Robot-assisted thoracic surgery for intercostal cavernous hemangioma.

Intercostal cavernous hemangioma is extremely rare among benign vascular tumors. Achieving a definitive diagnosis preoperatively by radiographic examination alone is difficult; surgical resection is usually needed. Occasional cases are found as giant tumors, and some grow substantially during observation without treatment. Such tumors require extended surgical resection; however, small tumors can be completely resected by tumor extirpation alone. Thus, immediate surgical resection while the tumor is small might help to avoid invasive surgery. We herein describe cases of intercostal cavernous hemangioma with no invasion to the surrounding tissues, successfully treated by complete tumor resection using robot-assisted thoracic surgery.

Induction immunotherapy followed by surgery for hilar unicentric Castleman disease.

Castleman disease is a rare disease borne of a B cell lymphoproliferative disorder of uncertain cause. Standard therapy for the unicentric type of Castleman disease localized as a single mass or single lymph-node station is surgical extirpation. Nevertheless, in the thoracic cavity, unresectable cases or cases of incomplete extirpation of the tumor without lung scarring owing to tumor size/location have been noted. In such cases, lung resection (e.g., lobectomy, pneumonectomy) or additional therapy (immunotherapy, chemotherapy, radiotherapy) after resection is required. However, few instances of patients receiving induction immunotherapy or chemotherapy followed by surgery have been reported. Here, we describe a 21-year-old woman with unicentric Castleman disease originating from the left hilum. The tumor seemed to involve/be in contact with the pulmonary vein and bronchus. Tumor location indicated that initial resection was necessary to sacrifice upper and lower pulmonary lobes. To avoid these pulmonary resections, induction therapy followed by surgery was selected. Induction therapy using rituximab was very efficacious. Resection after induction therapy was completed only by tumor extirpation, and resulted in preservation of pulmonary function. Thoracic surgeons might consider induction therapy followed by resection if the tumor is resectable UCAD, but initial resection is needed and sacrifices a large amount of pulmonary function.

Resection of Pulmonary Metastases 12 Years after Initial Surgery for a Benign Pheochromocytoma.

We describe a rare case of newly discovered pulmonary metastases and surgical confirmation 12 years after initial surgery for a pheochromocytoma. A 61-year-old asymptomatic man was referred because of an abnormal shadow in the right lung field upon chest radiography. Computed tomography (CT) showed two well-demarcated tumors in the basal segment of the right lung. Twelve years previously, he underwent right adrenalectomy and was pathologically diagnosed as having a benign pheochromocytoma. Thereafter, he received a medical check-up annually. To confirm the diagnosis of two pulmonary tumors, video-assisted thoracic surgery was done and wedge resection of the right lower lobe completed. Pathology studies revealed these tumors as pulmonary metastases from the pheochromocytoma, which indicated that the true diagnosis was a malignant pheochromocytoma. Patients with a benign pheochromocytoma should continue to undergo careful monitoring for a long time after the initial surgical procedure. Thoracic surgeons should be aware of the possibility of pulmonary metastases even if >10 years have passed since initial resection of a benign pheochromocytoma.

Impact of Preoperative Immunonutritional Support in Patients Undergoing Elective Thoracic Surgery.

INTRODUCTION: Several immunonutritional supplements have recently been developed. However, improvements in preoperative immunonutritional conditions using these supplements have not been analyzed in patients undergoing thoracic surgery. METHODS: This prospective, single-arm, single-institution pilot study involved patients planning to undergo thoracic surgery. Forty adults with a poor preoperative immunonutritional status were enrolled. The patients freely selected one of three oral immunonutritional supplements (IMPACTⓇ, MEINⓇ, or AboundⓇ) and started taking it on an outpatient basis from 7 to 14 days before thoracic surgery. The primary endpoint was the rate of improvement in three immunonutritional parameters on the hospitalization day: body mass index (BMI), prognostic nutritional index (PNI), and geriatric nutritional risk index (GNRI). These improvement rates were compared with those of a matched historical control group. RESULTS: The PNI and GNRI improvement rates were significantly higher in the immunonutritional support group than in the control group (PNI: 103.1% ± 0.6% vs. 98.9% ± 1.3%, p = 0.0391; GNRI: 101.7% ± 0.8% vs. 99.3% ± 0.8%, p = 0.0266), although there was no significant difference in the BMI improvement rate (101.0% ± 0.6% vs. 100.2% ± 0.7%, p = 0.3626). The PNI and GNRI improvement rates were significantly higher in the IMPACTⓇ support group than in the control group (PNI: 104.5% ± 2.4% vs. 98.9% ± 1.3%, p = 0.0212; GNRI: 101.6% ± 1.1% vs. 99.3% ± 0.8%, p = 0.0415). CONCLUSIONS: The present study revealed that short-term preoperative immunonutritional support can actually improve immunonutritional parameters immediately before surgery. In particular, preoperative immunonutritional support using IMPACTⓇ supplementation might be the most promising agent in patients with a poor immunonutritional condition undergoing elective thoracic surgery. TRIAL REGISTRATION: University Hospital Medical Information Network 000035851.

Cumulative experience of the anterior approach in robot-assisted thoracic surgery for lung cancer patients.

BACKGROUND: Robot-assisted thoracic surgery (RATS) lobectomy for lung cancer is now performed all around the world. The camera and robotic devices are generally inserted from a low position via the thorax. We previously reported our original anterior approach (AA) for performing RATS lobectomy with a camera and robotic devices inserted via the anterior chest wall. However, whether AA is comparable or superior to the conventional approach (CA) remains unclear. METHODS: A total of 108 patients who underwent RATS lobectomy were included in the current study. We compared the AA with the CA for performing RATS lobectomy in terms of the operative and postoperative features, such as total operation/console time, blood loss and postoperative complications. RESULTS: Eighty-seven and 21 patients underwent the AA and CA in RATS lobectomy, respectively. The console and total operation time were significantly shorter in the AA group than in the CA group for RATS lobectomy (median console time: AA vs. CA, 112 vs. 148 min, P=0.0001; median total operation time: AA vs. CA, 193 vs. 243 min, P=0.0002), especially left upper lobectomy. Intraoperative blood loss and the frequency of postoperative complications were significantly reduced in the AA group compared with the CA group (median intraoperative blood loss: AA vs. CA, 20 vs. 105 mL, P<0.0001; postoperative complications: AA vs. CA, 8.0% vs. 28.6%, P=0.0088). CONCLUSIONS: These results suggest that our AA of RATS lobectomy can be very easily and safely performed.

Dramatic response to pembrolizumab with chemotherapy followed by salvage surgery in a lung cancer patient.

Immune checkpoint inhibitors with chemotherapy have been shown to exhibit remarkable efficacy for advanced non-small-cell lung carcinoma and are under investigation as an induction therapy. However, the significance of preoperative therapy with pembrolizumab + chemotherapy for surgically resectable non-small-cell lung carcinoma still remains unclear. Here, we report a case of stage IIIB non-small-cell lung carcinoma that underwent salvage surgery after three cycles of pembrolizumab + carboplatin + nab-paclitaxel. Computed tomography revealed the remarkable decrease in tumor volume by 81%. A pathological examination showed that viable neoplastic cells were observed in <1% of the total tumorous lesion suggesting near pathological complete response. This case suggests that this regimen might be a good option as induction therapy for non-small-cell lung carcinoma.

ALK-positive lung cancer in a patient with recurrent brain metastases and meningeal dissemination who achieved long-term survival of more than seven years with sequential treatment of five ALK-inhibitors: A case report.

The incidence of central nervous system (CNS) metastases in patients with anaplastic lymphoma kinase (ALK) fusion gene-positive (ALK+) non-small cell lung cancer (NSCLC) is high, ranging from approximately 20%-70%. Although ALK inhibitors (ALKis) are generally effective for CNS metastases in patients with ALK+ NSCLC, relapse with CNS metastases is frequently observed. A 37-year-old woman with a high level of carcinoembryonic antigen was diagnosed with right lung adenocarcinoma (pathological stage IIIA) and underwent right lower lobectomy. Despite the administration of postoperative chemotherapy, her carcinoembryonic antigen (CEA) level remained elevated. Although crizotinib was administered due to the positivity for ALK fusion, brain metastases appeared at 19.0 months after the start of treatment. Treatment with alectinib following crizotinib resulted in the complete disappearance of brain metastases. However, brain metastases relapsed, and meningeal dissemination appeared at 38.3 months after the start of treatment with alectinib. Although ceritinib, brigatinib, and alectinib rechallenge were attempted, the CNS lesions worsened. Lorlatinib was then administered, resulting in the normalization of the CEA level (4.5 ng/ml) 4.1 months after the start of lorlatinib. The brain metastases and meningeal dissemination almost disappeared. The overall time from the start of crizotinib to lorlatinib is 89.5 months at present, and the patient continues to be treated with lorlatinib without relapse. Lorlatinib was effective in this case with brain metastases and meningeal dissemination after resistance to first- and second-generation ALKis. Appropriate sequential treatment with first-, second- and third-generation ALKis can lead to a long-term survival in ALK+ patients with brain metastases and meningeal dissemination.

Weakly-supervised learning for lung carcinoma classification using deep learning.

Lung cancer is one of the major causes of cancer-related deaths in many countries around the world, and its histopathological diagnosis is crucial for deciding on optimum treatment strategies. Recently, Artificial Intelligence (AI) deep learning models have been widely shown to be useful in various medical fields, particularly image and pathological diagnoses; however, AI models for the pathological diagnosis of pulmonary lesions that have been validated on large-scale test sets are yet to be seen. We trained a Convolution Neural Network (CNN) based on the EfficientNet-B3 architecture, using transfer learning and weakly-supervised learning, to predict carcinoma in Whole Slide Images (WSIs) using a training dataset of 3,554 WSIs. We obtained highly promising results for differentiating between lung carcinoma and non-neoplastic with high Receiver Operator Curve (ROC) area under the curves (AUCs) on four independent test sets (ROC AUCs of 0.975, 0.974, 0.988, and 0.981, respectively). Development and validation of algorithms such as ours are important initial steps in the development of software suites that could be adopted in routine pathological practices and potentially help reduce the burden on pathologists.

Complete Blood Cell Count-Derived Inflammatory Biomarkers in Early-Stage Non-Small-Cell Lung Cancer.

BACKGROUND: Complete blood cell count (CBC)-derived inflammatory biomarkers are widely used as prognostic parameters for various malignancies, but the best predictive biomarker for early-stage non-small-cell lung cancer (NSCLC) is unclear. We retrospectively analyzed early-stage NSCLC patients to investigate predictive effects of preoperative CBC-derived inflammatory biomarkers. PATIENTS AND METHODS: We selected 311 consecutive patients with pathological stage IA NSCLC surgically resected from April 2006 to December 2012. Univariate and multivariate Cox proportional analyses of recurrence-free survival (RFS) were used to test the preoperative systemic immune inflammation index (SII), neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and monocyte-lymphocyte ratio (MLR). RESULTS: Preoperative high MLR levels were significantly associated with patient sex, smoking status, and postoperative recurrence (p <0.0001, p = 0.0307, and p = 0.0146, respectively), and preoperative high SII levels were significantly correlated with postoperative recurrence (p = 0.0458). Neither NLR nor PLR were associated with any related factors. Only preoperative MLR levels (p = 0.0269) were identified as an independent predictor of shorter RFS. The relative risk (RR) for preoperative high MLR level versus low level patients was 2.259 (95% confidence interval [CI]: 1.094-5.000). Five-year RFS rates in patients with preoperatively high MLR levels were significantly lower than in those with low MLR levels (82.21% vs. 92.05%, p = 0.0062). In subgroup analysis by tumor size and MLR level, the high MLR level subgroup with tumors >2 cm had significantly shorter RFS than other subgroups (p = 0.0289). CONCLUSIONS: The preoperative MLR level is the optimal predictor of recurrence in patients with pathological stage IA NSCLC.

Preoperative Immune-Nutritional Abnormality Predicts Poor Outcome in Elderly Non-Small-Cell Lung Cancer Patients with Comorbidities.

BACKGROUND: Elderly non-small-cell lung cancer (NSCLC) patients are increasing. In general, elderly patients often have more comorbidities and worse immune-nutritional condition. PATIENTS AND METHODS: In total, 122 NSCLC patients aged 75 years or older, underwent thoracic surgery between January 2007 and December 2010. In all, 99 of 122 patients (81.1%) who had preoperative comorbidities were retrospectively analyzed. We evaluated the preoperative immune-nutritional condition using the controlling nutritional status (CONUT) score. RESULTS: We decided the best cutoff value for CONUT score was 1; as a result, 42 of 99 patients (42.4%) had abnormal preoperative CONUT score. Univariate analyses showed sex (P = 0.0099), smoking status (P = 0.0176), pathological stage (P = 0.0095), and preoperative CONUT score (P = 0.0175) significantly affected overall survival (OS). In multivariate analysis, pathological stage (relative risk (RR): 2.12; 95% confidence interval (CI): 1.10-3.90; P = 0.0268) and preoperative CONUT score (RR: 2.10; 95% CI: 1.20-3.67; P = 0.0094) were shown to be independent prognostic factors. In Kaplan-Meier analysis of OS, the preoperative abnormal CONUT score group had significantly shorter OS than did the preoperative normal CONUT score group (P = 0.0152, log-rank test); however, there were no statistical differences both in disease-free survival (DFS) and cancer-specific survival (CSS; P = 0.9238 and P = 0.8661, log-rank test, respectively). In total, 22 patients (46.8%) were dead caused by other diseases such as pneumonia or other organs malignancies. CONCLUSION: Preoperative abnormal CONUT score is a poor prognostic factor for the elderly NSCLC patients with preoperative comorbidities and might predict poor postoperative outcome caused by not primary lung cancer but other diseases.

Prognostic Impact of Postoperative Skeletal Muscle Decrease in Non-Small Cell Lung Cancer.

BACKGROUND: Preoperative skeletal muscle loss was reported to be associated with a postoperative poor prognosis in non-small cell lung cancer (NSCLC) patients. The aim of this study was to elucidate the relationship between the change in skeletal muscle mass after surgery and the postoperative outcomes in NSCLC patients. METHODS: The data were analyzed for 204 NSCLC patients who had undergone curative lung resection and whose preoperative and postoperative (1-year) computed tomographic images were available. The skeletal muscle area (SMA) at the 12th thoracic vertebra level was used. Postoperative/preoperative ratio was defined as postoperative normalized SMA (cm2/m2) divided by preoperative normalized SMA. The cutoff value was set to a postoperative/preoperative ratio of 0.9. The neutrophil-lymphocyte ratio, the platelet-lymphocyte ratio, modified Glasgow prognostic score, and prognostic nutritional index were used to estimate change in the nutritional status. RESULTS: There were 70 patients (34.3%) classified into the SMA-decreased group. Low body mass index was significantly associated with the SMA-decreased patients (P = .019). The SMA-decreased status was an independent prognostic factor for poor overall survival (P < .001) and disease-free survival (P = .001). The SMA-decreased status was significantly associated with the postoperative exacerbation of the neutrophil-lymphocyte ratio (P = .009), platelet-lymphocyte ratio (P = .026), modified Glasgow prognostic score (P = .003), and prognostic nutritional index (P = .013). CONCLUSIONS: Skeletal muscle loss after surgery is significantly associated with poor postoperative outcomes in NSCLC patients. Further studies investigating the clinical impact of postoperative nutritional intervention are needed.

Pretreatment prognostic nutritional index as a novel biomarker in non-small cell lung cancer patients treated with immune checkpoint inhibitors.

OBJECTIVES: Immune checkpoint inhibitors (ICIs) have been established as a novel strategy for non-small cell lung cancer (NSCLC) therapy. However, a definitive biomarker that can predict response to ICI therapy remains unestablished. The prognostic nutritional index (PNI) is used to assess immune-nutritional conditions and is a prognostic factor in patients with various malignancies; however, its usefulness as a biomarker of response to ICI therapy and survival outcomes in NSCLC patients is unknown. Thus, we retrospectively analyzed the clinicopathological features of advanced-stage or recurrent NSCLC patients treated with ICI therapy to identify predictors of response to ICI therapy and investigate the effects of pretreatment PNI levels on survival after ICI therapy. MATERIALS AND METHODS: We selected 102 consecutive NSCLC patients who were treated with ICI therapy from November 2015 to February 2019. We measured their pretreatment PNI levels and performed univariate and multivariate Cox regression analyses of progression-free survival (PFS) or overall survival (OS) after ICI therapy. RESULTS: Pretreatment PNI levels were significantly associated with response to ICI therapy (objective response rate:P = 0.0131; disease control rate: P = 0.0002), PFS (P = 0.0013), and OS (P = 0.0053). In univariate and multivariate analyses of the associations between PNI, C-reactive protein (CRP) or neutrophil-lymphocyte ratio (NLR) and PFS or OS, NLR and PNI, but not CRP, are independent prognostic factors for PFS (NLR: relative risk [RR]=1.655, 95% confidence interval [CI]: 1.012-2.743, P = 0.0449, PNI: RR=1.704, 95% CI: 1.039-2.828, P = 0.0346). Only PNI showed a trend towards being an independent prognostic factor for OS (RR=1.606, 95% CI: 0.952-2.745, P = 0.0761). CONCLUSION: The pretreatment PNI has the potential to be a simple and novel predictive biomarker of ICI response in NSCLC patients and might help to identify patients who will obtain a survival benefit from ICI therapy.

Prognosis of Early-stage Part-solid and Pure-solid Lung Adenocarcinomas.

BACKGROUND/AIM: In the new TNM classification (8th edition) of lung cancer, T category is defined based on the solid component size; therefore, part solid type (PST) with and solid type (ST) without ground glass opacity (GGO) are categorized as same T value according to their solid component sizes. However, differences between these tumors have not been clarified. Patients and Methods The study included 274 pStage I lung adenocarcinoma patients who had undergone surgery at our Institution from 2003 to 2012. Their tumors were classified as pure GGO, PST, and ST. After propensity score matching for solid component size, we compared prognoses between PST and ST. RESULTS: The same percentage was noted for PST and ST tumors (119/274; 43.4%). After propensity score matching, the disease-free survival (DFS) was significantly worse in ST than PST (5-year DFS: 69.2% versus 88.7%; p=0.0241). CONCLUSION: Prognoses of PST and ST adenocarcinomas differ even when their solid component sizes are the same.

The association and prognostic impact of enhancer of zeste homologue 2 expression and epithelial-mesenchymal transition in resected lung adenocarcinoma.

OBJECTIVES: Epithelial-mesenchymal transition (EMT) and the histone methyltransferase Enhancer of Zeste Homologue 2 (EZH2) are important regulators of lung cancer progression and metastasis. Although recent studies support the correlation between EZH2 expression and EMT, no reports have investigated their association using immunohistochemistry or explored their prognostic impact on lung adenocarcinoma. The aim of this study was to elucidate the association between EZH2 and EMT, and their prognostic significance. METHODS: EZH2 and the EMT markers E-cadherin and Vimentin were examined by IHC in lung adenocarcinoma specimens that were resected from 2003-2012. Associations between EZH2 and EMT markers and their correlations with survival were analyzed. RESULTS: We enrolled 350 patients, approximately 70% of whom were diagnosed as pathological stage I. The rates of positive E-cadherin, Vimentin, and EZH2 expression were 60.3%, 21.4%, and 52.0%, respectively. There was a significant positive correlation between EZH2 and Vimentin expression (p = 0.008), and EZH2 scores were higher in the Mesenchymal group (p = 0.030). In multivariate analysis, EZH2 was an independent predictor of Vimentin expression, and vice versa. EMT and EZH2 overexpression were significantly correlated with poor disease-free and overall survival. Furthermore, the Epithelial group with high EZH2 expression had significantly worse disease-free and overall survival. Positive staining for EMT markers was unfavorable regarding disease-free survival among patients with low EZH2 expression. CONCLUSIONS: EMT and high EZH2 expression were associated with poor NSCLC prognoses. Vimentin is a key factor linking EMT and EZH2 in lung adenocarcinoma.

Clinical and Prognostic Significance of the Epithelial-Mesenchymal Transition in Stage IA Lung Adenocarcinoma: A Propensity Score-Matched Analysis.

BACKGROUND: The epithelial-mesenchymal transition (EMT) describes the process through which cells lose epithelial characteristics and gain a mesenchymal phenotype. The EMT contributes to tumor invasion and cancer progression, and is associated with metastasis and poor survival of patients with non-small-cell lung cancer. However, little is known about the relationships between the EMT and the clinicopathologic characteristics of patients with stage IA lung adenocarcinoma. PATIENTS AND METHODS: We conducted immunohistochemical analysis of the expression of the EMT markers E-cadherin and vimentin of specimens acquired from 183 consecutive patients with stage IA lung adenocarcinoma. The clinicopathologic significance of the association of the EMT status with E-cadherin and vimentin expression was analyzed after propensity score matching. RESULTS: E-cadherin and vimentin were detected in 68.3% and 18.6% of stage IA lung adenocarcinomas, respectively. The presence of cells with EMT conversion was associated with older patient age. A propensity score-matched cohort (128 patients) was used for further analyses. Computed tomography revealed that tumors with EMT conversion showed solid-dominant nodules compared to those without conversion. Survival analysis after propensity score matching showed that the EMT correlated with poor disease-free survival (hazard ratio = 2.57, P = .0451) and overall survival (hazard ratio = 4.23, P = .0471). Multivariate analysis revealed that the EMT was an independent predictor of shorter disease-free survival. CONCLUSION: The EMT was a significant predictor of poor prognosis of patients with stage IA lung adenocarcinoma. The EMT status may serve as an indicator for administering adjuvant therapy.

A novel prognostic marker in patients with non-small cell lung cancer: musculo-immuno-nutritional score calculated by controlling nutritional status and creatine kinase.

BACKGROUND: Controlling nutritional status (CONUT) and skeletal muscle area (SMA) are both useful prognostic factors in patients with non-small cell lung cancer (NSCLC). We hypothesized that low serum creatine kinase (CK) would be a surrogate of decreased SMA, and defined a novel prognostic factor, CONUT/CK score (CNKS). The aim of this study was to elucidate the clinical significance of CNKS in NSCLC patients. METHODS: One hundred and eighty-nine patients who underwent surgical resection of NSCLC and whose preoperative computed tomography images were available were enrolled. The CNKS was calculated by summing CONUT score and CK score, which was defined as 0 if the CK concentration is within normal range, and 2 if it is under lower limit. The optimal cut-off values of CNKS and CONUT score were 4 and 2, respectively. RESULTS: Low CK was significantly associated with decreased SMA (P=0.012). The high CNKS group was significantly associated with men and smoking history (P=0.006 and P=0.015, respectively). The high CNKS group had significantly shorter overall survival (OS) and disease-free survival (DFS) (P<0.001 and P=0.003, respectively) than the low CNKS group. The CNKS was found to be an independent prognostic factor for OS and DFS (P=0.012 and P=0.017, respectively), while CONUT score was not. The CNKS was a novel significant predictor of a poor prognosis in patients with NSCLC. CONCLUSIONS: The nutritional status combined with skeletal muscle index was suggested to provide more useful prognostic information than alone, which should be investigated in further prospective studies with a larger cohort.

The prognostic impact of obstructive lung disease on survival of never smokers with resected non-small-cell lung cancer: a comparison with smokers.

OBJECTIVES: The proportion of never smokers among non-small-cell lung cancer (NSCLC) patients has steadily increased in recent decades, suggesting an urgent need to identify the major underlying causes of disease in this cohort. Chronic obstructive pulmonary disease is a risk factor for lung cancer in both smokers and never smokers. The aim of this study was to investigate the association between obstructive lung disease and survival in never smokers and smokers with NSCLC after complete resection. METHODS: We retrospectively reviewed data from 548 NSCLC patients treated at our institution. The effects of obstructive lung disease on recurrence-free survival and cancer-specific survival following the resection of NSCLC were determined by univariable and multivariable Cox regression analyses. RESULTS: Among the 548 patients analysed, 244 patients (44.5%) were never smokers and 304 patients (55.4%) were current or former smokers. In the never-smoker group, 48 patients (19.7%) had obstructive lung disease, 185 patients (75.8%) were women and 226 patients (92.6%) had adenocarcinoma. Obstructive lung disease was significantly associated with shorter recurrence-free survival (P = 0.006) and cancer-specific survival (P = 0.022) in the never smokers, but not the smokers, on both univariable and multivariable analyses. The associations between obstructive lung disease and prognosis in never smokers remained significant after propensity score matching. CONCLUSIONS: Obstructive lung disease is an independent prognostic factor for recurrence-free survival and cancer-specific survival in never smokers, but not in smokers, with NSCLC. Based on this finding, further examination is warranted to advance our understanding of the mechanisms associated with NSCLC in never smokers.

HMGB1 blockade significantly improves luminal fibrous obliteration in a murine model of bronchiolitis obliterans syndrome.

BACKGROUND: Although high-mobility group box-1 (HMGB1), which is a nuclear protein, was reported to enhance the allogeneic responses in transplantation, the effect of HMGB1 on bronchiolitis obliterans syndrome (BOS) is unknown. METHODS: A murine heterotopic tracheal transplantation model was used. Protein concentrations of HMGB1, interferon-γ (IFN-γ), interleukin (IL)-10, and IL-17 were analyzed in the isografts, allografts, controls, and HMGB1-neutralizing antibody administered allografts (n = 6; Days 1, 3, 5, 7, 14, 21, and 28). The luminal fibrous occlusion was analyzed (n = 6; Days 7, 14, 21, and 28). Infiltrating CD8 and CD4 T lymphocytes around the allografts and serum levels of IFN-γ and IL-10 were evaluated (n = 6; Day 7). RESULTS: The HMGB1 levels in the allografts were significantly increased compared with the isografts at Day 7. HMGB1 blockade did not change the IL-17 level, but decreased the IFN-γ/IL-10 ratio in the early phase (Days 5 and 7) and significantly improved the fibrous occlusion in the late phase (Days 14, 21, and 28). HMGB1 blockade significantly suppressed the CD8 T lymphocytes infiltration and decreased the serum IFN-γ/IL-10 ratio compared with the control at Day 7. CONCLUSIONS: HMGB1 may be a trigger of the BOS pathogenesis and candidate target for the treatment of the disease.