Beginner Surgeon's Initial Experience with Distal Subtotal Gastrectomy for Gastric Cancer Using a Minimally Invasive Approach.

PURPOSE: Minimally invasive gastrectomy (MIG), including laparoscopic distal subtotal gastrectomy (LDG) and robotic distal subtotal gastrectomy (RDG), is performed for gastric cancer, and requires a learning period. However, there are few reports regarding MIG by a beginner surgeon trained in MIG for gastric cancer during surgical residency and fellowship. The aim of this study was to report our initial experience with MIG, LDG, and RDG by a trained beginner surgeon. MATERIALS AND METHODS: Between January 2014 and February 2015, a total of 36 patients (20 LDGs and 16 RDGs) underwent MIG by a beginner surgeon during the learning period, and 13 underwent open distal subtotal gastrectomy (ODG) by an experienced surgeon in Bundang CHA Medical Center. Demographic characteristics, operative findings, and short-term outcomes were evaluated for the groups. RESULTS: MIG was safely performed without open conversion in all patients and there was no mortality in either group. There was no significant difference between the groups in demographic factors except for body mass index. There were significant differences in extent of lymph node dissection (LND) (D2 LND: ODG 8.3% vs. MIG 55.6%, P=0.004) and mean operative time (ODG 178.8 minutes vs. MIG 254.7 minutes, P<0.001). The serial changes in postoperative hemoglobin level (P=0.464) and white blood cell count (P=0.644) did not show significant differences between the groups. There were no significant differences in morbidity. CONCLUSIONS: This study showed that the operative and short-term outcomes of MIG for gastric cancer by a trained beginner surgeon were comparable with those of ODG performed by an experienced surgeon.

Association of the miR-146aC>G, miR-149T>C, miR-196a2T>C, and miR-499A>G polymorphisms with gastric cancer risk and survival in the Korean population.

We investigated whether four common microRNA polymorphisms (miR-146aC>G [rs2910164], miR-149T>C [rs2292832], miR-196a2T>C [rs11614913], and miR-499A>G [rs3746444]) are associated with the susceptibility and prognosis of gastric cancer in the Korean population. The four microRNA single-nucleotide polymorphisms (SNPs) were identified in a case-control study (461 patients; 447 controls) by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis in the Korean population. When patients were stratified into diffuse and intestinal-type gastric cancer groups, subjects with the miR-499AG and AG + GG genotypes had reduced adjusted odds ratios (AORs) for diffuse-type gastric cancer (AOR = 0.54 with 95% confidence interval [CI] = 0.31-0.97; AOR = 0.57 with 95% CI = 0.33-0.97). In the stratified analyses for gastric cancer risk, the miR-146aGG and CG + GG genotypes were associated with increased risk of gastric cancers among the non-smokers, whereas the miR-149TC and TC + CC genotypes showed lower risk of gastric cancer in males. The miR-196a2CC genotype was associated with elevated gastric cancer risk among females. For gastric cancer prognosis, intestinal-type gastric cancer patients with miR-146aCG + GG genotypes had significantly higher survival rates (log-rank P = 0.030) than patients with the CC genotype, and patients with the miR-499AA genotype had significantly increased survival rates compared to patients with the AG + GG genotypes (log-rank P = 0.013). When miR-146aCG + GG and miR-499AA genotypes were combined, the survival rate of intestinal-type gastric cancer patients was elevated (log-rank P < 0.001). No association was found between gastric or diffuse-type cancer prognosis and other miRNAs. Our data demonstrate that specific miRNA SNPs are associated with gastric cancer susceptibility (miR-499A>G) and prognosis (miR-146aC>G and miR-499A>G) in the Korean population depending on gastric cancer type.

Hyperbilirubinemia is a significant indicator for the severity of acute appendicitis.

PURPOSE: This study aims to reveal more effective clinical or laboratory markers for the diagnosis of acute appendicitis and to score the severity based on a sufficiently large number of patients with acute appendicitis. METHODS: We identified 1,195 patients with acute appendicitis after excluding those with other causes of hyperbilirubinemia among the 1,271 patients that underwent a laparoscopic or an open appendectomy between 2009 and 2010. A retrospective chart review of the medical records, including laboratory and histologic results, was conducted. We then analyzed the data using univariate and multivariate analyses. RESULTS: Among the 1,195 patients, a laparoscopic appendectomy was performed in 685 cases (57.32%), and an open appendectomy was performed in 510 cases (42.68%). The univariate analysis demonstrated significant differences for white blood cell count (P < 0.0001), segmented neutrophils (P = 0.0035), total bilirubin (P < 0.0001), and systemic inflammatory response syndrome (SIRS) score between groups (P < 0.0001). The multivariate analysis demonstrated that total bilirubin (odds ratio, 1.772; 95% confidence interval, 1.320 to 2.379; P = 0.0001) and SIRS score (odds ratio, 1.583; 95% confidence interval, 1.313 to 1.908; P < 0.0001) have statistically significant diagnostic value for perforated appendicitis. CONCLUSION: Hyperbilirubinemia is a statistically significant diagnostic marker for acute appendicitis and the likelihood of perforation.

Notch3 and Jagged2 contribute to gastric cancer development and to glandular differentiation associated with MUC2 and MUC5AC expression.

AIMS: Notch signalling plays diverse roles in malignant tumours as well as in normal tissue development. In this study we investigated the expression of Notch signalling pathway genes and their clinicopathological significance in gastric carcinomas. METHODS AND RESULTS: Notch1, Notch3, Jagged1, Jagged2 and Hes1 expression were analysed by quantitative real-time polymerase chain reaction (qRT-PCR) (n = 81) and immunohistochemistry (n = 103) in gastric carcinomas. MUC2 and MUC5AC expression were also assessed, using immunohistochemistry only. With qRT-PCR, Notch1, Notch3, Jagged1 and Jagged2 expression were increased significantly in tumour compared to normal tissue (P < 0.001, P = 0.002, P = 0.008 and P < 0.001, respectively). Overexpression of Notch3 and Jagged2 was associated with intestinal-type carcinomas (P = 0.024) and better histological differentiation (P = 0.047), respectively. Immunohistochemistry showed a reverse correlation between MUC2 and Notch3 or Jagged1 (P = 0.033 and P = 0.005, respectively) and between MUC5AC and Jagged1 or Hes1 (P = 0.004 and P = 0.002, respectively). Notch3 and Jagged2 gene overexpression related to a favourable outcome on univariate (P = 0.046 and P = 0.042, respectively) and multivariate (P = 0.045, Notch3) analysis. CONCLUSION: The expression of Notch3 and Jagged2 is associated not only with gastric cancer development but also with the intestinal/glandular differentiation of gastric carcinoma cells, suggesting a role as a possible favourable prognostic indicator.

Relationship between Metabolic Syndrome and MTHFR Polymorphism in Colorectal Cancer.

PURPOSE: There have been studies on the relations between metabolic syndrome and colorectal cancer or on the relations between methylenetetrahydrofolate reductase (MTHFR) polymorphism and colorectal cancer, but reports on the relationship between metabolic syndrome, MTHFR polymorphism and colorectal cancer all together are rare. The aim of this study is to find the interrelation between metabolic syndrome and MTHFR polymorphism in colorectal cancer. METHODS: This study investigated 255 colorectal cancer patients (cancer group) who underwent surgery in our hospital from March 2003 to December 2008 and compared those patients to 488 healthy patients (control group). The diagnostic criterion for metabolic syndrome was based on the National Cholesterol Education Program-Adult Treatment Panel III (NCEP ATP III), and the MTHFR 677 polymorphism was analyzed. RESULTS: When colorectal cancer patients and patients in the control group were classified as MTHFR 677 subtypes, there was no difference between the two groups: CC 87 (34.1%), CT 134 (52.6%), and TT 34 (13.3%) for the cancer group and CC 145 (32.4%), CT 238 (53.1%), and TT 65 (14.5%) for the control group. Distributions of MTHFR 677C/T genotype and allele frequencies in the individuals with and without metabolic syndrome in the cancer group showed no differences. Moreover, we could find no differences in distributions of MTHFR 677C/T genotypes in the clinical and the biomedical variables of individuals with and without metabolic syndrome in the cancer group. CONCLUSION: Our results show no relation between metabolic syndrome and MTHFR polymorphism in colorectal cancer. However, a further prospective study, based on a precise diagnostic criterion for metabolic syndrome, is needed.

The role of 18F-FDG PET/CT in the evaluation of gastric cancer recurrence after curative gastrectomy.

PURPOSE: (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) scans are frequently performed for the screening or staging of malignant tumors. This study aimed to assess the usefulness of (18)F-FDG PET/CT in detection of gastric cancer recurrence after curative gastrectomy. MATERIALS AND METHODS: Eighty nine patients who had undergone curative gastrectomy due to gastric cancer and had (18)F-FDG PET/CT and contrast CT scans within 2 weeks for surveillance in asymptomatic patients (n = 11) or to clarify suspected recurrence (n = 78) were consecutively collected and retrospectively analyzed. They had clinical follow-up for at least 12 months after PET/CT and CT scans. RESULTS: Fifteen of the 89 patients (16.9%) were diagnosed with recurrent gastric cancer in 21 organs. Forty one organs showed an increase in FDG uptake, and only 9 of these organs were diagnosed with recurrent gastric cancer by (18)F-FDG PET/CT. The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of the (18)F-FDG PET/CT were 42.9%, 59.7%, 29.3%, 78.2%, and 57.3%, respectively. On the CT scan, 18 of 21 recurrent gastric cancers were detected, and 7 cases were in agreement with the (18)F-FDG PET/CT. The sensitivity and specificity of the CT scan were 85.8% and 87.3%, respectively, which are superior to the (18)F-FDG PET/CT. When we diagnosed a recurrence based on either (18)F-FDG PET/CT or CT scans, the sensitivity increased to 95.2% and the specificity decreased to 45.6%, when compared with the contrast CT scan alone. CONCLUSION: (18)F-FDG PET/CT is an insufficient diagnostic method in detection of recurrence after curative gastrectomy, and even less accurate than contrast CT scan alone.

Polymorphisms of thymidylate synthase gene 5'- and 3'-untranslated region and risk of gastric cancer in Koreans.

BACKGROUND: Thymidylate synthase (TS) plays an important role in the conversion of dUMP to dTMP. Polymorphisms of the TS gene affect the expression of the gene, which in turn may result in differences in the outcome of cancer chemotherapy and the progression of gastric cancer. PATIENTS AND METHODS: These types of TS polymorphism were investigated in 318 gastric cancer patients and 280 controls. A variable number of tandem repeats (VNTR; 2R or 3R) in the thymidylate synthase enhancer region (TSER), a G/C single nucleotide polymorphism within the second repeat sequence of 3R (3G or 3C), and a 6 bp insertion/deletion polymorphism (6 bp or 0 bp) in the TS 3'-untranslated region (3'-UTR) were determined using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Patients were sub-grouped by the Lauren classification. RESULTS: The TSER 2R/2R genotype had a high odds ratio in gastric cancer and for the intestinal type, but was not statistically significant (adjusted odds ratio, AOR=2.31, 95% confidence interval, CI=0.94-5.65; and AOR=2.53, 95% CI=0.98-6.54, respectively). Among the combined genotypes of TSER VNTR-3'-UTR 6 bp ins/del, 2R2R-6 bp/6 bp having 4 risk alleles conferred a significantly high risk of gastric cancer, particularly of the intestinal type (AOR=8.70, 95% CI=1.09-68.93; and AOR=10.86, 95% CI=1.32-89.09, respectively). CONCLUSION: Our results indicate that the 2R/2R-6 bp/6 bp combined genotype may be related to high gastric cancer susceptibility.

The diagnostic accuracy of endoscopic biopsy for gastric dysplasia.

PURPOSE: There is controversy over the treatment for low grade dysplasia, while resection is recommended for high grade dysplasia. But the concordance of the grade of dysplasia between pre- and post-resection is low because of sampling errors with endoscopic biopsy. We attempted to establish a clearer direction for the treatment of dysplasia by clarifying the discrepancy between the pre- and post-resection diagnoses. MATERIALS AND METHODS: We performed a retrospective review of 126 patients who had undergone resection with the diagnosis of dysplasia on biopsy at Bundang CHA Hospital from 1999 to 2009. RESULTS: Seventy patients were diagnosed with low grade dysplasia and 56 patients were diagnosed with high grade dysplasia. Among the 33 patients who received gastrectomy with lymph node dissection, 30 patients were revealed to have invasive cancers and 4 patients showed lymph node metastasis. Discordance between the diagnoses from biopsy and resection occurred in 55 patients (44%). There was no correlation on the comparative analysis between the size, location or gross type of lesion and the grade of dysplasia. CONCLUSIONS: The rate of discordance between the diagnoses of endoscopic biopsy and the post resection pathologic report was as high as 44%. Endoscopic mucosal resection was not sufficient for some patients who were diagnosed with dysplasia on biopsy due to the presence of lymph node metastasis. It is necessary to be prudent when determining the follow-up and treatment based solely on the result of the biopsy.

STAT3 expression in gastric cancer indicates a poor prognosis.

BACKGROUND AND AIM: Signal transducers and activators of transcription (STAT) behave as signal transducers in the cytoplasm and as transcription factors in the nucleus. In the current study, we analyzed the immunohistochemical staining patterns of gastrectomy tissue specimens. We investigated the expression of STAT3 and STAT5 and estimated the relationship between STAT and cancer prognosis. METHODS: One hundred patients who underwent gastrectomy due to gastric adenocarcinoma at Bundang CHA hospital between January 2000 and May 2005 were studied. Immunohistochemistry was carried out using antibodies against STAT3 and STAT5. The interpretation of the immunohistochemical staining was based on the proportion of stained cells in the field: positive, > 10% stained cells; and negative, < 10% stained cells. RESULTS: The longest diameter of tumor was 4.67 cm in the positive group and 3.76 cm in the negative group, and these results were not statistically different (P-value = 0.112). Higher T (primary tumor) value (P-value = 0.05), more regional lymph node invasion (P-value = 0.008) and higher TNM staging (P-value = 0.069) were significantly related to STAT3 positivity, but Helicobacter pylori infection or atrophic gastritis were not related. A lower survival rate was observed in the STAT3-positive group (P-value = 0.001). The results of STAT5 were not statistically different with respect to TNM staging and survival (P-value = 0.958). We thus report that the immunohistochemical results of STAT3 revealed a significant association with TNM staging and survival. CONCLUSION: We anticipate that STAT3 may be used as a molecular staging biomarker predicting poor prognosis of gastric cancer.

Gender-specific association between polymorphism of vascular endothelial growth factor (VEGF 936C>T) gene and patients with stomach cancer.

PURPOSE: Angiogenesis plays an important role in the growth, progression, and metastasis of tumors. Vascular endothelial growth factor (VEGF) overexpression has been associated with advanced stage and poor survival in several cancers. We investigated the present case-control study to determine whether there is an association between the VEGF 936C>T polymorphism and stomach cancer. PATIENTS AND METHODS: The association of functional single nucleotide polymorphisms (SNPs) of the VEGF gene with stomach cancer development was evaluated in a case-control study of 154 Korean stomach cancer patients. Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. RESULTS: Our results revealed significant association of T allele-bearing genotypes with increased risk for stomach cancer development. Genotype frequencies of the VEGF 936C>T polymorphisms were significantly different between patient and control groups (CT, AOR: 2.007, 95% CI: 1.277-3.156, TT, AOR: 4.790, 95% CI: 1.174-19.539, CT+TT, AOR: 2.147, 95% CI: 1.382-3.337). When stratified by gender and age, genotype frequencies were significantly different for stomach cancer in women and in patients younger than 55 years (in women, CT, OR: 3.049, 95% CI: 1.568-5.930, CT+TT, OR: 3.132, 95% CI: 1.638-5.990; in < 55 years, CT, OR: 3.306, 95% CI: 1.413-7.732, CT+TT, OR: 3.967, 95% CI: 1.729-9.104). In addition, this association partially remained in cases with intestinal and diffuse-type stomach cancer. CONCLUSION: Our present study suggests that the VEGF 936C>T polymorphism is a susceptibility factor for stomach cancer, at least in Korean. These observations, however, require further confirmation by a larger multi-ethnic study.

MUC5AC mucin gene regulation in pancreatic cancer cells.

MUC5AC is a secretory mucin normally expressed by the surface mucous cells of the human stomach and in the bronchial tract. It is absent from normal pancreas, but de novo expression of this mucin occurs in early-stage pancreatic intraepithelial neoplasias and in the invasive ductal adenocarcinoma of the pancreas, prompting this study of MUC5AC gene regulation in pancreatic cancer cells. Promoter deletion constructs and EMSA studies revealed that transcription factors Sp1 and AP-1 are both involved in basal transcription of the MUC5AC gene. Phorbol 12-myrisate 13-acetate (PMA) increased MUC5AC mRNA expression and transcriptional activities of MUC5AC promoter-reporter deletion constructs containing AP-1 consensus sites. EMSA studies showed that Fos/Jun binding to putative AP-1 sites is increased by PMA treatment. Western blot analysis showed that ERK, JNK and p38 are all activated by PMA treatment in SW1990 cells. Inhibitors of mitogen-activated protein/extracellular signal regulated kinase (MEK), such as ERK inhibitor PD98059 and JNK inhibitors dicumarol and SP60015, but not p38 inhibitor SB203580, inhibited PMA-induced MUC5AC reporter activity. Our studies indicate that Sp1 is involved in basal MUC5AC promoter activity while AP-1 is involved in basal and PMA-induced MUC5AC promoter activation in pancreatic cancer cells. Furthermore, PMA-induced MUC5AC gene transcription appears to be mediated by activating Sp1, PKC/ERK/AP-1 and PKC/JNK/AP-1 pathways.

[Clinical significance of thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphism in Korean patients with gastric cancer].

BACKGROUND/AIMS: Thymidylate synthase (TS) is a target enzyme of 5-fluorouracil (5-FU) and has a polymorphic 28 bp tandem repeated sequence. TS enhancer region (TSER) polymorphism has been associated with the efficacy of 5-FU-based chemotherapy in colon cancer. Methylenetetrahydrofolate reductase (MTHFR) plays a central role in converting folate to methyl donor for DNA methylation. The aim of this study was to determine the clinical value of TSER and MTHFR polymorphism in gastric cancer. METHODS: From October, 1995 to February, 2002, 40 gastric cancer patients underwent operation and 25 patients among those patients have received postoperative 5-FU-based chemotherapy (5-FU (+) group). Peripherial blood were sampled for TSER and MTHFR genotype analysis by PCR amplification of genomic DNA. The survival of patients according to TSER and MTHFR polymorphism were compared. RESULTS: We observed a longer survival in stage II than stage III of the patients (p=0.0037). However, the TSER and MTHFR C677T polymorphisms were not associated with better survival of gastric cancer patients as well as combined TSER and MTHFR genotypes with 5-FU chemotherapy. CONCLUSIONS: The TSER and MTHFR genotypes are not effective markers for tumor sensitivity to 5-FU-based chemotherapy in Korean gastric cancer patients after curative resection. These results may suggest further large-scale study about TSER and MTHFR polymorphism for the prediction of efficacy of 5-FU-based chemotherapy in gastric cancer in Korea.

TNF-alpha activates MUC2 transcription via NF-kappaB but inhibits via JNK activation.

The molecular mechanisms responsible for TNF-alpha-mediated MUC2 intestinal mucin up-regulation in HM3 colon adenocarcinoma cells were analyzed using promoter-reporter assays of the 5'-flanking region of the MUC2 gene. Chemical inhibitors, mutant reporter constructs, and EMSA confirmed I-kappaB/NF-kappaB pathway involvement. Wortmannin, LY294002 and dominant negative Akt, as well as dominant negative NF-kappaB-inducing kinase (NIK) inhibited MUC2 reporter transcription, indicating that both phosphatidylinositol-3-OH kinase (PI3K)/Akt signaling pathway and NIK pathways mediate the effects of TNF-alpha. Wortmannin inhibited NF-kappaB binding and transcriptional activity without inhibiting NF-kappaB translocation to the nucleus, indicating that PI3K/Akt signaling activates NF-kappaB transcriptional activity directly. Our results demonstrate that TNF-alpha up-regulates MUC2 in human colon epithelial cells via several signaling pathways, involving both NIK and PI3K/Akt, which converge at the common IKK/I-kappaB/NF-kappaB pathway. TNF-alpha activated JNK, but JNK inhibitor SP600125 and dominant negative cJun consistently activated transcription, revealing a negative role for this signaling pathway. Thus TNF-alpha causes a net up-regulation of MUC2 gene expression in cultured colon cancer cells because NF-kappaB transcriptional activation of this gene is able to counter-balance the suppressive effects of the JNK pathway. However, the existence of this inhibitory JNK pathways suggests a mechanism whereby--in the absence of NF-kappaB activation--TNF-alpha production during inflammation in vivo could actually inhibit MUC2 production, giving rise to the defective mucosal protection which characterizes inflammatory bowel disease.

Timetable for intestinal rotation in staged human embryos and fetuses.

BACKGROUND: The existing data on intestinal rotation during human development are contradictory regarding the timing of major events, and as such an exact timetable for rotation of the intestine in humans is not yet available. METHODS: We studied the initial formation and rotation of the intestine by microdissection and histological observations in 72 human embryos and fetuses at two to 12 weeks postfertilization. The embryos were classified according to the Carnegie staging system. RESULTS: The primordium of the primitive gut was first observed as a yolk sac at stage 5. With the formation of the embryonic foldings, three divisions of the primitive gut (the foregut, midgut, and hindgut) were observed at stage 10. At stage 12, the primitive gut was located on the midline. At stage 15, a 90 degrees counterclockwise rotation of the intestine began. At stage 16, herniation of the intestine into the umbilical cord was not evident in observations of the external form or a transversely sectioned embryo, but was evident in a sagittally sectioned embryo. There was another 90 degrees counterclockwise rotation at stage 20. Reduction of the intestine was a rapid process, since it was still in the cord in fetuses of <40 mm crown-rump length (CRL), and was reduced above 40 mm in general during nine weeks of development. When the intestine returned to the abdominal cavity, the cecum was located in the right lower quadrant (the adult position). CONCLUSIONS: We have developed a standard timetable to describe the rotation of the intestine. The current results will be helpful in studies describing the pathogenesis of some developmental abnormalities in the intestine due to abnormal rotation.

Phorbol 12-myristate 13-acetate up-regulates the transcription of MUC2 intestinal mucin via Ras, ERK, and NF-kappa B.

MUC2 is a secretory mucin normally expressed by goblet cells of the intestinal epithelium. It is overexpressed in mucinous type colorectal cancers but down-regulated in colorectal adenocarcinoma. Phorbol 12-myristate 13-acetate (PMA) treatment of colon cancer cell lines increases MUC2 expression, so we have undertaken a detailed analysis of the effects of PMA on the promoter activity of the 5'-flanking region of the MUC2 gene using stably and transiently transfected promoter reporter vectors. Protein kinase C inhibitors (bisindolylmaleimide, calphostin C) and inhibitors of mitogen-activated protein/extracellular signal regulated kinase kinase (MEK) (PD98059 and U0126) suppressed up-regulation of MUC2. Src tyrosine kinase inhibitor PP2, a protein kinase A inhibitor (KT5720), and a p38 inhibitor (SB 203580) did not affect transcription. Western blotting and reverse transcription-PCR analysis confirmed these results. In addition, co-transfections with mutants of Ras, Raf, and MEK showed that the induction of MUC2 promoter activity by PMA required these three signaling proteins. Our results demonstrate that PMA activates protein kinase C, stimulating MAP kinase through a Ras- and Raf-dependent mechanism. An important role for nuclear factor kappaB (NF-kappaB) was also demonstrated using the inhibitor caffeic acid phenethyl ester and electrophoretic mobility shift assays. Such identification of pathways involved in MUC2 up-regulation by PMA in the HM3 colon cancer cell line may serve as a model for the effects of cytokines and growth factors, which regulate MUC2 expression during the progression of colorectal cancer.