Significance of Wnt/ß-Catenin Signal Activation for Resistance to Neoadjuvant Chemoradiotherapy in Rectal Cancer.

Although a therapeutic response to neoadjuvant chemoradiotherapy (NACRT) is important to improve oncological outcomes after surgery in patients with locally advanced rectal cancer, there is no reliable predictor for this. The Wnt/ß-catenin signal is known to be crucial for the tumorigenesis of colorectal cancer. This study aimed to investigate the association of Wnt/ß-catenin signal activation with a pathological response to NACRT. The immunohistochemical expression of nuclear and membranous ß-catenin was analyzed in biopsy samples obtained from 60 patients with locally advanced rectal cancer who received curative surgery following NACRT. The association of Wnt/ß-catenin signal activation with their clinical outcomes was investigated. Notably, the body mass index of these patients was significantly higher in the low nuclear ß-catenin expression group. Moreover, patients in the high nuclear ß-catenin expression group tended to have more advanced disease and a higher rate of positive vascular invasion than those in the low expression group. Furthermore, the rate of good histological responses was significantly higher in the low nuclear ß-catenin expression group (72% vs. 37.1%, p < 0.01). Overall, relapse-free survival tended to be better in patients with low nuclear/high membranous ß-catenin expression (n = 9) than in other individuals (n = 51) (p = 0.093 and p = 0.214, respectively). Activation of the Wnt/ß-catenin signal pathway represented by nuclear ß-catenin accumulation was significantly associated with a poor response to NACRT in patients with rectal cancer. Analysis of nuclear ß-catenin accumulation before starting treatment might help predict the therapeutic response to NACRT.

[Two Cases of the Significant Liver Damage by Regorafenib].

There is a liver damage in a serious side effect of regorafenib. Case 1 was a 54-year-old woman, and she had an operation of rectal cancer and metastasized to multiple organs afterwards and started regorafenib as third-line. Erythema exudativum multiform developed on the 8th day after a start and regorafenib was canceled once and reduced on the 21st day when a skin symptom was relieved and restarted. However, because a significant rise of AST, ALT, T -Bil was recognized afterwards, regorafenib was canceled on the 27th day and enforced steroid pulse therapy and was relieved afterwards. Case 2 was a 61-year-old woman, and she had an operation of ascending colon cancer, ovarian metastasis and peritoneum dissemination. Regorafenib was started by frequent occurrence lung metastasis, cancerous pleurisy afterwards as fifth-line. Dissemination erythema developed on the 16th day and a liver damage developed on the 22nd day. Because a rise of AST, ALT went and was prolonged, liver biopsy was enforced in a cause close inspection purpose on the 45th day. A medicamentosus liver damage was diagnosed. The liver enzyme decreased afterwards. It may be easy to make the liver damage by regorafenib serious, and attention is necessary.

CDX2-induced intestinal metaplasia in human gastric organoids derived from induced pluripotent stem cells.

Intestinal metaplasia is related to gastric carcinogenesis. Previous studies have suggested the important role of CDX2 in intestinal metaplasia, and several reports have shown that the overexpression of CDX2 in mouse gastric mucosa caused intestinal metaplasia. However, no study has examined the induction of intestinal metaplasia using human gastric mucosa. In the present study, to produce an intestinal metaplasia model in human gastric mucosa in vitro, we differentiated human-induced pluripotent stem cells (hiPSC) to gastric organoids, followed by the overexpression of CDX2 using a tet-on system. The overexpression of CDX2 induced, although not completely, intestinal phenotypes and the enhanced expression of many, but not all, intestinal genes and previously reported intestinal metaplasia-related genes in the gastric organoids. This model can help clarify the mechanisms underlying intestinal metaplasia and carcinogenesis in human gastric mucosa and develop therapies to restitute precursor conditions of gastric cancer to normal mucosa.

Epithelial-derived factors induce muscularis mucosa of human induced pluripotent stem cell-derived gastric organoids.

Human gastric development has not been well studied. The generation of human pluripotent stem cell-derived gastric organoids (hGOs) comprising gastric marker-expressing epithelium without an apparent smooth muscle (SM) structure has been reported. We modified previously reported protocols to generate hGOs with muscularis mucosa (MM) from hiPSCs. Time course analyses revealed that epithelium development occurred prior to MM formation. Sonic hedgehog (SHH) and TGF-ß1 were secreted by the epithelium. HH and TGF-ß signal inhibition prevented subepithelial MM formation. A mechanical property of the substrate promoted SM differentiation around hGOs in the presence of TGF-ß. TGF-ß signaling was shown to influence the HH signaling and mechanical properties. In addition, clinical specimen findings suggested the involvement of TGF-ß signaling in MM formation in recovering gastric ulcers. HH and TGF-ß signaling from the epithelium to the stroma and the mechanical properties of the subepithelial environment may influence the emergence of MM in human stomach tissue.

[A Case of Pancreatic Adenocarcinoma with Inferior Vena Cava Invasion].

A 66-year-old Japanese woman was admitted to our hospital for jaundice. Abdominal computed tomography(CT) showed dilatation of the intra- and extra-hepatic bile duct, and a hypovascular lesion measuring 30mm in diameter in the head of the pancreas. This tumor was in contact with the(superior mesenteric vein: SMV)and(inferior vena cava: IVC), but there were no obvious signs of invasion. Upper gastrointestinal endoscopy showed obstruction of the duodenum. We chose to perform an upfront surgery, considering the patient's general condition being stable and the difficulties associated with endoscopic biliary drainage. During surgery, stiff attachment between the tumor and IVC was identified and wedge resection of the IVC wall was performed. SMV resection and end-to-end reconstruction were also carried out. Pathological studies of the surgical specimen revealed direct invasion by the pancreatic adenocarcinoma into the adventitia of the IVC. The postoperative course was uneventful, and the patient was discharged from the hospital on the 27th postoperative day; she underwent adjuvant chemotherapy(S-1 100mg/day)and is still alive without tumor recurrence, 21 months after surgery. Cases of resected pancreatic adenocarcinoma directly invading the IVC are rare. In this case, pancreaticoduodenectomy along with wedge resection of the IVC wall could safely be performed, and no complications were observed. There is a need for further accumulation of similar cases.