Byung-Sik Kim

Randomized clinical trial of D2 and extended paraaortic lymphadenectomy in patients with gastric cancer.

BackgroundThe survival of patients with advanced gastric cancer after D2 dissection is still poor. Asian surgeons have proposed a more radical lymph node dissection, designated as D4 dissection, where paraaortic lymph nodes are removed in combination with D2 dissection. To evaluate the survival benefit of D4 dissection, a multi-institutional randomized trial of D2 vs D4 gastrectomy was conducted.MethodsPatients enrolled in the study had potentially curable gastric adenocarcinoma at an advanced stage. Patients were randomized to undergo either D2 or D4 gastrectomy.ResultsTwo hundred and ninety-three patients were registered and 269 patients were eligible; 135 patients were allocated to the D2 group and 134 to the D4 group. Five-year survival was 52.6% after D2 surgery and 55.0% after D4 gastrectomy. There was no significant difference in survival between the D2 and D4 groups (χ2 = 0.064; P = 0.801). Hospital deaths occurred in 1 patients (0.7%) in the D2 group and 5 in the D4 group D4 gastrectomy is a more risky surgery than D2 dissection. Seven patients (5.2%) in the D2 and 15 (11.2%) in the D4 group died of causes other than gastric cancer recurrence. Sixty-three patients (46.7%) in the D2 group and 52 (38.8%) in the D4 group had disease recurrence.ConclusionProphylactic D4 dissection is not recommended for patients with potentially curable advanced gastric cancer.

Clinical Validation of Colorectal Cancer Biomarkers Identified from Bioinformatics Analysis of Public Expression Data

Purpose: Identification of novel biomarkers of cancer is important for improved diagnosis, prognosis, and therapeutic intervention. This study aimed to identify marker genes of colorectal cancer (CRC) by combining bioinformatics analysis of gene expression data and validation experiments using patient samples and to examine the potential connection between validated markers and the established oncogenes such as c-Myc and K-ras. Experimental Design: Publicly available data from GenBank and Oncomine were meta-analyzed leading to 34 candidate marker genes of CRC. Multiple case-matched normal and tumor tissues were examined by RT-PCR for differential expression, and 9 genes were validated as CRC biomarkers. Statistical analyses for correlation with major clinical parameters were carried out, and RNA interference was used to examine connection with major oncogenes. Results: We show with high confidence that 9 (ECT2, ETV4, DDX21, RAN, S100A11, RPS4X, HSPD1, CKS2, and C9orf140) of the 34 candidate genes are expressed at significantly elevated levels in CRC tissues compared to normal tissues. Furthermore, high-level expression of RPS4X was associated with nonmucinous cancer cell type and that of ECT2 with lack of lymphatic invasion while upregulation of CKS2 was correlated with early tumor stage and lack of family history of CRC. We also demonstrate that RPS4X and DDX21 are regulatory targets of c-Myc and ETV4 is downstream to K-ras signaling. Conclusions: We have identified multiple novel biomarkers of CRC. Further analyses of their function and connection to signaling pathways may reveal potential value of these biomarkers in diagnosis, prognosis, and treatment of CRC. Clin Cancer Res; 17(4); 700–9. ©2011 AACR.

TBXA2R gene polymorphism and responsiveness to leukotriene receptor antagonist in children with asthma

Background Thromboxane A2 receptor (TBXA2R) gene polymorphism has been associated with atopy and asthma, but few studies have reported the effect of this gene polymorphism on asthma‐related phenotype or responsiveness to leukotriene receptor antagonist (LTRA) in asthmatic children. This study investigated associations between asthma‐related phenotypes and TBXA2R polymorphism, and also analysed whether the TBXA2R polymorphism has an effect on the efficacy of the LTRA, montelukast, in asthmatic children with exercise‐induced bronchoconstriction (EIB).

TC1(C8orf4) Correlates with Wnt/β-Catenin Target Genes and Aggressive Biological Behavior in Gastric Cancer

Purpose: We have recently reported that TC1(C8orf4), a small protein present in vertebrates, functions as a novel regulator of the Wnt/β-catenin pathway. TC1 up-regulates β-catenin target genes that are implicated in the aggressive behavior of cancers. Our aim was to investigate the clinical and pathobiological relevance of TC1 in gastric cancer. Experimental Design: The expression of TC1 was analyzed using tissue microarray in correlation with clinicopathologic variables and β-catenin target genes in 299 gastric cancers. The biological effects of TC1 on Matrigel invasiveness and the proliferation of cancer cells were analyzed. TC1 expression was analyzed in gastric cancer cells after serial peritoneal implantation in nude mice. Results: TC1 expression was present in 111 carcinomas (37.1%), correlating with tumor stage (P < 0.002), poor differentiation (P < 0.001), lymphatic infiltration (P < 0.005), and lymph node metastasis (P < 0.006). TC1 also correlated with poor survival in diffuse type carcinomas (P < 0.0001), and even in patients with lymph node metastasis (P < 0.0014). TC1 also correlated with the expression of β-catenin target genes including laminin γ2, metalloproteinase-7 and metalloproteinase-14, cyclin D1, c-Met, and CD44. TC1 enhanced Matrigel invasiveness and proliferation, supporting its role in the aggressive biological behavior of cancers. The expression of TC1 increased in MKN45 cells after serial peritoneal seeding in nude mice. Conclusions: Our data suggests that TC1 coordinates the up-regulation of Wnt/β-catenin target genes that are implicated in the aggressive biological behavior of cancers. The strong clinical relevance, even in patients with lymph node metastasis, suggested that TC1 could be a potential therapeutic target of advanced gastric cancers.

Diagnostic value of preoperative RT-PCR-based screening method to detect carcinoembryonic antigen-expressing free cancer cells in the peritoneal cavity from patients with gastric cancer

Background: At present the most reliable method for the diagnosis of peritoneal micrometastasis of gastric cancer is peritoneal wash cytology, but the sensitivity of this method is low. The aim of the present study was to verify whether carcinoembryonic antigen (CEA) reverse transcriptase–polymerase chain reaction (RT‐PCR) assay can enhance the sensitivity and specificity of conventional cytology, and to determine how this technique can improve the accuracy of peritoneal recurrence.

Rapid oral desensitization to isoniazid, rifampin, and ethambutol

absence of reaction to normal saline. SPT and ID test for ibuprofen were negative after 20 min, but after 36 h, infiltrated erythema appeared at the site of the ID test (maximum diameter: 14 mm). SPT and ID test for ibuprofen and the immediate and delayed patch tests for ibuprofen, naproxen and ketoprofen were also performed on a control group of 10 people with a negative history of adverse reactions to drugs and their results were negative. Finally, oral tolerance exposure tests with naproxen and ketoprofen were performed. On the first day the patient received two placebo capsules, one every hour; after 7 days, divided doses of naproxen (125 mg initially and 375 mg 1 h later) and ketoprofen (50 mg initially and 150 mg 1 h later) were administered with negative results. NSAIDs can elicit nonallergic hypersensitivity depending on the potency of the COX inhibition. Other reactions suggest immediate-type hypersensitivity, mediated by IgE, being reproduced in the skin, respiratory tract and cardiovascular system (3). Some cases of urticaria (4), anaphylaxis (5), and also fatal asthma (6) induced by ibuprofen have been described. Finally, NSAIDs also produce delayed-hypersensitivity reactions, like contact dermatitis, erythema multiforme, and Stevens-Johnson syndrome. In this case, clinical findings, patch and ID testing are suggestive of delayed-type hypersensitivity to ibuprofen. Our patient, presensitized by topical application, developed an exanthematous eruption of eczematous and urticarioid type, to oral ibuprofen, which has not been described in the literature, to our knowledge. Both patch and ID tests are useful in evaluating this delayed reaction and the drug challenge test can be avoided. This drug-induced eruption may be with hardly distinguished from viral exanthema and, in order to verify this patient’s probable viral diseases, viral serologies were carried out with negative results. Further investigations were carried out to differentiate this adverse drug reactions which are generally benign from a severe form of adverse reaction termed hypersensitivity syndrome (7) that includes a similar rash and fever, often with hepatitis, arthralgia, lymphadenopathy, and eosinophilia. Valsecchi and Cainelli showed that cross-reactivity between some chemically related NSAIDs was possible (8). Then, it was evaluated if this patient was also sensitized to naproxen and ketoprofen. Patch testing proved useful to rule out such cross-sensitivity and naproxen and ketoprofen tolerances were also reported. This estimation is important in that, persons with adverse reactions to ibuprofen can safely take other NSAIDs, although additional cases should have to be evaluated.

Quality of life, immunomodulation and safety of adjuvant mistletoe treatment in patients with gastric carcinoma – a randomized, controlled pilot study

BackgroundMistletoe (Viscum album L.) extracts are widely used in complementary cancer therapy. Aim of this study was to evaluate safety and efficacy of a standardized mistletoe extract (abnobaVISCUM® Quercus, aVQ) in patients with gastric cancer.Patients and Methods32 operated gastric cancer patients (stage Ib or II) who were waiting for oral chemotherapy with the 5-FU prodrug doxifluridine were randomized 1:1 to receive additional therapy with aVQ or no additional therapy. aVQ was injected subcutaneously three times per week from postoperative day 7 to week 24 in increasing doses. EORTC QLQ-C30 and -STO22 Quality of Life questionnaire, differential blood count, liver function tests, various cytokine levels (tumor necrosis factor (TNF)-alpha, interleukin (IL)-2), CD 16+/CD56+ and CD 19+ lymphocytes were analyzed at baseline and 8, 16 and 24 weeks later.ResultsGlobal health status (p <0.01), leukocyte- and eosinophil counts (p ≤0.01) increased significantly in the treatment group compared to the control group. Diarrhea was less frequently reported (7% vs. 50%, p=0.014) in the intervention group. There was no significant treatment effect on levels of TNF-alpha, IL-2, CD16+/CD56+ and CD 19+ lymphocytes and liver function tests measured by ANOVA.ConclusionAdditional treatment with aVQ is safe and was associated with improved QoL of gastric cancer patients. ClinicalTrials.Gov Registration number NCT01401075.

Responsiveness to montelukast is associated with bronchial hyperresponsiveness and total immunoglobulin E but not polymorphisms in the leukotriene C4 synthase and cysteinyl leukotriene receptor 1 genes in Korean children with exercise-induced asthma (EIA)

Background As previous studies have shown that cysteinyl leukotrienes are important mediators in exercise‐induced bronchoconstriction (EIB), and leukotriene receptor antagonists (LTRAs) such as montelukast have been shown to improve post‐exercise bronchoconstrictor responses, we herein investigated whether clinical responsiveness to montelukast was associated with polymorphisms in the genes encoding leukotriene C4 synthase (LTC4S) and cysteinyl leukotriene receptor 1 (CysLTR1) and/or clinical parameters in Korean asthmatic children with EIB.

Differing Clinical Courses and Prognoses in Patients With Gastric Neuroendocrine Tumors Based on the 2010-WHO Classification Scheme

AbstractThe aim of this study is to test the prognostic accuracy of the 2010-WHO classification for postsurgery survival in nonmetastatic gastric neuroendocrine tumor (NET) cases. Whether the 2010-WHO classification of NETs can predict relapse after surgical resection has not yet been established.We selected 175 nonmetastatic gastric NET patients at Asan Medical Center, Seoul, Korea between 1996 and 2013. All tumors were classified using the WHO-2010 scheme.Among 175 patients with gastric NETs, we diagnosed 39 cases as WHO grade 1, 13 cases as grade 2, 66 cases as grade 3 (neuroendocrine carcinomas; NECs), and 57 cases as mixed with adenocarcinoma. Patients with grade 3 had a lower relapse-free survival (RFS) and overall survival (OS) than those with WHO grade 1/2 and had a lower OS than patients with mixed type tumors. Patients with grade 1/2 had a better OS than patients with mixed type. There was no significant difference in RFS and OS between small and large cell type lesions. Among WHO grade 1/2 patients with ⩽1 cm sized lesions, none exhibited lympho-vascular, perineural, mucosal, or submucosal invasion, and we detected no lymph node metastases or recurrences.Our findings strongly suggest that WHO grade 3 behaves more aggressively than adenocarcinoma. Additionally, the survival of cases with large and small cell NEC was similar. Among WHO grade 1/2 patients who had ⩽1 cm lesions, none exhibited lympho-vascular, perineural, mucosal, or submucosal invasion and all could be treated by endoscopic resection or minimally invasive surgery without node dissection.

Modified Techniques and Early Outcomes of Totally Laparoscopic Total Gastrectomy with Side-to-Side Esophagojejunostomy.

BACKGROUND Construction of an esophagojejunostomy is a major concern in totally laparoscopic total gastrectomy (TLTG). Use of a circular stapler can be technically challenging in laparoscopic procedures. We aimed to introduce our modified techniques and to assess the early outcomes following TLTG with side-to-side esophagojejunostomy using a linear stapler in patients with gastric cancer. SUBJECTS AND METHODS From December 2010 to June 2011, 27 patients who underwent TLTG for gastric cancer were retrospectively reviewed. Their clinicopathologic characteristics, surgical time, hospital stay, morbidity, and mortality were analyzed. RESULTS The mean age of patients was 59.1 years, and the average body mass index was 24.6 kg/m(2). The mean operating time was 126.2 minutes, and the hospital stay averaged 8.1 days. No conversion to open laparotomy was required. There were 2 luminal bleeding cases and 1 intra-abdominal bleeding case, but all were successfully managed with conservative treatment only. No patient experienced reoperation, anastomosis leakage, stricture, duodenal stump leakage, or wound problems. CONCLUSIONS Our TLTG with side-to-side esophagojejunostomy method can be a feasible and safe option for patients with gastric cancer.