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Background Use of neoadjuvant therapy for elderly patients with pancreatic cancer has been debatable. With FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, oxaliplatin) or gemcitabine plus nab-paclitaxel (GnP) showing tremendous effects in improving the overall survival of patients with borderline resectable and locally advanced pancreatic cancer, there is no definitive consensus regarding the use of this regimen in the elderly. Methods This study evaluated the eligibility of elderly patients with borderline resectable or locally advanced pancreatic cancer for neoadjuvant therapy. Patients registered in the database of pancreatic cancer at the University of Colorado Cancer Center, who underwent neoadjuvant treatment between January 2011 and March 2019, were separated into three age groups (less than 70, 70–74, 75 or more years) and respective treatment outcomes were compared. Results The study included 246 patients with pancreatic cancer who underwent neoadjuvant treatment, of whom 154 and 71 received chemotherapy with FOLFIRINOX and GnP respectively. Among these 225 patients, 155 were younger than 70 years, 36 were aged 70–74 years, and 34 were aged 75 years or older. Patients under 70 years old received FOLFIRINOX most frequently (124 of 155 versus 18 of 36 aged 70–74 years, and 12 of 34 aged 75 years or more; P Conclusion The safety and efficacy of multiagent chemotherapy in patients aged 75 years or over were similar to those in younger patients. Modern multiagent regimens could be a safe and viable treatment option for clinically fit patients aged at least 75 years.

The controlling nutritional status (CONUT) score has been reported to predict outcomes in patients with hepatocellular carcinoma (HCC). However, the prognostic significance of the CONUT score in patients with non-B non-C (NBNC) HCC remains to be established. The study comprised 246 patients who had undergone elective hepatic resection for HCC between April 2003 and October 2017. We retrospectively investigated the relation between preoperative CONUT score as well as clinicopathological characteristics and disease-free survival (DFS) as well as overall survival (OS). In univariate analyses, CONUT score was associated with DFS and OS in patients with NBNC-HCC (p ≤ 0.01), while there was no significant association of CONUT score with DFS and OS in patients with HBV- and HCV-related HCC (p ≥ 0.1). Of the 111 patients with NBNC-HCC, 97 (87.4%) had CONUT score ≤ 3 (low CONUT score) and the other 14 (12.6%) had CONUT score ≥ 4 (high CONUT score). In the patients with NBNC-HCC, multivariate analysis identified age ≥ 65 years (p = 0.03), multiple tumors (p < 0.01), and high CONUT score (p = 0.03) as the independent and significant predictors of DFS, while multiple tumors (p = 0.01), microvascular invasion (p < 0.01), and high CONUT score (p = 0.01) were the independent and significant predictors of OS. The CONUT score seems to be a reliable and independent predictor of both DFS and OS after hepatic resection for NBNC-HCC.

Remarkable progress has been made in treating pancreatic cancer over the past century, including refinement of our surgical techniques and improvements in adjuvant and neoadjuvant therapies. Despite these advances, the incidence of pancreatic cancer is rising globally, and it remains a deadly disease. In this review, we highlight the historical perspectives of pancreatic cancer treatment and outline the areas of future advancement that will assist progression towards better outcomes. Areas of future advancement include improving prevention strategies and early detection, refining our molecular understanding of pancreatic cancer, identifying more effective systemic therapies, and improving quality of life and surgical outcomes. Furthermore, systems need to be put in place to ensure all patients with pancreatic cancer receive high quality care and are given the appropriate options and sequence of therapy. This is best achieved through multidisciplinary care.

The recently identified G-protein-coupled receptor GPR171 and its ligand BigLEN are thought to regulate food uptake and anxiety. Though GPR171 is commonly used as a T cell signature gene in transcriptomic studies, its potential role in T cell immunity has not been explored. Here we show that GPR171 is transcribed in T cells and its protein expression is induced upon antigen stimulation. The neuropeptide ligand BigLEN interacts with GPR171 to suppress T cell receptor-mediated signalling pathways and to inhibit T cell proliferation. Loss of GPR171 in T cells leads to hyperactivity to antigen stimulation and GPR171 knockout mice exhibit enhanced antitumor immunity. Blockade of GPR171 signalling by an antagonist promotes antitumor T cell immunity and improves immune checkpoint blockade therapies. Together, our study identifies the GPR171/BigLEN axis as a T cell checkpoint pathway that can be modulated for cancer immunotherapy., Proliferative and effector functions of T cells are determined by T cell receptor signalling and modulated by activator and inhibitory co-receptors. Authors report here that the G-protein-coupled receptor GPR171 functions as a co-inhibitor of T cell signalling and might serve as a target for cancer immunotherapy.

Background/aim We aimed to assess surgical outcome and long-term survival after elective hepatic resection for hepatocellular carcinoma (HCC) and colorectal liver metastasis (CRLM) in patients aged 80 years or older. Patients and methods This study included 100 patients aged 70 years or older, who underwent hepatic resection for HCC or CRLM between January 2000 and December 2012. Outcomes and clinicopathological data were compared between the elderly (aged 70-79 years; n=84) and extremely elderly groups (aged 80 years or older; n=16). Results Incidence of postoperative complications, in-hospital mortality, and postoperative OS in the extremely elderly group were comparable with those of the elderly group. In patients with HCC, the extremely elderly group was associated with shorter DFS (p=0.030) in univariate analysis, while multivariate analysis showed significant and independent factors of cancer recurrence. Conclusion Hepatic resection for HCC and CRLM in patients aged 80 years and older may be safe and acceptable with appropriate selection. For HCC in patients aged 80 years and older, hepatic resection may be effective when negative surgical margins can be achieved.

Background Inflammation-based prognostic scores are associated with tumor recurrence and survival in various cancers. The aim of this study was to identify the significance of inflammation-based prognostic scores and to detect the most useful score in patients with distal extrahepatic bile duct cancer after pancreaticoduodenectomy. Methods Between 2000 and 2015, 121 patients were enrolled in this retrospective study. The relationship between clinicopathological variables including various prognostic scores and disease-free (DFS) as well as overall (OS) survival was investigated by univariate analysis. The area under the receiver operating characteristics curve was calculated to compare the predictive ability of each scoring system. Multivariate analysis was performed to identify the clinicopathological variables associated. Results In univariate analysis, Glasgow prognostic score (GPS), mGPS, C-reactive protein/Alb ratio score, prognostic index, and preoperative monocyte count were significant risk factors for both DFS and OS. The area under the receiver operating characteristics curve of GPS is consistently larger in comparison with other four scores in both DFS as well as OS. In multivariate analysis, GPS was an independent risk factor of both tumor recurrence and poor prognosis. Conclusions GPS score is an independent tumor recurrence and prognostic factor in patients with distal extrahepatic bile duct cancer and is superior to the other prognostic scores.

The benefit of preoperative biliary drainage for patients with operable periampullary cancers is controversial because biliary drainage would activate inflammatory response such as cholangitis. The aim of this study was to identify a novel prognostic score in patients with operable periampullary cancers including pancreatic cancer and extrahepatic distal bile duct cancer with a typical reference to preoperative biliary drainage and inflammatory status. Between 2000 and 2015, 246 patients were enrolled in this retrospective study. The patients were divided into four groups of the following three factors; the presence of preoperative biliary drainage, decreased serum albumin value ( 1.0 mg dl−1). The relationship between clinicopathological variables and disease-free survival (DFS) as well as over-all survival (OS) was investigated by univariate and multivariate analyses. To compare the sensitivity and specificity among the types of cancer, the area under the receiver operating characteristics curve (AUC) was evaluated in patients with pancreatic cancer and extrahepatic distal bile duct cancer. In multivariate analysis of DFS and OS, the novel prognostic factor combining preoperative biliary drainage and inflammatory status was an independent risk factor of tumor recurrence and prognosis as well as differentiation of the tumor and resected margin. The novel prognostic score combining preoperative biliary drainage and inflammatory status may be an independent predictor of tumor recurrence and prognosis in patients with periampullary cancers.

IgE-dependent/independent activation of mast cell (MC) has been assumed to play a host defensive role against venom injection in skin. However, its detailed mechanisms remain unknown. We aimed to investigate the contribution of MC-derived prostaglandin D2 (PGD2 )-mediated signaling in host defense against bee venom (BV). To achieve this, we utilized gene-deficient mice of a PGD2 receptor, chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). We first confirmed that subcutaneous injection of BV produced PGD2 equally in wild-type (WT) and CRTH2-deficient (Crth2-/- ) mice skins. The BV injection dropped body temperature and impaired kidney equally in both lines of mice. In WT mice, pre-injection of BV (3 weeks) significantly inhibited the hypothermia and kidney impairment caused by second BV injection. In contrast, this pre-injection was not effective for the second BV injection in Crth2-/- mice. We also found that BV injections increased serum BV-specific IgE levels in WT mice, and its serum transfused mice improved the BV-induced hypothermia in naive WT mice. In contrast, serum BV-specific IgE level was significantly lower in Crth2-/- mice. FACS analysis showed the BV injection stimulate migration of dendritic cells (DCs) into regional lymph nodes in WT mice. In Crth2-/- mice, its number was significantly smaller than that of WT mice. In conclusion, PGD2 /CRTH2 signaling plays defensive role against second BV injection. This signaling promotes BV-specific IgE production at least partially by promoting DCs migration into regional lymph node.

Owing to the poor prognosis of relapsed or refractory acute lymphoblastic leukemia (ALL), hematopoietic stem cell transplantation (HSCT) followed by effective salvage therapy is required. Inotuzumab ozogamicin (INO) was developed for ALL refractory to standard chemotherapy. However, previous reports suggest that sinusoidal obstruction syndrome (SOS) risk increases in patients with HSCT receiving INO, especially with dual alkylating agents. We report a case of relapsed Philadelphia chromosome-negative B-ALL where the patient underwent haploidentical HSCT using fludarabine/total body irradiation conditioning and posttransplant cyclophosphamide. Successful engraftment was achieved without SOS development.

The superiority of outcomes associated with anatomical resection (AR) versus those associated with non-anatomical resection (NAR) remains controversial in patients with hepatocellular carcinoma (HCC). The aim of this study was to evaluate the significance of AR on therapeutic outcomes of patients with small HCCs (≤ 5 cm), using propensity score–matched (PSM) analysis. A total of 195 patients who had undergone elective hepatic resection for small HCCs (≤ 5 cm) were included in this study. We conducted PSM analysis for baseline characteristics (age, sex, hepatitis virus status, retention rate of indocyanine green at 15 min, and Child-Pugh grade), preoperative serum α-fetoprotein, and tumor characteristics (tumor size, tumor number, portal vein invasion, and surgical margin status) to eliminate potential selection bias. The prognostic significance of AR on the disease-free and overall survival was analyzed in patients selected by PSM analysis. Applying PSM analysis, the patients were divided into PSM-AR (N = 66) and PSM-NAR (N = 66) groups. Disease-free survival was significantly better in the PSM-AR group than that of the PSM-NAR group (P = 0.018), while there was no significant difference in the overall survival between the PSM-AR and PSM-NAR groups (P = 0.292). The univariate HRs of the PSM-AR group were 0.55 (95% CI, 0.33–0.90) for disease-free survival and 0.61 (95% CI, 0.24–1.53) for overall survival, respectively. Remnant liver recurrence was significantly lower in the AR group (P = 0.014). AR may improve the disease-free survival in HCC patients with tumors of ≤5 cm diameter.

Treatment options for liver metastases (primarily colorectal cancer) are limited by high recurrence rates and persistent tumor progression. Surgical approaches to management of these metastases typically use heat energy including electrocautery, argon beam coagulation, thermal ablation of surgical margins for hemostasis, and preemptive thermal ablation to prevent bleeding or to effect tumor destruction. Based on high rates of local recurrence, these studies assess whether local effects of hepatic thermal injury (HTI) might contribute to poor outcomes by promoting a hepatic microenvironment favorable for tumor engraftment or progression due to induction of procancer cytokines and deleterious immune infiltrates at the site of thermal injury. To test this hypothesis, an immunocompetent mouse model was developed wherein HTI was combined with concomitant intrasplenic injection of cells from a well-characterized MC38 colon carcinoma cell line. In this model, HTI resulted in a significant increase in engraftment and progression of MC38 tumors at the site of thermal injury. Furthermore, there were local increases in expression of messenger ribonucleic acid (mRNA) for hypoxia-inducible factor-1α (HIF1α), arginase-1, and vascular endothelial growth factor α and activation changes in recruited macrophages at the HTI site but not in untreated liver tissue. Inhibition of HIF1α following HTI significantly reduced discreet hepatic tumor development (P = 0.03). Taken together, these findings demonstrate that HTI creates a favorable local environment that is associated with protumorigenic activation of macrophages and implantation of circulating tumors. Discrete targeting of HIF1α signaling or inhibiting macrophages offers potential strategies for improving the outcome of surgical management of hepatic metastases where HTI is used.

Objective We conducted an analysis using the Quick Environmental Exposure Sensitivity Inventory to examine the correlation between multiple chemical sensitivity (MCS) and personality traits by using temperament and character inventory, and environmental exposures. Methods An anonymous questionnaire was distributed to 667 employees working at an IT manufacturing plant in Japan. Variables including chemically sensitive population (CSP), personality, and environmental chemical exposure were individually evaluated using U-test, chi-squared test, and correlation analyses. We also did covariance structure analysis to build a structural equation model. Results There was little direct impact of temperament on the CSP, while there was a significant impact of character on the CSP. Women were more likely to exhibit symptoms of CSP. Conclusion MCS is correlated with personality, impacted more by character acquired later in life than innate temperament. There were sex differences in the incidence of MCS.

The immature and dysfunctional vascular network within solid tumors poses a substantial obstacle to immunotherapy because it creates a hypoxic tumor microenvironment that actively limits immune cell infiltration. The molecular basis underpinning this vascular dysfunction is not fully understood. Using genome-scale receptor array technology, we showed here that insulin-like growth factor binding protein 7 (IGFBP7) interacts with its receptor CD93, and we subsequently demonstrated that this interaction contributes to abnormal tumor vasculature. Both CD93 and IGFBP7 were up-regulated in tumor-associated endothelial cells. IGFBP7 interacted with CD93 via a domain different from multimerin-2, the known ligand for CD93. In two mouse tumor models, blockade of the CD93/IGFBP7 interaction by monoclonal antibodies promoted vascular maturation to reduce leakage, leading to reduced tumor hypoxia and increased tumor perfusion. CD93 blockade in mice increased drug delivery, resulting in an improved antitumor response to gemcitabine or fluorouracil. Blockade of the CD93 pathway triggered a substantial increase in intratumoral effector T cells, thereby sensitizing mouse tumors to immune checkpoint therapy. Last, analysis of samples from patients with cancer under anti-programmed death 1/programmed death-ligand 1 treatment revealed that overexpression of the IGFBP7/CD93 pathway was associated with poor response to therapy. Thus, our study identified a molecular interaction involved in tumor vascular dysfunction and revealed an approach to promote a favorable tumor microenvironment for therapeutic intervention.

Hematological diseases after solid organ transplant (SOT) are an emerging issue as the number of long-term SOT survivors increases. Expertise in managing patients requiring allogeneic hematopoietic stem cell transplantation (HSCT) after SOT from independent donors is needed; however, clinical reports of HSCT after SOT are limited, and the feasibility and risk are not well understood. In particular, HSCT in prior lung transplant recipients is thought to be complicated as the lung is immunologically distinct and is constantly exposed to the surrounding environment. Herein, we describe a case of successful HSCT in a patient with myelodysplastic syndromes who had previously received a lung transplant from a deceased donor for bronchiolitis obliterans syndrome. Reports about cases of HSCT after lung transplant are quite rare; thus, we discuss the mechanisms of immune tolerance through the clinical course of our case. This case suggests that HSCT after SOT can be considered a therapeutic option in cases where the transplanted organ is functionally retained and the hematological disease is in remission.

Background The preoperative systemic inflammation has been reported to predict tumor recurrence and survival in various cancers, including colorectal liver metastases (CRLM). However, more sensitive biomarker is required to improve perioperative management of CRLM. Therefore, we developed a novel indicator; C-reactive protein-to-lymphocyte ratio (CLR). The aim of this study is to evaluate the prognostic significance of CLR in patients with CRLM after hepatic resection. Materials and methods The study comprised 197 patients who had undergone hepatic resection for CRLM between January 2000 and December 2018. We retrospectively investigated the relation between CLR and disease-free survival and overall survival after hepatic resection and compared their prognostic significance with that of the C-reactive protein-to-albumin ratio and neutrophil-to-lymphocyte ratio. Results Optimal cutoff level of the CLR by receiver operating characteristics analysis was 62.8 × 10−6. By multivariate analysis, CLR was an independent predictor of disease-free survival [hazard ratio (HR): 1.463, 95% confidence interval (CI): 1.003-2.135, P = 0.048), whereas lymph node metastases>4 (HR: 1.804, 95% CI: 1.100-2.958, P = 0.019) and CLR (HR: 1.656, 95% CI: 1.007-2.724, P = 0.047) were independent predictors of overall survival, while the C-reactive protein-to-albumin ratio and neutrophil-to-lymphocyte ratio were not. Conclusions CLR may be an independent and significant indicator of poor long-term outcomes in patients with CRLM after hepatic resection.

Liver function in patients with hepatocellular carcinoma is generally graded according to the Child-Pugh system; however, some variables in the Child-Pugh grade are subjective. We developed a novel, objective score called the prothrombin time-international normalized ratio to albumin ratio. The aim of this study was to evaluate the prognostic value of this new score in patients with hepatocellular carcinoma after hepatic resection.The study comprised 199 patients who underwent elective hepatic resection for hepatocellular carcinoma between January 2003 and December 2014. We investigated retrospectively the relation between prothrombin time-international normalized ratio to albumin ratio, disease-free survival, and overall survival and compared the value of liver functional reserve between prothrombin time-international normalized ratio to albumin ratio and Child-Pugh grade.The optimal cut-off level of the prothrombin time-international normalized ratio to albumin ratio was 0.288. In multivariate analysis, the independent and significant predictors of cancer recurrence consisted of hepatitis C virus infection (P = .043), preoperative retention rate of indocyanine green at 15 minutes ≥15% (P = .039), the presence of multiple tumors (P = .001) or microvascular invasion (P.001), and prothrombin time-international normalized ratio to albumin ratio ≥0.288 (P = .022). The independent predictors of poor overall survival were microvascular invasion (P = .001) and prothrombin time-international normalized ratio to albumin ratio ≥0.288 (P = .001). In patients with a high prothrombin time-international normalized ratio to albumin ratio, pathologic liver cirrhosis (P.001), postoperative ascites (P = .039), and postoperative liver failure (P = .040) were greater than for their counterparts.The prothrombin time-international normalized ratio to albumin ratio may reflect liver function and may be a novel indicator of poor long-term outcome in patients with hepatocellular carcinoma after hepatic resection.

Introducing siRNA into human immune cells by an artificial delivery system continues to be a challenging issue. We previously developed a multifunctional envelope-type nanodevice (MEND) containing the YSK12-C4, a fusogenic cationic lipid, (YSK12-MEND) and succeeded in the efficient delivery of siRNA into human immune cell lines. Significant cytotoxicity, however, was observed at siRNA doses needed for gene silencing in NK-92 cells. NK-92 cells, a unique natural killer (NK) cell line, would be applicable for use in clinical NK therapy. Thus, reducing the cytotoxicity of the YSK12-MEND in NK-92 cells would strengthen the efficacy of NK-92 cell-based therapy. The amount of the YSK12-C4 in the MEND needed to be reduced to reduce the cytotoxicity, because the cytotoxicity was directly associated with the YSK12-C4. In the present study, we decreased the total amount of lipid, including the YSK12-C4, by introducing a core formed by electrostatic interactions of siRNA with a polycation (protamine) (siRNA core), which led to a decrease in cytotoxicity in NK-92 cells. We prepared a YSK12-MEND containing an siRNA core (YSK12-MEND/core) at charge ratios (CR: YSK12-C4/siRNA) of 10, 5, 3, and 2.5 and compared the YSK12-MEND/core with that for a YSK12-MEND (CR16.9). Cell viability was increased by more than 2 times at a CR5 or less. On the other hand, the YSK12-MEND/core (CR5) maintained the same gene silencing efficiency (60%) as the YSK12-MEND. Interestingly, the cellular uptake efficiency and hemolytic activity of the YSK12-MEND/core (CR5) was reduced compared to that for the YSK12-MEND. In calculating the silencing activity per cellular uptake efficiency and hemolytic activity, the value for the YSK12-MEND/core (CR5) was more than 2 times as high as that of the YSK12-MEND. The fact indicates that after endosomal escape, the process can be enhanced by using a YSK12-MEND/core (CR5). Thus, introducing an siRNA core into lipid nanoparticles can be a potent strategy for decreasing cytotoxicity without an appreciable loss of gene silencing activity in NK-92 cells.

Background The aim of this study is to investigate the association C-reactive protein to albumin (CRP/Alb) ratio, a novel inflammation based prognostic score, and long-term outcomes among patients with colorectal liver metastases (CRLM) after hepatic resection. Methods We retrospectively investigated 106 patients who underwent hepatic resection for CRLM and explored the relationship between CRP/Alb ratio and long-term outcomes. Results In multivariate analysis, more than 4 lymph node metastases ( p = 0.003), presence of neo-adjuvant chemotherapy ( p = 0.008) and CRP/Alb ratio ≥ 0.04 ( p = 0.021) were independent and significant predictors of cancer recurrence, while more than 4 lymph node metastases ( p = 0.001), presence of neo-adjuvant chemotherapy ( p p = 0.002) were independent and significant predictors of poor overall survival. Conclusions The CRP/Alb ratio seems to be a predictor of poor long-term outcomes in patients with CRLM after hepatic resection.

The anticoagulant effect of rivaroxaban, a direct inhibitor of activated factor X (FX), might be influenced by its dosing time because the activity of the coagulofibrinolytic system exhibits daily rhythmicity. In rats, FX activity follows a 24-h rhythm with a peak in the middle of the light phase and a trough at the beginning of the dark phase. Consistent with these findings, a single dose of rivaroxaban had a stronger inhibitory effect on FX activity after dosing at the beginning of the light phase than after dosing at the beginning of the dark phase. A similar chronopharmacological effect was seen in a quantitative model of venous stasis thrombosis. In comparison, the dosing time had minimal influence on the pharmacokinetics of rivaroxaban. These data indicate that the anticoagulant effect of rivaroxaban is influenced by the dosing time. Further studies should confirm this finding in a clinical setting.

Pancreatic cancer is often resistant to chemotherapy. We previously showed the efficacy of combination treatment using gemcitabine and nafamostat mesilate (FUT‐175) for patients with unresectable pancreatic cancer. However, the mechanisms that affect the sensitivity of FUT‐175 are not fully understood. The purpose of the present study was to clarify the mechanism of the sensitivity to FUT‐175, with a focus on the activity of glycogen synthase kinase‐3β (GSK‐3β). In vitro, we assessed sensitivity to FUT‐175 in human pancreatic cancer cell lines (PANC‐1 and MIAPaCa‐2) and difference of signaling in these cells by cell proliferation assay, Western blot analysis and microarray. Next, we assessed cell viability, apoptotic signal and nuclear factor‐kappa B (NF‐κB) activity in response to treatment with FUT‐175 alone and in combination with GSK‐3 inhibitor or protein phosphatase 2A (PP2A) by cell proliferation assay, Western blot analysis and enzyme‐linked immunosorbent assay. Phosphorylated GSK‐3β level was significantly higher in MIAPaCa‐2 (high sensitivity cell) than in PANC‐1 (low sensitivity cell). Cell viability and NF‐κB activity were significantly decreased by addition of GSK‐3 inhibitor to FUT‐175, and levels of cleaved caspase‐8 were increased by inhibition of GSK‐3. PP2A inhibitor increased the levels of phosphorylated GSK‐3β and sensitized both cell lines to FUT‐175 as measured by cell viability and apoptotic signal. The results indicate that GSK‐3β activity plays a key role in the antitumor effect of FUT‐175 in pancreatic cancer cells, and regulation of GSK‐3β by PP2A inhibition could be a novel therapeutic approach for pancreatic cancer.

Background The Barcelona Clinic Liver Cancer (BCLC) classification is the most widely used staging system for hepatocellular carcinoma (HCC), but its prognostic ability in patients after resection has not been yet validated. The aim of this study was to evaluate the BCLC classification among patients after resection. Methods The subjects were 196 patients who underwent hepatic resection for HCC between April 2003 and December 2014 at Jikei University Hospital. All patients were classified into a tumor stage according to the BCLC classification. Overall survival rate was calculated according to stages defined by the BCLC classification. Results Overall survival rates at 1, 3 and 5-year were 100%, 95.2% and 95.2% in BCLC 0, 96.7%, 90.0% and 78.4% in BCLC A solitary, 86.2%, 86.2% and 86.2% in BCLC A multiple, 100.0%, 78.8% and 78.8% in BCLC B and 86.5%, 63.3% and 57.6% in BCLC C, respectively. Postoperative complications and mortality rates in relation to BCLC stage were comparable. Conclusion The BCLC treatment algorithm should consider the role of resection also for multiple early, intermediate and advanced stages.

Although rare, second-generation antipsychotic drugs cause severe hyperglycemia within several days after the initiation of therapy. Because glucose tolerance exhibits circadian rhythmicity, we evaluated an effect of a dosing-time on quetiapine-induced acute hyperglycemia in mice. A single intraperitoneal dose of quetiapine dosing-time-independently induced insulin resistance in fasted C57BL/6J mice. However, acute hyperglycemic effect was detected only after dosing of the drug at the beginning of an active phase. Under the conditions in which hepatic glucose production was stimulated by pyruvate administration, hyperglycemic effect of quetiapine was dosing-time-independently observed. In addition, the dosing-time-dependent hyperglycemic effect of quetiapine disappeared in the liver-specific circadian clock-disrupted mice in which circadian rhythmicity in hepatic glucose production is deranged. Furthermore, the dosing-time had little impact on the pharmacokinetics of quetiapine in normal mice. These results suggest that quetiapine acutely causes hyperglycemia only when hepatic glucose production elevates. Therefore, quetiapine therapy with once daily dosing at a rest phase might be safer than that at an active phase. Further studies are needed to confirm the hypothesis.

BACKGROUND The aim of this study was to evaluate a novel prognostic value of preoperative platelet-to-albumin ratio (PAR) in patients resected for pancreatic cancer. PATIENTS AND METHODS A total of 107 patients who underwent pancreatic resection for pancreatic cancer were studied. The patients were divided into two groups as PAR ≥46.4×103 or

Post-transplant lymphoproliferative disorder (PTLD) is one of the most serious complications of allogeneic hematopoietic stem cell transplantation (HSCT). Rituximab is effective for PTLD; however, rituximab can produce adverse effects, including hypogammaglobulinemia. Here, we present the case of an 18-year-old female with refractory cytopenia of childhood who developed persistent selective hypogammaglobulinemia with low immunoglobulin G (IgG) 2 and IgG4 levels and monoclonal protein after rituximab therapy against probable PTLD. Despite B-cell recovery, the serum IgG levels gradually declined, reaching

The rapid rise in the prevalence of type 2 diabetes mellitus (T2DM) poses a huge healthcare burden across the world. Although there are several antihyperglycaemic agents (AHAs) available including addition of new drug classes to the treatment algorithm, more than 50% of patients with T2DM do not achieve glycaemic targets, suggesting an urgent need for treatment strategies focusing on prevention and progression of T2DM and its long‐term complications. Lifestyle changes including implementation of healthy diet and physical activity are cornerstones for the management of T2DM. The positive effects of diet and exercise on incretin hormones such as glucagon‐like peptide‐1 (GLP‐1) have been reported. We hypothesize an IDEP concept (Interaction between Diet/Exercise and Pharmacotherapy) aimed at modifying the diet and lifestyle, along with pharmacotherapy to enhance the GLP‐1 levels, would result in good glycaemic control in patients with T2DM. Consuming protein‐rich food, avoiding saturated fatty acids and making small changes in eating habits such as eating slowly with longer mastication time can have a positive impact on the GLP‐1 secretion and insulin levels. Further the type of physical activity (aerobic/resistance training), intensity of exercise, duration, time and frequency of exercise have shown to improve GLP‐1 levels. Apart from AHAs, a few antihypertensive drugs and lipid‐lowering drugs have also shown to increase endogenous GLP‐1 levels, however, due to quick degradation of GLP‐1 by dipeptidyl peptidase‐4 (DPP‐4) enzyme, treatment with DPP‐4 inhibitors would protect GLP‐1 from degradation and prolong its activity. Thus, IDEP concept can be a promising treatment strategy, which positively influences the GLP‐1 levels and provide additive benefits in terms of improving metabolic parameters in patients with T2DM and slowing the progression of T2DM and its associated complications.

BACKGROUND/AIM Prediction of local recurrence and distant metastasis is important for patients with pancreatic cancer following pancreatic resection. The aims of this study were to identify a novel prognostic score which combines distance from common hepatic artery (CHA) or superior mesenteric artery (SMA) and examine serum CA19-9 for predicting local recurrence in patients with pancreatic cancer following resection. PATIENTS AND METHODS This retrospective study comprised 149 patients who went through elective pancreatic resection for pancreatic cancer between June 2007 and December, 2017. We established new scores (CHA score and SMA score) using the distance between CHA or SMA and the tumor measured by preoperative CT scan in combination with preoperative serum CA19-9 values. We evaluated the relationship between the scores and local recurrence of pancreatic cancer. Finally, we investigated the relationship between the scores and local recurrence-free survival as well as the overall survival. RESULTS The optimal cut-off levels of the distance between CHA or SMA and the tumor, as determined by ROC analysis, were 20.55 and 10.9 mm, respectively. In a logistic progression model, demonstrated by multivariate analysis, lymphatic invasion (p=0.002), preoperative serum CA19-9 (p=0.007) and SMA score (p=0.004) were identified to be independent predictors of local recurrence in patients with pancreatic cancer following resection. In a Cox progression model, demonstrated by multivariate analysis, intraoperative blood loss (p=0.022), lymphatic invasion (p=0.001) and SMA score (p

Objectives Postoperative pancreatic fistula (POPF) is a life-threatening complication after pancreaticoduodenectomy (PD). The aim of this study is to evaluate the significance of pancreatic amylase level of pancreatic juice for PF after PD. Methods The subjects were 46 patients who underwent PD between January 2012 and August 2015 at Jikei University Hospital. We retrospectively investigated the relation between patient characteristics including pancreatic amylase level of pancreatic juice through the pancreatic drainage tube and the incidence of POPF (grade B or grade C according to the International Study Group on the Pancreatic Fistula) using univariate and multivariate analyses. The decline of pancreatic amylase level of pancreatic juice was evaluated by 1 - postoperative day 3/postoperative day 1 ratio. Results In univariate analysis, nonductal adenocarcinoma (P = 0.0252), soft pancreatic remnant (P = 0.0155), and decline of pancreatic amylase level of pancreatic juice ≥ 80% (P = 0.0010) were significant predictors of POPF. In multivariate analysis, decline of pancreatic amylase level of pancreatic juice of 80% or greater (P = 0.0192) was the only significant independent parameter. Conclusions Decline of pancreatic amylase level of pancreatic juice can predict POPF after PD.

Applying small interfering RNA (siRNA) to dendritic cell (DC) based therapy represents a potential candidate for cancer immunotherapy. However, delivering siRNA to DCs is a challenging issue for non-viral vectors. To date, only viral vectors have achieved efficient gene silencing in DCs. We report herein that a novel cationic lipid, YSK12-C4, when loaded in a nanoparticle with siRNA (YSK12-C4 multifunctional envelope type nano device [YSK12-MEND]), greatly facilitated gene silencing in mouse DCs. The use of the YSK12-MEND resulted in a gene silencing efficiency in excess of 90%, with a median effective dose (ED50) of 1.5 nM, whereas the maximum gene silencing efficiency of Lipofectamine RNAiMAX was less than 60% and the ED50 was 25 nM. Furthermore, suppressor of cytokine signaling 1, an immune suppressive molecule in DCs, silenced in the mouse DC by the YSK12-MEND showed a drastic enhancement in cytokine production, resulting in the significant suppression of tumor growth when it was applied to DC-based therapy against a mouse lymphoma. These results clearly indicate that YSK12-MEND overcomes the obstacle associated with non-viral vectors and can be considered to be a promising non-viral vector for siRNA delivery to DCs, thus accelerating DC-based therapies with siRNA. (C) 2016 Elsevier B.V. All rights reserved.

The C-reactive protein to albumin (CRP/Alb) ratio, a novel inflammation-based prognostic score, is associated with outcomes in septic patients. The prognostic value of CRP/Alb ratio has not been established in cancer patients. The aim of this study is to evaluate the significance of CRP/Alb ratio in therapeutic outcome after pancreatic resection for pancreatic cancer. The study comprised 113 patients who had undergone pancreatic resection for pancreatic cancer between April 2001 and December 2011. We retrospectively investigated the relation between CRP/Alb ratio and disease-free as well as overall survival. The optimal cut-off level of the CRP/Alb ratio was 0.03. For disease-free survival, preoperative biliary drainage (p = 0.011), advanced tumor-node-metastasis (TNM) classification (p = 0.002), and higher CRP/Alb ratio (p = 0.049) by univariate analysis, and advanced TNM classification (p = 0.003) by multivariate analysis, were independent and significant predictors of cancer recurrence. For overall survival, preoperative biliary drainage (p = 0.012), advanced TNM classification (p = 0.001), and higher CRP/Alb ratio (p = 0.023) by univariate analysis, and advanced TNM classification (p = 0.003) and higher CRP/Alb ratio (p = 0.035) by multivariate analysis, were independent and significant predictors of poor patient outcome. The CRP/Alb ratio may be an independent and significant indicator of poor long-term outcomes in patients with pancreatic cancer after pancreatic resection.

Objectives The objectives of this study were to assess the possibility of utilization of genetic testing and to determine the effect of participant characteristics on genetic testing awareness in Japanese workers. Methods The subjects of this study consisted of 998 workers from two companies located in Kyusyu, Japan, from June to July, 2014. We examined the participant characteristics and genetic testing awareness using paper questionnaires. Ultimately, the data from 737 subjects (73.8%) was included in our analysis. Results Regarding participant characteristics, the percentage of respondents who replied "I have heard of genetic testing" (including knowledge about genetic testing) and "I would like to have genetic testing" were 82.5% and 58.2%, respectively. A significant age difference in genetic testing awareness was also observed in our study. Logistic regression analysis revealed both significant adjust odds ratios (ORs) of 3.02 (95% CI 1.67-5.46) and 3.82 (95% CI 1.71-8.53) in the 40-49-year-old group and the over 50 year old group, respectively, compared with the 20-29-year-old group. In addition, females and the participants who graduated from graduate schools showed greater interest in genetic testing. Conclusions This survey showed that about 80% of Japanese workers know about genetic testing and about 60% would like to have a test. The results of our survey also suggest that the awareness of genetic testing is influenced by participant characteristics, namely age, sex, and education.

Prenatal exposure to environmental chemicals such as dioxins is known to have adverse effects on the developing central nervous system (CNS) in mammals. Because the fetal blood-brain barrier (BBB) is immature, dioxins are thought to exert their toxic effects on the CNS by crossing the BBB and acting on neural cells directly. However, little is known whether dioxins alter the BBB. In this study, to investigate the effects of dioxins on BBB function, we exposed an in vitro BBB system comprising rat endothelial cells, astrocytes, and pericytes to the toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) either before or after BBB formation. We assessed BBB permeability and the function of tight junctions by measuring transendothelial electric resistance (TEER) values following exposure. Subsequently, total RNA and proteins were obtained from the cells for analysis. TEER values following TCDD exposure before but not after BBB formation were lower than those of the control group. We also observed that the expression of the tight junction proteins ZO-1 and claudin-5 was suppressed following TCDD exposure. To examine the cause of this reduction in protein levels, we performed a real-time quantitative polymerase chain reaction assay and observed low expression of the glial cell line-derived neurotrophic factor (GDNF) mRNA in the exposed groups. Moreover, to rescue the effects of TCDD, we applied extrinsic GDNF with TCDD. The several disruptions caused by TCDD were rescued by the GDNF addition. Our findings suggest that exposure to TCDD during BBB formation disrupts and impairs BBB function in part by the suppression of GDNF action, which may contribute to the adverse effects of TCDD on the fetal CNS.

Several studies have suggested that an elevated neutrophil-lymphocyte ratio (NLR) is associated with a poorer prognosis in patients with pancreatic cancer (PC). The correlations between the NLR and immunohistochemical (IHC) analysis with regard to the prognosis of patients with PC remain to be elucidated. By using IHC findings, we determined the value of the NLR as a prognostic factor in patients with PC.We collected the clinico-pathological data of 28 consecutive patients who underwent surgical resection for PC between January 2008 and December 2012 at The Jikei University Kashiwa Hospital. We investigated whether the NLR and IHC results were related and ensured the consistency of the prognosis of patients with PC.The Kaplan-Meier curves for the disease-free survival (DFS) and the overall survival (OS) revealed that an NLR ≥ 5 is an implicit factor for decreased DFS and OS in patients with PC (p = 0.003, p 0.001, log-rank test). The density of CD163(+) macrophages and CD66b(+) neutrophils was significantly higher in the high NLR group; on the contrary, the density of CD20(+) lymphocytes was significantly higher in the low NLR group. Moreover, a Mann-Whitney U test showed that the NLR was significantly correlated with a high density of CD20(+) lymphocytes (p = 0.031) and CD163(+) macrophages (p = 0.023), while the NLR was not significantly correlated with CD66b(+) neutrophils (p = 0.397).Our results demonstrated the validity of the NLR by IHC analyses and we determined that a higher value of NLR is a trustworthy prognostic factor for patients with PC.

The CD28H/B7-H5 pathway is a newly identified pathway of the B7 family. In human peripheral blood, the receptor CD28H is preferentially expressed on naïve T cells and repetitive stimulation of T cells leads to the loss of CD28H expression. Here we examined the expression of the CD28H/B7-H5 pathway in human peripheral tissues, as well as in human cancers. We found that CD28H is preferentially expressed on T cells with tissue-resident phenotypes (T(RM)). Supporting that, stimulation via IL-15 and TGF-β, presumably major cytokines essential for T(RM) cell homeostasis, sustains CD28H expression on T cells. The ligand B7-H5 is constitutively expressed on normal epithelium of human oral-gastrointestinal tracts. In human cancers, CD28H is preferentially present on tumor infiltrating lymphocytes (TILs) with T(RM) features and identifies a T(RM) subset with less cytotoxicity. Taken together, our studies suggest that the CD28H/B7-H5 pathway involves the interactions between T(RM) cells and epithelium, and could be important for human T(RM) homeostasis and function.

Aim Prognostic factors of recurrence and survival in various cancer types have been reported and include C-reactive protein (CRP)-based measures as evidenced by the Glasgow prognostic score (GPS), as well as peripheral blood cell-based prognostic values such as the prognostic index (PI), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR). The aim of this study was to identify significant prognostic values and compare them for suitability for use in patients after curative pancreatic resection for pancreatic cancer. Materials and methods Between 2000 and 2015, 188 patients were enrolled in this retrospective study. The relationship between clinicopathological variables including various prognostic values and disease-free (DFS) and overall (OS) survival was investigated by univariate analysis. The area under the receiver operating characteristics curve (AUC) was evaluated to compare the predictive ability of each of these scoring systems. Multivariate analysis was then performed to identify clinicopathological variables that associated DFS and OS. Results In univariate analysis, GPS, modified GPS, CRP to albumin ratio and PI were significant risk factors for both DFS and OS. The AUC of CRP-based scores (GPS, modified GPS, and CRP to albumin ratio) were consistently larger in comparison with PI, which consists of both CRP and peripheral blood cell scores, at all time points for both DFS and OS. In multivariate analysis, GPS was the only independent risk factor of tumor recurrence and survival. Conclusion CRP-based prognostic scores have an independent value for both tumor recurrence and prognosis in patients after curative resection for pancreatic cancer, and are superior to other peripheral blood cell count-based prognostic scores.

Environmental chemicals are known to disrupt the endocrine system in humans and to have adverse effects on several organs including the developing brain. Recent studies indicate that exposure to environmental chemicals during gestation can interfere with neuronal differentiation, subsequently affecting normal brain development in newborns. Xenoestrogen, bisphenol A (BPA), which is widely used in plastic products, is one such chemical. Adverse effects of exposure to BPA during pre- and postnatal periods include the disruption of brain function. However, the effect of BPA on neural differentiation remains unclear. In this study, we explored the effects of BPA or bisphenol F (BPF), an alternative compound for BPA, on neural differentiation using ReNcell, a human fetus-derived neural progenitor cell line. Maintenance in growth factor-free medium initiated the differentiation of ReNcell to neuronal cells including neurons, astrocytes, and oligodendrocytes. We exposed the cells to BPA or BPF for 3 days from the period of initiation and performed real-time PCR for neural markers such as β III-tubulin and glial fibrillary acidic protein (GFAP), and Olig2. The β III-tubulin mRNA level decreased in response to BPA, but not BPF, exposure. We also observed that the number of β III-tubulin-positive cells in the BPA-exposed group was less than that of the control group. On the other hand, there were no changes in the MAP2 mRNA level. These results indicate that BPA disrupts neural differentiation in human-derived neural progenitor cells, potentially disrupting brain development.

The delivery of small interfering RNA (siRNA) to dendritic cells (DCs) is a challenging issue for siRNA-loaded lipid nanoparticles. The cause of this difficulty is unknown. The findings reported herein indicate that the rate-limiting step in gene silencing using siRNA-loaded lipid nanoparticles in DCs, as evidenced by a quantitative analysis of each process in siRNA delivery between mouse bone marrow derived DC (BMDC) and other cell lines, was not associated with the actual delivery of siRNA. A gene silencing of only 50% was observed in BMDC, even when a high dose was used. Contrary to our expectation, the interval between cellular uptake and the delivery of siRNA to the cytosol was not responsible for the low gene silencing. Meanwhile, a drastic difference was found in the relationship between the efficiency of gene silencing and the amount of intracellular intact siRNA. This fact indicates that the processes after cytosolic delivery of siRNA, namely the intracellular pharmacodynamics (PD) of siRNA, appear to be the rate-limiting step in gene silencing in BMDC. The findings reported here demonstrate the importance of the intracellular PD of siRNA delivered to cytosol in the development of siRNA delivery systems for gene silencing in DCs.

Prostate cancer (PCa) is one of the major causes of death among men. Our study investigated the association of ESR1 and ESR2 genotypes with susceptibility to PCa in relation to smoking status in Japanese.A case-control study was performed with 750 Japanese prostate cancer patients and 870 healthy controls. After age-matching in case-controls, 352 controls and 352 cases were enrolled in this study. By using logistic regression analysis, the different genotypes from ESR1 and ESR2 were analyzed according to case/control status.ESR2 rs4986938 AG and AG + AA genotypes were associated with significantly decreased risk of PCa (AG: OR = 0.68, 95 % CI 0.47-0.97, P 0.05 and AG + AA: OR = 0.67, 95 % CI 0.47-0.94, P 0.05). However, there was no significant association between ESR1 rs2234693 and PCa risk. When patients were grouped according to smoking status, the ESR2 rs1256049 AA genotype (OR = 0.48, 95 % CI 0.25-0.95, P 0.05) and ESR2 rs4986938 AG + AA genotype (OR = 0.64, 95 % CI 0.41-1.00, P 0.05) showed significantly decreased PCa risk in the ever-smoker group.Our results suggest that the estrogen receptor ESR2 has a very important function to predict PCa and that different SNPs have different predictive values. Smoking may influence estrogenic activity and may influence PCa together with the estrogen receptor.

Tissue factor (TF) triggers the extrinsic blood coagulation cascade and is highly expressed in various types of cancer. In this study, we investigated the antitumor effect of an antibody–drug conjugate (ADC) consisting of an anti‐TF monoclonal antibody and monomethyl auristatin E (MMAE). MMAE was conjugated to an anti‐human TF or anti‐mouse TF antibody using a valine‐citrulline linker that could be potentially hydrolyzed by cathepsin B in the acidic environment of the lysosome. The cytotoxic and antitumor effects of the ADCs against four pancreatic cancer cell lines were analyzed. Both the ADC with the anti‐human TF antibody and that with the anti‐mouse TF antibody were stable under physiological conditions. The anti‐human ADC was internalized in TF‐expressing human tumor cell lines, followed by effective MMAE release. The half maximal inhibitory concentration (IC50) of MMAE was approximately 1 nM for all of the cell lines used. Meanwhile, the IC50 of anti‐human ADC was 1.15 nM in the cell lines showing high TF expression, while exceeding 100 nM in the cells showing low TF expression levels. Anti‐human ADC with passive and active targeting ability exerted significant suppression of tumor growth as compared to that observed in the saline group (p, What's new? Tissue factor (TF) triggers normal blood coagulation, and is also highly expressed in various types of tumor, including pancreatic, malignant glioma, and gastric cancer. In this study, the authors developed a new antibody‐drug conjugate (ADC) consisting of an anti‐TF monoclonal antibody linked to monomethyl auristatin E (MMAE). The ADC accumulated selectively within tumors, and caused significant suppression of tumor growth in vivo. Because it penetrates tumors via their leaky vasculature, but is too large to pass through normal vessel walls, this ADC may provide a promising therapeutic strategy.

ZnO nano/microstructures have attracted much attention as building blocks for optoelectronic devices because of their high crystalline quality and unique structures. We have succeeded in synthesizing ZnO microspherical crystals by a simple atmospheric laser ablation method, and demonstrated ultraviolet whispering-gallery-mode lasing from the spheres. In the microsphere synthesis process, molten droplets formed into spherical shapes by surface tension, and crystalized during ejection from the ablation spot. In this study, we observed the generation of ZnO microspheres by high-speed camera. Now we are trying to control and manipulate the microspheres using a vortex beam.

BACKGROUND/AIM Preoperative biliary drainage (PBD) is often performed for jaundiced patients. However, the optimal duration of PBD remains unknown. The aim of this study was to investigate whether duration of PBD influenced the prognosis of patients after pancreaticoduodenectomy (PD) for pancreatic head cancer. PATIENTS AND METHODS Twenty-five patients who underwent PD for pancreatic head cancer with obstructive jaundice between 2007 and 2013 were included. Tumor and host factors were analyzed to evaluate their potential prognostic effects and patients' characteristics between the two groups according to the duration of PBD were analyzed. RESULTS In multivariate analysis, overall survival, duration of PBD ≥21 days and tumor-node-metastasis (TNM) stage III or IV were significant predictors. Duration of PBD ≥21 days was positively correlated with higher level of serum C-reactive protein (CRP), modified Glasgow prognostic score (mGPS) and neoadjuvant therapy. CONCLUSION Duration of PBD is an independent prognostic factor after PD for pancreatic head cancer with obstructive jaundice.

Central bisegmentectomy (CBS) of the liver is an en bloc hepatic resection of Couiaud segments 4, 5, and 8. The indications for CBS include benign and malignant tumors occupying both the left medial and right anterior segments. However, CBS has rarely been reported. Here, we investigate CBS in patients with suboptimal liver function for whom an extended lobectomy is not an optimal solution. Each case was 1 of 8 patients who underwent CBS for hepatocellular carcinoma (HCC) or colorectal cancer liver metastasis (CRLM) at the Department of Surgery, Jikei University Hospital. Indications for CBS consisted of CRLM in 3 patients and HCC in 5 patients. The median duration of operation was 552 minutes, and median blood loss was 2263 g. No postoperative nor in-hospital mortalities occurred. In this study, 1-, 2-, and 3-year disease-free survival rates were 62.5%, 12.5%, and 12.5%, respectively, and 1-, 2-, and 3-year overall survival rates were 100%, 100%, and 85.7%, respectively. CBS is advocated for central liver tumors in patients with suboptimal liver function for whom extended lobectomy could result in less than optimal remnant liver volume and function.