Design, synthesis, and biological evaluation of new biaryl derivatives of cycloalkyl diacetamide bearing chalcone moiety as type II c-MET kinase inhibitors.

Many human cancers have been associated with the deregulation of the mesenchymal-epithelial transition factor tyrosine kinase (MET) receptor, a promising drug target for anticancer drug discovery. Herein, we report the discovery of a novel structure of potent chalcone-based derivatives type II c-Met inhibitors which are comparable to Foretinib (IC50 = 14 nM) as a potent reference drug. Based on our design strategy, we also expected an anti-tubulin activity for the compounds. However, the weak inhibitory effects on microtubules were confirmed by cell cycle analyses implicated that the observed cytotoxicity against HeLa cells probably was not derived from tubulin inhibition. Compounds 14q and 14k with IC50 values of 24 nM and 45 nM, respectively, demonstrated favorable inhibition of MET kinase activity, and desirable bonding interactions in the ligand-MET enzyme complex stability in molecular docking studies.

Endocytoscopic microvasculature evaluation is a reliable new diagnostic method for colorectal lesions (with video).

BACKGROUND: We previously reported on the efficacy of endocytoscopic classification (EC-C). However, the correlation of the endocytoscopic vascular (EC-V) pattern with diagnoses was unclear. OBJECTIVE: To assess the diagnostic accuracy of the EC-V pattern for colorectal lesions. DESIGN: Retrospective. SETTING: A university hospital. PATIENTS: Patients who underwent endocytoscopy between January 2010 and March 2013. INTERVENTION: We evaluated 198 consecutive lesions according to the EC-V pattern (EC-V1, obscure surface microvessels; EC-V2, clearly observed surface microvessels of a uniform caliber and arrangement; and EC-V3, dilated surface microvessels of a nonhomogeneous caliber or arrangement). MAIN OUTCOME MEASUREMENTS: The diagnostic accuracy for predicting hyperplastic polyps and invasive cancer were compared between the EC-V pattern and other modalities (narrow-band imaging, pit pattern, and EC-C). RESULTS: The sensitivity, specificity, and accuracy of the EC-V1 pattern for diagnosing hyperplastic polyps were 95.5%, 99.4%, and 99.0%, respectively. The sensitivity, specificity, and accuracy of the EC-V3 pattern for diagnosing invasive cancer were 74.6%, 97.2%, and 88.6%, respectively. The diagnostic accuracy of the EC-V pattern for predicting hyperplastic polyps was comparable to the other modalities. For predicting invasive cancer, the EC-V pattern was comparable to narrow-band imaging and pit pattern, although EC-C was slightly more accurate (P = .04). In the substudy, the diagnosis time by using the EC-V pattern was shorter than that with the EC-C pattern (P < .001). LIMITATIONS: A single-center, retrospective study. CONCLUSIONS: The EC-V pattern saved more time than the EC-C pattern and had a diagnostic ability comparable to that of other optical biopsy modalities.

[A case of successful treatment of hepatocellular carcinoma lumbar metastasis by surgery, chemotherapy, and radiation].

The incidence of bone metastasis in patients with hepatocellular carcinoma (HCC) has reportedly been increasing. We report a progressive case that presented with a solitary HCC lumbar metastasis. A 44-year-old man was referred to us from a local clinic with a complaint of a painful lump. He was diagnosed with HCC due to liver cirrhosis and lumbar metastasis by contrast abdominal computerized tomography and magnetic resonance imaging. Then, he received radiation therapy (3 Gy/ time; total, 39 Gy) and zoledronate. Furthermore, transcatheter arterial embolization and posterior lumbar spinal fusion were performed to treat the lumbar metastasis. This decreased his pain and oxycodone was no longer required. In conclusion, for HCC patients with bone metastasis, combined treatment with radiation, zoledronate, and surgery, may possibly improve their quality of life resulting in a long clinical course.

Is it proper to use non-magnified narrow-band imaging for esophageal neoplasia screening? Japanese single-center, prospective study.

AIM: Most screening examinations in Japanese general hospitals are carried out by high-definition television-incompatible (non-HD) scopes and non-magnifying endoscopes. We evaluated the narrow-band imaging (NBI) real-time diagnostic yield of esophageal neoplasia in high-risk patients at a general hospital. METHODS: In a single-center, prospective, non-randomized controlled trial, 117 consecutive screening patients with high risk for esophageal cancer received primary white-light imaging (WLI) followed by NBI and iodine-staining endoscopy (59 by HDTV-compatible [HD] endoscopy and 58 by non-HD endoscopy). The primary aim was to evaluate the diagnostic yield of non-magnified images in diagnosing esophageal neoplasia. The secondary aim was to compare HD endoscopy and non-HD endoscopy in terms of diagnostic performance. RESULTS: Overall, the sensitivity of NBI for screening of esophageal neoplasia was superior to WLI, and equivalent to iodine staining (92% vs 42%; P < 0.05, 92% vs 100%; ns). The specificity of NBI was equivalent to WLI (89% vs 94%; ns). In HD, NBI sensitivity was equivalent to both iodine staining and WLI (100% vs 75%; ns). In non-HD, NBI sensitivity was equivalent to iodine staining, but WLI sensitivity was significantly inferior to NBI (88% vs 100%; ns, 25% vs 88%; P < 0.05). The NBI specificity was equivalent to WLI not only in HD but also in non-HD (90% vs 96%; ns, 88% vs 93%; ns). CONCLUSION: In both HD and non-HD endoscopy, NBI is less likely than WLI to miss a lesion. Even with non-HD endoscopy, NBI is suitable for esophageal standard examinations in general hospitals.

[Present state and foresight of endoscopic therapy].

The advent of magnifying chromoendoscopy has enabled endoscopists to observe the mucosal structures in great detail for precise diagnosis; the pit patterns, irregular vascular patterns with narrow band imaging(NBI), and intra-epithelial papillary capillary loop (IPCL) pattern. The achievement of high resolution images has also improved accuracy of diagnosis for neoplasm in gastroenterology. Endocytoscopy is developed from magnifying chromoendoscopy, and is now under clinical investigation for use. Many of early gastrointestinal carcinoma has been treated endoscopically, and ESD (endoscopic submucosal dissection) technique, resection of the neoplasm en bloc, has disseminated recent years. The indication for ESD will be broadened in the near future, and the precise diagnosis for the neoplasm is essential, not to loose the interest of patients.

Possible involvement of singlet oxygen species as multiple oxidants in p450 catalytic reactions.

Cytochrome P450 (P450) constitutes a superfamily of enzymes which activate dioxygen and carry out monooxygenation reactions of large numbers of endogenous and xenobiotic compounds. Drug metabolism is a particularly important P450 function, and, therefore, elucidating the metabolic products and pathways of drugs is essential for drug development. To explain the substrate selectivity of P450 reactions, it is necessary to understand the formation of multiple activated oxygen species to determine the type of catalyzed reactions, in addition to conducting structure analyses of P450s. Although an oxo-Fe(IV)-porphyrin-pi-cation radical is regarded as an activated oxygen species in P450 reactions, a nucleophilic Fe(III)-peroxo species has also been proposed as another oxidant. In the past decade, various studies indicated that P450-catalyzed oxygenations are complex, and that a single reaction pathway cannot explain all of the experimental results. In addition, the microsomal P450 system is known to generate reactive oxygen species (ROS). However, the contribution of ROS to P450 reactions remains unclear. We recently found that singlet oxygen (1O2) was involved in both several rat liver microsomal P450 reactions and four human CYP subfamily activities, as confirmed by the ESR spin-trapping method. In this review, we describe the studies that have been conducted on the detection and characterization of ROS in P450 reactions related to drug metabolism that involve the possibility of 1O2 in the P450 catalytic cycle. Gaining an understanding of the activated oxygen species that determine the type of drug metabolism will help us to predict the important metabolites formed.

Essential role of singlet oxygen species in cytochrome P450-dependent substrate oxygenation by rat liver microsomes.

Previously, we reported that singlet oxygen (1O2) was involved in rat liver microsomal P450-dependent substrate oxygenations in such reactions as p-hydroxylation of aniline, O-deethylation of 7-ethoxycoumarin, omega- and (omega-1)-hydroxylations of lauric acid, O-demethylation of p-nitroanisole, and N-demethylation of aminopyrine. In order to confirm the generality of 1O2 involvement, we have further investigated which kinds of reactive oxygen species (ROS) are formed during P450-dependent substrate oxygenation in microsomes. We examined CYP2E1-dependent hydroxylation of p-nitrophenol in rat liver microsomes in the presence of some ROS scavengers, because CYP2E1 has been reported to predominantly generate ROS in the hepatic microsomes and to relate with the oxidative stress in the body. The addition of 1O2 quenchers, beta-carotene, suppressed the hydroxylation of p-nitrophenol. Furthermore, a nonspecific P450 inhibitor, SKF525A, and a ferric chelator, deferoxamine, both suppressed the hydroxylation. No other ROS scavengers such as superoxide dismutase (SOD), catalase, or mannitol altered the reaction. 1O2 was detectable during the reaction in the microsomes as measured by an electron spin resonance (ESR) spin-trapping method when 2,2,6,6-tetramethyl-4-piperidone (TMPD) was used as a spin-trapping reagent. The 1O2 was quenched by additions of beta-carotene, p-nitrophenol, and SKF525A. The reactivity of p-nitrophenol and 1O2 correlated linearly with its hydroxylation rate in the microsomes. On the basis of these results, we conclude that 1O2 contributes to the p-nitrophenol hydroxylation in rat liver microsomes, by adding a new example of 1O2 involvement in the CYP2E1-dependent substrate oxygenations.

Characteristics of colorectal tumours in asymptomatic patients with negative immunochemical faecal occult blood test results.

The immunochemical faecal occult blood test (iFOBT) is a simple, non-invasive colorectal cancer (CRC) screening method for reducing CRC-related mortality. However, the sensitivity of iFOBT is imperfect and certain colonic neoplasms that require removal may be missed. The aim of this study was to investigate the incidence and characteristics of CRC in asymptomatic, iFOBT-negative patients who underwent opportunistic screening. A total of 919 subclinical patients (276 iFOBT-positive and 643 iFOBT-negative) in the health screening program of our hospital underwent total colonoscopy (TCS) within 2 years after iFOBT. The patients were divided into an iFOBT-positive and an iFOBT-negative group and the TCS findings were compared between the two groups. Although the incidence of advanced neoplasia (CRC, high-grade dysplasia, adenoma sized ≥10 mm and tubulovillous adenoma) was significantly higher in the iFOBT-positive group, these lesions were also found in 6.3% of iFOBT-negative patients. The lesions tended to be proximally located and non-protruding. In conclusion, screening with iFOBT remains clinically significant. However, colonoscopy is indispensable for reducing the incidence and mortality of CRC.

Endocytoscopic narrow-band imaging efficiency for evaluation of inflammatory activity in ulcerative colitis.

AIM: To assess the efficacy of endocytoscopic narrow-band imaging (EC-NBI) for evaluating the severity of inflammation in ulcerative colitis (UC). METHODS: This retrospective study was conducted at a single tertiary care referral center. We included UC patients who underwent colonoscopy with endocytoscopy from July 2010 to December 2013. EC-NBI was performed, and the images were evaluated by assessing visibility, increased vascularization, and the increased calibers of capillaries and were classified as Obscure, Visible or Dilated. Obscure was indicative of inactive disease, while Visible and Dilated were indicative of acute inflammation. This study received Institutional Review Board approval. The primary outcome measures included the diagnostic ability of EC-NBI to distinguish between active and inactive UC on the basis of histological activity. The conventional endoscopic images were classified according to the Mayo endoscopic score. A score of 0 or 1 indicated inactive disease, whereas a score of 2 indicated active disease. RESULTS: Fifty-two patients were enrolled. There was a strong correlation between the EC-NBI findings and the histological assessment (r=0.871, P<0.01). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of EC-NBI for diagnosing acute inflammation were 84.0%, 100%, 87.1%, 100%, and 92.3%, respectively, while those for the Mayo endoscopic score were 100%, 40.7%, 100%, 61.0%, and 69.2%, respectively. Compared with conventional endoscopy, EC-NBI was superior in diagnostic specificity, negative predictive value, and accuracy (P<0.001, P=0.001 and P=0.047, respectively). CONCLUSION: The EC-NBI finding of capillaries in the rectal mucosa was strongly correlated with histological inflammation and aided in the differential diagnosis between active and inactive UC.

Magnifying narrow-band imaging of surface patterns for diagnosing colorectal cancer.

Narrow-band imaging (NBI) of surface microvessels of colorectal lesions is useful for differentiating neoplasms from non-neoplasms and for predicting histopathological diagnosis. Furthermore, NBI of surface microstructure, or 'surface pattern', is valuable for predicting histopathology in colorectal cancer. The aim of the present study was to investigate whether surface patterns could be used to predict invasion depth in colorectal cancer, and to compare the accuracy of surface pattern diagnosis in each macroscopic type. Between January 2010 and March 2011, a series of 357 consecutive patients with 378 early colorectal cancers were observed by magnifying NBI and the surface pattern was prospectively evaluated. Surface pattern was classified into 3 types: type I, microstructure was clearly recognised with uniform arrangement and form; type II, microstructure was obscured with heterogeneous arrangement and form; and type III, microstructure was invisible. We also classified the macroscopic type into 3 categories: depressed, protruded and flat elevated. Assuming that type III was an index of massively invasive lesions in the submucosal layer (SMm), the sensitivity, specificity and accuracy were 56.9, 91.7 and 85.7%, respectively. The sensitivity, specificity and accuracy of type III for the diagnosis of SMm in each macroscopic type were: depressed, 88.9, 40.0 and 63.2%, respectively; protruded: 34.8, 96.4 and 90.0%, respectively; and flat elevated, 54.2, 92.7 and 85.0%, respectively. These results suggest that the diagnostic accuracy of surface pattern was insufficient and particularly poor for depressed-type lesions.

Epigenetic alteration of DNA in mucosal wash fluid predicts invasiveness of colorectal tumors.

Although conventional colonoscopy is considered the gold standard for detecting colorectal tumors, accurate staging is often difficult because advanced histology may be present in small colorectal lesions. We collected DNA present in mucosal wash fluid from patients undergoing colonoscopy and then assessed the methylation levels of four genes frequently methylated in colorectal cancers to detect invasive tumors. We found that methylation levels in wash fluid were significantly higher in patients with invasive than those with noninvasive tumors. Cytologic and K-ras mutation analyses suggested that mucosal wash fluid from invasive tumors contained greater numbers of tumor cells than wash fluid from noninvasive tumors. Among the four genes, levels of mir-34b/c methylation had the greatest correlation with the invasion and showed the largest area under the receiver operating characteristic curve (AUC = 0.796). Using cutoff points of mir-34b/c methylation determined by efficiency considerations, the sensitivity/specificity were 0.861/0.657 for the 13.0% (high sensitivity) and 0.765/0.833 for the 17.8% (well-balanced) cutoffs. In the validation test set, the AUC was also very high (0.915), the sensitivity/specificity were 0.870/0.875 for 13.0% and 0.565/0.958 for 17.8%. Using the diagnostic tree constructed by an objective algorithm, the diagnostic accuracy of the invasiveness of colorectal cancer was 91.3% for the training set and 85.1% for the test set. Our results suggest that analysis of the methylation of DNA in mucosal wash fluid may be a good molecular marker for predicting the invasiveness of colorectal tumors.