Adjustment of N stages of gastric cancer by the ratio between the metastatic and examined lymph nodes.

BACKGROUND: The present study attempted to determine whether N stage could be adjusted for the differences in survival rates based on the ratio between the examined and metastatic lymph nodes (LN ratio). METHODS: Five hundred and twenty-nine patients with both >15 lymph nodes examined and >or= N1 after R0 resection were enrolled in the present study. To determine the cutoff LN ratio, the ratios at each N stage were compared at intervals of 10% with the log-rank test of Kaplan-Meier estimates of the survival curves. RESULTS: The 5-year survival rate of patients with N1 was 71.7%. Those of N2 patients with LN ratio of <60% (n = 116) and >or=60% (n = 3) were 37.0% and 0%, respectively. Those of N3 patients with LN ratio of <30% (n = 32), between 30% and 60% (n = 67), and >or=60% (n = 26) were 31.0%, 16.3%, and 0%, respectively. Thus, adjusted N2 was obtained from the sum of N2 < 60% and N3 < 30%. N3 with an LN ratio between 30% and 60% was regarded as adjusted N3. N2 and N3 patients with an LN ratio of >or=60% were regarded as adjusted T4. The 5-year survival rate in patients with adjusted N2, N3, and N4 were 35.7%, 16.3%, and 0%, respectively. Multivariate analysis showed adjusted N stage and tumor depth were significant independent prognostic factors. CONCLUSIONS: The results of this study suggest that, since stage migration can be induced in the N staging system, such stage migration can be adjusted by the LN ratio based on the survival rate.

Prognostic factors for survival in patients with hepatic recurrence after curative resection of gastric cancer.

BACKGROUND: This study was done to evaluate the prognostic factors that may affect the survival of patients with recurrent hepatic metastasis after curative resection of gastric cancer. METHODS: We reviewed the medical records of 73 patients with recurrent hepatic metastasis after surgical treatment of gastric cancer from January 1995 to December 2005. Prognostic factors were classified into three groups: primary tumor factors, recurrent hepatic factors, and treatment factors. The prognostic values of these factors were assessed using univariate and multivariate analyses by the log-rank test in the Kaplan-Meier method and Cox's proportional hazard model. RESULTS: The overall median survival rate of the 73 study patients was 20.0 months [95% confidence interval (CI) 15.4-24.6 months]. The median survival rate after diagnosis of recurrent hepatic metastasis was 5 months (95% CI 3.5-6.5 months). Univariate analysis showed that the favorable prognostic factors were stage I and II among the primary tumor factors, no extrahepatic metastasis and unilobar distribution among the recurrent hepatic factors, and radiofrequency ablation (RFA) +/- chemotherapy among the treatment factors when operative treatment had been excluded. The independent favorable prognostic factors revealed by the multivariate analysis were no extrahepatic metastasis and RFA +/- chemotherapy. The median survival rate of patients who had two favorable prognostic factors was 27 months (95% CI 0-66.38 months). CONCLUSIONS: Improvement in the survival rate can be expected with RFA +/- chemotherapy for patients with recurrent gastric cancer in the liver without extrahepatic metastasis.

Epidemiologic Study of Human Epidermal Growth Factor Receptor 2 Expression in Advanced/Metastatic Gastric Cancer: an Assessment of Human Epidermal Growth Factor Receptor 2 Status in Tumor Tissue Samples of Gastric and Gastro-Esophageal Junction Cancer.

PURPOSE: The Trastuzumab for gastric cancer (GC) trial identified human epidermal growth factor receptor 2 (HER2) as a predictor of successful treatment with trastuzumab (HER2 receptor targeting agent) among patients with advanced/metastatic GC. To date, the prevalence of HER2 overexpression in the Korean population is unknown. The present study aimed to assess the incidence of HER2 positivity among GC and gastroesophageal (GE) junction cancer samples and the relationship between HER2 overexpression and clinicopathological characteristics in Korean patients. MATERIALS AND METHODS: Tumor samples collected from 1,695 patients with histologically proven GC or GE junction enrolled at 14 different hospitals in Korea were examined. After gathering clinicopathological data of all patients, HER2 status was assessed by immunohistochemistry (IHC) at each hospital, and IHC 2+ cases were subjected to silver-enhanced in situ hybridization at 3 central laboratories. RESULTS: A total of 182 specimens tested positive for HER2, whereas 1,505 tested negative. Therefore, the overall HER2-positive rate in this study was 10.8% (95% confidence interval=9.3%-12.3%). The HER2-positive rate was higher among intestinal-type cases (17.6%) than among other types, and was higher among patients older than 70 years and 50 years of age, compared to other age groups. CONCLUSIONS: Our evaluation of the HER2 positivity rate (10.8%) among Korean patients with GC and GE junction indicated the necessity of epidemiological data when conducting studies related to HER2 expression in GC and GE junction.

APIP, an ERBB3-binding partner, stimulates erbB2-3 heterodimer formation to promote tumorigenesis.

Despite the fact that the epidermal growth factor (EGF) family member ERBB3 (HER3) is deregulated in many cancers, the list of ERBB3-interacting partners remains limited. Here, we report that the Apaf-1-interacting protein (APIP) stimulates heregulin-ß1 (HRG-ß1)/ERBB3-driven cell proliferation and tumorigenesis. APIP levels are frequently increased in human gastric cancers and gastric cancer-derived cells. Cell proliferation and tumor formation are repressed by APIP downregulation and stimulated by its overexpression. APIP's role in the ERBB3 pathway is not associated with its functions within the methionine salvage pathway. In response to HRG-ß1, APIP binds to the ERBB3 receptor, leading to an enhanced binding of ERBB3 and ERBB2 that results in sustained activations of ERK1/2 and AKT protein kinases. Furthermore, HRG-ß1/ERBB3-dependent signaling is gained in APIP transgenic mouse embryonic fibroblasts (MEFs), but not lost in Apip-/- MEFs. Our findings offer compelling evidence that APIP plays an essential role in ERBB3 signaling as a positive regulator for tumorigenesis, warranting future development of therapeutic strategies for ERBB3-driven gastric cancer.

The Korean Gastric Cancer Cohort Study: Study Protocol and Brief Results of a Large-Scale Prospective Cohort Study.

PURPOSE: This study aimed to establish a large-scale database of patients with gastric cancer to facilitate the development of a national-cancer management system and a comprehensive cancer control policy. MATERIALS AND METHODS: An observational prospective cohort study on gastric cancer was initiated in 2010. A total of 14 cancer centers throughout the country and 152 researchers were involved in this study. Patient enrollment began in January 2011, and data regarding clinicopathological characteristics, life style-related factors, quality of life, as well as diet diaries were collected. RESULTS: In total, 4,963 patients were enrolled until December 2014, and approximately 5% of all Korean patients with gastric cancer annually were included. The mean age was 58.2±11.5 years, and 68.2% were men. The number of patients in each stage was as follows: 3,394 patients (68.4%) were in stage IA/B; 514 patients (10.4%), in stage IIA/B; 469 patients (9.5%), in stage IIIA/B/C; and 127 patients (2.6%), in stage IV. Surgical treatment was performed in 3,958 patients (79.8%), endoscopic resection was performed in 700 patients (14.1%), and 167 patients (3.4%) received palliative chemotherapy. The response rate for the questionnaire on the quality of life was 95%; however, diet diaries were only collected for 27% of patients. CONCLUSIONS: To provide comprehensive information on gastric cancer for patients, physicians, and government officials, a large-scale database of Korean patients with gastric cancer was established. Based on the findings of this cohort study, an effective cancer management system and national cancer control policy could be developed.

Treatment of gastrojejunal anastomotic leak with a covered metallic stent.

Although the incidence rates of anastomotic leaks after radical gastrectomy in a patient with gastric cancer are generally low, when the complication ensues, morbidity and mortality rates rise, varying between 18% and 30%. We used self-expandable, covered metallic stent to occlude the leakage site in a patient with recurrent postoperative anastomotic leaks. The deployment of the covered stent was successful, and immediate leak occlusion was obtained after the procedure. During follow-up, the patient had unrecognized passage of the stent per rectum and showed no anastomotic leak on upper gastrointestinal series. We suggest that implementation of covered metallic stent should be considered as a valuable, alternative therapeutic option for the treatment of intractable postoperative anastomotic leak after radical gastrectomy.

5-Fluorouracil, methotrexate, leucovorin, CDDP and epirubicin (FEPMTX): a wide-spectrum regimen of salvage chemotherapy for high-grade advanced gastric cancer.

BACKGROUND/AIMS: Twenty-one patients with primary stage IV gastric cancer were treated with a wide-spectrum regimen, designated as FEPMTX therapy to establish an effective salvage chemotherapy. METHODOLOGY: FEPMTX therapy consisted of 5-fluorouracil and the triple biochemical modulators in addition to epirubicin. The schedule comprised 3 days continuous administration of 5-fluorouracil (350 mg/m2/day) and; methotrexate (MTX; 35 mg/m2) on day 1, calcium leucovorin (LV; 30 mg/m2) on day 2 and 3, cisplatin (CDDP; 30 mg/m2) and epirubicin (20 mg/m2) on day 3 every 2 weeks in principle. RESULTS: Eleven partial responses, five no changes and five progressive diseases were obtained, and the response rate was 52%. Ten patients (partial response 7, no change 2, progressive disease 1) received gastrectomy (resectability rate 48%). The survival of responders was significantly longer than that of non-responders (median survival time, 356 days vs. 152 days) while there was no significant prolongation by resection of the primary lesion. Adverse effects such as myelosuppression, anorexia and fatigue sometimes occurred, but were mild and the regimen was well tolerated by all the patients. CONCLUSIONS: FEPMTX is thought to be an effective regimen for neoadjuvant chemotherapy with longer survival and little toxicity for patients with high-grade advanced gastric cancer.

Early Postoperative Retrograde Jejunojejunal Intussusception after Total Gastrectomy with Roux-en-Y Esophagojejunostomy: A Case Report.

Intussusception is a rare cause of postoperative intestinal obstruction in adults. Many retrograde intussusceptions occur during the period following gastrectomy. A 77-year-old woman visited our hospital because of detected gastric adenocarcinoma. She received radical total gastrectomy with Roux-en-Y esophagojejunostomy. On the fifth postoperative day, she complained of abdominal pain, and we found leakage at the esophagojejunostomy site and dilatation of the Roux limb and the afferent limb of the jejunojejunostomy. Emergency surgery was performed. Retrograde jejunojejunal intussusception accompanied with a nasojejunal feeding tube was found at the efferent loop of the jejunojejunostomy. No ischemic change was found; therefore, manual reduction and primary repair of esophagojejunostomy was performed. She was discharged without complications on the 23rd re-postoperativeday. We suggest that the nasojejunal feeding tube acted as a trigger of intussusception because there was no definitive small bowel mass or postoperative adhesion. We present our findings here along with a brief review of the literature.

Clinical utility of tumor marker cutoff ratio and a combination scoring system of preoperative carcinoembryonic antigen, carbohydrate antigen 19-9, carbohydrate antigen 72-4 levels in gastric cancer.

PURPOSE: The present study is to investigate the clinical utility of tumor marker cutoff ratio (TMR) and develop a TMR combination scoring system based on preoperative tumor marker (TM) levels to prognosis prediction in gastric cancer. METHODS: We include 1,142 patients for whom two or more TMs were measured and who underwent radical gastrectomy between 1990 and 2003. RESULTS: Five-year risk of recurrence (5 YRR) for carcinoembryonic antigen (CEA) TMRs were 18.3%, 29.8%, 61.4% for TMR < 1.0, 1.0 ≤ TMR < 2.0, TMR ≥ 2.0 respectively. 5 YRR for carbohydrate antigen 19-9 (CA 19-9) TMR were 19.7%, 35.6%, 58.4% for TMR < 1.0, 1.0 ≤ TMR < 3.0, TMR ≥ 3.0, respectively. 5 YRR for carbohydrate antigen 72-4 (CA 72-4) TMR were 15.2% and 33.6% for TMR < 1.0 and TMR ≥ 1.0, respectively. We defined high TMR (TMR ≥ 2.0 for CEA, TMR ≥ 3.0 for CA19-9), low TMR (1.0 ≤ TMR < 2 for CEA, 1.0 ≤ TMR < 3.0 for CA 19-9 and 1.0 ≤ TMR for CA72-4) and negative TMR (TMR < 1.0 for all TMs). A TMR combination scoring system was devised with negative scored as zero points, low as 1 and high as 2 for each TMR. TMR scores were divided into four categories (score 0, 1, 2, 3 and above) based on the calculated TMR score and 5 YRR were found to be 12.8%, 23.9%, 45.5%, and 68.3%, respectively (P < 0.05). Multivariate analysis showed that our scoring system was a significant independent prognostic factor. CONCLUSION: Preoperative TMRs such as CEA, CA 19-9, and CA 72-4 show a correlation with prognosis and the TMR combination scoring system could be a useful tool for the prediction of prognosis in gastric cancer.

Comparison of Learning Curves and Clinical Outcomes between Laparoscopy-assisted Distal Gastrectomy and Open Distal Gastrectomy.

PURPOSE: Most stomach surgeons have been educated sufficiently in conventional open distal gastrectomy (ODG) but insufficiently in laparoscopy-assisted distal gastrectomy (LADG). We compared learning curves and clinical outcomes between ODG and LADG by a single surgeon who had sufficient education of ODG and insufficient education of LADG. MATERIALS AND METHODS: ODG (90 patients, January through September, 2004) and LADG groups (90 patients, June 2006 to June 2007) were compared. The learning curve was assessed with the mean number of retrieved lymph nodes, operation time, and postoperative morbidity/mortality. RESULTS: Mean operation time was 168.3 minutes for ODG and 183.6 minutes for LADG. The mean number of retrieved lymph nodes was 37.9. Up to about the 20th to 25th cases, the slope decrease in the learning curve for LADG was more apparent than for ODG, although they both reached plateaus after the 50th cases. The mean number of retrieved lymph nodes reached the overall mean after the 30th and 40th cases for ODG and LADG, respectively. For ODG, complications were evenly distributed throughout the subgroups, whereas for LADG, complications occurred in 10 (33.3%) of the first 30 cases. CONCLUSIONS: Compared with conventional ODG, LADG is feasible, in particular for a surgeon who has had much experience with conventional ODG, although LADG required more operative time, slightly more time to get adequately retrieved lymph nodes and more complications. However, there were more minor problems in the first 30 LADG than ODG cases. The unfavorable results for LADG can be overcome easily through an adequate training program for LADG.

Ileal angiomyolipoma manifested by small intestinal intussusception.

Angiomyolipomas (AMLs), a form of benign mesenchymal hamartoma, arise primarily in the kidneys of patients with or without tuberous sclerosis. Extra-renal AMLs are very rare and are most commonly found in the liver. AMLs of the small intestine are exceedingly rare. Here, a case of a 28-year-old man, who presented with ileal intussusception caused by ileal AML is reported. The clinicopathological and immunohistochemical findings of ileal AMLs are discussed and the literature on small intestinal AMLs is reviewed.

Fluoroscopically guided feeding tube insertion for relief of postoperative gastrointestinal anastomotic obstruction and leakage.

PURPOSE: To evaluate the feasibility and effectiveness of feeding tube insertion and enteral feeding for the treatment of postoperative gastrointestinal anastomotic obstruction and leakage. MATERIALS AND METHODS: From June 1999 to June 2002, thirty-four cases of postoperative gastrointestinal anastomotic obstruction and leakage after surgery for gastric carcinoma were treated by insertion of a feeding tube under fluoroscopic guidance. Twenty-one patients were male and 13 were female. The patients' ages ranged from 39 to 74 years (mean age: 61 years). All the patients experienced vomiting, and 15 patients had anastomotic site or duodenal stump leakage. We evaluated the feasibility of feeding tube insertion for enteral feeding to improve the obstruction and facilitate leakage site closure, and the patients' nutritional benefit was also evaluated by checking the serum albumin level between pre- and post-enteral feeding via the feeding tube. RESULTS: Thirty-two patients (94%) were successfully managed by feeding tube insertion, but the remaining two were not managed, and this was due to severe angulations at the anastomotic site. The procedure times for feeding tube insertion ranged from 15 to 60 minutes (mean time: 45 minutes). Twenty-eight patients experienced symptomatic relief of gastrointestinal obstruction, and they were able to resume a normal regular diet after feeding tube removal. Three patients underwent stent insertion due to recurrent symptoms, and one patient underwent jejunostomy feeding due to the presence of a persistent leakage site. Eleven patients achieved leakage site closure after enteral feeding via a feeding tube. The serum albumin level was significant, increased from pre-enteral feeding (2.65 +/- 0.37 g/dL) to the post-enteral feeding (3.64 +/- 0.58 g/dL) via the feeding tube (p < 0.001). The duration of follow-up ranged from one to 53 months (mean: 23 months). CONCLUSION: The insertion of a feeding tube for enteral feeding under fluoroscopic guidance is safe, and it provides effective relief from gastrointestinal anastomotic site obstruction and leakage after gastric surgery. Moreover, our findings indicate that feeding tube insertion for enteral feeding may be used as the primary procedure to treat postoperative anastomotic obstruction and leakage.

Impact of PTEN on the expression of insulin-like growth factors (IGFs) and IGF-binding proteins in human gastric adenocarcinoma cells.

PTEN is a tumor suppressor gene that is frequently mutated or deleted in a variety of human cancers including human gastric cancer. PTEN functions primarily as a lipid phosphatase and plays a key role in the regulation of the PI3 kinase/Akt pathway, thereby modulating cell proliferation and cell survival. On the other hand, the IGF system plays an important role in cell proliferation and cell survival via the PI3 kinase/Akt and MAP kinase pathways in many cancer cells. To characterize the impact of PTEN on the IGF-IGFR-IGFBP axis in gastric cancer, we overexpressed PTEN using an adenovirus gene transfer system in human gastric adenocarcinoma cells, SNU-484 and SNU-663, which lack PTEN. Overexpression of PTEN inhibited serum-induced as well as IGF-I-induced cell proliferation as compared to control cells. PTEN overexpression resulted in a significant decrease in the expression of IGF-I, -II, and IGF-IR. Interestingly, amongst the six IGFBPs, only IGFBP-3 was upregulated by PTEN, whereas IGFBP-4 and -6 were reduced. The IGFBP-3 promoter activity assay and Western immunoblotting demonstrate that PTEN regulates IGFBP-3 at the transcriptional level. In addition, the PI3 kinase inhibitor, LY294002, upregulates IGFBP-3 expression but downregulates IGF-I and IGF-II, indicating that PTEN controls IGFBP-3 and IGFs by an Akt-dependent pathway. These findings suggest that PTEN may inhibit antiapoptotic IGF actions not only by blocking the IGF-IGFR-induced Akt activity, but also by regulating expression of components of the IGF system, in particular, upregulation of IGFBP-3, which is known to exert antiproliferative effects through IGF-dependent and IGF-independent mechanisms in cancer cells.