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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.

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.

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 (

The number of patients who die from causes other than gastric cancer after R0 resection is increasing in Japan, due in part to the aging population. However, few studies have comprehensively investigated the clinicopathological risks associated with deaths from other causes after gastrectomy. This study aimed to build a risk score for predicting such deaths.We retrospectively reviewed clinical data for 3575 patients who underwent gastrectomy for gastric cancer at nine institutions in Japan between January 2010 and December 2014.The final study population of 1758 patients were assigned to Group A (n = 187): patients who died from other causes within 5 years of surgery, and Group B (n = 1571): patients who survived ≥ 5 years after surgery. Multivariate analysis identified nine characteristics as risk factors for poor survival: age ≥ 75 years, male sex, body mass index 22 kg/mThe risk score defined here may be useful for predicting deaths from other causes after curative gastrectomy.

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.

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 (

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 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.

448 Background: Despite advances in multimodality treatment of esophageal squamous cell carcinoma (ESCC), the recurrence rate after curative resection remains high. Assessment of the risk of disease recurrences after curative resection of ESCC will be helpful for optimization of individual patient management. The close association between coagulation status and progression of malignant tumors has been previously reported. We herein sought to identify sensitive prognostic factors in ESCC by combining multiple coagulation markers. Methods: A total of 200 patients who underwent curative subtotal esophagectomy after neoadjuvant treatment for ESCC between January 2012 and December 2020 were included in the analysis. We retrospectively evaluated the correlation of preoperative plasma D-dimer (upper limit of normal, 1.0 μg/mL), fibrinogen (upper limit of normal, 350 mg/dL) levels and the coagulation score, which is calculated by combining levels of D-dimer and fibrinogen, with postoperative prognosis. The coagulation score was determined as follows. 0, neither D-dimer nor fibrinogen were elevated; 1, either D-dimer or fibrinogen was above the upper limit of normal; 2, both were elevated. Results: There was no significant difference in postoperative recurrence-free survival between the high and low groups for either preoperative D-dimer alone or preoperative fibrinogen alone. 59 patients (29.5%), 99 patients (49.5%) and 42 patients (21%) were categorized into coagulation score 0, 1 and 2, respectively. Patients in the coagulation score 1-2 group had a significantly shorter recurrence-free survival time than those in the coagulation score 0 group (hazard ratio 1.99, P = 0.0223). Conclusions: The coagulation score combining with plasma D-dimer and fibrinogen levels was suggested to be a simple predictor of postoperative recurrences in patients undergoing curative subtotal esophagectomy after neoadjuvant treatment for ESCC.

811 Background: Little knowledge is available for postsurgical changes in cognitive and physical functions that may be useful for considering indication for surgery in elderly patients with gastric cancer. We therefore conducted a prospective study aimed to determine the influence of gastrectomy on these patients. Methods: We recruited patients older than 75 years for whom gastrectomy for gastric cancer had been planned, and assessed their cognitive and physical functions, daily activities, episodes of depression, confusion, and delirium before surgery (baseline), upon discharge, and at 6 months after surgery (POM 6). Results: Among 54 elderly patients registered between February 2017 and February 2020. There were no significant decreases in MMSE scores between baseline and at POM 6, nor were there significant differences in physical function and indicators of depression and confusion between these time points. As many as 20% of patients were found to have the functional decline on the basic activities of daily living scores (BADL) after surgery compared with the baseline. The only variable significantly associated with a functional decline in BADL was postoperative complications. Conclusions: Postoperative cognitive functions did not significantly decline when compared with the baseline scores, although postoperative BADL scores of patients who experienced postoperative complications were significantly lower than those who did not.

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

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.

Peritoneal dissemination is the key to the prognosis of gastric cancer (GC) and can be detected early with peritoneal lavage cytology. No studies have examined preoperative prognostic factors in GC patients who have positive cytology but no other non-curative factors.We conducted a retrospective analysis using a multicenter database of 3575 patients who underwent gastrectomy between 2010 and 2014. Patients with positive peritoneal lavage cytology as a sole non-curative factor were retrieved, and correlations between parameters and the prognosis were compared.A total of 66 patients were identified as eligible. In the receiver operating characteristic (ROC) curve analysis, the neutrophil-to-platelet ratio (NPR) had the greatest area under the curve value and was selected. We divided the NPR into two groups based on the optimal cutoff value of the NPR (2.000), as determined by the ROC curve analysis. A high preoperative NPR was the only prognostic factor. The NPR-high group had shorter overall survival than the NPR-low group (hazard ratio 1.85, 95% confidence interval 1.05-3.28, P = 0.032).Our analysis indicated that the preoperative NPR serves as a prognostic factor in GC patients with positive peritoneal lavage cytology in the absence of other non-curative factors.

// 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.

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 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

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.

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

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

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 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.