Cholangiocarcinoma is a highly malignant cancer. Many patients need systemic chemotherapy to prevent tumor development and recurrence; however, their prognosis is poor due to the lack of effective therapy. Therefore, a new treatment option is urgently required. We recently identified glypican-1 (GPC1) as a novel cancer antigen of esophageal squamous cell carcinoma. We also demonstrated the efficacy and safety of GPC1-targeted ADC (GPC1–ADC) conjugating anti-GPC1 mAb possessing high internalization activity with monomethyl auristatin F (MMAF), which is a potent tubulin polymerizing inhibitor. In this study, we confirmed that GPC1 was highly expressed in cholangiocarcinoma cells and tissues. IHC analysis of 49 extrahepatic cholangiocarcinoma patient tumor specimens revealed high expression of GPC1 in 47% of patients. These patients demonstrated significantly poorer prognosis compared with the low-expression group in terms of disease-free survival and overall survival (P < 0.05). GPC1 was also expressed in tumor vessels of cholangiocarcinoma, but not on the vessels of nontumor tissues. MMAF-conjugated GPC1–ADC showed potent tumor growth inhibition against GPC1-positive cholangiocarcinoma cells in vitro and in vivo. In a GPC1 knockout xenograft model, GPC1–ADC partially inhibited tumor growth. Vascular endothelial cells in tumor tissues of GPC1-negative xenograft mice expressed GPC1 and were arrested in the G2–M phase of cell cycle by GPC1–ADC. GPC1–ADC exhibits direct as well as indirect antitumor effects via inhibition of tumor angiogenesis. Our preclinical data highlight GPC1–ADC as a promising therapy for GPC1-positive cholangiocarcinoma.

Background. Islet transplantation is an effective replacement therapy for type 1 diabetes (T1D) patients. However, shortage of donor organ for allograft is obstacle for further development of the treatment. Subcutaneous transplantation with stem cell-derived β-cells might overcome this, but poor vascularity in the site is burden for success in the transplantation. We investigated the effect of subcutaneous transplantation of vascularized β-cell spheroid tissue constructed 3-dimensionally using a layer-by-layer (LbL) cell-coating technique in a T1D model mouse. Methods. We used MIN6 cells to determine optimal conditions for the coculture of β-cell spheroids, normal human dermal fibroblasts, and human umbilical vein endothelial cells, and then, under those conditions, we constructed vascularized spheroid tissue using human induced pluripotent stem cell-derived β-cells (hiPS β cells). The function of insulin secretion of the vascularized hiPS β-cell spheroid tissue was evaluated in vitro. Furthermore, the function was investigated in T1D model NOD/SCID mice subcutaneously transplanted with the tissue. Results. In vitro, the vascularized hiPS β-cell spheroid tissue exhibited enhanced insulin secretion. The vascularized hiPS β-cell spheroid tissue also significantly decreased blood glucose levels in diabetic immunodeficient mice when transplanted subcutaneously. Furthermore, host mouse vessels were observed in the explanted vascularized hiPS βcell spheroid tissue. Conclusions. Vascularized hiPS β-cell spheroid tissue decreased blood glucose levels in the diabetic mice. This therapeutic effect was suggested due to host angiogenesis in the graft. This method could lead to a promising regenerative treatment for T1D patients.

Purpose Postoperative pancreatic fistula is a serious complication of distal pancreatectomy. Although many studies have described the incidence and risk factors associated with postoperative pancreatic fistula (POPF), few have focused on the healing time. This study investigated the healing time and potential factors associated with the healing time of POPF after distal pancreatectomy (DP). Methods Among 114 patients that underwent DP in our hospital from January 2010 to December 2020, we included 88 that developed POPF. The healing time for a postoperative pancreatic fistula was defined as the interval between the completion of DP and the removal of all drains related to the treatment for POPF. Based on the definition, three cases who required additional treatment after removal of all drains were excluded from this study. Clinical factors associated with the fistula healing times were investigated in the 85 patients. Results The average POPF healing time was 11 ± 10 days (median: 6 days, range: 3‐57). We found that the neutrophil‐to‐lymphocyte ratio, a marker of inflammatory and nutritional status, was the only factor independently associated with the POPF healing time; the mean healing time was significantly shorter in patients with neutrophil‐to‐lymphocyte ratio ≤2.1 (8 ± 6 days) than in those with neutrophil‐to‐lymphocyte ratio >2.1 (13 ± 12 days; P = .0139). Conclusion We demonstrated that the neutrophil‐to‐lymphocyte ratio could independently predict the POPF healing time after DP. These findings suggested that improving the neutrophil‐to‐lymphocyte ratio might shorten the healing times for POPF after DP.

Background. No effective therapies have yet been established for liver regeneration in liver failure. Autologous skeletal myoblast cell sheet transplantation has been proven to improve cardiac function in patients with heart failure, and one of the mechanisms has been reported to be a paracrine effect by various growth factors associated with liver regeneration. Therefore, the present study focused on the effect of myoblast cells on liver regeneration in vitro and in vivo. Methods. We assessed the effect of myoblast cells on the cells comprising the liver in vitro in association with liver regeneration. In addition, we examined in vivo effect of skeletal myoblast cell sheet transplantation in C57/BL/6 mouse models of liver failure, such as liver fibrosis induced by thioacetamide and hepatectomy. Results. In vitro, the myoblast cells exhibited a capacity to promote the proliferation of hepatic epithelial cells and the angiogenesis of liver sinusoidal endothelial cells, and suppress the activation of hepatic stellate cells. In vivo, sheet transplantation significantly suppressed liver fibrosis in the induced liver fibrosis model and accelerated liver regeneration in the hepatectomy model. Conclusions. Autologous skeletal myoblast cell sheet transplantation significantly improved the liver failure in the in vitro and in vivo models. Sheet transplantation is expected to have the potential to be a clinically therapeutic option for liver regeneration in liver failure.

Purpose Decreasing intraoperative blood loss is one reported advantage of laparoscopic surgery compared with open surgery. However, several reports indicate that blood loss during laparoscopic surgery may be underestimated. No studies have evaluated this possibility in laparoscopic distal pancreatectomy (LDP). Here we evaluated estimated blood loss (e-BL) compared to actual intraoperative blood loss (i-BL) during distal pancreatectomy (DP). Methods This study included 114 patients undergoing DP in our institution during the study period. We examined the relationship between i-BL and e-BL. Based on these results, we further investigated the relationship with LDP. Results The laparoscopic approach was used in a significantly higher percentage of patients in e-BL > i-BL group compared to e-BL < i-BL group (55.9% vs. 10.9%, p < 0.0001). Within LDP group (n = 39), e-BL was significantly more than i-BL (388 ± 248 mL vs. 127 ± 160 mL; p < 0.0001). Within open distal pancreatectomy (ODP) group (n = 75), e-BL was significantly less than i-BL (168 ± 324 mL vs. 281 ± 209 mL; p = 0.0017). The e-BL > i-BL trend in LDP group was consistent regardless of the indication for DP. In contrast, the finding of i-BL > e-BL in ODP group was limited to patients with pancreatic cancer. Conclusion During LDP, e-BL was significantly more than i-BL. During ODP, e-BL was significantly less than i-BL, only in patients with pancreatic cancer. These results suggested the possibility of i-BL underestimation during LDP, and overestimation during ODP in cases with pancreatic cancer.