Dual antiplatelet therapy inhibits neutrophil extracellular traps to reduce liver micrometastases of intrahepatic cholangiocarcinoma.

The involvement of neutrophil extracellular traps (NETs) in cancer metastasis is being clarified, but the relationship between intrahepatic cholangiocarcinoma (iCCA) and NETs remains unclear. The presence of NETs was verified by multiple fluorescence staining in clinically resected specimens of iCCA. Human neutrophils were co-cultured with iCCA cells to observe NET induction and changes in cellular characteristics. Binding of platelets to iCCA cells and its mechanism were also examined, and their effects on NETs were analyzed in vitro and in in vivo mouse models. NETs were present in the tumor periphery of resected iCCAs. NETs promoted the motility and migration ability of iCCA cells in vitro. Although iCCA cells alone had a weak NET-inducing ability, the binding of platelets to iCCA cells via P-selectin promoted NET induction. Based on these results, antiplatelet drugs were applied to these cocultures in vitro and inhibited the binding of platelets to iCCA cells and the induction of NETs. Fluorescently labeled iCCA cells were injected into the spleen of mice, resulting in the formation of liver micrometastases coexisting with platelets and NETs. These mice were treated with dual antiplatelet therapy (DAPT) consisting of aspirin and ticagrelor, which dramatically reduced micrometastases. These results suggest that potent antiplatelet therapy prevents micrometastases of iCCA cells by inhibiting platelet activation and NET production, and it may contribute to a novel therapeutic strategy.

[Clinical Outcome of Robot-Assisted Distal Pancreatectomy in Our Institutional Introduction].

We evaluated the clinical outcome and assessed the safety of robot-assisted distal pancreatectomy(RADP)of early 5 cases in our institutional introduction. We followed the guidelines for introduction of robot-assisted pancreatectomy proposed by Japanese Society of Endoscopic Surgery. Patients' characteristics were 2 men and 3 women, 45-79(median 52) years old, and 3 patients with neuroendocrine neoplasm, 1 with intraductal papillary neoplasm and 1 with mucinous cystic neoplasm. Spleen-preserving RADP was performed in 2 cases. Clinical outcomes of 5 cases underwent RADP were, operation time was 308-437(median 330)minutes, blood loss was 5-270(median 100)mL and none received transfusion. Postoperative pancreatic fistula and postoperative complication more than Grade Ⅲa(Clavien-Dindo classification)were none. Postoperative hospital stay was 7-11(median 8)days. RADP in our institution was safely introduced by following the proposal of guidelines.

Usefulness of Middle Colic Artery Transposition Technique for Hepatic Arterial Reconstruction in Conversion Surgery for an Initially Unresectable, Locally Advanced Pancreatic Cancer.

The outcomes of pancreatectomy with resection and reconstruction of the involved arteries for locally advanced pancreatic cancer following chemotherapy have improved in recent years. In pancreatic head cancers in which there is contact with the common and proper hepatic arteries, margin-negative resection requires pancreati-coduodenectomy, with the resection of these arteries and the restoration of hepatic arterial flow. Here, we describe a middle colic artery transposition technique in hepatic arterial reconstruction during pancreatoduo-denectomy for an initially unresectable locally advanced pancreatic cancer. This technique was effective and may provide a new option for hepatic artery reconstruction in such cases.

Extracellular vesicles shed from gastric cancer mediate protumor macrophage differentiation.

BACKGROUND: Peritoneal dissemination often develops in gastric cancer. Tumor-associated macrophages (TAMs) are present in the peritoneal cavity of gastric cancer patients with peritoneal dissemination, facilitating tumor progression. However, the mechanism by which macrophages differentiate into tumor-associated macrophages in the peritoneal cavity is not well understood. In this study, the interplay between gastric cancer-derived extracellular vesicles (EVs) and macrophages was investigated. METHODS: The association between macrophages and EVs in peritoneal ascitic fluid of gastric cancer patients, or from gastric cancer cell lines was examined, and their roles in differentiation of macrophages and potentiation of the malignancy of gastric cancer were further explored. RESULTS: Immunofluorescent assays of the ascitic fluid showed that M2 macrophages were predominant along with the cancer cells in the peritoneal cavity. EVs purified from gastric cancer cells, as well as malignant ascitic fluid, differentiated peripheral blood mononuclear cell-derived macrophages into the M2-like phenotype, which was demonstrated by their morphology and expression of CD163/206. The macrophages differentiated by gastric cancer-derived EVs promoted the migration ability of gastric cancer cells, and the EVs carried STAT3 protein. CONCLUSION: EVs derived from gastric cancer play a role by affecting macrophage phenotypes, suggesting that this may be a part of the underlying mechanism that forms the intraperitoneal cancer microenvironment.

Targeting neutrophil extracellular traps with thrombomodulin prevents pancreatic cancer metastasis.

Surgery is the only curative treatment option for pancreatic cancer, but patients often develop postoperative recurrence. Surgical invasiveness might be involved in the mechanism of recurrence. The associations among inflammation caused by surgery, neutrophils, and cancer metastasis were investigated. At first, neutrophil extracellular traps (NETs) were examined in clinical specimens, and NETs were observed around metastatic tumors. To explore how NETs were induced, neutrophils were cultured with pancreatic cancer or in cancer-conditioned medium. Neutrophils formed NETs when they were cultured with pancreatic cancer or even its conditioned medium. The effects of NETs on cancer cells were further investigated in vitro and in vivo. NETs induced the epithelial to mesenchymal transition in cancer cells and thereby promoted their migration and invasion. HMGB1 derived from NETs appeared to potentiate the malignancy of cancer cells. In a mouse model of liver metastasis with inflammation, NETs participated in the metastatic process by enhancing extravasation. Interestingly, thrombomodulin degraded HMGB1 and consequently inhibited the induction of NETs, thereby preventing pancreatic cancer metastasis to the liver. In conclusion, NETs interact reciprocally with pancreatic cancer cells, which play a pivotal role in inflammation-associated metastasis. Targeting NETs with thrombomodulin can be a novel strategy to improve the surgical outcome of pancreatic cancer patients.

Emergent cholecystectomy in patients on antithrombotic therapy.

The Tokyo Guidelines 2018 (TG18) recommend emergent cholecystectomy (EC) for acute cholecystitis. However, the number of patients on antithrombotic therapy (AT) has increased significantly, and no evidence has yet suggested that EC should be performed for acute cholecystitis in such patients. The aim of this study was to evaluate whether EC is as safe for patients on AT as for patients not on AT. We retrospectively analyzed patients who underwent EC from 2007 to 2018 at a single center. First, patients were divided into two groups according to the use of antithrombotic agents: AT; and no-AT. Second, the AT group was divided into three sub-groups according to the use of single antiplatelet therapy (SAPT), double antiplatelet therapy (DAPT), or anticoagulant with or without antiplatelet therapy (AC ± APT). We then evaluated outcomes of EC among all four groups. The primary outcome was 30- and 90- day mortality rate, and secondary outcomes were morbidity rate and surgical outcomes. A total of 478 patients were enrolled (AT, n = 123, no-AT, n = 355) patients. No differences in morbidity rate (6.5% vs. 3.7%, respectively; P = 0.203), 30-day mortality rate (1.6% vs. 1.4%, respectively; P = 1.0) or 90-day mortality rate (1.6% vs. 1.4%, respectively; P = 1.0) were evident between AT and no-AT groups. Between the no-AT and AC ± APT groups, a significant difference was seen in blood loss (10 mL vs. 114 mL, respectively; P = 0.017). Among the three AT sub-groups and the no-AT group, no differences were evident in morbidity rate (3.7% vs. 8.9% vs. 0% vs. 6.5%, respectively; P = 0.201) or 30-day mortality (1.4% vs. 0% vs. 0% vs. 4.3%, respectively; P = 0.351). No hemorrhagic or thrombotic morbidities were identified after EC in any group. In conclusion, EC for acute cholecystitis is as safe for patients on AT as for patients not on AT.

Recovery From Ropivacaine-Induced or Levobupivacaine-Induced Cardiac Arrest in Rats: Comparison of Lipid Emulsion Effects.

BACKGROUND: Lipid emulsion treatment appears to have application in the treatment of local anesthetic-induced cardiac arrest. To examine whether the efficacy of lipid resuscitation in the treatment of local anesthetic-induced cardiac arrest is affected by lipophilicity, the effects of lipid infusions were compared between levobupivacaine-induced (high lipophilicity) and ropivacaine-induced (lower lipophilicity) rat cardiac arrest model. METHODS: A total of 28 female Sprague-Dawley rats were anesthetized using sevoflurane, which subsequently underwent tracheostomy, followed by femoral artery and vein cannulation. Two hours after the discontinuation of sevoflurane, either levobupivacaine 0.2% (n = 14) or ropivacaine 0.2% (n = 14) was administered at a rate of 2 mg/kg/min to the awake rats. When the pulse pressure decreased to 0, the infusion of local anesthetic was discontinued, and treatment with chest compressions and ventilation with 100% oxygen were immediately initiated. The total doses of local anesthetics needed to trigger the first seizure and pulse pressure of 0 mm Hg were calculated. The 2 groups were each subdivided into a lipid emulsion group (n = 7) and a control group (n = 7). In the lipid emulsion group, 20% lipid emulsion was administered intravenously (5 mL/kg bolus plus continuous infusion of 0.5 mL/kg/min), while in the control group, the same volume of normal saline was administered. Chest compressions were discontinued when the rate-pressure product had increased by more than 20% of baseline. RESULTS: The cumulative doses of levobupivacaine and ropivacaine that produced seizures and 0 pulse pressure showed no significant difference. Mean arterial blood pressure (MAP) values were higher in the levobupivacaine group than in the ropivacaine group after resuscitation was initiated (P < .05). In levobupivacaine-induced cardiac arrest, heart rate and MAP values were higher in the lipid group than in the control group after starting resuscitation (P < .05); all rats in the lipid group achieved spontaneous circulation (rate-pressure product >20% baseline), while only 2 of 7 rats in the control group achieved spontaneous circulation at 10 minutes. In ropivacaine-induced cardiac arrest, there were no significant differences in heart rate and MAP between the lipid and control groups from the start of resuscitation to 10 minutes; spontaneous circulation returned in 6 of 7 lipid group rats, but in only 2 of 7 control group rats at 10 minutes. CONCLUSIONS: Lipid emulsion treatment was more effective for levobupivacaine-induced cardiac arrest than for ropivacaine-induced cardiac arrest. Although lipid therapy is also effective for ropivacaine-induced cardiac arrest, it takes more time than in levobupivacaine-induced cardiac arrest. This suggests that the lipophilicity of local anesthetics influences the efficacy of lipid infusion when treating cardiac arrest caused by these drugs.

Extra-Adrenal Retroperitoneal Paraganglioma with Extensive Duodenal Invasion and Inferior Vena Cava Tumor Thrombus.

We report a case of extra-adrenal retroperitoneal paraganglioma (RP) with extensive duodenal invasion and tumor thromboses both in the right testicular vein and in the inferior vena cava (IVC). Because there was rigid adherence between the RP and the abdominal aorta, pancreatoduodenectomy with replacement of the IVC and aorta was performed for complete surgical resection. In the present case, both the mode of progression of the RP and the surgical approach were extremely rare.