Tumour-associated myeloid cells expressing IL-10R2/IL-22R1 as a potential biomarker for diagnosis and recurrence of pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor survival rate, largely due to the lack of early diagnosis. Although myeloid cells are crucial in the tumour microenvironment, whether their specific subset can be a biomarker of PDAC progression is unclear. METHODS: We analysed IL-22 receptor expression in PDAC and peripheral blood. Additionally, we analysed gene expression profiles of IL-10R2+/IL-22R1+ myeloid cells and the presence of these cells using single-cell RNA sequencing and murine orthotropic PDAC models, respectively, followed by examining the immunosuppressive function of IL-10R2+/IL-22R1+ myeloid cells. Finally, the correlation between IL-10R2 expression and PDAC progression was evaluated. RESULTS: IL-10R2+/IL-22R1+ myeloid cells were present in PDAC and peripheral blood. Blood IL-10R2+ myeloid cells displayed a gene expression signature associated with tumour-educated circulating monocytes. IL-10R2+/IL-22R1+ myeloid cells from human myeloid cell culture inhibited T cell proliferation. By mouse models for PDAC, we found a positive correlation between pancreatic tumour growth and increased blood IL-10R2+/IL-22R1+ myeloid cells. IL-10R2+/IL-22R1+ myeloid cells from an early phase of the PDAC model suppressed T cell proliferation and cytotoxicity. IL-10R2+ myeloid cells indicated tumour recurrence 130 days sooner than CA19-9 in post-pancreatectomy patients. CONCLUSIONS: IL-10R2+/IL-22R1+ myeloid cells in the peripheral blood might be an early marker of PDAC prognosis.

Surgical Outcomes of Pancreatectomy with Resection of the Portal Vein and/or Superior Mesenteric Vein and Jejunal Vein for Pancreatic Head Cancer: A Multicenter Study.

OBJECTIVE: The aim of this study was to investigate the safety and survival benefits of portal vein and/or superior mesenteric vein (PV/SMV) resection with jejunal vein resection (JVR) for pancreatic ductal adenocarcinoma (PDAC). SUMMARY BACKGROUND DATA: Few studies have shown the surgical outcome and survival of pancreatic resection with JVR, and treatment strategies for patients with PDAC suspected of jejunal vein (JV) infiltration remain unclear. METHODS: In total, 1260 patients who underwent pancreatectomy with PV/ SMV resection between 2013 and 2016 at 50 facilities were included; treatment outcomes were compared between the PV/SMV group (PV/ SMV resection without JVR; n = 824), PV/SMV-J1 V group (PV/SMV resection with first jejunal vein resection; n = 394), and PV/SMV-J2,3 V group (PV/SMV resection with second jejunal vein or later branch resection; n = 42). RESULTS: Postoperative complications and mortality did not differ between the three groups. The postoperative complication rate associated with PV/ SMV reconstruction was 11.9% in PV/SMV group, 8.6% in PV/SMV-J1 V group, and 7.1% in PV/SMV-J2,3V group; there were no significant differences among the three groups. Overall survival did not differ between PV/SMV and PV/SMV-J1 V groups (median survival; 29.2 vs 30.9 months, P = 0.60). Although PV/SMV-J2,3 V group had significantly shorter survival than PV/SMV group who underwent upfront surgery ( P = 0.05), no significant differences in overall survival of patients who received preoperative therapy. Multivariate survival analysis revealed that adjuvant therapy and R0 resection were independent prognostic factors in all groups. CONCLUSION: PV/SMV resection with JVR can be safely performed and may provide satisfactory overall survival with the pre-and postoperative adjuvant therapy.

The comprehensive expression of BCL2 family genes determines the prognosis of diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a prevalent and aggressive non-Hodgkin's lymphoma, and 40% of patients succumb to death. Despite numerous clinical trials aimed at developing treatment strategies beyond the conventional R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen, there have been no positive results thus far. Although the selective BCL2 inhibitor venetoclax has shown remarkable efficacy in chronic lymphocytic leukemia, its therapeutic effect in DLBCL was limited. We hypothesized that the limited therapeutic effect of venetoclax in DLBCL may be attributed to the complex expression and interactions of BCL2 family members, including BCL2. Therefore, we aimed to comprehensively analyze the expression patterns of BCL2 family members in DLBCL. We analyzed 157 patients with de novo DLBCL diagnosed at Asan Medical Center and Ajou University Hospital. The mRNA expression levels of BCL2 family members were quantified using the NanoString technology. BCL2 family members showed distinct heterogeneous expression patterns both intra- and inter-patient. Using unsupervised hierarchical cluster analysis, we were able to classify patients with similar BCL2 family expression pattern and select groups with clear prognostic features, C1 and C6. In the group with the best prognosis, C1, the expression of pro-apoptotic and pro-apoptotic BH3-only group gene expressions were increased, while anti-apoptotic group expression was significantly increased in both C1 and C6. Based on this, we generated the BCL2 signature score using the expression of pro-apoptotic genes BOK and BCL2L15, and anti-apoptotic gene BCL2. The BCL2 signature score 0 had the best prognosis, score 1/2 had intermediate prognosis, and score 3 had the worst prognosis (EFS, p = 0.0054; OS, p = 0.0011). Multivariate analysis, including COO and IPI, showed that increase in the BCL2 signature score was significantly associated with poor prognosis for EFS, independent of COO and IPI. The BCL2 signature score we proposed in this study provides information on BCL2 family deregulation based on the equilibrium of pro-versus anti-apoptotic BCL2 family, which can aid in the development of new treatment strategies for DLBCL in the future.

CD74 Promotes a Pro-Inflammatory Tumor Microenvironment by Inducing S100A8 and S100A9 Secretion in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive form of pancreatic cancer with a poor prognosis and low survival rates. The prognostic and predictive biomarkers of PDAC are still largely unknown. The receptor CD74 was recently identified as a regulator of oncogenic properties in various cancers. However, the precise molecular mechanism of CD74 action in PDAC remains little understood. We investigated the role of CD74 by silencing CD74 in the pancreatic cancer cell line Capan-1. CD74 knockdown led to reductions in cell proliferation, migration, and invasion and increased apoptosis. Moreover, silencing CD74 resulted in the decreased expression and secretion of S100A8 and S100A9. An indirect co-culture of fibroblasts and tumor cells revealed that fibroblasts exposed to conditioned media from CD74 knockdown cells exhibited a reduced expression of inflammatory cytokines, suggesting a role of CD74 in influencing cytokine secretion in the tumor microenvironment. Overall, our study provides valuable insights into the critical role of CD74 in regulating the oncogenic properties of pancreatic cancer cells and its influence on the expression and secretion of S100A8 and S100A9. Taken together, these findings indicate CD74 as a potential diagnostic biomarker and therapeutic target for pancreatic cancer.

Comparison of oncologic outcomes between open and laparoscopic distal pancreatectomy for pancreatic ductal adenocarcinoma using data from the KOTUS-BP national database: overcoming selection bias and the necessity of definite indications.

BACKGROUND: Despite the lack of high-level evidence, laparoscopic distal pancreatectomy (LDP) is frequently performed in patients with pancreatic ductal adenocarcinoma (PDAC) owing to advancements in surgical techniques. The aim of this study was to investigate the long-term oncologic outcomes of LDP in patients with PDAC via propensity score matching (PSM) analysis using data from a large-scale national database. METHODS: A total of 1202 patients who were treated for PDAC via distal pancreatectomy across 16 hospitals were included in the Korean Tumor Registry System-Biliary Pancreas. The 5-year overall (5YOSR) and disease-free (5YDFSR) survival rates were compared between LDP and open DP (ODP). RESULTS: ODP and LDP were performed in 846 and 356 patients, respectively. The ODP group included more aggressive surgeries with higher pathologic stage, R0 resection rate, and number of retrieved lymph nodes. After PSM, the 5YOSRs for ODP and LDP were 37.3% and 41.4% (p = 0.150), while the 5YDFSRs were 23.4% and 27.2% (p = 0.332), respectively. Prognostic factors for 5YOSR included R status, T stage, N stage, differentiation, and lymphovascular invasion. CONCLUSION: LDP was performed in a selected group of patients with PDAC. Within this group, long-term oncologic outcomes were comparable to those observed following ODP.

Sphingosylphosphorylcholine blocks ovariectomy-induced bone loss by suppressing Ca2+ /calmodulin-mediated osteoclast differentiation.

Osteoporosis is a disease in which bone mineral density decreases due to abnormal activity of osteoclasts, and is commonly found in post-menopausal women who have decreased levels of female hormones. Sphingosylphosphorylcholine (SPC) is an important biological lipid that can be converted to sphingosine-1-phosphate (S1P) by autotaxin. S1P is known to be involved in osteoclast activation by stimulating osteoblasts, but bone regulation by SPC is not well understood. In this study, we found that SPC strongly inhibits RANKL-induced osteoclast differentiation. SPC-induced inhibitory effects on osteoclast differentiation were not affected by several antagonists of S1P receptors or pertussis toxin, suggesting cell surface receptor independency. However, SPC inhibited RANKL-induced calcineurin activation and subsequent NFATc1 activity, leading to decrease of the expression of Trap and Ctsk. Moreover, we found that bone loss in an experimental osteoporosis mouse model was recovered by SPC injection. SPC also blocked ovariectomy-induced body weight increase and Nfatc1 gene expression in mice. We also found that SPC inhibits RANKL-induced osteoclast differentiation in human macrophages. Since currently available treatments for osteoporosis, such as administration of female hormones or hormone receptor modulators, show serious side effects, SPC has potential as a new agent for osteoporosis treatment.

The Impact of Neoadjuvant Treatment on Survival in Patients Undergoing Pancreatoduodenectomy With Concomitant Portomesenteric Venous Resection: An International Multicenter Analysis.

OBJECTIVE: The aim of this study was to evaluate whether neoadjuvant therapy (NAT) critically influenced microscopically complete resection (R0) rates and long-term outcomes for patients with pancreatic ductal adenocarcinoma who underwent pancreatoduodenectomy (PD) with portomesenteric vein resection (PVR) from a diverse, world-wide group of high-volume centers. SUMMARY OF BACKGROUND DATA: Limited size studies suggest that NAT improves R0 rates and overall survival compared to upfront surgery in R/BR-PDAC patients. METHODS: This multicenter study analyzed consecutive patients with R/BR-PDAC who underwent PD with PVR in 23 high-volume centers from 2009 to 2018. RESULTS: Data from 1192 patients with PD and PVR were collected and analyzed. The median age was 68 [interquartile range (IQR) 60-73] years and 52% were males. Some 186 (15.6%) and 131 (10.9%) patients received neoadjuvant chemotherapy (NAC) alone and neoadjuvant chemoradiotherapy, respectively. The R0/R1/R2 rates were 57%, 39.3%, and 3.2% in patients who received NAT compared to 46.6%, 49.9%, and 3.5% in patients who did not, respectively (P =0.004). The 1-, 3-, and 5-year OS in patients receiving NAT was 79%, 41%, and 29%, while for those that did not it was 73%, 29%, and 18%, respectively (P <0.001). Multivariable analysis showed no administration of NAT, high tumor grade, lymphovascular invasion, R1/R2 resection, no adjuvant chemotherapy, occurrence of Clavien-Dindo grade 3 or higher postoperative complications within 90 days, preoperative diabetes mellitus, male sex and portal vein involvement were negative independent predictive factors for OS. CONCLUSION: Patients with PDAC of the pancreatic head expected to undergo venous reconstruction should routinely be considered for NAT.

Minimally Invasive Versus Open Pancreatectomy for Right-Sided and Left-Sided G1/G2 Nonfunctioning Pancreatic Neuroendocrine Tumors: A Multicenter Matched Analysis with an Inverse Probability of Treatment-Weighting Method.

BACKGROUND: Limited evidence exists for the safety and oncologic efficacy of minimally invasive surgery (MIS) for nonfunctioning pancreatic neuroendocrine tumors (NF-PNETs) according to tumor location. This study aimed to compare the surgical outcomes of MIS and open surgery (OS) for right- or left-sided NF-PNETs. METHODS: The study collected data on patients who underwent surgical resection (pancreatoduodenectomy, distal/total/central pancreatectomy, duodenum-preserving pancreas head resection, or enucleation) of a localized NF-PNET between January 2000 and July 2017 at 14 institutions. The inverse probability of treatment-weighting method with propensity scores was used for analysis. RESULTS: The study enrolled 859 patients: 478 OS and 381 MIS patients. A matched analysis by tumor location showed no differences in resection margin, intraoperative blood loss, or complications between MIS and OS. However, MIS was associated with a longer operation time for right-sided tumors (393.3 vs 316.7 min; P < 0.001) and a shorter postoperative hospital stay for left-sided tumors (8.9 vs 12.9 days; P < 0.01). The MIS group was associated with significantly higher survival rates than the OS group for right- and left-sided tumors, but survival did not differ for the patients divided by tumor grade and location. Multivariable analysis showed that MIS did not affect survival for any tumor location. CONCLUSION: The short-term outcomes offered by MIS were comparable with those of OS except for a longer operation time for right-sided NF-PNETs. The oncologic outcomes were not compromised by MIS regardless of tumor location or grade. These findings suggest that MIS can be performed safely for selected patients with localized NF-PNETs.

Antiviral activity by lecithin-induced fengycin lipopeptides as a potent key substrate against Cucumber mosaic virus.

In this study, the effect of different growth substrates on the production of biosurfactants in the PPL strain of Bacillus amyloliquefaciens-a biocontrol agent for diseases affecting pepper and tomato plants-and on the antiviral effect of the PPL strain on Cucumber mosaic virus (CMV)-infected pepper plants was investigated. The multifunctional PPL strain exhibited enhanced growth and increased production of biosurfactants upon lecithin supplementation and consequently exhibited potent anti-CMV activity. The enhanced anti-CMV activity of the lecithin-supplemented PPL culture could be attributed to the antiviral effect as well as to the upregulation of plant defense-related genes. Treatment with pure commercial fengycins elicited a defense response against CMV in pepper plants; this effect was similar to that observed upon treatment with the lecithin-supplemented PPL culture. To the best of our knowledge, this is the first study to report the antiviral activity of lecithin-induced fengycin lipopeptides. These results suggest that the growth substrate affects antimicrobial production by B. amyloliquefaciens PPL, and consequently its antiviral activity.

Intraoperative radiation therapy induces immune response activity after pancreatic surgery.

BACKGROUND: Pancreatic cancer has highly aggressive features, such as local recurrence that leads to significantly high morbidity and mortality and recurrence after successful tumour resection. Intraoperative radiation therapy (IORT), which delivers targeted radiation to a tumour bed, is known to reduce local recurrence by directly killing tumour cells and modifying the tumour microenvironment. METHODS: Among 30 patients diagnosed with pancreatic cancer, 17 patients received IORT immediately after surgical resection. We investigated changes in the immune response induced by IORT by analysing the peritoneal fluid (PF) and blood of patients with and without IORT treatment after pancreatic cancer surgery. Further, we treated three pancreatic cell lines with PF to observe proliferation and activity changes. RESULTS: Levels of cytokines involved in the PI3K/SMAD pathway were increased in the PF of IORT-treated patients. Moreover, IORT-treated PF inhibited the growth, migration, and invasiveness of pancreatic cancer cells. Changes in lymphocyte populations in the blood of IORT-treated patients indicated an increased immune response. CONCLUSIONS: Based on the characterisation and quantification of immune cells in the blood and cytokine levels in the PF, we conclude that IORT induced an anti-tumour effect by activating the immune response, which may prevent pancreatic cancer recurrence. CLINICAL TRIAL REGISTRATION: NCT03273374 .

Early removal of central venous catheter may not impact the in-hospital mortality in patients with acute leukemia.

Central venous catheters (CVCs) are generally required for chemotherapy in patients with acute leukemia, but catheter-related infection is one of the common causes of neutropenic fever. We investigated the in-hospital mortality according to early removal of CVCs and the factors influencing the mortality in patients with acute leukemia undergoing remission induction chemotherapy. This study retrospectively analyzed the hospital record data of 278 patients with acute leukemia treated with non-tunneled CVCs and remission induction chemotherapy in a single institution. Bloodstream infection was more common (p < 0.0001) and median peak C-reactive protein (CRP) levels after neutropenic fever were significantly higher (23.3 vs. 14.5 mg/dl, p = 0.003) in the group with early removal than in the group with maintenance of the CVC. Multivariate analysis of the patients revealed a significant decrease in the mortality with female gender (odds ratio (OR): 0.19, 95% confidence interval (CI): 0.06-0.54, p = 0.002) and a significant increase in the mortality according to the peak CRP (OR 1.12, 95% CI: 1.07-1.17, p < 0.0001). By contrast, early removal of the CVC had no significant effect on the mortality (OR = 1.16, 95% CI: 0.54-2.47, p = 0.706) in univariate analysis. Furthermore, subsequent bloodstream infection after clinical decision for maintenance or early removal of the CVC was confirmed more frequently in the group with early removal (early removal, 22.6%; maintenance, 7.6%, p < 0.0001). Early removal of the CVC had no benefit regarding the mortality and prophylaxis of bloodstream infection in patients with acute leukemia undergoing remission induction chemotherapy. Therefore, maintaining a CVC for as long as possible may be considered, if catheter-related bloodstream infection is not strongly suspected.

Risk Factors for Recurrence in Pancreatic Neuroendocrine Tumor and Size as a Surrogate in Determining the Treatment Strategy: A Korean Nationwide Study.

INTRODUCTION: The prognostic factors of pancreatic neuroendocrine tumor (PNET) are unclear, and the treatment guidelines are insufficient. This study aimed to suggest a treatment algorithm for PNET based on risk factors for recurrence in a large cohort. METHODS: Data of 918 patients who underwent curative intent surgery for PNET were collected from 14 tertiary centers. Risk factors for recurrence and survival analyses were performed. RESULTS: The 5-year disease-free survival (DFS) rate was 86.5%. Risk factors for recurrence included margin status (R1, hazard ratio [HR] 2.438; R2, HR 3.721), 2010 WHO grade (G2, HR 3.864; G3, HR 7.352), and N category (N1, HR 2.273). A size of 2 cm was significant in the univariate analysis (HR 8.511) but not in the multivariate analysis (p = 0.407). Tumor size was not a risk factor for recurrence, but strongly reflected 2010 WHO grade and lymph node (LN) status. Tumors ≤2 cm had lower 2010 WHO grade, less LN metastasis (p < 0.001), and significantly longer 5-year DFS (77.9 vs. 98.2%, p < 0.001) than tumors >2 cm. The clinicopathologic features of tumors <1 and 1-2 cm were similar. However, the LN metastasis rate was 10.3% in 1-2-cm sized tumors and recurrence occurred in 3.0%. Tumors <1 cm in size did not have any LN metastasis or recurrence. DISCUSSION/CONCLUSION: Radical surgery is needed in suspected LN metastasis or G3 PNET or tumors >2 cm. Surveillance for <1-cm PNETs should be sufficient. Tumors sized 1-2 cm require limited surgery with LN resection, but should be converted to radical surgery in cases of doubtful margins or LN metastasis.

Radical antegrade modular pancreatosplenectomy (RAMPS) versus conventional distal pancreatectomy for left-sided pancreatic cancer: findings of a multicenter, retrospective, propensity score matching study.

PURPOSE: Radical antegrade modular pancreatosplenectomy (RAMPS) has been reported to achieve high rates of a negative margin and resected metastatic lymph nodes. However, many studies have used historical controls and the results remain controversial. We conducted this study to compare the surgical and long-term outcomes of RAMPS vs. conventional distal pancreatectomy (DP). METHODS: The subjects of this multicenter retrospective study were 106 patients who underwent curative resection for left-sided pancreatic cancer between 2012 and 2017. Overall survival (OS) and recurrence-free survival (RFS) rates were compared using Kaplan-Meier estimates. RESULTS: The RAMPS group had more advanced T (T3/T4) and N stages (N1/N2) and a larger tumor size than the conventional group (T stage, p = 0.04; N stage, p = 0.02; tumor size, p = 0.04). The RAMPS group had more harvested metastatic lymph nodes (p = 0.02). After propensity-score matching, 37 patients from each group were included in the final analysis. There was no significant difference in RFS (p = 0.463) or OS (p = 0.383) between the groups. Multivariate analyses revealed the completion of chemotherapy to be an independent factor for RFS and OS (both p < 0.001). CONCLUSIONS: There was no difference in the RFS or OS between RAMPS and conventional DP in this series. RAMPS may be an option for R0 resection of advanced tumors; however, postoperative chemotherapy has a greater influence than the surgical procedure on the prognosis of patients with pancreatic cancer.

Defining Benchmark Outcomes for Pancreatoduodenectomy With Portomesenteric Venous Resection.

OBJECTIVE: The aim of this study was to establish clinically relevant outcome benchmark values using criteria for pancreatoduodenectomy (PD) with portomesenteric venous resection (PVR) from a low-risk cohort managed in high-volume centers. SUMMARY BACKGROUND DATA: PD with PVR is regarded as the standard of care in patients with cancer involvement of the portomesenteric venous axis. There are, however, no benchmark outcome indicators for this population which hampers comparisons of patients undergoing PD with and without PVR resection. METHODS: This multicenter study analyzed patients undergoing PD with any type of PVR in 23 high-volume centers from 2009 to 2018. Nineteen outcome benchmarks were established in low-risk patients, defined as the 75th percentile of the median outcome values of the centers (NCT04053998). RESULTS: Out of 1462 patients with PD and PVR, 840 (58%) formed the benchmark cohort, with a mean age was 64 (SD11) years, 413 (49%) were females. Benchmark cutoffs, among others, were calculated as follows: Clinically relevant pancreatic fistula rate (International Study Group of Pancreatic Surgery): ≤14%; in-hospital mortality rate: ≤4%; major complication rate Grade≥3 and the CCI up to 6 months postoperatively: ≤36% and ≤26, respectively; portal vein thrombosis rate: ≤14% and 5-year survival for patients with pancreatic ductal adenocarcinoma: ≥9%. CONCLUSION: These novel benchmark cutoffs targeting surgical performance, morbidity, mortality, and oncological parameters show relatively inferior results in patients undergoing vascular resection because of involvement of the portomesenteric venous axis. These benchmark values however can be used to conclusively assess the results of different centers or surgeons operating on this high-risk group.

Effects of Pancreatic Enzyme Replacement Therapy on Body Weight and Nutritional Assessments After Pancreatoduodenectomy in a Randomized Trial.

BACKGROUND & AIMS: We studied the effects of pancreatic enzyme replacement therapy (PERT) on body weight, nutritional status, and quality of life (QoL) in patients with pancreatic exocrine insufficiency after pancreatoduodenectomy. METHODS: We performed a randomized, double-blind trial of 304 patients who underwent pancreatoduodenectomy at 7 tertiary referral hospitals in South Korea. Patients with fecal levels of elastase of 200 µg/g or less, before and after surgery, were assigned randomly to groups that received PERT (a single capsule of 40,000 IU pancreatin, Norzyme (40,000 IU, Pankreatan; Nordmark Arzneimittel GmbH & Co, Uetersen, Germany), 3 times each day during meals for 3 months; n = 151) or placebo (n = 153). Protocol completion was defined as taking more than two thirds of the total dose without taking other digestive enzymes; the protocol was completed by 71 patients in the PERT group and 93 patients in the placebo group. Patients underwent a physical examination, oral glucose tolerance tests, and blood tests at baseline and at month 3 of the study period. The primary end point was change in body weight. Secondary end points were changes in bowel habits, nutritional parameters, and QoL. RESULTS: In the per-protocol analysis, 3 months after the study began, patients in the PERT group gained a mean of 1.09 kg in weight and patients in the placebo group lost a mean of 2.28 kg (difference between groups, 3.37 kg; P < .001). However, no difference in body weight was observed between groups in the intent-to-treat analysis. Three months after the study began, the mean serum levels of prealbumin increased by 10.9 mg/dL in the PERT group and increased by 7.8 mg/dL in the placebo group (P = .002). Poor compliance to PERT was a significant risk factor for weight loss (P < .001). There was no significant difference in QoL scores between groups. CONCLUSIONS: In the intent-to-treat analysis of data from a randomized trial, we found no significant effect of PERT on mean body weights of patients with pancreatic exocrine insufficiency after pancreatoduodenectomy. However, with active education and monitoring, PERT could increase body weight and nutritional parameters. ClinicalTrials.gov no: NCT02127021.

A membrane-tethering pepducin derived from formyl peptide receptor 3 shows strong therapeutic effects against sepsis.

Formyl peptide receptors (FPRs) are G protein-coupled receptors mainly expressed in inflammatory myeloid cells. Previous reports demonstrated that human neutrophils express only FPR1 and FPR2 but not FPR3. Here, we found that FPR3 is expressed in sepsis patient derived neutrophils and Fpr3 is expressed in the mouse neutrophils. To test the role of Fpr3 in neutrophil activity, we synthesized Fpr3 pepducins and successfully developed an agonistic pepducin that stimulates Fpr3, eliciting calcium increase and chemotactic migration of neutrophils. We also found that administration of an Fpr3 pepducin in an experimental mouse sepsis model significantly increased the survival rate. The pepducin markedly inhibited lung injury, splenocyte apoptosis, and inflammatory cytokine production. Bacterial counts were significantly decreased by the pepducin in septic mice. Based on these results, we suggest that FPR3 can be regarded as a new target to control sepsis, and the newly generated Fpr3-based pepducin can be used for the development of anti-septic agents.

Antifungal evaluation of fengycin isoforms isolated from Bacillus amyloliquefaciens PPL against Fusarium oxysporum f. sp. lycopersici.

Bacillus amyloliquefaciens PPL is known to have a broad spectrum antifungal activity against plant pathogenic fungi. We focused on the cyclic lipopeptides (CLPs) extracted from the culture broth that are known to promote the ability and the efficiency of B. amyloliquefaciens PPL to control fungal diseases in pepper and tomato. In this study, the PPL strain exhibited enhanced culture yield and increased production of fengycin lipopeptides upon lecithin supplementation. The purified iturin A fraction from strain PPL exhibited higher antifungal activity (73 - 80%) against pepper anthracnose than fengycin fraction in vitro and in vivo. However, the control of tomato Fusarium wilt by the PPL strain was mainly attributed to fengycin lipopeptides. A comparison of liquid chromatography-mass spectrometry (LC-MS) and LC-tandem MS analysis of the filtrate, we found that the antifungal compounds against Fusarium wilt present in the strain PPL culture filtrate were a series of isoforms of fengycin (type F1, F2, and F3). The purified fengycin F1 type showed better antifungal activity against Fusarium wilt compared the other isoforms. To the best of our knowledge, this is the first study to report the antifungal activity of fengycin isoform types in the context of Fusarium wilt. The CLPs produced by the PPL strain are potential candidates for controlling fungal disease in tomato and pepper plants.

Combination versus single-agent as palliative chemotherapy for gastric cancer.

BACKGROUND: Although combination chemotherapy (CC) is generally recommended in recurrent or primary metastatic gastric cancer (RPMGC), the results of randomized trials are conflicting. METHODS: A retrospective review was conducted on 687 RPMGC patients who received palliative chemotherapy. We compared the overall survival (OS) between CC and single-agent chemotherapy (SC) among these patients, and we analyzed the clinicopathological characteristics affecting outcome including neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). RESULTS: Although 521 patients (75.8%) underwent CC, SC was more frequently performed in elderly patients (57.6%) and ECOG performance status (PS) 2 or 3 (65.8%) patients (p < 0.0001, in each case). The median OS of patients who received CC was significantly longer than that of patients who received SC (11 vs. 8 months, p < 0.0001). No difference in OS between CC and SC was observed in elderly patients (p = 0.583), poor PS (p = 0.810), signet ring cell (p = 0.347), palliative surgical resection (p = 0.307), and high PLR (p = 0.120), with a significant interaction between age and type of regimen (p = 0.012). Moreover, there was no difference in OS between CC and SC after propensity score matching (p = 0.322). Multivariate analysis revealed that palliative resection and ≥ second-line chemotherapy were independently associated with favorable OS (p < 0.0001, in each case), whereas poor PS (p = 0.004), signet ring cell (p < 0.0001), peritoneal metastasis (p = 0.04), high NLR (p = 0.001), and high PLR (p = 0.033) were independent prognostic factors of poor OS. CONCLUSIONS: Although CC is the standard of care in RPMGC, SC can be considered a reasonable option in certain subgroups, such as elderly patients.

Propensity score-matched analysis of internal stent vs external stent for pancreatojejunostomy during pancreaticoduodenectomy: Japanese-Korean cooperative project.

BACKGROUND: Several studies comparing internal and external stents have been conducted with the aim of reducing pancreatic fistula after PD. There is still no consensus, however, on the appropriate use of pancreatic stents for prevention of pancreatic fistula. This multicenter large cohort study aims to evaluate whether internal or external pancreatic stents are more effective in reduction of clinically relevant pancreatic fistula after pancreaticoduodenectomy (PD). METHODS: We reviewed 3149 patients (internal stent n = 1,311, external stent n = 1838) who underwent PD at 20 institutions in Japan and Korea between 2007 and 2013. Propensity score matched analysis was used to minimize bias from nonrandomized treatment assignment. The primary endpoint was the incidence of clinically relevant pancreatic fistula. This study was registered on the UMIN Clinical Trials Registry (UMIN000032402). RESULTS: After propensity score matched analysis, clinically relevant pancreatic fistula occurred in more patients in the external stents group (280 patients, 28.7%) than in patients in the internal stents group (126 patients, 12.9%) (OR 2.713 [95% CI, 2.139-3.455]; P < 0.001). In subset analysis of a high-risk group with soft pancreas and no dilatation of the pancreatic duct, clinically relevant pancreatic fistula occurred in 90 patients (18.8%) in internal stents group and 183 patients (35.4%) in external stents group. External stents were significantly associated with increased risk for clinically relevant pancreatic fistula (OR 2.366 [95% CI, 1.753-3.209]; P < 0.001). CONCLUSION: Propensity score matched analysis showed that, regarding clinically relevant pancreatic fistula after PD, internal stents are safer than external stents for pancreaticojejunostomy.

New staining method using methionyl-tRNA synthetase 1 antibody for brushing cytology of bile duct cancer.

BACKGROUND AND AIMS: Identifying malignant biliary strictures using endobiliary brushing cytology specimens is important for treatment decision-making and prognosis prediction. The sensitivity of brushing cytology specimens based on Papanicolaou (Pap) staining is low, which hampers accurate diagnosis of indeterminate strictures. Here, we assessed the diagnostic value of immunohistochemical (IHC) and immunofluorescence (IF) staining for methionyl-tRNA synthetase 1 (MARS1). METHODS: Endobiliary brushing cytology specimens were obtained during ERCP from 80 patients with an extrahepatic biliary stricture. Pap and MARS1 IF staining were performed on liquid-based cytology slides derived from these specimens. Sections of bile duct adenocarcinoma and normal bile duct tissue were obtained from 45 patients who underwent surgery for malignant biliary stricture, and MARS1 levels were evaluated by IHC staining. RESULTS: MARS1 IF staining was applied to brushing cytology specimens, and the results showed strong signals in malignant biliary structures but not in the negative for malignancy specimens. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 70.4%, 96.2%, 97.4%, 56.8%, and 78.8%, respectively, for conventional Pap staining and 98.1%, 96.1%, 98.1%, 96.2%, and 97.5%, respectively, for MARS1 IF (P < .0001). When IHC staining was used, MARS1 was detected in 45 bile duct adenocarcinoma sections but not in 15 normal bile duct sections. Moreover, MARS1 mRNA and protein levels were significantly higher in bile duct adenocarcinoma sections according to polymerase chain reaction and Western blot, respectively. CONCLUSIONS: The high sensitivity and accuracy of MARS1 IF staining enabled detection of malignancy in patients with indeterminate biliary stricture. Further prospective studies are needed to validate our findings. (Clinical trial registration number: KCT 0003285.).