of eight lung cancer cell lines. A vector expressing a suicide gene, uracil phosphoribosyltransferase (UPRT), under the control of the STC-1 promoter, was constructed (pPSTC-1 -UPRT) and transfected into three STC-1-positive cell lines, PC-9, A549, and H1299. When stably transfected, we observed significant cell growth inhibition using 5-fluorouracil (5-FU) treatment. Furthermore, growth of the STC-1-negative lung cancer cell line, LK-2 was significantly arrested when combined with STC-1-positive cells transfected with pPSTC-1 -UPRT. We believe that conferring cytotoxicity in STC-1-positive lung cancer cells using a suicide gene may be a useful therapeutic strategy for lung cancer.

Pneumonia With Scedosporium apiospermum and Lomentospora prolificans in a Patient After Bilateral Lung Transplantation for Pulmonary Hypertension: A Case Report.

Infections caused by the Scedosporium genus have become recognized as a fatal complication after lung transplantation in Europe and Australia, but the reports have been rare from Asian countries including Japan. We present a case of pneumonia caused by a mixed infection of Scedosporium apiospermum (SA) and Lomentospora prolificans (LP) that developed after augmentation of immunosuppression for chronic lung allograft dysfunction (CLAD) after lung transplantation. A 13-year-old man underwent bilateral lung transplantation for pulmonary hypertension. One year after surgery, he was treated with a series of augmented immunosuppressive therapy for severe acute rejection and subsequent CLAD. Three months following the first steroid pulse therapy, his serum ß-D-glucan elevated without any sign of fungal infection by other tests. The serum ß-D-glucan once returned to a normal level by empirical administration of micafungin; however, the patient's condition worsened again by discontinuation of it. He did not recover by restarting micafungin, and computed tomography (CT) scans eventually demonstrated new infiltrates in his lung field 6 weeks after the elevation of serum ß-D-glucan. Microscopic findings of transbronchial lung biopsy specimens showed filamentous fungi, and the culture of bronchoalveolar lavage fluid revealed the growth of SA and LP. Despite subsequent voriconazole administration, he died 14 days after the start of voriconazole. Early and aggressive inspection including bronchoscopy should be performed for the diagnosis of Scedosporium infection in immunocompromised patients, even if CT scans and sputum culture show no evidence of infection.

Contralateral tension pneumothorax during video-assisted thoracic surgery for lung cancer in a patient with obesity and rib fractures: a case report and review of the literature.

BACKGROUND: Intraoperative contralateral pneumothorax during one-lung ventilation is a rare but life-threatening complication. Although the exact incidence is unknown, only 14 cases with this complication have been reported until now. CASE PRESENTATION: A 67-year-old Japanese man with a weight of 80 kg, height of 162.2 cm, and body mass index of 30.4 kg/m2 underwent three-port video-assisted thoracic surgery for lung cancer with one-lung ventilation. He had suffered from traumatic right rib fractures 6 weeks before the referral. Fifteen minutes before the end of the surgery, the systolic blood pressure suddenly dropped to about 50 mmHg, which was immediately recovered by intravenous injection of phenylephrine. This episode occurred during chest closure after the completion of the left upper lobectomy, and one-lung ventilation was soon switched to two-lung ventilation. Contralateral tension pneumothorax was noted by the postoperative chest x-ray. As the patient was complicated with obesity and a past history of rib fractures, increased airway pressure during one-lung ventilation related to obesity together with the persistent compression of the visceral pleura by the fractured ends of the ribs was considered to be the factors responsible for this critical complication. CONCLUSIONS: Patient backgrounds such as obesity and past history of rib fractures should be noted carefully as risk factors for intraoperative contralateral pneumothorax during one-lung ventilation. We present the clinical course and discuss the mechanism of development of this potentially life-threatening complication in the present case with a review of the literature.

The fraction of sensitization among lung transplant recipients in a transplant center in Japan.

BACKGROUND: Anti-human leukocyte antigen (HLA) antibody testing was approved by the Japanese government in 2018. As such, there was no longitudinal data regarding the HLA-sensitization of lung transplant (LTX) patients in Japan. We therefore set out to measure anti-HLA antibodies from all our LTX patients during their annual follow-up to characterize the sensitization status in the Japanese population. METHODS: The cross-sectional study was conducted for consecutive LTX recipients who underwent transplantation from January 2000 to January 2020 at Tohoku University Hospital (TUH). The serum from the recipients was screened for anti-HLA antibody with the panel-reactive assay (PRA) and the donor-specific antibodies (DSA). RESULTS: Sensitization was reviewed in 93 LTX recipients, showing 23 positive (24.7%) and 70 negative (75.3%) PRA. More sensitized recipients were found in recent transplantations (60.9% (14/23), ≤5 years post LTX) than in older transplantations (17.4% (4/23), 5-10 years or 21.7% (5/23), ≥10 years post LTX) (p = 0.04). Even fewer recipients had DSA (5.4%, 5/93), among whom 4/5 (80%) were recently transplanted. CONCLUSION: The rate of PRA positive LTX recipients in our population was lower compared with those in previous reports from US and Europe. More sensitized LTRs were found in recent transplantations than the older cohort, and DSA was identified primarily in the recent recipients. Due to several limitations, it is still unclear whether the sensitization would be related the development of CLAD or survival, yet this study would be fundamental to the future anti-HLA body study in Japanese population.

The outcomes of anatomical lung resection for nontuberculous mycobacterial lung disease.

BACKGROUND: The number of cases of nontuberculous mycobacterial (NTM) lung disease has been increasing in recent years, and the efficacy of surgical treatment has been recognized. We investigated the clinical characteristics and behavior of NTM lung disease and analyzed the outcomes of surgery. METHODS: The data of 25 patients who underwent anatomical resection for NTM lung disease in our institution between January 2004 and December 2014 were retrospectively examined. RESULTS: The patients included 10 men and 15 women (mean age, 63.1 years). Twenty patients had Mycobacterium avium, and 5 had Mycobacterium intracellular. The indications for lung resection in 20 definitively diagnosed patients included a remaining or worsening lesion despite medical treatment (n=16), massive hemoptysis or bloody sputum (n=5), and prolonged smear positivity (n=1); multiple reasons were allowed. In five cases without a definitive diagnosis, surgery was performed due to the suspicion of lung cancer. The surgical procedures included pneumonectomy, n=4; lobectomy, n=13; and segmentectomy, n=8. Complete resection was achieved in 10 cases (40.0%). Video-assisted thoracoscopic surgery (VATS) was performed in 17 cases (68.0%), especially in 6 of 8 cases (75.0%) that underwent segmentectomy and in 10 of 11 cases (90.9%) that received simple lobectomy. There was one case of hospital mortality. Among the 22 patients who were followed at our institution, relapse occurred in 4 patients, and new infection occurred in 1 patient. NTM lung disease was controlled in 17 patients (77.3%). In the four cases that relapsed, the median relapse-free interval was 29.5 months. CONCLUSIONS: Surgical resection was a feasible treatment for NTM lung disease and was associated with favorable outcomes, although there was 1 case of hospital mortality. VATS procedures were considered adequate for the treatment of NTM lung disease; however, the surgical indications must be carefully considered.