[A Case of Gastric Cancer Invading the Pancreas with Pathological Complete Response Treated by Preoperative S-1 plus Oxaliplatin Therapy].

A 66-year-old man with severe anemia was diagnosed with gastric cancer. CT examination revealed primary gastric tumor, which involved the pancreas body, with regional lymph nodes that were enlarged(T4b[panc], cN2, cM0, cStage ⅣA). He received three courses of preoperative S-1 plus oxaliplatin therapy. Primary tumor and metastatic lymph nodes were reduced remarkably. We performed a curative distal gastrectomy(D2)without pancreas resection. Histopathological examination revealed Grade 3 pathological complete response in both primary tumor and metastatic lymph nodes.

Overexpression of ZRF1 is related to tumor malignant potential and a poor outcome of gastric carcinoma.

Zuotin-related factor 1 (ZRF1) is a recently characterized epigenetic factor involved in transcriptional regulation and is highly overexpressed in several malignancies, but it is not known whether it plays a role in gastric cancer (GC). In this study, we investigated whether ZRF1 acts as a cancer-promoting gene through its activation/overexpression in GC. We analyzed five GC cell lines and 133 primary tumors, which had been curatively resected in our hospital between 2001 and 2003. Overexpression of ZRF1 was detected in GC cell lines (four out of five lines, 80.0%) and was detected in primary tumor samples of GC (52 out of 133 cases, 39.1%) and significantly correlated with differentiated histological type, venous invasion, lymphatic invasion, advanced stage and a higher recurrence rate. ZRF1-overexpressing tumors had a worse survival rate than those with non-expressing tumors (P < 0.01, log-rank test). ZRF1 positivity was independently associated with a worse outcome in the multivariate analysis (P < 0.01; hazard ratio 4.92; 95% confidence interval: 1.6-21.1). In ZRF1-overexpressing GC cells, knockdown of ZRF1 using specific siRNAs inhibited the cell proliferation, migration and invasion and induced apoptosis in a p53-dependent manner. These findings suggest that ZRF1 plays a crucial role in tumor malignant potential through its overexpression and highlight its usefulness as a prognostic factor and potential therapeutic target in GC.

[Novel Liver Retraction Method Using the FJ Clip and Silicon Disk for Laparoscopic Gastrectomy].

Laparoscopic gastrectomy(LG)has been developed, and its use has spread widely. One of the merits of this methodology for surgeons is its magnifying effect, which largely contributes to precise lymphadenectomy and lower blood loss. However, by contrast, its restricted view could be a demerit, and care should be taken to avoid trouble duringan operation. Liver retraction is an essential operative procedure to maintain a good surgical field and ensure sufficient working space during LG. We present a novel approach that uses the free jaw(FJ)clip and silicon disk. Our novel approach involved 1 ) exposingthe right crus of the diaphragm and grasping it using a FJ clip; 2 ) elevatingthe left lobe of the liver by usingfree loop plus with a 10- cm Penrose drain attached to the FJ clip grasping the right crus; and 3 ) insertingthe silicon disk between the Penrose drain and the left lobe of the liver. The FJ clip is reusable and easily maneuvered with the commonly used laparoscopy forceps. The last step enables prevention of intraoperative complications such as injury by forceps or energy devices. Therefore, we believe this procedure might be useful for LG, and we will prospectively confirm its usefulness in terms of hepatic function, operative time, and other factors.

Overexpression of PBK/TOPK relates to tumour malignant potential and poor outcome of gastric carcinoma.

BACKGROUND: PDZ-binding kinase/T-LAK cell-originated protein kinase (PBK/TOPK) is a serine-threonine kinase and overexpressed in various types of cancer by inhibiting the transactivation activities of p53 and PTEN. We tested whether PBK/TOPK acts as a cancer-promoting gene through its activation/overexpression in gastric cancer (GC). METHODS: We analysed five GC cell lines and 144 primary tumours, which were curatively resected in our hospital between 2001 and 2003. RESULTS: Overexpression of the PBK/TOPK protein was frequently detected in GC cell lines (4 out of 5 lines, 80.0%) was detected in primary tumour samples of GC (24 out of 144 cases, 16.6%) and was significantly correlated with venous invasion, tumour depth and recurrence rate. PDZ-binding kinase/T-LAK cell-originated protein kinase-overexpressing tumours had a worse survival rate than those with non-expressing tumours (P=0.0009, log-rank test). PDZ-binding kinase/T-LAK cell-originated protein kinase positivity was independently associated with a worse outcome in multivariate analysis (P<0.0001, hazard ratio 6.40 (2.71-14.49)). In PBK/TOPK-overexpressing GC cells, knockdown of PBK/TOPK inhibited the cell proliferation through the p53 activation in a TP53 mutation-dependent manner and inhibited the migration/invasion through the PTEN upregulation in a TP53 mutation-independent manner. CONCLUSIONS: These findings suggest PBK/TOPK plays a crucial role in tumour malignant potential through its overexpression and highlight its usefulness as a prognostic factor and potential therapeutic target in GC.

[A Case Report of Adenocarcinoma with Pagetoid Growth(Secondary Paget's Disease)of the Anal Canal].

Differentiating primary Paget's disease from secondary Paget's disease, which is also known as Pagetoid growth of other cancers, in the perianal region is difficult. Given that the treatment strategies of both disease are significantly different, diagnosis of such conditions should be performed with caution. We report a case of secondary Paget's disease. A 76-year-old man previously visited a hospital because of erythematous plaque around the anus. It was diagnosed as extramammary Paget's disease based on skin biopsy results; consequently, perianal skin resection was performed. Pathological examination of the resected specimen indicated Pagetoid growth of mucinous carcinoma, and it was positive for stump. Consequently, laparoscopic abdominoperineal resection was performed. Finally, the plaque was diagnosed as anal canal adenocarcinoma with Pagetoid growth, and all the previous results were deemed as initial diagnosis. CONCLUSION: Discriminating between primary and secondary Paget's disease, even with immunohistological techniques, is difficult. Novel methodology that might facilitatemoreaccuratediagnosis preoperatively for erythematous plaquearound theanus and morecurativethe rapeutic strategy are needed.

Prognostic impact of the number of retrieved lymph nodes in patients with gastric cancer.

BACKGROUND: In gastric cancer, although at least 16 lymph nodes of retrieved lymph nodes (RLNs) are recommended for nodal staging in Japanese Classification of Gastric Carcinoma and TNM classifications, we wished to clarify their appropriateness. STUDY DESIGN: A total of 1289 consecutive gastric cancer patients, who underwent gastrectomy between 1997 and 2011, were analyzed retrospectively. RESULTS: (i) The patients were divided into two groups using a cut-off RLN number of 16 (RLN < 16 or RLN ≥ 16). There were significant differences in the survival rates of patients in pStage II (P < 0.0001) and III (P = 0.0009), but not those of patients in pStage I (P = 0.0627) and IV (P = 0.1553). (ii) In 498 consecutive patients in pStage II and III, compared with patients in the RLN ≥ 16 group, those in the RLN < 16 group had a significantly higher incidence of older age (P = 0.0004) and positive lymph node ratio (PLNR) (P < 0.0001). Univariate and multivariate analyses showed that an RLN number of less than 16 was an independent poor prognostic factor (P < 0.0001, HR 2.48 [95% CI: 1.60-3.70]). (iii) A cut-off RLN number of 16 could cause the stage migration effect in pStage II or III patients. A cut-off RLN number of 25 or more could eliminate the prognostic effect. CONCLUSION: The RLN number may potentially affect the prognosis and the stage migration in pStage II or III gastric cancer patients. An RLN number of 25 or more could be sufficient for nodal staging.

Circulating MicroRNAs: A Next-Generation Clinical Biomarker for Digestive System Cancers.

MicroRNAs (miRNAs) are short noncoding RNAs that post-transcriptionally regulate gene expression and play important roles in various physiological and developmental processes such as oncogenic or tumor suppressive regulators. Specific miRNA expression signatures have been identified in a number of human cancers. Cell-free miRNAs have recently been stably detected in plasma and serum (circulating miRNAs), and their presence in blood has attracted the attention of researchers due to their potential as non-invasive biomarkers. Circulating miRNAs have emerged as tumor-associated biomarkers that reflect not only the existence of early-stage tumors, but also the dynamics and status of advanced stage tumors, tumor recurrence, and drug sensitivities. This methodology for liquid biopsy may provide non-invasive and reproductive biomarkers and individualized therapeutic strategies for cancer patients. We herein review the current phase of biological and clinical research on the circulating miRNAs of solid cancers, particularly digestive tract cancers, and discuss future perspectives. The present review may be beneficial for future research on miRNAs used to detect various cancers.

Plasma microRNA profiles: identification of miR-744 as a novel diagnostic and prognostic biomarker in pancreatic cancer.

BACKGROUND: This study aims to explore novel microRNAs in plasma for screening cancer and predicting clinical outcomes in pancreatic cancer (PCa) patients using a microRNA array-based approach. METHODS: We used the Toray 3D-Gene microRNA array-based approach to compare plasma levels between PCa patients and healthy volunteers. RESULTS: (1) Six oncogenic microRNAs (miR-615-5p, -744, -575, -557, -675, and -550a) with high expression in plasma were selected. (2) By quantitative RT-PCR using plasma samples from 94 PCa patients and 68 healthy volunteers, a significantly higher level of plasma miR-744 in PCa patients than in healthy volunteers was validated in small-scale analysis (P=0.0038), two independent cohort analyses, and large-scale analysis (P<0.0001, AUC 0.8307). (3) miR-744 expression was significantly higher in PCa tissues (P=0.0069) and PCa cell lines (P=0.0074) than in normal tissues and fibroblasts, respectively. Preoperative plasma level of miR-744 was significantly reduced in postoperative samples (P=0.0063). (4) A high level of plasma miR-744, which was correlated with lymph node metastasis (P=0.0407) and recurrences (P=0.0376), was an independent poor prognostic factor of PCa patients after pancreatectomy (P=0.0007, HR 21.2 (3.17-436)). Furthermore, a high level of plasma miR-744 contributed to poorer progression-free survival of non-operable PCa patients who underwent gemcitabine-based chemotherapy (P=0.0533). Overexpression of miR-744 in PCa cells induced significant chemoresistance to gemcitabine in vitro. CONCLUSIONS: Plasma miR-744 might be useful biomarker for screening PCa, monitoring, and predicting poor prognosis and chemoresistance in PCa patients.

[Clinical Risk Factors and Problems Associated with the Difference between Preoperative and Pathological Diagnosis of Tumor Depth in Patients with Upper Third Gastric Cancer].

BACKGROUND AND AIMS: The epidemiology of gastric cancer is changing with an increasing proportion of tumors in the upper stomach. This study was designed to identify risk factors and clinical problems related to the difference between clinical and pathological diagnosis of tumor depth in cases of upper third gastric cancer. PATIENTS AND METHODS: A total of 119 consecutive patients with upper third gastric cancer, who underwent curative gastrectomy between 2008 and 2012, were retrospectively analyzed. RESULTS: The patients were divided into 2 groups based on the pattern of the difference between the clinical (c) and pathological (p) diagnosis of the T factor. Thirty patients (25%) were included in the underestimated diagnosis group (UE group, cTpT or cT=pT). The number of cases showing undifferentiated type (TMN) and lymphatic invasion was significantly higher in the UE group compared to the OC group. Multivariate analysis revealed that the undifferentiated type (TMN) was an independent risk factor for underestimation (p<0.05). CONCLUSION: The presence of undifferentiated components in upper third gastric cancer was associated with a high incidence of underestimated diagnosis. Care should be taken in decision-making for surgical treatments based on the clinical diagnosis.

[Novel approach to laparoscopy and endoscopy cooperative surgery (LECS) in gastric submucosal tumors near the esophago-gastric junction].

BACKGROUND AND PURPOSE: Laparoscopy and endoscopy cooperative surgery (LECS) for gastric submucosal tumors is an excellent surgical procedure that enables prevention of excessive resection and deformity of the stomach. This procedure may be more useful for gastric submucosal tumors near the esophagogastric (EG) junction and the pylorus. We present a novel approach to LECS for gastric submucosal tumors near the EG junction. PATIENTS: From 2010 to 2013, seven consecutive patients underwent LECS for gastric submocosal tumors near the EG junction. Novel approach: Our novel approach to LECS involved (1) minimizing the resection of the stomach wall by using endoscopic mucosal resection for all types of submucosal tumor, (2) selecting the best anastomotic axis in order to avoid deformity of the stomach, (3) using hand sewing if anastomotic complications might occur and (4) sometimes combining anti-reflux surgery with LECS for tumors extremely close to the EG junction. RESULTS: No patient had any anastomotic complications or reflux esophagitis. CONCLUSIONS: LECS is safe and useful for gastric submucosal tumors near the EG junction.

[A case of advanced gastric cancer found to be remaining by gastrectomy after a clinically complete response to chemotherapy].

The patient was a 72-year-old woman diagnosed with advanced gastric cancer, hepatic portal lymph node and para-aortic lymph node metastases. After five courses of S-1/CDDP combination therapy, both the primary tumor and lymph node metastases disappeared clinically. She wished to continue chemotherapy instead of having a resection. After three more courses of S-1/CDDP therapy, gastric cancer and lymph node metastases were still completely regressed, but complications of carcinoma of the gallbladder were suspected. Gastrectomy was performed with cholecystectomy, and a histopathological examination revealed cancer cells remaining in the gastric submucosa and xanthogranulomatous cholecystitis. We consider surgical therapy for clinically completely disappearing advanced gastric cancer by chemotherapy, in addition to case report.

Correction: Overexpression of CTEN relates to tumor malignant potential and poor outcomes of adenocarcinoma of the esophagogastric junction.

[This corrects the article DOI: 10.18632/oncotarget.21109.].

Low plasma levels of miR-101 are associated with tumor progression in gastric cancer.

BACKGROUND: Several studies have identified the decreased expression of the tumor suppressor miR-101 in various cancers. In this study, we tested miR-101 as a potential therapeutic target and novel plasma biomarker for gastric cancer (GC). RESULTS: The miR-101 expression level was significantly lower in GC tissues (P = 0.0038) and GC cell lines (P = 0.0238) than in normal gastric mucosa. Both exosomal and plasma miR-101 were significantly downregulated in GC patients compared with healthy volunteers (P = 0.0281 and P < 0.0001, respectively). Low miR-101 plasma level was significantly associated with advanced T factor, advanced disease stage, and peritoneal metastasis and predicted poor prognosis in GC patients (P = 0.0368; hazard ratio, 3.079; 95% confidence interval: 1.06-11.08). Overexpression of miR-101 in GC cells induced apoptosis by inhibiting MCL1 and suppressed cell migration and invasion by regulating ZEB1. CONCLUSIONS: Depletion of the tumor suppressor miRNA-101 in plasma is related to tumor progression and poor outcomes. Low plasma miR-101 may be a biomarker for GC, and its restoration might be a novel anticancer treatment strategy.

Overexpression of CTEN relates to tumor malignant potential and poor outcomes of adenocarcinoma of the esophagogastric junction.

BACKGROUND: To detect a novel treatment target for adenocarcinoma of the esophagogastric junction (AEG), we tested whether C-terminal tensin-like (CTEN), a member of the tensin gene family and frequently overexpressed in various cancers, acts as a cancer-promoting gene through overexpression in AEG. MATERIALS AND METHODS: We analyzed 5 gastric adenocarcinoma (GC) cell lines and 104 primary AEG tumors curatively resected in our hospital between 2000 and 2010. RESULTS: CTEN overexpression was detected in GC cell lines (2/5 cell lines; 40%) and primary AEG tumor samples (35/104 cases; 34%). CTEN knockdown using several specific siRNAs inhibited the proliferation, migration, and invasion of CTEN-overexpressing cells. CTEN overexpression was significantly correlated with more aggressive venous and lymphatic invasion, deeper tumor depth, and higher rates of lymph node metastasis and recurrence. Patients with CTEN-overexpressing tumors had a worse overall rate of survival than those with non-expressing tumors (P < 0.0001, log-rank test) in an expression-dependent manner. CTEN positivity was independently associated with a worse outcome in the multivariate analysis (P = 0.0423, hazard ratio 3.54 [1.04-16.4]). CONCLUSIONS: CTEN plays a crucial role in tumor cell proliferation, migration, and invasion through its overexpression, which highlights its usefulness as a prognosticator and potential therapeutic target in AEG.

Liquid biopsy in patients with hepatocellular carcinoma: Circulating tumor cells and cell-free nucleic acids.

Hepatocellular carcinoma (HCC), with its high incidence and mortality rate, is one of the most common malignant tumors. Despite recent development of a diagnostic and treatment method, the prognosis of HCC remains poor. Therefore, to provide optimal treatment for each patient with HCC, more precise and effective biomarkers are urgently needed which could facilitate a more detailed individualized decision-making during HCC treatment, including the following; risk assessment, early cancer detection, prediction of treatment or prognostic outcome. In the blood of cancer patients, accumulating evidence about circulating tumor cells and cell-free nucleic acids has suggested their potent clinical utilities as novel biomarker. This concept, so-called "liquid biopsy" is widely known as an alternative approach to cancer tissue biopsy. This method might facilitate a more sensitive diagnosis and better decision-making by obtaining genetic and epigenetic aberrations that are closely associated with cancer initiation and progression. In this article, we review recent developments based on the available literature on both circulating tumor cells and cell-free nucleic acids in cancer patients, especially focusing on Hepatocellular carcinoma.

Overexpression of EGFR as an Independent Prognostic Factor in Adenocarcinoma of the Esophagogastric Junction.

BACKGROUND: Adenocarcinoma of the esophagogastric junction (AEG) has increased in Western and Eastern countries, and its prognosis remains poor. We tested whether epidermal growth factor receptor (EGFR), that is overexpressed in various tumors, acts as a cancer-promoting gene through overexpression in AEG. MATERIALS AND METHODS: We analyzed 104 primary AEG tumors which were curatively resected in our hospital between 2000 and 2010. RESULTS: Overexpression of EGFR protein was detected in 47% primary AEG tumor samples, and significantly associated with venous and lymphatic invasion, tumor depth and lymph node metastasis. The high-expression group had a significantly poorer prognosis than the low expression group for overall and disease-free survival. EGFR positivity was independently associated with a worse outcome in the multivariate analysis (p=0.0397, hazard ratio(HR)=2.048). CONCLUSION: EGFR plays a pivotal role in AEG through its overexpression, which highlights its usefulness as a prognosticator and potential therapeutic target in AEG.

Depleted tumor suppressor miR-107 in plasma relates to tumor progression and is a novel therapeutic target in pancreatic cancer.

This study explored decreased tumor suppressor microRNA (miRNA) plasma levels in pancreatic cancer (PCa) patients to clarify their potential as novel biomarkers and therapeutic targets. We used the microRNA array-based approach to select candidates by comparing plasma levels between PCa patients and healthy volunteers. Six down-regulated miRNAs (miR-107, miR-126, miR-451, miR-145, miR-491-5p, and miR-146b-5p) were selected. Small- and large-scale analyses using samples from 100 PCa patients and 80 healthy volunteers revealed that miR-107 was the most down-regulated miRNA in PCa patients compared with healthy volunteers (P < 0.0001; area under the receiver-operating characteristic curve, 0.851). A low miR-107 plasma level was significantly associated with advanced T stage, N stage, and liver metastasis and was an independent factor predicting poor prognosis in PCa patients (P = 0.0424; hazard ratio, 2.95). miR-107 overexpression in PCa cells induced G1/S arrest with the production of p21 and inhibited cell proliferation through the transcriptional regulation of Notch2. In vivo, the restoration and maintenance of the miR-107 plasma level significantly inhibited tumor progression in mice. Depletion of the tumor suppressor miR-107 in plasma relates to tumor progression and poor outcomes. The restoration of the plasma miR-107 level might be a novel anticancer treatment strategy for PCa.

Overexpression of YWHAZ as an independent prognostic factor in adenocarcinoma of the esophago-gastric junction.

Several studies have demonstrated that YWHAZ (14-3-3ζ), included in the 14-3-3 family of proteins, is implicated in the initiation and progression of cancers. To detect a novel treatment target for adenocarcinoma of the esophagogastric junction (AEG), we tested whether YWHAZ acted as a cancer-promoting gene through its overexpression in AEG. We analyzed YWHAZ protein expression in 92 consecutive primary AEG tumors, which had been curatively resected in our institution between 2000 and 2010. Overexpression of the YWHAZ protein was frequently detected in primary AEG tumor samples (46% (42/92)). Overexpression of YWHAZ was significantly correlated with Siewert type III tumor, larger tumor size (≥40 mm) and higher rates of lymph node metastasis and recurrence. Patients with YWHAZ-overexpressing tumors had a worse overall rate of survival than those with non-expressing tumors (P = 0.011, log-rank test) in an intensity expression-dependent manner. Patients with YWHAZ-overexpression tumors had worse overall survival rates than those with lower-expression tumors. YWHAZ positivity was independently associated with a worse outcome in the multivariate analysis (P = 0.0015, hazard ratio 4.49 [1.736-13.06]). In conclusion, YWHAZ plays a crucial role in poor outcomes of patients with AEG through its overexpression, which highlights its usefulness as a prognosticator and potential therapeutic target and indicator in AEG.

Circulating miR-21 as an independent predictive biomarker for chemoresistance in esophageal squamous cell carcinoma.

Only a few studies indentified the significance of circulating microRNAs in blood as a predictive biomarker for chemoresistance in esophageal squamous cell carcinoma (ESCC). In this study, we tested whether oncogenic miR-21 promoted chemoresistance in ESCC and served as a biomarker for predicting chemoresistance in plasma of patients with ESCC. All consecutive patients underwent the preoperative chemotherapy regimen (JCOG9907 trial) with cisplatin plus 5-fluorouracil. As a result, pretreatment plasma concentrations of miR-21 were significantly higher in ESCC patients with a low histopathological response than in those with a high histopathological response (P = 0.0416). Multivariate analysis revealed that a high pretreatment plasma concentration of miR-21 was an independent risk factor of chemoresistance (p = 0.0150; Odds Ratio 9.95 (range: 1.56-63.4)). The expression of miR-21 was also significantly higher in pretreatment ESCC tissues with a low histopathological response than in those with a high histopathological response (P = 0.0409). In vitro, although the growth of KYSE 170 ESCC cells transfected with the control mimics was markedly inhibited by the 5-fluorouracil or cisplatin treatment, the inhibitory effects of 5-FU (P < 0.05) or cisplatin (P < 0.05) were significantly reduced in KYSE170 cells that overexpressed miR-21. Taken together, the overexpression of miR-21 contributed to chemoresistance and circulating miR-21 in plasma of patients with ESCC could be a useful biomarker for predicting chemoresistance.

Circulating microRNA profiles in plasma: identification of miR-224 as a novel diagnostic biomarker in hepatocellular carcinoma independent of hepatic function.

AIMS: This study was designed to identify novel microRNAs (miRNAs) in plasma for detecting and monitoring hepatocellular carcinoma (HCC), independent of hepatic function and background liver diseases with different etiologies. RESULTS: (1) Four oncogenic miRNAs (miR-151, 155, 191 and 224) with high expression in HCC tissues were selected as candidates. (2) Quantitative RT-PCR using plasma samples from 107 HCC patients and 75 healthy volunteers revealed a significantly higher level of plasma miR-224 in HCC patients than in healthy volunteers according to a small-scale analysis (P < 0.0001), two independent large-scale cohort analysis (P < 0.0001, AUC 0.908). (3) miR-224 expression was significantly higher in HCC tissues and HCC cell lines than in normal hepatic tissues and fibroblasts, respectively. (P = 0.0011, 0.0150) (4) Plasma miR-224 reflected tumor dynamics; preoperative plasma levels of miR-224 were significantly reduced in postoperative samples (P = 0.0058), and plasma miR-224 levels were significantly correlated with paired miR-224 levels in HCC tissues (P = 0.0005). (5) Furthermore, plasma miR-224 levels significantly discriminated HCC patients from patients with chronic liver disease (P = 0.0008). A high plasma miR-224 level was significantly correlated with larger tumor size (P = 0.0005) and recurrences (P = 0.0027). The plasma miR-224 level could accurately detect small tumors less than 18 mm preoperatively. METHODS: We performed a systematic review of the NCBI database and selected candidate miRNAs reported as highly expressed in HCC tissue. CONCLUSIONS: Plasma miR-224 may be a sensitive biomarker for screening HCC and monitoring tumor dynamics.