Yun-k Suh

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.

Should adenocarcinoma of the esophagogastric junction be classified as esophageal cancer? A comparative analysis according to the seventh AJCC TNM classification.

Objective:The aim of this study was to evaluate the adequacy of esophageal classification for adenocarcinoma of the esophagogastric junction (AEJ) of the seventh American Joint Committee on Cancer (AJCC) TNM classification. Background:The seventh AJCC TNM classification proposed the new classification for AEJ as a part of esophageal cancer depending on the esophagogastric junction (EGJ) involvement. However, there are still many controversies over the classification system for AEJ. Methods:A review of pathologic reports and photographic findings at Seoul National University Hospital from 2003 to 2009 identified 4524 patients with single, primary adenocarcinoma of the EGJ (n = 497) and other regions of the stomach (GC, n = 4027) who underwent an operation with curative intent. We analyzed the clinicopathologic features and postoperative prognosis of AEJ using the Siewert classification and the seventh AJCC TNM classification. Results:There was no Siewert type I (AEJ I) in this study. The prognosis of AEJ was similar to that of GC. There was no difference in clinicopathologic features between AEJ II and AEJ III. Even though AEJ extending into the EGJ (AEJe) showed more advanced pathologic features than AEJ not extending into the EGJ (AEJg), the prognosis of AEJe and AEJg was not significantly different when stratified by T stage. Compared with the classification of gastric cancer applied for AEJ, esophageal classification for AEJ from the seventh AJCC TNM classification showed a loss of distinctiveness at each TNM stage. Conclusions:To evaluate the postoperative prognosis of AEJ within the stomach, AEJ II and AEJ III should be considered a part of gastric cancer irrespective of EGJ involvement.

Laparoscopy-assisted pylorus-preserving gastrectomy is better than laparoscopy-assisted distal gastrectomy for middle-third early gastric cancer.

Objective:The purpose of this study is to compare the surgical, oncologic safety and the nutritional, functional benefit of laparoscopy-assisted pylorus-preserving gastrectomy (LAPPG) with laparoscopy-assisted distal gastrectomy (LADG) for middle-third early gastric cancers (EGC). Background:Of those patients with middle-third EGC, it is still difficult to determine which procedure is better between LADG and LAPPG despite alleged advantages of LAPPG. Methods:For middle-third EGC, a retrospective analysis was performed comparing those who underwent LADG and those who underwent LAPPG. To evaluate surgical and oncologic safety, clinicopathologic differences including the postoperative morbidity, the pattern of lymph node metastasis and recurrence were analyzed. Postoperative protein, albumin, quantification of abdominal fat area using abdomen computed tomography, and the incidence of postoperative gallstone were compared for the evaluation of functional advantages. Results:The overall postoperative morbidity rate was similar between LADG (n = 176) and LAPPG (n = 116). Delayed gastric emptying was less frequent in LADG than in LAPPG (1.7% vs 7.8%); however, the rates of all the other complications were significantly higher in LADG than in LAPPG (17.0% vs 7.8%). The number of examined lymph nodes and metastatic lymph nodes at each lymph node station was not significantly different and 3-year recurrence-free survival rates were also similar between LADG and LAPPG (98.8% vs 98.2%). Decreases in serum protein and albumin in postoperative 1 to 6 months and abdominal fat area in postoperative 1 year were significantly greater in LADG than in LAPPG. The 3-year cumulative incidence of gallstone was significantly higher in LADG than in LAPPG (6.5% vs 0.0%). Conclusions:For middle-third EGC, LAPPG can be considered as a better treatment option than LADG in terms of nutritional advantage and lower incidence of gallstone.

The Combined Expression of Metaplasia Biomarkers Predicts the Prognosis Of Gastric Cancer

BackgroundOur previous study indicated that gene expression profiling of intestinal metaplasia (IM) or spasmolytic polypeptide-expressing metaplasia (SPEM) can identify useful prognostic markers of early-stage gastric cancer, and seven metaplasia biomarkers (MUC13, CDH17, OLFM4, KRT20, LGALS4, MUC5AC, and REG4) were selectively expressed in 17–50% of gastric cancer tissues. We investigated whether the combined expression of these metaplasia biomarkers could predict the prognosis of advanced stage gastric cancer.MethodsThe expression of seven metaplasia biomarkers was evaluated immunohistochemically using tissue microarrays comprised of 450 gastric cancer patients. The clinicopathologic correlations and the prognostic impact were analyzed according to the expression of multiple biomarkers.ResultsMUC13, CDH17, LGALS4, and REG4 were significant prognostic biomarkers in univariate analysis. No expression of four markers was found in 56 cases (14.2%); 1 marker was seen in 67 cases (17%), 2 in 106 cases (27%), 3 in 101 cases (25.7%), and 4 in 63 cases (16%). Patients in which two or fewer proteins were expressed (group B) showed younger age, undifferentiated or diffuse type cancer, larger tumor size, larger number of metastatic lymph nodes, and more advanced stage than those in which three or more proteins were expressed (group A). In undifferentiated or stage II/III gastric cancer, the prognosis of group B was significantly poorer than that of group A by multivariate analysis.ConclusionsThe combined loss of expression of multiple metaplasia biomarkers is considered an independent prognostic indicator in undifferentiated or stage II/III gastric cancer.

Laparoscopy-assisted distal gastrectomy compared to open distal gastrectomy in early gastric cancer.

Background: This study aimed to evaluate the feasibility of laparoscopy-assisted distal gastrectomy (LADG) in early gastric cancer (EGC) with special interest in a learning curve effect. Methods: The clinical outcomes of EGC patients who underwent LADG (n = 100) and sex-, age- and body mass index- (BMI) matched EGC patients who underwent open distal gastrectomy (ODG; n = 100) were compared retrospectively. In addition, the outcomes between the early (n = 50) and late LADG group (n = 50) were compared. Results: The mean number of retrieved lymph nodes was significantly smaller in the LADG group than in the ODG group (29.3 vs. 36.4, p < 0.001). The operative time of the LADG group was significantly longer than in the ODG group (249.1 vs. 152.9 min, p < 0.001). The complication rates were comparable between both groups (14 vs. 13%, p = 0.84). No cancer-related death was observed in either group. Between early and late LADG groups, the operative time was shorter (p < 0.001) and the number of retrieved lymph nodes was higher (p = 0.016) in the late group. Conclusions: LADG seems to be a safe and feasible procedure in treating EGC, as it shows comparable outcomes with ODG. The potential disadvantages of LADG, such as longer operation time and smaller number of retrieved lymph nodes, diminished after overcoming the learning curve.

Outcomes of surgery aiming at curative resection in good responder to induction chemotherapy for gastric cancer with distant metastases.

The aim of this study is to analyze the outcome of surgery with curative intent in good responder to induction chemotherapy for gastric cancer with distant metastases (M1 gastric cancer).

Screening and Early Detection of Gastric Cancer:East Versus West

Low ratio of mortality over incidence of gastric cancer in Asian countries including Korea and Japan could be explained by early detection after screening, different treatment strategy, or genetic disparity between the East and West. Early detection after screening program for gastric cancer and subsequent surgical treatment including appropriate lymph node dissection has been developed successfully in high risk areas such as East Asian countries. Even in countries with a low prevalence of gastric cancer, a specific screening program is recommended for any high-risk population.

Genomic alterations in BCL2L1 and DLC1 contribute to drug sensitivity in gastric cancer

Significance Gastric cancer (GC) is one of the major causes of cancer-related deaths worldwide, but targeted therapy for GC is limited. Here, we identified two druggable targets from genomic alteration profiling of 103 patients with GC from Asia and validated the target suitability using patient-derived GC xenograft models, which recapitulate the tumor biology observed in patients. Combination therapy of irinotecan (standard treatment) with a BCL2L1 (BCL2-like 1)-targeted drug was effective in size reduction of GC tumors having amplification of the BCL2L1 gene, and genomic mutations of deleted in liver cancer 1 (DLC1) were associated with increased sensitivity to a ROCK inhibitor. Therefore, our study strongly suggests that BCL2L1 and DLC1 can serve as targets for novel GC therapies. Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide. Recent high-throughput analyses of genomic alterations revealed several driver genes and altered pathways in GC. However, therapeutic applications from genomic data are limited, largely as a result of the lack of druggable molecular targets and preclinical models for drug selection. To identify new therapeutic targets for GC, we performed array comparative genomic hybridization (aCGH) of DNA from 103 patients with GC for copy number alteration (CNA) analysis, and whole-exome sequencing from 55 GCs from the same patients for mutation profiling. Pathway analysis showed recurrent alterations in the Wnt signaling [APC, CTNNB1, and DLC1 (deleted in liver cancer 1)], ErbB signaling (ERBB2, PIK3CA, and KRAS), and p53 signaling/apoptosis [TP53 and BCL2L1 (BCL2-like 1)] pathways. In 18.4% of GC cases (19/103), amplification of the antiapoptotic gene BCL2L1 was observed, and subsequently a BCL2L1 inhibitor was shown to markedly decrease cell viability in BCL2L1-amplified cell lines and in similarly altered patient-derived GC xenografts, especially when combined with other chemotherapeutic agents. In 10.9% of cases (6/55), mutations in DLC1 were found and were also shown to confer a growth advantage for these cells via activation of Rho-ROCK signaling, rendering these cells more susceptible to a ROCK inhibitor. Taken together, our study implicates BCL2L1 and DLC1 as potential druggable targets for specific subsets of GC cases.

Overexpression of Plasminogen Activator Inhibitor-1 in Advanced Gastric Cancer with Aggressive Lymph Node Metastasis

Purpose The purpose of this study is to investigate differentially expressed genes using DNA microarray between advanced gastric cancer (AGC) with aggressive lymph node (LN) metastasis and that with a more advanced tumor stage but without LN metastasis. Materials and Methods Five sample pairs of gastric cancer tissue and normal gastric mucosa were taken from three patients with T3N3 stage (highN) and two with T4N0 stage (lowN). Data from triplicate DNA microarray experiments were analyzed, and candidate genes were identified using a volcano plot that showed ≥ 2-fold differential expression and were significant by Welchs t test (p < 0.05) between highN and lowN. Those selected genes were validated independently by reverse-transcriptase–polymerase chain reaction (RT-PCR) using five AGC patients, and tissue-microarray (TMA) comprising 47 AGC patients. Results CFTR, LAMC2, SERPINE2, F2R, MMP7, FN1, TIMP1, plasminogen activator inhibitor-1 (PAI-1), ITGB8, SDS, and TMPRSS4 were commonly up-regulated over 2-fold in highN. REG3A, CD24, ITLN1, and WBP5 were commonly down-regulated over 2-fold in lowN. Among these genes, overexpression of PAI-1 was validated by RT-PCR, and TMA showed 16.7% (7/42) PAI-1 expression in T3N3, but none (0/5) in T4N0 (p=0.393). Conclusion DNA microarray analysis and validation by RT-PCR and TMA showed that overexpression of PAI-1 is related to aggressive LN metastasis in AGC.

Molecular evidence for the taxonomic identity of Korean Adonis (Ranunculaceae)

Abstract Although Korean Adonis has been traditionally recognized as Adonis amurensis Regel and Radde with various infraspecific taxa described, its taxonomic identity is still in dispute. We investigated the genetic variation in 60 individuals from 12 populations in Korea to elucidate the taxonomic identity of the Korean Adonis complex. Random amplified polymorphic DNA (RAPD) analysis revealed that Korean Adonis comprises three species: A. amurensis, A. pseudoamurensis, and A. multiflora. Adonis amurensis is distributed in northern central inland regions of Korea and A. pseudoamurensis is found in southern parts of the Korean peninsula. Adonis multiflora grows only on Cheju Island, which is the southernmost part of Korea. Phylogenetic analysis of nuclear ribosomal internal transcribed spacer (ITS) sequences partially supported the presence of three Adonis taxa in Korea as detected by RAPD analysis. The Adonis population on Jangbong Island located in the West Sea, which was referred to as A. pseudoamurensis on the basis of morphological examination, was separated from the other populations of A. pseudoamurensis. Otherwise, the molecular evidence is well congruent with the recent morphological study that proposes that Korean Adonis consists of these three species.