Correction to: Oxidative stress enhances the expression of IL-33 in human airway epithelial cells.

Figure 2 of this original publication was incorrectly formatted. The updated Fig. 2 is published in this correction article [1].

Oxidative stress enhances the expression of IL-33 in human airway epithelial cells.

BACKGROUND: Interleukin-33 (IL-33) is a cytokine belonging to the IL-1 family, and its possible involvement in the pathophysiology of COPD and viral-induced exacerbations has been demonstrated. IL-33 has been shown to be increased in the airway epithelial cells from COPD patients, but the regulating mechanism of IL-33 expression in airway epithelial cells remains largely unknown. In the current study, we examined whether oxidative stress, which participates in the pathogenesis of COPD, affects the expression of IL-33 in airway epithelial cells and also evaluated the effect during viral infection. METHODS: The involvement of oxidative stress in the expression of IL-33, and its signal pathway was examined after stimulation with hydrogen peroxide (H2O2), with or without stimulation by polyinosinic-polycytidylic acid [poly (I:C)], a synthetic analogue of dsRNA that mimics viral infection, or rhinovirus infection in NCI-H292 cells and primary human bronchial epithelial cells (HBECs). In addition, the effect of antioxidant, N-acetylcysteine (NAC) in the expression of IL-33 was compared between HBECs from healthy subjects and those from COPD patients. RESULTS: Treatment with H2O2 significantly potentiated IL-33 expression in NCI-H292 cells, and the potentiation was reversed by NAC treatment. Mitogen-activated protein kinase (MAPK) inhibitors, but not nuclear factor-kappa B inhibitors, also significantly decreased the H2O2-potentiated IL-33 expression. In addition, H2O2 significantly potentiated the poly (I:C)- or rhinovirus-stimulated IL-33 expression. In HBECs from healthy subjects, H2O2-potentiated IL-33 expression and its reversal by NAC was also confirmed. Under the condition without H2O2-stimulation, treatment with NAC significantly decreased the expression of IL-33 in HBECs from COPD patients, but not in those from healthy subjects. CONCLUSIONS: These results demonstrate that oxidative stress involves in the expression of IL-33 in airway epithelial cells via MAPK signal pathway and it augments IL-33 expression during viral infection. This mechanism may participate in the regulation of IL-33 expression in airway epithelial cells in COPD and the viral-induced exacerbations. Modulation of this pathway could become a therapeutic target for viral-induced exacerbations of COPD.

Definition and diagnosis of asthma-COPD overlap (ACO).

It is now widely recognized that asthma and COPD can coexist as asthma-COPD overlap (ACO), but the preliminary attempts at providing universal guidelines for the diagnosis of ACO still need to be improved. We believe that a case can be made for devising guidelines for the diagnosis of this increasingly common disease that are specific to Japan. In this paper, we present our consensus-based description of ACO which we believe is realistic for use in our country. In addition, we cite the scientific evidence for our own "objective" features used to develop the criteria for COPD and asthma diagnosis. We acknowledge that they will need to be validated and updated over time, but hope the results will encourage further research on the characteristics and treatment of this commonly encountered clinical problem.

Decreased phosphatase PTEN amplifies PI3K signaling and enhances proinflammatory cytokine release in COPD.

The phosphatidylinositol 3-kinase (PI3K) pathway is activated in chronic obstructive pulmonary disease (COPD), but the regulatory mechanisms for this pathway are yet to be elucidated. The aim of this study was to determine the expression and role of phosphatase and tensin homolog deleted from chromosome 10 (PTEN), a negative regulator of the PI3K pathway, in COPD. PTEN protein expression was measured in the peripheral lung of COPD patients compared with smoking and nonsmoking controls. The direct influence of cigarette smoke extract (CSE) on PTEN expression was assessed using primary lung epithelial cells and a cell line (BEAS-2B) in the presence or absence of l-buthionine-sulfoximine (BSO) to deplete intracellular glutathione. The impact of PTEN knockdown by RNA interference on cytokine production was also examined. In peripheral lung, PTEN protein was significantly decreased in patients with COPD compared with the subjects without COPD (P < 0.001) and positively correlated with the severity of airflow obstruction (forced expiratory volume in 1-s percent predicted; r = 0.50; P = 0.0012). Conversely, phosphorylated Akt, as a marker of PI3K activation, showed a negative correlation with PTEN protein levels (r = -0.41; P = 0.0042). In both primary bronchial epithelial cells and BEAS-2B cells, CSE decreased PTEN protein, which was reversed by N-acetyl cysteine treatment. PTEN knockdown potentiated Akt phosphorylation and enhanced production of proinflammatory cytokines, such as IL-6, CXCL8, CCL2, and CCL5. In conclusion, oxidative stress reduces PTEN protein levels, which may result in increased PI3K signaling and amplification of inflammation in COPD.

Decrease in an anti-ageing factor, growth differentiation factor 11, in chronic obstructive pulmonary disease.

RATIONALE: Cellular senescence is observed in the lungs of patients with COPD and may contribute to the disease pathogenesis. Growth differentiation factor 11 (GDF11) belongs to the transforming growth factor ß superfamily and was recently reported to be a circulating protein that may have rejuvenating effects in mice. We aimed to investigate the amounts of GDF11 in the plasma and the lungs of patients with COPD and elucidate the possible roles of GDF11 in cellular senescence. METHODS: The plasma levels of GDF11 were investigated in two separate cohorts by western blotting. The localisation and expression of GDF11 in the lungs were investigated by immunohistochemistry and quantitative reverse transcription PCR, respectively. The effects of GDF11 on both cigarette smoke extract (CSE)-induced cellular senescence in vitro and on elastase-induced cellular senescence in vivo were investigated. RESULTS: The levels of plasma GDF11 in the COPD group were decreased compared with the control groups in the two independent cohorts. The levels of plasma GDF11 were significantly positively correlated with pulmonary function data. The mRNA expression of GDF11 in mesenchymal cells from the COPD group was decreased. Chronic exposure to CSE decreased the production of GDF11. Treatment with GDF11 significantly inhibited CSE-induced cellular senescence and upregulation of inflammatory mediators, partly through Smad2/3 signalling in vitro. Daily GDF11 treatment attenuated cellular senescence and airspace enlargement in an elastase-induced mouse model of emphysema. CONCLUSIONS: The decrease in GDF11 may be involved in the cellular senescence observed in COPD.

Production of reactive persulfide species in chronic obstructive pulmonary disease.

BACKGROUND: Oxidative stress is a major aetiological factor driving chronic obstructive pulmonary disease (COPD). Recently recognised as potent antioxidants, reactive persulfide and polysulfide species are biosynthesised by cystathionine ß-synthase and cystathionine γ-lyase. The production of reactive persulfide and polysulfide species in the lungs of patients with COPD remain unknown. OBJECTIVES: The aim of this study was to examine the production of reactive persulfides and polysulfides, such as glutathione persulfide (GSSH), cysteine persulfide (CysSSH) and glutathione trisulfide (GSSSH), in lung-resident cells and epithelial lining fluid (ELF) obtained from patients with mild to moderate COPD. METHODS: Lung tissues, primary lung cells, ELF and sputum were obtained. The amounts of reactive persulfides and polysulfides in the cells and ELF were measured by liquid chromatography-tandem mass spectrometry with ß-(4-hydroxyphenyl) ethyl iodoacetamide as a trapping agent for hydroper/polysulfides. The amounts of synthases in the lung tissues, sputum and primary cells were quantified. RESULTS: The amounts of GSSH, CysSSH and GSSSH were decreased in the lung cells and ELF from patients with COPD. The amounts of reactive persulfides and polysulfides in the lung cells had a positive correlation with the degree of airflow limitation. By contrast, the amounts of the synthases were increased in the lung tissues and sputum cells of patients with COPD. CONCLUSIONS: We have identified a decrease in reactive persulfide and polysulfide species in the lungs of patients with COPD. These data suggest that the newly detected antioxidants reactive persulfides and polysulfides could be associated with the redox balance in the lungs of patients with COPD.

27-Hydroxycholesterol accelerates cellular senescence in human lung resident cells.

Cellular senescence is reportedly involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). We previously showed that 27-hydroxycholesterol (27-OHC) is elevated in the airways of COPD patients compared with those in healthy subjects. The aim of this study was to investigate whether lung fibroblasts of COPD patients are senescent and to determine the effects of 27-OHC on senescence of lung resident cells, including fibroblasts and airway epithelial cells. Localization of senescence-associated proteins and sterol 27-hydroxylase was investigated in the lungs of COPD patients by immunohistochemical staining. To evaluate whether 27-OHC accelerates cellular senescence, lung resident cells were exposed to 27-OHC. Senescence markers and fibroblast-mediated tissue repair were investigated in the 27-OHC-treated cells. Expression of senescence-associated proteins was significantly enhanced in lung fibroblasts of COPD patients. Similarly, expression of sterol 27-hydroxylase was significantly upregulated in lung fibroblasts and alveolar macrophages in these patients. Treatment with the concentration of 27-OHC detected in COPD airways significantly augmented expression of senescence-associated proteins and senescence-associated ß-galactosidase activity, and delayed cell growth through the prostaglandin E2-reactive nitrogen species pathway. The 27-OHC-treated fibroblasts impaired tissue repair function. Fibroblasts from lungs of COPD patients showed accelerated senescence and were more susceptible to 27-OHC-induced cellular senescence compared with those of healthy subjects. In conclusion, 27-OHC accelerates cellular senescence in lung resident cells and may play a pivotal role in cellular senescence in COPD.

Possible role of Krüppel-like factor 5 in the remodeling of small airways and pulmonary vessels in chronic obstructive pulmonary disease.

BACKGROUND: Small airway remodeling is an important cause of the airflow limitation in chronic obstructive pulmonary disease (COPD). A large population of patients with COPD also have pulmonary hypertension. Krüppel-like factor 5 (KLF5) is a zinc-finger transcription factor that contributes to tissue remodeling in cardiovascular diseases. Here, we evaluate the possible involvement of KLF5 in the remodeling of small airways and pulmonary vessels in COPD. METHODS: Lung tissues were obtained from 23 control never-smokers, 17 control ex-smokers and 24 ex-smokers with COPD. The expression of KLF5 in the lung tissues was investigated by immunohistochemistry. We investigated whether oxidative/nitrosative stress, which is a major cause of the pathogenesis in COPD, could augment the production of KLF5. We examined the role of KLF5 in the stress-mediated tissue remodeling responses. We also investigated the susceptibility of KLF5 expression to nitrosative stress using bronchial fibroblasts isolated from the lung tissues. RESULTS: The expression of KLF5 was up-regulated in the small airways and pulmonary vessels of the COPD patients and it was mainly expressed in bronchial fibroblasts and cells of the pulmonary vessels. The extent of the KLF5 expression in the small airway of the COPD group had a significant correlation with the severity of the airflow limitation. Oxidative/nitrosative stress augmented the production of KLF5 in lung fibroblasts as well as the translocation of KLF5 into the nuclei. Silencing of KLF5 suppressed the stress-augmented differentiation into myofibroblasts, the release of collagens and metalloproteinases. Bronchial fibroblasts from the patients with COPD highly expressed KLF5 compared to those from the control subjects under basal condition and were more susceptible to the induction of KLF5 expression by nitrosative stress compared to those from the control subjects. CONCLUSION: We provide the first evidence that the expression of KLF5 is up-regulated in small airways and pulmonary vessels of patients with COPD and may be involved in the tissue remodeling of COPD.

Comparing the Effectiveness of Afatinib and Osimertinib for Patients With PD-L1-positive EGFR-mutant Non-small Cell Carcinoma.

Background/Aim: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are effective for treating non-small cell lung cancer (NSCLC) harboring EGFR mutations. However, higher tumor programmed death ligand-1 (PD-L1) expression is associated with a poor response to EGFR-TKIs, and information on the comparison between afatinib and osimertinib in PD-L1-positive EGFR-mutant NSCLC is scarce. Patients and Methods: We retrospectively analyzed data of patients with PD-L1-positive EGFR-mutant NSCLC to compare the effectiveness of afatinib and osimertinib. Results: A total of 177 patients were included in the study. The Cox proportion hazard model was adjusted for age, sex, performance status, EGFR mutation status, PD-L1 expression level, and brain metastasis, revealing that there was no significant difference in risk for progression [hazard ratio (HR)=0.99, 95% confidence interval (CI)=0.64-1.53] or death (HR=0.96, 95% CI=0.54-1.73) between afatinib and osimertinib. Conclusion: In conclusion, the EGFR-TKI treatment duration and overall survival after the treatment with afatinib or osimertinib were similar in patients with PD-L1-positive EGFR-mutant NSCLC in the present study.

A retrospective study of the efficacy of combined EGFR­TKI plus VEGF inhibitor/cytotoxic therapy vs. EGFR­TKI monotherapy for PD­L1­positive EGFR­mutant non­small cell lung cancer: North Japan Lung Cancer Study Group 2202.

The present multicenter study was performed to compare the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) monotherapy with that of combined EGFR-TKI plus vascular endothelial growth factor receptor (VEGF) inhibitor/cytotoxic therapy in patients with programmed death-ligand 1 (PD-L1)-positive EGFR-mutant non-small cell lung cancer (NSCLC). Data from patients with PD-L1-positive EGFR-mutant NSCLC were collected from 12 institutes. Survival in patients treated with first- and second-generation EGFR-TKIs, osimertinib (third-generation EGFR-TKI), and combined EGFR-TKI plus VEGF inhibitor/cytotoxic therapy was analyzed by multiple regression analysis with adjustments for sex, performance status, EGFR mutation status, PD-L1 expression level, and the presence or absence of brain metastasis using a Cox proportional hazards model. Data from a total of 263 patients were analyzed, including 111 (42.2%) patients who had received monotherapy with a first- or second-generation EGFR-TKI, 132 (50.2%) patients who had received osimertinib monotherapy, and 20 (7.6%) patients who had received combined EGFR-TKI plus VEGF inhibitor/cytotoxic therapy (hereafter referred to as combined therapy). Multiple regression analysis using the Cox proportional hazards model showed that the hazard ratio (95% confidence interval) for progression-free survival was 0.73 (0.54-1.00) in the patients who had received osimertinib monotherapy and 0.47 (0.25-0.90) in patients who had received combined therapy. The hazard ratio for overall survival was 0.98 (0.65-1.48) in the patients who had received osimertinib monotherapy and 0.52 (0.21-1.31) in patients who had received combined therapy. In conclusion, combined therapy was associated with a significant reduction in the risk of progression compared with first- and second-generation EGFR-TKI monotherapy, and therefore, may be promising for the treatment of patients of NSCLC.

Inhibitory effects of theophylline on the peroxynitrite-augmented release of matrix metalloproteinases by lung fibroblasts.

The anti-inflammatory effects of theophylline have been reported to include inhibition of the release of proinflammatory mediators from macrophages and neutrophils. Overproduction of reactive nitrogen species (RNS) has been reported in the airways of patients with chronic obstructive pulmonary disease (COPD), and this causes tissue inflammation and injury. We investigated whether peroxynitrite stimulated the release of matrix metalloproteinases 2 and 9 (MMP-2 and -9; gelatinases) from human fetal lung fibroblasts (HFL-1 cell line) and whether theophylline inhibited the peroxynitrite-augmented release of MMPs. HFL-1 cells and primary lung fibroblasts were treated with peroxynitrite (an RNS), and gelatinases levels were evaluated by gelatin zymography. The inhibitory effect of theophylline on the peroxynitrite-augmented release of MMP-2 and MMP-9 was also investigated. To explore the cell signaling pathways involved in the peroxynitrite-induced gelatinases release and the inhibitory effect of theophylline, transforming growth factor-ß(1) (TGF-ß(1)), nuclear factor-κB (NF-κB), and histone deacetylase (HDAC) were measured. Peroxynitrite significantly augmented the release of MMP-2 and MMP-9 by fibroblasts (P < 0.01), as well as TGF-ß(1) release (P < 0.01), NF-κB activation (P < 0.01), and HDAC2 inactivation (P < 0.01). An NF-κB inhibitor diminished the RNS-augmented release of MMPs and TGF-ß(1) (P < 0.01), and a neutralizing TGF-ß antibody also diminished MMP release (P < 0.01). Theophylline significantly inhibited the peroxynitrite-augmented release of MMP-2 and MMP-9 in HFL-1 cells and normal adult lung fibroblasts, and it also inhibited the peroxynitrite-mediated HDAC2 inactivation, NF-κB activation, and TGF-ß(1) release in HFL-1 cells (all P < 0.01). These results suggest that peroxynitrite can influence tissue remodeling by promoting gelatinases release, while theophylline suppresses peroxynitrite-induced tissue remodeling via pathways involving NF-κB/TGF-ß(1) and/or HDAC in the HFL-1 cell line.

25-Hydroxycholesterol enhances cytokine release and Toll-like receptor 3 response in airway epithelial cells.

BACKGROUND: 25-hydroxycholesterol (25-HC) is one of the oxysterols, which are oxidized derivatives of cholesterol, and has been reported to be involved in the pathogenesis of atherosclerosis and Alzheimer's disease. In lung, the possible involvement of 25-HC in airway diseases has been revealed. In the present study, we examined whether 25-HC affects the release of cytokines and also modulates the responses of toll-like receptor 3 (TLR3) in airway epithelial cells. METHODS: The effect of 25-HC on the release of cytokines from primary human bronchial epithelial cells after stimulation with or without polyinosine-polycytidylic acid [poly(I:C)], a ligand for TLR3, and the signal transduction were examined. RESULTS: 25-HC significantly potentiated the release of interleukin-8 (IL-8) and IL-6 from the cells. This effect was more potent compared with that of other oxysterols, 22-HC and 27-HC. GW3965 and TO901317, synthetic agonists of liver X receptors that are receptors for oxysterols, did not augment the IL-8 release. 25-HC enhanced the nuclear factor-kappa B (NF-κB) DNA binding activity and translocation of phosphorylated c-Jun into the nucleus. The release of IL-8 was inhibited by the NF-κB inhibitor, caffeic acid phenethyl ester (CAPE), an inhibitor of nuclear factor kappa-B alpha (IκBα) inhibitor, BAY 11-7085, and an inhibitor of nuclear factor kappa-B kinase-2 (IKK-2) inhibitor, SC-514, but not by a c-Jun N-terminal kinase (JNK) inhibitory peptide, L-JNKi1. 25-HC significantly potentiated IL-8 release in poly(I:C)-treated cells and the augmentation was inhibited by CAPE, BAY 11-7085, and SC-514. Furthermore, 25-HC potentiated the translocation of interferon regulatory factor 3 into the nucleus and the release of interferon-beta (IFN-ß) in poly(I:C)-treated cells. CONCLUSIONS: These data demonstrated that 25-HC augments the release of IL-8 and IL-6 via NF-κB signalling pathway and enhances the release of IL-8 and IFN-ß after stimulation of TLR3 in airway epithelial cells. 25-HC may be involved in the neutrophilic airway inflammation through the stimulant effect of IL-8 and IL-6 release and also potentiate the TLR3-mediated innate immunity in airway diseases.

Cigarette smoke augments the expression and responses of toll-like receptor 3 in human macrophages.

BACKGROUND AND OBJECTIVE: Cigarette smoking is the main risk factor for the development of chronic obstructive pulmonary disease (COPD). Recently, toll-like receptor 3 (TLR3) was shown to recognize pathogen-associated molecular patterns, especially viral-derived double-stranded RNA, and to be involved in immune responses. However, the effects of cigarette smoke on TLR3 remain unclear. In this study, it was examined whether cigarette smoke affects the expression and responses of TLR3 in human macrophages. METHODS: The expression of TLR3 in alveolar macrophages from human lung tissues was analysed by immunohistochemistry, and the correlation of TLR3 expression with smoking history and lung function was evaluated. In addition, the effect of cigarette smoke on the expression and responses of TLR3 in macrophage lineage cells was investigated. RESULTS: TLR3-positive alveolar macrophage numbers were significantly increased in smokers and COPD patients compared with non-smoking control subjects, but there was no difference between smokers and COPD patients. TLR3-positive macrophage numbers were positively correlated with smoking history and inversely correlated with corrected carbon monoxide diffusing capacity, but were not correlated with % predicted forced expiratory volume in 1 s. Furthermore, cigarette smoke extract potentiated the expression of TLR3 in monocyte-derived macrophages and significantly augmented the release of interleukin-8, as well as total matrix metalloproteinase-9 activity, in cells treated with TLR3 ligand. CONCLUSIONS: These data suggest that cigarette smoke augments the expression and responses of TLR3 in human macrophages, and this may contribute to neutrophilic airway inflammation and parenchymal destruction in the lungs of smokers and patients with COPD.

Increased 25-hydroxycholesterol concentrations in the lungs of patients with chronic obstructive pulmonary disease.

BACKGROUND AND OBJECTIVE: 25-Hydroxycholesterol (25-HC) is produced from cholesterol by the enzyme cholesterol 25-hydroxylase and is associated with atherosclerosis of vessels. Recently, 25-HC was reported to cause inflammation in various types of tissues. The aim of this study was to assess the production of 25-HC in the airways and to elucidate the role of 25-HC in neutrophil infiltration in the airways of patients with chronic obstructive pulmonary disease (COPD). METHODS: Eleven control never-smokers, six control ex-smokers without COPD and 13 COPD patients participated in the lung tissue study. The expression of cholesterol 25-hydroxylase in the lung was investigated. Twelve control subjects and 17 patients with COPD also participated in the sputum study. The concentrations of 25-HC in sputum were quantified by liquid chromatography/mass spectrometry/mass spectrometry analysis. To elucidate the role of 25-HC in neutrophilic inflammation of the airways, the correlation between 25-HC levels and neutrophil counts in sputum was investigated. RESULTS: The expression of cholesterol 25-hydroxylase was significantly enhanced in lung tissue from COPD patients compared with that from control subjects. Cholesterol 25-hydroxylase was localized in alveolar macrophages and pneumocytes of COPD patients. The concentration of 25-HC in sputum was significantly increased in COPD patients and was inversely correlated with percent of predicted forced vital capacity, forced expiratory volume in 1 s and diffusing capacity of carbon monoxide. The concentrations of 25-HC in sputum were significantly correlated with sputum interleukin-8 levels and neutrophil counts. CONCLUSIONS: 25-HC production was enhanced in the airways of COPD patients and may play a role in neutrophilic inflammation.

Possibility of sandwiched liver surgery with molecular targeting drugs, cetuximab and bevacizumab on colon cancer liver metastases: a case report.

A 31-year-old man with sigmoid colon cancer with concomitant simultaneous multiple liver metastases had received FOLFIRI (leucovorin, fluorouracil and irinotecan) and FOLFOX6 (leucovorin, fluorouracil and oxaliplatin) after an ordinary sigmoidectomy. However, his serum carcinoembryonic antigen (CEA) level increased rapidly during the fifteen months after the operation while he was on FOLFOX6. Abdominal computed tomography revealed expanding multiple liver tumors. As the third line chemotherapy, a combination therapy of cetuximab with irinotecan was given, which markedly reduced his levels of serum CEA, and the size and number of liver tumors. He underwent lateral segmentectomy of the liver and microwave coagulation of the liver metastases in the remnant liver. Thereafter, a good quality of life with tumor dormancy was obtained for 6 months. However, his serum CEA started to rise again in the absence of liver tumors. Therefore, FOLFOX6 with bevacizumab was chosen as the fourth line chemotherapy, and the serum CEA was reduced with tumor dormancy. A good quality of life was obtained again at 3 years after the first surgery. This report indicates the effectiveness of sandwiched liver surgery with the molecular targeting drugs cetuximab and bevacizumab on multiple liver metastases of colon cancer, and suggests the possibility of a regimen consisting of bevacizumab following cetuximab.

Determination of circulating tumor cells for prediction of recurrent colorectal cancer progression.

BACKGROUND/AIMS: The aim of this study is to determine the relationship between circulating tumor cells (CTCs) and response to chemotherapy in patients with unresectable metastatic colorectal cancer. METHODOLOGY: CTCs of twelve consecutive patients with K-ras wild type colorectal cancer with synchronous and/or metachronous unresectable metastatic lesions were measured by the cell search system between January 2009 and December 2010. CTCs were measured before and after chemotherapy. The regimen consisted of four courses (three months) of SOX (TS-1+L-OHP) + panitumumab. RESULTS: Four patients (33%) had no detectable CTCs before chemotherapy. For these patients, no CTCs were detected after chemotherapy and their serum carcinoembryonic antigen (CEA) levels decreased after chemotherapy. Four of the other eight patients with positive CTCs had no detectable CTCs after chemotherapy and their serum CEA levels decreased after chemotherapy. The other four of eight patients with positive CTCs continued to have CTCs after chemotherapy and all four patients died of cancer within eight months after starting chemotherapy. On the other hand, all eight patients without CTCs after chemotherapy were alive over a year after starting chemotherapy. CONCLUSIONS: CTCs may be able to predict the response to chemotherapy in patients with unresectable metastatic colorectal cancer.

Lateral pelvic lymph node dissection using latero-vesical approach with aspiration procedure for advanced lower rectal cancer.

BACKGROUND/AIMS: The aim of this study was to evaluate the impact of complete dissection of areolar tissue surrounding lymph nodes in lateral pelvic lymphadenectomy on the outcome of advanced rectal cancer at or below the peritoneal reflection. METHODOLOGY: From 1995 to 2004, lateral pelvic lymph node dissection was performed in 141 consecutive patients with advanced rectal cancer at or below the peritoneal reflection by open surgery in our hospital. They were divided into two groups according to the techniques used for lymph node dissection, i.e. conventional method (CM) and our original method, latero-vesical approach with aspiration procedure (LVA), which eliminates not only lymph nodes but also the tissue surrounding the lymph nodes. RESULTS: The number of dissected lateral pelvic lymph nodes by LVA was significantly higher than that by CM. In patients without lateral pelvic lymph node metastasis, no significant difference in the outcome was observed between the two groups. On the contrary, among the patients with lateral pelvic lymph node metastasis, five-year survival rates of the group with CM or with LVA was 50% and 70% respectively. CONCLUSIONS: For patients with lateral pelvic lymph node metastasis, lateral pelvic lymphadenectomy, complete dissection of areolar tissue surrounding lymph nodes, may contribute to improve the prognosis of advanced rectal cancer at, or below, the peritoneal reflection.

Increase of nitrosative stress in patients with eosinophilic pneumonia.

BACKGROUND: Exhaled nitric oxide (NO) production is increased in asthma and reflects the degree of airway inflammation. The alveolar NO concentration (Calv) in interstitial pneumonia is reported to be increased. However, it remains unknown whether NO production is increased and nitrosative stress occurs in eosinophilic pneumonia (EP). We hypothesized that nitrosative stress markers including Calv, inducible type of NO synthase (iNOS), and 3-nitrotyrosine (3-NT), are upregulated in EP. METHODS: Exhaled NO including fractional exhaled NO (FENO) and Calv was measured in ten healthy subjects, 13 patients with idiopathic pulmonary fibrosis (IPF), and 13 patients with EP. iNOS expression and 3-NT formation were assessed by immunocytochemistory in BALf cells. The exhaled NO, lung function, and systemic inflammatory markers of the EP patients were investigated after corticosteroid treatment for 4 weeks. RESULTS: The Calv levels in the EP group (14.4 ± 2.0 ppb) were significantly higher than those in the healthy subjects (5.1 ± 0.6 ppb, p < 0.01) and the IPF groups (6.3 ± 0.6 ppb, p < 0.01) as well as the FENO and the corrected Calv levels (all p < 0.01). More iNOS and 3-NT positive cells were observed in the EP group compared to the healthy subject and IPF patient. The Calv levels had significant positive correlations with both iNOS (r = 0.858, p < 0.05) and 3-NT positive cells (r = 0.924, p < 0.01). Corticosteroid treatment significantly reduced both the FENO (p < 0.05) and the Calv levels (p < 0.01). The magnitude of reduction in the Calv levels had a significant positive correlation with the peripheral blood eosinophil counts (r = 0.802, p < 0.05). CONCLUSIONS: These results suggested that excessive nitrosative stress occurred in EP and that Calv could be a marker of the disease activity.