Impact of extranodal extension on prognosis in lymph node-positive gastric cancer.

BACKGROUND: The TNM classification system is used widely for tumour staging, and directs the treatment and prognosis of patients with cancer. The aim of this study was to assess the prognostic value of extranodal extension (ENE) in patients with early gastric cancer. METHODS: All patients who underwent gastrectomy with lymphadenectomy for primary gastric cancer with lymph node metastases between January 2003 and June 2006 were reviewed. Histological slides of metastatic nodes were reviewed by two gastrointestinal pathologists. The association of ENE with clinicopathological characteristics was assessed. The disease-specific survival rate was calculated by the Kaplan-Meier method, and a multivariable Cox regression model was used to identify independent prognostic factors. RESULTS: Some 1143 patients were included. ENE was associated with advanced pT and pN category, larger tumour size and lymphovascular/perineural invasion. In multivariable analysis, pT category, pN category, ENE, lymphovascular invasion and perineural invasion were found to be independent prognostic factors in node-positive gastric carcinoma. The 5-year survival rate of patients with ENE was 48·1 per cent, compared with 78·2 per cent for patients without ENE (P < 0·001). In the subgroup of patients with early gastric cancer, ENE was associated with a worse 5-year survival rate in patients with early (T1) gastric cancer: 75 per cent in patients with ENE versus 96·9 per cent in those without (P < 0·001). CONCLUSION: ENE is an independent prognostic factor in patients with early and advanced gastric cancer.

Adjuvant chemotherapy for gastric cancer: a randomised phase 3 trial of mitomycin-C plus either short-term doxifluridine or long-term doxifluridine plus cisplatin after curative D2 gastrectomy (AMC0201).

BACKGROUND: This phase 3 study evaluated the efficacy of new adjuvant chemotherapy (MFP), which intensified the mitomycin-C (MMC) plus short-term doxifluridine (Mf) for gastric cancer. PATIENTS AND METHODS: A total of 855 patients (424 in Mf, 431 in MFP) with pathological stage II-IV (M0) gastric cancer after D2 gastrectomy were randomly assigned to receive either Mf (MMC 20 mg m(-2), followed by oral doxifluridine 460-600 mg m(-2) per day for 3 months) or MFP (MMC 20 mg m(-2), followed by oral doxifluridine 460-600 mg m(-2) per day for 12 months with 6 monthly infusions of 60 mg m(-2) of cisplatin) chemotherapy. RESULTS: With a median follow-up of 6.6 years, there was no difference between the two groups in recurrence-free survival (RFS) (5-year RFS 61.1% in Mf and 57.9% in MFP; hazard ratio 1.10 (95% CI 0.89-1.35); P=0.39) and overall survival (OS) (5-year OS 66.5% in Mf and 65.0% in MFP; hazard ratio 1.11 (95% CI 0.89-1.39); P=0.33). CONCLUSION: Intensification of Mf adjuvant chemotherapy by prolonging the duration of oral fluoropyrimidine and adding cisplatin was safe but not effective to improve the survivals in curatively resected gastric cancer patients.

Suitability of endoscopic submucosal dissection for treatment of submucosal gastric cancers.

BACKGROUND: Endoscopic submucosal dissection (ESD) is not considered appropriate for all submucosal cancers owing to the risk of lymph node metastasis and difficulty estimating the deep margin status. This study aimed to determine predictive factors for lymph node metastases in submucosal cancer and to explore in which patients ESD might be feasible. METHODS: Details of patients who had curative gastrectomy for submucosal gastric cancer at Asan Medical Centre from 2007 to 2011 were reviewed retrospectively to determine the relationship between lymph node metastasis and clinicopathological characteristics, including age, sex, tumour location, size, gross appearance, depth of invasion, histological type/differentiation, presence of lymphovascular/perineural invasion, and immunohistochemical staining results for p53, human epidermal growth factor receptor (HER) 1 and HER2. RESULTS: A total of 1773 patients were analysed. The presence of lymphovascular invasion was related most strongly to lymph node metastasis. Multivariable analysis revealed that depth of invasion, tumour size, differentiation, gross appearance and perineural invasion were also related. Metastatic lymph nodes were found in four of 105 patients who met the classical criteria for ESD; all showed a moderately differentiated histological appearance. No lymph node metastases were observed in well differentiated SM1 tumours of any size (infiltration into upper third of submucosa), or in well differentiated SM2 (infiltration into middle third of submucosa) tumours of 2 cm or less without lymphovascular invasion. CONCLUSION: Patients with well differentiated SM1 cancer of any size and those with well differentiated SM2 cancer of 2 cm or less without lymphovascular invasion may be suitable candidates for ESD.

Prognostic factors and recurrence pattern in node-negative advanced gastric cancer.

AIMS: Despite better overall survival in node-negative advanced gastric cancer (AGC), a significant proportion of patients develop recurrence and they may benefit from adjuvant therapy. The aim of this study was to evaluate the prognostic factors and recurrence pattern of node-negative AGC. METHODS: A total of 424 patients who underwent curative gastrectomy with extended lymphadenectomy for node-negative AGC between 2003 and 2005 were retrospectively reviewed. Patients with tumor involvement of adjacent organs (T4b), gastric cancer recurrence, tumor in the remnant stomach, less than 15 harvested lymph nodes, and those who received neoadjuvant chemotherapy were excluded. RESULTS: Invasion to deeper layers, undifferentiated histology, signet ring cell type compared with tubular adenocarcinoma, and tumor size larger than 6.3 cm correlated with poorer prognosis in univariate analysis. In multivariate one, however, only differentiation and depth of invasion, especially the presence of serosa involvement were significant. The 5-year survival rates of the four groups classified by differentiation and depth of invasion [T2/3 (differentiated type), T2/3 (undifferentiated type), T4a (differentiated type), and T4a (undifferentiated type)] were 98%, 92%, 80%, and 72%, respectively (P < 0.01). In terms of recurrence pattern, Lauren's type and depth of invasion were significant. Recurrence with peritoneal seeding was associated with the diffuse type and invasion into the subserosa or serosa, while hematogenous metastasis was related to the intestinal type and invasion to the proper muscle or subserosa layer. CONCLUSIONS: Differentiation and serosa involvement should be considered to stratify patients with node-negative AGC for adjuvant treatment.

A prospective cohort study of pregnancy outcomes of women inadvertently exposed to methylephedrine in the 1st trimester of pregnancy.

No information is currently available on the safety of methylephedrine, a component of various cold medications available in South Korea. With previous approval by an Institutional Review Board, 349 women inadvertently exposed to methylephedrine during the 1st trimester of pregnancy and an age- and gravidity-matched control group, were enrolled in a prospective cohort study. Study outcomes, for example gestational age at birth, birth weight and major and minor malformations were evaluated in 282 cases and 280 controls. Exposure to methylephedrine was at a gestational age of 4.0 weeks (median), at doses ranging from 52.5 to 1,575 mg/day, for a median duration of 3 (range: 1-30) days. No differences were observed between cases and controls in any of the pregnancy outcomes studied. There were 4/265 (1.5%) babies born with major malformations in the case group and 4/260 (1.5%) in the control group. In conclusion, inadvertent exposure to methylephedrine as a component of over-the counter oral cold remedies in early pregnancy was not associated with an increased rate of adverse pregnancy outcomes. Co-exposure with acetaminophen, cigarette smoking or alcohol did not appear to modify the outcomes.

Unchanging trend of esophagogastric junction adenocarcinoma in Korea: experience at a single institution based on Siewert's classification.

The incidence of adenocarcinoma of the esophagogastric junction (AEG) has been increasing in Western countries. It is unclear, however, whether similar changes are occurring in Asia. We therefore investigated the incidence of AEG in Korea, and assessed the clinical characteristics of three types of AEG based on Siewert's classification. We retrospectively reviewed the medical records of 16 811 patients diagnosed with esophageal squamous cell carcinoma (ESC, n= 1450) or gastric noncardiac adenocarcinoma (GNCA, n= 14 751) between 1992 and 2006. The patients were divided into three 5-year cohorts (cohort A [1992-1996], n= 2734, cohort B [1997-2001], n= 5727, and cohort C [2002-2006], n= 8350), and the ratios of AEG (n= 610) to non-AEG (ESC and GNCA) in each cohort were compared. Using Siewert's classification, the tumors were categorized into one of three types, and patient demographic features and 5-year survival rates were compared. The ratio of AEG to non-AEG cases did not change over time (0.037, 0.034, and 0.039 for cohorts A, B, and C, respectively; P= 0.40). Of the 610 patients with AEG, 23 (3.7%) had type 1 tumors, 47 (7.7%) had type 2, and 540 (88.5%) had type 3. The 5-year survival rate of patients with type 1 AEG was much lower (4.8 +/- 4.7%) than that of those with type 2 (47.9 +/- 7.8%) and type 3 (47.4 +/- 2.5%) tumors. Unlike in Western countries, the ratio of AEG to non-AEG cases has not increased over time in Korea. Type 1 AEG was rarer and associated with a more unfavorable prognosis in Korea than in Western countries.

A phase II study of paclitaxel and capecitabine as a first-line combination chemotherapy for advanced gastric cancer.

Paclitaxel and capecitabine, which have distinct mechanisms of action and toxicity profiles, have each shown high activity as single agents in gastric cancer. Synergistic interaction between these two drugs was suggested by taxane-induced upregulation of thymidine phosphorylase. We, therefore, evaluated the antitumour activity and toxicities of paclitaxel and capecitabine as first-line therapy in patients with advanced gastric cancer (AGC). Patients with histologically confirmed unresectable or metastatic AGC were treated with capecitabine 825 mg m(-2) p.o. twice daily on days 1-14 and paclitaxel 175 mg m(-2) i.v. on day 1 every 3 weeks until disease progression or unacceptable toxicities. Between June 2002 and May 2004, 45 patients, of median age 57 years (range=38-73 years), were treated with the combination of capecitabine and paclitaxel. After a median 6 cycles (range=1-9 cycles) of chemotherapy, 43 were evaluable for toxicity and response. A total of 2 patients showed complete response and 20 showed partial response making the overall response rate 48.9% (95% CI=30.3-63.5%). After a median follow-up of 42.2 months (range=31.2-54.3 months), median time to progression was 5.6 months (95% CI=3.9-7.2 months) and median overall survival was 11.3 months (95% CI=8.1-14.4 months). Grade 3 or 4 adverse events include neutropaenia (46.5% of patients), hand-foot syndrome (9.3%), arthralgia (9.3%), and asthenia (4.7%). There was no neutropaenic fever or treatment-related deaths. Paclitaxel and capecitabine combination chemotherapy was active and highly tolerable as a first-line therapy for AGC.

Large metastatic lymph node size, especially more than 2 cm: independent predictor of poor prognosis in node-positive gastric carcinoma.

The presence of metastatic lymph nodes (MLNs) is the most important prognostic factor for gastric carcinoma, with the number of MLNs thought to be predictive of the prognosis. However, there have been long-standing debates on how to classify node-positive patients into prognostic groups appropriately. Recent findings in patients with colon and esophageal cancer have suggested that MLN size, more than MLN number, is an important prognostic factor; but less is known about the impact of MLN size on the prognosis of patients with gastric carcinoma. We therefore assessed the prognostic impact of large MLNs, especially those>or=2 cm, in patients with gastric carcinoma. A total of 1190 patients who underwent curative resection for gastric carcinoma between 2001 and 2003 and had lymph node metastases were divided into two groups according to the size of the largest MLN:>or=2 cm (n=51) vs. <2 cm (n=1139). Clinicopathologic data, including tumor recurrence and survival, were reviewed retrospectively. The median follow-up for living patients was 47 months (range 30-80 months). Age, sex ratio, type of surgery, and histologic classification did not correlate with MLN size. The depth of invasion did correlate with MLN size (T1-2 vs. T3-4, p=0.045) but not with the number of MLNs (N stage, p=0.311). The two groups showed similar distribution of stage according to the UICC/AJCC TNM staging system. Disease-free survival (34% vs. 53%, p<0.001) and overall survival (40% vs. 63%, p=0.011) were significantly worse in the large MLN group. Univariate analysis with the log-rank test showed that MLN>or=2 cm, type of surgery, T stage, N stage, and histologic classification had a significant impact on overall survival. Multivariate analysis with the Cox proportional hazard model showed that MLN>or=2 cm was an independent prognostic factor (hazard ratio 1.76, p=0.006), along with T stage and N stage. MLN>or=2 cm is an independent additional predictor of poor prognosis in patients with node-positive gastric carcinoma.

Prognostic significance of p53 gene mutations and protein overexpression in localized gastrointestinal stromal tumours.

AIMS: Mutation of c-kit is a relatively early event in the tumorigenesis of gastrointestinal stromal tumours (GISTs). The aim was to determine the prognostic significance of p53 alterations as an additional genetic change in GISTs. METHODS AND RESULTS: We reviewed 125 patients with localized GISTs subjected to complete resection between 1990 and 2002. Mutational analyses of c-kit exons 9, 11, 13 and 17, p53 exons 4-8 and immunohistochemistry for p53 protein were conducted using paraffin-embedded tissues. Alterations of p53 were observed in 50 patients (40.0%). Based on the National Institutes of Health's risk category, p53 alterations were noted more frequently in the higher risk categories (P = 0.041). With a median follow-up of 56.5 months (range: 2.3-126.8), 5-year relapse-free survival (RFS) rates were 61.7% without p53 alterations, compared with only 40.2% with p53 alterations (P = 0.009). Multivariate analysis indicated that p53 alterations comprised an independent, poor prognostic factor for RFS, in addition to c-kit mutations, large size, a high mitotic count and non-gastric primary sites. CONCLUSIONS: Alterations in p53 were more commonly observed in localized GISTs at higher risk of relapse. This suggests that they are significant as an independent, poor prognostic factor.

Cutaneous metastasis resembling acute dermatitis in patient with advanced gastric cancer.

The most common metastatic sites from gastric cancer are the liver, intra-abdominal lymph nodes, ovary and peritoneal cavity. Cutaneous metastasis of gastric cancer is rare, and most cutaneous metastases are typically solitary, nodular, have a firm consistency, and are red or hyperpigmented. Thus, cutaneous metastasis is easily distinguished from other skin disease. We report a case of a 60-year-old woman with cutaneous metastasis of gastric cancer, whose facial skin showed painless pruritic eczema, resembling acute dermatitis. She had earlier undergone a total gastrectomy for advanced gastric cancer in our hospital. After 14 months, she developed eczematous facial lesions; the presumptive diagnosis was acute dermatitis. However, skin biopsy unexpectedly revealed cutaneous metastasis of gastric cancer. After 6 months of systemic chemotherapy with capecitabine and cisplatin, the cutaneous metastasis was markedly improved and a clinically complete remission was accomplished.

Adjuvant chemotherapy with 5-fluorouracil, doxorubicin and mitomycin-C (FAM) for 6 months after curative resection of gastric carcinoma.

AIM: This study aimed to evaluate the efficacy and safety of 5-fluorouracil (5-FU), doxorubicin and mitomycin-C (FAM) adjuvant chemotherapy in patients who had undergone curative resection of gastric carcinoma. METHODS: From Nov 1999 to Jan 2002, 291 consecutive patients with stage IB-IIIB gastric adenocarcinoma were given FAM adjuvant chemotherapy. Chemotherapy comprised intravenous 5-FU 600 mg/m(2) (days 1, 8, 29 and 36), doxorubicin 30 mg/m(2) (days 1 and 29) and mitomycin-C 10 mg/m(2) (day 1), every 8 weeks for 6 months. RESULTS: The median follow-up time was 60.6 months, 92 patients died, and 93 patients had recurrent disease. The 5-year overall survival (OS) rates were 85.9% for stage IB, 72.1% for stage II, 58.0% for stage IIIA, and 48.2% for stage IIIB (p=0.002). The 5-year relapse-free survival (RFS) rates were 85.2% for stage IB, 71.2% for stage II, 53.3% for stage IIIA, and 39.2% for stage IIIB (p<0.001). A total of 769 cycles of chemotherapy were delivered, and 15 patients experienced grade 3 or higher leukopenia. The most common grade 3 or higher non-hematologic toxicity was nausea/vomiting (11 patients), followed by stomatitis (3 patients). CONCLUSIONS: Adjuvant chemotherapy with FAM for 6 months for gastric carcinoma indicated comparable RFS and OS with an acceptable toxicity profile.

Phase II study of capecitabine and cisplatin as first-line combination therapy in patients with gastric cancer recurrent after fluoropyrimidine-based adjuvant chemotherapy.

To evaluate the efficacy and safety of capecitabine and cisplatin in patients with recurrent gastric cancer after fluoropyrimidine-based adjuvant therapy. Patients with histologically confirmed and measurable advanced gastric cancer that had relapsed after fluoropyrimidine-based adjuvant chemotherapy received oral capecitabine (1250 mg m(-2) twice daily, days 1-14) and intravenous cisplatin (60 mg m(-2) over 1 h, day 1) every 3 weeks. In total, 32 patients were enrolled, of whom 30 were evaluable for efficacy and 32 for safety. A median of 5 cycles (range 1-10) was administered. One patient achieved a complete response and eight had partial responses, giving an overall response rate of 28% (95% CI, 13-44%). The median time to progression and median overall survival were 5.8 months (95% CI, 4.1-7.5 months) and 11.2 months (95% CI, 5.5-16.9 months), respectively. Grade 3 neutropenia and thrombocytopenia were observed in 38 and 6% of patients, respectively. Grade 2/3 nonhaematological toxicities included diarrhoea (19%), stomatitis (19%) and hand-foot syndrome (31%). No grade 4 toxicity, neutropenic fever or treatment-related deaths occurred. Capecitabine in combination with cisplatin was effective and well tolerated as first-line treatment in patients with recurrent gastric cancer after fluoropyrimidine-based adjuvant chemotherapy.

Phase II study of capecitabine plus cisplatin as first-line chemotherapy in advanced gastric cancer.

BACKGROUND: A phase II study was conducted to assess the efficacy and tolerability of combination therapy with capecitabine and cisplatin in patients with advanced gastric cancer. PATIENTS AND METHODS: Patients with previously untreated metastatic or unresectable measurable gastric adenocarcinoma received oral capecitabine 1250 mg/m(2) twice daily, days 1-14, and i.v. cisplatin 60 mg/m(2) on day 1. This cycle was repeated every 3 weeks. RESULTS: Forty-two patients were enrolled in this study. Of these, 38 patients were assessable for efficacy and 40 were assessable for toxicity. One patient achieved a complete response and 22 patients had partial responses, giving an overall response rate of 54.8% in the intention-to-treat population (95% confidence interval 39.8% to 69.8%). The median time to progression was 6.3 months and the median overall survival was 10.1 months. The principal adverse events were neutropenia and hand-foot syndrome. Grade 3/4 adverse events were neutropenia (32.5% of patients), thrombocytopenia (10%), stomatitis (2.5%) and diarrhea (5%). Grade 2 and 3 hand-foot syndrome occurred in 20% and 7.5% of patients, respectively. There were no treatment-related deaths. CONCLUSIONS: The combination of capecitabine and cisplatin is active and well tolerated in patients with advanced gastric cancer.

Efficacy of screening for gastric cancer in a Korean adult population: a case-control study.

While gastric cancer is the most common malignancy in the Korean adult population, little is known of the efficacy of gastric cancer screening among Koreans. To study the efficacy of gastric cancer screening, this case-control study was conducted. From November 1996 to July 1998, 441 newly diagnosed gastric cancer (321 advanced, 120 early) patients were enrolled at the Department of General Surgery and 107 controls were enrolled at the inpatient Department of Family Medicine and Otolaryngology. History of gastric examinations and possible risk factors were collected through interview with a structured questionnaire. Patients with advanced gastric cancer were 61% less likely to have had a gastric examination than those with early gastric cancer (OR 0.39; 95%CI 0.23-0.65). Patients with advanced gastric cancer were 53% less likely to have had a gastric examination within two years of diagnosis (OR 0.47; 95%CI 0.23-0.98) and 69% less likely to have had a gastric examination within three years of diagnosis (OR 0.31; 95%CI 0.11-0.86). The data, showing a significant relationship between the history of gastric examinations and severity of gastric cancer, suggests that gastric cancer screening is effective in catching gastric cancer at early stages. It also suggests less than three years for screening interval.

Usefulness of CT in patients with intestinal obstruction who have undergone abdominal surgery for malignancy.

OBJECTIVE: The purpose of this study was to evaluate the usefulness of CT in determining the causes of intestinal obstruction in patients who have undergone abdominal surgery for malignancy. MATERIALS AND METHODS: We analyzed the CT scans of 55 patients with benign (n = 26) or malignant (n = 29) intestinal obstruction that developed after abdominal surgery for malignancy. After calculating the diagnostic accuracy of interpretations by three radiologists, we compared CT findings for benign and malignant intestinal obstructions with respect to peritoneal involvement patterns and other ancillary findings. Multivariate logistic regression analysis was used to determine the diagnostic performance of CT in revealing causes of obstruction. RESULTS: Diagnostic accuracies of the three radiologists were 67%, 75%, and 78%. CT findings indicating malignant obstruction were a mass at the site of obstruction or prior surgery, lymphadenopathy, or an abrupt transition zone and irregular bowel wall thickening at obstructed sites (p < .05). Conversely, the chance for benign obstruction increased when CT revealed mesenteric vascular changes, a large amount of ascites, or a smooth transition zone and smooth bowel wall thickening at the obstructed site (p < .05). With multivariate logistic regression analysis using two variables (a mass at the site of obstruction or prior surgery and lymphadenopathy), we calculated the overall accuracy of CT as 84% (46/55 patients). CONCLUSION: CT is useful in differentiating benign from malignant intestinal obstructions in patients who have undergone abdominal surgery for malignancy. However, CT has limitations in patients not having a demonstrable peritoneal mass.