BackgroundPancreatic cancer is associated with an extremely poor prognosis, so new biomarkers that can detect the initial stages are urgently needed. The significance of serum microRNA (miR) levels in pancreatic neoplasm such as pancreatic cancer and intraductal papillary mucinous neoplasm (IPMN) diagnosis remains unclear. We herein evaluated the usefulness of miRs enclosed in serum exosomes (ExmiRs) as diagnostic markers.MethodsThe ExmiRs from patients with pancreatic cancer (n = 32) or IPMN (n = 29), and patients without neoplasms (controls; n = 22) were enriched using ExoQuick-TC™. The expression of ExmiRs was evaluated using a next-generation sequencing analysis, and the selected three miRs through this analysis were confirmed by a quantitative real-time polymerase chain reaction.ResultsThe expression of ExmiR-191, ExmiR-21 and ExmiR-451a was significantly up-regulated in patients with pancreatic cancer and IPMN compared to the controls (p < 0.05). A receiver operating characteristic curve analysis showed that the area under the curve and the diagnostic accuracy of ExmiRs were 5–20% superior to those of three serum bulky circulating miRs (e.g.; ExmiR-21: AUC 0.826, accuracy 80.8%. Circulating miR-21: AUC 0.653, accuracy 62.3%). In addition, high ExmiR-451a was associated with mural nodules in IPMN (p = 0.010), and high ExmiR-21 was identified as a candidate prognostic factor for the overall survival (p = 0.011, HR 4.071, median OS of high-ExmiR-21: 344 days, median OS of low-ExmiR-21: 846 days) and chemo-resistant markers (p = 0.022).ConclusionsThe level of three ExmiRs can thus serve as early diagnostic and progression markers of pancreatic cancer and IPMN, and considered more useful markers than the circulating miRs (limited to these three miRs).Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4006-5) contains supplementary material, which is available to authorized users.

Background/AimsVenous thromboembolism (VTE) is a major extraintestinal manifestation in inflammatory bowel disease (IBD), regarded as an independent risk factor for VTE according to reports from Western countries. However, the incidence and risk factors of VTE in Asian IBD patients are not fully understood. We aimed to reveal the incidence and risk factors of VTE in Japanese IBD inpatients.MethodsThe incidence of VTE in inpatients with IBD (n=340), gastrointestinal cancers (n=557), and other gastrointestinal diseases (n=569) treated at our hospital from 2009 to 2013 was retrospectively investigated. The characteristics and laboratory data of IBD inpatients with and without VTE were compared in univariate and multivariate analyses. Clinical courses of VTE in IBD were surveyed.ResultsVTE was detected in 7.1% of IBD inpatients, significantly higher than in gastrointestinal cancer inpatients (2.5%) and inpatients with other gastrointestinal diseases (0.88%). The incidence of VTE in ulcerative colitis (UC) patients (16.7%) was much higher than that in those with Crohn's disease (3.6%). In the univariate analysis, the risk factors were an older age, central venous catheter, prednisolone, surgery, low serum albumin, high serum C-reactive protein and D-dimer. According to a multivariate analysis, >50 years of age and surgery were the only risk factors. The in-hospital mortality rate of IBD inpatients with VTE was 4.2%.ConclusionsThe incidence of VTE with IBD, especially UC, was found to be high compared with other digestive disease, which was almost equivalent to that of Western countries. The efficacy of prophylaxis needs to be investigated in Asian IBD patients.

Pancreatic cancer is associated with a poor prognosis due to challenges in early detection, severe progression of the primary tumor, metastatic lesions, and resistance to antitumor agents. However, previous studies have indicated a relationship between the microbiome and pancreatic cancer outcomes. Our previous study demonstrated that ferrichrome derived from Lactobacillus casei, a probiotic bacteria, exhibited tumor-suppressive effects in colorectal and gastric cancer, and that the suppressive effects were stronger than conventional antitumor agents, such as 5-fluorouracil (5-FU) and cisplatin, suggesting that certain probiotics exert antitumorigenic effects. However, whether or not probiotic-derived molecules, including ferrichrome, exert a tumor-suppressive effect in other gastrointestinal tumors, such as pancreatic cancer, remains unclear. In the present study, it was demonstrated that probiotic-derived ferrichrome inhibited the growth of pancreatic cancer cells, and its tumor-suppressive effects were further revealed in 5-FU-resistant pancreatic cancer cells in vitro and in vivo in a mouse xenograft model. Ferrichrome inhibited the progression of cancer cells via dysregulation of the cell cycle by activating p53. DNA fragmentation and cleavage of poly (ADP-ribose) polymerase were induced by ferrichrome treatment, suggesting that ferrichrome induced apoptosis in pancreatic cancer cells. A transcriptome analysis revealed that the expression p53-associated mRNAs was significantly altered by ferrichrome treatment. Thus, the tumor-suppressive effects of probiotics may mediated by probiotic-derived molecules, such as ferrichrome, which may have applications as an antitumor drug, even in refractory and 5-FU-resistant pancreatic cancer.

<b><i>Background:</i></b> Venous thromboembolism (VTE) has been shown to be more frequent in inflammatory bowel disease (IBD) than in the general population in Western studies. However, the actual state of VTE in Asian IBD remains poorly understood. <b><i>Aims:</i></b> To reveal the incidence of VTE in IBD patients in Japan. <b><i>Methods:</i></b> Eighty-five patients admitted to 3 gastroenterology centers were registered from 2013 to 2018. The incidence of VTE in patients with IBD (<i>n</i> = 42) was prospectively compared to that among patients with other digestive diseases (<i>n</i> = 43). The presence of VTE was surveyed using contrast-enhanced computed tomography and/or ultrasonography at admission and at 1–2 weeks after admission. The patient characteristics and laboratory data of IBD patients with or without VTE were compared to determine the risk factors for VTE. <b><i>Results:</i></b> The incidence of VTE with IBD was 16.7%, which was significantly more frequent than with other digestive diseases (2.3%; <i>p</i> = 0.0296). In IBD patients, VTE was detected in 6 of 22 patients with ulcerative colitis (27.2%) but in only 1 of 20 patients with Crohn’s disease (5.0%). VTE was diagnosed at admission in 4 IBD patients and 2 weeks after admission in 3 IBD patients. The risk factors of VTE in IBD were the presence of an indwelling central venous catheter, a low level of total protein, a low activated partial thromboplastin time, and a high level of fibrinogen degradation products. <b><i>Conclusion:</i></b> VTE was frequently detected in Japanese IBD patients both at and after admission. Adequate screening and prophylaxis for VTE is deemed necessary in IBD.

Ferrichrome is known to be a siderophore, but it was recently identified as a tumor-suppressive molecule derived from Lactobacillus casei ATCC334 ( L. casei). In the present study, we investigated the effects of ferrichrome in gastric cancer cells. Cell lines and xenograft models treated with ferrichrome demonstrated growth suppression. The expression levels of cleaved poly (adenosine diphosphate-ribose) polymerase, and cleaved caspase-9 were increased by ferrichrome treatment. Although the tumor-suppressive effects of ferrichrome were almost completely diminished by the iron chelation, the reduction in the intracellular iron by ferrichrome did not correlate with its tumor-suppressive effects. An exhaustive docking simulation indicated that iron-free ferrichrome can make stable conformations with various mammalian molecules, including transporters and receptors. In conclusion, probiotic-derived ferrichrome induced apoptosis in gastric cancer cells. The iron binding site of ferrichrome is the structure responsible for its tumor suppressive function.