Abstract. Background Sepsis is a clinical syndrome of systemic inflammatory responses arising from an infectious process with a presumed or known focus (1, 2). Severe sepsis, defined as sepsis with acute organ dysfunction, is associated with high morbidity and mortality rates (3). Inflammation and coagulation play pivotal roles in the pathogenesis of sepsis (4, 5). Sepsis-induced multiple organ failure (MOF) has numerous causes, such as various types of shock, adult respiratory distress syndrome (ARDS), and disseminated intravascular coagulation (DIC) (6). Gando et al. (7) reported that DIC is frequently associated with systemic inflammatory response syndrome (SIRS; 83%) and that such patients have a high mortality rate (63%). Ogura et al. (4) evaluated coagulation activity, organ dysfunction, and SIRS in critically-ill patients with thrombocytopenia and examined the balance between coagulopathy and systemic inflammation. In critically-ill patients with thrombocytopenia, they found that coagulopathy and organ dysfunction progressed with a significant mutual correlation, depending on the increase in SIRS scores. Thus, SIRSassociated coagulopathy may play a critical role in inducing organ dysfunction after severe insult. 1051This article is freely accessible online.Correspondence to: Tomoharu Miyashita,
Background: Hepatic sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease, is a form of drug-induced liver injury, the initial morphological changes associated with which occur in liver sinusoidal endothelial cells (LSECs). Recombinant human soluble thrombomodulin (rTM) is reported to have anti-inflammatory and cytoprotective effects. Therefore, we investigated the ability of rTM to protect endothelial cells and enhance their functions in a monocrotaline (MCT)-induced model of SOS. Materials and Methods: Human umbilical vein endothelial cells were assessed in vitro following administration of MCT (2-4 mM) with/without rTM (10-100 ng/ml) to investigate the effect of rTM on cell proliferation and apoptosis. In vivo experiments were performed with Crl:CD1 mice divided into three groups: rTM (rTM + MCT), placebo (control diluent + MCT), and control (control diluent only). LSECs [cluster of differentiation (CD) 31+CD34+ vascular endothelial growth factor receptor 3 (VEGFR3)+ cells] from these mice were identified using fluorescence-activated cell sorting and assessed by quantitative real-time polymerase chain reaction (qPCR). Results: In vitro, caspase-3 and -7 activities were significantly lower and cell viability (as assessed by MTT assays) significantly higher in the rTM group than in the placebo group. Moreover, levels of p-AKT increased upon rTM administration. In vivo, damage to LSECs in zone 3 of the hepatic acinus was attenuated and the number of LSECs were maintained in the rTM group, in contrast to the placebo group. Furthermore, expression of Nos3 (encoding endothelial nitric oxide synthase) was higher and that of plasminogen activator inhibitor 1 (Pai1) lower in LSECs from mice in the rTM group than in those from the placebo group. Conclusion: rTM can attenuate SOS by protecting LSECs and enhancing their functions.
The effectiveness of preoperative (neoadjuvant) chemotherapy (NAC) for resectable pancreatic ductal adenocarcinoma (PDAC) remains unclear. The present study retrospectively evaluated the efficacy of NAC with gemcitabine (GEM)-based regimens or GEM monotherapy for resectable PDAC. Between 2006 and 2015, NAC with GEM was performed in 52 cases (head 31, and body and tail 21) and compared with 34 resection-only cases serving as controls (head 20, and body and tail 14). According to the Response Evaluation Criteria In Solid Tumors guidelines, the treatment effect was a partial response in 5 cases, stable disease in 45 cases, and progressive disease in 2 cases. Maximum standardized uptake values and carbohydrate antigen (CA19-9) values were significantly reduced after preoperative chemotherapy. Using the Evans grading system, the treatment effect was grade I in 31 patients, grade IIa in 8, and grade IIb in 3 cases. There were significant differences in the overall survival rate between the NAC and control groups, only in the patients with node-positive pancreatic head cancer. Significantly higher CA19-9 values in peripheral blood and higher lymph node metastasis and plexus invasion rates were observed in early-recurring cases within a year. The preoperative CA 19-9 cutoff value as an early recurrence risk factor was calculated as 30 U/ml in the NAC group and 88 U/ml in the control group. NAC with GEM prolonged survival in patients with node-positive pancreatic head cancer. High CA19-9 values before operation, lymph node metastases and plexus invasion were risk factors for early tumor recurrence after surgery. Preoperative chemotherapy would be necessary for resectable pancreatic head cancer as lymph node metastasis was observed in >60% with resectable PDAC. Moreover, if normalization of CA19-9 values is not achieved with NAC, extension of preoperative chemotherapy should be considered as for borderline resectable PDAC cases.
Cancer stem cells (CSCs) have self-renewal and pluripotency capabilities and contribute to cancer progression and chemoresistance. It has been proposed that the treatment resistance and heterogeneity of CSCs are deeply involved in the prognosis of patients with esophageal squamous cell carcinoma (ESCC). The objective of this study was to identify the influence of the expression status of the CSC markers CD44 and CD133 on chemotherapeutic efficacy and prognosis in ESCC patients who underwent radical esophagectomy after neoadjuvant chemotherapy (NAC). Endoscopically biopsied specimens taken before NAC and surgically resected specimens after NAC were immunohistochemically assessed for CD44 and CD133 expression for 47 ESCC patients who underwent NAC followed by radical esophagectomy. The correlation between CD44 and CD133 expression status and clinicopathological findings and the prognosis of ESCC patients after NAC followed by esophagectomy were analyzed. The percentages of CD44-positive cells and CD133-positive cells in specimens were increased after NAC. CD44 and CD133 expression status before NAC did not correlate with the degree of tumor progression and had no impact on the chemotherapeutic effect. However, strong expression of CD44 or CD133 and a high proportion of CD133-expressing cells before NAC were significantly associated with poorer esophageal cancer-specific survival. Patients with strong expression of CD44 or CD133 and those with a high ratio of CD133-positive tumor cells showed significantly poor prognosis regardless of the effect of chemotherapy. Multivariate analysis showed that simultaneous strong expression of CD44 and CD133 before NAC, a high rate of CD133-positive tumor cells before NAC, and primary tumor remission assessed by preoperative endoscopy were significant independent prognostic factors for ESCC. Our data indicate that CD44 and CD133 expression status prior to treatment dictates the malignant potential of ESCC and may be a novel predictor of recurrence and prognosis of ESCC patients after treatment.
Abstract. Background: In this study, the effects of neoadjuvant chemotherapy (NAC) on cancer-associated fibroblasts (CAFs
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