Takashi Yabana

Enhancing epithelial engraftment of rat mesenchymal stem cells restores epithelial barrier integrity.

The cellular origin, in vivo function and fate of donor bone marrow‐derived cells residing in the recipient intestinal epithelial cells, pericryptal myofibroblasts or endothelial cells remain obscure. Although ‘immunoprivileged’ mesenchymal stem cells (MSCs) are prime candidates for cell‐ and gene‐based therapy, their precise role in colitis remains largely undetermined. Using a dextran sulphate sodium (DSS) colitis with busulphan (BU)‐induced hypoplastic marrow model, we examined the therapeutic effects of MSC transplantation, focusing on the role of MSCs as both cell providers and immunomodulators. Donor‐derived MSCs were detected by eGFP immunofluorescence and fluorescence in situ hybridization for Y‐chromosome (Y‐FISH) analysis. Western blot analysis of apical‐most tight junction proteins was performed with antibodies against claudin‐2, ‐7, ‐8, ‐12, ‐13, ‐15 and ZO‐1. Cytokine and cell cycle profiles were analysed by semi‐quantitative RT‐PCR and flow cytometry. Susceptibility to DSS colitis was significantly increased by co‐existing BU‐induced bone marrow hypoplasia and this increase was significantly reduced by enhancing epithelial engraftment of MSCs, an effect depending on restoring epithelial barrier integrity rather than inhibiting host immune responses. We provide evidence that implicates MSCs in maintaining epithelial barrier function by reassembling apical‐most tight junction proteins, claudins. The therapeutic efficacy of extrinsic MSCs depends on enhancing epithelial engraftment in damaged crypts by busulphan conditioning. Such a role for the MSC‐derived intestinal cells in colitis therapy merits further examination and may offer a promising new treatment for inflammatory bowel disease (IBD). Copyright

Myogenic lineage differentiated mesenchymal stem cells enhance recovery from dextran sulfate sodium-induced colitis in the rat

BackgroundAlthough mounting evidence implicates mesenchymal stem cells (MSCs) in intestinal tissue repair, uncertainty remains concerning the distribution, function, and fate of repopulating MSCs in recipient colonic tissues. Therefore, we investigated the role of transplanted MSCs in the repair phase of DSS colitis.MethodsLacZ-labeled rat MSCs were transplanted into rats with colitis induced by 4% DSS on day 2. Regular water replaced the DSS solution on day 6. Therapeutic effect was evaluated on day 9 by clinicopathologic and growth factor/cytokine expression profiles. We analyzed the Notch signaling pathway by Western blotting and characterized immunofluorescence of lacZ-labeled MSCs with confocal laser microscopy. In vivo differentiation of MSC was confirmed by transmission electron microscopy (TEM).ResultsRecovery of colitis was modestly but significantly promoted by MSC transplantation due to proceeding cell cycle and inhibiting apoptosis in the epithelia. Tgfa mRNA expression increased significantly, while Notch signaling was inhibited in the colonic tissues with MSC transplantation. β-Galactosidase-positive cells, which expressed α-SMA, desmin, and vimentin, were infrequently detected in the lamina propria stroma. DSS exposure in vitro proved to be the most potent inducer for α-SMA in MSCs where TEM demonstrated myogenic lineage differentiation.ConclusionsWe found that MSCs transplantation modestly promoted the repair of DSS colitis. The donor-derived MSCs were likely reprogrammed to differentiate to myogenic lineage cells by cues from the micro milieu. Further characterization of these cells is warranted as a basis for applying cell-based therapy for inflammatory bowel disease.

Rare type of pancreatitis as the first presentation of anti-neutrophil cytoplasmic antibody-related vasculitis

A pancreatic tumor was suspected on the abdominal ultrasound of a 72-year-old man. Abdominal computed tomography showed pancreatic enlargement as well as a diffuse, poorly enhanced area in the pancreas; endoscopic ultrasound-guided fine needle aspiration biopsy and endoscopic retrograde cholangiopancreatography failed to provide a definitive diagnosis. Based on the trend of improvement of the pancreatic enlargement, the treatment plan involved follow-up examinations. Later, he was hospitalized with an alveolar hemorrhage and rapidly progressive glomerulonephritis; he tested positive for myeloperoxidase-anti-neutrophil cytoplasmic antibody (ANCA) and was diagnosed with ANCA-related vasculitis, specifically microscopic polyangiitis. It appears that factors such as thrombus formation caused by the vasculitis in the early stages of ANCA-related vasculitis cause abnormal distribution of the pancreatic blood flow, resulting in non-uniform pancreatitis. Pancreatic lesions in ANCA-related vasculitis are very rare. Only a few cases have been reported previously. Therefore, we report our case and a review of the literature.

Loss of HER2 Positivity after Trastuzumab in HER2-Positive Gastric Cancer: Is Change in HER2 Status Significantly Frequent?

Trastuzumab has recently been introduced as a treatment for HER2-positive metastatic and/or unresectable gastric cancer (MUGC); however, compared with breast cancer, some issues concerning HER2 and trastuzumab therapy for gastric cancer remain unclear. A 74-year-old woman received trastuzumab-containing chemotherapy for HER2-positive MUGC. She had a marked response to 8 months of chemotherapy, and gastrectomy and hepatic metastasectomy with curative intent were performed. The resected specimen showed complete loss of HER2 positivity in the residual tumor. For MUGC, a change in HER2 status during the course of the disease with or without chemotherapy has rarely been reported. However, in breast cancer, a significant frequency of change in HER2 status during the course of disease has been reported, and reevaluation of HER2 positivity in metastatic/recurrent sites is recommended. The choice of trastuzumab for MUGC is currently based on the HER2 status of the primary tumor at the time of initial diagnosis, without reassessment of HER2 status during the course of disease and/or in metastatic/recurrent sites, on the assumption that HER2 status is stable. However, our case casts doubt on the stability of HER2 in gastric cancer.

A Case of Xanthogranulomatous Cholecystitis with High CA19-9 Levels thatNormalized Post-Cholecystectomy

The patient was an 81-year-old male. His blood tests revealed a mild hepatic dysfunction and an abnormally high Carbohydrate antigen 19-9 (2,830 U/ml). Ultrasonography, contrast-enhanced computed tomography and magnetic resonance cholangiopancreatography were carried out, and showed that the gallbladder was filled with microcalculi, that the gallbladder was enlarged, and that the gallbladder wall had thickened; however, no calculi were found in the common bile duct, and positron emission tomography was performed for the detection of malignancies but the findings were poor; therefore, the condition was diagnosed as calculous cholecystitis, and cholecystectomy was performed. The pathological findings indicated a xanthogranulomatous cholecystitis, and the levels of Carbohydrate antigen 19-9 returned to normal immediately after surgery. The immunostaining of Carbohydrate antigen 19-9 showed that epithelial mucosa of the gallbladder, cytoplasm of multinucleated foreign-body giant cells, and infiltrating macrophages were positive, and suggested that the abnormally high levels of Carbohydrate antigen 19-9 may have been due to xanthogranulomatous cholecystitis. In some cases, Carbohydrate antigen 19-9 levels can be high in benign diseases such as cholangitis and pancreatitis, but markedly high levels are rare. Only two cases of xanthogranulomatous cholecystitis have been reported to have shown abnormally high Carbohydrate antigen 19-9 that returned to normal after cholecystectomy. We report our experience along with a discussion based on the literature.

EDUCATION AND IMAGING. Gastrointestinal: Needle tract implantation after endoscopic ultrasound-guided fine-needle aspiration of a pancreatic adenocarcinoma.

Figure 2 (a) HE-stained (×150) pathological tissue resected by distal gastrectomy showed moderately differentiated tubular adenocarcinoma mainly in the gastric mucosa over the muscular layer. This was similar to findings in pancreatic cancer tissue resected in the previous surgery, suggesting dissemination of pancreatic cancer to the stomach through EUS-FNA. (b) HE-stained (×150) pathological tissue resected by distal pancreatectomy. Atypical cubical epithelium formed large and small gland ducts.Moderately differentiated tubular adenocarcinoma was mainly noted and was diagnosed as infiltrating pancreatic duct cancer. Figure 1 (a, b) Upper gastrointestinal endoscopy revealed an about 25-mm submucosal tumor-like protrusion with erosion of the apex in the lower posterior wall of the stomach body.

[Perioperative primary thrombosis prophylaxis for colorectal cancer in an asymptomatic antiphospholipid antibody carrier -a case report and literature review-].

An 82-year-old woman presented with hematochezia and was diagnosed with resectable colon cancer. Laboratory analysis revealed prolonged activated partial thromboplastin time and false-positive reactions in serological tests for syphilis; results that were subsequently found to be caused by the presence of antiphospholipid antibody. Because she had no history of thrombotic events or pregnancy morbidity, she was considered to be an asymptomatic antiphospholipid antibody carrier (aaPL carrier). Throughout the perioperative period, anticoagulation was performed without complications, including thrombosis. aaPL carriers are not uncommon in clinical practice, and the attending gastroenterologist should assess the risk of future thrombotic events and the most effective means of preventing thrombosis. However, there are few evidence-based recommendations for primary thrombosis prevention in aaPL carriers over the long-term and in high-risk periods, such as the perioperative period. Here, we discuss aaPL carrier management with a focus on the perioperative period together with a review of the literature.

Needle tract implantation after endoscopic ultrasound‐guided fine‐needle aspiration of a pancreatic adenocarcinoma

Figure 2 (a) HE-stained (×150) pathological tissue resected by distal gastrectomy showed moderately differentiated tubular adenocarcinoma mainly in the gastric mucosa over the muscular layer. This was similar to findings in pancreatic cancer tissue resected in the previous surgery, suggesting dissemination of pancreatic cancer to the stomach through EUS-FNA. (b) HE-stained (×150) pathological tissue resected by distal pancreatectomy. Atypical cubical epithelium formed large and small gland ducts.Moderately differentiated tubular adenocarcinoma was mainly noted and was diagnosed as infiltrating pancreatic duct cancer. Figure 1 (a, b) Upper gastrointestinal endoscopy revealed an about 25-mm submucosal tumor-like protrusion with erosion of the apex in the lower posterior wall of the stomach body.