Impact of radiological and pathological splenic vein involvement in patients with resectable pancreatic body or tail cancer.

PURPOSE: Several studies have reported a negative impact on survival associated with splenic vessel involvement, especially splenic artery (SpA) involvement, in patients diagnosed with pancreatic body or tail cancer. However, there is limited research on splenic vein (SpV) involvement. Therefore, we aimed to elucidate the significance of splenic vessel involvement, especially SpV involvement, in patients with resectable pancreatic body or tail cancer. METHODS: Between January 2007 and December 2021, 116 consecutive patients underwent distal pancreatectomies for pancreatic body or tail cancer. Among them, this study specifically examined 88 patients with resectable pancreatic body or tail cancer to elucidate prognostic factors using a multivariable Cox proportional analysis. The Kaplan-Meier method evaluated the impact of SpV involvement in terms of both radiological and pathological aspects and the efficacy of neoadjuvant therapy. RESULTS: Higher pre-operative carcinoembryonic antigen levels, larger tumour size, pathological SpV invasion, and non-completion of adjuvant therapy were identified as independent poor prognostic factors for overall survival (OS) and recurrence-free survival (RFS). Additionally, patients with radiological SpV encasement had significantly worse prognoses in terms of OS (p = 0.039) and RFS (p < 0.001). The sensitivity and specificity of multidetector-row computed tomography for detecting pathological SpV invasion were 81.0% and 61.2%, respectively. However, the prognostic impact of neoadjuvant therapy could not be determined, regardless of radiological SpV involvement. CONCLUSION: Radiological and pathological SpV involvement is a poor prognostic factor for patients with resectable pancreatic body or tail cancer. New innovative treatments and effective neoadjuvant therapy regimens are required for patients with SpV involvement.

A comparison of pancreatojejunostomy using the modified Blumgart anastomosis with or without a four-needle three-loop suture device and continuous sutures for duct-to-mucosa anastomosis in robotic pancreaticoduodenectomy.

PURPOSE: Despite descriptions of different pancreatojejunostomy procedures using robotic pancreaticoduodenectomy (RPD), a standardized procedure has not yet been established. No prior report has described pancreatojejunostomy by RPD combined with modified Blumgart anastomosis with continuous suturing for duct-to-mucosa anastomosis. This study investigated this surgical technique and evaluated the short-term outcomes of the simplified pancreatojejunostomy procedure. METHODS: Between December 2021 and March 2024, 36 patients underwent pancreatojejunostomy using modified Blumgart anastomosis with continuous suturing for duct-to-mucosa anastomosis using RPD. Patients were divided into an early group (n = 15), without the use of the new four-needle three-loop suture device during the modified Blumgart anastomosis and a late group (n = 21) that did use this device. RESULTS: The late group had a significantly shorter pancreatojejunostomy duration (60 min vs. 49 min, p = 0.004) than the early group. Both groups showed equivalent postoperative outcomes; however, the late group exhibited a trend toward a lower rate of postoperative pancreatic fistula grade ≥ B (26.7% vs. 4.8%, p = 0.138). CONCLUSIONS: Pancreatojejunostomy using modified Blumgart anastomosis with a four-needle three-loop suture device and continuous suture for duct-to-mucosa anastomosis in patients undergoing RPD is simple and effective. This new suturing device may further reduce the incidence of postoperative pancreatic fistulas.

Disulfide-HMGB1 signals through TLR4 and TLR9 to induce inflammatory macrophages capable of innate-adaptive crosstalk in human liver transplantation.

Ischemia-reperfusion injury (IRI) during orthotopic liver transplantation (OLT) contributes to graft rejection and poor clinical outcomes. The disulfide form of high mobility group box 1 (diS-HMGB1), an intracellular protein released during OLT-IRI, induces pro-inflammatory macrophages. How diS-HMGB1 differentiates human monocytes into macrophages capable of activating adaptive immunity remains unknown. We investigated if diS-HMGB1 binds toll-like receptor (TLR) 4 and TLR9 to differentiate monocytes into pro-inflammatory macrophages that activate adaptive immunity and promote graft injury and dysfunction. Assessment of 106 clinical liver tissue and longitudinal blood samples revealed that OLT recipients were more likely to experience IRI and graft dysfunction with increased diS-HMGB1 released during reperfusion. Increased diS-HMGB1 concentration also correlated with TLR4/TLR9 activation, polarization of monocytes into pro-inflammatory macrophages, and production of anti-donor antibodies. In vitro, healthy volunteer monocytes stimulated with purified diS-HMGB1 had increased inflammatory cytokine secretion, antigen presentation machinery, and reactive oxygen species production. TLR4 inhibition primarily impeded cytokine/chemokine and costimulatory molecule programs, whereas TLR9 inhibition decreased HLA-DR and reactive oxygen species production. diS-HMGB1-polarized macrophages also showed increased capacity to present antigens and activate T memory cells. In murine OLT, diS-HMGB1 treatment potentiated ischemia-reperfusion-mediated hepatocellular injury, accompanied by increased serum alanine transaminase levels. This translational study identifies the diS-HMGB1/TLR4/TLR9 axis as potential therapeutic targets in OLT-IRI recipients.

The Evolution of Redo Liver Transplantation Over 35 Years: Analysis of 654 Consecutive Adult Liver Retransplants at a Single Center.

OBJECTIVE: To examine liver retransplantation (ReLT) over 35 years at a single center. BACKGROUND: Despite the durability of liver transplantation (LT), graft failure affects up to 40% of LT recipients. METHODS: All adult ReLTs from 1984 to 2021 were analyzed. Comparisons were made between ReLTs in the pre versus post-model for end-stage liver disease (MELD) eras and between ReLTs and primary-LTs in the modern era. Multivariate analysis was used for prognostic modeling. RESULTS: Six hundred fifty-four ReLTs were performed in 590 recipients. There were 372 pre-MELD ReLTs and 282 post-MELD ReLTs. Of the ReLT recipients, 89% had one previous LT, whereas 11% had ≥2. Primary nonfunction was the most common indication in the pre-MELD era (33%) versus recurrent disease (24%) in the post-MELD era. Post-MELD ReLT recipients were older (53 vs 48, P = 0.001), had higher MELD scores (35 vs 31, P = 0.01), and had more comorbidities. However, post-MELD ReLT patients had superior 1, 5, and 10-year survival compared with pre-MELD ReLT (75%, 60%, and 43% vs 53%, 43%, and 35%, respectively, P < 0.001) and lower in-hospital mortality and rejection rates. Notably, in the post-MELD era, the MELD score did not affect survival. We identified the following risk factors for early mortality (≤12 months after ReLT): coronary artery disease, obesity, ventilatory support, older recipient age, and longer pre-ReLT hospital stay. CONCLUSIONS: This represents the largest single-center ReLT report to date. Despite the increased acuity and complexity of ReLT patients, post-MELD era outcomes have improved. With careful patient selection, these results support the efficacy and survival benefit of ReLT in an acuity-based allocation environment.

Spleen volume is a predictor of posthepatectomy liver failure and short-term mortality for hepatocellular carcinoma.

BACKGROUND: The study aimed at retrospectively assessing the impact of spleen volume (SpV) on the development of posthepatectomy liver failure (PHLF) in patients who underwent hepatectomy for hepatocellular carcinoma (HCC). METHODS: 152 patients with primary HCC who underwent hepatectomy (sectionectomy or more) were classified into PHLF and non-PHLF groups, and then the relationship between PHLF and SpV was assessed. SpV (cm3) was obtained from preoperative CT and standardized based on the patient's body surface area (BSA, m2). RESULTS: PHLF was observed in 39 (26%) of the 152 cases. SpV/BSA was significantly higher in the PHLF group, and the postoperative 1-year survival rate was significantly worse in the PHLF group than that in the non-PHLF group (p = 0.044). Multivariable analysis revealed SpV/BSA as a significant independent risk factor for PHLF. Using the cut-off value (160 cm3/m2), the 152 cases were divided into small SpV and large SpV groups. The incidence of PHLF was significantly higher in the large SpV group (p = 0.002), the liver failure-related mortality rate was also significantly higher in the large SpV group (p = 0.007), and the 1-year survival rate was significantly worse in the large SpV group (p = 0.035). CONCLUSION: These results suggest SpV as a predictor of PHLF and short-term mortality in patients who underwent hepatectomy for HCC. Moreover, SpV measurement is a simple and potentially useful method for predicting PHLF in patients with HCC.

Role of Serum Carcinoma Embryonic Antigen (CEA) Level in Localized Pancreatic Adenocarcinoma: CEA Level Before Operation is a Significant Prognostic Indicator in Patients With Locally Advanced Pancreatic Cancer Treated With Neoadjuvant Therapy Followed by Surgical Resection: A Retrospective Analysis.

OBJECTIVE: The aim of the study was to identify the prognostic factors before neoadjuvant chemoradiotherapy (NCRT) in the patients with localized PDAC. Furthermore, to identify the post-surgical survival predictors of patients with LAPC. SUMMARY OF BACKGROUND DATA: Surgical resection may occupy an important position in multimodal therapy for patients with LAPC; however, its indication and who obtains the true benefits, is still uncovered. MATERIALS AND METHOD: From 2005 to 2017, 319 patients with localized PDAC who underwent NCRT were reviewed. Only 159 patients were diagnosed with LAPC, of these 72 patients underwent surgical resection. We examined the pre-NCRT prognostic factors in the entire cohort and conducted further subgroup analysis for evaluating the post-surgical prognostic factors in LAPC patients under the pretext of favorable local tumor control. RESULTS: In the entire cohort, pre-NCRT CEA value was recognized as the most significant prognostic indicator by multivariate analysis. In the 72 LAPC patients who underwent surgical resection, only high CEA level was identified as an independent dismal prognostic factor before surgery. At the cut-off value: 7.2ng/mL, survival of the 15 patients whose CEA value >7.2 ng/mL was significantly unfavorable compared to those of 57 patients with <7.2 ng/mL: Median disease-specific survival time: 8.0 versus 24.0 months (P < 0.00001). Moreover, the median recurrence-free survival time of the high CEA group was only 5.4 months and there was no 1-year recurrence-free survivor. CONCLUSIONS: CEA before NCRT is a crucial prognostic indicator for localized PDAC. Moreover, LAPC with a high CEA level, especially more than 7.2 ng/mL, should still be recognized as a systemic disease, and we should be careful to decide the indication of surgery even if tumor local control seems to be durable.

A 3-Decade, Single-Center Experience of Liver Transplantation for Cholangiocarcinoma: Impact of Era, Tumor Size, Location, and Neoadjuvant Therapy.

Liver transplantation (LT) for cholangiocarcinoma (CCA) remains limited to a small number of centers. Although the role of neoadjuvant therapy (NAT) has been explored over time, an in-depth analysis of NAT strategies remains limited. Furthermore, controversy exists regarding acceptable tumor size during patient selection for LT. This study explores the impact of era, tumor size, and NAT strategy on LT outcomes for CCA. We conducted a retrospective review of 53 patients with CCA treated with LT from 1985 to 2019; 19 hilar CCA (hCCA) and 30 intrahepatic CCA (iCCA) were included. The relative contributions of varying NAT (neoadjuvant chemotherapy [NAC], neoadjuvant local therapy [NALT], and combined NAC and NALT [NACLT]) as well as the implication of tumor size and era were analyzed. The primary endpoint was overall survival (OS). Compared with the old era (1985-2007), 5-year OS in patients who underwent LT in the recent era (2008-2019) showed a superior trend. The 5-year OS from initial treatment in patients receiving NACLT for hCCA and iCCA were 88% and 100% versus 9% and 41% in patients without it, respectively (P = 0.01 for hCCA; P = 0.02 for iCCA), whereas NAC or NALT alone did not show significant differences in OS versus no NAT (P > 0.05). Although 33 patients had large-size tumors (hCCA ≥ 30 mm, n = 12, or iCCA ≥ 50 mm, n = 21), tumor size had no impact on survival outcomes. Outcomes of LT for CCA seem to have improved over time. Multimodal NAT is associated with improved survival in LT for both iCCA and hCCA regardless of tumor size.

The usefulness of modified splenic hilum hanging maneuver in laparoscopic splenectomy, especially for patients with huge spleen: a case-control study with propensity score matching.

BACKGROUND: Although Laparoscopic splenectomy (LS) have been proven to the standard operation for removal of spleen, the rate of conversion to open surgery is still higher than those of other laparoscopic surgeries, especially for huge spleen. In order to reduce the rate of conversion to open surgery, we had developed LS using modified splenic hilum hanging (MSHH) maneuver: the splenic pedicle was transected en bloc using a surgical stapler after hanging splenic hilum with an atraumatic penrose drain tube. METHODS: Between January 2005 and December 2019, we retrospectively assessed 94 patients who underwent LS. MSHH maneuver was performed in 37 patients (39.4%). We compared the intra- and postoperative outcomes between patients with or without MSHH maneuver. To adjust for differences in preoperative characteristics and blood examination, propensity score matching was used at a 1:1 ratio, resulting in a comparison of 29 patients per group. Predictive factors of conversion from LS to open surgery were elucidated using the uni- and multi-variate analyses. RESULTS: After the propensity score matching, blood loss (268 ml vs. 50 ml), the rate of conversion to open surgery (27.6% vs. 0%), and postoperative hospital stays (15 days vs. 10 days) were significantly decreased in patients with MSHH maneuver, respectively. Among 94 patients, 19 patients (20.2%) underwent conversion to open surgery. In multivariate analysis, spleen volume (SV) and LS without MSHH maneuver were independent predictive factors of conversion to open surgery, respectively. Additionally, cut-off value of SV for conversion to open surgery was 802 ml (sensitivity: 0.684, specificity: 0.827, p < 0.001). CONCLUSIONS: LS using MSHH maneuver seems to be useful surgical technique to improve intraoperative outcomes and reduce the rate of conversion from LS to open surgery resulting in shorten postoperative hospital stay.

The Impact of Dabigatran Treatment on Sinusoidal Protection Against Hepatic Ischemia/Reperfusion Injury in Mice.

Thrombin is a key player in the coagulation cascade, and it is attracting much attention as a promotor of cellular injured signaling. In ischemia/reperfusion injury (IRI), which is a severe complication of liver transplantation, thrombin may also promote tissue damage. The aim of this study is to reveal whether dabigatran, a direct thrombin inhibitor, can attenuate hepatic IRI with focusing on a protection of sinusoidal endothelial cells (SECs). Both clinical patients who underwent hepatectomy and in vivo mice model of 60-minute hepatic partial-warm IRII, thrombin generation was evaluated before and after IRI. In next study, IRI mice were treated with or without dabigatran. In addition, hepatic SECs and hepatocytes pretreated with or without dabigatran were incubated in hypoxia/reoxygenation (H-R) environment in vitro. Thrombin generation evaluated by thrombin-antithrombin complex (TAT) was significantly enhanced after IRI in the clinical study and in vivo study. Thrombin exacerbated lactate dehydrogenase cytotoxicity levels in a dose-dependent manner in vitro. In an IRI model of mice, dabigatran treatment significantly improved liver histological damage, induced sinusoidal protection, and provided both antiapoptotic and anti-inflammatory effects. Furthermore, dabigatran not only enhanced endogenous thrombomodulin (TM) but also reduced excessive serum high-mobility group box-1 (HMGB-1). In H-R models of SECs, not hepatocytes, pretreatment with dabigatran markedly attenuated H-R damage, enhanced TM expression in cell lysate, and decreased extracellular HMGB-1. The supernatant of SECs pretreated with dabigatran protected hepatocytes from H-R damage and cellular death. Thrombin exacerbated hepatic IRI, and excessive extracellular HMGB-1 caused severe inflammation-induced and apoptosis-induced liver damage. In this situation, dabigatran treatment improved vascular integrity via sinusoidal protection and degraded HMGB-1 by endogenous TM enhancement on SECs, greatly ameliorating hepatic IRI.

Clinical significance and predictors of complete or near-complete histological response to preoperative chemoradiotherapy in patients with localized pancreatic ductal adenocarcinoma.

BACKGROUND: The clinical value and predictors of a favorable histological response to preoperative chemoradiotherapy (CRT) in pancreatic ductal adenocarcinoma (PDAC) remains undefined. OBJECTIVE: To assess the significance and predictors of a favorable histological response to preoperative CRT in patients with localized PDAC. METHODS: The study included 203 patients with localized PDAC undergoing curative-intent resection after CRT. The rate of R0 resection and overall survival (OS) and recurrence-free survival (RFS) were correlated with the grading of histological response to determine optimal stratification. Clinical factors associated with a significant histological response were evaluated using multivariate regression analysis. RESULTS: Among all patients, eight patients (3.9%) had a grade 4 (pCR); 40 (19.4%) had a grade 3 estimated rate of residual neoplastic cells <10% (near-pCR); and 155 (76.7%) had a grade 1/2 limited response. The 48 patients with pCR/near-pCR achieved significantly higher R0 resection rate (100%) than those with grade 1/2 (80.0%). The 5-year OS and RFS rates were significantly higher in the patients with pCR/near-pCR (45.3% and 36.5%) than in those with grade 1/2 (27.1% and 18.5%). Gemcitabine plus S-1 based CRT, serum CA19-9 level after CRT <83 U/mL, and interval from initial treatment to surgery ≥4.4 months were independent predictive factors for pCR/near-pCR. CONCLUSIONS: pCR or near-pCR to preoperative CRT contributed to achieving a high rate of R0 resection and improving survival for localized PDAC. The use of gemcitabine plus S-1 as a radiosensitizer, lower serum CA19-9 level after CRT, and longer preoperative treatment duration were significantly associated with pCR or near-pCR.

Proximal subtotal pancreatectomy as an alternative to total pancreatectomy for malnourished patients.

PURPOSE: To investigate whether proximal subtotal pancreatectomy (PSTP) is superior to total pancreatectomy (TP) for preserving postoperative endocrine function, and to identify the pre-operative risk factors influencing prognosis after TP and PSTP. METHODS: The subjects of this retrospective study were patients who underwent TP (n = 15) or PSTP (n = 16) between 2008 and 2018 in our hospital. First, we compared the incidence of hypoglycemia within 30 days after surgery and the total daily amount of insulin needed in the 30 days after TP vs. PSTP. Then, we compared the prognoses between the groups. RESULTS: The incidence of hypoglycemia in the 30 days after surgery was significantly lower in the PSTP group than in the TP group (n = 0 vs. n = 5; p < 0.001). The total amount of daily insulin given was also significantly lower after PSTP than after TP: (0 units vs. 18 units, p = 0.001). Lower lymphocyte counts (p = 0.014), lower cholinesterase (p = 0.021), and lower prognostic nutrition index (p = 0.021) were identified as significant risk factors for hypoglycemia in the TP group. Low cholinesterase (p = 0.015) and a low prognostic nutrition index (p = 0.048) were significantly associated with an unfavorable prognosis in the TP group, but not in the PSTP group. CONCLUSIONS: PSTP may be a feasible alternative to TP to preserve endocrine function, especially for malnourished patients.

High tumor budding is a strong predictor of poor prognosis in the resected perihilar cholangiocarcinoma patients regardless of neoadjuvant therapy, showing survival similar to those without resection.

BACKGROUND: Tumor budding (TB) is used as an indicator of poor prognosis in various cancers. However, studies on TB in perihilar cholangiocarcinoma are still limited. We examined the significance of TB in resected perihilar cholangiocarcinoma with or without neoadjuvant therapy. METHODS: Seventy-eight patients who underwent surgical resection at our institution for perihilar cholangiocarcinoma from 2004 to 2017, (36 with neoadjuvant therapy), were enrolled in this study. TB was defined as an isolated cancer cell or clusters (< 5 cells) at the invasive front and the number of TB was counted using a 20 times objective lens. Patients were classified into two groups according to TB counts: low TB (TB < 5) and high TB (TB ≥5). RESULTS: In this 78 patient cohort, high TB was significantly associated with advanced tumor status (pT4: 50.0% vs 22.2%, p = 0.007, pN1/2: 70.8% vs 39.6%, p = 0.011, M1: 20.8% vs 1.9%) and higher histological grade (G3: 25.0% vs 5.7%, p = 0.014). Disease specific survival (DSS) in high TB was significantly inferior compared to that in low TB group (3-y DSS 14.5% vs 67.7%, p < 0.001). Interestingly, DSS in high TB showed similar to survival in unresected patients. In addition, high TB was also associated with advanced tumor status and poor prognosis in patients with neoadjuvant therapy. Multivariate analysis identified high TB as an independent poor prognostic factors for DSS (HR: 5.206, p = 0.001). CONCLUSION: This study demonstrated that high TB was strongly associated with advanced tumor status and poor prognosis in resected perihilar cholangiocarcinoma patients. High TB can be a novel poor prognostic factor in resected perihilar cholangiocarcinoma regardless of neoadjuvant therapy.

Prolonged operating time is a significant perioperative risk factor for arterial pseudoaneurysm formation and patient death following hemorrhage after pancreaticoduodenectomy.

BACKGROUND: Arterial pseudoaneurysm is a rare but potentially fatal complication after pancreaticoduodenectomy (PD). This study aimed to evaluate the incidence and predictors associated with pseudoaneurysm formation and patient death caused by its rupture. PATIENTS AND METHOD: We retrospectively reviewed the data of 453 patients who underwent PD from April 2007 to February 2019. Uni- and multivariate analysis and receiver operating characteristic (ROC) curve analysis were performed to identify risk factors and optimal cutoff values. RESULTS: Among the 453 patients, 22 (4.9%) developed pseudoaneurysm after PD. Median duration from surgery to detection of pseudoaneurysm was 17.0 (1-51) days. The locations of pseudoaneurysms were hepatic artery in 8, splenic artery in 3, gastroduodenal artery in 4, gastric artery in 2 and others in 5 patients, and 72.7% (16/22) of patients presented with hemorrhage. All pseudoaneurysms were treated using angioembolization. Lower age (<65.5 years, p = 0.004), prolonged operation time (Cutoff ˃610 min, p = 0.026) and postoperative pancreatic fistula (POPF) (p = 0.013) were the independent risk factors for development of pseudoaneurysm. 6 (27.3%) patients died due to rupture of pseudoaneurysm and prolonged operation time (Cutoff ˃657 min, p = 0.043) was a significant risk factor for death related to pseudoaneurysm. CONCLUSION: Prolonged operating time was identified as a risk factor for both pseudoaneurysm formation and patient death following pseudoaneurysm bleeding. Interventional radiology treatment offered a central role in the treatment of pseudoaneurysms after PD. Therefore, it is important to have a high index of suspicion in high risk patients of the possibility of pseudoaneurysm formation and bleeding.

Synthesis of a Crystalline and Transparent Aerogel Composed of Ni-Al Layered Double Hydroxide Nanoparticles through Crystallization from Amorphous Hydrogel.

Enormous efforts have been devoted to the development of crystalline aerogels toward heterogeneous catalysis, energy storage, ion/molecular absorption, and luminescence. However, properties of aerogels are not fully exploited due to their low content of functional moieties embedded in their solid networks, low crystallinity, and limited chemical compositions. Herein, we develop a one-pot approach based on crystallization from amorphous metal hydroxides modified with a ß-diketone ligand, toward crystalline transition-metal hydroxide aerogels. Synthesis of monolithic and crystalline aerogels of layered double hydroxide (LDH) was performed in a Ni-Al system starting from aqueous ethanol solutions of NiCl2·6H2O and AlCl3·6H2O with acetylacetone (acac) as an organic ligand. Propylene oxide (PO) as an alkalization reagent was added into precursory solutions to yield monolithic wet gels. The successive pH increase induces the formation of a three-dimensional (3-D) solid framework composed of amorphous Al(OH)3. Then, amphoteric Al(OH)3 undergoes crystallization into Ni-Al LDH via an acetylacetone-driven dissolution-crystallization of metal hydroxides without destroying the preformed 3-D solid framework. The process allows us to obtain crystalline aerogel monoliths with high porosity and high transparency after supercritical CO2 drying of wet gels. The present scheme can be expected to synthesize functionalized aerogel composed of crystalline transition-metal oxide/hydroxide nanobuilding blocks (NBBs).

Antiapoptotic Effect by PAR-1 Antagonist Protects Mouse Liver Against Ischemia-Reperfusion Injury.

BACKGROUND: Coagulation disturbances in several liver diseases lead to thrombin generation, which triggers intracellular injury via activation of protease-activated receptor-1 (PAR-1). Little is known about the thrombin/PAR-1 pathway in hepatic ischemia-reperfusion injury (IRI). The present study aimed to clarify whether a newly selective PAR-1 antagonist, vorapaxar, can attenuate liver damage caused by hepatic IRI, with a focus on apoptosis and the survival-signaling pathway. METHODS: A 60-min hepatic partial-warm IRI model was used to evaluate PAR-1 expression in vivo. Subsequently, IRI mice were treated with or without vorapaxar (with vehicle). In addition, hepatic sinusoidal endothelial cells (SECs) pretreated with or without vorapaxar (with vehicle) were incubated during hypoxia-reoxygenation in vitro. RESULTS: In naïve livers, PAR-1 was confirmed by immunohistochemistry and immunofluorescence analysis to be located on hepatic SECs, and IRI strongly enhanced PAR-1 expression. In IRI mice models, vorapaxar treatment significantly decreased serum transaminase levels, improved liver histological damage, reduced the number of apoptotic cells as evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling staining (median: 135 versus 25, P = 0.004), and induced extracellular signal-regulated kinase 1/2 (ERK 1/2) cell survival signaling (phospho-ERK/total ERK 1/2: 0.96 versus 5.34, P = 0.004). Pretreatment of SECs with vorapaxar significantly attenuated apoptosis and induced phosphorylation of ERK 1/2 in vitro (phospho-ERK/total ERK 1/2: 0.66 versus 3.04, P = 0.009). These changes were abolished by the addition of PD98059, the ERK 1/2 pathway inhibitor, before treatment with vorapaxar. CONCLUSIONS: The results of the present study revealed that hepatic IRI induces significant enhancement of PAR-1 expression on SECs, which may be associated with suppression of survival signaling pathways such as ERK 1/2, resulting in severe apoptosis-induced hepatic damage. Thus, the selective PAR-1 antagonist attenuates hepatic IRI through an antiapoptotic effect by the activation of survival-signaling pathways.

Protruded duodenal tumor arising from Santorini's duct of the pancreas: a rare case of intraductal papillary mucinous neoplasm mimicking a duodenal polypoid tumor.

BACKGROUND: We experienced a rare case of intraductal papillary mucinous neoplasm arising from Santorini's duct (SD) forming a tumor protruding into the duodenum . CASE PRESENTATION: A 71-year-old woman was incidentally diagnosed with a 3 cm type Isp polypoid tumor in the second portion of the duodenum at another hospital. Enhanced CT and endoscopic ultrasound revealed that the origin of this protruding tumor was arising from SD and that the tumor mimicked a pedunculated duodenal tumor. Our preoperative diagnosis was a malignant pancreatic tumor arising from SD with invasion into the duodenum. She underwent a subtotal stomach-preserving pancreaticoduodenectomy, and the resected specimen showed a 25 mm tumor protruding into the duodenum with a villous surface. The pathological findings revealed that the tumor was intraductal papillary mucinous adenoma (IPMA) arising from SD. CONCLUSIONS: To the best of our knowledge, this is the first case of IPMA protruding into the duodenal lumen from SD, although most of the tumors arising from SD have been reported to be malignant.

Pancreas-visceral fat CT value ratio and serrated pancreatic contour are strong predictors of postoperative pancreatic fistula after pancreaticojejunostomy.

BACKGROUND: Our aim is to elucidate the true preoperative risk factors for postoperative pancreatic fistula (POPF) after pancreaticoduodenectomy (PD), making it possible to select POPF high-risk patients preoperatively regardless of intraoperative pancreatic consistency judged by the surgeon's hand. METHODS: Among the 298 patients who underwent PD with pancreaticojejunostomy from 2007 to 2016, 262 patients had preoperative CT configurations that could be precisely evaluated. Risk factor analyses were conducted using various perioperative factors, including preoperative CT findings, such as CT values of the pancreas, pancreas-visceral fat CT value ratio and pancreatic outer contour. Pancreatic outer contour was further divided into smooth- (smooth interlobular) and serrated-type contours (feathery, irregular interlobular) by preoperative CT. RESULTS: In terms of the incidence of POPF, among the 262 patients, POPF grade B/C was found in 27 (10.3%): grade B in 23 (8.8%) and grade C in 4 (1.5%). According to multivariate analysis, a high pancreas-visceral fat CT value ratio (p = 0.002), serrated-type contour (p = 0.02) and no history of chemoradiotherapy (p = 0.019) were identified as independent risk factors for POPF grade B/C. Even in patients with soft pancreas, the incidence of POPF grade B/C was 0% (0/57) in patients with a pancreas-visceral fat CT value ratio of less than - 0.4 and smooth-type contour, whereas the incidence was markedly high (45.0%, 9/20) in patients with a pancreas-visceral fat CT value ratio of - 0.4 or greater and serrated-type contour, indicating that patients with soft pancreas should be categorized into POPF high-risk and low-risk groups according to preoperative CT scan results. CONCLUSIONS: The pancreas-visceral fat CT value ratio and serrated-type pancreas are useful markers to preoperatively identify true POPF high-risk groups in patients undergoing PD, regardless of the pancreatic texture judged intraoperatively.

Xa inhibitor edoxaban ameliorates hepatic ischemia-reperfusion injury via PAR-2-ERK 1/2 pathway.

Hepatic ischemia-reperfusion injury causes liver damage during surgery. In hepatic ischemia-reperfusion injury, the blood coagulation cascade is activated, causing microcirculatory incompetence and cellular injury. Coagulation factor Xa (FXa)- protease-activated receptor (PAR)-2 signaling activates inflammatory reactions and the cytoprotective effect of FXa inhibitor in several organs. However, no studies have elucidated the significance of FXa inhibition on hepatic ischemia-reperfusion injury. The present study elucidated the treatment effect of an FXa inhibitor, edoxaban, on hepatic ischemia-reperfusion injury, focusing on FXa-PAR-2 signaling. A 60 min hepatic partial-warm ischemia-reperfusion injury mouse model and a hypoxia-reoxygenation model of hepatic sinusoidal endothelial cells were used. Ischemia-reperfusion injury mice and hepatic sinusoidal endothelial cells were treated and pretreated, respectively with or without edoxaban. They were incubated during hypoxia/reoxygenation in vitro. Cell signaling was evaluated using the PAR-2 knockdown model. In ischemia-reperfusion injury mice, edoxaban treatment significantly attenuated fibrin deposition in the sinusoids and liver histological damage and resulted in both anti-inflammatory and antiapoptotic effects. Hepatic ischemia-reperfusion injury upregulated PAR-2 generation and enhanced extracellular signal-regulated kinase 1/2 (ERK 1/2) activation; however, edoxaban treatment reduced PAR-2 generation and suppressed ERK 1/2 activation in vivo. In the hypoxia/reoxygenation model of sinusoidal endothelial cells, hypoxia/reoxygenation stress increased FXa generation and induced cytotoxic effects. Edoxaban protected sinusoidal endothelial cells from hypoxia/reoxygenation stress and reduced ERK 1/2 activation. PAR-2 knockdown in the sinusoidal endothelial cells ameliorated hypoxia/reoxygenation stress-induced cytotoxicity and suppressed ERK 1/2 phosphorylation. Thus, edoxaban ameliorated hepatic ischemia-reperfusion injury in mice by protecting against micro-thrombosis in sinusoids and suppressing FXa-PAR-2-induced inflammation in the sinusoidal endothelial cells.

Peritoneal washing cytology status as a crucial prognostic determinant in patients with localized pancreatic ductal adenocarcinoma who underwent curative-intent resection following preoperative chemoradiotherapy.

BACKGROUND: Prognostic implications of peritoneal washing cytology (CY) in patients with localized pancreatic ductal adenocarcinoma (PDAC) undergoing surgical resection following preoperative chemoradiotherapy (CRT) remain unclear. This study aimed to elucidate the prognostic significance and predictors of a positive CY status (CY+) after preoperative CRT. METHODS: Clinical data from 141 patients with localized PDAC who underwent curative-intent resection after preoperative CRT were retrospectively analyzed to examine the association between CY+ and clinicopathological factors and survival. RESULTS: CY+ was observed in six patients (4.3%). The CY+ group exhibited significantly higher preoperative serum levels of CA19-9 and a substantially greater incidence of tumor location in the pancreatic body or tail, along with pathological invasion to the anterior pancreatic capsule, than the CY- group. The CY+ group had a significantly higher incidence of peritoneal recurrence compared with the CY- group (83.3% vs. 18.5%, p = 0.002). Overall survival (OS) and recurrence-free survival (RFS) after surgery were significantly shorter in the CY+ group than in the CY- group (CY+ vs. CY-: 18.3 vs. 46.2 months, p = 0.001, and 8.9 vs. 17.7 months, p = 0.009, respectively). Multivariate analyses identified CY+ as an independent prognostic factor for worse OS (hazard ratio 5.00, 95% confidence interval 1.03-12.31) and RFS (hazard ratio 2.58, 95% confidence interval 1.04-6.43). Local invasion grade on imaging before CRT, limited histological response to CRT, and absence of adjuvant chemotherapy were independent predictors of worse OS and RFS. CONCLUSION: Despite the relatively low incidence of CY+ after preoperative CRT, it emerged as an independent prognostic factor in patients with localized PDAC undergoing curative-intent resection following preoperative CRT.

Laparoscopic Warshaw procedure in pediatric solid pseudopapillary neoplasm of the pancreas: Technical feasibility and oncological outcomes.

Achieving margin-negative resection is crucial in treatment of solid pseudopapillary neoplasm (SPN) of the pancreas, while preserving the spleen during distal pancreatectomy is highly desirable in pediatric cases. Laparoscopic Warshaw procedure (Lap-WT) is invaluable when tumor involvement in splenic vessels complicates preservation. However, the feasibility of Lap-WT in pediatric patients remains contentious. This study presents the clinical outcomes of three pediatric SPN cases who underwent Lap-WT. The median age was 10 years, with a median tumor size of 50 mm. Lap-WT demonstrated successful outcomes with a median operation time of 311 min and blood loss of 12 mL. No postoperative complications occurred, with a median length of hospital stay of 8 days. Long-term follow-up showed mild thrombocytopenia and increased spleen volume in two cases, perigastric varices in one, with no bleeding complications. No instances of tumor recurrence were observed. Lap-WT emerges as a feasible approach for pediatric SPN, ensuring spleen preservation without compromising oncological outcomes.