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Introduction: A tracheal bronchus is rarely observed, occurring in only 1% of all patients who undergo thoracic surgeries. We rarely encounter lung cancer in a patient with a tracheal bronchus; however, it is essential to know the distinctive perioperative management strategy for patients with a tracheal bronchus., Case Presentation: We report a 72-year-old man with lung cancer located in the right apical segment supplied by a tracheal bronchus. Annual chest computed tomography performed as follow-up after colon cancer resection showed an enlarging pulmonary nodule with pure ground-glass opacity, which was suspected to be lung adenocarcinoma. The nodule was located in the right apical segment. The apical segment was independently supplied by a single pulmonary artery superior trunk and a tracheal bronchus that branched directly from the trachea at 1.2 cm above the carina. The pulmonary vein branching pattern was uncommon in that the central vein that usually runs through B2 (posterior bronchus) and B3 (anterior bronchus) was missing. The patient underwent video-assisted thoracoscopic apical segmentectomy under one-lung ventilation using a left-sided double-lumen tube., Discussion: Anomalous venous return accompanied with tracheal bronchus has been described in some reports. Since pulmonary vein is important during segmentectomy, the surgeon should pay particular attention to the venous return., Conclusion: Preoperative three-dimensional graphic imagery helped us accurately identify the anatomical anomaly to enable the successful segmentectomy in a patient with a tracheal bronchus. We review the relevant literature regarding the perioperative management of patients with a tracheal bronchus., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We report a 69-year-old woman with spontaneous pneumothorax associated with cavitating pulmonary metastasis from breast cancer. She was treated for right breast cancer (invasive ductal carcinoma, ypT4bN1M0, stage IIIB) 2 years earlier, and was admitted for right pneumothorax and chest computed tomography, which showed multiple small cavitating lesions in bilateral lungs. The pneumothorax was treated conservatively with chest drainage, but subsequently recurred ipsilaterally. During video-assisted thoracic surgery, we detected small white nodules with visceral pleural rupture; therefore, we performed partial lung resection. The pathological findings revealed metastatic breast cancer with pleural invasion. Forty days later, ipsilateral pneumothorax recurred, and chemical pleurodesis was performed, which resolved the pneumothorax and prevented subsequent recurrence. Early diagnosis and definitive treatment, including pleurodesis, should be considered to prevent recurrence of spontaneous pneumothorax and improve patients' quality of life, even in patients with advanced malignancy.

Background: Interleukin (IL)-38 was discovered in 2001 and is a member of the IL-1 family of cytokines. IL-38 shows anti-inflammatory activity in several inflammatory diseases. In lung adenocarcinoma, we previously demonstrated that high IL-38 expression in tumor cells was associated with poor prognosis. However, the role of IL-38 in the tumor microenvironment has not been clarified., Methods: IL-38-plasmid-transfected Lewis lung carcinoma cells (LLC-IL38) and empty vector-transfected LLC cells (LLC-vector) were established. Cell proliferation in vitro and tumor growth in vivo were examined, and immunohistochemical staining was used to assess tumor-infiltrating lymphocytes (TILs). A CD8 + lymphocyte depletion model was established to show the association between IL-38 and CD8 + lymphocytes. Moreover, we examined the association between IL-38 expression and CD8 + TILs in human samples, analyzing immunohistochemical staining in 226 patients with radically resected lung adenocarcinoma., Results: Tumor growth of LLC-IL38 in vivo was significantly increased compared with that of LLC-vector, although cell proliferation of LLC-IL38 in vitro was lower than that of LLC-vector. CD8 + TILs were significantly decreased in LLC-IL38 tumor compared with LLC-vector tumor. The difference in tumor growth between LLC-IL38 and LLC-vector became insignificant after depletion of CD8 + lymphocytes. In immunohistochemical staining in tissues from patients with lung adenocarcinoma, multivariate analysis showed high IL-38 expression was an independent negative predicter of high density of CD8 + TILs., Conclusion: We demonstrated that high IL-38 expression in tumor cells was significantly associated with reduction of CD8 + TILs and tumor progression. These results suggest that IL-38 could be a therapeutic target for lung cancer.

Inflammatory biomarkers have been associated with clinical outcomes in non-small cell lung cancer (NSCLC). However, the best prognostic marker(s) has not been identified, and the association between inflammatory markers and clinical characteristics is poorly understood. We selected 1,237 patients with resected NSCLC from Kyushu University (2003-2015) and Kyushu Cancer Center (2009-2015) in Japan. Pearson product-moment correlation coefficient among inflammatory markers and area under curve (AUC) of receiver operating characteristic (ROC) curve analyses for overall survival (OS) were calculated. We analyzed the associations between inflammatory markers and clinical factors using Student's t-test. Univariate and multivariate analyses with Cox proportional hazards regression analyses were performed to evaluate the relationship between survival and clinical factors. The cut-off values for neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR), platelet-lymphocyte ratio, and derived NLR (dNLR) were determined by ROC curve analyses for OS. We found a strong positive correlation between NLR and dNLR (r = 0.9629). The AUC of LMR was the highest amongst the measured metrics, and the AUC of NLR was higher than dNLR. Levels of some inflammatory markers were associated with sex, smoking, squamous cell carcinoma, and pathological stage. LMR ≥ 5.11 and lactate dehydrogenase (LDH) concentration ≥ 222 (U/L) were independent predictors of both disease-free survival (DFS) and OS (LMR; P = 0.0009 and 0.0008, LDH; P = 0.0195 and 0.0187, respectively). Certain inflammatory markers, potentially linked to smoking, were associated with an advanced pathological stage in NSCLC. LMR and LDH were independent predictors of both DFS and OS., Competing Interests: The authors have declared that no competing interests exist.

Background: Initial surgical intervention for a first episode of primary spontaneous pneumothorax (PSP) is controversial. However, if air leak persists after initial drainage, surgical treatment is recommended. Therefore, we investigated risk factors for persistent air leak (PAL) in patients with a first episode of PSP., Methods: We retrospectively analyzed 122 patients with a first episode of PSP between January 2011 and April 2019. PAL was defined as air leak lasting 72 hours or longer. Early admission was defined hospital admission within 24 hours of symptom onset. Three methods were used to estimate pneumothorax size on chest X-rays taken at admission: interpleural distance, apex-cupola distance, and Light index., Results: Among 122 patients, 55 developed PAL (PAL group) and 67 did not (non-PAL group). The size of pneumothorax was significantly larger in the PAL group than in the non-PAL group in all three methods of assessment (P<0.001). Early hospital admission was significantly associated with PAL (P=0.026). Logistic regression analysis revealed that the odds ratio for PAL per unit increase in pneumothorax size evaluated with the interpleural distance was 1.304 (P<0.001). Multivariate logistic regression analysis showed that interpleural distance at the hilum and early admission (P<0.001, P=0.008, respectively) were independent predictors of PAL in patients with a first episode of PSP., Conclusions: In our study, we demonstrated that the interpleural distance at the hilum is a simple and effective predictor of PAL in patients with a first episode of PSP. Our data may help decision-making for initial surgical treatment in these patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jtd.2020.04.48). The authors have no conflicts of interest to declare., (2020 Journal of Thoracic Disease. All rights reserved.)

The expression levels of many cell-surface proteins vary with the time of day. Glycoprotein 2 (Gp2), specifically expressed on the apical surface of M cells in Peyer's patches, functions as a transcytotic receptor for mucosal antigens. We report that cAMP response element-binding protein (CREB) regulates the transcription of the Gp2 gene, thereby generating the circadian change in its expression in mouse Peyer's patches. The transcytotic receptor activity of Gp2 was increased during the dark phase when the Gp2 protein abundance increased. Rhythmic expression of clock gene mRNA was observed in mouse Peyer's patches, and expression levels of Gp2 mRNA also exhibited circadian oscillation, with peak levels during the early dark phase. The promoter region of the mouse Gp2 gene contains several cAMP response elements (CREs). Chromatin immunoprecipitation assays revealed that CREB bound to the CREs in the Gp2 gene in Peyer's patches. Forskolin, which promotes CREB phosphorylation, increased the transcription of the Gp2 gene in Peyer's patches. As phosphorylation of CREB protein was increased when Gp2 gene transcription was activated, CREB may regulate the rhythmic expression of Gp2 mRNA in Peyer's patches. These findings suggest that intestinal immunity is controlled by the circadian clock system., (© 2020 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)

Background: It is unclear whether or not the breakpoint (BP), at which the proportion of each of fat mass (FM) and fat-free soft tissue mass (FFSTM) to body mass (BM) alter, exists in male athletes. We examined the hypothesis that in male athletes, the regional FM and FFSTM-BM relationships have a BP, but the body mass at BP (BM BP ) differs among the arms, trunk, and legs., Methods: By using a dual X-ray absorptiometry, whole-body and regional FMs and FFSTMs in the arms, trunk, and legs were estimated in 198 male athletes (20.8 ± 2.1 years; 1.73 ± 0.07 m; 72.7 ± 14.8 kg). To detect the BP in the relationship between each of FM and FFSTM and BM, a piecewise linear regression analysis was used. If a BP was detected in the corresponding relationship, the significant difference between the regression slopes above and below the BP was examined., Results: The regression analysis indicated that the BM BP existed in the FM- and FFSTM-BM relationships regardless of region and whole body. For the whole body, BM BP was 81.8 kg for FM and 82.2 kg for FFSTM. In regional FM-BM relationships, BM BP was 80.5 kg for arms, 82.6 kg for trunk, and 63.3 kg for legs, and the regression slopes above the BM BP became higher than those below the BP, and vice versa in regional FFSTM-BM relationships (BM BP 104.6 kg for arms, 80.9 kg for trunk, and 79.0 kg for legs). The relative differences in the slopes between below and above BM BP in the regional FM-BM relationships were higher in the arms and trunk than in the legs, and those in the regional FFSTM-BM relationships in the legs than in the trunk., Conclusion: Whole-body and regional FM- and FFSTM-BM relationships for male athletes have breakpoints at which the proportion of the tissue masses to BM alters. The BM BP and differences in the distribution of regional FM and FFSTM around the breakpoint are region specific.

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 (cm 2 /m 2 ) 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., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Glycolaldehyde (GA) is a highly reactive hydroxyaldehyde and one of the glycolytic metabolites producing advanced glycation endproducts (AGEs), but its toxicity toward neurons and Schwann cells remains unclear. In the present study, we found that GA exhibited more potent toxicity than other AGE precursors (glyceraldehyde, glyoxal, methylglyoxal and 3-deoxyglucosone) against immortalized IFRS1 adult rat Schwann cells and ND7/23 neuroblastoma × neonatal rat dorsal root ganglion (DRG) neuron hybrid cells. GA affected adult rat DRG neurons and ND7/23 cells more severely than GA-derived AGEs, and exhibited concentration- and time-dependent toxicity toward ND7/23 cells (10 < 100 < 250 < 500 µM; 6 h < 24 h). Treatment with 500 µM GA significantly up-regulated the phosphorylation of c-jun N-terminal kinase (JNK) and p-38 mitogen-activated kinase (p-38 MAPK) in ND7/23 cells. Furthermore, GA-induced ND7/23 cell death was significantly inhibited due to co-treatment with 10 µM of the JNK inhibitor SP600125 or the p-38 MAPK inhibitor SB239063. These findings suggest the involvement of JNK and p-38 MAPK-signaling pathways in GA-induced neuronal cell death and that enhanced GA production under diabetic conditions might be involved in the pathogenesis of diabetic neuropathy.

Previous studies proposed calf circumference cutoff values for predicting dual-energy X-ray absorptiometry (DXA)-derived low muscle mass. However, DXA-derived appendicular lean mass (aLM) includes non-skeletal muscle components such as the appendicular fat-free component of adipose tissue fat cells (aFFAT). The purpose of this study was to compare the calf circumference method of classification before (Model #1) and after (Model #2) eliminating the influence of FFAT in healthy Japanese adults (50 to 79 years; mean age 70 (SD 7) years). Model 1, and Model 2 for classifying low muscle mass had a sensitivity of 78% and 64%, specificity of 76% and 75%, positive predictive value of 31% and 28%, and negative predictive value of 96% and 93%, respectively. Appendicular fat-free component of adipose tissue has the potential to influence the ability of calf circumference to accurately classify individuals with low muscle mass. Consideration should be made when using this as a screening tool for low muscle mass., Competing Interests: No conflicts of interest, financial or otherwise, are disclosed by the authors.

Background & Aims: B-mode ultrasound accurately measures both muscle mass, body density and percent body fat (% BF) in younger adults, but how well it can estimate % BF in middle-aged and older adults using DXA-derived %BF as the criterion is unclear. We sought to develop % BF prediction equations for middle-aged and older adults using ultrasound subcutaneous fat thickness (SFT)., Methods: A cross-sectional study of Japanese adults (n = 414, 50-79 years) where 276 subjects were randomly assigned to a model development group and the other 138 subjects were assigned to a cross-validation group. B-mode ultrasound measured SFT at nine sites. Dual energy X-ray absorptiometry (DXA) measured % BF, arm fat mass (FM) and leg FM. Stepwise multiple linear regression developed prediction equations from anthropometric data (body mass, height, waist and hip circumference) and ultrasound SFT sites. Bland-Altman plots assessed validity of the prediction equations to measure % BF in the cross-validation group., Results: The best prediction equation for % BF was the following: [% BF = 15.709 + (1.753*anterior trunk SFT) + (5.626*Sex) + (3.635*posterior upper arm SFT) - (4.428*anterior lower leg SFT) - (0.170*height) + (0.264*waist) + (anterior thigh SFT*2.241); r 2  = 0.809, standard error of the estimate (SEE) = 3.3 kg]. Arm FM and leg FM prediction equations had r 2 values ranging from 0.690 to 0.812 and SEEs of 0.29 and 0.75 kg. A small mean bias was noted for estimating % BF (-0.14%), but large limits of agreement were found (-8.0-7.7%) and systematic error was noted in all of the equations (r = 0.275 to 0.515, p < 0.05)., Conclusions: Despite high r 2 values and a small mean bias found between predicted and DXA % BF, wide limits of agreement were found with some systematic error present. Therefore, these prediction equations for middle-aged and older adults may not be sufficiently accurate to use in a clinical setting., (Copyright © 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

P-glycoprotein (P-gp/ABCB1) is an ATP-binding cassette drug efflux transporter expressed in a variety of tissues that affects the pharmacokinetic disposition of many drugs. Although several studies have reported gender-dependent differences in the expression of P-gp, the role of sex hormones in regulating the expression of P-gp and its transport activity has not been well understood. In this study, we demonstrated that 17β-estradiol has the ability to induce the expression of P-pg in mouse kidneys and cultured human renal proximal tubular epithelial cells. After intravenous injection of a typical P-gp substrate, digoxin, renal clearance in female mice was approximately 2-fold higher than that in male mice. The expression of murine P-gp and its mRNA (Abcb1a and Abcb1b) were also higher in female mice than in male mice. The expression of P-gp in cultured renal tissues prepared from female and male mice was significantly increased by 17β-estradiol, but not testosterone. Similar 17β-estradiol-induced expression of P-gp was also detected in cultured human tubular epithelial cells, accompanied by the enhancement of its transport activity of digoxin. The present findings suggest the contribution of estradiol to female-predominant expression of P-gp in renal cells, which is associated with sex-related disparities in the renal elimination of digoxin., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The small GTPase Rho and its effector Rho kinase (ROCK) are involved in the pathogenesis of diabetic kidney disease. Rho kinase has two isoforms: ROCK1 and ROCK2. However, it remains unclear which is mainly involved in the progression of diabetic glomerulosclerosis and the regulation of profibrotic mediators. Glomeruli isolated from type 2 diabetic db / db mice demonstrated increased gene expression of transforming growth factor (TGF)-β and its downstream profibrotic mediators. Chemical inhibition of ROCK suppressed the expression of profibrotic mediators in both isolated glomeruli and cultured mesangial cells. An investigation of mechanisms underlying this observation revealed activated ROCK functions through the phosphorylation of JNK and Erk and the nuclear translocation of NF-κB via actin dynamics. Knockdown by siRNA against ROCK1 and ROCK2 showed that ROCK2 but not ROCK1 controls this fibrotic machinery. Further in vivo experiments showed that ROCK2 activity in the renal cortex of db / db mice was elevated compared with control db / m mice. Importantly, oral administration of ROCK2 inhibitor attenuated renal ROCK2 activity, albuminuria, and glomerular fibrosis in db / db mice. These observations indicate that ROCK2 is a key player in the development of diabetic renal injury. Glomerular ROCK2 may be a potential therapeutic target for the treatment of diabetic kidney disease.

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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., Competing Interests: The authors have declared that no competing interests exist.

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., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: CD44 isoforms serve as a marker for cancer stem cells. CD44 variant 9 (CD44v9) contributes to the defense against reactive oxygen species, resulting in resistance to chemoradiotherapy. However, the significance of CD44v9 in patients with lung adenocarcinoma is unknown., Methods: We used immunohistochemical analysis to retrospectively analyze CD44v9 expression in 268 surgically resected lung adenocarcinomas and investigated the association between CD44v9 expression and patients' clinicopathological features., Results: The expression of CD44v9 in 193 of 268 (72.0%) patients was significantly associated with early-stage cancer, low-grade tumors, absence of vessel and pleural invasion, and a mutated epidermal growth factor receptor (EGFR) gene. Multivariate logistic analysis revealed that CD44v9 expression was significantly associated with early-stage disease [odds ratio (OR) 0.29, 95% confidence interval (CI) 0.14-0.59; p < 0.001] and mutant EGFR (OR 2.53, 95% CI 1.06-6.04; p = 0.036). The percentage of CD44v9-positive tumors was higher in the earlier stages of disease; however, there was no significant difference in the survival of patients in each stage of disease who had positive or negative CD44v9 expression., Conclusion: CD44v9 was highly expressed in EGFR-mutant tumors, particularly in early-stage lung adenocarcinoma, suggesting that CD44v9 expression may play an important role in EGFR-mutant tumors.

Background/objectives: To investigate the impact of eliminating fat-free adipose tissue (aFFAT) on the prevalence of low muscle mass in older adults., Subjects/methods: Three hundred and forty-three (153 men and 190 women) well-functioning Japanese older adults (aged 65-79) had their appendicular lean mass (aLM) and appendicular fat mass (aFM) measured using dual-energy X-ray absorptiometry (DXA). aFFAT was then estimated from DXA-derived aFM (aFM = (FM/0.15)*0.85). Both traditional cutoffs and those corrected for aFFAT were used for diagnosing low muscle mass., Results: With traditional cutoff values, the prevalence of low muscle mass using the unadjusted aLM index was 20.1%. After adjusting the aLM index for aFFAT, the prevalence increased to 49.0% (p < 0.001). However, when the cutoff values were also adjusted for aFFAT, the prevalence of low muscle mass only increased to 23.0% (p < 0.001). Further, ~5% of the participants (7 men and 8 women) were newly classified as having low muscle mass after correction for aFFAT. However, several women (n = 5) were not classified as having low muscle mass using the corrected cutoff value, although they would have been when using the non-corrected cutoff., Conclusions: Adjusting for the effect of aFFAT on DXA-derived aLM significantly increases the prevalence of low muscle mass in older adults. For clinical research and practice, the influence of aFFAT on DXA-derived aLM may need to be taken into consideration when diagnosing low muscle mass.

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., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: This study was performed to evaluate the influence of the body mass index (BMI) on disease-free survival and overall survival (DFS and OS) in patients with resected non-small cell lung cancer (NSCLC)., Patients and Methods: Overall, 546 of 780 (70%) patients with stage I to III NSCLC who underwent surgical resection were randomly selected. The patients were subdivided into three groups: low BMI (<18.5 kg/m 2 ), normal BMI (18.5 to <25.0 kg/m 2 ), and high BMI (≥25.0 kg/m 2 ). Cox proportional hazards regression analyses were performed to identify variables associated with survival., Results: In all patients, a low BMI was an independent prognostic factor for both DFS and OS (p=0.0175 and p=0.0134, respectively). In patients with stage I, a low BMI was also an independent prognostic factor for both DFS and OS (p=0.0066 and p<0.0001, respectively)., Conclusion: A low BMI was an independent prognostic factor after surgical resection of stage I NSCLC. Molecular targeted therapies, such as epidermal growth factor receptor inhibitors, anaplastic lymphoma kinase-tyrosine kinase inhibitors, and immune checkpoint inhibitors targeting the programmed cell death-1/programmed cell death-ligand 1 (PD-L1) pathway have greatly improved the clinical course for patients with non-small cell lung cancer (NSCLC), especially advanced-stage NSCLC (1-7). However, lung cancer remains the leading cause of cancer-related death worldwide (8). Even in patients with stage I to IIIA NSCLC, the clinical course is unsatisfactory despite the fact that surgical resection is the main treatment option (9). Therefore, it is important to identify useful, simple, and inexpensive prognostic markers in patients with resectable NSCLC., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The small GTPase Rho and its downstream effector, Rho-kinase (ROCK), regulate various cellular functions, including organization of the actin cytoskeleton, cell adhesion and migration. A pro-inflammatory lipid mediator, lysophosphatidic acid (LPA), is a potent activator of the Rho/ROCK signalling pathway and has been shown to induce the expression of chemokines and cell adhesion molecules (CAMs). In the present study, we aimed to elucidate the precise mechanism by which ROCK regulates LPA-induced expressions and functions of chemokines and CAMs. We observed that ROCK blockade reduced LPA-induced phosphorylation of IκBα and inhibited NF-κB RelA/p65 phosphorylation, leading to attenuation of RelA/p65 nuclear translocation. Furthermore, small interfering RNA-mediated ROCK isoform knockdown experiments revealed that LPA induces the expression of monocyte chemoattractant protein-1 (MCP-1) and E-selectin via ROCK2 in human aortic endothelial cells (HAECs). Importantly, we found that ROCK2 but not ROCK1 controls LPA-induced monocytic migration and monocyte adhesion toward endothelial cells. These findings demonstrate that ROCK2 is a key regulator of endothelial inflammation. We conclude that targeting endothelial ROCK2 is potentially effective in attenuation of atherosclerosis.

Background: Pleuroperitoneal communication is a serious complication in patients receiving continuous ambulatory peritoneal dialysis. However, few single-institutional reports discuss the details of pleuroperitoneal communication in continuous ambulatory peritoneal dialysis patients regarding the intraoperative findings, postoperative course, and outcomes., Methods: We retrospectively reviewed the records of consecutive pleuroperitoneal communication patients who were treated surgically from September 2008 to March 2016., Results: All four patients had right-sided hydrothorax. The time from introduction of continuous ambulatory peritoneal dialysis to the diagnosis of hydrothorax ranged from 1 to 12 months (average: 5.5 months). Case 1 and case 4 had bleblike lesions near the center of the diaphragm; case 2 had a small hole located near the cardiophrenic angle, and case 3 had thinning of the diaphragm near the cardiophrenic angle. All lesions except for case 3 were directly closed with absorbable suture and reinforced by fibrin glue and a polyglycolic acid sheet. In case 3, the thinned diaphragm was reinforced using fibrin glue, a sealing sheet, and pericardial fat pad tissue. Continuous ambulatory peritoneal dialysis was reinitiated an average period of 11 days (range: 4-15 days) postoperatively. During postoperative follow-up, there was no recurrence of hydrothorax. Continuous ambulatory peritoneal dialysis was continued for an average of 16.7 months (range: 3-34 months) after surgical treatment., Conclusions: Surgical treatment for pleuroperitoneal communication is a safe and acceptable procedure and could greatly benefit continuous ambulatory peritoneal dialysis patients., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)

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., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Lorlatinib is a novel third-generation tyrosine kinase inhibitor (TKI) which targets anaplastic lymphoma kinase (ALK) as well as receptor tyrosine kinase c-ros oncogene 1 (ROS1). A critical limitation of conventional ALK/ROS TKIs is their association with acquired resistance mutations (particularly ALK G1202R and ROS1 G2032R) in the ALK or ROS1 gene, although these are not the only resistance mechanisms. Another limitation of this class of drugs is their inadequate efficacy against central nervous system metastasis, likely attributable to the blood-brain barrier (BBB). Therefore, lorlatinib was developed to overcome these limitations by being more potent, selective and permeable to the BBB than previous-generation ALK/ROS1 TKIs and subsequently received breakthrough therapy designation from the U.S. Food and Drug Administration (FDA) in April 2017. In September 2018, Japan became the first country where lorlatinib received approval for treating patients with ALK-rearranged non-small cell lung cancer. Eventually, the FDA approved lorlatinib (Lorbrena; Pfizer) in November 2018. Lorlatinib use is expected to increase in importance, owing to its promising efficacy in clinical trials., (Copyright 2019 Clarivate Analytics.)

Disruption of circadian rhythms has been implicated in an increased risk for cancer development. The Period2 ( Per2 ) gene encodes one of the major components of the mammalian circadian clock, which plays a key role in controlling the circadian rhythms in physiology and behavior. PER2 has also been reported to suppress the malignant transformation of cells, but its role in the regulation of cancer susceptibility to chemotherapeutic drugs remains unclear. In this study, we found that oncogene-transformed embryonic fibroblasts prepared from Per2 -mutant ( Per2 m/m ) mice, which are susceptible to both spontaneous and radiation-induced tumorigenesis, were resistant against common chemotherapeutic drugs and that this resistance is associated with up-regulation of the aldehyde dehydrogenase 3a1 ( Aldh3a1 ) gene. Co-expression of the oncogenes H-ras V12 and SV40 large T-antigen induced malignant transformation of both WT and Per2 m/m cells, but the cytotoxic effects of the chemotherapeutic agents methotrexate, gemcitabine, etoposide, vincristine, and oxaliplatin were significantly alleviated in the oncogene-transformed Per2 m/m cells. Although introduction of the two oncogenes increased the expression of Aldh3a1 in both WT and Per2 m/m cells, the ALDH3A1 protein levels in the Per2 m/m cells were ∼7-fold higher than in WT cells. The elevated ALDH3A1 levels in the oncogene-transformed Per2 m/m cells were sufficient to prevent chemotherapeutic drug-induced accumulation of reactive oxygen species. Consequently, shRNA-mediated suppression of Aldh3a1 expression relieved the chemoresistance of the Per2 m/m cells. These results suggest a role for mutated PER2 in the development of multiple drug resistance and may inform therapeutic strategies for cancer management., (© 2019 Katamune et al.)

Purpose: Clock genes are components of the molecular clock. Their malfunction is thought to increase the risk of numerous diseases, including cancer. Vascular endothelial growth factor (VEGF) has a pivotal role in angiogenesis, and its expression levels are controlled by clock genes in tumor cells. Ophthalmic diseases such as age-related macular degeneration, proliferative diabetic retinopathy, and neovascular glaucoma are also associated with abnormal angiogenesis followed by upregulation of VEGF in the eye. In the present study, we aimed to uncover the relationship between clock genes and VEGF in the eye., Study Design: Laboratory investigation METHODS: Oxygen-induced retinopathy (OIR) mice were prepared to mimic hypoxic conditions in the eye. Deferoxamine (DFO) was used to mimic hypoxic conditions in human Müller cell line MIO-M1 cells. Expression levels of mRNA and protein were quantified by quantitative reverse transcription polymerase chain reaction and Western blot analysis, respectively., Results: In the retinas of OIR mice, the expression levels of Vegf and the clock gene Dec2 increased transiently, and their temporal profiles were correlated. Knockdown of DEC2 resulted in a significant (26.7%) reduction of VEGF expression in MIO-M1 cells under hypoxia-mimicking conditions induced by DFO (P < .05). Levels of HIF1α protein were also reduced significantly, by 60.2%, in MIO-M1 cells treated with siRNA against the DEC2 gene (P < .05). Moreover, HIF1α levels showed a significant (2.5-fold) increase in MIO-M1 cells overexpressing DEC2 (P < .05)., Conclusion: DEC2 could upregulate retinal VEGF gene expression through modulation of HIF1α levels under hypoxic conditions.

Background/aim: Alterations of microRNA expression in three-dimensional spheroids were examined to identify novel microRNAs that might be associated with tumorigenesis., Materials and Methods: Using microRNA microarray analysis, we screened for microRNAs that were dramatically up-regulated inside three-dimensional spheroids in genetically-modified HCT116 human colon cancer cells expressing Copepoda Green Fluorescent Protein under hypoxia., Results: miR-3148 was identified as a possible candidate onco-microRNA. A growth advantage of HCT116 cells stably expressing miR-3148 (HCT116-miR3148) was observed compared to parental cells in vivo, but not in vitro. Additionally, no change in growth under hypoxic or starvation conditions was seen in these cells cultured two-dimensionally; however, HCT116-miR3148 cells maintained as three-dimensional spheroids were highly resistant to hypoxic conditions. HCT116-miR3148 cells were more sensitive to mitogen-activated protein kinase (MAPK) kinase inhibitors and extracellular signal-regulated kinase (ERK) inhibitors., Conclusion: MiR-3148 may be a novel onco-microRNA that protects cancer cells from serious stress conditions through the MAPK/ERK pathway, especially in vivo., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Although some previous studies suggested that programmed cell death-ligand 1 (PD-L1) expression was significantly associated with a favorable postoperative prognosis in patients with small-cell lung cancer (SCLC), the prognostic significance of PD-L2 expression remains unknown. The aim of the current study was to investigate the prognostic significance of PD-L2 expression in patients with SCLC., Patients and Methods: Thirty-eight patients who underwent resection of SCLC were analyzed. A monoclonal anti-human PD-L1 antibody (clone SP142) and a monoclonal anti-human PD-L2 antibody (clone 176611) were used as the primary antibodies. Cut-off value for PD-L1 and PD-L2 expression was set to 1%., Results: Among 38 patients, 15 (39.5%) were positive for PD-L2 expression. No significant associations between PD-L2-positivity and clinicopathological factors, including PD-L1 positivity or prognosis were identified. No significant differences in disease-free survival and overall survival were observed between PD-L2-positive patients and PD-L2-negative patients (p=0.367 and p=0.726, respectively)., Conclusion: PD-L2 expression is not related to clinicopathological factors or postoperative prognosis in patients with SCLC, though this should be further investigated in studies involving larger populations., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Diarrhetic shellfish toxins (DSTs) are a group of phycotoxins that include okadaic acid (OA)/dinophysistoxin (DTX) analogues. At present, detailed data on the distribution of DST is insufficient, and studies of the appropriate sample sizes are lacking. This study investigated the DST frequency distribution in scallops and mussels by liquid chromatography-tandem mass spectrometry (LC/MS/MS) and a resampling analysis of existing data was carried out. The DST population-interval and the necessary sample size were also estimated. DSTs are localized in the scallop digestive-gland, and the DST concentrations in scallops were water-depth-dependent. DST concentrations in scallops and mussels showed normal distributions, but mussels tended to contain more DSTs than scallops. In the statistical resampling analysis of the acquired data on scallops and mussels, especially that using the bootstrap method, sample size was difficult to estimate when the DST variation was large. Although the DST population-interval could be statistically estimated from the sample standard deviation of three samples, the sample size corresponded to the risk management level, and the use of 13 or more samples was preferable. The statistical methods used here to analyze individual contents and estimate population content-intervals could be applied in various situations and for shellfish toxins other than DSTs.

The intensity of pain in diabetic neuropathy varies in a circadian time-dependent manner. It is well known that diabetes has two distinct types, which are differentiated based on the cause of the disease. Previous studies have yet to compare the circadian properties of the pain intensity of diabetic neuropathy between type I and type II diabetes. In this study, we demonstrated that the pain intensity of diabetic peripheral neuropathy in a db/db mouse model of type II diabetes showed a significant diurnal oscillation, but such time-dependent oscillation was not detected in a streptozotocin (STZ)-induced type I diabetic mouse model. The polyol pathway-induced accumulation of sorbitol in peripheral nerve cells suppresses Na + /K + -ATPase activity, which is associated with the intensity of pain in diabetic neuropathy. In db/db mice, this accumulation of sorbitol in peripheral nerve cells showed significant diurnal oscillation. In addition, pain intensity and Na + /K + -ATPase activity were decreased at the peak time of sorbitol accumulation in these mice. Although STZ-induced diabetic mice also showed sorbitol accumulation and Na + /K + -ATPase dysfunction, these measures did not oscillate in a time-dependent manner. These findings reveal differences in the circadian properties of pain hypersensitivity in mouse models of type I and type II diabetes, and also provide ideas for developing novel approaches to the management of diabetic neuropathy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Spread through air spaces (STAS) is a recently recognized invasive pattern of lung cancer defined by the World Health Organization as micropapillary clusters, solid nests, or single cells spreading within air spaces beyond the edge of the main tumor. Although STAS has been shown to be a significant prognosticator for the postoperative survival in early-stage lung cancer treated with limited resection, its prognostic impact on the survival in completely resected adenocarcinomas with lymph node metastasis remains unclear., Patients and Methods: STAS was assessed in a total of 63 adenocarcinomas with lymph node metastasis in patients who underwent complete resection. STAS was defined as tumor cells within air spaces in the lung parenchyma beyond the edge of the main tumor. We evaluated the association between STAS and the clinicopathologic characteristics and the postoperative survival., Results: Among 63 patients, 31 (49.2%) and 32 (50.8%) had disease that was pathologically positive for N1 and N2, respectively. STAS was observed in 45 patients (73.0%) and was not significantly associated with any clinicopathologic characteristics. Patients with the STAS had significantly shorter recurrence-free survival (RFS) but not overall survival than those without STAS (P = .04 and P = .35, respectively). The 5-year RFS in patients with and without STAS was 25.1% and 56.7%, respectively. According to a multivariate analysis, positivity for STAS remained an independent prognostic parameter for RFS (hazard ratio = 3.09; 95% confidence interval, 1.47-7.16; P < .01)., Conclusion: STAS was predictive of a poor RFS in completely resected adenocarcinomas with lymph node metastasis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The identification of anaplastic lymphoma kinase ( ALK ), an oncogenetic driver mutation, in lung cancer has paved the way for a new era in the treatment of non-small cell lung cancer (NSCLC). Targeting ALK using tyrosine kinase inhibitors (TKI) has dramatically improved the prognosis of patients with ALK -rearranged NSCLC. However, most patients relapse on ALK-TKI therapy within a few years because of acquired resistance. One mechanism of acquiring resistance is a second mutation on the ALK gene, and the representative mutation is L1996M in the gatekeeper residue. In particular, the solvent-front ALK G1202R mutation is the common cause of resistance against first- and second-generation ALK-TKIs. Another major concern regarding ALK-TKI is metastasis to the central nervous system, commonly observed in patients relapsing after ALK-TKI therapy. The next-generation ALK inhibitor lorlatinib (PF-06463922) has therefore been developed to inhibit resistant ALK mutations, including ALK G1202R, and to penetrate the blood-brain barrier. In a Phase I/II trial, the safety and efficacy of lorlatinib were demonstrated in patients with advanced ALK -positive NSCLC, most of whom had central nervous system metastases and had previous ALK-TKI treatment. In this review, we discuss the structure, pharmacodynamics, and pharmacokinetics of lorlatinib and compare its characteristics with those of other ALK inhibitors. Furthermore, clinical trials for lorlatinib are summarized, and future perspectives in the management of patients with ALK -rearranged NSCLC are discussed., Competing Interests: Disclosure Takashi Seto reports grants from Bayer Yakuhin, Eisai, Merck Serono, Novartis Pharma, and Verastem; personal fees from Bristol-Myers Squibb, Kyowa Hakko Kirin, Mochida Pharmaceutical, Nippon Kayaku, Ono Pharmaceutical, Roche Singapore, Sanofi, Showa Yakuhin, Taiho Pharmaceutical, and Takeda Pharmaceutical; grants and personal fees from Astellas Pharma, AstraZeneca, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, Kissei Pharmaceutical, MSD, Nippon Boehringer Ingelheim, Pfizer Japan, Yakult Honsha, outside the submitted work. The other authors report no conflicts of interest in this work.

The aim of this study was to elucidate the relationship between family-associated factors and the postoperative prognosis in patients with nonsmall cell lung cancer (NSCLC). Additionally, we investigated whether having children was associated with the postoperative maintenance of the nutritional status. We selected 438 NSCLC patients who had undergone curative lung resection between 2004 and 2011 at Kyushu University (Fukuoka, Japan), whose family-associated factors were available. Nutritional indices, including the prognostic nutritional index (PNI), were used to estimate the change in the nutritional status for 1 year after surgery. A propensity score analysis was conducted after adjusting the following variables: sex, age, smoking history, performance status, pathological stage, and histological type. Three hundred patients (68.5%) had both children and partners. Forty-nine patients (11.2%) only had children, and 56 (12.8%) patients only had a partner. Thirty-three patients (7.5%) did not have a partner or children. The overall survival (OS) and disease-free survival (DFS) of the partner-present and partner-absent patients did not differ to a statistically significant extent (P = .862 and P = .712, respectively). However, childless patients showed significantly shorter OS and DFS in comparison with patients with children (P = .005 and P = .002, respectively). The postoperative exacerbation of PNI was significantly greater in childless patients than in patients with children (P = .003). These results remained after propensity score matching. Childless patients had a significantly poorer postoperative prognosis than those with children. Surgeons caring for childless NSCLC patients should be aware of the poorer postoperative outcomes in this population., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Ontogenetic growth functions provide basic information in biological and ecological studies. Various growth functions classified into the Pütter model have been used historically, regardless of controversies over their appropriateness. Here, we present a novel growth function for fish and aquatic organisms (generalised q-VBGF) by considering an allocation schedule of allometrically produced surplus energy between somatic growth and reproduction. The generalised q-VBGF can track growth trajectories in different life history strategies from determinate to indeterminate growth by adjusting the value of the 'growth indeterminacy exponent' q. The timing of maturation and attainable body size can be adjusted by the 'maturation timing parameter' τ while maintaining a common growth trajectory before maturation. The generalised q-VBGF is a comprehensive growth function in which exponentials in the traditional monomolecular, von Bertalanffy, Gompertz, logistic, and Richards functions are replaced with q-exponentials defined in the non-extensive Tsallis statistics, and it fits to actual data more adequately than these conventional functions. The relationship between the estimated parameter values τ and rq forms a unique hyperbola, which provides a new insight into the continuum of life history strategies of organisms., Competing Interests: The authors have declared that no competing interests exist.

Background/aim: Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that is deeply involved in cancer pathogenesis. Although clinicopathological significance of EZH2 in non-small cell lung cancer has been gradually elucidated, such significance in small cell lung cancer (SCLC) has yet to be fully investigated., Patients and Methods: Forty patients with resected SCLC were analyzed for EZH2. EZH2 expression was evaluated using the Allred score (0-8) and was classified into negative (0-6) and positive (7 and 8). We evaluated the association between EZH2 and the clinicopathological characteristics and postoperative survivals., Results: Among 40 patients, 15 (37.5%) and 25 (62.5%) were classified as being negative and positive for EZH2, respectively. Fisher's exact test demonstrated no significant associations between the positivity for EZH2 and clinicopathological characteristics. No significant differences were observed in recurrence-free and overall survivals between EZH2-negative/low and EZH2-high patients., Conclusion: EZH2 was frequently observed in patients with resected SCLC, but no significant associations were found between its expression and the clinicopathological characteristics and postoperative survivals., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim: To investigate the radiological features on computed tomography (CT) of brain metastasis (BM) from epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC)., Patients and Methods: Thirty-four patients with NSCLC with BMs who underwent surgical resection of the BMs at the Department of Neurosurgery, Kyushu University from 2005 to 2016 were enrolled in the study. The EGFR statuses of the 34 BMs were investigated. Radiological features, including the number, size, and location of the tumor, were delineated by CT., Results: Patients with EGFR-mutated BMs had significantly higher frequencies of multiple metastases than those with the non-EGFR-mutated type (p=0.042). BMs harboring mutations in EGFR were more frequently observed in the central area of the brain compared to those without mutations in EGFR (p=0.037)., Conclusion: Careful follow-up of patients with EGFR-mutated NSCLC may be necessary given the high frequencies of multiple BMs and their location in the central area of the brain., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: "Spread through air spaces" (STAS) is a recently described invasive pattern of lung cancer that spreads within air spaces beyond the edge of the main tumor. In the current study, we investigated the significance of STAS in patients with pathologic stage I adenocarcinoma., Methods: We assessed STAS in a total of 276 patients with resected pathologic stage I adenocarcinoma. STAS was classified as either no STAS, low STAS (1-4 single cells or clusters of STAS), or high STAS (≥5 single cells or clusters of STAS) using a 20x objective and a 10x ocular lens. We evaluated the association between STAS and the clinicopathologic characteristics and postoperative survivals., Results: Among 276 patients, 123 (44.6%), 48 (17.4%), and 105 (38.0%) were classified as having no, low, and high STAS, respectively. The positivity for STAS was significantly associated with larger radiologic tumor diameter (p = 0.008), higher consolidation/tumor ratio (p < 0.001), higher maximum standard uptake value (p < 0.001), pathologically larger tumor size (p = 0.004), pleural invasion (p = 0.027), and histologically invasive type (p < 0.001); whereas STAS was not significantly associated with epidermal growth factor receptor mutations or programmed death ligand-1 expression (p = 0.129 and p = 0.872, respectively). Patients with STAS had significantly shorter recurrence-free and overall survival than patients without STAS (p < 0.001 and p = 0.002, respectively). According to a multivariate analysis, positivity for STAS remained an independent prognostic factor for both recurrence-free survival and overall survival., Conclusions: Spread through air spaces was associated with clinicopathologically invasive features and was predictive of worse survival., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Malignant pleural mesothelioma (MPM), a devastating neoplasm, is traditionally considered to be resistant to antitumor therapy. Identification of clinical prognostic indicators is therefore needed. Although the C-reactive protein/albumin ratio (CAR) has been used to predict the prognosis of many types of malignancy, its utility in patients with MPM is unknown., Methods: The data of 100 patients diagnosed as having MPM from 1995 to 2015 at the National Kyushu Cancer Center and Kyushu University were analyzed. The CAR was calculated as serum C-reactive protein concentration divided by albumin concentration. A cutoff for CAR was set at 0.58 according to a receiver operating characteristics curve for 1-year survival., Results: Thirty-five of the 100 (35.0%) patients were classified as having a high CAR. A high CAR was significantly associated with advanced clinical stage (p < 0.001) and chemotherapy alone (p = 0.002). Patients with a high CAR had significantly shorter overall survival (OS) (p < 0.001) and disease- or progression-free survival (DFS/PFS) (p < 0.001). These associations between CAR and prognosis remained significant after propensity score-matching. In multivariate analysis, a high CAR was an independent predictor of shorter OS and DFS/PFS (p = 0.003 and p = 0.008, respectively). Multivariate analyses of the subgroups of patients who had received chemotherapy and of patients who had undergone surgery also showed that a high CAR was an independent predictor of shorter OS and DFS/PFS., Conclusions: CAR is an independent predictor of prognosis in MPM patients. This prognostic index contributes to clinicians' ability to predict benefit from treatment. Further larger, prospective studies are necessary to validate these findings.

Takotsubo cardiomyopathy (TC) is a syndrome characterized by transient local systolic dysfunction of the left ventricle with no evidence of coronary artery disease or acute plaque rupture. We present the case of 71-year-old woman who developed TC after two-stage surgery for double primary lung cancer. On computed tomography, lung nodules were identified in the left upper and right middle lobes. Based on the diagnosis of double primary lung cancer, we performed two-stage surgery (left upper lobectomy followed by right middle lobectomy). One day after the second surgery, respiratory failure developed. Electrocardiography showed ST segment elevation, serum troponin levels were elevated, and chest x-ray showed acute pulmonary edema. Cardiac catheterization showed no coronary artery disease and apical akinesia. Based on these findings, we diagnosed TC and the patient recovered with supportive treatment., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: A relationship between sarcopenia diagnosed by skeletal muscle area (SMA) and poor prognosis in cancer patients has recently been reported. This study aimed to clarify the clinical significance of postoperatively decreased SMA in patients with early non-small cell lung cancer (NSCLC)., Methods: This study selected 101 patients with pathologic stage 1 NSCLC who had undergone pre- and postoperative (~ 1 year) computed tomography scans and lobectomy between 2005 and 2010 at Kyushu University Hospital. The post/pre ratio was defined as the postoperative normalized SMA (cm 2 /m 2 ) at the 12th thoracic vertebra level divided by the preoperative normalized SMA. The cutoff value for the post/pre ratio was set at 0.9., Results: The study classified 31 patients (30.7%) as having decreased SMA. Poor performance status (PS) was significantly associated with decreased SMA (p = 0.048). The patients with decreased SMA had a significantly shorter disease-free survival (DFS) (p < 0.001) and overall survival (OS) (p < 0.001) than the other patients. Decreased SMA was found to be an independent prognostic factor for DFS (p = 0.010) and OS (p = 0.0072). The independent risk factors for skeletal muscle loss included poor PS (PS ≥ 1) and obstructive ventilatory impairment [forced expiratory volume (FEV) 1% < 70%]., Conclusions: Skeletal muscle loss after surgery is significantly associated with postoperative poor outcomes for patients with early NSCLC. Patients with poor PS, obstructive ventilatory impairment, or both need careful support to maintain their skeletal muscle mass. Future prospective studies may clarify whether physical activity and nutritional support improve postoperative prognosis.

Co-culture models of neurons and Schwann cells have been utilized for the study of myelination and demyelination in the peripheral nervous system; in most of the previous studies, however, these cells were obtained by primary culture with embryonic or neonatal animals. A spontaneously immortalized Schwann cell line IFRS1 from long-term cultures of adult Fischer rat peripheral nerves has been shown to retain fundamental ability to myelinate neurites in co-cultures with adult rat dorsal root ganglion neurons and nerve growth factor-primed PC12 cells. Our current investigation focuses on the establishment of stable co-culture system with IFRS1 cells and NSC-34 motor neuron-like cells. NSC-34 cells were seeded at a low density (2 × 10 3 /cm 2 ) and maintained for 5-7 days in serum-containing medium supplemented with non-essential amino acids and brain-derived neurotrophic factor (BDNF; 10 ng/mL). Upon observation of neurite outgrowth under a phase-contrast microscope, the NSC-34 cells were exposed to an anti-mitotic agent mitomycin C (1 µg/mL) for 12-16 h, then co-cultured with IFRS1 cells (2 × 10 4 /cm 2 ), and maintained in serum-containing medium supplemented with ascorbic acid (50 µg/mL), BDNF (10 ng/mL), and ciliary neurotrophic factor (10 ng/mL). Double immunofluorescence staining carried out at day 28 of the co-culture showed myelin protein (P0 or PMP22)-immunoreactive IFRS1 cells surrounding the βIII tubulin-immunoreactive neurites. This co-culture system can be a beneficial tool to study the pathogenesis of motor neuron diseases (e.g., amyotrophic lateral sclerosis, Charcot-Marie-Tooth diseases, and immune-mediated demyelinating neuropathies) and novel therapeutic approaches against them.

Objectives: Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have been approved as a standard therapy for metastatic non-small cell lung cancer (NSCLC). Although PD-L1 expression serves as a predictive biomarker for the efficacy of immunotherapy, there are no established biomarkers to predict the expression of PD-L1. The inflammatory markers C-reactive protein (CRP) and neutrophil-lymphocyte ratio (NLR) were recently shown to predict the efficacy of nivolumab for NSCLC patients. Therefore, here we investigated the potential association of PD-L1 expression with systemic inflammatory markers, including CRP, NLR, lymphocyte-monocyte ratio and platelet-lymphocyte ratio., Methods: We retrospectively examined tumor PD-L1 expression in 508 surgically resected primary NSCLC cases by immunohistochemical analysis (cut-off value: 1%). The association of PD-L1 expression with preoperative systemic inflammatory markers was assessed by univariate and multivariate analyses. We generated a PD-L1 association score (A-score) from serum CRP level (cut-off value: 0.3 mg/dl) and smoking status to predict PD-L1 expression., Results: Among the total 508 patients, 188 (37.0%) patients were positive for PD-L1 expression at the 1% cut-off value and 90 (17.5%) had elevated serum CRP level. Multivariate logistic regression revealed that PD-L1 positivity was significantly associated with advanced stage, the presence of vascular invasion and high serum CRP level (P = .0336, .0106 and 0.0018, respectively). Though not significant, smoking history tended to be associated with PD-L1 protein expression (P = .0717). There was no correlation with other inflammatory markers. Smoking history with elevated CRP level (A-score: 2) was strongly associated with PD-L1 protein expression (odds ratio: 5.18, P < .0001), while it was inversely associated with EGFR mutation (odds ratio: 0.11, P < .0001)., Conclusions: Our results indicate that among all systemic inflammatory markers examined, serum CRP seems to predict PD-L1 expression in patients with NSCLC however the clinical applicability is limited given the obtained area under the receiver operating characteristic curve values., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Aim: We investigated the safety of simultaneous bilateral lung resection for lung metastases., Patients and Methods: We retrospectively analyzed 185 patients with pulmonary metastases who underwent unilateral or bilateral pulmonary resection from August 2009 to December 2016 at a single institution., Results: Single-stage bilateral lung resection was undertaken in 19 patients, and the other 166 patients underwent unilateral pulmonary resection, including 20 patients who underwent repeated resections for synchronous or metachronous metastases. Operative time and drainage days in the bilateral group were significantly longer than those in the unilateral group (220±20 vs. 152±6.9 min: p<0.01, and 2.79±0.3 vs. 2.08±0.1 days: p<0.01). Incidence of postoperative complications and postoperative in-hospital days did not differ between the two groups (p=0.33 and 0.66, respectively). The bilateral group was further divided into two groups, namely, those who underwent wedge resection on both sides (WW) and those who underwent wedge resection on one side and segmentectomy or lobectomy on an opposite side (WSL). Operative time in the WSL group was significantly longer than that in the WW group (260±19 vs. 201±18 min: p=0.03). However, there was no significant difference in duration of chest tube use and postoperative hospital days between the two groups (p=0.26 and p=0.89). No severe postoperative complications occurred in either group., Conclusion: One-stage bilateral pulmonary metastasectomy appears to be safe as long as only wedge resection is performed on at least one side., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Spread through air spaces (STAS) is a novel invasive pattern of lung cancer, especially adenocarcinoma and squamous cell carcinoma. However, its frequency and significance in patients with resected small cell lung cancer (SCLC) remains unclear., Patients and Methods: A total of 30 patients with resected SCLC were analyzed for STAS. STAS was classified as either no STAS, low STAS (1-4 single cells or clusters of STAS), or high STAS (≥5 single cells or clusters of STAS). We evaluated the association between STAS and clinicopathological characteristics and postoperative survivals., Results: Among 30 patients, 5 (17%), 6 (20%) and 19 (63%) were classified as having no, low and high STAS, respectively. Fisher's exact test demonstrated no significant associations between the positivity for STAS and clinicopathological characteristics. No significant differences were observed in recurrence-free and overall survival between STAS-negative/low and STAS-high patients., Conclusion: STAS was frequently observed in patients with resected SCLC., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objectives: The world's population is rapidly ageing, and the age of patients with lung cancer will increase as well. The prognostic nutritional index, controlling nutritional status and the geriatric nutritional risk index (GNRI) are useful parameters for evaluating immune-nutritional status. We aimed to perform a multicentre retrospective study to investigate the correlations of these immune-nutritional parameters with postoperative comorbidities or surgical outcomes of elderly patients with non-small-cell lung cancer (NSCLC)., Methods: We selected 272 consecutive patients with NSCLC aged >75 years treated from January 2005 to December 2012 and evaluated 3 preoperative immune-nutritional parameters as potential predictive factors of postoperative comorbidities or as prognostic factors for surgically resected elderly patients with NSCLC., Results: Prognostic nutritional index, GNRI, sex and preoperative respiratory comorbidities were significantly associated with postoperative comorbidities. Multivariate analyses revealed that preoperative GNRI, sex, preoperative serum carcinoembryonic antigen levels, preoperative serum cytokeratin 19 fragment levels, pathological N factor and pleural invasion were significantly associated with overall survival (OS). Abnormal GNRI was significantly associated with histology and outcomes. The Kaplan-Meier analysis of OS as a function of preoperative GNRI revealed that patients with an abnormal GNRI experienced significantly shorter OS compared with those with normal GNRI (5-year OS, 45.15% vs 64.10%, respectively; P = 0.0007, log-rank test). The controlling nutritional status score was not significantly associated with postoperative comorbidities or surgical outcomes., Conclusions: Preoperative GNRI is a novel preoperative predictor of postoperative comorbidities and a prognostic factor that may identify high-risk elderly patients with NSCLC., (© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: To develop regression-based equations for estimating dual-energy x-ray absorptiometry (DXA) derived appendicular fat-free adipose tissue (FFAT) using a single ultrasound image in the forearm, and to investigate the validity of those equations to calculate FFAT-free appendicular lean mass (aLM-minus-FFAT appendicular ) in 311 Japanese adults aged 60 to 79 years., Methods: Subjects were randomly separated into two groups: 215 in the model-development group (91 men and 124 women) and 96 in the cross-validation group (42 men and 54 women). Appendicular fat mass and aLM were measured by the DXA, and subcutaneous adipose tissue (AT-forearm) and muscle (MT-ulna) thicknesses were measured by ultrasound. Appendicular FFAT was calculated based on the results of a previous study (appendicular FFAT = appendicular fat mass/0.85 x 0.15). The aLM was estimated from MT-ulna using a previously published equation (aLM = 4.89 x MT-ulna x body height - 9.15). Stepwise linear regression analysis was used to determine predictive models for DXA-derived appendicular FFAT from AT-forearm, sex, age, and anthropometrical variables. The best ultrasound prediction equation for estimation of appendicular FFAT was developed and then cross-validated in a subsample of older adults., Results: There was no significant difference between the DXA-derived and ultrasound-predicted aLM-minus-FFAT appendicular . A strong correlation was observed between the DXA-derived and ultrasound-predicted aLM-minus-FFAT appendicular (r = 0.935, P < .001). Bland-Altman analysis did not indicate a bias in the prediction of the aLM-minus-FFAT appendicular for the validation group., Conclusions: Our results indicated that a single ultrasound forearm measurement can be used to accurately estimate DXA-derived aLM-minus-FFAT appendicular in Japanese older adults, which may be advantageous for community-based physical examinations., (© 2017 by the American Institute of Ultrasound in Medicine.)

Objectives: Radiologically small-sized adenocarcinomas are special entities of lung cancer, as their radiological and pathological invasiveness determines the surgical procedures applied; however, the clinicopathological features of small-sized lung adenocarcinoma adjoining cystic airspaces (Ca-ADJ) have yet to be fully clarified. The aim of this study was to elucidate the clinicopathological characteristics, including the programmed death ligand 1 (PD-L1) expression, in patients with Ca-ADJ ≤3.0 cm., Methods: A total of 283 patients with resected adenocarcinoma, whose radiological tumour size was ≤3.0 cm without lymph node or distant metastases on preoperative high-resolution computed tomography, were analysed for their clinicopathological and radiological features. Furthermore, the PD-L1 expression was evaluated by immunohistochemistry using an anti-human PD-L1 rabbit monoclonal antibody (clone SP142)., Results: Among the 283 patients, 31 (11.0%) patients were reported to have Ca-ADJ. The Fisher's exact test demonstrated that Ca-ADJ was significantly associated with male gender (P < 0.001), a history of smoking (P < 0.001), a high consolidation/tumour ratio (P = 0.026), advanced pathological stage (P < 0.001), the presence of pleural (P < 0.001) and vessel invasion (P < 0.001), histological invasive subtypes (P < 0.001) and wild-type epidermal growth factor receptor (P = 0.001). The patients with Ca-ADJ had a significantly higher maximum standardized uptake value than those without Ca-ADJ (8.4 vs 4.1, P < 0.001). Furthermore, Ca-ADJ was significantly associated with the PD-L1 expression (P < 0.001). Log-rank test showed that patients with Ca-ADJ had a significantly shorter disease-free survival than those without Ca-ADJ (P = 0.001)., Conclusions: This study showed that patients with radiologically small-sized Ca-ADJ might exhibit radiologically and pathologically invasive features., (© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)