Little attention has been paid to colorectal xanthoma. To clarify the clinical and pathological features of colorectal xanthoma, we report 28 colorectal xanthomas biopsied from 25 patients. All were composed of typical xanthoma cells and showed polypoid configuration. Median age of the patients was 64 years and there were 15 men and 10 women. Diabetes mellitus, constipation, and hyperlipidemia were found in two, one, and seven patients, respectively. Seventeen (60.7%) of the 28 polyps were located in the sigmoid colon and the remaining 11 in the rectum. Twenty-three polyps (82.1%) were sessile. Twelve (60.0%) of twenty polyps that were recorded were reddish in color. Only two polyps revealed a yellowish tone. Microscopically, foamy cells were present in the lamina propria, but the submucosa did not contain foamy cells. Immunohistochemically, the foamy cells invariably expressed extensive positivity for CD68. The colonic glands showed a deformity in the case with moderate to intense density of the foamy cells. The surface epithelium showed a hyperplastic change in 22 (78.6%) xanthomas. The colonic glands in four xanthomas were also associated with hyperplastic changes. The basement membrane of the surface epithelium was often thickened. Cell debris and proliferation of the capillaries were observed just below the surface epithelium in 19 (67.9%) and 22 (78.6%) xanthomas, respectively. Previous mucosal minute injury was suggested as the pathogenesis of colorectal xanthomas. Colorectal xanthomas were not identical to gastric and esophageal xanthoma, endoscopically or microscopically. We prefer the term "xanthomatous polyp" rather than xanthoma in the colorectal region. They may be regarded as a novel type of colorectal non-neoplastic polyp.

The antitumor activity of pladienolide B, a novel splicing inhibitor, against gastric cancer is totally unknown and no predictive biomarker of pladienolide B efficacy has been reported. We investigated the antitumor activity of pladienolide B and its derivative on gastric cancer cell lines and primary cultured cancer cells from carcinomatous ascites of gastric cancer patients. The effect of pladienolide B and its derivative on six gastric cancer cell lines was investigated using a MTT assay and the mean IC50 values determined to be 1.6 ± 1.2 (range, 0.6–4.0) and 1.2 ± 1.1 (range, 0.4–3.4) nM, respectively, suggesting strong antitumor activity against gastric cancer. The mean IC50 value of pladienolide B derivative against primary cultured cells from 12 gastric cancer patients was 4.9 ± 4.7 nM, indicative of high antitumor activity. When 18 SCID mice xenografted with primary cultured cells from three patients were administered the pladienolide B derivative intraperitoneally, all tumors completely disappeared within 2 weeks after treatment. Histological examination revealed a pathological complete response for all tumors. In the xenograft tumors after treatment with pladienolide B derivative, immature mRNA were detected and apoptotic cells were observed. When the expressions of cell-cycle proteins p16 and cyclin E in biopsied gastric cancer specimens were examined using immunohisctochemistry, positivities for p16 and cyclin E were significantly and marginally higher, respectively, in the low-IC50 group compared with the high-IC50 group, suggesting the possibility that they might be useful as predictive biomarkers for pladienolide B. In conclusion, pladienolide B was very active against gastric cancer via a mechanism involving splicing impairment and apoptosis induction.

Background and study aims  Although new image-enhanced endoscopy (IEE) technologies such as blue laser imaging (BLI), BLI-bright, and linked color imaging (LCI) have been developed, their utility for the detection of sessile serrated adenoma/polyps (SSA/Ps) is still unclear. This study aimed to evaluate the utility of BLI, BLI-bright, and LCI for SSA/P detection in still image examinations and in a prospective randomized controlled trial (RCT). Patients and methods  A group of 6 expert and non-expert endoscopists read 200 endoscopic still images containing SSA/P lesions using white light image (WLI), BLI, BLI-bright, and LCI. Color differences were calculated using the color space method. A prospective RCT of tandem colonoscopy with WLI and LCI was performed. Patients with SSA/P and those with a history of SSA/P that had been endoscopically removed were enrolled and randomly allocated to WLI-LCI or LCI-WLI groups. Additional endoscopic detection rates for SSA/P were compared between the 2 groups. Results  LCI showed the highest SSA/P detection rate among the 4 modes for both expert and non-expert endoscopists. The detection rate with LCI for the 6 expert endoscopists (mean 98.3 ± standard deviation 2.0 %) was significantly higher than that with WLI (86.7 ± 6.0 %, P  < 0.01). Likewise, the detection rate with LCI for the 6 non-expert endoscopists (92.3 ± 2.9 %) was significantly higher than that with WLI (72.7 ± 11.5 %, P  < 0.01). The color difference of SSA/P with LCI was the highest among the 4 modes, and was significantly higher than with WLI (median 15.9, (interquartile range 13.7 – 20.6) vs. 10.2, (7.6 – 14.2); P  < 0.0001). In the RCT, a total of 44 patients (WLI-LCI 22 vs. LCI-WLI 22) underwent colonoscopy. The additional detection rate for SSA/P in the second inspection in the WLI-LCI group (21.6 %, 8/37) was significantly higher than in the LCI-WLI group (3.2 %, 1/31; P  = 0.02). The small, flat, non-mucus and isochromatic SSA/Ps in the transverse colon were detected more frequently in the second inspection with LCI. Conclusions  LCI was the most sensitive mode for SSA/P detection among WLI, BLI, BLI-bright, and LCI in the still image examinations. Our RCT strongly suggests that LCI is superior to conventional WLI for SSA/P detection during colonoscopy. UMIN000017599.

An anti-CEA antibody with affinity for cancerous lesions and labeled with ICG-sulfo-OSu can therefore be imaged using this infrared fluorescence endoscope. Specific antibodies tagged with ICG-sulfo-OSu can label cancer cells and can generate a strong enough fluorescent signal to detect small cancers when examined with an infrared fluorescence endoscope.

Although pancreatic cancer often invades peripancreatic adipose tissue, little information is known about cancer‐adipocyte interaction. We first investigated the ability of adipocytes to de‐differentiate to cancer‐associated adipocytes (CAAs) by co‐culturing with pancreatic cancer cells. We then examined the effects of CAA‐conditioned medium (CAA‐CM) on the malignant characteristics of cancer cells, the mechanism underlying those effects, and their clinical relevance in pancreatic cancer. When 3T3‐L1 adipocytes were co‐cultured with pancreatic cancer cells (PANC‐1) using the Transwell system, adipocytes lost their lipid droplets and changed morphologically to fibroblast‐like cells (CAA). Adipocyte‐specific marker mRNA levels significantly decreased but those of fibroblast‐specific markers appeared, characteristic findings of CAA, as revealed by real‐time PCR. When PANC‐1 cells were cultured with CAA‐CM, significantly higher migration/invasion capability, chemoresistance, and epithelial‐mesenchymal transition (EMT) properties were observed compared with control cells. To investigate the mechanism underlying these effects, we performed microarray analysis of PANC‐1 cells cultured with CAA‐CM and found a 78.5‐fold higher expression of SAA1 compared with control cells. When the SAA1 gene in PANC‐1 cells was knocked down with SAA1 siRNA, migration/invasion capability, chemoresistance, and EMT properties were significantly attenuated compared with control cells. Immunohistochemical analysis on human pancreatic cancer tissues revealed positive SAA1 expression in 46/61 (75.4%). Overall survival in the SAA1‐positive group was significantly shorter than in the SAA1‐negative group (P = .013). In conclusion, we demonstrated that pancreatic cancer cells induced de‐differentiation in adipocytes toward CAA, and that CAA promoted malignant characteristics of pancreatic cancer via SAA1 expression, suggesting that SAA1 is a novel therapeutic target in pancreatic cancer.

The mechanism of resistance of hepatocellular carcinoma (HCC) to sorafenib is unknown and no useful predictive biomarker for sorafenib treatment has been reported. Accordingly, we established sorafenib-resistant HCC cells and investigated the underlying mechanism of resistance to sorafenib. Sorafenib-resistant cell lines were established from the HCC cell line PLC/PRF5 by cultivation under continuous exposure to increasing concentration of sorafenib. The IC50 values of the 2 resistant clones PLC/PRF5-R1 and PLC-PRF5-R2 were 9.2±0.47 μM (1.8-fold) and 25±5.1 μM (4.6-fold) respectively, which were significantly higher than that of parental PLC/PRF5 cells (5.4±0.17 μM) (p < 0.01 respectively), as determined by MTT assay. Western blot analysis of signal transduction-related proteins showed no significant differences in expression of AKT/pAKT, mTOR/pmTOR, or ERK/pERK between the 2 resistant clones versus parent cells, suggesting no activation of an alternative signal transduction pathway. Likewise, when expression of membrane transporter proteins was determined, there were no significant differences in expression levels of BSEP, MDR1, MRP2, BCRP, MRP4 and OCT1 between resistant clones and parent cells. However, the expression levels of MRP3 in the 2 resistant clones were significantly higher than that of parent cells. When MRP3 gene was knocked down by siRNA in PLC-PRF5-R2 cells, the sensitivity of the cells to sorafenib was restored. In the analysis of gene mutation, there was no mutation in the activation segment of Raf1 kinase in the resistant clones. Our data clearly demonstrate that the efflux transporter MRP3 plays an important role in resistance to sorafenib in HCC cells.

Parasympathetic hypofunction, sympathetic hyperfunction and portal hemodynamics were closely related with gastric motility in cirrhotic patients. In addition, gastric motility was decreased, at least in part, by the ingestion of food in cirrhotic patients because of abnormalities in autonomic functions and portal blood flow following a meal.

BackgroundNatriuretic peptides have been proposed as biomarkers of cardiovascular disease, especially heart failure. Brain natriuretic peptide (BNP) has also been shown to be upregulated at the transcriptional and translational levels by pro-inflammatory cytokines in cardiac myocytes. Although we often measure plasma BNP levels in cancer patients, it remains unknown whether cancer-related inflammation affects the plasma BNP levels. We investigated the relationship between the BNP and human cancers.MethodsWe retrospectively studied 2,923 patients in whom the plasma BNP levels and serum C-reactive protein (CRP) were measured and echocardiography was performed. Patients with clinically evident heart failure (NYHA II or higher), heart disease requiring medical treatment or surgery, renal dysfunction, and inflammatory disease were excluded. There were 234 patients in the final analysis. Blood sampling was performed before surgery and chemotherapy. In addition, we evaluated the relationship between the inflammation and plasma BNP levels in mouse models of colon cancer.ResultsOf the 234 patients, 80 were diagnosed with cancer. Both the plasma BNP and serum CRP levels were significantly higher in cancer patients than those without. There were no significant differences in the echocardiographic parameters. There was a significant positive correlation between the plasma BNP and serum CRP levels in cancer patients (r = 0.360, P<0.01) but not in those without. In cancer patients, only the CRP correlated with the BNP independent of the age, creatinine level, hypertension, and body mass index. In addition, in nude mice with subcutaneous colon cancer, the plasma BNP level was elevated compared with that in non-cancer mice, and there was a significant relationship between the plasma BNP and serum levels of the inflammatory markers.ConclusionsIn cancer patients, as well as colon cancer model mice, the plasma BNP levels were elevated, possibly due to cancer-related inflammation. The effect of cancer on the BNP levels should be considered when using BNP as an indicator of heart failure in cancer patients.