Background The optimal enzyme blend which maximizes human islets yield for transplantation remains to be determined. In this study, we evaluated 8 different enzyme combinations (ECs) in an attempt to improve islet yield. The ECs consisted of purified, intact, or truncated class 1 (C1) and class 2 (C2) collagenases from Clostridium histolyticum (Ch) as well as neutral protease (NP) from Bacillus thermoproteolyticus rokko (thermolysin) or Ch (ChNP). Methods We report the results of 249 human islet isolations, including 99 deceased donors (research n=57, clinical n=42) and 150 chronic pancreatitis pancreases. We prepared a new enzyme mixture (NEM) composed of intact C1 and C2 collagenases and ChNP instead of using thermolysin. The NEM was first tested in split pancreas (n=5) experiments and then used for islet autologous (n=21) and allogeneic transplantation (n=10). Islet isolation outcomes from 8 different Ecs were statistically compared using multivariate analysis. Results The NEM consistently achieved higher islet yields from pancreatitis (p<0.003) and deceased donor pancreases (p<0.001) than other standard ECs. Using the NEM, islet products met release criteria for transplantation from 8 of 10 consecutive pancreases, averaging 6510±2150 IEQ/g pancreas and 694,681±147,356 total IEQ/transplantation. In autologous isolation, the NEM yielded >200,000 IEQ from 19 of 21 pancreases (averaging 422,893±181,329 total IEQ and 5979±1469 IEQ/kg recipient body weight) regardless of the severity of fibrosis. Conclusions A new enzyme mixture composed of Clostridium histolyticum neutral protease with CIzyme high intact C1 collagenase recovers higher islet yield from deceased and pancreatitis pancreases while retaining islet quality and function.

Donor age is an independent, strong prognostic factor in adult-to-adult LDLT.

These data indicate the importance of intact C1 and the use of the appropriate analytical assays to correlate biochemical characteristics of TDEs to islet quality and yield.

There is a consensus that portal venous pressure (PVP) modulation prevents portal hypertension (PHT) and consequent complications after adult-to-adult living donor liver transplantation (ALDLT). However, PVP-modulation strategies need to be updated based on the most recent findings. We examined our 10-year experience of PVP modulation and reevaluated whether it was necessary for all recipients or for selected recipients in ALDLT. In this retrospective study, 319 patients who underwent ALDLT from 2007 to 2016 were divided into 3 groups according to the necessity and results of PVP modulation: not indicated (n = 189), indicated and succeeded (n = 92), and indicated but failed (n = 38). Graft survival and associations with various clinical factors were investigated. PVP modulation was performed mainly by splenectomy to lower final PVP to ≤15 mm Hg. Successful PVP modulation improved prognosis to be equivalent to that of patients who did not need modulation, whereas failed modulation was associated with increased incidence of small-for-size syndrome (SFSS; P = 0.003) and early graft loss (EGL; P = 0.006). Among patients with failed modulation, donor age ≥ 45 years (hazard ratio [HR], 3.67; P = 0.02) and ABO incompatibility (HR, 3.90; P = 0.01) were independent risk factors for graft loss. Survival analysis showed that PVP > 15 mm Hg was related to poor prognosis in grafts from either ABO-incompatible or older donor age ≥ 45 years (P < 0.001), but it did not negatively affect grafts from ABO-compatible/identical and young donor age < 45 years (P = 0.27). In conclusion, intentional PVP modulation is not necessarily required in all recipients. Although grafts from both ABO-compatible/identical and young donors can tolerate PHT, lowering PVP to ≤15 mm Hg is a key to preventing SFSS and consequent EGL with grafts from either ABO-incompatible or older donors.

Pancreatic islet transplantation provides an effective treatment option for patients with type 1 diabetes (T1D) with intractable impaired awareness of hypoglycemia and severe hypoglycemic events. Currently, the primary goal of islet transplantation should be excellent glycemic control without severe hypoglycemia, rather than insulin independence. Islet transplant recipients were less likely to achieve insulin independence, whereas solid pancreas transplant recipients substantially had greater procedure‐related morbidity. Excellent therapeutic effects of islet transplantation as a result of accurate blood glucose level–reactive insulin secretion, which cannot be reproduced by current drug therapy, have been confirmed. Recent improvement of islet transplantation outcome has been achieved by refinement of the pancreatic islet isolation technique, improvement of islet engraftment method, and introduction of effective immunosuppressive therapy. A disadvantage of islet transplantation is that donors are essential, and donor shortage has become a hindrance to its development. With the development of alternative transplantation sites and new cell sources, including porcine islet cells and embryonic stem/induced pluripotent stem (ES/iPS)‐derived β cells, “On‐demand” and “Unlimited” cell therapy for T1D can be established.

In the neoadjuvant setting, gemcitabine and S-1 improved the negative surgical margin rate in BRPC patients, but it did not improve survival. Thus, neoadjuvant chemotherapy should be given to BRPC patients at an earlier stage.

Vascular endothelial growth factor (VEGF) reportedly has an important role in the progression of malignant neoplasms and has been reported to induce myeloid-derived suppressor cells (MDSCs) that appear in cancer and inflammation. In the present study, serum concentrations of VEGF were measured in patients with digestive system cancer and the correlations with nutritional damage, immune suppression and systemic inflammation were analyzed. A significant increase in VEGF serum levels was observed in patients with esophageal, gastric and colorectal cancers compared with healthy volunteers. Levels of VEGF were inversely correlated with the serum concentrations of albumin, prealbumin and retinol-binding protein. The serum concentrations of VEGF were inversely correlated with the production of interleukin (IL)-12 and correlated with MDSC counts. VEGF levels were also correlated with neutrophil and neutrophil/lymphocyte counts and inversely correlated with lymphocyte count. Serum VEGF levels were divided at a cutoff of 500 pg/ml, with levels of prealbumin and retinol-binding protein significantly decreased in patients with higher VEGF levels. The stimulation index and IL-12 production were significantly decreased in the group with higher VEGF levels and MDSC counts tended to be higher in this group. These results demonstrated that increased production of VEGF was correlated with systemic inflammation, nutritional impairment and the inhibition of cell-mediated immunity involving MDSCs.

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