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Purpose: Malignant pleural mesothelioma (MPM) is a rare but aggressive disease with few therapeutic options. The tumor–stromal interface is important in MPM, but this is lost in cell lines, the main model used for preclinical studies. We sought to characterize MPM patient-derived xenografts (PDX) to determine their suitability as preclinical models and whether tumors that engraft reflect a more aggressive biological phenotype.Experimental Design: Fresh tumors were harvested from extrapleural pneumonectomy, decortication, or biopsy samples of 50 MPM patients and implanted subcutaneously into immunodeficient mice and serially passaged for up to five generations. We correlated selected mesothelioma biomarkers between PDX and patient tumors, and PDX establishment with the clinical pathologic features of the patients, including their survival. DNA of nine PDXs was profiled using the OncoScan FFPE Express platform. Ten PDXs were treated with cisplatin and pemetrexed.Results: A PDX was formed in 20 of 50 (40%) tumors implanted. Histologically, PDX models closely resembled the parent tumor. PDX models formed despite preoperative chemotherapy and radiotherapy. In multivariable analysis, patients whose tumors formed a PDX had significantly poorer survival when the model was adjusted for preoperative treatment (HR, 2.46; 95% confidence interval, 1.1–5.52; P = 0.028). Among 10 models treated with cisplatin, seven demonstrated growth inhibition. Genomic abnormalities seen in nine PDX models were similar to that previously reported.Conclusions: Patients whose tumors form PDX models have poorer clinical outcomes. MPM PDX tumors closely resemble the genotype and phenotype of parent tumors, making them valuable models for preclinical studies. Clin Cancer Res; 23(4); 1060–7. ©2016 AACR.

Table S1. Effects of clinical pathological covariates on survivals of patients whose tumor did or did no establish xenograft (XG). Table S2. Response of xenograft tumors to cisplatin or/and pemetrexed in mice Supplementary Figure S1. Response of representative xenograft models to the treatment with cisplatin. Supplementary Figure S2. Representative images of histology and biomarkers from selected matching patient and xenograft tumors.

Few studies have assessed the comprehensive skeletal muscle depletion associated with loss of muscle quantity (sarcopenia) and reduced muscle quality in cancer patients. This study aimed to clarify the impact of skeletal muscle depletion on outcomes after non-small cell lung cancer surgery.Data for 341 patients with pathologic stages 1 to 3A non-small cell lung cancer who underwent lobectomy and mediastinal lymph node dissection from 2009 to 2013 were retrospectively reviewed. The integrative pectoralis muscle index (IPMI) was assessed by multiplying the normalized pectoralis muscle area (area/body mass index) and mean radiodensity on chest images. Postoperative outcomes were compared among sex-specific quartiles of IPMI. The trend of continuous and categorical variables was analyzed using the Jonckheere-Terpstra test and the Cochrane-Armitage test, respectively.Respiratory strength declined with decreasing quartiles of IPMI (P0.001). The risk of major complications escalated with the decrease of IPMI among four quartiles (7.1 %, 16.7 %, 18.4 %, and 22.4 %; P = 0.008). The hospital stay was prolonged for patients with reduced IPMI (P = 0.001). Patients in the lowest and highest quartiles had the worst and best 5-year overall survival, respectively, compared with those in the two intermediate quartiles of IPMI (67.0 %, 87.9 %, and 81.2 %, respectively; P=0.001). Multivariate analysis identified the lowest quartile of IPMI as an independent poor prognostic factor (hazard ratio, 1.88; 95 % confidence interval, 1.11-3.19; P = 0.020).Comprehensive skeletal muscle profiling, including morphometric mass and componential density on chest imaging, has the potential to refine risk stratification and prognostication in non-small cell lung cancer.

OBJECTIVE: There is little evidence of the outcome of pulmonary metastasectomy for uterine tumors when comparing different histologies. This study aimed to delineate the primary histology that leads to more favorable outcomes after pulmonary metastasectomy. METHODS: The database of the Metastatic Lung Tumor Study Group of Japan for 1984 to 2016 was used to analyze the outcomes of patients with gynecologic malignancies who underwent pulmonary metastasectomy. Prognostic factors and long-term outcomes were compared according to the histology of the primary uterine tumors, specifically adenocarcinoma, squamous cell carcinoma, and sarcoma. The adjusted hazard risks according to disease-free intervals (DFIs) and the number and maximum size of resected tumors were also analyzed to delineate the pattern of risk trends. RESULTS: A total of 319 patients were included in the analysis (122 with adenocarcinomas, 113 with squamous cell carcinomas, 46 with sarcomas, and 38 with other types). The 5-year survival rate was 66.5% for the entire cohort, 71.6% for the patients with adenocarcinoma, 61.3% for those with squamous cell carcinoma, and 55.4% for those with sarcoma. Multivariate analyses identified the positive prognostic factors as DFI ≥12 months in adenocarcinoma and sarcoma and the primary site (corpus) of uterine tumors in adenocarcinoma. The nonlinear adjusted hazard risks indicated that a shorter DFI was associated with an elevated risk of death in patients with adenocarcinoma and sarcoma. CONCLUSIONS: The survival outcome after pulmonary metastasectomy varies according to primary tumor histology, and the prognostic factors differ among histologic subtypes. Surgical indications should be determined based on the prognostic factors for each histology.

The prognosis of patients with connective tissue disease (CTD) has improved significantly in recent years, but interstitial lung disease (ILD) associated with connective tissue disease (CTD-ILD) remains a refractory condition, which is a leading cause of mortality. Because it is an important prognostic factor, many observational and interventional studies have been conducted to date. However, CTD is a heterogeneous group of conditions, which makes the clinical course, treatment responses, and prognosis of CTD-ILD extremely diverse. To summarize the current understanding and unsolved questions, the Japanese Respiratory Society and the Japan College of Rheumatology collaborated to publish the world's first guide focusing on CTD-ILD, based on the evidence and expert consensus of pulmonologists and rheumatologists, along with radiologists, pathologists, and dermatologists. The task force members proposed a total of 27 items, including 7 for general topics, 9 for disease-specific topics, 3 for complications, 4 for pharmacologic treatments, and 4 for non-pharmacologic therapies, with teams of 2-4 authors and reviewers for each item to prepare a consensus statement based on a systematic literature review. Subsequently, public opinions were collected from members of both societies, and a critical review was conducted by external reviewers. Finally, the task force finalized the guide upon discussion and consensus generation. This guide is expected to contribute to the standardization of CTD-ILD medical care and is also useful as a tool for promoting future research by clarifying unresolved issues.

Patients with lung cancer with a history of treatment often undergo curative surgical resection. However, the impact of previous cancer treatment on the outcome of lung cancer remains unclear.We conducted a retrospective study of patients who underwent curative resection for non-small cell lung cancer between 1998 and 2011. We collected clinicopathologic data and patients were divided into groups by previous history of cancer treatment. Comparisons between groups, estimation of survival rates, and multivariate analyses were performed. Propensity score matching was used to create cohorts with reduced bias.Of 878 patients, 196 (22.3%) had previous extrathoracic malignancies, and stage I lung cancer was more frequent in this group (P.001). In multivariate analysis of the whole cohort, older patients, men, non-adenocarcinoma histologic type, more advanced pathologic stage of lung cancer, interstitial pneumonia, and previous extrathoracic malignancies were associated with appreciably worse prognosis. When propensity score matched cohorts were compared, prognosis was significantly worse in patients with previous extrathoracic malignancies than patients without (5-year survival rates, 75.3% vs 82.7%; P = .009), although recurrence was not frequently seen (5-year recurrence-free rates, 78.7% vs 83.0%; P = .491).Because treatment history of extrathoracic malignancy was not associated with postsurgical lung cancer recurrence, proposing curative resection could be justifiable if the previous cancer is deemed cured or controlled. However, the results showing that patients with previous cancer history have a worse survival rate than patients without should be taken into account when curative surgery is considered.

Introduction: Post-intensive care syndrome (PICS) is an emerging problem in critically ill patients and the prevalence and risk factors are unclear in patients with severe coronavirus disease 2019 (COVID-19). This multicenter prospective observational study aimed to investigate the prevalence and risk factors of PICS in ventilated patients with COVID-19 after ICU discharge. Methods: Questionnaires were administered twice in surviving patients with COVID-19 who had required mechanical ventilation, concerning Barthel Index, Short-Memory Questionnaire, and Hospital Anxiety and Depression Scale scores. The risk factors for PICS were examined using a multivariate logistic regression analysis. Results: The first and second PICS surveys were obtained at 5.5 and 13.5 months (mean) after ICU discharge, with 251 and 209 patients completing the questionnaires and with a prevalence of PICS of 58.6% and 60.8%, respectively, along with the highest percentages of cognitive impairment. Delirium (with an odds ratio of (OR) 2.34, 95% CI 1.1–4.9, and p = 0.03) and the duration of mechanical ventilation (with an OR of 1.29, 95% CI 1.05–1.58, and p = 0.02) were independently identified as the risk factors for PICS in the first PICS survey. Conclusion: Approximately 60% of the ventilated patients with COVID-19 experienced persistent PICS, especially delirium, and required longer mechanical ventilation.

Background Although the number of patients who undergo extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation is increasing worldwide, there are few reports on lung transplantation after long-term ECMO (more than 1 month). We report a rare case of successful bilateral lung transplantation in a Japanese patient after 5 months of veno-venous (VV)-ECMO support. Case presentation A 27-year-old man who underwent bone marrow transplantation (BMTx) with fully matched human leukocyte antigen typing was diagnosed with bronchiolitis obliterans caused by chronic graft-versus-host disease 3 years after the BMTx. One year later, his respiratory condition had exacerbated, with carbon dioxide retention that required conventional mechanical ventilation. He was then deemed a suitable candidate for lung transplantation by a multidisciplinary transplantation selection committee. While waiting for donor lungs, his hypercapnia and acidosis became barely manageable under care with mechanical ventilation and ultimately he was switched to VV-ECMO. He remained on VV-ECMO for the next 5 months, during which period the circuit was switched nine times. In addition, sophisticated intensive care was required to manage multiple episodes of sepsis and coagulopathy. A suitable donor was identified 5 months later, and bilateral lung transplantation was initiated with continuous VV-ECMO. The procedure itself was extremely challenging owing to severe adhesions resulting from previous thoracotomy, inflammation, infection, and intrapulmonary hemorrhage. The operative time for the transplantation was about 19 h. Currently, at 2 years 8 months postoperatively, the patient is alive and well. Conclusion Transplant surgery in this patient was extremely challenging because of the presence of severe pleural adhesions and stiff native lungs secondary to hemorrhagic complications due to the prolonged ECMO support. Surgeons must recognize that lung transplantation after long-term ECMO bridging can be technically more complicated and challenging than shorter-term ECMO.

Introduction The prognostic implications of having patients with idiopathic pleuroparenchymal fibroelastosis (IPPFE) on lung transplantation waiting lists have been unclear. In Japan, where a severe shortage of brain-dead donors remains a major limitation for organ transplantation, it is particularly important to predict the prognoses of patients when they are listed for transplantation. The purpose of this study was to investigate the characteristics of lung transplantation candidates with IPPFE and the influence of those characteristics on prognosis. Methods This was a retrospective review of 29 consecutive adult lung transplant candidates with idiopathic interstitial pneumonia between January 2014 and April 2018. Results Eight patients with IPPFE and 21 with other types of idiopathic interstitial pneumonia were included. Body mass index (median 17.1 kg/m2 vs 23.5 kg/m2, P Conclusions Patients with IPPFE waiting for transplantation have some distinctive characteristics and should be retained on waiting lists to receive transplants.

OBJECTIVES Spread through air space (STAS) is recognized as a pattern of invasion in lung adenocarcinoma and has been reported to be a predictor of recurrence and survival in patients with early-stage lung adenocarcinoma. However, this parameter has not been studied well in stage III (N2) lung adenocarcinoma. In this study, we evaluated the association between STAS invasion patterns and recurrence and survival in stage III (N2) lung adenocarcinoma. METHODS We retrospectively reviewed data from 76 patients at University of Tokyo with stage III (N2) lung adenocarcinoma who underwent surgery from August 1998 to December 2013. Statistical analysis was performed to determine the impact of STAS invasion clinicopathological features and clarify the relationship between this pattern of invasion and survival. RESULTS Tumour STAS was observed in 46 of 76 patients (60.5%) and was significantly associated with the presence of lymphatic invasion (P CONCLUSIONS The presence of STAS invasion pattern is a significant risk factor for recurrence in stage III (N2) lung adenocarcinoma.

Yendamuri et al. published an important work in the Journal of Thoracic and Cardiovascular Surgery in July 2018 on the effects of the number of resected lymph nodes (LNs) on the survival of patients with small-sized (≤2 cm) non-small cell lung cancer (NSCLC) who underwent sublobar resection (1). This retrospective analysis was based on the Surveillance, Epidemiology, and End Results (SEER) database in the United States with more than 3,900 cases (study period: 2004–2013).

Development of chronic lung allograft dysfunction involves various alloimmune-independent insults including those mediated by Toll-like receptor (TLR) signaling, which is known to activate alloimmune responses. We hypothesized that TLR signaling may also contribute to the activation of fibroblasts and promoting allograft airway fibrosis. Mouse orthotopic tracheal transplants were conducted between major histocompatibility complex (MHC)-mismatched Balb/c donor and wild-type C3H or C3H-derived TLR4 mutant recipients (nonfunctional TLR4). Immunohistochemistry on day 21 showed significantly smaller alpha-smooth muscle actin (α-SMA)-positive areas in TLR4 mutant recipients than wild-type recipients (P = .01). No difference was found for CD3+ T-cell infiltration. Proliferation of alloreactive T cells derived from the recipient spleen showed no difference between TLR4 mutant and wild-type recipients in a mixed lymphocyte reaction. The effect of TLR4 signaling was examined in primary pulmonary fibroblast cultures both with lipopolysaccharide (LPS) and transforming growth factor (TGF)-β1. Stimulation with LPS significantly increased expression of α-SMA mRNA in wild-type fibroblasts cultured with TGF-β1 compared with the control without LPS (P = .001). Taken together, these findings suggest disruption of TLR signaling leads to reduced activation of fibroblasts without affecting T-cell infiltration and proliferation in this model. TLR4-mediated activation of fibroblasts may be a potentially important mechanism of allograft remodeling.

In COVID-19 therapy with artificial lungs such as extracorporeal membrane oxygenation (ECMO) machines, platelets in the extracorporeal circulation are often activated by their contact with the artificial materials, leading to the formation of blood clots followed by serious complications such as stroke and heart attack. However, anticoagulation and antithrombotic management is challenging due to the lack of testing tools to evaluate the circulation. Here we demonstrate real-time monitoring of thrombogenesis in the circulation of an ECMO-equipped goat with an intelligent platelet aggregate characterizer (iPAC), which is based on imaging flow cytometry and deep-learning-based analysis of numerous platelet aggregates in blood.

Physical biomarkers to stratify patients with lung cancer into subtypes predictive of outcome beyond tumor-related characteristics are underexplored. This study was designed to investigate the clinical utility of preoperative sarcopenia based on respiratory strength and pectoralis muscle mass to predict the risk of death.This retrospective study included 346 consecutive patients undergoing curative-intent resection of non-small cell lung cancer from 2009 to 2013. Respiratory strength and muscle mass were assessed by peak expiratory flow rate and pectoralis muscle index (pectoralis muscle area/body mass index) using preoperative spirometry and chest axial images, respectively. Sarcopenia cutoff points were defined by gender-specific medians of peak expiratory flow rates and pectoralis muscle indices. Survival was compared between patients with sarcopenia and patients without.Sarcopenia was present in 98 patients (28.3%) and was significantly associated with advancing age (P .001). Patients with sarcopenia exhibited worse 5-year overall survival compared with patients without sarcopenia (69.9% vs 87.2%, P .001). Multivariate analysis revealed that sarcopenia was an independent adverse prognostic factor (hazard ratio, 1.88; 95% confidence interval, 1.09-3.24; P = .023) after adjustment for gender, age, smoking status, coronary heart disease, diffusing capacity for carbon monoxide, neutrophil-to-lymphocyte ratio, albumin, histologic type, and pathologic stage.Preoperative sarcopenia as identified by the criteria of low respiratory strength and reduced pectoralis muscle mass is significantly associated with poor overall survival. This may help to develop more individualized management strategies and optimize longitudinal care for patients.

Lung transplantation may be a final destination therapy in lung failure, but limited donor organ availability creates a need for alternative management, including artificial lung technology. This invited review discusses ongoing developments and future research pathways for respiratory assist devices and tissue engineering to treat advanced and refractory lung disease. An overview is also given on the aftermath of the coronavirus disease 2019 pandemic and lessons learned as the world comes out of this situation. The first order of business in the future of lung support is solving the problems with existing mechanical devices. Interestingly, challenges identified during the early days of development persist today. These challenges include device-related infection, bleeding, thrombosis, cost, and patient quality of life. The main approaches of the future directions are to repair, restore, replace, or regenerate the lungs. Engineering improvements to hollow fiber membrane gas exchangers are enabling longer term wearable systems and can be used to bridge lung failure patients to transplantation. Progress in the development of microchannel-based devices has provided the concept of biomimetic devices that may even enable intracorporeal implantation. Tissue engineering and cell-based technologies have provided the concept of bioartificial lungs with properties similar to the native organ. Recent progress in artificial lung technologies includes continued advances in both engineering and biology. The final goal is to achieve a truly implantable and durable artificial lung that is applicable to destination therapy.

We report two cases of severe SARS-CoV-2 infection successfully treated with venovenous extracorporeal membrane oxygenation (VV-ECMO) and continuous hemodiafiltration (CHDF). ECMO was indicated despite immediate anti-viral and anticoagulation therapy with maximal ventilatory support. Meticulous bronchoscopic drainage was necessary during treatment by ECMO due to copious fluid secretion. Renal replacement therapy with continuous hemodiafiltration was also required for both cases due to ongoing renal dysfunction. However, both patients recovered fully without any disability or neurological sequelae. VV-ECMO is a vital tool to maintain appropriate gas exchange for severe SARS-CoV-2 infection to facilitate functional recovery. Because subsequent renal impairment is common in such severe cases, hemodiafiltration undertaken in a timely manner may be necessary. Controlling secondary bacterial infection is also key for lung recovery, as it may otherwise compromise the chance to wean patients off ECMO.

The impact of sarcopenia on the outcome in patients following resection of non-small cell lung cancer is yet to be fully determined. This study aimed to evaluate the clinical utility of a computed tomography-based pectoralis muscle assessment, which reflects sarcopenia, to predict the risk of postoperative outcomes.This retrospective study included 347 consecutive patients undergoing curative-intent resection of non-small cell lung cancer from 2009 to 2013. The pectoralis muscle index (pectoralis muscle area/body mass index) was assessed at the level of the fourth thoracic vertebra on chest axial images. The primary outcomes were compared between the lowest gender-specific quintile (sarcopenia) and the other quintiles according to the index. The prognostic significance of low pectoralis muscle index was calculated by the Cox proportional hazards regression model. A propensity score matching analysis was performed to adjust the differences in clinical characteristics.Sixty-nine patients were identified with sarcopenia according to the lowest gender-specific quintile of pectoralis muscle index. Patients with sarcopenia exhibited worse 5-year overall survival rate compared with patients without sarcopenia (64.2 % vs. 86.7 %, P0.001). Even in stage I non-small cell lung cancer, the rate of 5-year overall survival in the sarcopenia group was lower than that in the non-sarcopenia group (74.2 % vs. 92.4 %, P = 0.001). Multivariate analysis revealed that low pectoralis muscle index was independently associated with adverse overall survival (hazard ratio: 2.09, 95 % confidence interval: 1.20-3.62, P = 0.009). After propensity score matching, the prognostic impact of sarcopenia based on low pectoralis muscle index was also robust for overall survival (hazard ratio: 3.23, 95 % confidence interval: 1.38-7.60, P = 0.007).Low pectoralis muscle index was significantly associated with poor long-term outcomes in patients with localized non-small cell lung cancer after curative surgery. This may help assist preoperative risk stratification and longitudinal management after surgery.

A standard treatment for patients with early-stage non-small cell lung cancer (NSCLC) who undergo surgery, and subsequently develop local failure or intrathoracic oligo-recurrence, has not yet been established. The present study aimed to assess the feasibility of stereotactic body radiotherapy (SBRT) for this subgroup of patients. Consequently, a retrospective analysis was conducted of patients with NSCLC recurrence who were treated with SBRT, and previously underwent curative surgical resection between October 2011 and October 2016. Post-SBRT survival [overall survival (OS); progression-free survival (PFS); and local control (LC)] and toxicity were analyzed. Prognostic factors for OS were identified using univariate and multivariate analysis. A total of 52 patients and 59 tumors were analyzed. The median follow-up time was 25 months (35 months for surviving patients), and median OS following salvage SBRT was 32 months. The 1- and 3-year OS rates were 84.4 and 67.8%, respectively. 1- and 3-year PFS rates were 80.8 and 58.7%, respectively. Only 4 patients (7.7%) developed local failure. Median LC was 71 months and 1- and 3-year LC rate were 97.9 and 94.9%, respectively. A total of 4 patients experienced grade 3 or higher adverse events (AEs) and two experienced grade 5 AEs (pneumonitis and hemoptysis). Central tumor location and the possibility of re-operation were independent prognostic factors for OS. The present study indicated that post-operative salvage SBRT is a promising therapeutic option for patients with NSCLC with locoregional or intrathoracic oligo-recurrence. We regard toxicity was also acceptable. However, further research is required on the appropriate selection of subjects, and stratification of the analysis by certain risk factors would increase the accuracy of the conclusions.

Purpose: Early lung adenocarcinoma has been more frequently found recently. The 8th edition of the Union for International Cancer Control (UICC)-Tumor Node Metastasis (TNM) classification for lung cancer has been effective since January 2017. This study aims to elucidate advantages of the current classification for patients with clinical stage 0-IA lung adenocarcinoma, in comparison with the older one. Methods: We retrospectively reviewed the data of clinical stage IA (7th edition) lung adenocarcinoma patients who underwent surgery at our institute from 2001 to 2012, and reclassified them by the 8th edition. Survival analysis was used to evaluate the impact of the two classifications. Results: In all, 281 cases were eligible. Clinical T-factors (8th) were significant prognostic factors for overall survival (P = 0.001), recurrence-free survival (P

The importance of neoantigens for cancer immunity is now well‐acknowledged. However, there are diverse strategies for predicting and prioritizing candidate neoantigens, and thus reported neoantigen loads vary a great deal. To clarify this issue, we compared the numbers of neoantigen candidates predicted by four currently utilized strategies. Whole‐exome sequencing and RNA sequencing (RNA‐Seq) of four non‐small‐cell lung cancer patients was carried out. We identified 361 somatic missense mutations from which 224 candidate neoantigens were predicted using MHC class I binding affinity prediction software (strategy I). Of these, 207 exceeded the set threshold of gene expression (fragments per kilobase of transcript per million fragments mapped ≥1), resulting in 124 candidate neoantigens (strategy II). To verify mutant mRNA expression, sequencing of amplicons from tumor cDNA including each mutation was undertaken; 204 of the 207 mutations were successfully sequenced, yielding 121 mutant mRNA sequences, resulting in 75 candidate neoantigens (strategy III). Sequence information was extracted from RNA‐Seq to confirm the presence of mutated mRNA. Variant allele frequencies ≥0.04 in RNA‐Seq were found for 117 of the 207 mutations and regarded as expressed in the tumor, and finally, 72 candidate neoantigens were predicted (strategy IV). Without additional amplicon sequencing of cDNA, strategy IV was comparable to strategy III. We therefore propose strategy IV as a practical and appropriate strategy to predict candidate neoantigens fully utilizing currently available information. It is of note that different neoantigen loads were deduced from the same tumors depending on the strategies applied.

Background Virtual-assisted lung mapping is a novel bronchoscopic preoperative lung marking technique in which virtual bronchoscopy is used to predict the locations of multiple dye markings. Post-mapping computed tomography is performed to confirm the locations of the actual markings. This study aimed to examine the accuracy of marking locations predicted by virtual bronchoscopy and elucidate the role of post-mapping computed tomography. Methods Automated and manual virtual bronchoscopy was used to predict marking locations. After bronchoscopic dye marking under local anesthesia, computed tomography was performed to confirm the actual marking locations before surgery. Discrepancies between marking locations predicted by the different methods and the actual markings were examined on computed tomography images. Forty-three markings in 11 patients were analyzed. Results The average difference between the predicted and actual marking locations was 30 mm. There was no significant difference between the latest version of the automated virtual bronchoscopy system (30.7 ± 17.2 mm) and manual virtual bronchoscopy (29.8 ± 19.1 mm). The difference was significantly greater in the upper vs. lower lobes (37.1 ± 20.1 vs. 23.0 ± 6.8 mm, for automated virtual bronchoscopy; p Conclusions Markings predicted by virtual bronchoscopy were dislocated from the actual markings by an average of 3 cm. However, surgery was accurately performed using post-mapping computed tomography guidance, demonstrating the indispensable role of post-mapping computed tomography in virtual-assisted lung mapping.

Aims Malignant mesothelioma is a highly aggressive cancer that is usually diagnosed at advanced stages; thus, highly sensitive and specific markers are necessary for its early definitive diagnosis. The aim of this study was to evaluate the diagnostic utility and prognostic significance of BAP1 and EZH2 in malignant mesothelioma. Methods and results The expression of BAP1 and EZH2 was investigated by immunohistochemistry in 32 malignant mesotheliomas and 44 benign mesothelial proliferative lesions, including well-differentiated papillary mesothelioma (n = 4), mesothelial inclusion cyst (n = 22), and reactive mesothelial hyperplasia (n = 18). BAP1 loss and high EZH2 expression were observed in 17 (53%) and 22 (66%) malignant mesothelioma cases, respectively, whereas none of the benign lesions showed BAP1 loss or high EZH2 expression. The combination of BAP1 loss and high EZH2 expression as markers to differentiate epithelioid/biphasic malignant mesothelioma from benign mesothelial lesions was highly sensitive (90%) and specific (100%). There were no statistically significant associations between parameters such as age and sex of patients, tumour location, asbestos exposure, treatment, histology, and BAP1 or EZH2 expression. Survival analysis revealed that BAP1 loss, but not high EZH2 expression, was associated with a better prognosis. Conclusions BAP1 loss and high EZH2 expression were highly specific to malignant mesothelioma in differentiating it from benign mesothelial proliferations, and the combination of these two markers improved the diagnostic accuracy.

The impact of red cell distribution width (RDW) on outcomes in elderly patients after surgery for non-small cell lung cancer (NSCLC) is not fully understood.We retrospectively analyzed 992 NSCLC patients who underwent curative resection between 1998 and 2012. The following variables were included in the analyses to evaluate the role of RDW: age, gender, smoking index, leukocyte count, neutrophil to lymphocyte ratio (NLR), hemoglobin, platelet count, albumin, C-reactive protein, carcinoembryonic antigen, respiratory function, histology, T factor, N factor, surgical approach, surgical procedures, complications and prognosis.High RDW (13.8) was an independent risk factor for morbidity [hazard ratio (HR) 2.1; P0.01], recurrence (HR 2.0; P=0.01), overall survival (OS) (HR 2.1; P0.01) and disease-free survival (DFS) (HR 2.0; P0.01) in elderly patients (age ≥75 years, n=275), whereas it was not in younger patients (age75 years, n=717). The surgical outcome was extremely poor in those older than 80 years with a RDW greater than 15% (morbidity, 56%; postoperative stay, 23 days; OS, 24%; DFS, 0%). RDW was unaffected by age (R =0.01; P=0.86) and elevated RDW without anemia was more prognostic than high RDW due to anemia in elderly patients.High RDW was significantly associated with high morbidity and reduced survival in elderly patients who underwent resection for NSCLC. Therefore, this parameter should be taken into account when surgery is considered in the elderly.

We report a case of giant solitary fibrous tumor( SFT) of the pleura postoperatively complicated with probable reexpansion pulmonary edema and atrial fibrillation. An 85-year-old woman was diagnosed to have a 13 cm sized intrathoracic neoplasm. Upon thoracotomy, the tumor was found to pedunculate from the right lung with no direct invasion to the surrounding structures. Complete resection of the tumor and expansion of the right lung was obtained. Histopathology revealed the tumor was a benign SFT arising from the visceral pleura. An infiltrative shadow in the right lower lung field soon after the surgery suggested a reexpansion pulmonary edema, which eventually recovered within a week. The patient suffered from a refractory atrial fibrillation that led to a congestive heart failure requiring an intensive medical treatment. It is emphasized that thoracic surgeons should be aware of these postoperative complications in treating such a case like this.

OBJECTIVESVenous thromboembolic events (VTE) after thoracic surgery (TS) can be prevented with mechanical and chemical prophylaxis. Unlike other surgical specialties, TS lacks evidence-based guidelines. In the process of developing these guidelines, an understanding of the current prophylaxis methods practiced internationally is necessary and is described in this article.METHODSA 26-item survey was distributed to members of the European Society of Thoracic Surgeons (ESTS), American Association of Thoracic Surgery (AATS), Japanese Association for Chest Surgery (JACS) and Chinese Society for Thoracic and Cardiovascular Surgery (CSTCS) electronically or in person. Participants were asked to report their current prophylaxis selection, timing of initiation and duration of prophylaxis, perceived risk factors and the presence and adherence to institutional VTE guidelines for patients undergoing TS for malignancies.RESULTSIn total, 1613 surgeons anonymously completed the survey with an overall 36% response rate. Respondents were senior surgeons working in large academic hospitals (≥70%, respectively). More than 83.5% of ESTS, AATS and JACS respondents report formal TS thromboprophylaxis protocols in their institutions, but 53% of CSTCS members report not having such a protocol. The regions varied in the approaches utilized for VTE prophylaxis, the timing of initiation perioperatively and the use and type of extended prophylaxis. Respondents reported that multiple risk factors and sources of information impact their VTE prophylaxis decision-making processes, and these factors vastly diverge regionally.CONCLUSIONSThere is little agreement internationally on the optimal approach to thromboprophylaxis in the TS population, and guidelines will be helpful and vastly welcomed.

Objectives This study aimed to develop an immunohistochemical (IHC) diagnostic algorithm for primary lung squamous cell carcinoma (LSCC) and pulmonary metastasis of head and neck SCC (HNSCC). Materials and methods We selected three antibodies (CK19, MMP3, and PI3) from a web-based gene expression database and an IHC analysis available online. We developed an IHC diagnostic algorithm using tissue microarrays from 39 LSCCs and 48 HNSCCs as the training set. It was validated using whole tumor sections of 32 LSCCs and 23 HNSCCs. The algorithm was applied to 28 cases with a history of HNSCC and who underwent resection of pulmonary squamous cell tumors. Results The sensitivity, specificity, and accuracy of the algorithm were 90%, 62%, and 77%, respectively, in the training set and 96%, 44%, and 65%, respectively, in the validation set. Twenty-three of 28 SCCs were diagnosed as metastasis of HNSCC; the remaining five tumors were diagnosed as LSCC. Among the patients in the HNSCC group, 18 developed postoperative recurrence and 11 died of the disease, whereas only one patient in the LSCC group had recurrence. Compared with the LSCC group, the HNSCC group had poorer prognosis (P = 0.07). IHC diagnosis coincided with the retrospective diagnosis in 22 (79%) of the 28 patients (sensitivity, 95%; specificity, 44%). Conclusion The IHC diagnostic algorithm may be clinically useful for distinguishing between LSCC and pulmonary metastasis of HNSCC.

Introduction Two strategies for selecting neoantigens as targets for non–small cell lung cancer vaccines were compared: (1) an “off-the-shelf” approach starting with shared mutations extracted from global databases and (2) a personalized pipeline using whole-exome sequencing data on each patient’s tumor. Methods The Catalogue of Somatic Mutations in Cancer database was used to create a list of shared missense mutations occurring in more than 1% of patients. These mutations were then assessed for predicted binding affinity to HLA alleles of 15 lung cancer patients, and potential neoantigens (pNeoAgs) for each patient were selected on this basis. In the personalized approach, pNeoAgs were selected from missense mutations detected by whole-exome sequencing of the patient’s own samples. Results The list of shared mutations included 22 missense mutations for adenocarcinoma and 18 for squamous cell carcinoma (SCC), resulting in a median of 10 off-the-shelf pNeoAgs for each adenocarcinoma (range 5–13) and 9 (range 5–12) for each SCC. In contrast, a median of 59 missense mutations were identified by whole-exome sequencing (range 33–899) in adenocarcinoma and 164.5 (range 26–232) in SCC. This resulted in a median of 46 pNeoAgs (range 13–659) for adenocarcinoma and 95.5 (range 10–145) for SCC in the personalized set. We found that only one or two off-the-shelf pNeoAgs were included in the set of personalized pNeoAgs—and then in only three patients, with no overlap seen in the remaining 12 patients. Conclusions Use of an off-the-shelf pipeline is feasible but may not be satisfactory for most patients with non–small cell lung cancer. We recommend identifying personal mutations by comprehensive genome sequencing for developing neoantigen-targeted cancer immunotherapies.

Extracorporeal membrane oxygenation (ECMO) is a temporary mode of providing life support by totally/partially augmenting heart and lung function over a few days to weeks. More than 30,000 cases involving ECMO usage in adults have been reported worldwide since the introduction of this unique therapy, and its applications continue to evolve rapidly. In recent times, ECMO plays a key role not only in the domain of critical care in intensive care units, but is also useful in the field of cardiothoracic surgery;it provides cardiopulmonary support intra- and post-operatively, respiratory support for primary graft dysfunction after lung transplantation and serves as a bridge to lung transplantation. The purpose of this review is to analyze the indications, modes of application, and complications of ECMO use in the field of cardiothoracic surgery.

Background: Clinical trials of anti-CCR4 antibody for solid cancers with or without other immune-modulating agents including immune checkpoint blockade therapy are currently underway. However, little is known about the roles of CCR4 + lymphocytes and their prognostic impact in lung cancer. We hypothesized that high CCR4 expression in the tumor microenvironment would be associated with a poor prognosis and would act as a biomarker in lung adenocarcinoma. Methods: First, the prognostic impact of CCR4 gene expression was explored using pooled data from public transcriptomic databases with online survival analysis software. Second, tissue microarrays (TMAs) were constructed from resected lung adenocarcinoma specimens from tumors up to 3 cm in size. The density of CCR4 + lymphocytes infiltrating the tumor was then assessed by immunohistochemistry and related to survival. Confounding factors were controlled for by multivariate analysis using the Cox proportional hazards model. Results: Higher than median expression of the CCR4 gene was identified as an independent poor prognostic factor for overall survival (OS) by multivariate analysis of 720 lung adenocarcinoma patients in the public databases [HR =1.55 (95% CI: 1.03–2.35), P=0.037]. Consistent with this, high CCR4 + tumor-infiltrating lymphocyte (TIL) density was found to be an independent poor prognostic factor for both OS [HR =2.24 (1.01–5.34), P=0.049] and recurrence-free survival (RFS) [HR =2.20 (1.16–4.39), P=0.017] in the patients from whom TMA were obtained (n=180). Age, male gender, predominantly non-lepidic histological subtype, nodal involvement, and low CD8 + TIL density were also independent poor prognostic factors. However, FOXP3 gene expression and Foxp3 + lymphocyte infiltration did not possess any prognostic value in either study. Conclusions: High CCR4 expression in the tumor microenvironment may be a poor prognostic factor in lung adenocarcinoma. Patients with high CCR4 + lymphocyte infiltration may have a poor prognosis and thus be suitable candidates for clinical trials of anti-CCR4 antibody treatment.

Objectives Depletion in skeletal muscle is closely associated with limited physical ability and high mortality. In this study, we evaluated the prognostic significance of skeletal muscle depletion in patients with early-stage non-small-cell lung cancer. Methods A retrospective analysis of patients with pathological stages I-II lung cancer, who underwent curative resection between 2009 and 2013, was conducted. The truncal muscle index (TMI) (area/height2) at the first lumbar vertebral level was measured by preoperative axial computed tomography. Overall survival and recurrence-free survival were compared between the lowest gender-specific quartile of the TMI and the other quartiles. Results A total of 314 subjects were included in the study. The cumulative 5-year recurrence-free and overall survival rates were significantly shorter in patients with lower TMIs (69% vs 83.5%, P = 0.028; 64.8% vs 80.1%, P = 0.003, respectively). In multivariable models, the TMI was identified as an independent prognostic factor for overall survival (P = 0.017, hazard ratio 1.84, 95% confidence interval 1.12-3.05), after adjusting for age, gender, preoperative serum albumin, carcinoembryonic antigen, neutrophil to lymphocyte ratio and pathological stage. Conclusions A low preoperative TMI was associated with a poor postoperative outcome in patients with early-stage non-small-cell lung cancer. This factor may be included in the preoperative assessment of patients, for whom surgical intervention is considered.

Patients with thymomas are at high risk of developing extrathymic malignancies. We investigated the impact of extrathymic malignancies on the prognosis of patients with thymoma who underwent surgery and the risk factors for postoperative extrathymic malignancies.A multicenter retrospective review of 252 patients who underwent surgical resection of thymomas from January 1977 to March 2016 was conducted. The exclusion criteria were recurrent thymoma, rare types of thymoma, and missing data. The overall number and incidence of extrathymic malignancies were calculated. Potential predictors of extrathymic malignancies were also evaluated.Two hundred twenty-eight patients were analyzed. Fifty-five extrathymic malignancies were observed (23 postoperative, 8 synchronous, and 24 preoperative). Among the overall cohort, the incidence of extrathymic malignancies significantly increased the patients' risk of death (hazard ratio [HR], 4.02; 95% confidence interval [CI], 1.72 to 9.40; p0.01). Among patients aged less than 70 years, the incidence of extrathymic malignancies was an independent risk factor for death. The incidence of postoperative extrathymic malignancies was significantly higher in patients with indolent forms of thymoma (type A/AB/B1) than aggressive forms (type B2/B3) (p = 0.02). In the multivariate analysis, indolent forms of thymoma (type A/AB/B1) (HR, 4.03; 95% CI, 1.12 to 14.6, p = 0.03) and a history of ever having smoked (HR, 5.29; 95% CI, 1.30 to 21.6; p = 0.02) were significant risk factors for the cumulative incidence of postoperative extrathymic malignancies.Extrathymic malignancies increased the risk of death in patients with thymomas. Indolent forms of thymoma and a history of ever having smoked were risk factors for postoperative extrathymic malignancies.

Thoracic outlet syndrome (TOS) is caused by heterogeneous factors that compress the brachial plexus and subclavian artery; tumor is rarely a cause of TOS. Here, we present the case of a 26-year-old man with secondary chondrosarcoma arising from osteochondroma of the left clavicle causing TOS, with a direct compression of the brachial plexus and subclavian artery. Immediately after surgery, the symptoms of TOS reduced. To our knowledge, this is the first case of a secondary chondrosarcoma of the clavicle causing TOS, which is possibly the key symptom for diagnosing malignant transformation of osteochondroma of the clavicle.

Purpose Recent progress in the treatment of pulmonary arterial hypertension (PAH) such as high-dose epoprostenol and upfront combination therapy brought a marked improvement in prognosis of PAH. However, severely ill cases with PAH still need lung transplantation. Considering the first-come-first-served system and resulting long waiting period Japan, the timing of referral for lung transplantation is critical. Methods Consecutive 31 patients with PAH (including pulmonary veno-occlusive disease) referred to our hospital to be considered eligibility for lung transplantation were enrolled in this study. We retrospectively analyzed patients’ characteristics at referral for lung transplantation and their clinical outcomes. Results Seventeen of 31 patients (55%) were female and average age at referral was 30.6±11.8 year-old. Twenty-six patients were idiopathic/heritable PAH, 4 were connective tissue disease associated PAH and 1 was pulmonary veno-occlusive disease. They were referred to our hospital 2127±1691 days after diagnosis. All but one patients were introduced parenteral prostanoid. Mean received dose of parenteral prostanoid was 98±56 ng/kg/min at referral. Although their mean pulmonary artery pressure was severely elevated (51.1±11.6 mmHg), cardiac index and six-minute walk distance were relatively maintained (3.63±0.98 L/min/m2 and 394±174m, respectively). Two patients were not registered as candidates for lung transplantation for medical or social reason. Three patients underwent successful lung transplantation, while eight patients died on the waiting list. Three-year survival after referral was 67% in total. Multivariate analysis revealed that heart rate (HR) and pulmonary vascular resistance (PVR) were independent predictors of all-cause mortality after referral (p=0.016 and p=0.016, respectively). Conclusion High HR and PVR are independent predictors of mortality in patients with PAH receiving parenteral prostanoid and awaiting lung transplantation. Although high-dose parenteral prostanoid improved hemodynamics in patients with PAH, the high output status and relatively maintained exercise capacity might have delayed referral for lung transplantation.