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Duodenal cancer is considered to be a small intestinal carcinoma in terms of clinicopathology. In Japan, there are no established treatment guidelines based on sufficient scientific evidence; therefore, in daily clinical practice, treatment is based on the experience of individual physicians. However, with advances in diagnostic modalities, it is anticipated that opportunities for its detection will increase in future. We developed guidelines for duodenal cancer because this disease is considered to have a high medical need from both healthcare providers and patients for appropriate management. These guidelines were developed for use in actual clinical practice for patients suspected of having non-ampullary duodenal epithelial malignancy and for patients diagnosed with non-ampullary duodenal epithelial malignancy. In this study, a practice algorithm was developed in accordance with the Minds Practice Guideline Development Manual 2017, and Clinical Questions were set for each area of epidemiology and diagnosis, endoscopic treatment, surgical treatment, and chemotherapy. A draft recommendation was developed through a literature search and systematic review, followed by a vote on the recommendations. We made decisions based on actual clinical practice such that the level of evidence would not be the sole determinant of the recommendation. This guideline is the most standard guideline as of the time of preparation. It is important to decide how to handle each case in consultation with patients and their family, the treating physician, and other medical personnel, considering the actual situation at the facility (and the characteristics of the patient).

Correlation of clinicopathological factors and ASGR2 expression levels

ASGR2 inhibitory assay of N87 cells.

Specific primers for PCR and small interfering RNA

Supplemental Methods

Gene set enrichment analysis of ASGR2 expression in GSE62254

Hematogenous recurrence is a challenging clinical finding that often leads to fatalities of patients with gastric cancer. Therefore, the identification of specific biomarkers and potential therapeutic target molecules for hematogenous recurrence is required to improve the outcomes of these patients. Here, transcriptome and bioinformatics analyses were conducted to uncover candidate molecules differentially expressed in patients with hematogenous recurrence of gastric cancer. One potential candidate identified was asialoglycoprotein receptor 2 (ASGR2), and siRNA experiments were conducted to determine the effect of manipulating ASGR2 expression has on cell phenotypes. ASGR2 mRNA expression analysis using quantitative real-time reverse-transcription PCR was conducted with stage II/III gastric cancer clinical specimens (n = 95). Transcript levels were increased in gastric cancer cells as compared with a control nontumorigenic epithelial cell line. Knockdown of ASGR2 decreased the adhesion and migration potential. Thus, although gastric cancer cell–invasive activity was significantly decreased by knockdown, forced expression of ASGR2 promoted invasive activity. Using a mouse hepatic metastasis model, knockdown of ASGR2 resulted in the absence of hepatic metastasis formation. High ASGR2 expression in primary gastric cancer tissues was an independent predictor of shorter disease-free and overall survival. Finally, patients with high ASGR2 expression were more likely to have a high cumulative rate of hematogenous recurrence but not peritoneal or nodal recurrence.Implications: ASGR2 expression is associated with the malignant phenotypes in gastric cancer and represents a specific biomarker of hematogenous recurrences after curative resection for gastric cancer. Mol Cancer Res; 16(9); 1420–9. ©2018 AACR.

ASGR2 expression status of cancer wide cell lines and the status of co-regulated genes.

Public database analyses

Effect of forced expression of ASGR2 on MKN1cell proliferation.

The axon guidance gene family, SLIT/ROBO pathway, controls neural network formation, which correlates with the development of several cancers.We found through analysis of the public database that ROBO4, one of the axon guidance molecules among the SLIT/ROBO family, is significantly downregulated in primary pancreatic cancer tissues compared with adjacent normal tissues. We carried out transfection experiments using three pancreatic cancer cell lines (MiaPaCa-2, BxPC-3, and SW1990) and one pancreatic duct epithelial cell line (HPDE6c7). A total of 51 clinical samples were then examined by immunohistochemical staining to find an association between ROBO4 expression at the protein level, clinical characteristics, and surgical outcomes.ROBO4 overexpression suppressed the invasion and migration abilities in MiaPaCa-2 and BxPC-3, while ROBO4 siRNA transfection to SW1990 and HPDE6c7 enhanced those activities. PCR-based profiling detected MMP-9 as a candidate downstream target of ROBO4, which was validated by decreased MMP-9 activity after the ROBO4 overexpression assay. High ROBO4 expression clinical samples had significantly better overall survival rather than low ROBO4 cases (P = 0.048).These findings suggest that decreased ROBO4 expression activates malignant phenotypes in cancer cells and is correlated with poor survival outcomes in pancreatic cancer.

Objective: Given the frequent adverse events with multidrug chemotherapy, not only the survival benefit but also the feasibility of using neoadjuvant chemotherapy to treat pancreatic cancer need to be clarified. Summary of Background Data: Although the development of multidrug chemotherapy regimens has improved the survival outcomes of patients with unresectable pancreatic cancer, the benefits of these treatments in the neo-adjuvant setting remain controversial. Methods: Patients with borderline-resectable pancreatic cancer were enrolled and randomly assigned to receive neoadjuvant chemotherapy with either FOLFIRINOX or gemcitabine with nab-paclitaxel (GEM/nab-PTX). After the completion of chemotherapy, patients underwent surgical resection when feasible. This study (NUPAT-01) was a randomized phase II trial, and the primary endpoint was the R0 resection rate. Results: Fifty-one patients were enrolled in this study [FOLFIRINOX (n = 26) and GEM/nab-PTX (n = 25)]. A total of 84.3% (n = 43/51) of the patients eventually underwent surgery, and R0 resection was achieved in 67.4% (n = 33/ 51) of the patients. Adverse events (grade >3) due to neoadjuvant treatment were observed in 45.1% of the patients (n = 23/51), and major surgical complications occurred in 30.0% (n = 13/43), with no mortality noted. The intention-to-treat analysis showed that the 3-year overall survival rate was 54.7%, with a median survival time of 39.4 months, and a significant difference in overall survival was not observed between the FOLFIRINOX and GEM/nab-PTX groups. Conclusions: These results indicate that neoadjuvant chemotherapy with FOLFIRINOX or GEM/nab-PTX is feasible and well tolerated, achieving an R0 resection rate of 67.4%. The survival of patients was even found to be favorable in the intention-to-treat analysis.

BACKGROUND/PURPOSE Patients with pancreatic ductal adenocarcinoma (PDAC) with peritoneal dissemination have a dismal prognosis because discontinuation of systemic chemotherapy is required for massive ascites or poor performance status. The natural history, diagnosis and treatment of PDAC with peritoneal dissemination have not been fully investigated. METHODS We systematically reviewed published information on the clinical diagnosis and treatment of PDAC with peritoneal dissemination using the PubMed database (2000-2020) and provided recommendations in response to clinical questions. This guideline was created according to the "Minds Clinical Practice Guideline Development Guide 2017". The literature quality and body of evidence were evaluated with the GRADE System and classified into four levels ("strong", "medium", "weak", "very weak"). The strength of each final recommendation was decided by a vote of committee members based on the GRADE Grid method. RESULTS These guidelines address 3 subjects: diagnostic, chemotherapeutic, and surgical approaches. They include 9 clinical questions and statements with recommendation strengths, evidence levels, and agreement rates, in addition to one "column". CONCLUSIONS This is the English synopsis of the 2021 Japanese clinical practice guideline for PDAC with peritoneal dissemination. It summarizes the clinical evidence for the diagnosis and treatment of PDAC with peritoneal dissemination and provides future perspectives.

Supplementary data contains additional methods and figures. The figures contain the following information: Supplementary Figure 1 extends Figure 1 providing evidence that Meflin is expressed in BM MSCs and PSCs in mice. Supplementary Figure 2 supports Figure 1 showing the development of the Meflin-ZDC mice. Supplementary Figure 3-5 extend Figure 1 providing additional evidence that Meflin is specifically expressed in PSCs and CAFs and its expression is regulated by calcipotriol. Supplementary Figure 6-9 support Figure 2 showing the detection of Meflin expression at the protein and mRNA levels in human and mouse PDAC. Supplementary Figure 10 and 11 support Figure 2 showing the data of single-cell RNA sequencing of CAFs isolated from PDAC and breast cancer mouse models. Supplementary Figure 12 supports Figure 3 showing the effects of Meflin depletion on the global gene expression profiles in mouse MSCs. Supplementary Figure 13 supports Figure 3 showing the analysis of tumors developed in WT and Meflin-KO KPC mice. Supplementary Figure 14 supports Figure 6 showing the development of the Meflin-CreERT2 mice. Supplementary Figure 15 and 16 support Figure 7 showing the effect of exogenous Meflin expression on MSC gene expression and the growth of xenograft tumors. Supplementary Figure 17 support Figure 7 showing the role of Meflin in collagen remodeling in mouse and human PDAC. Supplementary Table 1 and 2 show the description of the cohort of PDAC patients included in the analysis and univariate and multivariate Cox regression analysis of human PDAC cases.

Cancer-associated fibroblasts (CAF) constitute a major component of the tumor microenvironment. Recent observations in genetically engineered mouse models and clinical studies have suggested that there may exist at least two functionally different populations of CAFs, that is, cancer-promoting CAFs (pCAF) and cancer-restraining CAFs (rCAF). Although various pCAF markers have been identified, the identity of rCAFs remains unknown because of the lack of rCAF-specific marker(s). In this study, we found that Meflin, a glycosylphosphatidylinositol-anchored protein that is a marker of mesenchymal stromal/stem cells and maintains their undifferentiated state, is expressed by pancreatic stellate cells that are a source of CAFs in pancreatic ductal adenocarcinoma (PDAC). In situ hybridization analysis of 71 human PDAC tissues revealed that the infiltration of Meflin-positive CAFs correlated with favorable patient outcome. Consistent herewith, Meflin deficiency led to significant tumor progression with poorly differentiated histology in a PDAC mouse model. Similarly, genetic ablation of Meflin-positive CAFs resulted in poor differentiation of tumors in a syngeneic transplantation model. Conversely, delivery of a Meflin-expressing lentivirus into the tumor stroma or overexpression of Meflin in CAFs suppressed the growth of xenograft tumors. Lineage tracing revealed that Meflin-positive cells gave rise to α-smooth muscle actin-positive CAFs that are positive or negative for Meflin, suggesting a mechanism for generating CAF heterogeneity. Meflin deficiency or low expression resulted in straightened stromal collagen fibers, which represent a signature for aggressive tumors, in mouse or human PDAC tissues, respectively. Together, the data suggest that Meflin is a marker of rCAFs that suppress PDAC progression.Significance:Meflin marks and functionally contributes to a subset of cancer-associated fibroblasts that exert antitumoral effects.

BACKGROUND Oligometastatic cancer (OM) is possibly associated with relatively better survival outcomes. We attempted to identify cases in line with this OM concept. PATIENTS AND METHODS A total of 130 cases with unresectable metastatic pancreatic cancer underwent non-curative surgery from April 2001 to December 2019. Sites of metastasis, clinicopathological information, and surgical outcomes were collected to formulate a better definition of OM. RESULTS OM criteria were defined as having metastasis to a single organ, few countable lesions and low serum cancer antigen 19-9 level. The median overall survival after non-curative surgery of OM cases was 13.0 months and was significantly better than that of non-OM cases (8.4 months, p=0.003). CONCLUSION We propose single-organ metastasis of limited tumor volume (H1 or P1/2 by the Japanese Society of Cancer of the Colon and Rectum classification) and low serum cancer antigen 19-9 level (

Duodenal cancer is considered to be a small intestinal carcinoma in terms of clinicopathology. In Japan, there are no established treatment guidelines based on sufficient scientific evidence; therefore, in daily clinical practice, treatment is based on the experience of individual physicians. However, with advances in diagnostic modalities, it is anticipated that opportunities for its detection will increase in future. We developed guidelines for duodenal cancer because this disease is considered to have a high medical need from both healthcare providers and patients for appropriate management. These guidelines were developed for use in actual clinical practice for patients suspected of having non-ampullary duodenal epithelial malignancy and for patients diagnosed with non-ampullary duodenal epithelial malignancy. In this study, a practice algorithm was developed in accordance with the Minds Practice Guideline Development Manual 2017, and Clinical Questions were set for each area of epidemiology and diagnosis, endoscopic treatment, surgical treatment, and chemotherapy. A draft recommendation was developed through a literature search and systematic review, followed by a vote on the recommendations. We made decisions based on actual clinical practice such that the level of evidence would not be the sole determinant of the recommendation. This guideline is the most standard guideline as of the time of preparation. It is important to decide how to handle each case in consultation with patients and their family, the treating physician, and other medical personnel, considering the actual situation at the facility (and the characteristics of the patient).

OBJECTIVE We performed genome-wide expression profiling to develop an exosomal miRNA panel for predicting recurrence following surgery in patients with PDAC. SUMMARY BACKGROUND DATA Pre-treatment risk stratification is essential for offering individualized treatments to patients with pancreatic ductal adenocarcinoma (PDAC), but predicting recurrence following surgery remains clinically challenging. METHODS We analyzed 210 plasma and serum specimens from four cohorts of PDAC patients. Using a discovery cohort (n = 25), we performed genome-wide sequencing to identify candidate exosomal miRNAs (exo-miRNAs). Subsequently, we trained and validated the predictive performance of the exo-miRNAs in two clinical cohorts (training cohort: n = 82, validation cohort: n = 57) without neoadjuvant therapy (NAT), followed by a post-NAT clinical cohort (n = 46) as additional validation. RESULTS We performed exo-miRNA expression profiling in plasma specimens obtained before any treatment in a discovery cohort. Subsequently we optimized and trained a 6-exo-miRNA risk-prediction model, which robustly discriminated patients with recurrence (AUC: 0.81, 95% CI: 0.70-0.89) and relapse-free survival (RFS, P < 0.01) in the training cohort. The identified exo-miRNA panel was successfully validated in an independent validation cohort (AUC: 0.78, 95% CI: 0.65-0.88, RFS: P < 0.01), where it exhibited comparable performance in the post-NAT cohort (AUC: 0.72, 95% CI: 0.57-0.85, RFS: P < 0.01) and emerged as an independent predictor for RFS (HR: 2.84, 95% CI: 1.30-6.20). CONCLUSIONS We identified a novel, non-invasive exosomal miRNA signature that robustly predicts recurrence following surgery in patients with PDAC; highlighting its potential clinical impact for optimized patient selection and improved individualized treatment strategies.

Background The liver is the most common site for haematogenous metastasis of gastric cancer, and liver metastasis is fatal. Methods We conducted a transcriptomic analysis between metastatic foci in the liver, primary tumour and adjacent tissues from gastric cancer patients with metastasis limited to the liver. We determined mRNA expression levels in tumour tissues of 300 patients with gastric cancer via quantitative RT-PCR. The oncogenic phenotypes of GNG4 were determined with knockdown, knockout and forced expression experiments. We established and compared subcutaneous and liver metastatic mouse xenograft models of gastric cancer to reveal the roles of GNG4 in tumorigenesis in the liver. Results GNG4 was upregulated substantially in primary gastric cancer tissues as well as liver metastatic lesions. High levels of GNG4 in primary cancer tissues were associated with short overall survival and the likelihood of liver recurrence. Functional assays revealed that GNG4 promoted cancer cell proliferation, the cell cycle and adhesiveness. Tumour formation by GNG4-knockout cells was moderately reduced in the subcutaneous mouse model and strikingly attenuated in the liver metastasis mouse model. Conclusions GNG4 expression may provide better disease monitoring for liver metastasis, and GNG4 may be a novel candidate therapeutic target for liver metastasis.

Background Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies globally. We have previously explored the clinical efficacy of intraperitoneal (IP) paclitaxel therapy for patients with PDAC and peritoneal metastasis, which demonstrated favourable response and disease control rates. However, the real implications of conversion surgery after IP therapy remain unclear. Methods We conducted two multicenter clinical trials of IP therapy with paclitaxel in patients with PDAC and peritoneal metastasis. We focused on patients who underwent conversion surgery and investigated the long-term outcomes, particularly, initial recurrence patterns and long-term survival. Results Seventy-nine patients with PDAC and peritoneal metastasis were treated, and 33 (41.8%) patients received SP (intravenous IP paclitaxel with S-1) and 46 (58.3%) were administered GAP (intravenous gemcitabine + nab-paclitaxel combined with IP paclitaxel) combination therapy. Of the 79 patients, 16 (20.3%) underwent conversion surgery. The median time to surgery was 9.0 (range, 4.1-13.0) months after the initiation of chemotherapy. Finally, 13 (81.3%) patients underwent R0 resection. Evans grade was IIA in nine patients, IIB in four patients, III in two patients, and IV in one patient. The median overall survival time in patients who underwent conversion surgery was 32.5 (range, 13.5-66.9) months. Twelve (75.0%) patients were found to have experienced recurrence after conversion surgery. Especially, peritoneal recurrence was observed in 50% of patients as the initial recurrence pattern. The median recurrence-free survival time was 9.2 (range, 5.1-32.8) months, and three patients have survived without recurrence to date. Conclusions Our IP therapy displays promising clinical efficacy with acceptable tolerability in patients with PDAC and peritoneal metastasis. Although we could observe some super-responders in the cohort, further improvements in IP therapy are warranted.

Background: Occult-bacterial translocation (O-BT) has been reported as the condition in which microorganisms are detected in blood or lymph nodes by a highly sensitive method. However, the clinical impact of preoperative O-BT on postoperative complication is unclear. Study design: A prospective observational study with patients undergoing pancreatoduodenectomy for periampullary diseases was conducted. Blood samples were collected immediately after induction of anesthesia. The status of O-BT was investigated using bacterium-specific ribosomal RNA-targeted reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR). The impact of O-BT on surgical site infection (SSI) was analyzed. Results: A total of 155 patients were included. The positive rate in preoperative blood samples detected by RT-qPCR was significantly higher than that obtained by the culture method (32 of 155 vs 4 of 155, p < 0.001). Preoperative blood samples were contaminated with 1.0 to 19.2 bacterial cells/mL in positive patients, and 30 of the 41 detected microorganisms were obligate anaerobes. No differences in preoperative factors were observed between patients with positive and negative RT-qPCR results. The incidence of any SSI was significantly higher in patients with contaminated preoperative blood (≥1.2 bacterial cells/mL) than in other patients (14 of 27 vs 35 of 128, p = 0.013). Multivariable analysis indicated that contaminated preoperative blood was identified as one of the independent risk factors for SSI (odds ratio 2.71, 95% CI 1.04 to 7.24, p = 0.041). Conclusions: O-BT, predominantly with obligate anaerobes, was commonly observed in preoperative blood samples. In addition to the previously known risk factors, O-BT may be one of the risk factors for SSI after pancreatoduodenectomy.

Circular RNA (circRNA) is a type of non-coding RNA known to affect cancer-related micro RNAs and various transcription factors. circRNA has promise as a cancer-related biomarker because its circular structure affords high stability. We found using high-throughput sequencing that seven candidate circRNAs (hsa_circ_0041150, hsa_circ_0025624, hsa_circ_0001020, hsa_circ_0028129, hsa_circ_0008558, hsa_circ_0036683, hsa_circ_0058087) were downregulated in HCC. The expression of these circRNAs was examined by quantitative PCR in 233 sets of HCC and matched background normal liver tissues, and correlations between candidate circRNA expression and prognosis were evaluated. The results of quantitative PCR showed that expression of hsa_circ_0041150, hsa_circ_0001020 and hsa_circ_0008558 was significantly lower in HCC than in background normal liver tissues. Kaplan–Meier analysis revealed that low expression of hsa_circ_0001020, hsa_circ_0036683, and hsa_circ_0058087 was associated with poor recurrence-free (RFS) and overall survival (OS) in HCC. Additionally, multivariate analysis revealed that low hsa_circ_0036683 expression was a significant prognostic factor, independent from other clinicopathological features, for inferior RFS and OS. There was no significant association between the expression of these circRNAs and hepatitis B/C status or cirrhosis. This study therefore identified circRNAs as potential prognostic markers for patients who undergo curative surgery for HCC and highlighted hsa_circ_0036683 as the most useful biomarker.

Background Gastric cancer (GC) with hepatic metastasis has a poor prognosis. Understanding the molecular mechanisms involved in hepatic metastasis may contribute to the development of sensitive diagnostic biomarkers and novel therapeutic strategies. Methods We performed transcriptome analysis of surgically resected specimens from patients with advanced GC. One of the genes identified as specifically associated with hepatic metastasis was selected for detailed analysis. GC cell lines with knockout of the candidate gene were evaluated in vitro and in vivo. Expression of the candidate gene was analysed in GC tissues from 300 patients. Results Ethanolamine kinase 2 (ETNK2) was differentially upregulated in GC patients with hepatic metastasis. ETNK2 expression was elevated in GC cell lines derived from haematogenous metastases. ETNK2 knockout significantly suppressed proliferation, invasion, and migration; increased apoptosis; reduced Bcl-2 protein expression; and increased phosphorylated p53 expression. In mouse xenograft models, ETNK2 knockout virtually abolished hepatic metastasis. Stratification of GC patients based on ETNK2 mRNA level revealed significant associations between high ETNK2 tumour expression and both hepatic recurrence and worse prognosis. Conclusions Upregulation of ETNK2 in GC enhances hepatic metastasis, possibly via dysregulation of p53–Bcl-2-associated apoptosis. ETNK2 expression may serve as a biomarker for predicting hepatic recurrence and a therapeutic target.

Aim Right‐half dissection of the superior mesenteric artery (SMA) nerve plexus in pancreatoduodenectomy for pancreatic cancer was initiated to accomplish R0 resection; however, subsequent refractory diarrhea was a major concern. This study aimed to evaluate the necessity of this technique. Methods From April 2014 to June 2018, 74 patients with pancreatic head cancer were randomly allocated to either Group A, in which right‐half dissection of the SMA nerve plexus was performed (n = 37), or Group B, in which total preservation of the nerve plexus was performed (n = 37). Short‐term, long‐term, and survival outcomes were prospectively compared between the groups. Results The patient demographics, including the R0 resection rate, were not significantly different between the groups. Postoperative diarrhea occurred in 26 (70.3%) patients in Group A and 18 (48.6%) patients in Group B. There was a tendency for the development of severe diarrhea in Group A within 1 year postoperatively, and the frequency of diarrhea gradually decreased within 2 years, although that did not affect tolerance to adjuvant chemotherapy. There was no difference in either locoregional recurrence (27.0% vs 32.4%) or systemic recurrence (46.0% vs 46.0%). The median overall survival time in Groups A and B was 37.9 and 34.6 months, respectively (P = 0.77). Conclusion We did not demonstrate a clinical impact of right‐half dissection of the SMA nerve plexus on locoregional recurrence or survival. Therefore, the prophylactic dissection of the SMA nerve plexus is unnecessary given that refractory diarrhea could be induced by this technique (UMIN000012241)., The necessity of right‐half dissection of the SMA nerve plexus in pancreatoduodenectomy for pancreatic cancer was evaluated. We did not demonstrate the clinical impact of this technique on locoregional recurrence or survival. Therefore, the prophylactic dissection is unnecessary, given that refractory diarrhea could be induced by this technique.

Pancreatic intraductal papillary mucinous neoplasm (IPMN) involves multiple histopathological stages from benign to malignant lesions. Further, a biomarker to diagnose the malignant IPMN (IPMC) is clinically relevant. Recently, we found that serum fucosylated αThe fAGP level was retrospectively analyzed in preoperative sera from 109 patients with IPMN, and the clinical relevance of fAGP was compared with currently available predictors as standard.The fAGP level in IPMC was found to be significantly higher than in benign IPMN (P = .0012). At a cutoff value of 27.04 U/μg, its sensitivity, specificity, and accuracy for IPMC were determined to be 83.61%, 65.96%, and 75.93%, respectively. Multivariate analyses revealed that the fAGP level was the only independent risk factor for predicting IPMC. Additionally, a combination of the fAGP level andThe fAGP level appeared to be a relevant biomarker for malignant potential of IPMN.

Pancreatic ductal adenocarcinoma (PDAC) incidence is rising worldwide, and most patients present with an unresectable disease at initial diagnosis. Measurement of carbohydrate antigen 19-9 (CA19-9) levels lacks adequate sensitivity and specificity for early detection; hence, there is an unmet need to develop alternate molecular diagnostic biomarkers for PDAC. Emerging evidence suggests that tumor-derived exosomal cargo, particularly micro RNAs (miRNAs), offer an attractive platform for the development of cancer-specific biomarkers. Herein, genomewide profiling in blood specimens was performed to develop an exosome-based transcriptomic signature for noninvasive and early detection of PDAC.Small RNA sequencing was undertaken in a cohort of 44 patients with an early-stage PDAC and 57 nondisease controls. Using machine-learning algorithms, a panel of cell-free (cf) and exosomal (exo) miRNAs were prioritized that discriminated patients with PDAC from control subjects. Subsequently, the performance of the biomarkers was trained and validated in independent cohorts (n = 191) using quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays.The sequencing analysis initially identified a panel of 30 overexpressed miRNAs in PDAC. Subsequently using qRT-PCR assays, the panel was reduced to 13 markers (5 cf- and 8 exo-miRNAs), which successfully identified patients with all stages of PDAC (area under the curve [AUC] = 0.98 training cohort; AUC = 0.93 validation cohort); but more importantly, was equally robust for the identification of early-stage PDAC (stages I and II; AUC = 0.93). Furthermore, this transcriptomic signature successfully identified CA19-9 negative cases (37 U/mL; AUC = 0.96), when analyzed in combination with CA19-9 levels, significantly improved the overall diagnostic accuracy (AUC = 0.99 vs AUC = 0.86 for CA19-9 alone).In this study, an exosome-based liquid biopsy signature for the noninvasive and robust detection of patients with PDAC was developed.

BACKGROUND/AIM N6-Methyladenosine (m6A), the most abundant internal modification of RNA, plays a critical role in cancer development. However, the clinical implications of m6A in hepatocellular carcinoma (HCC) remain unclear. MATERIALS AND METHODS We analyzed 177 HCC and paired noncancerous liver tissues from patients who underwent hepatectomy according to global m6A quantification and expression of m6A demethylases fat mass and obesity-associated protein (FTO) and alpha-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5). RESULTS The global m6A quantification revealed no significant difference between HCC and non-cancerous tissue. The expression of m6A demethylases FTO and ALKBH5, was significantly lower in HCC than in non-cancerous tissues (both p

In patients with a reconstructed gastric tube, the right gastroepiploic artery is a very important feeding artery of the tube, which must be preserved when performing a pancreaticoduodenectomy. A 76-year-old man with a reconstructed gastric tube underwent pancreaticoduodenectomy for distal bile duct carcinoma. On postoperative day 8, he had an arterial hemorrhage from a drain, apparently from a ligation of the anterior superior duodenal artery. He, therefore, underwent stent-graft placement in the gastroduodenal artery. The stent-grafts were temporarily occluded, and the gastric tube was necrotizing. However, thrombolytic therapy allowed the stent-grafts to reopen and prevented gastric tube necrosis. We believe our case of stent-graft implantation in the gastroduodenal artery is the first of this kind to successfully prevent lethal necrosis of the gastric tube.

The clinical role of peritoneal lavage cytology (CY) in pancreatic ductal adenocarcinoma (PDAC) remains controversial, partly due to its low sensitivity. This study aimed to develop a new biomarker, defined as peritoneal lavage tumor DNA (ptDNA), using DNAs extracted from peritoneal lavage samples from patients with PDAC. Samples were collected intraoperatively from 89 PDAC patients who underwent pancreatectomy between 2012 and 2017. Droplet digital polymerase chain reaction (PCR) was used to measure ptDNA for detection of KRAS mutations. The ptDNA status and clinical characteristics were retrospectively evaluated. Positive ptDNA was found in 41 patients, including all 9 patients positive for CY (CY+) and 32 patients negative for CY (CY−). The mutant allele frequency was significantly higher in the CY+ patients than in the CY− patients. The disease-free survival (DFS) and overall survival (OS) were significantly poorer in the high-ptDNA group than in the low-ptDNA group (median DFS, 11.0 vs. 18.8 months; p = 0.007; median OS, 28.7 vs not reached; p = 0.001). The survival curves of DFS and OS in the CY+ group were almost equal to those in the CY− and high-ptDNA group. In a multivariable analysis, ptDNA was an independent predictive factor for DFS (p = 0.025) and OS (p = 0.047). The estimated cumulative incidence of peritoneal recurrence was 45.5% in the high-ptDNA group. The ptDNA biomarker had a much higher sensitivity for peritoneal recurrence than CY, whereas CY had higher specificity. As a promising biomarker, ptDNA may predict poor prognosis and peritoneal recurrence in PDAC, resolving the controversy surrounding CY.

Objective This study sought to investigate the characteristics of primary and repeated recurrent retroperitoneal liposarcoma. Methods Patients treated with primary or recurrent retroperitoneal liposarcoma between 2005 and 2018 were retrospectively reviewed. Survival time analysis of recurrence-free survival and overall survival was conducted using Kaplan–Meier analysis and log-rank test. Results Fifty-two patients with primary retroperitoneal liposarcoma were analysed. Amongst them, 46 patients (88%) had undergone surgery. Histologic grades included well-differentiated (n = 21), dedifferentiated (n = 21), myxoid (n = 3) and pleomorphic (n = 1) subtypes. The patients undergoing R0 resection in the first surgery had significantly higher recurrence-free survival rates compared with the patients undergoing non-R0 resection (3-year recurrence-free survival: 80 versus 38%; 5-year recurrence-free survival: 49 versus 29%, P = 0.033). Although overall survival rates tended to be higher in the patients undergoing R0 resection compared with the non-R0 resection, it did not reach to a statistical significant difference (5-year overall survival: 93 versus 75%; 10-year overall survival: 93 versus 59%, P = 0.124). The recurrence rates were 65, 67, 73 and 100%, and the median recurrence-free survival times were 46, 20, 9 and 3 months after the first, second, third and fourth surgeries, respectively. The 5-year overall survival rates were 82, 69, 40 and 0% after the first, second, third and fourth surgeries, respectively. Conclusions With repeated recurrence and surgeries, the time to recurrence decreased and the recurrence rate increased. R0 resection in the first surgery was considered the most important for longer recurrence-free survival and radical cure.

The Apolipoprotein-related MORtality RISk (AMORIS) study in Sweden revealed that serum uric acid (SUA) was significantly associated with hepatobiliary cancer occurrence. However, the association with postoperative hepatocellular carcinoma (HCC) recurrence has not been reported.A total of 256 surgically resected HCC patients were included (from January 2003 to December 2017) in this study. Comparisons in terms of clinicopathologic factors and long-term outcomes were made between patients with high SUA (6.1 mg/dl) at the time of hepatectomy and low SUA. Besides, SUA data at one postoperative year (1POY) of the same cohort were collected and analyzed in the same manner.About 88.8% of tumor relapse sites were the remnant liver. High SUA levels were associated with male and well-differentiated HCCs. Recurrence-free survival (RFS) of high SUA patients was significantly inferior to low SUA patients [median survival time (MST): 22.7 vs. 28.5 mo,High SUA implies a significant risk factor of activating hepatocarcinogenesis. Keeping the SUA level low may be recommended after HCC resections.

Bacterial contamination status may differ under different biliary drainage conditions. The purpose of this study was to determine the impact of qualitative and quantitative biliary bacterial contamination on the incidence of infection complications in patients undergoing pancreatoduodenectomy. Patients undergoing pancreatoduodenectomy for periampullary diseases with different biliary drainage conditions, such as external drainage (ED), internal drainage (ID), and no drainage (ND), were included. Bile was collected intraoperatively, and biliary contamination status was qualified and quantified using bacterium-specific ribosomal RNA-targeted reverse transcription–quantitative polymerase chain reaction (RT-qPCR). The impact of biliary contamination status on infection complications was analyzed. A total of 152 patients were included (38 with ED, 40 with ID, and 74 with ND). The positive rate of microorganisms in bile was higher in the ID group (98%) compared with the ED group (82%, p = 0.021) and the ND group (65%, p 600 mL), and biliary contamination by Atopobium cluster were identified as independent risk factors for infection complications. Biliary contamination by Atopobium cluster was significantly higher in the ID group compared with the other groups. Biliary bacterial contamination is more frequently induced by ID than either ED or ND. In addition to the previously known risk factors, biliary contamination with Atopobium cluster may be one of the risk factors of infection complications following pancreatoduodenectomy.

Liver metastasis is often fatal in patients with gastric cancer, therefore, we aimed to identify genes associated with the mechanisms of liver metastasis of gastric cancer (GC) and to investigate their potential to predict recurrence and to serve as targets of therapy. Recurrence pattern-specific transcriptome analysis was performed to identify liver metastasis-associated genes. A stable knockout cell line was generated to investigate metabolic pathways that contribute to the malignant phenotype in vitro and vivo. Three hundred GC patients were analyzed to demonstrate an association between gene expression levels and clinicopathological parameters. As a results extracellular matrix complex subunit 1 (FRAS1) was identified as a liver metastasis-associated gene. Pathway analysis revealed that FRAS1 expression was significantly correlated with the expression of genes encoding TGFB1, MAP1B, AHNAK, BMP2, MUC1, BIRC5, MET, CDH1, RB1 and MKI67. FRAS1 expression was associated with the activation of the EGFR and PI3K signaling pathways. The proliferation ability of FRAS1 knockout cell line (FRAS1-KO) was inhibited compared to that of the parent cell line through caspase activity increment and cell cycle alteration. FRAS1-KO cells exhibited increased responsiveness to oxygen stress and diminished stemness, invasiveness, and migration. Mouse models of GC revealed decreases in tumor formation and generation of metastasis by FRAS1-KO cells. Moreover, the cumulative liver recurrence rate was significantly increased in patients with GC with high FRAS1 expression levels. We concluded that FRAS1 contributes to the malignant phenotype of GC, especially liver metastasis, and may therefore serve as a predictive marker or a target for treating liver metastasis.

OBJECTIVES Understanding the disparity in clinical course because of differences in initial recurrence patterns could lead to a more accurate estimation of prognosis and optimal treatment. METHODS Patients who underwent resection for pancreatic cancer between January 2003 and December 2016 were identified from a prospective database. We analyzed the association between clinicopathological information or survival outcomes and initial recurrence patterns. RESULTS The most frequent recurrence pattern was locoregional recurrence (n = 84, 31.3%), followed by simultaneous multiple recurrences (n = 65, 24.2%), liver metastasis (n = 53, 19.8%), peritoneal dissemination (n = 41, 15.3%), and lung metastasis (n = 20, 7.5%). In addition, survival outcomes were significantly longer in the lung metastasis group than in the other recurrence pattern group (recurrence-free survival, 18.2 vs 8.2 months, P < 0.001; overall survival, 86.4 vs 21.0 months, P < 0.001; and survival after recurrence, 37.1 vs 9.3 months, P < 0.001). The lung metastasis group had a significantly higher proportion of pancreatic body and tail cancer (P < 0.002) and arterial invasion (P = 0.006) than the other recurrence pattern group. CONCLUSIONS Lung metastasis as an initial recurrence pattern frequently occurred in patients with body and tail cancer and patients with arterial invasion.

The aim of this study was to explore predictive factors for portal or splenic vein thrombosis (VT) that might cause serious problems after distal pancreatectomy (DP). A total of 230 patients who underwent DP between 2008 and 2017 were retrospectively reviewed to identify predictive factors for portal or splenic VT. Ultimately, 164 patients were analyzed. Portal or splenic VT was significantly correlated with age

Background/aim Epithelial-to-mesenchymal transition (EMT) plays important roles in cancer progression. This study aimed to identify the exosomal miRNA (exo-miRNA) profiles related to the EMT status in pancreatic cancer (PC). Materials and methods Comprehensive exo-miRNA-expression profiles in the culture media of PC cell lines were analyzed through microarray technology. The identified miRNAs were analyzed to investigate their clinical implication using The Cancer Genome Atlas (TCGA) dataset and clinical samples. Results We prioritized 291 exo-miRNAs differentially expressed between epithelial and mesenchymal cell types. Among them, survival analysis based on the TCGA dataset revealed that mir-196b and mir-204 significantly stratify the prognosis of PC cases. In addition, analysis of cell lines indicated miR-196b-3p as a mesenchymal marker and miR-204-3p as an epithelial marker. Finally, we demonstrated that miR-196b-3p and miR-204-3p in serum exosomes were differentially expressed among intraductal papillary mucinous neoplasms, mucinous cystic neoplasms, and PC. Conclusion Serum exo-miRNA biomarkers potentially identify the pancreatic tumor status through less-invasive methods.

We aimed to clarify the role of potassium voltage-gated channel subfamily J member 15 (KCNJ15) in esophageal squamous cell carcinoma (ESCC) cells and its potential as a prognosticator in ESCC patients. KCNJ15 transcription levels were evaluated in 13 ESCC cell lines and polymerase chain reaction (PCR) array analysis was conducted to detect coordinately expressed genes with KCNJ15. The biological functions of KCNJ15 in cell invasion, proliferation, migration, and adhesion were validated through small interfering RNA-mediated knockdown experiments. Cell proliferation was further evaluated through the forced expression experiment. KCNJ15 expression was detected in 200 ESCC tissues by quantitative real-time reverse transcription PCR (qRT-PCR) and analyzed in 64 representative tissues by immunohistochemistry. Correlations between KCNJ15 expression levels and clinicopathological features were also analyzed. The KCNJ15 expression levels varied widely in ESCC cell lines and correlated with COL3A1, JAG1, and F11R. Knockdown of KCNJ15 expression significantly repressed cell invasion, proliferation, and migration of ESCC cells in vitro. Furthermore, overexpression of KCNJ15 resulted in increased cell proliferation. Patients were stratified using the cut-off value of KCNJ15 messenger RNA (mRNA) levels in 200 ESCC tissues using receiver operating characteristic curve analysis; the high KCNJ15 expression group had significantly shorter overall and disease-free survival times. In multivariable analysis, high expression of KCNJ15 was identified as an independent poor prognostic factor. Staining intensity of in situ KCNJ15 protein expression tended to be associated with KCNJ15 mRNA expression levels. KCNJ15 is involved in aggressive tumor phenotypes of ESCC cells and its tissue expression levels may be useful as a prognosticator of patients with ESCC.

Background Despite advances in our understanding on the pathogenesis of gastric cancer (GC), patients face a poor prognosis. To improve clinical outcomes, effective approaches to diagnosis and treatment employing new diagnostic biomarkers are required to achieve early detection and predict recurrence and prognosis. Materials and methods Transcriptome analysis was conducted using surgically resected gastric tissues from four patients with metastatic GC. A total of 228 pairs of primary GC tissues and corresponding normal adjacent tissues were subjected to mRNA expression analysis. To validate our findings, we accessed an integrated microarray dataset and RNA sequencing data of GC cell lines. Results We identified stimulated by retinoic acid 6 (STRA6) as a differentially overexpressed gene, which encodes a transmembrane protein that mediates the cellular uptake of retinol. To investigate how STRA6 contributes to the malignant phenotype of GC cells, we mined public datasets and found the mRNA encoding retinol binding protein 1 (RBP1), which is associated with retinoid metabolism, was co-expressed with STRA6. Furthermore, STRA6 mRNA levels were significantly higher in GC tissues compared to the corresponding noncancerous adjacent tissues of 228 surgically resected gastric tissue samples. Moreover, patients with high levels of STRA6 mRNA experienced significantly shorter disease-free survival and overall survival. Multivariate analysis revealed that high levels of STRA6 served as a significant risk factor. Conclusion Patients with high levels of STRA6 mRNA experienced significantly worse clinical outcomes, indicating that STRA6 may serve as a diagnostic and prognostic biomarker of GC.

680 Background: Multidisciplinary treatment of borderline resectable (BR)/unresectable locally advanced (UR-LA) pancreatic adenocarcinoma (PDAC) has not yet been established. The purpose of this study is to explore factors that improve prognosis in radical surgery after multidisciplinary treatment for pancreatic cancer. Methods: We evaluated the following prognostic factors in 240 PDAC patients who underwent radical resection after multidisciplinary treatment. Patients were classified into 3 groups according to NCCN guidelines (BR PDAC invading the portal vein (BR-PV), BR pancreatic cancer in contact with the major arteries such as the hepatic artery, celiac axis and superior mesenteric artery (BR-A), and UR-LA), and prognostic factors were investigated. Patients with BR PDAC were treated with chemotherapy followed by surgery, while radiation therapy was added preoperatively in most cases with arterial invasion. All patients with UR-LA underwent surgery after nab-paclitaxel plus gemcitabine (GnP) followed by chemoradiotherapy (CRT) with S-1. Results: BR-PV/BR-A/UR-LA patients were 88/111/41, respectively. Prognosis was significantly better in the NAT group than in the upfront surgery group for both BR-PV/A (P=0.004/42.5 (P=0.022). In univariate analysis in 39 patients with BR-A, the following factors were significantly favorable prognostic factors; TM normalization (P=0.033), preoperative PNI>42.5 (P=0.013), intraoperative blood loss>830 ml (P=0.013). Multivariate analysis revealed that high preoperative PNI was an independent prognostic factor (hazard ratio 0.15 [0.02-0.85]; P=0.014) in BR-A patients. In patients with UR-LA who underwent radical resection after GnP and subsequent CRT, median duration of NAT was 8.8 months, and R0 resection was achieved in 36 patients (88%). 3-year OS was 77.4%, and 5-year OS 58.6%. Multivariate analysis revealed that CA19-9 normalization (hazard ratio 0.23 [0.02-0.88]; P=0.032) and PNI≥41.7 (HR 0.05 [0.01-0.62]; P=0.021) were independent prognostic factors. Conclusions: In both BR/UR-LA pancreatic cancer, normalization of TM and maintenance of good nutritional status during NAT until surgery may contribute to prolonged prognosis.

Background Local duodenectomy and primary closure is a simple option for some nonampullary duodenal neoplasms. Minimizing the resection area while ensuring curability is necessary for safe primary duodenal closure. However, it is often difficult to determine the appropriate resection line from the serosal side. We developed clip-guided local duodenectomy to easily determine the resection range and perform local duodenectomy safely, then performed a retrospective observational study to confirm the safety of clip-guided local duodenectomy. Methods The procedure is as follows: placing endoscopic metal clips at four points on the margin around the tumor within 3 days before surgery, identifying the tumor extent with the clips under X-ray imaging during surgery, making an incision to the duodenum just outside of the clips visualized by X-ray imaging, full-thickness resection of the duodenum with the clips as guides of tumor demarcation, and transversely closure by Gambee suture. We evaluated clinicopathological data and surgical outcomes of patients who underwent clip-guided local duodenectomy at two surgical centers between January 2010 and May 2020. Results Eighteen patients were included. The pathological diagnosis was adenoma (11 cases), adenocarcinoma (6 cases), and GIST (1 case). The mean ± SD tumor size was 18 ± 6 mm, and the tumor was mainly located in the second portion of the duodenum (66%). In all cases, the duodenal defect was closed with primary sutures. The mean operation time and blood loss were 191 min and 79 mL, respectively. The morbidity was 22%, and all complications were Clavien–Dindo grade II. No anastomotic leakage or stenosis was observed. In the 6 adenocarcinoma patients, all were diagnosed with pT1a, and postoperative recurrence was not observed. The 1-year overall and recurrence free survival rate was 100%. Conclusions Clip-guided local duodenectomy is a safe and useful surgical option for minimally local resection of nonampullary duodenal neoplasms such as duodenal adenoma, GIST, and early adenocarcinoma.

The adhesion G-protein-coupled receptors (GPCRs) play crucial roles in tumour pathogenesis, however, their clinical significance in pancreatic ductal adenocarcinoma (PDAC) remains unclear.We analysed 796 PDAC patients, including 331 from public data sets (TCGA, ICGC and GSE57495) and 465 from independent cohorts (training: n = 321, validation: n = 144). Using in-vitro studies, we confirmed the biological function of the candidate GPCRs.Analysis of all 33 adhesion GPCRs, led to identify GPR115, as the only significant prognostic factor in all public data sets. The patients with high GPR115 expression exhibited significantly poorer prognosis for OS and RFS, in training (P 0.01, P 0.01) and validation cohort (P 0.01, P = 0.04). Multivariate analysis indicated that GPR115 high expression was an independent prognostic factor in both cohorts (HR = 1.43; P = 0.01, HR = 2.55; P 0.01). A risk-prediction model using Cox regression by incorporating GPR115 and clinicopathological factors accurately predicted 5-year survival following surgery. In addition, GPR115 silencing inhibited cell proliferation and migration in PDAC cells.We demonstrated that GPR115 has important prognostic significance and functional role in tumour progression; providing a rationale that this may be a potential therapeutic target in patients with PDAC.

Background Pancreatic cancer is one of the lethal cancers among solid malignancies. Pathological diagnosis of surgical margins is sometimes unreliable due to tissue shrinkage, invisible field cancerization and skipped lesions like tumor budding. As a result, tumor recurrences sometimes occur even from the pathologically negative surgical margins. Methods We applied molecular surgical margin (MSM) analysis by tissue imprinting procedure to improve the detection sensitivity of tiny cancerous cells on the surgical specimen surface after pancreatoduodenectomy. Surgical specimens were collected from 45 pancreatic cancer cases who received subtotal stomach preserving pancreatoduodenectomy at Nagoya University Hospital during 2017–2019. Quantitative methylation-specific PCR (QMSP) of the original methylation marker panel (CD1D, KCNK12, PAX5) were performed and analyzed with postoperative survival outcomes. Results Among 45 tumors, 26 cases (58%) were QMSP-positive for CD1D, 25 (56%) for KCNK12 and 27 (60%) for PAX5. Among the 38 tumors in which at least one of the three markers was positive, CD1D-positive cancer cells, KCNK12-positive cancer cells, and PAX5-positive cancer cells were detected at the surgical margin in 8 cases, 7 cases and 10 cases, respectively. Consequently, a total of 17 patients had at least one marker detected at the surgical margin by QMSP, and these patients were defined as MSM-positive. They were associated with significantly poor recurrence-free survival (p = 0.002) and overall survival (p = 0.005) than MSM-negative patients. Multivariable analysis showed that MSM-positive was the only significant independent factor for worse recurrence-free survival (hazard ratio: 3.522, 95% confidence interval: 1.352–9.179, p = 0.010). On the other hand, a significant proportion of MSM-negative cases were found to have received neoadjuvant chemotherapy (p = 0.019). Conclusion Pancreatic cancer-specific methylation marker panel was established to perform MSM analysis. MSM-positive status might represent microscopically undetectable cancer cells on the surgical margin and might influence the postoperative long-term outcomes.

Background Radical antegrade modular pancreatosplenectomy (RAMPS) is an isolation procedure in pancreatosplenectomy for pancreatic body/tail cancer. Connective tissues around the bifurcation of the celiac axis are dissected, followed by median-to-left retroperitoneal dissection. This procedure has the potential to isolate blood and lymphatic flow to the area of the pancreatic body/tail and the spleen to be excised. This is achieved by division of the inflow artery, transection of the pancreas, and then division of the outflow vein in the early phases of surgery. In cases of pancreatic ductal adenocarcinoma (PDAC), the procedure has been shown to decrease intraoperative blood loss and increase R0 resection rate by complete clearance of the lymph nodes. This trial investigates whether the isolation procedure can prolong the survival of patients with pancreatic ductal adenocarcinoma who undergo distal pancreatosplenectomy (DPS) compared with those that undergo the conventional approach. Methods/design Patients with PDAC scheduled to undergo DPS are randomized before surgery to undergo either a conventional procedure (arm A) or to undergo the isolation procedure (arm B). In arm A, the pancreatic body, tail, and spleen are mobilized, followed by removal of the regional lymph nodes. The splenic vein is transected at the end of the procedure. The timing of division of the splenic artery (SA) is not restricted. In arm B, regional lymph nodes are dissected, then we transect the root of the SA, the pancreas, then the splenic vein. At the end of the procedure, the pancreatic body/tail and spleen are mobilized and removed. In total, 100 patients from multiple Japanese high-volume centers will be randomized. The primary endpoint is 2-year recurrence-free survival by intention-to-treat analysis. Secondary endpoints include intraoperative blood loss, R0 resection rate, and overall survival. Discussion If this trial shows that the isolation procedures can improve survival with a similar R0 rate and with a similar number of lymph node dissections to the conventional procedure, the isolation procedure is expected to become a standard procedure during DPS for PDAC. Conversely, if there were no significant differences in endpoints between the groups, it would demonstrate justification of either procedure from surgical and oncological points of view. Trial registration UMIN Clinical Trials Registry UMIN000041381. Registered on 10 August 2020. ClinicalTrials.gov NCT04600063. Registered on 22 October 2020.

Background: Nutritional and immunological statuses are attracting increasing attention for their ability to predict surgical outcomes in various cancers. The Naples prognostic score (NPS) consists of the serum albumin level, total cholesterol level, neutrophil-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio and could be useful for predicting survival. Patients and Methods: We retrospectively analyzed 196 patients with pancreatic cancer who underwent curative R0/R1 resection with a surgery-first strategy between June 2003 and August 2016. The NPS of the patients was calculated from preoperative data, and the patients were then divided into three groups based on their NPS. Clinicopathological characteristics, surgical outcomes, and long-term survival were compared, and multivariate analysis of overall survival was conducted. Results: Of a total of 196 patients, 22 were classified into group 0 (NPS 0), 113 into group 1 (NPS 1 or 2), and 61 into group 2 (NPS 3 or 4). Median survival time was 103.4 months in group 0, 33.3 months in group 1, and 21.3 months in group 2. Significant survival differences were observed among the 3 groups (group 1 vs. 2, group 0 vs. 2, P = 0.0380, P = 0.0022, respectively). On multivariate analysis, NPS was identified as an independent prognostic factor [hazard ratio (HR) = 1.78; P = 0.0131]; however, there were no significant differences in the incidence of postoperative morbidity among the NPS groups. Conclusions: The NPS could be an easy scoring system and an independent preoperative predictor of survival., ファイル公開：2021/03/01

Aim The aim of the study was to identify novel biomarkers that are vital for improving management of patients with gastric cancer (GC). Materials and methods An RNA-sequencing analysis was conducted using gastric tissue from patients with metastatic GC. In vitro cell functions were evaluated by siRNA-mediated knockdown assays. A total of 230 pairs of gastric tissue were subjected to expression analysis of mRNA and protein in situ. The serum levels of the candidate biomarker were determined by ELISA. Results MELTF was identified as a candidate biomarker. Inhibition of MELTF expression suppressed the invasion ability of GC cells. Increased tissue MELTF mRNA expression was associated with shorter survival. Furthermore, staining intensity of tissue MELTF protein was linked to recurrence rates. Serum MELTF levels gradually were increased from healthy controls to advanced GC. Patients with high serum MELTF levels had poor prognosis. Conclusion Both tissue and serum MELTF levels may serve as biomarkers of GC progression.