Jae Hyung Noh

Phase III Trial Comparing Capecitabine Plus Cisplatin Versus Capecitabine Plus Cisplatin With Concurrent Capecitabine Radiotherapy in Completely Resected Gastric Cancer With D2 Lymph Node Dissection: The ARTIST Trial

PURPOSE The ARTIST (Adjuvant Chemoradiation Therapy in Stomach Cancer) trial was the first study to our knowledge to investigate the role of postoperative chemoradiotherapy therapy in patients with curatively resected gastric cancer with D2 lymph node dissection. This trial was designed to compare postoperative treatment with capecitabine plus cisplatin (XP) versus XP plus radiotherapy with capecitabine (XP/XRT/XP). PATIENTS AND METHODS The XP arm received six cycles of XP (capecitabine 2,000 mg/m2 per day on days 1 to 14 and cisplatin 60 mg/m2 on day 1, repeated every 3 weeks) chemotherapy. The XP/XRT/XP arm received two cycles of XP followed by 45-Gy XRT (capecitabine 1,650 mg/m2 per day for 5 weeks) and two cycles of XP. RESULTS Of 458 patients, 228 were randomly assigned to the XP arm and 230 to the XP/XRT/XP arm. Treatment was completed as planned by 75.4% of patients (172 of 228) in the XP arm and 81.7% (188 of 230) in the XP/XRT/XP arm. Overall, the addition of XRT to XP chemotherapy did not significantly prolong disease-free survival (DFS; P = .0862). However, in the subgroup of patients with pathologic lymph node metastasis at the time of surgery (n = 396), patients randomly assigned to the XP/XRT/XP arm experienced superior DFS when compared with those who received XP alone (P = .0365), and the statistical significance was retained at multivariate analysis (estimated hazard ratio, 0.6865; 95% CI, 0.4735 to 0.9952; P = .0471). CONCLUSION The addition of XRT to XP chemotherapy did not significantly reduce recurrence after curative resection and D2 lymph node dissection in gastric cancer. A subsequent trial (ARTIST-II) in patients with lymph node-positive gastric cancer is planned.

Predictive factors for lymph node metastasis in early gastric cancer with submucosal invasion: analysis of a single institutional experience.

Objective:An accurate assessment of a potential lymph node metastasis is an important issue for the appropriate treatment of early gastric cancer. Minimizing the amount of invasive procedures used in cancer treatment is critical for improving the patients quality of life. Therefore, this study analyzed the predictive risk factors for a lymph node metastasis in early gastric cancer with a submucosal invasion. Methods:The data from 1043 patients surgically treated for early gastric cancer with submucosal invasion between 2002 and 2005 were reviewed retrospectively. The patients were divided into 3 layers according to their depth: SM1, SM2, and SM3. The clinicopathological variables predicting a lymph node metastasis were evaluated. Results:A lymph node metastasis was observed in 19.4% of patients. The tumor size, histologic type, Lauren classification, tumor depth, and perineural invasion showed a positive correlation with the rate of lymph node metastasis and N category by univariate analysis. Multivariate analyses revealed the tumor size (≥2 cm) and lymphatic involvement to be significantly and independently related to lymph node metastasis. The presence of lymphatic involvement was the strongest predictive factor for a lymph node metastasis, being observed in 43.8% of cases in which a lymph node metastasis had been revealed. No lymph node metastasis was observed in the 12 cases with no lymphatic involvement, SM1 invasion, and tumor size <1 cm. Conclusions:Lymphatic involvement and tumor size are independent risk factors for a lymph node metastasis in early gastric cancer with submucosal invasion. Minimal invasive treatment, such as endoscopic mucosal resection, may be possible in highly selective submucosal cancers with no lymphatic involvement, SM1 invasion, and tumor size <1 cm.

The difficult choice between total and proximal gastrectomy in proximal early gastric cancer

BACKGROUND Surgical results including postoperative complications, prognoses, body weight changes, and nutritional statuses were compared in patients with early gastric cancer in the upper third of the stomach who were treated by total gastrectomy or proximal gastrectomy. METHODS The authors reviewed clinicopathologic features, postoperative complications, survivals, body weight changes, and biochemical markers after surgery in 423 patients who underwent total or proximal gastrectomy for early gastric cancer in the upper third of the stomach. RESULTS The proximal gastrectomy group (n = 89) had smaller tumors, shorter resection margins, and smaller numbers of retrieved lymph nodes than the total gastrectomy group (n = 334). N stages and 5-year survival rates were similar after total and proximal gastrectomy. Postoperative complication rates after total gastrectomy and proximal gastrectomy were 12.6% and 61.8%, respectively, which was significant (P < .001). Rates of anastomotic stenosis and reflux esophagitis were 6.9% and 1.8% after total gastrectomy and 38.2% and 29.2% after proximal gastrectomy, respectively. The parameters that reflect nutritional status (ie, body weight, serum hemoglobin, total protein, albumin, glucose, and cholesterol) were similar in the proximal and total gastrectomy groups at 6, 12, 24, and 36 months postoperatively. CONCLUSION Although the surgical safeties and curabilities of proximal and total gastrectomy were similar, proximal gastrectomy was found to be associated with a markedly higher rate of complications such as anastomotic stenosis and reflux esophagitis and to provide no benefit in terms of postoperative weight loss. The authors conclude that proximal gastrectomy is not a better option for upper-third early gastric cancer than total gastrectomy.

Impact of MET amplification on gastric cancer: possible roles as a novel prognostic marker and a potential therapeutic target.

Identification of critical genes which play pivotal roles in controlling tumor growth and survival will establish the basis for developing therapeutic targets. With the aim of establishing personalized medicine for treatment of solid tumors, we focused on MET amplification in gastric cancer patients, given the extreme sensitivity to c-Met inhibitor in MET amplified gastric cancer cell lines. We tested MET amplification and activation of c-Met in various gastric cancer cell lines and tissue samples from 482 gastric cancer patients who underwent curative surgery. Gastric cancer cell lines with MET amplification by quantitative real-time PCR (qPCR) and FISH predicted sensitivity to PHA-665,752, a selective c-Met kinase inhibitor. Of the 472 patients who had DNA sample available for qPCR analysis, 100 patients (21.2%) had a MET copy number greater than 4.0 copies and demonstrated poorer survival following curative surgery with statistical significance (5-year OS; 50.0 vs. 59.1%; MET amplification (+) vs. MET amplification (-); P = 0.0134). These results suggest that the increased MET copy number measured by qPCR plays an important role in determining prognosis in gastric cancer patients. However, the predictive role of MET amplification for treatment response should be further explored in upcoming clinical trials.

Prognostic stratification of high-risk gastrointestinal stromal tumors in the era of targeted therapy.

Background:Recently, a trial of adjuvant imatinib for primary R0-resected intermediate and high-risk gastrointestinal stromal tumors (GISTs) significantly improved recurrence-free survival. But identifying patients having higher chances of recurrence will reduce economic losses and prevent adverse side effects caused by adjuvant treatment. Methods:Tissue samples from 93 patients with high-risk GISTs were studied for p16, CD34, and CD44 protein expression and mutations of KIT and PDGFRA gene. Clinicopathologic, immunohistochemical, and mutation results were compared with clinical outcome by univariate and multivariate analyses. Results:KIT mutations were observed in 75 cases (81%) including 46 exon 11 deletion mutations and 31 deletions affecting codons 557–558. A novel 12 bp deletion mutation (KHNG484-488) on KIT exon 9 was detected in a small intestinal GIST. For recurrence-free survival, R0 resection, organ-confined disease stage, and female sex are better prognostic factors in univariate analysis and disease stage was the only factor predicting recurrence (P = 0.02) in multivariate analysis. In overall survival, mutation types, presence of mutation, location of GISTs, and mitosis were significant by univariate analysis. After multivariate analysis, mitotic counts and presence of KIT mutation corresponded to independent prognostic factors. Moreover, mitosis, KIT exon 11 deletion mutation, and deletions affecting exon 557–558 predict recurrence in R0-resected high-risk GISTs (P < 0.05). Conclusion:Prognostic stratification in high-risk GISTs will help identify patients with high-risk GIST who may benefit from adjuvant therapy.

The relationships between perioperative CEA, CA 19-9, and CA 72-4 and recurrence in gastric cancer patients after curative radical gastrectomy.

The correlation between perioperative CEA, CA 19‐9, and CA 72‐4 and recurrence of gastric cancer has not been clarified. The aim of this study was to investigate the relationships between perioperative CEA, CA 19‐9, and CA 72‐4 and recurrence of gastric cancer.

Prognostic role of p-mTOR expression in cancer tissues and metastatic lymph nodes in pT2b gastric cancer

Despite the great interest in mammalian target of rapamycin (mTOR) as a potential anticancer therapy target, the prognostic role of mTOR in gastric cancer has not been elucidated. In this study, we investigated mTOR expression in gastric cancer tissues and in metastatic lymph nodes and examined its association with clinical outcome. A total of 290 patients with pT2b gastric cancer were enrolled in this study. Patients were divided into 3 groups according to metastatic lymph node status: Group 1 contained 96 patients without lymph node metastasis, Group 2 contained 102 patients with a few (1–2) metastatic lymph nodes and Group 3 contained 92 patients with extensive (>16) lymph node metastasis. Phosphorylated mTOR expression was determined immunohistochemically using tissue microarrays. p‐mTOR expression was observed in 36.5% of the gastric cancer tissues in Group 1, 39.2% in Group 2 and 60.9% in Group 3. A significant correlation was found between p‐mTOR expression in gastric cancer tissues and in metastatic lymph nodes. The Borrmann type in Group 1, perineural invasion and p‐mTOR expression in metastatic lymph nodes in Group 2 and p‐mTOR expression in metastatic lymph nodes in Group 3 were found to be independent prognostic factors of disease‐free survival. The 5‐year disease free survival rate of Group 2 patients was 84.4% in negative p‐mTOR and 66.1% in positive p‐mTOR expression in metastatic lymph nodes (p = 0.015). The 5‐year disease free survival rate of Group 3 patients was 37.3% in negative p‐mTOR and 14.9% in positive p‐mTOR expression in metastatic lymph nodes (p = 0.037). There was a linear correlation between the rate of tumor recurrence and mTOR expression scores in metastatic lymph nodes. In pT2b gastric cancer, p‐mTOR expression in gastric cancer is associated with the extent of lymph node metastasis, and p‐mTOR expression in metastatic lymph nodes is correlated with poor disease‐free survival. mTOR may harbor significant potential for a prognostic biomarker and therapeutic target for gastric cancer treatment.

Expression of activated signal transducer and activator of transcription 3 predicts poor clinical outcome in gastric adenocarcinoma

Lee J, Kang WK, Park JO, Park SH, Park YS, Lim HY, Kim J, Kong J, Choi MG, Sohn TS, Noh JH, Bae JM, Kim S, Lim DH, Kim K‐M, Park CK. Expression of activated signal transducer and activator of transcription 3 predicts poor clinical outcome in gastric adenocarcinoma. APMIS 2009; 117: 598–606.

Impact of E2F-1 Expression on Clinical Outcome of Gastric Adenocarcinoma Patients with Adjuvant Chemoradiation Therapy

Purpose: There are no reliable prognostic markers that identify gastric cancer patients who may benefit from adjuvant chemoradiation therapy. E2F-1 was shown to be associated with radiosensitivity and chemosensitivity in certain tumor types. Therefore, we analyzed expression and prognostic significance of E2F-1 along with thymidylate synthase (TS) in R0-resected gastric adenocarcinoma patients, who underwent adjuvant chemoradiation therapy with 5-fluorouracil (5-FU) and leucovorin. Experimental Design: The chemosensitivity to 5-FU and radiosensitivity were tested in three E2F-1–overexpressed gastric cancer cell lines in vitro. The expressions of TS and E2F-1 were analyzed in 467 R0-resected primary gastric cancer patients, who received adjuvant chemoradiation therapy with 5-FU and leucovorin using tissue microarray. Results: The E2F-1 immunopositivity rate was 22.2% (103 of 465 samples) with a cutoff value of 5% immunoreactivity, whereas the TS-positive expression occurred in 19.0% of the 463 tumors tested. Using stepwise Cox proportional hazards regression modeling, multivariate analyses showed that the E2F-1 immunopositivity predicted more favorable survival as compared with the E2F-1 immunonegativity with borderline statistical significance [P = 0.050, hazard ratio (HR) = 0.702, 95% confidence interval, 0.487, 1.013]. However, the E2F-1 immunopositivity did not retain its statistical significance at multivariate analysis for predicting disease-free survival (data not shown, P = 0.270), but stage was the only influential factor for disease-free survival in stages IB to IV (M0) patients (P < 0.001). TS immunopositivity did not influence survival (P = 0.459) or disease-free survival (P = 0.447). Conclusion: E2F-1 is a potentially novel independent prognostic factor that may identify gastric cancer patients who will likely benefit from adjuvant chemoradiation therapy following curative resection.

Expression Levels of Cyclin G2, But Not Cyclin E, Correlate With Gastric Cancer Progression

PURPOSE Cyclin G2 and cyclin E are important cell-cycle regulators in various cancer tissues. However, little is known about cyclin G2 expression in human gastric cancer tissues, and the role of cyclin E is quite controversial. This study evaluated their clinical significance in gastric cancer tissues. MATERIALS AND METHODS Immunohistochemical staining using the tissue array method was performed on 166 human gastric carcinomas. The clinicopathological features and prognostic significance were analyzed. RESULTS Cyclin G2 and cyclin E expressions were positive in 110 (66.3%) and 77 (46.4%) human gastric cancer tissues, respectively. The incidence of cyclin G2 positivity was lower in females and in cancers with the undifferentiated type of histology. Moreover, cyclin G2 expression was inversely correlated with the more advanced stages (P < 0.05), the presence of lymph-node metastasis (P < 0.05), and the presence of perineural invasion (P < 0.05). However, no significant correlation was observed between the expression of cyclin E and all of the clinicopathological factors examined. Cyclin G2 expression was associated with a better overall survival (OS; 5-y OS, 50.6% for cyclin G2-positive versus 35.0% for cyclin G2-negative; P < 0.05). However, multivariate analysis revealed lymph-node metastasis, distant metastasis, and lymphatic invasion to be independent prognostic factors but not cyclin G2 expression. CONCLUSION Our study could not demonstrate any significant relationship between cyclin E expression and the clinicopathological variables. However, cyclin G2 appears to be a negative cell-cycle regulator in gastric cancer, and its expression seems to be inversely related to gastric cancer progression.