Hyuk-Joon Lee

Morbidity and mortality of laparoscopic gastrectomy versus open gastrectomy for gastric cancer: an interim report--a phase III multicenter, prospective, randomized Trial (KLASS Trial).

Objective:The aim of this study was to evaluate the safety of this trial with respect to morbidity and mortality. Summary Background Data:Laparoscopic-assisted distal gastrectomy (LADG) is rapidly gaining popularity. However, there is limited evidence regarding its oncologic safety. We therefore conducted a phase III multicenter, prospective, randomized study comparing LADG with open gastrectomy (ODG). Methods:Patient eligibility criteria were pathologically-proven adenocarcinoma, 20 to 80 years of age, preoperative stage I, no history of other cancer, chemotherapy, or radiotherapy. The primary end point was to determine whether there is a difference in overall survival between 2 groups. The morbidity and mortality were compared to evaluate the safety of this trial. The time was decided on the hypothesis that the morbidity of this trial was not significantly different from that of previous reports on open gastric cancer surgeries (17%–20%). This study is registered at ClinicalTrials.gov and carries the following ID number: NCT00452751. Results:A total of 342 patients were randomized (LADG, 179 patients; ODG, 161 patients) between January 1, 2006 and July 19, 2007. There were no significant differences between the 2 groups in age, gender, and comorbidities. The postoperative complication rates of the LADG and ODG groups were 10.5% (17/179) and 14.7% (24/163), respectively (P = 0.137). Reoperations were required in 3 cases each group. The postoperative mortality was 1.1% (2/179) and 0% (0/163) in the LADG and ODG groups (P = 0.497), respectively. Conclusion:There was no significance difference in the morbidity and mortality between the 2 groups. Therefore, we conclude that this trial is safe and is thus ongoing.

Functional links between clustered microRNAs: suppression of cell-cycle inhibitors by microRNA clusters in gastric cancer

microRNAs (miRNAs) play integral roles in diverse processes including tumorigenesis. miRNA gene loci are often found in close conjunction, and such clustered miRNA genes are transcribed from a common promoter to generate polycistronic primary transcript. The primary transcript (pri-miRNA) is then processed by two RNase III proteins to release the mature miRNAs. Although it has been speculated that the miRNAs in the same cluster may play related biological functions, this has not been experimentally addressed. Here we report that the miRNAs in two clusters (miR-106b∼93 ∼ 25 and miR-222 ∼ 221) suppress the Cip/Kip family members of Cdk inhibitors (p57Kip2, p21Cip1 and p27Kip1). We show that miR-25 targets p57 through the 3′-UTR. Furthermore, miR-106b and miR-93 control p21 while miR-222 and miR-221 regulate both p27 and p57. Ectopic expression of these miRNAs results in activation of Cdk2 and facilitation of G1/S phase transition. Consistent with these results, both clusters are abnormally upregulated in gastric cancer tissues compared to the corresponding normal tissues. Ectopic expression of miR-222 cluster enhanced tumor growth in the mouse xenograft model. Our study demonstrates the functional associations between clustered miRNAs and further implicates that effective cancer treatment may require a combinatorial approach to target multiple oncogenic miRNA clusters.

Evaluation of the Seventh American Joint Committee on Cancer/International Union Against Cancer Classification of gastric adenocarcinoma in comparison with the sixth classification

The seventh TNM staging system for gastric cancer of the American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC) had a more detailed classification than the sixth TNM staging system for both the tumor (T) and lymph nodes (N). The authors compared survival rates assessed by the seventh staging system with those by the sixth system.

Long-Term Results of Laparoscopic Gastrectomy for Gastric Cancer: A Large-Scale Case-Control and Case-Matched Korean Multicenter Study

PURPOSE The oncologic outcomes of laparoscopy-assisted gastrectomy for the treatment of gastric cancer have not been evaluated. The aim of this study is to validate the efficacy and safety of laparoscopic gastrectomy for gastric cancer in terms of long-term survival, morbidity, and mortality retrospectively. PATIENTS AND METHODS The study group comprised 2,976 patients who were treated with curative intent either by laparoscopic gastrectomy (1,477 patients) or open gastrectomy (1,499 patients) between April 1998 and December 2005. The long-term 5-year actual survival analysis in case-control and case-matched population was conducted using the Kaplan-Meier method. The morbidity and mortality and learning curves were evaluated. RESULTS In the case-control study, the overall survival, disease-specific survival, and recurrence-free survival (median follow-up period, 70.8 months) were not statistically different at each cancer stage with the exception of an increased overall survival rate for patients with stage IA cancer treated via laparoscopy (laparoscopic group; 95.3%, open group: 90.3%; P < .001). After matching using a propensity scoring system, the overall survival, disease-specific survival, and recurrence-free survival rates were not statistically different at each stage. The morbidity of the case-matched group was 15.1% in the open group and 12.5% in the laparoscopic group, which also had no statistical significance (P = .184). The mortality rate was also not statistically significant (0.3% in the open group and 0.5% in the laparoscopic group; P = 1.000). The mean learning curve was 42. CONCLUSION The long-term oncologic outcomes of laparoscopic gastrectomy for patients with gastric cancer were comparable to those of open gastrectomy in a large-scale, multicenter, retrospective clinical study.

Gastric cancer in Korea

According to the Seoul cancer registry data, the crude annual incidence rate of all sites of cancer per 100000 population was 187.6 for males and 164.3 for females in 1993–1997 (Table 1). The age-standardized rate for the world population was 284.0 in males and 172.3 in females. Cancer was the third or fourth most common cause of death until the 1970s and had become the second in the 1980s. In 2000, cancer became the leading cause of death in Korea (Fig. 1), accounting for 23.9% of all deaths in 2000 (27.5% for males and 19.4% for females). From 1990 to 2000, cerebrovascular diseases, heart diseases, and liver diseases were decreasing, but the overall cancer mortality rate increased by 9.7% [3]. The crude annual death rate of all cancers was 157.9 per 100 000 for males and 90.2 for females, and the age-standardized death rate of all cancers was 184.2 per 100000 for males and 74.9 for females in 2000 (Table 1).

The impact of comorbidity on surgical outcomes in laparoscopy-assisted distal gastrectomy: a retrospective analysis of multicenter results.

Objective:The purpose of this study was to evaluate the impact of comorbidities on the surgical outcomes in laparoscopy-assisted distal gastrectomy (LADG). Summary Background Data:Although laparoscopic gastrectomy is less invasive than conventional open surgery, surgeons are still concerned with surgical outcomes associated with comorbidity. Methods:We retrospectively collected data on 1324 patients who underwent LADG between April 1998 and December 2005 by 10 surgeons in 10 hospitals. After excluding 87 patients who had an unusual medical history or surgical methods, 1237 patients were enrolled for analysis to evaluate the effect of comorbidities on the surgical outcomes. Results:Seven patients (0.6%) died during their hospitalization, and postoperative complications occurred in 162 (13.1%) of 1237 patients. According to univariate analysis, gender, number of comorbidities, reconstruction type, and the surgeons experience in laparoscopy-assisted gastrectomy (LAG) were related to postoperative local complications; age and comorbidity were related to systemic complications; and comorbidity was the only variable related to hospital mortality. Comorbidity was a predictive risk factor for local complications (odds ratio (OR): 1.79) and systemic complications (OR: 2.89) in multivariate analysis. The patients with pulmonary comorbidity were related to most types of immediate postoperative complications compared with other comorbidities. Conclusions:Our study suggests that comorbidities of patients could be a predictive risk factor for surgical complication after LADG. Therefore, patients with early gastric cancer having comorbidity should be considered for one of the limited surgeries. In addition, surgeons should carefully assess patients with comorbidities with full perioperative attention.

Nomogram Predicting Long-Term Survival After D2 Gastrectomy for Gastric Cancer

PURPOSE The aim of this study was to combine clinicopathologic variables associated with overall survival after gastric resection with D2 lymphadenectomy (D2 gastrectomy) for gastric cancer into a prediction nomogram. PATIENTS AND METHODS We retrospectively analyzed 7,954 patients who underwent D2 gastrectomy for gastric cancer at Seoul National University Hospital (SNUH) in Seoul, Korea. Two thirds of the patients were randomly assigned to the training set (n = 5,300), and one third were assigned to the validation set (n = 2,654). Multivariate analysis by Cox proportional hazards regression was performed using the training set, and the nomogram was constructed. Discrimination and calibration were performed using the SNUH validation set. Additional external validation was performed using the data set (n = 2,500) from Cancer Institute Ariake Hospital (CIAH) in Tokyo, Japan. RESULTS The multivariate Cox model identified age at diagnosis, sex, location, depth of invasion, number of metastatic lymph nodes, and number of examined lymph nodes as covariates associated with survival. In the SNUH validation set, the nomogram exhibited superior discrimination power compared with the seventh American Joint Committee on Cancer TNM classification (Harrells C-index, 0.78 v 0.69, respectively; P < .001). Calibration of the nomogram predicted survival corresponding closely with the actual survival. In the CIAH validation set, discrimination was good (C-index, 0.79), and the predicted survival was within a 10% margin of ideal nomogram. CONCLUSION We developed a nomogram predicting 5- and 10-year overall survival after D2 gastrectomy for gastric cancer. Validation using the SNUH and CIAH data sets revealed good discrimination and calibration, suggesting good clinical utility. The nomogram improved individualized predictions of survival.

Laparoscopy-assisted total gastrectomy for gastric cancer: A multicenter retrospective analysis

BACKGROUND Laparoscopy-assisted distal gastrectomy (LADG) has been applied to the treatment of gastric cancer, and there are now several publications regarding its safety and feasibility. In contrast, there have been few reports on laparoscopy-assisted total gastrectomy (LATG), because this procedure is performed less frequently and is technically more difficult to perform than LADG. The purpose of the present study was to evaluate short-term outcomes in a multicenter study of LATG, as well as its safety and feasibility. METHODS A retrospective multicenter study was carried out in Korea involving 1,485 patients who underwent laparoscopy-assisted gastrectomy for gastric cancer at 10 institutions between April 1998 and December 2005. Of these patients, 131 underwent LATG. We evaluated and analyzed the short-term outcomes and the clinicopathologic characteristics of the 131 patients. RESULTS The mean (+/- SD) operation time was 270 +/- 79 min; 1 patient required conversion to an open procedure. The mean number of retrieved lymph nodes was 34.7. The mean duration of hospital stay was 11.3 days, and first intake of soft diet was at 5.8 days. The rate of postoperative morbidity was 19% (25/131 patients); there was no mortality. The most common postoperative morbidity was wound complications at the mini-laparotomy site, and there were 3 cases of anastomotic leakage. Six patients (5%) had recurrence of cancer, and 9 patients (7%) died during the follow-up period. CONCLUSION Our results suggest that LATG is a safe and feasible procedure for gastric cancer patients. A prospective, multicenter, randomized trial of LATG is needed to confirm the efficacy of this procedure.

Loss of Rab25 promotes the development of intestinal neoplasia in mice and is associated with human colorectal adenocarcinomas

Transformation of epithelial cells is associated with loss of cell polarity, which includes alterations in cell morphology as well as changes in the complement of plasma membrane proteins. Rab proteins regulate polarized trafficking to the cell membrane and therefore represent potential regulators of this neoplastic transition. Here we have demonstrated a tumor suppressor function for Rab25 in intestinal neoplasia in both mice and humans. Human colorectal adenocarcinomas exhibited reductions in Rab25 expression independent of stage, with lower Rab25 expression levels correlating with substantially shorter patient survival. In wild-type mice, Rab25 was strongly expressed in cells luminal to the proliferating cells of intestinal crypts. While Rab25-deficient mice did not exhibit gross pathology, ApcMin/+ mice crossed onto a Rab25-deficient background showed a 4-fold increase in intestinal polyps and a 2-fold increase in colonic tumors compared with parental ApcMin/+ mice. Rab25-deficient mice had decreased beta1 integrin staining in the lateral membranes of villus cells, and this pattern was accentuated in Rab25-deficient mice crossed onto the ApcMin/+ background. Additionally, Smad3+/- mice crossed onto a Rab25-deficient background demonstrated a marked increase in colonic tumor formation. Taken together, these results suggest that Rab25 may function as a tumor suppressor in intestinal epithelial cells through regulation of protein trafficking to the cell surface.

Prospective randomized controlled trial (phase III) to comparing laparoscopic distal gastrectomy with open distal gastrectomy for gastric adenocarcinoma (KLASS 01)

A randomized controlled trial to evaluate the long-term outcomes of laparoscopic distal gastrectomy for gastric cancer is currently ongoing in Korea. Patients with cT1N0M0-cT2aN0M0 (American Joint Committee on Cancer, 6th edition) distal gastric cancer were randomized to receive either laparoscopic or open distal gastrectomy. For surgical quality control, the surgeons participating in this trial had to have performed at least 50 cases each of laparoscopy-assisted distal gastrectomy and open distal gastrectomy and their institutions should have performed more than 80 cases each of both procedures each year. Fifteen surgeons from 12 institutions recruited 1,415 patients. The primary endpoint is overall survival. The secondary endpoints are disease-free survival, morbidity, mortality, quality of life, inflammatory and immune responses, and cost-effectiveness (ClinicalTrials.gov ID: NCT00452751).