High-mobility group box 1 fragment ameliorates chronic pancreatitis induced by caerulein in mice.

BACKGROUND: Chronic pancreatitis (CP) is a progressive disease characterized by pancreatic fibrosis for which effective treatment options are lacking. Mesenchymal stem cells (MSCs) have shown potential for fibrosis treatment but face limitations in clinical application. The high-mobility group box 1 (HMGB1) fragment mobilizes MSCs from bone marrow into the blood and has emerged as a promising therapeutic agent for tissue regeneration in various pathological conditions. The aim of this study was to investigate the potential therapeutic effects of systemic administration of the HMGB1 fragment in a mouse model of CP. METHODS: A caerulein-induced CP mouse model was used, and the HMGB1 fragment was administered by tail vein injection. Parameters such as body weight, pancreatic tissue damage, fibrosis, inflammatory cytokine expression, and collagen-related gene expression were evaluated using various assays, including immunohistochemistry, real-time PCR, serum analysis, and single-cell transcriptome analysis. And the migration of MSCs to the pancreas was evaluated using the parabiosis model. RESULTS: Administration of the HMGB1 fragment was associated with significant improvements in pancreatic tissue damage and fibrosis. It suppressed the expression of inflammatory cytokines and activated platelet-derived growth factor receptor-α+ MSCs, leading to their accumulation in the pancreas. The HMGB1 fragment also shifted gene expression patterns associated with pancreatic fibrosis toward those of the normal pancreas. Systemic administration of the HMGB1 fragment demonstrated therapeutic efficacy in attenuating pancreatic tissue damage and fibrosis in a CP mouse model. CONCLUSION: These findings highlight the potential of the HMGB1 fragment as a therapeutic target for the treatment of CP.

Application of a laparoscopic device for cell-derived sheet transplantation on the liver in a porcine model.

BACKGROUND: Cell-derived sheets are of global interest for regenerative therapy. Transplanting a sheet for abdominal organs requires a device for laparoscopic delivery to minimize invasiveness. Here, using a porcine model, we aimed to confirm the feasibility of a device developed to deliver sheets to the thoracic cavity in a laparoscopic transplantation procedure. MATERIAL AND METHODS: We used the device to transplant human skeletal myoblast cell sheets onto the liver and measured extra-corporeal, intra-abdominal, and total procedure times for sheet transplantation. Tissues, including the liver and the sheet, were collected two days after transplantation and analyzed histologically. RESULTS: In all experiments (n = 27), all sheets were successfully placed at target locations. The mean (± standard deviation) extra-corporeal, intra-abdominal, and total procedure times were 44 ± 29, 33 ± 12, and 77 ± 36 s, respectively. We found no difference between the two surgeons in procedure times. Histological analyses showed no liver damage with the transplantation and that sheets were transplanted closely onto the liver tissue without gaps. CONCLUSION: We confirmed the feasibility of a simple universal device to transplant cell-derived sheets via laparoscopic surgery. This device could support a minimally invasive procedure for sheet transplantation.

Influence of Percutaneous Transhepatic Gallbladder Aspiration and Drainage for Severe Acute Cholecystitis on the Surgical Outcomes of Subsequent Laparoscopic Cholecystectomy: Post Hoc Analysis of the CSGO-HBP-017 (CSGO-HBP-017C).

OBJECTIVE: Percutaneous transhepatic gallbladder aspiration (PTGBA) and/or drainage (PTGBD) are useful approaches in the management of acute cholecystitis in patients who cannot tolerate surgery because of poor general condition or severe inflammation. However, reports regarding its effect on the surgical outcomes of subsequent laparoscopic cholecystectomy (LC) are sparse. The aim of this retrospective study was to investigate the influence of PTGBA on surgical outcomes of subsequent LC by comparing the only-PTGBA group, including patients who did not need the additional-PTGBD, versus the additional-PTGBD group, including those who needed the additional-PTGBD after PTGBA. PATIENTS AND METHODS: We conducted a post hoc analysis of our multi-institutional data. This study included 63 patients who underwent LC after PTGBA, and we compared the surgical outcomes between the only-PTGBA group (n = 56) and the additional-PTGBD group (n = 7). RESULTS: No postoperative complications occurred among the 63 patients, and the postoperative hospital stay was 11 ± 12 days. Fourteen patients (22.2%) had a recurrence of cholecystitis, of whom 7 patients (11.1%) needed the additional-PTGBD after PTGBA. Significantly longer operative time (245 ± 74 vs 159 ± 65 min, P = 0.0017) and postoperative hospital stay (22 ± 27 vs 10 ± 9 d, P = 0.0118) and greater intraoperative blood loss (279 ± 385 vs 70 ± 208 mL, P = 0.0283) were observed among patients in the additional-PTGBD group compared with the only-PTGBA group, whereas the rates of postoperative complications (Clavien-Dindo grade ≥3: 0% each) and conversion to open surgery (28.6% vs 8.9%, P = 0.1705) were comparable. CONCLUSION: PTGBA for acute cholecystitis could result in good surgical outcomes of subsequent LC, especially regarding postoperative complications. However, we should keep in mind that the additional-PTGBD after PTGBA failure, which sometimes happened, would be associated with increased operative difficulty and longer recovery.

Investigation of the variation of vessels around the pancreatic head based on the first jejunal vein anatomy at pancreaticoduodenectomy.

PURPOSE: Pancreaticoduodenectomy (PD) for pancreatic cancer carries a high risk of massive intraoperative blood loss. The artery first approach (AFA) prevents blood loss during PD, but the optimal approach is unclear. The first jejunal vein (FJV) often comprises multiple veins and broadly supports venous drainage of the proximal jejunum. Its ligation carries a risk of proximal jejunum congestion. Here we investigated the anatomical characteristics of PD-associated vessels and AFA approach selection based on FJV anatomy. METHODS: This study included 148 Japanese living donors for liver transplantation. We reviewed their computed tomography images and assessed the anatomical pattern of PD-associated vessels in terms of FJV anatomy. RESULTS: The FJV traveled posterior to the superior mesenteric artery in 128 patients (86.5%, dorsal group) and anterior in 20 (13.5%, ventral group). The predominant draining vein of the inferior pancreaticoduodenal vein was the superior mesenteric vein in the ventral group (87.5%) and the FJV in the dorsal group (97.9%). Compared with the dorsal group, the ventral group had a significantly greater percentage with the superior mesenteric vein ventral to the superior mesenteric artery (30.0% versus 10.9%) and a significantly larger posterior superior pancreaticoduodenal vein diameter (3.2 ± 0.9 versus 2.7 ± 0.6 mm, p = 0.0029). These results were validated in patients with pancreatic head cancer. CONCLUSIONS: The anatomical characteristics of PD-associated vessels differed significantly between groups defined by FJV anatomy. Understanding the venous anatomy, especially the FJV, could support selection of the best approach in AFA for PD.

Impact of Cytomegalovirus Infection and Disease on Graft Loss After Pancreas Transplantation: A Single-Institution Study in Japan.

BACKGROUND: Cytomegalovirus (CMV) is one of the most frequent infections after pancreas transplantation (PTx), and it is unclear whether CMV infection is associated with pancreas graft loss. A limited number of studies about the relationship between CMV infection and pancreas graft loss have been reported from Western countries, but there have been no reports from Japan. This study investigated the relationship between CMV infection and pancreas graft loss after PTx in a single Japanese institution. METHODS: This study included 58 patients who underwent PTx from deceased donors from April 2000 to March 2021 in our institution. We assessed pancreas graft loss based on CMV infection and disease and investigated the causes of graft loss, the time of onset of CMV disease, and the time of graft loss for each case. RESULTS: The numbers of patients in the 4 categories of donor (D) and recipient (R) pretransplant anti-CMV antibody status were as follows: 4 (6.9%) in the D-/R- group, 6 (10.3%) in the D-/R+ group, 34 (58.6%) in the D+/R+ group, and 14 (24.1%) in the D+/R- group. Of the 58 patients, 74.1% and 44.1% received diagnoses of CMV infection and disease after PTx, respectively. There were no significant differences in the survival rates of pancreas graft loss stratified by CMV infection (P = .1809) or disease (P = .6241). CONCLUSIONS: This study suggests that CMV infection and disease had no significant influence on pancreas graft loss in this Japanese institution.

Efficacy of Autologous Skeletal Myoblast Cell Sheet Transplantation for Liver Regeneration in Liver Failure.

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.

Change Impact of Body Composition During Neoadjuvant Chemoradiotherapy in Patients with Resectable and Borderline Resectable Pancreatic Ductal Adenocarcinoma Undergoing Pancreatectomy.

BACKGROUND: The change impact of body composition during neoadjuvant therapy on clinical outcomes in patients with pancreatic ductal adenocarcinoma (PDAC) remains unclear. The aim of this study was to investigate the association between changes in body composition during neoadjuvant chemoradiotherapy (NACRT) and postoperative outcomes in patients with PDAC undergoing pancreatectomy, using three-dimensional images. METHODS: We reviewed 66 consecutive patients with resectable/borderline resectable PDAC receiving gemcitabine and S-1 with radiotherapy between April 2010 and June 2016. Body compositions were evaluated pre- and post-NACRT. All patients were hospitalized and supplied with regulated diet during NACRT treatment. RESULTS: Psoas major muscle volume index (PMI), abdominal fat volume index, and visceral fat volume index decreased significantly after NACRT (P < 0.0001, P < 0.0001, P < 0.0001, respectively). The post-NACRT CA19-9 level decreased significantly in the small-PMI-decrease group compared with the large-PMI-decrease group (P = 0.046). Recurrence-free survival (RFS) and overall survival (OS) of the large-PMI-decrease group were significantly poorer than those of the small-PMI-decrease group (P = 0.002, P = 0.006, respectively). On the other hand, there were no significant differences in RFS and OS between groups with high and low PMI, at the point of either pre-NACRT (P = 0.117, P = 0.123, respectively) or post-NACRT (P = 0.065, P = 0.064, respectively). Multivariate analysis identified a large percentage decrease in PMI as an independent risk factor for recurrence and death (P = 0.003, P = 0.002, respectively). CONCLUSIONS: Loss of skeletal muscle mass during NACRT was an independent risk factor for survival in patients with PDAC.

Preoperative neutrophil-to-lymphocyte ratio predicts healing time for postoperative pancreatic fistula after distal pancreatectomy.

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.

Three-dimensional Vascularized ß-cell Spheroid Tissue Derived From Human Induced Pluripotent Stem Cells for Subcutaneous Islet Transplantation in a Mouse Model of Type 1 Diabetes.

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 ß-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 ß-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 ß-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 ß-cells (hiPS ß cells). The function of insulin secretion of the vascularized hiPS ß-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 ß-cell spheroid tissue exhibited enhanced insulin secretion. The vascularized hiPS ß-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 ß-cell spheroid tissue. CONCLUSIONS: Vascularized hiPS ß-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.

Anti-Glypican-1 Antibody-drug Conjugate as Potential Therapy Against Tumor Cells and Tumor Vasculature for Glypican-1-Positive Cholangiocarcinoma.

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.

[Long-Term Survival in a Patient with Stage â £ Gastric Cancer Successfully Treated with Multidisplinary Treatment].

A man in his 60s who had epigastric pain was referred to our hospital and diagnosed with advanced type 3 gastric cancer with multiple liver metastases, cT4acN2cN1(H1), cStage Ⅳ(HER2 3+). He underwent chemotherapy using capecitabine, cisplatin(CDDP), and trastuzumab(T-mab)(XPT). After 7 courses of XPT and 23 courses of XT, liver metastases disappeared, and we decided to perform open distal gastrectomy, D2+ #18 lymphadenectomy, and Billroth Ⅰ reconstruction as a conversion surgery. Despite adjuvant chemotherapy with S-1 plus T-mab, multiple lymph nodes recurrence occurred 3 months after the surgery. He was found to be in complete remission as assessed by CT after 5 courses of second-line CPT-11 treatment, which was discontinued after 17 courses. The patient is alive without recurrence at 57 months after the initial treatment and 22 months after the last treatment.

[A Case of Epithelial Cyst Occurring in Intrapancreatic Accessory Spleen].

Although accessory spleens are often found in clinical practice, it is rare to identify cystic disease in an intrapancreatic accessory spleen. Here, we report a case of an epithelial cyst that occurred in the intrapancreatic accessory spleen. The patient was a 54-year-old male. Liver dysfunction was identified by the primary care doctor, and abdominal CT showed a tumorous lesion in the pancreatic tail. The patient was then referred to our hospital. Contrast-enhanced CT revealed a multilocular cystic lesion in the pancreatic tail. In endoscopic ultrasound, there was no obvious solid tumor in the cyst. A cystic disease such as serous cystic neoplasm(SCN)or mucinous cystic neoplasm(MCN)was suspected, and we performed a laparoscopic distal pancreatectomy. Postoperative pathological examination revealed an accessory spleen in the tail of the pancreas. The identified epithelial cyst was present in this accessory spleen. An epithelial cyst that occurs in the intrasplenic accessory spleen is a rare disease, but it is necessary to keep in mind as a possible differential diagnosis.

[Clinical Efficacy and Safety of Nab-Paclitaxel plus Ramucirumab Therapy in Patients with Unresectable Advanced or Recurrent Gastric Cancer].

We retrospectively evaluated the efficacy and feasibility of the combination of nab-paclitaxel plus ramucirumab(nab-PTX plus RAM)for the treatment of unresectable or recurrent gastric cancer. Sixteen patients received nab-PTX plus RAM. The overall response rate was 37.5%, and disease control rate was 87.5%. The median progression-free survival was 5.0 months. Grade 3 or higher adverse events(neutropenia: 62.5%, leukopenia: 18.8%, decrease appetite: 6.3%, hypertension: 6.3%, and proteinuria: 12.5%)were observed. Although dose reduction of nab-PTX was required in 93.8% of the patients, no adverse event that led to the discontinuation of treatment. Nab-PTX plus RAM combination therapy showed promising efficacy and manageable toxicities and could be a viable treatment option for patients with advanced gastric cancer.

[A Case of Robot-Assisted Abdominoperineal Resection for Local Control for Lower Rectal Cancer with Synchronous Liver and Lung Metastases].

The patient was a 70s woman who was referred to our hospital with a complaint of bloody stool. Colonoscopy revealed type 2 tumor at a distance of 1 cm from the dentate line, without obstruction. The pathological diagnosis was adenocarcinoma. Enhanced CT revealed a tumor at the rectum below peritoneal reflection as well as swelling of the mesorectal lymph nodes. Multiple liver and lung metastases were also observed. The diagnosis was lower rectal cancer cT4aN2M1b(H2, PUL2), cStage Ⅳ. Chemotherapy was performed for disease control because of unresectable metastases. She received 7 courses of mFOLFOX plus bevacizumab. Further, as the metastatic lesion was inhibited, the primary lesion was excised for the purpose of symptom control. We judged that sphincter preservation was impossible because it was 1 cm away from the dentate line. She underwent robot-assisted abdominoperineal resection with D3 lymphadenectomy and sigmoid colostomy.

[A Case of Peritoneal Recurrence of HCC Who Achieved Long-Term Survival after a Multidisciplinary Treatment].

The treatment for peritoneal dissemination of hepatocellular carcinoma(HCC)remains to be established. Therefore, peritoneal recurrence ofHCC has a poor prognosis. Here, we report a case ofperitoneal recurrence ofHCC after a liver resection. The patient underwent surgery for peritoneal recurrence 5 times already and had taken sorafenib for 3 years. No recurrence occurred for 55 months during the last follow-up. Therefore, multidisciplinary treatment for peritoneal recurrence of HCC, including surgical resection, may improve prognosis.

[A Case of Gastric Schwannoma with Regional Lymphadenopathy].

Schwannomas are rarely observed in the gastrointestinal tract. A 63-year-old man was referred to our hospital with gastric submucosal tumor with central ulceration by upper gastrointestinal endoscopy. Biopsy was performed, but pathological diagnosis was not obtained. A contrast-enhanced computed tomography scan of the abdomen revealed a round mass in the lower part of the stomach and regional lymphadenopathies. A distal gastrectomy with dissection of the regional lymph nodes (D2)was performed. The submucosal tumor measuring 67×49mm was resected. Histopathological examination revealed spindle-shaped cells arranged in palisades. The specimen was positive for S-100 protein, but negative for desmin, SMA, c-kit, and CD34. No tumor cells were found in the resected enlarged lymph nodes, indicating reactive lymphadenopathies. Based on these findings, the tumor was identified as a benign gastric schwannoma. Our patient shows no recurrence at 6 month follow-up.

[Adjuvant Chemotherapy for Hemophilia B - A Case Report].

A 80s-year-old man with hemophilia B underwent operation for rectal cancer.Metastasis of the lymph nodes was revealed, so he was treated with adjuvant chemotherapy involving capecitabine and oxaliplatin(CapeOX).For safety, we measured tissue factor IX before every course of chemotherapy, and he completed 8 courses safely.