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World Lung Day 2023 - Access to prevention and treatment for all, leave no one behind Keywords: equal access; prevention; treatment EN equal access prevention treatment 989 991 3 10/20/23 20231101 NES 231101 Summary World Lung Day 2023 calls for increased global awareness for and action towards better respiratory health, which is particularly relevant for the Asian Pacific region given the burden of disease, large population and socio-economic conditions. Limited access to smoking cessation therapies, however, will lead to increasing chronic obstructive pulmonary diseases and lung cancer, and related co-morbidities of cardiac and cerebrovascular diseases, metabolic diseases and even more anxiety and depressive illness. [Extracted from the article]

The gastrointestinal microbiota was reported as an important factor for the response to cancer immunotherapy. Probiotics associated with gastrointestinal dysbiosis and bacterial richness may affect the efficacy of cancer immunotherapy drugs. However, the clinical impact of probiotics on the efficacy of cancer immunotherapy in patients with nonsmall cell lung cancer (NSCLC) is poorly understood. The outcomes of 294 patients with advanced or recurrent NSCLC who received antiprogrammed cell death‐1 (PD‐1) therapy (nivolumab or pembrolizumab monotherapy) at three medical centers in Japan were analyzed in our study. We used inverse probability of treatment weighting (IPTW) to minimize the bias arising from the patients' backgrounds. The IPTW‐adjusted Kaplan‐Meier curves showed that progression‐free survival (nonuse vs use: hazard ratio [HR] [95% confidence interval {CI}] = 1.73 [1.42‐2.11], log‐rank test P =.0229), but not overall survival (nonuse vs use: HR [95%CI] = 1.40 [1.13‐1.74], log‐rank test P =.1835), was significantly longer in patients who received probiotics. Moreover, the IPTW‐adjusted univariate analyses showed that nonuse or use of probiotics was significantly associated with disease control (nonuse vs use: odds ratio [OR] [95%CI] = 0.51 [0.35‐0.74], P =.0004) and overall response (nonuse vs use: OR [95%CI] = 0.43 [0.29‐0.63], P <.0001). In this multicenter and retrospective study, probiotics use was associated with favorable clinical outcomes in patients with advanced or recurrent NSCLC who received anti‐PD‐1 monotherapy. The findings should be validated in a future prospective study. What's new? Probiotics associated with gastrointestinal dysbiosis and bacterial richness may affect the efficacy of cancer immunotherapy drugs. However, the clinical impact of probiotics on the efficacy of cancer immunotherapy in patients with nonsmall cell lung cancer (NSCLC) is poorly understood. In this multicenter and retrospective study, probiotics use was associated with favorable clinical outcomes in patients with advanced or recurrent NSCLC who received anti‐PD‐1 monotherapy. Probiotics are a widely‐used drug in the clinical setting with few side effects. The results suggest that prescription of probiotics could be considered in patients with NSCLC who expect to receive immune checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

Background: Mps one binder kinase activator 1 (MOB1) is a core component of the Hippo signaling pathway and has been implicated as a tumor suppressor. Here, we evaluated the possible relationship of MOB1 expression in non‐small cell lung cancer (NSCLC) to prognosis. Methods: We retrospectively analyzed 205 lung adenocarcinoma patients treated at Kyushu University Hospital between November 2007 and October 2012. MOB1 expression in tumor cells of surgical specimens was evaluated by immunohistochemistry. Invasive activity of NSCLC cell lines in vitro was measured with a transwell assay. Results: Expression of MOB1 was classified as high in 105 of the 205 (51.2%) tumor specimens, and such high expression was significantly associated with poor disease‐free survival (P = 0.0161). Among the various clinicopathologic parameters examined, high MOB1 expression was significantly associated only with intratumoral vascular invasion (P = 0.0005). Multivariate analysis also identified high MOB1 expression as a significant independent risk factor for disease‐free survival (P = 0.0319). The invasiveness of H1299 cells in vitro was increased or attenuated by overexpression or knockdown of MOB1, respectively. Conclusions: Our results suggest that MOB1 might promote early recurrence of NSCLC by increasing vascular invasion by tumor cells. Key points: Significant findings of the study: We found that high MOB1 expression in surgical specimens of lung adenocarcinoma was associated with poor disease‐free survival and with intratumoral vascular invasion. MOB1 expression also promoted the invasiveness of NSCLC cells in vitro. What this study adds: Our results thus suggest that high MOB1 expression is a risk factor for early postoperative recurrence in lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Background: A randomized phase 3 study was performed to investigate the efficacy and safety of maintenance therapy with S-1 after induction therapy with carboplatin plus S-1 in patients with advanced squamous non-small cell lung cancer (NSCLC).Methods: Chemotherapy-naive patients with advanced or relapsed squamous NSCLC were treated with carboplatin (area under the curve of 5 on day 1 every 3 weeks) plus S-1 (40 mg/m2 twice per day on days 1-14 every 3 weeks) as induction therapy. Patients who did not progress after 4 cycles of induction therapy were randomized to receive either S-1 plus best supportive care (BSC) or BSC alone. The primary objective of the study was to confirm the superiority of S-1 plus BSC in comparison with BSC alone with respect to progression-free survival.Results: Of the 365 patients enrolled in the study, 347 participated in the induction phase, and 131 of these individuals were randomized to receive S-1 plus BSC (n = 67) or BSC alone (n = 64). The risk of disease progression was significantly lower for patients in the S-1 plus BSC arm than those in the BSC-alone arm (hazard ratio, 0.548; 95% confidence interval, 0.374-0.802; P = .0019). The most common toxicities during maintenance therapy with S-1 included anorexia, anemia, and fatigue, but most cases were not severe.Conclusions: Continued maintenance with S-1 plus BSC is an effective and well-tolerated treatment option for patients with advanced squamous NSCLC previously treated with carboplatin plus S-1. [ABSTRACT FROM AUTHOR]

The pathogenesis of lung cancer associated with idiopathic pulmonary fibrosis (IPF) has remained largely uncharacterized. To provide insight into this condition, we undertook genomic profiling of IPF‐associated lung cancer as well as of adjacent fibrosing lung tissue in surgical specimens. Isolated DNA and RNA from 17 IPF‐associated non‐small cell lung cancer and 15 paired fibrosing lung tissue specimens were analyzed by next‐generation sequencing with a panel that targets 161 cancer‐related genes. Somatic genetic alterations were frequently identified in TP53 (n = 6, 35.3%) and PIK3CA (n = 5, 29.4%) genes in tumor samples as well as in EGFR (n = 7, 46.7%), PIK3CA (n = 5, 33.3%), ERBB3 (n = 4, 26.7%), and KDR (n = 4, 26.7%) in IPF samples. Genes related to the RAS‐RAF signaling pathway were also frequently altered in tumor (n = 7, 41.2%) and IPF (n = 3, 20.0%) samples. The number of somatic alterations identified in IPF samples was almost as large as that detected in paired tumor samples (81 vs 90, respectively). However, only 6 of the 81 somatic alterations detected in IPF samples overlapped with those in paired tumor samples. The accumulation of somatic mutations was thus apparent in IPF tissue of patients with IPF‐associated lung cancer, and the RAS‐RAF pathway was implicated in lung tumorigenesis. The finding that somatic alterations were not frequently shared between tumor and corresponding IPF tissue indicates that IPF‐associated lung cancer does not develop through the stepwise accumulation of somatic alterations in IPF. [ABSTRACT FROM AUTHOR]

The formation of premetastatic niches creates a fertile environment for the seeding of disseminated cancer cells in selected secondary organs. This is crucial for the development of metastasis in various malignancies, including breast cancer (BC). We previously reported that the loss of FBXW7 in bone marrow‐derived stromal cells promoted cancer metastasis by increasing the production of the chemokine CCL2, which attracts myeloid‐derived suppressor cells and macrophages to the premetastatic niche. Furthermore, treatment with the CCL2 inhibitor propagermanium (PG), which has been used in Japan as a therapeutic agent against chronic hepatitis B, was shown to block the enhancement of metastasis in FBXW7‐deficient mice through inhibiting the formation of premetastatic niches. Here, we describe a phase I dose‐escalation study of PG used as an antimetastatic drug for perioperative patients with primary BC. The primary end‐point was the percentage of patients who experience dose‐limiting toxicity. Twelve patients were enrolled in the study. Dose‐limiting toxicity was not observed, and the maximum dose was determined to be 90 mg/body/day. The serum concentrations of PG were nearly within the normal range in all observation days. We observed an inverse correlation between FBXW7 mRNA levels in blood and the serum concentrations of CCL2 and interleukin (IL)‐6, in agreement with our previous mouse model. Also, IL‐6 was downregulated in a PG dose‐dependent manner, as observed in mice. Thus, PG was given safely and it is expected to have antimetastatic potential in BC. This trial is registered in the UMIN Clinical Trials Registry as UMIN000022494. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to evaluate the potential of liquid biopsy for prediction of the efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment and for assessment of the changes in genetic alterations during such treatment.Methods: Plasma samples were prospectively collected from non-small cell lung cancer patients with EGFR-activating mutations during EGFR-TKI treatment until disease progression and were analyzed for such mutations with droplet digital polymerase chain reaction and for other somatic alterations with next-generation sequencing.Results: One hundred patients, including 87 who were EGFR-TKI naïve, were enrolled. Median progression-free survival was significantly shorter for EGFR-TKI-naïve patients with EGFR-activating mutations detected in plasma at baseline than for those without them (7.9 vs 19.0 months; P < .001), with the values being significantly longer for initially positive patients who became negative for these mutations at 12 or 24 weeks than for those who remained positive. An increase in the number of alleles positive for EGFR-activating mutations in plasma during treatment was associated with disease progression, with a hazard ratio of 4.72 (95% CI, 2.07-10.79; P < .001) for EGFR-TKI-naïve patients showing an increase within 36 weeks. For 55 patients with available samples, the total number of somatic alterations (other than activating mutations or T790M of EGFR) in plasma was higher at disease progression than at baseline (33 vs 19; P = 0.04).Conclusion: Liquid biopsy shows potential for prediction of EGFR-TKI efficacy and elucidation of clonal tumor evolution during targeted therapy. [ABSTRACT FROM AUTHOR]

Liquid biopsy offers a potential alternative to tissue biopsy for detection of genetic alterations in cancer, and it has been introduced into clinical practice to detect the tyrosine kinase inhibitor (TKI) resistance‐conferring T790M mutation of epidermal growth factor receptor (EGFR) in patients with non‐small‐cell lung cancer (NSCLC). We prospectively collected tumor and plasma samples from 25 NSCLC patients who harbored activating mutations of EGFR and experienced failure of treatment with afatinib. The samples were analyzed by digital PCR (dPCR) and next‐generation sequencing (NGS). T790M was detected in plasma with a respective sensitivity and specificity of 83.3% and 70.0% by dPCR and 50.0% and 70.0% by NGS relative to analysis of corresponding tumor samples. Quantitation of T790M based on the ratio of the number of T790M alleles to that of activating mutation alleles (T/A ratio) improved the specificity of plasma analysis to 100% for both dPCR and NGS without a reduction in sensitivity. Although several afatinib resistance mechanisms other than T790M—including copy number gain of NRAS or MET—were identified in tumor samples, the corresponding genetic alterations were not detected in plasma. TP53 mutations were frequently identified in plasma and tumor samples, with most such mutations also having been detected before afatinib treatment. The presence of de novo TP53 mutations was associated with reduced progression‐free survival. Quantitation of T790M in plasma is thus a clinically relevant approach to determine the T790M status of tumors. In addition, genetic alterations coexisting with EGFR mutations can affect the efficacy of EGFR‐TKI treatment. Quantitation of T790M in plasma is a clinically relevant approach to determine the T790M status of tumors. [ABSTRACT FROM AUTHOR]

Patients with non‐small cell lung cancer (NSCLC) harboring common mutations of the epidermal growth factor receptor (EGFR) are sensitive to EGFR‐tyrosine kinase inhibitors (TKI). Although forms of EGFR harboring single uncommon mutations such as G719X or L861Q are thought to be less sensitive to EGFR‐TKI, the efficacy of these drugs in patients with double uncommon mutations has remained unclear. We here present an NSCLC patient found to be positive for double uncommon EGFR mutations (G719X and L861Q) by clinical genomic sequencing analysis of a pleural effusion specimen who showed a durable response to the EGFR‐TKI afatinib. The sensitivity of EGFR with single or double uncommon mutations to afatinib and the EGFR‐TKI erlotinib was also evaluated in vitro with a visual assay based on HEK293 cells transiently transfected with expression plasmids for yellow fluorescent protein (YFP)‐tagged fragments of the EGFR intracellular domain (ICD). Whereas forms of EGFR with double uncommon mutations were more sensitive to erlotinib than were those with single uncommon mutations, those with single or double uncommon mutations were similarly sensitive to afatinib, consistent with the patient's clinical outcome. Our data support the notion that afatinib is the most suitable EGFR‐TKI for NSCLC harboring uncommon mutations of EGFR. Furthermore, the YFP‐EGFR‐ICD assay is potentially applicable to prediction of EGFR‐TKI efficacy in patients with such mutations. We presented a patient with double uncommon mutations who demonstrated a remarkable response to afatinib. Furthermore, a consistent efficacy of afatinib on both single and double uncommon EGFR mutations was confirmed by YFP‐EGFR‐ICD assay in vitro. [ABSTRACT FROM AUTHOR]

Summary: Zebrafish embryos are useful to study haematopoietic gene function in vertebrates, although lack of antibodies to zebrafish proteins has limited the purification of specific cell populations. Here, we purified primitive zebrafish erythrocytes using 1, 5‐bis{[2‐(di‐methylamino)ethyl]amino}‐4, 8‐dihydroxyanthracene‐9, 10‐dione (DRAQ5TM), a DNA‐staining fluorescent dye. At 48‐h post‐fertilization, we sorted small‐sized cells from embryos using forward scatter and found that they consisted of DRAQ5high and DRAQ5low populations. DRAQ5high cells contained haemoglobin, lacked myeloperoxidase activity and expressed high levels of embryonic globin (hbae3 and hbbe1.1) mRNA, all characteristics of primitive erythrocytes. Following DRAQ5TM analysis of gata1:dsRed transgenic embryos, we purified primitive DRAQ5high dsRed+ erythrocytes from haematopoietic progenitor cells. Using this method, we identified docking protein 2 (Dok2) as functioning in differentiation of primitive erythrocytes. We conclude that DRAQ5TM‐based flow cytometry enables purification of primitive zebrafish erythrocytes. [ABSTRACT FROM AUTHOR]

In mouse fetal liver, hepatoblasts, sinusoidal endothelial cells and macrophages (or erythroblastic islands) promote differentiation and proliferation of hematopoietic cells through cell-cell interactions and secretion of cytokines and extracellular matrix factors. Until now, we have had little knowledge of the hematopoietic cytokines or extracellular matrix mRNAs expressed in hepatic stellate cells. Using p75 neurotrophin receptor (p75 NTR) to mark this cell population, we sorted 12.5, 14.5 and 16.5 dpc hepatic stellate cells and analyzed expression of cytokines and extracellular matrix mRNAs. Among cytokines, insulin-like growth factor 2 ( Igf2) was highly expressed at all three stages analyzed. The extracellular matrix molecule fibronectin ( Fn1) was highly expressed in 12.5 dpc cells, whereas vitronectin ( Vtn) was highly expressed in 14.5 and 16.5 dpc hepatic stellate cells. Among liver cells, Igf2 was predominantly expressed in hepatoblast-like cells at all three stages examined, suggesting that hepatoblast-like cells are an essential part of the niche that maintains homeostasis of hematopoietic cells in embryonic mouse liver. Defining these expression patterns could facilitate our understanding of cross talk between cytokine and extracellular matrix molecules in hepatic stellate cells and benefit research in developmental hematopoiesis as well as the study of liver biology. [ABSTRACT FROM AUTHOR]

Aim Hypoxia-inducible factor (HIF) contributes to the adaptation of tumor cells to hypoxic conditions, so genetic polymorphisms involved in this pathway may affect cellular response to hypoxia and be associated with cancer risk. Thus, we examined the association between the lung cancer risk and genetic polymorphisms involved in the HIF pathway. Methods This case-control study consists of 462 lung cancer cases and 379 controls from Japan. We examined the effect of HIF1A rs11549467, HIF1A rs11549465, HIF1A rs2057482, HIF2A rs13419896 and vascular endothelial growth factor A ( VEGFA) rs833061 on the risk of lung cancer using TaqMan real-time PCR assay. Logistic regression was used to estimate the odds ratio (OR) and its 95% confidence interval (CI) of lung cancer risk. The multiplicative and additive interactions with cigarette smoking were also examined. Results The AA genotype of HIF2A rs13419896 (OR = 0.54, 95% CI = 0.30-0.99) and the CC genotype of VEGFA rs833061 (OR = 0.42, 95% CI = 0.24-0.75) were significantly associated with a decreased risk of lung cancer after adjustment of potential covariates. Additive interactions between these two polymorphisms and cigarette smoking were also significant. Conclusion HIF2A rs13419896 and VEGFA rs833061 were significantly related to lung cancer risk, with possible interaction between polymorphisms and cigarette smoking. Further studies are needed to confirm these results. [ABSTRACT FROM AUTHOR]

Background Various polymorphisms have been detected in the UDP-glucuronosyltransferase 1 A ( UGT1A) gene, and UGT1A1 *28 and UGT1A1 *6 have important effects on the pharmacokinetics of irinotecan and the risk of severe toxicities during irinotecan therapy. This study was conducted to determine the maximum tolerated dose ( MTD) of irinotecan chemotherapy according to the UGT1A1 genotype in previously treated lung cancer patients with the UGT1A1 *28 or UGT1A1 *6 polymorphism. Methods The eligibility criteria were as follows: lung cancer patients that had previously been treated with anticancer agents other than irinotecan, possessed the UGT1A1 *28 or UGT1A1 *6 polymorphism (group A included *28/*28, *6/*6, and *28/*6, and group B included *28 /− and *6 /−), were aged ≤75 years old, had a performance score of 0-1, and exhibited adequate bone marrow function. The patients were scheduled to receive irinotecan on days 1, 8, 15, 22, 29, and 36. Results Four patients were enrolled in this trial. Two patients were determined to be ineligible. The remaining two patients, who belonged to group B, received an initial irinotecan dose of 60 mg/m2, but did not complete the planned treatment because of diarrhea and leukopenia. Thus, in group B patients, 60 mg/m2 was considered to be the MTD of irinotecan. The study was terminated in group A because of poor case recruitment. Conclusions The MTD of irinotecan for previously treated lung cancer patients that are heterozygous for the UGT1A1 * 28 or UGT1A1 * 6 gene polymorphism is 60 mg/m2. [ABSTRACT FROM AUTHOR]

The efficacy and safety of immune‐checkpoint inhibitors in non‐small cell lung cancer patients with idiopathic pulmonary fibrosis (IPF) remain unknown. Herein, we describe the case of a 62‐year‐old man with multiple pleural tumors and carcinomatous pleurisy. High‐resolution computed tomography indicated usual interstitial pneumonia, and a respiratory function test revealed a restrictive disorder and decreased diffusion capacity. He was diagnosed with lung adenocarcinoma and IPF. After failure of initial chemotherapy, he was treated with nivolumab and achieved a complete response without any sign of exacerbation of IPF. The response to nivolumab has persisted for > 1 year. This is the first report of a non‐small cell lung cancer patient with IPF who has been treated with immune‐checkpoint inhibitors for such a long period and achieved a sustained response. [ABSTRACT FROM AUTHOR]

Background: Uridine 5'-diphospho-glucuronosyltransferase 1A1 (UGT1A1*27) is known to impair the effect of UGT in basic research; however, little clinical investigation has been conducted. To evaluate the effect of the UGT1A1*27 polymorphism in irinotecan therapy, we conducted a prospective study. Methods: Eligibility criteria included: lung cancer patients; scheduled irinotecan therapy doses of single ≥ 80, combination ≥ 50, radiation with single ≥ 50, or radiation with combination ≥ 40 mg/m²; age ≥ 20; and Eastern Cooperative Oncology Group performance score (PS) 0-2. Patients were examined for UGT1A1*28 and *6 polymorphisms and received irinotecan. When the UGT1A1*28 polymorphism was detected, a search for UGT1A1*27 was conducted. Fifty patients were enrolled, with 48 patients determined eligible. Results: UGT1A1 polymorphisms *28/*28, *6/*6, *28/*6, *28/-, *6/-, -/- observed 0 (0%), 1 (2%), 1 (2%), 7 (15%), 17 (35%) and 22 (46%), respectively. UGT1A1*27 were examined in nine patients including one ineligible patient; however, no polymorphisms were found. The study ceased after interim analysis. In an evaluation of the side effects of irinotecan, patients with UGT1A1*28 and UGT1A1*6 polymorphisms had a higher tendency to experience febrile neutropenia than wild type (25% and 32% vs. 14%). Incidences of grade 3/4 leukopenia and neutropenia were significantly higher in patients with UGT1A1*28 polymorphisms compared with wild type (75% vs. 32%, P = 0.049; 75% vs. 36%, P = 0.039, respectively). Conclusion: Our prospective study did not locate the UGT1A1*27 polymorphism, suggesting that UGT1A1*27 does not significantly predict severe irinotecan toxicity in cancer patients. [ABSTRACT FROM AUTHOR]

Background: Bevacizumab combined with platinum-based chemotherapy has been established as a standard treatment option in the first-line setting for advanced nonsquamous non-small cell lung cancer (NSCLC). However, there has been no evidence to support the use of bevacizumab beyond disease progression in such patients.Methods: West Japan Oncology Group 5910L was designed as a multicenter, open-label, randomized, phase 2 trial of docetaxel versus docetaxel plus bevacizumab every 3 weeks for patients with recurrent or metastatic nonsquamous NSCLC whose disease had progressed after first-line treatment with bevacizumab plus a platinum-based doublet. The primary endpoint was progression-free survival (PFS).Results: One hundred patients were randomly assigned to receive docetaxel (n = 50) or docetaxel plus bevacizumab (n = 50), and this yielded median PFS times of 3.4 and 4.4 months, respectively, with a hazard ratio (HR) of 0.71 and a stratified log-rank P value of .058, which met the predefined criterion for statistical significance (P < .2). The median overall survival also tended to be longer in the docetaxel plus bevacizumab group (13.1 months; 95% confidence interval [CI], 10.6-21.4 months) versus the docetaxel group (11.0 months; 95% CI, 7.6-16.1 months) with an HR of 0.74 (95% CI, 0.46-1.19; stratified log-rank P = .11). No unexpected or severe adverse events were recorded.Conclusions: Further evaluation of bevacizumab beyond disease progression is warranted for patients with advanced NSCLC whose disease has progressed after treatment with bevacizumab plus a platinum-based doublet. [ABSTRACT FROM AUTHOR]

Aim Pneumonia is the third largest cause of death in Japan. Pneumonia continues to be one of the most common causes of morbidity, hospitalization and mortality, especially in the elderly. The aim of the present study was to evaluate the factors related to the development of pneumonia acquired outside hospitals among the Japanese elderly. Methods We carried out a hospital-based, case-control study. Cases were patients who had been newly diagnosed with pneumonia acquired outside hospitals. For each case, one to three controls were defined as outpatients with other diseases (not pneumonia) at the same hospitals. All participants (i.e. 50 cases and 110 controls) were aged 65 years and older. Results Compared with control participants, hypoalbuminemia (<3.5 g/dL) and low body mass index (<18.0) were more common in pneumonia patients, whereas the proportion of those who could go out by themselves (i.e. self-support in activities of daily living) and the vaccination rate of seasonal influenza were lower in patients with pneumonia than control participants. Even after controlling for age, sex, hospital and aforementioned four factors, hypoalbuminemia ( OR 9.19, 95% CI 3.70-22.81) increased the risk of pneumonia, whereas seasonal influenza vaccination ( OR 0.37, 95% CI 0.16-0.85) reduced the risk. Even after excluding those who lived in a nursing home, hypoalbuminemina ( OR 12.19, 95% CI 4.29-34.63) increased the risk of pneumonia. Conclusions Hypoalbuminemia might be a risk factor for pneumonia among the elderly living in the community. Geriatr Gerontol Int 2016; 16: 223-229. [ABSTRACT FROM AUTHOR]

The genetic backgrounds of the Japanese (or Asians) are, at least in part, different from those of Caucasians. It is necessary to recognize this difference to develop medicine that is both optimized and individualized. In particular, the consideration of ethnic differences is becoming increasingly important for lung cancer medicine. Japanese clinical practice guidelines indicate that some clinical biomarkers, such as epidermal growth factor receptor gene mutations, echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion gene and uridine diphosphate glucuronosyltransferase genotypes should be determined in appropriate lung cancer patients. At the present time, tests for these biomarkers are covered by the Japanese national health-care programme, as is treatment with certain targeted drugs and cytotoxic agents. Therefore, most patients with lung cancer in Japan receive these tests as part of daily practice if their performance status and organ function are judged to be eligible. In addition, ethnic differences in bone marrow toxicity caused by cytotoxic drugs are reflected in treatment choice, and the requirements for the development of treatment modalities suitable for rare targeted populations are also increasing. To meet these requirements, many collaborative groups in Japan that have improved their infrastructure for investigator-initiated trials and conducted important activities need to provide further optimal treatment modalities for Japanese and Asian patients with lung cancer. Here, the characteristics of lung cancer in Japanese patients, general aspects of medical treatment and the care system in Japan, and representative studies on lung cancer in Japan are reviewed. [ABSTRACT FROM AUTHOR]

The aim of this open-label, multicenter, randomized phase II trial was to evaluate the efficacy and safety of zoledronic acid in combination with docetaxel in previously treated patients with non-small-cell lung cancer ( NSCLC) and bone metastases. In this study, patients randomly received docetaxel (60 mg/m2) with (group DZ) or without (group D) zoledronic acid every 21 days. There were 50 patients in each group, and the primary endpoint was progression-free survival. In an efficacy analysis of 94 patients ( DZ, 48; D, 46), the median progression-free survival was 2.7 months (95% confidence interval [ CI], 1.5-3.5 months) for the DZ group and 2.6 months (95% CI, 1.5-3.4 months) for the D group (stratified log-rank test, P = 0.89). The median overall survival was 10.4 months (95% CI, 7.0-15.8 months) for the DZ group and 9.7 months (95% CI, 6.1-12.5 months) for the D group (stratified log-rank test, P = 0.62). There were no clinically relevant differences in the frequencies of grade 3 or 4 adverse events between the two groups. No treatment-related deaths occurred in the DZ group. Zoledronic acid combined with docetaxel was well tolerated but did not meet the primary endpoint of demonstrating a longer progression-free survival in advanced NSCLC patients with bone metastases compared with docetaxel alone. This trial was registered with the University Hospital Medical Information Network ( UMIN000001098). [ABSTRACT FROM AUTHOR]

Some Kampo medicines that are herbal and traditional in Japan have had beneficial effects when given to patients with anemia. However, molecular mechanisms underlying their effects are unclear. To address this question, four Kampo medicines used to treat anemia-ninjin'yoeito ( NYT), shimotsuto ( SMT), juzentaihoto ( JTT), and daibofuto ( DBT)-were tested separately using in vitro cultures of mouse bone marrow mononuclear cells. Among them, NYT was most effective in stimulating cell proliferation and up-regulating Myc expression. Flow cytometry analysis indicated that, among hematopoietic components of those cultures, myeloid cells expressing CD45/Mac-1/Gr-1/F4/80 increased in number, but Ter119/ CD71 erythroid cells did not. Accordingly, real-time PCR analysis showed up-regulation of the myeloid gene Pu.1, whereas the erythroid genes Gata1 and Klf1 were down-regulated. Overall, these findings provide molecular evidence that NYT accelerates myelopoiesis but not erythropoiesis in vitro. [ABSTRACT FROM AUTHOR]

Thioredoxin ( Trx) is a key player in redox homeostasis in various cells, modulating the functions of target proteins by catalyzing a thiol-disulfide exchange reaction. Target proteins of cytosolic Trx- h of higher plants were studied, particularly in the plasma membrane, because plant plasma membranes include various functionally important protein molecules such as transporters and signal receptors. Plasma membrane proteins from Arabidopsis thaliana cell cultures were screened using a resin Trx- h1 mutant-immobilized, and a total of 48 candidate proteins obtained. These included two calcium-sensing proteins: a phosphoinositide-specific phospholipase 2 ( At PLC2) and a calcium-dependent protein kinase 21 ( At CPK21). A redox-dependent change in At CPK21 kinase activity was demonstrated in vitro. Oxidation of At CPK21 resulted in a decrease in kinase activity to 19% of that of untreated At CPK21, but Trx- h1 effectively restored the activity to 90%. An intramolecular disulfide bond ( Cys97- Cys108) that is responsible for this redox modulation was then identified. In addition, endogenous At CPK21 was shown to be oxidized in vivo when the culture cells were treated with H2O2. These results suggest that redox regulation of At CPK21 by Trx- h in response to external stimuli is important for appropriate cellular responses. The relationship between the redox regulation system and Ca2+ signaling pathways is discussed. Structured digital abstract CPK21 physically interacts with TRXH1 by two hybrid (View interaction), TRXH1 physically interacts with AT1G56075, CPK21, PRX2B, HIR3, RAA4B, TC132, RAD2C, AT3G03270, AT3G53990, METK4, AT3G17020, AT1G20760, MPCP3, SKS2, AT5G23890, DTC, AT1G56070, TBB3, ACT8, TI110, DHSB1, TBA3, AOX1A, PLCD2, CLAH1, CLAH2, RSSA1, APX1, RAB1C, ACT7, ARF1, NRL1, ADT1, TBB7, RAD2A, G3PC1, TBB4, MD37E, DHSA1, TC159, AT4G22710, GPX6, RABC1, VATA, GPX2 and RAA2A by affinity chromatography technology (View interaction) [ABSTRACT FROM AUTHOR]

The presence of epidermal growth factor receptor ( EGFR) somatic mutations in non-small-cell lung cancer patients is associated with response to treatment with EGFR-tyrosine kinase inhibitors, such as gefitinib and erlotinib. More than 100 mutations in the kinase domain of EGFR have been identified. In particular there are many variations of deletion mutations in exon 19. In this study, using yellow fluorescent protein-tagged fragments of the EGFR intracellular domain, we examined the differences in sensitivity to gefitinib, erlotinib and afatinib between several exon 19 mutants and other common EGFR mutations. We also used serum of patients undergoing treatment with EGFR-tyrosine kinase inhibitors in this system. In addition, we examined the relative kinase activity of these mutants by measuring relative fluorescent intensity after immunofluorescence staining. We found that both sensitivity to EGFR-tyrosine kinase inhibitors and relative kinase activity differed among several EGFR mutations found in the same region of the kinase domain. This study underscores the importance of reporting the clinical outcome of treatment in relation to different EGFR mutations. [ABSTRACT FROM AUTHOR]

Background and objective: Although the association of hypertrophic pulmonary osteoarthropathy (HPO) with lung cancer was investigated in the 1960s, the recent incidence of clinically apparent HPO is not known. Data from a large series of patients with lung cancer were analysed, in order to assess the incidence of possible HPO, based on bone scintigraphy, as well as the incidence of clinically confirmed HPO. The clinical features of confirmed HPO were also evaluated. Methods: The medical records of patients admitted with lung cancer between January 1986 and August 2004 were reviewed. Bone scintigraphy showing symmetrical, abnormally high uptake in joints and/or long bones was considered to be suggestive of HPO. Patients who also had finger clubbing and joint pain were considered to have a confirmed diagnosis of HPO. Clinical histories and hormone levels were then investigated in these patients, to identify possible causal factors. Results: Among the 1226 lung cancer patients, 55 (4.5%) demonstrated abnormally high uptake on bone scintigraphy, suggesting possible HPO. Ten (0.8%) patients had clubbed fingers and joint pain and were eventually confirmed as having HPO. Serum hormone concentrations were abnormally high in the patients with confirmed HPO. Conclusions: This retrospective study indicated that 4.5% of lung cancer patients showed findings suggestive of HPO, a frequency similar to that reported previously. However, patients with HPO rarely showed the complete triad of signs. Although increased hormone concentrations may have caused the HPO, further investigation is required to confirm this. [ABSTRACT FROM AUTHOR]

Background and objective: A forkhead/winged-helix family transcriptional repressor, Foxp3, is highly expressed on CD4+CD25+ T regulatory cells. The role of Foxp3+CD4+CD25+ T regulatory cells in asthma remains to be elucidated. Using mouse models and peripheral blood mononuclear cells (PBMC) from subjects with allergic asthma, we aimed to explore whether Foxp3+CD4+CD25+ T regulatory cells associate with asthma phenotypes. Methods: Foxp3+CD4+CD25+ T cells were detected by FACS and the correlation between the frequency of Foxp3+CD4+CD25+ T cells and asthma phenotypes was assessed. Results: The frequency of Foxp3+CD4+CD25+ T cells among total CD4+CD25+ T cells in the lungs showed an inverse correlation with eosinophilic inflammation in BALB/c, A/J and C57BL/6 strains. In addition, the frequency of Foxp3+CD4+CD25+ T cells was inversely correlated with BHR and allergen-specific IgE levels in the serum of A/J mice. In BALB/c mice, the frequency of Foxp3+CD4+CD25+ T cells correlated with the level of IL-10 in BAL fluid. The inverse correlation between the frequency of Foxp3+CD4+CD25+ T cells and eosinophilic inflammation disappeared when mice were treated with anti-IL-10 receptor mAb during allergen challenge. Interestingly, intracellular cytokine staining of lung cells revealed that IL-10 was predominantly produced by Foxp3-CD4+CD25+ T cells. The frequency of Foxp3+CD4+CD25+ T cells among total CD4+CD25+ T cells in PBMC of asthmatics was significantly lower than that of healthy subjects, although there was no significant correlation between the frequency of Foxp3+CD4+CD25+ T cells and asthma severity. Conclusions: These results suggest a role for lung Foxp3+CD4+CD25+ T cells in the regulation of asthma phenotypes, presumably through an IL-10-mediated mechanism. [ABSTRACT FROM AUTHOR]

We report herein a case of laryngeal sarcoidosis that was refractory to systemic corticosteroids, but that improved spontaneously. A 49-year-old woman complained of dysphagia and hoarseness with accompanying edematous swellings of both arytenoid regions. She was referred to our hospital after systemic corticosteroid therapy failed to achieve any improvement. Laryngoscopy showed marked edema of the epiglottis and both arytenoid regions. The flow-volume curve on spirometry showed flattening of the expiratory flows. Histopathological examination of the arytenoid region showed non-caseating epithelioid granulomas, and laryngeal sarcoidosis was diagnosed with the result of BAL study. She was observed without treatment as symptoms were mild. Although edema of the left arytenoid region seemed to be somewhat worsened after 6 months, she continued to be followed closely because of improvements in the flow-volume curve and increasing peak expiratory flow. By 1 year after onset, symptoms and epiglottal swelling had spontaneously improved. [ABSTRACT FROM AUTHOR]

The recent clinical application of granulocyte macrophage colony-stimulating factor (GM-CSF)-transduced autologous tumor vaccines revealed substantial antitumor activity and valuable clinical results. However, for these vaccines to be optimally effective, the antitumor efficacies must be improved. Recently, Sendai virus (SeV) vectors, which are cytoplasmic RNA vectors, have emerged as safe vectors with high gene transduction. In the current study, the in vivo therapeutic antitumor efficacies of irradiated GM-CSF-transduced mouse renal cell carcinoma (RENCA) vaccine cells mediated by either fusion gene-deleted non-transmissible SeV encoding mouse GM-CSF (SeV/dF/G) or adenovirus (E1, E3 deleted serotype 5 adenovirus) encoding mouse GM-CSF (AdV/G) (respectively described as irRC/SeV/GM or irRC/AdV/GM) were compared in RENCA-bearing mice. The results showed that the antitumor effect was equivalent between irRC/SeV/GM and irRC/AdV/GM cells, even though the former produced less GM-CSF in vitro. The cell numbers of activated (CD80+, CD86+, CD80+CD86+) dendritic cells in lymph nodes from mice treated with irRC/AdV/GM or irRC/SeV/GM cells were increased significantly compared with those of mice treated with the respective controls, at both the earlier and later phases. In an in vitro cytotoxicity assay, splenocytes harvested from mice treated with both irRC/SeV/GM and irRC/AdV/GM cells showed tumor-specific responses against RENCA cells. The restimulated splenocytes harvested from mice treated with irRC/SeV/GM or irRC/AdV/GM cells produced significantly higher levels of interleukin-2, interleukin-4, and interferon-γ compared with their respective controls ( P < 0.05). Furthermore, vaccination with irRC/AdV/GM or irRC/SeV/GM cells induced significantly enhanced recruitment of the cytolytic effectors of CD107a+CD8+ T cells and CD107a+ natural killer cells into tumors compared with those induced by their respective controls ( P < 0.05). Taken together, our results suggest that the SeV/dF/G vector is a potential candidate for the production of effective autologous GM-CSF-transduced tumor vaccines in clinical cancer immune gene therapy. ( Cancer Sci 2008; 99: 2315–2326) [ABSTRACT FROM AUTHOR]

Background and objective: Erythropoietin (EPO) has recently been demonstrated to have a tissue protective role by acting as an anti-apoptotic agent in various tissues, such as brain, spinal cord, heart and kidney. The purpose of this study was to determine whether human recombinant EPO reduces epithelial cell apoptosis and attenuates bleomycin-induced pneumonitis in mice. Methods: Bleomycin was instilled intratracheally into C57BL/6 mice. Recombinant human EPO or saline was injected intraperitoneally, daily from day 5 to day 13 after bleomycin instillation. Results: EPO receptor was expressed in bronchiolar and alveolar type II cells. At 14 days after instillation, the number of terminal uridine deoxynucleotidyl transferase nick end-labelled positive cells in the lung was decreased, and the histological degree of inflammation and fibrosis was attenuated in mice injected with EPO compared with controls. Expression of phosphorylated Akt and Erk, which are thought to mediate the survival signalling pathway induced by EPO, tended to be increased in lung tissues from mice treated with EPO compared with those from mice treated with saline after bleomycin instillation. Conclusions: As it is likely that EPO protects epithelial cells from injury and apoptosis, EPO administration could be a potential therapeutic strategy for the prevention of lung injury. [ABSTRACT FROM AUTHOR]

Background and objective: A multi-institutional phase II trial combining uracil-tegafur (UFT) and cisplatin (CDDP) was conducted in patients with previously untreated advanced non-small cell lung cancer (NSCLC) to evaluate the safety and efficacy of this combined treatment regimen. Methods: The entry criteria for this study were previously untreated NSCLC, measurable disease, age <80 years, performance status <2, and adequate haematological, hepatic and renal function. Patients were treated with 400 mg/m2 oral UFT from day 1 to day 14 and 80 mg/m2 cisplatin on day 15. The treatment course was repeated every 3 weeks. Results: Of the 68 patients enrolled, 64 (27 with stage IIIB and 37 with stage IV disease) were eligible for treatment. Twenty of the 64 patients responded to the chemotherapy (response rate 31.3%; 95% CI 21.2–43.4%). The median survival time was 8.6 months, and the 1-year survival was 41.5%. Haematological toxicity ≥WHO grade 3 was seen in 3 (4.7%) patients. For non-haematological toxicities, anorexia with WHO grade 3 was seen in 8 (12.5%) patients, nausea and vomiting with WHO grade 3 in 4 (6.3%), diarrhoea with WHO grade 4 in 1 (1.6%), and liver dysfunction with WHO grade 4 in 1 (1.6%) patient. Conclusions: The combination of oral UFT plus cisplatin was found to be a safe and active treatment against advanced NSCLC. The observed low toxicity of this combined regimen may warrant its application to the treatment of elderly patients. [ABSTRACT FROM AUTHOR]

Abstract: Redox control of disulfide-bond formation in the H+-pyrophosphatase of Streptomyces coelicolor was investigated using cysteine mutants expressed in Escherichia coli. The wild-type enzyme, but not a cysteine-less mutant, was reversibly inactivated by oxidation. To determine the residues involved in oxidative inactivation, different cysteine residues were replaced. Analysis with a cysteine-modifying reagent revealed that the formation of a disulfide bond between cysteines 253 and 621 was responsible for enzyme inactivation. This result suggests that residues in different cytoplasmic loops are close to each other in the tertiary structure. Both cysteine residues are conserved in K+-independent (type II) H+-pyrophosphatases. [Copyright &y& Elsevier]

Different roles of interleukin-10 in onset and resolution of asthmatic responses in allergen-challenged miceMATSUMOTO K, INOUE H, TSUDA M, HONDA Y, KIBE A, MACHIDA K, YOSHIURA Y, NAKANISHI Y.Respirology2005;10: 18–26Although interleukin (IL)-10 is an immunoregulatory cytokine produced by various cells including T cells, its precise role in asthma remains uncertain. The aim of this study was to investigate the role of IL-10 in experimental asthma using ovalbumin (OVA)-sensitized mice.Mice were challenged with OVA aerosol, and airway responsiveness and inflammation were measured. OVA-specific IL-10-producing CD4+ T cells were counted from lung cells collected by enzymatic digestion and stimulatedex vivowith OVA. The effects of an anti-IL-10 antibody on airway responsiveness and inflammation were also evaluated.The OVA challenge caused airway hyperresponsiveness and eosinophilic inflammation. A significant increase in IL-10-producing CD4+ T cells was observed, mainly in the CD45RBlow subset, for several days after the OVA challenge. Anti-IL-10 antibody treatment before the OVA challenge did not affect eosinophilic inflammation but significantly inhibited airway hyperresponsiveness 24 h after the OVA challenge. However, anti-IL-10 antibody treatment just before the last OVA challenge significantly attenuated the resolution of eosinophilic inflammation without affecting airway responsiveness 2 weeks after the OVA challenge.Intrinsic IL-10 may have a distinct role in the early and late phases of asthmatic responses. In the early phase, IL-10 induces airway hyperresponsiveness, while in the late phase IL-10 contributes to the resolution of eosinophilic inflammation. [ABSTRACT FROM AUTHOR]

Abstract: A 49-year-old man with diabetes mellitus and alcoholic liver cirrhosis presented with dyspnoea and fever. A chest computed tomography scan revealed three areas of loculated pleural effusion. Initially, the patient was thought to have an intrapleural empyema and was treated with intravenous antibiotics and closed drainage. However, as he did not improve, he was then treated with open drainage. During open drainage, the patient was diagnosed to have an extrapleural empyema and improved following open drainage treatment. [ABSTRACT FROM AUTHOR]

The function of the translation products of six different cDNAs for Acetabularia V-ATPase proteolipid subunit (AACEVAPD1 to AACEVAPD6) was examined using a Saccharomyces cerevisiae VMA3-deficient strain that lacked its own gene for one of the proteolipid subunits of V-ATPase. Expression of the cDNAs in the strain revealed that four cDNAs from the six complemented the proton transport activity into the vacuole, visualized by fluorescence microscopy. The vacuolar-membrane-enriched fractions from the four transformants showed cross-reactivity with antibodies against the subunits a and A of S. cerevisiae V-ATPase. Two translation products from the other two cDNAs were demonstrated not to be localized in vacuolar membranes, and thus could not complement the function of the VMA3-deficient strain. As the primary structures deduced from the former four cDNAs are similar but clearly different from those of the latter two, the latter two translation products may not be able to substitute for theVMA3 gene product. [ABSTRACT FROM AUTHOR]

The Ca2+-transport activity and intracellular localization of the translation product of cDNA for mung bean Ca2+/H+ antiporter (VCAX1) were examined. When the cDNA was expressed in Saccharomyces cerevisiae that lacked its own genes for vacuolar Ca2+-ATPase and the antiporter, VCAX1 complemented the active Ca2+ transporters, and the microsomal membranes from the transformant showed high activity of the Ca2+/H+ antiporter. Treatment of the vacuolar membranes with a cross-linking reagent resulted in a clear band of the dimer detected with antibody specific for VCAX1p. The antibody was also used for immunolocalization of the antiporter in fractions obtained by sucrose-density-gradient centrifugation of the microsomal fraction from mung bean. The immunostained band was detected in the vacuolar membrane fraction and the slightly heavy fractions that exhibited activity of the Golgi marker enzyme. A fusion protein of VCAX1p and green fluorescent protein was expressed in tobacco cells. The green fluorescence was clearly observed on the vacuolar membrane and, in some cases, in the small vesicles. The subcellular fractionation of transformed tobacco cells confirmed the vacuolar membrane localization of the fusion protein. These results confirm that VCAX1p functions in the vacuolar membrane as a Ca2+/H+ antiporter and also suggest that VCAX1p may exist in the Golgi apparatus. [ABSTRACT FROM AUTHOR]

Examines the properties and molecular cloning of Ca[sup 2+]/H[sup +] antiporter in the vacoular membrane of mung bean hypocotyl. Increase of cytosolic calcium ions level; Role of calcium ions in the transduction of plant cells; Coexistence of two different systems of calcium ion accumulation in plant vacuoles.

We describe the rare case of a Japanese male with multifocal lupus vulgaris that preceded asymptomatic pulmonary tuberculosis and adult T-cell leukemia/lymphoma (ATL). He visited our hospital with multiple reddish plaques and erythema of 4-12 months duration. A skin biopsy revealed non-caseating epithelioid granulomas. Mycobacterium tuberculosis was detected by polymerase chain reaction (PCR)-hybridization from a skin biopsy specimen and was also isolated from a culture of the skin biopsy sample. The result of chest roentogenography was compatible with pulmonary tuberculosis. In addition, the diagnosis of ATL was based upon the presence of atypical lymphocytes with convoluted nuclei in his peripheral blood and a positive anti-ATL antibody reaction. Cases of cutaneous tuberculosis presenting with unusual clinical features may be on the increase, accompanying the spread of tuberculosis in immunosuppressed patients, including those with ATL and acquired immunodeficiency syndrome (AIDS).