BackgroundWith the recent widespread use of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), there have been occasional reports on complications associated with its use. Previous reviews on EBUS-TBNA have been limited to studies by skilled operators, thus the results may not always be applicable to recent clinical practice. To assess the safety of EBUS-TBNA for the staging and diagnosis of lung cancer in Japan, a nationwide survey on its current usage status and complications associated with its use was conducted by the Japan Society for Respiratory Endoscopy (JSRE).MethodsA questionnaire about EBUS-TBNA performed between January 2011 and June 2012 was mailed to 520 JSRE-accredited facilities.ResultsResponses were obtained from 455 facilities (87.5%). During the study period, EBUS-TBNA was performed in 7,345 cases in 210 facilities (46.2%) using a convex probe ultrasound bronchoscope, for 6,836 mediastinal and hilar lesions and 275 lung parenchymal lesions. Ninety complications occurred in 32 facilities. The complication rate was 1.23% (95% confidence interval, 0.97%-1.48%), with hemorrhage being the most frequent complication (50 cases, 0.68%). Infectious complications developed in 14 cases (0.19%) (Mediastinitis, 7; pneumonia, 4; pericarditis, 1; cyst infection, 1; and sepsis, 1). Pneumothorax developed in 2 cases (0.03%), one of which required tube drainage. Regarding the outcome of the cases with complications, prolonged hospitalization was observed in 14 cases, life-threatening conditions in 4, and death in 1 (severe cerebral infarction) (mortality rate, 0.01%). Breakage of the ultrasound bronchoscope occurred in 98 cases (1.33%) in 67 facilities (31.9%), and that of the puncture needle in 15 cases (0.20%) in 8 facilities (3.8%).ConclusionsAlthough the complication rate associated with EBUS-TBNA was found to be low, severe complications, including infectious complications, were observed, and the incidence of device breakage was high. Since the use of EBUS-TBNA is rapidly expanding in Japan, an educational program for its safe performance should be immediately established.

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Respiratory endoscopy was performed safely, but education regarding complications caused by new techniques is necessary.

Gemcitabine is one of the most commonly used agents for lung cancer chemotherapy, but the determinants of sensitivity and/or resistance to this agent are not yet fully understood. In this study we used quantitative RT-PCR to examine the expression levels of human equilibrative nucleoside transporter 1 (hENT1) and deoxycytidine kinase (dCK) genes in non-small cell lung cancer (NSCLC) cell lines in relation to sensitivity and resistance to gemcitabine. The basal expression levels of hENT1 were significantly correlated with the IC 50 values for gemcitabine (r = = = =-0.6769, P = = = =0.0005), whereas dCK expression levels were not. In a highly gemcitabinesensitive cell line, NCI-H23, the sensitivity to gemcitabine was inhibited by nitrobenzylmercaptopurine ribonucleoside (NBMPR), an inhibitor of hENT1, without significant modulation of hENT1 expression. These data suggest that hENT1 is associated with gemcitabine sensitivity in lung cancer. We also continuously exposed NCI-H23 cells to gemcitabine and subsequently established the drug-resistant clone H23/GEM-R, which showed a significant decrease of dCK expression; however, hENT1 expression was not altered in the continuously exposed sublines or in the resistant clone. We conclude that increased hENT1 expression is a determinant of gemcitabine sensitivity, while decreased dCK expression is associated with acquired resistance to gemcitabine in NSCLC cells. Thus, hENT1 and dCK might be useful as predictive markers for efficacy of gemcitabine therapy in NSCLC. (Cancer Sci 2004; 95: 753-757) ung cancer is one of the most common malignancies worldwide 1) and remains the leading cause of cancer-related deaths in Western countries.2) Several randomized clinical trials and meta-analyses have demonstrated that survival in patients with advanced stage III or IV non-small cell lung cancer (NSCLC) can be slightly but significantly prolonged with chemotherapy.3, 4) Several new anticancer agents have recently been shown to have encouraging activity against NSCLC, and a recent randomized study provided data supportive of the efficacy and safety of a regimen including gemcitabine. 5)

Pemetrexed (MTA) is a multitargeted antifolate with promising clinical activity in lung cancer. We exposed the small cell lung cancer cell line PC6 to stepwise-increasing pemetrexed concentrations of 0.4, 1.6, and 4.0 lM, and established three pemetrexed-resistant lung cancer cell lines: PC6 ⁄ MTA-0.4, PC6 ⁄ MTA-1.6, and PC6 ⁄ MTA-4.0 cells. To investigate the mechanisms of acquired resistance to pemetrexed, we measured the expression levels of the thymidylate synthase (TS), reduced folate carrier (RFC), and folylpolygamma-glutamate synthetase (FPGS) genes. TS gene expression was significantly increased in PC6 ⁄ MTA-1.6 and PC6 ⁄ MTA-4.0 cells relative to parental cells in a pemetrexed dose-dependent manner. In contrast, the levels of RFC gene expression in PC6 ⁄ MTA-0.4 cells and FPGS in PC6 ⁄ MTA-1.6 cells were significantly decreased, whereas the levels of both genes were restored in PC6 ⁄ MTA-4.0 cells. Knockdown of TS expression using siRNA enhanced pemetrexed cytotoxicity in PC6 ⁄ MTA-4.0 cells. The expression level of the TS gene was significantly correlated with the concentration of pemetrexed for 50% cell survival (IC 50 ) in 11 non-small cell lung cancer cell lines. These results suggest that the alteration of molecular pharmacological factors in relation with pemetrexed resistance is dose-dependent, and that up-regulation of the expression of the TS gene may have an important role in the acquired resistance to pemetrexed. In addition, TS may be a predictive marker for pemetrexed sensitivity in lung cancer. (Cancer Sci 2010; 101: 161-166) P emetrexed is an MTA that targets the folate-dependent enzymes TS, DHFR, GARFT, and AICARFT, all of which are involved in the de novo biosynthesis of thymidine and purine nucleotides.(1) Pemetrexed is transported intracellularly, predominantly via the RFC, where it is metabolized to polyglutamated forms. Pemetrexed was found to be one of the best substrates for mammalian FPGS, and it is believed that polyglutamation and the polyglutamated metabolites play important roles in determining both the selectivity and antitumor activity of this agent.(2,3) The polyglutamated metabolites of pemetrexed are most active against TS, followed by DHFR, GARFT and AI-CARFT, and natural folate competes with this inhibition in all cases.(4) Therefore, the primary mechanism of the action of pemetrexed is inhibition of TS, which results in a decrease in the available thymidine necessary for DNA synthesis. (2,4) Pemetrexed is a single agent that is currently approved for second-line treatment of advanced-stage NSCLC.(5,6) In chemotherapy-naïve patients with advanced NSCLC, double combinations of platinum compounds with gemcitabine, vinorelbine, paclitaxel, and docetaxel are standard regimens. A recent phase III trial found that cisplatin ⁄ pemetrexed provides equivalent efficacy with significantly fewer side effects and more convenient administration than cisplatin ⁄ gemcitabine in advanced NSCLC.(7) Preclinical examinations found that the combination of pemetrexed with gemcitabine or...

Multidrug-resistance -associated protein, MRP8/ABCC11 (ABCC11), is an efflux pump for nucleotide analogues and 5-fluoro-2 ¶-deoxyuridine 5 ¶-monophosphate (FdUMP). To test whether ABCC11 directly confers 5-fluorouracil (5-FU) resistance, we used the 5-FU -resistant subline PC-6/FU23-26 selected from PC-6 human small-cell lung cancer cells by 5-FU and found that it increases the resistance by f25-fold. The intracellular FdUMP accumulation was reduced in PC-6/FU23-26 cells concomitant with the overexpression of the ABCC11 gene. These findings suggest that ABCC11 confers 5-FU resistance in the sublines by enhancing the efflux for the active metabolite FdUMP. Previously, methotrexate also increased the efflux by ABCC11, and we found crossresistance to methotrexate in PC-6/FU23-26 cells. To confirm our hypothesis, we examined whether decreasing the expression of ABCC11 in PC-6/FU23-26 cells by small interfering RNA altered the cytotoxicity to 5-FU and methotrexate and found that this enhanced 5-FU and methotrexate cytotoxicity in PC-6/FU23-26 cells. These data indicate that expression of the ABCC11 gene is induced by 5-FU, and that ABCC11 is directly involved in 5-FU resistance by the efflux transport of the active metabolite FdUMP. [Mol Cancer Ther 2007;6(1):122 -7]

It has recently been shown that an insertion (I)/deletion (D) polymorphism exists in the angiotensin-converting enzyme (ACE) gene, and that this polymorphism affects the serum ACE level. There are three genotypes: DD, DI, and II, with the ACE level highest in DD, intermediate in DI, and lowest in II. In the present investigation of the possible significance of the polymorphism for sarcoidosis, a total of 207 patients and 314 normal control subjects were examined. There were no significant differences in the I/D ratio and the genotype distribution between the two groups, and no significant variation in organ involvement (i.e., eye, skin, and heart) was noted among the three genotypes. To determine any prognostic influence of the polymorphism, we examined the disappearance ratio of abnormal shadow on chest radiography over 3 and 5 yr. No significant difference among the three genotypes was observed. New normal ranges of serum ACE level were determined for each genotype, and found to be 22% more sensitive overall than the conventional normal range and 39% more so for II type, suggesting an advantage for diagnosis and assessment of the disease activity of sarcoidosis.

Several studies have investigated a possible association between the ABO blood group and the risk of pancreatic cancer (PC), but this association has not been fully evaluated in Asian populations. The present study aimed to assess the impact of genotype-derived ABO blood types, particularly ABO alleles, on the risk of PC in a Japanese population. We conducted a case-control study using 185 PC and 1465 control patients who visited Aichi Cancer Center in Nagoya, Japan. Using rs8176719 as a marker for the O allele, and rs8176746 and rs8176747 for the B allele, all participants' two ABO alleles were inferred. The impact of ABO blood type on PC risk was examined by multivariate analysis, with adjustment for potential confounders to estimate odds ratios (OR) and 95% confidence intervals (CI). An increased risk of PC was observed with the addition of any non-O allele (trend P = 0.012). Compared with subjects with the OO genotype, those with AO and BB genotypes had significantly increased OR of 1.67 (CI, 1.08-2.57) and 3.28 (CI, 1.38-7.80), respectively. Consistent with earlier reports showing a higher risk of PC for individuals with the non-O blood type, the previously reported protective allele (T) for rs505922 was found to be strongly correlated (r 2 = 0.96) with the O allele. In conclusion, this case-control study showed a statistically significant association between ABO blood group and PC risk in a Japanese population. Further studies are necessary to define the mechanisms by which the ABO gene or closely linked genetic variants influence PC risk. (Cancer Sci 2011; 102: 1076-1080 T he incidence of pancreatic cancer (PC) is increasing in Japan, and this cancer is now the sixth leading cause of cancer death.(1,2) Early detection of PC in its operable stage is difficult and curative treatment such as complete surgical removal is limited, which together give PC a 5-year relative survival rate of only 5.5%.(3) This suggests that epidemiological approaches to predicting the risk of PC may play an important role in identifying PC high-risk groups and ultimately decreasing the number of PC deaths.Risk factors for PC include advancing age, smoking, obesity, diabetes mellitus, family history of PC, alcohol consumption and chronic pancreatitis. (2,(4)(5)(6)(7)(8) Recently, a large prospective cohort study also showed a statistically significant association between ABO blood type and risk of PC.(9) Specifically, this study suggested that people with blood type O have a lower risk of PC than those with blood type A, B or AB. A genome-wide association study (GWAS) comparing PC cases and controls (PanScan), which includes the forementioned prospective cohort study population, (9) identified a single-nucleotide polymorphism (SNP) within the first intron of the ABO gene (rs505922) that was associated with PC risk.(10) Furthermore, using almost the same population as PanScan, Wolpin et al. (11) reported that the ABO blood type could be inferred from two SNPs (rs505922 and rs8176746), and concluded the relationship between PC risk a...