Operational Definition of Liver Cancer in Studies Using Data from the National Health Insurance Service:A Systematic Review

Data from the Korean National Health Insurance Service (NHIS) have been widely used to provide real-world evidence. Due to the nature of claims data, researchers use operational definitions to define patients with specific diseases. This study aimed to conduct a systematic review of the operational definitions of liver cancer used in studies based on the NHIS database and to suggest the most appropriate operational definition. Literature search was completed on January 6, 2021, using PubMed and KoreaMed.We applied the most frequently used operational definitions of liver cancer to the NHIS–National Sample Cohort and calculated age-standardized incidence rates (ASRs) of liver cancer by year. The ASRs using each operational definition were compared with the ASR from the Korea Central Cancer (KCCR) data. Among 236 articles, 90 were selected for review, covering histologically various kinds of liver cancer and varied by study subjects. Most studies (n = 79) did not mention whether the codes for the operational definition were from only the main diagnosis or from both the main and sub-diagnosis. The most frequently used operational definition was C22 (n = 39); however, the most similar operational definition was the ASR using “C22.0 or C22.9” for men and “C22.0” for women as the main diagnosis to the ASR from the KCCR. Based on the comparison with KCCR data, we suggest using “C22.0 or C22.9” for men and “C22.0” for women as the main diagnosis for the operational definition of liver cancer when using the NHIS data.

Operational Definitions of Colorectal Cancer in the Korean National Health Insurance Database / 예방의학회지

Objectives@#We reviewed the operational definitions of colorectal cancer (CRC) from studies using the Korean National Health Insurance Service (NHIS) and compared CRC incidence derived from the commonly used operational definitions in the literature with the statistics reported by the Korea Central Cancer Registry (KCCR). @*Methods@#We searched the MEDLINE and KoreaMed databases to identify studies containing operational definitions of CRC, published until January 15, 2021. All pertinent data concerning the study period, the utilized database, and the outcome variable were extracted. Within the NHIS-National Sample Cohort, age-standardized incidence rates (ASRs) of CRC were calculated for each operational definition found in the literature between 2005 and 2019. These rates were then compared with ASRs from the KCCR. @*Results@#From the 62 eligible studies, 9 operational definitions for CRC were identified. The most commonly used operational definition was “C18-C20” (n=20), followed by “C18-C20 with claim code for treatment” (n=3) and “C18-C20 with V193 (code for registered cancer patients’ payment deduction)” (n=3). The ASRs reported using these operational definitions were lower than the ASRs from KCCR, except for “C18-C20 used as the main diagnosis.” The smallest difference in ASRs was observed for “C18-C20,” followed by “C18- C20 with V193,” and “C18-C20 with claim code for hospitalization or code for treatment.” @*Conclusions@#In defining CRC patients utilizing the NHIS database, the ASR derived through the operational definition of “C18-C20 as the main diagnosis” was comparable to the ASR from the KCCR. Depending on the study hypothesis, operational definitions using treatment codes may be utilized.

Effects of Genetic Polymorphisms of Glutathione S-transferase P1 on Helicobacter pylori-associated Gastric Cancer

BACKGROUND/AIMS: Glutathione S-transferase P1 (GSTP1) scavenges radicals via its peroxidase activity. The purpose of this study was to determine the association of GSTP1 genetic polymorphisms with the expression of H. pylori-associated gastroduodenal disease. METHODS: This study involved 1,911 subjects, comprising patients with four diseases (gastric cancer, dysplasia, benign gastric ulcer, and duodenal ulcer disease) and controls. Biallelic polymorphisms were genotyped by restriction fragment length polymorphism techniques. RESULTS: The frequency of the genetic polymorphism at nucleotide 313 of GSTP1 did not differ among the five study groups. However, when the gastric cancer group was subdivided into advanced gastric cancer (AGC) and early gastric cancer, the frequency of the G/G genotype was significantly higher in the AGC group than in all the control subgroups (OR: 1.2, 95% CI: 1.1-4.9). The frequency of this genotype differed significantly in the H. pylori-positive AGC group (OR: 2.7, 95% CI: 1.1-6.3) but not in the H. pylori-negative group. Furthermore, the difference was greater in the intestinal type, and was not found in diffuse types of disease. CONCLUSIONS: This study found that genetic polymorphisms of GSTP1 were associated with H. pylori-associated gastric cancer only during the advanced stage of gastric cancer, with intestinal-type histology evident in H. pylori-positive subjects.

HO-1 Mediates Intracellular Calcium Modulation and Inhibits TNF-alpha-induced NF-kappaB Activity in Human Colonic Epithelial Cell Line / 대한해부학회지

Heme oxygenage-1 (HO-1) is the rate-limiting enzyme in heme catabolism, which leads to the generation of carbon monoxide (CO), biliverdin, and free iron. HO-1 has been known to show strong immunosuppressive properties although its mechanisms are not completely understood. In this study, it was therefore investigated anti-inflammatory properties of HO-1 in HT-29 cell, human colonic epithelial cell line. CoPPIX, HO-1 inducer, induced HO-1 expression without NF-kappa B activation and significantly blocked the I kappa B-alpha degradation by TNF-alpha in HT-29. Inhibition of HO-1 activity by ZnPPIX reversed the suppressive effects of CoPPIX on I kappa B-alpha degradation by TNF-alpha. Calcium chelating agent BAPTA/AM and calcium channel blockers, Verapamil and Flunarizine suppressed I kappa B-alpha degradation by TNF-alpha in HT-29 cells like CoPPIX while calcium ionophore A23187 also dose-dependently reversed the suppressive effects of CoPPIX on I kappa B-alpha degradation by TNF-alpha like a ZnPPIX. Interestingly, treatment of ZnPPIX increased basal intracellular calcium in HT-29 cells. Collectively, these results suggest that HO-1 exerts anti-inflammatory effects by down-regulation of NF-kappa B activity via suppression of intracellular calcium during pathogenesis of colitis in colonic epithelium.

The Effects of Heme Oxygenase-1 on Collagen Induced Arthritis Model / 대한해부학회지

Heme oxygenase-1 (HO-1), an inducible heme-degrading enzyme, is expressed by macrophages and endothelial cells in response to inflammatory stresses. It has been known to show strong immunosuppressive properties although its mechanisms are not completely understood. This study was designed to determine the effects of HO-1 modulation on collagen induced arthritis (CIA) model. CIA model was induced by subcutaneous injection of collagen on tail of DBA/1J mice. For evaluation of HO-1 effects, an inducer of HO-1, cobalt protoporphyrin IX (CoPPIX), or an inhibitor of HO-1, tin protoporphyrin IX (SnPPIX), were administered every other days into peritoneal cavity from day 1 to day 42 after CIA induction. The macrocopic clinical findings of CIA were evaluated and histo-pathologic findings and radiographic analysis were carried out. The expressions of TNF-alpha, IL-6, and VEGF which have important roles in pathogenesis of rheumatoid arthritis were observed by immuno-histochemical staining. Collagen on DBA/1J mice induced arthritis at knee joint and ankle joint. Administration of CoPPIX significantly aggravated the severity of arthritis while SnPPIX protected collagen induced arthritis. SnPPIX strongly suppressed inflammatory cell infiltration, swelling of synovial membrane, and erosion and destruction of bone on CIA mice. Furthermore subcutaneous injection of collagen also increased expression of TNF-alpha, IL-6, and VEGF which are important pro-inflammatory mediators in rheumatoid arthritis. SnPPIX suppressed expression of the pro-inflammatory mediators on CIA mice. Finally, we suggest that HO-1 mediates the expression of pro-inflammatory mediators and bone destruction during pathogenesis of CIA, which indicates modulation of HO-1 can be a new therapeutic target of rheumatoid arthritis.

Granulocyte Colony Stimulating Factor (G-CSF) Attenuates 2,4,6-Trinitrobenzene Sulfonic Acid (TNBS)-induced Colitis in Mice

BACKGROUND: Granulocyte colony stimulating factor (G-CSF) is known as a cytokine central to the hematopoiesis of blood cells and to modulate their cellular functions. Besides granulocytes and their precursors, monocytes/macrophages and endothelial cells are direct target cells of G-CSF action. G-CSF influences immune cells in an anti-inflammatory way. METHODS: To evaluate whether G-CSF has a potential for preventing or ameliorating diseases characterized by mucosal inflammation, we used a mouse model with trinitrobenzene sulfonic acid (TNBS)-induced inflammatory colitis. To the mice model G-CSF was administrated daily by intraperitoneal injection. Macroscopic evaluation and immunohistochemical analysis of colonic tissues were performed. RESULTS: Recombinant human G-CSF significantly inhibited LPS-induced TNF-alpha mRNA expression in THP-1 cells. As for in vivo relevance, G-CSF dramatically reduced the weight loss of mice, colonic damage, and mucosal ulceration that characterize TNBS colitis. Moreover, G-CSF suppressed the expression of tumor necrosis factor-alpha, interleukin-1beta, and intercellular adhesion molecule-1 in TNBS colitis. CONCLUSION: Current results demonstrate that G-CSF may be an effective agent for the treatment of diseases characterized by mucosal inflammation.

Rebamipide Protects TNBS Induced Colonic Damage Through Down-regulation of NF-kappaB Activation and Induction of Heme Oxygenase -1 Expression / 대한해부학회지

Crohn 's disease is characterized by a chronic relapsing inflammation of the bowel in which pro-inflammatory cytokines play an important role. Rebamipide is an anti-gastric ulcer drug with anti-inflammatory properties in vivo and in vitro. The effects of rebamipide on Crohn 's disease have not been carefully evaluated. This study investigated the potential of rebamipide to protect Crohn 's disease using a murine model of colitis induced by trinitrobenzene sulfonic acid (TNBS). Rebamipide dramatically improved histopathological symptom involving myeloperoxidase (MPO)activation and increase of microscopic damage score in TNBS induced colitis. Rebamipide suppressed IL-8 secretion, ICAM-1 induction and nuclear factor-kappaB (NF-kappaB) activation by TNF-alpha and induced heme oxygenase-1(HO-1)in HT-29 cells. HO-1 inducer cobalt protoporphyrin IX (CoPPIX)suppressed NF-kappaB activation by TNF-alpha in HT-29 cells like rebamipide, and mimicked the protective effects of rebamipide on TNBS induced colitis. This suggests that rebamipide exerts anti-inflammatory effects by down-regulating NF-kappaB activity via inducting HO-1 expression. In conclusion, this study suggests that rebamipide represents a potential therapeutic agent and HO-1 is an important therapeutic target for the treatment of Crohn's disease.

Rebamipide Protects Colonic Damage Induced by Trinitrobenzene Sulfonic Acid (TNBS) via Down-Regulation of TNF-alpha IL-1beta and ICAM-1 / 대한해부학회지

During inflammation of the colon, cells of the gut mucosa produce or express numerous inflammatory mediators, such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1 beta), and intercellular adhesion molecule 1 (ICAM-1). These mediators have been implicated as contributory factors to the inflammatory process, which results in colitis during inflammatory bowel disease (IBD). Rebamipide is an anti-gastric ulcer drug with anti-inflammatory properties in vivo and in vitro. The effects of Rebamipide on IBD have not been largely evaluated. Therefore, this study investigated the potential of Rebamipide to regulate the production of inflammatory mediators such as TNF-alpha, IL-1beta, and ICAM-1. Mice with trinitrobenzene sulfonic acid (TNBS)-induced colitis (IBD animal model), were treated intrarectally with 2 mM Rebamipide. Body weight, macro- and micro-histological scores, and activity were evaluated. As an index of tissue edema, the thickness of the colonic wall was measured between the serosal surface and the luminal surface of the mucosa. TNF-alpha, IL-1 beta, and ICAM-1 were detected by immunohistochemical staining. Rebamipide treatment of mice exhibiting TNBS-induced colitis dramatically improved the clinical and histopathological findings of inflammation. In addition, Rebamipide suppressed TNF-alpha, IL-1 beta, and ICAM-1 expression in TNBS-treated animals. Taken together, these findings suggest that Rebamipide is a potential therapeutic agent for treating patients with IBD.

Heme Oxygenase-1 is Involved in the Down-regulation of Nuclear Transcription Factor kappa B Activation in the Colonic Epithelium During Inflammation / 대한해부학회지

Heme oxygenase-1 (HO-1) is a stress-inducible enzyme with anti-inflammatory activity, but the mechanisms underlying this activity are incompletely understood. Nuclear transcription factor kappa B (NF-kappa B) activation is an important factor in the pathogenesis of inflammatory bowel disease (IBD). We investigated the suppressive effects of HO-1 on the activation of NF-kappa B by pro-inflammatory cytokines in cultured colonic epithelial cells and by trinitrobenzene sulfonic acid (TNBS) in the colon of mice. The expression level of HO-1 in the colonic epithelium of a patient with inflammatory bowel disease and pseudo-membranous colitis was lower than that in a healthy control subject. In cultured human colonic epithelial HT-29 cells, pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha ) and IL-1 beta down-regulate HO-1 expression. The HO-1 inducer, cobalt protoporphyrin IX (CoPPIX), dramatically down-regulated NF-kappa B activation in HT-29 cells by TNF-alpha. In addition, bilirubin-a product of heme catabolism by HO-1-and the carbon monoxide donor tricarbonyldichlororuthenium (II) dimer also suppressed NF-kappa B activation by TNF-alpha. However, iron, another heme metabolite, did not suppress NF-kappa B activation by TNF-alpha. Furthermore, CoPPIX diminished the macroscopic and histopathological symptoms of TNBS-induced colitis and down-regulated NF-kappa B activation in mice. In conclusion, this study suggests that HO-1 plays an important role in the down-regulation of NF-kappa B activation, which is a key factor in the pathogenesis of IBD and is thus an excellent therapeutic target for the treatment of IBD.