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For many solid tumors, immune checkpoint blockade therapy has become first line treatment, yet a large proportion of patients with immunologically cold tumors do not benefit due to the paucity of tumor infiltrating lymphocytes. Here we show that the orphan G Protein-Coupled Receptor 182 (GPR182) contributes to immunotherapy resistance in cancer via scavenging chemokines that are important for lymphocyte recruitment to tumors. GPR182 is primarily upregulated in melanoma-associated lymphatic endothelial cells (LECs) during tumorigenesis, and this atypical chemokine receptor endocytoses chemokines promiscuously. In GPR182-deficient mice, T cell infiltration into transplanted melanomas increases, leading to enhanced effector T cell function and improved antitumor immunity. Ablation of GPR182 leads to increased intratumoral concentrations of multiple chemokines and thereby sensitizes poorly immunogenic tumors to immune checkpoint blockade and adoptive cellular therapies. CXCR3 blockade reverses the improved antitumor immunity and T cell infiltration characteristic of GPR182-deficient mice. Our study thus identifies GPR182 as an upstream regulator of the CXCL9/CXCL10/CXCR3 axis that limits antitumor immunity and as a potential therapeutic target in immunologically cold tumors., Immunologically cold tumours don’t respond to immune checkpoint blockade inhibition due to poor recruitment of anti-tumour T cells. Authors show here that melanoma-associated lymphatic endothelial cells express G Protein-Coupled Receptor 182 that scavenges CXCL9 and other chemokines necessary for T cell recruitment.

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.

A 62-year-old female was presented to the hospital of the current study for pancytopenia and was diagnosed with severe aplastic anemia. She was treated with a combination therapy of antithymocyte globulin, cyclosporine A, and eltrombopag. The patient also presented with febrile neutropenia after commencement of the treatment and did not respond to the various antibiotics and antifungal agents. Echocardiography showed a giant vegetation attached to the tricuspid valve on Day 78 of the immunosuppressive therapy, and the tricuspid valve replacement was performed. The vegetation was formed by Cunninghamella bertholletiae, a mucor type, and was treated with high-dose liposomal amphotericin B (L-AMB), which was terminated after six weeks due to decreased renal function. In addition, mucormycosis was controlled by posttreatment with posaconazole (PSCZ). This is a rare case of mucormycosis that developed into a giant vegetation during the immunosuppressive therapy for aplastic anemia. It was believed to be a valuable case to consider in future mucormycosis treatment, including the success of the treatment by switching from L-AMB to PSCZ.

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.

Progression-free survival in patients with untreated follicular lymphoma (FL) has significantly improved with obinutuzumab plus chemotherapy followed by obinutuzumab maintenance, compared with rituximab plus chemotherapy. However, the survival outcome and adverse event profile in Japanese FL patients treated with obinutuzumab plus bendamustine (GB) therapy are not well investigated. Recently, we encountered some cases of grade 3-4 thrombocytopenia during GB therapy in patients with FL. This retrospective multicenter survey aimed to identify the characteristics of patients who received GB therapy and developed thrombocytopenia. A total of 54 patients with FL treated by GB therapy between August 2018 and December 2020 were investigated. After a median follow-up of 12.6 months, thrombocytopenia of any grade was observed in 48 (88.9%) patients, including 9 (16.7%) patients with grade 3-4 thrombocytopenia. Notably, although eight of nine patients with grade 3-4 thrombocytopenia were female, no patient characteristics (including gender) were significantly associated with grade 3-4 thrombocytopenia. Importantly, grade 3-4 thrombocytopenia frequently occurred in the first GB therapy cycle, which suggests that platelet count should be monitored carefully in patients who have just started GB therapy.

Adjuvant chemotherapy is recommended for patients with pancreatic cancer after curative resection. However, there is limited evidence regarding the efficacy and prognostic factors for adjuvant chemotherapy in patients with stage I pancreatic cancer. This study aimed to identify patients in whom chemotherapy was effective and to detect prognostic factors for stage I pancreatic cancer based on guidelines of the 8Between 2009 and 2017, 108 patients diagnosed with stage I pancreatic cancer were enrolled in this study. They were distributed into invasion (n = 68) and non-invasion (n = 40) groups. The relationship between clinicopathological variables, including various prognostic factors, disease-free survival (DFS), and overall survival (OS), were investigated by univariate and multivariate analyses.Five-year survival in all patients with stage I pancreatic cancer was 38.9%. Adjuvant chemotherapy failed to improve DFS or OS in patients with stage I cancer (DFS, p = 0.26; OS, p = 0.30). In subgroup analysis, adjuvant chemotherapy significantly improved DFS (multivariate-adjusted hazard ratio (HR), 0.40; 95% confidence interval [CI], 0.21-0.78; p = 0.007) and OS (multivariate-adjusted HR, 0.32; 95% CI, 0.15-0.68; p = 0.003) in the invasion group than in non-invasion group. In contrast, in the non-invasion group, adjuvant chemotherapy failed to improve DFS and OS in univariate analysis (DFS, p = 0.992; OS, p = 0.808).For stage I pancreatic cancer, based on guidelines of the UICC 8

A 77-year-old man diagnosed with mixed-phenotype acute leukemia (MPAL (B/Myeloid), NOS) achieved complete remission (CR) after eight courses of hyper-CVAD/MA therapy. However, 6 months later, blasts were observed on peripheral blood smear, and bone marrow aspiration revealed that the disease had relapsed as B lymphoblastic leukemia (ALL). At this time, he had left pleural effusion. He received two courses of inotuzumab ozogamicin (InO) and achieved second hematological CR, but the left pleural effusion worsened over time, suggesting poor disease control. After changing the regimen to blinatumomab, aspiration biopsy cytology showed that the blasts in the pleural fluid disappeared and respiratory distress improved after one course of treatment. Flow cytometry results showed increased populations of CD3-positive T-cells, suggesting that blinatumomab may have migrated into the pleural fluid and exerted an antitumor effect. Although new ALL-specific antibody drugs, such as InO and blinatumomab, are expected to improve prognosis, only few reports have described their tissue migration. The difference between InO and blinatumomab in terms of efficacy of treating malignant pleural effusion remains unclear and should be explored in additional cases.

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.

Second allogeneic stem cell transplantation (allo-SCT) is a potentially curative therapy for patients who relapse after first allo-SCT. Human leukocyte antigen (HLA)-haploidentical related donors provide the broad opportunity to conduct second SCT at the appropriate time, but the efficacy of second SCT from haploidentical donors after relapse has not been established. We retrospectively analyzed the records of 33 patients who underwent second SCT. Twenty patients underwent haplo-SCT with low-dose antithymocyte globulin (ATG), and the other 13 patients underwent conventional- SCTs, including HLA-matched related peripheral blood, unrelated bone marrow or cord blood. Three years after the second SCT, the overall survival (OS) and progression-free survival (PFS) of all patients were 32.5% and 23.9%. Multivariate analyses indicated that non-complete response at second SCT, less than 1-year interval to relapse after first- SCT, and total score ≥ 3 on the hematopoietic cell transplantation-specific comorbidity index were significantly associated with a lower PFS rate. The haplo- and conventional- SCT groups showed equivalent results regarding OS, PFS, cumulative incidences of relapse, non-relapse mortality and graft-versus-host disease. The neutropenic period after transplantation was significantly shorter in haplo- SCT than conventional- SCT (10.5 days vs. 16 days, p=0.001). Our analysis revealed that haplo-SCT could be an alternative therapeutic option for relapsed patients after first SCT.

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.

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.

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.

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

The effects of two introductory styles on substantive information provided by Japanese children were investigated. Children aged 5–6 years (n = 42) and 7–8 years (n = 40) took a simulated physical examination. One week later, the participants were interviewed about the examination in a narrative introductory condition using open-ended questions, or a non-narrative introductory condition using directive and yes/no questions. Substantive information provided by the children in the two conditions was compared. Results indicated that in the narrative condition, the participants provided more accurate information about the examination in response to open-ended questions. Additionally, the 7–8 year-old children in the narrative condition provided a wider range of critical information. These findings suggest that an open-ended introductory style is effective in eliciting more accurate information from children, including preschoolers, and more varied information from school-age children.

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

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.

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.

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.

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.

A 76-year-old woman was operated on for rectal cancer in 2011 without chemotherapy and was followed up in the outpatient department. Decrease in white blood cell count was observed from 2013, and she developed anemia in 2015. Bone marrow aspiration was performed, and she was diagnosed with acute myeloid leukemia with myelodysplasia-related changes (AML/MRC). First, remission induction therapy was initiated with idarubicin and cytarabine administration, but pneumonia and vertebral osteomyelitis developed during the neutropenic period. Although the progress of antibiotics aided in the improvement of the recent prognosis of vertebral osteomyelitis compared with the past, poor prognosis with high death rate was still inevitable. Then, consolidation therapy was initiated with azacitidine (AZA) administration, and treatment was carried out for vertebral osteomyelitis with several antibiotics in parallel, which together led to the successful treatment of vertebral osteomyelitis while maintaining a remission state of AML. Because AZA is known to be well-tolerated and neutropenic phase is shorter than intensive chemotherapy in general, it can be an effective treatment option for patients who need both infection control and AML treatment.

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.

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.

Postoperative bile leakage is one of the most common complications after hepatic surgery. The relationship between the inflammatory response and postoperative bile leakage has not been fully investigated. Therefore, we retrospectively investigated the relation between postoperative peripheral blood monocyte count and bile leakage in patients with colorectal liver metastases (CRLM) after elective hepatic resection. The study comprised 105 patients who had undergone hepatic resection for CRLM between January 2000 and March 2012. Perioperative risk factors pertinent to development of bile leakage were investigated using univariate and multivariate analyses. Bile leakage developed in 9 (8.6 %) of 105 patients. In multivariate analysis, intraoperative fresh frozen plasma (FFP) transfusion (p = 0.009) and lower monocyte count of the peripheral blood on postoperative day 1 (p = 0.038) were found as independent risk factors of bile leakage. Postoperative lower monocyte count and intraoperative FFP transfusion were associated with the development of postoperative bile leakage after elective hepatic resection in patients with CRLM.

Gene silencing by small interfering RNA (siRNA) is useful for analyzing the functions of human immune cells. However, the transfection of siRNA to human immune cells is difficult. Here, we used a multifunctional envelope-type nanodevice (MEND) containing YSK12-C4 (YSK12-MEND) to efficiently introduce siRNA to human immune cell lines, Jurkat, THP-1, KG-1 and NK92. The YSK12-MEND was transfected to human immune cell lines at a siRNA dose range of 1–30 nM, resulting that maximum gene silencing efficiencies at the mRNA level in Jurkat, THP-1, KG-1 and NK92 were 96%, 96%, 91% and 75%, respectively. The corresponding values for Lipofectamine RNAiMAX (RNAiMAX) were 37%, 56%, 43% and 19%, respectively. The process associated with cellular uptake played a role in effective gene silencing effect of the YSK12-MEND. The small size and high non-aggregability of the YSK12-MEND were advantageous for the cellular internalization of siRNA to immune cell lines. In the case of RNAiMAX, a drastic increase in particles size was observed in the medium used, which inhibited cellular uptake. The YSK12-MEND reported in herein appears to be appropriate for delivering siRNA to human immune cells, and the small particle size and non-aggregability are essential properties.

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.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.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.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.

Angiogenesis is a known factor for the development of hepatocellular carcinoma (HCC). The aim of this study was to assess the property of iguratimod, that is an anti-inflammatory drug for rheumatoid arthritis, on anti-angiogenesis and anti-carcinogensis for HCC.In vitro, human umbilical vein endothelial cells were cultured under interleukin-8 (IL-8) with or without iguratimod. In vivo, a rat model with HCC received iguratimod or distilled water for 6 weeks. Diameter of the largest tumor, number of tumors and serum interleukin-8 concentration were compared between iguratimod and control groups.By an in vitro angiogenesis assay, it was found angiogenesis in iguratimod group was significantly lower than that in control group (p=0.013). In vivo, largest tumor diameter (p=0.036), number of the tumor (p=0.011) and serum interleukin-8 concentration (p=0.036) in the iguratimod group were significantly smaller and lower than those in the control group.Iguratimod may inhibit hepatocellular carcinogensis by inhibition of interleukin-8 production in a rat model.

Antibody-drug conjugates (ADCs) are a class of immunotherapeutic agents that enable the delivery of cytotoxic drugs to target malignant cells. Because various cancers and tumour vascular endothelia strongly express anti-human tissue factor (TF), we prepared ADCs consisting of a TF-specific monoclonal antibody (mAb) linked to the anticancer agent (ACA) monomethyl auristatin E (MMAE) via a valine-citrulline (Val-Cit) linker (human TF ADC). Identifying the most efficient drug design in advance is difficult because ADCs have complicated structures. The best method of assessing ADCs is to examine their selectivity and efficiency in releasing and distributing the ACA within tumour tissue. Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) can be used to directly detect the distributions of native molecules within tumour tissues. Here, MALDI-IMS enabled the identification of the intratumour distribution of MMAE released from the ADC. In conclusion, MALDI-IMS is a useful tool to assess ADCs and facilitate the optimization of ADC design.

Multiple chemical sensitivity (MCS) is an acquired chronic disorder characterized by nonspecific symptoms in multiple organ systems associated with exposure to low-level chemicals. Diagnosis of MCS can be difficult because of the inability to assess the causal relationship between exposure and symptoms. No standardized objective measures for the identification of MCS and no precise definition of this disorder have been established. Recent technological advances in mass spectrometry have significantly improved our capacity to obtain more data from each biological sample. Metabolomics comprises the methods and techniques that are used to determine the small-level molecules in biofluids and tissues. The metabolomic profile-the metabolome-has multiple applications in many biological sciences, including the development of new diagnostic tools for medicine. We performed metabolomics to detect the difference between 9 patients with MCS and 9 controls. We identified 183 substances whose levels were beyond the normal detection limit. The most prominent differences included significant increases in the levels of both hexanoic acid and pelargonic acid, and also a significant decrease in the level of acetylcarnitine in patients with MCS. In conclusion, using metabolomics analysis, we uncovered a hitherto unrecognized alteration in the levels of metabolites in MCS. These changes may have important biological implications and may have a significant potential for use as biomarkers.

Preoperative systemic inflammatory response is associated with a poor long-term prognosis after resection of malignant tumors. Several indicators of systemic inflammation have been reported to be predictive of outcomes, but have not been fully investigated. The aim of the present study was to evaluate the significance of the preoperative neutrophil to lymphocyte ratio (NLR) in therapeutic outcomes after pancreaticoduodenectomy for carcinoma of the ampulla of Vater.The study comprised of 37 patients who had undergone pancreaticoduodenectomy for carcinoma of the ampulla of Vater between January 2000 and December 2011. We retrospectively investigated the relation between preoperative NLR and disease-free as well as overall survival.In multivariate analysis, preoperative biliary drainage (p=0.044) and pN2 or pN3 (p=0.027) status were independent and significant predictors of cancer recurrence, while significant predictors of overall survival consisted of pN2 or pN3 (p=0.025) and NLR ≥3 (p=0.026).Preoperative NLR is an independent and significant indicator of long-term outcome in patients with carcinoma of the ampulla of Vater after pancreaticoduodenectomy. Measurement of NLR may help decision making in the postoperative management of patients with carcinoma of the ampulla of Vater.

Constitutive NF-κB activation is considered to play a key role in the aggressive behavior of pancreatic cancer. Although NF-κB in tumors may contribute to aggressive characteristic features via transcription of angiogenesis and invasion-related factors, there is no definitive evidence showing a correlation between quantitated NF-κB activity and prognosis. In this study, we quantitated NF-κB activity of various human pancreatic cancer cell lines and evaluated whether NF-κB activity was related to tumor progression and prognosis for pancreatic cancer in mice. We quantitated NF-κB activity in six pancreatic cancer cell lines (AsPC-1, BxPC-3, Capan-2, MIAPaCa-2, Panc-1 and PL45) and evaluated downstream target genes of NF-κB such as VEGF, IL-8 and MMP-9 in vitro. Next, we evaluated tumor progression and prognosis using subcutaneous tumor model in vivo between cell lines with the highest and lowest NF-κB activity. BxPC-3 had the highest and AsPC-1 had the lowest NF-κB activity in the 6 cell lines. Expression of VEGF, IL-8 and MMP-9 in BxPC-3 was significantly higher than those in AsPC-1 cells in vitro (p

Intraperitoneal (i.p.) administration of paclitaxel is useful for treating malignant tumors with peritoneal dissemination, but the therapeutic efficacy is limited. Chemoresistance due to paclitaxel-induced nuclear factor-kappa B (NF-κB) activation is an important cause of suboptimal therapeutic efficacy. The purpose of this study was to prove that addition of nafamostat mesilate (FUT-175), a synthetic serine protease inhibitor and an NF-κB inhibitor, to i.p. paclitaxel enhances antitumor effects of paclitaxel against gastric cancer with peritoneal dissemination. In vitro, we assessed NF-κB activity and apoptosis in response to treatment with FUT-175 alone, paclitaxel alone, or a combination of FUT-175 and paclitaxel in a human gastric cancer cell line (MKN-45). In vivo, we established peritoneal dissemination in nude mice by i.p. injection of MKN-45 cells. The animals received i.p. injections of FUT-175 alone three times a week (FUT-175 group), of paclitaxel alone once a week (paclitaxel group), or a combination of FUT-175 and paclitaxel (combination group) three times and once a week, respectively. In the combination group, paclitaxel-induced NF-κB activation was inhibited and apoptosis was enhanced in comparison with those in the other groups both in vitro and in vivo. In the combination group, number and weight of peritoneal nodules were significantly lower than those in the paclitaxel group (p = 0.0009 and p = 0.0417, respectively). In the survival analysis, the combination group had a significantly better survival than the paclitaxel group (p = 0.0048). FUT-175 enhances the antitumor effect of i.p. paclitaxel against gastric cancer with peritoneal dissemination by inhibiting NF-κB activation in mice.

Constitutive activation of nuclear factor kappa-B (NF-κB) contributes to the aggressive behavior of pancreatic cancer. Over-expression of downstream target genes of NF-κB such as intercellular adhesion molecule-1 (ICAM-1), interleukin-8 (IL-8), vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) leads to the promotion of cell adhesion, angiogenesis, invasion and metastasis. We previously reported that nafamostat mesilate, a synthetic serine protease inhibitor, blocks NF-κB activation in pancreatic cancer. We hypothesized that nafamostat mesilate may inhibit cell adhesion, angiogenesis, invasion and metastases in peritoneal dissemination of pancreatic cancer.In vitro, we assessed inhibition of NF-κB, phosphorylated IκBα, ICAM-1, VEGF and MMP-9 activity by nafamostat mesilate using human pancreatic cancer cell lines (AsPC-1, BxPC-3 and PANC-1). Changes in adhesion and invasion abilities of cancer cells were then evaluated by nafamostat mesilate treatment. In vivo, the efficacy of nafamostat mesilate treatment was assessed using peritoneal dissemination of pancreatic cancer in mice.In vitro, nafamostat mesilate inhibited activities of NF-κB, phosphorylated IκBα, ICAM-1, VEGF and MMP-9. Moreover, nafamostat mesilate not only inhibited cell adhesion and invasion but also increased the sensitivity of anoikis. In vivo, tumor growth using AsPC-1 cells of the treatment group was significantly slower, and survival rate was significantly better, than those in control group (p0.05).Nafamostat mesilate reduced peritoneal metastasis and prolonged survival of pancreatic cancer-bearing mice.

In spite of improvements in surgical management, hepatocellular carcinoma (HCC) still recurs after operation in 60–70% of patients. Therefore, we investigated the relation between perioperative change in white blood cell count (WBC) and tumor recurrence as well as survival in patients with HCC after hepatic resection. Subjects were 53 patients who underwent elective hepatic resection for HCC. We retrospectively examined the relation between perioperative change in WBC and recurrence of HCC as well as overall survival. Advanced tumor stage and increasing of WBC on postoperative day (POD) 1 were positively associated with worse disease-free survival rate on both univariate and multivariate analysis (P

Introduction Radiation therapy, alone or in combination with chemotherapy, is effective for patients with locally advanced and recurrent pancreatic cancer. Ionizing radiation induces cell cycle arrest and cell apoptosis through enhancement several signals such as p53, p21 Waf1/Cip1 , and caspase. However, the therapeutic efficacy is attenuated by radiation-induced activation of NF-κB. Nafamostat mesilate, a synthetic serine protease inhibitor, inhibits NF-κB activation in pancreatic cancer. Therefore, we hypothesized that nafamostat mesilate inhibited radiation-induced activation of NF-κB and improves therapeutic outcome. Results In combination group, NF-κB activation was significantly inhibited in comparison with that of radiation group. Nafamostat mesilate obviously down-regulated the expression levels of Mdm2 compared with control cells or irradiated cells. Consequently, p53 expression was stabilized inversely in correlation with Mdm2 protein expression level. The expression levels of p53, p21 Waf1/Cip1 , cleaved caspase-3 and -8 were the highest in the combination group. Nafamostat mesilate enhanced ionizing radiation-induced cell apoptosis and G2/M cell cycle arrest. In combination group, cell proliferation and tumor growth were significantly slower than those in other groups. Conclusion Combination therapy of radiation with nafamostat mesilate exerts enhanced anti-tumor effect against human pancreatic cancer.

The perioperative immunological response predicts long-term outcomes after resection for malignant tumors. The aim of the study was to evaluate the significance of perioperative change in the peripheral blood monocyte count regarding therapeutic outcome after pancreaticoduodenectomy for bile duct cancer.The study comprised of 51 patients who had undergone pancreaticoduodenectomy for bile duct cancer between January 2000 and December 2012. We retrospectively investigated the relation between perioperative change in peripheral blood monocyte count and disease-free as well as overall survival.In multivariate analysis, advanced TNM stage, and decrease in monocyte count on postoperative day 1 in comparison with those before surgery were independent and significant predictors of poor disease-free survival and overall survival (p=0.014 and 0.004, and 0.010 and 0.006, respectively).Perioperative change in peripheral blood monocyte count is an independent and significant indicator of therapeutic outcome after pancreaticoduodenectomy in patients with bile duct cancer.

Patients with obstructive jaundice due to cancer of the pancreatic head often undergo preoperative endoscopic biliary drainage (EBD). The aim of the study was to evaluate the long-term impact of preoperative EBD following pancreaticoduodenectomy (PD) for pancreatic ductal adenocarcinoma.We studied 106 patients who underwent PD for pancreatic ductal adenocarcinoma between May 2000 and November 2013 at the Jikei University Hospital. We retrospectively examined perioperative findings as predictors of prognosis and the relationship between preoperative EBD and recurrence rate as well as overall survival.In univariate analysis, significant factors associated with poor disease-free survival consisted of the presence of EBD (p=0.0213), poor tumor differentiation (p=0.0023) and tumor-node-metastasis (TNM) classification IV (p=0.0027), while significant factors associated with poor overall survival consisted of the presence of EBD (p=0.0047), poor tumor differentiation (p0.0001), TNM classification IV (p=0.0031) and microscopic or macroscopic residual tumor (p=0.0184). In multivariate analysis, poor tumor differentiation (p=0.0033) and TNM classification IV (p=0.0020) were independent factors for poor disease-free survival, while the presence of EBD (p=0.0435), poor tumor differentiation (p=0.0009), TNM classification IV (p=0.0447) and microscopic or macroscopic residual tumor (p=0.0184) were independent factors for poor overall survival.Preoperative EBD may have a negative impact on prognosis after PD for pancreatic ductal adenocarcinoma.