Analysis of patient-dropouts from the critical pathways for gastric cancer.

PURPOSE: This study was designed to determine the factors affecting completion of critical pathway for elective gastrectomy. METHODS: Since 2008, a critical pathway has been applied for elective gastrectomy at Chosun University Hospital. We retrospectively analyzed 252 patients who underwent elective gastrectomies from January 2009 to April 2013. The completion rate was determined, and risk factors for patient dropout were examined. RESULTS: The completion rate of the critical pathway was 45.6% (115/252). Mean length of stay was 11.7 ± 8.6 days (8-59 days). Readmission rates were 4.4% (11/252). Causes of failure for clinical pathway were systemic complications (21/137, 15.3%), intra-abdominal complications (44/137, 32.8%), patient factors (41/137, 29.9%), and wound complications (30/137, 21.9%). There were no significant differences between the two groups in age, sex, American Society of Anesthesiologists (ASA) score, operation time, readmission, and underlying disease (P > 0.05). Body mass index (P = 0.008) and pathologic stage (P = 0.001) were significantly different between the two groups. In multivariate analysis, the conventional approach (odds ratio, 2.0), and total gastrectomy (odds ratio, 5.3) were determined to be independent risk factors to drop the critical pathway. But there were no significant differences between total and distal gastrectomy groups in age, gender, underlying diseases, ASA score, readmission, operation time, and cause of dropout (P > 0.05). CONCLUSION: We concluded that total gastrectomy may not be suitable for the critical pathway. We suggest that the critical pathway for elective distal gastrectomy is divided 2 subgroups, according to the surgical approach.

Poorly differentiated cecal adenocarcinoma showing prominent rhabdoid feature combined with appendiceal mucinous cystadenoma: A case report and review of the literature.

Extrarenal rhabdoid tumors (ERRTs) are extremely rare neoplasms; of these, colorectal ERRTs are the most rare, and only nine cases have been previously described in the English language literature. The current study reports the pathological features of a case of poorly differentiated cecal adenocarcinoma with prominent rhabdoid feature, which was combined with mucinous cystadenoma of the appendix in a 73-year-old male, and additionally reviews the previously reported cases. Microscopically, the majority of tumor cells were non-cohesive or loosely cohesive, with a polygonal morphology and prominent rhabdoid feature, showing eccentric vesicular nuclei, prominent nucleoli and abundant eosinophilic cytoplasm. Immunohistochemically, the tumor cells were positive for cytokeratin (CK) and vimentin, but negative for CK20, CK7, desmin and smooth muscle actin. This indicated a diagnosis of poorly differentiated adenocarcinoma with prominent rhabdoid features, combined with appendiceal mucinous cystadenoma. At two months following surgery the patient succumbed to peritoneal seeding and metastasis of liver and bone The emergence of the rhabdoid phenotype is invariably associated with an aggressive and almost always fatal clinical course. The present case is the 10th example of such a tumor in the colon, and to the best of our knowledge, this is the first case of colonic rhabdoid tumor coinciding with appendiceal benign mucinous neoplasm.

SMA Syndrome Treated by Single Incision Laparoscopic Duodenojejunostomy.

Superior mesenteric artery (SMA) syndrome is a mechanical duodenal obstruction by the SMA. The traditional approach to SMA syndrome was open bypass surgery. Nowadays, a conventional approach has been replaced by laparoscopic surgery. But single incision laparoscopic approach for SMA syndrome is rare. Herein, we report the first case of SMA syndrome patient who was treated by single incision laparoscopic duodenojejunostomy.

Consideration of cardia preserving proximal gastrectomy in early gastric cancer of upper body for prevention of gastroesophageal reflux disease and stenosis of anastomosis site.

PURPOSE: The aim of this study is to evaluate the feasibility and safety of cardia preserving proximal gastrectomy, in early gastric cancer of the upper third. MATERIALS AND METHODS: A total of 10 patients were diagnosed with early gastric cancer of the upper third through endoscopic biopsy. The operation time, length of resection free margin, number of resected lymph nodes and postoperative complications, gastrointestinal symptoms, nutritional status, anastomotic stricture, and recurrence were examined. RESULTS: There were 5 males and 5 females. The mean age was 56.5±0.5 years. The mean operation time was 188.5±0.5 minutes (laparoscopic operation was 270 minutes). Nine patients were T1 stage (T2 : 1), and N stage was all N0. The mean number of resected lymph nodes was 25.2±0.5. The length of proximal resection free margin was 3.1±0.1 cm and distal was 3.7±0.1 cm. Early complications were surgical site infection (1), bleeding (1), and gastro-esophageal reflux disease (1) (this symptom was improved with medication). Late complications were dyspepsia (3) (this symptom was improved without any treatment), and others were nonspecific results of endoscopy or symptom. CONCLUSIONS: Cardia preserving proximal gastrectomy was feasible for early gastric cancer of the upper third. Further evaluation and prospective research will be required.

Ewing's Sarcoma of the Stomach; Rare Case of Ewing's Sarcoma and Suggestion of New Treatment Strategy.

Ewing's sarcoma is a neoplasm of the undifferenciated small round cells, which generally affects the bone and deep soft tissues of children and adolescents. We present a case of gastric Ewing's sarcoma; a 35-year-old female who had no symptoms. While she was at a routine medical checkup, a protruding mass in her gastric antrum was incidentally found on esophagogastroduodenoscopy. Endoscopic ultrasonogram showed a submucosal mass on the same lesion and a laparosopic wedge resection was done. Pathologic gross findings showed a granular grape appearance tissue and histoloigc examination revealed a small round cell tumor with CD 99 immunoexpression positive. In general, a combined modality therapy for Ewing's sarcoma such as surgical resection with chemotherapy, is accepted as an effective method. However, this patient had no adjuvant chemotherapy after surgery and she has no recurrence for eleven months.

Impacts of cytosolic phospholipase A2, 15-prostaglandin dehydrogenase, and cyclooxygenase-2 expressions on tumor progression in colorectal cancer.

PURPOSE: In addition to cyclooxygenase-2 (COX-2) which is related to prostaglandin E2 synthesis, other enzymes such as cytosolic phospholipase A2 (cPLA2), microsomal prostaglandin E2 synthase-1 (mPGES-1), and 15-prostaglandin dehydrogenase (15-PGDH) have been suggested to be related to carcinogenesis of colorectal cancer (CRC). The aim of this study was to investigate the roles of cPLA2, COX-2, mPGES-1, and 15-PGDH in tumor progression. MATERIALS AND METHODS: cPLA2, COX-2, mPGES-1, 15-PGDH, and vascular endothelial growth factor (VEGF) expressions were immunohistochemically examined in 89 CRC, and their expressions were compared with each other or clinicopathologic parameters as well as VEGF as tumor progression parameters. RESULTS: cPLA2 was expressed in 54.5%, COX-2 in 80.5%, mPGES-1 in 96.4%, 15-PGDH in 46.1%, and VEGF in 65.9%. The expression of cPLA2 correlated with VEGF expression. COX-2 expression was correlated with the depth of invasion, tumor stage, cPLA2, and VEGF expressions. Moreover, VEGF revealed the highest expression in the tissues positive for both cPLA2 and COX-2. Furthermore, 15-PGDH expression was inversely correlated with VEGF expression. CONCLUSION: The present study demonstrates that cPLA2 and mPGES-1, in addition to COX-2, are constitutively overexpressed, and that 15-PGDH might be attenuated in colorectal cancer. Furthermore, cPLA2 and 15-PGDH as well as COX-2 could have an important role in tumor progression.

Epigenetic mechanisms involved in differential MDR1 mRNA expression between gastric and colon cancer cell lines and rationales for clinical chemotherapy.

BACKGROUND: The membrane transporters such as P-glycoprotein (Pgp), the MDR1 gene product, are one of causes of treatment failure in cancer patients. In this study, the epigenetic mechanisms involved in differential MDR1 mRNA expression were compared between 10 gastric and 9 colon cancer cell lines. METHODS: The MDR1 mRNA levels were determined using PCR and real-time PCR assays after reverse transcription. Cytotoxicity was performed using the MTT assay. Methylation status was explored by quantification PCR-based methylation and bisulfite DNA sequencing analyses. RESULTS: The MDR1 mRNA levels obtained by 35 cycles of RT-PCR in gastric cancer cells were just comparable to those obtained by 22 cycles of RT-PCR in colon cancer cells. Real-time RT-PCR analysis revealed that MDR1 mRNA was not detected in the 10 gastric cancer cell lines but variable MDR1 mRNA levels in 7 of 9 colon cancer cell lines except the SNU-C5 and HT-29 cells. MTT assay showed that Pgp inhibitors such as cyclosporine A, verapamil and PSC833 sensitized Colo320HSR (colon, highest MDR1 expression) but not SNU-668 (gastric, highest) and SNU-C5 (gastric, no expression) to paclitaxel. Quantification PCR-based methylation analysis revealed that 90% of gastric cancer cells, and 33% of colon cancer cells were methylated, which were completely matched with the results obtained by bisulfite DNA sequencing analysis. 5-aza-2'-deoxcytidine (5AC, a DNA methyltransferase inhibitor) increased the MDR1 mRNA levels in 60% of gastric cells, and in 11% of colon cancer cells. Trichostatin A (TSA, histone deacetylase inhibitor) increased the MDR1 mRNA levels in 70% of gastric cancer cells and 55% of colon cancer cells. The combined treatment of 5AC with TSA increased the MDR1 mRNA levels additively in 20% of gastric cancer cells, but synergistically in 40% of gastric and 11% of colon cancer cells. CONCLUSION: These results indicate that the MDR1 mRNA levels in gastric cancer cells are significantly lower than those in colon cancer cells, which is at least in part due to different epigenetic regulations such as DNA methylation and/or histone deacetylation. These results can provide a better understanding of the efficacy of combined chemotherapy as well as their oral bioavailability.

Prognostic significance of cyclooxygenase-2 expression and nuclear p53 accumulation in patients with colorectal cancer.

BACKGROUND: Cyclooxygenase (COX)-2 is believed to be an important enzyme related to the pathogenesis of colorectal cancer (CRC). p53 has been reported to be a negative regulator of COX-2 expression in in vitro studies. The aim of this study was to investigate COX-2 expression and its relationship with nuclear p53 accumulation and their prognostic significance in CRC. METHODS: COX-2 expression and nuclear p53 accumulation were examined by immunohistochemistry in 231 sporadic CRCs. Their prognostic significance and interrelationship were statistically evaluated. RESULTS: We found 42.4% of the 231 cases of CRCs with positive COX-2 expression. Nuclear p53 accumulation was observed in 46.8% of cases. There was no significant correlation between COX-2 expression and nuclear p53 accumulation. COX-2 expression had no correlation with patient survival, whereas nuclear p53 accumulation was significantly correlated with poor patient survival on univariate and multivariate analysis. CONCLUSIONS: These results suggest that COX-2 expression does not play a role in the prognosis of CRC and COX-2 expression is not affected by the status of nuclear p53 accumulation in CRC. In addition, our findings support that nuclear p53 accumulation may be a useful prognostic marker for patients with CRC.

Expression of cyclooxygenase-2 and its relationship to p53 accumulation in colorectal cancers.

PURPOSE: Cyclooxygenase (COX)-2 is an inducible isoform responsive to cytokines, mitogens, and growth factors, and is believed to be an important enzyme related to colorectal cancer (CRC). Existing evidence suggests that COX-2 expression is normally suppressed by wild-type p53 but not mutant p53, suggesting that loss of p53 function may result in the induction of COX-2 expression. The aim of this study was to determine the relationship between COX-2 expression and p53 levels in CRC. MATERIALS AND METHODS: Patients with sporadic colorectal adenocarcinoma (n=161) who underwent curative surgery in Chosun University Hospital were enrolled in this study. Expression of COX-2 and p53 proteins was examined by immunohistochemistry in paraffin-embedded cancer tissue blocks, and the relationship between COX-2 and/or p53 expression with clinicopathologic parameters was analyzed. RESULTS: Expression of COX- 2 was positive in 47.8% of colorectal cancers, and significantly associated with the depth of tumor invasion (p= 0.042). In contrast, p53 was positive in 50.3% of the cases, and was associated with both age (p=0.025) and the depth of tumor invasion (p=0.014). There was no correlation between COX-2 expression and p53 expression (p=0.118). CONCLUSION: These results suggest that COX-2 expression might play an important role in the progression of colorectal cancer. However, COX-2 expression was not associated with mutational p53. Further studies are needed to clarify the regulatory mechanisms governing COX-2 overexpression in colorectal cancers.

The effect of anchoring suture on the anastomotic blood flow in a rat model of human esophagojejunostomy.

PURPOSE: An impairment of anastomotic blood flow (ABF) and the resulting hypoxia readily lead to the complications such as leakage and stricture. We performed an animal study to evaluate the effect of anchoring suture for minimizing the impairment of ABF caused by tensile loading. MATERIALS AND METHODS: An end-to-side jejunojejunostomy was done in 20 rats, and this followed the modeling of a human end-to-side esophagojejunostomy. Laser Doppler flowmetry was checked in three different tensile conditions to evaluate the influence of anchoring suture on the ABF. RESULTS: Before anchoring suture, the mean ABF was 129.06 perfusion unit (PU), 96.99 PU, and 69.04 PU, in the order of tensile stress. After anchoring suture, the mean ABF was 121.68, 103.30, and 87.06 PU (P < 0.01). CONCLUSION: Anchoring suture is a novel method to reduce the impairment of the anastomotic blood flow that is caused by tension.

Concentration-dependent collateral sensitivity of cisplatin-resistant gastric cancer cell sublines.

The cisplatin-resistant gastric cancer cell sublines, SNU-601/Cis2 and /Cis10, were 49 and >530 times more resistant to cisplatin, respectively, compared with the drug-sensitive cells, SNU-601/WT. The SNU-601/Cis2 showed cross-resistance to carboplatin, heptaplatin, doxorubicin, mitomycin C, and 5-fluorouracil compared with the SNU-601/WT whereas the SNU-601/Cis10 displayed collateral sensitivity to these drugs with the exception of cisplatin compared with the SNU-601/Cis2, suggesting that the cross-resistance and collateral sensitivity of cisplatin-resistant gastric cancer cells are dependent upon cisplatin concentrations. Altered expression of the antioxidant and transporter genes (metallothionein, catalase, superoxide dismutases, P-glycoprotein, and the breast cancer resistance protein) was involved in these phenotypes of the cisplatin-resistant gastric cancer cell lines.

Molecular mechanisms of heptaplatin effective against cisplatin-resistant cancer cell lines: less involvement of metallothionein.

BACKGROUND: Heptaplatin is a new platinum derivative with anticancer activity against various cancer cell lines, including cisplatin-resistant cancer cell lines (Cancer Chemother Pharmacol 1995; 35: 441). METHODS: Molecular mechanisms of heptaplatin effective against cisplatin-resistant cancer cell lines has been investigated in connection with metallothionein (MT). Cytotoxicity was determined by an MTT assay. MT mRNA, was determined by RT-PCR assay. Transfection study was carried out to examine the function of MT. RESULTS: Of various gastric cancer cell lines, SNU-638 and SNU-601 showed the highest and lowest levels of MT mRNA, respectively, showing 80-fold difference. The IC50 values of SNU-638 to cisplatin, carboplatin and heptaplatin were 11.2-fold, 5.1-fold and 2.0-fold greater than those of SNU-601, respectively. Heptaplatin was more effective against cisplatin-resistant and MT-transfected gastric cancer sublines than cisplatin or carboplatin was. In addition, heptaplatin attenuated cadmium, but not zinc, induction of MT. CONCLUSION: These results indicate that molecular mechanisms of heptaplatin effective against cisplatin-resistant gastric cancer sublines is at least in part due to the less involvement of MT in heptaplatin resistance as well as its attenuation of MT induction.

Differential induction of Mn-containing superoxide dismutase by paraquat in peripheral lymphocytes of normal subjects and gastric cancer patients.

Reactive oxygen species (ROS) cause macromolecular damage and may play an important role in tumor development. Superoxide dismutase (SOD) and metallothionein (MT) serve as initial and final defense mechanisms, respectively, against ROS. We hypothesized that the inducibility of Mn-SOD and MT mRNA by paraquat, an intracellular superoxide generator, might be altered in lymphocytes of gastric cancer patients. The inducibility of Mn-SOD mRNA by paraquat in lymphocytes of 19 normal subjects and the 14 gastric cancer patients was 162.4 +/- 16.7% and 87.9 +/- 9.5%, respectively (P = 0.001). The inducibility of MT mRNA by paraquat in the normal subjects and the gastric cancer patients was 126.7 +/- 15.8% and 115.4 +/- 12.9%, respectively. This suggests that the failure of Mn-SOD mRNA induction by oxidative stress in peripheral lymphocytes may be involved in the development of gastric cancer and may be of value in predicting the future occurrence of gastric cancer. In addition, the wide variation in Mn-SOD and MT mRNA levels among normal subjects may reflect different susceptibilities to diseases including cancer.

Reversal of P-glycoprotein-mediated multidrug resistance by protopanaxatriol ginsenosides from Korean red ginseng.

The overexpression of P-glycoprotein (Pgp) or the multidrug resistance-associated protein (MRP) confers multidrug resistance (MDR) to cancer cells. MDR cells can be sensitized to anticancer drugs when treated concomitantly with an MDR modulator. In this study, we investigated whether or not ginseng saponins could reverse MDR mediated by Pgp or MRP. The chemosensitization and drug accumulation effects of ginseng saponins such as the total saponin, protopanaxadiol ginsenosides (PDG), protopanaxatriol ginsenosides (PTG), ginsenosides-Rb 1, -Rb 2, -Rc, -Rg 1 and -Re were tested on the daunorubicin- and doxorubicin-resistant acute myelogenous leukemia sublines (AML-2/D100 and AML-2/DX100), which overexpress Pgp and MRP, respectively. PTG showed cytotoxicity in both sublines and was able to reverse resistance in the AML-2/D100 subline in a concentration-dependent manner. Conversely, other ginseng saponins at concentrations less than 300 microg/mL showed neither cytotoxicity nor chemosensitizing activity in both resistant sublines. Flow cytometry analysis showed that the effect of PTG (100 microg/mL) on drug accumulation of daunorubicin in the AML-2/D100 subline was 2-fold higher than that observed in the presence of verapamil (5 microg/mL) and 1.5 times less than cyclosporin A (3 microg/mL). The maximum non-cytotoxic concentrations of PTG did not appear to increase the Pgp levels, which is in contrast to verapamil and cyclosporin A. PTG at 200 microg/mL or more completely inhibited the azidopine photolabeling of Pgp. The results suggest that PTG has a chemosensitizing effect on Pgp-mediated MDR cells by increasing the intracellular accumulation of drugs through direct interaction with Pgp at the azidopine site. In addition, PTG may have a beneficial effect on cancer chemotherapy with respect to the possibility of long-term use without the concern of Pgp activation.

Fas (Apo-1/CD95) and Fas ligand interaction between gastric cancer cells and immune cells.

BACKGROUND AND AIMS: It has been proposed that the expression of Fas ligand (Fas L) in tumors may play an important role in immune escape. This study was undertaken to test a 'counterattack' theory as a mechanism of immune escape in gastric carcinoma. METHODS: Expression of Fas and Fas L was examined in the human gastric cancer cell lines using reverse transcription-polymerase chain reaction. Cytotoxicity was determined by the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay. Apoptosis of target Jurkat cells was examined after coculture with the effector gastric cancer cells in vitro. Immunohistochemical staining was performed for the detection of Fas and FasL in tumor-infiltrating lymphocytes (TIL) and gastric cancer cells in vivo. Apoptosis was detected by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) method in vitro and in vivo. RESULTS: Fas and FasL mRNA were found to be differentially expressed in gastric cancer cell lines. The coculture experiment showed that apoptosis of Jurkat was induced by a FasL-overexpressing effector gastric cell SNU-484. In a Fas-expressing gastric cell SNU-638, Fas expression was upregulated by the treatment of gamma-interferon in a time- and concentration-dependent manner. SNU-638 treated with gamma-interferon was more sensitive to anti-Fas antibody-mediated cytotoxicity than was the control cell line, suggesting an increase of functional Fas in gastric cancer cells. The expression of FasL in gastric cancer cells and of Fas in apoptotic TIL was also detected in vivo. CONCLUSION: The data indicate that the FasL expression of gastric cancer cells supports a 'counterattack theory' in gastric cancer cells and that the upregulation of Fas by IFN-gamma in SNU-638 may accelerate the apoptosis pathway through the Fas and FasL interaction between gastric cancer cells and immune cells. This result is supported by the expression of FasL in gastric cancer cells and apoptotic TIL in vivo. It is implicated that the different biological behaviors of gastric cancer cells could be at least in part explained by Fas and FasL interaction with immune cells.