Cho Hyun Park

Comparison of gastric cancer survival following R0 resection in the United States and Korea using an internationally validated nomogram.

Objective:To compare disease-specific survival (DSS) between the US and Korea following R0 resection for gastric carcinoma (GC). Summary Background Data:Many studies have described decreased 5-year survival after curative gastrectomy for GC in the West compared with the East. Although clinicopathological presentations of GC are known to vary widely between Eastern and Western countries, including histology, tumor location, and stage at presentation, it remains unclear whether these factors account for differences in survival. Methods:All patients undergoing curative intent resections (R0) for GC (1995–2005) were evaluated in 2 independent, single-institution prospectively maintained databases from the US (711 patients) and Korea (1646 patients). Patients receiving neoadjuvant chemotherapy were excluded from this analysis. Patient, surgical and pathologic variables were compared. DSS was determined via multivariate analysis using prognostic variables from an internationally validated GC nomogram that estimates the probability of 5- and 9-year survival. Results:Age and body mass index were significantly higher in US patients. Location of tumors was more often proximal in the United States (39% vs. 9%, P < 0.0001) and distal in Korea (54% vs. 33%, P < 0.0001). Korean patients had more early stage tumors (42% vs. 28% stage Ia, P < 0.0001) with a higher number of lymph nodes identified (97% vs. 79%, ≥15 lymph nodes, P < 0.0001). The 5-year DSS was higher in Korea than in the United States. After multivariate analysis, applying factors used in the nomogram, DSS of Korean GC patients remained significantly better than that of US patients (HR = 1.3, 95% CI; 1.0–1.6, P = 0.008). Conclusions:This study demonstrates better survival for GC patients in Korea compared with the US as determined by multivariate analysis with a validated gastric cancer nomogram. Multiple possibilities can explain this difference.

Somatic Mutations of ERBB2 Kinase Domain in Gastric, Colorectal, and Breast Carcinomas

Purpose: Recent reports revealed that the kinase domain of the ERBB2 gene is somatically mutated in lung adenocarcinoma, suggesting the mutated ERBB2 gene as an oncogene in human cancers. However, because previous reports focused the mutational search of ERBB2 primarily on lung cancers, the data on ERBB2 mutations in other types of human cancers have been largely unknown. Experimental Design: Here, we did a mutational analysis of the ERBB2 kinase domain by PCR single-strand conformational polymorphism assay in gastric, colorectal, and breast carcinoma tissues. Results: We detected the ERBB2 kinase domain mutations in 9 of 180 gastric carcinomas (5.0%), in 3 of 104 colorectal carcinomas (2.9%), and in 4 of 94 breast carcinomas (4.3%). All of the detected ERBB2 mutations except for one in-frame deletion mutation were missense mutations. Of the 16 ERBB2 mutations detected, 4 affected Val777 in the exon 20 site, and 3 affected Leu755 in the exon 19 site. We simultaneously analyzed the somatic mutations of EGFR, K-RAS, PIK3CA, and BRAF genes in the 16 samples with ERBB2 mutations, and found that all of the 3 colorectal carcinoma samples with ERBB2 mutations harbored K-RAS mutations. Conclusion: This study showed that in addition to lung adenocarcinomas, ERBB2 kinase domain mutation occurs in other common human cancers such as gastric, breast, and colorectal cancers, and suggested that alterations of ERBB2-mediated signaling pathway by ERBB2 mutations alone or together with K-RAS mutations may contribute to the development of human cancers.

Expression of Viral MicroRNAs in Epstein-Barr Virus-Associated Gastric Carcinoma

ABSTRACT Epstein-Barr virus (EBV) is associated with about 6 to 16% of gastric carcinoma cases worldwide. Expression of the EBV microRNAs (miRNAs) was observed in B cells and nasopharyngeal carcinoma cells infected with EBV. However, it is not clear if the EBV miRNAs are expressed in EBV-associated gastric carcinomas (EBVaGCs). We found that BART miRNAs but not BHRF1 miRNAs were expressed in EBV-infected gastric carcinoma cell lines and the tumor tissues from patients as well as the animal model. The expression of viral miRNAs in EBVaGCs suggests that these EBV miRNAs may play important roles in the tumorigenesis of EBVaGCs.

Inactivating mutations of the caspase-10 gene in gastric cancer.

We have analysed the genetic alteration of the entire coding region and all splice sites of caspase-8 and -10 genes in 99 gastric cancers by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) and sequencing. We found LOH of the caspase-8 and -10 in nine (28%) of 32 and in four (15%) of 26 informative cases, respectively. Overall, three of 99 gastric cancers (3%) were found to have the caspase-10 mutations, which were identified in the coding regions of the death effector domain (codon 147) and the p17 large protease domain (codons 257 and 410), whereas no mutation was detected in caspase-8. In vitro expression studies, the M147T and Q257stop mutants severely impaired caspase-10-mediated apoptosis, whereas the V410I which was the same mutation detected in ALPS patient had a significant, albeit less severe, effect on apoptosis. The data presented here suggest that somatic alterations of the caspase-10 gene might contribute to the pathogenesis in a subset of gastric cancers through the loss of their apoptotic function.

Genetic alterations of the KLF6 gene in gastric cancer

The KLF6 is a zinc-finger tumor suppressor that is frequently mutated in several human cancers and broadly involved in differentiation and development, growth-related signal transduction, cell proliferation, apoptosis, and angiogenesis. To determine whether genetic alterations of KLF6 gene are involved in the development and/or progression of gastric cancer, we have screened a set of 80 sporadic gastric cancers for mutations and allele loss of the KLF6 gene. Four missense mutations, S155R, P172 T, S180L, and R198 K, were detected in transactivation domain of the KLF6 gene and one of them had biallelic mutations with somatic mutation of one allele and loss of the remaining allele. All of the cases with mutation were of advanced intestinal-type gastric cancer with lymph node metastasis. In addition, 16 (43.2%) of 37 informative cases showed allelic loss at KLF6 locus. Interestingly, allelic loss was also frequent in intestinal-type gastric cancer. Therefore, our data suggest that genetic alterations of KLF6 gene might play an important role in the development or progression of sporadic gastric cancers.

Effect of early oral feeding after gastric cancer surgery: a result of randomized clinical trial.

BACKGROUND To date, early oral feeding after gastrectomy for gastric cancer has not been accepted universally. Therefore, we performed a randomized clinical trial to determine whether early oral feeding after curative surgery for gastric cancer can be tolerated and whether it has an effect on recovery. METHODS From July 2008 to February 2009, 58 patients were enrolled and 4 were excluded according to set criteria. The patients in the early feeding group began a liquid diet on the second postoperative day, and then were fed a soft diet from the third day until the day they were discharged. The patients in the control group began a liquid diet on the fourth day. The primary endpoint of this study was the duration of postoperative hospitalization. RESULTS No significant differences were found in the clinico-operative characteristics between the 2 groups. The duration of hospitalization (P = .044) and time until flatus (P = .036) in the early group were decreased significantly. With regard to the rates of morbidity, cost of hospitalization, postoperative symptoms, and pain scales, no significant differences were found. The quality of life scores were decreased significantly at the fatigue (P = .007) and nausea and vomiting (P = .048) immediately after operation in the early feeding group. CONCLUSION Early oral feeding after gastric cancer surgery is feasible and can result in shorter hospitalization and improvements in several aspects of quality of life in the early postoperative period.

Validation of the seventh edition of the American Joint Committee on Cancer TNM staging system for gastric cancer.

The seventh edition of the American Joint Committee on Cancer (AJCC) TNM classification for gastric cancer was published in 2010 and included major revisions. The aim of the current study was to evaluate the validity of the seventh edition TNM classification for gastric cancer based on an Asian population.

Overexpression of S100A4 is closely related to the aggressiveness of gastric cancer

Elevated levels of the calcium‐binding protein S100A4 cause metastasis of benign rat mammary tumor cells. To investigate whether S100A4 plays an important role in the invasion and metastasis of gastric cancers, we examined the gene mutations in the coding regions and expression patterns of the S100A4 in gastric adenocarcinoma in Korea. Moderate to strong expression of S100A4 was found in 53 (68.8%) of the 77 gastric adenocarcinomas, whilst normal gastric epithelium either failed to stain or showed weak staining. Interestingly, S100A4 expression was more frequently observed in gastric cancer patients with advanced gastric cancer (p=0.039), positive lymph node metastasis (p=0.001), and peritoneal dissemination (p=0.022). No gene mutations were found in the analyzed genomic area in 77 gastric adenocarcinomas and 15 gastric cancer cell lines. We found one single nucleotide polymorphism without an amino acid change, A99G, in two cases. These data suggest that the overexpression of S100A4 may be closely related to the aggressiveness of gastric cancer in Korea.

Immunohistochemical analysis of Smac/DIABLO expression in human carcinomas and sarcomas†

Second mitochondria‐derived activator of caspases (Smac/DIABLO) is released from mitochondria into the cytosol during apoptosis, promoting caspase activation by neutralizing the inhibition of inhibitor of apoptosis proteins (IAPs) on caspases. Alteration of apoptosis is essential for cancer development, and cancer cell death by radiation and chemotherapy is largely dependent upon apoptosis. In this study, archival tissues of 100 carcinomas and 50 sarcomas from various origins were analyzed by immunohistochemistry for the expression of Smac/DIABLO. Smac/DIABLO immunoreactivity was seen in 62 of 100 (62%) carcinomas, including 42 of 60 stomach carcinomas, 7 of 10 colorectal carcinomas, 4 of 10 lung carcinomas, 7 of 10 ovarian carcinomas, and 2 of 10 prostate carcinomas. Smac/DIABLO is expressed in 11 of 50 (22%) sarcomas, including 2 of 8 malignant schwannomas, 5 of 11 rhabdomyosarcomas, 2 of 7 malignant fibrous histiocytomas, 1 of 6 leiomyosarcomas, 0 of 8 angiosarcomas, 0 of 8 liposarcomas, and 1 of 2 Ewings sarcomas. These data demonstrated that Smac/DIABLO expression levels vary depending on the individual cancer types. Furthermore, the present study showed that many human cancers do not express Smac/DIABLO, and suggest that lack of Smac/DIABLO expression in the cancer cells may inhibit apoptosis, thereby promoting their survival.

Negative impact of leakage on survival of patients undergoing curative resection for advanced gastric cancer.

Leakage has been shown to adversely affect survival in patients undergoing surgery for gastrointestinal malignancies. However, the effect of leakage following radical gastrectomy in patients with gastric cancer remains unclear.