Chan Young Kim

Expression of DBC1 and SIRT1 Is Associated with Poor Prognosis of Gastric Carcinoma

Purpose: SIRT1 (silent mating-type information regulation 2 homologue 1) expression has been reported to predict poor survival in some cancers. We therefore investigated the expression levels of SIRT1 and its negative regulator, DBC1 (deleted in breast cancer 1), in gastric cancer patients. Experimental Design: We evaluated immunohistochemical expression of DBC1, SIRT1, and p53 using 3-mm tumor cores from 177 gastric cancer patients for tissue microarray. Results: Positive expressions of DBC1 and SIRT1 were seen in 62% (109 of 177) and in 73% (130 of 177) of patients, respectively. Expression of DBC1 was significantly correlated with tumor stage (P = 0.007), lymph node metastasis (P < 0.001), tumor invasion (P = 0.001), venous invasion (P = 0.001), histologic types (P < 0.001), p53 expression (P < 0.001), and SIRT1 expression (P < 0.001). SIRT1 expression was also significantly correlated with tumor stage (P < 0.001), lymph node metastasis (P < 0.001), tumor invasion (P < 0.001), histologic types (P < 0.001), and p53 expression (P = 0.001). In addition, expression of DBC1 was significantly associated with shorter overall survival and relapse-free survival by univariate analysis (P < 0.001 and P < 0.001, respectively). SIRT1 expression was also significantly associated with shorter overall survival and relapse-free survival by univariate analysis (P = 0.001 and P = 0.001, respectively). Multivariate analysis showed that tumor stage and expression of DBC1 were independent prognostic factors significantly associated with overall survival and relapse-free survival. Conclusion: This study shows that expression of DBC1 and SIRT1 is a significant prognostic indicator for gastric carcinoma patients.

Decreased Morbidity of Laparoscopic Distal Gastrectomy Compared With Open Distal Gastrectomy for Stage I Gastric Cancer Short-term Outcomes From a Multicenter Randomized Controlled Trial (KLASS-01)

OBJECTIVE To determine the safety of laparoscopy-assisted distal gastrectomy (LADG) compared with open distal gastrectomy (ODG) in patients with clinical stage I gastric cancer in Korea. BACKGROUND There is still a lack of large-scale, multicenter randomized trials regarding the safety of LADG. METHODS A large-scale, phase 3, multicenter, prospective randomized controlled trial was conducted. The primary end point was 5-year overall survival. Morbidity within 30 postoperative days and surgical mortality were compared to evaluate the safety of LADG as a secondary end point RESULTS : A total of 1416 patients were randomly assigned to the LADG group (n = 705) or the ODG group (n = 711) between February 1, 2006, and August 31, 2010, and 1384 patients were analyzed for modified intention-to-treat analysis (ITT) and 1256 were eligible for per protocol (PP) analysis (644 and 612, respectively). In the PP analysis, 6 patients (0.9%) needed open conversion in the LADG group. The overall complication rate was significantly lower in the LADG group (LADG vs ODG; 13.0% vs 19.9%, P = 0.001). In detail, the wound complication rate of the LADG group was significantly lower than that of the ODG group (3.1% vs 7.7%, P < 0.001). The major intra-abdominal complication (7.6% vs 10.3%, P = 0.095) and mortality rates (0.6% vs 0.3%, P = 0.687) were similar between the 2 groups. Modified ITT analysis showed similar results with PP analysis. CONCLUSIONS LADG for patients with clinical stage I gastric cancer is safe and has a benefit of lower occurrence of wound complication compared with conventional ODG.

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).

Calcifying fibrous tumor of the stomach: a case report

Calcifying fibrous tumor (CFT) is a rare, benign mesenchymal tumor usually affecting children and young adults, and it shows a predilection for the soft tissue and the abdominal cavity. Intrinsic visceral CFT is extremely rare and we present herein the case of a 59-year-old man with an asymptomatic gastric lesion, incidentally detected 1 month before this presentation. Thus, gastric endoscopy revealed a polypoid submucosal mass in the fundus, covered by an erythematous mucosa. The polypoid mass was a 3.9 × 2.7 cm-sized well-defined tumor located in the proper muscle, with extension to the subserosa. The tumor showed characteristic hypocellular sclerosis with coarse collagen, mononuclear inflammatory infiltrates, sparse fibroblastic spindle cells and occasional, psammomatous or dystrophic calcifications. Immunohistochemically, the spindle cells were negative for CD117, CD34, platelet-derived growth factor receptor-alpha, S100, smooth muscle actin, desmin and anaplastic lymphoma kinase.

CK2α phosphorylates DBC1 and is involved in the progression of gastric carcinoma and predicts poor survival of gastric carcinoma patients

CK2α has diverse effects on the tumorigenesis owing to its kinase activity, which phosphorylates various proteins involved in tumorigenesis. We, therefore, investigated the expression and role of CK2α in the phosphorylation of deleted in breast cancer 1 (DBC1) in gastric carcinomas. We used 187 gastric carcinomas and human gastric cancer cells to investigate the roles and relationship between CK2α and DBC1 in gastric carcinomas. Positive expression of CK2α and phospho‐DBC1 predicted shorter overall survival and relapse‐free survival by univariate analysis. Especially, CK2α expression was an independent prognostic indicator for gastric carcinoma patients. In gastric carcinoma cells, CK2α was bound to DBC1 and phosphorylated DBC1. The phosphorylation of DBC1 by CK2α was evidenced by co‐immunoprecipitation of CK2α and DBC1 in a GST pull‐down assay, an in vitro kinase assay, and immunofluorescence staining. Inhibition of both CK2α and DBC1 decreased proliferation and invasive activity of cancer cells. Decreased migration and invasive activity was associated with a downregulation of MMP2, MMP9 and the epithelial–mesenchymal transition. A mutation at the phosphorylation site of DBC1 also downregulated the signals related with the epithelial–mesenchymal transition. Our study demonstrated that CK2α is an independent prognostic indicator for gastric carcinoma patients and is involved in tumorigenesis by regulating the phosphorylation of DBC1. In addition, the blocking of CK2α and DBC1 inhibited the proliferation and invasive potential of gastric cancer cells. Therefore, our study suggests that CK2α–DBC1 pathway might be a new therapeutic target for the treatment of gastric carcinoma.

Survival Nomogram for Curatively Resected Korean Gastric Cancer Patients: Multicenter Retrospective Analysis with External Validation

Background A small number of nomograms have been previously developed to predict the individual survival of patients who undergo curative resection for gastric cancer. However, all were derived from single high-volume centers. The aim of this study was to develop and validate a nomogram for gastric cancer patients using a multicenter database. Methods We reviewed the clinicopathological and survival data of 2012 patients who underwent curative resection for gastric cancer between 2001 and 2006 at eight centers. Among these centers, six institutions were randomly assigned to the development set, and the other two centers were assigned to the validation set. Multivariate analysis using the Cox proportional hazard regression model was performed, and discrimination and calibration were evaluated by external validation. Results Multivariate analyses revealed that age, tumor size, lymphovascular invasion, depth of invasion, and metastatic lymph nodes were significant prognostic factors for overall survival. In the external validation, the concordance index was 0.831 (95% confidence interval, 0.784–0.878), and Hosmer-Lemeshow chi-square statistic was 3.92 (P = 0.917). Conclusions We developed and validated a nomogram to predict 5-year overall survival after curative resection for gastric cancer based on a multicenter database. This nomogram can be broadly applied even in general hospitals and is useful for counseling patients, and scheduling follow-up.

Tumor suppressive effect of PARP1 and FOXO3A in gastric cancers and its clinical implications.

Poly (ADP-ribose) polymerase1 (PARP1) has been reported as a possible target for chemotherapy in many cancer types. However, its action mechanisms and clinical implications for gastric cancer survival are not yet fully understood. Here, we investigated the effect of PARP1 inhibition in the growth of gastric cancer cells. PARP1 inhibition by Olaparib or PARP1 siRNA could significantly attenuate growth and colony formation of gastric cancer cells, and which were mediated through induction of G2/M cell cycle arrest but not apoptosis. FOXO3A expression was induced by PARP1 inhibition, suggesting that FOXO3A might be one of downstream target of the PARP1 effect on gastric cancer cell growth. In addition, by performing tissue microarrays on the 166 cases of gastric cancer patients, we could observe that the expression status of PARP1 and FOXO3A were significantly associated with overall survival (OS) and relapse-free survival (RFS). Strikingly, combined expression status of PARP1 and FOXO3A showed better prediction for patients clinical outcomes. The patient group with PARP1+/FOXO3A− expression had the worst prognosis while the patient group with PARP1−/FOXO3A+ had the most favorable prognosis (OS: P = 6.0 × 10−9, RFS: P = 2.2 × 10−8). In conclusion, we suggest that PARP1 and FOXO3A play critical roles in gastric cancer progression, and might have therapeutic and/or diagnostic potential in clinic.

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.

Heterotopic pancreas in the stomach diagnosed by endoscopic ultrasound-guided fine needle aspiration cytology

and metastatic tumors. Sarcomas comprise only 0.1% of the total. LMS at this site may be pulmonary, mediastinal or intravascular in location. Even though LMS is the most common primary sarcoma of the lung, its occurrence at this site is quite rare. On the other hand, the lung is the favoured site for metastasis from LMS, with as much as 21% of visceral tumours eventually developing lung metastasis. Most of these are high grade lesions on histology; however, as studied by Kelvin et al., up to 17% may appear cytologically bland. The criteria for benignity is a controversial topic in smooth muscle tumours, especially for certain sites such as the pelvis and retroperitoneum. Although retroperitoneal benign leiomyomas are a well-known occurrence in females; in males, they have not been well described. Kilpatrick et al. have shown that even in the absence of cytological atypia, a single mitosis in 50 high power fields is sufficient to label a smooth muscle tumour in the retroperitoneum as malignant. A subset of these tumours in females have been referred to as benign metastasizing leiomyomas . However, due to the scarcity of reports in the literature, the frequency and behaviour of such lesions in males are not well characterized. Delayed metastasis similar to the present case has been reported in LMS previously, with a tumour to metastasis interval of more than 23 years. This case highlights the importance of thorough evaluation, cautious interpretation and careful follow-up of retroperitoneal smooth muscle tumours. Moreover, the importance of history taking and thorough examination of the patient while performing FNAC cannot be overemphasized. The present case is unique not only because it brings out a rare cause of SVC syndrome, but also because it changes the whole perspective of looking at smooth muscle tumours.

Correlation between lymph node count and survival and a reappraisal of lymph node ratio as a predictor of survival in gastric cancer: A multi-institutional cohort study.

PURPOSE The purpose of this study is to evaluate the correlation between lymph node count (LNC) and survival and to evaluate whether lymph node ratio (LNR) which is related to LNC is a better predictor of survival for gastric cancer than the N category of UICC/AJCC through a multi-institutional cohort study. METHODS The study cohort included 3284 patients from eight institutions. Lower and upper quartiles of LNC were used for comparisons. The cut-off values (0, 0.06, 0.27, and 0.49) for the LNR categories were based on Classification and Regression Trees techniques. Akaike information criteria (AIC) for Cox regression models was used to evaluate goodness of fit between competing predictor variables (LNR vs. N category). RESULTS The 5-year disease-specific survival (DSS) rates of lower and upper quartiles of LNC were 82.2% and 84.8%. In the subgroup analysis of pN category, the upper quartile of LNC showed better survival than the lower quartile in pN2, pN3a, and pN3b subgroups. Regarding LNR, 5-year DSS of LNR 0, 0-0.06, 0.06-0.27, 0.27-0.49, and >0.49 was 95.3%, 88.7%, 70.6%, 42.7%, and 17.2% respectively. Multivariate analysis showed that pT, pN, LNR, residual tumor status, distant metastasis, and tumor differentiation significantly affected survival. The analysis also confirmed superiority of LNR compared with N category in the AIC analysis. CONCLUSION Higher LNC correlated with better survival in patients with pN2, pN3a, and pN3b gastric cancer. Our data indicate that LNR is a better predictor of survival than N category of UICC/AJCC.