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Background The expression of solute carrier (SLC) 7 family genes is reportedly associated with several malignancies. Here, we focused on SLC7A9 and investigated its expression, function, and clinical significance in esophageal squamous cell carcinoma (ESCC). Methods SLC7A9 transcription levels were evaluated in 13 ESCC cell lines, and polymerase chain reaction (PCR) array analysis was conducted to detect coordinately expressed genes with SLC7A9. SLC7A9 contributions to proliferation, invasion, and migration were evaluated in ESCC cells subjected to siRNA-mediated gene knockdown and pCMV6-entry plasmid-mediated overexpression. SLC7A9 expression was detected in 189 ESCC tissues by quantitative reverse-transcription (qRT)-PCR and correlated with clinicopathological parameters. Results The expression levels of SLC7A9 varied widely in ESCC cell lines and correlated with FGFBP1 expression. Knockdown of SLC7A9 significantly suppressed the proliferation, invasion, and migration of the ESCC cell lines. Moreover, overexpression of SLC7A9 enhanced cell proliferation and migration. In analyses of clinical specimens, SLC7A9 mRNA was overexpressed in the ESCC tissues compared with the adjacent normal esophageal tissues. High mRNA expression was significantly associated with high levels of squamous cell carcinoma-related antigen and carcinoembryonic antigen, advanced disease stage, and lymph node metastasis. High SLC7A9 expression was also significantly associated with poor disease-specific and disease-free survival, and lymph node recurrence after radical surgery, but not with the other recurrence patterns. On multivariate analysis, high SLC7A9 expression was an independent predictor of lymph node recurrence. Conclusions SLC7A9 influences the malignant behavior of ESCC cells. Tumor SLC7A9 expression may serve as a novel biomarker for predicting lymph node metastasis and recurrence in ESCC patients.

Background: Accumulating evidence indicates tumor-promoting roles of synaptotagmin 13 (SYT13) in several cancers, however, no studies have investigated its expression in breast cancer (BC). This study aimed to clarify the significance of SYT13 in BC. Methods: SYT13 mRNA expression levels were evaluated in BC cell lines. Polymerase chain reaction (PCR) array analysis was conducted to determine the correlation between expression levels of SYT13 and other tumor-associated genes. Then, the association of SYT13 expression levels in the clinical BC specimens with patients’ clinicopathological factors was evaluated. These findings were subsequently validated using The Cancer Genome Atlas (TCGA) database. Results: Among 13 BC cell lines, estrogen receptor (ER)-positive cells showed higher SYT13 mRNA levels than ER-negative cells. PCR array analysis revealed positive correlations between SYT13 and several oncogenes predominantly expressed in ER-positive BC, such as estrogen receptor 1, AKT serine/threonine kinase 1, and cyclin-dependent kinases 4. In 165 patients, ER-positive specimens exhibited higher SYT13 mRNA expression levels than ER-negative specimens. The TCGA database analysis confirmed that patients with ER-positive BC expressed higher SYT13 levels than ER-negative patients. Conclusion: This study suggests that SYT13 is highly expressed in ER-positive BC cells and clinical specimens, and there is a positive association of SYT13 with the ER signaling pathways.

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.

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 Disease recurrence is frequently observed after curative resection of advanced gastric cancer resulting in a poor prognosis. In the present study, we identified a candidate biomarker to predict recurrence and prognosis after curative resection of gastric cancer. Materials and methods A transcriptome analysis was conducted using surgically resected cancerous tissue from patients with metastatic gastric cancer to identify genes that are upregulated in primary and metastatic tissues. Results Ring finger protein, transmembrane 2 (RNFT2) mRNA expression was upregulated in primary gastric cancer tissues and metastases compared with non-cancerous tissues. RNFT2 expression in gastric cancer cell lines was positively correlated with the EMT-related molecules GSC, MMP9, and RAC1. The RNFT2 high expression group exhibited a significantly shorter postoperative overall survival. Peritoneal recurrence was significantly higher in the RNFT2 high expression group. Conclusion RNFT2 mRNA expression predicts peritoneal recurrence and is a potential prognostic biomarker for gastric cancer following curative gastrectomy.

Patients with peritoneal metastasis of gastric cancer have dismal prognosis, mainly because of inefficient systemic delivery of drugs to peritoneal tumors. We aimed to develop an intraperitoneal treatment strategy using amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides (ASOs) targeting synaptotagmin XIII (SYT13) and to identify the function of SYT13 in gastric cancer cells. We screened 71 candidate oligonucleotide sequences according to SYT13-knockdown efficacy, in vitro activity, and off-target effects. We evaluated the effects of SYT13 knockdown on cellular functions and signaling pathways, as well as the effects of intraperitoneal administration to mice of AmNA-modified anti-SYT13 ASOs. We selected the ASOs (designated hSYT13-4378 and hSYT13-4733) with the highest knockdown efficiencies and lowest off-target effects and determined their abilities to inhibit cellular functions associated with the metastatic potential of gastric cancer cells. We found that SYT13 interfered with focal adhesion kinase (FAK)-mediated intracellular signals. Intraperitoneal administration of hSYT13-4378 and hSYT13-4733 in a mouse xenograft model of metastasis inhibited the formation of peritoneal nodules and significantly increased survival. Reversible, dose- and sequence-dependent liver damage was induced by ASO treatment without causing abnormal morphological and histological changes in the brain. Intra-abdominal administration of AmNA-modified anti-SYT13 ASOs represents a promising strategy for treating peritoneal metastasis of gastric cancer., Graphical Abstract, To propose a novel treatment option for patients with peritoneal metastasis of gastric cancer, we designed amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides (ASOs) targeting synaptotagmin XIII (SYT13). Intra-abdominal administration of AmNA-modified anti-SYT13 ASOs represents a promising strategy for treating peritoneal metastasis of gastric cancer.

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

// Mitsuro Kanda 1 , Kenta Murotani 2 , Haruyoshi Tanaka 1 , Takashi Miwa 1 , Shinichi Umeda 1 , Chie Tanaka 1 , Daisuke Kobayashi 1 , Masamichi Hayashi 1 , Norifumi Hattori 1 , Masaya Suenaga 1 , Suguru Yamada 1 , Goro Nakayama 1 , Michitaka Fujiwara 1 and Yasuhiro Kodera 1 1 Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan 2 Clinical Research Center, Aichi Medical University Hospital, Nagakute, Japan Correspondence to: Mitsuro Kanda, email: m-kanda@med.nagoya-u.ac.jp Keywords: gastric cancer; expression panel; prognosis; biomarker Received: January 05, 2018 Accepted: February 27, 2018 Published: April 10, 2018 ABSTRACT Most of the proposed individual markers had limited clinical utility due to the inherent biological and genetic heterogeneity of gastric cancer. We aimed to build a new molecular-based model to predict prognosis in patients with gastric cancer. A total of 200 patients who underwent gastric resection for gastric cancer were divided into learning and validation cohorts using a table of random numbers in a 1:1 ratio. In the learning cohort, mRNA expression levels of 15 molecular markers in gastric tissues were analyzed and concordance index (C-index) values of all single and combinations of the 15 candidate markers for overall survival were calculated. The multigene expression panel was designed according to C-index values and the subpopulation index. Expression scores were determined with weighting according to the coefficient of each constituent. The reproducibility of the panel was evaluated in the validation cohort. C-index values of the 15 single candidate markers ranged from 0.506–0.653. Among 32,767 combinations, the optimal and balanced expression panel comprised four constituents ( MAGED2, SYT8, BTG1 , and FAM46 ) and the C-index value was 0.793. Using this panel, patients were provisionally categorized with scores of 1–3, and clearly stratified into favorable, intermediate, and poor overall survival groups. In the validation cohort, both overall and disease-free survival rates decreased incrementally with increasing expression scores. Multivariate analysis revealed that the expression score was an independent prognostic factor for overall survival after curative gastrectomy. We developed an integrated multigene expression panel that simply and accurately stratified risk of patients with gastric cancer.

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.

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 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.

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

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.

β-1,4-N-Acetyl-galactosaminyltransferase 4 (B4GALNT4), an enzyme involved in ganglioside synthesis, is upregulated in many cancers. We examine B4GALNT4 expression and its relationship to prognosis in esophageal squamous cell carcinoma (ESCC). Expression of B4GALNT4 mRNA and B4GALNT4 protein was analyzed by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry, respectively, in 17 human ESCC cell lines and/or clinical specimens from two independent cohorts of 147 and 159 ESCC patients. The contributions of B4GALNT4 to proliferation, invasion, migration, and adhesion was evaluated in ESCC cells subjected to siRNA-mediated gene knockdown. Correlations between clinicopathological parameters and B4GALNT4 expression in clinical specimens were analyzed in both patient cohorts. B4GALNT4 mRNA expression levels varied widely in ESCC cell lines, regardless of differentiation status or the originating tissue. Knockdown of B4GALNT4 significantly suppressed the proliferation, invasion, migration, and adhesion of ESCC cell lines compared with control cells. B4GALNT4 mRNA was overexpressed in ESCC tissues compared with adjacent normal esophageal tissues. High mRNA expression was significantly associated with poor disease-free survival and hematogenous recurrence, and high B4GALNT4 protein expression was also significantly related to poor disease-specific survival. On multivariable analysis, high B4GALNT4 expression was an independent predictor of poor prognosis. In both patient cohorts, high B4GALNT4 expression did not correlate with known prognostic factors, such as disease stage, lymphovascular invasion, or squamous cell-carcinoma-related antigen level. B4GALNT4 influences the malignant behavior of ESCC cells. B4GALNT4 expression may serve as a novel prognostic marker, independent of established risk factors, for ESCC patients.

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

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

The prognosis of patients with type 4 scirrhous gastric cancer remains poor due to a high risk of peritoneal metastasis. We have previously developed combined chemotherapy regimens of intraperitoneal (IP) paclitaxel (PTX) and systemic chemotherapy, and promising clinical efficacy was reported in gastric cancer with peritoneal metastasis. Herein, a randomized, phase III study is proposed to verify the efficacy of IP PTX to prevent peritoneal recurrence. Gastric cancer patients with type 4 tumors and without apparent distant metastasis, including peritoneal metastasis, will be randomized for standard systemic chemotherapy or combined IP and systemic chemotherapy based on peritoneal lavage cytology findings. Those with negative peritoneal cytology will receive radical gastrectomy and adjuvant chemotherapy of S-1 plus docetaxel (control arm), or S-1 plus intravenous and IP PTX (experimental arm). Those with positive peritoneal cytology will receive three courses of S-1 plus oxaliplatin (control arm), or S-1 plus oxaliplatin and IP PTX (experimental arm). Subsequently, they undergo gastrectomy and receive postoperative chemotherapy of S-1 plus docetaxel (control arm), or S-1 plus intravenous and IP PTX (experimental arm). The primary endpoint is disease free survival after a 3-year follow-up period. Secondary endpoints are overall survival, survival without peritoneal metastasis, safety, completion rate, curative resection rate, and histological response of preoperative chemotherapy. A total of 300 patients are to be enrolled.

In Japan, esophagectomy after two courses of 5-fluorouracil plus cisplatin is regarded a standard strategy for treating resectable stage II or III esophageal squamous cell carcinoma (ESCC). However, 5-fluorouracil plus cisplatin does not benefit cohorts with clinical stage III ESCC, suggesting the requirement for a more effective regimen. We are conducting a single-arm phase II study to assess the safety and efficacy of neoadjuvant docetaxel, oxaliplatin plus S-1 (DOS) for treating patients with clinical stage III ESCC. The primary endpoint is the pathological response rate, and the target number is 45 patients. Safety, response rate, R0 resection rate, and survival are secondary endpoints. This trial is registered in the Japan Registry of Clinical Trials as jRCTs041210023. We are conducting a prospective phase II trial to evaluate the safety and efficacy of three courses of neoadjuvant DOS treatment followed by radical esophagectomy for clinical stage III ESCC.

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.

// Mitsuro Kanda 1 , Kenta Murotani 2 , Hiroyuki Sugimoto 1 , Takashi Miwa 1 , Shinichi Umeda 1 , Masaya Suenaga 1 , Masamichi Hayashi 1 , Norifumi Hattori 1 , Chie Tanaka 1 , Daisuke Kobayashi 1 , Suguru Yamada 1 , Michitaka Fujiwara 1 and Yasuhiro Kodera 1 1 Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan 2 Clinical Research Center, Aichi Medical University Hospital, Nagakute, Japan Correspondence to: Mitsuro Kanda, email: m-kanda@med.nagoya-u.ac.jp Keywords: hepatocellular carcinoma, biomarker, prognosis, expression panel Received: June 22, 2017 Accepted: July 25, 2017 Published: August 19, 2017 ABSTRACT Hepatocellular carcinoma (HCC) frequently recurs even after curative hepatectomy. To develop an integrated multigene expression panel, 144 patients were randomly assigned to either discovery or validation set in a 1:2 ratio. Using surgically resected HCC specimens, expression levels of 12 candidate molecular markers were determined using quantitative reverse-transcriptase PCR. In the discovery set, an expression panel was developed according to the concordance index (C-index) values for overall survival from all 4095 combinations of the 12 candidate molecular markers. Expression scores was determined with weighting according to the coefficient in a Cox regression, and patients were classified into grade 1, 2 and 3. Reproducibility was then tested in the validation set. A panel consisting of four markers, PRMT5 , MAGED4 , DPYSL3 and AJAP1 was selected as the optimal and most well-balanced set with a C-index value of 0.707. Patient prognosis was clearly stratified by the expression grade using this panel. In the validation set, both overall and disease-free survival rates decreased incrementally with as the grade increased. Higher grades were significantly associated with tumor multiplicity and vessel invasion. The prevalence of extrahepatic recurrences was increased in grade 3 patients. The integrated multigene expression panel clearly stratified HCC patients into low, intermediate and high risk.

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 To investigate the function of preferentially expressed antigen of melanoma (PRAME) in esophageal squamous cell carcinoma (ESCC). Materials and methods mRNA expression levels of PRAME were analyzed in resected esophageal tissues of 150 ESCC patients and correlated with clinicopathological parameters. We also investigated the potential function of PRAME by analyzing coordinately expressed genes in 13 ESCC cell lines. Results RT-qPCR analysis of clinical samples revealed aberrantly high PRAME expression in tumors compared with normal esophageal tissues. High PRAME expression was significantly associated with shorter disease-specific survival and hematogenous recurrence, but not with overall recurrence. The cumulative incidence of hematogenous recurrence was significantly greater for patients with high compared to those with low PRAME expression. In vitro, PCR array analysis revealed that PRAME was coordinately expressed with EGFR, ITGB, and TCF3. Conclusion PRAME is overexpressed in ESCC tissues and may serve as a novel biomarker for predicting hematogenous recurrence.

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.

Liver metastasis of gastric cancer (GC) is highly associated with poor prognosis. The development of sensitive biomarkers for detecting and predicting liver metastasis is required for better clinical outcome. In this study, we aimed to identify novel genes associated with liver metastasis of GC. Global expression profiling of 57,749 genes was performed using surgically resected gastric tissues from four patients with liver metastasis to identify candidate genes. The mRNA expression levels of the selected candidate gene were analyzed in the resected gastric tissues of 300 GC patients and correlated with clinicopathological parameters. Fourteen GC cell lines were subjected to mRNA expression and polymerase chain reaction (PCR) array analysis. Among 25 candidate genes identified by transcriptome analysis, preferentially expressed antigen of melanoma (PRAME) was selected for subsequent analyses. mRNA expression analysis of clinical samples revealed the aberrant expression of PRAME in GC tissues, and its high expression was significantly related to differentiated phenotype and vessel invasion, as well as liver metastasis. High PRAME expression was significantly associated with hepatic recurrence after curative surgery, and cumulative incidences of hepatic recurrence were significantly greater in patients with high PRAME expression compared with patients with low PRAME expression. In an in vitro analysis, overexpression was observed in all GC cell lines compared with a normal epithelial cell line. PCR array analysis revealed the coordinate expression of MMP9, OCLN, IL1RN, and MST1R. PRAME is related to the malignant potential of GC and could serve as a novel biomarker for the detection and prediction of liver metastasis.

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.

Development of high-performance serum biomarkers will likely improve treatment outcomes of patients with gastric cancer (GC). We previously identified the candidate serum markers, anosmin 1 (ANOS1), dihydropyrimidinase-like 3 (DPYSL3), and melanoma-associated antigen D2 (MAGE-D2) and evaluated their clinical significance through a single-center retrospective analysis. Here we conducted a prospective multicenter observational study aimed at validating the diagnostic performance of these potential markers. We analyzed serum levels before and after surgery of the three potential biomarkers in patients with GC and healthy volunteers. Quantification of serum and GC tissue levels was performed using an ELISA. Area under the curve (AUC) values that discriminated patients with GC from healthy controls were − 0.7058, 0.6188, and 0.5031 for ANOS1, DPYSL3, and MAGED2, respectively. The sensitivity and specificity of the ANOS1 assay were 0.36 and 0.85, respectively. The AUC value of ANOS1 that discriminated patients with stage I GC from healthy controls was 0.7131. Serum ANOS1 levels were significantly elevated in patients with stage I GC compared with those of healthy controls (median 1179 ng/ml and 461 ng/ml, respectively, P

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.

Objective:This study aimed to develop a gene-expression signature for identification of lymph node (LN) metastasis in esophageal squamous cell carcinoma (ESCC) patients.Summary of Background Data:LN metastasis is recognized as the most important independent risk factor for therapeutic decision-makin

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.

The detection of molecules and mechanisms affecting the malignant phenotype of gastric cancer cells may contribute to the identification of biomarkers for metastasis and recurrence, and such molecules may serve as targets of therapy. For this purpose, in this study transcriptome analysis was performed using surgically resected specimens from patients with gastric cancer with synchronous metastasis. We identified homeobox C10 (HOXC10) as the most highly expressed gene in gastric cancer tissues compared with the adjacent noncancerous gastric mucosa. Polymerase chain reaction (PCR) array analysis was performed to identify genes coordinately expressed with HOXC10. The effects of inhibiting HOXC10 on malignant phenotype was evaluated using HOXC10 knockout gastric cancer cell lines, and antibody array analysis was performed to assess the effect of HOXC10 knockout on intracellular signaling. We used a mouse subcutaneous xenograft model to evaluate the tumorigenicity. HOXC10 expression was determined in gastric cancer tissues acquired from 300 patients with gastric cancer. PCR array analysis revealed that the levels of HOXC10 messenger RNA positively correlated with those of FGFBP1 and SOX10. The phosphorylation of ERK1/2 was decreased in HOXC10 knockout cells. HOXC10 knockout significantly suppressed proliferation by increasing apoptosis and reducing the migration and invasiveness of gastric cancer cells. Mouse xenograft models revealed that the tumorigenicity of HOXC10 knockout cells was attenuated compared with the parental cells. The relatively high expression levels of HOXC10 in gastric cancer tissues were significantly associated with hepatic and peritoneal recurrence, as well as worse prognosis. Our results indicated that HOXC10 enhances the malignant phenotype of gastric cancer cells. The expression levels of HOXC10 may therefore serve as a prognostic biomarker and the products of HOXC10 may provide targets of therapy.

AIM To evaluate the prognostic significance of perioperative carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) levels in stage II/III gastric cancer. METHODS From a multi-institutional retrospective database compiled by integrating clinical data from nine institutions, data of 998 patients who underwent curative resection for stage II/III gastric cancer between 2010 and 2014 were retrieved and analyzed. The prognostic impact of the preoperative and postoperative levels and chronological changes in CEA, CA19-9 and their combination were evaluated. To test whether postoperative adjuvant chemotherapy alters the prognostic impact of perioperative CEA and CA19-9 levels, the hazard ratios for mortality were compared between patients who underwent surgery alone and patients who underwent surgery followed by adjuvant chemotherapy. RESULTS The prognostic impact of postoperative CEA and CA19-9 was superior to that of the preoperative levels. Multivariable analysis identified high postoperative CEA and CA19-9 levels as independent prognostic factors for overall survival. Disease-free survival rates clearly decreased in a stepwise manner in association with postoperative CEA and CA19-9 levels, and patients with high levels of both markers showed significantly poorer prognosis than other patient groups. When we analyzed perioperative changes in serum CEA and CA19-9 levels, patients with high levels before and after surgery had the worst disease-free survival rates among all patient groups. Patients with normalized CEA levels after surgery had a significantly lower disease-free survival rate than those with normal perioperative levels, whereas patients with normalized CA19-9 levels after surgery had equivalent survival to those with normal perioperative levels. The prognostic impact of high CEA levels was observably smaller in patients who underwent adjuvant chemotherapy than in patients who underwent surgery alone, whereas that of high CA19-9 was greater in patients who underwent adjuvant chemotherapy. High postoperative CEA levels were significantly associated with an increased prevalence of liver, lung and bone recurrences, and high postoperative CA19-9 levels were significantly associated with increased frequencies of lymph node and liver recurrences. CONCLUSION The evaluation of serum CEA and CA 19-9 levels both before and after surgery provides useful information for precise risk stratification after curative gastrectomy.

Background Neoadjuvant chemotherapy (NAC) has become the standard of care for resectable esophageal squamous cell carcinoma (ESCC) which is one of the most lethal cancers, to improve resectability and prognosis. On this basis, to provide individually optimized therapy for ESCC, a minimally-invasive biomarker for response to NAC is strongly desired. This study aimed to identify the miRNA signature in serum specimens taken from ESCC patients undergoing NAC through genome-wide microarray technology. Methods Comprehensive miRNA-expression profiles of serum specimens from ESCC patients before initial treatment were analyzed using microarray. A qPCR assay was performed to test the robustness of identified serum-based miRNA signature for discriminating response to NAC with serum specimens taken from 100 ESCC cases undergoing NAC. Results We prioritized 62 miRNAs differentially expressed between responders and non-responders (absolute log2 fold change > 1.0, corresponding P

This study aimed to evaluate the predictive value of the preoperative Controlling Nutritional Status (CONUT) score, which comprehensively reflects protein and lipid metabolism as well as the immunocompetence among patients with stage 2 or 3 gastric cancer. From a retrospective database of 3484 patients who underwent gastrectomy for gastric cancer at nine Japanese institutions between 2010 and 2014, data for 626 patients with stage 2 or 3 cancer were retrieved. The study evaluated the significance of the associations between the optimal CONUT score cutoff values with the prognosis and the incidence of postoperative complications. The study determined that 2 was the optimal CONUT score cutoff value for predicting mortality 2 years after surgery. The patients with a CONUT score of 2 or higher (CONUT-high group) were significantly older and had a worse Eastern Cooperative Oncology Group performance status, lower body mass index, and more advanced tumor-node-metastasis stage than the patients with a CONUT score lower than 2 (CONUT-low group). Overall, the survival time was significantly shorter in the CONUT-high group than in the CONUT-low group [hazard ratio (HR) 1.97; P

Splenectomy for proximal gastric cancer was found to have no survival benefit in a randomized trial clarifying the role of splenectomy (JCOG0110 study). However, since tumor with invasion to the greater curvature and Type 4 tumor were excluded in JCOG0110, the benefit of splenectomy for these tumors is not known. A multicenter dataset of patients with gastric cancer who underwent gastrectomy between 2010 and 2014 was created. From the dataset, 114 eligible patients with proximal advanced gastric cancer with invasion to the greater curvature or Type 4 tumor were enrolled. There were 60 patients in the gastrectomy with splenectomy (Spx) group and 54 patients in the spleen-preserving (Prs) group. To balance the essential variables, propensity score analysis was performed, estimating the propensity score with a logistic regression model. Adjusted overall survival (OS) and adjusted disease-free survival (DFS) were estimated using the inverse probability of treatment weighting (IPTW) method. There were significant differences in age, performance status, comorbidity, macroscopic type, and clinical T stage between the Spx and Prs groups. The model for estimating the propensity score was well adapted (c-statistic: 0.830, 95%CI: 0.754–0.906). Adjusted OS was identical between the two groups (HR = 1.089, 95%CI: 0.759–1.563; p = 0.644). The DFS curve of Prs group was consistently tended to be lower than Spx, but the difference was not significant (HR = 0.813, 95%CI: 0.572–1.156; p = 0.249). The efficacy of splenectomy was minimal for proximal advanced gastric cancer even with invasion to the greater curvature or Type 4 tumor.