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Usefulness of various nutritional indices for management of patients with esophageal squamous cell carcinoma (ESCC) has been reported. Although Controlling Nutritional Status (CONUT) score is among promising indices to predict outcome, the optimal timing for its measurement during the perioperative period remains unknown. Here the prognostic value of the CONUT score was assessed among patients with ESCC.We analyzed 464 patients who underwent subtotal esophagectomy of ESCC, of which 276 patients were treated with neoadjuvant treatment (NAT). The significance of the associations between candidate parameters including the CONUT score and postoperative prognosis were evaluated.Among the 25 candidate predictors, the preoperative CONUT score had the highest correlation with overall survival (OS) after surgery. Patients were categorized as follows: normal, mild, and moderate or severe, on the basis of the preoperative CONUT score. OS was significantly shortened as the CONUT score worsened. Multivariable analysis revealed that the CONUT scores of the subgroups mild (Hazard ratio [HR] 1.69) and moderate or severe (HR 2.18) were independent predictors of poor prognosis for OS. Furthermore, in an analysis limited to patients who underwent NAT, OS was significantly shortened as the preoperative CONUT score worsened. On the contrary, there was no significant difference in RFS among patient groups stratified by the CONUT score determined before NAT.Our study indicates that the preoperative CONUT score serves as a prognosticator in resectable ESCC. The preoperative CONUT value was more useful than that before NAT in patients administered NAT.

Novel therapeutic targets are needed to improve the poor prognosis of patients with advanced gastric cancer. The aim of this study was to identify a novel therapeutic target for the treatment of GC and to investigate the potential therapeutic value of an antibody raised against the target.We identified gamma-aminobutyric acid type A receptor subunit delta as a candidate therapeutic target by differential transcriptome analysis of metastatic GC tissue and adjacent nontumor tissues. GABRD mRNA levels were analyzed in 230 pairs of gastric tissue by quantitative reverse-transcription polymerase chain reaction. GABRD function was assessed in proliferation, invasion, and apoptosis assays in human GC cell lines expressing control or GABRD-targeting small interfering RNA (siRNA). Mouse anti-human polyclonal GABRD antibodies were generated and assessed for inhibition of GC cell growth in vitro and in a mouse xenograft model of peritoneal GC dissemination.High GABRD mRNA expression level in primary human GC tissue was associated with poor prognosis. Expression of siGABRD in GC cell lines significantly decreased cell proliferation and invasion and increased apoptosis compared with control siRNA expression. Anti-GABRD polyclonal antibodies inhibited GC cell proliferation in vitro and decreased peritoneal tumor nodule size in the mouse xenograft model.We identified GABRD as novel regulator of GC cell growth and function. GABRD is upregulated in GC tissue and is associated with poor prognosis, suggesting that it may be a potential therapeutic target for GC.

The regimen of nanoliposomal irinotecan plus 5-fluorouracil and leucovorin (Nal-IRI/FL) was approved in Japan as second-line chemotherapy after gemcitabine-based treatment for pancreatic ductal adenocarcinoma (PDAC) in 2020. We examined the difference in outcome between patients treated with second-line folinic acid, fluorouracil, irinotecan hydrochloride and oxaliplatin (FOLFIRINOX) and those treated with nal-IRI/FL after first-line gemcitabine and nab-paclitaxel (GnP).The outcomes of 34 patients with PDAC who received second-line FOLFIRINOX (n=21) or nal-IRI/FL (n=13) after GnP at our Department from January 2016 to June 2021 were reviewed retrospectively.Patient backgrounds did not differ between the groups. Dose reduction was more frequently required for treatment with FOLFIRINOX than with nal-IRI/FL (86% vs. 46%, p=0.022). Pegfilgrastim and aprepitant were used more frequently in the FOLFIRINOX group (both p0.01). Progression-free survival (5.9 vs. 8.3 months) and overall survival (9.1 vs. 11.2 months) did not differ significantly between the groups. The frequency of grade 3 (Common Terminology Criteria for Adverse Events) or higher adverse events was similar between the groups. All-grade peripheral neuropathy was more common in the FOLFIRINOX group (100% vs. 77%, p=0.048).FOLFIRINOX and nal-IRI/FL as second-line therapy after GnP provided similar prognoses, although supportive treatment and dose reduction were more frequently required for FOLFIRINOX.

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.

The albumin-bilirubin (ALBI) score was originally developed to assess the severity of liver dysfunction in patients with hepatocellular carcinoma and has subsequently been used as a prognostic marker for that disease. Here, we examined the value of the preoperative ALBI score as a prognostic marker for patients with esophageal squamous cell carcinoma (ESCC) after radical esophagectomy.We retrospectively analyzed data from 449 patients who underwent curative resection for ESCC. The ALBI score was calculated as (logOf the 449 ESCC patients, 232 and 217 were assigned to mALBI Grade 1 or Grade 2 groups based on preoperative ALBI scores of ≤ - 3.33 or- 3.33, respectively. Preoperative mALBI grade was significantly associated with age, excessive alcohol consumption, squamous cell carcinoma antigen level, and clinical disease stage. The mALBI Grade 2 group had significantly shorter disease-specific and recurrence-free survival than the mALBI Grade 1 group. Multivariate analysis demonstrated that mALBI Grade 2 was an independent prognostic factor for disease-specific survival (hazard ratio 1.86, 95% confidence interval 1.18-2.93, P = 0.0074). In most subgroup analyses, mALBI Grade 2 was associated with a greater risk of disease-specific death.mALBI grade serves as a simple and useful prognostic marker for disease-specific survival in patients with ESCC after radical esophagectomy.

The docetaxel and cisplatin plus 5-fluorouracil (5-FU) (DCF) regimen is expected to be superior to cisplatin plus 5-FU for the preoperative treatment of esophageal cancer. However, a high risk of adverse effects, including febrile neutropenia (FN), has been reported. To evaluate the effectiveness and safety of DCF with prophylactic pegfilgrastim, we conducted a phase II study.The regimen consisted of intravenous administration of docetaxel (70 mg/mThirty-seven eligible patients were enrolled and received DCF. Thirty-four patients underwent esophagectomy. Two patients received chemoradiotherapy or radiotherapy without surgery. One patient withdrew consent and ended his hospital visit. One patient received additional radiotherapy before surgery. Histopathological responses of grade 3, grade 2, grade 1b, and grade 1a were observed in two (5.4%), 14 (37.8%), 10 (27.0%), and seven (18.9%) patients, respectively, and the primary endpoint was met. Of the 37 eligible patients, 11 (29.7%) developed FN in the first cycle.Since the histopathological responses were as expected, DCF with prophylactic pegfilgrastim is considered to be effective as preoperative chemotherapy. However, the prophylactic use of pegfilgrastim on day 7 was insufficient to prevent FN.

MicroRNAs (miRNAs) are abnormally expressed and involved in the pathogenesis of various carcinomas. The present study aimed to identify novel miRNA genes associated with the pathogenesis and prognosis of oesophageal squamous cell carcinoma (ESCC).The miRNA profiling of 873 genes was performed using surgically resected oesophageal tissues from 35 patients with ESCC to identify candidate miRNAs. To examine the biological activities of candidate miRNAs, their proliferative, invasive, and migratory abilities were evaluated in ESCC cells subjected to miRNA mimic-mediated over-expression. The miRNA expression levels of the selected candidate miRNAs were analysed in the resected oesophageal tissues of 76 patients with ESCC from the two cohorts and correlated with the clinicopathological parameters.Among the four candidate miRNAs identified by miRNA profiling, miR-877-3p was selected for subsequent analyses. In vitro analyses showed that the over-expression of miR-877-3p significantly suppressed the proliferation, invasion, and migration of ESCC cell lines compared with those of control cells. In the analyses of clinical specimens, the expression of miR-877-3p was down-regulated in ESCC tissues compared with that in adjacent normal oesophageal tissues. The down-regulation of miR-877-3p expression in ESCC tissues was significantly associated with advanced local progression and lymphatic involvement. The miR-877-3p down-regulation was also significantly associated with poor disease-free and disease-specific survival.miR-877-3p acts as a tumour suppressor gene in ESCC cells, and its down-regulation in ESCC tissues is associated with a poor prognosis. Thus, miR-877-3p may serve as a novel prognostic marker and promising therapeutic target.

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 (

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.

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.

Purpose: Gastric cancer peritoneal carcinomatosis is fatal. Delay in detection of peritoneal metastases contributes to high mortality, highlighting the need to develop biomarkers that can help identify patients at high risk for peritoneal recurrence or metastasis. Experimental Design: We performed a systematic discovery and validation for the identification of peritoneal recurrence prediction and peritoneal metastasis detection biomarkers by analyzing expression profiling datasets from 249 patients with gastric cancer, followed by analysis of 426 patients from three cohorts for clinical validation. Results: Genome-wide expression profiling identified a 12-gene panel for robust prediction of peritoneal recurrence in patients with gastric cancer (AUC = 0.95), which was successfully validated in a second dataset (AUC = 0.86). Examination of 216 specimens from a training cohort allowed us to establish a six gene–based risk-prediction model [AUC = 0.72; 95% confidence interval (CI): 0.66–0.78], which was subsequently validated in an independent cohort of 111 patients with gastric cancer (AUC = 0.76; 95% CI: 0.67–0.83). In both cohorts, combining tumor morphology and depth of invasion further improved the predictive accuracy of the prediction model (AUC = 0.84). Thereafter, we evaluated the performance of the identical six-gene panel for its ability to detect peritoneal metastasis by analyzing 210 gastric cancer specimens (prior 111 patients plus additional 99 cases), which discriminated patients with and without peritoneal metastasis (AUC = 0.72). Finally, our biomarker panel was also remarkably effective for identifying peritoneal micrometastasis (AUC = 0.72), and its diagnostic accuracy was significantly enhanced when depth of invasion was included in the model (AUC = 0.85). Conclusions: Our novel transcriptomic signature for risk stratification and identification of high-risk patients with peritoneal carcinomatosis might serve as an important clinical decision making in patients with gastric cancer.

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.

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

To improve the outcome of gastric cancer, novel markers that predict postoperative prognosis are required. For this purpose, the function of cellular retinoic acid binding protein 1 (

Preoperative chemotherapy for gastric cancer may be effective from the standpoint of compliance, although there is insufficient evidence of its efficacy. We analyzed a multicenter database to clarify whether preoperative chemotherapy influenced the short-term outcomes of gastrectomy. We analyzed, retrospectively, 3571 patients who underwent gastrectomy between January, 2010 and December, 2014. Patients with clinical stage-III gastric adenocarcinoma were divided into a neoadjuvant chemotherapy (NAC) group and a non-NAC group. We performed propensity-matched comparative analysis to stratify the groups according to age, sex, tumor region, tumor type, preoperative stage, procedure, lymph node dissection, and tumor differentiation. Preoperative blood data, surgical findings, and postoperative complications were analyzed. Analysis of the matched NAC (n = 64) and non-NAC (n = 128) groups revealed that the preoperative values of neutrophils, platelets, and Hb were significantly lower in the NAC group. Blood loss during surgery was significantly higher, surgical times were longer, and the rate of repeat surgery was significantly lower in the NAC group; however, the rates of rehospitalization did not differ between the groups and mortality was 0% in both groups. Postoperative complications were not significantly different between the groups. NAC did not increase the complication rate of gastrectomy for gastric cancer.

The actin‐binding protein Girdin is a hub protein that interacts with multiple proteins to regulate motility and Akt and trimeric G protein signaling in cancer cells. Girdin expression correlates with poor outcomes in multiple human cancers. However, those findings are not universal, as they depend on study conditions. Those data suggest that multiple aspects of Girdin function and its role in tumor cell responses to anticancer therapeutics must be reconsidered. In the present study, we found that Girdin is involved in DNA damage‐induced cancer cell apoptosis. An esophageal cancer cell line that exhibited high Girdin expression showed a marked sensitivity to UV‐mediated DNA damage compared to a line with low Girdin expression. When transcriptional activation of endogenous Girdin was mediated by an engineered CRISPR/Cas9 activation system, sensitivity to DNA damage increased in both stationary and migrating HeLa cancer cells. High Girdin expression was associated with dysregulated cell cycle progression and prolonged G1 and M phases. These features were accompanied by p53 activation, which conceivably increases cancer cell vulnerability to UV exposure. These data highlight the importance of understanding complex Girdin functions that influence cancer cell sensitivity to therapeutics., The present study suggests that Girdin overexpression perturbs cell cycle distribution with prolonged G1 and M phases and aberrant p53 activation, which leads to an increase in sensitivity to DNA damage. It also showed that the upregulation of the spindle checkpoint protein Mad2 in Girdin‐overexpressing cells could be involved in dysregulated cell cycle progression.

We aimed to clarify the utility of lymph node ratio (LNR) for assessing the prognosis of patients with node-positive gastric cancer after curative gastrectomy. We retrospectively analyzed data of 973 patients with node-positive gastric cancer who had undergone curative gastrectomy at nine institutions from 2010 to 2014. Survival analysis was performed by comparing LNR low and high groups according to the optimal cutoff value of LNR, which was determined using receiver operating characteristic curve analysis. LNR high was significantly associated with shorter disease-free survival and was an independent predictor of recurrence in all patients. Moreover, we obtained the similar results from analysis of each N stage. The prevalence of lymph node and peritoneal recurrence appeared to be higher in the LNR high group. Correlation analysis showed that LNR was negatively correlated with the number of retrieved nodes within every N stage; however, disease-free survival did not differ significantly between LNR low and high groups of each N stage with 16–30, 31–40, or >40 retrieved nodes. LNR is a strong prognostic factor and predictor of recurrence in patients with node-positive gastric cancer who have undergone curative gastrectomy. The combination of LNR and N staging permits more accurate prognostic stratification of patients with gastric cancer and may contribute to developing novel prognostic models.

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.

Aging societies comprise an increasing number of elderly gastric cancer (GC) patients. We herein attempted to determine whether D2 lymphadenectomy is beneficial for older GC patients. We retrospectively analyzed a multi-institutional dataset including 3484 patients who received surgical resection for GC. For the analysis, we selected patients aged ≥ 80 years who were clinically diagnosed with T1N + or T2-4 GC. To balance the essential variables including the type of gastrectomy and the stage of progression, propensity score matching was conducted, and we compared the background clinical factors and postoperative outcomes of the patients allocated to the D2 (n = 87) and non-D2 (n = 87) dissection groups. The D2 group had significantly longer operative times, more blood loss, and more retrieved lymph nodes (median 32 vs 24, P

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.

Many studies investigating postoperative pancreatic fistula (POPF) after gastrectomy, including studies measuring drain amylase content (D-AMY) as a predictive factor have been reported. This article reviews previous studies and looks to the future of measuring D-AMY in patients after gastrectomy. The causes of pancreatic fluid leakage are; the parenchymal and/or thermal injury to the pancreas, and blunt injury to the pancreas by compression and retraction. Measurement of D-AMY to predict POPF has become common in clinical practice after pancreatic surgery and was later extended to the gastric surgery. Several studies have reported associations between D-AMY and POPF after gastrectomy, and the high value of D-AMY on postoperative day (POD) 1 was an independent risk factor. To improve both sensitivity and specificity, attempts have been made to enhance the predictive accuracy of factors on POD 1 as well as on POD 3 as combined markers. Although several studies have shown a high predictive ability of POPF, it has not necessarily been exploited in clinical practice. Many problems remain unresolved; ideal timing for measurement, optimal cut-off value, and means of intervention after prediction. Prospective clinical trial could be imperative in order to develop D-AMY measurement in common clinical practice for gastric surgery.

INTRODUCTION In laparoscopic gastrectomy, a method to locate the margin of an early-stage cancerous lesion that is invisible from the serosal surface and impalpable during laparoscopic procedures is needed to determine an appropriate transection line. We conducted a prospective study to develop a new marking method using preoperative submucosal injection of indocyanine green (ICG). METHODS Patients undergoing laparoscopic gastrectomy for T1 gastric cancer were recruited. The first 11 patients comprised the learning set and the subsequent 18 patients the validation set. ICG was endoscopically injected in the submucosal layer of the stomach approximately 1 cm away from the tumor edge 1 or 3 days before surgery. The diameters of the visualized ICG were compared with those of a conventional marking method using India ink in 10 historical controls. RESULTS In the learning set, the optimal amount of ICG was determined to be 0.1 mL at a concentration of 0.5 mg/mL. In the validation set, the same procedure was repeated. No technical problems or adverse reactions related to ICG injection were observed. In all cases, ICG was successfully detected, and negative surgical margins were pathologically confirmed. The mean long diameter of the visualized ICG fluorescence measured at the mucosal surface of the stomach was significantly smaller in the current study than in the historical controls in whom India ink was used (21 vs 52 mm, P

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.

Background/aim To investigate the function of chromobox 2 (CBX2) in oesophageal squamous cell carcinoma (OSCC). Materials and methods We used real-time quantitative reverse transcription PCR (qRT-PCR) and immunohistochemistry to determine CBX2 expression levels in 13 human OSCC cell lines and clinical specimens of two independent cohorts of patients with OSCC. Results PCR array analysis revealed that CBX2 was co-ordinately expressed with WNT5B in OSCC cell lines. RT-qPCR analysis of clinical samples revealed a high tumour-specific CBX2 expression compared with normal oesophageal tissues. High CBX2 expression was significantly associated with shorter disease-specific survival, hematogenous recurrence, and overall recurrence. Analysis of tissue microarrays of one cohort revealed that patients with higher CBX2 levels tended to have a shorter disease-specific survival. Conclusion CBX2 overexpression in OSCC tissues may serve as a novel biomarker for predicting survival and hematogenous recurrence.

Background Differences in the geographical distributions of esophageal cancer (EC) are associated with environmental influences and genetic risk factors. The inhabitants of the Republic of Uzbekistan are at high-risk for EC; however, detailed epidemiological data regarding the dynamics of EC are not available. Methods To address this gap in our knowledge, here we reviewed trends in the incidence of EC in Uzbekistan from 2000 through 2018. We acquired the epidemiological data for 17,144 patients with EC from the national epidemiological data base of Uzbekistan. Results The mean incidence (per 100,000 persons) during the study period was 2.8, which peaked at 3.9 in 2007 and decreased below 2.5 in 2014 and thereafter. The incidence was highest for patients aged 61 years to 70 years (37.5%). Among patients with EC, 13,331 (80.0%) and 3,333 (20.0%) were diagnosed with squamous cell carcinoma or adenocarcinoma, respectively. The incidences of patients with EC with adenocarcinoma were 0.6 from 2010-2018 and 0.4 from 2000 to 2009. The majority of patients were diagnosed with stage III EC, which was associated with a 5-year survival rate that increased from approximately 15% (2000-2009) and plateaued at approximately 25% (2012-2018). Conclusions We conclude that preventing the progression of EC to stage III is required to improve the prognosis of patients with EC who reside in Uzbekistan.

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

Background Majority of gastric cancers (GC) are diagnosed at advanced stages which contributes towards their poor prognosis. In view of this clinical challenge, identification of non-invasive biomarker for early diagnosis is imperative. Herein, we aimed to develop a non-invasive, liquid-biopsy based assay by using circular RNAs (circRNAs) as molecular biomarkers for early detection of GC. Methods We performed systematic biomarker discovery and validation of the candidate circRNAs in matched tissue specimens of GC and adjacent normal mucosa. Next, we translated the discovered circRNA based biomarker panel into serum samples in a training and validation cohort of GC patients (n = 194) and non-disease controls (n = 94) and evaluated their diagnostic performance. In addition, we measured the expression of circRNAs in serum samples of pre- and post-surgical GC patients and evaluated the specificity of circRNAs biomarker panel with respect to other gastro-intestinal (GI) malignancies. Results We identified 10-circRNAs in the discovery phase with subsequent validation in a pilot cohort of GC tissue specimens. Using a training cohort of patients, we developed an 8-circRNA based risk-prediction model for the diagnosis of GC. We observed that our biomarker panel robustly discriminated GC patients from non-disease controls with an AUC of 0.87 in the training, and AUC of 0.83 in the validation cohort. Notably, the biomarker panel could robustly identify even early-stage GC patients, regardless of their tumor histology (diffuse vs. intestinal). The decreased expression of circRNAs in post-surgery serum specimens indicated their tumor-specificity and their potential source of origin in the systemic circulation. Conclusions We identified a panel of 8-circRNAs as non-invasive, liquid-biopsy biomarkers which might serve as potential diagnostic biomarkers for the early detection of GC.

The platelet isoform of phosphofructokinase (PFKP) is one of the key enzymes in the glycolytic pathway. PFKP is highly expressed in several cancers, and it has been reported to be involved in the progression of cancer cells. However, its oncological role in breast cancer (BC) remains unclear. The present study aimed to evaluate the function of PFKP in BC cells and its expression level in patients with BC. Firstly, the mRNA and protein expression of PFKP was evaluated in BC and non‑cancerous mammary cell lines. Polymerase chain reaction (PCR) array analysis was conducted to evaluate the correlation between PFKP and 84 cancer‑related genes. Then, PFKP knockdown was conducted using small interfering RNA, and cell proliferation, invasiveness and migration were analyzed. Furthermore, the association between PFKP mRNA expression and clinicopathological factors was investigated in 167 patients with BC. PFKP was highly expressed in estrogen receptor‑negative and human epidermal growth factor receptor 2‑negative BC cell lines. PCR array analysis demonstrated that the expression level of PFKP was significantly correlated with that of transforming growth factor‑β1 and MYC proto‑oncogene. PFKP knockdown significantly decreased the proliferation and invasiveness of MCF7, SK‑BR‑3, and MDA‑MB‑231 cells. Furthermore, cell migration was inhibited in SK‑BR‑3 and MDA‑MB‑231 cells. In the clinical specimens, patients with T2/T3/T4, lymph node metastasis, or stage II/III/IV exhibited higher expression of PFKP mRNA than patients with less severe disease. In conclusion, the present findings indicated that PFKP is involved in promoting tumor‑progressive oncological roles in BC cells across different subtypes and is considered a possible novel therapeutic target for BC.

Metastatic gastric cancer (GC) has a poor prognosis, and elucidating the molecular mechanisms involved in metastasis may lead to the development of novel therapeutic modalities.Transcriptome analysis of surgically resected metastatic tissue from GC patients and noncancerous tissue was performed to identify novel metastasis-related genes. Analyses of in vitro cell function, apoptosis, the cell cycle and cancer stemness were performed using GC cell lines with a stable knockout of a candidate gene. In vivo percutaneous, peritoneal dissemination and liver metastasis xenograft models were also generated. PCR array and proteome analyses were performed. Expression of the candidate gene was analyzed in GC tissues from 300 patients.Lysosomal Associated Membrane Protein Family Member 5 (LAMP5) was upregulated in the metastatic tissues. LAMP5 knockout significantly suppressed proliferation, invasion, and migration of GC cells and increased apoptosis, cell cycle arrest and cancer stemness. LAMP5 knockout virtually suppressed tumor growth in in vivo percutaneous, peritoneal dissemination and liver metastasis models. EMT- and autophagy-related genes were associated with LAMP5. High LAMP5 mRNA levels were significantly associated with a worse prognosis.LAMP5 plays a vital role in metastasis formation and may be a promising novel target of drug development for metastatic GC in the future.

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.

Key Points Question Can circulating microRNAs be used to derive clinically significant noninvasive diagnostic biomarkers for gastric cancer? Findings This diagnostic study used a multistep and comprehensive biomarker discovery approach to establish a novel, noninvasive, microRNA-based signature for the early detection of gastric cancer, which was retrospectively and prospectively validated in multicenter patient cohorts. Meaning For patients with gastric cancer and individuals with a high risk for gastric cancer, a microRNA-based signature may improve the early detection of gastric cancer., This diagnostic study describes the development and validation of a microRNA-based liquid biopsy assay for early detection of gastric cancer., Importance Noninvasive detection of early-stage disease is a key strategy for reducing gastric cancer (GC)-associated patient mortality. Objective To establish a novel, noninvasive, microRNA (miRNA)-based signature for the early detection of GC using a comprehensive biomarker discovery approach with retrospective and prospective validation. Design, Setting, and Participants This diagnostic study was conducted in 4 phases using publicly available genome sequences and tissue samples from patients at an academic medical center in Japan, and validated with retrospective multicenter cohorts of patients with GC. Three tissue miRNA data sets were used to identify a miRNA signature that discriminated GC vs normal tissues. The robustness of this signature was assessed in serum from 2 retrospective cohorts of patients with GC. A risk-scoring model was derived, then the performance of the miRNA signature was evaluated in a prospective cohort of patients with GC. The robustness of the miRNA signature was compared with current blood-based markers, and a cost-effectiveness analysis of the miRNA signature against the current practice of endoscopy was performed. All clinical samples used for this study were collected and data analyzed between April 1997 and March 2018. Main Outcomes and Measures Assessment of diagnostic efficiency on the basis of area under the curve (AUC), specificity, and sensitivity. Results The data sets for the genome-wide expression profiling analysis stage included 598 total patient samples (284 [55.4%] from men; mean [SE] patient age, 65.7 [0.5] years). The resulting 10-miRNA signature was validated in 2 retrospective GC serum cohorts (586 patients; 348 [59.4%] men, mean [SE] age, 66.0 [0.7] years), which led to the establishment of a 5-miRNA signature (AUC, 0.90; 95% CI, 0.85-0.94) that also exhibited high levels of diagnostic performance in patients with stage I disease (AUC, 0.89; 95% CI, 0.83-0.94). A risk-scoring model was derived and the assay was optimized to a minimal number of miRNAs. The performance of the resulting 3-miRNA signature was then validated in a prospective cohort of patients with GC (349 patients; 124 [70.5%] men, median [range] age, 66.0 [0.66] years). The final 3-miRNA signature (miR-18a, miR-181b, and miR-335) exhibited high diagnostic accuracy in all stages of patients (AUC, 0.86; 95% CI 0.83-0.90), including in patients with stage I disease (AUC, 0.85; 95% CI, 0.79-0.91). Furthermore, this miRNA signature was superior to currently used blood markers and outperformed the endoscopic screening in a cost-effectiveness analysis (incremental cost-effectiveness ratio, CNY ¥16162.5 per quality-adjusted life-year [USD $2304.80 per quality-adjusted life-year]). Conclusions and Relevance These results suggest the potential clinical significance of the 3-miRNA signature as a noninvasive, cost-effective, and facile assay for the early detection of GC.

This study aimed to evaluate the estimation of the physiological ability and surgical stress (E-PASS) scoring system for predicting the short- and long-term outcomes in gastric cancer (GC) surgery. We analyzed a multi-institutional dataset to study patients who underwent gastrectomy with a curative intent between 2010 and 2014. This study evaluated the associations between the optimal E-PASS score cutoff value and the following outcomes: (1) the incidence of postoperative complications in stage I–III GC patients and (2) the prognosis in stage II–III GC patients. A total of 2495 GC patients were included. A cutoff value of 0.419 was determined using the ROC curve analysis. Postoperative complications were observed more frequently in the E-PASS-high group than that in the E-PASS-low group (30% vs. 17%, p

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.

Background/aim We previously reported that expression of melanoma-associated antigen (MAGE)-D4 mRNA was a prognostic factor for esophageal squamous cell carcinoma (ESCC). The aim of this study was to validate the expression of MAGE-D4 in two additional patient cohorts, and to investigate its biological functions. Materials and methods The role of MAGE-D4 in cell proliferation, adhesion, and migration was determined by gene knockdown experiments in the KYSE590 cell line. MAGE-D4 protein expression was analyzed in ESCC tissues by immunohistochemistry. A second validation cohort consisted of an ESCC mRNA dataset from The Cancer Genome Atlas. Results Knockdown of MAGE-D4 significantly decreased cell proliferation and migration. Expression of MAGE-D4 protein was significantly associated with disease-free survival. In the second validation cohort, high MAGE-D4 mRNA expression was associated with significantly shorter overall survival and disease-free survival. Conclusion MAGE-D4 plays an important role in the malignant behavior of ESCC. MAGE-D4 was validated as a prognostic indicator in two independent ESCC patient cohorts.

OBJECTIVE: This study aimed to do a genomewide transcriptomic profiling to develop a miRNA-based signature for the identification of peritoneal metastasis (PM) in patients with gastric cancer (GC). SUMMARY BACKGROUND DATA: Even though PM in patients with GC has long been recognized to associate with poor survival, currently there is lack of availability of molecular biomarkers for its robust diagnosis. METHODS: We performed a systematic biomarker discovery by analyzing miRNA expression profiles in primary tumors from GC patients with and without PM, and subsequently validated the expression of candidate miRNA biomarkers in three independent clinical cohorts of 354 patients with advanced GC. RESULTS: Five miRNAs (miR-30a-5p, -134-5p, -337-3p, -659-3p, and -3917) were identified during the initial discovery phase; three of which (miR-30a-5p, -659-3p, and -3917) were significantly overexpressed in the primary tumors from PM-positive patients in the testing cohort (p=0.002, 0.04 and 0.007 respectively), and distinguished patients with vs. without peritoneal metastasis with the value of area under the curve (AUC) of 0.82. Furthermore, high expression of these miRNAs also associated with poor prognosis (HR=2.18, p=0.04). The efficacy of the combination miRNA-signature was subsequently validated in an independent validation cohort (AUC=0.74). Finally, our miRNA signature when combined together with the macroscopic Borrmann’s type score offered a much superior diagnostic in all three cohorts (AUC=0.87, 0.76, 0.79, respectively), and led us to establish a risk-prediction nomogram for the diagnosis of PM in GC patients. CONCLUSIONS: We have established a miRNA-based signature that have a potential to identify peritoneal metastasis in GC patients.

This study aimed to explore the prognostic significance of the resection margin (R) status of pancreatic ductal adenocarcinoma (PDAC) patients receiving neoadjuvant therapy (NAT) or adjuvant chemotherapy (AC). We retrospectively reviewed 427 consecutive patients, and the overall survival (OS) and disease-free survival (DFS) were analyzed based on the R status by a propensity score analysis (PSA). The R0 ratio of the NAT (+) group was significantly higher than that of the NAT (−) group (97.2% vs. 69.6%, P

Background The global increase in elderly populations is accompanied by an increasing number of candidates for esophagectomy. Here we aimed to determine the postoperative outcomes after subtotal esophagectomy in elderly patients with esophageal cancer. Methods Patients (n = 432) with who underwent curative-intent transthoracic subtotal esophagectomy with 2- or 3-field lymphadenectomies for thoracic esophageal cancer were classified as follows: non-elderly (age n = 373) and elderly (age ≥ 75 years, n = 59) and groups. To balance the essential variables including neoadjuvant treatment and stage of progression, we conducted propensity score analysis, and clinical characteristics, perioperative course and prognosis were compared. Results After two-to-one propensity score matching, 100 and 50 patients were classified in the non-elderly and elderly groups. The elderly group had more comorbidities and lower preoperative cholinesterase activities and prognostic nutrition indexes. Although incidences of postoperative pneumonia, arrhythmia and delirium were slightly increased in the elderly group, no significant differences were observed in overall incidence of postoperative complications, rates of repeat surgery and death caused by surgery, and length of postoperative hospital stay between the two groups. There were no significant differences in disease-free and disease-specific survival as well as overall survival between the two groups. Conclusion Older age (≥75 years) had limited impact on morbidity, disease recurrence, and survival after subtotal esophagectomy. Therefore, age should not prevent older patients from benefitting from surgery.

Little is known about the changes in prognostic factors after adjuvant S-1 monotherapy has become widespread as a standard of care for patients with gastric cancer (GC) in East Asia. The present study compared prognostic factors of patients with stage II/III GC treated with or without S-1 adjuvant to formulate appropriate risk stratification strategies. We designed a large multicenter dataset and retrospectively analyzed 847 patients with GC stage II or III, who underwent curative gastrectomy between 2010 and 2014. Clinicopathological features and prognostic factors were compared between the two patient groups: surgery-alone (n = 266) and S-1 adjuvant (n = 581). There were no significant differences in pathological tumor depths, nodal status, and disease stages between groups. Recurrence-free survival was significantly longer in the S-1 adjuvant group. For the surgery-alone group, independent prognostic factors were (in order of hazard ratio): (1) invasive growth, (2) high preoperative carcinoembryonic antigen levels, (3) total gastrectomy. For the S-1 adjuvant group, macroscopic tumor size (≥50 mm) was identified as another independent prognostic factor next only to pN2/3. There was overlap between the survival curves of patients with tumor size ≥50 mm in both groups. After receiving adjuvant S-1 monotherapy, ≥50 mm patients had significantly higher prevalence of peritoneal and lymph node metastasis as initial recurrences compared with

Background Insufficient data are available on the prognostic significance of complications after resection of gastric cancer. Therefore, we aimed to assess this gap in our knowledge by studying patients with resectable gastric cancer. Methods A multi‐institutional retrospective database comprising clinical information of 3575 patients who received resection of gastric cancer from 2010 to 2014 at nine institutions. Grades 2 or greater complications of the Clavien‐Dindo classification were judged as clinically relevant postoperative complications, and their associations with postoperative survival were assessed. We assessed the effect of complications on times of initiation and continuation of postoperative adjuvant chemotherapy by S‐1. Results A total of 2954 patients were included in the analysis. Clinically relevant postoperative complications occurred in 664 (23%) patients. Patients’ recurrence‐free survival rate incrementally decreased as the grade of complications became greater. Patients with abdominal complications (eg, leakage of pancreatic fluids, intra‐abdominal abscess, and anastomotic leakage) and those with nonabdominal complications (eg, pneumonia) experienced worse recurrence‐free survival compared to those without complications. Patients who had complications were generally at greater risk of disease recurrence, except for those who underwent laparoscopic surgery and those with pathological stage I. Delayed initiation and shorter continuation of adjuvant S‐1 chemotherapy was experienced by patients with postoperative complications. Conclusions Postoperative complications adversely affected the prognosis in patients with resectable gastric cancer.

Objective This multicenter, single-arm phase II study (UMIN000008429) aimed to evaluate the efficacy and safety of capecitabine plus oxaliplatin (CapOX) as postoperative adjuvant chemotherapy for patients with locally advanced rectal cancer. Methods Patients with resectable clinical Stage II or III rectal cancer were enrolled to receive eight cycles of CapOX therapy (130 mg/m2 oxaliplatin on day 1 and 2000 mg/m2 oral capecitabine on days 1–14, every 3 weeks) after curative surgical resection. The primary endpoint was 3-year relapse-free survival (RFS) rate, and secondary endpoints were 3-year overall survival (OS) rate, treatment compliance, and safety. Results A total of 40 patients (Stage II, 21; Stage III, 19) were enrolled between September 2012 and November 2015 from seven institutions. Thirty-nine patients (97%) received R0 resection, and 32 patients (84%) received postoperative CapOX therapy. The completion rate of all eight cycles of CapOX therapy was 66%. Relative dose intensities were 87% for oxaliplatin and 84% for capecitabine. At a median follow-up period of 46 months, disease recurrence was observed in nine patients, including three with local recurrence. Three-year RFS and OS rates were 75% (95% CI 57–86%) and 96% (95% CI 80–99%), respectively. Frequencies of Grade ≥ 3 hematological and non-hematologic adverse events were 19% and 38%, respectively. Conclusion CapOX therapy is feasible as adjuvant chemotherapy for locally advanced rectal cancer.

Gastrectomy with radical lymph node dissection is the most promising treatment avenue for patients with gastric cancer. However, this procedure sometimes induces excessive intraoperative blood loss and requires perioperative allogeneic blood transfusion. There are lasting discussions and controversies about whether intraoperative blood loss or perioperative blood transfusion has adverse effects on the prognosis in patients with gastric cancer. We reviewed laboratory and clinical evidence of these associations in patients with gastric cancer. A large amount of clinical evidence supports the correlation between excessive intraoperative blood loss and adverse effects on the prognosis. The laboratory evidence revealed three possible causes of such adverse effects: anti-tumor immunosuppression, unfavorable postoperative conditions, and peritoneal recurrence by spillage of cancer cells into the pelvis. Several systematic reviews and meta-analyses have suggested the adverse effects of perioperative blood transfusions on prognostic parameters such as all-cause mortality, recurrence, and postoperative complications. There are two possible causes of adverse effects of blood transfusions on the prognosis: Anti-tumor immunosuppression and patient-related confounding factors (e.g., preoperative anemia). These factors are associated with a worse prognosis and higher requirement for perioperative blood transfusions. Surgeons should make efforts to minimize intraoperative blood loss and transfusions during gastric cancer surgery to improve patients' prognosis.

BACKGROUND & AIMS: Although identification of lymph node (LN) metastasis is a well-recognized strategy for improving outcomes in patients with gastric cancer (GC), currently there is lack of availability of adequate molecular biomarkers that can identify such metastasis. Herein we have developed a robust gene-expression signature for detecting LN metastasis in early stage GC by using a transcriptomic-wide biomarker discovery and subsequent validation in multiple clinical cohorts. METHODS: A total of 532 patients with pathological T1 and T2 GC from 4 different cohorts were analyzed. Two independent datasets (n=96, and n=188) were used to establish a gene signature for the identification of LN metastasis in GC patients. The diagnostic performance of our gene-expression signature was subsequently assessed in two independent clinical cohorts using qRT-PCR assays (n = 101, and n = 147), and subsequently compared against conventional tumor markers and image-based diagnostics. RESULTS: We established a 15-gene signature by analyzing multiple high throughput datasets, which robustly distinguished LN status in both testing (AUC = 0.765, 95% CI 0.667 - 0.863) and validation cohorts (AUC = 0.742, 95% CI 0.630 - 0.852). Notably, the 15-gene signature was significantly superior compared to the conventional tumor markers, CEA (P = 0.04) and CA19-9 (P = 0.005), as well as computed tomography-based imaging (P = 0.04). CONCLUSIONS: We have established and validated a 15-gene signature for detecting LN metastasis in GC patients, which offers a robust diagnostic tool for potentially improving treatment outcomes in gastric cancer patients. FUNDING STATEMENT: The present work was supported by the grants CA72851, CA181572, CA184792, CA202797 and CA187956 from the National Cancer Institute; a grant (RP140784) from the Cancer Prevention Research Institute of Texas (CPRIT), pilot grants from the Baylor Sammons Cancer Center, as well as funds from the Baylor Scott & White Research Institute awarded to Ajay Goel, and a VPRT grant (9610337) from the City University of Hong Kong, grants from the Research Grants Council of the Hong Kong Special Administrative Region, China (Project No. CityU 21101115, 11102317, 11103718), a grant from The Science Technology and Innovation Committee of Shenzhen Municipality (JCYJ20170307091256048) awarded to Xin Wang, and was partially supported by the Shenzhen Research Institute, City University of Hong Kong. DECLARATION OF INTERESTS: None of the authors has any potential conflicts to disclose. ETHICS APPROVAL STATEMENT: Written informed consent was obtained from all patients, and the study was approved by the institutional review boards of all the participating institutions.

Discontinuation of postoperative S-1 adjuvant monotherapy is a frequent problem in the management of patients with gastric cancer. A total of 355 stage II/III gastric cancer patients who underwent gastrectomy and adjuvant S-1 were retrospectively analyzed using a multicenter dataset. We randomly assigned patients into either discovery or validation cohort in a 2:1 ratio. In the discovery cohort, 29 parameters were assessed as candidate factors to predict discontinuation of S-1 adjuvant within 6 months. A scoring system was designed using independent risk factors identified by the multivariate analysis. Reproducibility was tested in the validation cohort. Overall, 92 patients (25.9%) discontinued the treatment within 6 months because of adverse effects. Age, preoperative urea nitrogen (UN) and the preoperative albumin-to-bilirubin index (ALBI) showed the highest area under the curve (AUC) for the discontinuation of S-1 adjuvant within 6 months in each category: body status, blood tests and indices. In the multivariate analysis, age ≥ 64 years, preoperative UN ≥ 15.2 mg/dl and preoperative ALBI ≥ −0.265 were identified as independent risk factors. A scoring scale consisting of these three factors was developed for the prediction of drug discontinuation and demonstrated a greater AUC (0.728) than that of each of the three constituents. The time to treatment discontinuation decreased incrementally as the risk score increased. The reproducible findings were confirmed in the validation cohort. We identified risk factors and developed a scoring scale to predict S-1 adjuvant monotherapy discontinuation in patients with stage II/III gastric cancer.